Parkinson's Disease and Related Disorders Part I: Handbook of Clinical Neurology

Obituary William C. Koller, MD, PhD 1945–2005 William C. Koller died unexpectedly on October 3, 2005, in Chapel Hill, ...

Author: William C. Koller MD PhD | Eldad Melamed MD

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Obituary William C. Koller, MD, PhD 1945–2005

William C. Koller died unexpectedly on October 3, 2005, in Chapel Hill, North Carolina, while this volume, which he was co-editing, was in preparation. Bill was born in Milwaukee on July 12, 1945, where he graduated with a BS degree from Marquette University in 1968. He went on to Northwestern University in Chicago, where he received a Masters degree in pharmacology in 1971, a PhD in pharmacology in 1974, and an MD in 1976. After completing his internship and residency at Rush Presbyterian St. Luke’s Medical Center in Chicago, he held positions at the Rush Medical College, University of Illinois, Chicago VA, Hines VA, and Loyola University. In 1987, he was appointed Professor and Chairman of Neurology at the University of Kansas Medical Center, where he remained until 1999, when he moved to the University of Miami and became the National Research Director for the National Parkinson Foundation. He subsequently moved on to direct the Movement Disorders clinical program at the Mount Sinai Medical Center in New York, and then to the University of North Carolina, where he laid the foundation for yet another superb clinical and academic program. Bill was a world-renowned neurologist who specialized in Parkinson’s disease, essential tremor and related disorders. He published more than 270 peer-reviewed manuscripts, over 160 review papers and numerous books. His research interests included the epidemiology and experimental therapeutics of parkinsonism and essential tremor, and his work contributed enormously to the current treatment of these disorders. His collaborations were worldwide and many current experts in movement disorders worked with him at one time or another. He was a Fellow of the American Academy of Neurology, Treasurer of the Movement Disorder Society (1999–2000), Executive Board Member of the Parkinson Study Group (1996–1999), President of WE MOVE (2001–2002), a founding member of the Tremor Research Group and founder of the International Tremor Foundation. Dr. Koller will be especially remembered for his humor, warmth and the youthful vigor and enthusiasm that he brought to his work. He was the consummate physician, befriending many of his patients who were encouraged to call him on his cell phone at any time. Whether lecturing in South America, fishing on the boat he shared with several colleagues, traveling with one of his sons to an international meeting or seeing patients in the clinic, Bill’s smile and the sparkle in his eye endeared him to all who knew him. The movement disorders community has lost a valued colleague, mentor and friend. He is survived by his wife and three sons. Kelly Lyons Matthew B. Stern

Photo courtesy of Professor Lindsey and the European Parkinson’s Disease Association.

Foreword

The Handbook of Clinical Neurology was started by Pierre Vinken and George Bruyn in the 1960s and continued under their stewardship until the second series concluded in 2002. This is the fifth volume in the new (third) series, for which we have assumed editorial responsibility. The series covers advances in clinical neurology and the neurosciences and includes a number of new topics. In order to provide insight to physiological and pathogenic mechanisms and a basis for new therapeutic strategies for neurological disorders, we have specifically ensured that the neurobiological aspects of the nervous system in health and disease are covered. During the last quarter-century, dramatic advances in the clinical and basic neurosciences have occurred, and those findings related to the subject matter of individual volumes are emphasized in them. The series will be available electronically on Elsevier’s Science Direct site, as well as in print form. It is our hope that this will make it more accessible to readers and also facilitate searches for specific information. The present volume deals with Parkinson’s disease and related disorders. This group of disorders constitutes one of the most common of neurodegenerative disorders and is assuming even greater importance with the aging of the population in developed countries. The volume has been edited by Professor William Koller (USA) and Professor Eldad Melamed (Israel). It is with particular sadness that we must record the sudden and untimely death of Professor Koller while the volume was coming to fruition. An experienced clinician, neuroscientist, author and editor, he was a friend of many of the contributors to this volume, as well as of the series editors, and we shall greatly miss him. It is our hope that he would have been proud of this volume, which he did so much to craft. As series editors, we reviewed all of the chapters in the volume and made suggestions for improvement, but we were delighted that the volume editors had produced such a scholarly and comprehensive account of the parkinsonian disorders, which should appeal to clinicians and neuroscientists alike. When the Handbook series was initiated in the 1960s, understanding of these disorders was poor, any genetic basis of them was speculative, several of the syndromes described here had not even been recognized, the prognosis was bleak and the therapeutic options were almost unchanged since the late Victorian era. Advances in understanding of the biochemical background of parkinsonism during the 1960s and early 1970s led to dramatic pharmacological advances in the management of Parkinson’s disease and profoundly altered the approach to other degenerative disorders of the nervous system. The pace of advances in the field has continued, and the exciting new insights being gained have mandated a need for a thorough but critical appraisal of recent developments so that future investigative approaches and therapeutic strategies are based on a solid foundation, the limits of our knowledge are clearly defined and an account is provided for practitioners of the clinical features and management of the various neurological disorders that present with parkinsonism. It has been a source of great satisfaction to us that two such eminent colleagues as the late William Koller and Professor Eldad Melamed agreed to serve as volume editors and have produced such an important compendium, and we thank them and the contributing authors for all their efforts. We also thank the editorial staff of the publisher, Elsevier B.V., and especially Ms Lynn Watt and Mr Michael Parkinson in Edinburgh for overseeing all stages in the preparation of this volume. Michael J. Aminoff Franc¸ois Boller Dick F. Swaab

Preface

James Parkinson described Parkinson’s disease in his memorable Essay on the Shaking Palsy in 1817. Since then, and particularly in recent years, there has been tremendous progress in our understanding of this complex and fascinating neurological disorder. Briefly, we have learned that it is not only manifest by motor symptoms but also that there is a whole range of non-motor features, including autonomic, psychiatric, cognitive and sensory impairments. We now know how to distinguish better clinically between Parkinson’s disease and the various parkinsonian syndromes. Likewise, it is now well established that in this disorder not only the substantia nigra but many other central as well as peripheral neuronal cell populations are involved. Novel diagnostic imaging technologies have become available. The nature of the Lewy body, the intracytoplasmic inclusion body that is a characteristic element of Parkinson’s disease pathology, is being unraveled. There are new insights in the etiology and pathogenesis of this illness. Experimental models are now available to understand better modes of neuronal cell death and help develop new therapeutic approaches. There has been dramatic progress in discovering the genetic causes of dominant and recessive forms of hereditary Parkinson’s disease with the identification of mutations in several genes. There is new knowledge in the intricate circuitry of the basal ganglia and the physiology of the connections in the healthy state and in Parkinson’s disease. There is more understanding of the role of dopamine and other neurotransmitters in the control and regulation of movement by the brain. All of the above led to the development of many novel pharmacological treatments to improve the motor as well as non-motor phenomena. There is better understanding of the mechanisms responsible for the complications caused by long-term levodopa administration. Futuristic approaches using deep brain stimulation with electrodes implanted in anatomically strategic central nervous system sites are now in common use to improve basic symptoms and the side-effects of levodopa therapy. Potentially effective neuroprotective strategies are in development to modify and slow disease progression. Likewise, cell replacement therapy with stem cells offers great promise. The best of experts in the field joined in this book and contributed chapters that make up an exciting coverage of all the exhilarating developments in the many aspects of Parkinson’s disease. This volume will certainly expand the current knowledge of its readers and it is also hoped that it will stimulate further research that will eventually lead to finding both the cause and the cure of this common and disabling neurological disorder. William C. Koller Eldad Melamed Dr. William Koller died suddenly, unexpectedly and prematurely on October 3, 2005, before this volume went to press. His loss is painful to all his friends and colleagues. His leadership, wisdom and expertise were the main driving force behind the creation of this very special book. It is the belief of all involved that Dr. Koller would have been pleased and proud of this volume in its final form. We hope it will be a tribute to his memory.

List of contributors

L. Alvarez Movement Disorders Unit, Centro Internacional de Restauracio´n Neurolo´gica (CIREN), La Habana, Cuba M. Baker European Parkinson’s Disease Association (EPDA), Sevenoaks, Kent, UK Y. Balash Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel E. R. Bauminger Racah Institute of Physics, Hebrew University, Jerusalem, Israel M. F. Beal Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA P. J. Be´dard Centre de Recherche en Neurosciences, CHUL, Faculte´ de Me´dicine, Universite´ Laval, Quebec, Canada A. Berardelli Department of Neurological Sciences and Neuromed Institute, Universita` La Sapienza, Rome, Italy R. Betarbet Department of Neurology, Emory University, Atlanta, GA, USA K. P. Bhatia Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK

R. Bhidayasiri The Parkinson’s and Movement Disorder Institute, Fountain Valley, CA, USA R. E. Breeze Department of Neurosurgery, University of Colorado School of Medicine, Denver, CO, USA C. Brefel-Courbon Department of Clinical Pharmacology, Clinical Investigation Centre and Department of Neurosciences, University Hospital, Toulouse, France D. J. Brooks MRC Clinical Sciences Centre and Division of Neuroscience and Mental Health, Imperial College London, Hammersmith Hospital, London, UK R. E. Burke Departments of Neurology and Pathology, Columbia University, New York, NY, USA D. J. Burn Institute of Ageing and Health, University of Newcastle upon Tyne, Newcastle upon Tyne, UK M. G. Cerso´simo Program of Parkinson’s Disease and Other Movement Disorders, Hospital de Clı´nicas, University of Buenos Aires, Buenos Aires, Argentina A. Chade The Parkinson’s Institute, Sunnyvale, CA, USA K. R. Chaudhuri Regional Movement Disorders Unit, King’s College Hospital, London, UK Y. Chen Morris K. Udall Parkinson’s Disease Research Center of Excellence, University of Kentucky College of Medicine, Lexington, KY, USA

xii

LIST OF CONTRIBUTORS

K. L. Chou Department of Clinical Neurosciences, Brown University Medical School and NeuroHealth Parkinson’s Disease and Movement Disorders Center, Warwick, RI, USA C. Colosimo Dipartimento di Scienze Neurologiche, Universita` La Sapienza, Rome, Italy Y. Compta Neurology Service, Hospital Clinic, University of Barcelona, Barcelona, Spain E. Cubo Unit of Neuroepidemiology, National Centre for Epidemiology, Carlos III Institute of Health, Madrid, Spain B. Dass Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA M. R. DeLong Department of Neurology, Emory University, Atlanta, GA, USA G. Deuschl Department of Neurology, Christian-AlbrechtsUniversity, Kiel, Germany V. Dhawan Regional Movement Disorders Unit, King’s College Hospital, London, UK The´re`se Di Paolo Centre de Recherche en Endocrinologie Mole´culaire et Oncologique, CHUL, Faculte´ de Pharmacie, Universite´ Laval, Quebec, Canada R. Djaldetti Department of Neurology, Rabin Medical Center, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel M. Emre Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey G. Fabbrini Dipartimento di Scienze Neurologiche, Universita` La Sapienza, Rome, Italy

C. Fox National Center for Voice and Speech, Denver, CO, USA S. H. Fox Toronto Western Hospital, Movement Disorders Clinic, Division of Neurology, University of Toronto, Toronto, Ontario, Canada J. Frank Department of Neurology, Mount Sinai Medical Center, New York, NY, USA C. R. Freed University of Colorado School of Medicine, Denver, CO, USA A. Friedman Department of Neurology, Medical University, Warsaw, Poland J. H. Friedman Department of Clinical Neurosciences, Brown University Medical School and NeuroHealth Parkinson’s Disease and Movement Disorders Center, Warwick, RI, USA V. S. C. Fung Department of Neurology, Westmead Hospital, Sydney, NSW, Australia J. Galazka-Friedman Faculty of Physics, Warsaw University of Technology, Warsaw, Poland C. Gallagher Department of Neurobiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA D. M. Gash Morris K. Udall Parkinson’s Disease Research Center of Excellence, University of Kentucky College of Medicine, Lexington, KY, USA G. Gerhardt Morris K. Udall Parkinson’s Disease Research Center of Excellence, University of Kentucky College of Medicine, Lexington, KY, USA O. S. Gershanik Department of Neurology, Centro Neurolo´gico-Hospital Frances, Laboratory of Experimental Parkinsonism, ININFA-CONICET, Buenos Aires, Argentina

LIST OF CONTRIBUTORS

xiii

C. G. Goetz Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

J. S. Hui Department of Clinical Neurology, University of Southern California, Los Angeles, CA, USA

J. G. Goldman Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

J. Jankovic Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA

D. S. Goldstein Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

P. Jenner Neurodegenerative Disease Research Center, School of Health and Biomedical Sciences, King’s College, London, UK

J.-M. Gracies Department of Neurology, Mount Sinai Medical Center, New York, NY, USA

M. Kasten The Parkinson’s Institute, Sunnyvale, CA, USA

J. T. Greenamyre Department of Neurology, Emory University, Atlanta, GA, USA

H. Kaufmann Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA

J. Guridi Department of Neurology and Neurosurgery, University Clinic and Medical School and Neuroscience Division, University of Navarra and CIMA, Pamplona, Spain T. D. Ha¨lbig Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA N. Hattori Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan M. A. Hely Department of Neurology, Westmead Hospital, Sydney, NSW, Australia C. Henchcliffe Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA B. Ho¨gl Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria X. Huang Departments of Neurology and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, USA

W. C. Kollery Department of Neurology, University of North Carolina, NC, USAyDeceased. A. D. Korczyn Sieratzki Chair of Neurology, Tel-Aviv University Medical School, Ramat-Aviv, Israel J. H. Kordower Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA V. Koukouni Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK A. E. Lang Toronto Western Hospital, Movement Disorders Clinic, Division of Neurology, University of Toronto, Toronto, Ontario, Canada M. Leehey Department of Neurology, University of Colorado School of Medicine, Denver, CO, USA A. J. Lees Reta Lila Weston Institute of Neurological Studies, University College London, London, UK y

Deceased.

xiv

LIST OF CONTRIBUTORS

F. A. Lenz Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA

Y. Mizuno Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan

N. Lev Laboratory of Neuroscience and Department of Neurology, Rabin Medical Center, Petah-Tikva, Tel Aviv University, Tel Aviv, Israel

H. Mochizuki Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan

M. F. Lew Department of Neurology, University of Southern California, Los Angeles, CA, USA M. Lugassy Department of Neurology, Mount Sinai Medical Center, New York, NY, USA R. B. Mailman Departments of Psychiatry, Pharmacology, Neurology and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, USA C. Marin Laboratori de Neurologia Experimental, Fundacio´ Clı´nic-Hospital Clı´nic, Institut d’Investigacions Biome´diques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain P. Martı´nez-Martı´n Unit of Neuroepidemiology, National Centre for Epidemiology, Carlos III Institute of Health, Madrid, Spain I. McKeith Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK K. St. P. McNaught Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA E. Melamed Department of Neurology, Rabin Medical Center, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel M. Merello Movement Disorders Section, Raul Carrea Institute for Neurological Research, FLENI, Buenos Aires, Argentina F. E. Micheli Program of Parkinson’s Disease and Other Movement Disorders, Hospital de Clı´nicas, University of Buenos Aires, Buenos Aires, Argentina

J. C. Mo¨ller Department of Neurology, Philipps-Universita¨t Marburg, Marburg, Germany J.-L. Montastruc Department of Clinical Pharmacology, Clinical Investigation Center, University Hospital, Toulouse, France E. B. Montgomery Jr National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA J. G. L. Morris Department of Neurology, Westmead Hospital, Sydney, NSW, Australia J. A. Obeso Department of Neurology and Neurosurgery, University Clinic and Medical School and Neuroscience Division, University of Navarra and CIMA, Pamplona, Spain W. H. Oertel Department of Neurology, Philipps-Universita¨t Marburg, Marburg, Germany D. Offen Laboratory of Neuroscience and Department of Neurology, Rabin Medical Center, Petah-Tikva, Tel Aviv University, Tel Aviv, Israel F. Ory-Magne Department of Neurosciences, University Hospital, Toulouse, France B. Owler Department of Neurosurgery, Westmead Hospital, Sydney, NSW, Australia D. P. Perl Mount Sinai School of Medicine, New York, NY, USA R. F. Pfeiffer Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

LIST OF CONTRIBUTORS S. Przedborski Departments of Neurology, Pathology and Cell Biology, Columbia University, New York, NY, USA J. M. Rabey Department of Neurology, Assaf Harofeh Medical Center, Zerifin, Israel A. Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada A. H. Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada L. O. Ramig Department of Speech, Language and Hearing Sciences, University of Colorado-Boulder Department of Speech, and National Center for Voice and Speech, Denver, CO, USA J. Rao Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, LA, USA O. Rascol Department of Clinical Pharmacology, Clinical Investigation Centre and Department of Neurosciences, University Hospital, Toulouse, France J. Rasmussen Merstham Clinic, Redhill, Surrey, UK W. Regragui Department of Neurosciences, University Hospital, Toulouse, France P. F. Riederer Clinical Neurochemistry, Department of Psychiatry and Psychotherapy, National Parkinson Foundation (USA) Center of Excellence Research Laboratories, University of Wu¨rzburg, Wu¨rzburg, Germany M. C. Rodrı´guez-Oroz Department of Neurology and Neurosurgery, University Clinic and Medical School and Neuroscience Division, University of Navarra and CIMA, Pamplona, Spain C. Rouillard Centre de Recherche en Neurosciences, CHUL, Faculte´ de Me´dicine, Universite´ Laval, Quebec, Canada

xv

P. Samadi Centre de Recherche en Endocrinologie Mole´culaire et Oncologie, CHUL, Faculte´ de Pharmacie, Universite´ Laval, Quebec, Canada S. Sapir Department of Communication Sciences and Disorder, Faculty of Social Welfare and Health Studies, University of Haifa, Haifa, Israel A. H. V. Schapira University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, London, UK J. Shahed Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Department of Neurology, Houston, TX, USA T. Slaoui Department of Neurosciences, University Hospital, Toulouse, France M. B. Stern Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA F. Stocchi Department of Neurology, IRCCS San Raffaele Pisana, Rome, Italy N. P. Stover Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA C. M. Tanner The Parkinson’s Institute, Sunnyvale, CA, USA E. Tolosa Neurology Service, Hospital Clinic, University of Barcelona, Barcelona, Spain C. Trenkwalder Paracelsus Elena-Klinik, Center of Parkinsonism and Movement Disorders, Kassel, and University of Go¨ttingen, Go¨ttingen, Germany D. D. Truong The Parkinson’s and Movement Disorder Institute, Fountain Valley, CA, USA W. Tse Department of Neurology, Mount Sinai Medical Center, New York, NY, USA

xvi

LIST OF CONTRIBUTORS

J. Volkmann Department of Neurology, Christian-AlbrechtsUniversity, Kiel, Germany

T. Wichmann Department of Neurology and Yerkes National Primate Center, Emory University, Atlanta, GA, USA

H. C. Walker Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA

M. B. H. Youdim Department of Pharmacology, Technion-Bruce Rappaport Faculty of Medicine, Eve Topf and NPF Neurodegenerative Diseases Centers, Rappaport Family Research Institute, Haifa, Israel

R. H. Walker Movement Disorders Clinic, Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, and Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA R. L. Watts Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA D. Weintraub Departments of Psychiatry and Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

W. M. Zawada Division of Clinical Pharmacology, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA W. Zhou Division of Clinical Pharmacology, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA

Contents of Part I

Obituary vi Foreword vii Preface ix List of contributors xi

SECTION 1 Scientific foundation 1. Anatomy and physiology of the basal ganglia: relevance to Parkinson’s disease and related disorders Thomas Wichmann and Mahlon R. DeLong (Atlanta, GA, USA)

3

2. Functional neurochemistry of the basal ganglia Pershia Samadi, Claude Rouillard, Paul J. B edard and Th er ese Di Paolo (Quebec, Canada)

19

3. Neurophysiology of basal ganglia diseases Alfredo Berardelli (Rome, Italy)

67

4. Dopamine receptor pharmacology Richard B. Mailman and Xuemei Huang (Chapel Hill, NC, USA)

77

SECTION 2 General aspects of Parkinson’s disease 5. History of Parkinson’s disease Jennifer G. Goldman and Christopher G. Goetz (Chicago, IL, USA)

109

6. Epidemiology of Parkinson’s disease Meike Kasten, Annabel Chade and Caroline M. Tanner (Sunnyvale, CA, USA)

129

7. Neurochemistry of Parkinson’s disease Jayaraman Rao (New Orleans, LA, USA)

153

8. The neuropathology of parkinsonism Daniel P. Perl (New York, NY, USA)

205

9. Genetic aspects of Parkinson’s disease Yoshikuni Mizuno, Nobutaka Hattori and Hideki Mochizuki (Tokyo, Japan)

217

10. Imaging Parkinson’s disease David J. Brooks (London, UK)

245

xviii

CONTENTS

11. Parkinson’s disease: animal models Ranjita Betarbet and J. Timothy Greenamyre (Atlanta, GA, USA)

SECTION 3

265

Clinical aspects

12. Scales to measure parkinsonism Pablo Martı´nez-Martı´n and Esther Cubo (Madrid, Spain)

291

13. Motor symptoms in Parkinson’s disease Joohi Shahed and Joseph Jankovic (Houston, TX, USA)

329

14. Autonomic dysfunction in Parkinson’s disease Horacio Kaufmann and David S. Goldstein (New York, NY and Bethesda, MD, USA)

343

15. Sleep in Parkinson syndromes Claudia Trenkwalder and Birgit H€ ogl (Kassel and G€ ottingen, Germany and Innsbruck, Austria)

365

16. Sensory symptoms in Parkinson’s disease Ruth Djaldetti and Eldad Melamed (Petah Tiqva and Tel Aviv, Israel)

377

17. Speech disorders in Parkinson’s disease and the effects of pharmacological, surgical and speech treatment with emphasis on Lee Silverman voice treatment (LSVTW) Lorraine Olson Ramig, Cynthia Fox and Shimon Sapir (Denver, CO and New York, NY, USA and Haifa, Israel) 18. Clinical features, pathophysiology and treatment of dementia associated with Parkinson’s disease Murat Emre (Istanbul, Turkey)

385

401

19. Disorders of mood and affect in Parkinson’s disease Daniel Weintraub and Matthew B. Stern (Philadelphia, PA, USA)

421

20. Neurobehavioral disorders in Parkinson’s disease Jose Martin Rabey (Ramat Aviv, Israel)

435

21. Early detection of Parkinson’s disease Catherine Gallagher and Erwin B. Montgomery Jr (Madison, WI, USA)

457

SECTION 4

Etiology

22. Mitochondria in the etiology of Parkinson’s disease Anthony H. V. Schapira (London, UK)

481

23. Iron as a trigger of neurodegeneration in Parkinson’s disease Andrzej Friedman, Jolanta Galazka-Friedman and Erika R. Bauminger (Warsaw, Poland and Jerusalem, Israel)

493

24. Oxidative stress and Parkinson’s disease Peter Jenner (London, UK)

507

25. Neurotrophic factors and Parkinson’s disease Don M. Gash, Yan Chen and Greg Gerhardt (Lexington, KY, USA)

521

CONTENTS

xix

26. Neuroinflammation and Parkinson’s disease Serge Przedborski (New York, NY, USA)

535

27. Excitotoxicity Claire Henchcliffe and M. Flint Beal (New York, NY, USA)

553

28. Protein-handling dysfunction in Parkinson’s disease Kevin St. P. McNaught (New York, NY, USA)

571

29. Programmed cell death in Parkinson’s disease Robert E. Burke (New York, NY, USA)

591

Subject index Color plate section

607 615

Section 1 Scientific foundation

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 1

Anatomy and physiology of the basal ganglia: relevance to Parkinson’s disease and related disorders THOMAS WICHMANN1,2 AND MAHLON R. DELONG1* 1

2

Department of Neurology, and Yerkes National Primate Center, Emory University, Atlanta, GA, USA

1.1. Circuit models 1.1.1. Overview The basal ganglia are a group of subcortical nuclei, including the neostriatum (caudate nucleus and putamen), the ventral striatum, the external and internal segments of the globus pallidus (GPe, GPi, respectively), the subthalamic nucleus (STN), and the substantia nigra pars reticulata and pars compacta (SNr, SNc, respectively). These structures neither receive direct sensory input nor have direct projections to spinal cord or brainstem motor neurons, but rather receive from, and project to, cerebral and brainstem areas with such direct relations. The basal ganglia are generally considered to be components of larger cortical–subcortical circuits which take origin from almost the entire cortex, and engage the basal ganglia and thalamus (Fig. 1.1). Throughout their subcortical course, these circuits are highly topographic and highly segregated. The basal ganglia–thalamocortical loops are arranged in functional modules, broadly grouped into motor, associative and limbic circuits, which appear to operate largely independent from one another. The striatum and STN are the primary entry points for cortical, brainstem and thalamic inputs into the basal ganglia. From these input nuclei, information is conveyed over multiple pathways to the principal basal ganglia output nuclei, GPi and SNr. Basal ganglia outflow from GPi and SNr is directed at frontal areas of the cerebral cortex (via the thalamus) and at various brainstem

structures (superior colliculus, pedunculopontine nucleus (PPN), parvocellular reticular formation). 1.1.1.1. Histologic organization and discharge characteristics of basal ganglia neurons Each basal ganglia nucleus is histologically distinctive. The most abundant striatal cell type is the GABAergic medium spiny projection neuron, which represents 90–95% of all striatal neurons. These cells derive their name from the abundance of spines on their dendrites on to which inputs from the cerebral cortex as well as from the centromedian and parafascicular nuclei of the thalamus terminate. Medium spiny neurons receive additional intrinsic inputs from several classes of inhibitory striatal interneurons, including large cholinergic neurons and smaller cells containing somatostatin, neuropeptide Y, calbindin or nitric oxide synthetase, as well as extrinsic modulatory inputs from dopaminergic and serotonergic projections originating in the midbrain. The dopaminergic fibers terminate on the neck of the dendritic spines of striatal medium spiny neurons and are thus in a position to modulate corticostriatal information flow. In contrast to the heterogeneous composition of the striatum, the neuronal cell groups in GPe, GPi and SNr are homogeneous with few (if any) interneurons. Pallidal neurons are large and GABAergic neurons whose dendritic trees form flattened disks that are traversed orthogonally, and are contacted by, striatal efferents. The SNr is histologically similar to GPi. It contains GABAergic neurons, which interdigitate and interact

*Correspondence to: Mahlon R. DeLong, M.D., Emory University, Department of Neurology, Suite 6000, Woodruff Memorial Research Building, 101 Woodruff Circle, Atlanta, GA 30322, USA. E-mail: [email protected], Tel: þ1-404-727-9107, Fax: þ1-404-727-3157.

4

T. WICHMANN AND M. R. DELONG Normal

spinal cord

Parkinsonism

spinal cord

Fig. 1.1. Diagrams demonstrating the anatomical connections within the basal ganglia circuitry (left), and changes in the activity of basal ganglia nuclei associated with the development of parkinsonism (right). GPe, external pallidal segment; STN, subthalamic nucleus; GPi, internal pallidal segment; SNr, substantia nigra pars reticulata; SNc, substantia nigra pars compacta; PPN, pedunculopontine nucleus; CM, centromedian nucleus of the thalamus; VA, ventral anterior nucleus of the thalamus; VL, ventrolateral nucleus of the thalamus. Gray arrows denote excitatory connections, black arrows identify inhibitory connections.

with the dopaminergic cell groups of the neighboring SNc. The STN is a densely packed structure whose neurons, unlike those in the other basal ganglia nuclei, are excitatory and glutamatergic. Most of these cell types are also identifiable by electrophysiologic methods. Thus, striatal medium spiny neurons have low spontaneous discharge rates, but are activated by cortical inputs (Alexander and Crutcher, 1990; see below), or microstimulation (Alexander and DeLong, 1985a, b). Of the remaining striatal cell types, the cholinergic interneurons appear to correspond to a group of neurons with a low tonic firing rate, the socalled tonically active neurons. Primate GPe neurons, recorded in vivo, discharge spontaneously at rest in two different patterns, namely a high-frequency discharge pattern which is interrupted by pauses, and a low-frequency discharge pattern, accentuated by bursts, whereas GPi and SNr neurons fire more tonically at high frequencies (in the 60–80 spikes/s range; DeLong, 1971). The STN is composed of neurons with a firing rate in primates of about 20 spikes/s, and an irregular discharge pattern. Finally, the SNc consists of cells with a low tonic firing rate (around 5–10 spikes/s). Their discharge is frequently accentuated by short bursts or pauses of activity (Schultz and Romo, 1987), often in association with salient behavioral events (see below). 1.1.2. Inputs to the basal ganglia Of all basal ganglia structures, the striatum receives by far the most abundant cortical input to the basal ganglia.

These inputs impose a topographic organization upon the striatum (Alexander et al., 1986; Parent, 1990; Haber et al., 1995), and on the basal ganglia regions which receive input from it. In primates, projections from motor areas, including the somatosensory, motor and premotor cortices, terminate in the postcommissural putamen, prefrontal cortical areas project to the caudate nucleus and precommissural putamen and limbic projections terminate preferentially in the ventral striatum. The segregation between pathways traversing the basal ganglia has most recently been confirmed by viral tracer injections (Hoover and Strick, 1993, 1999; Middleton and Strick, 1997, 2002; Kelly and Strick, 2004). The relationship between corticostriatal and corticospinal projection neurons is somewhat uncertain, but these projections likely arise from different groups of cortical neurons. Electrophysiologic experiments in primates have shown that, in comparison to corticospinal projection neurons, corticostriatal projection neurons discharge at lower rates and have slower conduction velocities and much lower responsivity to somatosensory inputs (Bauswein et al., 1989; Turner and DeLong, 2000). More recent studies in rats have suggested an even more intricate corticostriatal projection pattern in which the source neurons of the corticostriatal projection may respect to a large degree the intrinsic basal ganglia organization into ‘direct’ and ‘indirect’ pathways (Lei et al., 2004; discussed in section 1.1.3 below). The STN is the second major recipient of excitatory cortical inputs. Projections from the frontal lobe to the

ANATOMY AND PHYSIOLOGY OF THE BASAL GANGLIA STN are also topographically arranged (Hartmann-von Monakow et al., 1978; Nambu et al., 1996), and impose a functional topography on this nucleus which is similar to that imposed by inputs to the striatum. Afferents from the primary motor cortex reach the dorsolateral part of the STN, while afferents from premotor and supplementary motor areas innervate mainly the medial third of the nucleus (Takada et al., 2001). The prefrontal/limbic cortices project to the ventral and most medial portions of the STN. Topographically organized inputs to striatum and STN also arise from portions of the thalamus, particularly from those thalamic nuclei which receive basal ganglia output. In primates, the centromedian thalamic nucleus projects to the motor portions of putamen and STN, whereas the parafascicular nucleus projects to associative and limbic territories (Smith and Parent, 1986; Sadikot et al., 1992). Recent tracer injection studies have confirmed that there is a substantial projection to the basal ganglia from the ventrolateral (VL) and ventral anterior (VA) nuclei. The functional role of these (potential) feedback circuits is not known at this point. 1.1.3. ‘Direct’ and ‘indirect’ striatofugal pathways Striatal output influences the basal ganglia output nuclei, GPi and SNr, via two separate pathways, the so-called direct and indirect pathways. The direct pathway is a monosynaptic connection linking striatum with GPi and SNr, whereas the indirect pathway is a polysynaptic pathway which involves GPe and STN en route to GPi and SNr (Albin et al., 1989; Alexander and Crutcher, 1990). The concept of a dichotomy between direct and indirect pathways is strongly supported by anatomical and functional studies, which will be reviewed below. Recent studies have indicated that some of the striatofugal outputs collateralize to GPe, GPi and SNr, thus creating a hybrid of direct and indirect pathways. These results are based on reconstruction studies of cells whose axonal collaterals were labeled by juxtacellular injections of the tracer biotynilated dextrane amine (BDA). It is clear that such collaterals can be identified in both rodents and primates (Parent et al., 1995). However, even cells with extensive collaterals show a clear preference for one target (GPe or GPi/SNr) over the other, and it remains unclear what the functional significance of the lesser collaterals are. The direct pathway arises from a set of striatal neurons that project monosynaptically to neurons in GPi and SNr. These neurons are identifiable by their expression of the neuropeptides substance P and dynorphin, and by the fact that they carry dopamine

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D1-receptors on their dendrites and on their axon terminals in GPi and SNr. Dopamine D1-receptors on axon terminals strongly modulate GABA release from the striatonigral and striatopallidal pathways (Trevitt et al., 2002; Galvan et al., 2005). Recent studies in rodents have indicated that direct-pathway neurons receive input from a specific class of cortical neurons, which also project to the opposite striatum (Lei et al., 2004). It is not clear which information is carried by these ‘intratelencephalically’ projecting cells (‘IT cells’). In addition, direct-pathway neurons appear to be targeted specifically by efferents from the intralaminar nuclei of the thalamus (Sidibe and Smith, 1996; Parthasarathy and Graybiel, 1997). The indirect pathway arises from a different set of striatal neurons, which project primarily to GPe. These neurons preferentially express the neuropeptide enkephalin, as well as dopamine D2-receptors on their dendrites and axon terminals in GPe (Gerfen et al., 1990; Surmeier et al., 1996). Studies in monkeys, using the expression of the immediate early gene c-fos as a marker for activity, induced by electrical cortical stimulation, have indicated that there is a substantial preference of inputs from sensorimotor cortex to target indirect-pathway neurons in the striatum (Parthasarathy and Graybiel, 1997). Recent ultrastructural and tracing studies in rodents have suggested that indirect-pathway neurons receive cortical input primarily from cells that also project to the pyramidal tract (so-called ‘PT’ cells; see Lei et al., 2004). It is difficult to reconcile this result with the above-mentioned studies in non-human primates in which anatomical evidence for the same organization is lacking, and very few of the pyramidal tract projecting cells appeared electrophysiologically to project to the striatum as well (Bauswein et al., 1989; Turner and DeLong, 2000). The indirect pathway from striatum to GPi/SNr is completed by additional projections from GPe to STN, and from STN to GPi and SNr. There are also direct connections from GPe to GPi/SNr (Shink et al., 1996; Smith et al., 1998). Rather than being a simple information relay, it is clear that considerable processing occurs along the indirect pathway, particularly in the STN, where inputs arising from cortex appear to be integrated with inputs from GPe (Hartmann-von Monakow et al., 1978; Smith and Bolam, 1990; Nambu et al., 1996; Takada et al., 2001). The projection from striatal neurons which give rise to direct and indirect pathways are highly topographic (Shink et al., 1996; Smith et al., 1998). For instance, populations of GPe neurons which receive inputs from striatal sensorimotor, cognitive or limbic territory are connected with populations of neurons in the same functional territories of STN, and neurons in each of

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these regions, in turn, innervate the territories subserving the same functions in GPi and SNr (Shink et al., 1996; Smith et al., 1998). The current model of the basal ganglia–thalamocortical circuitry predicts that activation of striatal neurons that give rise to the direct pathway reduces inhibitory basal ganglia output from targeted neurons with subsequent disinhibition of related thalamocortical neurons. The net effect of this would be increased activity in appropriate cortical neurons. By contrast, activation of the striatal neurons that give rise to the indirect pathway would lead to increased (inhibitory) basal ganglia output on thalamocortical neurons. It is noteworthy that there are no convincing experimental studies to date which would demonstrate this point. Furthermore, it remains unclear how information from a given striatal location, transmitted over the direct and indirect pathways, is actually integrated at the level of the output nuclei, GPi and SNr. 1.1.4. The substantia nigra pars compacta The SNc does not directly participate in the transfer of information along the basal ganglia–thalamocortical pathways, but is part of the brainstem catecholaminergic systems, providing dopaminergic inputs to striatum and other targets. It receives input from other basal ganglia nuclei, including the neighboring SNr and STN (Celada et al., 1999; Iribe et al., 1999; Lee et al., 2004), as well as sources outside the basal ganglia, including the prefrontal and orbitofrontal cortices, the superior colliculus (Coizet et al., 2003; Comoli et al., 2003), the raphe nuclei and the PPN. Neurons in the SNc show a tonic pacemaker-like firing pattern. In studies combining behavioral monitoring with single-neuron recording, phasic bursts or pauses are found to be related to salient behavioral events that predict upcoming rewards (Hollerman and Schultz, 1998). Accordingly, current models of basal ganglia function ascribe dual roles to dopamine released in the striatum. One function of dopamine, related to phasic fluctuations of neuronal activity in the SNc, may be to provide reward-related signals to the striatum. This function will be discussed in greater detail in section 1.2, below. Another of the proposed roles is to provide a tonic background of dopamine which serves to modulate the balance between direct and indirect pathways. In this function, dopamine acts on D1-receptors preferentially located on medium spiny neurons that give rise to the direct pathway, and on D2-receptors, which are thought to be preferentially located on medium spiny neurons that give rise to the indirect pathway. The segregation of D1- and D2-receptors between direct and indirect pathways may not be as

strict as initially proposed (Surmeier et al., 1996; Aizman et al., 2000), but they still appear to regulate striatal output differentially. Striatal dopamine is thought to modulate the activity of GPi and SNr neurons via facilitation of transmission over the direct pathway and inhibition of transmission over the indirect pathway (Gerfen, 1995). The net effect of striatal dopamine release appears to be to reduce basal ganglia output to the thalamus and other targets. Dopamine may also more directly influence discharge patterns and rates locally in the STN, GPi and GPe. Dopamine is dendritically released in substantial quantities in the SNr. The dopamine supply to STN and GPi is much smaller. Dopamine receptors are known to exist in all of the extrastriatal basal ganglia. This may imply that some of the therapeutic effects of dopamine agonists, a group of drugs which is frequently used in the treatment of Parkinson’s disease and other movement disorders, may be explicable by actions on these extrastriatal receptors (Parent and Cossette, 2001). 1.1.5. Basal ganglia output The segregation of basal ganglia thalamocortical pathways is further maintained at the level of the basal ganglia output nuclei. For instance, in primates, the caudoventral motor territory of GPi projects almost exclusively to the posterior part of the VL nucleus which sends projections towards the supplementary motor area (Schell and Strick, 1984; Inase and Tanji, 1995), the primary motor cortex (M1) and premotor cortical areas (Hoover and Strick, 1993). Virus-tracing studies have revealed that the outflow from pallidal motor areas directed at cortical areas M1, premotor and supplementary motor area arise from separate populations of pallidothalamic and thalamocortical neurons (Hoover and Strick, 1993). Rostromedial associative areas of GPi project preferentially to the parvocellular part of the ventral anterior (VA) and the dorsal VL nucleus (VLc in macaques) (DeVito and Anderson, 1982; Sidibe et al., 1997), and may be transmitted in turn to prefrontal cortical areas (Goldman-Rakic and Porrino, 1985; Middleton and Strick, 1994), as well as motor and supplementary motor regions (Darian-Smith et al., 1990; Inase and Tanji, 1995). As mentioned above, these ‘basal ganglia-receiving’ areas of thalamus are also a source of input to the striatum. Although the overlap between motor and non-motor areas is probably greater in SNr than in GPi (Hedreen and DeLong, 1991), the SNr can be broadly subdivided into a dorsolateral sensorimotor and a ventromedial associative territory (Deniau and Thierry, 1997).

ANATOMY AND PHYSIOLOGY OF THE BASAL GANGLIA Projections from the medial SNr to the thalamus mostly terminate in the medial magnocellular division of the ventral anterior nucleus (VAmc) and the mediodorsal nucleus (MDmc) which, in turn, innervate anterior regions of the frontal lobe, including the principal sulcus and the orbital cortex in monkeys (Ilinsky et al., 1985). Neurons in the lateral SNr project preferentially to the lateral posterior region of VAmc and to parts of MD, which are predominantly related to posterior regions of the frontal lobe, including the frontal eye field and portions of the premotor cortex (Ilinsky et al., 1985). The SNr also sends projections to the PPN (Rye et al., 1988; Steininger et al., 1992). Additional projections reach the parvocellular reticular formation, a region whose neurons are directly connected with orofacial motor nuclei (von Krosigk et al., 1993), and the superior colliculus, which plays a critical role in the control of saccades and orienting behaviors (Wurtz and Hikosaka, 1986). Other output projections from the basal ganglia output nuclei arise mostly as collaterals from the pallidothalamic projection. Thus, prominent axon collaterals are sent in a segregated manner to the centromedian–parafasicular nucleus complex, which not only projects to cortex but also sends a substantial projection to the striatum (see above), constituting one of the many feedback circuits in the basal ganglia–thalamocortical circuitry (Sidibe et al., 1997). Additional pallidal axon collaterals reach the PPN of the midbrain (Harnois and Filion, 1982; Rye et al., 1988) which, in turn, gives rise to ascending projections to basal ganglia, thalamus and basal forebrain and to descending projections to pons, medulla and spinal cord (Inglis and Winn, 1995). The reciprocal connections between the PPN and the basal ganglia, as well as the fact that they share the thalamus as a common projection target, have given rise to the notion that the PPN should perhaps best be considered a portion of the basal ganglia circuitry itself (MenaSegovia et al., 2004).

1.2. Functional considerations 1.2.1. Methods to assess basal ganglia function The basal ganglia have undergone a remarkable expansion through evolution, paralleling that of related cortical areas. This may underline the fact that cortex and basal ganglia are closely related, and that the basal ganglia contribute in some critical (and evolutionary advantageous) way to cortical function. The fact that basal ganglia and cortex are anatomically and functionally closely related has made it difficult to assign specific functions to these structures which could be separated from those of related cortical areas.

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One source of information about the function of the basal ganglia has been the study of patients with basal ganglia disorders. The clinical outcome of these conditions is frequently a parkinsonian syndrome with akinesia (poverty of movement), bradykinesia (slowness of movement), tremor, rigidity, inflexible postural reflexes and impaired motor learning, or a hyperkinetic phenotype in which uncontrolled movement of limb(s) (chorea) or trunk is observed. Inferred from these observations is the view that the basal ganglia may control the overall amount of movement, and, more specifically, may participate in movement initiation, reflex gating, movement scaling and postural set. Another source of information regarding the function of the basal ganglia has been studies in animals in which the basal ganglia output nuclei are lesioned. Such lesions prolong movement times (bradykinesia) and result in agonist/antagonist co-contractions or in a postural flexion bias contralateral to the lesion (Ranson and Berry, 1941; MacLean, 1978; DeLong and Coyle, 1979; Horak and Anderson, 1984; Mink, 1996; Wenger et al., 1999). As in Parkinson’s disease, uncued movements appear to be more strongly impaired than cued movements. The inferred functions from these lesion experiments are that the basal ganglia may have a role in controlling movement scaling, that they may suppress antagonist activation, and that they may have a particular impact on internally generated movements. A puzzling aspect of these experiments is, however, that in most cases pallidal lesioning has, in fact, very little impact on motor performance, an observation that is confirmed by the recent experience with patients receiving GPi lesion as treatment of parkinsonism. The approach of using the results of diseases or lesions of the basal ganglia as a source of information regarding the function of these structures is problematic for several reasons. The most obvious problem is that the link between the lesion and the resulting deficit may be highly indirect. Thus, a lesion may non-specifically affect related brain circuitry which then results in the observed deficits. Given this scenario, the lesion effects may differ significantly from the physiologic functions of the lesioned structure. A second problem, specific to attempts to use deficits resulting from basal ganglia disorders in humans as source of information regarding the physiologic role of these structures, is that in most of these diseases pathology is present outside the basal ganglia, including cortex and brainstem, which may contribute to the development of clinical signs of the disease. Physiologic studies circumvent some of these issues by assessing in intact organisms the response properties of individual basal ganglia neurons with

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electrophysiologic single-cell recordings, or of whole sections of the circuitry with multielectrode recordings or functional imaging techniques. These techniques have resulted in some of the most detailed and testable hypotheses regarding basal ganglia function. In the following we will provide a brief overview of the most commonly proposed functions of the basal ganglia. 1.2.2. Scaling and focusing Some of the most commonly discussed functions of the basal ganglia are corollaries of the idea that activation of the direct pathway will reduce basal ganglia output, and thereby disinhibit thalamocortical circuits, while activation of the indirect pathway will result in the opposite. One of the proposed functions based on the dichotomy of direct and indirect pathways is the ‘scaling’ hypothesis, which states that the basal ganglia help to regulate specific kinematic parameters. There is, in fact, direct evidence that under some circumstances basal ganglia neurons respond in a graded manner to movement parameters such as the amplitude or direction of limb movement (Mitchell et al., 1987; Hamada et al., 1990; Turner et al., 1998). In addition, recent positron emission tomography (PET) studies in humans have demonstrated a relationship between pallidal activation and movement speed (Turner et al., 1998). In terms of the circuit models, scaling could be explained by an interplay between direct and indirect pathways in which influence of impulses reaching GPi (or SNr) early would allow movement, while the delayed impulses traveling via the indirect pathway would terminate movements, and, thus, control their scale. A second hypothesis based on the interaction of direct and indirect pathways is the idea that the basal ganglia may act to ‘focus’ cortical activation so that only intended movements are carried out while non-intended movements are suppressed (Mink, 1996; Boraud et al., 2000; Nambu et al., 2000). In terms of the circuit model, focusing would rely on the activation or suppression of different neurons in GPi/SNr in relation to unintended and intended movements. Neurons suppressed by activation of the direct pathway would permit intended movements, while neurons activated via the indirect pathway would inhibit unintended movements. Both hypotheses are generally supported by the finding that the GABAergic basal ganglia output neurons have a high discharge rate and, thus, provide tonic inhibition to the thalamic recipient nuclei. By this mechanism, they may suppress cortical activation. In addition, most studies have shown that most motorrelated responses in GPi and SNr are (initially)

increases in discharge, which would presumably increase the thalamic inhibition, and suppress movement, and that the ratio of neurons which are inhibited to those that are excited by movement increases in hypokinetic diseases (Boraud et al., 2000). However, in light of many of the newer physiologic and anatomic findings, scaling and focusing models of basal ganglia function appear to be overly simplistic. The most significant argument against both hypotheses is the fact that lesions of the basal ganglia output structures in otherwise healthy animals do not normally result in significant movement abnormalities, such as involuntary movements or inappropriately scaled motions. Another problem is that it is unclear which information is transmitted to the striatal source neurons of the direct and indirect pathways. Recent physiologic and anatomic studies (Bauswein et al., 1989; Turner and DeLong, 2000; Lei et al., 2004) have made it clear that these neurons very likely do not only receive strictly movementrelated inputs, and that inputs to direct and indirect pathway neurons may differ substantially. Additional (and perhaps related) problems are that many of the motor-related responses that can be recorded in the basal ganglia are multiphasic, and thus not strictly inhibitory or excitatory, and are strongly modulated by the experimental context under which the movements are performed (Gdowski et al., 2001), and the anatomic finding that direct and indirect pathways may not be as strictly separated as previously thought (see above). With regard to the focusing hypothesis, it has also been pointed out that most neuronal responses recorded in the basal ganglia in the context of movement occur late, often around the time of the first agonist burst in the electromyogram, so that it is difficult to see how these structures could be involved in meaningful action selection or suppression of competing movement. In addition, the ‘focusing’ argument is based on an anatomic model in which STN efferents diffusely innervate GPi in order to provide a level of background activity, which then can be regionally inhibited by direct-pathway actions, thus forming the ‘focus’. However, more recent anatomic work has shown that the STN–GPi interaction is more regionally specific than initially thought, so that the anatomic foundation of focusing may not hold (Shink et al., 1996; Smith et al., 1998). There is, of course, also no clear evidence that unselected motor programming occurs at the cortical level which would be in need of ‘focusing’ through the basal ganglia. 1.2.3. Contribution to internally generated movement Another function attributed to the basal ganglia is that they may contribute to the generation of internally

ANATOMY AND PHYSIOLOGY OF THE BASAL GANGLIA generated movements. This hypothesis is in large part based on findings in parkinsonian patients who often have greater deficits with internally generated rather than externally cued movements (Hocherman and Giladi, 1998). In fact, teaching patients to use external cues is a common procedure by which physical therapists help patients with parkinsonian freezing episodes partially to overcome their disability. Conceivably, some of the deficits with internally generated movements may also be generated at the cortical level, either as a non-specific consequence of reduced activation of cortical (premotor) areas involved in the generation of internally triggered movements, or as a consequence of cortical (rather than striatal) dopamine loss in Parkinson’s disease. However, the hypothesis that the basal ganglia in some way contribute to the generation of internally triggered movement remains attractive. To date there are no clear physiologic studies which would unequivocally demonstrate or rule out this potential role of the basal ganglia. 1.2.4. Learning 1.2.4.1. Procedural learning There is substantial evidence that the basal ganglia are involved in learning of procedures, habits and motor sequences. As mentioned above, a contribution of the basal ganglia in this type of learning can be inferred from the fact that patients with basal ganglia diseases frequently suffer from specific learning deficits. For instance, it is known that Alzheimer’s and Parkinson’s disease patients differ fundamentally in their learning capacity. Although patients with Alzheimer’s disease have substantial difficulty memorizing explicit knowledge, they do not differ from controls in their performance in procedural learning tasks (Knowlton et al., 1996). Parkinsonian patients, on the other hand, perform at the level of controls in explicit learning tasks, but have great difficulty with procedural learning. A specific form of this type of learning, sequence learning, appears to be particularly affected by the disease (Nakamura et al., 2001). Although the studies in humans have not specifically addressed the possibility that some of the noted deficits may arise from dysfunction at cortical rather than subcortical areas, a specific involvement of the basal ganglia in sequence learning has been shown in primate experiments. These studies have suggested that the caudate nucleus may be particularly important in the acquisition of new sequence memories, while the putamen may have a greater role in the performance of learned sequences (Miyachi et al., 1997).

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1.2.4.2. Reward-based learning There is also considerable evidence that the basal ganglia are involved in reward-based learning. Central to this idea is the finding that dopamine neurons in the SNc discharge in a manner that provides a prediction error signal to the striatum (Schultz et al., 1998; Waelti et al., 2001). It has also been shown that SNc neurons appear to discharge at the detection of the earliest environmental predictor of upcoming reward (Schultz, 1998, 2000). According to the commonly discussed actor–critic models of learning, providing a surrogate predictive signal related to an upcoming reward to the striatum may solve the temporal difference problem, i.e. the fact that optimal learning requires instantaneous feedback, but that, in actuality, primary reinforcement is usually delayed. By providing precisely timed early predictive feedback, dopaminergic inputs to the striatum may optimize the efficiency of the process of learning. Subsequent to the discovery of the essential role of dopamine in learning, dopamine was found to have a substantial impact on long-term depression and longterm potentiation at corticostriatal synapses (Calabresi et al., 1999, 2000; Centonze et al., 1999, 2001). In addition, studies in rodents and primates (Jog et al., 1999; Courtemanche et al., 2003) have suggested that striatal output neurons change their discharge characteristics in behavioral tasks that require learning. A problem related to the proposed role of the SNc in learning is that it remains unclear how the error prediction or reward signals are generated in the SNc. Given the very early timing of these signals in relation to the upcoming reward, it seems unlikely that the input to the SNc from the other basal ganglia structures such as the SNr or STN could be responsible. Other inputs such as those from the orbitofrontal cortex or a recently described input from the superior colliculus (Coizet et al., 2003; Comoli et al., 2003) may be in a better position to provide such early indicators of upcoming rewards. 1.2.5. The possible role of oscillatory basal ganglia activity In recent years, many studies have demonstrated that individual basal ganglia neurons or ensembles of such cells have oscillatory discharge properties, ranging in frequency from ultraslow oscillations with periods lasting seconds to minutes (Wichmann et al., 2002; Ruskin et al., 2003), recorded in single cells, to oscillations at very high frequencies (300 Hz or more; see Foffani et al., 2003), recorded as local field potentials (LFPs) in human patients undergoing stereotactic

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implantation of leads for deep brain stimulation (DBS) into the STN or GPi which can also be used to record LFPs in the target regions (Brown et al., 2001). The origin of any of these oscillatory phenomena is still unclear. There is evidence that they may arise from local circuit interactions (Plenz and Kitai, 1999; Bevan et al., 2002) or through long-range interactions between cortex and basal ganglia (Magill et al., 2001, 2004; Bevan et al., 2002; Gatev and Wichmann, 2003; Sharott et al., 2005). In fact, a recent analysis of the corticobasal ganglia interaction, using the technique of event-related spectral perturbation (Makeig et al., 2004), has demonstrated that basal ganglia discharge appears to be embedded in a large-scale frequency context which spans at least seconds of cortical activity, and may involve frequencies ranging from delta to beta bands (Gatev and Wichmann, unpublished). While oscillations at low frequencies may be the result of direct connections between individual neurons (perhaps best demonstrated by the coculture experiments of Plenz and Kitai, 1999), oscillations at higher frequencies (certainly above 50/s) are very likely not mediated by single neuronal interactions, but may represent resonances that engage larger portions (and multiple neurons) of the basal ganglia– thalamocortical network. LFP recordings in patients have been particularly instructive in the study of oscillatory activity in the basal ganglia. These recordings, done in patients with Parkinson’s disease, have shown that there is a preponderance of oscillatory LFP activity in the 0–30 Hz range in the parkinsonian state (see also below), which can be reversed by treatment with levodopa. Levodopa treatment enhances high-frequency oscillations (above 60 Hz) instead (Brown et al., 2001; Brown, 2003), resulting in the proposal that low-frequency oscillations may be antikinetic, while oscillations at frequencies above 50–60 Hz may be a normal phenomenon, and may act to allow movement, i.e. be prokinetic (Brown, 2003). The general role of oscillations as a mode of communication in the basal ganglia remains speculative, particularly due to the fact that virtually no data are available from normal individuals.

1.3. Circuit models of Parkinson’s disease 1.3.1. Rate changes The afore-mentioned models have helped in the understanding of the pathophysiology of movement disorders. Only one of them, Parkinson’s disease, will be discussed here in some detail. Parkinson’s disease is the most common hypokinetic disorder. It is characterized by progressive degeneration of brain cells,

including areas in the brainstem, midbrain, olfactory tubercle and cortex (Braak et al., 2003). Most of the movement abnormalities seen in parkinsonism are due to degeneration of the dopaminergic nigrostriatal projection, resulting clinically in the combination of akinesia (poverty of movement), bradykinesia (slowness), rigidity (muscle stiffness) and a 4–6 Hz lowfrequency tremor at rest. The study of circuit changes in parkinsonism has been facilitated by the development of the primate model of parkinsonism induced by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Monkeys treated with this toxin develop a behavioral and pathologic phenotype that closely mimics Parkinson’s disease in humans (Burns et al., 1983; Forno et al., 1993). Early studies in MPTP-treated primates have indicated that metabolic activity (as measured with the 2-deoxy-glucose technique) is increased in both pallidal segments (Crossman et al., 1985, Schwartzman and Alexander, 1985). This was interpreted as evidence for increased activity of the first portion of the indirect pathway (the striatum–GPe connection) as well as the STN–GPi pathway, or, alternatively, as evidence for increased activity via the projections from the STN to GPi and GPe. Subsequent microelectrode recordings of neuronal activity in the primate MPTPmodel of parkinsonism showed directly that neuronal discharge is reduced in GPe, and increased in the STN and GPi, as compared to normal controls (see Fig. 1.1, right side, and Miller and DeLong, 1987; Filion et al., 1988; Bergman et al., 1994). Some of these findings have been supported by studies in parkinsonian patients undergoing microelectrode recording-guided neurosurgical interventions (Vitek et al., 1993; Dogali et al., 1994; Lozano et al., 1996). More recently, experiments in MPTP-treated monkeys have suggested that SNr neurons are also hyperactive in parkinsonism (Wichmann et al., 1999). The changes in discharge rates in the basal ganglia have been interpreted as indicating that striatal dopamine depletion leads to increased activity of striatal neurons of the indirect pathway, resulting in inhibition of GPe, and subsequent disinhibition of STN and GPi/ SNr. It is likely that other structures and feedback loops, such as those involving the PPN and thalamic nuclei (see above) may enhance or ameliorate the abnormalities of discharge in the basal ganglia output nuclei. PET studies in parkinsonian patients have consistently shown reduced activation of motor and premotor areas (Ceballos-Baumann and Brooks, 1997; Eidelberg and Edwards, 2000), which may be a consequence of altered discharge in the basal ganglia output nuclei.

ANATOMY AND PHYSIOLOGY OF THE BASAL GANGLIA Apart from their possible involvement in feedback circuits, brainstem areas such as the PPN may also be directly involved in the development of parkinsonian signs, particularly akinesia. Changes in PPN activity have not been explored directly in parkinsonian monkeys. According to the afore-mentioned circuit models, one would expect a decrease in PPN activity in parkinsonism, but there is at least one report in rodents indicating the opposite (Breit et al., 2001). Lesions of this nucleus in normal monkeys are known to result in akinesia and bradykinesia (Kojima et al., 1997; MunroDavies et al., 1999), while activation of the PPN by local injections of the GABA-A receptor antagonist bicuculline ameliorate parkinsonian signs in MPTPtreated monkeys (Nandi et al., 2002). One of the possible explanations for these findings is that PPN interacts locally with other brainstem areas to modulate the degree of movement. Another possible explanation is that activation or inactivation of the PPN interferes with the glutamatergic drive on to SNc neurons from the PPN. For instance, lesioning may reduce the excitatory input from PPN to the SNc, perhaps resulting in a reduction of striatal dopamine release. To date, a reduction of striatal dopamine release after PPN lesions, or reversibility of hypokinesia by dopaminergic drugs, has not been shown. Further support for the hypothesis that PPN inactivation acts via the intercalated SNc to induce bradykinesia and akinesia comes from studies in which the proparkinsonian consequences of MPTP treatment in monkeys were partially avoided by prelesioning of the PPN (Takada et al., 2000). These studies were interpreted to indicate a role of excitotoxic glutamate release from PPN terminals in MPTP-related death of dopamine cells in the SNc. The general pathophysiologic model in which overactivity along the indirect pathway is a major contributor to the development of parkinsonism is supported by the demonstration that lesions of STN, GPi or SNr in MPTP-treated primates reverse some or all signs of parkinsonism (Bergman et al., 1990; Lieberman et al., 1999; Wichmann et al., 2001). Over the last decade, these results have revitalized interest in functional neurosurgical approaches as treatments of Parkinson’s disease. This was first employed in the form of GPi lesions (pallidotomy) (Laitinen et al., 1992; Dogali et al., 1995; Lozano et al., 1995; Baron et al., 1996) and, more recently, with STN lesions (Gill and Heywood, 1997; Alvarez et al., 2001). In addition, highfrequency DBS of STN or GPi has been shown to reverse parkinsonian signs (Starr et al., 1998; see below). PET studies in pallidotomy patients and in patients with DBS of the STN or GPi have shown that frontal motor areas whose metabolic activity was reduced in the parkinsonian state became active again

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after the procedure (Ceballos-Bauman et al., 1994; Eidelberg et al., 1996; Eidelberg and Edwards, 2000). Although the rate-based circuit models of parkinsonism have had tremendous value in generating testable hypotheses, detailed studies of the results of lesions in human patients with parkinsonism have brought to light several findings that are incompatible with the models. For instance, lesions of the VA/VL nuclei of the thalamus do not lead to parkinsonism, as would be predicted by the model, and are, in fact, beneficial in the treatment of tremor and rigidity (Tasker et al., 1997; Giller et al., 1998). Similarly, lesions of GPi in the setting of parkinsonism improve all aspects of Parkinson’s disease without producing dyskinesias or other obvious detrimental effects. In fact, these procedures are highly effective in reducing drug-induced dyskinesias (Dogali et al., 1995; Rabey et al., 1995; Baron et al., 1996). In contrast to the hypokinetic features of parkinsonism, dyskinesias appear to arise from pathologic reduction in basal ganglia outflow (Papa et al., 1999), and thus should not respond to but are made worse by further reduction of pallidal outflow (Marsden and Obeso, 1994). 1.3.2. Pattern changes These seemingly paradoxical findings may be explained by the realization that parkinsonism may result, in part, from changes in basal ganglia activity other than altered discharge rates. Such additional changes may include altered processing of proprioceptive input, as well as abnormal timing, patterning and synchronization of discharge that introduces errors and non-specific noise into the thalamocortical signal. Altered discharge patterns (Figs. 1.2 and 1.3) and synchronization between neighboring neurons have been extensively documented in parkinsonian monkeys and patients. For instance, neuronal responses to passive limb manipulations in STN, GPi and thalamus (Miller and DeLong, 1987; Filion et al., 1988; Bergman et al., 1994) have been shown to occur more often, to be more pronounced and to have widened receptive fields after treatment with MPTP. In addition, the proportion of neurons showing increased discharge in response to somatosensory inputs increases, supporting the view that somatosensory processing is fundamentally altered in this disease (Boraud et al., 2000). There is also a marked change in the synchronization of discharge between neurons in the basal ganglia. In contrast to the virtual absence of synchronized discharge of such neurons in normal monkeys (Wichmann et al., 1994), a substantial proportion of neighboring neurons in globus pallidus and STN discharge in unison in parkinsonian primates (Bergman et al., 1994).

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2

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Fig. 1.2. Activity changes in subthalamic nucleus (STN) and globus pallidus internus (GPi) in primate parkinsonism. The data are shown as raster diagrams, where each individual line represents a single neuronal discharge. Each diagram shows 20 consecutive 1000-ms segments of data from STN and GPi. The neuronal activity is increased in STN and GPi. In addition to the rate changes, there are also obvious changes in the firing patterns of neurons in these structures, with a prominence of bursts and oscillatory discharge patterns in the parkinsonian state.

The proportion of cells in STN, GPi and SNr which discharge in oscillatory or non-oscillatory bursts is also greatly increased in parkinsonism (Figs. 1.2 and 1.3; Miller and DeLong, 1987; Filion and Tremblay, 1991; Bergman et al., 1994; Soares et al., 2004). Oscillatory burst discharge patterns are relatively rare in the normal basal ganglia, but are often seen in conjunction with tremor, which may reflect tremor-related proprioceptive input or a more active participation of the basal ganglia in the generation of tremor. As mentioned above, other forms of oscillations may involve not single cells, but larger portions of the basal ganglia thalamocortical network. Such oscillations are now recordable in patients with Parkinson’s disease, using LFP recordings from implanted DBS electrodes, as described in section 1.2.5 of this chapter. These studies have pinpointed oscillations in STN and GPi at low frequencies (below 30 Hz) as being

particularly disruptive for movement (‘antikinetic’; see Brown, 2003). The therapeutic benefits of GPi and STN lesions suggest that in Parkinson’s disease and other movement disorders the total lack of basal ganglia output is more tolerable than disruptive abnormal output on brainstem and thalamocortical systems. Functional imaging studies have demonstrated that the surgical interventions do not necessarily normalize cortical motor mechanisms in parkinsonian subjects, but rather may allow the intact portions of the thalamocortical and brainstem system to compensate more effectively for the loss of the basal ganglia contribution to movement. A related mechanism may be at work in DBS treatments for Parkinson’s disease. DBS is a highly effective treatment modality for this disorder (Obeso et al., 1997; Starr et al., 1998; Olanow et al., 2000; Ashkan et al., 2004; Lozano and Mahant, 2004). Despite the similarity in the results of lesions and

ANATOMY AND PHYSIOLOGY OF THE BASAL GANGLIA

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Fig. 1.3. Summary representation of changes in discharge rates (A), the neuron’s tendency to discharge in burst, expressed as the number of spikes occurring in bursts as compared to the total number of spikes (B), and changes in the proportion of cells with significant autocorrelation peaks suggesting oscillatory discharge in the 3–8 Hz range (C) and in the 8–15 Hz range (D). GPe, globus pallidus externus; STN, subthalamic nucleus; GPi, globus pallidus internus; MPTP, 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine. Data from Soares et al. (2004).

DBS interventions, there is evidence that DBS works not through inactivation, but through true stimulation of fibers and neurons in the vicinity of the stimulating electrode (Hashimoto et al., 2003; Brown et al., 2004; McIntyre et al., 2004), which may alter the oscillatory characteristics of basal ganglia output (Brown et al., 2004). Basal ganglia output is clearly not normalized in patients who are successfully treated with DBS. Rather, it seems that the disease-related abnormalities of basal ganglia output are modulated by stimulation in a way that is less disruptive.

1.4. Conclusion Recent studies of basal ganglia anatomy and physiology have resulted in a more refined view of the intricate networks in which these structures are involved and the functions with which they may be concerned. Yet, the explosion of anatomic and physiologic knowledge has also resulted in the realization that previous models of the basal ganglia circuitry were simplistic in detail and scope. Meaningful revisions of these models require incorporation of the many newly discovered or emphasized intrinsic and extrinsic connections of these nuclei, and a more dynamic view of these structures, which

appear to interact with cortex over long time scales and a wide range of frequencies which may not always rely simply on connections between individual neurons, but may involve larger ensembles of cells, which may be engaged on information exchange via oscillatory interactions. In addition, future updates of the models will have to incorporate the newly gained knowledge regarding the types of information which reach the basal ganglia, and how they are incorporated into basal ganglia activity. Detailed knowledge of these network aspects of basal ganglia function will help to a better understanding of the many diseases which result from basal ganglia dysfunction.

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ANATOMY AND PHYSIOLOGY OF THE BASAL GANGLIA Rye DB, Lee HJ, Saper CB et al. (1988). Medullary and spinal efferents of the pedunculopontine tegmental nucleus and adjacent mesopontine tegmentum in the rat. J Comp Neurol 269: 315–341. Sadikot AF, Parent A, Smith Y et al. (1992). Efferent connections of the centromedian and parafascicular thalamic nuclei in the squirrel monkey: a light and electron microscopic study of the thalamostriatal projection in relation to striatal heterogeneity. J Comp Neurol 320: 228–242. Schell GR, Strick PL (1984). The origin of thalamic inputs to the arcuate premotor and supplementary motor areas. J Neurosci 4: 539–560. Schultz W (1998). Predictive reward signal of dopamine neurons. J Neurophysiol 80: 1–27. Schultz W (2000). Multiple reward signals in the brain. Nat Rev Neurosci 1: 199–207. Schultz W, Romo R (1987). Responses of nigrostriatal dopamine neurons to high-intensity somatosensory stimulation in the anesthetized monkey. J Neurophysiol 57: 201–217. Schultz W, Tremblay L, Hollerman JR (1998). Reward prediction in primate basal ganglia and frontal cortex. Neuropharmacology 37: 421–429. Schwartzman RJ, Alexander GM (1985). Changes in the local cerebral metabolic rate for glucose in the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson’s disease. Brain Res 358: 137–143. Sharott A, Magill PJ, Bolam JP et al. (2005). Directional analysis of coherent oscillatory field potentials in the cerebral cortex and basal ganglia of the rat. J Physiol 562: 951–963. Shink E, Bevan MD, Bolam JP et al. (1996). The subthalamic nucleus and the external pallidum: two tightly interconnected structures that control the output of the basal ganglia in the monkey. Neuroscience 73: 335–357. Sidibe M, Smith Y (1996). Differential synaptic innervation of striatofugal neurones projecting to the internal or external segments of the globus pallidus by thalamic afferents in the squirrel monkey. J Comp Neurol 365: 445–465. Sidibe M, Bevan MD, Bolam JP et al. (1997). Efferent connections of the internal globus pallidus in the squirrel monkey: I. Topography and synaptic organization of the pallidothalamic projection. J Comp Neurol 382: 323–347. Smith AD, Bolam JP (1990). The neural network of the basal ganglia as revealed by the study of synaptic connections of identified neurones. Trends Neurosci 13: 259–265. Smith Y, Parent A (1986). Differential connections of caudate nucleus and putamen in the squirrel monkey (saimiri sciureus). Neuroscience 18: 347–371. Smith Y, Bevan MD, Shink E et al. (1998). Microcircuitry of the direct and indirect pathways of the basal ganglia. Neuroscience 86: 353–387. Soares J, Kliem MA, Betarbet R et al. (2004). Role of external pallidal segment in primate parkinsonism:

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comparison of the effects of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine-induced parkinsonism and lesions of the external pallidal segment. J Neurosci 24 (29), 6417–6426. Starr PA, Vitek JL, Bakay RA (1998). Deep brain stimulation for movement disorders. Neurosurg Clin N Am 9: 381–402. Steininger TL, Rye DB, Wainer BH (1992). Afferent projections to the cholinergic pedunculopontine tegmental nucleus and adjacent midbrain extrapyramidal area in the albino rat. I. Retrograde tracing studies. J Comp Neurol 321: 515–543. Surmeier DJ, Song WJ, Yan Z (1996). Coordinated expression of dopamine receptors in neostriatal medium spiny neurons. J Neurosci 16: 6579–6591. Takada M, Matsumura M, Kojima J et al. (2000). Protection against dopaminergic nigrostriatal cell death by excitatory input ablation. Eur J Neurosci 12: 1771–1780. Takada M, Tokuno H, Hamada I et al. (2001). Organization of inputs from cingulate motor areas to basal ganglia in macaque monkey. Eur J Neurosci 14: 1633–1650. Tasker RR, Lang AE, Lozano AM (1997). Pallidal and thalamic surgery for Parkinson’s disease. Exp Neurol 144: 35–40. Trevitt T, Carlson B, Correa M et al. (2002). Interactions between dopamine D1 receptors and gamma-aminobutyric acid mechanisms in substantia nigra pars reticulata of the rat: neurochemical and behavioral studies. Psychopharmacology (Berl) 159: 229–237. Turner RS, DeLong MR (2000). Corticostriatal activity in primary motor cortex of the macaque. J Neurosci 20: 7096–7108. Turner RS, Grafton ST, Votaw JR et al. (1998). Motor subcircuits mediating the control of movement velocity: a PET study. J Neurophysiol 80: 2162–2176. Vitek JL, Kaneoke Y, Turner R et al. (1993). Neuronal activity in the internal (GPi) and external (GPe) segments of the globus pallidus (GP) of parkinsonian patients is similar to that in the MPTP-treated primate model of parkinsonism. Soc Neurosci Abstr 19: 1584. von Krosigk M, Smith Y, Bolam JP et al. (1993). Synaptic organization of GABAergic inputs from the striatum and the globus pallidus onto neurons in the substantia nigra and retrorubral field which project to the medullary reticular formation. Neuroscience 50: 531–549. Waelti P, Dickinson A, Schultz W (2001). Dopamine responses comply with basic assumptions of formal learning theory. Nature 412: 43–48. Wenger KK, Musch KL, Mink JW (1999). Impaired reaching and grasping after focal inactivation of globus pallidus pars interna in the monkey. J Neurophysiol 82: 2049–2060. Wichmann T, Bergman H, DeLong MR (1994). The primate subthalamic nucleus. I. Functional properties in intact animals. J Neurophysiol 72: 494–506. Wichmann T, Bergman H, Starr PA et al. (1999). Comparison of MPTP-induced changes in spontaneous neuronal

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discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates. Exp Brain Res 125: 397–409. Wichmann T, Kliem MA, DeLong MR (2001). Antiparkinsonian and behavioral effects of inactivation of the substantia nigra pars reticulata in hemiparkinsonian primates. Exp Neurol 167: 410–424.

Wichmann T, Kliem MA, Soares J (2002). Slow oscillatory discharge in the primate basal ganglia. J Neurophysiol 87: 1145–1148. Wurtz RH, Hikosaka O (1986). Role of the basal ganglia in the initiation of saccadic eye movements. Prog Brain Res 64: 175–190.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 2

Functional neurochemistry of the basal ganglia PERSHIA SAMADI1,2, CLAUDE ROUILLARD2, PAUL J. BE´DARD2 AND THE´RE`SE DI PAOLO1* 1

Centre de Recherche en Endocrinologie Mole´culaire et Oncologique, CHUL, Faculte´ de Pharmacie, and 2 Centre de Recherche en Neurosciences, CHUL, Faculte´ de Me´dicine, Universite´ Laval, Que´bec, Canada

Proper execution of voluntary movements results from the correct processing of feedback loops involving the cortex, thalamus and basal ganglia (BG). The BG include a subset of subcortical structures involved in a variety of processes including motor behavior and also motor learning and memory process (Graybiel et al., 1994; Graybiel, 1998; Packard and Knowlton, 2002). The BG are located in the basal telencephalon and consist of interconnected structures. The dorsal division of the BG is associated with motor and associative functions and consists of the striatum, including the caudate nucleus and putamen; the globus pallidus or pallidum which comprises the internal (GPi) and external (GPe) regions; the subthalamic nucleus (STN); and the substantia nigra divided into two main parts, the pars compacta (SNc) and pars reticulata (SNr). The ventral division of the BG is associated with limbic functions and consists of the ventral striatum and nucleus accumbens, the ventral pallidum and ventral tegmental area (Blandini et al., 2000; Bolam et al., 2000; Parent et al., 2000).

2.1. Functional basal ganglia circuit The striatum, the input structure of the BG, receives two major inputs: 1. a massive excitatory glutamatergic projection from most areas of the cerebral cortex organized in a highly topographical manner, and 2. a dopaminergic projection from the SNc (Parent et al., 1995b, 2000; Smith et al., 1998; Bolam et al., 2000). The striatum also receives glutamatergic inputs from the amygdala, the hippocampus and the centromedian–

parafascicular thalamic complex (Parent et al., 2000; Smith et al., 2004) and serotoninergic afferents from the raphe and caudal linear nuclei (Parent et al., 1995b; Blandini et al., 2000). In addition, the activity of the BG components in controlling movements is modulated by the pedunculopontine nucleus (PPN) (Delwaide et al., 2000; Parent et al., 2000). The mammalian striatum has two anatomical compartments: the striosomes (patches) and the matrix with distinct chemical compositions and connections (Graybiel et al., 2000; Prensa and Parent, 2001; Levesque et al., 2004). High densities of m opioid receptor binding and low levels of acetylcholinesterase staining define striosomes, while the matrix has high levels of the Ca2þ-binding protein, calbindin (Graybiel and Ragsdale, 1978). Striosomes express a higher density of gamma-aminobutyric acid (GABA)A receptor compared to the matrix (Waldvogel et al., 1999). The areas of cortex associated with the limbic system innervate striosomes whereas the neocortical inputs to the matrix originate from the association and sensorimotor cortices, which innervate medial and lateral parts of the striatum, respectively (Graybiel et al., 2000). It has been suggested that the balance of activity between the matrix and striosomal compartments has an important role in the modulation of BG motor functions (Graybiel et al., 2000). The principal output nuclei of the BG are SNr and GPi (Parent and Hazrati, 1995a, b; Parent et al., 2000). These nuclei, SNr and GPi, tonically inhibit the ventral anterior and ventral lateral (VA/VL) motor nuclei of the thalamus, thereby reducing excitatory thalamic innervation of cortical motor areas (Alexander and Crutcher, 1990). Movement occurs when the

*Correspondence to: Dr The´re`se Di Paolo, Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL), 2705 Laurier Boulevard, Que´bec PQ, G1V 4G2, Canada. E-mail: [email protected], Tel: 418654-2296; Fax: 418-654-2761.

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thalamus is disinhibited, facilitating excitation of cortical motor areas and resulting in increased motor output to the brainstem and spinal cord (Pollack, 2001). According to the current model for the organization of the BG, the cortical information is received by striatal medium spiny neurons. These neurons relay this information to the SNr and GPi via direct and indirect pathways. In the direct pathway, GABA containing medium spiny neurons project directly to the output nuclei (SNr-GPi). These striatonigral neurons also express dopamine D1 receptors, the neuropeptides substance P (SP) and dynorphin (Dyn). Stimulation of the direct pathway inhibits the target neurons in SNr-GPi, thus facilitating the thalamocortical activity by disinhibition of the thalamus. This facilitatory action of the direct pathway is modulated by the indirect pathway. In the indirect pathway, the GABAergic medium spiny neurons project indirectly to the output nuclei via a complex network interconnecting the GPe and STN. These GABAergic medium spiny neurons express dopamine D2 receptors and the neuropeptide enkephalin (Enk) and project directly to the GPe (striatopallidal neurons). The GPe sends GABAergic projections to the STN or sends direct projections to the SNr-GPi (Alexander and Crutcher, 1990; Wichmann and DeLong, 1996; Bolam et al., 2000; Parent et al., 2000; Hornykiewicz, 2001). The segregation of the striatonigral (direct) and striatopallidal (indirect) pathways is not complete; indeed, striatonigral neurons give minor axon collaterals to the globus pallidus (GPe in primates) (Kawaguchi et al., 1990). A subpopulation of GPe neurons sends an inhibitory feedback selectively to the striatal GABAergic interneurons. Cortical input is also received by these inhibitory interneurons, which in turn innervate medium spiny neurons. Thus, by synchronizing the activity of medium spiny neurons, these neurons are in the position to modulate the flow of cortical information through the BG (Bolam et al., 2000). Disinhibition of STN by pallidal projection neurons leads to glutamate-mediated excitation of the output nuclei. Consequently, inhibitory control over the thalamus increases and motor activity decreases. The STN sends projection neurons to GPe and output nuclei of the BG. Besides inhibitory GABAergic neurons from GPe, the STN also receives inhibitory projections from ventral pallidum and nucleus accumbens, excitatory input from PPN, parafascicular nucleus of the thalamus, the sensory motor cortex and dopaminergic inputs from SNc. In the current models of BG circuitry, the STN holds a strategic position in the circuitry (Alexander and Crutcher, 1990; Wichmann and DeLong, 1996; Smith et al., 1998; Bolam et al., 2000; Parent et al., 2000; Hornykiewicz, 2001).

Voluntary movement is mediated by a balanced activity of the direct and indirect pathways. In contrast, imbalance in the activity of these two pathways and the resulting alterations in the output nuclei are thought to account for the hypo- and hyperkinetic features of BG disorders (Be´dard et al., 1999; Parent et al., 2000). The major connections of the BG structures are summarized in Fig. 2.1.

2.2. Chemical transmission systems in the basal ganglia More than 99% of all synapse in the brain use chemical transmission, referred to as fast and slow synaptic transmission (Greengard, 2001). Neuronal activity in the BG is under the control of different neurotransmitter systems that regulate the duration and intensity of cellular communications. In recent years, it has become clear that information exchange at the synapse is bi-directional. In classical anterogade signaling neuronal information coded by the action potential is transmitted through a chemical synapse in the anterograde direction by release of neurotransmitters, neuropeptides and neuromodulators from the presynaptic terminal. The transmitter molecules then diffuse across the synaptic cleft and bind to their receptors on the postsynaptic cell membrane. This in turn activates the receptors, leading to immediate changes in membrane potential as well as long-term structural and metabolic changes in the postsynaptic cell. This form of transmission has the important property of amplification and, by the discharge of just one synaptic vesicle, several thousand molecules of transmitter stored in that vesicle are released. Because of the rapid dynamic of synthesis and release, much of the small transmitter molecules in the neuron must be synthesized at the terminal. In contrast, the protein precursors of neuroactive peptides are only synthesized in the cell body where they are packaged in dense-core vesicles and transported anterogradely from the cell body to the terminals. The co-release of several neuroactive substances on to appropriate postsynaptic receptors allows an extraordinary diversity of information to be transferred in a single synaptic action (Kandel et al., 2000). In recently discovered retrograde signaling, the postsynaptic cell provides a variety of retrograde signals either constitutively or triggered by synaptic activity on the postsynaptic neuron. The retrograde signaling could occur through: (1) signaling by membrane-permeant factors; (2) signaling by secreted factors; and (3) signaling by membranebound factors. The retrograde signaling is now recognized as a mechanism of synaptic regulation in the brain where it plays a critical role in the differentiation

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA

21

Cerebral cortex

+

+

+

+

+

+

Striatum D2/A2A D1/A1 Enk Dyn, SP -

SNc

GPe + +

DA

-

-

DA

+

-

SNr/GPi -

+

5-HT

STN

DA

Thalamus

Raphe nuclei

PPN Brainstem and spinal cord

+ -

5-HT DA Glu GABA Glu and/orACh

Fig. 2.1. Major circuits of the basal ganglia. GPi, internal globus pallidus; GPe, external globus pallidus; PPN, pedonculopontine tegmental nucleus; STN, subthalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; 5-HT, serotonin; DA, dopamine; Glu, glutamate; GABA, gamma-aminobutyric acid; ACh, acetylcholine; Enk, enkephalin; Dyn, dynorphin; SP, substance P.

and maintenance of presynaptic cells, as well as in the formation, maturation and plasticity of the synapse (Fitzsimonds and Poo, 1998; Tao and Poo, 2001; Alger, 2002). Transmitters are removed from the synaptic cleft by three different mechanisms: diffusion, enzymatic degradation and reuptake by specific neurotransmitter transporters (Kandel et al., 2000). The processing and storage of motor information in the BG depend on the signal transduction induced by different neurotransmitters and neuromodulators. Table 2.1 summarizes the most important of these chemical messengers in the BG.

2.3. Dopamine The mesostriatal dopaminergic pathway is composed of: (1) the dorsal part, corresponding to the dopaminergic nigrostriatal projection of the SNc; and (2) the ventral part, corresponding to the dopaminergic neurons of the ventral tegmental area, which terminates in the ventral striatum (Parent et al., 1995b). The role of dopamine as the main neurotransmitter in the functional organization of the BG is drawn from the severe motor disturbances resulting from the degeneration of the nigrostriatal pathway in Parkinson’s disease (PD)

(Marsden, 1984). Dopaminergic innervation of the STN and GPi originating from the SNc has been also demonstrated (Cossette et al., 1999). Dopaminergic and glutamatergic systems interact closely at the level of medium spiny neurons. Dopaminergic nigrostriatal neurons synapse mainly on to the necks of dendritic spines of medium spiny projection neurons (Smith and Bolam, 1990b; Hanley and Bolam, 1997) whereas glutamatergic cortical afferents synapse specifically on the head of the same dendritic spines (Smith et al., 1994). These findings suggest that glutamate activates medium spiny neurons while dopamine released from the nigrostriatal terminal acts on dopamine receptors within the synapse and extrasynaptic sites to modulate striatal glutamatergic input (Starr, 1995; Yung et al., 1995; Pollack, 2001). In addition, recent studies suggest that dopamine may also modulate striatal interneuron activity. Since the activity of medium spiny neurons is also finely regulated by interneurons, by modulating the activity of these interneurons dopamine exerts an indirect but potent control on the striatal output neurons (Bracci et al., 2002; Centonze et al., 2003b). Therefore, dopamine, by providing strong modulation of striatal neuronal activity, plays an important role in the control of the whole BG circuitry and ensures voluntary movements.

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Table 2.1 Major neurotransmitters and neuromodulators in the basal ganglia and their receptors Neurotransmitter/neuromodulator

Ionotropic receptor

Metabotropic receptor

Dopamine Glutamate

D1, D2, D3, D4, D5 NMDA subunits: NR1 NR2A NR2B NR2C NR2D NR3A

AMPA subunits: GluR1 GluR2 GluR3 GluR4

Kainate subunits: GluR5 GluR6 GluR7 KA1 KA2

Group I mGluR1 mGluR5

Group II mGluR2 mGluR3

Group III mGluR4 mGluR6 mGluR7 mGluR8

GABA

GABAA, GABAC

GABAH(GABABR1 - GABABR2)

Acetylcholine

Nicotinic

Muscaritic (M1, M2, M3, M4, M5)

Adenosine

A1, A2A, A2B, A3

Cannabinoid

CB1, CB2, CB3?

Serotonin

5-HT3

Neurokinins (NKs) (Substance P/NK-1, Substance K/NK-2, Neuromedin K/NK-3)

5-HT1A, B, D, E, F; 5-HT2A, B, C, 5HT4; 5-HT5A, B; 5-HT6; 5-HT7 NK-1R (SPR), NK-2R (SKR), NK-3R (NKR)

Opioids (Enlephalin; Dynorphin)

m, k, d

Neurotensin

NTS1, NTS2, NTS3

Neuropeptide Y (NPY)

NPYRs (6 known receptors)

Somatostatin (SOM)

SSTRs (5 known receptors)

Angiotensin

AT1, AT2, AT3

Cholecystokinin

CCKAR, CCKBR

2.3.1. Dopamine biosynthesis, reuptake and degradation The precursors of dopamine, phenylalanine and tyrosine, but not dopamine itself, are able to cross the blood–brain barrier. The biosynthesis of dopamine takes place within the cytosol of nerve terminals in two steps. First, tyrosine is converted to levodopa (l-dihydroxyphenylalanine) by the enzyme tyrosine hydroxylase, which is present in catecholaminecontaining neurons. Then, dopamine is synthesized from decarboxylation of levodopa by the enzyme

dopa-decarboxylase, also known as aromatic amino acid decarboxylase (AADC). Dopamine is finally degraded by the activity of monoamine oxidase (MAO) and aldehyde dehydrogenase to dihydroxyphenylacetic acid (DOPAC). Dopamine can also be metabolized by the enzymatic activity of catechol-Omethyltransferase to form 3-methoxytryptamine. DOPAC and 3-methoxytryptamine are then degraded to form homovanillic acid (Webster, 2001b; von Bohlen und Halbach and Dermietzel, 2002). The summary of the synthesis, transport and degradation of dopamine is illustrated in Fig. 2.2.

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA

23

HVA MT CO

3-MT DOPAC

TH

MAO

CO

MT

L-DOPA O

3-MT C OMT

Presynaptic dopaminergic terminal

AA

DA

DA

AT 2

VM

T

DA

DC

MA

DA

HVA

DOPAC

CO MT

Tyrosine

Glial cell

DA

Fig. 2.2. Schematic illustration of the synthesis, release, transport and degradation of dopamine in dopaminergic nerve terminals. TH, tyrosine hydroxylase; L-DOPA, L-dihydroxyphenylalanine; AADC, amino acid decarboxylase; DA, dopamine; MAO, monoamine oxidase; COMT, catechol-O-methyl transferase; DOPAC, 3,4-dihydroxyphenylacetic acid; 3-MT, 3-methoxytyramine; HVA, homovanillic acid; DAT, membrane dopamine transporter; VMAT2, vesicular monoamine transporter 2.

The dopamine transporters, which are key factors in the control of extracellular dopamine concentrations, can be classified into two main families: (1) the monoamine vesicular transporter (VMAT2) and (2) plasma membrane transporter (dopamine transporter (DAT)). VMAT2 is distinct from VMAT1 in the adrenal medulla and is responsible for packaging dopamine and other monoamines from cytoplasm into synaptic vesicles. Reduction of VMAT2 binding in the nigrostriatal system has been demonstrated in animal models of PD (Vander Borght et al., 1995; Kilbourn et al., 2000), and has also been reported in patients with PD (Frey et al., 1996). The vesicular monoamine uptake, including dopamine, involves the exchange of lumenal Hþ for cytoplasmic transmitters by HþATPase located in the vesicular membrane (Piccini, 2003). DAT is responsible for the uptake of dopamine from the extracellular space into the cytoplasm (Piccini, 2003). Like other monoamine transporters, DAT is a transmembrane protein, containing 12 putative domains. The mechanism by which DAT mediates dopamine uptake involves sequential binding and

cotransport of two Naþ ions and one Cl ion generated by the plasma membrane Naþ/Kþ-ATPase (Torres et al., 2003). DAT functions are regulated by presynaptic receptors, protein kinases and membrane trafficking and changes in DAT levels can clearly alter motor activity (Marshall and Grosset, 2003; Schenk et al., 200; Uhl, 2003). Agents that alter protein kinase C (PKC), inositol triphosphate (PI3) kinase and mitogen and signal-regulated kinase (MEK1 and 2) alter DAT function (Vrindavanam et al., 1996; Carvelli et al., 2002; Uhl, 2003). Transporters can also function in reverse and they possess channel-like activity (Torres et al., 2003). Since PD is a progressive neurodegenerative disease, neuroimaging techniques that reflect the conversion of levodopa to dopamine through aromatic AADC, VMAT2 and DAT, can be used to evaluate the status of the nigrostriatal dopaminergic system (Brooks et al., 2003). Furthermore, DAT and VMAT2 localization provides markers for presynaptic dopaminergic loss in parkinsonism and allows parkinsonism to be differentiated from other movement disorders without presynaptic dopaminergic loss, such as essential tremor,

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vascular pseudoparkinsonism and psychogenic parkinsonism (Marshall and Grosset, 2003). 2.3.2. Receptors and signal transduction Dopamine receptors belong to the seven transmembranelike G-protein-coupled receptor superfamily. According to the similarity of a-subunits, G-proteins are divided into four main families: Gas/olf, Gai/o, Gaq/11 and Ga12/13. Each family preferentially regulates specific classes of effector molecules, for example Gas/olf and Gai/o are positively and negatively coupled to adenylyl cyclase, respectively (Cabrera-Vera et al., 2003). To date, five distinct dopamine receptors subtypes (D1–D5) have been isolated and characterized (Missale et al., 1998). These receptors are classified into two main families: D1-like (D1 and D5) and D2-like (D2–D4) dopamine receptors, based on positive (D1) or negative (D2) coupling to adenylyl cyclase and the regulation of intracellular cyclic adenosine monophosphate (cAMP) levels (Kebabian and Calne, 1979; Missale et al., 1998). Dopamine, through activation of D1-like receptors and cAMP-dependent protein kinase A (PKA) phosphorylates a key component of dopaminergic signaling in medium spiny neurons, the dopamine- and cAMP-regulated phosphoprotein (DARPP-32) at threonine 34 (Thr-34). The phosphorylation converts DARPP-32 from an inactive molecule into an inhibitor of protein phosphatase1 (PP-1), which controls the state of phosphorylation and activity of numerous physiologically important effectors, including transcription factors such as cAMP response element-binding protein (CREB), fos-family, ion channels and ionotropic receptors. Conversely, activation of D2-like receptors counteracts the effect of D1-like receptors on phosphorylation of DARPP32 at Thr-34 by activating PP-2B and by reducing cAMP levels (Nishi et al., 1997; Greengard, 2001). D1-like receptors could also act on inositol phosphate production and mobilization of intracellular Ca2þ (Undie et al., 1994). On the other hand, D2-like receptors suppress N-type Ca2þ currents (Yan et al., 1997). Although D1 and D2 receptors in the striatum appear to be largely segregated, there is evidence of co-localization of D1 and D2 receptors on medium spiny neurons (Surmeier et al., 1996; Aizman et al., 2000), the collateralization of striatofugal axons (Parent et al., 1995a, 2000), and the presence of D2 receptors on striatal interneurons (Betarbet et al., 1997). D1 receptors may be exclusively localized on postsynaptic elements in striatal medium spiny neurons (Hersch et al., 1995; Caille et al., 1996), while D2 receptors are reported to be localized on pre- and postsynaptic elements, including corticostriatal terminals (Hersch et al., 1995; Wang and Pickel, 2002).

Recent studies revealed that dopamine selectively inhibits particular subsets of corticostriatal afferents via activation of D2 receptors on glutamatergic presynaptic terminals (Bamford et al., 2004). Inactivation of L-type voltage-dependent Ca2þ channels is a main mechanism involved in the D2 receptor-mediated inhibition of striatopallidal neuronal activity (HernandezLopez et al., 2000). GABAergic interneurons which have dense arborization and contact several striatal neurons, including interneurons themselves, also express D2 receptors (Delle Donne et al., 1997). It has been shown that D2 receptors cause presynaptic inhibition of both GABAergic and cholinergic interneurons (Pisani et al., 2000). By a mechanism of alternative splicing, the D2 receptor genes encode two isoforms, D2L and D2S (Usiello et al., 2000). These two isoforms have different functions in vivo; D2S is principally a D2 presynaptic autoreceptor, while D2L acts mainly at postsynaptic sites (Usiello et al., 2000). The D3 receptor has a higher expression in nucleus accumbens while is less expressed in the dorsal striatum (Levesque et al., 1992; Missale et al., 1998). Moderate levels of D4 receptor expression in dorsal striatum with greater abundance in striosome than in matrix has been shown (Rivera et al., 2002b). It has been reported that D4 receptors are located on corticostriatal projections to the dorsal and ventral striatum (Tarazi et al., 1998). The expression of D5 receptor in the striatum has been demonstrated (Yan and Surmeier, 1997; Rivera et al., 2002a) and is reported to be preferentially expressed in striatal interneurons (Rivera et al., 2002a). A variety of G-proteins, ion channels and second messenger systems modulated by dopamine receptor activation can induce both immediate and long-term changes in cell physiology (Sealfon and Olanow, 2000). Dopamine D1 and D2 receptors on striatal medium spiny neurons serve to modulate glutamatemediated activity (Calabresi et al., 2000a). The D1 receptor activation produces different effects on Ca2þ currents, reducing N- and P-type but enhancing L-type conductances (Surmeier et al., 1995). Dopamine potentiates NMDA-induced currents in medium spiny neurons by enhancement of L-type Ca2þ conductances and the cAMP-dependent PKA and PKC cascades (Smart, 1997; Cepeda et al., 1998). Recently, it has been reported that the D1 and D5 dopamine receptor activation induces long-term potentiation (LTP) and long-term depression (LTD) in distinct subtypes of striatal neurons and could exert distinct roles in motor activity and corticostriatal synaptic plasticity (Centonze et al., 2003a). According to these studies, while LTP induction requires the stimulation of the D1-PKA pathway in the

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA medium spiny neurons, LTD depends on the activation of D5-PKA signaling in a neuronal subtype other than medium spiny neurons (Centonze et al., 2003a). The homo- and heterodimerization of G-proteincoupled receptor can generate numerous possibilities in the regulation of their function (Bouvier, 2001). Dopamine D2 receptor homodimerization (Lee et al., 2003) and also heterodimerization of D2/D3 (Maggio et al., 2003), dopamine/somatostatin (Rocheville et al., 2000) and dopamine/adenosine (Franco et al., 2000) receptor families have been shown. These receptor homo- and heterodimerizations might be involved in the development of neuronal plasticity contributing to learning and memory (Franco et al., 2000).

2.4. Glutamate The striatum receives glutamatergic projections from the cortex and the thalamus. The corticostriatal afferents are the main extrinsic pathways of the BG and they are highly topographic and impose a functional compartmentation of striatal regions. The STN is the principal intrinsic glutamatergic structure of these brain nuclei. Despite its relatively small size, the STN is currently considered as one of the main driving forces of the BG (Parent et al., 1995b; Parent, 2002).

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2.4.1. Glutamate biosynthesis and reuptake L-glutamic acid or glutamate is the most abundant excitatory neurotransmitter in the brain. Glutamate cannot cross the blood–brain barrier and therefore it is synthesized locally from glucose via pyruvate, the Krebs cycle, the transmission of a-oxoglutamate or by deamination of glutamine in nerve terminals. Glutamate is then accumulated in synaptic vesicles (Dickenson, 2001; von Bohlen und Halbach and Dermietzel, 2002). After release, the high-affinity membrane transporters remove glutamate from the synapse into the nerve terminals or into the adjacent glial cells. The imported glutamate in glial cells is converted to glutamine by glutamine synthetase. Glutamine is then released from the glial cells by glutamine transporter for subsequent uptake by glutamate nerve terminals. Glutamine is then transformed into glutamate by neuronal mitochondrial glutaminase (Dickenson, 2001; von Bohlen und Halbach and Dermietzel, 2002). The summary of the synthesis, transport and degradation of glutamate is illustrated in Fig. 2.3. The storage of glutamate in synaptic vesicles requires the presence of vesicular glutamate transporter (VGLUT), which is independent of Naþ and Kþ and requires Hþ-ATPase exchange (Danbolt, 2001; Montana et al., 2004). Three isoforms of VGLUT have

Gln

G

Gln

ine am se ut a Gl ynth s

Glucose

lu ta m

Glu

in as

Glu

Glial cell

AT

EA

T

U VGL

EA AT

e

Glu

Presynaptic glutamatergic terminal

Glu Fig. 2.3. Schematic representation of the biosynthesis, release, transport and degradation of glutamate in glutamatergic nerve terminal. Glu, glutamate; Gln, glutamine; EAAT, excitatory amino acid transporter; VGLUT, vesicular glutamate transporter.

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been identified in glutamatergic neurons and also in subpopulations of GABAergic, cholinergic and monoaminergic neurons (Bai et al., 2001; Fremeau et al., 2002; Gras et al., 2002; Dal Bo et al., 2004). The cotransmission of glutamate in dopamine neurons may provide novel insight into pathophysiological processes that underlie PD (Plaitakis and Shashidharan, 2000; Dal Bo et al., 2004). Furthermore the glial cells, astrocytes, could modulate synaptic transmission by releasing glutamate in a Ca2þ-dependent manner (Kang et al., 1998) and recent studies suggest that VGLUTs also play a functional role in exocytotic glutamate release from astrocytes (Montana et al., 2004). The only rapid way to remove the glutamate released from nerve terminals by exocytosis is the reuptake of glutamate from the extracellular space. Until now, a family of five high-affinity uptakes of the excitatory amino acid transporters (EAATs) have been identified (Danbolt, 2001). These cytoplasmic membrane transporters are located presynaptically in glutamatergic nerve terminals, postsynaptically in dendrites and spines and extrasynaptically in glial cells. The EAATs termed EAAT1–EAAT5 cotransport Naþ and Hþ into the cells in the exchange of Kþ and they are also called Naþ- and Kþ-coupled glutamate transporters. In addition, postsynaptic glutamate transporters have a relatively high associated Cl channel activity (Danbolt, 2001). In the rat striatum, glutamate aspartate transporter (GLAST, EAAT1) and GLT1 (EAAT2) are expressed in astrocytes and EAAC (EAAT3) in neurons (Danbolt, 2001). A lesion of glutamatergic corticostriatal projection has been shown to downregulate the GLT1 and GLAST (Levy et al., 1995a). However, nigrostriatal denervation in the rat model of PD does not affect GLT1 mRNA expression, although chronic levodopa treatment increases GLT1 mRNA and protein expression in this model. This effect is suggested to be a compensatory mechanism involving astrocytes in order to prevent neurotoxic overactivity of glutamate (Lievens et al., 2001; Robelet et al., 2004). Furthermore, it has recently been shown that the inhibitory influence of A2A receptor activation on glutamate uptake may be one of the putative mechanisms responsible for the neuroprotective effects of A2A receptor antagonists in the striatum (Popoli et al., 2002; Pintor et al., 2004). Accordingly, all these results indicate the important role of glutamate transporters in neurodegenerative processes that underlie PD. 2.4.2. Receptors and signal transduction Glutamate receptors (GluRs) are classified into two main groups of ionotropic or metabotropic receptors

based on their structure and mechanisms of action (Stone and Addae, 2002). 2.4.2.1. The ionotropic glutamate receptors These receptors are ligand-gated ion channels (Glu-sensitive) and open on activation, allowing the influx of Naþ, Kþ and/or Ca2þ, which subsequently mediate fast excitatory synaptic transmission. Three subtypes of ionotropic glutamate receptors have been identified: N-methyl-d-aspartate (NMDA), a-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA) and kainate (Dingledine and McBain, 1999; Dickenson, 2001; von Bohlen und Halbach and Dermietzel, 2002). The NMDA receptors consist of a combination of at least four subunits belonging to three families: NMDA R1 (NR1), NMDA R2 (NR2A, NR2B, NR2C and NR2D) and NR3A (Mori and Mishina, 1995; Das et al., 1998; Laube et al., 1998). NR1 subunits are ubiquitous to all NMDA receptors and are necessary for their function. In addition to the conventional agonist-binding site occupied by glutamate, the binding of glycine at a co-agonist site is required for receptor activation (Kleckner and Dingledine, 1988). Additionally, unlike the non-NMDA receptor channels, NMDA receptor channels are physiologically blocked by Mg2þ at resting membrane potential and the NMDA channel opening requires simultaneous occurrence of neurotransmitter binding and membrane depolarization. In addition, the receptor is highly permeable to Ca2þ, a well-known second messenger able to activate multiple signaling cascades and long-lasting changes in regulation of gene expression (Ghosh and Greenberg, 1995; Finkbeiner and Greenberg, 1998). These unique properties of NMDA receptors indicate their important physiological functions such as synaptic plasticity and synapse formation, which determine learning and memory (Yamakura and Shimoji, 1999). The AMPA receptors are hetero-oligomeric proteins made of the subunits GluR1–GluR4. Each receptor complex is thought to contain four subunits (Rosenmund et al., 1998). Finally, the kainate receptors are heteromeric combinations of the high-affinity kainite-binding subunits (GluR5–7 and Kainate1–2) (Hollmann and Heinemann, 1994). The AMPA and kainate receptors have permeability to Naþ and Kþ and, based on the RNAediting sites, some of them are permeable to Ca2þ (Gu et al., 1996). Striatal ionotropic glutamate receptors could regulate mitogen-activated protein kinase (MAPK) cascades that contribute to the development of neuroplasticity (Wang et al., 2004). Electrical or chemical stimulation of corticostriatal pathways induce phosphorylation of ERK1/2, which is one of the MAPK subfamilies in striatal neurons involved in response to glutamate (Sgambato et al., 1998). Activation

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA of all three subtypes of ionotropic glutamate receptors is believed to possess the ability to phosphorylate ERK1/2 (Wang et al., 2004). Pharmacological activation of NMDA receptors strongly increases ERK1/2 activation in striatal neurons and this effect is sensitive to NMDA receptor antagonists (Perkinton et al., 2002; Mao et al., 2004). The NMDA receptor is believed to initiate its activation of ERK1/2 via Ca2þ influx since the absence or low concentrations of extracellular Ca2þ impair NMDA activation of ERK1/2 (Perkinton et al., 2002). Ca2þ-calmodulin-dependent protein kinase II (CAMKII), a major Ca2þ-sensitive kinase, relays Ca2þ signals in the postsynaptic NMDA receptor complex (Wang et al., 2004). Interestingly, more recent studies reveal that the CAMKII hyperphosphorylated state plays a causal role in the pathophysiology of parkinsonian motor disability and in the maladaptive striatal plasticity after dopamine denervation (Picconi et al., 2004). 2.4.2.2. The metabotropic glutamate receptors The metabotropic glutamate receptors (mGluRs) belong to G-protein-coupled receptor family 3, which also includes GABAB receptors. These receptors modulate excitatory synaptic transmission by at least two mechanisms: first, an inhibition of glutamate release from afferent nerve terminals, and second, a regulation of the activity of voltage-dependent ion channels or ionotropic glutamate receptors (particularly NMDA receptors) at postsynaptic sites (Picconi et al., 2002). The mGlu receptors are classified into three groups. Group I, including mGluR1 and 5, are positively linked to the activation of phospholipase C and PI3 hydrolysis via Gq. Their activation leads to an increase in intracellular Ca2þ levels, stimulation of PKC, potentiation of L-type voltage-dependent Ca2þ channels and inhibition of Kþ conductances that generally mediate postsynaptic excitatory effect (Conn and Pin, 1997; Gubellini et al., 2004). Group II (mGluR2, 3) and group III (mGluR4, 6–8) mGlu receptors are negatively coupled to adenylyl cyclase via Gi/Go, or pertusis toxin-sensitive G-protein, respectively. Their activation inhibits the formation of cAMP and also exerts an inhibitory action on L-N and P/Q type of voltage-dependent Ca2þ channels and activates hyperpolarizing Kþ conductance. In addition, pharmacological blockade of mGluR1 or mGluR5, or pharmacological activation of mGluR2/3 or mGluR4/7/8, produces neuroprotection shown in a variety of central nervous system (CNS) disorder models (Bruno et al., 2001). These receptors are generally found presynaptically where they exert an inhibitory action on the release of glutamate and other neurotransmitters (Cartmell and Schoepp, 2000; Gubellini et al., 2004).

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Furthermore, mGlu receptors also have the potential to regulate the MAPK pathway. It has been shown that intracaudate injection of a group I mGlu receptor agonist upregulates ERK1/2 phosphorylation (Choe and Wang, 2001). However, currently there are no available data regarding the influence of group II and III mGlu receptors on striatal MAPK cascades (Wang et al., 2004). The interaction between mGlu receptors and other G-protein-coupled receptors, in particular dopamine, adenosine and muscarinic acetylcholine receptors, has also been demonstrated (Pin and Acher, 2002; Moldrich and Beart, 2003; Gubellini et al., 2004). 2.4.2.3. Glutamate receptors in the BG NR1 subunit mRNA is expressed in the striatum, STN and SNc, whereas in globus pallidus (GPe, GPi and ventral pallidum) and SNr the mRNA expression of NR1 subunit is less intense (Ravenscroft and Brotchie, 2000). Although all striatal neurons express NMDAR2 receptors, their subunit expressions are different among various neuronal populations. NR2B mRNA is expressed prominently over all striatal neurons (caudate and putamen). NR2A mRNA is of relatively lower abundance in the striatum. While no labeling for NR2A is observed on somatostatinergic and cholinergic interneurons, it is expressed over glutamic acid decarboxylase (GAD) 67 immunoreactive neurons. NR2D mRNA expression has been observed strongly in the globus pallidus (GPe and GPi) and moderately in the striatum. NR2C mRNA is expressed weakly all over striatal neurons, except for a moderate expression in cholinergic interneurons (Kosinski et al., 1998; Kuppenbender et al., 2000; Smith et al., 2001). As the NMDA receptor complex represents a key molecular element in motor abnormalities in PD, the pattern of NMDA receptor expression should be considered for therapeutic approaches targeting specific NMDA receptor subtypes in PD. In the human striatum, which is enriched in AMPA receptors, both striatal output projection neurons and large interneurons express GluR1, GluR2 and GluR3 subunits. However, the GluR4 subunit expression is restricted to a small population of large and mediumsized neurons (Bernard et al., 1996; Tomiyama et al., 1997; Smith et al., 2001). AMPA and NMDA receptor subunits are also expressed at subthalamopallidal glutamatergic synapses in the globus pallidus (Clarke and Bolam, 1998). In the monkey striatum kainate receptors (GluR6/7 and kainate-2) are expressed intracellularly in presynaptic glutamatergic terminals and may control glutamate release from the thalamus and cerebral cortex. Postsynaptic kainate receptors are also expressed in

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dendrite and spine throughout the striatum (Charara et al., 1999; Kieval et al., 2001). On the other hand, more than 60% of pre- and postsynaptic plasma membrane kainate receptors are expressed extrasynaptically (Kieval et al., 2001). The roles of kainate receptors in the striatum and the exact mechanism by which kainic acid has toxic effects on striatal projection neurons are still poorly understood. However, it has been demonstrated that the activation of presynaptic kainate receptors like postsynaptic kainate receptors may lead to increased Naþ and Ca2þ conductances and consequently to the depolarization of nerve terminals. This could facilitate the opening of voltage-dependent Ca2þ channels and potentiate glutamate release with excitotoxic effects (Perkinton and Sihra, 1999). Other studies have demonstrated that kainate receptors in the monkey striatum could downregulate GABAergic synaptic transmission indirectly via release of adenosine (acting on A2A receptors) (Chergui et al., 2000). Since kainate receptors are also expressed extrasynaptically and their metabotropic-like functions have also been reported (Rodriguez-Moreno and Lerma, 1998), it was suggested that these receptors probably mediate slow modulatory effects rather than fast synaptic transmission (Kieval et al., 2001). Recent studies reveal that the density of kainate receptors is increased in the striatum of 6hydroxydopamine (6-OHDA) rats (Tarazi et al., 2000). Interestingly, AMPA and kainate receptor antagonists, but not NMDA antagonists, are known to protect dopaminergic terminals of rat striatum against 1-methyl-4phenylpyridinium ion (MPPþ) toxicity. Further investigations in animal models of PD are needed to clarify the role of these receptors in PD. The group I mGlu receptors, mGluR1 and mGluR5, are expressed by striatal medium spiny neurons and by subpopulations of interneurons, including cholinergic interneurons (Testa et al., 1994, 1995, 1998; Smith et al., 2000; Pisani et al., 2001). Recent studies demonstrated the presynaptic localization of mGluR5 at dopaminergic synapses and also in glutamatergic terminals, preferentially in thalamostriatal over corticostriatal afferents (Paquet and Smith, 2003). The localization of group I mGlu receptors not only at glutamatergic but also at GABAergic striatal synapses in GPe, GPi and SNr has been shown (Hanson and Smith, 1999). Since mGlu receptors have high affinity for glutamate, a small amount of spilled-over neurotransmitter could be one of the sources that activate these receptors. Other possibilities are extrasynaptic diffusion of glutamate released from astrocytes or, under certain circumstances, glutamate released from striatal terminals (Smith et al., 2001). At GABAergic synapses, these postsynaptic mGlu receptors could regulate GABA currents in pallidal or SNr neurons either

by changing membrane excitability through modulation of Ca2þ and Kþ channels (Conn and Pin, 1997) or via direct physical interactions with GABAA or GABAB receptors (Smith et al., 2001). At STN synapses in GPe and GPi, activation of presynaptic mGluR1 and 5 by glutamate released from overactive STN could lead to increased activity of BG output nuclei through various mechanisms, including potentiation of ionotropic glutamatergic transmission and reduction of Kþ conductances (Smith et al., 2001). Therefore, antagonists of group I mGlu receptors has been suggested as a potential target to reduce the overactivity of pallidal neurons generated by STN in PD (Pisani et al., 1997; Ossowska et al., 2002; Picconi et al., 2002). Activation of mGluR5 (group I) could reduce striatal dopamine uptake by phosphorylation of the transporter through activation of CAMKII and PKC (Page et al., 2001). This regulatory interaction demonstrates that the two glutamatergic and dopaminergic systems interact closely in the striatum and glutamate can potentially regulate dopaminergic transmission. Group II and III mGlu receptors are mostly found presynaptically on corticostriatal glutamatergic terminals. Furthermore, regarding the high expression of group II mGluRs in STN neurons and the inhibitory action of these receptors on glutamate release, the selective agonists of group II mGlu receptors could have a beneficial effect in PD by reducing the hyperactivity of excitatory corticostriatal and subthalamopallidal neurons that is developed after dopaminergic denervation (Rouse et al., 2000; Ossowska et al., 2002). Accordingly, the alleviation of akinesia after activation of group III mGluRs in reserpine-treated rats has been demonstrated (MacInnes et al., 2004). Although pallidal neurons do not express group II mGlu receptor mRNA, the mGluR4 and mGluR7 (group III) are expressed in GABAergic striatopallidal neurons (Bradley et al., 1999). The group III mGluRs at striatopallidal synapses are thought to play a role in modulating GABAergic transmission at these synapses (Smith et al., 2000) and the selective agonist of these receptors could be a target to reduce the parkinsonian syndrome by attenuation of overactivity of the striato-GPe pathway. The mGluR2/3 also promote the synthesis and release of neurotrophic factors in astrocytes (Bruno et al., 2001). Indeed, these results suggest that appropriate therapeutic interventions with mGlu receptors may alleviate the symptoms of PD and also delay the progress of neurodegeneration in this movement disorder.

2.5. Gamma-aminobutyric acid The amino acid GABA is the main inhibitory neurotransmitter in the CNS, including the BG. The principal

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA neurons in the striatum, i.e. about 77–97.7%, are medium spiny projection neurons, which utilize GABA as a transmitter (Tepper et al., 2004). These GABAergic medium spiny neurons are innervated by glutamatergic, dopaminergic and GABAergic afferent fibers and the interaction between these inputs at the striatal level plays an important role in the regulation of the BG function and in the pathophysiology of PD. The remaining neurons in the striatum are various types of interneurons thought to play an important role in the processing of information in the striatum. These interneurons have been classified, based on cell diameters, neurochemistry and physiology, into one population of large cholinergic interneurons and at least three types of medium GABAergic interneurons (Kawaguchi et al., 1995). The two types of GABAergic interneurons colocalize the Ca2þ-binding protein, parvalbumin or calretinin and the third class contains somatostatin, neuropeptide Y, the enzyme nicotinamide adenine dinucleotide phosphatase (NADPH-d) or nitric oxide synthase (NOS) (Kawaguchi et al., 1995; Cicchetti et al., 2000). NOS-containing neurons receive synaptic inputs from parvalbuminergic interneurons and innervate striatal output neurons (Morello et al., 1997). Calretinin interneurons seem to modulate striatal local circuits in response to inputs from striatal and cortical neurons (Figueredo-Cardenas et al., 1997). Moreover, GABA is also the transmitter utilized by GPe and the output nuclei of the BG (SNr-GPi). A recent study revealed that in primates, but not in rodents, GABA is synthesized more in striosome than in matrix (Levesque et al., 2004). Accordingly, it was suggested that GABA may have a greater inhibitory effect on the processing of limbic information than sensorimotor information which is processed in the striosome and matrix, respectively (Levesque et al., 2004). 2.5.1. GABA biosynthesis, transport and degradation GABA is synthesized by decarboxylation of glutamate, a reaction catalyzed by the enzyme GAD (Olsen and Delorey, 1999). GAD exists in two different isoforms, termed GAD65 and GAD67, which differ in their size, cofactor association and subcellular distribution (Augood et al., 1995). The majority of medium spiny neurons highly express GAD65 mRNA while the GABAergic interneurons are preferentially enriched in GAD67 mRNA (Mercugliano et al., 1992). Within nerve terminals, GABA, like other neurotransmitters, is stored in synaptic vesicles before its release into the synaptic cleft (McIntire et al., 1997). The storage of GABA into vesicles is dependent on

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the vesicular GABA transporter containing 520 amino acids with 10 transmembrane domains (McIntire et al., 1997; Jin et al., 2003). The transport of GABA into secretory vesicles relies on the electrochemical proton gradient created by the Hþ-ATPase (Takamori et al., 2000; Piccini, 2003). Specific high-affinity Naþ/Cl-dependent transporters in both GABAergic and glial cells regulate the maintenance of the extracellular levels of GABA (Masson et al., 1999). Four distinct genes encoding GABA transporters (GATs) have been identified (Conti et al., 2004). These transporters mediate GABA uptake, terminating GABA’s action and regulating GABA’s diffusion to neighboring synapses. In the rat BG, the globus pallidus, STN and substantia nigra show high expression of GAT-1 mRNA and also dense labeling for GAT-1 protein, whereas the dorsal striatum, caudate and putamen show moderate and light labeling for GAT-1 mRNA and protein, respectively (Yasumi et al., 1997). The expression of GAT-1 protein by GABAergic interneurons, containing GAD67 mRNA, is also shown in dorsal striatum (Augood et al., 1995). Another study in the monkey BG demonstrates dense labeling of GAT-1 in GPe and GPi, moderate labeling in STN and substantia nigra and low labeling in the dorsal striatum (Wang and Ong, 1999). Interestingly, the human glutamatergic STN neurons, coexpressing parvalbumin and/or calretinin, are also enriched in mRNA encoding GAT-1. This indicates that the STN neurons may be able to accumulate synaptically released GABA via interaction with this brain specific high-affinity GABA uptake protein, in the vicinity of their terminal projections. This effect may be considered as a potential non-dopaminergic target for therapy in PD (Augood et al., 1999). Expression of GATs, as for glutamate transporters, is regulated by different factors, including phosphorylation of the transporter protein by PKA and PKC, transcription and activity-dependent trafficking of transporter protein between the cytosol and plasma membrane (Bernstein and Quick, 1999; Schousboe, 2003). GABA is inactivated by transamination with alphaketoglutarate. This reaction is catalyzed by the mitochondrial enzyme 4-aminobutyrate aminotransferase (GABA transaminase; GABA-T). In this process the amino group from GABA is transferred on to alphaketoglutarate, producing glutamate and succinic acid semialdehyde. The latter is further metabolized to form succinic acid, which is an intermediate of the Krebs cycle. The glutamate formed from the degeneration of GABA is then converted into glutamine by the cytosolic enzyme glutamine synthetase. GABA-T is also present in the mitochondria of glial cells and glial glutamine

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Gln

Glu syn tami tha ne se

Glu Gln

Glu

GABA

Glial cell

AT G

BA GAT GA V

GABA

5 D6 GA D67 GA

T

GA BA -T

GA

KREBS CYCLE

GAB A-T

se ina tam Glu

KREBS CYCLE

Presynaptic GABAergic terminal

GABA Fig. 2.4. Diagram showing the synthesis, release, transport and degradation of GABA in a GABAergic nerve terminal. GABAT, GABA transaminase; Gln, glutamine; Glu, glutamate; GAT, GABA membrane transporter; VGAT, vesicular GABA transporter; GAD, glutamic acid decarboxylase isoforms 65 and 67.

is an important precursor for both glutamatergic and GABAergic neurons (Olsen and Delorey, 1999; Farrant, 2001; von Bohlen und Halbach and Dermietzel, 2002). A summary of the synthesis, transport and degradation of GABA is illustrated in Fig. 2.4. 2.5.2. Receptors and signal transduction Three types of receptors, termed GABAA, GABAB and GABAC, mediate the effect of GABA in the CNS. Although GABAA and GABAB are present in the BG, there is no evidence for the existence of GABAC in these structures. The fast inhibitory synaptic transmission results from the stimulation of ionotropic chloride-gated GABAA and GABAC receptor channels (Macdonald and Olsen, 1994; Johnston, 1996). GABAA receptors are defined by their sensitivity to the antagonist bicuculline whereas GABAC receptors are insensitive to this antagonist. These ionotropic GABA receptors are composed of a heteromeric structure consisting of five subunits assembled from a group of 18 different subunits, which have been characterized in mammalian brain (Barnard et al., 1998; Waldvogel et al., 2004). The GABAA receptor possesses three different binding sites. The first one binds

GABA, the second one is a specific binding site for benzodiazepines and the third binding site is specific for barbiturates. The two latter sites seem to be absent from the GABAC receptor (Mehta and Ticku, 1999; Smith et al., 2001). Metabotropic GABAB receptors belong to the family of G-protein-coupled receptors and mediate slow inhibitory synaptic transmission via an increase in Kþ currents (Bettler et al., 1998; Galvan et al., 2004). Activation of GABAB receptor via G-protein can also reduce Ca2þ conductance and inhibit adenylyl cyclase (Bormann, 1988; Smith et al., 2000). Functional GABAB receptors are heterodimers of GABABR1 subunit and GABABR2 subunit. This heterodimerization is important in receptor folding and transport to the cell surface and is also necessary for agonist binding to GABAB receptors (Jones et al., 1998; White et al., 1998). GABA-mediated inhibition in the striatum arises from axon collaterals of spiny projection neurons (Parent and Hazrati, 1995a; Wu et al., 2000; Tunstall et al., 2002), GABAergic interneurons (Bolam et al., 2000; Cicchetti et al., 2000), GPe (Kita et al., 1999) and SNr (Hanley and Bolam, 1997). Activation of spiny neurons rarely triggers synaptic transmission in other nearby neurons (Tunstall et al., 2002) whereas action

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA potentials evoked by interneurons are capable of producing stronger GABA-mediated synaptic transmission in spiny neurons (Koos and Tepper, 1999). Hence, it was suggested that most of the strong inhibition of medium spiny neurons is principally controlled by GABAergic interneurons even though there are many times more collateral synapses with medium spiny neurons than interneurons (Kita, 1993; Tepper et al., 2004). A recent study reports that dopamine plays a critical role in the modulation of striatal interneurons activity through postsynaptic dopamine D5 receptors and presynaptic dopamine D2 receptors located on GABAergic nerve terminals (Centonze et al., 2003b). This study demonstrates that both isoforms of dopamine D2 receptors, D2L and D2S, are involved in the presynaptic inhibition of dopamine on GABA transmission. More recently, it has been demonstrated that GABAA receptor stimulation is able to rescue the locomotor deficits of the dopamine D2 R/ mice, suggesting that this receptor interacts with GABAA receptors to control the motor circuits in the BG (An et al., 2004). In addition, the dopamine D5 receptor physically interacts with the ionotropic GABAA receptor. In cells coexpressing the two receptors, the D5-mediated stimulation of adenylyl cyclase was inhibited by GABAA, while the GABAinduced chloride current was decreased by the activation of the dopamine receptor, indicating reciprocal receptor cross-talk (Liu et al., 2000). The inhibitory postsynaptic potential induced by the collateral of the medium spiny neurons could attenuate or block the transient effects of nearby corticostriatal or thalamostriatal excitatory postsynaptic potentials. Therefore, these axon collaterals, by attenuating glutamate-mediated excitatory postsynaptic potentials, may play an important role in Ca2þ-dependent changes in the synaptic efficacy of corticostriatal or thalamostriatal synapses. It seems that GABAB receptors are involved in the presynaptic regulation of glutamate release (Calabresi et al., 1991, 2000a; Tepper et al., 2004). Activation of GABAA receptors by synaptically released GABA causes a fast membrane depolarization in striatal neurons via chloride conductance. The synaptic depolarizing effect of this inhibitory transmitter is due to the high resting potential of medium spiny neurons (–80 mV) (Calabresi et al., 2000a). In addition, synaptically released GABA exerts a feedback control on its own release in the striatum via presynaptic GABAB receptors and it may also be able to reduce GABA-mediated depolarizing synaptic potentials (Calabresi et al., 1991). Accordingly, it was suggested that feedback inhibition by axon collaterals also plays a significant role in the information-processing operation of the striatum (Tunstall et al., 2002). However, the functional role of this feedback inhibition by axon

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collaterals in the striatum is complex and remains to be better clarified (Tepper et al., 2004). 2.5.2.1. GABAA receptors in the BG The distribution of GABAA receptors in the BG of human and monkey in normal and parkinsonian conditions has been reported using benzodiazepine-binding studies with GABAA receptor. These studies demonstrated that GABAA/benzodiazepine receptors are distributed in caudate and putamen according to the patch and matrix compartments (Waldvogel et al., 1998, 1999). In human BG, GABAA receptors are found in highest concentrations on the GABAergic interneurons of the striatum and on the output neurons of the globus pallidus and SNr (Waldvogel et al., 2004). It has been suggested that presynaptic GABAA receptors in the globus pallidus may be involved in the modulation of release of GABA (Waldvogel et al., 1998; Smith et al., 2001). In 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) parkinsonian monkeys, the density of GABAA/benzodiazepine-binding sites is decreased in the medial anterior part of the caudate and putamen and it remains unchanged after treatment with pulsatile or continuous dopamine D1 receptor agonist (Calon et al., 1999). In dorsal striatum, GABAA/benzodiazepine-binding sites remained reduced in parkinsonian monkeys treated with long-acting dopamine D2 receptor agonist, but was not significantly lower than untreated MPTP monkeys (Calon et al., 1999). The effects of the GABAA receptor are suggested to be postsynaptic and are thought to be mediated by striatal interneurons containing parvalbumin (Koos and Tepper, 1999) or by a striatonigral feedback loop (Smolders et al., 1995). The density of GABAA/benzodiazepine-binding sites in the globus pallidus is lower than in the striatum and is more important in GPe than in GPi (Waldvogel et al., 1998, 1999). After MPTP treatment in the primate animal model of PD, the density of GABAA/benzodiazepine-binding sites is increased and decreased, respectively, in GPi and GPe (Robertson et al., 1990; Calon et al., 1995, 1999). The current model of BG circuitry is consistent with the hypoactivity of the striatonigral and hyperactivity of striatopallidal pathways after degeneration of dopaminergic nigrostriatal neurons in PD. Interestingly, cabergoline, the longacting dopamine D2 agonist, but not SKF 82958, the dopamine D1 agonist, could reverse the increased level of GABAA/benzodiazepine-binding in GPi of MPTP monkeys (Calon et al., 1999). The pattern of GABAA receptor expression in the SNr is similar to that in the GPi and treatment with MPTP in monkeys increases the level of GABAA/benzodiazepine-binding sites in the SNr (Smith et al., 2001).

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STN neurons also demonstrate strong immunoreactivity for GABAA receptor subunits in rats and monkeys (Smith et al., 2001). Indeed, infusion of the GABAA receptor agonist, muscimol, into the STN has a beneficial effect in the symptomatic relief in patients with advanced PD (Levy et al., 2001). 2.5.2.2. GABAB receptors in the BG GABAB receptors are expressed by most neurons in the BG. Both the R1 and R2 subunits of the GABAB are distributed throughout the monkey and human striatum. Most striatal interneurons containing parvalbumin or calretinin, 50% of those containing neuropeptide Y and 80% of cholinergic interneurons express GABAB receptor and generally these interneurons are more strongly labeled than medium spiny neurons (Charara et al., 2000; Waldvogel et al., 2004). These GABAB receptors are located at a presynaptic location to medium spiny neurons either on GABAergic terminals or on GABAergic interneurons (Nisenbaum et al., 1993; Waldvogel et al., 2004). In addition GABAB receptors are also located on glutamatergic terminals in the striatum and it has been suggested that these presynaptic GABAB receptors could modulate the release of glutamate and dopamine (Nisenbaum et al., 1992, 1993; Smith et al., 2000; Waldvogel et al., 2004). In monkeys, following treatment with MPTP and dopaminergic agents, no changes in the density of GABAB receptors were seen in the striatum (Calon et al., 2000c). GABAB R1 and GABAB R2 are also localized over 90% of the neurons of the globus pallidus, SNr and SNc (Waldvogel et al., 2004). In the substantia nigra, dopaminergic neurons in the SNc were more intensely labeled for GABAB receptors than GABAergic neurons in the SNr (Charara et al., 2000) and it has been shown that the release of dopamine is modulated by GABA receptors (Waldvogel et al., 2004). Moreover, in MPTP monkeys a significant decrease in GABAB receptors is seen in SNc, suggesting that SNc neurons express GABAB receptors, whereas no change is seen in the SNr of these parkinsonian monkeys (Calon et al., 2000c). There is also evidence that GABAB receptors can control the release of glutamate as well as GABA in the SNr (Shen and Johnson, 1997). In the globus pallidus, the postsynaptic GABAB receptors may also be involved in modulating synaptic transmission in addition to the GABAA-mediated inhibitory effect (Smith et al., 2000). Furthermore, localization of the presynaptic GABAB receptors in GPe and GPi has been demonstrated (Smith et al., 2000). Consistent with these morphological results, functional studies showed that activation of GABAB receptors in the globus pallidus reduces the release of GABA and glu-

tamate by activating presynaptic auto- and heteroreceptors and hyperpolarizes pallidal neurons by activating postsynaptic receptors (Chen et al., 2002, 2004a). In MPTP parkinsonian monkeys, the level of GABAB receptors is significantly increased in the GPi. However, no changes have been seen in the GPe (Calon et al., 2000c). GABAB receptors are also expressed by subthalamic terminals and glutamatergic afferents to STN neurons (Charara et al., 2000; Galvan et al., 2004). It is thought that GABAB receptor stimulation could modulate the postsynaptic response to glutamate through presynaptic receptors (Chen et al., 2004a). In addition, GABAB receptors may control the activity of STN neurons by presynaptic inhibition of neurotransmitter release from extrinsic and/or intrinsic glutamatergic terminals (Smith et al., 2001). Electrophysiological studies demonstrated that GABAB receptors modulate glutamate release in the STN (Shen and Johnson, 2001). Therefore, therapeutic agents such as GABAB receptor agonists could have beneficial effects in PD by attenuating the hyperactivity of STN neurons. Indeed, the application of baclofen was found to decrease the evoked synaptic currents mediated by glutamate in the SNr (Shen and Johnson, 1997). Because GABAB R1 and GABAB R2 need to dimerize to form a functional receptor, it is expected that these two subtypes display a similar pattern of distribution. Recent studies in the primate BG demonstrate that the distribution of GABAB R2 is largely consistent with that of GABAB R1. However, there are some exceptions. For example, low expression levels of GABAB R2 compared with GABAB R1 are found in the striatum, or a larger proportion of presynaptic elements labeled for GABAB R1 than GABAB R2 are found in the globus pallidus and substantia nigra. This raises the hypothesis that other mechanisms may relay the formation of functional GABAB receptors in specific regions of BG (Charara et al., 2004).

2.6. Acetylcholine Striatal cholinergic interneurons, also called tonically active neurons, fire tonically and do not exhibit long periods of silence (Zhou et al., 2002). These neurons are indispensable in controlling striatal neuronal activity and extrapyramidal motor movement. Evidence indicates that the imbalance between dopaminergic and cholinergic systems is one of the neurochemical bases that play a fundamental role for movement abnormalities observed in PD (Di Chiara et al., 1994; Kaneko et al., 2000; Saka et al., 2002). The almost exclusive source of acetylcholine in the striatum originates from interneurons (Parent et al.,

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA 1995b). Nevertheless, a large proportion of BG neurons appear to receive a prominent cholinergic input from the upper-brainstem neurons (Parent et al., 1995b). The cholinergic interneurons, which account for <2% of the entire striatal neuronal population, are distinguished from the medium spiny neurons by their large somata and extensive dendritic and axonal arbors. Moreover, the density of cholinergic varicosities is high (Izzo and Bolam, 1988; Smith and Bolam, 1990a; Contant et al., 1996). Furthermore, the high and precisely overlapping distribution of acetylcholine, dopamine, tyrosine hydroxylase and enzymes involved in the synthesis and degradation of acetylcholine in the striatum ensure that the cholinergic and dopaminergic systems are positioned to interact within this structure (Zhou et al., 2001). These anatomical characteristics suggest that these interneurons may be important for integrating diverse synaptic inputs and they exert a strong and direct influence on BG output structures (Calabresi et al., 2000b; Kaneko et al., 2000; Ragozzino, 2003). 2.6.1. Acetylcholine synthesis, transport and degradation Acetylcholine is synthesized in nerve terminals from its precursor choline and acetylcoenzyme A. Choline used in acetylcholine synthesis is thought to come from two sources: the main source is derived from metabolization of acetylcholine by acetylcholine esterase and the other source is the breakdown of phosphatidylcholine, which may be stimulated by locally released acetylcholine (Webster, 2001a). Choline is then taken up into the cholinergic neurons by a highaffinity Naþ-dependent choline uptake system (Taylor and Brown, 1999; Webster, 2001a). The choline levels in the brain and plasma seem to be relatively stable at 5–10 mM (Lockman and Allen, 2002). The reaction of choline with mitochondrial-bound acetylcoenzyme A is catalyzed by the cytoplasmic enzyme choline acetyltransferase (ChAT) present in the presynaptic terminal of cholinergic neurons (Webster, 2001a; Sarter and Parikh, 2005). ChAT itself is synthesized in the rough endoplasmic reticulum of the cell body and transported to the axon terminal. The rate of acetylcholine synthesis is controlled by the capacity of choline transporter to transport choline into presynaptic terminals (Lockman and Allen, 2002; Sarter and Parikh, 2005). Moreover, the choline transporter is also highly regulated and the cellular mechanisms that modulate its capacity show considerable plasticity. Choline transporters are localized predominantly onto synaptic vesicles that are immunopositive for the vesicular acetylcholine transporter (VAChT). VAChT transports

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acetylcholine into storage vesicles following its synthesis. Interestingly, the gene encoding the vesicular transporter is located within an intron of the ChAT gene, suggesting a mechanism for co-regulation of gene expression for ChAT and VAChT. Acetylcholine uptake in the vesicle is driven by a proton-pumping ATPase (Hþ exchange) (Taylor and Brown, 1999; Webster, 2001a). In response to an action potential, acetylcholine is released by exocytosis into the synaptic cleft and could act on two distinct receptors. Acetylcholine is metabolized by membrane-bound acetylcholine esterase, also called true or specific cholinesterase to distinguish it from butyrylcholinesterase, a pseudo- or non-specific plasma cholinesterase (Webster, 2001a). The summary of the synthesis, transport and degradation of acetylcholine is illustrated in Fig. 2.5. 2.6.2. Receptors and signal transduction The actions of acetylcholine are the results of fast or slow synaptic transmission mediated by nicotinic and muscarinic receptors, respectively. 2.6.2.1. Nicotinic acetylcholine receptors Nicotinic acetylcholine receptors (nAChRs) consist of transmembrane proteins and are members of a superfamily of ligand-gated ion channels (Karlin and Akabas, 1995). nAChRs are constituted by five spanning subunits forming a cylinder-like structure in the membrane around the central ion channel which is permeable to Naþ, Kþ and Ca2þ (Taylor and Brown, 1999; Webster, 2001a). Neuronal nAChRs are composed of a and b subunits. Five types of a subunits (a2–a6) and three types of b subunit (b2–b4) constitute a- and b-type heteromeric nAChRs, whereas a7 subunits constitute homomeric nAChRs. Multiple receptor subtypes are localized in the striatum and substantia nigra, including a4b2, a6b2, a4a6b2 and others. However, a6 receptor subtypes are selectively localized to the nigrostriatal pathway (Quik, 2004). nAChRs are located mainly presynaptically, modulating synaptic activity by regulation of neurotransmitter release (Wonnacott, 1997; MacDermott et al., 1999; Zhou et al., 2001). a7nAChR is expressed at glutamatergic terminals in the striatum (Nomikos et al., 2000) and its activation stimulates the release of glutamate from corticostriatal terminals (Marchi et al., 2002). Glutamate, through the activation of ionotropic GluRs at dopaminergic terminals, could stimulate dopamine release. Other subtypes of nAChR could also directly modulate dopamine release from nigrostriatal dopaminergic terminals (Hamada et al., 2004). Moreover, electrophysiological studies indicate the

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Ac-CoA ChAT ChAT

ACh

CoA

AC h Ch T

Choline

VA

Choline Presynaptic acetylcholinergic terminal

Acetic acid

ACh

AChE

Fig. 2.5. Schematic representation of biosynthesis, release, transport and degradation of acetylcholine in acetylcholinergic nerve terminals. ACh, acetylcholine; ChAT, choline acetyltransferase; CoA, coenzyme A; Ac-CoA, acetylcoenzyme A; AchE, acetylcholine esterase; VAChT, vesicular acetylcholine transporter.

presence of nAChRs on the striatal GABAergic interneurons. It was hypothesized that activation of these nAChRs could reduce the inhibitory effect of striatal projection neurons and cause some disinhibition of output nuclei of the BG (Zhou et al., 2003). Nicotine at low concentrations mainly activates, at dopaminergic terminals, high-affinity b2-containing nAChRs with rapid desensitization properties (Picciotto, 2003; Hamada et al., 2004). However, nicotine at high concentration could activate both high-affinity and low-affinity (a7) nAChRs in the striatum. This latter, localized at glutamatergic terminals, is less susceptible to desensitization and their activation results in longerlasting actions of nicotine (Hamada et al., 2004). Furthermore, it has been shown that nicotine at these low and high concentrations by activation of dopamine D2 and D1 receptors might differentially regulate the state of phosphorylation of DARPP-32 at Thr-34 (Hamada et al., 2004). These differential effects of nicotine in the two major outputs of the striatum could contribute to a better understanding of the modulatory effect of the cholinergic system in PD. In PD, most reports indicate a reduction in nicotine binding in caudate and putamen in parallel with the decline in dopaminergic markers (Court et al., 2000a, b; Quik and Kulak, 2002; Pimlott et al., 2004). Moreover, reduced nicotine binding has also been demonstrated in the substantia nigra in PD, highlighting the

loss of dopaminergic neurons projecting to the striatum (Perry et al., 1995; Pimlott et al., 2004). Studies in animal models of PD also show that a decline in nAChRs is paralleled by a decrease in nicotine-evoked dopamine release (Quik et al., 2003b). Accordingly, it was suggested that drugs targeting the subtypes of nAChR that decline with nigrostriatal degeneration might be useful in treating PD (Quik, 2004). Additionally, coadministration of an nAChR agonist with a low dose of levodopa improves parkinsonian syndrome similar to a high dose of levodopa, while the involuntary movements are reduced (Schneider et al., 1998). Levodopa treatment has been reported to decrease nAChR expression in unlesioned animals, but not in animals with severe nigrostriatal damage, suggesting that levodopa affects nAChRs associated with dopaminergic terminals (Quik et al., 2003a). This effect may be relevant to the reduction of the effectiveness of levodopa with time in parkinsonian patients (Quik et al., 2003a). Furthermore, it has been reported that acetylcholine, through both nicotinic and muscarinic receptor activation, may regulate striatal dopaminergic transmission, in part by modulating DAT availability (Tsukada et al., 2001). The effects of nAChR activation on dopamine transport function appear to be mediated in part through PKC (Gulley and Zahniser, 2003). Some evidence also suggests that nicotine has a neuroprotective efficacy against nigrostriatal damage in the

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA long term. This effect could result from nicotine-evoked dopamine release, which competes with toxins for entry into neurons via the same uptake system (Di Monte, 2003; Quik, 2004). The neuroprotective effect of nicotine could also be through a variety of neuronal mechanisms ranging from the inhibition of apoptosis and/or production of growth factors such as fibroblast growth factor (Belluardo et al., 2000; Roceri et al., 2001), reduction of superoxide anion generation in brain mitochondria (Cormier et al., 2003) and antioxidant action (Newman et al., 2002). More recently, it was reported that a nicotine neuroprotection effect might result from negative regulation of microglia activation through a7nAChRs (Shytle et al., 2004). 2.6.2.2. Muscarinic acetylcholine receptors Muscarinic acetylcholine receptors (mAChRs) belong to the seven transmembrane G-protein coupled receptor family. Molecular cloning has identified five distinct mAChRs: M1–M5 (Caulfield and Birdsall, 1998). M1, M3 and M5 receptors, also called M1-like mAChRs, couple to similar G-proteins (Gq family) that activate phospholipases and metabolize intracellular Ca2þ (Zhou et al., 2003). M2 and M4 receptors, also called M2-like mAChRs, by coupling to G-proteins of the Gi/Go family, can inhibit adenylyl cyclase and reduce the level of cAMP and neuronal activity by inhibiting different classes of Ca2þ channels (Zhou et al., 2003). Striatal medium spiny neurons express primarily M1 and M4 mAChRs. The main population of M1 receptors is expressed with striatopallidal neurons that also express dopamine D2 receptors (Ince et al., 1997; Kayadjanian et al., 1999) while M4 receptors and dopamine D1 receptors are coexpressed on striatonigral neurons (Ince et al., 1997; Bernard et al., 1999; Santiago and Potter, 2001). The coexpression of dopamine D1 receptors with M4 mAChRs on striatal medium spiny neurons and their opposing action on cAMP formation may have a regulatory action on medium spiny neurons (Zhou et al., 2003). The M2 and M4 receptors are also present on the somatodendritic areas and the axon terminals of striatal cholinergic interneurons (Bernard et al., 1998). The presence of muscarinic receptors on striatal afferents has also been reported, for example, M5 receptor mRNA is detectable in dopaminergic neurons of SNc, suggesting that M5 receptors are located on dopaminergic nerve terminals (Zhang et al., 2002b). M3 receptor is expressed at a low level in a subset of GABAergic nerve terminals in the striatum (Zhang et al., 2002b). Acetylcholine could regulate the release of dopamine, GABA and glutamate in the striatum via presynaptic mechanisms (Sugita et al., 1991). Recently, it has been shown that mAChRs are involved in the regulation of

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striatal dopamine release. M3 receptors located on GABAergic nerve terminals inhibit dopamine release by stimulating GABA release, whereas activation of M4 and M5 receptors facilitates this release (Zhang et al., 2002b). While the M4 and M2 mAChRs are involved in the autoinhibition of striatal acetylcholine release (Zhang et al., 2002a) presynaptic M1 or M1/M2 receptors have been reported to reduce GABAergic inputs in the striatum (Calabresi et al., 2000b). Moreover, activation of presynaptic M2 receptors could reduce the release of glutamate from corticostriatal neurons (Calabresi et al., 2000b). Both striatal medium spiny neurons and cholinergic interneurons receive glutamatergic inputs from cortex and thalamus. The fact that striatal projection neurons are the main target of cholinergic interneurons suggests that these interneurons mediate the processing input from the cortex to the medium spiny neurons (Calabresi et al., 2000b). It was suggested that M1 receptors located at postsynaptic sites on medium spiny neurons might modulate postsynaptic glutamate receptors. Indeed, activation of cholinergic transmission in the striatum has been shown to influence LTP at corticostriatal synapses (Calabresi et al., 1998, 2000b). The M1-like mAChR antagonist pirenzepine blocks the induction of striatal LTP, whereas it is significantly enhanced by methoctramine (Calabresi et al., 1999a). Accordingly, activation of mAChRs in the striatum influences corticostriatal synaptic plasticity and may facilitate long-term changes in striatal output patterns that enable the shifting of behavioral strategies (Ragozzino, 2003). Striatal acetylcholine release is under a complex regulation involving dopaminergic, glutamatergic and GABAergic inputs (Koos and Tepper, 2002). Activation of dopamine D5 receptor, expressed on all cholinergic interneurons (Rivera et al., 2002a), could depolarize these interneurons while activation of dopamine D2 receptors inhibits acetylcholine release (Centonze et al., 2003b; Zhou et al., 2003). Indeed, in neuroleptic-induced parkinsonism, since dopamine D2 receptors are blocked, dopamine excitation of cholinergic interneurons could increase acetylcholine release (Zhou et al., 2003). This potential mechanism may, in part, explain the efficacy of antimuscarinic drugs in parkinsonism induced by neuroleptic (Zhou et al., 2003). The mGlu2 receptors are also expressed on cholinergic interneurons and their activation, interfering with Ntype Ca2þ channel, reduces the activity of cholinergic interneurons and could lead to a decreased acetylcholine release in the striatum (Pisani et al., 2002, 2003). According to the hyperactivity of cholinergic interneurons in PD and dopamine and glutamate modulation of synaptic plasticity in the striatal cholinergic interneurons, careful management of these interneurons may be

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helpful in the treatment of PD. Indeed, pharmacological enhancement of muscarinic receptors can induce a parkinsonian syndrome, whereas antimuscarinic drugs presented one of the earliest therapies in PD (Carlsson, 2002). The recognition that striatal cholinergic interneurons play a significant role in BG circuitry by modifying the excitability of striatal output neurons could present an alternative intervention for drug developments targeting AchRs in the treatment of PD.

2.7. Serotonin (5-HT) Serotonergic afferents to the BG principally originate from the dorsal raphe nuclei (Parent, 1996). Although all the core structures of the BG in primates receive a significant serotonergic input, the densities and patterns of innervation vary markedly from one structure to another (Lavoie and Parent, 1990). The dorsal raphe– striatal projection is mainly ipsilateral and arborizes profusely within the entire caudate–putamen complex, but slightly more heavily in the ventrocaudal region (Lavoie and Parent, 1990; Parent, 1996). Surprisingly, only 10– 15% of 5-HT varicosities exhibit a typical synaptic junction in the striatum of rats (Arluison and De La Manche, 1980; Soghomonian et al., 1989). This suggests that the effects of 5-HT in the striatum are exerted on a multiplicity of cellular target sites in addition to the restricted number of dendritic spines and shaft synaptically contacted by 5-HT terminals. Interestingly, dorsal raphe neurons projecting to the striatum also send axon collaterals to the substantia nigra. The 5-HT afferent input from the dorsal raphe nucleus to midbrain dopamine neurons is one of the most prominent (Dray et al., 1976; Fibiger and Miller, 1977; Wirtshafter et al., 1987; Lavoie and Parent, 1990; Vertes, 1991). In summary, anatomical data on the 5-HT connectivity within BG indicate that 5-HT is in a position to modulate BG function by interacting with dopamine systems both at the level of substantia nigra where dopamine neurons are found and at the level of their main target structure, i.e. the striatum. It is thus likely that 5-HT receptors play a role in regulating the appropriate selection of voluntary movement by the BG, and abnormalities in 5-HT transmission may contribute to the neural mechanisms of PD and complications associated with long-term treatment with levodopa (Hornykiewicz, 1998; Nicholson and Brotchie, 2002). 2.7.1. Serotonin biosynthesis, transport, release and degradation The neurotransmitter 5-HT is synthesized from the amino acid tryptophan in two biochemical steps. The

primary source of tryptophan is dietary protein. The entry of tryptophan into brain is not only related to its concentration in blood, but is also a function of its concentration in relation to the concentrations of other neutral amino acids. The initial step in the synthesis of 5-HT is the conversion of l-tryptophan to 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan hydroxylase. This enzyme is only found in brain cells that synthesize 5-HT (serotonergic neurons); its distribution in brain is similar to that of 5-HT itself. The conversion of tryptophan to 5-HTP is the rate-limiting step in the 5-HT metabolic pathway. Therefore, inhibition of this initial step by an enzyme inhibitor such as para-chlorophenylalanine results in a marked and long-lasting depletion of the content of 5-HT in brain. The second enzyme involved in the synthesis of 5-HT is AADC, which converts 5-HTP to 5-HT. This second enzyme, AADC, is the same for both catecholamines and 5-HT. Under appropriate conditions, the synthesis of brain 5-HT in rats can be enhanced by the consumption of a high-carbohydrate, low-protein meal. Administration of an amino acid mixture lacking tryptophan has been used to deplete 5-HT temporarily in human studies (Frazer and Hensler, 1993; Meyer and Quenzer, 2005). As with other biogenic amine transmitters, 5-HT is stored primarily in vesicles and is released by an exocytotic mechanism. As expected for a classical neurotransmitter, 5-HT terminals make the usual specialized synaptic contacts with target neurons and release 5-HT following nerve stimulation. However, there are numerous areas of the mammalian CNS where 5-HT is released and no evidence for synaptic specialization can be found. In this case, it is believed that 5-HT can diffuse over distances as great as several hundred microns (Jacobs and Amiztia, 1992) and may act as a neuromodulator, i.e. adjusting or tuning ongoing synaptic activity. As previously mentioned, a low percentage of 5-HT exhibits typical synaptic junctions in the striatum of rats (Arluison and De La Manche, 1980; Soghomonian et al., 1989), suggesting a diffuse and less specific effect of 5-HT on striatal neurons. 5-HT is transported into synaptic vesicles using the same vesicular transporter, VMAT2, found in dopaminergic and noradrenergic neurons. As with catecholamines, storage of 5-HT in vesicles plays a critical role in protecting the transmitter from enzymatic breakdown in the nerve terminal. Consequently, the VMAT blocker reserpine depletes 5-HT neurons of 5-HT, just as it depletes catecholamines in dopaminergic and noradrenergic neurons (Frazer and Hensler, 1993; Meyer and Quenzer, 2005). The rate of 5-HT release is dependent on the firing rate of 5-HT neurons in the raphe nuclei. 5-HT release

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA is inhibited by the somatodendritic 5-HT1A autoreceptors and by presynaptic 5-H1B or 5-HT1D, depending on the species, located on terminals of 5-HT neurons. Release of 5-HT can be directly stimulated by a family of drugs based on the structure of amphetamine. These compounds include para-chloroamphetamine, fenfluramine and the recreational and abused drug 3,4-methylenedioxymethamphetamine (MDMA). Synaptic effects of 5-HT are terminated by binding of the neurotransmitter molecules to a specific transporter, the 5-HT transporter (5-HTT) (Frazer and Hensler, 1993; Meyer and Quenzer, 2005). 5-HTTs are located on 5-HT neurons and terminals. The 5-HTT turns out to be a key target for drug action. Examples include antidepressant drugs known as selective serotonin reuptake inhibitors (SSRIs) and other non-selective drugs such as cocaine and MDMA that also influence the dopamine transporter. Glial cells also appear to be able to take up 5-HT by a high-affinity transport system. The primary catabolic pathway for 5-HT is oxidative deamination by the enzyme MAO which yields to the formation of the metabolite 5-hydroxyindoleacetic acid. The level of 5-hydroxyindoleacetic acid in the brains of animals or in the cerebrospinal fluid of humans or animals is often used as a measure of the activity of 5-HT neurons (Frazer and Hensler, 1993; Meyer and Quenzer, 2005). 2.7.2. Receptors and signal transduction 5-HT neurotransmission is mediated by at least 14 structurally and pharmacologically distinct 5-HT receptor subtypes categorized into seven distinct families (5-HT1–5-HT7) on the basis of their molecular biology, signal transduction mechanisms and pharmacology. Some of these receptor subtypes fall within groups, such as the large family of 5-HT1 receptors (5-HT1A, 1B, 1D, 1E, 1F) and the smaller 5-HT2 receptor family (5-HT2A, 2B, 2C). The remaining 5-HT receptor subtypes are designated as 5-HT3, 5-HT4, 5-HT5A, 5B, 5-HT6 and 5-HT7. All of the 5-HT receptors are metabotropic, except for the 5-HT3 receptor, which is an excitatory ionotropic receptor (Barnes and Sharp, 1999). Many of these 5-HT receptor subtypes are distributed in low to high density in the BG. Although 5-HT1A receptors are found in low density in the caudate putamen of primates (Frechilla et al., 2001), they may modulate BG function by an effect outside the BG. These somotadendritic autoreceptors are located on neurons of the dorsal raphe that send prominent efferents to the BG and therefore control 5-HT release in those structures. 5-HT1B sites have predominantly been found on terminals of 5-HT neurons in the striatum and on GABAergic striatal output neurons in the

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globus pallidus and substantia nigra (Maroteaux et al., 1992; Boschert et al., 1994; Doucet et al., 1995; Riad et al., 2000), suggesting a role for these receptors in the modulation of dopamine neurotransmission and GABA release. The 5-HT1E receptor subtype (McAllister et al., 1992) is also found at high density in the striatum, where it is thought to be located postsynaptically (Barone et al., 1993; Barnes and Sharp, 1999). 5-HT2A and 5-HT2C receptor subtypes are found in moderate to high densities in the caudate nucleus and output regions of the BG such as the globus pallidus and substantia nigra pars reticulata (Barnes and Sharp, 1999). They have been shown to modulate striatal dopamine release both in vivo and in vitro (Benloucif and Galloway, 1991; Benloucif et al., 1993). In rodent models of PD, 5-HT2C receptors play a key role in controlling BG outputs (Nicholson and Brotchie, 2002), since antagonists increase locomotion and enhance the behavioral response to dopamine agonists (Fox and Brotchie, 2000). The 5-HT4 and 5-HT6 receptor subtypes are positively coupled to adenylate cyclase and found in high densities in the caudate nucleus (Barnes and Sharp, 1999), although their functional role is still unknown.

2.8. Neuropeptides In addition to the classical neurotransmitters described above, the BG contains a great diversity of neuroactive peptides (Graybiel, 1990; Parent et al., 1995b); they are listed in Table 2.1. Unlike classical neurotransmitters, there is no mechanism for reuptake and recycling of neuropeptides after receptor activation (Dockray, 1995). Their action is terminated by internalization and degradation of receptor-bound peptide or mainly by metabolism by proteolytic enzymes (Konkoy and Davis, 1996). Replacement of neuropeptides after release is dependent on new synthesis in nerve cell body and axonal transport. This is a relatively slow process compared to classical neurotransmitters that are synthesized locally in nerve terminals and replaced by reuptake mechanisms. Repeated or prolonged stimulation will therefore more easily exhaust neuropeptide release. Many neuropeptides identified in the brain have their highest concentration in the BG and their related structures. In the BG the principal site of synthesis is the striatum (Graybiel, 1986). Neuropeptides are involved in fast and slow synaptic transmission (Graybiel, 1990). They can exert their biological effects as neurotransmitters, neuromodulators or neurotrophic-like factors (Graybiel, 1990; Chen et al., 2004b).

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The neuropeptides that have been mostly investigated in the BG are the neurokinin peptide SP and the opioid peptides Enk and Dyn (Parent et al., 1995b). 2.8.1. Neurokinins Neurokinins are a group of neuropeptides including SP (or neurokinin-1, NK-1), substance K (SK or neurokinin2, NK-2 or neurokinin A) and neuromedin K (NK or neurokinin-3, NK-3 or neurokinin-B) (Chen et al., 2004b). Their biological functions are mediated by three distinct receptors, the SP receptor (SPR or NK-1 receptor, NK or NK-1R), the SK receptor (SKR or NK-2R) and the NK receptor (NKR or NK-3R), respectively. These receptors are coupled to Gi proteins and modulate intracellular signaling cascades such as adenylate cyclase, calcium and potassium channel activity (Chen et al., 2004b). Pharmacological studies indicate that SP, neurokinin-A and neurokinin-B preferentially interact with NK-1R, NK-2R and NK-3R, respectively (Arenas et al., 1991; Glowinski and Beaujouan, 1993; Khawaja and Rogers, 1996; Chen et al., 2004b). The neurokinins SP, neurokinin-A and neurokininB possess a common carboxy-terminal sequence PheX-Leu-Met-NH2 that accounts for their biological properties (Chen et al., 2004b). The neurokinins are synthesized from the expression of the preprotachykinin genes A and B (PPT-A gene and PPT-B gene). The PPT-A gene generates alpha-, beta- and gammaPPT-A mRNAs whereas the PPT-B gene generates PPT-B mRNA. SP is produced from alpha-, beta- or gamma-PPT-A mRNAs whereas neurokinin-A is produced from beta- or gamma-PPT-A mRNAs and neurokinin-B from PPT-B mRNA (Chen et al., 2004b). SP is the most abundant in the CNS, followed by neurokinin-A and neurokinin-B. They are abundant in the BG and their molar ratio is relatively constant in the striatum–substantia nigra system. The distribution of these neurokinins and their receptors is well documented by binding, in situ hybridization and immunocytochemical studies (Chen et al., 2004b). In the rat caudate putamen and substantia nigra the three neurokinins were found concentrated in the synaptosomal fraction and in fractions containing heavy synaptic vesicles (Diez-Guerra et al., 1988). This localization in vesicles is consistent with a role of neurotransmitter and neuromodulator for neurokinins. In situ hybridization and immunohistochemistry further confirmed the localization of all three neurokinins in the striatum, globus pallidus and substantia nigra (Inagaki and Parent, 1984; Bolam et al., 1986; Hokfelt et al., 1991; Manley et al., 1994; Lee et al., 1997; Chen et al., 2004b). The spiny neurons of the direct output pathway of the striatum express SP, Dyn and dopamine

D1 receptors, whereas spiny neurons of the indirect pathway express Enk and D2 receptors (Fig. 2.1). SP is important in mediating the functions of the direct striatonigral pathway (Emson et al., 1977; Jessell et al., 1978; Chen et al., 2004b). In situ hybridization and immunohistochemical studies also show the abundant distribution of neurokinin receptors in the BG of mammals mostly localized to neuronal cell bodies and dendrites (Chen et al., 2004b). Double-labeling methods have shown that neurons of the neostriatum and the substantia nigra display distinct subclasses of neurokinin receptors (Chen et al., 2004b). About two-thirds of substantia dopamine neurons are found to display NK-3R but not NK-1R immunoreactivity, whereas in the neostriatum NK-1R immunoreactivity is found (Chen et al., 1998). In the neostriatum, NK-1R immunoreactivity was detected in large and medium-sized aspiny neurons and virtually all NR-1R-immunoreactive neurons contained ChAT or somatostatin (Kaneko et al., 1993, 2000). These results suggest that different neurokinins and their receptors have distinct functional roles in the BG. The distribution of SP and its receptor SPR does not match in some brain regions (Shults et al., 1984; Nakaya et al., 1994). This has been explained by the fact that, in contrast to more ‘classical’ synapses, where the receptor immediately apposes the site of neurotransmitter storage and release, much of the surface of SPR-expressing neurons can be targeted by SP that diffuses a considerable distance from its site of release (Chen et al., 2004b). Numerous studies show that neurokinins affect the physiology of neurons in the BG. They are involved in the firing and neurotransmitter release of striatal and substantia nigra neurons (Otsuka and Yoshioka, 1993; Khawaja and Rogers, 1996; Chen et al., 2004b). NK-1, NK-2 and NK-3 receptor activation by specific agonists are shown to increase striatal dopamine and acetylcholine release (Glowinski et al., 1993). Furthermore, 5-HT metabolism is shown to be increased with SP and a selective NK-3 ligand (Humpel et al., 1991; Humpel and Saria, 1993). Neurokinins were also shown to play a role in the neuroprotection of dopamine neurons. There is evidence that neurokinins may play a role in neuroprotection of neurons through antiglutamate excitotoxicity (Arenas et al., 1993; Sanberg et al., 1993; Wenk et al., 1995, 1997; Calvo et al., 1996; Chen et al., 2004b). Furthermore, neurokinins have been suggested to have activity to promote neuronal cell growth that is analogous to neurotrophic factors (Barker, 1986, 1991, 1996; Iwasaki et al., 1989; Barker and Larner, 1992; Barker et al., 1993). A decrease of SP and SPR is observed in the striatum and substantia nigra of postmortem

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA PD brains (Tenovuo et al., 1984, 1990; Levy et al., 1995b). This decrease is also observed in 6-OHDA rats and MPTP-lesioned monkeys (Arai et al., 1987; PerezOtano et al., 1992). 2.8.2. Endorphins Endogenous opioids or endorphins form a complex family generated from three genes encoding precursors (Akil et al., 1998). The first to be characterized was proopiomelanocortin, the common protein precursor for b-endorphin as well as the stress hormone adrenocorticotropic hormone (Nakanishi et al., 1979). The other two opioid precursors are proenkephalin and prodynorphin. Proenkephalin encodes multiple copies of Met-enkephalin, a heptapeptide and octapeptide, and one copy of Leu-enkephalin. Prodynorphin encodes three opioid peptides of various lengths that all begin with the Leu-enkephalin sequence: dynorphin-A, dynorphin-B and neo-endorphin (Akil et al., 1998). There are three major classes of opioid receptors: m, k and d. All three receptors belong to the superfamily of G-protein-coupled receptors and share significant sequence homology, with 61% identity at the amino acid level (Akil et al., 1998). All three opioid receptors inhibit adenylate cyclase. An orderly pattern of association between the three families of endogenous ligands and the three opiate receptors is not observed. Although proenkephalin products are generally associated with d receptors and prodynorphin with k receptors, a fair amount of ‘cross-talk’ exists (Mansour et al., 1995). The k-receptor exhibits the greatest degree of selectivity across endogenous ligands, with 1000-fold more affinity for dynorphin-A (1–7) than Leu-enkephalin. m and d receptors only have a 10-fold difference between the least and most preferred ligands, with a majority of endogenous ligands exhibiting greater affinity towards d than m receptors (Akil et al., 1998). Hence, high-affinity interactions are possible between each precursor family and each of the three receptors. The only exception is the lack of high affinity of proopiomelanocortin peptides for the k receptor. The striatum is among the brain regions with the highest levels of opioid peptides and receptors (Steiner and Gerfen, 1998). Both direct and indirect striatal output pathways use the inhibitory neurotransmitter GABA (Kita and Kitai, 1988), but differ in the neuropeptides they express (Fig. 2.1). Striatonigral neurons generally contain Dyn and SP, whereas striatopallidal neurons express Enk (Brownstein et al., 1977; Vincent et al., 1982; Beckstead and Kersey, 1985; Gerfen and Young, 1988; Reiner and Anderson, 1990; Curran and Watson, 1995; Le Moine and Bloch, 1995). DA

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regulates in opposite direction the expression of neuropeptides in the direct and indirect output pathways of the striatum. For example, dopamine depletion leads to a decrease in SP and Dyn expression in striatonigral neurons and an increase in Enk expression (Young et al., 1986; Voorn et al., 1987; Gerfen et al., 1990, 1991; Li et al., 1990; Engber et al., 1992). This effect can be reversed, respectively, by D1 agonists for the striatonigral neurons and by D2 agonists for the striatopallidal neurons (Gerfen et al., 1990; Engber et al., 1992). Consistent with these observations, D1 receptor knockout mice have decreased expression of SP and Dyn, whereas D2 receptor knockout mice show mostly increased expression of Enk (Drago et al., 1994; Xu et al., 1994; Baik et al., 1995). Postmortem studies in tissue from patients with idiopathic PD have been generally less conclusive than those in animal models. Expression of preproenkephalin (PPE) in the brain of levodopa-treated PD patients was shown to be either unaltered (Levy et al., 1995b) or increased in the caudate nucleus and the putamen (Nisbet et al., 1995). Met-enkephalin and SP were found to be subnormal in PD BG (Fernandez et al., 1996). Studies in human brains have often not taken into account the development of motor complications following levodopa therapy. Indeed, several lines of evidence suggest that alteration of neuropeptides may be linked to the pathogenesis of levodopa-induced dyskinesias (Henry and Brotchie, 1996; Brotchie, 1998; Calon et al., 2000a, b). In situ hybridization studies in parkinsonian monkeys (Morissette et al., 1997) and human PD patients (Calon et al., 2002) suggest that an increased expression of PPE mRNA is associated with levodopainduced dyskinesias. Increased striatal prodynorphin (also called preproenkephalin-B) expression was also observed to be associated with dyskinesias in PD (Henry et al., 2003). Recent behavioral results proposed that the increased production of opioids in the two major striatal output pathways might have a protective role as a compensatory mechanism, which attempts to attenuate the changes in synaptic transmission caused by the lack of striatal dopamine as well as by the abnormal stimulation of dopamine receptors in PD leading to dyskinesias (Samadi et al., 2003, 2004). Data on Enk and Dyn suggest that both opioid peptides function, at least in part, as autoregulatory mechanisms to modulate the pathways they are contained in. The synthesis of both neuropeptides is upregulated by chronic drug/treatment and/or lesions that activate these pathways. These changes in gene regulation are likely adaptive responses in the neurons in order to restore homeostasis by counteracting perturbations produced by the drug exposure and/or lesion.

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2.8.3. Neurotensin

2.8.4. Other neuropeptides

Neurotensin (NT) is a tridecapeptide with widespread distribution in the brain, suggesting that it may play an important role as a neurotransmitter or neuromodulator (Jennes et al., 1982; Zahm et al., 1985). One species of proneurotensin mRNA exists in the brain, the product of a single gene which gives rise to NT and a related peptide neuromedin N (Kislauskis et al., 1988). Three NT receptors, NTS1, NTS2 and NTS3, have been cloned to date (Vincent et al., 1999; Kitabgi, 2002). Most of the known central effects of NT are mediated through NTS1 (Kitabgi, 2002). NTS1 belongs to the family of G-protein-coupled receptors with seven transmembrane domains. Unlike Dyn and Enk, which are expressed throughout the caudate putamen at relatively high levels, NT expression is segregated in dorsomedial and ventromedial subregions of the striatum (White, 1987; Zahm and Heimer, 1988). Moderate to abundant levels of NT receptors were observed in the rat striatum, whereas NT receptor mRNA was not observed (Elde et al., 1990). This is consistent with lesion studies in rats suggesting localization of NT-binding sites on dendrites and axon terminals of nigrostriatal dopaminergic neurons (Goedert et al., 1984). In primates the effect of MPTP on NT-binding sites suggests only partial localization of NT receptors on nigrostriatal dopaminergic projections (Goulet et al., 1999). Several lines of evidence suggest an interaction between NT and central dopaminergic systems, mainly the nigrostriatal and mesolimbic DA pathways (Palacios and Kuhar, 1981; Rostene et al., 1992, 1997; Azzi et al., 1994; Lambert et al., 1995; Fernandez et al., 1996). Experimental observations suggest that proneurotensin mRNA and peptide abundance in the striatum and accumbens are under tonic inhibitory control by midbrain dopaminergic neurons (Angulo and McEwen, 1994). Conversely, neurotensin exerts effects on dopaminergic systems of the midbrain and striatum, facilitating dopamine release and motor activation in midbrain and inhibiting amphetamine activation of motor activity when infused into the accumbens (Angulo and McEwen, 1994). Depletion of NT receptors in PD and in animal models of this disease has been reported for the substantia nigra and the striatum (Sadoul et al., 1984; Uhl et al., 1984; Waters et al., 1987; Chinaglia et al., 1990; Goulet et al., 1999). The NT content in the caudate and putamen was reported to be decreased in the caudate and putamen (Bissette et al., 1985; Fernandez et al., 1995) of PD patients and increased in the substantia nigra (Fernandez et al., 1995, 1996).

Other peptides present in the BG, such as neuropeptide Y, somatostatin, cholecystokinin and angiotensin, are listed in Table 2.1. Neuropeptide Y is the most abundant and widely distributed neuropeptide in mammalian brain (Kask et al., 2002; Balasubramaniam, 2003). It exhibits a wide spectrum of central activities mediated by at least 6 G-protein-coupled receptors. Neuropeptide Y and somatostatin are found in the striatum where they colocalized in a specific subset of interneurons which also express NADPH-d (Smith et al., 1985; Smith and Parent, 1986; Desjardins and Parent, 1992). Neuropeptide Y receptors are also found in moderate to high concentrations in the striatum (Desjardins and Parent, 1992). Neuropeptide Y levels are unaltered in PD (Allen et al., 1985). The striatum contains the largest number of somatostatinergic neurons in the BG (Johansson et al., 1984; Chesselet et al., 1995). The actions of somatostatin are mediated by 5 G-protein-coupled receptors that are widely distributed with high concentrations in the striatum (Hoyer et al., 1994; Patel, 1999). Somatostatin mRNA is decreased in the striatum after lesion of the dopaminergic nigrostriatal pathway (Graybiel, 1990; Soghomonian and Chesselet, 1991; Chesselet et al., 1995). In PD both cerebrospinal fluid and neocortical somatostatin levels have been found to be decreased, whereas in the BG they remain normal (Leake and Ferrier, 1993). The biochemical pathways of the renin–angiotensin system lead to the formation of angiotensin peptides of different lengths and the tissue level of octapeptide angiotensin II is high in the BG (Wright and Harding, 1997). There are three angiotensin receptor subtypes identified in the mammalian brain (AT1, AT2 and AT3), the AT2 and AT3 receptors are present in BG structures such as the caudate putamen, the globus pallidus and the substantia nigra (Wright and Harding, 1997). There is no report of altered angiotensin concentrations or its receptors in PD (Graybiel, 1986; Leake and Ferrier, 1993). Cholecystokinin levels, a neuropeptide found in the gut and the brain, are reported to be decreased in the cerebrospinal fluid and BG but not in the neocortex of patients with PD (Studler et al., 1982; Verbanck et al., 1984; Graybiel, 1986; Leake and Ferrier, 1993). Cholecystokinin and dopamine coexist in some neurons of the ventral midbrain tegmentum and this peptide has been implicated in dopaminergic regulation (Hokfelt et al., 1980). Two cholecystokinin receptors have been cloned and sequenced in humans (CCKAR and CCKBR) (Wei and Hemmings, 1999).

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA A recent study suggests that the cholecystokinin system may influence the development of hallucinations in PD subjects (Goldman et al., 2004). Most other neuropeptides (such as corticotropin, arginine vasopressin, galanin, a-melanocyte-stimulating hormone, vasoactive intestinal peptide) show minimum changes in either the cerebrospinal fluid or the brain of patients with PD (Graybiel, 1986; Leake and Ferrier, 1993).

2.9. Adenosine Purine and purine nucleotides are present in all cells. Adenosine, a ‘purinergic messenger’ that regulates many physiological processes, is released from all cells, including neurons and glia (Dunwiddie and Masino, 2001; Ribeiro et al., 2002). In the BG, adenosine interacts closely with dopamine and plays an important role in the function of striatal GABAergic efferent neurons (Ferre et al., 2004). The role of adenosine in modulating excitatory glutamatergic transmission is also demonstrated (Ferre et al., 2002; Domenici et al., 2004). Recently adenosine has received more attention because its interaction with dopamine and glutamate could have important implications for the development of therapeutic strategies of BG disorders, such as PD. 2.9.1. Synthesis, transport and degradation Adenosine is neither stored in synaptic vesicles nor released as a classical neurotransmitter and there is no evidence for synapses where the primary transmitter is adenosine. Therefore, adenosine belongs to the group of neuromodulators and influences synaptic transmission as an extracellular signal molecule (Ribeiro et al., 2002). The extracellular adenosine which is produced from dephosphorylation of adenine nucleotide AMP, by ecto-50 -nucleotidase, is the last step in the catalysis of extracellular adenine nucleotides such as adenosine triphosphate. Another potential source of extracellular adenosine is cAMP. The latter can be released from neurons and converted into AMP and then adenosine by phosphodiesterases and ecto-50 -nucleotidase, respectively (Svenningsson et al., 1999). Finally, the release of adenosine from cells via transporters is another source of extracellular adenosine (Lindskog et al., 1999). Regulation of adenosine levels in the extracellular space is prominently mediated by facilitated diffusion nucleoside transporters (Cass et al., 1998). These transporters are passive and they do not depend on adenosine triphosphate or ionic gradients to transport adenosine (Dunwiddie and Masino, 2001). The direc-

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tion of the transport (release or reuptake) is dependent on the gradient concentration of adenosine across cellular membrane. The existence of an active transport mechanism for adenosine, which depends on the Naþ gradient to provide energy for transport, has also been demonstrated; however their role in the regulation of extracellular adenosine concentration is unclear (Dunwiddie and Masino, 2001). Adenosine metabolic transformation to inosine by adenosine deaminase is an alternative pathway for regulating extracellular adenosine concentrations (Dunwiddie and Masino, 2001). The intracellular production of adenosine is mediated either via dephosphorylation of AMP by 50 -nucleosidases or by hydrolysis of S-adenosyl-homocysteine (Svenningsson et al., 1999). Intracellularly, adenosine can be converted to AMP by phosphorylation via adenosine kinase or degraded to inosine by adenosine deaminase (Lloyd and Fredholm, 1995; Svenningsson et al., 1999). 2.9.2. Receptors and signal transduction Neuromodulatory effects of adenosine are mediated through activation of four G-protein-coupled receptor subtypes: the A1, A2A, A2B and A3 receptors (Fredholm et al., 2001). The A1 and A3 receptors usually couple to inhibitory G-proteins (Gi and Go), whereas A2A and A2B receptors couple to stimulatory G-proteins (Gs) (Ribeiro et al., 2002). Among adenosine receptors the subtypes A1 and A2A are the main receptors localized in the BG and more precisely in the striatum (Ferre et al., 1997). The A1 receptors are highly expressed in the CNS at both the pre- and postsynaptic sites. These receptors are present in the striatonigral as well as in striatopallidal GABAergic and corticostriatal glutamatergic neurons (Ferre et al., 1997). These anatomical localizations indicate that A1 receptors exist in both D1 and D2-containing neurons (Ferre et al., 1997). Activation of A1 receptor can cause inhibition of adenylyl cyclase and some voltage-dependent Ca2þ channels, as well as activation of Kþ channels, phospholipase C and phospholipase D (Ribeiro et al., 2002). A1 receptor stimulation is linked to inhibition of the neurotransmitter release, most prominently the excitatory glutamatergic transmission (Dunwiddie and Masino, 2001). In the striatum activation of A1 receptors at corticostriatal terminals inhibits glutamate release (Svenningsson et al., 1999). The adenosine A1 receptor may also control the function of GABAergic interneurons indirectly, by inhibiting their glutamatergic input, a process relevant during hypoxia (Ribeiro et al., 2002). Another action of A1 receptors is hyperpolarization of the resting membrane potential and

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reduction of excitability and firing rate (Dunwiddie and Masino, 2001). Besides its direct neuromodulatory effects, adenosine has also receptor–receptor interaction with dopamine in the CNS, including BG (Franco et al., 2000). Dopamine via D1 receptor activation increases the activity of A1 receptors by potentiating NMDA-mediated adenosine release (Harvey and Lacey, 1997). Adenosine A1 and dopamine D1 receptor interaction may involve the formation of A1/D1 heterodimers leading to the reduction of D1 receptors in the high-affinity state or uncoupling of D1 receptors to the G-protein (Fuxe et al., 1998). A2A receptors are mainly coupled to Golf, a protein abundant in the striatum which activates adenylyl cyclase (Kull et al., 2000). Stimulation of A2A receptors by increasing the activity of this enzyme enhances the phosphorylation of DARPP-32 at Thr-34 while decreasing the phosphorylation of DARPP-32 at Thr75 (Lindskog et al., 2002). The phosphorylation of DARPP-32 at Thr-34 and Thr-75 converts this protein into an inhibitor of PP-1 and of PKA, respectively (Greengard, 2001). In contrast to A2A agonism, A2A blockade, by phosphorylation of DARPP-32 at Thr75, decreases PKA activation and therefore relieves the DARPP-32-mediated inhibition of PP-1. PP-1 activity decreases the hyperphosphorylation state of target proteins, including glutamatergic receptor subunits and transcription factors, such as c-fos, occurring after dopaminergic denervation in PD (Ribeiro et al., 2002; Chase et al., 2003; Ferre et al., 2004). A2A receptors are abundant in the striatum and they modulate the input and/or output activity of GABAergic medium spiny projection neurons (Hettinger et al., 2001; Rosin et al., 2003). A2A receptors are mainly found at postsynaptic sites of striatopallidal GABAergic neurons, which also express dopamine D2 receptors. However, presynaptic and glial A2A receptors are also present in the striatum (Rosin et al., 2003). The presynaptic localization of A2A receptors at glutamatergic corticostriatal terminals suggests that these receptors could modulate the glutamatergic cortical input by stimulating glutamate release (Rosin et al., 2003). The presence of pre- and postsynaptic A2A receptors on corticostriatal glutamatergic and striatopallidal GABAergic neurons, respectively, suggests that these receptors may increase the excitability of medium spiny neurons and, in this manner, play an important role in the regulation of synaptic plasticity (Svenningsson and Fredholm, 2003). Presynaptic A2A receptors located on the terminals of striatal axon collaterals (Hettinger et al., 2001) and cholinergic interneurons (Jin et al., 1993) could also modulate GABAergic and cholinergic inputs to medium spiny neurons (Rosin et al., 2003; Mori and Shindou, 2003).

Furthermore, A2A receptors are also expressed presynaptically in the GPe at striatopallidal GABAergic terminals where they may enhance the release of GABA (Mori and Shindou, 2003; Rosin et al., 2003). This directly suppresses the excitability of GPe projection neurons, resulting in disinhibition of STN and its overactivity, leading to parkinsonian syndrome. All these results suggest that adenosine transmission plays an important role in the modulation of motor function and adenosine A2A antagonists, by reducing excessive striatopallidal and STN neuronal activity, could be considered as a novel approach in PD therapy (Kase, 2001; Chase et al., 2003; Mori and Shindou, 2003). Accordingly, several behavioral studies in animal models and in parkinsonian patients have demonstrated the beneficial effect of A2A receptor antagonism in the treatment of PD and its related motor complications (Grondin et al., 1999; Kanda et al., 2000; Morelli and Pinna, 2001; Fredduzzi et al., 2002; Chase et al., 2003; Calon et al., 2004). 2.9.3. Adenosine and dopamine receptor heterodimerization The anatomic localization of dopamine and adenosine receptor subtypes in striatal projection neurons supports the existence of functional interactions between dopamine and adenosine receptors (Franco et al., 2000). Dopamine D1 and adenosine A1 receptors can interact with each other to form the heteromer D1/A1. This heteromerization is essential for the desensitization and receptor trafficking of D1 receptor agonist-induced accumulation of cAMP in combined pretreatment with D1 and A1 receptor agonists. This antagonistic mechanism may contribute to the D1/A1 functional antagonism found in the brain and offers a basis for the design of a novel agent to treat PD based on the pharmacological properties of the D1–A1 heteromeric complex (Gines et al., 2000). A2A receptor agonist-induced reduction of D2 receptor affinity involves conformational changes in the binding site of D2 receptors and is caused by the A2A–D2 heteromeric receptor complex (Salim et al., 2000). Striatal A2A receptor seems to be involved in the increased striatal expression of c-fos when D2 receptor signaling is interrupted (Pinna et al., 1999). It has been suggested that the antiparkinsonian action of A2A antagonists results from blocking the action of A2A–D2 receptor interaction, leading to the enhancement of D2 receptor signaling and blockade of increased A2A receptor signaling in the denervated striatum (Salim et al., 2000). Recent experiments using optical sectioning techniques found that A2A and mGluR5 are also

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA co-localized in rat striatal cultures (Fuxe et al., 2003). A2A receptor-induced phosphorylation of DARPP-32 at Thr-34 via an extracellular signal-regulated kinase (ERK) pathway and induction of c-fos expression are prominently increased in striatopallidal neurons only when A2A and mGluR5 are co-activated (Ferre et al., 2002; Nishi et al., 2003). This mechanism can take place after the overactivity of glutamatergic transmission, which can induce adenosine release (Ferre and Fuxe, 2000; Nash and Brotchie, 2000). A recent study also showed that the mGluR5-mediated effect in the striatum is abolished by blockade of A2A receptors (Domenici et al., 2004). Additionally, it has been demonstrated that A2A and mGluR5 could synergistically reduce the affinity of D2 receptors in the striatum (Ferre et al., 1999). Interestingly, chronic but not acute treatment with an mGluR5 antagonist can reverse parkinsonian symptoms in a rat model of PD (Breysse et al., 2002). This effect may be caused by desensitization of the A2A–mGluR5 heteromeric complex, leading to removal of the blockade of D2 receptor-induced signaling effect (Fuxe et al., 2003). According to all these results, it has been suggested that the striatal A2A–D2– mGluR5 multimeric receptor complexes may be involved in striatal plasticity and could be relevant for the management of PD (Ferre et al., 2002; Fuxe et al., 2003). 2.9.4. Neuroprotection by A2A receptor antagonists Striatal A2A receptor stimulation by increasing the release of GABA in the GPe reduces the activity of the GABAergic projection from the GPe to the STN and leads to disinhibition of the STN. Since STN projects to SNc, enhanced release of glutamate from STN can exert an excitotoxic effect on the dopaminergic nigrostriatal neurons and, conversely, A2A antagonists may protect dopaminergic neurons from degeneration (Blandini et al., 2000; Schwarzschild et al., 2003). The stimulation of striatal glutamate release by mGluR5 agonists also involves A2A receptors (Pintor et al., 2000). According to the positive regulation of striatal glutamate outflow by A2A receptor activation, one of the other mechanisms responsible for the neuroprotective effects of A2A receptor antagonists could be the modulation of striatal glutamate release. In agreement with this hypothesis, blockade of striatal A2A receptor reduced quinolinic acid-induced excitotoxicity in the rat striatum (Popoli et al., 2002). In addition, deficient A2A receptor mice were shown to be more resistant to MPTP-induced dopaminergic degeneration (Chen et al., 2001). Moreover, activation of A2A receptors in cultured glial cells from the cortex and brainstem increased extracellular glutamate levels,

43

while A2A antagonists reduced glutamate efflux (Li et al., 2001; Nishizaki et al., 2002). It has been suggested that A2A receptor regulation of glial GLT1 may be implicated in this effect (Schwarzschild et al., 2003). Interestingly, more recently it has been shown that A2A receptor antagonists prevent the increase in striatal glutamate levels by removal of the inhibitory influence exerted by A2A receptors on glutamate uptake (Pintor et al., 2004). Nevertheless, a recent study suggests that, whereas presynaptic A2A receptor activation by facilitation of glutamate release has excitotoxic effects, postsynaptic A2A receptor stimulation by induction of trophic factors and inhibition of NMDA effects is potentially beneficial (Tebano et al., 2004). According to the results of this study, it has been suggested that the neuroprotective potential of A2A antagonists is mainly evident in models of neurodegenerative diseases in which presynaptic mechanisms play a prominent role (Tebano et al., 2004). In conclusion, A2A receptor antagonists, based on their application in the improvement of parkinsonian symptoms and their neuroprotective effects, seem to be promising therapeutic candidates in PD.

2.10. Endocannabinoids The principal psychoactive component of Cannabis sativa (for example, marijuana and hashish) is 9-tetrahydrocannabinol (9-THC) (Matsuda et al., 1990). 9-THC exerts a large number of effects in the CNS, including analgesia (Richardson et al., 1998), catalepsy (Compton et al., 1996), impairment of learning and memory (Mallet and Beninger, 1998) and positive reinforcement (Martellotta et al., 1998). Two endogenous ligands for cannabinoid receptors, termed endocannabinoids, have been identified in the brain (Kreitzer and Regehr, 2002). Endocannabinoids have been shown to be involved in the retrograde regulation of synaptic transmission at a variety of brain synapses. Furthermore, a close interaction between dopamine and endocannabinoids in motor function has also been suggested (Beltramo et al., 2000; Meschler and Howlett, 2001). The mechanism of action of these retrograde signals is of interest, especially in association with activity-dependent synaptic plasticity related to the processing and storage of motor information in the BG. 2.10.1. Brain synthesis of endocannabinoids Unlike neurotransmitters and neuropeptides, which are released from synaptic terminals via vesicle secretion,

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endocannabinoids are produced and released on demand (Piomelli, 2003). Anandamide was the first molecule isolated and characterized as an endocannabinoid (Devane et al., 1992). Anandamide is synthesized from the cleavage of phospholipid precursor, N-arachidonoylphosphatidylethanolamine (NAPE) by phospholipase D (PLD) (Di Marzo et al., 1994): N-acyltransferse Phosphatidylethanolamine

NAPE PLD Anandamide

A second endocannabinoid, 2-arachidonylglycerol, is formed through a distinct biosynthetic pathway, involving phospholipases and diacylglycerol lipase, from phosphatidylinositol (Sugiura et al., 1995; Stella et al., 1997):

PLC

1,2 DAG

DAG lipase

PI

2-AG PLA1

Lyso-PI

Lvso-PLC

PLC, phospholipase C PLA1, phospholipase A1

The formation of these endocannabinoids can be initiated by postsynaptic membrane depolarization, which opens voltage-gated Ca2þ channels. The increase in the concentration of intracellular Ca2þ then activates enzymes involved in the synthesis of endocannabinoids from lipid precursor (Alger, 2002; Wilson and Nicoll, 2002). Endocannabinoid synthesis can also be triggered by activation of G-proteincoupled receptors. For example, the dopamine D2 receptor agonist quinpirole causes an increase in anandamide levels in the rat striatum, which is prevented by the dopamine D2 receptor antagonist raclopride (Giuffrida et al., 1999). Activation of group I mGluRs and also muscarinic acetylcholine receptors could enhance the release of endocannabinoids (Alger, 2002; Wilson and Nicoll, 2002).

2.10.2. Release, diffusion and uptake of endocannabinoids Physiological experiments have shown that endocannabinoids could leave postsynaptic cells to activate cannabinoid receptors on adjacent presynaptic

axon terminals (Wilson and Nicoll, 2002; Piomelli, 2003). Extracellular lipid-binding proteins such as lipocalins, which are expressed at high levels in the brain, may help to deliver endocannabinoids to their cellular targets (Piomelli, 2003). Recently, it has been shown that postsynaptic transport mechanisms are responsible for the release of endocannabinoid from striatal medium spiny neurons (Ronesi et al., 2004). How far are the endocannabinoid molecules able to travel from their point of release to affect other cells? In dorsolateral striatum, physiological activation of cells does not cause spread of endocannabinoids to nearby cells unless endocannabinoid uptake is inhibited by the transport inhibitor AM-404 (Gerdeman et al., 2002). Therefore, it has been suggested that endocannabinoids are quite local signals, but conditions that favor their synaptic synthesis and release with a reduction in endocannabinoid uptake may induce their diffusion to neighboring cells (Alger, 2002; Wilson and Nicoll, 2002). After having been released into the extracellular space, two mechanisms could attenuate endocannabinoid signaling in the brain: first, transport of endocannabinoid into cells, which is not mediated by transmembrane Naþ gradients but by specific transport protein present in both neurons and glial cells (Beltramo et al., 1997; Piomelli, 2003). Indeed, an antagonist of this transporter, AM-404, potentiates the effect of exogenous anandamide on cultured neuron (Beltramo et al., 1997). Second, after being removed from the extracellular space, endocannabinoids are degraded by intracellular enzymes. Anandamide is catalyzed (broken) to arachidonic acid and ethanolamine by fatty acid amine hydrolase (FAAH) (Wilson and Nicoll, 2002; Piomelli, 2003). 2.10.3. Receptors, signal transduction and function Two forms of cannabinoid receptor, CB1R and CB2R, which belong to the family of G-protein-coupled receptors, have been cloned (Matsuda et al., 1990; Onaivi et al., 2002). Brain endocannabinoids, anandamide and 2-arachidonylglycerol, exert most of their action in the brain via CB1R. CB1R is one of the most abundant neuromodulatory receptors in the brain and is expressed at high levels in the BG (Matsuda et al., 1990; Herkenham et al., 1990; Wilson and Nicoll, 2002). CB2R is enriched in immune tissues but absent from the brain (Munro et al., 1993). New data demonstrate that brains of CB1R-deficient mice have still significant binding with a synthetic cannabinoid agonist (Breivogel et al., 2001). These data may suggest

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA the existence of a third cannabinoid receptor (Wilson and Nicoll, 2002). In the striatum CB1Rs are twice as numerous as dopamine D1 receptors (Herkenham et al., 1991b) and 12 times as numerous as m opioid receptors (Sim et al., 1996). They are expressed by three distinct neuronal elements: 1. 89.3% of GABAergic striatal projection neurons in matrix and 56.4% of medium spiny neurons in patch are labeled for CB1R (Fusco et al., 2004). 2. Local circuit of GABAergic interneurons also expresses CB1Rs (Hohmann and Herkenham, 2000). Recent studies demonstrate that 86.5% of parvalbumin interneurons, which mediate a feedforward inhibition on striatal projection neurons, contain CB1Rs. One-third (30.4%) of NOS-containing neurons and one-third (39.2%) of striatal cholinergic interneurons are also labeled for CB1Rs (Fusco et al., 2004). 3. CB1Rs are also localized in glutamatergic corticostriatal terminals (Gerdeman and Lovinger, 2001, Huang et al., 2001, Piomelli, 2003). CB1Rs are also abundant in the globus pallidus and the SNr, the output nuclei of the BG (Herkenham et al., 1991a; Piomelli, 2003). The activation of CB1Rs causes inhibition of both Ntype and P/Q-type Ca2þ channels which are known to regulate neurotransmitter release (Pertwee, 1997; Twitchell et al., 1997; Huang et al., 2001), and stimulation of Gprotein-coupled inward-rectifying Kþ channels (Henry and Chavkin, 1995). Inhibition of adenylyl cyclase and consequent decrease in cAMP concentration, stimulation of A-type Kþ currents (Childers and Deadwyler, 1996) and activation of kinases that phosphorylate tyrosine, serine and threonine residues in proteins (Piomelli, 2003) also contribute to CB1R-mediated signaling. Depolarization-induced suppression of inhibition and of excitation are the most convincing examples of rapid retrograde signaling in the brain produced by endocannabinoids (Alger, 2002). A transient depolarization of a postsynaptic cell elicits Ca2þ-dependent endocannabinoid production. The endocannabinoid could then activate CB1Rs on inhibitory terminals to reduce GABA release from postsynaptic axons (Alger, 2002; Kreitzer and Regehr, 2002; Wilson and Nicoll, 2002). It has been found that CB1R activation could inhibit GABAergic responses evoked by local stimulation of the striatum (Szabo et al., 1998). In addition, local administration of cannabinoid agonists in the striatum inhibits GABA release and affects motor behaviors (Romero et al., 2002). The expression of CB1Rs on striatal parvalbumin and NOS GABAergic interneurons as well as cholinergic interneurons

45

demonstrates the involvement of endocannabinoid (anandamide) in the modulation of motor activity. Interestingly, the ability of cannabinoids to inhibit the release of acetylcholine has been demonstrated in hippocampus and prefrontal cortex both in vivo and in vitro (Schlicker and Kathmann, 2001). However, if locally released anandamide has access to these striatal interneurons or this endocannabinoid primarily acts on medium spiny neurons and corticostriatal afferents is not yet clearly known (Piomelli, 2003). Anandamide via activation of CB1Rs can also mediate the inhibition of glutamatergic transmission in the striatum (Gerdeman and Lovinger, 2001) and SNr (Szabo et al., 2000). However, whether such effects reflect the existence of regional depolarization-induced suppression of excitation phenomenon is an important question to be addressed (Piomelli, 2003). The release of anandamide from medium spiny neurons is stimulated by membrane depolarization, increase in the intracellular Ca2þ levels and also dopamine D2 receptor activation (Giuffrida et al., 1999). More recently, it has been shown that anandamide release is involved in the induction of a longlasting form of plasticity, LTD of excitatory transmission in the striatum (Gerdeman et al., 2002). Striatal LTD is expressed as a decreased probability of glutamate release at corticostriatal synapse (Choi and Lovinger, 1997). LTD is absent in the striatum of CB1R-deficient mice and is blocked by a CB1Rantagonist (Gerdeman et al., 2002). Furthermore, recent studies reveal that CB1R activation is necessary for induction, but not the maintenance, of striatal LTD since CB1R-antagonists reverse agonist-induced synaptic depression but do not alter established LTD (Ronesi et al., 2004). This transient action interacts with another putative presynaptic signal to established LTD. As previously reported, increased activity of corticostriatal neurons in PD reflects the loss of dopamine D2 receptor-mediated control of glutamatergic transmission (Cepeda et al., 2001). Recent studies have revealed that CB1R activation reduces the release of glutamate in the striatum via an indirect pathway involving inhibition of glutamate transport function. This results in an increase in the extracellular glutamate concentration, which activates the presynaptic mGluRs. Finally, the latter mediates reduction of glutamate release and depression of corticostriatal synaptic transmission (Brown et al., 2003). Interestingly, dopamine D2 and CB1Rs share the same effect in the negative regulation of corticostriatal inputs (Meschler and Howlett, 2001). After dopamine denervation in 6-OHDA lesioned rats, increased levels of anandamide are paralleled by

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an abnormal downregulation of anandamide membrane transporter and FAAH activity, without changes in the level of CB1R and anandamide binding to this receptor (Gubellini et al., 2002). However, these changes in endocannabinoid system as a compensatory mechanism, trying to control abnormal overactivity of glutamatergic transmission in the striatum, seem not to be sufficient (Gubellini et al., 2002; Maccarrone et al., 2003). Recently, it has been shown that further increase of anandamide by inhibition of its degradation and blockade of FAAH restores the normal corticostriatal function (Maccarrone et al., 2003). In addition, depression of striatal glutamatergic activity produced by FAAH blockade was much stronger than in shamoperated and levodopa-treated lesioned rats. Therefore, inhibition of FAAH may be beneficial to decrease abnormal synaptic transmission in PD (Maccarrone et al., 2003). Moreover, the beneficial effect of the CB1R agonist nabilone to decrease levodopa-induced dyskinesias in the parkinsonian MPTP monkeys and parkinsonian patients has also been reported (Sieradzan et al., 2001; Fox et al., 2002). Dopamine D1 receptor activation of adenylyl cyclase can be blocked by CB1R stimulation (Meschler and Howlett, 2001). Therefore, this beneficial effect of CB1R activation to improve levodopa-induced dyskinesias could be explained by reduction of both overactive glutamatergic transmission in the striatum and enhanced signaling by dopamine D1 receptor (Brotchie, 2003). CB1R activation could also affect motor activity by modulating both inhibitory and excitatory input to SNrGPi from striatum and STN, respectively (Sanudo-Pena et al., 1999). Finally, CB1R activation of the endocannabinoid system could provide an on-demand protective cascade against excitotoxicity and may become a promising therapeutic target for the treatment of neurodegenerative diseases (Marsicano et al., 2003). Together, these results suggest that endocannabinoid signaling provides a mechanism for regulating synaptic strength in the BG, which are involved in movement control and in pathologies such as PD.

2.11. Other putative neurotransmitters in the basal ganglia 2.11.1. Nitric oxide and carbon monoxide Nitric oxide (NO) is formed in neurons through the oxidation of the amino acid arginine by the enzyme NOS, a Ca2þ-calmodulin-dependent enzyme, in response to glutamate acting through NMDA receptors and requiring an influx of Ca2þ ions (Kandel, 2000b). The half-life of NO is considered to be less than a few seconds. However, it is not a polar molecule and

therefore can easily penetrate neuronal membranes to diffuse to adjacent neurons (Ohkuma and Katsura, 2001). The major action of NO, as a gaseous messenger, is to stimulate the production of cyclic guanosine monophosphate (cGMP) by the intracellular enzyme guanylyl cyclase. Two forms of guanylyl cyclase, the enzyme that converts GTP to cGMP, have been identified. One form is a membrane protein with an extracellular receptor domain and an intracellular catalytic domain that synthesized cGMA. cGMP is a freely diffusible cytoplasmic second messenger that activates protein kinases (Kandel, 2000b). It has been reported that NO can also stimulate the release of various types of neurotransmitter, such as dopamine, glutamate, acetylcholine and GABA (Ohkuma and Katsura, 2001). The mechanisms for the NO-induced release of neurotransmitters are not well understood; however, this can be mediated via both Ca2þ-dependent and -independent processes (Ohkuma and Katsura, 2001). A part of Ca2þ-dependent release of neurotransmitters by NO is due to the opening of voltage-dependent Ca2þ channels followed by increased Ca2þ influx subsequent to neuronal membrane depolarization induced by NO (Ohkuma and Katsura, 2001). Furthermore, NO shows cytotoxic effects and plays a role in various neurological diseases, which are caused by excessive production of NO (Ohkuma and Katsura, 2001). Accordingly, it has been reported that 7-nitroindazole, a relatively selective inhibitor of the neuronal NOS, can protect against MPTP-induced neurotoxicity in experimental animals (Hantraye et al., 1996). A recent study also suggests that the protective effect of NOS inhibitor may be partly produced by the reduction of neuronally derived NO and peroxynitrite caused by MPTP (Watanabe et al., 2004). Therefore, the neuronal NOS inhibitors may have therapeutic efficiency in neurodegenerative diseases such as PD (Watanabe et al., 2004). Recent pharmacological and genetic experiments have identified NO as one of the possible retrograde messengers involved in synaptic plasticity (Kandel, 2000a). Striatal NOS-positive interneurons represent the main source of NO in the striatum (Centonze et al., 1999). It has been suggested that dopamine stimulates NO production by activating D1 receptors located on striatal NOS-positive neurons. NO, in turn, might cooperate with postsynaptic D2 receptors to induce striatal LTD (Calabresi et al., 1999b; Centonze et al., 2003c). Therefore, these interneurons, by receiving direct cortical inputs and innervating the medium spiny neurons, mediate feed-forward processing of the cortical input to the striatal projection neurons (Centonze et al., 1999).

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA Carbon monoxide (CO) is also considered as a gaseous neurotransmitter (Deutch and Roth, 2003). CO is produced endogenously by the NADPH-dependent enzymatic peroxidation of microsomal membrane lipids and by heme oxygenase (HO) enzymes (Riedl et al., 1999). The brain contains the two isoforms of HO, the oxidative stress-inducible HO-1 and the constitutive HO-2. In PD prominent annular HO-1 immunoreactivity is found in cytoplasmic Lewy bodies (Schipper, 2004). 2.11.2. Cytokines and growth factors The cytokine (‘cell movement factor’) family is a group of secreted proteins that mediate diverse biological responses such as changes in the immune system (interleukins), tumor cytotoxicity (tumor necrotic factors) and inhibition of viral replication or cell growth (interferons) (Oppenheim and Johnson, 2003). Many cytokines important for the development and maintenance of peripheral organs are also widely expressed in the nervous system, although their role in the brain has yet to be defined. The neuropoietic cytokines, ciliary neurotrophic factor and leukemia inhibitory factor, possess widespread neurotrophic activity (Oppenheim and Johnson, 2003). Cytokines and growth factors have been grouped into families based on their protein sequences and receptor usage rather than on their biological properties. The growth factor family is a group of proteins that support the growth, development, plasticity, differentiation and maintenance of neurons. Growth factors are stored and released from neurons, suggesting that they may also act as neurotransmitters (Oppenheim and Johnson, 2003). Representative members of the neurotrophic factor family (also called neurotrophin or nerve-feeding factors) include nerve growth factor, brain-derived nerve growth factor (BDNF), neurotrophins or nerve-feeding factors (NT-3, NT4/5 and NT-6). The neurotrophins act through high- and low-affinity receptors. There are three tyrosine receptor kinase or trk receptors – trkA, trkB and trkC – accounting for most of the biological responses of neurons to neurotrophins. Each member of the neurotrophin family binds with one or more of the trk receptors. All neurotrophins bind p75LNTR or the low-affinity neurotrophin receptor; this receptor lacks a cytoplasmic kinase domain. p75LNTR can facilitate ligand binding to, and enhance signaling through, trkA and independently initiate signaling. Splice variants of trks lacking signaling capabilities are also present and they may modulate neurotrophin activity by limiting access of full-length receptors to their ligand

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(Huang and Reichardt, 2001; Oppenheim and Johnson, 2003). Neurotrophins and their receptors are present in the BG and have a specific striatal distribution. The receptor for BDNF, trkB, is the most abundant and is mainly found in medium-sized spiny projecting neurons, whereas these neurons contain lower levels of the trkC receptor for NT-3 (Merlio et al., 1992). In contrast, the high-affinity receptor for nerve growth factor, trkA, is restricted to cholinergic interneurons (Holtzman et al., 1995). In agreement with their receptor distribution, BDNF and NT-3 have trophic effects on GABAergic projecting neurons (Mizuno et al., 1994; Ventimiglia et al., 1995; Ivkovic et al., 1997) and nerve growth factor on striatal cholinergic neurons (Martinez et al., 1985; Mobley et al., 1985). Striatal neurotrophins and their receptors were shown to be regulated by ionotropic and metabotropic glutamate receptor agonists (Alberch et al., 2002). In the substantia nigra a partial 6-OHDA lesion of dopaminergic neurons increases BDNF mRNA levels in the subtantia nigra pars reticulata (Aliaga et al., 2000). Representative members of the tissue growth factor family includes glial-derived neurotrophic factors (GDNF), insulin-like growth factors (IGF), tumor growth factors, epidermal growth factors and plateletderived growth factors (Oppenheim and Johnson, 2003). Because knowledge of the basic cellular biology of each growth factor is still incomplete, those more concerned with the BG will be discussed briefly. GDNF signals through the receptor tyrosine kinase Ret (Jing et al., 1996). GDNF family ligands are potent survival factors of midbrain dopamine neurons (Saarma, 2000). Intracerebral injections of GDNF can provide almost complete protection of nigral dopamine neurons against 6-OHDA or MPTP-induced damage, promote axonal sprouting and regrowth of lesioned dopamine neurons and stimulate dopamine turnover and function in neurons spared from the lesion (Bjorklund et al., 1997; Gash et al., 1998). Five PD patients receiving GDNF showed significant clinical improvement and reduction of dyskinesias without side-effects (Gill et al., 2003). Furthermore, GDNF was shown by positron emission tomography to increase dopamine storage significantly in the putamen, suggesting a direct GDNF effect on dopamine function (Behrstock and Svendsen, 2004). The main source of IGF-I is the liver but the brain also synthesizes this peptide. Furthermore, systemic IGF-I enters the brain, thus both locally synthesized and peripheral IGF-I may affect brain function (Cardona-Gomez et al., 2001). IGF-I acts through the IGF-IR, a member of the growth factor tyrosine kinase receptor family that signals through PI3 kinase and MAPK cascade (LeRoith et al., 1993). IGF-I was

48

Corticostriatal Nerve terminal

Synaptic vesicle

M2 or M3 mACh receptor

Acetylcholine

Corticostriatal Nerve terminal

Synaptic vesicle

M2 or M3 mACh receptor

Opioid receptor

Opioid receptor

-

-

Acetylcholine Endogenous -

Ac

m Opioid

A1

+

-

-

cAMP

Dopamine

+

Ca2+

D2

-

Gi

cAMP signaling cascade ATP

+

Protein kinase activation

-

-

Ca2+

PP-1 inhibition

Short term responses

Long-term adaptive responses Motor behavior

GABAergic striatopallidal neuron

-

Opioid receptor

Protein kinase activation DARPP-32 phosphorylation

+

Ca2+

PP-1 inhibition

+

-

PP-2B

LOG

IEG

Ca2+

cAMP signaling cascade

-

CREB-P Fos-P

cAMP

+

Gs

ATP cAMP

DARPP-32 phosphorylation

NMDA receptor

cAMP

Ac

Opioid receptor

Ac

ATP

D1

ATP

Adenosine

-

receptor

A2a

Ac

NMDA receptor

Gs

+

Endogenous opioids

-

PP-2B

CREB-P Fos-P

M1 mACh receptor IEG Short term responses

LOG Long-term adaptive responses Motor behavior

GABAergic striatonigral neuron

M1 mACh receptor

P. SAMADI ET AL.

Adenosine

Glutamate

opioids

Gi

Glutamate

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA shown to protect striatal neurons against quinolinic acid toxicity (Alexi et al., 1999) and dopaminergic nigral neurons against 6-OHDA (Guan et al., 2000). Interestingly, IGF-I was shown to interact with estrogens in the brain and this has been implicated in neuroprotection (Cardona-Gomez et al., 2001).

2.12. Functional integration of neurotransmitters Acquisition of motor or procedural learning is implicit and memory is reflected by a progressive reduction of the response time or the error rate over repeated exposure to the procedure (Dujardin and Laurent, 2003). The striatum, the largest input structure of the BG circuit that receives afferents from all regions of the cerebral cortex, is a part of the motor learning system of the mammalian brain (Graybiel, 2004). A functional deficit in this system induced by the loss of nigrostriatal neurons in PD contributes to the neurological disorders seen in parkinsonian patients. In humans, the dorsal striatum is essential not just for motor learning but also for acquiring the gradual, incremental learning of stimulus–response association that is the characteristic of implicit or habit learning (Knowlton et al., 1996). In humans and in other animals, habit learning can be dissociated from explicit learning and from affect-related learning mediated by the hippocampal– medial temporal cortical systems and limbic structures, respectively (Graybiel, 1998). Lesions of the dorsal striatum in rats and in monkeys lead to the selective impairment of the stimulus–response (habit) learning without affecting spatial task, a form of explicit memory (Packard and McGaugh, 1992; FernandezRuiz et al., 2001). In addition, in patients with PD, impaired performance of stimulus–response learning but entirely normal declarative memory has also been demonstrated (Knowlton et al., 1996). In cellular transduction pathways, long-term storage of implicit memory involves the cAMP, PKA, MAPK and CREB pathways (Kandel et al., 2000; Kandel,

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2001). cAMP mediates many intracellular events that are involved in long-term cellular adaptation, including phosphorylation of DARPP-32 at Thr-34 in striatal output neurons and consequently regulation of activity of transcription factors such as CREB and fos-family (Greengard, 2001). Dopamine and glutamate, as well as their interactions, are key elements in the control of the neuronal plasticity in the corticobasal ganglia circuit affecting motor learning (Canales et al., 2002). Some of the changes occurring during learning involve altering the parameters of corticostriatal transmission (Graybiel, 1998). When corticostriatal excitation and dopaminergic activation are temporally coordinated, they trigger intracellular signaling that leads to short- and long-term changes in gene expression and also longlasting enhancement of synaptic strength in medium spiny neurons (Fig. 2.6) (Wickens et al., 1996; Kelley et al., 2003). Accordingly, recent studies have proposed that learning and memory of habitual movements involve the relative balance between dopamine and glutamate receptor signaling that determines which intracellular cascades will be activated in which striatal output neurons (Gerfen et al., 2002). More recently it has been demonstrated that dopamine, by filtering less active inputs, via activation of presynaptic D2 receptors, reinforces particular subsets of corticostriatal afferents (Bamford et al., 2004). On the other hand, activation of NMDARs recruits dopamine D1 receptors to the plasma membrane and thus increases D1-like receptor signaling pathway (Scott et al., 2002; Pei et al., 2004). This D1–NMDA interaction plays an essential role in the control of learningrelated plasticity (Kelley et al., 2003). In addition to dopamine and glutamate receptors, striatal cholinergic receptors also have a significant role in triggering the intracellular changes responsible for corticostriatal synaptic plasticity (Calabresi et al., 2000b; Ragozzino, 2003). Indeed, the release of acetylcholine in different neuronal systems provides a marker of activation of those systems during learning (Chang and Gold, 2003). Furthermore, GABAergic interneurons, including

Fig. 2.6. For full color version, see plate section. Interaction of dopamine, adenosine, glutamate, acetylcholine and opioids in the striatum and possible sequence of events leading to motor behavior. The phosphorylation state of a protein is a balance between its kinases and phosphatases. In the striatum DARPP-32 plays a key role in the interactions amongst various signaling pathways (Greengard, 2001). Increase in the level of cyclic adenosine monophosphate (cAMP) causes the activation of protein kinases and phosphorylation of dopamine- and cAMP-regulated phosphoprotein (DARPP-32) at threonine 34 (Thr-34). The phosphorylation converts DARPP-32 from an inactive molecule into an inhibitor of protein phosphatase-1 (PP-1), which controls the state of phosphorylation and activity of numerous physiologically important effectors, including transcription factors such as cAMP-response element-binding protein (CREB) and fos-family. Modification of immediate early genes (IEG) or lateonset genes (LOG), following activation of transcription factors, may trigger the short- and long-term adaptive changes that are responsible for adaptive synaptic plasticity leading to motor learning. Modified from Samadi et al. (2003).

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NOS-containing neurons, by modulating the activity of medium spiny neurons in response to cortical inputs, also play an important role in the expression of synaptic plasticity at corticostriatal synapses (Centonze et al., 1999, 2003c). Therefore, the striatum, by processing the information flow from various inputs and sending output to targets that generate behaviors (Grace, 2000), plays a key role in adaptive plasticity in corticobasal ganglia as well as in pathological responses in PD.

Acknowledgments The authors would like to thank Laurent Gregoire for helping in the management of the references in the text and Gilles Chabot for preparing the figures. This work is supported by grants from the Canadian Institutes of Health Research (CIHR) to TDP, PJB and CR. PS holds a fellowship from CIHR-RX&D.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 3

Neurophysiology of basal ganglia diseases ALFREDO BERARDELLI* Department of Neurosciences and Neuromed Institute, Universita` La Sapienza, Rome, Italy

The anatomical structures of the basal ganglia are connected to each other by a network of interconnections and the functional organization is based on the connections with thalamus and cortical territories (Albin et al., 1989; Alexander and Crutcher, 1990; Mink, 1996; Parent and Hazrati, 1995). Movement disorders (parkinsonisms, dystonias and choreas) can be considered the result of alterations in the cortico-striato-thalamo-cortical circuit (DeLong, 1990). Functional connections of the basal ganglia with other structures of the nervous system (brainstem and spinal cord) are also relevant in the pathophysiology of movement disorders. A significant part of our speculations on the physiological role of the basal ganglia in human beings derives from studies correlating neurophysiological deficits with specific lesions of the basal ganglia structures (Berardelli & Curra`, 2002). In this chapter we will review the neurophysiological findings described in patients with Parkinson’s disease (PD), dystonia and Huntington’s disease (HD).

3.1. Parkinson’s disease In recent years, considerable advances have taken place in the understanding of the pathophysiology of PD. In experiments conducted on animals rendered parkinsonian through the administration of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), and more recently in parkinsonian patients undergoing surgery for deep brain stimulation, the activity from specific neuron populations can be recorded through electrodes implanted directly into the basal ganglia nuclei. After nigral degeneration there is an altered neuronal output from the subthalamic nucleus and globus pallidus (Hutchison et al., 1997). This abnormal neuronal activity brings about a functional change in the motor circuits that link the basal ganglia to the motor cortical area. Striatal dopa-

mine depletion in PD reduces the activity of thalamic nuclei projecting to the frontal lobe, leading to cortical deafferentation. Such alterations are held responsible for the motor disturbances typical of PD (Berardelli et al., 2001). Movement slowness (bradykinesia), together with muscular rigidity and tremors, are among the principal symptoms of PD. Pathophysiological studies have demonstrated that bradykinesia is in part caused by defective preparation of voluntary movement. The usual way of investigating movement preparation of a voluntary movement is to study the reaction time (RT). The RT refers to the interval elapsing between the stimulus to move and movement initiation. The RT includes stimulus processing, the use of working memory for the retrieval of stimulus mappings and the generation of predictions and decision-making. Several studies have provided evidence that parkinsonian patients have an increased RT (Evarts et al., 1981; Jahanshahi et al., 1992), particularly for the more difficult tasks. Preparation of movements can also be studied by recording the slow-rising negative electroencephalogram (EEG) potentials generated before the onset of a voluntary movement (premotor potentials). The premotor potential begins about 2 s before the onset of a voluntary movement and is thought to be generated in the primary and non-primary cortical motor areas. In patients with PD, the premotor potentials have reduced amplitude, probably owing to reduced activation of cortical motor areas, particularly of supplementary motor areas (Dick et al., 1989; Jahanshahi et al., 1995). Besides causing defective movement preparation, PD also leads to alterations in movement execution. Studies on electromyogram (EMG) and kinematic activity show that parkinsonian patients have difficulty

*Correspondence to: Professor Alfredo Berardelli, Department of Neurological Sciences and Neuromed Institute, Universita` La Sapienza, Viale dell’ Universita`, 30, 00185 Roma, Italy. E-mail: [email protected], Tel: þ39-06-4991-4700, Fax: 39-06-4991-4700.

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in performing simple rapid movements. The triphasic EMG pattern, present in normal subjects, is substituted by multiple EMG activation. Patients have difficulty in achieving the degree of muscular activity required to perform the movement (‘scaling’ defect) (Berardelli et al., 1986b, 2001). Besides arm movements, patients with PD also have difficulty in performing finger movements. A study of sequential finger oppositions in PD showed that bradykinesia impairs individual more than non-individual finger movements (Agostino et al., 2003). This finding implies that finer cortical control is needed to sustain the fractionated motor output responsible for individual finger movements. Studies of voluntary movement have also demonstrated the difficulty parkinsonian patients have in carrying out simultaneous and sequential movements (Benecke et al., 1986, 1987; Berardelli et al., 1986a; Agostino et al., 1992, 1994; Desmurget et al., 2004). Patients also take longer to complete each sequential submovement when they perform it during a complex movement task than when they perform it separately. The time elapsing after one movement ends and the next begins is also longer, demonstrating compromised assemblage of the two motor programs in a sequence. This anomaly worsens as the sequence progresses (‘sequential effect’) (Agostino et al., 1992). Sensorimotor integration refers to the processes that link sensory input to motor output to produce appropriate voluntary movements (Abbruzzese and Berardelli, 2003). Sensory information and particularly visual feedback are important for motor preparation and execution in parkinsonian patients. Several studies have investigated the importance of visual cues and other sensory information in motor tasks (Georgiou et al., 1993, 1994; Klockgether et al., 1995; Fellows et al., 1998). In all these studies parkinsonian patients invariably have greater difficulty in performing movements when no external cues are provided. Cortical activity relating to the preparation of movement is significantly improved when a cognitive strategy is used (Cunnington et al., 1999). In a study comparing sequential arm movements performed with an internally programmed and externally programmed condition, the investigators concluded that the slowness of movement reflects patients’ inability to maximize their movement speed when they are required to drive their motor output internally (Curra` et al., 1997). Current evidence shows that bradykinesia arises more from abnormalities of movement execution than from faulty motor preparation and when parkinsonian patients have to perform internally guided movements (Berardelli et al., 2001). The technique of transcranial magnetic stimulation (TMS) has provided important information on the

activity of cortical motor areas in patients with PD (Dick et al., 1984; Curra` et al., 2002). A single TMS stimulus applied to the motor cortex evokes a muscle evoked potential (MEP) in the contralateral side, due to the activation of corticospinal axons. When TMS is delivered during voluntary contraction, the MEP is followed by an EMG silence, the silent period. The duration of the silent period reflects the function of inhibitory mechanisms in cortical motor areas and is largely determined by the activation of cortical inhibitory gamma-aminobutyric acid (GABA-B) interneurons. The cortical silent period is shorter in parkinsonian patients than in normal subjects (Priori et al., 1994a; Berardelli et al., 1996). By applying magnetic stimuli delivered at various interstimulus intervals (ISIs), the integrity of interneuronal inhibitory circuits can be tested at the motor cortex level (Kujirai et al., 1993). In normal subjects, a subthreshold conditioning stimulus delivered at ISIs of less than 6 ms inhibits the potential evoked by a suprathreshold test stimulus, whereas stimuli delivered at longer ISIs (8–30 ms) elicit a facilitatory effect (Kujirai et al., 1993). Inhibition of the test response is seen when longer ISIs (100–200 ms) are used (Berardelli et al., 1996). Neuropharmacological studies suggest that intracortical inhibition and facilitation at short ISIs both originate from interneuronal GABAergic (GABA-A) and glutamatergic activity. Paired stimuli delivered at short ISIs have disclosed that the excitability of inhibitory circuits in the primary motor cortex is deficient in PD (Ridding et al., 1995a). A study on the effects of repetitive TMS (rTMS) of premotor cortex of PD patients has shown that trains of stimulation delivered at 1 Hz normalized the excitability of the motor cortex (Buhmann et al., 2004). The abnormal excitability reflects an increased facilitatory input from the premotor to motor cortex. Studies using repetitive TMS of cortical motor areas in patients with PD underline reduced excitability of the motor cortical area (Gilio et al., 2002). The abnormalities described with TMS techniques can be reversed by levodopa or dopamine agonists, proving that a defect in dopaminergic modulation includes changes in the neural pathways that modulate the corticospinal output. The pathophysiology of muscular rigidity in parkinsonian patients is largely unclear. The increase in muscular tone seems to be related primarily to the difficulty patients have in trying to remain in a state of complete muscular rest, but also to the increase in stretch reflexes. Numerous studies in parkinsonian patients and normal subjects show that the monosynaptic spinal component of the stretch reflexes is normal, whereas that of the long-latency reflexes is increased. Parkinsonian rigidity could therefore arise from an increase in

NEUROPHYSIOLOGY OF BASAL GANGLIA DISEASES the long-latency stretch reflexes (Tatton and Lee, 1975; Berardelli et al., 1983; Rothwell et al., 1983). Because these responses travel through transcortical circuits (thalamus, sensorimotor cortex), the basal ganglia dysfunction in PD causes their hyperactivity. An alternative hypothesis, at least for the long-latency stretch reflexes in the lower limbs, is an increased activity of the group II fibers (Berardelli et al., 1983; Simonetta-Moreau et al., 2002). Other possible pathophysiological mechanisms responsible for muscular rigidity in PD include an increase in the shortening reaction to passive movements generated by joint and tendon organ afferents (Berardelli and Hallett, 1984), an increase in reciprocal inhibition between agonist and antagonist muscles, and reduced Ib tendon inhibition (Delwaide et al., 1991; Meunier et al., 2000). Recent studies suggest that the neurons of the pedunculopontine nucleus may contribute to the pathophysiology of motor symptoms in PD, including rigidity. In patients with PD, tremor typically manifests at rest with a frequency of 4–5 Hz. The EMG recordings show alternate activation of the agonist and antagonist muscles. Some patients also manifest an action tremor oscillating at a variable frequency ranging from 6 to 12 Hz. Experimental observations in monkeys with parkinsonism induced by MPTP show that the pallidal cells of the globus pallidus internal segment (GPi) and the subthalamic nucleus discharge periodically at a frequency similar to that of the tremors. Other structures that play an important role in producing tremors are the thalamus and cerebral motor cortex: lesions to these structures suppress tremor. The thalamic site of lesion yielding the maximum reduction in limb oscillations lies in the intermediate ventral nucleus, Dopaminergic depletion increases the synchronization of cortical motor circuits, thereby causing oscillatory activity to appear in the GPi, subthalamic nucleus, thalamus and motor cortical area. The subthalamic nucleus plays an especially important role in synchronizing neuronal activity. Studies using positron emission tomography have demonstrated the role of the cerebellum in parkinsonian tremors (Deiber et al., 1993). EMG analysis of tremor activity in the neck, arm and leg muscles has identified multiple oscillators for tremor in the various body parts (Raethjen et al., 2000).

3.2. Dystonia Dystonia is a syndrome of excessive and sustained muscle contractions causing abnormal postures or twisting and repetitive movements. Primary dystonia is classified as focal, segmental or generalized. Focal dystonia (cranial, cervical and hand dystonia are the

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most common forms) affects only a single part of the body and is the most common form in adults. Segmental dystonia affects two contiguous body parts. Generalized dystonia is more widespread and is more common in young persons. In analogy with the forms of secondary dystonias due to focal lesions of the basal ganglia (putamen, but also the caudate and globus pallidus) and thalamus (Bathia and Marsden, 1994; Chuang et al., 2002), primary dystonia is generally attributed to basal ganglia dysfunction, hence to a functional disturbance of the cortico-striato-thalamic-cortical circuits. In accordance with the currently accepted model of basal ganglia organization (Wichmann and DeLong, 1996), in dystonia, the abnormalities of the basal ganglia nuclei reduce the inhibition normally exerted by the GPi on the thalamic nuclei, and consequently, cause an excessive activation of the premotor cortical area. Initial intraoperative recordings, during pallidal procedures, provided evidence of overall lower rates of discharge in patients with generalized dystonia than in patients with PD (Lenz et al., 1998; Vitek et al., 1999). Subsequent observations showed similar mean firing rates in patients with segmental and generalized dystonia and parkinsonian patients. No correlation was found between the dystonic symptoms and GPi firing rates (Hutchison et al., 2003; Merello et al., 2004). The main changes in the discharge pattern therefore probably refer to its characteristics (frequency and duration of bursts and temporal–spatial synchronization). In patients with cranial dystonia, studies of brainstem reflexes have demonstrated abnormalities in the excitability of the orbicularis oculi reflex in the brainstem (Berardelli et al., 1985). There is an increased excitability of the R2 component of the blink reflex and an abnormal gating of the R2 component by sensory stimulation (Gomez-Wong et al., 1998). Abnormalities in the blink reflex are also present in patients without cranial dystonia but with dystonia in other body parts (Pauletti et al., 1993). Similarly to patients with cranial dystonia, patients with cervical dystonia also have abnormalities in brainstem circuits. These abnormalities, like cranial dystonia, are characterized by an enhancement of the recovery cycle of the R2 component of the blink reflex and suggest increased excitability of the brainstem interneurons (Pauletti et al., 1993). Abnormalities of the auditory startle response (reduced probability and reduced magnitude as well as prolonged EMG activity after the startle response) have been reported in patients with cervical dystonia (Muller et al., 2003). The auditory startle response is mediated by pathways comprising the cochlear nucleus and the nucleus reticularis pontis caudalis, which projects to

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cranial and spinal motor neurons. The nucleus reticularis pontis caudalis receives projections directly from the pedunculopontine nucleus and indirectly from the basal ganglia. Studies using TMS show that the cortical silent period recorded in the facial muscles has a shorter duration in patients with cranial dystonia than in normal subjects; the silent period shortening is more evident when dystonia affects both upper and lower facial muscles (Curra` et al., 2000c). Changes in the duration of the cortical silent period suggest changes in the excitability of cortical inhibitory interneurons of facial cortical motor areas in patients with cranial dystonia. In patients with hand dystonia, ample evidence indicates abnormalities at spinal cord level. The reciprocal inhibition between agonist–antagonist muscles (Nakashima et al., 1989, Priori et al., 1995) and the inhibition evoked by tendon stimulation (Priori et al., 1998), a procedure that provides information on group III-elicited presynaptic inhibition of group I afferents, are both abnormal (Lorenzano et al., 2000). These spinal circuit abnormalities reflect altered processing of Ia input to the spinal cord or abnormal supraspinal control of the interneurons that mediate presynaptic inhibition. Overall these studies suggest that patients with hand dystonia have increased excitability or a lack of inhibition of spinal cord mechanisms. Patients with focal and segmental dystonia have abnormalities in sensorimotor integration (Abbruzzese and Berardelli, 2003). Changes in spindle activity have been described in patients with arm dystonia (Kaji et al., 1995; Grunewald et al., 1997). For example, patients with focal hand dystonia have impairment of graphesthesia (Byl et al., 1996a, b), spatiotemporal discrimination (Bara-Jimenez et al., 2000; Sanger et al., 2001) and temporal processing of visuotactile and tactile stimuli (Tinazzi et al., 2000; Aglioti et al., 2003; Fiorio et al., 2003). In focal dystonia, spatial discrimination thresholds were significantly increased in both hands, showing that these abnormalities also involve unaffected body parts. Several studies have tested cortical function in patients with hand dystonia. The reported abnormalities in the long-latency reflexes evoked by median nerve stimulation suggest altered thalamocortical outflow to the supplementary motor area (Naumann and Reiners, 1997). A shortening of the cortical silent period is present in hand muscles in patients with dystonia involving the arm (Rona et al., 1998). With TMS studies the reduced inhibition of the test response in patients with hand or arm dystonia suggests decreased intracortical inhibition of the cortical hand motor area (Ridding et al., 1995b; Gilio et al., 2000). This

abnormality is also present in patients with blepharospasm but without hand dystonia (Sommer et al., 2002). A study on the effects of subthreshold low-frequency rTMS suggested that not only the primary motor cortex but also the connectivity of the frontal non-primary motor cortex to the primary motor cortex play a role in the pathophysiology of dystonia (Murase et al., 2005). Mapping studies with TMS have also demonstrated an enlarged and altered corticomotor representation in cortical motor areas (Byrnes et al., 1998).The mechanism of surrounding inhibition (excitability in an area surrounding an activated neural network) appears to be abnormal in patients with limb dystonia. During index finger flexion, MEP amplitudes of abductor digiti minimi muscles are suppressed in normal subjects but enhanced in size in patients with hand dystonia (Sohn and Hallett, 2004). In a study of taskdependent modulation of inhibition, Butefish et al. (2005) found that in patients with task-specific dystonia performing a highly selective task, intracortical inhibition in areas representing muscles in the inhibitory surround are disturbed. An abnormal surround inhibition could enhance the excitability of surrounding muscles, thereby producing co-contraction and dystonia. Further information on the excitability and changes of plasticity of motor cortex in dystonia also comes from experiments testing the effects of peripheral stimulation coupled with TMS. The inhibitory effect of peripheral stimulation on MEPs evoked by TMS in normal subjects is lost in patients with hand dystonia (Abbruzzese et al., 2001). Stefan et al. (2000) have proposed a technique termed paired associative stimulation, entailing median-nerve stimulation paired with TMS of the hand motor cortex, designed to test associative plasticity. After paired stimulation, the MEP in median nerve-innervated hand muscles increases in size. This increase is believed to reflect long-term potentiation of excitatory synapses (Stefan et al., 2000). In patients with writer’s cramp, the paired associative stimulation-induced facilitation was greater and less focal (increases in MEPs in muscles innervated by median and ulnar nerves) (Quartarone et al., 2003). An altered sensorimotor integration may favor maladaptive plasticity during repetitive hand movements. The altered integration of sensory signals could, therefore, contribute to temporospatial distortion of motor commands, or even to a plastic reorganization of the cortical connections (Quartarone et al., 2003). Similar abnormalities are also present if the subject imagines the movement without actually performing it (Quartarone et al., 2005). The conclusion from the above studies is that in hand dystonia there is an increase of motor cortical excitability and abnormal cortical plasticity.

NEUROPHYSIOLOGY OF BASAL GANGLIA DISEASES Dystonia often worsens or is even triggered by voluntary action. Studies investigating how voluntary movements are prepared and performed in dystonia have been performed in patients with focal or segmental forms. Alterations in cortical excitability are present in the phase preceding a voluntary movement (Gilio et al., 2003). Before movement intracortical inhibition decreases less in patients than in healthy controls. The amplitude of the premotor EEG potential that precedes the execution of voluntary movements and the amplitude of the contingent negative variation is depressed in patients with hand dystonia (Deuschl et al., 1995; van der Kamp et al., 1995). In patients with segmental (and generalized) dystonia, abnormalities in the execution of voluntary arm movements are characterized by reduced movement speed, by prolonged co-contraction and by unusually evident EMG activity in remote muscles not involved in the motor task (van der Kamp et al., 1989; Curra` et al., 2000b). Finger movements are also performed with reduced speed in patients with dystonia involving hand muscles (Curra` et al., 2004). Owing to the high motor cortex activation for individual oppositions the slowness of finger movement is probably due to the underactivation of the primary motor cortex during movement. In conclusion, patients with different forms of focal dystonia share abnormalities in sensory processing, in sensorimotor organization and in motor cortex excitability. In patients with focal dystonia, disturbed central processing of sensory input may distort cortical representation, thus leading to abnormal and maladaptive plasticity of cortical motor areas. Investigating the effects of focal muscle vibration on corticospinal excitability, Rosenkranz et al. (2005) found that writer’s cramp and musician dystonia both show a loss of spatial organization of sensorimotor interactions, but sensory information plays a smaller role in provoking pathological changes in writer’s cramp than in musician dystonia. Unlike patients with focal dystonia, patients with generalized dystonia have normal sensory discrimination. This finding suggests that sensory input does not play a primary role in generalized dystonia and that there are differences in the pathophysiological mechanisms of generalized and focal dystonias (Molloy et al., 2003). In focal and segmental dystonia neurophysiological abnormalities are also present in the unaffected side of focal dystonia (Berardelli et al., 1998), and in generalized dystonia abnormalities are also present in clinically unaffected carriers of the DYT1 gene mutation (Edwards et al., 2003).The presence of neurophysiological changes in unaffected segments supports the hypothesis that dystonia causes widespread dysfunction of neurophysiological abnormalities.

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3.3. Huntington’s disease The principal neuropathological alteration of HD consists of neuronal degeneration in the caudate, putamen and globus pallidus. In the initial stages of the disease, imaging studies show a selective loss of striatal GABA/encephalinergic neurons that project on to the GPe (‘indirect pathway’), which correlates with the clinical presence of choreic movements. This loss reduces the excitatory projections from the subthalamic nucleus to the globus pallidus, thus reducing the inhibitory influence of the globus pallidus and substantia nigra on the thalamus. The reduced inhibitory pallidothalamic influence increases the facilitatory thalamocortical output and finally increases cortical activity. As the disease progresses, the striatal neurons projecting on to the GPi (‘direct pathway’) diminish in number and, clinically, rigidity and bradykinesia may also appear (Albin et al., 1992, Hedreen and Folstein, 1995). Some evidence suggests parallel reductions of both pathways (Ginovart et al., 1997). Polymyography of choreic movements shows bursts of EMG activity of variable duration and a random pattern of muscle activation (Thompson et al., 1988; Berardelli et al., 1999). Patients with HD may also have dystonic movements and myoclonic jerks. In HD, numerous neurophysiological studies described dysfunction of the spinal cord, brainstem and cortical areas (Berardelli et al., 1999). There is a reduction in presynaptic inhibition tested in forearm muscles, one of the spinal mechanisms responsible for regulating reciprocal inhibition between agonist and antagonist muscles (Priori et al., 2000). Other neurophysiological studies reported alterations in the polysynaptic circuits of the brainstem and, in particular, abnormalities in the ‘blink reflex’ circuit, principally an increase in latency and a greater habituation of the R2 response in patients than in healthy subjects (Agostino et al., 1988). The physiological interpretation of these abnormal findings is an altered suprasegmental regulation exerted by the basal ganglia rather than a primary disorder of the spinal cord and brainstem (Berardelli et al., 1999). Numerous experiments provide evidence of abnormalities at cortical level. Somatosensory cortical evoked potentials are altered without changes at the subcortical level (Noth et al., 1984; Abbruzzese et al., 1990). The hypothesis is that the hyperactivity in the thalamic reticular nucleus reduces the relay of somatosensory inputs from the ventral posterior thalamic nuclear complex to the cortex. Reflex recordings show a reduction or an absence of the long-latency stretch reflexes in hand and arm muscles (Noth et al., 1985; Thompson et al., 1988), implying that the transcortical

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loop underlying the long-latency reflexes is interrupted. The abnormalities in somatosensory cortical potentials and long-latency reflexes suggest that also in HD sensorimotor integration is abnormal (Abbruzzese and Berardelli, 2003). Evidence indicating altered movement preparation in HD comes from changes in movement-related MEPs (Johnson et al., 2001, 2002) and from the increased RTs for simple and complex voluntary movements (Curra` et al., 2000a). A distinctive feature of HD is the presence of bradykinesia in both simple and complex voluntary movements (Hefter et al., 1987; Thompson et al., 1988). The EMG recording of wrist flexion movements shows an abnormal pattern, with prolonged bursts from the agonist and antagonist muscles, co-contraction and increased variability. Furthermore, an excessive dependence on external stimuli is apparent during the execution of voluntary sequential movements (Georgiou et al., 1995). Moreover, acoustic stimuli did not improve the execution of simultaneous bimanual movement, or gait and the absence of visual control causes the – already slow – motor performance to worsen further (Johnson et al., 2001). In addition, differently from normal subjects, cortical activity patients with HD did not produce a rising premovement potential in the absence of a cognitive strategy (Johnson et al., 2002). In a study investigating the kinematic variables of sequential movements performed when patients had to initiate movements in response to an external go signal or when they had to start the movement at will, it was concluded that in HD internal cueing mechanisms are more impaired than external cueing mechanisms (Curra` et al., 2000a). In HD, cortical function has also been studied with the technique of TMS. Studies investigating the cortical silent period show that the duration of the cortical silent period is sometimes longer in patients than in healthy subjects (Priori et al., 1994b; Modugno et al., 2001). The loss of striatal neurons could result in an excessive thalamocortical facilitation, thereby increasing the activity of cortical inhibitory interneurons. Alternatively, the prolonged silent periods could indicate an excessive delay in the process of restarting a motor task that has been interrupted by TMS. Slow restarting after TMS agrees with the finding of a delayed RT during movements and with the observation that patients with HD have a reduced activation of motor and sensory cortical areas (Bartenstein et al., 1997; Weeks et al., 1997). Studies using paired magnetic shocks report controversial findings (Hanajima et al., 1996; Abbruzzese et al., 1997; Priori et al., 2000) and did not demonstrate clear changes in the excitability of cortical motor areas in patients with HD.

Neurophysiological studies provide evidence that, in patients with HD, choreic movements and bradykinesia coexist. The concomitant presence of hypokinetic and hyperkinetic motor disturbances in HD suggests that abnormal cortical inhibitory and excitatory mechanisms coexist. TMS findings in general provide no support for the increased motor cortical excitability hypothesized in the functional model of hyperkinesia (Wichmann and DeLong, 1996). Some of the abnormal neurophysiological findings reported in HD may also reflect neuropathological lesions at cortical level.

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Fellows SJ, Noth J, Schartz M (1998). Precision grip and Parkinson’s disease. Brain 12: 1771–1784. Fiorio M, Tinazzi M, Berolasi L et al. (2003). Temporal processing of visuotactile and tactile stimuli in writer’s cramp. Ann Neurol 53: 630–635. Georgiou N, Iansek R, Bradshaw JL et al. (1993). An evaluation of the role of internal cues in the pathogenesis of parkinsonian hypokinesia. Brain 116: 1575–1587. Georgiou N, Bradshaw JL, Iansek R et al. (1994). Reduction in external cues and movement sequencing in Parkinson’s disease. J Neurol Neurosurg Psychiatry 57: 368–370. Georgiou N, Bradshaw JL, Philips JG et al. (1995). Reliance on advance information and movement sequencing in Huntington’s disease. Mov Disord 10: 477–481. Gilio F, Curra` A, Lorenzano C et al. (2000). Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia. Ann Neurol 48: 20–26. Gilio F, Curra` A, Inghilleri M et al. (2002). Repetitive magnetic stimulation of cortical motor areas in Parkinson’s disease: implications for the pathophysiology of cortical function. Mov Disord 17: 467–473. Gilio F, Curra` A, Inghilleri M et al. (2003). Abnormalities of motor cortex excitability preceding movement in patients with dystonia. Brain 126 (8): 1745–1754. Ginovart N, Lundin A, Farde L et al. (1997). PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington’s disease. Brain 120: 503–514. Gomez-Wong E, Marti MJ, Tolosa E et al. (1998). Sensory modulation of the blink reflex in patients with blepharospasm. Arch Neurol 55: 1233–1237. Grunewald RA, Yoneda Y, Shipman JM et al. (1997). Idiopathic focal dystonia: a disorder of muscle spindle afferent processing? Brain 120: 2179–2185. Hanajima R, Ugawa Y, Terao Y et al. (1996). Ipsilateral cortico-cortical inhibition of the motor cortex in various neurological disorders. J Neurol Sci 140: 109–116. Hedreen JC, Folstein SE (1995). Early loss of neostriatal striosome neurons in Huntington’s disease. J Neuropathol Exp Neurol 54: 105–120. Hefter H, Homberg V, Lange HW et al. (1987). Impairment of rapid movement in Huntington’s disease. Brain 110: 585–612. Hutchison WD, Levy R, Dostrovsky JO et al. (1997). Effects of apomorphine on globus pallidus neurons in parkinsonian patients. Ann Neurol 42: 767–775. Hutchison WD, Lang AE, Dostrovsky JO et al. (2003). Pallidal neuronal activity: implications for models of dystonia. Ann Neurol 53 (4): 480–488. Jahanshahi M, Brown RG, Marsden CD (1992). Simple and choice reaction time and the use of advance information for motor preparation in Parkinson’s disease. Brain 115: 539–564. Jahanshahi M, Jenkins IH, Brown RG et al. (1995). Selfinitiated versus externally triggered movements. I. An investigation using measurement of regional cerebral blood flow with PET and movement-related potentials in normal and Parkinson’s disease subjects. Brain 118: 913–933.

Johnson KA, Cunnington R, Iansek R et al. (2001). Movementrelated potentials in Huntington’s disease: movement preparation and execution. Exp Brain Res 138: 492–499. Johnson KA, Cunnington R, Bradshaw JL et al. (2002). Effect of an attentional strategy on movement related potentials recorded from subjects with Huntington’s disease. Mov Disord 17: 998–1003. Kaji R, Rothwell JC, Katayama M et al. (1995). Tonic vibration reflex and muscle afferent block in writer’s cramp. Ann Neurol 38: 155–162. Klockgether T, Borutta M, Spieker S et al. (1995). A defect of kinestesia in parkinson’s disease. Mov Disord 10: 460–465. Kujirai T, Caramia MD, Rothwell JC et al. (1993). Corticocortical inhibition in human motor cortex. J Physiol 471: 501–519. Lenz FA, Suarez JI, Verhagen Metman L et al. (1998). Pallidal activity during dystonia: somatosensory reorganisation and changes with severity. J Neurol Neurosurg Psychiatry 65: 767–770. Lorenzano C, Priori A, Curra` A et al. (2000). Impaired EMG inhibition elicited by tendon stimulation in dystonia. Neurology 26: 1789–1793. Merello M, Cerquetti D, Cammarota A et al. (2004). Neuronal globus pallidus activity in patients with generalized dystonia. Mov Disord 19: 548–553. Meunier S, Pol S, Houeto JL et al. (2000). Abnormal reciprocal inhibition between antagonist muscles in Parkinson’s disease. Brain 123 (5), 1017–1026. Mink JW (1996). The basal ganglia: focused selection and inhibition of competing motor programs. Prog Neurobiol 50: 381–425. Modugno N, Curra` A, Giovannelli M et al. (2001). The prolonged cortical silent period in patients with Huntington’s disease. Clin Neurophysiol 112: 1470–1474. Molloy FM, Carr TD, Zeuner KE et al. (2003). Abnormalities of spatial discrimination in focal and generalized dystonia. Brain 126: 2175–2182. Muller J, Koffer M, Wenning G et al. (2003). Auditory startle response in cervical dystonia. Mov Disord 18: 1522–1527. Murase N, Rothwell JC, Kaji R et al. (2005). Subthreshold low-frequency repetitive transcranial magnetic stimulation over the premotor cortex modulates writer’s cramp. Brain 128: 104–115. Nakashima K, Rothwell JC, Day BL et al. (1989). Reciprocal inhibition between forearm muscles in patients with writer’s cramp and other occupational cramps, symptomatic hemidystonia and hemiparesis due to stroke. Brain 112: 681–697. Naumann M, Reiners K (1997). Long-latency reflexes of hand muscles in idiopathic focal dystonia and their modification by botulinum toxin. Brain 120: 409–416. Noth J, Engel L, Friedemann HH et al. (1984). Evoked potentials in patients with Huntington’s disease and their off-spring. Electroencephalogr Clin Neurophysiol 32: 134–141. Noth J, Podoll K, Friedemann HH (1985). Long loop reflexes in small hand muscles studied in normal subjects and in patients with Huntington’s disease. Brain 108: 65–80.

NEUROPHYSIOLOGY OF BASAL GANGLIA DISEASES Parent A, Hazrati LN (1995). Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Rev 20: 91–127. Pauletti G, Berardelli A, Cruccu G et al. (1993). Blink reflex and the masseter inhibitory reflex in patients with dystonia. Mov Disord 8: 495–500. Priori A, Berardelli A, Inghilleri I et al. (1994a). Motor cortical inhibition and the dopaminergic system. Brain 117: 317–323. Priori A, Berardelli A, Inghilleri M et al. (1994b). Electromyographic silent period after transcranial brain stimulation in Huntington’s disease. Mov Disord 9: 178–182. Priori A, Berardelli A, Mercuri B et al. (1995). Physiological effects produced by BoNT treatment of upper limb dystonia. Changes in reciprocal inhibition between forearm muscles. Brain 118: 801–807. Priori A, Berardelli A, Inghilleri M et al. (1998). Electrical stimulation over muscle tendons in humans. Evidence favouring presynaptic inhibition of Ia fibres due to the activation of group III tendon afferents. Brain 121: 373–380. Priori A, Polidori L, Rona S et al. (2000). Spinal and cortical inhibition in Huntington’s disease. Mov Disord 15: 938–946. Quartarone A, Bagnato S, Rizzo V et al. (2003). Abnormal associative plasticity of the human motor cortex in writer’s cramp. Brain 126: 2586–2596. Quartarone A, Bagnato S, Rizzo V et al. (2005). Corticospinal excitability during motor imagery of a simple tonic finger movement in patients with writer’s cramp. Mov Disord. 20: 1488–1495. Raethjen J, Lindemann M, Schmaljohann H et al. (2000). Multiple oscillators are causing parkinsonian and essential tremor. Mov Disord 15: 84–94. Ridding MC, Inzelberg R, Rothwell JC (1995a). Changes in excitability of motor circuitry in patients with Parkinson’s disease. Ann Neurol 37: 181–188. Ridding MC, Sheean G, Rothwell JC et al. (1995b). Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia. J Neurol Neurosurg Psychiatry 53: 493–498. Rona S, Berardelli A, Vacca L et al. (1998). Alterations of motor cortical inhibition in patients with dystonia. Mov Disord 13: 118–124. Rosenkranz K, Williamon A, Butler K et al. (2005). Pathophysiological differences between musician’s dystonia and writer’s cramp. Brain 128: 918–931.

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Rothwell JC, Obeso JA, Traub MM et al. (1983). The behaviour of the long-latency stretch reflex in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 46: 35–44. Sanger T, Tarsy D, Pascual-Leone A (2001). Abnormalities of spatial and temporal sensory discrimination in writer’s cramp. Mov Disord 16: 94–99. Simonetta-Moreau M, Meunier S, Vidailhet M et al. (2002). Transmission of group II heteronymous pathways is enhanced in rigid lower limb of de novo patients with Parkinson’s disease. Brain 125: 2125–2133. Sohn YH, Hallett M (2004). Disturbed surround inhibition in focal hand dystonia. Ann Neurol 56: 595–599. Sommer M, Ruge D, Tergau F et al. (2002). Intracortical excitability in the hand motor representation in hand dystonia and blepharospam. Mov Disord 17: 1017–1025. Stefan K, Kunesch E, Cohen LG et al. (2000). Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 123: 572–584. Tatton WG, Lee RG (1975). Evidence for abnormal longloop reflexes in rigid parkinsonian patients. Brain Res 100: 671–676. Thompson PD, Berardelli A, Rothwell JC et al. (1988). The coexistence of bradykinesia and chorea in Huntington’s disease and its implications for theories of basal ganglia control of movement. Brain 111: 223–244. Tinazzi M, Priori A, Bertolasi L et al. (2000). Abnormal central integration of a dual somatosensory input in dystonia. Evidence for sensory over flow. Brain 123: 42–50. van der Kamp W, Berardelli A, Rothwell JC et al. (1989). Rapid elbow movements in patients with torsion dystonia. J Neurol Neurosurg Psychiatry 52: 1043–1049. van der Kamp W, Rothwell JC, Thompson PD et al. (1995). The movement related cortical potential is abnormal in patients with idiopathic torsion dystonia. Mov Disord 5: 630–633. Vitek JL, Chockkan V, Zhang J et al. (1999). Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballism. Ann Neurol 46: 22–35. Weeks RA, Ceballos-Baumann A, Piccini P et al. (1997). Cortical control of movement in Huntington’s disease: a PET activation study. Brain 120: 1569–1578. Wichmann T, De Long RR (1996). Functional and pathophysiological models of basal ganglia. Curr Opin Neurobiol 6: 751–758.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 4

Dopamine receptor pharmacology RICHARD B. MAILMAN1,2* AND XUEMEI HUANG2 1

Departments of Psychiatry, 1Pharmacology, 2Neurology and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, USA

4.1. Dopamine receptor biology 4.1.1. Background Despite a half-century of research since the first drugs that bind to dopamine receptors (e.g. chlorpromazine) were used in clinical medicine, the underlying mechanisms are still poorly understood. The biochemical assays developed by Arvid Carlsson and others (Carlsson, 1959), as well as histological techniques (Hillarp et al., 1966), paved the way for understanding dopamine function in the brain. These studies showed there were three major dopamine pathways, including the nigrostriatal (from cells in the A9 region), the mesolimbic-cortical (from cells in the A10 or ventral tegmentum) and the tuberoinfundibular (hypothalamic) system (Ungerstedt, 1971a). This early awareness of the chemoarchitecture of dopamine systems opened the doors to an understanding of the functional role of dopamine in complex phenomena mediated by the brain areas modulated by dopamine. Indeed, soon after the discovery of chlorpromazine, it was demonstrated that decreases in acute agitation, hallucinations and other psychotic signs and symptoms were frequently accompanied by disturbing and unwanted neurological side-effects (drug-induced parkinsonism, akathesia and acute dystonic reactions), now known as extrapyramidal side-effects. This similarity of acute drug-induced neurological side-effects and Parkinson’s disease (Ehringer and Hornykiewicz, 1960; Hornykiewicz, 1971) suggested a mechanistic relationship (Carlsson and Lindqvist, 1963) that marked the beginning of the field of dopamine receptor pharmacology.

Although dopamine receptors had been hypothesized for nearly a decade, the first direct biochemical mechanism linked to them came from the laboratory of Paul Greengard, who demonstrated that dopamine could dose-dependently stimulate the synthesis of the second-messenger cyclic adenosine monophosphate (cAMP: Kebabian et al., 1972) in a fashion that was antagonized by antipsychotic drugs (Clement-Cormier et al., 1974). The fact that both phenothiazine and thioxanthine antipsychotics competitively inhibited the dopamine-stimulated activity of adenylate cyclase in proportion to their clinical potency led to the notion that this was the major functional mechanism of dopamine in the central nervous system (Clement-Cormier et al., 1974; Iversen, 1975). However, with the introduction of new antipsychotics in still newer structural classes (e.g. butyrophenones and benzamides), marked discrepancies became apparent. For example, many of these new behaviorally potent antipsychotics had little potency in inhibiting dopamine-stimulated adenylate cyclase (Trabucchi et al., 1975). This discrepancy led to the idea that two types of dopamine receptors existed. One class was the original adenylate cyclase-linked receptor first reported by Greengard’s group (Kebabian et al., 1972), that bound with high-affinity thioxanthines and phenothiazine antipsychotics, but not drugs of the butyrophenone or benzamide classes (Garau et al., 1978). The other class of dopamine receptor was not linked to stimulation of adenylate cyclase, but bound all of these drugs in proportion to their clinical potency (Burt et al., 1976; Creese et al., 1976; Seeman et al., 1976). This differentiation, coupled with other information about the localization and function of dopamine receptors, led to the specific hypothesis

*Correspondence to: Dr Richard B. Mailman, CB # 7160, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160, USA. E-mail: [email protected], Tel: þ1-919-966-3205, Fax: þ1-966-1844.

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that there were two types of dopamine receptor (Garau et al., 1978). The field then settled on nomenclature proposed later by Kebabian and Calne (1979) in which the receptors linked (usually) to stimulation of cAMP synthesis are termed ‘D1’ and those that inhibit cAMP synthesis and selectively bind a class of drugs called benzamides (e.g. sulpiride) are called ‘D2’. As discussed in the next section, the era of molecular biology led to the discovery of the five mammalian genes that code for dopamine receptors and an explosion of information related to the molecular pharmacology, cell biology and neuropsychopharmacology of these receptors and their ligands. In terms of Parkinson’s disease, ligands that bind to and activate dopamine receptors directly (dopamine agonists) have been in use for decades, although levodopa still remains the gold standard of symptomatic treatment. As such, there is a view held by many that no further advances can result from the targeting of dopamine receptors and that the next generation of pharmacotherapeutic agents will come from drugs acting at other, non-dopamine, receptor systems. Moreover, many researchers believe that the sole focus should be on non-symptomatic approaches aimed at preventing or reversing the disease. It is our view, however, that there are many ‘dopaminergic opportunities’ to improve symptomatic treatment of Parkinson’s disease that are not exploited by current drugs. An understanding of the basic aspects of dopamine receptor pharmacology and biology are critical to achieving this end. This chapter is organized around the issues that form the foundation for this optimism. First, there have been dramatic increases in our knowledge about the cellular and subcellular localization of the dopamine receptors and the molecular mechanisms by which signaling occurs and is regulated. Second, this increase in knowledge about the physiology of the dopamine receptors has occurred concomitantly with continued advances in understanding of basal ganglia circuitry. Third, although a variety of agonists for the D2 family (see below) have been in the laboratory and clinic for decades, it is only within the last decade that the first useful D1 agonists, as well as drugs selective for different members of the D2 family, have become available in the clinic or for research. Finally, there have been advances in molecular pharmacology that have shown that drugs can differentially activate signaling pathways mediated by a single receptor (an idea termed ‘functional selectivity’ (Mailman and Gay, 2004b; Urban et al., 2007) or ‘agonist trafficking’(Kenakin, 1995)). This concept opens the door to changing the therapeutic versus side-effect profile mediated by a single receptor.

Together, these factors offer the following possibilities. First, it may be possible to discover a direct agonist (selective for a single isoform or targeting several simultaneously) that matches levodopa in efficacy in Parkinson’s disease, yet retains efficacy with disease progression because of not needing to be bioconverted like levodopa. Second, although it is controversial whether there is neuroprotection elicited by current dopamine agonists (Clarke, 2004), drugs that restore normal function may actually cause indirect neuroprotection (see Ch. 31 for an indepth review of this area) by preventing what might be termed ‘neuronal disuse atrophy’ (Lewis et al., 2006). Third, based on the view that a major factor in the occurrence of dyskinesias may be the pulsatile way one or more classes of dopamine receptors are activated during clinical treatment, new drugs that decrease this pulsatility at the critical populations of receptors can markedly decrease the induction of dyskinesias. Lastly, it may be possible to design drugs that differentially activate known receptors and markedly improve their side-effect profile (e.g. eliciting the motor benefits of a drug like ropinirole with decreased liability for psychosis or nausea). It is our prediction that at least two of these four possibilities will come to pass within the next decade and the aim of this chapter is not only to understand how existing drugs work, but also to provide a foundation for understanding why these advances will happen.

4.2. Molecular biology of dopamine receptors The dopamine receptors, members of the heptahelical G-protein-coupled receptor (GPCR) superfamily, have historically been divided into two subfamilies: the ‘D1-like’ and ‘D2-like’ (Garau et al., 1978; Kebabian and Calne, 1979). The molecular biology of the dopamine receptors has been the subject of numerous recent chapters and books (Jenner and Demirdemar, 1997; Sealfon and Olanow, 2000; Huang et al., 2001). Dopamine receptors are encoded by five genes. Both of the ‘D1-like’ receptor genes are intron-less and include the D1 (called the D1A in rodents) and the D5 (sometimes called the D1B: Dearry et al., 1990; Monsma et al., 1990; Zhou et al., 1990; Sunahara et al., 1991). The ‘D2-like’ receptors include two major splice variants of the D2 gene, D2L (long) and D2S (short), that together are the most highly expressed of the D2-like receptors (Dal Toso et al., 1989; Giros et al., 1989; Monsma et al., 1989; Chio et al., 1990). The other D2-like receptors are D3- and D4-receptors, of which multiple splice variants of the D3-receptor have been isolated, but expression of more than one variant has only been observed in mice (Giros et al., 1989; Sokoloff et al.,

DOPAMINE RECEPTOR PHARMACOLOGY 1990). The D4-receptor has variable 16-nucleotide repeats in the region coding for the third intracellular loop that can vary between individuals in periodicity from 4 to 16 repeats (van Tol et al., 1991; O’Malley et al., 1992). Some of these alleles have been suggested to have major effects on behavioral phenotype (Swanson et al., 1998; Mill et al., 2001; Schmidt et al., 2001), although this has been controversial (Kotler et al., 2000; Jonsson et al., 2001, 2002). In this chapter, D1 is used to refer to primate D1 (rodent D1A), whereas D5 refers to primate D5 and rodent D1B. 4.2.1. The localization of D2-like dopamine receptors Although seemingly out of order, we shall first discuss the D2-like receptors as they were the earliest and, until recently, most extensively investigated targets in psychiatric and neurological research. All of the current dopamine agonists used for Parkinson’s disease have their highest affinity for one or several isoforms of this subclass of receptors. The localization of dopamine receptors has been accomplished using techniques that include receptor binding, immunological methods and in situ hybridization, the former two techniques locating the protein itself and the latter the message for the protein. Quantitative receptor autoradiography studies of dopamine D2-like receptors began in the 1980s and used a variety of radioligands from several chemical classes, including [3H]spiperone, [3H]sulpiride, [125I]iodosulpiride and [125I]epidepride (Gehlert and Wamsley, 1984; Jastrow et al., 1984; Boyson et al., 1986; Bouthenet et al., 1987; Joyce and Marshall, 1987; Richfield et al., 1987; De Keyser et al., 1988). A survey of D2-like receptors in brain detected with [125I]-iodosulpiride revealed the highest receptor density in the major dopamine terminal fields of forebrain, including caudate putamen, nucleus accumbens and olfactory tubercule (Bouthenet et al., 1987). Dopamine D2-like receptors were also found in the substantia nigra (dense labeling in pars compacta and ventral tegmental area and lighter labeling in the pars reticulate) and represent autoreceptors as they are dramatically reduced following lesion with the selective cytotoxicant 6-hydroxydopamine (6-OHDA). Mesocorticolimbic areas with known dopamine innervation were labeled moderately, including anterior olfactory nuclei and lateral septal nucleus. Other brain areas expressing moderate densities of D2-like receptors included the olfactory bulb, inferior and superior colliculi and subthalamic nucleus. Brainstem, hippocampus and anterior thalamic nucleus also expressed D2-binding sites. Occipital and frontal cortices were very lightly labeled.

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Studies in primate and rodent brain indicate a significantly lower overall density and different laminar patterning of D2- versus D1-receptors in cortex (De Keyser et al., 1988; Richfield et al., 1989; Lidow et al., 1991), suggesting a unique and preferential participation of D1- versus D2-receptors in cognitive functions. In contrast, D2-receptors have exclusivity for affecting neuroendocrine function via their localization in pituitary (Mansour et al., 1990; Ariano et al., 1991). D2-receptor ligand-binding sites are also notable in the neurointermediate lobe of the pituitary, with moderate binding in the anterior lobe. Cloning of the D2-receptor allowed the localization of its message to be compared with the distribution of ligand-binding sites, with the distribution of D2 mRNA often matching the pattern observed with D2 radioligands (Meador-Woodruff et al., 1989, 1991; Weiner and Brann, 1989; Weiner et al., 1991; Landwehrmeyer et al., 1993; Gurevich and Joyce, 1999). A very good correspondence was obtained in caudate putamen, pituitary, nucleus accumbens, olfactory tubercule, globus pallidus, ventral tegmental area and substantia nigra. The later availability of D2-receptor-selective antibodies produced results consistent with the prominent distribution of this receptor in the basal ganglia and associated elements (Levey et al., 1993). Despite the general concordance of D2-receptor and mRNA localization data, some differences have been found. For example, differences between D2 transcript and receptor-binding data have been observed in neocortex, hippocampus and olfactory bulb (Mansour et al., 1990) that may be due either to technical issues and/or transport of mRNA to distant terminal fields. The extent and pattern of distribution of D2-receptors in cortical areas have been particularly troublesome, with different results obtained from application of the same localization methodology. For example, use of distinct D2-receptor antibodies has revealed results ranging from little or no labeling to extensive labeling throughout the cortical laminae (Ariano et al., 1993; Levey et al., 1993; Sesack et al., 1994). Such differences are likely to reflect the low abundance of the D2-receptor in these areas, coupled with differences in selectivity and/or sensitivity of the reagents employed. Comparisons have also been made between the alternatively spliced variants of the D2-receptor, one containing a 29-amino-acid insert within the third cytoplasmic loop. Most reports of mRNA abundance indicated that the long version (D2LONG, sometimes known as D2L or D2A) was the predominant D2receptor expressed in a variety of brain areas (Ariano et al., 1989; Giros et al., 1989; Neve et al., 1991; Snyder et al., 1991). A study using selective antibodies suggested that the short version (D2SHORT, D2S, or D2B)

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is preferentially expressed by dopamine neurons in primate brain, whereas the long form is prominent in most target cells (Khan et al., 1998b). D3-receptor mRNA in rodent brain (Sokoloff et al., 1990; Bouthenet et al., 1991) was originally reported to have a much lower overall abundance of this transcript relative to that of the D2-receptor. D3 message was primarily restricted to ventral striatum, nucleus accumbens, islands of Calleja, bed nucleus of the stria terminalis, dentate gyrus of the hippocampus and mamillary hypothalamic nuclei. Low levels of mRNA transcripts were also observed in the ventral tegmental area, suggesting that this receptor subtype may serve a role as a dopamine autoreceptor. Studies in primate brain confirmed a preferential localization in ventral striatum, but have also revealed the presence of D3 mRNA in a number of cortical areas and various components of the basal ganglia, including caudate nucleus and putamen (Meador-Woodruff et al., 1994, 1996; Murray et al., 1994; Suzuki et al., 1998; Gurevich and Joyce, 1999). [3H]-quinpirole and [3H]-7-OHDPAT were the first radioligands used to visualize D3 receptors, based on their apparent selectivity for D3- versus D2-receptors in vitro (Levesque et al., 1992; Levant et al., 1993). It should be noted that the selectivity of these compounds may have been overestimated by the in vitro studies. Later, the D3-selective agonist [3H]-PD 128907 was developed and used in autoradiographic studies (Hall et al., 1996), although its selectivity for D3-versus D2-receptors has been estimated to be no greater than 40-fold. D4-receptors initially attracted great interest because of the suggestion that this receptor was primarily responsible for the novel actions of the atypical antipsychotic clozapine (van Tol et al., 1991). D4receptor mRNA localization in rodent and primate brain shows selective expression in limbic and cortical regions, with sparse expression in striatal areas (van Tol et al., 1991; O’Malley et al., 1992; Meador-Woodruff et al., 1994, 1996; Suzuki et al., 1995). Immunological mapping of D4-receptors in rodent and primate brain supported the restricted distribution of this receptor (Ariano et al., 1997a; Defagot et al., 1997; Khan et al., 1998a). Ariano et al. (1997a) observed antibody staining in several cortical areas, including frontal and parietal cortices and in hippocampus in rodent brain, with lower density in globus pallidus, thalamus, cerebellum and substantia nigra. Little or no labeling was found in the caudate putamen. Results obtained by direct comparison of D4-receptor antibody staining in rodent and primate brain suggest that D4-receptors are expressed in greater abundance in rodent versus primate cortex (Khan et al., 1998a). When selective D4 radioligands became available (Primus et al., 1997; Bour-

rain et al., 1998; De La and Madras, 2000), use of such high-affinity D4 radioligands as NGD 94–1 showed binding in entorhinal and prefrontal cortex, hippocampus and thalamus in postmortem human brain (Primus et al., 1997), with no binding sites detectable in striatum. The sparse localization of D4-receptors in the basal ganglia, coupled with a lack of effect of selective D4-antagonists on motor function (Bristow et al., 1997; Kramer et al., 1997), suggests that activation of D4-receptors is not a useful way to approach treatment of the motor aspects of Parkinson’s disease, although other uses are possible (Oak et al., 2000). 4.2.2. Localization of D1-like receptors At present, there are no radioligands that can differentiate the two D1-like receptors (D1 and D5), but several radioligands (e.g. [3H]-SCH39166, [125I]SCH23982 and [3H]-SKF83566), having high affinity and selectivity for both receptors (Schulz et al., 1984, 1985) enabled the use of quantitative receptor autoradiography (Boyson et al., 1986; Savasta et al., 1986; Altar and Marien, 1987; Wamsley et al., 1991). In general, patterns of [3H]-SCH23390 binding parallel the distribution of dopamine terminals (Schulz et al., 1984, 1985), with the highest levels of binding occurring in forebrain areas, including caudate putamen, nucleus accumbens and olfactory tubercle. In general, the density of D2-like receptors in these areas is lower than that of D1-like receptors. Labeling is evident in structures comprising the basal ganglia outflow pathways, including the entopeduncular and subthalamic nuclei and the substantia nigra pars reticulate and D1receptors are also expressed in a number of limbic areas, notably the dentate gyrus of the hippocampus and several amygdaloid nuclei. Moderate to low densities of D1-binding sites were observed in several cortical divisions, with a preferential distribution in deeper layers. The highest cortical densities occurred within the anteromedial and suprarhinal prefrontal areas. Studies in primate and rodent brain indicate a significantly higher overall density and different laminar patterning of D1- versus D2-receptors in cortex, suggesting a unique and preferential participation of D1- versus D2-receptors in cognitive functions. A direct comparison of D1-receptor ligand-binding sites in several species, including rodent and primates, revealed remarkable similarities in neuroanatomical distribution of sites within the basal ganglia (Richfield et al., 1987; De Keyser et al., 1988; Lidow et al., 1991; Hall et al., 1993, 1994; Montague et al., 1999; Piggott et al., 1999), although differences were noted in patterns of cortical lamination (Richfield et al., 1989). A detailed study of [3H]-SCH23390-labeled sites in rhesus brain

DOPAMINE RECEPTOR PHARMACOLOGY revealed a bilaminar pattern in most cytoarchitectonic cortical areas (Lidow et al., 1991). The highest concentrations of D1-receptors were observed in supragranular layers I, II and IIIa and infragranular layers V and VI. D1-receptor-binding sites showed a marked gradient along the rostral–caudal neuraxis, with highest densities in the prefrontal cortical areas and lower concentrations in occipital cortex. D1 mRNA localization is generally consistent with the results obtained from D1-receptor-binding and antibody localization studies (Mansour et al., 1990; Fremeau et al., 1991; Meador-Woodruff et al., 1991; Levey et al., 1993; Ariano and Sibley, 1994; Yung et al., 1995). This correspondence suggests that D1receptors are typically expressed on cell soma and proximal dendrites rather than at distant sites, although cortical laminar distribution and overall level of expression may vary between rat and primate (Levey et al., 1993; Smiley et al., 1994). Interestingly, there is a dearth of D1 mRNA in substantia nigra, enterpeduncular nucleus and subthalamic nucleus, areas with clearly defined D1-receptor-binding sites, indicating that D1-receptors are transported to axon terminals from other nuclei (Gerfen et al., 1990; Harrison et al., 1990). The D5-receptor has limited expression relative to that of the D1-receptor, with D5 mRNA being restricted to hippocampus, lateral mamillary nuclei and parafasicular nucleus (Tiberi et al., 1991; Meador-Woodruff et al., 1992). A study of D1 null mutant mice (Montague et al., 2001) showing binding sites in only one area, the hippocampus. The density of these sites was close to the limits of detection, however, leaving open the possibility that some regions may have even lower receptor densities. D5 mRNA localization studies in primate brain have shown a more widespread distribution than predicted from the rodent mRNA studies (Huntley et al., 1992; Rappaport et al., 1993), a finding confirmed by the use of antibodies in both rodent and primate brain (Ariano et al., 1997b, Ciliax et al., 2000, Khan et al., 2000). For example, using D5-selective antisera, intense staining was found in frontal and parietal cortices of rat brain (Ariano et al., 1997b). Significant staining was also observed in hippocampus and dentate gyrus, whereas a lower-intensity signal was observed in olfactory tubercle, dorsal aspects of the caudate putamen and the cerebellar vermis. Comparisons between D1- and D5-receptor immunoreactivity in primate brain have shown interesting differences in localization (Bergson et al., 1995). Both D1- and D5-receptors are widespread in prefrontal and premotor cortex, cingulate and entorhinal cortex and hippocampus and dentate gyrus and both receptors are expressed in pyramidal cells in layers II, III and V in many cortical regions. On the other hand,

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D5-receptors are expressed preferentially on apical dendritic shafts, whereas D1-receptors were expressed more frequently on dendritic spines. Within the caudate nucleus, D1- and D5-receptors are expressed on medium spiny neurons, with D1-receptors found at much higher densities. Interestingly, large, presumably cholinergic, neurons expressed only D5-receptors. 4.2.3. Implications and clinical relevance of dopamine receptor localization Much as the previous data influenced views on how dopamine receptors play a role in therapy or etiology of psychiatric disorders (Levant, 1997; Wilson et al., 1998; Tarazi and Baldessarini, 1999; Schwartz et al., 2000), so did the neuroanatomical evidence for segregation of D1- and D2-receptors in the two principal striatal outflow pathways affect our concepts of basal ganglia function and dysfunction (Robertson et al., 1992; Starr, 1995; Gerfen, 2000a, b). Much of this was derived from models of basal ganglia functional neuroanatomy that first emerged more than a decade ago (Albin et al., 1989; Alexander et al., 1990; DeLong, 1990; Graybiel, 1990; Smith and Bolam, 1990). At the simplest level, such models showed how coordinated movement is regulated by two parallel and segregated pathways through the basal ganglia that are formed by the GABAergic medium spiny projection neurons of the striatum. Ultimately, these circuits enable movement via disinhibition of thalamocortical circuitry. More recent studies have underscored the critical role various dopamine receptors play in a variety of aspects of central nervous system function (see Chs 1-3 for a review of the relevant neuroarchitecture). Dopamine is a primary modulator of basal ganglia outflow and the distribution of dopamine receptor isoforms is therefore of great relevance (Surmeier et al., 1993). Studies of the distribution of mRNA in brain slices generally support the segregation of D1- and D2-receptors, with D1-receptors expressed in substance P/dynorphin-containing neurons that form the direct pathway and D2-receptors coexpressed with enkephalin in neurons that form the indirect pathway (Gerfen et al., 1990; Le Moine et al., 1991; Gerfen, 1992; Le Moine and Bloch, 1995), although some degree of D1 and D2 colocalization exists (Meador-Woodruff et al., 1991; Lester et al., 1993). Immunological studies have yielded more mixed results, showing both minimal and extensive segregation (Hersch et al., 1995; Larson and Ariano, 1995; Yung et al., 1995). When considered together, however, the weight of available evidence suggests a preferential distribution of D1- and D2-receptors in the direct and indirect pathway, respectively. One consequence of this D1:D2 segregation was the notion

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that dopamine has stimulatory actions on D1-receptorbearing neurons that form the direct pathway and inhibitory actions mediated by D2-receptors expressed on neurons that comprise the indirect pathway (Gerfen et al., 1990; Gerfen, 1992). Although this simple model has considerable appeal, functionally important colocalization of D1-/D2-receptors in a minor proportion of striatal neurons also occurs and cannot be addressed by this model. Functionally significant colocalization has been supported by elegant experiments that combined electrophysiological recordings and single-cell polymerase chain reaction analysis of mRNA content in identified striatal neurons (Surmeier et al., 1992). Consideration of the role(s) of D3-, D4- and D5-receptors is also needed in light of recent data indicating that the colocalization of D1-like and D2-like receptors may occur by coexpression of a less abundant isoform (D3, D4 or D5) (Surmeier et al., 1996). 4.2.3.1. Striatal cholinergic neurons In addition to the medium spiny projection neurons, a variety of other neuronal classes are present within the striatum and function as interneurons (see review by Kawaguchi et al., 1995). Giant cholinergic neurons can be identified by their large soma (20–50 mm) and by cholinergic phenotype (e.g. expression of choline acetyltransferase). Although representing only a few percent of striatal neurons, the physiological importance is well known, especially in how disruption of normal dopamine-acetylcholine balance plays a role in parkinsonism induced by D2-receptor antagonists. These neurons express both D2 and D5 dopamine receptors (Le Moine et al., 1990; Bergson et al., 1995), receive some direct dopaminergic input and have been proposed to function as associative neurons on the basis of their widespread dendritic trees and primary synaptic contact with projection neurons. One hypothesis is that the primary role of acetylcholine release in striatum is to facilitate corticostriatal N-methyl-d-aspartate (NMDA) receptor-mediated long-term potentiation (LTP) in medium spiny projection neurons (Calabresi et al., 2000). 4.2.3.2. Prefrontal cortical circuits involved in working memory During the past decade dopamine neurotransmission in prefrontal cortex has become of great interest because of its critical role in working memory and executive function (Goldman-Rakic et al., 2000, 2004; Castner and Goldman-Rakic, 2004). The localization of dopamine receptor subtypes in prefrontal pyramidal and non-pyramidal neurons, coupled with a host of pharmacological studies, has supported an essential role

of D1-like receptors in the elemental basis of these working-memory processes (Sawaguchi and GoldmanRakic, 1991, 1994; Arnsten et al., 1994; Williams and Goldman-Rakic, 1995; Murphy et al., 1996; Zahrt et al., 1997; Muly et al., 1998, 2001; Castner and Goldman-Rakic, 2004; Castner et al., 2004; Goldman-Rakic et al., 2004). There is a great deal of evidence for this being a highly regulated, interactive system in which D1-receptors located on aspects of pyramidal cells and interneurons of several types play a major role in the physiology of working memory. There is a widely held view that this highly regulated system functions at less than optimal efficiency with either too much or too little D1 activation. D2-like receptors are also expressed in prefrontal cortex, albeit at much lower levels than D1-like receptors. D4-receptors have been localized to both pyramidal and non-pyramidal prefrontal neurons, whereas D2- and D3-receptors are primarily expressed on non-pyramidal GABAergic interneurons (Mrzljak et al., 1996; Khan et al., 1998a). The participation of D2-like receptors in working-memory processes has not yet been thoroughly elucidated, although the primary localization of D2-like receptors on GABAergic interneurons suggests that any D2-receptor-mediated effects on pyramidal neuron memory fields are achieved indirectly. 4.2.3.3. D1-/D5-receptors in the hippocampus Dopaminergic cells from the substantia nigra and the ventral tegmental area project to the dentate gyrus and CA1 region of the hippocampus and the role dopamine plays in memory-related functions has been studied. Dopamine can modulate the activation of NMDA receptors (Frey et al., 1990, 1991) known to be crucial for the induction of LTP, the mechanism thought to underlie initial memory consolidation. As noted earlier, both D1-like and D2-like receptors have been localized to the hippocampus (Yokoyama et al., 1994; Bergson et al., 1995). Dopamine modulation appears to rely on the activation of both D1-like receptors, such that D1like agonists potentiate the late phase of LTP in the CA1 region (Huang and Kandel, 1995; Matthies et al., 1997). D1-like receptors also potentiate the early phase of LTP in the CA1 region (Otmakhova and Lisman, 1996) and inhibit depotentiation via a cAMP-dependent mechanism (Otmakhova and Lisman, 1998). Memory defects are associated with defects in late-phase LTP and spatial memory deficits in aged mice can be improved with D1-/D5-agonists (Bach et al., 1999). These and other findings illustrate the important role D1-like receptors play in the hippocampus and suggest that these processes should be studied if a D1-agonist becomes clinically available.

DOPAMINE RECEPTOR PHARMACOLOGY 4.2.3.4. Peripheral dopamine receptors Although this chapter and the majority of published research focus on dopamine receptors in the central nervous system, there are key functional roles for dopamine receptors in the periphery. In the heart, dopamine increases myocardial contractility and cardiac output, while causing vasodilatation in the vasculature. In the kidney, dopamine causes natriuresis and vasodilatation. The precise role dopamine plays in other tissues is less clear and the knowledge of the role of specific dopamine receptor subtypes in the peripheral system is also limited, but may contribute to the clinical pharmacology of dopaminergic therapies. This area has been the subject of several scholarly reviews (Amenta et al., 2001; Velasco et al., 2002; Hussain and Lokhandwala, 2003; Jose et al., 2003).

4.3. Dopamine receptor pharmacology 4.3.1. Animal models of Parkinson’s disease The ability to evaluate potential new therapies (symptomatic, preventive and/or curative) is a major research need. In recent years, there have been many attempts to develop Parkinson’s relevant models using either in vitro or non-vertebrate systems (Palfreyman, 1998; Feany and Bender, 2000; Nass et al., 2001, 2002; Auluck and Bonini, 2002; Muqit and Feany, 2002; Nass and Blakely, 2003). Review of these approaches is beyond the scope of this chapter, but although these models are often of great heuristic interest, to date they have not led to useful therapeutic approaches. At present, mammalian animal models have been of greatest utility. Transgenic mouse models have been developed for the mouse homologs of most of the genes that have been identified in familial Parkinson’s disease and these models have been extremely useful in learning about the role of these genes and their products in cellular function (Sommer et al., 2000; Barbieri et al., 2001; Goldberg et al., 2003; Lindsten et al., 2003; Fernagut and Chesselet, 2004; Chen et al., 2005). One issue, however, is whether they provide a compelling model of sporadic Parkinson’s disease and similar concerns exist in the use of toxicant-generated animal models that are in wide use. 4.3.1.1. Rat 6-hydroxydopamine models The most widely used animal model in Parkinson’s research was first described by Ungerstedt (1971b). In this model, a unilateral lesion of the nigrostriatal dopaminergic pathway is produced by injecting 6-OHDA into one substantia nigra (or medial forebrain bundle) of the rat. This lesion results in death of nigral dopamine

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neurons and concomitant loss of dopamine terminals and a permanent depletion of dopamine in the ipsilateral striatum. After recovery, behavioral supersensitivity (i.e. contralateral circling) is seen when the rat is challenged with a direct-acting dopamine agonist, either D1- or D2like. The turning makes a readily quantifiable and robust endpoint, contributing to the utility of the model. Because Parkinson’s disease often has a unilateral onset and because it involves asymmetric loss of dopamine, many have felt this was an excellent model of the disease. The mechanism(s) underlying the increased sensitivity to dopamine agonists on the lesioned side is of scientific importance. Initially, it was hypothesized that changes in receptor regulation played a key role because there was an increase in striatal dopamine D2-receptor density ipsilateral to the 6-OHDA lesion (Creese et al., 1977; Goldstein et al., 1980; Mishra et al., 1980; Heikkila et al., 1981). Such denervation also resulted in profoundly enhanced responsiveness to administration of agonists for the denervated system, as had been shown in other systems (Sporn et al., 1976). Later work, however, suggested that the denervation supersensitivity was not simply explicable by receptor upregulation (Staunton et al., 1981; Mileson et al., 1991). Although the ‘supersensitivity’ in the unilateral 6-OHDA model may not be directly linked to changes in receptor properties, the model is still widely viewed to be a valid predictor of human antiparkinsonian responses. The model shows robust responses to a variety of pharmacological perturbations that are known to be involved in the rat basal ganglia circuitry. This includes not only D1- and D2- agonists, but also antagonists for cholinergic (Ondrusek et al., 1981; Olianas and Onali, 1996), glutamate (Loschmann et al., 1991, 1997; Morelli et al., 1992), adenosine (Vellucci et al., 1993), 5-HT2C (Fox and Brotchie, 1996; Fox et al., 1998) and opioid (Matsumoto et al., 1988) receptors. Indeed, such data formed the basis for suggesting that these receptor classes might be novel targets for antiparkinsonian drugs. Unfortunately, validation in either primate models (see below) or, in some cases, clinical studies have generally not occurred. Many drugs that cause robust responses in the rat unilateral 6-OHDA model have often given modest responses at best in human or non-human primates, even after promising early data. Drugs ranging from the new dopamine D2-/D3-agonists to the NMDA antagonist remacemide have been found to have modest effects that do not approach that of the current gold-standard levodopa (Pinter et al., 2000). Thus, the unilateral 6-OHDA model has clear heuristic value (e.g. for studying sensitization, priming and tolerance), but in our view does not meet the goal of being a predictive rat ‘model’ of Parkinson’s disease.

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4.3.1.2. MPTP-induced lesions of dopamine systems 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)lesioned non-human primates can have striking phenotypic similarities to the targeted human disorder (Davis et al., 1979; Langston et al., 1983; Bedard et al., 1992), maybe more so than any other animal model of an idiopathic disorder. There have been numerous reviews of this area (Nagatsu, 2002; Dauer and Przedborski, 2003; Hirsch et al., 2003; Linazasoro, 2004), but we would like to highlight several editorial points that are often forgotten. First, there is often excellent concordance between the symptomatic responses seen between Parkinson’s patients and MPTP-lesioned primates (especially in bilateral models). As such, this is the most predicative model of symptomatic response in Parkinson’s disease. On the other hand, the etiology of the MPTP model likely bears little relationship to idiopathic Parkinson’s disease, where, if chemical insult plays a role, it is likely to be in interaction with complex genetic mechanisms. Similarly, MPTP lesions are not progressively neurodegenerative and the use of this model for the evaluation of preventive approaches is clearly problematic. Intermediate is this model’s utility for ‘curative approaches’, where, although progressive neurodegeneration is not addressed, evaluation of improvements in function (e.g. from gene therapy, cellular transplants or trophic factors) may still provide viable data. Like 6-OHDA, MPTP lesions can be either unilateral or bilateral (systemic). Some of the inconsistencies in the literature may be a result of the disparities between these models, a point to which the rat 6-OHDA models may offer guidance. For example, Smith et al. (1993) have reported that the hemiparkinsonian model has a limited subset of parkinsonian features and it has been reported that the rotation behavior in hemiparkinsonian animals does not correlate well with parkinsonian behaviors (Wolters et al., 1988; Smith et al., 1993). In addition, although rats are very insensitive to MPTP, mice can also be lesioned by very high doses of MPTP, albeit sometimes incompletely. Clearly mice are much more convenient for research purposes (especially for genetic manipulations), but, like the 6-OHDA rat, the pharmacological responses of MPTP-lesioned mice often do not predict the responses in humans, especially compared to the bilateral MPTP primate. 4.3.1.3. Other animal models (rotenone and ubiqutin protease inhibitors) The role of mitochondrial defects in Parkinson’s disease has led to several animal models, including a Parkinson-like syndrome in rats caused by chronic high-dose administration of rotenone (Betarbet et al., 2000). This

model has several interesting features, but neither it nor other models of environmental toxicant exposure (manganese, organophosphates, etc.) seems to have the face validity in terms of behavioral phenotypes that is found in the MPTP primate model. Recently, McNaught et al. (2004) reported that systemic administration of proteasome inhibitors into adult rats over a period of 2 weeks caused progressive bradykinesia, rigidity, tremor and abnormal posture. This was accompanied by decreases in striatal dopamine transporters and striatal dopamine depletion and dopaminergic cell death, with apoptosis and inflammation in the substantia nigra pars compacta and loss of cells in the locus coeruleus, dorsal motor nucleus of the vagus and the nucleus basalis of Meynert. Intracytoplasmic, eosinophilic, a-synuclein/ubiquitin-containing inclusions resembling Lewy bodies were present in some of the remaining neurons. This model closely recapitulates key features of Parkinson’s disease and may be valuable in studying etiopathogenic mechanisms and putative neuroprotective therapies for the illness, but its pharmacological utility may not be better than the rat 6-OHDA model. 4.3.2. Receptor function and its relevance to Parkinson’s pharmacology It is commonly accepted that ligands (drugs) will cause a single type of functional response for all effectors linked to a given receptor. Thus, from classical theoretical quantitative pharmacology, we would describe the functional actions of a drug (i.e. its intrinsic efficacy) with the terms full agonist, partial agonist, antagonist or, more recently, inverse agonist. The characteristics of a specific compound can be assessed in various functional assay systems, usually in vitro. For example, as will be discussed below, the D1-receptor can almost always couple to increased synthesis of cAMP. A compound that equals dopamine in its ability to increase cAMP production is called a ‘full agonist’, whereas a compound that only causes a fraction of the activity of dopamine, even at high concentrations, is called a partial agonist. An antagonist binds to the receptor, but causes no activation of its own. There are several factors – receptor reserve often being foremost (Watts et al., 1995) – that can influence the behavior of a ligand. In the Parkinson’s arena, an indepth awareness of the characteristics of both current and experimental drugs can be particularly useful in understanding or predicting clinical responses. As an example, apomorphine, pergolide and bromocriptine are correctly recognized as having high affinity for D2-like receptors. These three compounds are also thought to have similar

DOPAMINE RECEPTOR PHARMACOLOGY actions at the D1-receptor where they have more modest affinity. Despite these apparent similarities, apomorphine is clearly more efficacious when used in monotherapy (Anon., 2005) than is bromocriptine or pergolide. One of the mechanisms explaining these differences in clinical efficacy may be that the efficacy of these three drugs at the D1-receptor is quite different. Thus, apomorphine has very high D1 intrinsic activity, pergolide has extremely modest intrinsic activity and bromocriptine is actually a D1-antagonist, possibly explaining the clinical differences between these drugs (see also section 4.4.2). In addition to the classical framework described above, there is a new concept of molecular pharmacology termed ‘functional selectivity’ (Lawler et al., 1999; Gay et al., 2004; Mailman and Gay, 2004b; Simmons, 2005) that has challenged the traditional view of the receptor as operating in a digital fashion (i.e. as active or inactive for all functions mediated by a single receptor). The evidence shows that some ligands, working at a single receptor, can cause markedly dissimilar degrees of activation depending on the effector pathway being assessed. This phenomenon has been called ‘functional selectivity’ (dopamine D2L-receptors (Lawler et al., 1999; Kilts et al., 2002; Mottola et al., 2002; Shapiro et al., 2003)), but also ‘agonist-directed trafficking of receptor signaling’ (5-HT2A and 5-HT2A (Berg et al., 1998), a2A-adrenergic receptors (Brink et al., 2000; Kukkonen et al., 2001)); ‘functional dissociation’ (m-opioid receptors (Whistler et al., 1999)); ‘biased agonism’ (neuropeptide cytokine receptors (Jarpe et al., 1998)); ‘biased inhibition’ (A1 adenosine receptors (Kudlacek et al., 2002)); ‘trafficking of receptor stimulus’ (human calcitonin type 2 receptor (Watson et al., 2000)); ‘differential engagement’ (Manning, 2002), ‘discrete activation of transduction’ (muscarinic cholinergic receptors (Gurwitz et al., 1994)), as just some examples. The ubiquitous nature of this mechanism has been suggested by several groups (Kenakin, 2002; Gurwitz and Haring, 2003; Hermans, 2003; Mailman and Gay, 2004a). In terms of Parkinson’s disease, functional selectivity has already been shown for functions mediated by both the D1- (Ryman-Rasmussen et al., 2005, 2007) and D2-receptors (Lawler et al., 1999; Kilts et al., 2002; Mottola et al., 2002; Shapiro et al., 2003; Gay et al., 2004). There are two ways in which this new concept impacts on Parkinson’s disease pharmacology. First, it can no longer be assumed that a drug that is called a ‘full agonist’ will activate all functions mediated through a single receptor to the same degree. Although unexpected clinical responses are often automatically ascribed to actions at non-targeted receptors, func-

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tional selectivity may sometimes play a key role. A corollary is that as the role of key receptor-signaling pathways (see below) in mediating clinical responses is elucidated, it may be possible to discover functionally selective drugs that have improved therapeutic side-effect profiles. 4.3.3. Dopamine receptor signaling All of the dopamine receptors are GPCRs that signal, in large measure, by activation of heterotrimeric guanosine triphosphate (GTP)-binding proteins (Gproteins) composed of a and bg subunits. Members within each subclass of dopamine receptor share some signaling properties due to similarities in structure within the class (e.g. large versus small third cytoplasmic loop). Thus, D1-like signaling is mediated by the heterotrimeric G-proteins utilizing primarily GaS and GaOLF that initially activate adenylate cyclase and secondarily cause increases in cAMP-dependent protein kinase and dopamine- and cAMP-regulated phosphoprotein (DARPP-32). D2-like receptor signaling is mediated by different, often GaO and GaI isoforms. Unlike GaS and GaOLF, the D2-linked G-proteins are usually pertussis toxin-sensitive and also usually regulate and inhibit, rather than stimulate, adenylate cyclase. There is rich signaling not only via a, but also via bg subunits (e.g. modulation of ion channels, phospholipases, protein kinases and receptor tyrosine kinases). There is also evidence that dopamine receptors (and G-proteins) can have other protein–protein interactions such as receptor oligomerization or interactions with scaffolding or other regulatory proteins that also affect dopamine receptor signaling. There are some excellent recent reviews of this subject area (Neve et al., 2004). 4.3.3.1. D1-like signaling D1-like receptors will stimulate adenylate cyclase in virtually any cell line, as well as in most tissues. In addition, both the D1- and D5-receptors couple to GaS, a ubiquitous G-protein most commonly associated with stimulation of adenylate cyclases (Sidhu, 1998). The neostriatum, however, the brain region with the densest dopamine innervation and the highest expression of the D1-receptor, has abundant expression of GaOLF and little of GaS (Zhuang et al., 2000). The nucleus accumbens and olfactory tubercle also express abundant GaOLF and little GaS (Herve et al., 2001). In mice with genetically deleted GaOLF, there is no D1-mediated stimulation of adenylate cyclase in the striatum and D1-agonist responses are greatly diminished (Corvol et al., 2001). From such data, the conclusion might be

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lon Channels

D1 heterodimers

D2

D 2 h ho eter mo odim an ers d

cAMP MAPK

K+ Channels

PLCβ

PKA Ca2−

Na+ Channels

PKC

PP2A DARPP-32

IEG expresslon

AA

PLA2

Na,K-ATPase

CREB

PP1

Fig. 4.1. Simplified schematic of some aspects of the signaling of D1- and D2-receptors. Stimulatory effects are indicated with a solid line and arrows and effects with dotted lines and arrows. Most intervening mechanisms are ignored for the sake of simplicity. Both homo- and heterodimers of the dopamine receptors have been shown to occur and have potential functional roles, but these mechanisms are not shown. CREB, cyclic adenosine monophosphate (cAMP) response element-binding protein; DARPP-32, dopamine-related 32 kDa phosphoprotein; MAPK, mitogen-activated protein kinase; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PP1/PP2A, protein phosphatase 1/2A; IEG, intermediate early genes.

drawn that D1-like receptors signal through GaS and GaOLF via activation of adenylate cyclase and subsequent cAMP effects on phosphokinase A. Since D2-like receptors can often inhibit adenylate cyclases and decrease cAMP concentrations (see below), a yin–yang relationship might be suggested for the subclasses of dopamine receptors. Yet this would be a very misleading oversimplification. For example, in some areas of brain like the amygdala, there is a moderate density of D1-receptors and high concentrations of GaS, yet D1receptors do not upregulate adenylate cyclase activity (Leonard et al., 2003). The mechanisms of D1 signaling in the amygdala are not known, but are also probably relevant in brain regions where adenylate cyclase is stimulated. Less is known about the bg subunits that form heterotrimers with GaS or GaOLF and their role in D1-like signaling. In at least one cell line, depletion of endogenous g7 subunits decreases D1-mediated stimulation of adenylate cyclase, but interestingly, not D5 effects (Wang et al., 2001). In neostriatal medium spiny neurons, g7 is abundantly expressed in neurons that also express D1-receptor mRNA (Watson et al., 1994; Wang et al., 2001), suggesting that neostriatal D1receptors may signal via a G-protein heterotrimer that includes GaOLF and g7. Suggestions that the D1-receptor couples to other heterotrimeric G-proteins, such as Gao and Gaq, have been made (Kimura et al., 1995; Wang et al., 1995; Jin et al., 2001) and, if true, potential D1 signaling through Gaq would mean that phos-

phokinase C/Ca2þ mechanisms, as well as the cAMP/ protein kinase A cascade, would be critical. There remain issues to be resolved in this regard. It may be that D1-like receptor activation of phospholipase C is indirect, requiring priming from another Gaq-coupled receptor (Lezcano et al., 2000), and this may be region-dependent (Lezcano and Bergson, 2002). The obvious mechanism is the direct activation of Gaq with subsequent activation of phospholipase C (Undie and Friedman, 1990; Pacheco and Jope, 1997), although the available data clearly suggest this may be an artifact. The regional distribution and pharmacological profile of stimulation of phospholipase C by D1-agonists are two factors of concern. Of special note is the suprapharmacological concentrations of D1 drugs that are required and the lack of correlation of receptor affinity and phospholipase C functional potency. Finally, this function is unaffected by knockout of the D1-receptor, leading to the hypothesis of a novel D1-receptor (Undie et al., 1994; Friedman et al., 1997), a suggestion first offered to explain the nonadenylate cyclase-linked D1-receptor in the amygdala (Mailman et al., 1986). On the other hand, the numerous pharmacological anomalies noted above, the failure to find high-affinity binding sites for D1 radioligands after knockout of the drd1 gene (Montague et al., 2001) and the fact that this purported D1-like Gaq-coupled receptor does not react with a D1-receptor antibody (Jin et al., 2001) clearly suggest this is a non-dopamine receptor-binding site that can bind, with

DOPAMINE RECEPTOR PHARMACOLOGY low affinity, one class of dopamine ligands (Leonard et al., 2003). In any event, the signaling cascades initiated by D1like receptors are complex and involve a host of biochemical mechanisms that are often finely interregulated (Fig. 4.1). This includes the proximal effects on stimulation of cAMP synthesis via activation of several subtypes of adenylate cyclases, actions of cAMP on protein kinase A, subsequent effects on CREB (a cAMP response element-binding protein important in synaptic plasticity) and DARPP-32 (a regulatory phosphoprotein), activation of aspects of the mitogen-activated protein (MAP) kinase cascade and effects on many voltage- and ligand-gated ion channels by various combinations of direct protein kinase A-catalyzed phosphorylation of channel subunits and DARPP-32-mediated inhibition. It is noteworthy that D1-like receptor signaling can be regulated by both positive feedback and feed-forward mechanisms (Greengard et al., 1999). 4.3.3.2. D2-like signaling D2-like signaling is primarily mediated by activation of the Gai/o class of G-proteins that are inactivated by pertussis toxin-catalyzed adenosine diphosphate ribosylation (Bokoch et al., 1983; Kurose et al., 1983). In addition to a few interesting allelic variants (e.g. with the D4-receptor), two isoforms of the D2receptor are expressed via an alternatively spliced insert in the third cytoplasmic loop that yields what are termed D2Long (D2L) and D2Short (D2S). In theory, this should influence G-protein interactions and possibly result in differential G-protein selection, but such differential effects are seldom found, leading to disagreement concerning which G-proteins interact with D2S and D2L. It seems likely that both receptor isoforms are inherently able to activate multiple Gai/o subtypes, including Gai2, Gai3 and Gao and factors such as compartmentalization and availability of different effectors, scaffolding proteins and other regulators may be as important as the structural differences between D2L and D2S (for a review, see Neve et al., 2003). Although both D2S and D2L can activate the pertussis toxin-insensitive G-protein Gaz (Wong et al., 1992; Obadiah et al., 1999), the weight of available data is that Gao is the subtype most robustly activated by both D2L and by D2S. As noted earlier, these two D2 isoforms are likely to be by far the most important dopamine receptors in terms of basal ganglia function and the treatment of Parkinson’s disease. With the approval of the D3-/D2-selective agonists pramipexole and ropinirole, there was some speculation that D3 activation was a key mechanism for dopa-

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mine-mediated antiparkinson effects (Piercey, 1998; Bennett and Piercey, 1999, Joyce, 2001), despite the fact that this receptor had a much lower expression than the D2 isoforms in the basal ganglia (see above). An unusual feature of the D3-receptor is that it binds agonists with a high affinity that is relatively insensitive to GTP (Sokoloff et al., 1992), suggesting that the receptor might be constrained in a conformation with high affinity for agonists regardless of interactions with G-proteins (Vanhauwe et al., 2000). D3 signaling has been hypothesized to involve Gao, as well as Gaz and Gaq/11 (Newman-Tancredi et al., 1999; Zaworski et al., 1999), but again cell-specific compartmentalization will be very important. The D4-receptor can also activate multiple pertussis toxin-sensitive G-proteins, including GaI2, GaI3 and Gao as well as Gaz and the pertussis toxin-sensitive transducin Gat2. As with the D1-receptor, the first signaling pathway identified for D2-like receptors was inhibition of cAMP accumulation (De Camilli et al., 1979; Stoof and Kebabian, 1981) and it is clear that this pathway can be important behaviorally (Lee et al., 2002). Both D2- and D4-receptors inhibit adenylate cyclase activity in most tissues and cell lines (Huff, 1997; Oak et al., 2000). Conversely, inhibition of adenylate cyclase by the D3-receptor is usually undetectable. D2-receptor signaling via inhibition of adenylate cyclase would be expected to act in opposition to agents that stimulate adenylate cyclase, decreasing the phosphorylation of protein kinase A substrates. Whereas this may sometimes be true, such a simplistic yin–yang view would make it hard to explain apparently contradictory findings that are much more easily reconciled by taking into account documented cellular and intracellular compartmentalization of the dopamine receptors as well as of their signaling partners (see above). As an example, the effects of both D1and D2-receptors on DARPP-32 lead to inhibition of the Naþ, Kþ-ATPase in neostriatal neurons (Nishi et al., 1999). The functional effects of activation of D2-like receptors are numerous, although the molecular mechanisms are often not completely understood. D2-like inhibition of adenylate cyclase can lead to presynaptic/autoreceptor decreases in tyrosine hydroxylase activity and in firing of nigrostriatal dopamine neurons. As is typical of Gai/o-coupled receptors, D2-like receptors modulate many signaling pathways, including phospholipases, ion channels, MAP kinases and the Naþ/Hþ exchanger, as well as adenylate cyclases (Huff et al., 1998). Many of these actions are regulated by G-protein bg subunits that are released after receptor activation of Gai/o-containing heteromers. D2-like receptor

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activation of Gbg-stimulated adenylate cyclase response has only been reported in heterologous expression systems and it is not known how it affects D2-like receptor signaling in neurons. D2 activation has major effects on Kþ currents via dissociation of Gbg subunits and, unlike the generally excitatory effect of D1-receptor activation, D2 stimulation decreases cell excitability by increasing Kþ currents. D2-like receptors activate a G-protein-regulated inwardly rectifying potassium channel (GIRK or Kir3), modulating several potassium currents in tissues like midbrain dopamine neurons (Lacey et al., 1987; Liu et al., 1994) and neostriatal D2-receptor-expressing neurons (Greif et al., 1995). Dopamine release-regulating autoreceptors are coupled to potassium channels (Cass and Zahniser, 1991) rather than to inhibition of adenylate cyclase (Memo et al., 1986) and there is robust regulation of GIRK currents by D2-receptors in substantia nigra dopamine neurons (Davila et al., 2003). This suggests that D2-receptor activation of GIRK currents contributes to D2 autoreceptor inhibition of dopamine release and dopamine neuronal activity. The D2-like receptors also decrease the activity of L-, N- and P/Q-type channels via pertussis toxinsensitive G-proteins (Lledo et al., 1992; Seabrook et al., 1994a, b; Kuzhikandathil and Oxford, 1999; Okada et al., 2003) and this may involve Gbg actions (Yan et al., 1997, Zamponi and Snutch, 1998). A functional consequence of this can be regulation of neurotransmitter release via N-type Ca2þ channels (Dunlap et al., 1995; Koga and Momiyama, 2000; Svensson et al., 2003). D2 activation also stimulates MAP kinases, including the two isozymes of extracellular signal-regulated kinase (ERK) (Voyno-Yasenetskaya et al., 1994; Huff, 1996; Luo et al., 1998; Welsh et al., 1998; Choi et al., 1999; Ghahremani et al., 2000; Oak et al., 2001; Kim et al., 2004) and stressactivated protein kinase/Jun amino-terminal kinase (SAPK/JNK) (Luo et al., 1998), although the exact pathway(s) from D2-like receptors to ERK have not been thoroughly elucidated and are probably dependent on cell type and localization, as well as receptor subtype. Another effect of the D2-receptor is potentiation of arachidonic acid release induced by calciummobilizing receptors, a response mediated by cytosolic phospholipase A2 (Kanterman et al., 1991; Piomelli et al., 1991; Chio et al., 1994; Vial and Piomelli, 1995). The D4-, but not D3-, receptor also activates this pathway (Vial and Piomelli, 1995; Nilsson et al., 1999). Arachidonic acid and its lipooxygenase and cyclooxygenase metabolites have numerous effects on cellular function, including feedback regulation of D2-like signaling and dopamine transport (Piomelli and Greengard, 1990; DiMarzo and Piomelli, 1992;

L’hirondel et al., 1995; Zhang and Reith, 1996). The D2-receptor can also stimulate phospholipase D, catalyzing the hydrolysis of phosphatidylcholine to form choline and phosphatidic acid (Mitchell et al., 1998; Senogles, 2000). Finally, another major effect of D2-like receptors can be regulation of Naþ channels. D2-like receptor stimulation can either increase or decrease Naþ currents in neostriatal neurons, perhaps depending on the subtype of D2-like receptors expressed by a given cell (Surmeier et al., 1992; Surmeier and Kitai, 1993). In most D2-agonist-responsive neurons, D2-like receptor stimulation decreases Naþ currents that may involve binding of Gbg subunits to the Naþ channels (Surmeier and Kitai, 1993). Agonist effects at heterologously expressed D2-, D3-, or D4-receptors can activate the widely expressed Naþ/Hþ exchanger NHE1 (Neve et al., 2004). 4.3.3.3. Receptor heteromers and other protein– protein interactions As if there were not adequate complexity in dopamine receptor signaling, studies during the past decade have provided compelling evidence for the possibility of receptor polymers playing a crucial role. This includes homodimers of the dopamine receptors, as well as heterodimers with receptors of many superfamilies (e.g. D1 with NMDA; D5 with gamma-aminobutyric acid (GABAA); D2/D4 with epidermal growth factor (EGF) and platelet-derived growth factor (PDGF); and D2 with adenosine A2A-receptors). Intramembrane interactions of the D2-receptor with neurotensin and metabotropic glutamate receptors are also potentially mediated by direct receptor–receptor interactions (Rimondini et al., 1999), although competition for a limiting pool of another receptor-interacting protein is another possible mechanism. The formation of heteromers can be constitutive (Canals et al., 2003) or stimulated by the binding of ligands, particularly agonists (Rocheville et al., 2000). For example, there is much behavioral and functional evidence for interactions between brain dopamine and adenosine systems and between dopamine and somatostatin, with receptor heteromerization being a key molecular mechanism (Agnati et al., 2003). In some cases, the formation of such heteromers may change the pharmacology of the resulting complex in significant ways (Leonard and Mailman, 2006). Finally, a number of interactions between the third cytoplasmic loop of D2-like receptors and other proteins is likely to influence D2-like receptor signaling. D2- and D3-receptors (but not D1 or D4) bind the actin-binding protein filamin A (ABP-280), with potential effects on signaling (Li et al., 2000). The third cytoplasmic loop of the

DOPAMINE RECEPTOR PHARMACOLOGY D2-receptor includes a binding site for spinophilin, a scaffolding protein that also binds protein phosphatase 1 that is critical for dopamine-induced modulation of glutamate receptor activity (Smith et al., 1999, Yan et al., 1999). Other proteins that can play a role include calmodulin Nek, Grb2, c-Src and a variety of G-protein regulators, including various RGS proteins (Zhong and Neubig, 2001; Boutet-Robinet et al., 2003; Rahman et al., 2003).

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overview of investigational drugs (Fig. 4.2). The strategy of ‘dopamine replacement’ using levodopa is acknowledged as the gold standard, but equally well known are the limited periods of full efficacy and other subsequent problems that occur after the ‘honeymoon’ period. It is accepted that the problems of loss of levodopa efficacy occur because of progressive, cumulative loss of dopamine neurons (Muenter et al., 1974; Marsden and Parkes, 1976; Spencer and Wooten, 1984; Nutt, 1987). In theory, it should be possible to match levodopa in efficacy by a dopamine agonist (or mixture of dopamine agonists) that target the ‘right’ dopamine receptor isoform(s). One contribution of dopamine receptor pharmacology can be an answer to the question of which receptor(s) this should be. We hope that the material reviewed earlier in this chapter is a useful starting point. The relatively low expression of both the D4- and D5-receptors in the basal ganglia suggests these two

4.4. Future goals and directions in dopamine receptor pharmacology 4.4.1. The D2 dogma: an unresolved conundrum in the pharmacology of Parkinson’s disease Chapters 32 and 33 in this volume provide a detailed overview of both levodopa and its adjuvants, as well as dopamine agonists, and Chapter 40 provides an

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Fig. 4.2. Some of the dopamine (D2/D3) agonists currently approved for use in Parkinson’s disease and related compounds. Ropinirole (Requip) and pramipexole (Mirapex) have largely replaced bromocriptine and pergolide in common use. Rotigotine is in late-stage clinical trials and may have been approved by the time this volume is published, whereas quinpirole is the most commonly used D2 agonist in laboratory studies, both in vitro and in vivo. Apomorphine is a high-affinity D2-agonist that may also have important D1 properties (see text and Fig. 4.3).

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receptors are unlikely targets for antiparkinson medication. Indeed, while no D4-agonists are currently in clinical trial, the results of human studies with selective D4-antagonists (Merchant et al., 1996; Bristow et al., 1997; Truffinet et al., 1999) are consistent with a lack of utility in D4 agonism in treating motor deficits. The matter becomes more controversial in evaluating the relative importance of the D1-, D2- and D3receptors. The parallel between parkinsonism induced by typical antipsychotic drugs (D2 dopamine antagonists) and some of the signs and symptoms of Parkinson’s disease led to the widely held belief that the beneficial actions of levodopa were primarily due to activation of D2-like receptors (Cederbaum and Schleifer, 1990). The currently approved dopamine agonists (Calne, 1999; Hobson et al., 1999) are (with one exception) a series of both selective and nonselective drugs primarily targeting these two D2-like receptors. There has been some enthusiasm for the potential of D3-receptor activation. Two recently approved dopamine agonists (pramipexole and ropinirole) have apparent D3-/D2-selectivity and, although they have a clear clinical role (Hubble et al., 1995; Shannon et al., 1997), levodopa remains a far more effective drug. Indeed, the weight of the current evidence suggests that it is the D2-, not D3-, receptor that mediates most of these effects. For example, sumanirole, a D2selective analog of ropinirole (Mccall et al., 2005), has equal antiparkinson efficacy, but causes less drowsiness (Gomez-Mancilla et al., 2002). Other experimental studies with selective D2- and D3-agonists, as well as D3-antagonists, are consistent with the hypothesis that D2-, not D3-, receptors mediate the useful antiparkinson effects of almost all of the currently approved dopamine agonists. It must be remembered that the efficacy of either selective, or non-selective, D2-agonists is suboptimal, especially in later stages of Parkinson’s disease, with their use primarily in early stages of the disease to delay the use of levodopa, or as adjunctive to levodopa therapy (see Ch. 33). In general, such data suggest that the hypothesis widely extant over the past 20 years, that D2-receptors should be the primary target for therapy of Parkinson’s disease, may not be correct. On the other hand, one must reconcile the apparently anomalous actions of apomorphine. Despite being limited by short duration of action and the need to be injected, apomorphine can be nearly as efficacious as levodopa for advanced Parkinson’s disease patients (Poewe et al., 1988; Anon., 2005). Its clinical use as an oral formulation is limited by drug-related nephrotoxicity with azotemia, although the rapid onset of action with short duration has made the compound

useful as a diagnostic tool for predicting responsiveness to levodopa treatment (Poewe et al., 1993; Colzi et al., 1998). Its use has also been limited by sideeffects, including nausea, vomiting, orthostatic hypotension, local skin irritation, plus the inconvenience of the injection or pump required for the subcuteanous administration (Kapoor et al., 1990; Van Laar et al., 1992, 1996; Hughes et al., 1993). The co-administration of peripheral D2-antagonists like domperidone or trimethobenzamide attenuates many of these sideeffects. What properties make apomorphine so much more effective than the other dopamine (i.e. D2-like) agonists? We have proposed that this is a consequence of the fact that apomorphine has near-full efficacy at D1-receptors, unlike any of the other dopamine agonists, some of which (e.g. bromocriptine) are actually D1-antagonists (Mailman et al., 2006). 4.4.2. Possible role of D1-agonists in Parkinson’s disease In the early 1980s, the involvement of D1-receptors in motor control and their interaction with D2-receptors was first demonstrated (Mailman et al., 1984). Although this suggested a possible role for D1-agonists in the treatment of Parkinson’s disease, studies with the two D1-agonists then available (SKF38393 and CY208– 243) failed to demonstrate dramatic antiparkinsonian actions in the bilateral MPTP primate model (Close et al., 1985; Falardeau et al., 1988; Nomoto et al., 1988; Temlett et al., 1988; Bedard and Boucher, 1989; Boyce et al., 1990; Gomez-Mancilla and Bedard, 1991; Elliott et al., 1992; Blanchet et al., 1993; GomezMancilla et al., 1993; Nomoto and Fukuda, 1993), hemiparkinsonian monkeys (Domino and Sheng, 1993), or humans (Braun et al., 1987; Temlett et al., 1989; Tsui et al., 1989; Emre et al., 1992). Indeed, SKF38393 actually decreased the efficacy of levodopa and the D2-agonist quinpirole (Nomoto et al., 1988; Bedard and Boucher, 1989; Elliott et al., 1992), although CY208–243 had some effects against tremors in humans (Tsui et al., 1989) but not MPTP-treated monkeys (Gomez-Mancilla and Bedard, 1991). The failure of the early D1-agonists to demonstrate dramatic effects in Parkinson’s disease pharmacotherapy, coupled with the parkinsonism caused by D2 antagonists, led to the generally accepted view that ‘most investigators believe that the beneficial effects of levodopa (and other dopaminergic agonists) in parkinsonism are mediated via D2 receptors’ (Cederbaum and Schleifer, 1990). What was not fully appreciated, however, was that both SKF38393 and CY208–243 were partial, not full, D1-agonists. When dihydrexidine, the first high-affinity full D1 dopamine receptor agonist,

DOPAMINE RECEPTOR PHARMACOLOGY became available (Lovenberg et al., 1989; Brewster et al., 1990; Mottola et al., 1992), it was found, unlike the partial agonist, to have dramatic antiparkinson effects (Taylor et al., 1991). There have been later reports that other full D1-agonists have the potential to cause profound antiparkinson effects in primates, both non-human (Kebabian et al., 1992; Gnanalingham et al., 1995; Asin et al., 1997; Grondin et al., 1997; Goulet and Madras, 2000) and human (Blanchet et al., 1998; Rascol et al., 1999, 2001) (Fig. 4.3). The dramatic antiparkinsonian effects of D1-agonists predicted by dihydrexidine in non-human primates has been confirmed in many studies using other full D1-agonists (Shiosaki et al., 1996). Of particular note has been ABT-431, a drug chemical and pharmacologically similar to dihydrexidine (Michaelides et al., 1995; Shiosaki et al., 1996). A doubleblind, placebo-controlled study of ABT-431 on patients with mild to severe Parkinson’s disease showed a significant dose-related progressive increase in the median of maximum percent improvement in the UPDRS motor scores. The maximum percentage improvement (at a 30 mg dose) was comparable to the maximum improvement from levodopa (Rascol

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et al., 1999), with somewhat less dyskinesia. More recently, Rascol et al. (2001) reported the effects of ABT-431 in advanced Parkinson’s disease patients who had fluctuating responses to levodopa, complicated by dyskinesia. The authors demonstrated that ABT-431 can induce an antiparkinsonian response comparable to levodopa, but in contrast to their earlier study (Rascol et al., 1999), the authors noted that the induction of dyskinesia was similar to levodopa. As noted in the previous section, this notion is supported by the D1 propertries and high antiparkinson efficacy of apomorphine. The consistent and extensive non-human primate literature, coupled with the limited human studies outlined above, suggest that the D1-receptor may be a useful Parkinson’s target. 4.4.3. Can dopamine receptor pharmacology influence dyskinesias? Dyskinesias induced by levodopa remain one of the troubling consequences of long-term therapy (see Ch. 40). Levodopa-induced dyskinesias have been attributed to denervation supersensitivity of dopamine receptors, but the mechanisms are far more complex, with no

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Fig. 4.3. Drugs and experimental ligands that have affinity for D1-receptors shown in approximate order of discovery (from left to right and top to bottom). Apomorphine is generally considered a high-affinity D2-agonist, but unlike other approved dopamine agonists, also has significant D1 intrinsic activity. SKF38393 was the first selective D1-agonist, albeit of low intrinsic activity. Dihydrexidine was the first high-affinity full D1 agonist. More recent compounds of research interest are shown in the second row. A-86929, an analog of dihydrexidine, is the active species produced from ABT-431, a drug that equaled levodopa in efficacy in two clinical trials. Dinapsoline is the newest agent that is reported not to induce tolerance in rats, unlike A-77636 that induces tolerance in murine and primate species.

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single receptor identified as the responsible culprit. Although some form of denervation supersensitivity may play a role, it is not a response simply to changes in bulk expression of dopamine receptors and may well involve other neurotransmitter systems, such as GABA, excitatory amino acids and peptides (Bedard et al., 1992). The contribution of dopamine receptors to the genesis of dyskinesia is a subject of long debate; the current data have suggested that dyskinesia cannot be solely ascribed to the D2- or D1-receptor and that some cooperation between the two receptors appears necessary for their manifestation. 4.4.3.1. The role of D1-receptors in the genesis of dyskinesia A role for the D1-receptor in the genesis of dyskinesia was hypothesized by Boyce et al. (1990), who showed that co-administration of the D1-antagonist SCH23390 prevented levodopa-induced chorea at the time of peak effect. Mehta et al. (2000) suggested that subthalamic D1-receptors may play a role in the development of dyskinesia, whereas Boyce et al. (1990) observed a rebound exaggeration of chorea after the SCH23390 treatment, at the time when levodopa-induced chorea would normally be subsiding. Some studies have reported that D1-agonists have beneficial effects on pre-existing dyskinesias, either in animals (Blanchet et al., 1993) or humans (Rascol et al., 1999), sometimes improving motor symptoms without concomitant dyskinesia. D2-agonists or levodopa generally produce some dyskinesia with improvement in motor function. Several studies have shown that D1-agonists were somewhat superior in abolishing dyskinesias while retaining antiparkinsonian activity. A later study from this group showed that two D1-agonists, A-86929 and A-77636, had greater antiparkinsonian action and less propensity to produce dyskinesia in levodopa-primed MPTP-lesioned subjects (Pearce et al., 1995, 1999). Although there are only a few published human studies with D1-agonists, Rascol et al. (1999) reported that ABT-431 showed clear efficacy in relieving parkinsonian motor symptoms comparable with levodopa, at the mean time with reduced tendency to induce dyskinesia. While these data were consistent with many of the non-human primate studies, this same group recently reported that ABT-431 causes similar responses to levodopa in terms of both antiparkinsonian effects and induction of dyskinesias (Rascol et al., 2001). In the one limited human trial, dihydrexidine also caused the same degree of dyskinesia as levodopa (Blanchet et al., 1998). Clearly, additional studies in humans will be needed to resolve these issues, especially in levodopa-naive Parkinson’s patients.

4.4.3.2. The role of the D2-receptor in the genesis of dyskinesia A role for the D2-receptor has also been implied, but data showing that all D2-agonists (full or partial), including quinpirole, (þ)-4-propyl-9-hydroxynaphthoxazine (PHNO), bromocriptine, terguride and (–)-3-(3hydroxyphenyl)-N-n-propylpiperone reproduced the same dyskinesia, the intensity and duration of which were dose-dependent and paralleled the therapeutic effect (Gomez-Mancilla and Bedard, 1991). The partial D1-agonist CY-208,243 induced antiparkinsonian effects at a low dose, but also a dyskinetic effect at a higher dose. The effect of either D1- or D2-agonist was totally suppressed by the dopamine-depleting agent a-methyl-p-tyrosine, but the effect was restored by a small subthreshold dose of the other (complementary) agonist (Gomez-Mancilla and Bedard, 1992). Two newer clinical available D2 dopamine agonists (pramipexole and ripinorole), however, have been shown to decrease the incidence of dyskinesia when used as initial treatment (Parkinson Study Group, 2000; Rascol et al., 2000). These drugs also reduce dyskinesia and fluctuations in advanced Parkinson’s disease when used as an adjunctive to levodopa (Wermuth, 1998). 4.4.3.3. The role of pulsatile delivery of dopamine in the genesis of dyskinesia While considering the role of the dopamine receptor subtypes in dyskinesia, the duration and fashion (such as smooth or pulsatile) of the receptor occupancies may also play an important role. Because long-acting dopamine agonist drugs induce a lower incidence of dyskinesia in MPTP-treated primates and patients with Parkinson’s disease compared to pulsatile treatment with levodopa, it is suspected that continuous dopaminergic stimulation is a means of avoiding induction of dyskinesia. Recently, it was reported that multiple small doses of levodopa plus entacapone reduced dyskinesia induction in MPTP-treated drug-naive primates compared to less frequent higher-dose administration (Smith et al., 2005). These data support the notion that pulsatile stimulation contributes to the development of dyskinesia. Given the facts that the dopamine agonists such as pramipexole and ripinorole have longer halflives than does levodopa, the decreased dyskinesia of these two agents in clinical trials may reflect better continuous dopamine receptor stimulation than a ‘better receptor profile’ in dyskinesia. It is unclear whether novel agonists may play a major role in preventing or treating these dyskinesias, yet several points should be noted. First, D1-agonists clearly have antiparkinson efficacy at least equal to levodopa and greater than any other pharmacothera-

DOPAMINE RECEPTOR PHARMACOLOGY peutic intervention that has been reported. Second, while D1-agonists may always induce dyskinesia in levodopa-primed patients, monotherapy with D1-agonists under carefully controlled conditions could possibly provide long-term symptomatic relief without induction of dyskinesia: the data are too preliminary and contradictory to know for sure. Finally, while D1 activation is clearly the most important effect of levodopa, the degree and type of D2 activation are unknown, especially for best long-term responses. These and other questions make for a fertile research ground for the next several years. 4.4.4. Cognition and non-motor beneficial effects due to activation of dopamine receptors Whereas levodopa and D2-agonists have been known to have cognitive side-effects such as confusion and psychosis, D1 stimulation may have cognitive benefits. As summarized earlier, D1-receptors are present in high concentration in prefrontal cortex in non-human primates (Lidow et al., 1991) and optimal receptor stimulation here can improve the working-memory process (Goldman-Rakic et al., 2004). The cognitive function of the prefrontal cortex is known to be modulated by ascending monoaminergic and cholinergic systems in rats and primates (Muir et al., 1994; Granon et al., 1995; Arnsten, 1997; Robbins et al., 1998). Lesions of the mesocortical dopamine projection impair workingmemory performance in monkeys (Brozoski et al., 1979) and rats (Simon, 1981). D1-receptor activation may provide cognitive benefits based on findings that local injection of a D1-antagonist (but not a D2-antagonist) into the prefrontal cortex induced deficits in working memory in rhesus monkeys (Sawaguchi and Goldman-Rakic, 1994). It has also been demonstrated that D1-agonists can improve cognitive function in both rodents (Hersi et al., 1995b; Steele et al., 1997) and non-human primates (Arnsten et al., 1994; Schneider et al., 1994; Cai and Arnsten, 1997). The partial agonist SKF38393 improves the memory performance of reserpine-depleted monkeys, although it does not improve young control animals. The full agonist dihydrexidine improved the memory performance in both young control monkeys as well as in a subset of aged monkeys (Arnsten et al., 1994). Schneider et al. (1994) also demonstrated that dihydrexidine can cause performance improvements in MPTP-lesioned non-human primates. Finally, one of the most striking recent reports indicated that brief administration of ABT-431 can induce long-lasting reversal of antipsychotic-induced working-memory deficits in monkeys (Castner et al., 2000). Although there are overwhelming data supporting the beneficial

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effects of D1 stimulation in cognition and memory, there is also a clear dose-dependency for these effects and, paradoxically, higher doses have been demonstrated to impair memory performance in aged monkeys (Castner et al., 2000). The mechanism by which D1-receptors affect memory and cognition is not fully understood. It has been shown that dihydrexidine increases extracellular acetylcholine levels in the rat striatum and frontal cortex (Steele et al., 1997) and SKF38393 increases hippocampal acetylcholine release in memory-impaired aged rats (Hersi et al., 1995a; Mercuri et al., 1997). As noted earlier, D1receptors in both pyramidal and non-pyramidal neurons may interact with glutamatergic inputs and a recent model of dopamine modulation of working memory posits a central role of D1-receptors in enhancing glutamatergic input to such neurons (Muly et al., 1998). These and other mechanisms will, no doubt, be further explored, but it is clear that the D1-receptor has an important role in modulating cognitive performance under the control of the prefrontal cortex. It supports the potential use of D1-agonists in the treatment of cognitive deficits and/or negative symptoms in a variety of conditions, including schizophrenia, Parkinson’s disease and age-related memory decline.

Declaration of conflict of interest The authors have a potential conflict of interest based on an equity interest in DarPharma, Inc. that licensed technology from the University of North Carolina and Purdue University of which they are co-inventors.

Acknowledgments This work was supported, in part, by Public Health Service research grants MH40537 (RBM), NS39036 (RBM) and AG21491 (XH).

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Section 2 General aspects of Parkinson’s disease

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 5

History of Parkinson’s disease JENNIFER G. GOLDMAN* AND CHRISTOPHER G. GOETZ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

5.1. Introduction Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward and to pass from a walking to a running pace: the senses and intellects being uninjured (Parkinson, 1817) More than 250 years after James Parkinson’s birth (1755–1824), it is only fitting to introduce this chapter on the history of Parkinson’s disease with one of the most famous passages from An Essay on the Shaking Palsy (1817). This celebrated quotation aptly describes clinical signs and symptoms of the eponymous Parkinson’s disease but does not capture all features associated with Parkinson’s disease today. As the first known published case series, his Essay remains a pivotal piece in the history of Parkinson’s disease. Many researchers and clinicians from the 19th century to the present day have heeded Parkinson’s pleas, expressed in his Essay, to decipher the nature of this disease, first to understand its pathological basis and then explore treatments for this malady. Since the 19th century, the field of Parkinson’s disease has witnessed remarkable discoveries in pathological, neurochemical and genetic substrates and advances in medical and surgical therapeutics. This chapter aims to outline seminal events in the history of Parkinson’s disease and expand the topic as last presented in the Handbook of Clinical Neurology in 1986. We hope to provide the reader with a tour of the discoveries related to Parkinson’s disease and other points critical to our current understanding of Parkinson’s disease. Since it is only possible within the scope of this chapter to focus on a small selection of events and publications, we regret that we are unable to

acknowledge all of those whose contributions have advanced our knowledge of Parkinson’s disease.

5.2. Early descriptions 5.2.1. Parkinson’s historical accounts of tremor and scelotyrbe In the second chapter of An Essay on the Shaking Palsy, Parkinson explores each cardinal feature of paralysis agitans and cites supporting medical literature known at that time. He discusses classification schemes for tremor, recognizing the observation of tremor since the second century. In his text De Tremore (169 and 180 AD), Galen categorized movements as either ‘voluntary: due to impulse or will and mediated by nerves and muscles’ or ‘vital: acting through arteries and through the heart’ (Koehler and Keyser, 1997). Weakness in the force supporting the body caused tremor, as manifested by alternating upwards motion of muscle and downwards movement of the subject’s weight. Lack of nourishment, gastric or cardiac disease, violent or excessive chills, or carrying heavy objects worsened tremor and treatments focused on nourishment and purges. In contrast to tremor, palpitations affected any body part at rest (muscles, arteries or skin) and resulted from expansion and collapse of the cavities. Exacerbating factors and treatment modalities were similar to those of tremor. Juncker divided tremors into ‘Active, those proceeding from sudden affection of the minds, as terror, anger, &c. and Passive, dependent on debilitating causes, such as advanced age, palsy, &c.’ (Parkinson, 1817). More akin to the description of the ‘shaking palsy’ was the division of tremor based on presence at rest and voluntary movement provided by Sylvius de la Boe¨ (1614–1672), professor of medicine at

*Corresponding author: Jennifer G. Goldman, M.D., Rush University Medical Center, Department of Neurological Sciences, 1725 W. Harrison Street, Suite 755, Chicago, IL 60612, USA. E-mail: [email protected], Tel: þ1-312-5632900, Fax: þ1-312-563-2024.

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Leiden. The Frenchman Sauvages (1706–1767) similarly distinguished tremor by its associated activity–rest tremor (tremor coactus) and action tremor. Parkinson quotes Sauvages’ depiction of tremor coactus: ‘the tremulous parts leap and as it were vibrate, even when supported: whilst every other tremor . . . ceases, when the voluntary exertion for moving the limbs stops, or the part is supported, but returns when we will the limb to move; whence, he says, tremor is distinguished from every other kind of spasm’. In addition, Parkinson alludes to rest and action tremors described by Gerard van Swieten (1700–1772), a Dutch physician, philosopher and pupil of Boerhaave. In the historical context of rest tremor as ‘palpitations’ or tremor coactus, Parkinson writes that palpitation ‘is distinguishable from tremor, by the agitation, in the former, occurring whilst the affected part is supported and unemployed and being even checked by the adoption of voluntary motion; whilst in the latter, the tremor is induced immediately on bringing the parts into action’. In addition to historical references provided in the Essay, Parkinson demonstrates an understanding of tremor in his other medical writings. He defines ‘tremor’ in Medical Admonitions (1801), his medical handbook for the lay public, as ‘in fever, a sign of great disability’. This illustrates the confluence of terms to describe fever, rigor, palpitations and tremor and that tremor of the ‘shaking palsy’ remained to be defined. Many biographical sketches of Parkinson have remarked on the possible influence of John Hunter (1728–1793), the English surgeon and experimentalist, on Parkinson’s knowledge of tremor. In Hunterian Reminiscences, John William Keys Parkinson transcribed cases of tremor from his father’s short-hand notes. Although it is not known whether Parkinson actually attended Hunter’s lectures, his notes include two cases with tremors: ‘A lady, at the age of seventy-one, had universal palsy: every part of the body shook which was not fully supported’ and Lord L, whose ‘hands were [are] almost perpetually in motion and he never feels the sensation in them of being tired. When he is asleep his hands, &c. are perfectly at rest; but when he wakes in a little time they begin to move’ (Currier, 1996). Parkinson also discussed the origins of festinating gait, the ‘propensity to bend the trunk forwards and to pass from a walking to a running pace’ in the Essay. This scelotyrbe festinans was first described in 1758 by Hieronymus David Gaub or Gaubius (1705–1780), professor of chemistry and medicine at Leiden and physician to the Prince of Orange. Quoting Gaubius, Parkinson writes: cases occur in which the muscles duly excited into action by the impulse of the will, do then,

with an unbidden agility and with an impetus not to be repressed, accelerate their motion and run before the unwilling mind. It is a frequent fault of the muscles belonging to speech, not yet of these alone: I have seen one, who was able to run, but not to walk. Sauvages contrasted this scelotyrbe with chorea viti as scelotyrbe festinans occurred in older individuals. Although Parkinson’s review of medical literature demonstrated shared features of tremors, palpitations and gait disorders, he truly believed that the ‘shaking palsy’ represented a unique disease warranting report and further study. 5.2.2. Other early descriptions Since Parkinson’s Essay, many authors have speculated on the earliest descriptions of tremor and parkinsonism. Ancient Indian ayurvedic literature, including texts written in Sanskrit as early as 2500 BC, contains references to tremor. The ancient text Charaka Samhitha (c. 2500 BC) describes possible parkinsonian features using multiple terms: kampa vata (tremors due to vata, a force composed of ether and air and responsible for movement and sensation), sirahkampa (head tremor), cestapranasa (akinesia), stabdhagatratratva (rigidity), cittanasa (dementia) and buddi pramaha (confusion) (Manyam and Sanchez-Ramos, 1999). A later Sanskrit text, Basavarajiyam (1400 AD), further elaborates on ‘tremors of hand and feet, difficulty in body movements, disturbed sleep and dementia’ as symptoms of kampa vata. Kampa vata is used today to designate Parkinson’s disease. In fact, ayurvedic treatments for kampa vata include herbal seeds from atmagupta (Mucuna pruriens) and Hyoscyamus reticulatus, dopaminergic and anticholinergic agents, respectively. In 1937, chemical analysis demonstrated the presence of levodopa in M. pruriens seeds and, subsequently, several open-label studies have investigated this herb in Parkinson’s disease (Parkinson Study Group, 1995; Nagashayana et al., 2000). Ancient Chinese descriptions of tremor and stiffness appear as early as 425–221 BC with The Yellow Emperor’s Internal Classic, as compiled in the system of traditional Chinese medicine (Zhang et al., 2006). Ancient Chinese treatments of tremor or stiffness resulting from altered wind included Jinya wine, Gastrodia tuber and other herbals that may contain anticholinergic and dopaminergic properties. Other authors have proposed descriptions of parkinsonism and tremor during the Renaissance based on artistic references by Da Vinci and Rembrandt, although these remain

HISTORY OF PARKINSON’S DISEASE controversial (Calne et al., 1989; Stern, 1989; Lakke, 1994). Literary references of the Enlightenment have chronicled suspected parkinsonism in the renowned philosopher Thomas Hobbes (1588–1679): ‘He had the shaking Palsey in his handes; which began in France before the year 1650 [aged 62] and haz growne upon him by degrees, ever since, so that he haz not been able to write very legibly since 1655 or 1666’ (Freedman, 1989). In a 1776 medical treatise, Johannes Baptiste Sagar (1732–1813) observed likely parkinsonian features from afar, as did Parkinson: ‘In Vienna, I saw a man above the age of fifty who was running involuntarily, being also incapable of keeping direction so as to avoid obstacles; in addition, he suffered from ptyalism’ (Stern, 1989). While these historical references illustrate clinical descriptions comparable with parkinsonism in the literature, Parkinson’s Essay remains noteworthy in unifying a series of cases with similar features and coalescing signs into a syndromic entity.

5.3. James Parkinson (1755–1824) 5.3.1. Parkinson’s multifaceted career Although most often associated with the eponymous neurological disorder, Parkinson was a prolific and esteemed writer in medicine, politics, social welfare, mental health, chemistry and geology. Born into a medical family in the late 18th century in Hoxton, UK, he followed the footsteps of his father, John Parkinson, apothecary and surgeon for many years in Hoxton. Young James often accompanied his father on resuscitation and recovery operations for the Royal Humane Society and served as an apprentice to him. Two subsequent generations carried on the family medical legacy, as one of James Parkinson’s sons, John William Keys Parkinson and his son, James Keys, practiced with their respective fathers in Hoxton. It is known that James Parkinson studied at the London Hospital Medical College as one of the earliest pupils, obtained his diploma of the Company of Surgeons in 1784 and was elected as a Fellow to the Medical Society of London in 1787 after the presentation of his first paper, ‘Some accounts of the effects of lightning’ (1789). In 1785, as part of his medical training, it is believed that Parkinson attended the surgical lectures of John Hunter, as his short-hand lecture notes on tremor and paralysis were later transcribed and published by his son, John W. K., in Hunterian Reminiscences. Parkinson’s multifaceted career involved forays into politics, social reform and science, as well as

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medicine. Writings early in his medical career focused on the political reforms and revolutions in late 18thcentury England and France. He wrote numerous pamphlets (1793–1796) under the pseudonym Old Hubert and belonged to the Society for Constitutional Information (established in 1780) and the London Corresponding Society (established in 1792), political societies demanding parliamentary reform and increased popular representation. His political endeavors culminated with the Pop-Gun Plot (1795), which implicated several London Corresponding Society members in an assassination attempt on King George III with an air gun. As a critical witness, Parkinson appeared before the Privy Council, cleverly trying to avoid incriminating himself but eventually admitting his authorship of various political writings as Old Hubert. Subsequently, Old Hubert retired, but Parkinson continued his social activism in writings on child abuse, education for the poor, work reforms, mental health care and establishment of fever wards in works such as The Villager’s Friend and Physician (1804), Remarks on Mr. Whitbread’s Plan for the Education of the Poor; with Observations of Sunday School and on the State of the Apprenticed Poor Observations on the Act of Regulating Mad-Houses (1811) and On the Treatments of Infectious or Typhoid fever (1824). Parkinson’s medical and scientific writings encompass a broad spectrum of topics. He outlines views on medical education and training in the 19th century in The Hospital Pupil (1800). Publications, such as Some Accounts of the Effects of Lightning (1789) and Dangerous Sports (1800), share a common theme of accidents and injuries. Lay-person handbooks, Medical Admonitions (1801) and Villager’s Friend and Physician (1804), define common medical symptoms, instruct families to differentiate serious medical ailments from minor ones and offer opinions on health preservation. Personal experiences and medical controversies relating to gout appear in Observations on the Nature and Cure of Gout (1805). He published several works with his son, James W. K., on appendicitis, fever wards and trismus. Parkinson also achieved high acclaim for writings on chemistry and, in particular, geology or oryctology (known today as paleontology). The Chemical Pocket Book (1800), a short book for chemists of all levels, carried up-to-date 19thcentury information on chemical properties of earths, calorics, gases, metals and vegetable and animal substances. Parkinson was well respected for his texts and articles on geology, Organic Remains of a Former World (1804), Observations on Some of the Strata in the Neighbourhood of London and on the Fossil Remains Contained in Them (1811) and Outlines of Oryctology: An Introduction to the Study of Fossil

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Organic Remains (1822). He provided hundreds of figures and plates of fossil specimens in these works, often from his personal collection. A founding member of the Geological Society (1807), he acquired a notable collection of fossils, shells, metals, coins and medals that were housed at No. 1 Hoxton Square and can now be found in British museums. In geological circles, Parkinson’s name is preserved in the classification of several species: a tropical cephalopod mollusk, Nautilus parkinsoni and fossils ammonite Parkinsonia parkinsoni, crinoid Apiocrinus parkinsoni, gastropod Rostellaria parkinsoni and stemless palm Nipa parkinsoni. In spite of Parkinson’s prolific and active career, no portrait of him has ever been verified. 5.3.2. An Essay on the Shaking Palsy Parkinson’s An Essay on the Shaking Palsy (1817) likely represents his best-known medical work (Fig. 5.1). The five chapters of this 66-page octavo volume examine symptoms and cases, discuss differential diagnoses, propose etiologies and, finally, consider treatments. Parkinson describes six cases, three of whom were merely observed casually in the street. Despite his incomplete assessment of cases

and conjectures regarding pathogenesis, Parkinson states his ‘duty to submit his opinions to the examination of others, even in their present state of immaturity and imperfection’. In fact, he quite accurately and perceptively described many features of the disease – its insidious onset and slow progression, asymmetry and presence of rest tremor, flexed posture and festinating gait. He recognized more advanced states with increased immobility and dependence as well as disturbances in sleep and bodily functions of bowels, saliva, speech and swallowing. Even though bradykinesia and rigidity were not demonstrated until later in the 19th century, Parkinson identified that weakness in the shaking palsy ‘depends not on general weakness, but merely on the interruption of the flow of the nervous influence to the affected parts’. Descriptions of the six cases, all men over the age of 50, vary in the level of detail observed and presented. Parkinson instructs the reader that almost every symptom mentioned previously in the first chapter could be seen in Case I, a gardener with left upper-extremity tremor. Although half of the cases were not formally examined, Parkinson keenly observed their agitation and tremor, speech disturbances and abnormalities of gait and posture. In two of the three distantly

Fig. 5.1. James Parkinson’s An Essay on the Shaking Palsy, 1817.

HISTORY OF PARKINSON’S DISEASE witnessed cases, he describes (1817) particular gait disturbances and techniques to overcome them: Case III: He was entirely unable to walk; the body being so bowed and the head thrown so forward, as to oblige him to go on a continued run and to employ his stick every five or six steps to force him more into an upright posture, by projecting the point of it with great force against the pavement. Case IV: It seemed to be necessary that the gentleman should be supported by his attendant, standing before him with a hand placed on each shoulder, until, by gently swaying backward and forward, he had placed himself in equipoise; when, giving the word, he would start in a running pace, the attendant sliding from before him and running forward, being ready to receive him and prevent his falling, after his having run about twenty paces. Early allusions to epidemiological factors of occupations (gardener, sailor, magistrate’s attendant), habits (‘remarkable temperance and sobriety’ versus ‘indulgence in spirituous liquors’), medical ailments (rheumatism, rib inflammation, lumbago) and preceding events (cold drafts, trauma) appear as possible remote causes but lack sufficient information to establish causation. Case VI reveals not only the dramatic suppression of tremor after a stroke paralyzed the patient’s right arm and leg but also the reappearance of the shaking as his strength returned. Curiously, this occurrence did not spark any hypotheses of clinical–pathological correlation. In the third chapter, Parkinson differentiates tremor of the shaking palsy from that associated with apoplexy, epilepsy, worms, alcohol, caffeine and old age. He astutely acknowledges problems in using past terminology to codify signs and symptoms in a new disorder: Treating of a disease resulting from an assemblage of symptoms, some of which do not appear to have yet engaged the general notice of the profession, particular care is required whilst endeavouring to mark its diagnostic characters. It is sufficient, in general, to point out the characteristic differences which are observable between diseases in some respects resembling each other. But in this case more is required: it is necessary to show that it is a disease which does not accord with any which are marked in the systematic arrangements of nosologists; and that the name by which it is here distinguished has been hitherto vaguely applied to diseases very different from each other, as well as from that to which it is now appropriated.

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Parkinson delves into the ‘supposed proximate causes’ of the shaking palsy in his fourth chapter, proposing the superior part of the medulla spinalis as the neuroanatomical site of injury. His rationale for involvement of the medulla spinalis was based on the following: by the nature of the symptoms we are taught, that the disease depends on some irregularity in the direction of the nervous influence; but the wide range of parts which are affected, that the injury is rather in the source of this influence than merely in the nerves of the parts . . . that the proximate cause of the disease is in the superior part of the medulla spinalis; and by the absence of any injury to the senses and to the intellect, that the morbid state does not extend to the encephalon . . . Assuming however the state just mentioned as the proximate cause, it may be concluded that this may be the result of injuries of the medulla itself, or of the theca helping to form the canal in which it is inclosed. The great degree of mobility in that portion of the spine which is formed by the superior cervical vertebrae, must render it, and the contained parts, liable to injury from sudden distortions. Hence therefore may proceed inflammation of quicker or of slower progress, disease of the vertebrae, derangement of structure in the medulla, or in its membranes, thickening or even ulceration of the theca, effusion of fluids, &c. However, Parkinson did not obtain a history of trauma in his cases and arguments for remote causes of alcohol, cold exposure or rheumatism were unsatisfactory. He cites two cases in this section, albeit complicated by spine fractures, venereal disease and rheumatism, to illustrate how pathology in the medulla region might underlie weakness, gait problems and bulbar dysfunction in these cases and in the shaking palsy. Parkinson concludes the Essay with a chapter on treatments and cures. He even entertains the idea of neuroprotection: there appears to be sufficient reason for hoping that some remedial process may ere long be discovered, by which, at least, the progress of the disease may be stopped. It seldom happens that the agitation extends beyond the arms within the first two years; which period, therefore, if we were disposed to divide the disease into stages, might be said to comprise the first stage. In this period, it is very probable, that remedial means might be employed with success: and even, if unfortunately deferred to a later period, they

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might then arrest the farther progress of the disease, although the removing of the effects already produced, might be hardly to be expected.

from various causes and exhibiting different phenomena. The importance of his remarks, however, demands an early attention in our analytical department.

While typical treatments focused on bleeding from the upper neck, application of vesicatories and draining resultant purulent discharges, the use of internal medicines was not recommended until a better understanding of the shaking palsy was achieved. In closing, Parkinson implored that others study this condition:

However, The Medico-chirurgical Journal more leniently excused his conjectures based on his respected reputation as ‘the name of the author would be a sufficient passport to publicity and security from aspersion, for a much less respectable performance’. Other laudatory reviews, such as one in The London Medical Repository, extolled Parkinson’s ‘characteristic modesty and the acuteness of his observation’ (Herzberg, 1990). Gradually awareness of Parkinson’s Essay and the clinical entity of paralysis agitans or shaking palsy spread among medical communities in 19th-century England. References to the Essay and case reports of paralysis agitans appeared in medical literature or lectures at London medical centers as early as the 1830s, only 13 years after Parkinson’s publication (Louis, 1997, Elmer, 2005). However, many of these references merely duplicated Parkinson’s clinical descriptions, thereby demonstrating dissemination of his Essay in medical communities but not necessarily increasing one’s knowledge of disease, etiology or localization. Several British physicians, such as Drs John Elliotson (1791–1868), Marshall Hall (1790–1857) and Thomas Watson (1792–1882), to name a few, presented original case reports of paralysis agitans in lectures at London hospitals and Lancet publications. The immediate period following Parkinson’s initial description was marked by reports of various types of tremors and neurologic symptoms classified as paralysis agitans. This inevitable step in the natural history of defining a novel condition, however, generated much confusion as features of other neurological illnesses were not distinguished from true paralysis agitans. For example, Dr. Elliotson, practitioner at St. Thomas’ Hospital in London, described tremor and neurologic symptoms ascribed to paralysis agitans in cases of young men and women with variable shaking, tremors occurring after frights and spontaneous resolution of symptoms; in contrast, these conditions probably represented multiple sclerosis, conversion disorders or other neurological illnesses. Along with his weekly cases of lead-induced wrist palsy, intermittent hemiplegia, hysteria and stomach inflammation admitted under his service at St. Thomas’ hospital, Dr. Elliotson (1830) describes a case of paralysis agitans with more typical parkinsonian features. Elliotson’s articulate description of paralysis agitans with particulars of this case is reminiscent of Parkinson’s earlier descriptions. The 38-year-old patient, F.E., a schoolmaster with a previous mild head

Before concluding these pages, it may be proper to observe once more, than an important object proposed to be obtained by them is, the leading of the attention of those who humanely employ anatomical examination in detecting the causes and nature of diseases, particularly to this malady. By their benevolent labours its real nature may be ascertained and appropriate modes of relief, or even of cure, pointed out ... Little is the public aware of the obligations it owes to those who, led by professional ardour and the dictates of duty, have devoted themselves to these pursuits, under circumstances most unpleasant and forbidding. Every person of consideration and feeling, may judge of the advantages yielded by the philanthropic exertions of a Howard; but how few can estimate the benefits bestowed on mankind, by the labours of a Morgagni, Hunter, or Baillie.

5.4. Parkinsonism after 1817 5.4.1. Reception of the Essay and subsequent British observations Overall, Parkinson’s Essay on the Shaking Palsy was well received in the English medical community. Accounts of three reviews in 1817–1818 London medical journals have been documented by Herzberg (1990). Although these reviews are primarily praiseworthy, Parkinson’s mere speculation on localization and etiology did not elude notice of The London Medical and Physical Journal and The Medico-chirurgical Journal reviewers. Bold comments from The London Medical and Physical Journal include the following: He very modestly apologises for the hypothetical nature of his speculations on this head. In this we think he hardly does himself justice. At the same time, he appears to us to have marked only one cause for a variety of diseases arising

HISTORY OF PARKINSON’S DISEASE injury, anxiety, intermittent increased alcohol use and mercurialization, revealed an 18-month history of gradually progressive tremor (beginning in his head and tongue before spreading to his right arm), festinating speech and gait, headache, anxiety and constipation. Intrigued by tremor onset in the head and tongue, Elliotson writes that speech caused the patient’s tongue ‘to quiver like the tongue of a serpent; presently a confused murmur [was] heard and then suddenly he [brought] out his words with extreme rapidity; and such is the effort that he cannot stop himself, but repeats the few last words again and again. It is a phenomenon analogous to the running which occurs on the attempt to walk’. Since traditional treatments had failed, two drachms of subcarbonate of iron were prescribed. A subsequent lecture by Elliotson (1830) provides disappointing follow-up of iron’s efficacy: It is a curious thing that St. Vitus’s dance is a disease that will yield in a very marked manner to the exhibition of iron and that I was first led to know this by giving the carbonate of iron in a case of paralysis agitans with complete success, after it had proved intractable to every other means. Thinking that paralysis agitans and St. Vitus’s dance were very much alike, I gave the remedy in chorea and cured a large number of cases, but I have never since been able to cure a case of paralysis agitans, though I have had five or six cases of the disease and given the carbonate of iron very freely. I believe the reason is, that in paralysis agitans the disease depends generally upon a structural change – that the nervous system is in a state of organic disease; and when that is the case, you cannot expect any relief to be produced by such remedies. I am aware of only one dissection in such a case and that is related by the late Mr. Parkinson, in which he said, that many of the nerves had become indurated like tendons, the medulla oblongata and pons variolii were greatly condensed. I have no doubt that if other cases were examined, an organic change would also be found. ‘Organic’ types of paralysis agitans encompassed those occurring in older age groups and were marked by treatment difficulties, in contrast to cases presenting in younger patients, resulting from fright or spontaneously remitting. In developing tremor classification schemes, British physicians also differentiated the tremor of paralysis agitans from tremor related to alcohol, tobacco, stimulants and narcotics. Neuropathological advances remained dormant despite Elliotson’s notice of Parkinson’s ‘curious case’ who experienced temporary suppression of tremor in

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the setting of hemiplegia. A single case report of ‘hemiplegic paralysis agitans’ was added to the literature by Dr. Marshall Hall (1838). Notable for rightsided ‘weakness and agitation . . . a peculiar lateral rocking motion of the eyes and a degree of stammering and defective articulation’ in a 28-year-old male, this case would probably not be diagnosed as Parkinson’s disease today. Neuropathology nevertheless revealed involvement of the tuber annulare or tubercula quadrigemina, perhaps suggesting alternative localization in the brain. Although this period spawned observations and isolated case reports of tremor and paralysis agitans, a wide range of neurological signs and symptoms was depicted as paralysis agitans, with some cases likely inappropriately designated. Clinical observations, particularly by Charcot and his students at the Salpeˆtrie`re, would be necessary to refine the core clinical features of true parkinsonism. 5.4.2. Observations of paralysis agitans in Europe Outside England in the middle to late 19th century, other physicians studied the symptoms and pathology of paralysis agitans. The French physician Dr. Armand Trousseau (1801–1867) distinguished paralysis agitans from chorea and believed ‘paralysis agitans’ to be a misnomer as paralysis was not a true feature. Acknowledging the lack of pathological study in France, Trousseau drew attention to the work of the Viennese professor Johann Oppolzer (1808–1871), who performed an autopsy on a case of paralysis agitans, thought to be the first recorded pathology after Parkinson’s Essay. His case involved a 72-year-old male whose symptoms arose following shock from the 1848 bombardment of Vienna. Autopsy findings included induration of the pons varolii and medulla oblongata with increased connective tissue in the lateral spinal cord columns. As manual examination of tone developed later in the 19th century, Trousseau noted contracted muscles and stiffness in paralysis agitans (Morris and Rose, 1989). 5.4.3. Charcot and Parkinson’s disease A seminal figure in the history of Parkinson’s disease was the French physician, Jean-Martin Charcot (1825–1893), who practiced and taught at the Hoˆpital de la Salpeˆtrie`re in Paris. His elaboration of motor and non-motor features of the disorder, distinction of paralysis agitans from multiple sclerosis and amyotrophic lateral sclerosis, advocacy of clinicopathological studies and, of course, coining the eponym Parkinson’s disease remain his legacy. Both his formal Friday lectures and more casual case presentations at his lec¸ons du mardi (Tuesday lectures) at the

116 J. G. GOLDMAN AND C. G. GOETZ frequency tremors were found in hysteria and mercurialSalpeˆtrie`re highlighted his neurological teachings and ism. He described rest tremor as ‘the parts of the hand demonstrations. Whereas these amphitheater settings oscillate in almost a pathognomonic manner. The fingers provided visual patient displays, many medical eleapproach the thumb as if to spin wool and simultaments were captured by artistic means and recorded in neously the wrist and forearm flex to and fro’ (Charcot, La Nouvelle Iconographie de la Salpeˆtrie`re (Fig. 5.2). 1887). Charcot demonstrated many of his observations Having finally obtained a copy of Parkinson’s Essay and tenets to a medical audience. Using a cleverly from Dr. Windsor, Librarian at the University of Mandesigned headband with a long thin rod and attached chester, after a frustrating search, Charcot stated that feather, Charcot illustrated his belief that head tremor ‘as short as the work is, it contains a number of superb was not part of paralysis agitans. Head tremor in paralyideas and I would encourage any one of you here [his sis agitans merely reflected overflow from body tremor students] to embark on a French translation’. As of as head motion (and feather motion) stopped when the 1887, there was still no French translation of this work. trunk or arms were supported. Charcot acknowledged that Parkinson would always be Charcot characterized bradykinesia as distinct from recognized for the first description of this condition but, rigidity and also recognized non-motor features of noting errors in the Englishman’s generality, he sought Parkinson’s disease. Slowness and poverty of moveto add his own contributions (Goetz, 1986, 2002). ment were typical: Charcot was instrumental in illuminating features of paralysis agitans. His responsibility for large numbers In some of the various patients I showed you, of patients in Salpeˆtrie`re’s wards allowed the opportunity you can easily recognize how difficult it is for to observe and treat a vast array of neurological illnesses. them to do things even though rigidity or tremor These observations led Charcot not only to characterize is not the limiting feature. Instead even a cursory different tremors by their associated frequencies and exam demonstrates that their problem relates provoking actions but also to record and study tremors more to slowness in execution of movement with devices such as sphygmographs. He noted that the rather than to real weakness. In spite of tremor, tremors of both paralysis agitans and multiple sclerosis a patient is able to do most things, but he perwere of slow frequency (4–6 oscillations/s). Tremor of forms them with remarkable slowness . . . paralysis agitans occurred at rest and was associated with Between the thought and the action, there is a slowness of movement and gait disturbances, whereas considerable time lapse. One would think neural tremor in multiple sclerosis developed with activity and activity can only be effected after remarkable increased with effort. Fast-frequency tremors (8–9 oscileffort; in reality the execution of the slightest lations/s) were associated with alcoholism, Basedow’s movement causes extreme fatigue for the patient. disease and general paresis, whereas intermediate-

Fig. 5.2. Drawing by Charcot depicting the typical flexion posture of Parkinson’s disease, in contrast to a variant with extended posture.

HISTORY OF PARKINSON’S DISEASE These phenomena have often been interpreted as weakness, but you may be assured that until late in the disease these patients are remarkably strong (Charcot, 1887, lec¸on 9). Charcot is credited with identifying rigidity and distinguishing it from spasticity: Spasticity, as you know, is of spinal origin and is more or less directly related to a physiologic or structural dysfunction of the descending spinal pyramidal tracts. What is the physiologic explanation for rigidity in Parkinson’s disease: As far as I know, nothing is known and it is just this ignorance that I plan to demonstrate to you today. I have two goals, first to stimulate you to study the phenomenon of rigidity and second to impress on you the essential distinction between rigidity and pyramidal or spinal hypertonicity, that is the absence of reflex accentuation in rigidity (Charcot, 1887, lec¸on 22). Charcot also appreciated non-motor features of fatigue, cramps, pain, characteristic joint deformities and hand postures and autonomic dysfunction. Furthermore, drawings, sculptures and photography from the Salpeˆtrie`re drew attention to the physiognomy of Parkinson’s disease patients. Artist–physician Paul Richer (1849–1932) created a statuette in 1892–1893 accurately and artistically demonstrating the parkinsonian features of a patient, Madame Gell. Charcot stressed the importance of clinicopathological correlates in neurological diseases but was not aware of the exact neuropathology of Parkinson’s disease. As such, he classified Parkinson’s disease as a ne´vrose, a term reserved for neurologic conditions without identifiable neuroanatomical lesions. Similar to Parkinson, Charcot proposed two precipitating factors: prolonged exposures to cold, damp environments and sudden encounters with intense emotional situations. He also observed cessation of tremor in late stages of the illness and suggested that tremor was absent in some cases. Suggestions of two distinct types of the disease foreshadowed today’s classification of tremor-predominant and akinetic-rigid forms of Parkinson’s disease and atypical parkinsonian syndromes. Treatments used in Charcot’s time did not reveal significant advances in efficacy. Although medications such as strychnine, ergot of rye, belladonna and opium were tried with limited benefit, hyoscyamine, an anticholinergic agent, provided some palliative action. Charcot’s contributions to Parkinson’s disease include not only his studies but also the legacy of his pupils at the Salpeˆtrie`re and the development of neurology. Pupils of Charcot such as Ordenstein wrote his medical thesis

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on Parkinson’s disease (1867) and introduced belladonna as a treatment. Eduard Brissaud (1852–1909) described midbrain lesions in Parkinson’s disease while at the Salpeˆtrie`re in 1895. The stage was set for future investigations of phenotypes and clinicopathological correlates of neurological diseases.

5.5. Pathological studies 5.5.1. Early neuropathological findings Pathological investigations of the late 19th and early 20th centuries ultimately led to the discovery of neuroanatomical lesions of Parkinson’s disease. Admittedly unsure, Parkinson proposed that abnormalities in the medulla oblongata were responsible. Subsequently Hughlings Jackson and Gowers entertained involvement of the cerebellum and motor cortex, respectively (Elmer, 2005). In his thesis on paralysis agitans and multiple sclerosis, Ordenstein (1867) analyzed clinical features of 30 patients, presenting five detailed cases and pathology in two; although one case revealed softening of the substantia nigra, this was not pursued further. In 1871, Meynert depicted damage to the corpus striatum and lenticular nucleus, suggesting basal ganglia involvement. Still, localization of Parkinson’s disease to either spinal cord or brain was debated. Diffuse sclerosis of the spinal cord with perivascular thickened neuroglia was proposed in several Lancet publications by M. Teisser (1888) and von Ketscher (1893) (Morris and Rose, 1989). A turning point arose with the report by Blocq and Marinesco (1894) of a case of hemiplegic parkinsonism and tremor due to a right cerebral peduncle tuberculoma destroying the substantia nigra. In his medical thesis, Bechet (1892) had previously reported clinical findings of this 38-year-old woman with masked facies and left-sided tremor who died from pulmonary tuberculosis (Pearce, 1989, Duvoisin, 1992). This observation generated hypotheses that the substantia nigra was the anatomic site for Parkinson’s disease. Although others reported cases with peduncular lesions and contralateral tremor, it was not until Trietiakoff’s 1919 medical thesis at the University of Paris that recognition of the substantia nigra occurred. Tretiakoff’s examination of the substantia nigra in 54 neurologic patients with Parkinson’s disease (9), hemiparkinsonism (1) and acute fatal cases of encephalitis lethargica (2) demonstrated that all cases shared degeneration of the locus niger. In those with Parkinson’s disease, Tretiakoff found depigmentation of the nigra, cellular degeneration of neurons and gliosis. Cell degeneration resulted in acute hyaline degeneration, granular degeneration or formation of de´ge´ne´rescence grumeleuse. He also found

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neuronal inclusions in 6 Parkinson’s disease cases, findings previously described by Fritz Lewy (1885– 1950), the German-born physician. In addition to loss of nerve cells in lenticular and caudate nuclei with neurofibrillary changes in some remaining cells and in the substantiae innominatae, Lewy reported spherical intra- and extracellular bodies in the nucleus basalis and dorsal motor nucleus of the vagus. The extracellular bodies resembled corpora amylacea described by Lafora in myoclonic epilepsy but the intracellular inclusions differed (Greenfield and Bosanquet, 1953; Pearce, 2001). Lewy presented the findings of neuronal inclusion bodies in the nucleus basalis and dorsal motor nucleus of the vagus in his paper, ‘Zur Pahologischen Anatomie der Paralysis agitans’ in 1910 at the Seventh annual meeting of the Society of German Neurologists and in other publications in 1912 and 1913, almost 100 years after Parkinson’s Essay. He depicted the Kugeln (‘balls’) in the globus pallidus: stained bright red with eosin, but fit to be presented with basophilic dyes, of very variable size with the chorea corpuscles of the authors; they are insoluble in either alcohol, benzol or chloroform, hence they possess a protein component. Others do dissolve in these liquids. Next to their protein, they also have a lipoid and an iron constituent. They finally become brown with osmium

and appear able to pass through the limitans gliae (Schiller, 2000). In conjunction with Trietiakoff’s observations, the inclusions gradually became known as Lewy bodies or corps de Lewy (Fig. 5.3). Pathological findings in the substantia nigra, however, remained controversial as others focused on the role of the striatum, particularly the globus pallidus. The influential husband-and-wife team, Cecile Mugnier (1875–1962) and Oskar Vogt (1870–1955), described neuroanatomical projections and structure of the striatum and thalamus, organization of cerebral cortex and basal ganglia pathology in chorea and athetosis (Vogt and Vogt, 1920; Goetz et al., 2001). The Vogts are also remembered for their creation of a multidisciplinary brain research institute, the Kaiser Wilhelm Institute in Berlin in 1920 and for Oskar Vogt’s pathological examination of Lenin’s brain, suggesting that the large number and size of pyramidal neurons in cortical regions reflected Lenin’s ‘associated thinking’, personality and genius (Haas, 2002). The first complete anatomical study of the brain in Parkinson’s disease by Foix and Nicolesco (1925) supported pathological lesions in both the striatum and substantia nigra with shrinkage of substantia nigra pigmented cells, locus coeruleus neurofibrillary changes and dorsal vagal nucleus and substantia innominata degeneration.

Fig. 5.3. Early depictions of Lewy bodies and neuropathology of parkinsonism by Max Heinrich Lewandosky (1876–1918). From (1910–1914). Handbuch der Neurologie. J. Springer, Berlin.

HISTORY OF PARKINSON’S DISEASE 5.5.2. Lessons from encephalitis lethargica Studies of postencephalitic parkinsonism fostered new clinical and pathological developments. Encephalitis lethargica or von Economo’s encephalitis occurred in Europe and North America as a result of the influenza pandemic of 1915–1926. The Baron Constantin von Economo (1876–1931) began studying the unusual ‘sleeping sickness’ in 1916 and termed this condition encephalitis lethargica. His early descriptions capture the somnolence and abnormal ocular movements: It seems strange when sleep appears as a symptom of an illness. ‘Sleeping sickness’ where the phenomenon of people falling asleep while eating or working was first described in two cases in our clinic in Vienna in 1916. Usually headache, nausea and fever were followed, often the next day, by sleeping, frequently in a most uncomfortable position. One can wake them, but in severe cases, coma can rapidly lead to death. Malfunction of eye muscles, especially oculomotor dysfunction and ptosis, was common (Dickman, 2001). Investigation of encephalitis lethargica triggered his childhood memories of the 1890–1891 Italian influenza outbreak associated with a stuporous illness, nona. In acute phases of encephalitis lethargica, patients, predominantly children and young adults, exhibited a flu-like prodrome, accompanied by somnolence, ocular and bulbar palsies, oculogyric crises, autonomic dysfunction and behavioral changes. Von Economo reported three distinct clinical presentations: (1) somnolentophthalmoplegic; (2) hyperkinetic with chorea and myoclonus; and (3) amyostatic-akinetic, similar to parkinsonism. Mortality was about 40% with chronic effects developing in many survivors; chronic neurological effects were seen in over 50% of survivors within 5 years and 80% within 10 years (Duvoisin and Yahr, 1965). Chronic symptoms included parkinsonism with prominent bradykinesia and rigidity, oculogyric crises, dystonia and behavioral features; lack of tremor, young onset and associated flu differentiated postencephalitic parkinsonism from idiopathic Parkinson’s disease. In 1917, about 100 years after Parkinson’s Essay, von Economo presented the neuropathology of encephalitis lethargica to the Psychiatric Society in Vienna. He described widespread inflammation, particularly localized to the midbrain tegmentum, thereby linking both parkinsonism and somnolence with midbrain structures. Subsequent autopsies revealed perivascular inflammatory changes in brain and spinal cord, specifically brainstem, basal ganglia and cerebellum, in the acute phase. Chronic changes involved marked degeneration, gliosis, neuronal loss

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and neurofibrillary tangles in neurons of the substantia nigra, subthalamic nucleus and hypothalamus. In 1937–1938, Hassler studied cases of presenile paralysis agitans in the Vogt collection (9 cases), those described by the Vogts as ‘status desintegrationis’ (10) and postencephalitic parkinsonism (11). The presenile cases exhibited a variety of findings but shared locus coeruleus and substantia nigra neuronal loss, particularly the stratum compactum, and postencephalitic cases demonstrated marked substantia nigra injury (Hassler, 1938). Additional study of postencephalitic parkinsonism cases by Hallervorden (1935) and Klaue (1940) confirmed substantia nigral cell loss and the presence of spherical inclusions, similar to idiopathic Parkinson’s disease. In a study of idiopathic paralysis agitans (19 cases), encephalitis lethargica (10), atypical cases (5) and neurological controls (19), Greenfield and Bosanquet (1953) further demonstrated nigral loss with even profound damage in postencephalitic cases and most apparent loss in the zona compacta, a finding consistent with Hassler’s prior work. Lewy inclusions appeared in the brainstem in all Parkinson’s disease cases but neurofibrillary tangles were more common in postencephalitic brains. In addition, Greenfield and Bosanquet described saccules of lipochrome granules found particularly in the postencephalitic cases that likely corresponded to Tretiakoff’s de´ge´ne´rescence grumeleuse. These seminal studies helped define the role of the substantia nigra, brainstem and striatum in both idiopathic Parkinson’s disease and postencephalitic parkinsonism. Interestingly, recently devised neuropathological stages of Parkinson’s disease by Braak and colleagues (2004) demonstrate initial Lewy neurite and Lewy body pathology localized in the medulla oblongata, pontine tegmentum and anterior olfactory structures in presymptomatic stages, with subsequent spread to substantia nigra, midbrain and cortex with disease progression. Although his cases were clearly symptomatic, it can be posited that Parkinson was not too far off course when he proclaimed the involvement of the medulla oblongata.

5.6. Neurochemistry, the dopamine story and basal ganglia circuitry 5.6.1. Early research on catecholamines The next phase of dramatic progress in Parkinson’s disease occurred in the early and mid 20th century, with advances in neurochemistry and the discovery of dopamine. The idea of chemical neurotransmission developed in the early 20th century with physiological

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and chemical studies of the autonomic nervous system and heart. Epinephrine (adrenaline), norepinephrine (noradrenaline), acetylcholine and eventually dopamine and serotonin were identified. Pivotal work on the initial concept of synaptic chemical transmission by British scientist T.R. Elliott (1904), the presence of parasympathetic and sympathetic nervous system substances (Vagusstoff and Acceleransstoff or acetylcholine and norepinephrine, respectively) by Viennese physiologist Otto Loewi (1921), isolation of acetylcholine from mammalian organs with demonstration of its presence at all preganglionic and selective postganglionic synapses by British physiologist Sir Henry Dale (1929–1936) and the finding of norepinephrine as the sympathetic nervous system adrenergic transmitter by Swedish scientist, Ulf von Euler (1950s), paved the way for research on neurotransmitters and the discovery of dopamine or 3,4-dihydroxyphenylethylamine as the precursor to norepinephrine (Sabbatini, 2003, Murrin, 2005). 5.6.2. The dopamine miracle The dopamine story dates back to 1910, with its initial synthesis by George Barger and James Ewens in the London Wellcome laboratories and subsequent synthesis of the D, L racemate by Casimir Funk in 1911 (Hornykiewicz, 2002a, b). Casimir Funk, along with Marcus Guggenheim, who isolated levodopa from seedlings of Vicia faba beans in 1913, hypothesized that this amino acid might be a precursor to epinephrine. Around this time, Guggenheim actually experimented with oral administration, ingesting 2.5 g of levodopa and inducing emesis; this self-administration portended later work in the discovery of Parkinson’s disease therapeutics. Biochemical studies led to the discovery of conversion of levodopa to dopamine by aromatic amino acid decarboxylase (Holtz, 1938–1939), the production of dopamine as an intermediary in norepinephrine and epinephrine synthesis and, subsequently, the dopaminergic pathway beginning with tyrosine (Blaschko, 1939; Holtz, 1939). Animal experiments in the 1930s and 1940s demonstrated D, levodopa’s vasodepressor effects, opposite those of epinephrine. Dopamine was a natural, biologically active, physiologically independent substance in both animals and humans, especially in peripheral tissues related to the autonomic nervous system. In 1951, dopamine’s presence was established in urine, adrenal glands, cardiac tissue and eyes (Goodall, 1951) and in brain, termed ‘enkephalin’ by Raab and Gigee (1951). Wilhelm Raab (1895–1970), a Viennese-born cardiologist who fled to the USA in 1938, also noted the regional distribution of encepha-

lin, with greatest amounts in the caudate nucleus. He studied the brains of 11 schizophrenic patients and 22 controls but did not find abnormalities in enkephalin. Moreover, in rats, he found that, out of a variety of toxins or chemicals administered, only dopa increased enkephalin levels in the whole rat brain. In retrospect, Raab had many clues to the dopamine puzzle but, for whatever reason, did not piece the mystery together. Later reports by Kathleen Montagu (1957) found varying amounts of catechol compounds (norepinephrine, epinephrine and hydroxytyramine) in whole brains of different animals (rats, guinea pigs, chicks, rabbits) and 3,4-dihydroxyphenylalanine in human brains. Shortly after Montagu’s report in 1958, Arvid Carlsson (1923–) et al. described new assay techniques detecting 3-hydroxytyramine in the rat brain at an amount roughly equal to norepinephrine in tissue, thereby suggesting that 3-hydroxytyramine was not just a precursor. In the 1950s, several studies focused on the catecholamine-depleting properties of reserpine, an indole alkaloid derived from the plant Rauwolfia serpentine and catecholamine restoration by levodopa. Carlsson et al. (1958) demonstrated that, like norepinephrine, 3-hydroxytyramine almost completely disappeared from brain with intravenous injection of reserpine but dramatically increased with the addition of 3,4-dihydroxyphenylalanine, accompanied by central excitement. The monoamine oxidase inhibitor iproniazid also markedly enhanced these effects. Levodopa partially restored postganglionic adrenergic neurons decreased by reserpine (Burn and Rand, 1960) and antagonized the central sedating effects of reserpine behaviorally and on electroencephalogram correlates (Carlsson et al., 1957; Degkwitz et al., 1960). Interestingly, Carlsson stumbled upon dopamine research rather fortuitously as his previous work at the University of Lund in Sweden focused on calcium metabolism. After hearing that calcium metabolism was not central to pharmacology, he went to work with Professor Bernard Brodie at the National Heart Institute in Bethesda, Maryland, USA; Brodie had been studying reserpine’s depletion of serotonin in the brain (Carlsson, 2000). Carlsson began investigating reserpine’s effects on catecholamines in adrenal medulla, heart and brain, ultimately studying dopamine. In fact, based on the localization of dopamine to the basal ganglia and the occurrence of reserpine-induced parkinsonism, he presented hypotheses that levodopa might alleviate parkinsonism by restoring dopamine levels at the First International Catecholamine Symposium in 1958. However, at another meeting in 1960, many eminent researchers rejected this hypothesis and his work on dopamine, stating that this chemical did not have a future! In the meantime, experiments in dogs and

HISTORY OF PARKINSON’S DISEASE humans (1959) demonstrated high concentrations of dopamine in the corpus striatum (basal ganglia), areas with relatively little norepinephrine (Bertler and Rosengren, 1959; Carlsson, 1959; Sano et al., 1959). Bertler and Rosengren (1959) concluded that ‘results favor the assumption that dopamine is concerned with the function of the striatum and thus with control of movement’ (Hornykiewicz, 2002b). 5.6.3. Dopamine in Parkinson’s disease: from bench to bedside Research on dopamine in human brains and ultimately Parkinson’s disease brains followed. In 1959, Oleh Hornykiewicz, Professor of Biochemical Pharmacology at the University of Vienna, and his postdoctoral fellow Ehringer began studying dopamine in the brains of normal human controls and patients with Parkinson’s disease, other extrapyramidal disorders and Huntington’s disease. Although analytic methods for catecholamines in autopsy brains were primitive, Ehringer and Hornykiewicz (1960) demonstrated a severe reduction in dopamine concentration in the striatum of 6 Parkinson’s disease brains (4 postencephalitic, 2 idiopathic). In 1961, Hornykiewicz collaborated with neurologist Walther Birkmayer, head of the neurological ward of the largest Municipal Home for the Aged in Vienna to administer intravenous levodopa to 20 parkinsonian patients (Birkmayer and Hornykiewicz, 1961). The two were amazed at the patients’ responses, which lasted several hours, and eloquently captured this dramatic improvement in bradykinesia, rigidity and motor dysfunction in both writing and film. They wrote: The effect of a single i.v. administration of Ldopa was, in short, a complete abolition or substantial relief of akinesia. Bed-ridden patients who were unable to sit up; patients who could not stand up when seated; and patients who when standing could not start walking, performed after L-dopa all these activities with ease. They walked around with normal associated movements and even could run and jump. The voiceless, aphonic speech, blurred by pallilalia and unclear articulation, became forceful and clear as in a normal person. For short periods of time, the patients were able to perform motor activities which could not be prompted to any comparable degree by any other known drug (Hornykiewicz, 2002b). A video of a 52-year-old female with postencephalitic parkinsonism documenting her baseline condition and response to intravenous 50 mg levodopa accompanies

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an article by Hornykiewicz chronicling the dopamine story in the Movement Disorders journal. Unfortunately, the original black-and-white movie of 5 patients made in Wien-Lainz Municipal Home in August 1961 has been lost. Professor Hornykiewicz has augmented the scientific literature of dopamine discoveries with his narrative accounts in papers and lectures of the many trials and tribulations of the dopamine story (2001, 2002a, b). Although the transition from bench to bedside began with the work of Hornykiewicz and Birkmayer, neurologist Andre´ Barbeau and researchers Theodore Soukes and Gerald Murphy in Montreal demonstrated a positive effect of small oral levodopa doses on parkinsonian rigidity in 1962. Five years later, at the Brookhaven National Laboratory in New York, George Cotzias (1918–1977) introduced high-dose, oral levodopa therapy to patients with symptomatic improvement (Dole, 2006). After initial study of hypertension and catecholamines at Rockefeller Institute in New York, Cotzias turned his attention to enzymes acting on catecholamines and moved to Brookhaven Laboratory. While studying chemical properties of manganese, he noted parkinsonian features in Chilean miners with manganese toxicity. Cotzias experimented with dopamine replacement in parkinsonism, devising ways to cross the blood–brain barrier in sufficient amounts without producing severe toxicity. He recognized the advantages of levodopa over D, levodopa, as the latter caused 50% of toxicity without additional benefit. In the section entitled ‘How much DOPA should be given?’ he stated: When my mother was dying of cancer of the pancreas, the physicians were afraid of making her a drug addict. They didn’t want to give her more than 15 milligrams of morphine for pain. I wanted them to give enough to stop the pain even if they gave grams of morphine. The proper dose of morphine is enough to stop the pain. The proper dose of DOPA is enough to stop the disease (Patten, 1983). Cotzias et al. (1967) studied dopa and matching placebo in 17 parkinsonian patients in metabolic wards with laboratory studies, making twice-daily detailed assessments of motor function and cinematographic records in several cases. This trial demonstrated the requirement of high doses of dopa (range 1.5–6 g/day) for symptomatic improvement, particularly tremor; the presence of gastrointestinal and hematological side-effects; and observations of better responses in more advanced cases, intermittent athetoid movements (early descriptions of dyskinesias) and possible longduration effects. Since levodopa had less toxicity and

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greater brain penetration than its isomer D, levodopa, further published trials by Cotzias et al. (1969) and Yahr et al. (1969) focused on levodopa. Cotzias et al. (1969) reported the results of chronic levodopa treatment in parkinsonism with the addition of a dopa decarboxylase inhibitor – a novel way to decrease dopa-induced peripheral side-effects and enhance dopamine penetration of the brain. Chronic levodopa therapy, especially with a dopa decarboxylase inhibitor, led to overall dose reduction, decreased toxicity and greater symptomatic improvement compared to D, levodopa. However, levodopa’s miraculous effect was tempered by the motor complications of wearing off, off-period anxiety and peak dose dyskinesias observed in some patients. These motor complications would later prove to be a major challenge in the treatment of Parkinson’s disease. Besides studying dopamine in Parkinson’s disease, Cotzias et al. included a Huntington’s disease patient in this trial, hypothesizing that alpha-methyldopa hydrazine’s reduction of the unwanted effects of increased dopaminergic stimulation might render it useful in treating chorea. In 1970, Larodopa (levodopa) was approved by the US Food and Drug Administration (FDA) and levodopa was introduced worldwide (Kapp, 1992). After studies with the decarboxylase inhibitor, carbidopa, a combination of levodopa and carbidopa was approved in the USA as Sinemet (from the Latin translation, without emesis) in 1973 and combined levodopa/ benserazide in Europe as Madopar in 1975 (Rinne et al., 1973). Despite the miraculous effects of levodopa, treatment complications emerged and the development of dopamine agonists, different levodopa preparations and non-dopaminergic agents was needed. The clinically effective, direct-acting dopamine agonist bromocriptine became available in the 1970s (Calne et al., 1974) and the ergot-derived pergolide (1989) and non-ergot pramipexole (1997) and ropinirole (1997) were later approved. Apomorphine, a short-acting agonist first studied in 1951, has witnessed a resurgence with recent approval as a rescue therapy for off-periods (Schwab et al., 1951, Dewey et al., 2001). 5.6.4. Understanding basal ganglia circuitry While some researchers investigated the biochemical properties and uses of dopamine, others studied basal ganglia functionality and pathophysiology. Historically, Denny-Brown (1960a, b) proposed that the basal ganglia were a ‘clearing house’, enhancing some cortical input while suppressing others. C. David Marsden and Mahlon DeLong posited that motor control was the primary function of the basal ganglia. A renowned figure in the history of movement disorders, the British

Professor of Neurology at the National Hospital for Nervous Diseases (now called the National Hospital for Neurology and Neurosurgery) in Queen’s Square, London, Marsden (1938–1998) outlined many concepts and clinical descriptions of movement disorders, devised rating scales, co-founded the Movement Disorder Society (1985) with Stanley Fahn and left a legacy of research and worldwide movement disorder experts who were once his pupils. Marsden’s study of Parkinson’s disease, dystonia, chorea and hemiballism led to the belief that abnormalities of motor action in basal ganglia were responsible for hypoand hyperkinetic movement disorders. The main basal ganglia abnormality in Parkinson’s disease was the inability to execute learned motor plans automatically. Animal and human studies paved the way for basal ganglia models which delineated the indirect and direct pathways, interactions among the cortex, basal ganglia and thalamus and ultimately codified these findings into diagrams depicting hypo- and hyperkinetic disorders (Fig. 5.4). With further understanding of neurotransmitters, other parallel dopaminergic circuits and microelectrode cell recordings, these models have grown in complexity. However, the fundamental schemes remain vital to an understanding of basal ganglia disorders.

5.7. Insights into etiopathogenesis 5.7.1. The MPTP story As little was known about the etiopathogenesis of Parkinson’s disease, the story of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism provided many insights regarding parkinsonism, the potential pathogenic roles of toxins and oxidative stress and the development of animal models. Davis et al. (1979) described clinical and pathological features of the initial case: a 23-year-old-male with substance abuse who developed acute parkinsonism several days after injecting a ‘sloppy batch’ of synthetic opiates; this ‘sloppy batch’ was due to a short-cut taken in the production of the opiate derivative 4-propyloxy-4-phenyl-N-methylpiperidine. Upon psychiatric ward admission with a diagnosis of catatonic schizophrenia, the patient exhibited ‘muteness, severe rigidity, weakness, tremor, flat facial expression and altered sensorium’. Laboratory tests were normal; a short course of haloperidol produced no improvement but electroconvulsive therapy led to mild motor improvement. After neurological evaluation, he received levodopa/carbidopa, benztropine and diazepam with marked improvement. Examination after 3 months on 1500 mg levodopa (with carbidopa) and 1.5 mg benztropine per day revealed mild blepharospasm, bradykinesia and bradyphrenia; removal

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Normal motor circuit

Motor circuit in PD

Cortex

Cortex

Putamen

Putamen

SNc

SNc

GPe

GPe VL

VL STN

STN GPi

GPi

SNr

SNr

PPN

Inhibitory

PPN

Excitatory

Fig. 5.4. Evolution of basal ganglia anatomy and circuitry: an early sketch by Mahlon DeLong (from the collection of C. Goetz) and a contemporary schematic of motor circuits. From Obeso JA et al (2002), reproduced with permission from the American Physiological Society.

of medications resulted in acute, severe bradykinesia, rigidity, tremor, speech and swallowing impairment. Despite his neurologic condition, the patient continued to abuse cocaine, codeine, dihydromorphinone and levodopa and 18 months later died of a drug overdose. Neuropathology revealed substantia nigra destruction with extraneuronal or microglial neuromelanin, intact locus ceruleus and a single Lewy body in the substantia nigra. Several years later, injection of a new ‘synthetic heroin’ sold by a group in northern California produced similar cases of acute parkinsonism. Similar to the 1976 case, the ‘synthetic heroin’ contained MPTP and varying amounts of the meperidine analog, 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). Langston et al. described 4 individuals who in 1982 developed initial visual hallucinations, limb jerking and stiffness within a week of injecting this meperidine-like drug, followed by bradykinesia and gait disturbance within 14 days. Hospital examination of 3 patients revealed: near total immobility, marked generalized increase in tone, a complete inability to speak intelligibly, a fixed stare, marked diminution of blinking, facial seborrhea, constant drooling, a positive glabellar tap test and cogwheel rigidity

in the upper extremities. One patient exhibited a ‘pill-rolling’ tremor (5 to 6 cycles per second) at rest in the right hand. All patients exhibited a flexed posture typical of fully developed Parkinson’s disease . . . Additional findings in these patients included apraxia of eyelid opening in three patients and limitation of vertical gaze in two patients (Langston et al., 1983). All patients responded to levodopa/carbidopa and dopamine agonists; none had remission and all developed dopaminergic motor complications. The toxicity of MPTP involves deamination of MPTP by monoamine oxidase (MAO)-B glial cells to yield 1-methyl-4-phenylpyridinium ion (MPPþ), which, once transported into cells by the dopamine transporter, is selectively toxic to dopamine neurons. MPPþ generates hydrogen peroxide and other free radicals in the dopamine nerve terminals, thereby damaging complex I of the mitochondrial respiratory chain and leading to cell death. Although unfortunate stories, the pivotal MPTP cases have provided examples of neurotoxin-induced parkinsonism sharing clinical and pathological features with idiopathic Parkinson’s disease, led to development of animal models of parkinsonism and fostered etiopathogenic theories on mitochondrial dysfunction (Langston et al., 1984).

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5.7.2. Environmental risk factors Since neither environment nor heredity has been shown definitively to cause Parkinson’s disease (with the exception of known single-gene mutations), lessons in the history of Parkinson’s disease have suggested that complex combinations and interactions of environmental factors and genetic susceptibility exist. Evaluations of remote causes of Parkinson’s disease in one’s environment, occupation and lifestyle even date back to Parkinson’s Essay and Charcot’s observations. Epidemiological studies on environmental risk factors related to agriculture (rural living, well-water consumption and pesticide use), occupation (welding, metal work, manganese exposure), infectious agents (influenza), head trauma and personal habits (caffeine intake, smoking and exercise) have received much attention today but often lack evidence for causation. Inverse relationships between cigarette smoking and caffeine intake have been suggested in several studies of Parkinson’s disease (Ross et al., 2000). Several studies from diverse geographic regions (Sweden, Italy and Taiwan) have reported increased Parkinson’s disease risk with exposure to pesticides and agriculture (Liou et al., 1997; Smarigiassi et al., 1998; Fall et al., 1999). Paraquat and rotenone, both pesticides, share properties with MPTP as selective inhibitors of complex I of the mitochondrial respiratory chain. Regarding occupational exposure, manganese-induced neurological symptoms date back to the 19th century and manganese-induced parkinsonism also sparked Cotzias’ interest in neurological research. Large epidemiological studies on occupational exposures are needed to clarify potential associations with Parkinson’s disease. 5.7.3. Genetic discoveries in Parkinson’s disease Remarkable genetic advances in the history of Parkinson’s disease have increased our understanding of etiologic, clinical and pathologic features. To date, 10 loci for genetic mutations and five causative genes have been identified in Parkinson’s disease, although the exact role of genetic and hereditary factors remains to be determined. Several familial aggregations studies have demonstrated mildly increased rates of disease in cases with affected parents or siblings (Marder et al., 1996; Rocca et al., 2004). Tanner et al. (1999) studied almost 20 000 World War II veteran twins and found greater concordance among twins with the onset of Parkinson’s disease before age 50 but not in those with later disease onset. Studies of select family pedigrees have led to specific gene mutations and, thus, theories regarding pathogenesis of Parkinson’s disease. As

these genetic mutations will be discussed in greater detail in other chapters, this section will only highlight several initial discoveries. The discovery of specific Parkinson’s disease mutations (PARK mutations) began with the Contursi kindred, now classified as PARK1. Golbe et al. (1990) reported two large kindreds with fully penetrant, autosomal-dominantly inherited Parkinson’s disease who had immigrated to New Jersey and New York between 1890 and 1920 from Contursi, a village in the hills of Salerno province in southern Italy. Clinical and neuropathological features were similar to idiopathic Parkinson’s disease except for younger onset age (average 46.5 years; range 28–68 years), decreased tremor frequency and mean survival of 9.2 years. Subsequent linkage analysis mapped the alpha-synuclein gene to chromosome 4q21–23, revealing a missense mutation in exon 4 causing an Ala53Thr substitution (Polymeropoulos et al., 1996, 1997) in the Italian and Greek families and an Ala30Pro substitution in a German family (Papadimitriou et al., 1999). Although alphasynuclein had been studied in Alzheimer’s disease and amyloid plaques, the alpha-synuclein mutation in Parkinson’s disease soon demonstrated that alphasynuclein was a key component of Lewy bodies (Spillantini et al., 1997). Hypotheses regarding abnormal protein degradation, alpha-synuclein protein aggregation and formation of Lewy bodies ensued and additional animal models with transgenic mice and flies were developed. Subsequently a mutation in ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) on chromosome 4p14–15 was found in two German siblings with parkinsonism (PARK5) (Leroy et al., 1998). Since the UCH-L1 protein is part of a deubiquitinating enzyme family responsible for recycling ubiquitin monomers from degraded protein fragments, PARK5 is thought to participate in the ubiquitin-proteosome system. Deficits in this system may lead to protein aggregates and intracellular inclusions, perhaps providing clues to the pathogenesis of Parkinson’s disease (McNaught and Olanow, 2003). Also involved in the ubiquitinproteosome pathway is PARK2, due to the parkin mutation (Matsumine et al., 1997). PARK2, an autosomal-recessive form characterized by young onset, slow progression, dystonia, sleep benefit, good levodopa response and high incidence of motor fluctuations and dyskinesias, was initially described in Japanese families but has since been found in western populations and in up to 18% of sporadic young-onset Parkinson’s disease cases (Lucking et al., 2000). As an E3 ubiquitin ligase that polyubiquitinates proteins targeted for proteosomal degradation, PARK2, along with PARK1 and PARK5, is implicated in the ubiquitin-protesome system. Although nigral degeneration

HISTORY OF PARKINSON’S DISEASE occurs, neuropathology lacks Lewy bodies, a finding warranting further attention. Overall, these specific mutations and their links to the ubiquitin-proteosomal pathway may help us understand the pathogenesis and genetics of Parkinson’s disease.

5.8. Advances in treatments and clinical trials 5.8.1. Medical therapeutics Several advances in the pharmacological treatment of Parkinson’s disease have already been highlighted. Although Parkinson viewed the use of internal medicines as premature, early treatments often had anticholinergic and dopaminergic properties, albeit with modest effect. The advent of levodopa truly represents one of the major breakthroughs in Parkinson’s disease. However, dramatic improvement in motor function soon became clouded by the occurrence of levodoparelated motor fluctuations and dyskinesias. As a result, strategies using longer-acting preparations (dopamine agonists), immediately acting parenteral injections (apomorphine), different preparations of levodopa (controlled-release formula), enzyme inhibition (selegiline (MAO-B), tolcapone and entacapone (catecholO-methyltransferase), non-dopaminergic medications (amantadine, N-methyl-D-aspartate antagonist) and unique formulations such as transdermal patches and duodenal infusions have been employed. In addition to novel therapeutics, the history of Parkinson’s disease has witnessed a return to Parkinson’s original plea for neuroprotective strategies with studies regarding selegiline (DATATOP study: Parkinson Study Group 1989) and coenzyme Q10, among others (Shults et al., 2002). Moreover, our pharmacological journey in Parkinson’s disease has increased our sensitivity to trial design; we have learned lessons regarding the symptomatic effects of medications and drug wash-out periods, the employment of neuroimaging surrogate markers, delayed start designs and use of futility analyses in neuroprotection studies (Parkinson Study Group, 2000, 2004; Whone et al., 2003, Fahn et al., 2004). We have utilized standardized rating scales such as the Hoehn and Yahr staging (1967) and the Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn and Elton, 1987) and continue to refine these tools to meet expansions and discoveries in the field of Parkinson’s disease. 5.8.2. Surgical interventions The history of surgical treatment for Parkinson’s disease dates back to the mid 20th century with lesional procedures. One of the earliest reports involved lesions of

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pallidofugal fibers which improved parkinsonism and tremor without corticospinal tract deficits (Meyers, 1940). Shortly thereafter, Spiegel and Leksell (1949) and Hassler (1955) worked to outline the anatomy of thalamic and striatal pathways and devise stereotactic neurosurgical procedures. An early and notable surgical report was Cooper’s (1956) discovery of tremor relief by accidental ligation of the anterior choroidal artery, thereby lesioning part of the thalamus. Thalamotomy was a frequently used stereotaxic neurosurgical procedure in the 1950s and 1960s, particularly for tremor, but the success of levodopa led to decreased numbers of surgical procedures performed. Recognition of limitations of medical therapies renewed interest in surgical procedures, particularly pallidotomy targeting the internal segment of the globus pallidus for parkinsonism and thalamotomy for tremor. Lesional surgeries were limited by permanent ablative effects and cognitive and speech disturbances when performed bilaterally. As a result, deep brain stimulation (DBS) procedures of the thalamus, globus pallidus and subthalamus were introduced; thalamic DBS for tremor was approved by the US FDA in 1997 and subthalamic DBS for Parkinson’s disease in 2002. Despite remarkable effects, the specific mechanisms of DBS are not fully understood. Surgical approaches in Parkinson’s disease have not been limited to lesions or stimulation but have encompassed fetal mesencephalic tissue transplantation, glial cell linederived neurotrophic factor (GDNF) intraventricular and intraputaminal infusions, cortical stimulation, implantation of retinal epithelial cells and the use of viral vector delivery systems. Although difficulties with fetal mesencephalic tissue transplantation and GDNF studies have recently been reported, novel surgical and restorative therapies warrant appropriate and careful evaluation.

5.9. Conclusion Although many unanswered questions remain regarding Parkinson’s disease, the history of Parkinson’s disease, as marked by the achievements and events highlighted, represents a rich journey into clinical observation, scientific discoveries and novel therapeutics. Many of the lessons in Parkinson’s disease evoked historically in this chapter will be further explored by other authors in this edition of the Handbook of Clinical Neurology. The historical events depicted here have shaped and will continue to shape our understanding of Parkinson’s disease – the past, present and future of its clinical identity, etiology, pathophysiology and treatments. Historical study of Parkinson’s disease allows contemporary readers and researchers to explore and

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expand upon theories proposed over the centuries. James Parkinson’s keen observations regarding changes in sleep and autonomic function, but preservation of senses and intellect, provide a foundation for modern researchers to investigate the non-motor features of Parkinson’s disease. As a result, a greater understanding of non-motor disturbances such as hallucinations and psychosis, sleep problems, pain and sensory abnormalities and autonomic dysfunction has emerged. Contrary to Parkinson’s impression, neurologists have learned that the ‘senses and intellect’ are not ‘uninjured’ but that cognitive impairment and dementia are one of several non-motor manifestations of Parkinson’s disease. Appreciation of Parkinson’s disease as a complex, multifaceted disorder affecting both motor and non-motor systems and involving brain regions beyond the substantia nigra continues to grow and underlies future research directions. Just as Parkinson, Charcot and von Economo contemplated various etiologies for shaking palsy and parkinsonism, such as occupational hazards, damp air, frights and infections, researchers today search for etiological clues with epidemiological, environmental and genetic studies, uniting clinicians and basic science researchers in the common goal of unraveling Parkinson’s disease. In addition, speculations by James Parkinson about the possible role of neuroprotection now form a core part of current clinical and basic science research efforts. Moreover, James Parkinson’s requests to follow in the footsteps of ‘Morgagni, Hunter, or Baillie’ to elucidate the pathology of this disease have not been neglected. In fact, recent pathological studies reflect the evolution of neuropathological theories on Parkinson’s disease, from brainstem to basal ganglia and cortex. As clinicians and basic scientists pursue current and future research endeavors in Parkinson’s disease, they build on a remarkable legacy of discoveries of clinical manifestations, neuropathology, neurochemistry, neural circuitry and treatments of Parkinson’s disease that continues to motivate and inspire. Parkinson’s challenge to ascertain the real nature of ‘the disease’ remains at the forefront of current research. Although the endeavors of astute clinicians and focused laboratory scientists has led to many concrete results that span medical, rehabilitative and surgical lines, there are many more key questions still to be answered. Patients today, whether they are London citizens, church leaders, sports figures or movie stars afflicted with Parkinson’s disease, benefit from novel therapeutics and prospects for neuroprotection, but they all eagerly await the discovery of Parkinson’s quest for the first step toward a cure.

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Lucking CB, Durr A, Bonifati V et al. (2000). Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engle J Med 342: 1560–1567. Manyam BV, Sanchez-Ramos JR (1999). Traditional and complementary therapies in Parkinson’s disease. Adv Neurol 80: 565–574. Marder K, Tang MX, Mejiz H et al. (1996). Risk of Parkinson’s disease among first-degree relatives: a community based study. Neurology 47: 155–160. Matsumine H, Saito M, Shimoda-Matsubayashi S et al. (1997). Localization of a gene for an autosomal recessive form of juvenile parkinsonism to chromosome 6q25.2–27. Am J Hum Genet 60: 588–596. McNaught K St P, Olanow CW (2003). Proteolytic stress: a unifying concept for the etiopathogenesis of Parkinson’s disease. Ann Neurol 53 (Suppl 3): S73–S86. Meyers R (1940). Surgical procedure for postencephalitic tremor, with notes on the physiology of the premotor fibres. Arch Neurol Psychiatry 44: 455–459. Montagu KA (1957). Catechol compounds in rat tissues and in brains of different animals. Nature 180: 244–245. Morris AD, Rose FC (1989). James Parkinson: his life and times. Birkhauser, Boston. Murrin LC (2005). The role of dopamine in Parkinson’s disease: a historical review. In: M. Ebadi, RF Pfeiffer (Eds.), Parkinson’s Disease. CRC Press, Boca Raton, pp. 21–26. Nagashayana N, Sankarankutty P, Nampoothiri MR et al. (2000). Association of L-DOPA with recovery following Ayurveda medication in Parkinson’s disease. J Neurol Sci 176: 124–127. Obeso JA, Rodriguez-Oroz MC, Rodriguez M et al. (2002). The basal ganglia and disorders of movement: pathophysiological mechanisms. News Physiol Sci 17: 51–55. Ordenstein L (1867). Sur la paralysie agitante et la scle´rose en plaques ge´ne´ralise´es. Thesis, Paris. Papadimitriou A, Veletza V, Hadjigeorgiou GM et al. (1999). Mutated alpha-synuclein gene in two Greek kindreds with familial PD: incomplete penetrance. Neurology 52: 651–654. Parkinson J (1801). Medical Admonitions to Families, Respecting the Preservation of Health and the Treatment of the Sick, 4th ed HD Symonds, London. Parkinson J (1817). An Essay on the Shaking Palsy. Sherwood, Neely & Jones, London. Parkinson Study Group (1989). DATATOP: a multi-center controlled clinical trial in early Parkinson’s disease. Arch Neurol 46: 1052–1060. Parkinson Study Group (1995). An alternative medicine treatment for Parkinson’s disease: results of a multicenter clinical trial. HP-200 in Parkinson’s Disease Study Group. J Altern Complement Med 1:249–255. Parkinson Study Group (2000). Pramipexole vs levodopa as initial treatment for Parkinson disease. JAMA 284: 1931–1938. Parkinson Study Group (2004). A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 61: 561–566. Patten BM (1983). A personal tribute to Dr. George C. Cotzias, clinician and scientist. Perspect Biol Med 27: 156–161.

Pearce JMS (1989). Aspects of the history of Parkinson’s disease. J Neurol Neurosurg Psychiatry (Suppl): 6–10. Pearce JMS (2001). The Lewy body. J Neurol Neurosurg Psychiatry 71: 214–215. Polymeropoulos MH, Higgins JJ, Golbe LI et al. (1996). A gene for Parkinson’s disease maps to 4q21–23. Science 274: 1197–1199. Polymeropoulos MH, Lavedan C, Leroy E et al. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276: 2045–2047. Raab W, Gigee W (1951). Concentration and distribution of ‘encephalin’ in the brain of humans and animals. Proc Soc Exp Biol Med 76: 97–100. Rinne UK, Sonninen V, Siirtola T (1973). Treatment of parkinsonian patients with levodopa and extracerebral decarboxylase inhibitor, Ro 4-4602. Adv Neurol 3: 59–71. Rocca WA, McDonnell SK, Strain KJ et al. (2004). Familial aggregation of Parkinson’s disease: the Mayo Clinic family study. Ann Neurol 56: 495–502. Ross GW, Abbott RD, Petrovitch H et al. (2000). Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA 283: 2674–2679. Sabbatini RME (2003). Neurons and synapses: the history of its discovery. Brain Mind 17. Sano I, Gamo T, Kakimoto Y et al. (1959). Distribution of catechol compounds in human brain. Biochim Biophys Acta 32: 586–587. Schiller F (2000). Fritz Lewy and his bodies. J Hist Neurosci 9: 148–151. Schwab RS, Amador LV, Levine JY (1951). Apomorphine in Parkinson’s disease. Trans Am Neurol Assoc 76: 273–279. Shults CW, Oakes D, Kieburtz K et al. (2002). Effects of coenzyme Q10 in early Parkinson’s disease: evidence of slowing of the functional decline. Arch Neurol 59: 1541–1550. Smarigiassi A, Mutti A, DeRosa A et al. (1998). A case-control study of occupational and environmental risk factors for Parkinson’s disease in the Emilia-Romagna region of Italy. Neurotoxicology 19 (4–5): 709–712. Spiegel EE, Leksell L (1949). A stereotaxic apparatus for intracerebral surgery. Acta Chir Scand 99: 229–233. Spillantini MG, Schmidt ML, Lee VM et al. (1997). Alphasynuclein in Lewy bodies. Nature 388: 839–840. Stern G (1989). Did parkinsonism occur before 1817? J Neurol Neurosurg Psychiatry (Suppl): 11–12. Tanner CM, Ottman R, Goldman S et al. (1999). Parkinson disease in twins: an etiologic study. JAMA 281: 341–346. Trietiakoff C (1919). Contribution a` l’e´tude de l’anatomie du locus niger de Soemmering. Thesis, Paris. Vogt O, Vogt C (1920). Zur Lehre der Erkrankungen des striaren Systeme. J Psychol Neurol Lpz. Whone AL, Watts RL, Stoessel AJ et al. (2003). Slower progression of Parkinson’s disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 54: 93–101. Yahr MD, Duvoisin RC, Schear MJ et al. (1969). Treatment of parkinsonism with levodopa. Arch Neurol 21: 343–354. Zhang ZX, Dong ZH, Schear GC (2006). Early descriptions of Parkinson’s disease in ancient China. Arch Neurol 63 (5): 782–784.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 6

Epidemiology of Parkinson’s disease MEIKE KASTEN, ANNABEL CHADE AND CAROLINE M. TANNER* The Parkinson’s Institute, Sunnyvale, CA, USA

6.1. Introduction 6.1.1. Overview Parkinson’s disease (PD) was first described as ‘paralysis agitans’ by James Parkinson in 1817 (Parkinson, 1817). Classically, PD refers to progressive parkinsonism due to loss of pigmented aminergic brainstem neurons without an identifiable cause, while ‘parkinsonism’ refers simply to the syndrome of bradykinesia, resting tremor, rigidity and postural reflex impairment. Over nearly two centuries, Parkinson’s clinical description has provided the framework for clinical investigations, including epidemiologic ones. More recently, investigations of a few families with genetic parkinsonism have revealed a wide range of clinical and pathological features in persons sharing a single disease-causing mutation, calling into question the assumptions underlying the strict syndromic classification employed by most studies to date. Whether a similar heterogeneity applies to the common ‘idiopathic’ disorder is not known. Although our current clinicopathological definition of PD may merit revision, further work is needed to determine what an appropriate new definition should be, and the classical definitions will be used in this discussion. Descriptions of PD were limited to selected clinical settings until the middle of the 20th century, when several population-based epidemiologic studies were published (Kurland, 1958; Gudmundsson, 1967). Since then, epidemiologic approaches have been used not only to investigate the population distribution of PD, but also as a way to glean clues as to the cause of this ‘idiopathic’ disorder. Heredity, infection, toxicant exposure and multifactorial gene–environment interactions have been proposed. Although single genetic or

environmental causes have been identified, these explain only a small proportion of all cases (Marras and Tanner, 2002; Korell and Tanner, 2005). This chapter will provide an overview of this work, beginning with descriptive studies, followed by studies investigating the determinants of PD. Because other chapters in this volume thoroughly address the genetics of PD, this topic will be considered briefly here. 6.1.2. Special considerations for epidemiologic studies Epidemiologic investigations of PD must overcome practical challenges (Table 6.1). PD is relatively uncommon, and even studies of large populations will find relatively few cases. Therefore, the potential error in any single study may be significant. In analytic studies, this can be particularly problematic if the causes of disease differ across populations. Moreover, to the extent that the cause of PD is multifactorial, large populations will be necessary to test hypotheses involving multiple determinants. Identification of the cases of PD within a community is typically not a trivial effort. Population-based registries of PD are not common, and voluntary registries cannot be assumed to be representative. Because PD is relatively infrequent, a fairly large base population must be surveyed to identify sufficient numbers of cases for a study. In some instances, PD cases can be identified through health service rosters within defined geographic areas or in enumerated populations. In others, cases of PD are sought independently of the health care system, such as through door-to-door surveys. While the latter approach is theoretically least likely to exclude cases, the time and cost involved are also greatest using this approach.

*Correspondence to: Caroline M. Tanner, M.D., Ph.D., The Parkinson’s Institute, 1170 Morse Avenue, Sunnyvale, CA 94089, USA. E-mail: [email protected], Tel: 408-734-2800.

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Table 6.1 Some challenges in the epidemiological study of Parkinson’s disease No diagnostic test Examination by expert most reliable No criterion always predicts pathology Long preclinical period Exposure may be years before signs Late-life disorder Risk factor identification retrospective Diagnostic accuracy in relatives poor Relatively rare Large base population needed No registries; not reported ‘True’ distribution of disease not certain

Population surveys of PD are further complicated because there is no diagnostic test for PD. Clinical features remain the only way to diagnose PD during life. Clinical diagnostic accuracy can vary with the experience of the practitioner. Essential tremor, for example, may be confused with PD in up to 40% of diagnoses in some settings (Mutch et al., 1986). Conversely, actual cases of PD may be missed, particularly in older age groups, where slowness and tremor may be discounted as ‘normal’ or misdiagnosed as one of several other common disorders affecting this age group (for example, arthritis, stroke, dementia). A further difficulty is presented by persons with both parkinsonism and dementia, who may be classified as either primary disorder in different epidemiologic surveys. The common use of neuroleptics in institutionalized elderly, especially those with cognitive impairment, can further confound diagnosis in this age group. Postmortem validation of clinical diagnosis, although ideal, is rarely available in a population-based setting. First, because survival with PD typically involves many years or even decades, very long follow-up is necessary. In addition, clinical diagnostic criteria do not perfectly predict ‘classic’ postmortem features of PD. Error rates of more than 20% were seen in one clinicopathological series by Hughes et al. (1993). The same authors later suggested that the use of standard clinical criteria (e.g. the UK PD brain bank criteria) improved accuracy of a clinical diagnosis in 100 patients (Hughes et al., 2001) in which 90 were shown to have idiopathic PD at postmortem and 10 had other parkinsonian syndromes. In a report published the following year (n ¼ 143), Hughes et al. (2002) estimated that the positive predictive value of the clinical diagnosis for the whole group was 85.3%, with 122 cases correctly clinically diagnosed, 98.6% (72 out of 73)

for idiopathic PD, and 71.4% (50 out of 70) for other parkinsonian syndromes. However, since autopsy is most likely performed when the clinical diagnosis is not certain, misclassification may be overestimated in published series (Maraganore et al., 1999). Nonetheless, in the few settings where postmortem validation of PD is possible, valuable insights can result (Ross et al., 2004). The uncertainty of clinical diagnosis can be an important consideration in the design and critical analysis of epidemiologic studies of PD. Inclusion of those without disease and exclusion of those with disease can produce under- or overestimates of the distribution of PD. In either case-control studies or family studies, including case subjects who do not actually have PD can obscure a causative association or even result in associations with factors determining a different disorder. In families, the mode of inheritance of a genetic defect can also be misinterpreted. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are imaging techniques that detect and display the distribution of radiolabeled tracers within the body. Patients with PD show reduced tracer accumulation in the striatum contralateral to the affected limbs using markers of the presynaptic dopaminergic system in the very early stages of the disease (Marek et al., 1996; Wenning et al., 1998; Benamer et al., 2003). Others have suggested that ultrasound may be a useful way of identifying nigral injury in PD (Berg et al., 2002). Although these approaches are promising, their abilities to distinguish normal from abnormal and to distinguish PD from other forms of parkinsonism have not yet been developed to the extent that any of these techniques can be used outside the research setting. In epidemiologic research, broad application of these techniques remains difficult, as they are not widely available. However, combining these tools with other, more easily characterized, potential biomarkers, such as olfactory testing, may be useful in prospective studies to identify those ‘at risk’ for developing parkinsonism, to identify those persons appropriate for interventions to protect against PD and to provide better methods for case definition in studies of genetic and environmental risk factors, where incorrect classification of cases and controls could significantly alter results (Siderowf et al., 2005; Stiasny-Kolster et al., 2005). Investigations of new cases of PD present additional uncertainties, because the definition of a new case is particularly problematic. Onset of the motor features of PD is insidious. It is commonly held that at least 50% of substantia nigra pars compacta cells are damaged before the symptoms of PD prompt

EPIDEMIOLOGY OF PARKINSON’S DISEASE medical attention (Bernheimer et al., 1973). It has long been observed in autopsy series that the pathologic changes of PD can be identified in the brains of persons who were not diagnosed during life; these ‘incidental Lewy body’ cases increase with increasing age of the population surveyed, and may represent clinically unrecognized PD (Gibb and Lees, 1991). More recently, improved neuropathological methods led to the proposal that neuropathologic injury in PD begins in lower brainstem and olfactory nuclei, and progresses through predictable stages over time, involving the substantia nigra and producing classical parkinsonism only relatively late, at stage 4 (Braak et al., 2003a, 2004). Lewy neurite pathology can also be seen in autonomic ganglia outside the central nervous system, leading to the further hypothesis that PD may begin outside the central nervous system, well before the classic signs of parkinsonism develop (Braak et al., 2003b). If this is correct, the true onset of the disease process may begin long before the neurological syndrome is diagnosed. This research hypothesis merits further investigation. To be effective, studies of risk or protective factors, as well as investigations of preventive therapies, may need to target time periods decades before the onset of disease.

6.2. Demographics 6.2.1. Incidence Incidence, the number of new cases of a disorder diagnosed during a specific time interval within a defined population, provides the most complete description of the number of cases of disease, as this measurement is least affected by factors influencing survival. This is particularly important for a slowly progressive disorder such as PD. However, as discussed above, because the time of onset of PD is not easily determined, incidence can vary depending on the definition of disease, as well as by factors such as method of ascertainment and access to health care. Studies using more intensive ascertainment methods, such as inperson screening, may find higher rates (de Lau et al., 2004). Crude estimates of incidence can also vary due to the age and gender distribution of the population studied, and crude rates must be compared with this in mind. For example, reported incidence of PD varies fourfold, from 4.5 to 19 per 100 000 population per year when the entire age spectrum of the population is considered (Rosati et al., 1980; Harada et al., 1983; Ashok et al., 1986; Granieri et al., 1991; Mayeux et al., 1995; Sutcliffe and Meara, 1995; Fall et al., 1996; Kusumi et al., 1996; Bower et al., 1999; Kuopio et al., 1999; MacDonald et al., 2000; Twelves

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et al., 2003; Van Den Eeden et al., 2003). However, when studies using similar methods are compared, and rates are adjusted to a reference population, this range is markedly reduced (11.0–13.9/100 000 population per year; Van Den Eeden et al., 2003). Age is a key determinant of PD incidence. In all populations studied, PD is very rare before age 50 (Kurland, 1958; Brewis et al., 1966; Rosati et al., 1980; Ashok et al., 1986; Granieri et al., 1991; Wang et al., 1991; Tanner et al., 1992; Harada et al., 1983; Mayeux et al., 1995; Morens et al., 1996a; Marras and Tanner, 2002; Van Den Eeden et al., 2003; Korell and Tanner, 2005). PD incidence increases steadily in the sixth through the eighth decades in most populations, but a decrease in late life is seen in some studies. Whether this apparent decline in PD incidence is the result of methodologic challenges, such as the greater difficulty identifying and diagnosing PD in the very old (Bower et al., 2000), rather than an actual decline in disease frequency, is not certain. If the decline is real, a biological ‘window of vulnerability’ for PD may exist. Investigation of the determinants of this could provide important insights into the causes of PD. PD incidence is also higher in men than in women in most populations studied, although gender-specific differences show more variability worldwide than do differences associated with increasing age. In a large study in northern California, PD incidence in men was 91% higher than for women (19/100 000 for men versus 9.9/100 000 for women, age-adjusted; Van Den Eeden et al., 2003). Whether PD incidence varies by racial or ethnic group has been addressed in only a few studies. In a northern California population, estimated PD incidence, adjusted for age and gender to a comparison population, was highest in Hispanics (16.6/100 000), then non-Hispanic whites (13.2/100 000), then Asians (11.3/100 000) and lowest in blacks (10.2/100 000; Van Den Eeden et al., 2003). When rates in other incidence studies were adjusted to the same comparison population, PD incidence in northern Manhattan was higher in blacks (18/100 000) than in whites (12.9/100 000) or ‘other’ (11.8/100 000), and PD incidence in men of Japanese and Okinawan descent in Honolulu was 13.1/100 000 (Mayeux et al., 1995; Morens et al., 1996a). Whether these variations within and across populations reflect real differences, or simply poor precision, resulting from small numbers of PD cases, will only be answered by additional race- and ethnicity-specific studies. Has PD incidence changed over time? Periodic fluctuation in incidence could result from any episodic exposure, such as an infectious process. A steady increase over the past several decades could implicate exposures increasingly present, such as those due to

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industrialization or lifestyle practices. Conversely, if PD incidence has remained stable over time, recent environmental factors are unlikely to be important causes of PD. Only two reports have addressed this possibility, with differing results. Reviews of the Mayo Clinic database from Olmsted County, Minnesota, found no change in age-specific PD incidence between 1935 and 1990 (Rajput et al., 1984; Rocca et al., 2001). One limitation to this work is the small population size. Only 154 PD cases were incident in 15 years, resulting in poor precision of these estimates. In contrast, in southwestern Finland, based on a larger number of cases, estimated incidence of PD was increased in men, particularly those aged 60 and older, in 1992 as compared to 1971 (Kuopio et al., 1999). Although it is possible that these differences may reflect temporal changes in environmental exposures in Finland, but not in Minnesota, this cannot be determined from the published studies. 6.2.2. Prevalence Because PD is relatively uncommon and associated with a long survival, estimates of prevalence are more easily obtained than estimates of incidence. PD prevalence is most commonly estimated through national or local reporting systems. In locations where health care is universally available, such methods provide a good estimate of correctly diagnosed cases, but exclude persons who have not sought medical care. Misclassification is dependent on the methods used to define cases, with those diagnosed by experts being likely the best estimates of PD in the population. Estimates of prevalence based on populations identified by other methods (such as participants in a hospital clinic) do not accurately reflect the general population of an area, since cultural, economic or other factors may influence case selection.

Ideally, both incidence and prevalence are determined by screening all members of entire populations defined by specific geographic or political boundaries. Door-to-door surveys of all households in an area, followed up by examination of individuals suspected of having parkinsonism based on the screen, is the generally the best measure of true prevalence. If cooperation is good, a door-to-door survey is the most likely means of identifying all cases of PD in a community. Typical community-based and door-to-door prevalence studies utilize health professionals or, more often, trained survey assistants who screen the population using a set of questions designed to identify all individuals who may have the disease (Anca et al., 2002), even those who have not received medical attention (Tanner et al., 1990; Mutch et al., 1991; Duarte et al., 1995; Giroud-Benitez et al., 2000). After the initial screening process, individuals suspected of having the disease are asked to have a careful evaluation performed by a neurologist and possibly ancillary diagnostic tests. The estimated PD prevalence derived from medical care reporting systems in North America and Europe find rates between 100 and 200 cases/100 000 population, although rates in developing countries are reported to be as little as one-tenth of these rates (Kurland, 1958; Brewis et al., 1966; Jenkins, 1966; Marttila and Rinne, 1967; Kessler, 1972a, b; Rosati et al., 1980; Nishitani et al., 1981; Harada et al., 1983; Sutcliffe et al., 1985; Ashok et al., 1986; Chalmanov, 1986; Mutch et al., 1986; Shi, 1987; Okada et al., 1990; Granieri et al., 1991; Wang et al., 1991; Caradoc-Davies et al., 1992; Mayeux et al., 1992, 1995; Tanner et al., 1992; Morens et al., 1996a; Hobson et al., 2005). Table 6.2 shows examples of crude estimated prevalence from door-todoor studies (Li et al., 1985; Schoenberg et al., 1985, 1988; Bharucha et al., 1988; Acosta et al., 1989; Morgante et al., 1992; Wang et al., 1994). Recently,

Table 6.2 Parkinson’s disease prevalence rates from selected door-to-door surveys

Location of survey

Age groups screened

Crude prevalence/ 100 000 persons

Chinese cities (Li et al,. 1985) Igbo-ora, Nigeria (Schoenberg et al., 1988) Kin-Hu, Kinmen, Taiwan, ROC (Wang et al., 1994) Sicily, Italy (Morgante et al., 1992) Vejer de la Frontera, Cadiz, Spain (Acosta et al., 1989) Copiah County, Mississippi, USA (Schoenberg et al., 1985) Parsi community, Bombay, India (Bharucha et al., 1988) Bankstown, Sydney, Australia (Chan et al., 2005)

> 50 years > 39 years > 50 years > 12 years All ages > 39 years All ages 55 years

44.0 58.6 170.0 257.2 270.0 347.0 328.3 780.0

Note: Studies listed should not be compared directly as the age and gender distributions of the underlying populations differ.

EPIDEMIOLOGY OF PARKINSON’S DISEASE estimates as high as 780/100 000 have been reported in Sydney, Australia (Chan et al., 2005). Comparison of prevalence studies worldwide suggests that PD may be more common in the developed world. Because there are many methodological differences among studies, as well as differences in culture and health care among countries, this observation must be viewed with caution. Importantly, crude prevalence rates cannot be compared directly, since different age groups were surveyed, and the age distribution in the underlying populations differ. Longevity increases the number of PD cases one can expect in a population. While age adjustment reduces differences across populations, the range of estimated PD prevalence remains broad. Comparisons of prevalence for PD from different populations can also reflect the relationship between prevalence and methodology used. For example, apparent age-specific prevalence differences among studies may actually be quite similar when data are re-evaluated according to the same diagnostic criteria (Anderson et al., 1998). In one study, PD prevalence has been estimated at two time points. In southwestern Finland, PD prevalence appears to be increasing in men and in rural areas in 1992 as compared to 1971 (Kuopio et al., 1999). Because ascertainment methods were similar at both time points, this may reflect a true difference in prevalence in this region, possibly the result of changes in exposure to risk factors. Lending more credence to this is the observation that similar changes in incidence were observed, making it less likely that the prevalence changes are due to improved survival of persons with PD in 1992. 6.2.2.1. Age Although PD is rare before age 40, after age 50 the prevalence rises almost exponentially (Kurland, 1958; Brewis et al., 1966; Jenkins, 1966; Marttila and Rinne, 1967; Kessler, 1972a, b; Rosati et al., 1980; Harada et al., 1983; Li et al., 1985; Schoenberg et al., 1985, 1988; Sutcliffe et al., 1985; Ashok et al., 1986; Mutch et al., 1986; Shi, 1987; Acosta et al., 1989; Mayeux et al., 1992, 1995; Morgante et al., 1992; Tanner et al., 1992; Wang et al., 1994; Morens et al., 1996a). By the eighth decade, estimated prevalence in European and North American populations is between 1000 and 3000 cases per 100 000 population. Although differences in the age distributions in these populations, diagnostic criteria, ascertainment methods, access to health care or disease survival rates may explain much of this variation, international variation in PD frequency is seen even after adjusting for many of these inconsistencies (Zhang and Roman, 1993). Risk factors, which may vary geogra-

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phically, include both genetic differences in disease susceptibility and exposure to causative and protective environmental factors. Although PD is intimately related to aging, it has been well documented that its underlying process is distinct from natural aging (McGeer et al., 1988; Fearnley and Lees, 1991; Gibb and Lees, 1991). An age-determined process, such as an acquired defect in cellular metabolism, or a process requiring a long period of time to manifest – as might result from prolonged toxicant exposure or the cumulative effects of many individual injuries to nerve cells – might cause a similar pattern. It is also possible that both age-related vulnerability and time-dependent processes explain the late-life preponderance of PD. 6.2.2.2. Gender Men are diagnosed with PD about twice as often as women, irrespective of geographic location or race (Tanner and Goldman, 1996; Baldereschi et al., 2000). This pattern is seen in both prevalence and incidence studies. In a meta-analysis of seven incidence studies, men were found to have a 1.5-times greater relative risk for PD than women (Wooten et al., 2004). This increased risk in men may reflect biological differences between men and women, such as the effects of sex hormones or X-chromosome-linked susceptibility genes. Alternatively, culturally determined differences in male and female behavior, with associated differences in exposure to risk factors, could explain the pattern. The latter hypothesis is supported by a large Finnish study showing a dramatic increase in the male-to-female relative risk from 0.9 in 1971 to 1.9 in 1992 (Kuopio et al., 1999). Others have suggested that hormonal differences between men and women explain these differences, although the relationship does not appear to be a simple one (see also section 6.3.7). Further epidemiologic studies, along with experimental laboratory studies, will be necessary to determine whether men are at greater risk for PD. 6.2.2.3. Race Although there are a surprising number of observations in the literature suggesting whites are at increased risk for PD, it has been thought that lower rates in non-whites might be related to socioeconomic or cultural differences, leading to ascertainment bias (Kessler, 1972a, b; Tanner and Goldman, 1996). Nevertheless, two multiracial population-based studies estimating the incidence of PD in upper West-Side Manhattan (Mayeux et al., 1995) and in Northern California (Van Den Eeden et al., 2003) suggest racial differences in PD incidence. In the Manhattan study, African-American women had lower rates, but African-American men had higher

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rates than whites (Mayeux et al., 1995). The Northern California study, a much larger evaluation of PD incidence, showed a lower frequency of PD in both men and women of African or Asian descent than in nonHispanic whites (Van Den Eeden et al., 2003). Results remain equivocal in both studies, however, as even in this large study the numbers of non-whites were low and between-group confidence intervals for race-specific PD incidence overlapped. If there are true differences in PD risk among groups defined by race or ethnicity, this may reflect differences in biologic susceptibility. For example, mutations in the LRRK2 gene account for about 2% of parkinsonism in northern European populations, but 15–20% in persons of Ashkenazi Jewish and North African origin (LeSage et al., 2005; Ozelius et al., 2006). Others have suggested that dermal melanin may protect against PD by trapping potential neurotoxins before they reach the brain (Mars and Larsson, 1999). Because dermal melanin is regularly sloughed with keratinized skin, persons with more dermal melanin may be protected from the passage of toxicant compounds into the central nervous system. Alternatively, differences in non-genetic risk factors may explain differences among populations. For example, PD prevalence is high in the Inuit population of Greenland (Wermuth et al., 2004). This population is at risk for dietary and other exposures to persistent organic pollutants (Dewailly et al., 1999), agents suggested to be risk factors for PD.

ently across gender or age groups in a selected group of otherwise healthy clinical trial participants (Marras et al., 2005a). In other clinical trial populations, mortality has been higher than expected, however (Hely et al., 1999; Lees et al., 2001; Fall et al., 2003). Among participants in the DATATOP study, severity, rate of worsening of parkinsonism and response to levodopa are related to survival (Marras et al., 2005b), suggesting that differences in these factors among studies may also account for the observed differences in PD-related mortality among these studies.

6.3. Risk factors for Parkinson’s disease 6.3.1. Introduction to epidemiologic clues The demographic studies reviewed in the previous section may provide clues to the causes of PD (Table 6.3). Demographic differences in the frequency of PD, particularly differences in PD incidence, may be the result of ascertainment bias. Alternatively, differences in risk factors for PD among different demographic groups may explain these patterns. Some of these possibilities have been discussed above. Disease clusters, representing more than the expected number of new cases of PD at a certain time and/or in a certain place, are

Table 6.3 Factors associated with the risk of Parkinson’s disease in one or more studies

6.2.3. Mortality Studying mortality of PD based on information from death certificates is problematic because PD is a chronic disorder that is not the direct cause of death; thus, the frequency of the disease can be underestimated from such evaluations. Compared to persons of the same age and gender, mortality is increased approximately twofold among individuals with PD (Di Rocco et al., 1996; Morens et al., 1996a; Louis et al., 1997; Morgante et al., 2000). An observed north–south gradient of decreasing PD mortality (Lilienfeld et al., 1990), although possibly reflecting true differences in regional mortality, could also be an artifact of differential access to medical care or death certificate completion inconsistencies among physicians (Pressley et al., 2005). Mortality in a clinical trial population may be affected by the influence of the health benefit obtained from participating in the study. After a 13-year followup, results from the DATATOP cohort study show that the mortality rate was similar to that of the general population and that PD did not affect survival differ-

Factors directly associated Increasing age Male gender White race Drinking well water Diet: animal fat, milk, iron Obesity Hysterectomy and/or supplemental estrogen Midlife constipation Rapid-eye movement sleep disorder Physical and emotional stress Family history of Parkinson’s disease Rural residence Pesticides Farming Teaching/health care work Metals Factors inversely associated Smoking/tobacco Caffeine intake Non-steroidal anti-inflammatory drug use Alcohol Greater physical activity

EPIDEMIOLOGY OF PARKINSON’S DISEASE another type of pattern that may suggest a shared cause of disease and provide clues to the underlying etiology of all cases. An example is the cluster of parkinsonism in narcotics addicts caused by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) exposure (Langston et al., 1983) (Fig. 6.1). MPTP induces parkinsonism that is similar to PD, with key symptoms that improve with levodopa treatment and a similar side-effect profile. Differences include the more rapid onset of symptoms in MPTP-induced parkinsonism than in PD, and possibly some differences in neuropathologic features as well. Although MPTP injection is clearly not a cause of most PD, investigation of this cluster provided an important animal model. Investigation of the mechanism of MPTP toxicity led to the hypothesis that toxicants may cause PD, and has focused interest on compounds with structural or functional similarities (Fig. 6.2). Other proposed clusters, such as the syndrome of motor neuron disease–parkinsonism–dementia in certain areas of the Western Pacific (Spencer, 1987) or several clusters in Canada (Kumar et al., 2004) have yet to reveal specific etiologic factors. Familial clusters are generally interpreted to indicate a genetic cause for disease, but certain patterns within families, such as temporal clustering of disease, may be more suggestive of shared environmental risks. A number of case-control studies have found increased PD risk if a first-degree relative has PD (Semchuk et al., 1993; Morano et al., 1994; Payami et al., 1994; Bonifati et al., 1995; DeMichele et al., 1996; Marder et al., 1996). Because persons with disease may be more aware of disease in relatives, these studies in part may reflect reporting bias. Elbaz et al. (2003a) showed evidence for family information bias whereby cases with PD are more likely to report a relative with PD than are control subjects, increasing the risk estimate CH3

CH3

CH3

N

N+

N+

N+ CH3 MPTP

MPP

PARAQUAT

Fig. 6.1. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) and structurally related compounds. MPP, 1-methyl-4-phenylpyridinium.

Complex I Dysfunction (TIQs, MPP+, rotenone PINK1 mutations may contribute)

Free radicals (LPS, paraquat, head injury may contribute)

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Smoking, caffeine protective?

Antioxidants Anti-inflammatories protective?

Alpha-synuclein aggregation (some pesticides, metals may contribute)

Proteosomal Dysfunction (streptomyces, chemicals may DJ1, Parkin mutations may aggravate)

Cell death

Fig. 6.2. Epidemiologic clues and mechanisms of neuronal injury. TIQs, tetrahydroisoquinolines; MPPþ, 1-methyl-4phenylpyridinium ion; LPS, lipopolysaccharide.

by 133%. Studies in twins do not support a genetic cause for typical age at PD onset, although genetic factors appear to be increased in those with younger age at onset (Duvoisin et al., 1981; Marsden, 1987; Marttila et al., 1988; Vieregge et al., 1992; Tanner and Goldman, 1994; Wirdefeldt et al., 2004). Many proposed risks for PD will be reviewed here. 6.3.2. Single genes causing parkinsonism Genetic defects responsible for parkinsonism have been identified in some families (Bonifati et al., 1995; Polymeropoulos et al., 1996, 1997; Hattori et al., 1998; Kitada et al., 1998; Paisan-Ruiz et al., 2004; Zimprich et al., 2004). In many of these cases, the clinical features resemble typical PD. However, within affected families there are often clinical features that are unusual for PD. At present, mutations in at least five genes have been firmly associated with parkinsonism: (1) a-synuclein (SNCA or PARK1; Polymeropoulos et al., 1997); (2) parkin (PRKN or PARK2; Kitada et al., 1998); (3) DJ-1 (DJ1 or PARK7; Bonifati et al., 2003); (4) PTEN-induced putative kinase I (PINK1 or PARK6; Polymeropoulos et al., 1997); and (5) leucine-rich repeat kinase 2 or dardarin (LRRK2 or PARK8; Paisan-Ruiz et al., 2004, Zimprich et al., 2004) (Table 6.4). PINK1 homozygous mutations have been reported to be an important cause of disease among Italian sporadic patients with early-onset parkinsonism, whereas the role of single heterozygous

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Table 6.4 Genes causing parkinsonism Locus/gene

Map position

Characteristics

Dominantly inherited PARK1 (a-synuclein)

4q21–22

PARK8 (LRRK2/dardarin)

12p11.2-q13.1

Rare point mutations, duplication/triplication of normal gene Atypical features, young onset Sporadic and familial, heterogeneous signs and pathology Old and young onset

Recessively inherited PARK2 (parkin) PARK6 (PINK1) PARK7 (DJ-1) Uncertain inheritance PARK5 (UCHL1)

6q25–27 1p35–36 1p36

Many mutations, atypical, most onset < 30 years of age Two mutations in three consanguineous families Point mutation, deletion, few families, atypical

4p14

Normal protein products of PARK1, 2, 5, 6 and 7 are all likely involved in protein degradation and/or cellular response to toxicant injury or oxidative stress.

mutations is less clear (Bonifati et al., 2005). The LRRK2 G2019S mutation is the most common pathogenic mutation linked to parkinsonism, accounting for 1–2% of cases, including cases of not only younger but also older age at disease onset (Kay et al., 2006). Other candidate PD loci have been proposed, including putative disease-causing mutations in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) (Leroy et al., 1998) and in a nuclear receptor of subfamily 4 (NR4A2 or NURRI) (Le et al., 2003). These candidates do not map to known PD linkage regions, but polymorphisms in both genes have been associated with PD in some case-control studies (as reviewed by Bertram and Tanzi, 2005). The GSK3B polymorphism has been reported to alter transcription and splicing and interact with tau haplotypes to modify PD risk (Kwok et al., 2005). From an epidemiologic perspective, the monogenic causes of PD appear to constitute a proportion of cases worldwide. However, investigation of the protein products of these genes can further our understanding of the process of nerve cell death in parkinsonism. Investigation of these forms has emphasized the role of key proteins (like a-synuclein) and molecular pathways leading to neurodegeneration. Intriguingly, mitochondrial mechanisms, oxidative stress and protein clearance appear to be pathogenic in animal models derived both from toxicant and genetic forms of parkinsonism (Dawson and Dawson, 2003; DiMonte, 2003).

It is likely that years, and possibly even decades, pass between the time of risk factor exposure and the clinical onset of parkinsonism. Case-control studies are an efficient way to study proposed disease risk factors, particularly in relatively uncommon disorders, such as PD. Potential limitations to this design include biased recall, the lack of validation of exposure and, in prevalent studies, survivor bias. Prospective cohort studies, assessing risk factors in advance of disease, avoid many of the biases of case-control studies, but risk factor investigation is limited to those selected for study and diagnostic accuracy may be less certain. 6.3.3.1. Rural living, farming, well water Numerous studies worldwide have identified rural living, farming, gardening and drinking well water as risk factors for PD (Semchuk et al., 1991; Butterfield et al., 1993; Hubble et al., 1993a; Morano et al., 1994; Ferraz et al., 1996; Gorell et al., 1998; Marder et al., 1998; Zorzon et al., 2002; Korell and Tanner, 2005), but the results are somewhat inconsistent because of differences in the way the studies assessed the effects of rural living. Overall, risk of PD appears to be increased in rural dwellers – especially in the USA. Meta-analysis results (Priyadarshi et al., 2000) also support that risk factors include farm living and use of well water and pesticides. Although the specific associations are varied, the consistency of the general finding is remarkable.

6.3.3. Proposed environmental risk factors for Parkinson’s disease

6.3.3.2. Pesticides

Risk factor investigation in PD is challenging, as the time of life most important to investigate is not known.

Pesticide exposure is associated with an increased risk of PD in many reports. A meta-analysis of 19 published studies found a combined odds ratio (OR) of 1.94 (95%

EPIDEMIOLOGY OF PARKINSON’S DISEASE confidence interval (CI) 1.49–2.53) for pesticide exposure (Priyadarshi et al., 2000). However, the category of pesticides is very broad, and includes chemicals with many different mechanisms of action. Only a few studies have identified specific compounds or compound classes, including herbicides, insecticides, alkylated phosphates, organochlorines, wood preservatives, dieldrin and paraquat (Firestone et al., 2005; Korell and Tanner, 2005). Most of these studies have been limited by very broad measures of exposure. In many studies, the proportion of exposed persons was low, little was known about specific exposures and validation of exposure was not possible. Gene–environment interaction may also be important, and those with impaired pesticide metabolism may be most vulnerable. A recent report (Elbaz et al., 2004) indicates an increased risk of PD with pesticide exposure in normal metabolizers, and about twofold increase in risk with pesticide exposure for CYP2D6 poor metabolizers, and no effect of the metabolizing status on risk for PD without pesticide exposure. 6.3.3.3. Metals Iron has been shown to cause a higher susceptibility to oxidative stress in two ways. By depleting stores of glutathione, iron may have a role in the progression of parkinsonism associated with exposure to other chemicals that are metabolized to free radicals and/or contribute to the adverse effects of oxidative stress (Kaur et al., 2003). Also, since iron has a strong catalytic power to generate highly reactive hydroxyl radicals from iron (II) and hydrogen peroxide, increased levels of iron in the brain can increase oxidative stress (Fenton reaction). Excessive iron accumulation in the brain is also a potential risk for neuronal damage, which may be promoted by other triggering factors (Lan and Jiang, 1997). A combined high dietary intake of iron and manganese may increase the risk of developing PD (Powers et al., 2003). Dietary intake of manganese alone does not seem to have toxic effects, except among individuals with liver failure (Hauser et al., 1994). Although dietary intake is the main source of non-occupational exposure to manganese, occupational exposure seems to be a more influential PD risk factor. Case-control studies suggest that occupational exposure to metals (Gorell et al., 2004; Racette et al., 2005) may be at increased risk of PD, although cohort studies have not replicated this (Fryzek et al., 2005; Fored et al., 2006). 6.3.3.4. Polychlorinated biphenyls (PCBs) PCBs are among the group of compounds classified as persistent environmental pollutants. In the USA, industrial use was common until 1977. Today, PCBs

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continue to cycle in the environment. Common sources of human exposure are fish and marine mammals, meat and dairy products. In laboratory studies, PCBs have been shown to reduce dopamine levels in the brain areas affected in PD (Seegal et al., 1986; Chu et al., 1996). The association between PCBs and PD has been studied in a blinded comparison of postmortem determinations of caudate PCB concentrations in PD patients and controls (Corrigan et al., 1998). PD brains had significantly higher levels of PCB congener 153, and several other congeners tended to be higher in PD caudate. Also increased in PD brains were the organochlorine pesticide dieldrin and the dichloro-diphenyl-trichloroethane (DDT) metabolite 1,1-dichloro-2,2-bis(4-chlorophenyl)ethene (DDE). In a previous investigation, frontal cortex of PD patients and controls did not show differences in PCB or organochlorine levels. This regional specificity lends indirect support to an association between PCBs and PD. 6.3.3.5. Occupation Given the increasing evidence that environmental factors play a role in PD, there has been an increasing effort to identify occupational risk factors, but to date few have been identified. A higher frequency of PD has been reported among teachers and health care workers (Tsui et al., 1999). These findings were replicated in a casecontrol study in twin pairs discordant for PD (Tanner et al., 2003), and in very large occupational mortality studies in the USA (Schulte et al., 1996) and the UK (Coggon et al., 1995). It has been suggested that an infectious etiology could explain the increased risk in these occupational groups. Alternatively, these associations could be related to some other unrecognized occupation-associated risk factor, to premorbid personality characteristics predisposing to certain occupations (Menza, 2000) or to issues of study design, such as ascertainment bias or confounding by age or other factors. A higher frequency of PD has also been reported in carpenters and cleaners (Fall et al., 1999) and in workers chronically exposed to metals (Gorell et al., 2004). Welding has been proposed as a risk factor (Racette et al., 2005), but this finding is controversial (Fryzek et al., 2005), with recent results from a nationwide linkage study indicating no support for an association between welding and PD, or any other specific basal ganglia and movement disorders (Fored et al., 2006). Overall, results from the available studies are inconclusive, reported findings need confirmation and not all occupations have been evaluated. Differences within even one type of occupation make occupation groups heterogeneous and comparisons difficult. Querying occupation in such a way that it triggers exposure-specific questions as described by Stewart and Stewart (1994) may be more useful, but the potential

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misclassification of specific exposures will be appreciable and tend to bias effect measures toward the null – occupational exposures in community-based studies are rare, which compounds the problem (Tielemans et al., 1999). Ideally, in addition to asking about occupation and exposure, there should be a quantitative measure in exposure-response analyses – for most chronic diseases the exposure measure of choice is the level of exposure multiplied by the duration of exposure. The use of a single variable for primary lifetime occupation is problematic. Undoubtedly, most people work at a number of different jobs throughout their lives, and important associations may be missed or misclassified. A lifelong, job task-specific occupational history has the potential to provide more complete information, and direct interviews may improve historical accuracy. Studies within specific at-risk groups such as occupational cohorts can be important in clarifying whether there is a relationship between occupation and PD. 6.3.4. Diet, obesity, physical activity 6.3.4.1. Diet Diet is a very difficult exposure to measure both because of its complexity and the fact that most individuals have qualitatively relatively similar diets (Willett, 1990). Despite these challenges, several dietary factors have been associated with PD. Excess intake of dairy products has been associated with increased risk of PD in two large prospective cohorts (Chen et al., 2002b; Park et al., 2005). In a study of health professionals, whether the effect was due to calcium or milk could not be determined. Moreover, the risk was most marked in men, and not clearly observed in women. In the second study, PD incidence was more than twice as high in men drinking more than 16 ounces (approximately 450 grams) daily in midlife, compared to those who consumed no milk. This effect was independent of calcium. No women were included in this cohort. The reason for this association is unclear. One explanation is that milk may be a vehicle for potential neurotoxicants such as organochlorine pesticides or tetrahydroisoquinolines. Other studies suggested different dietary risk factors for PD. PD risk was mildly raised in association with high dietary iron intake, but the risk markedly increased with high intake of both iron and manganese (Powers et al., 2003). Another study (Scheider et al., 1997) indicated increased risk with high vitamin C, carotenoids and sweet food, including fruit intake, but the number of cases studied was small (n ¼ 57). Among those with

PD, homocysteinemia has been indicated as a potentially reversible risk factor for depression or cognitive decline (O’Suilleabhain et al., 2004). Studies of dietary antioxidant intake have been largely inconclusive. It is biologically plausible that dietary antioxidants may protect against nigral damage, analogous to their potential role in preventing heart disease and stroke (Rimm et al., 1993; Knekt et al., 1994, 1996; Gale et al., 1995). One prospective cohort study of 41 836 women indicated a significant protective effect seen for both vitamin C and manganese consumption; however, vitamin A intake was associated with an increased risk of PD (Cerhan et al., 1994). A sibpair study (Maher et al., 2002) reported a 3.2-year older mean age at onset for affected siblings who reported taking multivitamins. Protective effects were proposed for B vitamins and folate, because of their shared pathways with homocysteine and ability to lessen oxidative stress (Duan et al., 2002). Comparison of two large prospective cohorts (Chen et al., 2004a) with 415 cases indicated PD risks did not differ in relation to dietary intakes of B vitamins and folate (relative risk 1.0 (95% CI 0.7–1.5) comparing the lowest to the highest intake quintile in men and 1.3 (95% CI 0.8–2.3) in women). Dietary insufficiency has also been proposed as a risk factor for the development of PD, although evidence for this is indirect. In a 20–30-year follow-up of a cohort of ex-Far-East prisoners of war, who experienced severe dietary insufficiency between 1942 and 1945 (Gibberd and Simmonds, 1980), 24 PD cases were identified out of 4684 subjects, producing a crude prevalence rate of 512 per 100 000. This is particularly high considering the relatively young age of the cohort and the observation that 15 cases (63%) had disease onset under the age of 50 years. Emotional and physical stress has also been implicated in increased frequencies of PD in another study of prisoners of war (Page and Tanner, 2000), although a relationship to dietary insufficiency could not be determined. Certain exotic dietary exposures have been proposed to cause atypical forms of parkinsonism, including ingestion of indigenous species from Guam (Spencer, 1987; Murch et al., 2004), or the British West Indies (Champy et al., 2005), although these reports are controversial. 6.3.4.2. Obesity Conversely, oxidative stress may be increased by lipid consumption and higher caloric intake, and eating foods high in animal fat has been associated with increased risk of PD in several studies (Korell and Tanner, 2005). The link between measures of body composition and obesity and risk of PD is unclear.

EPIDEMIOLOGY OF PARKINSON’S DISEASE A large study in Japanese-American men in Hawaii observed higher prevalence of PD with higher triceps skinfold thickness, subscapular skinfold thickness and body mass index (Abbott et al., 2002). A similar analysis in the Nurses’ Health and the Health Professionals’ study did not find an association between body mass index and risk of PD but, among never smokers, both waist circumference and waist–hip ratio showed significantly positive associations with PD risk as compared to smokers (Chen et al., 2004b). 6.3.4.3. Physical activity Animal models have also been used to study the role of physical activity in PD. Results of studies of forced limb use in 6-hydroxydopamine-injected rats (Cohen et al., 2003) suggest that preinjury forced limb use can prevent the behavioral and neurochemical deficits. In treadmill tests of MPTP-injected rats (Tillerson et al., 2003), exercise following the nigrostriatal damage ameliorated related motor symptoms and neurochemical deficits. Physical activity in epidemiological studies includes cohort results by Chen et al. (2005a) that show either that higher levels of physical activity may lower the risk of PD in men, or that men predisposed to PD tend to avoid strenuous activity in their early adult years. A significantly lower level of physical activity was present before diagnosis (men, 12 years prior; women, 2–4 years prior), and there was a sustained decrease in physical activity after diagnosis. Case-control studies, however, have shown inconsistent results. In one Chinese hospital-based study investigating risk factors for classic-onset versus youngonset PD, the duration of exercise was substantially longer in the young-onset group than in controls or in the classic-onset PD group (Tsai et al., 2002). In another small study assessing the lifetime physical activity via sports/leisure activity and participation using visual analog scales, there was no difference in lifetime physical activity between cases and controls; however, there was a greater decline in activity after age 50 years in those with PD (Fertl et al., 1993). In a nested case-control study of male Harvard students, moderate physical activity was associated with a lower risk of PD, but this association was not seen at higher levels of physical activity (Sasco et al., 1992). 6.3.5. Inflammation, infection, head trauma, non-steroidal anti-inflammatory drugs (NSAIDs) 6.3.5.1. Inflammation Several lines of evidence support the idea that inflammation is involved in the pathogenesis of PD (Hirsch et al., 2003). Postmortem analyses showed gliosis

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and clustering of microglial cells around nerve cells in 3 subjects who had presented with MPTP-induced parkinsonism 3–16 years earlier (Langston et al., 1999). In cell culture experiments injection of lipopolysaccharides (LPS), which activate glia, killed dopaminergic neurons in mixed neuron–glia but not in pure neuron cultures (Bronstein et al., 1995). In an animal model, a single intranigral injection of LPS damaged dopaminergic but not serotonergic or GABAergic neurons (Herrera et al., 2000; Gao et al., 2002). Application of dexamethasone before LPS injection prevented the loss of catecholaminergic content, tyrosine hydroxylase activity and immunostaining, and the microglia-macrophage activation seen previously (Castano et al., 2002). Human studies revealed elevated cytokine levels, which induce glia activation, in the brain and cerebrospinal fluid of PD patients compared to controls (Nagatsu et al., 2000). Additionally, increased expression of tumor necrosis factor-a, interleukin-b and interferon-g was observed in the substantia nigra of PD patients (Boka et al., 1994; Hunot et al., 1999). In recent epidemiologic studies, intake of NSAIDs was inversely associated with PD risk (Chen et al., 2003); more detailed analysis indicated that the association was significant for ibuprofen but not other NSAIDs (Chen et al., 2005b). Higher levels of uric acid, a potent antioxidant, during midlife were associated with a 40% reduced risk of PD in one prospective cohort (Davis et al., 1996). This observation was recently replicated in a nested case-control study in the health professional prospective cohort study (Weisskopf et al., 2006, unpublished; see Ascherio et al., 2006 for abstract). However, uric acid levels can be increased by several agents inversely associated with PD, including alcohol, caffeine and aspirin, as well as by levodopa. Further studies are needed to determine whether this is a primary or secondary association. 6.3.5.2. Infections The observation that encephalitis lethargica often resulted in parkinsonism during the influenza pandemic of the early 1900s suggested a possible infectious etiology for PD. Since that time, however, clinical and neuropathological criteria have clearly differentiated postencephalitic parkinsonism from typical idiopathic PD. Although subsequent studies have been unable to identify an infectious agent in PD (Marttila et al., 1977; Wang et al., 1993), a number of studies have continued to suggest that infection may play a role in idiopathic PD. As described previously, increased PD frequency in health care workers and teachers has been linked to infection (Schulte et al.,

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1996). One study observed elevated coronavirus antibody levels in the cerebrospinal fluid of PD patients, supporting a possible link of PD with coronavirus infections (Fazzini et al., 1992), a common cause of respiratory infections. Another study noticed reduced risk for PD associated with most viral childhood infections, especially measles (Sasco and Paffenbarger, 1985); both studies await replication. The soil pathogen Nocardia asteroides causes a levodoparesponsive movement disorder and nigral degeneration in mice (Kobbata and Beaman, 1991), but a serologic case-control study did not support its role in human PD (Hubble et al., 1995).

the association between NSAID use and PD risk in humans. An inverse association of NSAID use with risk of PD has been observed in two prospective studies for non-aspirin NSAIDs, as well as for aspirin (Abbott et al., 2003; Chen et al., 2003). Interestingly, in a cross-sectional study of 1258 PD cases and 6638 controls from the General Practice Research Database, this inverse association was again observed for men, but not women, in whom non-aspirin NSAID use was associated with a higher risk of PD (Hernan et al., 2006). Whether this reflects a characteristic of the study population or method, or a true gender difference in risk, will require studies in other populations.

6.3.5.3. Head trauma

6.3.6. Smoking, caffeine, alcohol

Previous head trauma has been associated with PD in numerous case-control studies (Bharucha et al., 1986; Tanner et al., 1987; Stern, 1991; Semchuk et al., 1993; Van Den Eeden et al., 2000; Bower et al., 2003). Head injury can trigger an inflammatory cascade, or conceivably disrupt the blood–brain barrier, increasing risk of exposure to toxicants or infectious agents. In a sibpair study (Maher et al., 2002) and a study of twin pairs concordant for PD (Goldman et al., 2006), the sibling with younger-onset PD was more likely to have sustained a head injury. In twins discordant for PD, a previous head injury with amnesia or loss of consciousness was associated with a nearly fourfold increased risk of PD. Significant head injury is rare, however, and there may be a latency up to 30 years between injury and PD diagnosis, minimizing the chance that disease-related disability caused the injury (Factor and Weiner, 1991; Seidler et al., 1996; Taylor et al., 1999). Severity of head injury is likely to be important and there may be a dose effect; there is no association with PD and mild head injury without loss of consciousness. Nevertheless, medical record validation suggests that this is a real association, not explained by recall bias. 6.3.5.4. Non-steroidal anti-inflammatory drugs Inflammatory mechanisms appear to contribute to neurodegeneration in PD, and animal studies suggest that NSAIDs have neuroprotective properties (McGeer and McGeer, 2004) by reducing general inflammation. Studies of Alzheimer’s disease have shown that the regular use of NSAIDs may reduce the risk of Alzheimer’s in humans (Breitner and Zandi, 2001, in t’ Veld et al., 2001; McGeer and McGeer, 2004). The similarities in the pathogenetic background of PD and Alzheimer’s disease and animal data suggesting that anti-inflammatory drugs may protect against PD (Ferger et al., 1999) have encouraged investigation of

Although there are a number of health risks associated with smoking tobacco and drinking alcohol, cigarette, coffee and alcohol intakes are all inversely associated with risk for developing PD, suggesting they may be neuroprotective agents. 6.3.6.1. Smoking Not smoking cigarettes is the most consistently observed risk factor for PD. An inverse association between cigarette smoking and PD has been observed in studies spanning more than 30 years, involving diverse populations and including several large prospective investigations (Doll et al., 1994; Grandinetti et al., 1994; Benedetti et al., 2000; Willems-Giesbergen et al., 2000). A meta-analysis (Hernan et al., 2002a) indicated a 40% reduced risk of PD in smokers. Three basic categories of smoking were evaluated: ever smoking, past smoking and current smoking behavior. Long duration (highest pack/year) correlated with dose, and smoking more than 5 years prior to PD onset was not protective; recent smoking appeared more protective. Other research suggests cigarette smoking, on average, appears to lower the risk of developing PD by about half (Sugita et al., 2001). This inverse association has been reported in nearly every population studied over more than 30 years (Quik, 2004), and a recent study in a population characterized by a high prevalence of occupational pesticide exposure confirms an inverse correlation between cigarette smoking and PD in this potentially ‘high-risk’ group as well (Galanaud et al., 2005). One report suggests the inverse association of smoking and PD is only present in those with a specific monoamine oxidase-B allele (Checkoway et al., 1998), although this was not replicated (Hernan et al., 2002b), and other single observations suggest other interactions of genes and smoking (Tan et al., 2002).

EPIDEMIOLOGY OF PARKINSON’S DISEASE Non-smoking behavior in people fated to develop PD may be the result of a lower reward of smoking due to low dopaminergic tone, a genetically conferred decreased propensity to smoke or a premorbid personality (Menza, 2000). Indeed, the personalities of those who have gone on to develop PD have been described as shy, cautious, inflexible, punctual and depressive (Hubble et al., 1993b); such persons may be less likely to smoke or drink. In contrast, indirect evidence against this theory derives from a study in twin pairs discordant for PD (Tanner et al., 2002). The twins without PD had smoked more than their brothers. Despite a high correlation for smoking in monozygotic twin pairs, this difference was more marked in the monozygotic pairs, known to be remarkably similar in personality. Similar results have been reported in other studies of twins (Bharucha et al., 1986) and siblings (Scott et al., 2005) discordant for PD. If there is a biologic effect of smoking, whether this is due to nicotine or a combustion product is not known. Indirect evidence supporting a role for nicotine is provided by the observation that PD was less commonly reported among users of smokeless tobacco in a large prospective cohort (O’Reilly et al., 2005). Animal studies suggest that nicotine may protect against experimental parkinsonism (Janson and Moller, 1993; Prasad et al., 1994) (Table 6.5). Nicotine has been found to protect against transection-induced and MPTP-induced dopaminergic neuronal cell loss in rodent substantia nigra (Janson and Moller, 1993; Prasad et al., 1994). In addition, nicotine has antioxidant properties (Ferger et al., 1998), and increases striatal trophic factors (Maggio et al., 1997). Alternatively, smoking may afford indirect protection by inducing peripheral detoxifying enzymes, or by reducing bioactivation of protoxins. This latter hypothesis is supported by the observation that cigarette smoking reduces monoamine oxidase-B activity in humans (Fowler et al., 1996). Table 6.5 Cigarette smoking and Parkinson’s disease: some possible biologic mechanisms Nicotine Blocks nigral cell loss (hemitransection, MPTP) Increases growth factors Cigarette smoke Reduces MAO-B activity Gene–environment interaction of smoking and MAO-B allele Complex mixture of combustion products – other actions? MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; monoamine oxidase B.

MAO-B,

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Assuming smoking is neuroprotective, one might expect it to delay the onset of PD and improve the course of the disease in people already affected. Neither hypothesis has yet been proven. Two studies compared clinical features and did not find differences between smokers and non-smokers (Alves et al., 2004; Papapetropoulos et al., 2005). Although a study by Kuopio et al. (1999) reported the mean age at onset in ever-smoking men was significantly higher than in never-smoking men, results of four other studies assessing age at onset of PD in relation to smoking status (Haack et al., 1981; Rajput et al., 1987; Morens et al., 1996b; Levy et al., 2002, De Reuck et al., 2005) revealed the same or a younger age of PD onset in smokers. Interestingly, however, in several prospective cohort studies, survival of those persons with PD who continue to smoke cigarettes appears to be similar to, or even somewhat better than, survival of nonsmokers with PD (Grandinetti et al., 1994; Elbaz et al., 2003b; Chen et al., 2006), in contrast to the typically increased mortality observed in cigarette smokers. This tantalizing preliminary information suggests that some aspect of smoking may not only modify disease risk, but also improve survival once PD is manifest. 6.3.6.2. Coffee and caffeine An inverse association of both coffee and caffeine consumption and PD has been reported in case-control and cohort studies (Fall et al., 1999; Benedetti et al,. 2000; Ross et al,. 2000; Ascherio et al., 2001; Paganini-Hill, 2001). For example, a longitudinal study and two case-control studies of incident PD cases provide provocative evidence that coffee drinking may be inversely associated with PD risk. A longitudinal study of Japanese-American men indicated greater use of coffee was inversely associated with PD risk in a dose-dependent fashion (Ross et al., 2000). A very provocative finding in the same cohort was that greater use of coffee was inversely associated with incidental Lewy bodies at postmortem (Ross et al., 1999). A similar dose-dependent inverse association between coffee drinking and PD was observed in two prospective studies (Benedetti et al., 2000; Willems-Giesbergen et al., 2000), and retrospectively an incident case-control study in Northern California (Nelson et al., 1999). In each case, the inverse association between PD and coffee drinking continued to be observed in multivariate analyses adjusting for cigarette smoking, alcohol use and other potential confounders. Similar associations had previously been reported in a few case-control studies of prevalent cases, but these results were inconsistent, and a dose–response gradient was not

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described (Tanner and Goldman, 1996, Checkoway and Nelson, 1999). The effect of coffee appears to differ between men and women, with a direct dose–response association in men (higher consumption associated with lower risk) but a U-shaped pattern in women, although fewer women have been studied. It has been suggested a potential interaction between hormone exposure, primarily estrogen, and caffeine consumption may mediate PD. In participants of the Cancer Prevention Study II, caffeine intake was associated with a significantly lower mortality of PD in men but not in women (Ascherio et al., 2004). In women, the association depended on estrogen use, with a relative risk for PD of 0.47 (95% CI 0.27–0.8) in caffeine consumers not using hormones and of 1.31 (95% CI 0.75–2.3) in hormone users. Caffeine may be neuroprotective through its antagonist action on the adenosine A2A-receptor (Chen et al., 2002a), which in laboratory studies, modulates dopaminergic neurotransmission (Popoli et al., 1991; Nehlig et al., 1992) and protects against striatal dopamine loss caused by MPTP (Richardson et al., 1997; Kanda et al., 1998). A2A-receptor antagonists are receiving increasing attention as potential treatments, in particular for on/off fluctuations and dyskinesia in combination with levodopa therapy (Xu et al., 2005), but also as a possible monotherapy in early-stage PD because of positive results from animal studies and a small clinical trial (Hauser et al., 2003; Jenner, 2003). 6.3.6.3. Alcohol Alcohol use has been found by some to be inversely associated with PD even after controlling for possible confounding by smoking (Hellenbrand et al., 1996; Fall et al., 1999; Paganini-Hill, 2001). A biologic explanation for this observation has not been articulated. One study found that fewer cases with PD had a diagnosis of alcoholism than controls (Benedetti et al., 2000). The variability across studies is great and, overall, the current evidence for an association between alcohol intake and risk of PD is weak. In the Nurses’ Health and the Health Professionals’ cohorts, no association between incidence of PD and overall alcohol consumption was observed (Hernan et al., 2003); however, an inverse association of beer (but not wine or liquor) consumption was seen. Comparison of alcoholics and non-alcoholics in a large database found comparable PD incidence in both groups (Hernan et al., 2004). Interestingly, in a stratified analysis for men and women separately, male alcoholics had a significantly lower incidence of PD whereas female alcoholics had a twofold increased

incidence. Low consumption of alcohol in PD has commonly been attributed to the reserved personality that has been observed prior to PD manifestation (Menza, 2000). 6.3.7. Gender As noted above, men appear to be at greater risk of developing PD than are women. This could reflect an intrinsic difference in risk, such as might be due to an X-chromosome-linked genetic characteristic or a sex hormone-related factor. Alternatively, genderdetermined differences in risk factor exposure may be the cause or a combination of biologic predisposition and differences in risk factors might explain this pattern. Benedetti et al. (2001) used a population-based case-control method to determine whether reproductive factors may influence PD risk in women. Hysterectomy with or without an oophorectomy and early menopause were associated with increased risk of PD (OR ¼ 3.36 and 2.18, respectively) and estrogen use after menopause was inversely associated with PD risk (OR ¼ 0.47), although the latter two differences were not statistically significant. Several subsequent casecontrol studies have similarly suggested that factors associated with estrogen deficiency such as hysterectomy and early menopause may increase PD risk (Currie et al., 2004; Ragonese et al., 2004). Recently, Popat et al. (2005) found that the association of postmenopausal hormone use with PD risk depended on the type of menopause. Among women with history of a hysterectomy with or without an oophorectomy, estrogen use alone was associated with a 2.6-fold increased risk and the risk of PD increased with increasing duration of estrogen use. In contrast, among women with natural menopause, no increased risk of PD was observed with hormone use. Gender may also determine the effects of risk or protective factors associated with PD. Women appear to have different risk profiles to at least some of the exposures linked to PD in men, as discussed in previous sections. Although the explanation for these differences is not known, investigation of the combined effects of risk factors may explain some of these differences. For example, in two prospective cohort studies, PD risk was influenced by the combined effects of caffeine consumption and supplemental estrogen use. Women using supplemental estrogens with low caffeine consumption were at a lower risk of PD, but this effect was attenuated or reversed in women who had a high caffeine consumption and were at higher risk of PD (Ascherio et al., 2003, 2004). Future studies including populations of women of

EPIDEMIOLOGY OF PARKINSON’S DISEASE sufficient size to allow the separate assessment of risk factors in women will be important to clarify the question of gender and PD risk.

6.4. Gene–environment interactions Research in the area of gene–environment interactions is complicated in that multiple genes and various environmental factors may combine to determine the level of risk for PD in any one individual. As described previously, several environmental factors, including pesticide and chemical exposure, have been consistently shown to modify the risk for PD in epidemiologic studies. If PD results from a combination of genetic and environmental factors, then an interaction of genetic factors with certain exposures could result in a high level of disease risk. For example, increased risk from an environmental toxin could be influenced by the genetically determined level of activity of metabolizing enzymes. Few gene–environment interactions have been investigated. One case-control study suggests that smoking history modifies the effect of family history on the risk for PD, such that the odds ratio is highest in those with a history of smoking and a family history of PD (OR 10.0; Elbaz et al., 2000). This is a surprising finding given the increasing body of evidence that smoking is negatively associated with the occurrence of PD. Other interactions have also been reported, including possible interactions between monoamine oxidase-B gene polymorphisms and smoking behavior. A reduced risk of PD with increasing number of pack-years of smoking was found in the presence of the G allele, whereas PD risk decreased with increasing pack-years smoked in the presence of the A allele (Checkoway et al., 1998). Interactions between xenobiotic metabolizing enzyme genotype and pesticide exposure in the risk of PD have also been studied (Menegon et al., 1998; Taylor et al., 2000). The association between pesticide exposure and PD may be modified by glutathione transferase P1 polymorphisms (Menegon et al., 1998). In a study of 96 patients and 95 controls, no overall difference in the distribution of glutathione S-transferase (GST) P1 genotypes was found between cases and controls. In those with pesticide exposure, however, the GST P1 AA genotype was associated with the lowest risk for PD. Confirmation of each of these observations in additional populations may provide important clues to disease etiology. Polymorphisms of many genes have been found to be associated with an increase or decrease in risk for PD in at least one or more studies. Unknown gene–gene or gene–environment interactions may produce misleading results if cases and controls are

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not appropriately matched, perhaps explaining some of the conflicting data seen in these studies. Whether the inconsistent results obtained to date are due to study design issues or to limited generalizability of the findings to different patient groups is not known.

6.5. The future of Parkinson’s disease epidemiology An emerging direction of epidemiologic research in PD also deserves mention. Recent work involves investigation of those ‘at risk’ for PD, before disease is manifest. A variety of disorders may precede formal diagnosis of PD, including olfactory dysfunction, rapid-eye movement sleep behavior disorders, QT or rate-corrected QT (QTc) interval prolongation on the electrocardiogram, adiposity and constipation. In vivo imaging of the dopamine transporter with (99mTc) TRODAT-1 (TRODAT) and olfactory testing have both been proposed as potential biomarkers in PD, and impaired smell recognition correlated with lower TRODAT uptake (Siderowf et al., 2005). Rapid-eye movement sleep behavior disorder is strongly predictive of PD, and RBD patients have been shown to have impaired olfactory function compared to controls (Stiasny-Kolster et al., 2005). In addition to olfactory dysfunction and rapid-eye movement sleep behavior disorders, a number of patients with PD and multiple system atrophy, have QT or QTc interval prolongation on the electrocardiogram. In one prospective cohort, these findings were highly predictive of PD incidence (LR White, personal communication). Although these QT or QTc interval abnormalities are likely related to autonomic dysfunction, the pathophysiology remains unknown (Deguchi et al., 2002). Other characteristics in midlife associated with increased PD risk include increased triceps skinfold thickness (Abbott et al., 2002) and constipation. Men with less than one bowel movement per day at midlife had a 4.1-fold excess incidence of PD when compared with men with more frequent bowel movements (Abbott et al., 2001). Taken together, these observations suggest that PD may begin decades before nervous system symptoms are observed. PD may be first a disorder of the peripheral autonomic nervous system. If an environmental trigger is involved, the gastrointestinal tract or the olfactory epithelium may be portals of entry. This hypothesis is indirectly supported by neuropathologic findings, suggesting that nigral pathology is a relatively late event in the pathogenesis of PD (Braak et al., 2004). Further studies to identify those at risk will be essential in determining the causes of PD, and methods for its prevention.

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In the next half-century, the average age of individuals in both developed and developing countries is expected to show a progressive increase. In the USA alone, this phenomenon of population aging is predicted to result in a three- to fourfold increase in PD frequency, or several million persons with the disease. The impact of PD can also be expected to affect disease-associated health expenditures, lost income and personal suffering. As described in this chapter, despite intensive research efforts during the past several decades, the cause (or causes) of typical PD remains unknown. Likely, PD will be understood to be multifactorial, and both genetic and environmental determinants will be important. For example, estimated lifetime penetrance in parkinsonism caused by LRRK2 in the Ashkenazi Jewish population is only about 30% (Ozelius et al., 2006). Both genetic and environmental factors may determine expression of this monogenic form of parkinsonism. Typical PD may similarly be due to many different combinations of genetic or environmental determinants. The investigation of possible gene–environment interaction in PD is just beginning. In the next decade, investigations involving careful characterization of genetic and environmental factors will be essential to defining the causes of PD.

Acknowledgments Drs Chade and Kasten are Michael J. Fox Foundation Fellows at The Parkinson’s Institute. Thank you to Jennifer Wright for editorial assistance.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 7

Neurochemistry of Parkinson’s disease JAYARAMAN RAO* Department of Neurology, Parkinson’s Disease and Movement Disorders Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA

7.1. Introduction Parkinson’s disease (PD) is the second most common neurodegenerative disorder. By now, it is common knowledge, not just to the scientists and medical professionals, but to millions of lay public, that dopamine deficiency is the major neurochemical problem in PD. Our understanding of the neurochemical abnormalities of PD began with the suggestion that dopamine might have regulating functions of its own (Blaschko, 1957) rather just being an intermediary product in the synthesis of norepinephrine and epinephrine from tyrosine. This suggestion was soon followed by the localization of dopamine not just in the periphery, but also in the brain of many animals (Montagu, 1957) and that 80% of dopamine in the brain is localized in the striatum (Bertler and Rosengren, 1959; Sano et al., 1959). It was the breakthrough observation of Carlsson and his associates (1957; Carlsson 2000, 2001) that the complete ptosis and lethargy of reserpinized animals improved dramatically after intravenous administration of dopa, but not 5-hydroxytryptophan, the precursor of serotonin (5-HT), that provided the first clue to our understanding of the neurochemical basis of PD. Sano is credited as the first to have attempted to treat PD with levodopa (Foley, 2000; Hornykiewicz, 2001b), albeit unsuccessfully, but the careful and methodic neurochemical, neuropathological and clinical studies of Ehringer, Birkmayer and Hornykiewicz (Hornykiewicz, 2001b) finally established the fact that PD is a dopamine-deficiency disorder. Research focused on dopamine metabolism and the biology of dopamine receptors that followed these early and pioneering studies linking dopamine deficiency and PD has led to the successful development of drugs that have decreased mortality and improved the quality of life

of patients with PD. This chapter will focus primarily on our current understanding of the neurochemical changes noted in PD and references to observations in normal and animal models of PD will be made when appropriate to clarify and complement the results in PD.

7.2. Neurochemistry of the basal ganglia in Parkinson’s disease 7.2.1. Neurochemistry of neurons of ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) 7.2.1.1. Neurotransmitter of neurons of VTA and SNpc 7.2.1.1.1. Site of maximum degeneration The pathognomonic feature of PD is the progressive degeneration of the dopaminergic neurons of the ventral midbrain. The mesencephalic dopaminergic neurons are classified into three groups: (1) the A9 group consists of densely packed cells in the SNpc; (2) the A10 group is located in the VTA of Tsai; and (3) the A8 group is located in the retrorubral regions of the midbrain (Bjorklund and Lindvall, 1984; Hirsch et al., 1988). Hassler (1938) divided SNpc into dorsal and ventral subdivisions and these two subdivisions were further divided into several subnuclei. A recent and much simpler classification of cell groups of dopaminergic neurons in substantia nigra has identified the dopamine neurons to be located both in the calbindin D28K-rich ‘matrix’ regions and in five calbindin D28K-poor pockets of densely aggregated dopamine neurons called ‘nigrosomes’ (Damier et al., 1999a). In PD, 98% of the dopaminergic neurons in nigrosome 1, located in the ventrolateral tier of the SNpc and corresponding to

*Correspondence to: Jayaraman Rao, MD, Parkinson’s Disease and Movement Disorders Center, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA. E-mail: [email protected], Tel: 1-504-842-3980; Fax: 1-504-8420041.

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the spedd, sped, spez and spev divisions of Hassler (1938), degenerate early (Damier et al., 1999b). As the disease worsens, there is a medial and dorsal spatiotemporal pattern of progression of degeneration, ultimately including the dopamine cells of VTA (A10) and the retrorubral nucleus (A8) (Damier et al., 1999b). 7.2.1.1.2. Melanized versus unmelanized neurons The dopamine neurons of VTA and SNpc contain cells that are densely melanized and cells that are nonmelanized. In SNpc 84–98% of cells are melanized and the ratio between the melanized and non-melanized neurons in VTA is about 50:50 (Kingsbury et al., 1999; Tong et al., 2000). Almost all of the melanized cells in SNpc and VTA express TH protein or mRNA (Hirsch et al., 1988; Tong et al., 2000). The melanized cells degenerate more than the non-melanized cells (Hirsch et al., 1988); accordingly, loss of neurons in VTA in PD is less severe than in SNpc (Tong et al., 2000). 7.2.1.1.3. Enzymes of dopamine synthesis The midbrain dopamine neurons express mRNA and protein of TH, the rate-limiting enzyme of dopamine synthesis, and are exclusively dopaminergic, since they lack the expression of dopamine b-hydroxylase and phenoxymethyltransferase (Bjorklund and Lindvall, 1984, Tong et al. 2000), enzymes that synthesize norepineprhine and epinephrine from dopamine respectively. In PD, all the typical phenotypic markers of dopaminergic system are decreased in both VTA and SNpc, but most intensely in the dopaminergic cells in SNpc. In control brains, TH mRNA is expressed densely in the neurons throughout the entire SNpc and VTA and the intensity of expression of TH mRNA appears to be the same in both the melanized and non-melanized cells (Kingsbury et al., 1999; Tong et al., 2000). In PD brains, the number of TH immunoreactive neurons is significantly decreased and the level of TH mRNA and protein in the surviving melanized neurons has been reported to be decreased (Javoy-Agid et al., 1990; Kastner et al., 1993) or demonstrating a compensatory increase (Joyce et al., 1997) or unchanged (Kingsbury et al., 1999; Tong et al., 2000). The surviving non-degenerating non-melanized cells of SNpc and VTA, however, show an increase in the intensity of TH mRNA expression (Kingsbury et al., 1999; Tong et al., 2000). These results suggest that the surviving nonmelanized neurons exhibit, at best, a minimal compensatory increase in TH expression, and an increased turnover of dopamine at the terminals may actually be one of the major mechanisms of compensation for the loss of dopamine in animal models of PD and in PD (Zigmond, 1997; Hornykiewicz, 2001a). Chronic administration of

levodopa during the life of these patients does not modify the pattern of expression of TH mRNA in the remaining melanized cells of SNpc and VTA, suggesting that chronic levodopa may not be neurotoxic (Kingsbury et al., 1999). Along with the reduction of TH mRNA and protein, levels of tetrahydrobiopterin (BH4), a cofactor of TH, and aromatic amino acid decarboxylase (AADC), the enzyme that converts dopa to dopamine, are also decreased significantly in SNpc in PD (Nagatsu et al., 1984; Nagatsu and Ichinose, 1996, 1999). 7.2.1.1.4. Dopamine The level of dopamine in nigra is second only to that of the striatum (Hornykiewicz, 2001a). The soma of a SNpc DA cell is located in SNpc and the different afferent systems converge upon the dendrites of SNpc dopamine neurons that are located in substantia nigra pars reticulata (SNpr). Dopamine synthesized by SNpc neurons is released not only at the terminals in the striatum, but also in soma and the dendrites of SNpc neurons located in SNpr. In PD, there is 80% loss of dopamine in the nigra (Hornykiewicz, 2001a). 7.2.1.1.5. Vesicular monoamine transporter (VMAT) Vesicular transporters transport neurotransmitters into vesicles of nerve terminals and neuroendocrine cells and make them available for regulated release. VMAT1 is localized predominantly in the neuroendocrine cells, whereas VMAT2 is widely distributed in monoaminergic terminals and dendrites. In the dopaminergic nerve terminal, VMAT2 transports cytoplasmic dopamine into the vesicles. The extent of melanization of midbrain dopamine neurons is directly proportional to the extent of expression of VMAT2, since highly active VMAT2 will incorporate cytoplasmic dopamine more efficiently into the vesicle, thereby reducing the formation of neuromelanin. Cells that express VMAT2 less intensely are more vulnerable to neurotoxins (Miller et al., 1999). In concordance with these observations in animals, VMAT2 expression is low in SNpc and high in VTA, which corresponds not only to the ratio of melanized to non-melanized cells in the VTA and SNpc but also to the loss of increased number of cells in SNpc. VMAT2 expression is higher in VTA than SNpc and may be an indicator of relatively decreased vulnerability of cell death of VTA than SNpc (Liang et al., 2004). Striatal VMAT2 levels are significantly decreased in PD (Hornykiewicz, 1998, 2001). 7.2.1.1.6. Dopamine transporter Dopamine transporter (DAT) facilitates reuptake of 95% of dopamine in the synaptic cleft and ends dopamine neurotransmission (Uhl, 2003). DAT actively

NEUROCHEMISTRY OF PARKINSON’S DISEASE participates in the somatodendritic release of dopamine by reversely transporting dopamine from the dendrite of a SNpc cell to the extracellular space (Falkenburger et al., 2001). Unlike TH, DAT is an important and specific marker for dopaminergic neurons (Uhl, 2003) and several DAT ligands have been developed as markers to measure the pattern of survival of dopaminergic neurons and their terminals. In primate and nigra, the extent of DAT expression is the highest in the melanized neurons of SNpc. The intensity of expression of DAT in primate and nigra is maximal at the caudal, ventral and lateral group of dopamine neurons and gradually decreases medially in the VTA regions (Uhl, 2003; Gonzalez-Hernandez et al., 2004). In PD, there is significant loss of DAT expression in the mesencephalic dopamine neurons and the pattern of loss is directly proportional to the intensity of expression of DAT in these cells. The SNpc cells that express DAT very densely are the most severely affected in PD, and those VTA neurons expressing DAT less intensely demonstrate a less severe pattern of degeneration. The dopamine-containing cells of the arcuate and the paraventricular nuclei of the hypothalamus, for example, express DAT less intensely and do not degenerate in PD (Uhl, 2003). These findings suggest that the intensity of expression of DAT may be a major factor for the vulnerability of dopamine cells to endogenous and exogenous neurotoxins (Uhl, 1998; Bannon, 2005). The conclusions are supported by the observations that mice that overexpress DAT are more vulnerable to neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and DAT knockout mice are completely resistant to the neurotoxic effects of MPTP (Miller et al., 1999). 7.2.1.2. Neuropeptides of neurons of VTA and SNpc 7.2.1.2.1. Cholecystokinin-8 (CCK-8) Among the different peptides synthesized from procholecystokinin, CCK-8 is the predominant peptide in the central nervous system. CCK colocalizes with dopamine in VTA and SNpc in rats, cats and monkeys (Artaud et al., 1989; Seroogy et al., 1989; Jayaraman et al., 1990; Sirinathsinghji et al., 1992) and significantly influences release of dopamine in the striatal regions. So far, mRNA for CCK has not been demonstrated in human midbrain dopamine neurons. The level of CCK is reported to be significantly decreased in MPTP-treated primates (Sirinathsinghji et al., 1992) or almost absent in PD brains (Studler et al., 1982) and it has also been proposed that the midbrain dopamine neurons of adult human brain may not express CCK at all (Palacios et al., 1989).

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7.2.1.2.2. Neurotensin In human brains, a high level of neurotensin has been noted in SN and other regions of the brain, similar to that of the distribution pattern seen in rats and monkeys (Manberg et al., 1982). Significant interactions between dopamine and neurotensin occur in the basal ganglia (Binder et al., 2001). Neurotensin mRNA is expressed by a small group of neurons in the ventral tegmental regions in rats (Jayaraman et al., 1990). In PD, neurotensin levels are high in SN and the neurotensinergic striatonigral projection neurons are the source of the high neurotensin levels in SN (Fernandez et al., 1995). 7.2.1.3. Receptors localized in dopamine neurons of SNpc 7.2.1.3.1. Neurotransmitter receptors 7.2.1.3.1.1. Dopamine receptors The diverse effects of dopamine are mediated by D1 and D2 subfamilies of dopamine receptors, which are members of the superfamily of G-protein-coupled receptors (GPCRs). The D1- and D5-receptor subtypes, belonging to the D1 class, are coupled to G-proteins Gs and Golf, resulting in an increase in adenylyl cyclase and cyclic adenosine monophosphate (AMP) levels postsynaptically. The D2 class consists of D2-, D3- and D4-receptors, which are coupled to the inhibitory Gi, Go class of G-proteins, result in a decrease in adenylyl cyclase and cyclic AMP levels, and modulate ion channels (Civelli et al., 1993; Missale et al., 1998; Gether, 2000). All the subtypes of dopamine receptors have been localized to the striatum. Earlier studies using in situ hybridization techniques could not detect any mRNA for D1- or D5-receptors in midbrain dopamine neurons but modern reverse transcriptase polymer chain reaction (RT-PCR) suggests that the non-dopaminergic cells of SNpr as well as dopamine neurons and/or the glial cells in SNpc may express the mRNA and protein for D1-receptor. In PD, the mRNA and protein level of D1-receptors is decreased in SNpc (Hurley et al. 2001). The D1-receptors are also preferentially localized in the terminals of striatonigral axons in human midbrain (Thibaut et al., 1990). D2-receptor mRNA and protein are expressed very densely by the dopamine neurons of SNpc in brain (Meador-Woodruff et al., 1994; Hurd et al., 2001). The D2-receptors, localized in the perikarya, dendrites and nigrostriatal terminals, play a significant role in dopamine synthesis and release at the nigral and striatal levels (Kalivas, 1993; Sesack et al., 1994). The D2receptor gene codes for two isoforms of D2-receptor proteins. The D2 long (D2L) form has an additional 29 amino acids in the third cytoplasmic loop when

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compared to the D2 short (D2S) form (Missale et al., 1998). In the dopaminergic neurons of SNpc, VTA and the A8 group, the D2S form is expressed solely (Khan et al., 1998). In PD, there is loss of D2-receptor expression in SNpc and VTA (Murray et al., 1995). The TH-positive neurons of SNpc and non-THpositive cells in SNpr express mRNA for D3-receptors (Gurevich and Joyce, 1999). The mRNA for D4(Matsuomoto, 1996) and D5-receptors (Choi et al., 1995; Khan et al., 2000) is expressed in SNpc. 7.2.1.3.1.2. Glutamate receptors Glutamate provides the excitatory input to almost the entire central nervous system and its effects are mediated through ionotropic glutamate receptors (iGluR) and metabotropic glutamate receptors (mGluR) (Ozawa et al., 1998). The iGluRs are named after the agonist compound that elicits a specific physiological response and are called a-amino-3-hydroxy-5-methyl4-isoxazole-propionic acid (AMPA), kainate receptor (KA), and N-methyl-D-aspartate (NMDA). The different glutamate receptors may have individual but overlapping contributions to neuronal excitability, long-term potentiation and depression, different components of memory mechanisms, epileptogenesis and excitotoxic cell death (Meldrum, 2000). 7.2.1.3.1.2.1. Ionotropic glutamate receptors Activation of AMPA receptors by glutamate mediates most of the fast, excitatory neurotransmission in the central nervous system. AMPA receptors, along with NMDA receptors, play an important role in long-term potentiation and depression mechanisms. The functions of KA receptors are being established. Like other ligandgated ion channels, the AMPA receptors are composed of several distinct subunits. GluR1–GluR4 (also known as GluRA–GluRD) are AMPA receptor subunits, which can assemble in various combinations to form functional receptors. Alternative splicing of the RNA of each of GluR1–GluR4 AMPA receptor subunits, termed ‘flip’ and ‘flop’, adds to the complexity in the composition of AMPA receptors (Sommer et al., 1990). Kainate is a powerful agonist of the AMPA receptors and five subtypes of kainate receptors (GluR5–7, KA1 and 2) have been recognized. The NMDA receptors are further classified into two subdivisions. The NR1 subunit exists in at least eight alternatively spliced variants (NR1a–h), which differ in their properties and distributions. Each of these subunits can combine with the NR1 subunit to form NMDA receptors. The other family of NMDA receptor subunits, NR2A–D, shows a much more restricted anatomic distribution (Ozawa et al., 1998). (a) AMPA/kainate receptors. In the primate midbrain, almost all TH-positive neurons of SNpc and VTA

express mRNA and protein for all the subtypes of GluRs. The intensity of expression of protein for GluRs, especially that of GluR2, is more prominent in the SNpc cells than TH-positive cells in VTA (Paquet et al., 1997). GluR1 immunoreactivity is decreased in rat and primate models of PD (Betarbet et al., 2000). (b) NMDA receptors. The intensity of expression of mRNA for NMDA receptors in SN is lower than in the striatum. The mRNA for NR1 and NR2D are the most abundant in the DA cells of SN. Low levels of mRNA for NR2A, NR2B and NR2C are expressed in all subdivisions of nigra (Counihan et al., 1998). NMDA receptors are highly permeable to Ca2þ. NMDA receptors may be responsible for mediating glutamate-induced excitotoxic damage and NMDA antagonists prevent excitotoxic damage in several models of neurodegeneration (Ozawa et al., 1998). Glutamate-induced excitotoxicity has been speculated to play a role in the continuing degeneration of dopaminergic neurons of SNpc. The pattern of distribution of different mRNAs for various NMDA subunits, however, does not account for the specific pattern of neuronal loss in SNpc in PD (Counihan et al., 1998). 7.2.1.3.1.2.2. Metabotropic glutamate receptors The mGluRs belong to the family C type of GPCR and are classified into three groups. Group I mGluRs, consisting of mGluR1 and mGluR5, stimulate phospholipase C (PLC) and increase levels of inositol triphosphate and intracellular calcium. In contrast, groups II (mGluR2 and mGluR3) and III (mGluR4–8) inhibit adenylyl cyclase and thus decrease cyclic AMP levels. Six of eight mGluRs are expressed in the brain; however, the overall intensity of expression of mRNAs for various subunits of mGluRs is very low in SNpc and SNpr (Testa et al., 1994). Among the group I mGluRs, the intensity of expression of mRNA for mGluR1 is denser than any other mGluR subunits (Testa et al., 1994; Kosinski et al., 1998a; Hubert et al., 2001; Smith et al., 2001). mGluR3 is expressed in moderate intensity in SNpc, but mGluR2 (Phillips et al., 2000); mGluR4mGluR8 is either very low or undetectable in SNpc (Testa et al., 1994; Kosinski et al., 1999). The role of mGluRs in PD remains to be established. 7.2.1.3.1.3. GABAergic receptors Gamma-aminobutyric acid (GABA) is the commonest inhibitory neurotransmitter in the brain. The different nuclei of the basal ganglia have very high levels of GABA. GABA receptors are classified into ionotropic GABAA, GABAC receptors and metabotropic GABAB1, and GABAB2 receptors. All the subtypes of GABA receptors are localized in all the subnuclei of the basal ganglia (Waldvogel et al., 2004). 7.2.1.3.1.3.1. Ionotropic receptors Similar to nicotinic, serotonergic and glycinergic receptors, the GABAA

NEUROCHEMISTRY OF PARKINSON’S DISEASE receptors belong to the superfamily of the ligand-gated ion channel receptor (Sieghart and Sperk, 2002). GABAA receptor, a pentameric structure that forms a central Cl2 ion channel, is composed of a combination of different types of a, b, and g subunits. So far, 19 such subunits (a1–6, b1–3, g1–3, d, E, y, p and r1–3) have been cloned (Bormann, 2000; Sieghart and Sperk, 2002). In spite of the potential to form an enormous number of receptors through various combinations of these subunits, only very few well-established patterns have been identified so far (Okada et al., 2004a). For example, the commonest type of GABAA receptor consists of a combination of the a1, b2 and g2 subunits, constitutes 50% of all GABAA receptors in the brain, and is the classic benzodiazepine (BZ) receptor. In addition to the BZs, barbiturates, ethanol and neurosteroids also bind prominently to GABAA receptor-binding sites. The primate (Kultas-Ilinsky et al., 1998) and human (Petri et al., 2002) TH-positive SNpc neurons express the greatest number of the BZ1 subtype (made of a1, b2 and g2 subunits) of GABAA receptor. 7.2.1.3.1.3.2. Metabotropic receptors GABAB receptors couple to Ca2þ and Kþ channels via G-proteins and second-messenger systems; they are activated by baclofen and are resistant to drugs that modulate GABAA receptors. In midbrain, mRNA for GABAB1 is expressed by the melanized cells more prominently than GABAB2 (Berthele et al., 2001). In mice and primate models of PD, mRNA for GABAB receptors as well as GABAB receptor binding is significantly reduced in SN (Calon et al., 2001). 7.2.1.3.1.4. Serotonergic receptors There are seven different families of 5-HT receptors (5-HT1–5-HT7) and 14 different 5-HT receptors. All but the 5-HT3 family, which is a ligand-gated cation channel, are G-protein-linked metabotropic receptors (Barnes and Sharp, 1999). The protein of 5-HT receptors is found in the target sites of the terminals of the striatal output neurons, namely Gpe, SNpr. The mRNA for 5-HT1B is absent in the SNpc and pallidum. In PD, 5-HT2C receptor-binding levels are increased in SNpr by 108% when compared to controls (Fox and Brotchie, 2000). 7.2.1.3.1.5. Cholinergic receptors The ligand-gated ion channel nicotinic acetylcholinergic receptor (nAchR) family (Changeux et al., 1998; Klink et al., 2001) and the G-protein-coupled muscarinic acetylcholinergic receptor (mAchR) family (Caulfield and Birdsall, 1998) mediate the cholinergic effects of the central nervous system. All the subnuclei of the basal ganglia express significant density of various nAchRs and mAchRs. 7.2.1.3.1.5.1. Ionotropic (Nicotinic) receptors The ionotropic nAchR has a pentameric structure consisting

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of two copies of one of eight a subunits, a2–a9, separated by a copy of one of the three b subunits and/or g subunit (Changeux et al., 1998). The mRNAs for a3–7 subunits and b2–4 subunits have been localized to the SN and VTA. The a7 expression may be more prominent in VTA than in SN. The a4b2-containing nAchR, a receptor with very high binding affinity to nicotine, is very densely expressed in SNpc and these receptors are found on the dopaminergic terminals in the striatum (Changeux et al., 1998; Klink et al., 2001). The b2 subunit is expressed in all VTA and SN neurons and plays a major role in nicotine addiction and cognition (Maskos et al., 2005). Nicotinic receptors in the basal ganglia appear to be mostly located in the presynaptic nerve terminals and facilitate the release of dopamine in the striatum. 3 H-nicotine has very high binding affinity to a4 and b2 subunits of the nicotinic receptors. 3H-nicotine binding is significantly reduced (65–75%) in SN regions in PD, especially in its lateral regions (Perry et al., 1995) Since nicotinic receptors are most commonly expressed in the nigrostriatal dopaminergic terminals, there is also a concomitant decrease in 3H-nicotine binding sites (47–67%) in the striatum in PD (Court et al., 2000). In MPTP primate models of PD and in PD, the level of mRNA for a4, a7 and b2 is normal in SN, but the level of expression of b3 mRNA is decreased (Martin-Ruiz et al., 2002). Accordingly, the protein levels of these subunits in the putamen are also normal in PD. In addition there is a significant loss of a3/a6 binding (Kulak et al., 2002), but an increase in a7 binding in the dorsolateral striatum in MPTP models of PD (Kulak and Schneider, 2004) and in PD (Guan et al., 2002). In PD, the SNpc neurons are capable of expressing mRNA and protein of many of the subunits of nAchRs in nigra and the striatum; the molecular machinery that is required to assemble these subunits into a functioning nAchR is defective (Martin-Ruiz et al., 2002). 7.2.1.3.1.5.2. Metabotropic (Muscarinic) receptors The five distinct subtypes of mAchRs are members of the family A group of the GPCR superfamily. The m1, m3 and m5 receptors are functionally related and are coupled to Gaq11 and Ga13 subtypes of Gproteins, which lead to activation of PLC and phospholipase D (PLD). The m2 and m4 couple to the inhibitory Gi and Go proteins, leading to inhibition of adenylyl cyclase and a decrease in cyclic AMP levels (Caulfield and Birdsall, 1998). The dopaminergic neurons in SN are one of few sites in the brain with m5 mRNA (Weiner et al., 1990) and with no other reported receptor subtypes. Although there are only very low levels of m5 protein, this receptor might be localized on nigrostriatal terminals, because dopamine release in striatum is recognized to

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be regulated by a muscarinic receptor (Yasuda et al., 1993). The role played by mAchRs in PD remains to be explored further. 7.2.1.3.1.6. Adenosine receptors Methlyxanthine-sensitive adenosine receptors A1 and A2A are localized within several nuclei of the basal ganglia. The lowest level of A2 mRNA is noted in SNpc and A2 receptors. mRNA levels are increased in SNpr, but not in SNpc in PD (Hurley et al., 2000). 7.2.1.3.2. Peptidergic receptors 7.2.1.3.2.1. Opioid receptors The different opioid peptides of the brain are derived from genes encoding proopiomelanocortin, proenkephalin and prodynorphin. These peptides interact with m, k and d receptors. The distribution pattern of these receptors in the brain varies between animals and within different regions of the brain. For example, when compared to the distribution pattern in rat brain, in brain k receptors are more densely distributed and d opioid receptors are less prominent (Peckys and Landwehrmeyer, 1999). The mRNA for m opioid receptors are very low or even absent in the dopamine neurons of SNpc and VTA, but the protein for m opioid receptors localized in the terminals of striatonigral direct pathway are dense in SNpc and VTA. The dopamine neurons of SNpc and VTA in midbrain do not express any mRNA for d opioid receptors (Peckys and Landwehrmeyer, 1999). The mRNA for dynorphin-sensitive k opioid receptors is densely expressed by the melanized dopaminergic neurons of SNpc and VTA and protein for the receptors is expressed on the dopaminergic perikarya and the terminals in the striatum. In PD, along with a significant decrease in melanized neurons, the mRNA for k opioid receptor and protein are significantly decreased (Yamada et al., 1997). 7.2.1.3.2.2. Substance P (SP) receptors The different tachykinin peptides are derived from preprotachykinin I (PPT I), II (PPT II) and III (PPT III), but peptides encoded by PPT I and PPT II only are found in the central nervous system (Pennefather et al., 2004). The dopamine neurons of SNpc or the VTA do not express mRNAs for SP or any other related tachykinin peptides (Warden and Young, 1988). Interestingly, even though greater levels of SP are found in SN than any other nucleus in the rat brain (Severini et al., 2002) the presence of tachykinin receptors in these dopamine neurons has been difficult to demonstrate. The G-protein-coupled tachykinin receptors are of three types: (1) SP-sensitive neurokinin-1 (NK-1) receptor; (2) neurokinin A-sensitive NK-2 receptor;

and (3) neurokinin B-sensitive NK-3 receptor. Among the three types of tachykinin receptors, a high percentage of the dopamine neurons of SNpc and VTA in rats (Futami et al., 1998) and human brain (Whitty et al., 1997) express NK-1. The SNpc neurons of rats also express NK-3 (Chen et al., 1998) and NK-2 types of receptors (Bannon and Whitty, 1995). SP receptor binding is not decreased in PD (Fernandez et al., 1994). 7.2.1.3.2.3. Neurotensin receptors Three different neurotensin receptors have been cloned. The neurotensin-1 subtype (NTS1) is the predominant receptor in the brain and the basal ganglia. The neurotensin-2 subtype (NTS2) is distributed in the brain but not in the basal ganglia. The role played by NTS3 remains to be established (Vincent et al., 1999). NTS1 has very high affinity to neurotensin when compared to NTS2 and the vast majority of melanized and nonmelanized dopaminergic cells of SNpc and VTA in midbrain express mRNA for NTS1 (Nicot et al., 1995). The NTS-1 receptors are expressed more densely in poorly melanized cells in SNpc and VTA than those cells that are highly melanized (Yamada et al., 1995) and, in PD, NTS1 mRNA and neurotensin receptor binding are significantly reduced in SNpc (Uhl et al., 1984; Chinaglia et al., 1990; Fernandez et al., 1994). 7.2.1.3.2.4. Cholecystokinin receptors The CCK-1 and CCK-2 receptors belong to the GPCR superfamily. The CCK-1 receptor is considered predominantly ‘alimentary’ and is localized in SNpc (Mercer and Beart, 2004). The mRNA of CCK-2 receptor, the ‘brain’ receptor of CCK, is expressed in the dopamine neurons of the midbrain (Honda et al., 1993) and CCK-2 receptor protein in the dopamine terminals in the nucleus accumbens and the glutamatergic corticostriate terminals in the striatum. There is a lack of information about the nature of CCK receptor expression in nigra in experimental models of PD or in PD. 7.2.1.3.2.5. Cannabinoid receptors Tetrahydracannabinol mediates its addictive and psychoactive properties through the G-protein-linked cannabinoid receptors that are distributed diffusely within the brain and especially in the basal ganglia (Howlett et al., 2002). The cannabinoid receptors are classified into CB1- and CB2-receptors. The presence of CB2-receptors within the brain has not been established, but CB1-receptors are expressed by all the nuclei of the basal ganglia (Howlett et al., 2002). The mRNA and protein for CB1-receptors are expressed in the melanized TH-positive neurons of SNpc and VTA and their levels are reported to be unaltered in the substantia nigra of PD (Hurley et al., 2003a).

NEUROCHEMISTRY OF PARKINSON’S DISEASE 7.2.1.4. Neuromelanin and metallic ions 7.2.1.4.1. Neuromelanin One of the most characteristic features of the dopaminergic neurons of the substantia nigra is that they contain neuromelanin. Neuromelanin shares several biochemical characteristics with cutaneous melanin (Fedorow et al., 2005) but has 10 times more affinity to iron than cutaneous melanin (Double et al., 2003). Neuromelanin is distributed mostly in cells that synthesize dopamine and norepinephrine, but not epinephrine. Levodopa is the precursor of neuromelanin and it is derived from dopamine, dopaquinone and their oxidized products and from catecholamines that are not stored in the vesicles (Sulzer et al., 2000). Tetrabenazine and reserpine, drugs that block incorporation of dopamine in the presynaptic vesicles, increase accumulation of neuromelanin and overexpression of VMAT2, which facilitates the incorporation of cytoplasmic dopamine into the vesicles, decreasing neuromelanin synthesis (Sulzer et al., 2000). Neuromelanin concentration in SN is undetectable during the first decade and may reach a value of 3.7 mg/mg in the eighties, and in PD the level of neuromelanin decreases significantly (Zecca et al., 2002b). Even though highly melanized dopamine neurons of SNpc and VTA degenerate the most, the precise role played by neuromelanin in these neurons is unknown. Neuromelanin is proposed to play a role in the neurodegenerative process of dopamine and locus ceruleus neurons in PD; however, even amidst a densely degenerating group of nigral cells in the ventral and lateral nigrosome regions of SNpc, pigmented neurons do survive. In SNpc nigrosomes 98% of the melanized cells degenerate, whereas even though almost all locus ceruleus neurons contain neuromelanin, only about 50–63% of melanized cells of locus ceruleus degenerate in PD. The SNpc dopamine neurons of rats, unlike mice and primates, do not contain neuromelanin (Fedorow et al., 2005). Even in the absence of neuromelanin, administration of rotenone in rats, but not MPTP, causes significant degeneration of the mesencephalic dopamine neurons (Betarbet et al., 2000), providing additional support to the concept that neuromelanin may not be required for neurodegeneration in this animal model of PD. The most important function of neuromelanin may be to store and regulate iron, copper, zinc and manganese ions which play an important role in the normal function of TH and cytochrome a, b and c within the catecholaminergic neurons (Zecca et al., 2002a). It has been proposed that neuromelanin may actually play a neuroprotective role in normal brain by preferentially sequestering pesticides, MPTP, paraquat and other neurotoxins, iron and other metallic ions for a

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significant duration, but when this storage capacity exceeds or decompensates, then iron and pesticides may act as neurotoxic factors (Sulzer et al., 2000; Zecca et al. 2002a, Zucca et al., 2004). 7.2.1.4.2. Neuromelanin and iron There is a general tendency for a gradual metallization of neuromelanin with increasing age. Some of the metallic ions may play a much greater role in the degeneration of SNpc and VTA dopamine neurons than others. Along with copper, zinc and manganese, iron plays an important role in the normal functions of TH. Iron accumulates in neuromelanin and is required for the synthesis of neuromelanin since iron-chelating agents block the synthesis of neuromelanin (Sulzer et al., 2000). The level of iron in SN of control brains is 20 ng/mg in the first year of life and then may increase to 200 ng/mg until 40 years of age, paralleling the gradual increase of neuromelanin in the dopamine cells (Zecca et al., 2002a). The concentration of iron in neuromelanin is greater than copper and zinc and iron levels are higher in neuromelanin in PD than controls (Zecca et al., 2002a). In PD patients there may be a 30–35% increase in iron in SN (Dexter et al., 1991). Iron-related protein dysfunctions have been noted in PD. In MPTP mouse models of PD (Fillebeen et al., 1999) and in PD (Faucheux et al., 1995) levels of lactotransferrin, an iron-binding protein that has more affinity to iron than transferrin, as well as levels of lactotransferrin receptors, are increased, suggesting that more iron may be actively and preferentially transported into SN in PD patients than in controls (Double et al., 2000). Accumulation of iron in SNpc has been speculated to play a major role in the degeneration of dopaminergic neurons of SN via oxidative reaction through Fenton pathway (Berg et al., 2001; Zucca et al., 2004). Recent studies also suggest the possibility that iron accumulation may be a consequence of dopaminergic cell death since, at least in MPTP models of PD, dopaminergic cell death precedes iron accumulation (He et al., 2003). 7.2.1.4.3. Neuromelanin and copper Besides iron, zinc, copper and manganese ions are also found in neuromelanin (Zecca et al., 2002a). Copper plays an important role as a cofactor of the antioxidant Cu/Zn superoxide dismutase I as well as cytochrome c oxidase, ceruloplasmin and copper-dependent transcription factors (Uauy et al., 1998). Glutathione is involved in the intracellular transport of copper (Harris, 2003), and even low doses of copper may be adequate to promote aggregation of a-synuclein and, more importantly, amyloid precursor protein and prion protein (Rasia et al., 2005). In control brains the intensity of expression

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of mRNA for Cu-Zn superoxide dismutase is higher in the melanized than in non-melanized dopamine neurons of the midbrain (Zhang et al., 1993). In MPTP models of PD and in PD mRNA for Cu-Zn, superoxide dismutase is significantly decreased (Kunikowska and Jenner, 2003). 7.2.1.4.4. Neuromelanin and zinc Zinc is the second most common element, after calcium, in the brain and the zinc levels are the highest in the brain than any other organ (Weiss et al., 2000). Zinc plays an important role in the proper functioning of zinc-dependent enzymes (e.g. the antioxidant Cu/Zn superoxide dismutase), transcription factors (e.g. zinc fingers) and the neuroprotective metallothioneins (Berg and Shi, 1996, Frederickson et al., 2005). Zinc is packaged into the presynaptic vesicles and released into the synaptic cleft by the glutamatergic neurons of the cerebral cortex and the amygdaloid complex (also called ‘gluzinergic’ neuron or zinc-enriched neuron) and GABAergic and glycinergic neurons in the spinal cord where it can alter the excitability of potentially several types of receptors (Frederickson et al., 2005). An excess amount of free zinc is neurotoxic and plays a role in glutamate-induced excitotoxicity (Weiss et al., 2000). Although the potential role of zinc in the formation of b-amyloid plaque and in motor neuron disease is widely recognized (Frederickson et al., 2005), zinc’s role in the pathogenesis of PD remains to be established. Zinc levels are increased by 50–54% in SN of PD and 18–35% in the caudate nucleus and lateral putamen of PD (Dexter et al., 1991). The source of increased levels of zinc in SN in PD is not known. The dense thalamostriate, cerebral cortical, pedunculopontine nucleus (PPN) and subthalamic nucleus (STN) glutamatergic inputs to the SN and the striatonigral GABAergic synaptic endings have not been identified, so far, to release zinc at their terminals, raising the possibility of an altered homeostasis of zinc in SN as the source of the higher zinc level noted in PD. Zinc, along with several other metals, is sequestrated in neuromelanin (Zecca et al., 2002a). The mRNA for copper/zinc superoxide dismutase is significantly higher in the melanized cells of SNpc (Zhang et al., 1993), which are more vulnerable to degeneration than the non-melanized cells, and in PD the mRNA for Cu/Zn SOD is significantly decreased (Kunikowska and Jenner, 2003). 7.2.1.4.5. Neuromelanin and manganese Manganese is present ubiquitously in the body and brain and is essential for the functions of numerous enzymes, metalloproteins and free-radical scavenging in the mitochondria (Dobson et al., 2004). Within the basal ganglia

the SN, putamen and GP contain high levels of manganese (Dobson et al., 2004). Manganese is mostly concentrated in the mitochondria (Maynard and Cotzias, 1955) and is an important component of the manganese superoxide dismutase enzyme. Experimental overload of manganese in neonatal rats does not increase the levels of mitochondrial manganese any further, indicating the possibility that, in case of a higher level of intracellular manganese, it may be diverted to other sources of storage. In neurons that contain neuromelanin, manganese is stored in neuromelanin (Zecca et al., 2002a). Manganese level in SN of PD is unchanged (Dexter et al., 1991) and the level of manganese superoxide dismutase is normal in sporadic PD (Shimoda-Matsubayashi et al., 1997). In manganese toxicity, however, manganese accumulates not just in GP and striatum, but also in SN. High levels of manganese can trigger oxidative stress and a-synuclein fibrillary deposits (Uversky et al., 2001; Dobson et al., 2004). 7.2.1.5. Neurochemistry of VTA and SNpc afferents The various inputs to the mesencephalic dopamine neurons are organized compactly and topographically in a reticulate fashion in SNpr. The physiology of the dopamine neuron is regulated by many of these neurotransmitters and neuropeptides that are released in the terminals of the afferents and by the receptors that are localized in the dopamine neurons. The pattern of release of the neuropeptides and transmitters is profoundly affected, in turn, by somatodendritically released dopamine. In PD the loss of dopamine in SNpc is >80% parallel to the level of loss in the striatum. How progressive loss of dopamine influences the normal physiological activity and the neurochemistry of these afferents and how these various afferents, in turn, modulate the degenerating as well as the surviving dopamine neurons has not been studied in detail. 7.2.1.5.1. Neurotransmitters of VTA and SNpc afferents 7.2.1.5.1.1. Glutamatergic afferents The mesencephalic dopamine neurons receive glutamatergic inputs from the STN, cerebral cortex and the PPN. The glutamatergic terminals express both D1- and D2-receptors and make direct synaptic contacts on the dendritic portion of dopamine neurons. Dendritically released dopamine exerts an inhibitory effect on the dopamine receptor-mediated glutamate release. In dopamine-denervated states, as after 6hydroxydopamine (6-OHDA) injections, loss of dopamine and stimulation of dopamine receptors on the glutamatergic terminals result in an increased level of glutamate in the nigra (Morari et al., 1998). Using a

NEUROCHEMISTRY OF PARKINSON’S DISEASE chronic MPTP model of PD in mice, it has been proposed that in the early and presymptomatic stage of the disease, glutamate released by a hyperactive STN may stimulate dopamine neurons to fire in a bursting fashion instead of the normal pattern of firing randomly, and that the burst firing pattern may release more dopamine in the striatum to compensate for the loss of dopamine in the striatum (Bezard and Gross, 1998). In PD, however, glutamate level in SN is normal (Hornykiewicz, 2001a). 7.2.1.5.1.2. GABAergic afferents The midbrain dopaminergic neurons directly influence the GABAergic output neurons of both direct and indirect pathways. The mRNA for glutamic acid decarboxylase (GAD) 67 and GABA level is increased in the dorsolateral striatum in animal models of PD as well as in PD (Kish et al., 1986; Soghomonian et al., 1994). The increase in GAD mRNA level is noted selectively in the preproenkephalin A (PPE A)-containing GABAergic neurons of the indirect pathway and not the SP/dynorphin-containing GABAergic direct pathway (Soghomonian and Laprade, 1997) and accordingly, GABA levels in SN are within normal limits in PD (Kish et al., 1986). 7.2.1.5.1.3. Cholinergic afferents The PPN is the major source of cholinergic input to the VTA and SN (Garcia-Rill, 1991). Cholinergic neurons located, especially at the rostral pole of PPN, send mostly ipsilateral projections to SN and the VTA receives bilateral projections from the cholinergic neurons of PPN. The PPN cholinergic neurons that project to the dopaminergic neurons of VTA and SN also project to the thalamus and contain SP and NADPH-diaphorase (Oakman et al., 1999). Significant loss of SP-containing neurons of PPN has been observed in PD (Halliday et al., 1990b). The many subtypes of mAchRs localized to the soma and the terminals of the PPN cholinergic fibers regulate the release of dopamine in the mesencephalon and the striatum by the dopaminergic neurons of VTA and STN (Miller and Blaha, 2005). 7.2.1.5.1.4. Serotonergic afferents Among the different nuclei of the basal ganglia, the substantia nigra receives the heaviest serotonergic innervations (Tork, 1990; Parent et al., 1995). Axons from dorsal raphe nucleus terminate more densely in the caudal and lateral third than the rostral and medial substantia nigra corresponding to the region of substantia nigra that degenerates the earliest in PD and is vulnerable to the mitochondrial toxins MPTP and rotenone (Damier et al., 1999b; Betarbet et al. 2000). The DRN neurons that project to the nigra also project to the striatum by axon collaterals (van der Kooy and Hattori, 1980). In PD, 5-HT levels are decreased in substantia nigra (Hornykiewicz, 1998).

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7.2.1.5.1.5. Histaminergic afferents The only source of neuronal histamine in the brain is the tuberomammillary complex in the caudal and lateral hypothalamus (Schwartz et al., 1991; Haas and Panula, 2003). Histamine plays a major role in alertness, hibernation, feeding and memory (Brown et al., 2001). The tuberomamillary nucleus provides dense histaminergic fibers to many areas of the brain and all the nuclei of the basal ganglia. The large neurons of the tuberomammillary nucleus, which provide the histaminergic input to the nigra, degenerate in multiple system atrophy but not in PD (Nakamura et al., 1996). The histamine levels are significantly increased in SNpc in PD (Anitchik et al., 2000). 7.2.1.5.2. Neuropeptides of VTA and SNpc afferents 7.2.1.5.2.1. Opioids The medium spiny neurons of the direct pathway, which express different opioid peptides derived from prodynorphin, terminate densely in SN. The rat nigra demonstrates the highest concentration of prodynorphin-derived peptides (Zamir et al., 1984). Among these opioid peptides, in rat SN, a-neoendorphin concentration is the highest, followed by other peptides of prodynorphin. Met and Leu enkephalins are also found in SN, but they are derived solely from the processing of prodynorphin. The molar ratio of DynA1–17: DynA1–8 is 1:1 in the striatum of rat, monkey and human, but it is 1:6 in monkey nigra and 1:16 in rat nigra (Dores and Akil, 1985). In MPTP primate models of PD, met-enkephalin levels are low in SN but the levels of all other opioid peptides are normal (Zamir et al., 1984). 7.2.1.5.2.2. Substance P The axons of medium spiny neurons of the direct pathway that contain peptides derived from PPT terminate diffusely in SN. In PD, the level of SP in SN has been reported to be increased (Grafe et al., 1985) or decreased (Tenuvuo et al., 1990; Perez-Otano et al., 1992). Several animal models of PD also demonstrate inconclusive reports concerning the level of SP in SN (Betarbet and Greenamyre, 2004). The level of expression of mRNA and protein for SP in SN and other target sites of the direct pathway may be dependent on the extent of dopamine denervation and dopamine denervation hypersensitivity of D1-receptors, since a loss of dopamine <50% has been associated with decreased level of SP in the striatum and loss of dopamine >80% is associated with an increased level of SP in the striatum and internal segment of GP (GPi: de Ceballos et al., 1993). 7.2.1.5.2.3. Neurotensin Neurotensin levels are twice as high in SNpc and SNpr (Fernandez et al., 1995) and the medium spiny neurons

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in the striatum that express mRNA for neurotensin may be the source of the high levels of neurotensin noted in SN (Castel et al., 1993a). 7.2.1.6. What is preserved in VTA and SNpc? Even though there is a profound loss of dopamine neurons of SNpc, SN neurons that contain calbindin 28 (Yamada et al., 1990; Lavoie and Parent, 1991) and calretinin (Mouatt-Prigent et al., 1994) are preserved in primate models of PD and in PD. In MPTP-induced animal models of PD the dopaminergic cells that project directly to GPi may be preserved (Schneider and Dacko, 1991). A small percentage of SNpc cells are recognized to synthesize GABA and they may be interneurons (Hebb and Robertson, 2002). The TH-positive and non-TH-positive neurons of SNpc also synthesize acetylcholinesterase (Emmett and Greenfield, 2005) and several other enzymes and release these enzymes in the striatum (Greenfield et al., 1983). The nature of involvement of the GABAergic neurons of SNpc and acetylcholinesterase in PD remains to be established. The SNpr contains mostly parvalbumin/GABAergic neurons and they degenerate in progressive supranuclear palsy, but not in PD (Hardman et al., 1996). 7.2.2. Neurochemistry of the striatum in Parkinson’s disease 7.2.2.1. Neurochemistry of striatal afferents 7.2.2.1.1. Neurotransmitters of striatal afferents 7.2.2.1.1.1. Dopamine 7.2.2.1.1.1.1. Pattern of loss The level of dopamine in the striatum represents 80% of all dopamine in the brain (Hornykiewicz, 2001a). The terminals of the A8, A9 and A10 groups of mesencephalic dopaminergic neurons are the source of dopamine in the striatum. The A10 group of VTA dopamine neurons project to the limbic striatum and the dopamine terminals from the A9 groups of dopamine neurons from the SNpc complex provide the dopamine supply to the caudate and putamen. The dopamine nerve fibers from the A8 group project diffusely to the striatum and to many other extrastriatal regions in the rat brain (Deutch et al., 1988; Francois et al., 1999) and are recognized to degenerate in PD (Hirsch et al., 1988). In normal brain, dopamine is distributed unevenly and heterogeneously into TH-rich matrix and TH-poor striosomal compartments (Holt et al., 1997; Prensa et al., 2000). In PD, dopamine levels as well as levels of all the markers of dopaminergic system are significantly decreased. Neurochemical and immunocytochemical

studies show that TH, BH4, guanosine triphosphate cyclohydralase I, VMAT2 and DAT levels are decreased in the striatum in PD (Nagatsu et al., 1984; Nagatsu and Ichinose, 1999; Hornykiewicz, 2001a). The activity and protein level of TH are much lower than AADC and the level of DAT is much lower than VMAT2 (Hornykiewicz, 2001a). This would suggest that the capacity of the dopaminergic terminal to synthesize levodopa from tyrosine is more severely affected than its capacity to convert exogenously administered levodopa to dopamine. This also suggests that in animal models of PD and in PD the rate-limiting enzyme for the synthesis of dopamine shifts from TH to AADC (Lee et al., 2000). In early stages, dopamine depletion is more severe in the dorsolateral putamen and the motor striatum than the caudate nucleus or the nucleus accumbens (Kish et al., 1988). This is consistent with the observation that the earliest dopamine cells to degenerate are localized in the ventrolateral tier of SNpc that projects to the dorsolateral motor striatum. This pattern also coincides with the upregulation of D2-receptors in putamen in the early stages (Rinne et al., 1995; Kaasinen et al., 2000). Nevertheless, as the degeneration of dopaminergic neurons progresses dorsally and medially, dopamine depletion spreads more medially and ultimately the dopamine level decreases in the entire dorsal and ventral striatum. Loss of dopamine within the striatum is denser than other monoamines. The >80% loss of dopamine in the striatum is accompanied by a 50% decrease in 5-HT levels and the level of norepinephrine is unchanged from that of the control levels (Wilson et al., 1996). 7.2.2.1.1.1.2. Compensatory mechanisms in dopamine-denervated striatum It has been estimated that the signs and symptoms of PD are not noted until there is a degeneration of >50% of midbrain dopamine neurons and 80% loss of dopamine in the striatum. Several mechanisms that may be in play simultaneously compensate for the loss of dopamine in the striatum in early stages of PD. Unilateral lesioning of nigrostriatal system with 6-OHDA in rats suggests that, after a loss of 50% dopaminergic neurons in the nigra, there is a compensatory increase in dopamine synthesis and turnover by the remaining dopamine terminals in the striatum and at the dendritic levels in the nigra. The postsynaptic denervation hypersensitivity of dopamine receptors occurs only after a loss of 90% of dopamine in the striatum (Hefti et al., 1980). In order to compensate for loss of dopamine in the striatum, during the early stages of dopamine denervation, the activity of AADC may be upregulated. The upregulated AADC activity will result in an increased synthesis of dopamine and lower levels of DAT

NEUROCHEMISTRY OF PARKINSON’S DISEASE expression and activity due to loss of dopamine terminals will decrease reuptake of dopamine (Lee et al., 2000). A combination of these two factors, along with an increase in volume transmission, will facilitate an increase in the synaptic dopamine levels and may be adequate to compensate for the loss of dopamine during the early preclinical phase of the disease. The continuing denervation due to progressive dopamine neuronal loss, however, applies further demands on these compensatory mechanisms. Besides the upregulation of AADC in dopamine terminals, exogenously administered levodopa may be converted into dopamine in the striatum by a group of neurons designated as D cells (Ikemoto, 2004). The D cells express only AADC, but not TH or tryptophan hydroxylase, and are distributed diffusely in the brain (Jaeger et al., 1984). Within the striatum, D cells are more prominently dispersed in the nucleus accumbens than the putamen or caudate nucleus (Ikemoto, 2004). The number of D cells increases after 6-OHDA in rats and administration of levodopa results in an increased synthesis of dopamine, presumably by the newly formed cells that contain AADC (Mura et al., 1995). Levodopa is converted into dopamine not only by dopamine terminals in dopamine-denervated striatum, but also by AADC found in serotonergic terminals and in several types of interneuron within the striatum (Melamed et al., 1980; Arai et al., 1991; Lopez-Real et al., 2003). Yet another level of compensation may be reflected by the induction of dopamine-synthesizing enzymes in neurons that are strictly intrinsic to the striatum and normally do not express these enzymes. Acute and severe depletion of striatal dopamine in rats and primates results in the appearance of AADC and TH-immunoreactive neurons in the striatum (Tashiro et al., 1989; Tashiro et al., 1990; Meredith et al., 1999). The number of these neurons increases in MPTP models of PD in primates, indicating that these striatal dopamine neurons are generated as a consequence of striatal dopamine denervation (Betarbet et al., 1997). In primate and striatum, two types of neurons exhibit TH immunoreactivity (Prensa et al., 2000). Most of these newly formed TH-positive neurons in striatum bear significant similarities to morphological and neurochemical properties of a GABAergic interneuron (Cossette et al., 2005) and express GluR1 and AMPA receptors (Betarbet and Greenamyre, 1999) and mRNA for DAT, suggesting that dopamine is transported actively into these neurons (Betarbet et al., 1997). In spite of these all-out reparative efforts, these presynaptic compensatory mechanisms are inadequate to reverse the widespread, severe and continuing loss of dopamine in the striatum. The progressive difficulties to store and deliver smooth levels of dopamine at

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the synaptic cleft lead to the emergence of the uncompensated and symptomatic phase of the disease and subsequently to the on–off, yo-yo phenomenon and predictable and unpredictable wearing-off phenomena noted in PD. 7.2.2.1.1.2. Glutamate Glutamate is the principal excitatory neurotransmitter in the brain. Within the basal ganglia circuitry, it plays a prominent role in the physiology of the cerebral cortex, striatum, GP, STN, SN and the thalamus. The highest level of glutamate is in the striatum (Hornykiewicz, 2001a). The striatum receives an extensive glutamatergic projection from virtually all areas of the neocortex centromedian and parafascicular thalamic nuclei amygdaloid nuclei and the STN. Neurochemical studies in striatum have shown a significant increase in glutamate levels, especially in the dorsolateral striatum, in a pattern that coincides with the pattern of severe loss of dopamine in the dorsolateral quadrant of the putamen (Hornykiewicz, 2001a). Several mechanisms may underlie such an increase in glutamate levels in the striatum. The corticostriate terminals express D2-receptors and, on acute stimulation by either dopamine or D2- but not D1-selective dopamine agonists, inhibit the release of glutamate in the striatum. During dopamine denervation, D2-receptor-mediated inhibition is lost, resulting in increased levels of glutamate in the striatum (Morari et al., 1998). In 6-OHDA models of PD in rats, chronic levodopa administration results in a significant increase in the levels of extracellular glutamate and an increased expression of glutamate transporter 1 in the glial cells (Robelet et al., 2004). In addition to the enhanced levels of extracellular glutamate, dopamine denervation and levodopa treatment result in an increased tyrosine and serine phosphorylation of NR2B and possibly the NR2A subunits of the glutamate receptors and glutamate receptor mediated postsynaptic signaling mechanisms (Oh et al., 1999; Chase and Oh, 2000). These factors collectively contribute to an increased glutamate transmission that may lead to dyskinesia. These observations may support the hypothesis that many of the signs and symptoms of advanced stages of PD may be driven by an increase in glutamate in the striatum (Carlsson and Carlsson, 1990; Schimdt, 1998). 7.2.2.1.1.3. Serotonin The striatum receives less dense 5-HT innervations than the substantia nigra and the GP. The nucleus accumbens and the ventro- and dorsomedial limbic striatum receive denser 5-HT innervations than the associative striatum and the dorsolateral motor striatum (Lavoie and Parent, 1990). The 5-HT terminals are dense in the TH-rich compartment compared to the TH-poor striosomes,

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suggesting that the limbic and non-limbic compartments of the striatum may be influenced by different serotonergic mechanisms (Lavoie and Parent, 1990). The striatal 5-HT levels are decreased (40%) in PD – more so in the depressed PD patients than in the nondepressed patients (Kish, 2003). The decreased levels of 5-HT may be more prominent in the caudate nucleus than in the putamen. In the early stages of PD, 5-HT level is reduced to 35% but as the disease progresses and in late stages the loss of 5-HT may reach 50%. This observation suggests that the contribution of serotonergic dysfunction becomes more severe as the disease progresses. 7.2.2.1.1.4. Histamine The tuberomamillary nucleus is the sole source of neuronal histamine in the brain. The level of histamine is significantly increased in the striatum in PD (Rinne et al., 2002). 7.2.2.1.2. Neuropeptides of striatal afferents 7.2.2.1.2.1. Cholecystokinin The peptide CCK, originally recognized as a peptide of the gastrointestinal system, is present more abundantly in the brain than in the intestine (Beinfeld, 2001). Among all regions of the brain, levels of CCK are highest in the caudate nucleus followed by the cerebral cortex (Beinfeld et al., 1981). The corticostriate neurons that express CCK (Morino et al., 1994) promote the release of glutamate in the striatum (Snyder et al., 1993). Yet another source of CCK to the striatum may be the midline thalamic nuclei that project to the nucleus accumbens and the limbic striatum (Hu and Jayaraman, 1987). The striatal CCK levels are not altered in MPTP-induced models of PD in marmosets (Taquet et al., 1988). In PD, CCK-8 level has been reported to be unchanged (Fernandez et al., 1992) or slightly increased (Hornykiewicz, 1998). 7.2.2.1.2.2. Other peptides Axons that demonstrate immunoreactivity to several other peptides have been observed in the striatum (Hu and Jayaraman, 1987). Details of these potential sources of peptides to the striatum remain to be established. 7.2.2.2. Neurochemistry of striatal neurons in Parkinson’s disease The striatum consists of at least five types of neuron. The medium spiny GABAergic neurons are the output neurons and constitute 85% of the cells in the striatum. The interneurons constitute about 10–15% of the cells of the striatum. The GABA/calretinin-positive cells constitute 10% of striatal neurons, and the GABA/neuropeptide Y (NPY)/somatostatin (SOM)/NASDPH cells

about 2.5%. The large cholinergic aspiny interneurons and the GABA/parvalbumin neurons are about 1% or less (Cicchetti et al., 1998). The different types of interneuron form the intricate microcircuitry that, along with the afferent inputs, regulates the medium spiny output neurons of the striatum. The exceptionally high levels of acetylcholine and acetylcholinesterase and GABA within striatum are mostly derived from the large aspiny cholinergic interneuron, the GABAergic interneurons and the output neurons of the striatum respectively. 7.2.2.2.1. Striatal interneurons 7.2.2.2.1.1. GABA interneurons 7.2.2.2.1.1.1. GABA/calretinin The medium and large-sized aspiny GABAergic interneurons that also co-express calretinin is the most common type of interneuron in the striatum (Cicchetti et al., 1998, 2000). These neurons also express AMPA receptors prominently. The anatomical connectivity, neurophysiology and neurochemical characterization of these neurons remain to be defined further. 7.2.2.2.1.1.2. GABA/parvalbumin Large and medium-sized aspiny neurons that stain for GABA and parvalbumin are the second most common type of interneurons in the striatum (Cicchetti et al., 1998, 2000). Parvalbumin levels are markedly decreased in the nigra, but not in the striatum in MPTP-induced mouse models of PD (Muramatsu et al., 2003). 7.2.2.2.1.1.3. GABA/NPY/SOM/NOS The type of interneurons that express GABA, the peptides NPY and SOM as well as the enzyme NADPH-diaphorase constitute about 1% of interneurons in the striatum (Cicchetti et al., 2000). (a) Neuropeptide Y. The number of NPY neurons as well as the grain density of NPY mRNA per cell are increased in PD and this upregulation may be due to dopamine denervation (Canizzaro et al., 2003). (b) Somatostatin. The levels of SOM expression is increased by glutamatergic stimulation and decreased by haloperidol, a predominantly D2 dopaminergic receptor blocker but not clozaril, a D4-blocker (Chesselet et al., 1995). SOM levels are increased in the dorsolateral putamen rather than in the ventromedial striatum in control striatum and this dorsolateral to ventromedial gradient is lost in PD (Eve et al., 1997). (c) NADPH-diaphorase. The enzymes NADPHdiaphorase and neuronal nitric oxide synthase (nNOS) distinctly colocalize within the same neurons in the brain (Dawson et al., 1991). The enzyme nNOS synthesizes the neurotransmitter nitric oxide (NO) and also free radicals through the perioxynitrite mechanisms and cause nigral neurotoxicity (Przedborski et al.,

NEUROCHEMISTRY OF PARKINSON’S DISEASE 1996). Although levels of NOS increase 5 h after MPTP and subsequently decrease significantly in SN, the increased levels of NOS precede dopaminergic cell death (Muramatsu et al., 2003). The level of NOS is unchanged throughout the striatum in MPTP-induced PD models in mice. In PD, striatal interneurons that express NADPH-diaphorase are preserved (Mufson and Brandabur, 1994) and NOS mRNA in the striatum is decreased (Eve et al., 1998). 7.2.2.2.1.2. Cholinergic interneurons The giant aspiny interneurons constitute 2% of total striatal neurons (Zhou et al., 2002) and are the exclusive source of cholinergic innervation to the striatum. These large cholinergic interneurons receive mostly glutamatergic input from the cerebral cortex and less prominent dopaminergic input from SN and VTA (Zhou et al., 2002). The cholinergic terminals of these neurons ramify extensively and synapse predominantly on the direct and indirect output neurons of the striatum and the GABA/parvalbumin interneurons (Pisani et al., 2003). These cholinergic neurons are tonically active, fire at about 5 Hz, and pause their tonic firing on conditioned motor task, facilitating dopamine release during this pause (Zhou et al., 2002). After MPTP injection in primates, the large aspiny cholinergic neurons as well as GPi neurons develop an oscillatory firing rate similar to that of tremor frequencies noted in animal models of PD and PD (Raz et al., 2001), suggesting that the cholinergic interneurons may be an important component in the genesis of tremors in PD. A profound loss of striatal cholinergic interneurons has been observed in progressive supranuclear palsy, schizophrenia and in rotenone models of PD (Hoglinger et al., 2003), but not in PD. 7.2.2.2.2. Striatal output neurons The output neurons are the medium spiny neurons, which constitute >85% of cells in the striatum. All major afferents with their different transmitters converge upon the dendrites of the medium spiny neurons and influence each other. Based on neuroanatomical connectivity and neurochemical features the output neurons of the striatum have been classified into two groups. The medium spiny neuron that expresses GABA, D2-, A2A-receptors and enkephalin (PPE A) projects to GPe and indirectly to the GPi via the STN, forming the indirect pathway. The spiny neuron that expresses GABA, D1-receptors, opioid peptide dynorphin (PPE B) and SP (PPT) and projects directly to GPi and SNpr forms the direct pathway. Currently one of the major controversies in our understanding of the organization of the striatal output

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system is whether the striatal direct and indirect pathways are derived from two distinct but segregated neuronal populations or whether the molecular pathways of these two output systems are colocalized within a single striatal output neuron. There is considerable evidence to suggest that these two sets of output neurons are in most part segregated (Gerfen et al., 1990; Le Moine and Bloch, 1995; Aubert et al., 2000). In monkey striatum, the colocalization pattern is high for D1 and SP mRNA (91–99%) and D2-receptor and PPE A (96–99%). D1 and D2 are colocalized (2–5%) rarely (Aubert et al., 2000). In striatum, 66% of the medium-sized spiny output neurons express enkephalin, 58% of the spiny neurons express SP mRNA, and in 15–30%, these two peptides may be colocalized (Nisbet et al., 1995). Studies in striatal cell culture and in slices of neostriatum and nucleus accumbens from adult rats, however, have clearly demonstrated that in virtually all of the output neurons, D1-, D2- and/or D3-receptors are colocalized. The key factor that dictates which one of the three colocalized dopaminergic receptors would be activated is dependent on how the dopaminergic agent alters the sodium channel current and excitability (Surmeier et al., 1992, 1993; Lester et al., 1993; Surmeier and Kitai, 1993; Ridray et al., 1998; Schwartz et al., 1998; Aizman et al., 2000). 7.2.2.2.2.1. Medium spiny neurons of the indirect pathway 7.2.2.2.2.1.1. Neurotransmitter of the medium spiny neurons of the indirect pathway (a) GABA. GABA innervation to the striatum is almost totally derived from neurons intrinsic to the striatum. The spiny efferent neurons of the striatum are GABAergic and send collaterals to the dendrites and axons of other spiny neurons. Three different subtypes of interneurons synthesize and release GABA. GABA levels are high in all nuclei of the basal ganglia. In PD, GABA levels in the striatum are higher than control, especially in the dorsolateral striatum. The increased level of GABA in the dorsolateral putamen, along with an increased glutamate level in this region, is inversely proportional to the loss of dopamine in the motor striatum (Kish et al., 1986; Hornykiewicz, 2001a). Two isoforms of GAD, namely GAD67 and GAD65, are involved in GABA synthesis (Lindefors, 1993). GAD67 is responsible for most of GABA synthesized at the cytoplasmic level in neurons and GAD65 may be involved in the synthesis of GABA for vesicular release (Soghomonian and Martin, 1998). Dopamine denervation leads to a significant increase in GAD67 and GAD65 mRNA and GABA level in the

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striatum: this increase is selectively noted in the indirect pathway, but not the direct pathway (Soghomonian and Laprade, 1997). Whether the three different types of GABAergic interneuron also contribute to the increase in the striatal level of GABA is not known. 7.2.2.2.2.1.2. Neuropeptides of the medium spiny neurons of the indirect pathway (a) Enkephalin. The medium spiny neurons that constitute the indirect pathway and project to GPe express enkephalin. Experimental dopamine denervation by any method results in an increase in the levels of enkephalin in the indirect pathway. Administration of 6-OHDA (Engber et al., 1991), MPTP (Herrero et al., 1995), reserpine (Jaber et al., 1992) and haloperidol (Jaber et al., 1994) leads to an increased expression of PPE A mRNA levels. The elevated enkephalin levels may continue to remain elevated even after administration of levodopa (Salin et al., 1997; Tel et al., 2002; Gross et al., 2003), or may even elevate the PPE A level further (Pirker et al., 2001). The increased expression of enkephalin in the indirect pathway is due to D2 denervation and an increased corticostriate glutamate transmission (Campbell and Bjorklund, 1994), since continuous but not pulsatile administration of D2/D3 agonists (Morissette et al., 1999; Tel et al., 2002) and AMPA antagonists (Perier et al., 2002) or cortical ablation (Uhl et al., 1988) decrease or normalize the levels of enkephalin in the indirect pathway. In PD, enkephalin levels are higher in the indirect pathway (Nisbet et al., 1995). 7.2.2.2.2.2. Medium spiny neurons of the direct pathway 7.2.2.2.2.2.1. Neurotransmitter of the medium spiny neurons of the direct pathway (a) GABA. Dopamine denervation leads to a significant increase in GAD67 and GAD65 mRNA and GABA level in the striatum. This increase is selectively noted in the indirect pathway, but not the direct pathway (Soghomonian and Laprade, 1997). 7.2.2.2.2.2.2. Neuropeptides of the medium spiny neurons of the direct pathway (a) Preprotachykinin (substance P). The different tachykinin peptides are derived from PPT I, PPT II and PPT III, but only peptides encoded by PPT I and PPT II are found in the brain (Pennefather et al., 2004). The PPT I gene encodes for a, b and g-PPT mRNA and among these, b-PPT is the predominant tachykinin mRNA that is expressed in the output neurons of the striatum (Bannon et al., 1992). The b-PPT generates SP, neurokinin A, neurokinin A (3–10) and neuropeptide K (Helke et al., 1990). The peptide neurokinin B is encoded by the PPT II gene. Among these peptides, a majority of spiny output neurons of the direct pathway express SP densely and a small number

of the spiny output neurons express mRNA for neurokinin B that is derived from the PPT II gene. The striatum also demonstrates diffuse and dense SP, neurokinin A and neuropeptide K immunoreactive axon collaterals of the SP output neurons of the direct pathway. SP mRNA is not expressed in any other nucleus of the basal ganglia (Warden and Young, 1988). Experimental dopamine denervation leads to a decreased level of expression of SP mRNA (PerezOtano et al., 1992; Tel et al., 2002), especially in symptomatic animals (Wade and Schneider, 2004). In PD, a decrease in the expression of PPT mRNA is noted in the output neurons of the striatum (Rinne et al., 1984; Tenovuo et al., 1984; Fernandez et al., 1994; Levy et al., 1995) and this decrease is reversed by dopamine D1 agonists (Morissette et al., 1999). In MPTP primate models of PD, SP immunoreactivity is prominent more in the matrix than striosomes, and this pattern is a reversal of a normal pattern of a high SP immunoreactivity in striosomes than matrix regions (Betarbet and Greenamyre, 2004). (b) Preproenkephalin B (dynorphin). The mediumsized spiny striatal output neurons express mRNA for PPE B (preprodynorphin). The mRNA of PPE B codes for prodynorphin. Prodynorphin codes for three opioid peptide domains: neoendorphin, dynorphin A 1–17 and dynorphin B. Further processing of these three peptide domains results in the synthesis of other members of the dynorphin peptide family, namely a- and bneoendorphin, dynorphin A 1–17, dynorphin A 1–8, dynorphin B and leu-enkephalin (Zamir et al., 1984). All of these peptides are found in the primate striatum and in an equal molar ratio. The molar ratio of dynorphin A 1–17 and dynorphin A 1–8 is also 1:1 in primate striatum, whereas in rat striatum, dynorphin A 1–8 is the predominant peptide (Dores and Akil, 1985). In non-dyskinetic MPTP models of PD and in PD, the level of mRNA for preprodynorphin is within normal limits. The emergence of dyskinesia, however, is associated with a dramatic increase in the expression of mRNA for preprodynorphin in mice and primate models of PD as well as in PD (Tel et al., 2002). Recent studies show that PPE B, a precursor for dynorphin, may be increased 185% in the direct spiny neurons that project to GPi directly in PD patients and animals with dyskinesia (Henry et al., 2003). Accordingly, the D1-mediated second-messenger system is also enhanced in dyskinetic models of PD (Gerfen, 2003). Even though a high expression of mRNA for preprodynorphin has been recognized, the pattern of processing of the high levels of prodynorphin and the molar ratio of the different peptides of the dynorphin family in dyskinetic animals and in PD brains have not yet been studied.

NEUROCHEMISTRY OF PARKINSON’S DISEASE (c) Neurotensin. The basal level of neurotensin mRNA expression in striatal neurons is low and the levels of mRNA for neurotensin/neuromedin N increase significantly after neurochemical manipulation (Castel et al., 1993b; Merchant et al., 1994; Zahm et al., 1998). A distinct neurotensinergic projection from the medium spiny neurons of the putamen and the accumbens may form yet another component of the striatonigral pathway in rats (Sugimoto and Mizuno, 1987; Castel et al., 1993a) and possibly in human brains (Faull et al., 1989; Fernandez et al., 1994). In rats, the mRNA level of neurotensin is modified by both D1and D2-receptors (Sugimoto and Mizuno, 1987; Castel et al., 1994). In PD, neurotensin levels are normal in the striatum and GP, but are twofold higher in SNpc and VTA (Fernandez et al., 1995). 7.2.2.3. Receptors for neurotransmitters and neuropeptides in the striatal interneurons and output neurons in Parkinson’s disease 7.2.2.3.1. Neurotransmitter receptors 7.2.2.3.1.1. Dopamine receptors 7.2.2.3.1.1.1. D1-receptor The striatum shows the maximum expression of D1-receptors in the brain (Dearry et al., 1990; Hurd et al., 2001). D1-receptor mRNA is more densely expressed in the nucleus accumbens and the medial caudate nucleus than the lateral regions of the putamen, thereby suggesting a pattern of decreasing intensity from a medial to lateral direction in human brain. The mRNA for D1-receptor is expressed in the GABA/SP output neurons that project directly to GPi and SNr. Recent studies suggest that in PD, D1-receptor mRNA levels may be increased in selective regions of the nucleus accumbens and that D1-receptors may express denervation supersensitivity, as manifested by a 50% increase in the levels of Ga and Gg7, two proteins that are closely linked with D1-receptor-mediated transmission (Corvol et al., 2004) and the molecular cascades associated with D1-receptors (Gerfen, 2003; Aubert et al., 2005). 7.2.2.3.1.1.2. D5-receptor The D5-receptor exhibits 10-fold higher affinity to dopamine than the D1-receptor, indicating its important role in the functions of the basal ganglia and the brain (Sunahara et al., 1991). The medium spiny neurons and the large cholinergic interneurons of the striatum express mRNA for D5receptor (Rappaport et al., 1993) and the D5-receptor protein is expressed in the terminals of GABA/SP striatopallidal neurons. Immunocytochemical studies in rats clearly show that the D5-receptor is localized more prominently in all types of striatal interneurons than the output neurons. All of the large cholinergic

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aspiny interneurons express D5-receptor and the GABA/SOM and GABA/parvalbumin stain more intensely for D5-receptor than the GABA/calretinin interneurons (Rivera et al., 2002). How dopamine denervation affects the functions of the D5-receptor in experimental models of PD or PD is not known. 7.2.2.3.1.1.3. D2-receptor The D2-receptor gene codes for two isoforms of D2-receptor proteins. The D2L form has an additional 29 amino acids in the third cytoplasmic loop when compared to the D2S form (Missale et al., 1998). In striatum, the D2L is expressed more specifically and intensely by the GABA/enkephalin neurons of the indirect pathway (Khan et al., 1998). In the early and untreated stages of PD, there is upregulation of D2-receptor mRNA and receptor binding (Ryoo et al., 1998) in the dorsolateral striatum but not in the caudate nucleus (Rinne et al., 1995; Antonini et al., 1997; Kaasinen et al. 2000). This pattern of upregulation of D2-receptors corresponds to the pattern of dense loss of dopamine and increased levels of GABA and glutamate in the dorsolateral putamen but not in the caudate nucleus in early stages of PD (Hornykiewicz, 2001a). Levodopa treatment may normalize the upregulation (Guttman, 1987) and after 3–5 years and very advanced stages of the disease, D2-receptor stays downregulated significantly (Antonini et al., 1997). The downregulation of D2-receptors is related to chronic treatment with dopaminergic agonists, since even in very advanced stages the D2-receptor reverses to an upregulated state after withdrawal of dopaminergic drugs (Thobois et al., 2004). 7.2.2.3.1.1.4. D3-receptor The D3-receptor is expressed more densely in the limbic striatum than in other regions of the brain and the nucleus accumbens and the associative striatum shows the highest concentration of D3-receptors of all brain regions (Levant, 1997; Suzuki et al., 1998; Morissette et al., 1998). D3 mRNA is localized in the spiny neurons of nucleus accumbens that show colocalization of neurotensin and SP (Landwehrmeyer et al., 1993; Gurevich and Joyce, 1999). The mRNA for D3-receptor is colocalized with mRNAs for D1-receptor and SP in a large percentage of neurons of the nucleus accumbens (Schwartz et al., 1998). In an MPTP-induced model of primate PD and in PD, D3 expression is decreased by 40–45%, especially in the nucleus accumbens and the putamen, and the downregulation of D3 was especially noted in those PD patients who received treatment with dopaminergic agents for 10 years or more (Ryoo et al., 1998). The D3-receptor has been speculated to play a major role in cognitive, motivational and addictive behavior (Morissette et al., 1998; Sokoloff et al., 2001; Heidbreder et al., 2005). The loss of D3 stimulation may contribute to amotivational state and cognitive difficulties of PD and an excessive

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stimulation of D3-receptors by dopamine agonists with greater affinity to D3-receptors than D2-receptors may be responsible for obsessive and addictive behavior that has been observed in PD. 7.2.2.3.1.1.5. D4-receptor Among all the dopamine receptor subtypes, the D4-receptors exhibit the lowest intensity of expression in the striatum. D4-receptors are expressed in the soma, dendritic shaft and the spines of the medium spiny neurons of both direct and indirect pathways of the limbic striatum (Rivera et al., 2002). The different interneurons of the rat striatum are completely devoid of D4-receptors (Rivera et al., 2003). 7.2.2.3.1.2. Glutamate receptors 7.2.2.3.1.2.1. Ionotropic glutamate receptors (a) AMPA/kainate receptors. In striatum, AMPA receptor expression is higher than KA receptors. The medium spiny neurons and the large interneurons express mRNA for GluR1, GluR2/3, but the level of expression of GluR4 is less intense (Bernard et al., 1996). The mRNA (Tremblay et al., 1995) and protein (Betarbet et al., 2000) level of GluR1 is significantly increased in the anterior but not caudal regions of the striatum in rat and MPTP models of primate PD. In PD, the level of expression of mRNA for GluR1–4 is unaltered (Bernard et al., 1996). (b) NMDA receptors. NMDA receptors (NMDAR) are found throughout the basal ganglia but are most abundant in striatum (Albin et al., 1992; Ravenscroft and Brotchie, 2000; Smith et al., 2001). All striatal neurons express NMDA receptors (Kuppenbender et al., 2000). Among the different subtypes, the NR1 gene product shows an extremely widespread distribution over all types of striatal neurons, with moderate to intense staining in striatum, and lower but detectable levels in other nuclei of the basal ganglia. The mRNAs for the NR2 family of subunits are differentially distributed in basal ganglia structures. In the striatum, NR2B is the predominant subtype, but NR2A is also detectable. Within the striatum, differences in cellular expression of NR2-receptor subunit genes and isoforms have been described. Enkephalin-positive projection neurons have higher levels of NMDAR 1 and NR2B message than intrinsic SOM and cholinergic neurons. In contrast, the interneurons express NR2A and NR2D mRNA is preferentially expressed in the SP/D1-containing direct pathway than the enkephalin neurons. The interneurons also express NR2B, NR2C and NR2D subtypes prominently (Kuppenbender et al., 2000). In MPTP models of PD, the mRNA for NR1 and receptor binding does not change, but supersensitivity of NR1/2A/2B may be involved in the generation of dyskinesia (Calon et al., 2003a).

7.2.2.3.1.2.2. Metabotropic receptors In the striatum, all subtypes of mGluRs are expressed, but expression of mGluR5 is more prominent than other subtypes (Testa et al., 1995; Smith et al., 2001). Both SP and enkephalin-containing medium-sized projection neurons express mRNA and proteins for mGluR1 and mGluR5, but not the large cholinergic interneuron or the SOM-expressing interneurons of the striatum (Testa et al., 1995). Among the group II mGluRs, mGluR2 mRNA is mostly expressed in the large striatal interneurons, and mGluR3 mRNA in most striatal neurons. Only low levels of the group III family members are expressed in the striatum (Testa et al., 1994). 7.2.2.3.1.3. GABA receptors 7.2.2.3.1.3.1. Ionotropic receptors In the striatum, a4 and b3 subunits of GABAA receptors are the most prominently expressed but mRNA for a2, a3, b2, g2 and d is also moderately expressed (Kultas-Ilinsky et al., 1998). The intensity of receptor binding for GABAA receptor is unchanged in untreated and treated PD; however, striatal GABAA binding increases after patients develop the phenomenon of ‘wearing off ’ (Calon et al., 2003b). 7.2.2.3.1.3.2. Metabotropic receptors MPTP-induced dopamine denervation in mice and primates does not alter GABAB mRNA level or GABAB binding in the striatum, but in PD GABAB binding is significantly reduced after the development of motor complications (Calon et al., 2003b). 7.2.2.3.1.4. Cholinergic receptors 7.2.2.3.1.4.1. Nicotinic receptors The mRNA for nAchRs has not been localized in any of the striatal neurons. As discussed earlier, the protein for nicotinic receptors, however, is distributed densely in the nigrostriatal terminals and they are significantly decreased in PD (Perry et al., 1995). 7.2.2.3.1.4.2. Muscarinic receptors All mAChR mRNAs and proteins have been detected in basal ganglia (Weiner et al., 1990; Bernard et al., 1992; Yan et al., 2001). The m1, m2 and m4 receptors account for the vast majority of striatal muscarinic binding sites (Levey et al., 1991; Hersch et al., 1994). The m4 subtype is the most abundant mAChR in neostriatum, accounting for 50% of total mAChR, and may be the key target for anticholinergic drugs used in movement disorders. The m4 immunoreactivity is dense in patches high in D1 and glutamate receptor subunit GluR1. The m4 mRNA and protein are present in about 70% of spiny neurons of striatum (Weiner et al., 1990; Bernard et al., 1992; Yan et al., 2001), particularly those that express SP. The m4 mRNA is also noted in 50% of D2/enkephalin spiny neurons of the striatum. The m1 subtype is

NEUROCHEMISTRY OF PARKINSON’S DISEASE expressed in all of the spiny projection neurons, whereas the m2 receptor is expressed in the cholinergic interneurons only (Bernard et al., 1992; Yan et al., 2001). In PD, m1 and m2 receptor density is decreased in the dorsolateral striatum, in a region that demonstrates maximal intensity of dopamine denervation (Joyce, 1993). 7.2.2.3.1.5. Serotonergic receptors The mRNAs for 5-HT1A,1B/1D, 5-HT2A,2C, 5-HT3, 5-HT4,5-HT5 and 5-HT6 are predominantly localized postsynaptically in the GABAergic output neurons of the striatum and have significant interaction with the dopaminergic system. The mRNA for 5-HT2B and 5-HT7 receptors has not yet been localized to any nucleus of the basal ganglia (Barnes and Sharp, 1999). The 5-HT2C receptor is the most prominent receptor in the basal ganglia (Wolf and Schutz, 1997). The role played by 5-HT2A/C in the striatum has been studied in greater detail than any other groups of 5-HT receptors. The mRNA for 5-HT2A, 5-HT2C and 5-HT6 are localized in the medium spiny neurons of the striatum (Ward and Dorsa, 1996). Dopamine denervation induces, in both neonatal and adult animals, significant 5-HT hyperinnervation (Reader and Dewar, 1999), as evidenced by increased density of 5-HT terminals, increased serotonin turnover (Karstaedt et al., 1994) and upregulation of 5-HT2A receptors (Numan et al., 1995) postsynaptically in the medium spiny neurons of the striatum. para-choloramephtamine (Gresch and Walker, 1999a) and fenfluramine (Rouillard et al., 1996), drugs that release endogenous 5-HT, induce an increased PPT mRNA level in the medium spiny neurons of the direct pathway. 5-HT also facilitates the actions of dopamine on the SP-expressing medium spiny neurons of the direct pathway and increases SP mRNA level (Gresch and Walker, 1999b). Stimulation of striatal 5-HT2A/C receptors increases PPT mRNA (Walker et al., 1991, 1996; Gresch and Walker, 1999b) and 5-HT2A/C receptor antagonists decrease PPT mRNA level. Dopamine denervation decreases PPT mRNA level significantly and this decrease is reversed by 5-HT2A/C receptor agonists (Gresch and Walker, 1999a). These studies point to an important dopamine-facilitating role for the serotonergic system in the regulation of neuropeptides in the direct pathway. In animal models of PD, the level of expression of 5-HT1A (Frechilla et al., 2001), 5-HT1B and 5-HT2A is upregulated (Numan et al., 1995; Reader and Dewar, 1999). 7.2.2.3.1.6. Adenosine receptors Among the A1 and A2A adenosine receptors, the A1 adenosine receptor is expressed at the corticostriate terminals and when stimulated inhibits glutamate release. The A2A, which has a higher affinity to adenosine than A2B, is colocalized in virtually all of the medium spiny

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indirect output neurons of the striatum that also express D2 and PPT A mRNAs (Svenningsson et al., 1998). A2A agonists oppose the effects of D2 (Svenningsson et al., 1998). A small number of the large aspiny cholinergic interneurons also express A2A receptors (Kawaguchi, 1997). Levels of A2-receptor mRNA are significantly reduced in anterior, posterior and dorsal areas of caudate and putamen, but not in the nucleus accumbens in patients with PD who were treated with dopaminergic agents chronically (Hurley et al., 2000). In patients with severe dyskinesia, when compared to non-dyskinetic patients, however, the level of A2 mRNA is significantly increased in the putamen, but not in the GP (Calon et al., 2004). 7.2.2.3.1.7. Cannabinoid receptors CB1 receptor binding is increased in the caudate nucleus, but not in GPe or SN in PD and MPTPinduced PD in primates. Levodopa treatment reverses the increased binding (Lastres-Becker et al., 2001). 7.2.2.3.2. Peptidergic receptors 7.2.2.3.2.1. Opioid receptors The mRNA for dynorphin-sensitive k receptors is expressed more intensely in the striatum than m and d opioid receptors (Peckys and Landwehrmeyer, 1999). The mRNA for k receptors is expressed densely by the medium spiny neurons of the direct pathway (Spadoni et al., 2004) and when stimulated they alter the excitability of these neurons. The k-binding sites are downregulated in the striatum (and the nigra) in 6-OHDA-treated rats that are dyskinetic with chronic levodopa administration (Johansson et al., 2001). The mRNA for m opioid receptors is colocalized within the medium spiny neurons that express mRNA for preprodynorphin (Peckys and Landwehrmeyer, 1999). The d opioid receptors localized in the terminals of GABAergic fibers (Rawls and McGinty, 2000) regulate glutamate release. Dopamine denervation results in the downregulation of opioid receptors in the striatum, but m and d receptormediated G-protein activity may be enhanced (Chen et al., 2005). In PD, k agonists improve PD symptoms and m and d opioid receptor antagonists decrease dyskinesia. Morphine, an opioid agonist, reduces dyskinesia and increases akinesia (Berg et al., 1999). Naltrexone, a non-selective opioid receptor antagonist, inhibits the beneficial effects of levodopa and subsequently induces severe dyskinesia (Samadi et al., 2005). Studies using positron emission tomography scans suggest that, in PD, opioid receptor binding is significantly decreased in dyskinetic but not in non-dyskinetic patients (Piccini et al., 1997). Even though the levels of mRNA of PPE A and PPE B are significantly increased in

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levodopa-induced dyskinetic PD animals and in PD, it is not clear whether the increased levels are actually responsible for inducing dyskinesia or reflect chronic molecular changes resulting from dopamine denervation (Schneider et al., 1999; Quik et al., 2002; Samadi et al., 2003). The roles played by opioid and opioid receptors in PD are under intense scrutiny. 7.2.2.3.2.2. PPT receptors All three types of tachykinin receptors are expressed within the striatum. The SP-sensitive NK-1 is the most common type of tachykinin receptor expressed in the spiny output neurons (Mantyh et al., 1989), as well as in 95% of the GABA/SOM/NOS interneurons and the large aspiny cholinergic neurons. In PD there is a loss of NK-1 receptors in the putamen (Tenovuo et al., 1990; Fernandez et al., 1994). 7.2.2.3.2.3. Neurotensin receptors The medium-sized neurons of the striatum express mRNA and protein for NTS2 and NTS3/sortilin receptors (Sarret et al., 2003a, b). In MPTP mice models of PD (Tanji et al., 1999) and in PD (Chinaglia et al., 1990; Fernandez et al., 1994) 3H-neurotensin binding is significantly decreased in the nucleus accumbens, caudate nucleus and putamen. 7.2.2.3.2.4. Somatostatin receptors The mRNA for SOM receptors SSTR1–5 is localized to the striatum in human brain (Bruno et al., 1993), but cellular localization of these receptors within the striatum remains to be elaborated (Schindler et al., 1996). 7.2.2.3.2.5. NPY receptors There are five types of NPY receptor: Y1, Y2, Y4, Y5 and Y6. Even though a group of GABAergic striatal interneurons expresses NPY, very low or negligible levels of mRNA for the NPY1–5 receptors have been localized to the striatum (Gustafson et al., 1997; Parker and Herzog, 1999). 7.2.2.4. Chronic levodopa-induced dyskinesia and alterations of neuropeptide mRNAs in the striatal direct and indirect pathways Our understanding of the extraordinarily complex pattern of localization of numerous subtypes of receptors of different neurotransmitters and neuropeptides in the dendrites, soma and axon terminals of individual neurons in the different nuclei of the basal ganglia and their interactions with levodopa and other drugs is incomplete and still evolving (Table 7.1). How dopamine denervation and chronic levodopa and other dopaminomimetic drugs affect the output of direct and indirect pathways and the rest of basal ganglia circuitry is under intense scrutiny. Although levodopa is

the drug of choice in the treatment of PD, aggressive and chronic use of levodopa eventually induces severe motor fluctuations in most patients. The incidence of motor fluctuations and dyskinesia may be higher in those patients receiving a higher dose of levodopa than in those receiving a lower dose (Fahn et al., 2004). Whereas the presynaptic difficulties in storing and delivering smooth levels of dopamine at the synaptic cleft may contribute to the on–off, yo-yo phenomenon and predictable and unpredictable wearingoff (de la Fuente-Fernandez et al., 2004), the disabling dyskinesias are associated with dopamine denervation hypersensitivity of D1-, D2-, NMDA and AMPA receptors in the medium spiny projection neurons of the direct and indirect pathways. An extensive literature about the molecular and neurochemical basis of levodopa-induced dyskinesia that has accumulated allows us to draw the following conclusions. 7.2.2.4.1. In normal (non-dopamine denervated) animals Even normal mice (Gross et al., 2003) and primates (Zeng et al., 2000); Pearce et al., 2001; Togasaki et al., 2005), if chronically treated with large but not low doses of levodopa, will develop peak dose dyskinesia. The occurrence of dyskinesia is associated with an increase in expression of enkephalin in the indirect pathway and a normal level of PPT/SP and PPE B (dynorphin) mRNA in the direct pathway (Gross et al., 2003; Zeng et al., 2000), suggesting that dyskinesia may be associated with peptidergic alterations in the indirect pathway alone. 7.2.2.4.2. In dopamine denervated but non-dyskinetic animals In MPTP-induced animal models of PD that are nondyskinetic, dopamine denervation leads to an upregulation of enkephalin expression in the medium spiny neurons of the indirect pathway and downregulation of PPT and PPE B in the direct pathway (Tel et al., 2002). The upregulation of enkephalin mRNA may occur even before the onset of motor deficits (Bezard et al., 2001). The increased expression of enkephalin in the indirect pathway in dyskinetic animals is due to D2 denervation and an increased glutamate transmission, since dopamine agonists (Morissette et al., 1999; Tel et al., 2002) and AMPA antagonists (Perier et al., 2002) normalize the levels of enkephalin in the indirect pathway. The increased expression in enkephalin mRNA in the indirect pathway in normal or dyskinetic animals stays increased even after chronic levodopa treatment (Westin et al., 2001; Tel et al., 2002; Gross et al., 2003), but is reversed by continuous administration of D2/D3 agonists (Tel et al., 2002).

NEUROCHEMISTRY OF PARKINSON’S DISEASE 7.2.2.4.3. In dopamine denervated and dyskinetic animals In 6-OHDA-treated rats (Cenci et al., 1998) and in MPTP-induced primate models of PD, the occurrence of dyskinesia after chronic levodopa treatment is associated with a very significant increase in dynorphin mRNA expression in the medium spiny neurons of the direct pathway but without any further increase in the enkephalin mRNA expression of the indirect pathway (Zeng et al., 2000; Gross et al., 2003). The prominent increased dynorphin expression in the direct pathway is correlated with the severity of dyskinesia in a dose- and duration-dependent fashion (Cenci et al., 1998; Gross et al., 2003). The dramatic increase in PPE B mRNA is directly related to an increased expression and supersensitivity of the D1-receptors, as evidenced by modified and enhanced signaling of D1-mediated molecular cascades (Gerfen et al., 2002; Gerfen, 2003; Aubert et al., 2005). Pulsatile stimulation by D1 agonists induces a significant increase in dynorphin expression and corrects the lowered expression of PPT (Morissette et al., 1999). The increased dynorphin level in the direct pathway is also associated with an increase in GABAA binding in GPi in primates (Calon et al., 2000).

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disabling dyskinesia occurring in PD after chronic levodopa treatment is associated with a cumulative effect of peptidergic changes in both the direct and indirect pathways. Dyskinesia is associated with chronic levodopa use; drugs that stimulate D2/D3-receptors (bromocriptine, cabergoline, pramipexole and ropinirole) reduce the incidence and severity of dyskinesia; drugs that stimulate D1-receptors (levodopa; SKF 82958) increase dyskinesia; drugs that block glutamatergic receptors (amantadine, MK 801) decrease dyskinesia, probably by acting through NMDA and AMPA receptors in both direct and indirect pathways. Currently available drugs that interact with opioid receptors have had conflicting results. The individual functions of the direct and indirect pathway are unknown and the mechanisms by which these peptidergic changes alter the functions of indirect and direct pathways and ultimately lead to disabling dyskinesia remain to be explored. 7.2.3. Neurochemistry of globus pallidus externa in Parkinson’s disease 7.2.3.1. Neurochemistry of GPe afferents 7.2.3.1.1. Neurotransmitters of GPe afferents

7.2.2.4.4. In non-Parkinson’s disease patients In non-PD humans, the use of large doses of levodopa chronically, for example, in patients with essential tremor, has not been recognized to induce dyskinesia. 7.2.2.4.5. In non-dyskinetic Parkinson’s disease patients Dopamine denervated but untreated or treated but nondyskinetic PD brains demonstrate, similar to 6-OHDA or MPTP-induced dopamine denervation states in primates, an increased expression of enkephalin in the indirect pathway and decreased expression of PPT and PPE B in the direct pathway (Nisbet et al., 1995). 7.2.2.4.6. In dyskinetic Parkinson’s disease patients The striatum of PD patients with dyskinesia, similar to all the animal models, demonstrates a significant increase in the levels of enkephalin in the spiny neurons of the indirect pathway (Calon et al., 2002) and a dramatic increase – up to 172% – in dynorphin mRNA levels (Henry et al., 2003) and lowered levels of PPT mRNA in spiny neurons of the direct pathway. 7.2.2.4.7. Summary The results from animal models of PD with or without dyskinesia correspond with the observations that the

7.2.3.1.1.1. Gaba The GPe is characterized by its very intense staining for enkephalin immunoreactivity. The major source of afferents to GPe is the topographically organized GABA/enkephalin fibers from the striatal spiny neurons of the indirect pathway. Dopamine denervation results in an increased expression of mRNA and protein and activity of GAD67, resulting in an increased synthesis and release of GABA in GPe by the GABA/enkephalin neurons of the indirect pathway (Soghomonian and Laprade, 1997). Consistent with these observations in animal models of PD, GABA level in GPe is slightly higher in PD (Kish et al., 1986). 7.2.3.1.1.2. Glutamate A glutamatergic input from the STN is the second largest source of afferent to GPe (Carpenter and Jayaraman, 1990) and probably is the source of glutamate observed in GPe. Glutamate levels are normal in GPe in PD (Hornykiewicz, 2001a). 7.2.3.1.1.3. Dopamine The GPe also receives a small projection from the midbrain dopamine neurons. The level of dopamine is low in GPe but 5–6 times higher than the level noted in GPi (Hornykiewicz, 2001a). In PD progressive degeneration of midbrain dopamine neurons leads to a loss of 80% of dopamine in GPe (Hornykiewicz, 2001a).

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Table 7.1 The pattern of expression of mRNA for receptors of neurotransmitters and neuropeptides in the basal ganglia Nucleus

Striatum

Morphology Neurotransmitter Peptide

Spiny GABA Enkephalin Neurotensin? Calbindin

Calcium binding protein Enzymes

Spiny GABA SP/Dynorp Neurotensin? Calbindin

Large aspiny Acetylcholine

Globus pallidus Aspiny GABA NPY/SOM

Calretinin

Aspiny GABA

Aspiny GABA

Gpe GABA Enkephalin

Parvalb

Calretinin

Parvalbumin

Gpi GABA

STN

SNpc/VTA

SNpr

Glutamate

DA CCK/NT

GABA

NADPH

AchE

Glutamate receptors Ionotrophic GluR AMPA

NMDA

Metabotrophic GluR Group I Group II

Group III

þþ þþþ þþ þ þ þ þ þ þ þþþ þ þþ

þþ þþþ þþ þ þ þ þ þ þ þþþ þþ þþ þ

þþ þþþ þþþ þþþ þþ þþ þþþ þþ þ þ

mGluR1 mGluR5 mGluR2 mGluR3 mGluR4 mGluR6 mGluR7 mGluR8

þ þþþ þþ þ þ þ þ

þ þþþ þþ þ þ þ þ

þ þ þ þ þ

þþ þþ þ

þþþ þþþ þþ þ

þ

þ þþ þ þþþ þ þ þ þ þ þ þþ

þ þþ þ þþþ þ þ þ þ þ þ þþ

þþþ

þ þ

þ þ

þ þþ þþ þ

þþ þþ þþ þþ

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Kainate

GluR1 GluR2 GluR3 GluR4 GluR5 GluR6 GluR7 KA1 KA2 NR1 NR2A NR2B NR2C NR2D NR3A

þþþ þ þ þþþ þþ þ þ

þ

GABA receptors Ionotrophic GABA-R þþþ

þþ

þþþ

þþþ

þþþ

þþþ

þþ

þþþ

þ

þ þ þ

þ þþþ þþ þ þ

þ þþ

þþþ þþþ þþþ þþþ þþþ þþþ þþ þ

þþþ þþþ þþ þ þ þ þþ þ

Metabotrophic GABA-R þþ

þþ

þþ

D1 D2 D3 D4 D5

þþþ þþþ þþ þ

þþþ þþþ þ þþ

þ þþþ þ þþþ

M1 M3 M5 M2 M4 a4 b2 a3 b3 a5 a6 a7 b4 a2

þþþ þ þ þþ

þþþ þ þþþ

þþþ þþ þþ

GABA B Dopaminergic receptors

þ

þ þ

þ þþþ þþ

þ þþ

Cholinergic receptors Muscarinic

Nicotinic

NEUROCHEMISTRY OF PARKINSON’S DISEASE

GABA A GABA C

(Continued)

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Table 7.1 (Continued) Nucleus

Striatum

Morphology Neurotransmitter Peptide

Spiny GABA Enkephalin Neurotensin? Calbindin

Calcium binding protein Enzymes

Spiny GABA SP/Dynorp Neurotensin? Calbindin

Large aspiny Acetylcholine

Globus pallidus Aspiny GABA NPY/SOM

Calretinin

Aspiny GABA

Aspiny GABA

Gpe GABA Enkephalin

Parvalb

Calretinin

Parvalbumin

Gpi GABA

STN

SNpc/VTA

SNpr

Glutamate

DA CCK/NT

GABA

NADPH

AchE

Serotonergic receptors þ þ

þ þ þ

þþ þþþ

þþþ þþþ

þ

þ

þþ

þþ

H1 H2 H3 H4

þþ þþ þþþ

þþ þþ þþþ

A2A

þþþ

þ

þþ

CB1 CB2

þþ

þþþ

þþ

þþ

þ þ

þ

þþ

þþ þþ

þþ

þ

þ

þ

þ

þþ

– þ

þ

þþ

þ

þ

þ

Histaminergic receptors

Adenosine receptors

Cannabinoid receptors

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5HT1A 5HT1B 5HT1D 5HT1E 5HT1F 5HT2A 5HT2B 5HT2C 5HT3 5HT4 5HT5 5HT6 5HT7

Neuropeptide receptors Opioid receptors þþþ þþþ

þþ

þþ

þþ

þþþ

NTS1 NTS2 NTS3

þ þþ

þ þþ

NPY1 NPY2 NPY4 NPY5 NPY6

þþ þþ

þ

þþþ

þþþ þþ

þ þ

þ

þ

þþ þþ þþ

þ

þþ þ þ þþ

þþ þ þ þ

Tachykinin receptors NK1 NK2 NK3

þþþ

Neurotensin receptors

þ þ

þþ

NPY receptors

Somatostatin receptors

NEUROCHEMISTRY OF PARKINSON’S DISEASE

þþþ þþþ –

Kappa Mu Delta

sst1 sst2 sst3 sst4 sst5 þþþ, þþ, þ represent high, moderate and low intensity of expression of mRNA of different receptors. represents the absence of mRNA. Empty “boxes” represent that the information is incomplete or unavailable. References in text.

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Cortex

Cerebral cortex Loss of NE > 5HT > DA Loss of acetylcholine Thalamus Hypothalamus Loss of NE > 5HT Normal or slight loss of DA

N

GPi

TuberoMamillary nuc.

GPe

Hypothalamus

Striatum

ST

Basal ganglia Loss of DA > 5HT Normal NE Increased histamine Increased Glutamate Increased GABA

A11 Midbrain

VTA-SNpc Pons Brain stem Loss of NE = or > 5HT > DA Decreased Acetylcholine

Raphe-oral PPN

Medulla Locus ceruleus

NE

Raphe-caudal Medulla A2/C2

DA 5HT Spinal cord Loss of NE = or > 5HT Normal DA

NEUROCHEMISTRY OF PARKINSON’S DISEASE 7.2.3.1.1.4. Serotonin Serotonergic innervation to GPe is less intense than GPi (Lavoie and Parent, 1990) and 5-HT levels are lower in GPe in MPTP models of PD (Pifl et al., 1991). 7.2.3.1.1.5. Acetylcholine The GPe receives a small cholinergic input from PPN (Garcia-Rill, 1991). The significance of cholinergic input in the regulation of GPe neurons remains to be explored. 7.2.3.1.2. Neuropeptide of GPe afferents 7.2.3.1.2.1. Enkephalin The GPe is characterized by the presence of dense immunoreactivity to enkephalin. The level of enkephalin in GPe is second only to that of striatum. Enkephalin immunoreactivity is derived from the striatopallidal projection of the indirect pathway as well as neurons that are intrinsic to GPe that also express GABA and enkephalin (Hoover and Marshall, 1999). In MPTP models of primate PD, along with an increased release of GABA, the level of enkephalin in GPe is also increased (Betarbet and Greenamyre, 2004). 7.2.3.2. Neurochemistry of GPe neurons Neurons intrinsic to GPe are of two types: those neurons that contain GABA and parvalbumin and project to STN, GPi and nigra and those that express GABA and PPE A (enkephalin) that project to the parvalbumin containing interneurons of the striatum (Bevan et al., 1998; Hoover and Marshall, 1999). Dopamine denervation by either 6-OHDA lesioning of nigra or by administration of D2-antagonists but not D1-antagonists increases GAD67 mRNA levels in both types of GPe neurons and this increase is reversed by STN lesioning (Billings and Marshall, 2004). In PD, GABA levels are increased in GPe (Kish et al., 1986). In control brains, the GPe neurons do not express mRNA for neurotensin. Dopamine denervation with

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6-OHDA, however, results in the expression of immunoreactivity for neurotensin in neurons of GP in rats (Martorana et al., 2003). The SP/dynorphin-containing axons of the direct pathway traverse through GPe, but neurons of GPe do not normally express mRNA for SP or for SP receptors. After 6-OHDA destruction of SN in rats, several neurons in GP in rats express immunoreactivity for SP (Martorana et al., 2003). 7.2.3.3. Neurochemistry of GPe receptors 7.2.3.3.1. Neurotransmitter receptors 7.2.3.3.1.1. Dopamine receptors D1 mRNA as well as D1-receptor protein from afferent terminals is expressed in the neurons and neurophil of GPe. The level of expression of D1 mRNA in control and PD is not altered (Hurley et al., 2001). D2-receptors are densely distributed in both types of GPe neuron and possibly in the nigropallidal terminals and play a significant role in the regulation of GAD67 in both types of pallidal neuron (Hoover and Marshall, 2004). In GPe, immunoreactivity for both D2S and D2L forms has been observed, but the immunoreactive pattern of D2L form shows a higher intensity than the D2S form (Khan et al., 1998). The striatal neurons express the D2L form more intensely than the D2S form (Khan et al., 1998). Terminals of the dense projections from the medium spiny neurons of the indirect pathway to GPe may be the source of the D2L immunoreactivity in GPe. GPe also receives a small but significant projection from SNpc, which expresses mainly the D2S form in their soma and axons, thereby suggesting that the nigropallidal projections may be the source of D2S immunoreactivity observed in GP. D3-receptor binding is low in both pallidal segments but it is upregulated after MPTP (Morissette et al., 1998).

Fig. 7.1. For full color figure, see plate section. Diagrammatic representation of neurochemical changes in PD. (See section 7.6.2.) The red dot/dashed line represents the degenerating dopaminergic nigrostriatal, mesostriatal and mesolimbic input. The blue dashed line represents the degeneration of the ascending serotoninergic projections from the oral raphe to the basal ganglia and the cerebral cortex. The red dotted line represents the degenerating ascending norepinephrinergic projections from locus ceruleus to the cerebral cortex. Note that the basal ganglia receive very little direct norepinephrinergic projection from locus ceruleus. The solid orange line represents an increased histaminergic input to the basal ganglia and the cortex. The descending purple dotted line represents the degeneration of the norepinephrinergic input from the locus ceruleus and A2/C2 to the spinal cord. The blue dashed line depicts the degeneration of serotoninergic input to the spinal cord from caudal raphe pallidus. The descending dopaminergic projection to the spinal cord from the hypothalamic A11 group of THpositive neurons, shown as a solid red line, does not degenerate in PD. The pattern of loss of cholinergic neurons is not shown in the figure. The text boxes show that the pattern of loss of various neurotransmitters varies at different levels of the PD brain.

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7.2.3.3.1.2. Glutamate receptors 7.2.3.3.1.2.1. Ionotropic (a) AMPA/kainate. Both pallidal segments express mRNA and protein for all GluRs, but only for KA1 and KA2 receptors among the kainate receptors (Smith et al., 2001). (b) NMDA. The mRNA and receptor protein for all subtypes of NMDA receptor have been identified in the GPe neurons, but the intensity of expression is significantly lower than the striatum (Kosinski et al., 1998b; Smith et al., 2001). NR1 gene product shows an extremely widespread distribution, wherease NR2D is most abundant in both pallidal segments (Kosinski et al., 1998b). 7.2.3.3.1.2.2. Metabotropic The intensity of expression of mRNA for different mGluRs in GPe is very low. Among the different subtypes, mGluR3 is expressed more intensely than the other subtypes (Testa et al., 1994). mGluR1 and mGluR5 was strongly immunolabeled in both pallidal segments as well as, preferentially, in the glutamatergic subthalamopallidal synapses. Group III mGluR may be expressed in the striatopallidal terminals (Smith et al., 2001). 7.2.3.3.1.3. GABAergic receptors 7.2.3.3.1.3.1. Ionotropic receptors In primate GPe, mRNA for a1, b2 and g2 subunits is expressed at high levels (Kultas-Ilinsky et al., 1998). All subunits other than b1 are expressed at a mild to moderate intensity. Increased GABAA binding is noted in GPe whereas GABAA binding is normal in untreated and treated PD patients, but the intensity of binding of GABAA receptors is increased after the onset of motor complications (Calon et al., 2003b). 7.2.3.3.1.3.2. Metabotropic receptors The level of GABAB binding and mRNA of GABAB receptor is unchanged in mice and primate models of PD, but in PD, GABAB binding is reduced in GPe once motor complications are manifest (Calon et al., 2003b). 7.2.3.3.1.4. Cholinergic receptors 7.2.3.3.1.4.1. Nicotinic receptors Autoradiographic studies using 125I-a conotoxin MII, which binds to the a6/a3 subtype of nicotinic receptors, demonstrate moderate intensity of binding in GPe and GPi (Quik et al., 2004). 7.2.3.3.1.4.2. Muscarinic receptors Receptor-binding studies suggest that all subtypes of mAchRs are present in human GPe (Piggott et al., 2002). In PD, the mAchR binding pattern is unchanged from that of control brains (Piggott et al., 2003). 7.2.3.3.1.5. Serotonin receptors The protein of 5-HT receptors is found in the target sites of the terminals of the striatal output neurons,

namely GPe and SNpr. The protein for 5-HT1A is localized to the somatodendritic portion of GP in rats and 5-HT1B receptors are localized in serotonergic axons (Riad et al., 2000). 7.2.3.3.1.6. Adenosine receptors The mRNA of A2-receptor is denser in the external segment of the GP than in the internal segment and the expression pattern of A2-receptors is unchanged in PD (Hurley et al., 2000; Calon et al., 2004). 7.2.3.3.2. Peptidergic receptors 7.2.3.3.2.1. Opioid receptors The GPe neurons express k (Ogura and Kita, 2000) and m receptors (Delfs et al., 1994). The d opioid receptors are located presynaptically in the GABAergic terminals (Stanford and Cooper, 1999) and along with m receptors regulate GABA release. In animal models of PD, m receptor binding is decreased and remains decreased even after reversal of dopamine denervation (Schroeder and Schneider, 2002). 7.2.3.3.2.2. Neurotensin receptors The protein for NTS2 receptor is found in GPe (Sarret et al., 2003a) and the level of NT receptor is decreased in PD (Fernandez et al., 1994). 7.2.4. Neurochemistry of subthalamic nucleus (STN) in PD 7.2.4.1. Neurochemistry of STN afferents 7.2.4.1.1. Gaba STN stains intensely for GABAergic immunoreactivity. The dense projections from GPe (Carpenter and Jayaraman, 1990) and a small but significant projection from PPN (Bevan and Bolam, 1995) provide the major source of GABAergic innervations to STN. A very small number of STN neurons are GABAergic interneurons and contribute to the GABAergic levels in STN. In PD, GABA level is normal in STN (Kish et al., 1986; Hornykiewicz, 2001a). 7.2.4.1.2. Glutamate The STN receives rich glutamatergic inputs from the cerebral cortex, thalamic intralaminar nuclei and the PPN (Parent and Hazrati, 1995). In PD, STN neurons are hyperactive and this hyperactivity has been proposed to be due to disinhibition of the GABAergic input from the indirect pathway and possibly due to increased activation of STN neurons by the glutamatergic projection from the cerebral cortex. In PD, glutamate levels are slightly increased in STN (Hornykiewicz, 1998).

NEUROCHEMISTRY OF PARKINSON’S DISEASE 7.2.4.1.3. Dopamine

7.2.4.3. Neurochemistry of STN receptors

The dopaminergic neurons of SNpc and possibly the A8 retrorubral nucleus send TH-immunopositive axons to the STN. There is a 50–65% loss of dopamine in MPTP-treated primates as well as in PD (Francois et al., 2000; Hornykiewicz, 2001a).

7.2.4.3.1. Dopamine receptors

7.2.4.1.4. Serotonin The STN receives serotonergic input from raphe (Lavoie and Parent, 1990). 7.2.4.1.5. Acetylcholine The STN demonstrates significant density of choline acetyltransferase immunoreactive terminals and the Ch5 group of PPN and Ch6 group provide the major cholinergic input to STN (Bevan and Bolam, 1995). In PD, cholinergic PPN neurons degenerate significantly. Since most of the cholinergic neurons send axon collaterals that terminate in multiple nuclei of the basal ganglia, it is logical to suspect that STN undergoes cholinergic denervation in PD. 7.2.4.2. Neurochemistry of STN neurons 7.2.4.2.1. Neurotransmitters of STN neurons 7.2.4.2.1.1. Gaba The STN consists mostly of projection neurons and a few interneurons (about 7.5% of the total population of STN neurons) that synthesize GABA are noted in selective regions of STN (Levesque and Parent, 2005).

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A combination of RT-PCR technique and ligand-binding studies in rats shows that the STN neurons express mRNA for dopamine receptors D1, D2 and D3, but not D4. STN neurons in basal ganglia, however, do not express mRNA for D1 or D2 subtypes of receptors, although a weak binding site only for D1-receptors has been observed (Augood et al., 2000). Receptor-binding studies suggest that all subtypes of dopamine receptor are present in rat STN and that 6-OHDA lesions have no effect on D1-receptors, increase the density of D2-receptors and decrease D3 density in STN (Flores et a1., 1999). 7.2.4.3.2. Glutamate receptors 7.2.4.3.2.1. Ionotropic receptors 7.2.4.3.2.1.1. AMPA/KA receptors The primate STN neurons express protein for GluR1 (Betarbet et al., 2000; Wang et al., 2000) and the level of GluR1 is unchanged in STN after MPTP treatment in primates (Betarbet et al., 2000). 7.2.4.3.2.2. Metabotropic receptors 7.2.4.3.2.2.1. NMDA receptors The STN neurons express all types of mGluR except mGluR4. The expression pattern of mGluR2 is more prominent in STN than any other basal ganglia structure in rats (Testa et al., 1994), but in STN the mRNA for mGLuR2 is expressed less intensely (Phillips et al., 2000). 7.2.4.3.3. GABA receptors

7.2.4.2.1.2. Glutamate The projection neurons of STN are glutamatergic. Almost all of the STN neurons also express either parvalbumin or calretinin (Hardman et al., 1997). Along with its connectivity with GPe, STN plays a major role as the pacemaker for the generation of normal and abnormal movements (Plenz and Kitai, 1999). The STN neurons are overactive in PD and this overactivity is mostly due to the loss of inhibitory input from GABAergic projections from GPe. The STN overactivity may also be due to a direct excitatory effect of the glutamatergic projections from the parafascicular nucleus of the thalamus and PPN (Hirsch et al., 2000). The increased stimulation of the inhibitory GABAergic pallidothalamic outflow pathway by the glutamatergic STN input has been considered to be responsible for the many clinical features of PD. In PD, glutamate level in STN is slightly higher than controls (Hornykiewicz, 2001a). The STN neurons degenerate significantly in PSP but not in PD (Hardman et al., 1997).

7.2.4.3.3.1. Ionotropic receptors Similar to GPe and GPi, the neurons of STN express a1, b2 and g2 subunits intensely: all other subunits are expressed with moderate to low intensity (KultasIlinsky et al., 1998). 7.2.4.3.3.2. Metabotropic receptors The mRNA for all subtypes of GABAB receptors is expressed by rat STN neurons (Johnston and Duty, 2003). GABAB receptor bindings are unchanged when compared to control in mice models of PD (Calon et al., 2003b). 7.2.4.3.4. Cholinergic receptors 7.2.4.3.4.1. Ionotropic (nicotinic) receptors The pattern of distribution of different subtypes of nicotinic receptors in STN needs to be established. A moderate to high density of a-bungarotoxin-binding sites has been observed in STN (Clarke et al., 1985; Schulz et al., 1991). Neurophysiologic studies suggest a limited role for nicotinic receptors in STN (Feger et al., 1979).

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7.2.4.3.4.2. Metabotropic (muscarinic) receptors Microiontophoretic injection of acetylcholine induces excitation of STN neurons and the excitation is blocked by antimuscarinic but not antinicotinic agents, suggesting an important role for muscarinic receptors in STN in comparison to nicotinic receptors. The subthalamus also expresses relatively high levels of m3 mRNA (Weiner et al., 1990) and protein (Levey et al., 1994). The neurons of the Ch5 and Ch6 group in the mesopontine tegmentum may be the source of the cholinergic input to STN. 7.2.4.3.5. Serotonin receptors The expression pattern of mRNA for 5-HT2C and 5-HT4 receptors is high and 5-HT1A and 5-HT2A mRNA is low in STN (Pompeiano et al., 1994). 5-HT2C and 5-HT4 may be colocalized within a single STN neuron and are involved in excitatory response of STN neurons (Xiang et al., 2005). 7.2.5. Neurochemistry of globus pallidus interna (GPi) in Parkinson’s disease 7.2.5.1. Neurochemistry of GPi afferents

cause increased excitation of the GABAergic neurons of GPi. In PD, glutamate level is normal or only slightly elevated in GPi (Hornykiewicz, 2001a). 7.2.5.1.1.3. Gaba The GABAergic neurons of GPe, in addition to providing dense projections to STN, also send a less intense projection to GPi. MPTP-induced dopamine denervation increases GAD67 mRNA levels in GPi neurons and this increase is reversed by levodopa treatment (Herrero et al., 1996). In PD, GABA level in GPi is increased (Kish et al., 1986; Hornykiewicz, 2001a). 7.2.5.1.1.4. Acetylcholine The GPi receives prominent cholinergic input from PPN (Garcia-Rill, 1991; Lavoie and Parent, 1994). The role played by acetylcholine in GPi remains to be established. 7.2.5.1.1.5. Serotonin The GPi stains more intensely for 5-HT-immunopositive terminals than GPe (Lavoie and Parent, 1990; Charara and Parent, 1994). In PD, the density of 5HT transporter binding is significantly decreased in GPi (Chinaglia et al., 1993).

7.2.5.1.1. Neurotransmitters of GPi afferents

7.2.5.1.2. Neuropeptides of GPi afferents

7.2.5.1.1.1. Dopamine Collaterals from the nigrostriatal fibers innervate GPi densely (Parent et al., 1990). The GPi also receives dopaminergic input from a select subgroup of SNpc neurons different from that of the nigrostriatal projections (Smith et al., 1989). GPi has denser dopamine innervation than GPe (Hornykiewicz, 2001a). The SNpc cells that project to the pallidal segments are resistant to MPTP (Parent et al., 1990; Schneider and Dacko, 1991). In PD, there is a 60% loss of dopamine in GPi (Jan et al., 2000; Hornykiewicz, 2001a). Although striatal dopamine levels may be decreased in early PD, the levels of dopamine in GPi may be increased in early stages of PD, as supported by an increase in 18F-dopa uptake in GPi and the levels decrease once motor fluctuations manifest (Brooks, 2003).

7.2.5.1.2.1. Substance P The neurons of GPi do not express any mRNA for tachykinin peptides or receptors, but demonstrate significant intensity of SP immunoreactive terminals derived from the direct pathway. The levels of SP are significantly increased in MPTP primate models of PD (Betarbet and Greenamyre, 2004) and in PD (de Ceballos et al., 1993).

7.2.5.1.1.2. Glutamate The dense glutamatergic nerve terminals observed in GPi are mostly derived from STN. The centromedian and parafascicular nuclei of the thalamus also contribute to the glutamatergic input to GPi (RouzaireDubois and Scarnati, 1987; Mouroux and Feger, 1993). The PPN, which projects to GPi more densely than GPe, consists of neurons that are glutamatergic, but it is not known whether PPN provides glutamate to GPi. The STN neurons are hyperactive in PD and the hyperactive STN neurons have been speculated to

7.2.5.2. Neurochemistry of GPi neurons

7.2.5.1.2.2. Dynorphin The concentration of opioid peptides processed from prodynorphin, especially that of a-neoendorphin, is high in GPi of control brains (Zamir et al., 1984). The levels of Met-enkephalin, processed from prodynorphin, are increased by threefold in GPi in PD (de Ceballos et al., 1993).

The GPi neurons are exclusively GABAergic (Smith et al., 1987). Parvalbumin may be colocalized in some of the GPi GABA neurons. MPTP-induced dopamine denervation results in an increased expression of mRNA for GAD67 in the GABAergic neurons of both GPe and GPi, but such an increased expression of GAD67 mRNA level is more prominent in GPi than GPe neurons (Soghomonian et al., 1994). In PD, GABA levels are increased in GPi (Hornykiewicz, 2001a).

NEUROCHEMISTRY OF PARKINSON’S DISEASE 7.2.5.3. Neurochemistry of GPi receptors 7.2.5.3.1. Neurotransmitter receptors 7.2.5.3.1.1. Dopamine receptors The GPi neurons do not express mRNA for D1-receptor, but a weak pattern of expression of D2 mRNA has been observed (Hurd et al., 2001). D1, D2 and D4 immunoreactivity is noted in GPi. The nigropallidal axons may be the source of the D2S immunoreactivity in GPi (Khan et al., 1998). 7.2.5.3.1.2. Glutamate receptors 7.2.5.3.1.2.1. Ionotropic receptors (a) AMPA/kainite. The GPi neurons express mRNA and protein for GluR1, GLuR2/3 and GluR4 subtypes, but among the kainate receptors, only for KA1 and KA2 receptors. The level of expression of mRNA and protein of only GluR1 but not other subtypes of GluRs is significantly decreased after 6-OHDA and MPTPinduced dopamine denervation in rats and primates as well as in PD (Bernard et al., 1996; Betarbet et al., 2000). (b) NMDA. The distribution pattern and intensity of expression of NMDA receptors in GPi are similar to those of GPe (Kosinski et al., 1998b). 7.2.5.3.1.2.2. Metabotropic receptors The pattern of expression of mGluRs in GPi may be very similar to that of GPe (Smith et al., 2001). 7.2.5.3.1.3. GABA receptors 7.8.9.1.2.3.1. Ionotropic receptors In GPi of primates, the distribution pattern of the different subunits of GABAA receptors is similar to that of GPe, with a high-intensity expression of mRNA for a1, b2 and g2 subunits and moderate to low intensity of expression of all other subunits. In PD, GABAA binding is moderately increased in GPi after the onset of dyskinesia and this increase is in conjunction with an increased expression of PPE A mRNA in the striatum (Calon and DiPaolo, 2002). 7.8.9.1.2.3.2. Metabotropic receptors In primate models of PD, GABAB binding is moderately increased in GPi after the onset of dyskinesia (Calon et al., 2003b). 7.2.5.3.1.4. Cholinergic receptors 7.2.5.3.1.4.1. Ionotropic (Nicotinic) receptors Receptor-binding studies using 125I-A85380, which has specific affinity for the a4b2 subtype of nicotinic receptors, show very little binding in human GPi (Quik et al., 2004). Autoradiographic studies using 125I-a conotoxin MII, which binds to the a6/a3 subtype of nicotinic receptors, show moderate intensity of binding in GPe and GPi (Quik et al., 2004).

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7.2.5.3.1.4.2. Metabotropic (muscarinic) receptors Among other basal ganglia structures, the m4 receptor protein is highly enriched in GPi. Because mAChR mRNAs are not detected in GPi (Weiner et al., 1990) the protein is probably synthesized and transported to the GABAergic terminals of the striatal projection neurons, which express m4 mRNA and protein (Yan et al., 2001). Another possibility, however, is that m4 is present on glutamatergic terminals derived from the subthalamus, which also expresses m4 mRNA. The mAChR-binding sites in GPi are substantially upregulated in PD, perhaps secondary to reduced cholinergic transmission from PPN (Griffiths et al., 1990). 7.2.5.3.1.5. Serotonin receptors The protein of 5-HT receptors is found in the target sites of the terminals of the striatal output neurons, including GPi (Barnes and Sharp, 1999). The 5HT2C subtype is denser in GPi than any other basal ganglia structure and this receptor is upregulated in PD (Nicholson and Brotchie, 2002). 7.2.5.3.1.6. Adenosine receptor The level of expression of mRNA for A2 is higher in GPe than GPi. A2-receptor levels are unchanged in GPi in PD (Calon et al., 2004). 7.2.5.3.2. Neuropeptide receptors 7.2.5.3.2.1. Opioid receptors The mRNA for m, but not k or d opioid receptor, has been localized to GPi neurons in human brains (Peckys and Landwehrmeyer, 1999). 7.2.5.3.2.2. Neurotensin receptors The protein for NTS2 receptor is found in GPi (Sarret et al., 2003a).

7.3. Neurochemistry of nuclei other than the basal ganglia in Parkinson’s disease 7.3.1. Spinal cord The spinal cord receives a mostly ipsilateral dopaminergic innervation specifically from the A11 group of dopamine neurons of the hypothalamus (Skagerberg and Lindvall, 1985), a noradrenergic projection from the locus ceruleus (Proudfit and Clark, 1991) and serotonergic afferents from the raphe system (Tork, 1990). Two small groups of TH-immunoreactive neurons intrinsic to the spinal cord are found, one at the level of the cervical enlargement that may be the spinal extension of the caudal medullary noradrenergic cells and another group exclusively at the first sacral segments that may be dopaminergic (Mouchet

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et al., 1986). The dopamine terminals are distributed diffusely throughout the laminae, but most intensely in the intermediolateral column, laminae III and IV, periependymal regions, sexually dimorphic cremaster nucleus and Onuf’s nucleus and the ventral horn of the rat, cat and monkey spinal cord (Holstege et al., 1996). The D1-receptors are localized in the ventral horn of the cervical and lumbar cord, suggesting a direct role for dopamine in the functions of motor neurons (Dubois et al., 1986). mRNA and the protein for D2-receptor are distributed in areas of the spinal cord that play a role in nociception, autonomic functions and sexually dimorphic motor neurons of the lumbosacral spinal cord (van Dijken et al., 1996). In PD, levels of norepinephrine and 5-HT are decreased, but not of dopamine (Scatton et al., 1986), consistent with the observation that >50% of neurons degenerate in locus ceruleus and the raphe system, but the hypothalamic dopaminergic neurons do not degenerate (see below). Lewy body formation and significant loss of neurons in the intermediolateral column of the cervical have also been observed in PD (Wakabayashi and Takahashi, 1997a, b). 7.3.2. Medullary catecholaminergic neurons The many groups of TH-immunopositive neurons at the level of rat and medulla oblongata (Kalia et al., 1985a, b; Saper et al., 1991) have been further defined to be either dopamine beta hydroxylase (DBH)-positive noradrenergic or phenylethanolamine N-transferase (PNMT)-positive adrenergic groups of cells. The ventrolateral A1/C1 group is closely linked to the nucleus ambiguus and the dorsomedial group of A2/C2 group is closely associated with the dorsomotor vagal nucleus and the nucleus solitarius. Significant numbers of neurons in these two groups are also heavily and lightly melanized cells (Saper et al., 1991; Gai et al., 1993). In PD among the noradrenergic A1 and A2 groups, lightly melanized neurons of A2 groups degenerate selectively and significantly (Saper et al., 1991) and the A1 group of noradrenergic neurons does not degenerate. Among the adrenergic neurons, although some investigators did not observe any degeneration (Saper et al., 1991), others noted a >50% loss of neurons in the C1 group (Gai et al., 1993). These observations suggest that the noradrenergic neurons in the medial regions of nucleus solitarius, which receive baroreceptor afferents from the carotid sinus (Saper et al., 1991), as well as the adrenergic sympathetic premotor neurons of the C1 group, degenerate significantly. Degeneration of the noradrenergic and adrenergic neurons of the medulla may be responsible for the severe autonomic manifestations of PD.

7.3.3. PPN and other nuclei of the cholinergic system Although PD is mostly considered a dopamine deficiency disease, recent studies have suggested that neurons of the cholinergic system also degenerate significantly. Several groups of neurons, extending from the pons to the forebrain, labeled intensely by choline acetyltransferase immunoreactivity, constitute the cholinergic system of the brain (cholinergic groups Ch1–Ch8) (Mesulam et al., 1984; Mufson et al., 1986). In PD, a marked degree of degeneration of neurons has been noted in almost all of the subnuclei of the cholinergic groups. 7.3.3.1. Pedunculopontine nucleus The PPN (Ch5 group) is located in the pontomesencephalic tegmentum. The rostral PPN is a part of the ascending reticular activating system that plays a role in cognitive and reward mechanisms (Inglis and Winn, 1995; Winn et al., 1997) and the caudal descending connections of PPN to the lower brainstem and the spinal cord play a major role as the mesencephalic locomotor center (Garcia-Rill, 1991; Pahapill and Lozano, 2000). Because of its intricate connections with the basal ganglia, it has been suggested that PPN should be included as a member of the basal ganglia family (Mena-Segovia et al., 2004). The PPN comprises the PPN compacta (PPNc) and PPN dissipata (PPNd) subdivisions. The PPNc contains large and medium-sized cholinergic neurons that constitute >60% of its cell population and PPNd consists of 25–75% of cholinergic cells (Pahapill and Lozano, 2000). These cholinergic neurons, unlike the cholinergic neurons in the forebrain Ch1–4 groups, do not express NGF receptor (NGFr) mRNA, but have a higher expression of NADPH than the forebrain cholinergic neurons (Mesulam et al., 1989). In PD, there is >50% loss of cholinergic neurons in lateral areas of PPNc (Hirsch et al. 1987; Jellinger, 1988; Zweig et al., 1989). The PPN also has neurons that express glutamate, GABA, dopamine and NADPH and it is not known whether the non-cholinergic neurons of PPN also degenerate in PD. 7.3.3.2. Nucleus basalis of Meynert (Ch4 group) Neurons of the Ch4 group are prominently labeled by markers of the cholinergic system and are the major source of cholinergic projections to the cerebral cortex (Mesulam et al., 1984). In PD, degeneration of Ch4 neurons is greater than in senile dementia of Alzheimer’s type (Candy et al., 1983). The percentage of loss of neurons in Ch4 in PD is reported to range between 37% and 68% (Rogers et al., 1985; Zarow et al., 2003).

NEUROCHEMISTRY OF PARKINSON’S DISEASE 7.3.3.3. Ch1–Ch3 groups Cholinergic neurons are distributed in the medial septal nucleus (Ch1) as well as in the vertical (Ch2) and the horizontal (Ch3) bands of the diagonal band of Broca. Along with the Ch4 group of Meynert neurons, the cholinergic neurons of Ch1–Ch3 also express mRNA for NGFr (Mufson and Kordower, 1989). In many cases of PD, there is a significant loss of neurons in the Ch1–Ch3 group of forebrain cholinergic neurons (Mufson and Kordower, 1989). Neurons of the lateral dorsal tegmental cholinergic group (Ch6 group) do not degenerate in PD (Hirsch et al., 1987) and it is not known whether cholinergic neurons of Ch8 of parabigeminal nucleus (Ch8 group) degenerate in PD. It is of interest to note that injection of MPTP does not result in loss of cholinergic neurons of nucleus basalis of Meynert, choline acetyltransferase or acetylcholinesterase immunoreactivity in the cerebral cortex (Garvey et al., 1986). It is not known whether MPTP causes degeneration of PPN and other brainstem cholinergic neurons. On the contrary, rotenone, an inhibitor of mitochondrial complex I similar to MPTP, causes diffuse degeneration of cholinergic neurons, including loss of neurons in PPN and the large aspiny cholinergic interneurons within the striatum (Hoglinger et al., 2003). 7.3.4. Locus ceruleus The locus ceruleus consists of 45 000–60 000 neurons (German et al., 1988; Baker et al., 1989). In PD, degeneration of locus ceruleus neurons is noted diffusely throughout the rostrocaudal extent of the nucleus (Chan-Palay and Asan, 1989; Chan-Palay, 1991). Even though almost all locus ceruleus neurons are melanized in the brain, only 60% of locus ceruleus neurons degenerate in PD (German et al., 1992) and the magnitude of loss is unrelated to the duration of the disease. The locus ceruleus is the major source of norepiephrine to the ipsilateral hypothalamus and the cerebral cortex. The different nuclei of the basal ganglia, especially the striatum, receive very few direct projections from locus ceruleus (Aston-Jones et al., 1995). A small noradrenergic projection from the medullary noradrenergic centers to the nucleus accumbens exists (Delfs et al., 1998). Noradrenergic terminals of locus ceruleus are present in the midbrain region and a loss of 80% of norepinephrine has been reported in SNpc in PD (Taquet et al., 1982). Even in advanced stages of PD, the loss of striatal norepinephrine is minimal when compared to dopamine and 5-HT (Wilson et al., 1996), suggesting a limited direct role for norepinephrine in striatal-mediated dysfunctions in PD. The larger decrease (>50%) of hypothalamic norepinephrine

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levels (Shannak et al., 1994) may contribute to the significant abnormalities of autonomic functions, attentional mechanisms and sleep–wake cycle noted in PD rather than the common motor manifestations of PD. 7.3.5. Raphe nucleus Based on neuronal connectivity the serotonergic system may be classified into several functionally distinct groups (Lowry, 2002). The dorsal raphe neurons (B5 group) that project to the basal ganglia are functionally distinct and respond to a group of cells that respond physiologically to altered muscle tone and sleep–wake and arousal states (Jacobs and Fornal, 1997). About 35% of neurons from the rostral and dorsal aspect of the dorsal raphe nucleus contribute to 80% of 5-HT in the different nuclei of the basal ganglia (Steinbusch et al., 1981). Consistent with the general pattern of a typical serotonergic neuron that sends afferents to functionally related targets by collateral branches, the dorsal raphe neurons provide the densest serotonergic projections to SN and of a gradually declining intensity to GPi, STN, GPe and the striatum by axon collaterals (Lavoie and Parent, 1990). Neuropathological studies using traditional techniques and immunocytochemical methods using antibodies specific to phenylalanine hydroxylase have confirmed that, in PD, the rostrally projecting system of dorsal raphe neurons degenerates the most (Halliday et al., 1990a; Paulus and Jellinger, 1991) and the degeneration of caudally projecting serotonergic neurons is less severe (Kovacs et al., 2003). The raphe neuron counts may be normal in the early stages of PD; the loss is significant in patients in late stages of PD but still not as severe as the dopaminergic neurons of SN. 7.3.6. Cerebellum Several lines of evidence suggest that the cerebellar functions may be influenced by the dopaminergic system. A reciprocal connection between the mesencephalic dopamine neurons and the cerebellum exists in rats (Perciavalle et al., 1989; Ikai et al., 1994) and TH and DAT immunoreactive fibers are present in the Purkinje and granule cell layers of the primate cerebellum and several other species of animals (Nelson et al., 1997; Melchitzky and Lewis, 2000). TH immunoreactivity is present in Purkinje cells of cerebellum and in mice TH-positive Purkinje cells are noted during the early stages of maturation of the cerebellum; the number of TH-positive cells increases during later stages (Fujii et al., 1994; Yew et al., 1995). The mRNA and protein for different subtypes of dopamine

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receptors have been localized to the cerebellar neurons (Bouthenet et al., 1991; Barili et al. 2000). This evidence strongly suggests a role for dopamine in the modulation of cerebellar functions. In PD, mRNA for TH, DAT, D1- and D3-, but not D2-receptors, is decreased in lobules IX and X (Hurley et al., 2003b). The cerebellum receives a prominent noradrenergic projection from the locus ceruleus. Along with a loss of >50% of locus ceruleus neurons in PD, the level of norepinephrine in the cerebellum of PD is significantly low (Kish et al., 1984).

decrease in the level of dopamine in the hypothalamus (Shannak et al., 1994). 3. The levels of peptides synthesized from proopiomelanocortin neurons, which are regulated by dopamine, are normal (Pique et al., 1985). The current evidence suggests that the hypothalamic dopamine neurons do not degenerate significantly in PD and the decrease of norepinephrine and 5-HT levels and not dopamine may contribute to some of the non-motor features that do not respond to traditional dopamine-promoting drugs in PD.

7.3.7. Hypothalamus

7.3.8. Retinal amacrine cells

Earlier studies have raised the possibility that hypothalamic pathology may contribute to hormonal as well as autonomic dysfunctions in PD. The presence of Lewy bodies in the tuberoinfundibular and lateral hypothalamic regions (Langston and Forno, 1978), decreased level of dopamine (Javoy-Agid et al., 1984) and alteration in dopamine-mediated release of growth hormone have been considered as indicators of hypothalamic dysfunction in PD. The arcuate nucleus and the paraventricular nucleus of the hypothalamus are the two major subgroups of neurons that consist of TH-positive neurons that synthesize dopamine and exhibit DAT immunoreactivity (Spencer et al., 1985; Cerruti et al., 1993). A small proportion of cells in these two subnuclei also contain neuromelanin (Spencer et al., 1985). In the paraventricular nucleus of the hypothalamus, oxytocin and vasopressin are colocalized within the TH-positive neurons (Purba et al., 1994). Dopaminergic terminals from these two groups densely innervate the hypothalamic neurons that synthesize different peptides of the proopiomelanocortin family, vasopressin and oxytocin in the supraoptic and paraventricular nuclei, and gonadotrophic and growth hormone and their releasing factors in the tuberoinfundibular regions of the hypothalamus. Recent studies suggest that, in the hypothalamus of PD:

A significant number of amacrine and interplexiform cells in the retina are TH-, GABA- and NOS-positive (Nguyen-Legros, 1988; Crooks and Kolb, 1992; Andrade de Costa and Hokoc, 2003) and multiple dopamine receptors are distributed throughout the retina (Djamgoz et al., 1997; Nguyen-Legros et al., 1999). Dopamine plays a significant role in visual acuity, spatial sensitivity and color vision (Djamgoz et al., 1997). Injections of MPTP in mice produce dose-dependent but reversible loss of TH-positive amacrine but not cholinergic cells of the retina (Tatton et al., 1990). The level of retinal dopamine is decreased in untreated PD due to loss of TH-immunoreactive amacrine cells and dopamine level normalizes after levodopa administration (Harnois and DiPaolo, 1990).

1. Even though there is a slight loss in the number of oxytocin-expressing neurons, the number of TH-immunoreactive neurons in the paraventricular nucleus of the hypothalamus (Purba et al., 1994) as well as dopamine neurons of the arcuate nucleus of the hypothalamus is normal (Matzuk and Saper, 1985; Uhl, 2003). 2. A study of region-specific changes of levels of monoamines in the hypothalamus showed marked lowering of norepinephrine levels (>50%), a moderate decrease of 5-HT levels in the intermediate regions of the hypothalamus and an insignificant

7.3.9. Olfactory system Patients with PD suffer from hyposmia, a feature of PD that may actually precede the onset of motor dysfunction by several years (Berendse et al., 2001; Ponsen et al., 2004). Hyposmia is unrelated to the duration of the disease and is unaltered after levodopa treatment (Doty et al., 1988). Dopaminergic neurons are scattered in many areas of the olfactory bulb, but 98% of the TH-immunoreactive cells are located in and around the glomerular region (Smith et al., 1991). A recent study has demonstrated a 100% increase in the TH-immunoreactive cells in the olfactory bulb of PD patients (Huisman et al., 2004). The increase but not decrease in the number of TH cells in olfactory bulb in patients who have had long-term treatment with levodopa clearly suggests that levodopa is not toxic, at least to the dopaminergic neurons of the olfactory bulb. The precise function of dopamine in olfactory bulb remains to be established. It has been supposed that hyposmia noted in PD may be due to too much dopamine suppressing the sense of smell (Huisman et al., 2004). On the contrary, it has also been proposed that

NEUROCHEMISTRY OF PARKINSON’S DISEASE hyposmia of PD may be due to a decrease in the motor component of olfaction – sniffing – and not due to abnormalities of the sensory component of olfaction – smelling (Sobel et al., 2001). 7.3.10. Other areas Significant loss of neurons and formation of Lewy body and ubiquitin filaments have been identified in the central and basolateral nuclei of the amygdale. This abnormality is more severe in patients with PD who are demented than in non-demented PD patients (Harding et al. 2002). A 30–40% loss of neurons in the caudal centromedianum (CM)–parafascicular (PF) complex of the thalamus has been reported. Of the PF neurons, there was a 50% loss of parvalbumin-positive neurons and 70% loss of non-parvalbumin-positive neurons in CM. The neurons of the dorsomedial nucleus, which is adjacent to the CM–PF complex, do not degenerate in PD (Henderson et al., 2000a, b). Loss of corticocortical projecting pyramidal neurons in the presupplementary motor area has also been recognized (MacDonald and Halliday, 2002). The cerebral cortex is a major destination site for noradrenergic, serotonergic and dopaminergic projections. The pattern of termination of projections from the monoaminergic brainstem nuclei varies from one cortical site to another. Progressive degeneration of neurons of locus ceruleus, dorsal raphe and the A8 and A10 dopaminergic system that project to the cerebral cortex via axon collaterals leads to decreased levels of monoamines in functionally different cortical areas in PD and MPTP-induced primate models of PD. In primate models of MPTP-induced PD, the gradient of loss of cerebral cortical monoamines is norepinephrine > 5-HT > dopamine (Pifl et al., 1991). The pattern of loss of monoamines in the cerebral cortex in primates is in contrast to the dopamine > 5-HT > norepineprhine pattern of loss of monoamines observed in the basal ganglia of PD. It is not unreasonable to consider that loss of monoamines in the cerebral cortex must be playing a major role in alertness, attentional and cognitive dysfunctions of PD.

7.4. Neurochemical alterations in neural tissue outside the central nervous system The Lewy body, a classic neuropathological hallmark of PD, is present prominently in SN, locus ceruleus and other brainstem nuclei that degenerate in PD. Ubiquitin and a-synuclein are the primary constituents of Lewy body, but proteins from many other sources are also incorporated into a Lewy body (Rao, 2003). Lewy body and a-synuclein-positive neurites are present

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in the sympathetic ganglion, enteric nervous system, sinoatrial node in the heart and cardiac plexus (Wakabayashi et al., 1990, 1993; Iwanaga et al., 1999; Okada et al., 2004b) and may contribute significantly to the cardiac (Goldstein et al., 2000), visceral and other autonomic dysfunctions that are very common in PD (Siddiqui et al., 2002).

7.5. Neurochemical alterations in non-neural tissue 7.5.1. Lymphocytes Peripheral lymphocytes do synthesize dopamine (Musso et al., 1996) and express D1, D2, D3, D4 and D5 dopamine receptors (Takahashi et al., 1992; Bondy et al., 1996; Nagai et al., 1996; Meredith et al., 2005), and in PD, the levels of TH, dopamine and DAT are decreased (Caronti et al., 1999, 2001). A significantly increased level of D1- and D2-receptors (Barbanti et al., 1999) and normal level of D5 have been noted in the peripheral lymphocytes of PD. The levels of D3-receptor, however, are decreased in direct proportion to the duration of the disease (Nagai et al. 1996). The lymphocytes also demonstrate a decrease in nicotinic but not muscarinic receptor-binding sites (Adem et al., 1986). Besides these receptor changes, several markers of apoptosis are also significantly altered in the lymphocytes of treated and untreated PD (Blandini et al., 2003, 2004). Measurements of markers of dopamine metabolism and apoptotic factors in the lymphocytes may become a potential tool for early diagnosis and monitoring the progression of PD in the future.

7.6. Conclusion The spectrum of clinical features of PD is due to progressive degeneration of midbrain dopaminergic neurons and other areas of the brain. The neurochemical alterations in PD can be broadly classified into three categories: (1) neurochemical changes in the basal ganglia; (2) neurochemical changes in the rest of the central nervous system; and (3) neurochemical changes in ‘non-neural’ tissue. 7.6.1. Neurochemical changes in the basal ganglia The neurochemical changes noted in the basal ganglia can be summarized as follows. 1. The profound loss of dopamine and its consequences observed, not just in the striatum, but also in both segments of GP and the STN, dominate the neurochemical pathology in the basal ganglia. Loss of >50% 5-HT in the striatum adds to the

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2.

3.

4.

5.

6.

7.

J. RAO clinical spectrum of PD in the later stages of the disease. The melanized dopaminergic neurons of SNpc and VTA are selectively more vulnerable to neurodegeneration than the dopaminergic neurons of other areas of the brain. A high DAT-to-VMAT2 ratio is neurotoxic and a high VMAT2-to-DAT ratio is neuroprotective. The neurochemical alterations observed in SNpc and VTA, in most part, reflect the consequences of cell death. Increased mitochondrial stress may be a key factor in the degeneration of the dopaminergic neurons in SNpc and VTA. The modern-day proteinomic studies (Grunblatt et al., 2004), although confirming many of the earlier observations of molecular and neurochemical pathology, have so far not revealed any dramatic clues to the cause(s) of degeneration of SNpc and VTA neurons. More recent studies have suggested that several molecular properties that are unique to the dopaminergic neurons of SNpc might contribute to an increased vulnerability of SNpc cells for neurodegeneration than the dopamienegic neurons of VTA (Rao, 2007). A slowly progressive dopamine denervation of the striatum results in an all-out effort to maintain homeostasis by synthesizing more dopamine intrinsically by the striatum, but these efforts are inadequate to compensate for the relentlessly progressive degeneration of DA neurons of SNpc. The compensatory changes include increased levels of glutamate and GABA as well as hypersensitivity of glutamate and dopamine receptors in the striatum (Table 7.2). Dopamine denervation and chronic levodopa administration affect the indirect and the direct pathways differently. A combination of presynaptic and postsynaptic mechanisms contributes to the wearing-off phenomenon and dyskinesia. Chronic levodopainduced dyskinesia is associated with a significant increase in the expression of preprodynorphinderived peptides. The neurochemical changes in the two pallidal segments and STN and the precise roles played by these subnuclei of the basal ganglia in normal and disease states remain to be elaborated further. Clinically, depletion of almost 98% of dopamine in the motor striatum, 95% in the associative striatum and >50% of dopamine in the limbic striatum may lead to a lack of reinforcement of the motor, cognitive and emotional components of procedural memory that is required to face an acute chal-

lenge, resulting in bradykinesia, bradyphrenia and amotivational state, the three salient features of PD. 7.6.2. Neurochemical changes in the rest of the central nervous system The neurochemical changes in PD are mostly, but not exclusively, in the basal ganglia. Even though dopamine denervation in the basal ganglia is the predominant feature of PD, it is important to emphasize that the decreased levels of monoamines in the cerebral cortex, hypothalamus, brainstem and spinal cord could play an equally formidable role in PD. The decrease in norepinephrine level is >50% in PD. This decrease is not noted in the basal ganglia but is more prominent in the cerebral cortex, hypothalamus, lower-brainstem nuclei and the spinal cord. The loss of norepinephrine to the cerebral cortex is compounded by the loss of serotonergic innervations to the cerebral cortex, hypothalamus and the basal ganglia and a higher level of histamine in the different nuclei of the basal ganglia (Fig. 7.1 on page 176). The common denominator among the locus ceruleus, raphe, and tuberomamillary and PPN systems is that these nuclei are organized into an ‘oral’ system that consists of neurons that are located rostrally within the nuclei, project rostrally and terminate predominantly in the hypothalamus, thalamic nuclei and in functionally diverse regions of the entire cerebral cortex. These nuclei also consist of a well-defined ‘caudal’ projection system that has intricate connections with the oculomotor nuclei, reticular formation, lower-brainstem autonomic centers and spinal cord. The noradrenergic system of locus ceruleus, the serotonergic system of raphe and the cholinergic system of the brainstem are individual components of the ascending reticular activating system and play an important role in alertness, attention, sleep–wake cycle, cognitive and reinforcement behavior. The histaminergic system has been speculated to play an equally important role in sleep–wake phenomena and hibernation. The caudal projection system has a profound influence on coordinated movements of the neck and the eyes, the motor and non-motor functions of the reticular formation, the brainstem autonomic centers and the outflow systems of the spinal cord. The attention, awake, alert and sleep, anxiety and several other non-motor manifestations of PD may be attributed to degenerations of neurons in the ‘oral’ system and degeneration of neurons in the caudal system may contribute to dysautonomia, oculomotor and balance dysfunctions.

Table 7.2

Neurotransmitters Dopamine Norepineprhine Serotonin Histamine Acetylcholine Glutamate GABA Neuropeptides Enkephalin Dynorphin Substance P Cholecystokinin - 8 Neurotensin NPY Somatostatin

SN

Striatum

Gpe

STN

Gpi

Hypothalamus

Spinal cord

Cerebellum

Cerebral cortex

### #### ### ""

#### Unchanged ## ""

###

##

##

# """

#

# ""

# ### ##

Unchanged ## ##

# ##

# #### ##

Unchanged Unchanged

"" ""

Unchanged ""

" Unchanged

Unchanged ""

Unchanged Unchanged #-" Undetectable ""

" - "" "" #-" " " " "

"

""" ""

#

NEUROCHEMISTRY OF PARKINSON’S DISEASE

Changes in the levels of neurotransmitters and neuropeptides in PD

References in text. Neurotransmitter changes in MPTP model of PD are similar (Pifl and Hornykiewicz, 1998).

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Other features that are common to the pattern of degeneration among these brainstem nuclei are: (1) the degree of loss of neurons in these nuclei is not as severe as in the dopaminergic neurons of SNpc and VTA; (2) both melanized and unmelanized neurons of the brainstem degenerate; and (3) in most, if not all, patients, the non-motor consequences resulting from degeneration of these brainstem neurons are not that severe in the early stages of the disease. However, as the disease progresses, disability arising from the non-motor manifestations are as severe as the motor dysfunctions and less responsive to traditional treatments. The observations summarized above also demand a re-evaluation of our medical approach to PD. The class of drugs that is most commonly used in the modern-day treatment of PD are drugs that promote dopaminergic transmission. A comprehensive and more aggressive treatment with the addition of those drugs that enhance noradrenergic, serotonergic and cholinergic neurotransmission may actually provide a more global improvement of both motor and non-motor features of human PD than our current approach. This point of view is strongly supported by the original observations of Carlsson and his associates (1957) that the improvement of ptosis and lethargy noted in reserpinized animals was ‘more complete and longer-lasting’ if a mixture of an equal amount of 5-hydroxytryptophan and dopa was administered rather than when dopa was administered alone. 7.6.3. Neurochemical changes in ‘non-neural’ tissues Even though degeneration of the dopaminergic neurons is the predominant feature of human PD, several groups of neurons outside the basal ganglia and neurites outside the brain as well as peripheral lymphocytes demonstrate significant degeneration and/or neurotransmitter changes that are parallel to the changes noted in SN. The etiologic factors that cause degeneration of the melanized nigral neurons appear not to be specific to the dopaminergic neurons of SN and VTA, but appear to induce neuronal loss in the entire monoaminergic system, the cholinergic system and even in extraneural tissue such as the lymphocytes. Since the original observation localizing dopamine in the central nervous system almost 50 years ago, our knowledge of the neurochemical basis of human PD has gradually evolved to enable us to develop a medical treatment for PD that has significantly reduced the mortality and morbidity of the disease.

Within the next few decades, the emerging more sensitive technologies will assist us to identify the cause(s) of human PD and to manipulate the molecular cascades involved in the nigral cell death to develop innovative treatment modes that are truly neuroprotective and neuroregenerative.

Acknowledgments This chapter is dedicated to Bill Koller. The author has been supported by the Grace and Tom Benson Parkinson’s disease research fund.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 8

The neuropathology of parkinsonism DANIEL P. PERL* Mount Sinai School of Medicine, New York, NY, USA

8.1. Introduction A variety of disorders of the nervous system result in parkinsonian symptoms. Virtually all involve damage to various components of the basal ganglia. Some of these conditions are rather common whereas others are exceedingly rare. Here, the neuropathologic features of many of these conditions will be summarized. First and foremost will be a discussion of the neuropathologic finding in cases of Parkinson’s disease, the prototype condition. Some of the other, better-characterized forms of parkinsonism will then be reviewed.

8.2. Parkinson’s disease (paralysis agitans) James Parkinson’s 1817 classic monograph An Essay on the Shaking Palsy is well known for its elegant description of the clinical features of the disorder that would ultimately bear his name (Parkinson, 1955, originally published 1817). However, it also includes Parkinson’s comment that he was reluctant to speculate on the nature and cause of the disease he was describing. This hesitation was caused by the fact that, as he noted, he was hampered ‘not having had the advantage, in a single case, of that light which anatomical examination yields’. At the time little neuropathologic expertise was available and it would be almost 100 years until some of the underlying anatomical features would first be identified. Indeed, in the later portion of the 19th century, Jean-Martin Charcot failed to find a characteristic abnormality in the brains of patients who had suffered from Parkinson’s disease. Based on his inability to recognize an identifiable neuropathologic lesion, Charcot began to lecture that Parkinson’s disease might be functional in nature. It was not until 1912 that Frederick Lewy first described the diagnostic

intranuclear inclusion body associated with Parkinson’s disease (Lewy, 1912). Interestingly, Lewy’s descriptions of the inclusions that bear his name were first seen in neurons of the substantia innominata and the dorsal motor nucleus of the vagus but in his original report he failed to recognize their presence in the substantia nigra pars compacta. It was not until 1919, in Tre´tiakoff’s thesis at the University of Paris (Tre´tiakoff, 1919), that the importance of involvement of the substantia nigra pars compacta in cases of Parkinson’s disease, especially with involvement by Lewy bodies, first became recognized. It would be many decades until the neuroanatomic and neurochemical details of basal ganglia structure and function would eventually become clarified, ultimately leading to the introduction of the primary form of therapy for the disease, levodopa, and then to other secondary forms of treatment that are currently in use. 8.2.1. Gross morphologic abnormalities In patients with Parkinson’s disease the gross external appearance of the brain does not reveal any distinguishing features. However, on further dissection of the specimen, the cut surface of the midbrain reveals a loss of pigmentation of the substantia nigra that is readily apparent (Fig. 8.1). This loss of pigmentation may be complete or, more commonly, partial. When some visible pigmentation remains in the substantia nigra aside from a lessening of the black coloration, there is typically some blurring of its edges. In such cases the observer may be forced to compare this appearance to that of a normal brain in order to verify the presence of pigmentary loss. The locus ceruleus is similarly depigmented in almost all cases. Importantly, the gross appearance of the globus pallidus, caudate nucleus and putamen remains intact and these important basal ganglia structures are

*Correspondence to: Daniel P. Perl, MD, Professor of Pathology (Neuropathology), Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1134, New York, NY 10029, USA. E-mail: [email protected], Tel: þ1-212-241-7371, Fax: þ1-212-996-1343.

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Fig. 8.1. Gross appearance of the midbrain, two levels, in a case of Parkinson’s disease. Notice the lack of pigmentation of the substantia nigra pars compacta.

without significant shrinkage, discoloration or changes in consistency. 8.2.2. Microscopic features 8.2.2.1. Substantia nigra pars compacta Within the substantia nigra pars compacta there is dramatic loss of pigmented neurons. However, the neuronal loss is not complete and isolated neurons or groups of neurons will remain intact (Fig. 8.2). The neurons

that are lost are dopaminergic and provide input to the striatum by way of the nigrostriatal pathway. Within the remaining neurons, some will contain large spherical brightly eosinophilic inclusion bodies, which are referred to as Lewy bodies (see below). Neuromelanin pigment derived from neurons that have been lost will be found in the nearby neuropil where it is referred to as incontinent pigment. Additionally, some of this pigment will have been phagocytosed by local macrophages (Fig. 8.3). It appears that macrophages are incapable of fully breaking down the neuromelanin and this pigment will remain visible within the macrophage cytoplasm. Finally, within the substantia nigra one can identify a variable degree of gliosis, although reactive astrocytes are rarely encountered in the region, even when there is evidence of severe neuronal damage. 8.2.2.2. Locus ceruleus and other locations The pigmented neurons of the locus ceruleus undergo a process of neurodegeneration, incontinent pigment and Lewy body formation that is virtually identical to that seen in the substantia nigra pars compacta. Although Parkinson’s disease is generally considered to be a disorder of dopamineric neurons, these adrenergic neurons appear to go through a similar form of neurodegeneration. Furthermore, in cases of Parkinson’s disease

Fig. 8.2. For full color figure, see plate section. Photomicrograph of substantia nigra pars compacta of a case of Parkinson’s disease (left panel) and control (right panel). Hematoxylin and eosin stain.

THE NEUROPATHOLOGY OF PARKINSONISM

Fig. 8.3. For full color figure, see plate section. Photomicrograph of substantia nigra pars compacta of a case of Parkinson’s disease. Neuromelanin pigment is seen in the cytoplasm of macrophages and incontinent in the neuropil. Hematoxylin and eosin stain.

neurodegeneration and Lewy body formation are encountered in neurons of the basal forebrain (basal nucleus of Meynert), despite the fact that these cells are cholinergic and non-pigmented. A number of other brain regions show evidence of neurodegeneration in cases of Parkinson’s disease, including the olfactory bulbs, dorsal motor nucleus of the vagus and glossopharyngeal nerves, amygdale and neocortex (see below). 8.2.2.3. Lewy bodies In Parkinson’s disease, Lewy bodies are encountered in some of the remaining intact neurons within areas of neurodegeneration. Identification of their presence in remaining pigmented neurons in the substantia nigra pars compacta is considered to be essential to making a diagnosis of the disease. Lewy bodies are relatively large intracytoplasmic inclusions, measuring 4–30 mm in diameter. They have a rather uniform hyaline eosinophilic appearance and at times are surrounded by a halo of paler concentric rings (Fig. 8.4). The inclusions are usually solitary, although within the substantia nigra and, in particular, the locus ceruleus, multiple inclusions may be encountered within the same neuron. The number of Lewy bodies encountered in the substantia nigra does not correlate with the severity of disease or its duration. Indeed, in situations where there has been severe neuronal loss, there may be so few neurons remaining that only a few cells exist in which these lesions might be found. It is in such cases that one may be left with a clinical diagnosis of Parkinson’s disease and evidence of severe nigral neuronal loss, and yet be unable to identify a Lewy body.

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Fig. 8.4. For full color figure, see plate section. Photomicrograph of neuron in the substantia nigra pars compacta of a case of Parkinson’s disease showing a Lewy body with prominent internal concentric ring formation. Hematoxylin and eosin stain.

In such a situation one is urged to exhibit patience and search with diligence as well as examine additional sections of substantia nigra and locus ceruleus in order to make the diagnosis. The locus ceruleus generally shows a less complete loss of neurons when compared to the substantia nigra and therefore is a good site to examine for the presence of Lewy bodies. If after careful examination of these sections a Lewy body still cannot be identified, then an alternative diagnosis must be considered. Lewy bodies are composed primarily of a-synuclein, a 140-amino-acid protein which is a normal constituent of the presynaptic apparatus (Spillantini et al., 1997). Immunohistochemical preparations using antibodies raised against a-synuclein typically show a ring of immunoreactivity at the periphery of the inclusion body (Fig. 8.5). Lewy bodies also stain for ubiquitin, indicating that the aggregated proteins have been tagged for degradation by the ubiquitin-proteosome system (McNaught et al., 2001; Dawson and Dawson, 2003; Snyder and Wolozin, 2004). The use of immunohistochemical preparations employing antibodies raised against either a-synuclein or ubiquitin has demonstrated that most cases of Parkinson’s disease show a rather widespread distribution of intraneuronal inclusions. Ultrastructurally, the central core of the inclusion consists of densely arranged filaments in association with electron-dense granular material (Forno, 1996). The outer ring of the Lewy body contains a radially arranged halo of 7–20 nm intermediate filaments along with electron-dense granular material and vesicular profiles. An additional finding encountered in areas of neurodegeneration is that of Lewy neurites. These are enlarged, dysmorphic neuronal processes (neurites) that stain for ubiquitin and a-synuclein and are found in regions undergoing neurodegeneration (Fig. 8.6).

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Fig. 8.5. For full color figure, see plate section. Photomicrograph of neuron in the substantia nigra pars compacta of a case of Parkinson’s disease showing a Lewy body. a-Synuclein immunostain. Notice the peripheral decoration of the inclusion.

Fig. 8.6. For full color figure, see plate section. Photomicrograph of amygdala of a case of Parkinson’s disease showing a Lewy body. a-Synuclein immunostain demonstrates Lewy bodies in neurons as well as Lewy neurites in the neuropil.

They are best seen in the substantia nigra pars compacta, dorsal motor nucleus of the vagus, the nucleus basalis of Meynert and in the CA2–3 region of the hippocampus. In the process of the neuropathologic examination of brain specimens derived from elderly individuals, one encounters cases which display Lewy bodies within neurons of the substantia nigra but with no accompanying clinical history of a diagnosis of Parkinson’s disease or even clinical reports of parkinsonian features being present. Such cases are typically associated with a more modest degree of neuronal loss in the substantia nigra. Indeed, in some cases accompanying evidence of neuronal loss may be difficult to demonstrate. These specimens are typically referred to as representing incidental Lewy body cases (Forno, 1969). It is generally felt that these represent individuals with preclinical forms of

Parkinson’s disease and that individuals showing these changes at the time of death had not yet accumulated a sufficient burden of neurodegeneration to attract clinical attention. It is further assumed that had such patients survived longer, they would have progressed to become more overtly symptomatic and been clinically diagnosed with the disorder. In recent years, Braak and colleagues (2003) studied the distribution of Lewy body formation and demonstrated a widespread pattern of involvement extending well beyond the usually cited pigmented neurons of the brainstem. They have also further defined the distribution of Lewy bodies and Lewy neurites in incidental Lewy body cases. By studying brains derived from large numbers of autopsies, they propose a progressive process of successive brain involvement by Parkinson’s disease pathology that they have classified into six sequential stages (Braak et al., 2003). The initial stage (stage 1) involves Lewy bodies that are confined to the dorsal motor nuclei of the vagus and glossopharygeal nerves of the medulla. Stage 2 demonstrates the features of stage 1 plus involvement of the caudal raphe nuclei and the locus ceruleus and subceruleus. Stage 3 shows the preceding pathology plus involvement of the substantia nigra pars compacta. Following this, stage 4 demonstrates involvement of transentorhinal cortex and CA2 of the hippocampus. Stages 5 and 6 demonstrate progressively increasing involvement of the neocortex. Importantly, their data indicate that this stepwise, progressively more widespread involvement is rather stereotypic with little variation among the numerous cases they examined (Del Tredici et al., 2002). These studies are based on a-synuclein immunostaining of numerous regions of autopsy-derived cases. All of the cases that had been clinically diagnosed as Parkinson’s disease were at least at stage 3, suggesting that the clinical features associated with the two earlier stages are either extremely subtle or truly silent clinically. The involvement of cerebral cortical neurons by Lewy bodies is a phenomenon that has become increasingly recognized through the ability to identify such lesions readily using immunohistochemical methods. These inclusions are referred to as cortical Lewy bodies and are difficult to locate using routine morphologic stains such as hematoxylin and eosin, but, using either antiubiquitin or a-synuclein antibodies, a very high percentage of cases of Parkinson’s disease will show evidence of some cortical Lewy body involvement. Indeed, some have claimed that involvement is universal if these lesions are carefully searched for (Hughes et al., 2001), In some cases the extent and distribution of cortical Lewy body formation are considerable and in such cases dementia is generally encountered clinically.

THE NEUROPATHOLOGY OF PARKINSONISM 8.2.3. Genetic forms of Parkinson’s disease In the vast majority of cases of Parkinson’s disease, the disease is considered to be sporadic and its etiology remains unknown, but on rare occasions the disease is encountered in a familial fashion and appears to be inherited as a simple mendelian trait. In such instances the age of onset tends to be younger than in the sporadic form and atypical clinical features are more commonly seen. In recent years, a number of genetic loci have been linked to the appearance of cases in such familial cases. These genetic loci are referred to as PARK1–PARK9 and these various familial forms are associated with either an autosomal-dominant or recessive inheritance pattern (West and Maidment, 2004). To date, only a small number of such cases have been subjected to autopsy and reported in the literature. In the coming years, further information regarding the neuropathologic substrate associated with each locus will yield important insights. In 1997, Polymeropolous et al. (1996, 1997) identified a mutation of the gene encoding for the protein asynuclein in a number of large families of Greek or Sicilian ancestry with autosomal-dominant Parkinson’s disease. With this information, it was subsequently determined that a-synuclein represents the major protein constituent of the Lewy body (Spillantini et al., 1997). Study of numerous cases of sporadic Parkinson’s disease has failed to show the presence of mutations within the asynuclein gene (Chan et al., 1998; Warner and Schapira, 1998). However, additional a-synuclein gene mutations have now been identified in other kindreds and these cases are collectively referred to as PARK1. Several of these cases have now undergone autopsy and degeneration of the substantia nigra pars compacta with Lewy bodies in remaining neurons has been described. In other cases dementia has also been noted and in these cases extensive, widespread Lewy body formation, including prominent involvement of the cerebral cortex, has been described. Mutations of the gene encoding parkin (PARK2) are associated with juvenile-onset parkinsonism (i.e., onset less than 30 years of age) and, although autopsies have shown evidence of nigrostriatal degeneration, this has been without the presence of Lewy bodies. Whether such cases should be referred to as examples of familial Parkinson’s disease is a matter of debate in the literature since, as noted above, the diagnosis of sporadic Parkinson’s disease requires the presence of this inclusion body. In other Parkinson’s disease kindreds, linkage has been made to another genetic locus (2p13 or PARK3) where inheritance is seen in an autosomal-dominant pattern. In these cases the onset of disease is approximately 60 years of age, with a tendency for demen-

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tia to develop in association with the parkinsonism. Neuropathologic findings have included neuronal loss in the substantia nigra pars compacta accompanied by Lewy bodies plus evidence in the cerebral cortex of Lewy bodies and Alzheimer’s disease changes (neurofibrillary tangles and senile plaques) (Denson et al., 1997; Wszolek et al., 1999). Most of the other familial parkinsonism kindreds with reported other genetic loci have not yet had autopsy findings described in the affected family members.

8.3. Postencephalitic parkinsonism In 1917–1918, Constantine Von Economo, an Austrian neurologist practicing in Vienna, began to notice patients who developed a form of encephalitis that was associated with extreme somnolence (Von Economo, 1931). The degree of somnolence was so severe that many of the patients affected by the disorder fell asleep in midsentence while talking, or while eating. The patients showed other signs and symptoms, including slowness of movement, psychiatric disturbances and a wide range of other neurologic abnormalities. Noting the prominent tendency to sleepiness, Von Economo referred to it as encephalitis lethargica. Soon after his initial description, numerous other cases began to be reported in additional locations in the world. Ultimately, the distribution of the disease spread until it was encountered in virtually every major city in the world. The disease was acutely fatal in about one-third of cases and at autopsy showed the typical features of viral encephalitis with perivascular inflammatory cell infiltrates accompanied by focal neuronal death with neuronophagia. The primary region affected by the acute encephalitis was the midbrain. Although the cause of the outbreak was never identified, it is presumed that the disease was due to a neurotropic virus. Although the pandemic of encephalitis lethargica temporally overlapped, to some degree, with the great influenza pandemic of 1917 (the ‘Spanish flu’), there is not convincing evidence that this form of highly fatal influenza virus was also responsible for the cases of encephalitis lethargica (Ravenholt and Foege, 1982). Encephalitis lethargica continued in repeated waves until about 1928, and was rarely seen thereafter. In all, it is estimated that approximately 1 million patients developed encephalitis lethargica worldwide. Of the two-thirds of patients who suffered from encephalitis lethargica and survived the acute attack, virtually all subsequently developed a severe chronic parkinsonian syndrome which is referred to as postencephalitic parkinsonism. The time interval between their recovery from the acute encephalitis to the development of parkinsonism varied from a few months to over 20 years. An interval of 1 or 2 years was said to have been

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typical. The clinical features of postencephalitic parkinsonism could include virtually any sign or symptom encountered in cases of idiopathic Parkinson’s disease. It had been claimed that the presence of oculogyric crises represented a distinguishing sign of postencephalitic parkinsonism; however, these may also be seen in some cases of Parkinson’s disease (Yahr, (1968)). The gross appearance of the brain in postencephalitic parkinsonism is indistinguishable from that of Parkinson’s disease, with apparent pallor of the substantia nigra and locus ceruleus. Microscopically, there is severe neuronal loss in the substantia nigra pars compacta and locus ceruleus. In the few surviving pigmented neurons one sees neurofibrillary tangles rather than Lewy bodies (Hallervorden, 1935; Greenfield and Bosanquet, 1953). Since these neurons are large and rounded, as opposed to the pyramidal shape of cerebral cortical neurons, these neurofibrillary tangles take on a swirling rounded configuration and are referred to as globoid tangles. As noted above, it is usually stated that Lewy bodies are not seen in postencephalitic parkinsonism cases, but this represents an oversimplification. Some cases of non-postencephalitic idiopathic Parkinson’s disease, especially when seen in the advanced elderly, may show some globoid tangles in nigral neurons (along with Lewy bodies). Similarly, there are well-documented cases of postencephalitic parkinsonism where both neurofibrillary tangles and Lewy bodies were noted in the pigmented neurons (Greenfield and Bosanquet, 1953). Nevertheless, the predominance of the neuronal inclusion pathology represents a reliable means by which these two entities may be distinguished. For patients with postencephalitic parkinsonism who have survived for many years there is a tendency to demonstrate extensive neurofibrillary tangle formation in the hippocampus, entorhinal cortex and the neocortex, in general. The involvement by tangles in the neocortex tends to involve the superficial cortical layers, as opposed to the deeper-layer involvement that is seen in Alzheimer’s disease (Hof et al., 1992). With the passage of time, clinical examples of cases of postencephalitic parkinsonism have become quite rare and, similarly, postmortem diagnoses are now exceedingly uncommon. Nevertheless, occasional rare cases are still encountered and the possibility remains of another pandemic in the future.

had been considered to be separate neurologic conditions and this was an attempt to combine what had been a rather diverse nosology. The conditions included olivopontocerebellar atrophy, Shy–Drager syndrome and striatonigral degeneration. Although used by some, this attempt at a more encompassing nosology was, at the time, on somewhat shaky ground until the finding of Papp and Lantos that all of these disorders were linked by the presence of glial cytoplasmic inclusions (Papp et al., 1989). Based on this neuropathologic finding, the all-encompassing term ‘multiple system atrophy’ received biologic confirmation and is now rather widely accepted. Cases of MSA display various combinations of parkinsonism, cerebellar and pyramidal signs and/or autonomic failure. Clinically, patients with MSA are subclassified as having either predominantly parkinsonian features (referred to as MSA-P) or predominantly cerebellar dysfunction (referred to as MSA-C). The overwhelming majority of MSA patients show some features of parkinsonism and many will also display evidence of autonomic failure in the form of orthostatic hypotension, impotence and urinary problems. The gross appearance of the brain in cases of MSA will depend on the clinical predominance, with cases displaying predominantly parkinsonian features (that is, MSA-P) having shrinkage and gray-brown discoloration of the putamen (Fig. 8.7). Loss of pigmentation of the substantia nigra pars compacta and locus ceruleus is also generally noted. However, in cases with a clinical predominance of cerebellar dysfunction (MSA-C), there will be evident atrophy of the cerebellar cortex as well as a variable degree of atrophy of the cerebellar peduncles, the pons and inferior olives. Upon microscopic examination, there will be a variable degree of neuronal loss with accompanying gliosis in the areas of atrophy noted above. In the substantia

8.4. Multiple system atrophy ‘Multiple system atrophy’ (MSA) was a term that was introduced by Graham and Oppenheimer (1969) to refer collectively to several diverse hereditary and sporadic system degenerations involving aspects of the basal ganglia and other neuroanatomic sites. Previously, these

Fig. 8.7. Gross appearance of the cut surface of the basal ganglia in a case of multiple system atrophy showing graybrown discoloration of the putamen.

THE NEUROPATHOLOGY OF PARKINSONISM nigra pars compacta and locus ceruleus a variable degree of loss of pigmented neurons is noted and the extent of neuronal loss will correlate, more or less, with the prominence of the parkinsonian features. In cases of MSA-P there will also be neuronal loss and accompanying gliosis in the putamen, caudate and globus pallidus. MSA-C cases show loss of Purkinje cells in the cerebellum as well as the neurons of the inferior olives. Those cases with features of autonomic failure will demonstrate neuronal loss in the intermediate column of the thoracic portion of the spinal cord. Importantly, in all forms of MSA one will find a widespread distribution of glial cytoplasmic inclusions, otherwise known as Papp–Lantos inclusions. These small, argyrophilic inclusion bodies are encountered adjacent to the nuclei of oligodendroglial cells (Papp et al., 1989). They may be seen using a variety of silver impregnation stains but are commonly shown well with the Gallyas stain (Fig. 8.8). They are also well demonstrated with immunohistochemical preparations using antibodies against a-synuclein. They appear as sickle or triangularshaped bodies. They are typically found in the supplementary and primary motor cortex and its subcortical white matter and in the globus pallidus, putamen, cerebellar peduncles and basis pontis.

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This disorder is characterized by bradykinesia, muscular rigidity, axial dystonia and a supranuclear gaze palsy. In later life, dementia may commonly occur. Although early in the condition levodopa therapy may produce some improvement, its effects are short-lived and the condition subsequently progresses relentlessly.

The external appearance of the cerebral cortex of patients with progressive supranucelar palsy is either normal or shows a modest degree of frontal atrophy. Upon dissection of the brain the major abnormality seen is of the midbrain, where the aqueduct of Sylvius is dilated, as is the caudal aspect of the third ventricle. Although one generally appreciates a loss of pigmentation of the substantia nigra, the locus ceruleus is typically described as retaining a normal pigmentation. The superior cerebellar peduncles tend to be shrunken and gray in color, reflecting loss of myelin related to degeneration of neurons in the dentate nucleus. Microscopically, a number of regions show evidence of neuronal loss with accompanying gliosis. These include the globus pallidus, thalamus, subthalamic nucleus, periaqueductal gray matter and substantia nigra pars compacta. Additional areas may be affected, including the vestibular nuclei of the medulla and the dentate nucleus of the cerebellum. Silver impregnation stains, such as the modified Bielschowsky stain, show widespread neurofibrillary tangle formation in remaining neurons of those regions undergoing degeneration. These neurofibrillary tangles are different from those of Alzheimer’s disease in that they stain poorly with antiubiquitin antibodies and have ultrastructural differences. Within glial cells, astrocytes and, in particular, oligodendroglial cells of the cerebral white matter and the basal ganglia, one sees argyrophilic comma-shaped inclusion bodies using silver impregnation stains (Fig. 8.9). Such inclusion bodies, also referred to as coiled bodies, are immunoreactive using anti-tau antibodies. Because these inclusions do not stain with antibodies raised against a-synuclein, they may be differentiated from the Papp–Lantos bodies of multiple system atrophy.

Fig. 8.8. For full color figure, see plate section. Photomicrograph of subcortical white matter showing numerous Papp– Lantos glial cytoplasmic inclusions in the case of multiple system atrophy. Gallyas stain.

Fig. 8.9. For full color figure, see plate section. Photomicrograph of subthalamic nucleus, progressive supranuclear palsy, showing coiled bodies. Modified Bielschowsky stain.

8.5. Progressive supranuclear palsy

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8.6. Carbon monoxide, manganese, methanol and other neurotoxin-induced forms of parkinsonism There are a number of regionally selective neurotoxins which are capable of inducing clinical parkinsonism. These are not to be confused with Parkinson’s disease and, with the exception of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) toxicity, do not lead to damage to the substantia nigra pars compacta with subsequent nigrostriatal denervation. Their mode of action relates to causing selective damage to other components of the basal ganglia, including the striatum and, in particular, the globus pallidus. This results in destruction of the downstream targets of the nigrostriatal pathways and thus leads to a form of parkinsonism that is relatively resistant to levodopa therapy. Carbon monoxide poisoning occurs primarily in situations where the burning of fuel occurs without adequate ventilation and/or incomplete combustion. In situations of acute carbon monoxide poisoning well-circumscribed bilateral softenings develop, most commonly of the inner segment of the globus pallidus. In cases with long-term survival following carbon monoxide poisoning, these areas of damage undergo cystic healing with the development of a parkinsonian syndrome (Lapresle and Fardeau, 1967). In situations with more severe poisoning, laminar necrosis of the cerebral cortex and loss of the Sommer’s sector of the hippocampi may also be seen and this is accompanied by more profound functional deficits. Manganese is an abundant metal in nature that is widely used in industrial processes. Manganese poisoning has been reported following heavy exposure primarily in association with the mining of manganese-containing ore and in smelting operations related to the production of hardened steel. Manganese selectively accumulates in the striatum and globus pallidus, where it can be identified in vivo as a hyperdense T1weighted image using magnetic resonance imaging. Clinically, manganese-induced parkinsonism is characterized by gait dysfunction with a propensity to fall backwards, bradykinesia, masked facies and dystonic features. At autopsy, the substantia nigra pars compacta remains intact whereas there is evidence of severe neuronal damage to the globus pallidus, especially its internal segment (Yamada et al., 1986). Some damage to the striatum is also reported. Methanol poisoning produces a variety of neurotoxic lesions to the putamen as well as a loss of retinal ganglion cells and damage to the cerebellar cortex (Halliday et al., 2002). In this context it is the selective bilateral hemorrhagic necrosis of the putamen that leads to

dystonia and parkinsonian features. Again, the neurons of the substantia nigra pars compacta remain intact. MPTP represented a contaminant in the synthesis of synthetic heroin analogs that was inadvertently included in intravenous injections taken by a group of drug abusers. This led to the acute development of a parkinsonian syndrome. Autopsies of individuals who died after MPTP exposure showed evidence of severe neuronal loss in the substantia nigra pars compacta in the absence of Lewy body or neurofibrillary tangle formation in the remaining neurons (Forno et al., 1988). Other regions of the basal ganglia appear to remain intact in exposed individuals.

8.7. Parkinsonism–dementia complex of Guam Following the end of World War II, it was recognized that among the native Chamorro population living on the island of Guam in the western Pacific, there was a remarkable concentration of patients suffering from a form of neurodegeneration with features of all three age-related neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) (Perl, 2001). The disease is referred to as amyotrophic lateral sclerosis/parkinsonism–dementia complex (ALS/PDC) of Guam. Although it was originally described as two separate and distinct disorders, namely ALS and PDC of Guam, it remains unclear if this is indeed the case or if the condition represents a wide spectrum of a single disease entity with a broad range of clinical and pathologic manifestations. The cases of ALS seen on Guam are virtually indistinguishable clinically from the disorder as it is seen elsewhere in the world. Neuropathologically it is also virtually identical to ALS cases encountered in other populations except for the appearance of widespread and severe neurofibrillary tangle formation in the Guam cases, a feature that is not observed in ALS cases elsewhere (Malamud et al., 1961; Hirano and Zimmerman, 1962). The cases with PDC show evidence of bradykinesia, muscular rigidity and, to a lesser extent, resting tremor. This is accompanied by a progressive dementia typically presenting with short-term memory impairment, disorientation and inability to perform simple calculations. Neuropathologically, these cases show prominent cerebral atrophy accompanied by almost total loss of visible pigmentation of the substantia nigra and locus ceruleus. Microscopically, within the substantia nigra pars compacta and locus ceruleus the few remaining pigmented neurons contain globoid neurofibrillary tangles and not Lewy bodies (Fig. 8.10). In addition, there is extensive widespread neurofibrillary

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involvement by neurofibrillary tangles, there is little in the way of b-amyloid deposition in the Guam cases.

8.8. Frontotemporal dementia and parkinsonism linked to chromosome 17

Fig. 8.10. For full color figure, see plate section. Photomicrograph of neuron in substantia nigra pars compacta showing globoid neurofibrillary tangle, parkinsonism–dementia complex of Guam. Modified Bielschowsky stain.

tangle formation involving entorhinal cortex, hippocampus, neocortex, periaqueductal gray matter and dentate nucleus of the cerebellum. In some cases, the extent of involvement can be quite remarkable with, for example, virtually all pyramidal neurons of CA1 region of the hippocampus being involved (Fig. 8.11). The pattern of neurofibrillary tangle formation in the neocortex shows a predominance of involvement in the superficial layers (primarily layers II and III) as opposed to deeper layers (layers V and VI) (Hof et al., 1991). This pattern is distinctly different from what is seen in cases of Alzheimer’s disease where involvement favors the deeper layers. Finally, despite extensive

Fig. 8.11. For full color figure, see plate section. Photomicrograph of hippocampus, CA1 region of a case of parkinsonism–dementia complex of Guam showing virtually complete involvement by neurofibrillary tangles. Modified Bielschowsky stain.

Frontotemporal dementia and parkinsonism linked to chromosome 17 is a relatively recently characterized condition. It typically presents as early-onset (age 30–60 years) parkinsonism in a familial setting with an associated dementia. The parkinsonian features include bradykinesia, postural instability and rigidity. Patients with this condition are not prone to a resting tremor and they respond poorly to levodopa therapy. The associated dementia shows typical frontotemporal features, including non-fluent aphasia with so-called semantic dementia (episodic memory is preserved but semantic memory is severely impaired). Disinhibition and poor judgment may also be seen. In individual patients the dementing features may predominate while in others the parkinsonism represents the prominent clinical phenotype. As its name implies, frontotemporal dementia and parkinsonism linked to chromosome 17 is a genetic disorder and is related to mutations of the tau gene (Goedert, 2005; Goedert and Jakes, 2005). A large number of different tau mutations have been reported in various families with this disorder. Interestingly, among affected members of families carrying forms of the disorder, the clinical manifestations may be either rather stereotyped or highly variable, despite the presence of a single specific tau mutation (Galariotis et al., 2005). The brains of affected patients show prominent frontotemporal atrophy with selective sparing of the parietal and occipital cortex. The atrophic regions show severe cerebral cortical thinning with symmetrically widened lateral ventricles and a variable degree of atrophy of the striatum and globus pallidus. Prominent atrophy of the amygdala and hippocampus may also be noted. Finally, there is loss of pigmentation of the substantia nigra and locus ceruleus that is visibly apparent. Histologically, the areas of atrophic cortex show neuronal loss and spongiosis of the neuropil with gliosis. Remaining neurons in these regions show prominent tau-positive inclusions which have the appearance of neurofibrillary tangles. Some cases have also shown the development of Pick bodies whereas others have shown tau-positive inclusions in astrocytes and oligodendroglial cells. Lewy bodies are not encountered in these cases.

8.9. General comments In past years, many of the diseases discussed in this chapter were identified and diagnosed by neuropathologists

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based on the presence and distribution of specific inclusion bodies, which were thought to define the diseases. The primary example of this is the Lewy body. Although the presence of Lewy bodies is required to make a diagnosis of sporadic Parkinson’s disease, Lewy bodies are encountered in association with a number of other conditions. As discussed above, there are other rare forms of genetically based Parkinson’s disease which may or may not demonstrate Lewy body formation. Whether such non-Lewy body forms of familial parkinsonism should still be called Parkinson’s disease or a separate disorder is a matter for debate (Calne and Mizuno, 2004; Forman et al., 2005). Such arguments boil down to the classic philosophic ‘splitter’ versus ‘lumper’ dichotomy and the relative importance one attaches to the presence of this marker of neuronal degeneration. More recently, attention has been focused on the protein constituents of such intracellular aggregates with the introduction of concepts that these individual disorders are examples of ‘synucleinopathies’ or ‘tauopathies’, depending on the primary protein that is found to have accumulated. Others have noted the conjugation of ubiquitin on virtually all such protein aggregates and have argued that dysfunction of the ubiquitin-proteosome machinery may underlie a basic inability to clear specific damaged proteins, leading to their accumulation. At the present time, it remains unclear which, if any, of these mechanisms represents the primary defect, increasing aggregation of damaged constituent proteins or their failure to be cleared by the ubiquitin-proteosome system. Nevertheless, this has opened the field to a long list of studies involving animal models and in vitro testing of these hypotheses. Some have argued that the accumulated proteins are toxic to neuronal function while others have claimed that they are secondary to neuronal damage itself. Finally, others have suggested that the protein inclusions actually represent a protective mechanism. It is anticipated that within a relatively short period of time a better understanding of these concepts will emerge. With this, it is anticipated that our approaches to diagnosis will be further and more rationally defined, based on a more functional pathogenetic basis. It is at that point that we will have truly fulfilled James Parkinson’s promise, made almost 185 years ago, to provide ‘that light which anatomical examination yields’.

Acknowledgments The author acknowledges research support from the National Institutes of Health (P01 AG-14382, P50 AG05138, P01 AG02219 and R01 NS045999).

References Braak H, Del Tredici K, Rub U et al. (2003). Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24: 197–211. Calne DB, Mizuno Y. (2004). The neuromythology of Parkinson’s disease. Parkinsonism Relat Disord 10: 319–322. Chan P, Jiang X, Forno LS et al. (1998). Absence of mutations in the coding region of the alpha-synuclein gene in pathologically proven Parkinson’s disease. Neurology 50: 1136–1137. Dawson TM, Dawson VL (2003). Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302: 819–822. Del Tredici K, Rub U, De Vos RA et al. (2002). Where does Parkinson’s disease pathology begin in the brain? J Neuropathol Exp Neurol 61: 413–426. Denson MA, Wszolek ZK, Pfeiffer RF et al. (1997). Familial parkinsonism, dementia, and Lewy body disease: study of family G. Ann Neurol 42: 638–643. Forman MS, Lee VM, Trojanowski JQ (2005). Nosology of Parkinson’s disease: looking for the way out of a quagmire. Neuron 47: 479–482. Forno LS (1969). Concentric hyalin intraneuronal inclusions of Lewy type in the brains of elderly persons (50 incidental cases): relationship to parkinsonism. J Am Geriatr Soc 17: 557–575. Forno LS (1996). Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55: 259–272. Forno LS, Langston JW, DeLanney LE et al. (1988). An electron microscopic study of MPTP-induced inclusion bodies in an old monkey. Brain Res 448: 150–157. Galariotis V, Bodi N, Janka Z et al. (2005). Frontotemporal dementia–Part II. Differential diagnosis, genetics, molecular pathomechanism and pathology. Ideggyogy Sz 58: 220–224. Goedert M (2005). Tau gene mutations and their effects. Mov Disord 20 (Suppl 12): S45–S52. Goedert M, Jakes R (2005). Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta 1739: 240–250. Graham JG, Oppenheimer DR (1969). Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 32: 28–34. Greenfield J, Bosanquet F (1953). The brain stem lesions in parkinsonism. J Neurol Neurosurg Psychiatry 16: 213–216. Hallervorden J (1935). Anatomische untersuchungenzur pathologenese des postencephalitischen parkinsonismus. Dtsch Z Nervenheilk 136: 68–77. Halliday G, Ng T, Rodriguez M et al. (2002). Consensus neuropathological diagnosis of common dementia syndromes: testing and standardising the use of multiple diagnostic criteria. Acta Neuropathol (Berl) 104: 72–78. Hirano A, Zimmerman HM (1962). Alzheimer’s neurofibrillary changes. A topographic study. Neurology 7: 227–242. Hof PR, Perl DP, Loerzel AJ et al. (1991). Neurofibrillary tangle distribution in the cerebral cortex of parkinsonism-dementia

THE NEUROPATHOLOGY OF PARKINSONISM cases from Guam: differences with Alzheimer’s disease. Brain Res 564: 306–313. Hof PR, Charpiot A, Delacourte A et al. (1992). Distribution of neurofibrillary tangles and senile plaques in the cerebral cortex in postencephalitic parkinsonism. Neurosci Lett 139: 10–14. Hughes AJ, Daniel SE, Lees AJ (2001). Improved accuracy of clinical diagnosis of Lewy body Parkinson’s disease. Neurology 57: 1497–1499. Lapresle J, Fardeau M (1967). The central nervous system and carbon monoxide poisoning. II. Anatomical study of brain lesions following intoxication with carbon monixide (22 cases). Prog Brain Res 24: 31–74. Lewy FH (1912). Paralysis agitans 1. Pathologisch Anatomie. In: MH Lewandowsky (Ed.), Handbuch der Neurologie, Vol. 3. Springer, Berlin, pp. 920–933. Malamud N, Hirano A, Kurland LT (1961). Pathoanatomic changes in amyotrophic lateral sclerosis on Guam. Neurology 5: 401–414. McNaught KS, Olanow CW, Halliwell B et al. (2001). Failure of the ubiquitin-proteasome system in Parkinson’s disease. Nat Rev Neurosci 2: 589–594. Papp MI, Kahn JE, Lantos PL (1989). Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94: 79–100. Parkinson J (1955). An Essay on the Shaking Palsy. Sherwood, Neely & Jones, London, 1817. In: M Critchley (Ed.), James Parkinson (1755–1824). MacMillan, London, pp. 145–218. Perl DP (2001). Amyotrophic lateral sclerosis/parkinsonism dementia complex of Guam. In: PR Hof, CV Mobbs (Eds.), Functional Neurobiology of Aging. Academic Press, San Diego, pp. 183–201.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 9

Genetic aspects of Parkinson’s disease YOSHIKUNI MIZUNO*, NOBUTAKA HATTORI AND HIDEKI MOCHIZUKI Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan

9.1. Genetics of familial forms of Parkinson’s disease To date, 13 forms of familial Parkinson’s disease (PD) have been mapped to certain loci on chromosomes and they are designated as PARK1, PARK2, and so on (Table 9.1). PARK1, PARK4, PARK5, PARK8 and PARK11 are autosomal-dominant forms and PARK2, PARK6, PARK7 and PARK9 are autosomal-recessive forms. The causative genes have been identified in seven forms (a-synuclein, parkin, ubiquitin carboxyterminal hydrolase L1 (UCH-L1), DJ-1, PINK1, leucine-rich repeat kinase 2 (LRRK2), and ATP131A as the order of discovery). These discoveries contributed greatly to the understanding of molecular mechanism of nigral neuronal death in sporadic PD. Recent progress in familial forms of PD will be reviewed below. 9.1.1. Autosomal-dominant familial Parkinson’s disease due to a-synuclein mutations (PARK1) 9.1.1.1. Clinical features of PARK1 PARK1 is an autosomal-dominant familial PD caused by mutations of the a-synuclein gene. Clinical features were first described by Golbe et al. (1990), who reported two large, probably related, kindreds with autopsy-confirmed PD. The mode of inheritance was autosomal dominant. The researchers found 41 affected individuals in two kindreds. Both kindreds immigrated to the New Jersey/New York area between 1890 and 1920 from Contursi, a village in the hills of Salerno province in southern Italy (Golbe et al., 1990). Both kindreds had their common origin in a single small town in southern Italy, suggesting the common origin

of the two kindreds, and in fact this common origin was later confirmed. The average age of onset was 46.5 10.8 years (range 28–68, n ¼ 33). Death occurred at the age of 53.5 9.2 years (range 42–74, n ¼ 31). Tremor was not a predominant feature: 2 out of 41 affected patients examined had prominent tremor and only 8 had tremor at all. Otherwise, clinical features were typical of idiopathic PD. Dementia was said to be unusual, mild or late. Those patients treated with levodopa showed improvement in their parkinsonism and some of them developed motor fluctuations. Thus the age of onset in these kindreds was younger than that of sporadic PD and the disease duration was shorter. The causes of death were usually complications from PD. Golbe et al. reported 2 autopsied patients who showed severe neuronal loss in the substantia nigra with Lewy bodies in remaining neurons and in cell ghosts. Gliosis was marked. The locus ceruleus and dorsal motor nucleus of the vagus also showed mild to moderate cell loss with Lewy bodies. The substantia innominata revealed mild cell loss, moderate gliosis and numerous Lewy bodies. In 1996, Golbe et al. reported follow-up of this family. They were able to detect a total of 60 patients with average age of onset at 45.6 13.5 years (range 20–85 years). A mean course to death was 9.2 4.9 years (range 2–20 years). A segregation ratio was 40.1% for kindred members aged 50 years and older. The authors found a highly variable degree of dementia in many of the affected members. Markopoulou et al. (1995) reported a Greek-American kindred with clinically typical PD in 16 individuals in three generations. Clinical features were similar to those of the Contursi family with mean onset age in the 40s and mean survival time of 9 years. Golbe et al. (1996)

*Correspondence to: Yoshikuni Mizuno, MD, Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan. E-mail: [email protected], Tel: þ3-3813-3111, Ext. 3807; Fax: þ3-5800-0547.

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Table 9.1 Loci of familial forms of Parkinson’s disease Name

Locus

Gene

Inheritance

Lewy body

PARK1 PARK2 PARK3 PARK4 PARK5 PARK6 PARK7 PARK8 PARK9 PARK10 PARK11 PARK12 PARK13

4q21–23 6q25.2–27 2p13 4q21–23 4p14 1p35–36 1p36 12p11.2–q13.1 1p36 1p32 2q36–37 Xq21–25 2p13

a-synuclein parkin Unknown a-synuclein UCH-L1 PINK1 DJ-1 LRRK2, dardarin Unknown Unknown Unknown Unknown Omi/HtrA2

AD AR AD AD AD AR AR AD AR

þ þ þ

þ/

AD XR AD?

AD, autosomal dominant; AR, autosomal recessive. PARK10 locus was found by genomewide scanning and it includes sporadic cases.

raised a possibility that the Contursi kindred and the Greek-American family shared a common ancestor. Dementia is not uncommon in PARK1. The autosomal-dominant family of the Basque country, Spain, reported by Zarranz et al. (2004) with Glu46Lys mutation of the a-synuclein gene showed parkinsonism and dementia. The age of onset was 50–65 years and the age at death 64–75 years; patients died before levodopa was available. Affected patients had dementia in addition to parkinsonism. Lewy bodies were found not only in brainstem nuclei but also in many cortical areas. Additional features included central hypoventilation, orthostatic hypotension, prominent myoclonus and urinary incontinence, which were described in 5 out of 9 siblings in an Australian family of Greek origin with Ala53Thr mutation of the a-synuclein gene reported by Spira et al. (2001). Autosomal-dominant PD due to triplication of the a-synuclein gene (Singleton et al., 2003) is also associated with parkinsonism and dementia (PARK4). Spellman (1962) reported an autosomal-dominant family with PD in the USA. Muenter et al. (1998) made extensive clinical studies on the family reported by Spellman (1962). The autosomal-dominant family reported by Waters and Miller (1994), that reported by Spellman (1962) and that reported by Muenter et al. (1998) were found to have a common ancestor and this group is called the Spellman–Muenter– Waters–Miller family or Iowan family. Clinical features of this large kindred consisted of levodoparesponsive parkinsonism and dementia. In autopsied patients, many cortical Lewy bodies were found and the pathological diagnosis suggested diffuse Lewy body disease. Thus dementia appears to be a frequent

feature of PD due to a-synuclein gene mutations. On the other hand, families with PD due to duplication of the a-synuclein gene reported by Chartier-Harlin et al. (2004) and Ibanez et al. (2004) were not associated with dementia. However, a family reported by Nishioka et al. (2006) showed dementia. 9.1.1.2. Genetics of PARK1 Polymeropoulos et al. (1996) did a genome scan using 140 genetic markers on the Contursi kindred. Genetic markers at the cytogenetic location 4q21–q23 showed linkage to the disease phenotype with a Zmax (maximum logarithm of the likelihood ratio for linkage score, lod score) of 6.00 for marker D4S2380. This chromosome locus was close to the a-synuclein gene locus. The asynuclein gene locus had been mapped to 4q21.3–q22 (Campion et al., 1995; Chen et al., 1995; Shibasaki et al., 1995). Polymeropoulos et al. (1997) analyzed the Contursi family for a mutation in the a-synuclein gene and found an Ala53Thr (G209A) mutation, which was segregated with PD phenotype. They also found the same mutation in three Greek kindreds. The second mutation of the a-synuclein gene was reported by Kru¨ger et al. (1998), who analyzed a family of German origin with autosomal-dominant PD and found Ala30Pro (G88C) substitution; the ages of onset (52–56 years) were slightly older than those of the Contursi kindreds. The third mutation was reported by Zarranz et al. (2004); they found Glu46Lys (G188A) transition in the a-synuclein gene; clinical features were parkinsonism and dementia. Other interesting mutations are triplication (Singleton et al., 2003) and duplication (Chartier-Harlin et al., 2004; Ibanez et al., 2004; Nishioka et al., 2006) of the

GENETIC ASPECTS OF PARKINSON’S DISEASE a-synuclein gene. Farrer et al. (1999) made a linkage analysis on the Spellman–Muenter–Waters–Miller kindred described before; they reported linkage of this kindred to the short arm of chromosome 4 that was named PARK4. But later on, Singleton et al. (2003) found triplication of the a-synuclein gene in the affected members of this family; the 1.5 Mb region, including introns on both sides of the a-synuclein gene, was triplicated in a tandem fashion. Therefore at the protein level, the amount of a-synuclein is expected to be twofold compared to the normal level. The 1.5 Mb region contains several genes, including the asynuclein gene. Thus PARK4 is caused by different mutations of the a-synuclein gene. Chartier-Harlin et al. (2004) and Ibanez et al. (2004) independently reported familial PD caused by duplication of the asynuclein gene. In these families, dementia was not a clinical feature and the neuropathological change was brainstem-type Lewy body disease. Mutations of the a-synuclein gene reported in the literature are shown in Fig. 9.1. Regarding polymorphisms, in the promoter region there is a complex dinucleotide repeat polymorphism (NACP-repeat 1, where NACP signifies non-amyloid component of the senile plaqueprecursor) (Kru¨ger et al., 1999; Chiba-Falek and Nussbaum, 2001); this repeat composition significantly influences the a-synuclein expression level (Chiba-Falek and Nussbaum, 2001; Holzmann et al., 2003). This dinucleotide repeat polymorphism was reported to be associated with an increased risk for sporadic PD (Kru¨ger et al., 1999; Farrer et al., 2001b; Holzmann et al., 2003; Tan et al., 2003; Pals et al., 2004).

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More recently, polymorphisms in intron 4 and 30 -flanking region were reported to be highly associated with increased risk for sporadic PD (Mueller et al., 2005; Mizuta et al., 2006). 9.1.1.3. Pathogenesis of PARK1 a-Synuclein is a natively unfolded brain-specific protein without a significant secondary structure, consisting of 140 amino acids (Weinreb et al., 1996). It appears to be related to neurotransmitter regulation; however, its exact function is not known. a-Synuclein has a tendency to self-aggregation and oligomer formation. Soluble oligomers ultimately form insoluble aggregates, which form a major component of Lewy bodies (Spillantini et al., 1997). The insoluble aggregate of a-synuclein is highly phosphorylated (Fujiwara et al., 2002). Mutant forms of a-synuclein (Ala30Pro, Glu46Lys, Ala53Thr) have an increased tendency for self-aggregation, and this may be reflected as an earlier age of onset compared to that of sporadic PD. Substitution of Ala53Thr is predicted to disrupt the a-helix and to extend the b-sheet structure; b-pleated sheets are involved in the self-aggregation of proteins leading to amyloid-like structures (Polymeropoulos et al., 1997). Substitution of Glu46Lys significantly increases the ability of a-synuclein to bind to negatively charged liposomes and increases the rate of filament assembly for aggregation to the same extent as the Ala53Thr mutation (Choi et al., 2004; Greenbaum et al., 2005). Thus a-synuclein oligomers and insoluble fibril formation appear to be the most important pathogenetic mechanism of nigral neuronal death in PARK1. El Agnaf et al. (1998) showed apoptotic death of neuroblastoma

Dup Tri 1

2

3

4

5

N

6 C

Ala30Pro

Glu46Lys

Vesicular binding

Ala53Thr

KTKEGV repeat NAC

domain

Fig. 9.1. Exons of the a-synuclein gene and locations of mutations in PARK1. a-Synuclein gene is located at chromosome 4q21–23. The gene is called SNCA. a-Synuclein protein consists of 140 amino acids. Exon 1 is spliced out from the mature protein. Three missense mutations, as indicated by small arrows, and duplication and triplication of the a-synuclein gene have been reported. Black bars within exons indicate locations of the repeat structures, of which KTKEGV is common to all. NAC represents the non-amyloid component of the senile plaque. The vesicular-binding domain is the area where a-synuclein protein binds to the membrane of transport vesicles.

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cells by self-aggregation and amyloid-like filament formation when mutated or wild-type a-synuclein proteins were also overexpressed or The lag time for the formation of precipitable aggregates was about 280 h for the wild-type protein, 180 h for the Ala30Pro mutant and only 100 h for the Ala53Thr mutant protein. Apoptotic cell death by a-synuclein overexpression is also supported by rat primary culture of dopaminergic cells (Zhou et al., 2000). a-Synuclein oligomers (protofibrils) increase the permeability of synaptic vesicles; Volles and Lansbury (2002) studied the effects of protofibrillar a-synuclein on vesicular permeability. They found that protofibrillar Ala30Pro, Ala53Thr and mouse variants had greater permeabilizing activities per mole than the wild-type protein. The leakage of vesicular contents induced by protofibrillar a-synuclein exhibited a strong preference for low-molecular-mass molecules such as dopamine, suggesting a pore-like mechanism for permeabilization. Enhanced release of dopamine from synaptic vesicles would induce oxidative damage in the nigral neurons. Substitution of Ala30Pro disrupts lipid binding of a-synuclein. a-Synuclein has seven unique 11-mer repeat sequences (Fig. 9.1), of which six amino acids, Lys-Thr-Lys-Glu-Gly-Val, are conserved (Maroteaux et al., 1988). These repeat sequences are important for a-helix formation and reversible lipid-binding function (Bussell and Eliezer, 2003). Transport of asynuclein is at least in part mediated by fast axonal flow by binding to transport vesicles. This vesicular binding takes place at the amino-terminal region, which includs the first three repeat sequences. The Ala30Pro mutation is located between the second and the third repeat (Fig. 9.1) and the presence of this mutation impairs vesicular binding of a-synuclein (Jensen et al., 1998). Thus a-synuclein proteins which cannot bind to transport vesicles are expected to undergo fibril formation and aggregation in the cytoplasm. a-Synuclein oligomers inhibit 26S proteasome activity by interacting with the 19S regulatory unit (Snyder et al., 2003) and inhibition of the proteasome enhances a-synuclein aggregates and dopaminergic neuronal death (Rideout et al., 2001). Thus a vicious cycle will be established within nigral neurons. There are differences in the metabolism of wild- and mutated-type a-synuclein. Bennett et al. (1999) reported that catabolism of mutated a-synuclein (Ala53Thr) by the ubiquitin-proteasome pathway was 50% slower than that of the wild type in SH-SY5Y cells. Mutant a-synuclein proteins, when expressed in differentiated PC12 cells, decrease the activity of proteasome and increase sensitivity to mitochondria-

dependent apoptosis (Tanaka et al., 2001). Furthermore, A53T-mutated a-synuclein was reported to disrupt the ubiquitin-proteasome system (UPS) and catecholaminergic synaptic vesicles (Stefanis et al., 2001). Impairment of the UPS is one of the most important molecular mechanisms for neurodegeneration. More recently, Cuervo et al. (2004) reported that wild-type a-synuclein was selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway. The pathogenic Ala53Thr and Ala30Pro asynuclein mutants bound to the receptor for this pathway on the lysosomal membrane, but appeared to act as uptake blockers, inhibiting both their own degradation and that of other substrates. These findings may underlie the toxic gain-of-function by the mutants. Familial PD caused by triplication of the a-synuclein gene (Singleton et al., 2003) indicates that overexpression of normal a-synuclein itself is sufficient to cause extensive neuronal degeneration not only in the substantia nigra but also in the cortical regions with diffuse Lewy body formation. Interestingly, before the discovery of this mutation, Gwinn-Hardy et al. (2000) had reported the presence of unusually highmolecular-weight a-synuclein in autopsied brains in a patient belonging to this family in which triplication of a-synuclein was discovered. Neurotoxic effects of overexpression of wild-type a-synuclein have been shown in many experimental conditions (Hashimoto et al., 1998; Giasson et al., 1999; Kirik et al., 2002; Yamada et al., 2004). Yamada et al. (2004) used the recombinant adeno-associated viral vector system for human a-synuclein gene transfer to rat substantia nigra and observed approximately 50% loss of dopaminergic neurons at 13 weeks after transfection; this was associated with phosphorylation of a-synuclein at Ser129 and activation of caspase-9 – findings common to human PD. Thus, by reviewing the literature, it is likely that PD-causing mutations of human a-synuclein more easily cause a-synuclein oligomer formation, cytotoxic b-sheet formation and insoluble aggregate formation compared to wild-type a-synuclein. In addition, an a-synuclein pore-like structure is more easily formed by mutant a-synucleins and such a pore-like structure damages synaptic vesicles, inducing the release of dopamine and subsequently causing oxidative damage. Such differences in the properties of mutated a-synuclein appear to account for the earlier onset of familial PD and more extensive neuronal damage. The molecular mechanism of nigral neuronal death in PARK1 is summarized in Fig. 9.2. As the molecular mechanism of a-synuclein toxicity against nigral neurons is being elucidated, many experimental trials to reverse nigral neurotoxicity by

GENETIC ASPECTS OF PARKINSON’S DISEASE Mitochondrial damage

Oxidative damage

221 DA release

α-Synuclein Proteasome damage

Synaptic vesicle damage

Oligomers Cytochromec release α-Synuclein aggregation Lewy body Apoptosis

Axonal flow damage

Nigral neuronal death

Lewy body

Fig. 9.2. Molecular mechanism of nigral neuronal death in PARK2. Mutated a-synuclein proteins have increased tendency for oligomer and aggregate formation. The oligomers impair mitochondrial and proteasome functions. As 26S proteasome is adenosine triphosphate (ATP)-dependent and impairment of 26S proteasome enhances aggregation of a-synuclein, a vicious circle develops. Oligomers of a-synuclein induce release of dopamine, creating oxidative stress. Oxidative stress enhances a-synuclein oligomer formation. Thus another vicious circle develops. These reactions are repeated and eventually lead to nigral neurodegeneration. DA: dopamine.

overexpression of a-synuclein have been reported. Lo Bianco et al. (2004) reported that co-transfection of the parkin gene reduced a-synuclein-induced nigral neuronal death. We also confirmed that parkin was able to prevent neuronal death caused by a-synuclein overexpression (Yamada et al., 2005). Hsp70 (Auluck et al., 2005) and its enhancer, geldanamycin (McLean et al., 2004), were also reported to be neuroprotective against a-synuclein-induced nigral neuronal loss in a Drosophila model of PD. Hsp70 is a multipurpose stress response chaperone protein that mediates both refolding and degradation of misfolded proteins; it is able to block both a-synuclein toxicity and aggregation (Klucken et al., 2004). Rifampicin was also reported to inhibit a-synuclein fibrillation and to enhance disaggregation of exiting fibrils in vitro (Li et al., 2004). bSynuclein by lentivirus transfer was also effective in reducing nigral neuronal death in human-a-synuclein transgenic mice (Hashimoto et al., 2004). 9.1.2. Autosomal-recessive familial Parkinson’s disease due to parkin mutation (PARK2) 9.1.2.1. Clinical features of PARK2 PARK2 was first described as a distinct clinical entity by Yamamura et al. in 1973, who reported 16 patients (13 familial in five unrelated families and 3 sporadic cases); clinical features of 11 patients from the initial four families were essentially identical. Ages of onset were between 17 and 28 years in 10 out of 11 patients and 42 in the remaining one. Female preponderance

was noted (M:F ¼ 1:10); all the patients showed tremor, rigidity, bradykinesia and postural instability. Sleep benefit, i.e., temporary improvement in parkinsonism after a nap or sleep, and dystonic postures in the feet during walking (talipes equinovarus) were characteristic features of their patients. Dementia was absent. Consanguineous marriage was seen in two families; none of the affected parents had parkinsonism, indicating an autosomal-recessive mode of inheritance. Later, Ishikawa and Tsuji (1996) and Yamamura et al. (1998) summarized clinical features (Table 9.2). Clinical features were thought to be initially uniform, i.e. onset usually before 40 years of age, gait disturbance more often than tremor as an initial symptom, manifesting four cardinal symptoms of PD, good response to levodopa and high incidence of levodopa-induced dyskinesia and motor fluctuations. Consanguineous marriage of the parents is not always documented. According to Matsumine et al. (1998a), consanguineous marriages were found in 9 out of 17 families linked to PARK2 locus, and Yamamura et al. (1998) reported consanguineous marriage in 16 out of 22 families. Periquet et al. (2001) reported a very low incidence of consanguinity, which was found in only four out of 36 families; all the families with consanguineous marriages had homozygous mutations and 28 out of 32 families without consanguineous marriages had compound heterozygous mutations of the parkin gene. Khan et al. (2003) also reported very low consanguinity, which was found in only one out of 16 families; among them, only 1

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Table 9.2 Clinical features of PARK2

Number of families Consanguinity Number of patients Male Female Age of onset (years) Range Sleep benefit Initial symptom Dystonic gait Parkinsonian gait Rest tremor Bradykinesia Upper-limb dystonia Dystonia Hyperreflexia Levodopa response

Yamamura et al. (1998)

Ishikawa and Tsuji (1996)

Combined

22 10 43 16 27 26.1 7.8 13–42 95.3%

12 11 17 5 12 27.8 9.0 9–43 100% ND

34 21 60 21 39 266 8.1 9–43 96.7%

62.5% 64.7% 100%

73.3% 85.0% 100%

18 8 13 3 1 77.5% 92.5% 100%

ND: not described.

patient (no consanguinity) had homozygous mutation of the parkin gene, whereas all of the remaining patients had compound heterozygous mutations. The age of onset is usually before 50; however, since analysis of the parkin gene became possible, patients with later onset have been found. The highest age of onset with two mutations in parkin reported in the literature was 72 years (Lincolon et al., 2003); this patient, living in the USA, carried compound heterozygous mutations consisting of exon 4 deletion and a missense mutation in exon 7, Arg275Try, which is a relatively common mutation in the USA. The initial symptom is more often gait disturbance rather than rest tremor – 60% versus 30% (Yamamura et al., 1998). Usually gait disturbance starts on one side; therefore, patients drag one foot when they walk. Dystonia in the upper limb is rare, but can be seen. In addition, when the age of onset is young, pes equinovarus posture may develop while walking (Yamamura et al., 1998). Dystonia may be a presenting symptom when the age of onset is before 20 (Tassin et al., 2000; Khan et al., 2003); dystonia may be generalized or focal, such as writer’s cramp and/or blepharospasm. Cognitive impairment and autonomic symptoms are rare, but can be seen in some patients (Yamamura et al., 1973). Atypical features include brisk tendon reflexes (Yamamura et al., 1973, 1998; Ishikawa and Tsuji, 1996; Tassin et al., 1998), axonal and/or peripheral neuropathy (Tassin et al., 1998; Khan et al., 2003; Okuma et al., 2003), painful dystonia (Tassin et al.,

1998), dementia (Benbunan et al., 2004), psychosis and behavioral disorder (Khan et al., 2003). Plantar response is usually flexor. Regarding autonomic dysfunction, constipation is common but other disturbances are rare. Yamamura et al. (1998) reported hyperhidrosis in 10 out of their 43 patients. Other autonomic features include urinary urgency, impotence and orthostatic hypotension (Khan et al., 2003). An unusual clinical feature reported by Pramistaller et al. (2002) was hemiparkinsonism hemiatrophy in a 37-year-old woman carrying compound heterozygous missense mutation of Arg275Trp in exon 7 and duplication of exon 7. She showed left-sided hemiatrophy and hemiparkinsonism, which responded to levodopa. The age of onset was 29. Three Japanese patients from two families with exon 3–4 deletions showed cerebellar and pyramidal dysfunction in addition to parkinsonism (Kuroda et al., 2001). Since the mapping of PARK2 to the long arm of chromosome 6 at 6q25–27.2 (Matsumine et al., 1997) and subsequent molecular cloning of the causative gene as parkin (Kitada et al., 1998), the clinical diversity of PARK2 has been widely recognized. Response to levodopa is excellent; however, many patients develop drug-induced motor fluctuations and dyskinesia, particularly when the age of onset is young (Ishikawa and Tsuji, 1996; Yamamura et al., 1998). Progression is slow and if these patients are treated with levodopa, most can live an independent life for 30–40 years from the onset (Yamamura et al., 1998). Generally, early-onset PD patients with parkin

GENETIC ASPECTS OF PARKINSON’S DISEASE mutations tend to have slower progression of the disease than age-matched early-onset PD patients without a parkin mutation (Rawal et al., 2003). Regarding the pathology of PARK2, Takahashi et al. (1994) reported a 67-year-old woman from a consanguineous family with early-onset familial parkinsonism. The patient had an onset of gait disturbance at age 10. She died of pontine infarct at age 67. Autopsy findings revealed severe depigmentation of the substantia nigra and the locus ceruleus. The medial part of the intermediate group and the ventrolateral group of the substantia nigra showed loss of pigmented neurons and gliosis, but the remaining parts of the nigra appeared intact. Lewy bodies could not be seen. The researchers noted that the apparently normal looking neurons were somewhat smaller and contained less neuromelanin. Locus ceruleus showed similar but less pronounced changes. The patient reported by Yamamura et al. (1998) died at age 52, 33 years after onset. This patient showed marked depigmentation of the substantia nigra, neuronal loss and gliosis without Lewy body formation. Locus ceruleus showed much milder neuronal loss. Other structures were uninvolved. The patient we examined had deletion of exon 4 parkin (Mori et al., 1998). This patient noted hand tremor at age 27 and died at age 62. The substantia nigra showed marked depigmentation. Interestingly, tau-positive tangles were seen in nigral neurons. Another patient with homozygous exon 4 deletion reported by Hayashi et al. (2000) showed fibrillary gliosis and mild depletion in non-pigmented neurons in the pars reticulata of the substantia nigra in addition to marked loss of pigmented neurons in the pars compacta of substantia nigra. Again, no Lewy bodies were found. The patient reported by Gouider-Khouja et al. (2003), who had homozygous 101–102AG deletion in exon 2, also did not show Lewy bodies. In contrast to the above findings, patients reported by Farrer et al. (2001a) are very interesting. This group reported two apparently autosomal-dominant families with parkin mutations. In family Ph, a 93-year-old woman who was a carrier of a 40 basepair deletion in exon 3 was neurologically normal. Her autopsy findings were also unremarkable, indicating that a carrier state of a parkin mutation does not necessarily cause PD. In family Pw, a 52-year-old man who had parkinsonism since the age of 41 and carried compound heterozygous mutations of parkin consisting of a 40 basepair deletion of exon 3 and a missense mutation in exon 7 (Arg275Try) came to autopsy. Neuropathologic examination revealed clear-cut loss of pigmented neurons and Lewy bodies as well as pale bodies in the substantia nigra and locus ceruleus. Neuropathological findings were essentially similar to those of sporadic

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PD. In this patient, truncated parkin protein originating from 40 basepair deletion in exon 3 was expressed in lymphoblastoid cells. Mutated parkin protein from missense mutation in exon 7 was also likely to be expressed in the brain. Therefore, the presence of parkin protein, even if mutated, may lead to Lewy body formation. Our patient with exon 4 deletion did not form Lewy bodies and parkin protein was totally absent from the brain (Shimura et al., 1999). The patient reported by Sasaki et al. (2004) with homozygous exon 3 deletion showed basophilic inclusion bodies, which were a-synuclein-positive, in the neuropils of the pedunculopontine nucleus; however, Lewy bodies were not detected. An additional interesting neuropathological observation with parkin mutation is the patient reported by van de Warrenburg et al. (2001). This patient was 18 years old when he first noted the onset of tremor in both legs. Later, full-blown parkinsonism appeared with gait disturbance and start hesitation. The patient died at age 75. Intelligence was normal at an examination at age 70. This patient carried compound heterozygous mutations of parkin consisting of exon 3 deletion and a missense mutation of Lys211Asn. The substantia nigra and locus ceruleus showed marked neuronal loss and gliosis without Lewy body formation. What is interesting is gliosis and demyelination found in the gracile fascicles. Clark’s nucleus in the spinal cord showed moderate neuronal loss. No tau accumulation was found in neurons; however, tau-positive thorn-shaped astrocytes were found in the caudate, putamen, subthalamic nucleus and nigra. Another interesting patient was reported by Morales et al. (2002). This patient was 82 years old when he died. He carried a single heterozygous missense mutation of the parkin protein consisting of Cys212Tyr. Clinical features were consistent with progressive supranuclear palsy (PSP) and postmortem examination also showed typical changes of PSP with tau accumulation. This may be just a coincidental finding of PSP associated with heterozygous parkin mutation. However, it is interesting to note that in some parkin patients, tau accumulation was found in the brain (Mori et al., 1998; van de Warrenburg et al., 2001). The pattern of 18F-dopa positron emission tomography (PET) scan in PARK2 is different from that of sporadic PD. In sporadic PD, a predominant decrease of 18F-dopa uptake is seen in the putamen, and caudatal uptake is relatively preserved. But in PARK2, not only the putamen but also the caudate shows a marked decrease in uptake (Portman et al., 2001; Scherfler et al., 2004). In addition, Scherfler et al. (2004) reported a widespread decrease in 11C-racropride binding potential, a marker for dopamine receptor, in striatal, thalamic and cortical areas. They suggested that this decrease might be a direct consequence of the

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parkin genetic defect and that cortical reduction might contribute to the behavioral problems sometimes seen in parkin patients. [123I]FP-CIT (FP-CIT, N-[omega]fluoropropyl-2[beta]-carboxymethoxy-3[beta]-(4-[123I] iodophenyl)nortropane) single photon emission computed tomography (SPECT) scanning showed essentially the same findings as 18F-dopa PET in parkin patients (Varrone et al., 2004). 9.1.2.2. Genetics of PARK2 PARK2 is caused by mutations of parkin. We discovered parkin in the following way. While we were studying genetic risk factors of sporadic PD, we found an autosomal-recessive young-onset familial PD, which was linked to the Mn superoxide dismutase (SOD) locus (Shimoda-Matsubayashi et al., 1996). The Mn SOD locus had been mapped to the long arm of choromosome 6 at 6q25 (Church et al., 1992). Then we did linkage analysis on 13 autosomal-recessive youngonset PD families and mapped the disease gene locus at 6q25.2–q27 (Matsumine et al., 1997). The maximum cumulative pairwise lod score was 7.26 at D6S305 (y ¼ 0.03) and 7.71 at D6S253 (y ¼ 0.02). Jones et al. (1998) confirmed the linkage of early-onset parkinsonism to 6q25.2–q27 in four different ethnic groups and Tassin et al. (1998) reported the presence of early-onset parkinsonism linked to the chromosome 6 locus in seven European and one Algerian families. While we were doing linkage analysis, we found a patient who showed deletion of one of the microsatellite markers, D6S305, which we were using in the linkage analysis (Matsumine et al., 1998a) (Fig. 9.3). We thought this microsatellite marker might be located within the disease gene. Using this microsatellite marker as the starting probe, we screened the Keio bacterial artificial chromosome (BAC) library, a comprehensive cDNA library of human genomes, and we were eventually able to clone a cDNA consisting of 2960 basepairs, of which 1395 basepairs constituted the protein-coding region (Kitada et al., 1998). The profile of parkin is summarized in Table 9.3. Parkin was the second largest gene after dystrophin; as

Fig. 9.3. An autosomal recessive-juvenile parkinsonism (ARJP) patient who lacked a microsatellite marker used in linkage analysis. The AR-JP patient indicated as a black circle showed absence of a band corresponding to the marker D6S305. Reproduced from Matsumine et al. (1998b).

Table 9.3 Profile of parkin Name

Parkin

Chromosome locus Total size Number of exons cDNA Coding region N-terminal C-terminal

6q25.2–q27 1.4 Mb 12 2960 bp 1395 bp 30% homology to ubiquitin 2 RING-finger motives and in between RINGs 465 amino acids 51 652

Gene product Molecular weight

it was a novel gene, we named it parkin. Gene product was of average size, consisting of 465 amino acids with a deduced molecular weight of 51 652. Parkin protein has a unique structure in that there is 30% homology in the amino acid sequence in the amino-terminal region and there are two Really Interesting New Gene (RING) finger structures near the carboxyl-terminal side. We found a large homozygous deletion expanding from exon 3 to 7 in one family and a homozygous deletion of exon 4 in another family. We studied an additional 12 families and found homozygous deletions of exon 3 in two families, exons 3–4 in three families, exon 4 in three families, exon 5 in two families and one basepair deletion in exon 5 in two families (Hattori et al., 1998b). We also found two families with a point mutation, Thr240Arg in one family and Gln311Stop in another family (Hattori et al. (1998a)). Since then, many kinds of mutations have been found, not only in Japan but also in many other countries; mutations reported include homozygous exonic deletions (Hattori et al., 1998b; Lu¨cking et al., 1998, 2000; Nisipeanu et al., 1999; Maruyama et al., 2000; Hedrich et al., 2001), exonic duplications and triplications (Lu¨cking et al., 2000; Kann et al., 2002; Poorkaj et al., 2004), point mutations (Hattori et al., 1998a; Abbas et al., 1999; Lu¨cking et al., 2000; Maruyama et al., 2000; Hedrich et al., 2001, 2002; Terrini et al., 2001; Wu et al., 2005), small deletions (Hattori et al., 1998b; Abbas et al., 1999; Lu¨cking et al., 2000; Mun˜oz et al., 2000; Alvarez et al., 2001), homozygous and heterozygous insertions (Abbas et al., 1999; Lu¨cking et al., 2000), compound heterozygous mutations of various combinations of deletions and point mutations (Abbas et al., 1999; Lu¨cking et al., 2000; Maruyama et al., 2000; Bonifati et al., 2001; Periquet et al., 2001), single heterozygous mutations (Oliveira et al., 2003a), in which only one of the two parkin alleles had a mutation, and intronic mutations (Illarioshkin et al., 2003; Oliveira et al., 2003a; Bertoli-Avella et al., 2005). Intronic mutations

GENETIC ASPECTS OF PARKINSON’S DISEASE may cause splice variants. Break points of exonic deletion mutations were not usually identified. They exist somewhere in introns. Clarimon et al. (2005) studied break points of homozygous exon 4 deletions in two families. In one of the families, the deletions involved 1069 basepairs in one allele and 1750 basepairs in another allele. In the second family, the deletion involved 156 203 basepairs, indicating that these mutations were not caused by a single founder mutation. Mutations reported in parkin are summarized in Figs. 9.4 and 9.5. Parkin mutations have now been seen worldwide, including in Japan (Hattori et al., 1998b), China (Wang et al., 2003), Taiwan-China (Lu et al., 2001; Wu et al., 2005), Korea (Jeon et al., 2001), Turkey

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(Hattori et al., 1998a; Bertoli-Avella et al., 2005; Dogu et al., 2004), Israel (Nisipeanu et al., 1999, 2001), Russia (Illarioshkin et al., 2003), the UK, France, Germany (Kann et al., 2002), Italy (Bertoli-Avella et al., 2005), Spain (Alvarez et al., 2001; Mun˜oz et al., 2002), the Netherlands (van de Warrenburg et al., 2001), Serbia (Djarmati et al., 2004), Tunisia (Gouider-Khouoja et al., 2003), the USA (Nichols et al., 2002; Chen et al., 2003; Foround et al., 2003; Lincolon et al., 2003), Canada (Nichols et al., 2002), Cuba (Bertoli-Avella et al., 2005), Brazil (Rawal et al., 2003; Bertoli-Avella et al., 2005; Khan et al., 2005a), and Colombia (Pineda-Trujillo et al., 2001). Certain types of mutation have been reported to be relatively frequent in certain

465aa

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Fig. 9.4. Mutations of parkin: exon rearrangements. Lines above exons indicate duplication (solid line) and triplication (dotted line). Lines below exons indicate deletion of exons. Collected mainly from Hattori et al. (1998b), Abbas et al. (1999), Lu¨cking et al. (2000), Oliviera et al. (2003a) and Hedrick et al. (2004b). Figure reproduced from Mizuno et al. (2006), J Neural Transm (Suppl) 70: 191–204, with permission of the publisher, Springer-Wein, New York. K211N C212Y R256C M192V C253Y R275W G328E R402C T415N C431F M192L T240M D280N T240R G284R R334C G430D P437L

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Fig. 9.5. Mutations of parkin: missense, nonsense mutations and small deletions. Mutations above exons indicate missense mutations and below exons nonsense mutations and small deletions. Collected mainly from Hattori et al. (1998a), Abbas et al. (1999), Lu¨cking et al. (2000), Oliviera et al. (2003a) and Hedrick et al. (2004b). Figure reproduced from Mizuno et al. (2006), J Neural Transm (Suppl) 70: 191–204, with permission of the publisher, Springer-Wein, New York.

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countries; for instance, c.255delA in Spain (Mun˜oz et al., 2002) and 40 basepair deletions in exon 3 and Arg275Trp missense mutations in the USA (Nichols et al., 2002). Hedrich et al. (2004b) made an extensive literature review collecting information on 379 parkin mutation carriers. They found mutational hot spots at exons 3 and 4 (exon rearrangements) and in exons 2 and 7, with most frequent mutations being 255/256delA in exon 2 and 924C>T in exon 7. Although PARK2 is an autosomal-recessive disease, consanguineous marriages are not frequent, as discussed above. Patients without consanguineous parental marriage frequently show compound heterozygous mutations (Periquet et al., 2001; Khan et al., 2003), suggesting that the prevalence of parkin mutation carriers may be more common than thought. But analysis of carrier state is by no means easy, because heterozygous deletion mutations cannot be detected by conventional polymerase chain reaction (PCR); quantitative analysis of the gene dosage by real-time PCR, which is a time-consuming process, is necessary. A further interesting finding is that parkin mutations may be seen in apparently autosomal-dominant families (Klein et al., 2000; Lu¨cking et al., 2001; Kobayashi et al., 2003). Klein et al. (2000) reported a large kindred living in South Tyrol in Italy. They found 8 patients with a disease that was clinically indistinguishable from late-onset sporadic PD. Four of the 8 patients had compound heterozygous mutations of parkin (a large deletion involving exons 1–8 in one chromosome and one base deletion in exon 9 in another chromosome). The age of onset in these patients was 64, 49, 48 and 31, respectively. In contrast, 3 patients were heterozygous for a parkin mutation on one allele and apparently normal in other allele. The age of onset in these 3 patients was 60, 76 and 65, respectively. Two other patients did not carry a parkin mutation. Their age of onset was 55 and 75, respectively. The highest known age of onset with two parkin mutations is 64 and the highest known age of onset with one parkin mutation is 76. Apparently, patients with a single parkin mutation had higher age of onset. In these patients, the presence of a single mutation may have been a risk factor for sporadic PD. But confirmation is awaited for the neuropathological observations. All patients presented with tremor as the initial symptom. In contrast, Maruyama et al. (2000) reported on a pseudoautosomaldominant family. Affected patients were seen in three generations and homozygous deletion mutation of exon 4 was found, indicating that both parents were likely to have been carriers of exon 4 deletion. We also reported two apparently autosomal-dominant families with parkin mutations (Figs. 9.6 and 9.7;

Kobayashi et al., 2003). One of our families had multiple consanguineous marriages and carried homozygous exon 3 deletion. The affected members of the second family had homozygous deletion of exon 5. Therefore, apparent inheritance was autosomal dominant but the mode of pathogenesis was autosomal-recessive, in that all the affected members had homozygous deletions and unaffected members were heterozygotes. In the second family, there was no consanguineous marriage; it appeared to be extremely autosomal dominant until we did parkin analysis. As the mutational analysis of parkin progresses, the implication of single mutation has become an interesting topic. Single mutation refers to a carrier state of mutation, in that a mutation can be found in only one of the two alleles of parkin. Usually carriers are apparently normal, but at times they develop parkinsonism. The question is whether some single mutations may be sufficient to cause nigral neurodegeneration with a similar mechanism to double mutations of parkin, or whether single parkin mutations may predispose to late-onset sporadic PD. Foround et al. (2003) compared 41 patients who carried two mutations with 62 patients in whom only one mutation was found; mean age of onset was 41.3 years for the former and 56.3

75+ 18

50 21

45. 24

Fig. 9.6. An example of pseudoautosomal-dominant PARK2. Black squares and circles are affected members. White ones are unaffected members. Numbers below the square and the circle indicate age at examination (above) and age of onset (below). Homozygous deletion of exon 3 of parkin was detected in affected members. Therefore, the mode of pathogenesis is autosomal recessive. The mother of affected siblings in the last generation is believed to be a carrier of exon 3 deletion. In this family, consanguineous marriages suggest autosomal-recessive inheritance. Adapted from Kobayashi et al. (2003).

GENETIC ASPECTS OF PARKINSON’S DISEASE

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Fig. 9.7. A pseudoautosomal-dominant PARK 2 family. In this family, no consanguineous marriage was apparent. The mode of inheritance appears to be autosomal dominant. However, polymerase chain reaction (PCR) showed homozygous deletion mutation of exon 5 of parkin. The numbers of the PCR correspond to cases indicated in the pedigree. Black boxes are patients with parkinsonism; white boxes indicate unaffected individuals. Adapted from Kobayashi et al. (2003).

years in the latter group. However, the onset of age in patients with single mutations can be as early as in those with double mutations. Therefore, single mutations with parkinsonism may not always be sporadic late-onset PD. West et al. (2002a) analyzed 20 heterozygous patients and suggested the possibility of single mutations causing PD phenotype due to haploinsufficiency (where the mutant allele is negatively dominant, affecting the expression or function of the normal allele). Among the 16 families with parkin mutations reported by Oliveira et al. (2003a), single heterozygous mutations were found in 10 families. In these 10 families, mutations were concentrated in exon 7, in that six out of those 10 families showed a missense mutation in exon 7, one family showed missense mutations in exon 7 and 12 on the same chromosome, and the remaining three families showed 40 basepair deletion in exon 3. The age of onset in these patients, particularly those who had exon 7 mutations, was significantly older – 49.2 13.1 (exon 7 mutations) versus 31.5 11.2 years (non-exon 7 mutations); the highest age of onset among the former group was 71. The authors postulated that exon 7 heterozygous mutations may predispose to late-onset sporadic PD. Exon 7 is a mutational hot spot and the first RING is located here, and is a functionally important part of parkin protein. Therefore, a single mutation may have a neurotoxic effect on nigral neurons. Reduced uptake in the striatum was shown in parkin carriers by 18F-dopa PET study; Khan et al. (2005b) studied 13 parkin carrier subjects from families with known patients with parkin mutations by 18F-dopa PET scanning. Mean parkin

carrier caudate Ki value was 0.0120 0.003 (controls, 0.0153 0.0026, P ¼ 0.0008) and that of putamen 0.0126 0.0029 (controls 0.0169 0 0031, P ¼ 0.0022). Four out of 13 patients showed subtle extrapyramidal symptoms such as poor arm swing, facial masking, rest tremor or combinations of these. These patients were aged 30–69. Khan et al. suggested that parkin heterozygosity might contribute to late-onset PD. With regard to clinicogenetic correlation, no clear relationship has been found between the types of mutations and clinical features, except for the age of onset. Patients with point mutations tended to have later onset of age compared with those with deletion mutations (Abbas et al., 1999). This group divided their patients and patients from the literature into three groups according to the type of mutations: (1) patients with exonic mutations of parkin; (2) those with truncating mutations; and (3) those with missense mutations. The age of onset was 33.9 16.3 (range 7–58), 38.2 8.0 (range 27– 53) and 42.5 8.5 years (range 30–56), respectively. Thus there was a correlation with the type of mutation and the age of onset, but there are overlaps among these three groups. Probably patients with missense mutations have mutated parkin proteins in the brain. Regarding polymorphisms of the parkin gene, the following variations have been reported: Glu100His (Chen et al., 2003), His124His (Chen et al., 2003), Ser167Asn (Abbas et al., 1999; Wang et al., 1999), Arg271Ser (Chen et al., 2003), Ala339Ser (Chen et al., 2003), Arg366Try (Wang et al., 1999), Val380Leu (Abbas et al., 1999; Wang et al., 1999), Asp394Asn (Abbas et al., 1999),

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Arg402Try (Poorkaj et al., 2004), -258 T>G (West et al., 2002b), -324 A>G (Mata et al., 2002), -797 A>G (Mata et al., 2002) – the latter three polymorphisms are located in the promoter region – IVS2þ25T>C (West et al., 2002a), IVS3–20G>T (Oliveira et al., 2003a) and IVS7-35>G (West et al., 2002a) – the latter three polymorphisms are located in introns. None of these markers has been explicitly shown to be associated with increased or decreased risk for sporadic PD, although in some studies statistical differences were reported between frequency of PD and the type of polymorphism. Wang et al. (1999) reported lower frequency of Arg366Try polymorphic mutation in PD patients compared with controls (1.2 versus 4.4%). Mata et al. (2002) analyzed two single nucleotide polymorphisms (-324 A/G and -797 A/G) in the promoter regions and two previously described polymorphisms (Ser167Asn and Asp394Asn), but they found no association with sporadic PD. West et al. (2002b) reported genetic association of -258 T/G with sporadic PD; this is located in a promoter region of DNA that binds nuclear protein and functionally affects gene transcription. Lu¨cking et al. (2003) examined 194 patients with PD (92 familial and 102 sporadic) and 125 control subjects for the allele and genotype frequencies of Ser167Asn, Arg366Trp, Val380Leu and Asp394Asn polymorphisms. These authors found that homozygous Val380Leu was significantly associated with sporadic PD (P ¼0.008). There was also a trend toward an association of homozygous Asp394 with familial PD (P ¼ 0.07). Peng et al. (2003) found significantly higher genotype frequency of Ser167Asn in PD patients in China (17.3 versus 11.3%; P ¼ 0.04). On the other hand, Asn167 allele was more frequent in PD (46.6% versus 35.1%). However, Oliveira et al. (2003b) did not find any association with sporadic PD and seven common polymorphic variants of parkin. 9.1.2.3. Pathogenesis of PARK2 Parkin protein is more concentrated in the substantia nigra in human brain (Shimura et al., 1999; Solano et al., 2000), in contrast to rat brain, suggesting that it plays an important role in the survival of nigral neurons in humans. Solano et al. (2000) studied the expression of parkin, a-synuclein and UCH-L1 mRNA in 11 normal human brains using radiolabeled and digoxygenin-labeled cRNA probes. The expression of these three genes was predominantly neuronal. a-Synuclein and parkin mRNAs were expressed in a restricted number of brain regions, whereas UCH-L1 mRNA was more uniformly expressed throughout the

brain. The melanin-containing dopamine neurons of the substantia nigra had particularly robust expression. Because of the unique sequence of the parkin protein, we thought parkin was related to the UPS. The UPS is an important intracellular proteolysis system responsible for a wide variety of biologically important cellular processes, such as cell cycle progression, signaling cascades, developmental programs, the protein quality control system, DNA repair, apoptosis, signal transduction, transcription, metabolism, immunity and neurodegeneration (Hershko et al., 2000; Tanaka et al., 2004). The ubiquitin system consists of three enzymes: (1) a ubiquitin-activating enzyme (E1); (2) a ubiquitinconjugating enzyme (E2); and (3) a ubiquitin-protein ligase (E3) (Fig. 9.8). Ubiquitin (Ub), consisting of 76 amino acid residues, is first activated ATP-dependently by an E1, forming a high-energy thioester bond between ubiquitin and an E1, and the activated ubiquitin is then transferred to an E2. Then the E2 and a target protein are attached to an E3 and ubiquitin is transferred to the target protein and is covalently attached through its C-terminal Gly residue to the E-NH2 group of the Lys residue on the target proteins. Finally, a polyubiquitin chain is formed by repeated reactions, through which another ubiquitin links a Lys residue at position 48 (Tanaka et al., 2004). Shimura et al. (2000) first reported that parkin was involved in protein degradation as an E3. Parkin interacted with UbcH7 and UbcH8, ubiquitin-conjugating enzymes, and high-molecular-weight polyubiquitinated protein smears were found by Western blotting when 26S proteasome activity was inhibited by a specific inhibitor, MG132, in cultured cells. Imai et al. (2000) confirmed that parkin was a RING-type E3 ubiquitin-protein ligase which binds to E2 ubiquitin-conjugating enzymes (UbcH7 and UbcH8), through its RING-IBR-RING motif. Zhang et al. (2000b) also confirmed that parkin was an E2-dependent ubiquitinprotein ligase and found that CDCrel-1 interacted with parkin, suggesting that CDCrel-1 might be a substrate for parkin. These findings suggest that accumulation of a protein or proteins that have to be polyubiquitylated by parkin as an E3 ligase may be responsible for the nigral degeneration in PARK2. In line with this, many parkin-interacting proteins have been reported in the literature, including a synaptic vesicle-associated protein, CDCrel-1 (Zhang et al., 2000b), a cytoskeletal protein, actin filament (Huynh et al., 2000), glycosylated a-synuclein (Shimura et al., 2001), an endoplasmic reticulum membrane protein, PAEL receptor (Imai et al., 2001), a Lewy body-associated protein, synphilin-1 (Chung et al., 2001), a synaptic vesicle

GENETIC ASPECTS OF PARKINSON’S DISEASE

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Fig. 9.8. Ubiquitin-proteasome system. See text for details. Courtesy of Dr. Keiji Tanaka.

protein, CASK (Fallon et al., 2002), a chaperon, HSP70 (Imai et al., 2002), a HSP70-binding protein, CHIP (Imai et al., 2002), microtubule-associated proteins, aand b-tubulin (Ren et al., 2003), a structural component of the mammalian aminoacyl-tRNA synthetase complex, p38 (Corti et al., 2003), Rpn10 subunit of 26S proteasome (Sakata et al., 2003), an apoptosis-regulating protein, cyclin E (Staropoli et al., 2003), a septin family protein, SEPT5_v2, known as cell division control-related protein 2 (Choi et al., 2003), expanded polyglutamine protein (Tsai et al., 2003), bcl-associated athanogene 5, BAG5 (Kalia et al., 2004), DJ-1 (Moore et al., 2005), LRRK2 (Smith et al., 2005), protein-1 (Ko et al., 2006) and 14-3-3Z (Sato et al., 2006). Most of these parkin-interacting proteins were polyubiquitylated in vitro studies, except for CASK and Rpn10. Parkin co-localized with CASK, but parkin did not ubiquitylate CASK, suggesting a targeting or scaffolding role for parkin within the postsynaptic complex (Fallon et al., 2002). Rpn10 is a subunit of the regulatory subunit of the 26S proteasome; Rpn10 binds to the ubiquitin-like domain of parkin, so that 26S protea-

some comes close to polyubiquitylated proteins that are going to be destroyed by 26S proteasome (Sakata et al., 2003). Parkin also ubiquitinylated itself and promoted its own degradation (Zhang et al., 2000b). Although many parkin-interacting proteins have been reported in the literature, none has yet been explicitly shown to be accumulated in increased amounts in the brains of PARK2 patients. Therefore, the molecular mechanism of nigral neuronal death in the absence of normal parkin remains unknown. Further studies are needed to elucidate this question. Another interesting aspect regarding the pathogenesis of nigral neurodegeneration in PARK2 is the involvement of oxidative damage. We observed extensive accumulation of iron in the substantia nigra of three brains with known parkin mutations (Takanashi et al., 2001). Iron is known to promote oxidative damage. CDCrel-1, a putative substrate for parkin as E3 ligase, is a member of the septin family predominantly expressed in synaptic vesicle membranes negatively regulating the release of neurotransmitters (Beites et al., 1999). Therefore, if CDCrel-1 accumulates because of loss

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of function of parkin as E3 ligase, it can increase cytoplasmic dopamine, which can induce oxidative damage. But accumulation of CDCrel-1 in parkin mutated brain has not yet been documented. Hyun et al. (2002) examined the effect of parkin overexpression on cellular levels of oxidative damage, antioxidant defenses, nitric oxide production and proteasomal enzyme activity. Increasingly, overexpression of parkin by gene transfection in cultured cells led to increased proteasomal activity, decreased levels of protein carbonyls, 3-nitrotyrosine-containing proteins and a trend to a reduction in ubiquitinated protein levels. Transfection of these cells with DNA encoding three mutant parkins (Del 3–5, T240R and Q311X) gave smaller increases in proteasomal activity and led to elevated levels of protein carbonyls and lipid peroxidation. Rises in levels of nitrated proteins and increased levels of NO2–/NO3– were also observed in cells transfected with mutant parkins, apparently because of increased levels of neuronal nitric oxide synthase. Hyun et al. concluded that the presence of mutant parkin in substantia nigra in juvenile parkinsonism might increase oxidative stress and nitric oxide production, sensitizing cells to death induced by other insults. In addition, parkin has an antiapoptotic activity in experimental conditions (Jiang et al., 2004) amd parkin mutations were reported to affect complex I activity in peripheral leukocytes (Muftuoglu et al., 2004). Questions as to which function of parkin is essential for the survival of nigral neurons and what kind of abnormal function of parkin is responsible for nigral neuronal death in PARK2 remain unanswered. Petrucelli et al. (2002) reported that overexpression of parkin reversed the proteasome dysfunction induced by a-synuclein overexpression and neuronal death in cultured neurons. Proteasome dysfunction has been implicated as one of the most important mechanisms of neuronal death in sporadic and a-synulcein-mutated PD. Haywood and Staveley (2004) produced asynuclein transgenic Drosophila; the transgenic fly showed loss of climbing ability and degeneration of ommantidial array in the eyes. Coexpression of parkin prevented these a-synuclein-induced damages. Lo Bianco et al. (2004) used lentiviral vector to overexpress a-synuclein locally in the substantia nigra in rat; coexpression of parkin rescued a-synuclein-induced nigral neuronal loss. We used adeno-assciated viral vector to overexpress a-synuclein in rat and observed essentially similar neuronal rescue by coexpression of parkin (Yamada et al., 2005). As the expression patterns of a-synuclein and parkin mRNAs are similar, parkin protein and a-synuclein may be involved in common pathways contributing to the pathophysiology of PD (Solano et al., 2000).

Parkin-deficient mice produced by Goldberg et al. (2003) exhibited nigrostriatal dysfunction without loss of dopaminergic neurons. These authors did quantitative in vivo microdialysis which showed an increase in extracellular dopamine concentration in the striatum of parkin–/– mice. Intracellular recordings of mediumsized striatal spiny neurons showed greater currents that were required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Steady-state levels of parkin-interacting proteins, CDCrel-1, synphilin-1 and a-synuclein were unaltered in parkin–/– brains. Rodent nigral neurons, which do not have neuromelanin, may not require parkin for their survival. 9.1.3. Autosomal-dominant familial Parkinson’s disease linked to chromosome 2 (PARK3) PARK3 is an autosomal-dominant familial PD linked to the short arm of chromosome 2 (2p13). Gasser et al. (1998) reported six families with late-onset parkinsonism. Clinical features are essentially similar to those of sporadic late-onset PD; the age of onset was 36–89 years. Interestingly, penetrance was 40%, suggesting that some apparently sporadic PD patients may represent PARK3. In two families out of six patients developed dementia. Autopsy findings in two of those families showed nigral neurodegeneration and neurofibirillary tangle formation in cortical neurons. The causative gene has not yet been identified. West et al. (2001) sequenced 14 genes in the candidate region, but could not find a disease-associated mutation. 9.1.4. Autosomal-dominant familial Parkinson’s disease due to triplication of a-synuclein (PARK4) PARK4 is an autosomal-dominant familial PD caused by triplication or duplication of the a-synuclein gene (Singleton et al., 2003). In the triplication family, clinical features are those of diffuse Lewy body disease, i.e. late onset, levodopa-responsive parkinsonism and dementia. The initial family, an autosomal-dominant family with PD in the USA, was reported by Spellman in 1962. Muenter et al. (1998) made extensive clinical studies on the family reported by Spellman (1962). The autosomal-dominant family later reported by Waters and Miller (1994) was found to be another branch of the kindred reported by Spellman and Muenter. Since then this family has been called the Spellman–Muenter–Waters–Miller family. In autopsied patients, many cortical Lewy bodies were found in addition to nigral neurodegeneration with Lewy body formation and the pathological diagnosis suggested diffuse Lewy body disease.

GENETIC ASPECTS OF PARKINSON’S DISEASE This family was reported to be linked to the short arm of chromosome 4 (Farrer et al., 1999) but later, Singleton et al. (2003) found triplication of the a-synuclein gene in the affected members of this family; the 1.5 Mb region, including introns on both sides of the a-synuclein gene, was triplicated in a tandem fashion. Therefore, PARK4 should be reclassified as a form of PARK1. 9.1.5. Autosomal-dominant familial Parkinson’s disease due to UCH-L1 mutation (PARK5) 9.1.5.1. Clinical features of PARK5 PARK5 is an autosomal-dominant familial PD linked to the short arm of chromosome 4 (4p14–p15.1). To date only one family is reported (Leroy et al., 1998). Clinical features are very similar to those of late-onset sporadic PD, with the age of onset from 49 to 50 years. 9.1.5.2. Genetics of PARK5 The disease gene was reported as UCH-L1 (Leroy et al., 1998). Ile93Met missense mutation was found in the affected members of this family (Fig. 9.9). As only one family with this mutation was reported, the possibility of polymorphism for this mutation cannot be completely ruled out. Interestingly, Ser18Tyr polymorphism of UCH-L1 was associated with reduced risk of sporadic PD (Maraganore et al., 1999; Zhang et al., 2000a; Satoh and Kuroda, 2001; Elbaz et al., 2003). But there is still controversy about this issue (Mellick and Silburn, 2000). Deletion of exon 7 and 8 in mouse UCH-L1 causes gracile axonal dystrophy (gad) in mouse; this is an autosomal-recessive condition characterized by axonal degeneration and the formation of spheroid bodies in motor and sensory nerve terminals (Saigoh et al., 1999). 9.1.5.3. Pathogenesis of PARK5 UCH-L1 is an enzyme that cleaves carboxyterminal peptide bond of polyubiquitine chains. Thus UCH-L1 is an ubiquitin-recycling enzyme. Ubiquitin is an important protein to give proteins the signal for 26S 1

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proteasome degradation (Honore et al., 1991); UCH-L1 is a neuron-specific enzyme. Catalytic activity of Ile93Met-mutated UCH-L1 was reported to be half of the wild enzyme (Leroy et al., 1998). Thus it is expected that the supply of ubiquitin for 26S proteasome is reduced with this mutation. In addition, UCH-L1 undergoes dimerization and the dimers of UCH-L1 has a ubiquityl ligase activity (Liu et al., 2002). The natural substrate of UCH-L1 dimer as an E3 ligase is not known. The Ile93Met mutant form has increased ligase activity and the Ser18Tyr polymorphism, which may confer reduced risk for PD, has reduced ligase activity (Liu et al., 2002). Therefore, the dimerization of UCH-L1 appears to be related in some way to the pathogenesis of nigral neurodegeneration in PARK5 9.1.6. Autosomal-recessive familial Parkinson’s disease due to PINK1 mutations (PARK6) 9.1.6.1. Clinical features of PARK6 Clinical features of PARK6 are similar to those of PARK2, but the age of onset is somewhat older than that of PARK2. The age of onset of the original family studied by Valente et al. (2001) ranged from 32 to 48 years. Age of onset at 68 was also reported (Valente et al., 2002). Bentivoglio et al. (2001) studied 9 patients from three unrelated families with PARK6. Mean age at disease onset was 36 4.6 years. Clinical features were essentially similar to those of adult-onset sporadic PD. Dystonia and sleep benefit, which are common in young-onset PARK2, are not usually seen in PARK6 (Bentivoglio et al., 2001; Valente et al., 2002). But dystonia may be seen when the age of onset is young (Rohe et al., 2004). Cognition is normal (Bentivoglio et al., 2001). As with PARK2, 18F-dopa PET scan shows more extensive loss of uptake compared with sporadic PD. Khan et al. (2002) studied 4 patients who were homozygous for PARK6 and 3 asymptomatic relatives who were heterozygous for PARK6. The clinically affected

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Gracile axonal dystrophy mouse

Fig. 9.9. A schematic presentation of exons of ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1). Ile93Met mutation was found in an autosomal-dominant family with Parkinson’s disease. Ser18Tyr is a polymorphism that may confer neuroprotection against Parkinson’s disease. Deletion of exon 7 and 8 was found in the giant axonal degeneration in mice. The gene product consists of 223 amino acids. Figure reproduced from Mizuno et al. (2006), J Neural Transm (Suppl) 70: 191–204, with permission of the publisher, Springer-Wein, New York.

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Y. MIZUNO ET AL. 10, mutated in many human tumors (Steck et al., 1997). Hatano et al. (2004a) reported six families with PINK1 mutations, three Japanese carrying Arg246Stop, His271Gln or Glu417GLy, one Israeli family carrying Arg246Stop, one Filipino family carrying Leu347Pro and one Taiwan-Chinese family carrying compound heterozygous mutations of Glu239Stop and Arg492Stop. Since then the following mutations have been reported in PINK1: Arg147His missense mutation in exon 2 in Ireland (Healy et al., 2004b), 1573–1574 insTTAG causing a frameshift and truncation at the C-terminus of the PINK1 protein, outside the kinase catalytic domain (Rohe et al., 2004), Compound heterozygous and heterozygous mutations (single mutations) were also found (Valente et al., 2004a), as is the case of PARK2. Rogaeva et al. (2004) studied a series of 289 PD patients and 80 neurologically normal control subjects living in the USA; they identified 27 variants, including compound heterozygous mutations (Glu240Lys and Leu489Pro) and a homozygous Leu347Pro mutation in 2 unrelated young-onset PD patients. They concluded that PINK1 mutations are a rare cause of young-onset PD, Mutations of PINK1 in the literature are summarized in Fig. 9.10. PINK1 variants do not appear to be a risk factor for sporadic PD (Healy et al., 2004a). Groen et al. (2004) tested three common coding variations (Leu63Leu, Ala340Thr and Asn521Thr) in a series of 91 PD cases (Caucasian of Canadian origin) and 182 normal controls. They did not find any evidence of association between sporadic PD and any of the three SNPs (single nucleotide polymorphisms) at the allelic or genotypic levels (P > 0.25). Furthermore, they did not detect a modifying effect for any genotype on the age of onset in the PD group (P > 0.19).

PARK6 patients had 85% reduction in posterior dorsal putamen which was similar to that of sporadic PD, but they showed significantly greater involvement of head of caudate and anterior putamen. The group of asymptomatic PARK6 carriers showed a significant mean 20– 30% reduction in caudate and putamen. These changes are quite similar to those of PARK2-affected and carrier subjects (Portman et al., 2001; Scherfler et al., 2004). 9.1.6.2. Genetics of PARK6 PARK6 was delineated from other autosomal-recessive PD by linkage analysis; Valente et al. (2002) studied a large Sicilian family with four definitely affected members (the Marsala kindred). A genome-wide homozygosity screen and linkage analysis map-ped the disease locus at 1p35–p36 on chromosome 1. Then Hatano et al. (2004b) reported eight families, including three Japanese, two Taiwanese, one Turkish, one Israeli and one Philippine, linked to PARK6 locus with multipoint lod score of 9.88 at D1S2732. Valente et al. (2004a) identified PINK1 (PTENinduced kinase 1) as the causative gene for PARK6. They found two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families, a truncating nonsense mutation (W437X) and a missense mutation (Gly309Asg) at highly conserved amino acids. The cDNA of PINK1 comprises 1.8 kb with eight exons encoding a protein consisting of 581 amino acids. PINK1 is ubiquitously expressed in systemic organs as well as in brain. It is interesting to note that PINK1 is a mitochondrial protein (Valente et al., 2004a). Mitochondrial respiratory failure is an important pathogenetic factor in sporadic PD. PTEN stands for protein tyrosine phosphatase with homology to tensin and it is a tumor suppressor gene on chromosome

1

156 1

2

R68P R147H C92F

Ser/Thr protein kinase domain 3

4

H271Q P296L

A168P E240K Q239K D246X

5

L347P

G309D

6

581

509 7

8

L489P E476K D525N R464H I442T R492X 1573_4insTTAG W437X

E417G

Mitochondria targeting peptide

Fig. 9.10. A schematic presentation of exons of PINK1 and its mutations. Serine/threonine kinase domain is located from amino acid 156–509. As PINK1 is a mitochondrial protein, it has a mitochondrial targeting sequence, which is not incoorperated into the mature proteins. Summarized from Hatano et al. (2004a), Healy et al. (2004b), Rohe et al. (2004) and Valente et al. (2004a). Figure reproduced from Mizuno et al. (2006), J Neural Transm (Suppl) 70: 191–204, with permission of the publisher, Springer-Wein, New York.

GENETIC ASPECTS OF PARKINSON’S DISEASE 9.1.6.3. Pathogenesis of PARK6 Functions of the PINK1 protein are not known. As it has a kinase domain, there must be proteins that are phosphorylated predominantly by PINK1 within mitochondria. But candidate substrates for PINK1 are not known. 9.1.7. Autosomal-recessive familial Parkinson’s disease due to DJ-1 mutation (PARK7) 9.1.7.1. Clinical features of PARK7 PARK7 is an autosomal-recessive young-onset familial PD linked to the short arm of chromosome 1 at 1p36 (van Duijin et al., 2001). Bonifati et al. (2002) reported additional families; clinical features were essentially similar to those of PARK2. The age of onset was younger than that of PARK6. Clinical features include levodopa-responsive parkinsonism of varying severity with levodopa-induced motor fluctuation and dyskinesia. Interestingly, 3 out of 4 patients in the original family showed psychiatric disturbances (anxiety attacks) (Dekker et al., 2003). Atypical clinical features include short statue and brachydactyly, which were found in a Dutch kindred (Dekker et al., 2004). 9.1.7.2. Genetics of PARK7 Van Duijin et al. (2001) identified a family with earlyonset parkinsonism with multiple consanguinity loops in a genetically isolated population. Homozygosity mapping resulted in significant evidence for linkage on chromosome 1p36. The region defining the disease haplotype could be separated, by 25 cM, from the more centromeric PARK6 locus on chromosome 1p35–36. Bonifati et al. (2003) found mutations in DJ-1 in patients with early-onset PD linked to 1p36; they

1a

1b

2

M26I

3

E64D

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found compound heterozygous mutations consisting of a 14 kb deletion from exon 1 to exon 5 and a Leu166Pro missense mutation. Genomic DNA of human DJ-1 comprises 9 exons spanning about 24 kb, in which 2–7 exons encode the 189-amino-acid protein (Taira et al., 2001). Exons 1a and 1b are spliced and non-coding. DJ-1 protein is ubiquitously expressed in the cytoplasm of brain. Hague et al. (2003) found two new mutations in DJ-1 (Arg98Gln and Ala104Thr) and additional heterozygous mutations (c.56delC c57G->A, IVS6-G->C); the second mutation could not be found. Abou-Sleiman et al. (2003) found two additional missense mutations (Met26Ileu, Asp149Ala). Hering et al. (2004) found a novel Glu64Asp mutation in a German family. DJ-1 mutations are rare. Abou-Sleiman et al. (2003) studied 185 unrelated young-onset (below the age of 40) PD patients and a separate cohort of 190 pathologically proven cases of PD. Estimated frequency of DJ-1 mutations was approximately 1% among young-onset cases. No mutations were found in their cohort of later-onset sporadic pathologically confirmed cases. Healy et al. (2004c) studied 39 autosomal-recessive families for DJ-1 mutations, but they could not find a case and Hedrich et al. (2004a) studied 100 early-onset cases and found only 2 patients with DJ-1 mutations; in contrast, parkin mutations were found in 17 of the same population. Ibanez et al. (2003) also failed to find a DJ-1 mutation in a large series of early-onset autosomal-recessive PD families. Lockhart et al. (2004) also failed to find a DL-1 mutation in 41 Taiwanese ethnic Chinese patients with early-onset parkin-negative PD patients. Tan et al. (2004) failed to find a DJ-1 mutation in Chinese, Malay and Indian cohorts. Mutations of DJ-1 reported in the literature are summarized in Fig. 9.11. Regarding the polymorphisms of DJ-1, Hague et al. (2003) reported seven non-coding variants in DJ-1. Eerola et al. (2003) studied the frequency of

4

5

R98Q A104T

6

7

D149A L166P

Non-coding c56delG c57G>A,

IVS6-G>C

Fig. 9.11. A schematic presentation of exons of DJ-1 and mutations reported in the literature. Bars above the exons indicated deletion mutations and arrows below the exons indicate missense mutations and small deletions. Exons 1a and 1b are spliced out from the mature protein. The total number of amino acids is 189. Summarized from Abou-Sleiman et al. (2003), Bonifati et al. (2003), Hague et al. (2003) and Hering et al. (2004). Figure reproduced from Mizuno et al. (2006), J Neural Transm (Suppl) 70: 191–204, with permission of the publisher, Springer-Wein, New York.

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g.168–185del in Finnish sporadic PD patients; no significant change from the controls was found. Morris et al. (2003) also found no association with polymorphisms of DJ-1 with sporadic PD or with dementia with Lewy bodies, including the exon 1 deletion polymorphism. Clark et al. (2004) studied a cohort of 89 early-onset PD and found no disease-associated mutations; however, they found a polymorphism in the coding region in exon 5 (Arg98Gln), three polymorphisms in the 50 untranslated region (exon 1A/1B) and two polymorphisms in intronic regions (IVS1 and IVS5). Thus polymorphism of DJ-1 does not constitute a risk factor for sporadic PD. 9.1.8. Pathogenesis of PARK7 DJ-1 has been identified as a novel oncogene that transforms mouse NIH3T3 cells in cooperation with activated ras and maps them to 1p36.2-p36.3 (Nagakubo et al., 1997). This has been shown to be a hot spot of chromosome abnormalities in several tumor cells (Taira et al., 2001). The function of DJ-1 protein is not yet elucidated. In autopsied human brains, DJ-1 protein is mainly expressed in astrocytes and ubiquitously present in the brain (Bandopadhyay et al., 2004; Neumann et al., 2004). Interestingly DJ-1 protein was reported to colocalize with tau inclusions of tauopathies (Rizzu et al., 2004). Furthermore, tau inclusions in Pick disease, corticobasal degeneration, progressive supranuclear palsy and Alzheimer’s disease were DJ-1 protein-positive (Neumann et al., 2004), indicating that DJ-1 protein is also present within neurons. DJ-1 protein undergoes dimer formation to become active (Honbou et al., 2003; Tao and Tong, 2003) and one of the PD-inducing point mutations, Leu166Pro, interferes with dimer formation (Wilson et al., 2003) and is more rapidly degraded than wild DJ-1 protein by UPS (Macedo et al., 2003; Miller et al., 2003) or by autoproteolysis (Gorner et al., 2004). Furthermore, this mutant DJ-1 protein is mislocalized to mitochondria; on the other hand, wild-type DJ-1 protein is ubiquitously localized within cells (Bonifati et al., 2003). Downregulation of endogenous DJ-1 protein of the neuronal cell line by siRNA was reported to enhance the cell death which was induced by oxidative stress, endoplasmic reticulum (ER) stress and proteasome inhibition, but not by proapoptotic stimulus (Yokota et al., 2003). Furthermore, DJ-1 protein rescued the cell death caused by overexpression of Pael receptor, a putative substrate of Parkin. DJ-1 protein is readily oxidized at cysteine 106 and the oxidized DJ-1 protein relocalized to mitochondria (Canet-Aviles et al., 2004); this modification appears to be a molecular mechanism of the antioxidative property of DJ-1

protein. The Leu166Pro mutant DJ-1 protein has reduced antioxidative activity (Takahashi-Niki et al., 2004). DJ-1 protein expression is increased on oxidative stress induced by paraquat (Mitsumoto et al., 2001). Thus DJ-1 protein appears to be acting as an important antioxidant protein in the substantia nigra. It is interesting to note that parkin also has an antioxidative property (see section 9.1.2). As nigral neurons are exposed to high oxidative stress because of the presence of dopamine, the hypothesis that DJ-1 protein is acting as a strongly antioxidative protein appears to be a plausible one. Although no autopsy has been reported on PARK7, from the clinical features, the substantia nigra is probably the main lesion. Nondopaminergic neurons with low oxidative stress may not need DJ-1 protein. This hypothesis explains well selective nigral lesions despite the widespread absence of normal DJ-1 protein in PARK7 patients. 9.1.9. Autosomal-dominant familial Parkinson’s disease due to LRRK2 mutation (PARK8) 9.1.9.1. Clinical features of PARK8 The clinical features of PARK8 were first described by Nukada et al. in a Japanese journal in 1978. These authors described a large kindred with PD of autosomal dominant inheritance. The number of affected patients was 36 in five generations. Men and women were equally affected (men ¼ 18, women ¼ 18). The age of onset ranged from 38 to 68 years (mean 53). Later the mean age of onset was reported as 51 6 years, as the number of affected members increased (Funayama et al., 2002). Among the 10 patients in whom detailed examination was possible, the initial symptom was gait disturbance in 5 and rest tremor in 5. All of these 10 patients had three cardinal symptoms of PD: rest tremor, cogwheel rigidity and bradykinesia. At the time of evaluation, 1 patient was at stage V on the Hoehn and Yahr scale, 2 were at stage III, 5 were at stage II and 2 were at stage I. Eight of these 10 patients were being treated with levodopa with good response and the remaining 2 patients were being treated with an anticholinergic drug, which was also effective. Two of the 10 patients had motor fluctuations and two had psychiatric side-effects. Thus the clinical features of this family are very similar to those of sporadic PD, except for the slightly younger age of onset. No cognitive impairment was observed. Postmortem examination was performed on 4 patients and they showed pure nigral degeneration without Lewy body formation (Funayama et al., 2002). But later on another patient who came to autopsy showed nigral degeneration with Lewy bodies (K. Hasegawa, personal communication).

GENETIC ASPECTS OF PARKINSON’S DISEASE The western Nebraska family (family D) reported by Wszolek et al. (1995) turned out to be PARK8. These researchers reported 18 patients (men ¼ 6, women ¼ 12) over five generations. The mode of inheritance was autosomal dominant. The age of onset was 48–78 years (mean 63). The initial symptom was bradykinesia or tremor. Four cardinal symptoms of PD were observed in most of the examined patients. No atypical features such as dementia, autonomic failure, pyramidal signs or cerebellar ataxia were seen. Patients showed good response to levodopa. One of the patients came to autopsy and showed nigral degeneration, gliosis and occasional Lewy bodies; no cortical Lewy bodies were seen. Later on 3 additional patients from this family were examined postmortem (Wszolek et al., 2004). The second patient showed total loss of pigmentation of the nigra and locus ceruleus with marked gliosis. Senile plaques were seen in frontal, temporal, parietal and entorhinal cortices, amygdala and hippocampus. Cortical Lewy bodies and Lewy neurites were also seen. The pathological diagnosis was consistent with diffuse Lewy body disease. The third patient showed nigral neuronal loss and gliosis: no Lewy bodies were found anywhere; instead neurofibrillary tangles and a few tau-positive glia were present in the basal forebrain, striatum, subthalamic nucleus and brainstem nuclei. The fourth patient showed marked neuronal loss and gliosis in the nigra and locus ceruleus. No Lewy bodies or tau-positive neurons were found in any place in the brain. The substantia nigra showed simple atrophy. Four different pathological findings in the same family are very interesting, indicating the difficulty of defining a disease entity by neuronal inclusions. Family A, reported by Denson and Wszolek in 1995, also turned out to be linked to the PARK8 locus (Zimprich et al., 2004a). Clinical features of this family included average age of onset at 51 years (range 35–60), tremor as the initial symptom in all affected patients examined, and four cardinal symptoms of PD. One of these patients showed distal muscle weakness, atrophy and the presence of fasciculation. All the patients responded well to levodopa. 9.1.9.2. Genetics of PARK8 Funayama et al. (2002) made a linkage analysis on the family reported by Nukada et al. (1978). They studied 15 affected and 12 unaffected patients and 4 spouses from this family, using 382 microsatellite markers covering chromosomes 1–22. They mapped the disease locus at 12p11.2–q13.1, 16-cM region of chromosome 12. The maximum multipoint lod score was 24.9 at D12S345. Then Zimprich et al. (2004b) did a linkage analysis on autosomal-dominant families living

235

in western societies, including families A (Denson & Wszolek, 1995) and D (Wszolek et al., 1995), reported previously. Both of these families reached significant linkage on their own, with a combined maximum multipoint lod score of 3.33. The authors mapped the disease locus between a CA repeat polymorphism on genomic clone AC025253 and marker D12S1701. Then two groups (Paisan-Ruiz et al. (2004); Zimprich et al., 2004a) reported the discovery of the PARK8 gene almost simultaneously. Paisan-Ruiz et al. (2004) studied four autosomal-dominant families with PD in the Basque region of Spain and a family from the UK that each showed positive linkage to the PARK8 locus. Clinical phenotypes were remarkably similar to those of sporadic PD, with age of onset around 65 years. The researchers found two mutations that segregated with affected patients in a putative kinase domain-containing transcript, which contained 7449 basepair open-reading frame-encoding 2482 amino acids, including a leucine-rich repeat, a kinase domain, a Ras domain and a WD40 domain. They identified a variant, Arg1396Gly (Arg1441Gly according to the numbering of Zimprich et al., 2004b), in all the affected members in Basque families and Tyr1654Cys (Tyr1699Cys according to the numbering of Zimprich et al., 2004a) that was segregated with the affected members of the family in the UK. Arg1396Gly variants were found in 11 Spanish PD patients and in 10 Basque PD patients, of whom 6 had a positive family history for PD. They named this gene dardarin, which means tremor in the Basque dialect. Zimprich et al. (2004a) studied family A (Denson and Wszolek, 1995) and family D (Wszolek et al., 1995), reported previously. They sequenced a total of 29 genes in the candidate region. They found missense mutations in a large gene, LRRK2, in family A (Tyr1669Cys) and in family D (Arg1441Cys). Then they analyzed 44 additional families with PD. They found two additional missense and one putative splice site mutation (Ile1122Val; 3364A>G, Ile2020Thr; 6059T>C, Leu1114Leu; 3342A>G). The gene spanned over 144 kb with an open reading frame consisting of 7449 basepairs in 51 exons encoding 2527 amino acids with a molecular weight of 9 kD. The LRRK2 protein was expressed in most brain regions. The difference in the numbering system between that of Paisan-Ruiz et al. (2004) and Zimprich et al. (2004a) was ascribed to the fact that exon 6 was not included in the gene cloned by Paisan-Ruiz et al. (2004). Today the numbering system of Zimprich et al. (2004a) is used. Then Nichols et al. (2005) reported a novel mutation (Gly2019Ser) and analyzed the frequency of this

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mutation in 767 patients with PD from 358 multiplex families. Thirty-five individuals (5%) were either heterozygous (34) or homozygous (one) for the mutation, and had typical clinical findings of idiopathic PD. Then Di Fonzo et al. (2005) analyzed 61 unrelated families originating from Italy, Portugal and Brazil; they found the Gly2019Ser mutation in 4 of 61 (6.6%). Gilks et al. (2005) examined 482 sporadic PD patients for the Gly2019Ser mutation. They found this mutation in 8 (1.6%) patients. Mutations of LRRK2 reported in the literature are summarized in Fig. 9.12. 9.1.9.3. Pathogenesis of PARK8 LRRK2 belongs to the recently characterized Roco protein family; Roco protein is the name given to a family of proteins that contain both ROC and COR domains (Bosgraaf and Haastert, 2003). ROC stands for Ras (a group of guanosine triphosphate (GTP)binding small proteins) in complex proteins and belongs to the Ras/GTPase superfamily. COR stands for C-terminal of ROC and consists of 300–400 amino acids without any significant sequence homology to other known proteins. In many Roco proteins mitogeninduced kinase kinase kinase (MPKKK) domain follows after COR. Furthermore, in many Roco proteins the Roc domain is preceded by 3–16 leucine-rich repeats (Fig. 9.12). The WD domain after the MPKKK domain in LRRK2 represents a domain rich in tryptophan (W) and aspartate (D) repeats. The functions of most WD-repeat domains are poorly understood (Smith et al., 1999). The functions of Roco proteins are not well known; some of the Roco proteins are

related to signal transduction, cell proliferation, cell evolution, apoptosis, cell death, and so on (Bosgraaf and Haastert, 2003). The function of LRRK2 is also unknown. As with the MPKKK domain, it may be regulating phosphorylation of a-synuclein in some way. 9.1.10. Autosomal-recessive familial Parkinson’s disease linked to chromosome 1 (PARK9) PARK9 is an autosomal-recessive disorder characterized by levodopa-responsive parkinsonism, supranuclear gaze palsy, pyramidal sign and dementia, called Kufor–Rakeb syndrome. The age of onset is 10–20 years. The gene locus has been mapped to the short arm of chromosome 1 at 1p36 (Hampshire et al., 2001). Recently, Ramirez et al. (2006) identified mutations in a lysosomal ATPase gene, ATP13A. Neuropathological findings revealed neurodegeneration not only in the substantia nigra but also in the pyramidal tract, putamen and pallidum. 9.1.11. Parkinson’s disease linked to chromosome 1 (PARK10, Icelandic) The PARK10 locus was found by genome-wide scanning on familial as well as sporadic cases of PD living in Iceland (Hicks et al., 2002). Hicks et al. did a genome-wide scan on 117 Icelandic PD patients and 168 of their unaffected relatives within 51 families using 781 microsatellite markers. Allele-sharing, model-independent analysis of their results showed linkage to a region on chromosome 1p32 with a lod

aa 1000

2527

LRR 3342A>G Ex24

I1122V Ex25

Leucinerich repeat

Protein-protein interaction

ROC

R1441C Ex31 Belongs to Ras/GTPase superfamily

MAPKKK

COR

Y1699C Ex35

G2019S I2020T Ex41 Ex41

C-terminal of Roc

Reorganization of actin cytoskeleton

WD

Signal transduction Tyrosine kinase catalytic domain

Transfer of gamma-P of ATP to Tyr

Fig. 9.12. A schematic presentation of the homology region of LRRK2 protein and mutations reported in the literature. The amino-terminal side of the protein in the upstream of amino acid 1000 is a non-homology region. LRR, leucine-rich repeat; ROC, ras of complex protein; COR, carboxy-terminal of ROC; MAPKKK, mitogen-induced protein kinase kinase kinase; WD, tryptophan and aspartate (a region rich in WD repeats); ATP, adenosine triphosphate. The schema was adapted from Zimprich et al. (2004a) and mutations were summarized from Zimprich et al. (2004b), Paisan-Ruiz et al. (2004) and Kachergus et al. (2005).

GENETIC ASPECTS OF PARKINSON’S DISEASE score of 4.9. The researchers designated this region PARK10. The disease gene has not yet been identified. Thus clinical features are essentially similar to those of sporadic PD and the mean age of onset was 65.8 years. 9.1.12. Autosomal-dominant familial Parkinson’s disease linked to chromsome 2 (PARK11) PARK11 is an autosomal-dominant familial PD linked to the long arm of chromosome 2 at 2q36–q37 (Pankratz et al., 2003a). Clinical features are essentially similar to those of sporadic PD, with the mean age of onset at 58 years. Neuropathological findings are not known and the disease gene has not yet been identified. 9.1.13. Other forms of familial Parkinson’s disease PARK12 locus (Xq21–25) was found by genome-wide association studies on sporadic PD patients (Panratz et al., 2003b). In PARK13-associated PD (2p13), Strauss et al. (2005) found a missense mutation in Omi/HtrA2 gene in 4 sporadic PD patients. Omi/HtrA2 protein has a serine protease domain and a mitochondrial targeting sequence. There are many other families in which linkage analysis failed to show linkage to any one of the known loci that are associated with familial forms of PD. Such reports are increasing every year. Progress in the molecular cloning of new genes for familial PD and elucidation of the functions of the disease genes will definitely contribute to the understanding of the molecular mechanism of nigral neurodegeneration of sporadic PD. Such information will help the development of disease-modifying new treatments for PD.

Acknowledgments This study was supported in part by Grant-in-Aid for Scientific Research on Priority Areas and Grant-inAid for High Technology Centers from the Ministry of Education, Science, Sports, and Culture, Japan; Grant-in-Aid for Health Science Promotion and Grant-in-Aid for Neurodegenerative Disorders from Ministry of Health and Welfare, Japan; and by the Center of Excellence Grant from the National Parkinson Foundation, Miami, USA.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 10

Imaging Parkinson’s disease DAVID J. BROOKS* MRC Clinical Sciences Centre and Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK

10.1. Introduction 10.1.1. Imaging approaches Imaging the changes associated with the pathology of Parkinson’s disease (PD) broadly falls into two categories: (1) detecting alterations in brain structure; and (2) examining functional changes in brain metabolism and receptor availability. Using high-field magnetic resonance imaging (MRI), brain structural changes can be evidenced as regional or whole-brain reductions in volume, signal alterations in water relaxation, e.g.T2weighted scans, water diffusion (diffusion-weighted or tensor imaging) and magnetization transfer coefficients. Additionally, MRI allows structural lesions, such as basal ganglia tumors and calcification, multi-infarct disease and hydrocephalus, to be excluded. Recently it has been reported that transcranial ultrasonography can detect structural midbrain changes in parkinsonian disorders, manifested as hyperechogenicity. Functional imaging (positron emission tomography (PET), single photon emission computed tomography (SPECT), MRI and proton magnetic resonance spectroscopy (MRS)) provide a means of detecting and characterizing the regional changes in brain metabolism and receptor binding associated with parkinsonian disorders. These approaches can be of diagnostic value and also help to throw light on the pathophysiology and pharmacology underlying parkinsonian syndromes. PET and SPECT are both radiotracer-based and they potentially provide a sensitive means of detecting subclinical disease in subjects at risk for subcortical degenerations and biomarkers for objectively following disease progression. PET has the highest sensitivity of these functional imaging modalities, being able to detect femtomolar

levels of positron-emitting radioisotopes at a spatial resolution of 2–4 mm. It allows quantitative in vivo examination of alterations in regional cerebral blood flow (rCBF), glucose, oxygen and dopa metabolism, and brain receptor binding. SPECT is less sensitive but more widely available and provides measures of rCBF and receptor binding with a resolution of 5 mm in state-of-the-art systems. MRS has far lower sensitivity and spatial resolution than the two radioisotope imaging approaches, requiring millimolar metabolite levels and providing a spatial resolution of around 1 cm. Proton MRS can detect N-acetyl aspartate, lactate, creatine and phospholipid signals whereas 31P-MRS can measure creatine phosphate, adenosine triphosphate and adenosine diphosphate levels. Finally, with the blood oxygenation level imaging (BOLD) technique functional MRI can detect activation-induced changes in venous blood oxygenation draining brain regions when subjects perform tasks. Although structural MRI has submillimeter resolution, fMRI activation studies are usually smoothed to a spatial resolution of around 3 bmm to improve signal-to-noise ratios. The changes in regional cerebral function that characterize parkinsonian disorders can be examined in two main ways: first, focal changes in resting levels of regional cerebral metabolism, blood flow and neuroreceptor availability can be measured. Second, abnormal patterns of brain activation or levels of neurotransmitter release can be detected when patients with PD perform motor and cognitive tasks or are exposed to drug challenges. 10.1.1.1. Pathological considerations The pathology of the degenerative typical and atypical parkinsonian disorders targets the dopamine cells in the substantia nigra. In the case of PD, neuronal loss

*Correspondence to: David J Brooks MD DSc FRCP FMed Sci, Imperial College London, Cyclotron Building, Hammersmith Hospital, Du Cane Rd, London W12 0NN, UK. E-mail: [email protected], Tel: þ44-(0)208-383-3172, Fax: +44-(0) 208-1783/2029.

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occurs in association with the formation of intraneuronal Lewy inclusion bodies. Serotonergic cells in the median raphe, noradrenergic cells in the locus ceruleus and cholinergic cells in the nucleus basalis are also involved, but to a lesser extent, as are other pigmented and brainstem nuclei. Multiple system atrophy (MSA) is characterized pathologically by argyrophilic, a-synuclein-positive inclusions in glia and neurons in substantia nigra, striatum, brainstem and cerebellar nuclei, and intermediolateral columns of the cord. Progressive supranuclear palsy (PSP) is associated with neurofibrillary tangle inclusions and neuronal loss in the substantia nigra, pallidum, superior colliculi, brainstem nuclei and the periaqueductal gray matter. Corticobasal degeneration (CBD) cases have collections of swollen, achromatic, tau-positive staining Pick cells without argyrophilic Pick bodies targeting the posterior frontal, inferior parietal and superior temporal lobes, the substantia nigra and the cerebellar dentate nuclei. Loss of cells from the substantia nigra in parkinsonian disorders results in profound dopamine depletion in the striatum. In PD and MSA the lateral nigral projections to the posterior dorsal putamen are most affected whereas in PSP and CBD the nigrostriatal projections are uniformly targeted. In non-demented cases of PD it is also possible to detect Lewy body inclusions at postmortem in the anterior cingulate cortex and frontal, parietal and temporal association areas. Currently, it remains unclear whether dementia of Lewy body type, PD dementia and non-demented PD all represent a spectrum of Lewy body disease. Dementia of Lewy body type has overlapping clinical features with Alzheimer’s disease, though is associated with a higher prevalence of fluctuating confusion, hallucinations, early-onset rigidity and gait difficulties. Alzheimer’s disease is twice as prevalent in PD and, at postmortem, cases of PD with dementia can show a mixture of Alzheimer changes and cortical Lewy body inclusions. 10.1.1.2. Imaging the presynaptic dopaminergic system In PD the integrity of the substantia nigra and its dopaminergic projections can be examined with both structural and functional imaging approaches, as described below. 10.1.1.2.1. Transcranial sonography Transcranial sonography (TCS) is capable of detecting increased midbrain echogenicity in parkinsonian syndromes (Berg et al., 2001a). A total of 103 out of 112 patients with established PD showed midbrain hyperechogenicity (employing a threshold of 1 standard

deviation (SD) above the normal mean). This increased signal was most noticeable contralateral to the more clinically affected limbs and pathological studies have suggested that it may represent increased iron deposition in the substantia nigra (Berg et al., 2002). Increased midbrain echogenicity has also been reported in clinically affected homozygous or compound heterozygote parkin gene carriers along with reduced striatal 18 F-dopa uptake (Walter et al., 2004). In a 5-year follow-up study of PD cases, however, it was reported that there was no significant change in TCS findings (Berg et al., 2005). This suggests that the presence of midbrain hyperechogenicity may be a trait rather than state marker for susceptibility to parkinsonism. 10.1.1.2.2. MRI High-field MRI, utilizing special gray- and white-matter signal-suppressing inversion recovery sequences, has detected abnormal signal from the substantia nigra compacta in PD patients. In one series (Hutchinson and Raff, 2000), all 6 cases with established disease showed altered nigral signal whereas in a second series (Hu et al., 2001), 7 out of 10 patients showed nigral MRI abnormalities. All 10 PD cases in this second series had reduced putamen 18F-dopa uptake. The true sensitivity and specificity of this MRI approach for diagnosing PD remain to be established. 10.1.1.2.3. PET and SPECT The function of dopamine terminals in PD can be examined in vivo in several ways (Brooks et al., 2003): (1) terminal dopa decarboxylase activity can be measured with 18F-dopa PET; (2) the availability of presynaptic dopamine transporters (DAT) can be assessed with tropane-based PET and SPECT tracers; (3) vesicle monoamine transporter (VMAT2) density in dopamine terminals can be examined with 11C-dihydrotetrabenazine (DHTBZ) PET (Fig. 10.1). In early hemiparkinsonian cases these radiotracerbased imaging approaches all show bilaterally reduced putamen dopaminergic function: activity is most depressed in the putamen contralateral to the affected limbs. The head of caudate and ventral striatal function is generally spared or only mildly impaired. PET and SPECT can, therefore, detect subclinical disease evidenced as involvement of the ‘asymptomatic’ putamen contralateral to clinically unaffected limbs. It has been estimated that clinical parkinsonism occurs when PD patients have lost around 50% of their posterior putamen dopamine terminal function, the most targeted region. On average, PD patients with established disease show a 60–80% loss of specific putamen dopamine

IMAGING PARKINSON’S DISEASE

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123I-β-CIT

123I-FP-CIT

11C-DTBZ

18F-dopa

DAT

DAT

VMAT2

DDC

Healthy

PD

Fig. 10.1. For full color figure, see plate section. Images of striatal b-CIT single photon emission computed tomography (SPECT) (dopamine transporter: DAT), FP-CIT SPECT (DAT), 11C-dihydrotetrabenazine (11C-DTBZ) positron emission tomography (PET) (vesicle monoamine transporter: VMAT2) and 18F-dopa PET (dopa decarboxylase: DDC) uptake in (top) healthy volunteers and (bottom) early Parkinson’s disease (PD). [b-CIT: 2-b-carboxymethoxy-3(4-iodophenyl tropane); FP-CIT: ioflupane] It can be seen that the four imaging modalities all show asymmetrically reduced posterior putamen dopaminergic function in Parkinson’s disease.

terminal function in life. This compares with a reported 60–80% loss of ventrolateral nigra compacta cells and 95% loss of putamen dopamine at postmortem. These findings suggest that imaging measures of striatal dopamine terminal activity may underestimate the loss of endogenous dopamine in PD. It is known that the pathology of PD is not uniform; ventrolateral nigral dopaminergic projections to the dorsal putamen are more affected than dorsomedial projections to the head of caudate. 18F-dopa PET reveals that, in patients with unilateral PD [Hoehn and Yahr (H & Y) stage 1 disability], contralateral dorsal posterior putamen dopamine storage is first reduced (Morrish et al., 1995). As all limbs become clinically affected, ventral and anterior putamen and dorsal caudate dopaminergic function also become involved. Finally, when PD is well advanced, ventral head of caudate 18F-dopa uptake starts to fall. Not all dopamine fibers degenerate in early PD. Nigrostriatal projections comprise the densest dopamine pathway but there is a lesser medial nigral-internal pallidal pathway. The striatum is the main input and the globus pallidus interna (GPi) the main output nucleus of the basal ganglia; nigral dopamine projections modulate the function of both these structures. Whereas 18 F-dopa uptake in the putamen is reduced overall by 30–40% at the onset of parkinsonian rigidity and brady-

kinesia, uptake of this tracer in the GPi is increased by 50% but subsequently falls below normal as the disease advances (Whone et al., 2003a). Reduced pallidal 18 F-dopa storage coincides with the onset of accelerated disability and treatment complications, such as fluctuating responses to levodopa, suggesting that both putamen and GPi require an intact dopamine system to facilitate efficient fluent limb movements. PET radiotracers available for measuring DAT binding on nigrostriatal terminals include 11C-CFT ([11C]2-carbomethoxy-3-(4-fluorophenyl) tropane) and 18 F-CFT, 11C-RTI-32 (methyl(1R-2-exo-3-exo)-8methyl-3-(4-methylphenyl)-8-azabicyclo-octane-2-carboxylate), 11C-nomifensine and 11C-phenylethylamine (Brooks et al., 2003). These ligands bind to both dopamine and norepinephrine reuptake sites. SPECT tracers available include the tropane analogs 123I-b-CIT, 123 I-FP-CIT,123I-altropane, and 99mTc-TRODAT-1. 123 I-b-CIT gives the highest striatal-to-cerebellar uptake ratio of these SPECT tracers but this reflects low cerebellar non-specific rather than higher striatalspecific uptake and so this tracer provides a potentially noisy reference signal. It binds non-selectively to dopamine, norepinephrine, and serotonin transporters and has the disadvantage that it takes 24 h to equilibrate throughout the brain following intravenous injection, so scanning has to be delayed until the following

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day. For this reason, SPECT tracers such as 123I-FP-CIT and 123I-altropane have been developed as, despite their lower striatal-to-cerebellar uptake ratios, a diagnostic scan can be performed within 2–3 h of tracer injection. More recently, a technetium-based tropane tracer, 99m Tc-TRODAT-1, has been developed. This gives a lower 2:1 striatal-to-cerebellar uptake ratio than the 123 I-based tracers and is less well extracted by the brain but has the advantage that 99mTc is readily available (Mozley et al., 2000). In series where clinically probable PD and essential tremor cases were compared, imaging the dopamine system with PET and SPECT has been shown to differentiate these conditions with a sensitivity and specificity of around 90% (Brooks et al., 1992b; Benamer et al., 2000). Given this, a positive PET or SPECT scan can be valuable for supporting a diagnosis of PD where there is diagnostic doubt. Three studies have now examined the role of DAT imaging in aiding the diagnosis of gray parkinsonian cases. All three concluded that management of these cases could be rationalized and improved by including SPECT in the work-up though, as the pathology of these cases still remains unclear, clinical follow-up remained the gold standard (Booij et al., 2001; Catafau and Tolosa, 2004; Jennings et al., 2004). It is unclear whether the finding of normal dopaminergic function with PET or SPECT fully excludes a diagnosis of PD. Long-term follow-up studies on patients clinically thought to have PD but with normal 18F-dopa PET imaging have continued to show discordance between clinical impression and imaging findings though no cases, to date, have developed loss of dopaminergic function or clinically progressed (Brooks, unreported observations). This would suggest that a finding of normal presynaptic

Healthy Volunteer

dopaminergic function on imaging is associated with a good prognosis whatever the ultimate diagnosis. Putamen uptake of PET and SPECT dopaminergic tracers shows an inverse correlation with degree of locomotor disability in PD, reflecting limb bradykinesia and rigidity rather than rest tremor severity (Vingerhoets et al., 1997). Relative to the dopamine vesicle transporter marker, 11C-DHTBZ, it has been shown that putamen 18 F-dopa uptake is relatively upregulated and binding of the DAT marker 11C-methylphenidate is relatively downregulated in PD (Lee et al., 2000). This finding makes physiological sense as increased dopamine turnover and decreased reuptake in a dopamine deficiency syndrome should help to preserve synaptic transmitter levels.

10.2. Serotonergic, noradrenergic and cholinergic function in Parkinson’s disease In PD there is loss not only of dopamine but also serotonin, norepinephrine and cholinergic projections. Median raphe serotonin HT1A binding in the midbrain, measured with 11C-WAY100635 PET, reflects the functional integrity of serotonergic cell bodies. In PD one series has reported a mean 25% loss of median raphe HT1A binding which, interestingly, correlated with severity of rest tremor but not rigidity or bradykinesia (Fig. 10.2; Doder et al., 2003). This suggests that midbrain tegmentum pathology involving serotonin projections rather than nigrostriatal projection loss may be more relevant to the etiology of PD tremor. There was no correlation with depressive symptoms and midbrain 11C-WAY100635 uptake in PD, arguing against a direct role of serotonergic dysfunction. b-CIT binds to serotonergic transporters in the midbrain.

Median Raphe

PD

Fig. 10.2. For full color figure, see plate section. Images of 11C-WAY100635 positron emission tomography in a normal subject (left) and Parkinson’s disease (PD) patient (right) showing reduced median raphe serotonin HT1A binding in PD.

IMAGING PARKINSON’S DISEASE A recent b-CIT SPECT study has also reported no correlation between midbrain levels of tracer uptake and depressive symptoms in PD (Kim et al., 2003). 11 C-RTI-32 PET is a marker of both norepinephrine and dopamine terminal function. Patients with PD and depression compared to those equivalently disabled but without depression have been reported to show additional loss of thalamic and locus ceruleus 11C-RTI 32 uptake, probably reflecting reduced noradrenergic input, along with lower signals in the limbic areas (amygdala and ventral striatum) (Remy et al., 2005). These findings would suggest that the presence of depression in PD is influenced more by the integrity of noradrenergic and limbic monoaminergic projections rather than by the serotonergic system per se. Cholinergic function can be assessed presynaptically with 123I-benzovesamicol SPECT, whereas 11C-MP4A PET is a marker of postsynaptic muscarinic receptor availability. In PD there is a significant reduction of parietal and occipital 123I-vesamicol uptake, while 11 C-NMPB binding remains normal (Kuhl et al., 1996; Asahina et al., 1998). PD patients with dementia, however, show more globally reduced 123I-vesamicol binding and have raised frontal 11C-NMPB binding. This would suggest that the presence of dementia is associated with a more severe loss of cholinergic projections, resulting in increased muscarinic receptor availability to the PET tracer.

10.3. Detection of preclinical Parkinson’s disease It has been estimated from postmortem studies that for every patient who presents with clinical PD there may be 10–15 subclinical cases with incidental brainstem Lewy body disease in the community. Subjects likely to be at risk of developing PD include carriers of genes known to be associated with parkinsonism, relatives of patients with the disorder, elderly subjects with idiopathic hyposmia, and patients suffering from rapid-eye movement sleep behavior disorders. Subclinical midbrain hyperechogenicity has been reported with TCS in around 10% of elderly normal individuals (Berg et al., 2001b). This echogenicity correlated with the presence of soft signs of parkinsonism. Increased midbrain echogenicity has also been reported in 4 out of 7 asymptomatic parkin gene carriers. Only 2 of these 7 asymptomatic parkin gene carriers were found to have reduced striatal 18F-dopa uptake (Walter et al., 2004). In a third series, these workers investigated hyposmic subjects with TCS. In all, 11 out of 30 cases of idiopathic olfactory loss showed midbrain hyperechogenicity and 5 of these 11 had reduced striatal FP-CIT binding (Sommer

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et al., 2004). It would therefore appear that, although increased nigral echogenicity can be detected on occasion in subjects at risk for PD, this finding correlates with reduced dopaminergic function in fewer than 50% of cases. It has been recognized for some time that elderly subjects with an impaired sense of smell (hyposmia) are more at risk for PD. Recently it has been shown that 4 out of 40 (10%) elderly relatives of PD patients who had no overt parkinsonism but who manifested hyposmia on olfactory screening converted to clinical PD over a 2-year follow-up period (Ponsen et al., 2004). Seven of these 40 relatives showed reduced 123 I-b-CIT uptake in one or more striatal subregions and it was the four with lowest DAT binding who subsequently converted to clinical PD. These findings suggest that 123I-b-CIT SPECT is capable of detecting preclinical dopaminergic dysfunction when present in at-risk subjects for PD. 18 F-dopa PET has been used to study 32 asymptomatic adult relatives in seven kindreds with familial PD (Piccini et al., 1997a). In five of these kindreds the pathology was unknown, the sixth kindred was subsequently found to have parkin gene mutations, while the seventh kindred was known to have diffuse Lewy body disease. Of the asymptomatic adult relatives scanned, 25% showed levels of putamen 18F-dopa uptake more than 2.5 SD below the normal mean. Three of the 8 asymptomatic relatives with reduced putamen 18 F-dopa uptake subsequently developed clinical parkinsonism over a 5-year follow-up period. 18 F-dopa PET findings for 34 asymptomatic cotwins of idiopathic sporadic PD patients aged 23–67 years have also been reported (Piccini et al., 1999b). A total of 18 co-twins were monozygotic (MZ), while 16 were dizygotic (DZ). Of the 18 MZ, 10 (55%) and three (18%) of the 16 DZ co-twins showed reduced putamen 18F-dopa uptake. The finding of a significantly higher concordance (55% versus 18%, P ¼ 0.03) for dopaminergic dysfunction in MZ compared with DZ PD co-twins supports a genetic contribution towards this apparently sporadic disorder. Over 7 years of follow-up, 2 MZ and 1 DZ co-twins died without developing symptoms whereas 4 MZ co-twins became clinically concordant for PD (14, 2, 9 and 20 years after the onset of PD in their co-twin), resulting in a clinical concordance of 22.2% at follow-up. None of the DZ twin pairs became clinically concordant.

10.4. Microglial activation in Parkinson’s disease Microglia constitute 10–20% of white cells in the brain and form its natural defense mechanism.

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They are normally in a resting state but local injury causes them to activate and swell, expressing human leukocyte antigens on the cell surface, and to release cytokines such as tumor necrosis factor-a and interleukins. The mitochondria of activated but not resting microglia express peripheral benzodiazepine sites which may play a role in preventing cell apoptosis via membrane stabilization. 11 C-PK11195 is an isoquinoline which binds selectively to peripheral benzodiazepine sites and so provides an in vivo PET marker of microglial activation. Loss of substantia nigra neurons in PD has been shown to be associated with microglial activation and, more recently, histochemical studies have shown that microglial activation can also be seen in other basal ganglia, the cingulate, hippocampus and cortical areas in PD (Imamura et al., 2003). 11C-PK11195 PET has been used to study microglial activation in PD (Fig. 10.3). One series reported increased midbrain signal in PD which correlated inversely with levels of poetrior putamen DAT binding (Ouchi et al., 2005). A second series also reported increased signal in the substantia nigra along with microglial activation in the striatum, pallidum and frontal cortex (Gerhard et al., 2004). Interestingly, these workers found little change in the extent of microglial activation over a 2-year follow-up period, although the patients deteriorated clinically. This could imply that microglial activation is merely an epiphenomenon in PD; however, postmortem studies have shown that these cells continue to express cytokine mRNA, suggesting that they are driving disease progression.

10.5. Monitoring the progression of Parkinson’s disease Assessing the progression of PD clinically can be problematic. Timed motor tests can be insensitive whereas semiquantitative rating scales are somewhat subjective, non-linear, consider multiple aspects of the disorder and are generally biased towards bradykinetic symptoms. More importantly, after some months most PD patients require symptomatic medication and this can mask disease progression (Brooks, 2003a). Attempts to achieve a full washout of drug therapies are poorly tolerated in practice and 2-week washouts would seem to be insufficient. PET and SPECT imaging potentially provide complementary biomarkers for objectively monitoring disease progression in vivo in PD (Brooks, 2003a). They are limited, however, to providing information concerning particular aspects of the disorder – usually dopamine terminal function. They may also be influenced by changes in medication, though this has yet to be established in human studies (Brooks et al., 2003). Striatal 18 F-dopa uptake has been shown to correlate with subsequent postmortem dopaminergic cell densities in the substantia nigra and striatal dopamine levels of both human PD sufferers and of monkeys lesioned with the nigral toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In subjects with an intact dopamine system, striatal 18F-dopa uptake does not appear to be influenced by dopaminergic medication. Striatal 123I-b-CIT uptake has also been shown to be unaffected by several weeks of exposure to levodopa and dopamine agonists. Several series have now shown that loss of striatal 18 F-dopa uptake occurs more rapidly in PD than in

Fig. 10.3. For full color figure, see plate section. 11C-PK11195 positron emission tomography scans of a healthy subject (left) and Parkinson’s disease patient (right) . Microglial activation is evident in the midbrain and basal ganglia of the Parkinson’s disease patient.

IMAGING PARKINSON’S DISEASE age-matched controls (Brooks, 2003a). In early levodopa-treated PD, putamen 18F-dopa uptake has been reported to decline by 6–12% per annum whereas caudate uptake falls at about half that rate. Parallel rates of loss of putamen dopamine transporter binding have been reported with 18F-CFT PET and 123I-b-CIT, 123 I-FP-CIT and 123I-IPT SPECT. Annual loss of striatal 123I-b-CIT uptake in early PD has been reported to correlate with initial levels of striatal transporter binding, suggesting an exponential disease process. Extrapolations have suggested a preclinical disease window of only a few years in late-onset sporadic PD (Morrish et al., 1998). 10.5.1. Testing possible neuroprotective agents As PET and SPECT can follow loss of dopamine terminal function in PD, they provide a potential means of monitoring the efficacy of putative neuroprotective and restorative agents (Ravina et al., 2005). Dopamine agonists are one such possible class as they suppress endogenous dopamine production in vivo, so attenuating its oxidative metabolism and reducing hydroxyl free radical formation. They are also weak antioxidants and free radical scavengers in their own right and some act as mitochondrial membrane stabilizers, so blocking the apoptotic cascade. Two different trials have examined the relative rates of loss of dopamine terminal function in early PD in patients randomized to a dopamine agonist or levodopa. The REAL PET trial was a 2-year doubleblind multinational study where 186 de novo PD patients were randomized (1:1) to ropinirole or levodopa (Whone et al., 2003b). The primary endpoint was change in putamen 18F-dopa uptake (Ki) measured with PET. A total of 74% of the ropinirole and 73% of the levodopa group completed the study; only 14% of the ropinirole and 8% of the levodopa group required open supplementary levodopa. Interestingly, 11% of the untreated patients thought to have PD by referring clinicians were found to have normal caudate and putamen 18F-dopa uptake at entry (identified by blinded review). This subgroup was analyzed separately and over 6 years has shown no significant change in PET findings despite exposure to dopaminergic agents (unpublished observations). Reduction in mean putamen Ki was significantly slower over 2 years in the PD patient group taking ropinirole (13.4%) than in that taking levodopa (20.3%; P ¼ 0.022). Clinically, the incidence of dyskinesia was 26.7% with levodopa but only 3.4% with ropinirole (P < 0.001). Improvements in mean Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores rated while taking medication were, however, superior

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(by 6.34 points) for the levodopa cohort. The second trial comprised a subgroup of the CALM-PD study where a cohort of 82 early PD patients were randomized 1:1 to the dopamine agonist pramipexole (0.5 mg t.d.s.) or levodopa (100 mg t.d.s.) and had serial 123 I-b-CIT SPECT over a 4-year period (Parkinson Study Group, 2002). Open supplementary levodopa was allowed if there was lack of therapeutic effect. Patients treated initially with pramipexole (n ¼ 42) showed a significantly slower mean relative decline of striatal b-CIT uptake compared to subjects treated initially with levodopa (n ¼ 40) at 2 (47%), 3 (44%) and 4 (37%) years. Again, the incidence of complications was significantly reduced in the pramipexole cohort but improvement in UPDRS score in those taking medication was greater in the levodopa cohort. These two imaging studies, therefore, produced parallel findings, both suggesting that treatment with an agonist in early PD relatively slows loss of dopamine terminal function by around one-third and delays treatment-associated complications. However, the functional imaging findings favoring use of agonists as early treatment for PD were not paralleled by a better clinical outcome in the PD agonist cohorts, as judged by UPDRS motor scores rated while subjects were medicated. One possible confounder contributing towards the discordant imaging and clinical findings could be that the PET and SPECT signals were differentially influenced by the effects of levodopa and agonist medications. Conceivably, levodopa could directly downregulate dopa decarboxylase activity and DAT binding, so suppressing striatal 18F-dopa and 123 I-b-CIT uptake relative to agonists. Currently there is no evidence to support this viewpoint, but the findings of these two trials remain controversial. The real test will be whether early use of agonists delays the need for institutional care or deep brain stimulation (DBS) in the longer term. In an attempt to assess whether levodopa is toxic, the ELLDOPA trial compared rates of progression of 361 de novo PD patients randomized to 150, 300 or 600 mg of medication or placebo (Fahn et al., 2004). Subjects were followed for 9 months and then had a 2-week washout of their medication. Clinical disability was rated with the UPDRS and, in a subgroup of 142, striatal DAT binding was measured with 123I-b-CIT SPECT. Locomotor function improved most in those patients treated with 600 mg of levodopa daily and remained superior to placebo after 2 weeks of washout. However, 30% of these cases developed fluctuating treatment responses and 17% dyskinesias compared to 13% and 3% in the placebo arm. SPECT imaging suggested that loss of striatal DAT binding occurred most rapidly (7%) in the high-dose

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levodopa arm of the trial compared with placebo (1%). These discordant clinical and imaging findings make it difficult to draw firm conclusions about the toxicity of levodopa and a further trial is now under way with a randomized delayed wash in to try and eliminate any confounding symptomatic effects of levodopa on assessments of underlying disease progression. 18 F-dopa PET has been used to study the possible neuroprotective action of the glutamate release inhibitor riluzole in PD (Rascol et al., 2002). This agent was shown to slow disease progression and delay mortality of amyotrophic lateral sclerosis patients. De novo PD patients were blindly randomized to placebo, 50 mg, and 100 mg riluzole daily and the clinical primary endpoint was time to requiring dopaminergic medication. No differences were found between the three PD cohorts either in time to reaching the clinical endpoint or in reduction in putamen 18F-dopa uptake.

10.6. Restorative approaches in Parkinson’s disease Possible approaches to restorative therapy in PD include striatal implants of: (1) human and porcine fetal mesencephalic cells; (2) retinal cells that release levodopa; (3) transformed cells that secrete dopamine or nerve growth factors, or express antiapoptotic genes; (4) neural progenitor cells; and (5) cannulae infusing nerve growth factors. 10.6.1. Human fetal cell implantation trials Early open series suggested that advanced PD patients showed a good clinical response to implantation of fetal mesencephalic cells or tissue into striatum which was accompanied by increases in striatal 18F-dopa uptake (Lindvall, 1999). An 11C-raclopride PET study showed that striatal grafts could release dopamine after a metamphetamine challenge (Piccini et al., 1999a), whereas H215O PET demonstrated restored levels of frontal activation in 4 PD patients 2 years after bilateral grafting (Piccini et al., 2000). Given the encouraging findings of a pilot open series, two major double-blind controlled trials on the efficacy of implantation of human fetal cells in PD were sponsored by the US National Institutes of Health. The first of these involved 40 patients 34–75 years of age who had severe PD (mean duration 14 years) (Freed et al., 2001). They were randomized either to receive an implant of human fetal mesencephalic tissue or to undergo sham surgery and were followed for 1 year, with a subsequent extension to 3 years. In the transplant recipients, mesencephalic tissue from four embryos cultured for up to 1 month

was implanted into the putamen bilaterally (two embryos per side) via a frontal approach. In the patients who underwent sham surgery, holes were drilled in the skull but the dura was not penetrated. No immunotherapy was used. The transplanted patients showed no significant improvement in the primary endpoint, clinical global impression, at 1 year but there was a significant mean 18% improvement in mean UPDRS motor score compared with the sham-surgery group when tested in the morning before receiving medication (P ¼ 0.04). This improvement was more evident for patients under 60 years old (34% improvement; P ¼ 0.005). At 3 years mean total UPDRS score was improved 38% in the younger and 14% in the older transplanted groups (both P < 0.01). An increase in putamen 18F-dopa uptake was shown in 16 out of 19 transplanted patients individually (group mean increase 40%) and increases were similar in the younger and older cohorts. A drawback was that ‘off’ dystonia and dyskinesias developed in 15% of the patients who received transplants in this series, even after the reduction or discontinuation of levodopa. In the second trial National Institutes of Health trial (Olanow et al., 2003), 34 patients were randomized to receive: (1) bilateral implants of fetal mesencephalic tissue from four fetuses per side or from one fetus per side into posterior putamen; or (2) sham surgery (a partial burrhole without penetration of the dura). Fetal tissue was cultured for less than 48 h before transplantation and all patients received immunosuppression for 6 months after surgery. The trial duration was 2 years and the primary outcome variables were the UPDRS motor score and quality of life. Putamen 18 F-dopa uptake was assessed with PET in a subset of patients. Of the 34 patients, 31 completed and 2 died during the trial; another 3 died subsequently from unrelated causes. At postmortem these 2 transplanted patients showed significantly higher tyrosine hydroxylase staining in the putamen relative to the sham-grafted treated patients with graft innervation of the host evident. However, microglial activation surrounding the graft was also a feature. Putamen 18F-dopa uptake was unchanged in the control patients but showed a one-third increase in patients receiving tissue from four fetuses. Unfortunately, no significant differences were seen between the groups in clinical rating scores at 2 years, though there was trend favoring the fourfetus group which had been significant at 6 months prior to withdrawal of immunosuppression. The mean UPDRS motor score off medication deteriorated by 9.4, 3.5 and 0.7 points over 2 years for the controls, one-fetus and four-fetus groups (four-fetus group versus controls, P ¼ 0.096). ‘Off’-period dyskinesias

IMAGING PARKINSON’S DISEASE were evident in 13 of 23 implanted patients but were not seen in the control arm. To conclude, despite both histological and 18F-dopa PET evidence of graft function, neither of these blinded controlled trials demonstrated clinical efficacy of grafts with their primary endpoints and in both studies ‘off’-period dyskinesias were problematic. There were indications, however, that grafts of human fetal dopamine cells could be efficacious in some younger, more severely affected patients. 10.6.2. Intraputaminal glial-derived neurotrophic factor infusions Glial-derived neurotrophic factor (GDNF) is a potent nerve growth factor known to protect dopamine neurons against nigral toxins in rodent and primate models of PD. The safety and efficacy of infusing GDNF directly into the posterior putamen were first tested in a small open pilot trial (Gill et al., 2003). Five PD patients had indwelling catheters inserted and all tolerated continuous GDNF delivery at levels ranging from 14 to 40 mg/day (6 ml/h) for over 2 years, unilaterally in 1 and bilaterally in 4 patients, without serious side-effects. Significant improvements were reported in UPDRS subscores: 39% and 61% improvements in the off-medication motor III and activities of daily living II subscales, respectively, at 12 months. There were 18–24% increases in putaminal 18F-dopa Ki at the catheter tip. More recently, a double-blind trial of GDNF efficacy in PD has studied 34 advanced patients who were randomized 1:1 to receive bilateral continuous intraputamen infusions of liatermin 15 mg/putamen per day or placebo. The primary endpoint was the change in UPDRS motor score in the practically defined off condition at 6 months. Secondary endpoints included posterior putamen 18F-dopa uptake. At 6 months there was no significant difference in mean percent reductions in ‘off’ UPDRS motor scores between the GDNF and placebo groups (10.0% and 4.5%, respectively). A 32% treatment difference favoring GDNF in mean posterior putamen 18F-dopa influx constant (P ¼ 0.0061) was present, equivalent to that seen in the open-label pilot study. It was concluded that GDNF infusions did not confer significant clinical benefit to patients with PD, despite inducing local increases in 18F-dopa uptake. Following completion of this clinical trial, 4 patients have developed persistent, high-affinity, anti-GDNF antibodies and 3 of these subsequently developed blocking antibodies. The dissociated clinical and imaging outcomes in the double-blind controlled transplant and GDNF trials raise important issues about the information generated

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by imaging biomarkers. In these trials 18F-dopa PET showed increased dopaminergic function after both grafting and GDNF infusion, although significant clinical efficacy was not evident. It must be remembered that 18F-dopa PET is primarily a marker of dopa decarboxylase activity in striatal dopamine terminals but does not provide information about vesicular dopamine levels or effective release of dopamine during movement. It is also unable to reveal whether new dopamine terminals formed by grafts or under trophic influence are appropriately located next to postsynaptic receptors. The increased levels of dopamine storage seen after grafting and GDNF infusions may, therefore, fail to translate into physiologically effective dopamine release during motor function. 10.6.3. Fluctuations and dyskinesias PD patients with fluctuating responses to levodopa show 20% lower mean putamen 18F-dopa uptake than those with early disease and sustained therapeutic responses (De La Fuente-Fernandez et al., 2000). There is, however, considerable overlap of fluctuator and non-fluctuator individual ranges. Given this, while loss of putamen dopamine terminal function predisposes PD patients towards development of levodopa-associated complications, it cannot be the only factor responsible for determining the timing of onset of fluctuations and involuntary movements. Dopamine receptors broadly fall into D1-type (D1, D5) and D2-type (D2, D3, D4). PET studies with spiperone-based tracers and 123I-IBZM (iodobenzamide) SPECT have reported normal levels of striatal D2 binding in untreated PD, whereas 11C-raclopride PET has shown a 10–20% increase in putamen D2 site availability (Playford and Brooks, 1992; Antonini et al., 1994). In treated PD putamen D2 binding is normal, explaining the good locomotor response to levodopa. 11 C-SCH23390 PET, a marker of D1 site binding, reveals normal striatal uptake in de novo PD, whereas patients who have been exposed to levodopa for several years show a 20% reduction in striatal binding. Cohorts of levodopa-exposed dyskinetic and nondyskinetic PD patients with similar clinical disease duration, disease severity and daily levodopa dosage show similar levels of striatal dopamine D1- and D2receptor availability (Turjanski et al., 1997). Putamen D1 and D2 binding are normal, although caudate D2 binding is mildly reduced. These findings, therefore, suggest that onset of motor complications in PD is not primarily associated with alterations in striatal total dopamine receptor availability. 11 C-raclopride PET allows changes in levels of dopamine in the synaptic cleft to be monitored

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(Fig. 10.4). The higher the extracellular dopamine level, the lower the dopamine D2 site availability to the tracer. When early non-fluctuating PD patients are given 3 mg/kg of levodopa as an intravenous bolus, they show a mean 10% fall in posterior putamen 11 C-raclopride binding whereas advanced cases with fluctuations show a 23% fall (Torstenson et al., 1997). These falls in receptor availability have been estimated to correspond to four- and 10-fold rises in extracellular dopamine and indicate that, as loss of dopamine terminals in PD progresses, the ability of the striatum to buffer dopamine levels fails when clinical doses of exogenous levodopa are administered. This regulation failure reflects a combination of upregulation of striatal dopamine synthesis and release by the remaining terminals following administration of levodopa along with a severe loss of dopamine transporters preventing reuptake. It is this phenomenon, rather than changes in postsynaptic dopamine D1and D2-receptor binding, that is likely to be the explanation for the more rapid response of advanced PD patients to oral levodopa. The failure to buffer dopamine levels by the striatum in advanced PD will also result in high non-physiological swings in synaptic dopamine levels. This, in turn, may promote excessive dopamine receptor internalization, leading to fluctuating and unpredictable treatment responses. In support of this viewpoint, De La Fuente-Fernandez and colleagues (2001) have measured striatal 11C-raclopride

Baseline

binding in PD at 1 and 4 h after oral levodopa challenges. These workers found that: (1) fluctuators show transiently raised synaptic dopamine levels, whereas sustained responders generated a progressive rise in striatal dopamine; and (2) ‘off’ episodes could coincide with apparently adequate synaptic dopamine levels. Medium spiny neurons in the caudate and putamen project to external (GPe) and internal pallidum (GPi) where, along with gamma-aminobutyric acid (GABA), they release enkephalin (GPe) or dynorphin and substance P (GPi). Enkephalin binds mainly to d opioid sites and inhibits GABA release in the GPe. Dynorphin binds to k opioid sites and inhibits glutamate release in the GPi from subthalamic projections. Under normal physiological conditions, phasic firing of striatal projection neurons results primarily in GABA release in the pallidum, whereas sustained tonic firing causes additional modulatory opioid and substance P release. The caudate and putamen contain high densities of m, k and d opioid sites and also neurokinin 1 (NK1) sites which bind substance P. Opioid receptors are located both presynaptically on dopamine terminals, where they regulate dopamine release, and postsynaptically on interneurons and medium spiny projection neurons. There is now strong evidence supporting the presence of increased opioid and substance P transmission in the basal ganglia of end-stage PD patients from both postmortem and animal lesion model studies.

After 250 mg L-dopa

Fig. 10.4. For full color figure, see plate section. 11C-raclopride positron emission tomography scans for a Parkinson’s disease patient before (left) and after (right) an oral 250 mg dose of levodopa. The levodopa results in a 10% reduction in striatal 11 C-raclopride uptake as the increase in synaptic levels of dopamine generated reduces D2-receptor availability to the tracer.

IMAGING PARKINSON’S DISEASE C-diprenorphine PET is a non-selective marker of m, k and d opioid sites and its binding is sensitive to levels of endogenous opioids. If raised basal ganglia levels of enkephalin and dynorphin are associated with levodopa-induced dyskinesias (LIDs), then PD patients with motor complications would be expected to show reduced binding of 11C-diprenorphine. Piccini and coworkers (1997b) have reported significant reductions in 11Cdiprenorphine binding in caudate, putamen, thalamus and anterior cingulate in dyskinetic patients compared with sustained responders. Individual levels of putamen 11 C-diprenorphine uptake correlated inversely with severity of dyskinesia. 18F-L829165 PET is a selective marker of NK1 site availability. In a preliminary study thalamic NK1 availability has been shown to be reduced in dyskinetic PD patients but normal in non-dyskinetic cases (Whone et al., 2002). These in vivo findings support the presence of elevated levels of endogenous peptides in the basal ganglia of dyskinetic PD patients and suggest that this, rather than a primary alteration in dopamine receptor availability, leads to abnormal pallidal burst firing and may be responsible for the appearance of levodopa-induced involuntary movements. 11

10.7. Dementia and Parkinson’s disease 10.7.1. Resting brain metabolism 18

FDG (2-fluoro-2-deoxyglucose) PET scans of frankly demented PD patients show an Alzheimer pattern of impaired resting brain glucose utilization: the posterior parietal and temporal association areas are most affected, frontal association areas less affected and primary cortical regions, basal ganglia and cerebellum are spared (Bohnen et al., 1999). Interestingly, up to one-third of non-demented PD patients with established disease also show this pattern of reduced cortical metabolism but to a lesser extent, suggesting they may be at risk for later dementia (Hu et al., 2000). Currently, it remains unclear whether this pattern of resting glucose hypometabolism in demented PD patients reflects coincidental Alzheimer’s disease, cortical Lewy body disease, loss of cholinergic projections or some other degenerative process. Clinicopathological series suggest that there is considerable overlap in the cortical FDG PET findings of coincidental Alzheimer’s disease and cortical Lewy body disease but that cortical Lewy body disease cases show a greater reduction in resting glucose metabolism of the primary visual cortex (Bohnen et al., 1999). There are now PET imaging agents based on naphthol (18FFDDNP: 2-(1-(6-[(2-[18F]fluoroethyl)(methyl)amino]-2naphthyl)ethylidene)malononitrile) and thioflavin (11C-PIB: Pittsburgh compound B (N-methyl-[11C]2-

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(4-methylaminophenyl)-6-hydroxybenzothiazole) structures capable of imaging b-amyloid plaque load in dementia patients (Klunk et al., 2004). Using these markers it should be possible in the future to assess the contribution of amyloid pathology to PD dementia. 10.7.2. Dopaminergic function In around 20% of cases with a clinical picture of Alzheimer’s disease, the pathological diagnosis is found to be diffuse Lewy body (DLB), whereas other dementia cases have mixed pathology. Whether DLB and PD represent opposite ends of a spectrum is unclear but DLB patients show not only cerebral cortical neuronal loss, with Lewy bodies in surviving neurons, but also loss of nigrostriatal dopaminergic neurons. In contrast nigral pathology is mild in Alzheimer’s disease. Using 123I-FP-CIT SPECT, Walker and colleagues (2002, 2004) examined striatal DAT binding in patients with clinically presumed DLB, Alzheimer’s disease, drug-naive patients with PD and healthy controls. The presumed DLB and PD patients had significantly lower uptake of caudate and putamen 123I-FP-CIT than patients with Alzheimer’s disease (P < 0.001) and controls (P < 0.001), but DLB cases showed greater involvement of caudate than PD (Fig. 10.5). The authors were subsequently able to correlate their SPECT findings with 10 postmortem examinations. Nine of 10 dementia cases were thought to have DLB in life but only 4 had this diagnosis at autopsy. All 4 had reduced striatal 123I-FP-CIT uptake, whereas 5 of the 10 cases had Alzheimer’s disease pathology (4 of these 5 had normal 123I-FP-CIT SPECT). These clinicoimaging correlations suggest that 123I-FP-CIT SPECT may be helpful in discriminating DLB from Alzheimer’s disease. 18 F-dopa PET findings in PD patients with and without dementia but matched for locomotor disability have also been compared (Ito et al., 2002). The two PD cohorts showed equivalent levels of putamen dopamine storage capacity but cingulate and mesial prefrontal 18F-dopa uptake was reduced in the PD dementia group. Frontal 18F-dopa uptake has previously been shown to correlate with performance on executive tasks by non-demented PD patients (Rinne et al., 2000). 10.7.3. Brain activation findings in Parkinson’s disease PET studies on resting brain function have shown relatively increased levels of both oxygen and glucose metabolism in the contralateral lentiform nucleus of hemiparkinsonian patients with early disease, although this normalizes in PD patients with established bilateral involvement (Brooks, 1993). Covariance

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Normal

Alzheimer

PD

DLB

Fig. 10.5. For full color figure, see plate section. FP-CIT single photon emission computed tomography images in a healthy control (top left), Parkinson’s disease (top right), Alzheimer’s disease (bottom left) and diffuse Lewy body (DLB) dementia case (bottom right). The DLB dementia case image mirrors that of Parkinson’s disease (images from Walker et al; 2002).

analysis has revealed an abnormal profile of relatively raised resting lentiform nucleus and lowered frontal metabolism in non-demented PD patients with established disease (Eidelberg et al., 1994). The degree of expression of this profile correlates with clinical disease severity and normalizes after dopaminergic and DBS treatments (Feigin et al., 2001; Su et al., 2001). Although studies of resting cerebral blood flow and metabolism provide insight into the basal cerebral dysfunction underlying movement disorders, measuring changes in rCBF with H215O PET or functional MRI while patients perform motor or cognitive tasks or after pharmacological challenges can be more revealing. When normal subjects perform freely selected limb movements there are associated rCBF increases in

contralateral sensorimotor cortex (SMC) and lentiform nucleus and bilaterally in anterior cingulate, anterior supplementary motor area (SMA), lateral premotor cortex (PMC) and dorsolateral prefrontal cortex (DLPFC) (Brooks, (2003b)). When PD patients, scanned after stopping levodopa for 12 h, perform similar movements, normal or increased activation of SMC, caudal SMA, PMC and lateral parietal association areas are seen but there is impaired activation of the contralateral lentiform nucleus and the anterior cingulate, anterior SMA and DLPFC, that is, of those frontal areas that receive direct input from the basal ganglia. It is well recognized that, although patients with PD can perform isolated limb movements efficiently, attempts to perform repetitive or sequences of movements result in a fall in amplitude and motor

IMAGING PARKINSON’S DISEASE arrest. Underactivity of mesial frontal and deactivation of dorsolateral prefrontal areas when patients perform prelearned sequential opposition finger–thumb movements with one or both hands has been demonstrated. Lateral premotor and parietal cortex and cerebellum were relatively overactivated, suggesting adaptive recruitment of a network normally used to facilitate externally cued rather than freely chosen movements. It has been proposed (Passingham, 1987) that: (1) dorsal prefrontal cortex plays a crucial role in motor decision-making; (2) once selected, the anterior SMA prepares and optimizes volitional motor programs and facilitates non-mirror bimanual movements; and (3) lateral PMC has a primary role in facilitating motor responses to external visual and auditory stimuli. An inability to activate DLPFC and anterior SMA during freely selected and sequential movements could explain the difficulty that PD patients experience in initiating such actions. In contrast, their ability to overactivate lateral premotor and primary motor cortex allows them to respond well to visual and auditory cues, such as stepping over lines on the floor or marching to a drum beat to aid their walking. If a loss of dopamine is responsible for the impaired activation of striatofrontal projections in PD, it should be possible to restore it by administering dopaminergic medication. Administration of apomorphine and levodopa and implants of fetal midbain dopamine cells have all been shown to increase activation of anterior SMA and prefrontal cortex during arm and finger movements in association with a reduction of bradykinesia (Jenkins et al., 1992; Rascol et al., 1992; Piccini et al., 2000). Imptrovement of mood after levodopa has been shown to correlate with increased blood flow in limbic areas (Black et al., 2005). Lesions or high-frequency electrical stimulation of the motor GPi have been observed to improve bradykinesia and reduce dyskinesias in PD by mechanisms that are still being debated. High-frequency DBS of the subthalamic nucleus may be even more effective. Regional cerebral activation has been studied in PD before and after these surgical interventions. In general, surgery has resulted in significantly increased activation of SMA, lateral PMC and dorsal prefrontal cortex in PD patients off medication when performing volitional and paced limb movements (Brooks, 2003b).

10.8. Atypical parkinsonian syndromes 10.8.1. Multiple system atrophy This condition is characterized pathologically by argyrophilic, a-synuclein-positive inclusions in glia and neurons in substantia nigra, striatum, brainstem

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and cerebellar nuclei, and intermediolateral columns of the cord. It manifests as a parkinsonian syndrome with autonomic failure and ataxia and includes striatonigral degeneration (SND), progressive autonomic failure and olivopontocerebellar atrophy within its spectrum. Patients are often non-responsive to levodopa. The striatum appears normal on T2-weighted MRI in PD but in SND and MSA the lateral putamen can show reduced signal due to iron deposition and this may be bordered by a rim of increased signal due to gliosis (Fig. 10.6; Schrag et al., 2000). If concomitant pontocerebellar degeneration is also present, the lateral as well as longitudinal pontine fibers become evident as high signal on T2 MRI, manifesting as the ‘hotcross bun’ sign. Cerebellar and pontine atrophy may be visually obvious with increased signal evident in the cerebellar peduncles. These changes are usually only evident in patients with well-established disease where putamen and brainstem atrophy can also be demonstrated with formal magnetic resonance volumetry. More recently, the use of diffusion-weighted imaging (DWI) and diffusion tensor MRI have been developed for discriminating atypical from typical parkinsonian syndromes. DWI reflects the movement of water molecules along fiber tracts in the brain – so-called anisotropy of diffusion. This anisotropy can be quantified as an apparent diffusion coefficient (ADC) by applying field gradients. In intact brain the central nervous system is organized in bundles of fiber tracts along which water molecules move. Degenerative disease removes restrictions to water molecule movement, so reducing anisotropy and increasing the ADC. It has been reported that all cases with clinically probable MSA-P could be discriminated from typical PD patients as they showed significantly higher regional ADC values in the putamen (Seppi et al., 2003). How sensitive this approach is for classifying gray parkinsonian cases is currently being determined. 18 FDG PET studies in patients with clinically probable SND reveal reduced levels of striatal glucose metabolism in 80–100% of cases over different series, in contrast to PD where striatal metabolism is preserved (Eidelberg et al., 1993). Parkinsonian patients with low levels of striatal glucose metabolism, irrespective of their levodopa response, show little improvement after pallidotomy (Eidelberg et al., 1996). Patients with the full syndrome of MSA have reduced mean levels of cerebellar along with putamen and caudate glucose hypometabolism. 18FDG PET, therefore, also provides a sensitive means of detecting the presence of striatal dysfunction where atypical parkinsonism is suspected.

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Fig. 10.6. T2-weighted magnetic resonance images of a multiple system atrophy case. Left: decreased lateral putamen signal; right: the pontine ‘hot-cross bun’ sign.

Proton magnetic resonance spectroscopy may also be helpful for discriminating SND from PD. N-acetylaspartate (NAA) is a metabolic marker of neuronal integrity present in millimolar concentrations. Reduced NAA-to-creatine proton MRS signal ratios were reported from the lentiform nuclei in 6 out of 7 clinically probable SND cases, whereas 8 out of 9 probable PD cases showed normal levels of putamen NAA (Davie et al., 1995). The function of both the pre- and postsynaptic dopaminergic systems is impaired in patients with SND. As in PD, putamen 18F-dopa uptake is asymmetrically reduced and individual levels of putamen 18F-dopa uptake correlate with disability (Brooks et al., 1990; Brooks, 1993). Patients with the full syndrome of MSA show a significantly greater reduction in mean caudate 18F-dopa uptake than equivalently rigid PD patients, though individual ranges overlap. However, discriminant analysis was only able to separate 70% of clinically probable MSA cases from PD cases on the basis of the pattern of their striatal 18F-dopa uptake. Pirker and colleagues (2000) examined striatal DAT binding in PD and MSA patients and concluded that, although 123I-b-CIT SPECT reliably discriminates PD and MSA from normal, it cannot reliably discriminate between these two parkinsonian conditions. SND patients show reductions in mean striatal D2 binding, though on an individual basis this is an inconsistent finding (Brooks et al., 1992a). Putamen D2

binding is normal or raised in PD but there is an overlap between SND, normal and PD ranges, so striatal D2 binding does not provide a sensitive discriminator of SND from PD. 123I-IBZM SPECT found reduced striatal D2 binding in only two-thirds of de novo parkinsonian patients who showed a negative apomorphine response (Schwarz et al., 1992). In a recent series it was concluded that 123I-IBZM SPECT had a sensitivity and specificity of 80% and 71% for discriminating MSA-P from PD compared with corresponding values of 93% and 100% for DWI (Seppi et al., 2004). Given that a significant number of parkinsonian patients who respond poorly to levodopa show normal levels of striatal D2 binding, it seems likely that degeneration of pallidal and brainstem rather than striatal projections is responsible for their refractory status. 123I-IBZM SPECT has been used to follow longitudinally striatal degeneration in a group of early MSA cases (Seppi et al., 2001). An annual 10% loss of striatal D2 binding was reported in this 18-month study. 123 I-MIBG ([123I]meta-iodobenzylguanidine) SPECT can be used to study the functional integrity of cardiac sympathetic innervation in PD and MSA (Braune et al., 1999; Druschky et al., 2000). Most MSA cases have normal cardiac MIBG signals, whereas PD cases show a reduction, even where no clinical evidence of autonomic failure is present. This finding suggests a greater involvement of postganglionic sympathetic innervation of the

IMAGING PARKINSON’S DISEASE myocardium in PD compared with MSA. Despite this, a recent series reported only 88% of PD (60% of Hoehn and Yahr stage 1) cases individually showed reduced cardiac MIBG uptake, raising questions about the sensitivity of this approach (Nagayama et al., 2005). 11 C-PK11195 PET, an in vivo marker of microglial activation, has been used to study glial activation in MSA. More widespread subcortical increases in 11CPK11195 uptake are seen compared with PD, targeting nigra, putamen, pallidum, thalamus and brainstem (Gerhard et al., 2003). It remains to be determined whether striatal 11C-PK11195 uptake will provide a sensitive discriminator of MSA and PD. In summary, DWI and 18FDG PET appear to be the most robust imaging approaches for discriminating typical PD from MSA, though MIBG SPECT is also of value. 10.8.2. Progressive supranuclear palsy This condition is characterized pathologically by neurofibrillary tangle formation and neuronal loss in the substantia nigra, pallidum, superior colliculi, brainstem nuclei and the periaqueductal gray matter (Fig. 10.7). There is a lesser degree of cortical involvement. Patients with PSP do not show the putamen signal changes characteristic of MSA but may show third ventricular widening and midbrain atrophy. Diffusionweighted MRI has been reported to discriminate 90% of clinically probable PSP cases from PD based on their putamen regional ADC values (Seppi et al., 2003).

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A number of series have reported changes in resting regional cerebral glucose metabolism in patients with clinically probable PSP, several of whom have later had the diagnosis confirmed at autopsy. Cortical metabolism is globally depressed and frontal areas are particularly targeted; the levels of metabolism correlate with disease duration and performance on psychometric tests of frontal function (Foster et al., 1988). Hypofrontality is not specific for PSP; it can be seen in PD, SND, Pick’s disease, Huntington’s disease and depression. Basal ganglia, cerebellar and thalamic resting glucose metabolism are also depressed in PSP, so distinguishing it from PD, where metabolism is preserved. Proton MRS studies show reduced lentiform nucleus NAA-to-Cr ratios in PSP, in contrast to PD (Davie et al., 1997). Although 18 FDG PET, DWI and proton MRS will all discriminate at least 80% of PSP cases from PD, they are unable to discriminate PSP reliably from SND/MSA, as striatal and frontal hypometabolism can be a feature of both these disorders. The pathology of PSP uniformly targets nigrostriatal dopaminergic projections and so, in contrast to PD, putamen and caudate 18F-dopa uptake are equivalently reduced in PSP (Brooks et al., 1990). In one series 18F-dopa PET was able to discriminate 90% of PSP from PD cases on the basis of uniform caudate and putamen involvement in the former. Messa and colleagues (1998) have also reported equivalent loss of putamen 123I-b-CIT uptake in PD and PSP but significantly greater caudate involvement in the latter. There is no clear correlation between levels of striatal

PSP

Fig. 10.7. For full color figure, see plate section. FDG positron emission tomography images in Parkinson’s disease (PD: left) and progressive supranuclear palsy (PSP: right). The PSP case shows reduced resting basal ganglia glucose metabolism.

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F-dopa uptake in PSP and the degree of disability. Unlike PD and SND, where locomotor impairment appears to correlate with loss of dopaminergic fibers, loss of mobility in PSP is probably determined by degeneration of non-dopaminergic pallidal and brainstem projections. Dopamine D2-receptor binding in PSP has been studied with both PET and SPECT. Reductions in mean striatal binding have been consistently reported, though only 50–70% of patients individually show significant receptor loss (Brooks et al., 1992a; Brooks, 1993). It is likely that degeneration of downstream pallidal and brainstem projections is responsible for the poor levodopa responsiveness of PSP rather than loss of dopamine receptors alone. 10.8.3. Corticobasal degeneration This condition classically presents with an akineticrigid, apraxic limb which may exhibit alien behavior. Cortical sensory loss, dysphasia, myoclonus, supranuclear gaze problems and bulbar dysfunction are also features, although intellect is spared until late. Eventually, all four limbs become involved and the condition is invariably poorly levodopa-responsive. The pathology consists of collections of swollen, achromatic, tau-positive-staining Pick cells in the absence of argyrophilic Pick bodies, which target the posterior frontal, inferior parietal and superior temporal lobes, the substantia nigra and the cerebellar dentate nuclei. In CBD asymmetric hemispheric atrophy may be present on structural imaging and MRI can usefully exclude multi-infarct disease and multifocal leukoencephalopathy as differential diagnoses. PET and SPECT studies on patients with the clinical syndrome of CBD have shown greatest reductions in resting cortical oxygen and glucose metabolism in posterior frontal, inferior parietal and superior temporal regions (Eidelberg et al., 1991; Sawle et al., 1991). The thalamus and striatum are also involved and the metabolic reductions are strikingly asymmetrical, being most severe contralateral to the more affected limbs. This contrasts with PD patients who have preserved and symmetrical levels of striatal and thalamic glucose metabolism. Striatal 18F-dopa uptake is also reduced in CBD in an asymmetric fashion, being most depressed contralateral to the more affected limbs (Sawle et al., 1991). Like PSP, but in contrast to PD, caudate and putamen 18F-dopa uptake are similarly depressed in CBD. 123I-b-CIT SPECT also shows an asymmetric reduction in striatal dopamine transporter binding in CBD, whereas 123I-IBZM SPECT shows a severe

asymmetrical reduction of striatal D2 binding (Frisoni et al., 1995). The above imaging findings may help discriminate CBD from Pick’s disease, where inferior frontal hypometabolism predominates; from PD, where striatal metabolism is preserved and caudate 18F-dopa uptake is relatively spared; and from PSP, where frontal and striatal metabolism tend to be more symmetrically involved. However, both Pick’s and PSP pathology have been subsequently reported in clinically apparent CBD cases.

10.9. Conclusions In parkinsonian syndromes PET and SPECT: (1) provide a sensitive and objective means of detecting dopamine terminal dysfunction in parkinsonian syndromes where diagnostic doubt exists; (2) may be helpful in demonstrating altered striatal glucose hypometabolism or reduced D2 binding in suspected atypical PD variants; (3) can detect subclinical dopaminergic dysfunction when present in subjects at risk for PD (relatives, susceptibility gene carriers, hyposmic and rapid-eye movement sleep behaviour disorder cases); (4) enable PD progression to be objectively monitored and the efficacy of putative neuroprotective and restorative approaches to be evaluated; and (5) have shown that, although implants of fetal midbrain tissue and infusions of GDNF lead to increased striatal dopamine storage capacity, this does not consistently translate into clinical efficacy TCS can detect midbrain hyperechogenicity when present in suspected cases of PD and subjects at risk for this disorder. MRI can: (1) detect altered nigral signal in PD; (2) separate atypical from typical PD on the basis of raised striatal ADCs; and (3) detect and follow basal ganglia volumetric loss in atypical PD. Blood flow and ligand activation studies have: (1) established that the akinesia of PD is associated with selective underfunctioning of the SMA and dorsal prefrontal cortex; (2) found that parkinsonian ‘off’ periods do not correlate well with levels of striatal dopamine, suggesting that other mechanisms such as abnormal receptor internalization may play a role; and (3) striatal grafts of fetal midbrain cells can release normal amounts of dopamine after amphetamine challenges.

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IMAGING PARKINSON’S DISEASE ger movements and effects of apomorphine. Arch Neurol 49: 144–148. Rascol O, Olanow W, Brooks D et al. (2002). A 2-year, multicenter, placebo-controlled, double-blind, parallel-group study of the effect of riluzole on Parkinson’s disease progression. Mov Disord 17 (Suppl): P80. Ravina B, Eidelberg D, Ahlskog JE et al. (2005). The role of radiotracer imaging in Parkinson’s disease. Neurology 64: 208–215. Remy P, Doder M, Lees AJ et al. (2005). Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128: 1314–1322. Rinne JO, Portin R, Ruottinen H et al. (2000). Cognitive impairment and the brain dopaminergic system in Parkinson disease: [18F]fluorodopa positron emission tomographic study. Arch Neurol 57: 470–475. Sawle GV, Brooks DJ, Marsden CD et al. (1991). Corticobasal degeneration: a unique pattern of regional cortical oxygen metabolism and striatal fluorodopa uptake demonstrated by positron emission tomography. Brain 114: 541–556. Schrag A, Good CD, Miszkiel K et al. (2000). Differentiation of atypical parkinsonian syndromes with routine MRI. Neurology 54: 697–702. Schwarz J, Tatsch K, Arnold G et al. (1992). 123I-iodobenzamide-SPECT predicts dopaminergic responsiveness in patients with de-novo parkinsonism. Neurology 42: 556–561. Seppi K, Donnemiller E, Riccabona G et al. (2001). Disease progression in PD vs MSA: a SPECT study using 123-I IBZM. Parkinsonism Relat Disord 7: S24. Seppi K, Schocke MF, Esterhammer R et al. (2003). Diffusion-weighted imaging discriminates progressive supranuclear palsy from PD, but not from the Parkinson variant of multiple system atrophy. Neurology 60: 922–927. Seppi K, Schocke MF, Donnemiller E et al. (2004). Comparison of diffusion-weighted imaging and [123I] IBZM-SPECT for the differentiation of patients with the Parkinson variant of multiple system atrophy from

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those with Parkinson’s disease. Mov Disord 19: 1438–1445. Sommer U, Hummel T, Cormann K et al. (2004). Detection of presymptomatic Parkinson’s disease: combining smell tests, transcranial sonography, and SPECT. Mov Disord 19: 1196–1202. Su PC, Ma Y, Fukuda M et al. (2001). Metabolic changes following subthalamotomy for advanced Parkinson’s disease. Ann Neurol 50: 514–520. Torstenson R, Hartvig P, Lngstrm B et al. (1997). Differential effects of levodopa on dopaminergic function in early and advanced Parkinson’s disease. Ann Neurol 41: 334–340. Turjanski N, Lees AJ, Brooks DJ (1997). PET studies on striatal dopaminergic receptor binding in drug naive and L-dopa treated Parkinson’s disease patients with and without dyskinesia. Neurology 49: 717–723. Vingerhoets FJG, Schulzer M, Calne DB et al. (1997). Which clinical sign of Parkinson’s disease best reflects the nigrostriatal lesion? Ann Neurol 41: 58–64. Walker Z, Costa DC, Walker RW et al. (2002). Differentiation of dementia with Lewy bodies from Alzheimer’s disease using a dopaminergic presynaptic ligand. J Neurol Neurosurg Psychiatry 73: 134–140. Walker Z, Costa DC, Walker RW et al. (2004). Striatal dopamine transporter in dementia with Lewy bodies and Parkinson disease: a comparison. Neurology 62: 1568–1572. Walter U, Klein C, Hilker R et al. (2004). Brain parenchyma sonography detects preclinical parkinsonism. Mov Disord 19: 1445–1449. Whone AL, Rabiner EA, Arahata Y et al. (2002). Reduced substance P binding in Parkinson’s disease complicated by dyskinesias: an F-18-L829165 PET study. Neurology 58 (Suppl 3): A488–A489. Whone AL, Moore RY, Piccini P et al. (2003a). Plasticity in the nigropallidal pathway in Parkinson’s disease: an 18Fdopa PET study. Ann Neurol 53: 206–213. Whone AL, Watts RL, Stoessl J et al. (2003b). Slower progression of PD with ropinirol versus L-dopa: the REALPET study. Ann Neurol 54: 93–101.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 11

Parkinson’s disease: animal models RANJITA BETARBET* AND J. TIMOTHY GREENAMYRE Department of Neurology, Emory University, Atlanta, GA, USA

11.1. Introduction Animal models are an essential tool to study human diseases, not only to enable a thorough investigation into the mechanisms involved in the pathogenesis of a disease but also to help in the development of therapeutic strategies. It was through the use of an animal model that striatal dopamine deficiency was first associated with symptoms of Parkinson’s disease (PD) and levodopa was first used to compensate for striatal dopamine loss (Carlsson et al., 1957). However, the mechanisms involved in PD pathogenesis and therefore its cure remain elusive to this day. It is therefore important to develop animal model(s) to understand the pathogenesis of PD and to develop therapeutic strategies to treat it. In the present chapter we will describe genetic as well as pharmacological manipulations used to develop animal models that mimic PD and discuss the advantages and disadvantages of the various models. In order to discuss which model best simulates the disease, it is essential first to recapitulate the known characteristics of PD. PD, first described by James Parkinson in 1817, is a basal ganglia-related movement disorder characterized by tremor, rigidity or stiffness of movement and bradykinesia or slowness of movement. It is a late-onset, progressive, neurodegenerative disease involving the degeneration of the nigrostriatal pathway and dopaminergic neurons of substantia nigra (Fig. 11.1). Striatum (including caudate nucleus and putamen), the basal ganglia input nucleus, receives dopaminergic input from neurons of the substania nigra pars compacta via the nigrostriatal pathway (Moore et al., 1971; Albin et al., 1989). Progressive retrograde degeneration of the nigrostriatal

pathway and subsequent degeneration of the nigral dopaminergic neurons result in profound dopamine deficiency in the striatum. Striatal dopamine deficiency (>80%) and the resultant changes in the basal ganglia circuitry (circuitry involved in motor activity) are believed to underlie the clinical manifestations of PD (Albin et al., 1989; Crossman, 1989; DeLong, 1990). An additional, important pathological hallmark of PD is the presence of eosinophilic, cytoplasmic inclusions called Lewy bodies (LB) in nigral neurons (Fig. 11.2). Morphologically, the LBs have a dense core surrounded by a halo. The precise biochemical composition of LBs is as yet unknown, though proteins including a-synuclein, parkin, ubiquitin and various components of the protein degradation pathway have been identified to be constituents of LBs. The mechanism by which these proteinaceous aggregates are formed and the pathological significance are as yet unknown. Both neurodegeneration and the presence of LBs are not restricted to nigral neurons. Locus ceruleus (noradrenergic), cerebral cortex, raphe nucleus (serotonergic), nucleus basalis of Meynert (cholinergic), olfactory bulb (dopaminergic) and central and peripheral divisions of the autonomic systems (Takahashi and Wakabayashi, 2001; Del Tredici et al., 2002) are some of the affected nuclei and systems in PD. Inflammation in the brain, in particular activation of the microglia, is associated with PD pathology (McGeer et al., 1988). Microglia are the brain’s resident immune cells and play a role in immune surveillance under normal conditions. However, in response to immunological stimuli and neuronal injuries, microglia become activated and alter their morphology. They enlarge and develop short stubby processes and produce potentially

*Correspondence to: Dr R. Betarbet, Emory University, Center for Neurodegenerative Diseases, Whitehead Biomedical Research Building, Room 525, 615 Michael Street, Atlanta, GA 30322, USA. Email: [email protected], Tel: þ1-404-7279216, Fax: þ1-404-727-3728.

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Dopaminergic terminals

Caudate putamen

Nigrostriatal pathway Dopaminergic cell body

Substantia nigra

A

B

Fig. 11.1. Schematic diagram showing the nigrostriatal dopaminergic pathway, which undergoes progressive degeneration, an important hallmark of Parkinson’s disease (PD) pathogenesis. (A) Cross-section of the human forebrain shows the caudate and the putamen, which constitute the striatum. Section through the midbrain shows the ventrally located substantia nigra (SN). Dopaminergic neurons located in the SN send projections that terminate in the striatum. (B) Following degeneration of the dopaminergic pathway, the dopaminergic terminals release progressively less dopamine in the striatum. Striatal dopamine deficiency, in turn, results in complex changes in the basal ganglia circuitry resulting in motor deficits characteristic of PD. A report by Hornykiewicz (1966) has indicated >90% loss of striatal dopamine as compared to <80% dopamine loss in the SN in PD patients, suggesting retrograde degeneration of the dopaminergic pathway starting at the level of the terminals.

Fig. 11.2. Lewy body in a neuron from substantia nigra of a patient with Parkinson’s disease. Hematoxylin and eosinstained intraneuronal inclusion (arrow) has a dense core surrounded by a halo typical of Lewy body.

neurotoxic reactive oxygen species (Gao et al., 2002). Activated microglia produce numerous cytotoxic factors, including nitric oxide and reactive oxygen species

that have the potential to induce neurodegeneration (Hirsch, 2000; Liu et al., 2002a). Evidence of microglial activation, derived from postmortem analysis of the substantia nigra of PD patients, has implicated microglia in the late stages of PD pathogenesis. Interestingly, epidemiological studies have suggested that inflammation increases the risk of developing PD (Gao et al., 2002). The biochemical characteristics of PD have been associated with mitochondrial dysfunction and oxidative stress. Numerous reports have demonstrated modest but reproducible reductions in mitochondrial complex I function in a variety of tissues from PD patients, including brain, platelets, muscle and fibroblasts (Bindoff et al., 1989; Parker et al., 1989; Schapira et al., 1989; Shoffner et al., 1991; Mann et al., 1992; Cardellach et al., 1993; Blin et al., 1994). These findings suggest a systemic complex I defect in PD. The role of mitochondria in PD has been further accentuated by the observation that 1-methyl-4-phenylpyridinium (MPPþ), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and an inhibitor of complex I of the mitochondrial electron transport chain (ETC), causes an

PARKINSON’S DISEASE: ANIMAL MODELS acute parkinsonian syndrome (Langston et al., 1983). At several locations along the mitochondrial ETC, there are sites of ‘electron leaks’ (Fig. 11.3). These electrons can combine with molecular oxygen and form reactive oxygen species (ROS), such as superoxide (O2–) and hydrogen peroxide (H2O2). The ROS can readily react with DNA, lipids and proteins and cause oxidative damage. Of particular relevance to PD is the site of electron leak within complex I of the ETC (Turrens and Boveris, 1980; Hasegawa et al., 1990; Hensley et al., 1998). Partial inhibition of complex I at ETC greatly increases ROS production, which may overwhelm the cells’ protective mechanisms, leading to damage to DNA, lipids and proteins (Fig. 11.4). Targets of oxidative damage could also include ETC components, setting up a positive feedback loop of ETC inhibition, increased ROS production and further ETC inhibition (Turrens and Boveris, 1980; Hasegawa et al., 1990; Cassarino et al., 1997). Similarly, chemical oxidation of dopamine (Fig. 11.4), which generates ROS, can participate in a positivefeedback loop responsible for progressive oxidative damage (Turrens and Boveris, 1980; Hasegawa et al., 1990; Cassarino et al., 1997; Jenner, 1998). The activities of tyrosine hydroxylase and monoamine oxidase, two enzymes involved in dopamine metabolism, produce H2O2 as a normal byproduct. Additionally, auto-oxidation of dopamine results in dopamine quinones (Graham, 1978), along with the formation of ROS (Lotharius and O’Malley, 2000). Furthermore,

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disruption of vesicular storage of dopamine, due to energy failure (Dauer and Przedborski, 2003) or defective a-synuclein (Sulzer, 2001), could increase the levels of free dopamine and consecutive generation of ROS and oxidative stress. Thus dopaminergic neurons and terminals, the primary targets in PD, are believed to exist in a constant state of oxidative stress. Oxidative stress-related changes have been detected in brains of PD patients (Jenner, 1998). These include elevated oxidative damage to DNA, proteins and lipids, decreased levels of reduced glutathione and increased superoxide dismutase and monoamine oxidase (MAO) activity in PD substantia nigra, implicating oxidative damage as a mechanism of central importance in PD neurodegeneration. A defective protein degradation pathway, the ubiquitin-proteasome system (UPS), has also been associated with PD (McNaught et al., 2001). The UPS is essential for non-lysosomal degradation and clearance of abnormal (i.e., mutated or oxidatively damaged) proteins. Through a series of enzyme-mediated reactions, proteins are first identified and then linked with multiple ubiquitin molecules as a signal for degradation. Activated ubiquitin is generated by a ubiquitin-activating enzyme (E1) through an adenosine triphosphate (ATP)-dependent mechanism. It is then transferred to ubiquitin-conjugating enzymes (E2) and ligated to lysine residues of protein substrates in a reaction catalyzed by many different ubiquitin protein ligases (E3), such as parkin, that, together with specific E2s,

Fig. 11.3. Schematic diagram of the mitochondrial electron transport chain. Note the site of complex I inhibition by rotenone and 1-methyl-4-phenylpyridinium (MPPþ) and reactive oxygen species production.

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ROS DJ-1

Nucleus

PINK1

Parkin

DA cell body in SN

UCH-L1 a-synuclein

DA

ROS

3-NT

UPS inhibition

DA

ROS

6-OHDA Rotenone

Methamphetamine

Paraquat

Reserpine

ROS

ROS

DA

DA

DA ROS ROS

DA

DA

ROS

DA terminal in striatum

MPP+ mitochondrion DA

dopamine aggregated synuclein

proteasomal complex ROS

free radicalls dopamine transporter

Fig. 11.4. Molecular mechanisms used to develop animal models for Parkinson’s disease. This schematic diagram illustrates the site of action of pharmacological agents or genetic manipulations in a representative nigral dopaminergic neuron with cell body in the nigra and terminals in the striatum that result in striatonigral degeneration and striatal dopamine depletion. Reserpine and methamphetamine deplete dopamine at the nerve terminals, resulting in striatal dopamine deficiency. 6-Hydroxydopamine (6-OHDA) can affect all catecholaminergic neurons; therefore it is stereotactically targeted into the substantia nigra, the nigrostriatal tract or the striatum. 6-OHDA neurotoxic effects are suggested to involve oxidative stress-related mechanisms. 1-methyl-4-phenylpyridinium (MPPþ), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is selectively taken up by the dopaminergic neurons via its affinity for the dopamine transporter. MPPþ toxicity results from inhibition of complex I of the electron transport chain and oxidative stress. The mechanism of action of paraquat is not known but is thought to be due to oxidative stress. Rotenone, a potent inhibitor of complex I, is a lipophilic compound with easy access across the cell membrane. It is believed that rotenone-induced partial inhibition of complex I and subsequent oxidative stress render the dopaminergic cells specifically vulnerable to chronic low levels of mitochondrial dysfunction. Direct administration of 3-nitrotyrosine (3-NT) into the striatum tests the involvement of oxidative stress, specifically peroxynitrite, in nigrostriatal dopaminergic degeneration. Inhibition of the ubiquitin proteasome system can also lead to selective neurodegeneration of the nigrostriatal pathway. Mutations in various genes, including a-synuclein, parkin, UCH-L1, DJ-1, PINK1, linked to a small group of familial Parkinson’s disease cases, have been suggested to play a role in neuronal degeneration and increased protein aggregation. DA, dopamine; SN, substantia nigra; UPS, ubiquitin-proteasome system.

ensure specific protein targeting. Ubiquitin-protein conjugates are subsequently recognized and degraded by 26S proteasomes, which are multi-subunit proteases

found in eukaryotic cells. The degraded products are short peptide fragments and amino acids that can be recycled to produce new proteins. At the same time,

PARKINSON’S DISEASE: ANIMAL MODELS the polyubiquitin chains are disassembled by ubiquitin carboxy-terminal hydrolases (such as UCHL-1) to produce monomeric ubiquitin molecules that re-enter the UPS pathway. Evidence in support of PD pathogenesis and impaired UPS and protein aggregation comes from the occurrence of elevated levels of oxidatively damaged proteins (Alam et al., 1997), increased protein aggregation (Lopiano et al., 2000) and impaired proteolysis (McNaught and Jenner, 2001) in the substantia nigra of patients with sporadic PD. Furthermore, in familial forms of PD, mutations in components of the UPS, parkin and UCHL-1, have been associated with pathogenesis of the disease (Fig. 11.4). Missense or triplication mutations of the a-synuclein gene have also been associated with disease onset. Though a-synuclein is not a component of the UPS, mutant or increased levels of a-synuclein can inhibit the UPS and result in protein aggregation (Stefanis et al., 2001; Tanaka et al., 2001; Snyder et al., 2003). Thus, a defective UPS may have a significant role in PD pathogenesis.

11.2. Etiology of Parkinson’s disease PD is essentially a sporadic disorder with no known cause. However, the studies that discovered the genetic mutations responsible for familial PD as well as epidemiologic studies suggesting a role for environmental factors have advanced our understanding of sporadic PD pathogenesis (Siderowf and Stern, 2003). 11.2.1. Genetic mutations and Parkinson’s disease 11.2.1.1. a-Synuclein The association of a-synuclein to PD pathogenesis followed the discovery of missense mutations in the a-synuclein gene as a cause of autosomal dominantly inherited PD (Polymeropoulos et al., 1997). An Ala53 ! Thr (A53T) mutation resulting from a G to A transition at position 209 was identified in a large Italian-American kindred, and an Ala30 ! Pro (A30P) mutation resulting from a G to C transition at position 88 was identified in a small German kindred (Kruger et al., 1998). Further, a genomic triplication of wild-type a-synuclein leading to overexpression of wild-type a-synuclein is the disease-causing mutation in familial PD in the Iowan kindred and the PARK4 locus (Singleton et al., 2003). Even though mutations in a-synuclein are rare causes of PD, the discovery that a-synuclein is a major constituent of LBs, commonly featured in sporadic PD, has suggested a major role for a-synuclein in PD pathogenesis.

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11.2.1.2. Parkin, UCHL-1 Mutations in the genes encoding for parkin (Kitada et al., 1998) and UCH-L1 (Leroy et al., 1998) linked to PD have further implicated a dysfunctional UPS in PD pathogenesis. Autosomal-recessive juvenile parkinsonism (AR-JP), one of the commonest familial forms of PD, has been described in a series of Japanese kindreds (Kitada et al., 1998). Parkin has been identified to be a ubiquitin-protein ligase (E3) that acts along with the ubiquitin-conjugating enzymes (E2s) UbcH7 and UbcH8 (Imai et al., 2000; Shimura et al., 2001). Familial-associated mutations in parkin impair its binding to UbcH7 and UbcH8 and are defective in E3 ligase activity of parkin, which suggests that disruption of E3 ubiquitin-protein ligase activity of parkin may cause AR-JP. It appears that a decrease in enzyme activity rather than complete ‘loss of function’ may underlie AR-JP pathogenesis. A missense mutation (Ile93M) in the gene coding for UCH-L1 has been identified in two siblings of a German family with autosomal-dominant familial PD that is characterized by levodopa-responsive motor symptoms (Leroy et al., 1998). UCH-L1 is a ubiquitous protein making up to 2% of all proteins in the brain. It belongs to a family of de-ubiquitinating enzymes that are responsible for the hydrolysis of polyubiquitin chains into monomeric ubiquitin (Pickart, 2000). Mutations in the UCH-L1 gene result in a 50% decrease of catalytic activity, implying that loss of UCH-L1 activity in PD might lead to reduced ubiquitination and therefore impaired clearance of abnormal proteins. Accumulation of certain proteins may be toxic to neurons, leading to neurodegeneration. Mutations in parkin and UCH-L1, components of the UPS, have suggested a role for UPS in PD pathogenesis. 11.2.1.3. DJ-1 Mutations in DJ-1 have been associated with autosomal-recessive PD in two consanguineous European families. The human DJ-1 gene maps to chromosome 1p36, the PARK7 locus. A large 14-kb deletion encompassing exons 1–5 of the gene has been found in a Dutch family and an Italian family carries a missense mutation at L166P (Bonifati et al., 2003). The gene encodes a 189-amino-acid protein of approximately 20 kDa. A putative function ascribed to DJ-1 is its role in neuroprotection, and it has been predicted that a complete loss of function is the most likely pathogenic mechanism for DJ-1 in PD. DJ-1 protein has been shown to localize in cytoplasmic and nuclear regions in various cell lines. An oxidative modification of DJ-1 to a more acidic (pI 5.8) isoform has been reported to accumulate under oxidative stress, such as following

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MPPþ or paraquat exposure. Further, DJ-1 locates to the mitochondria following oxidative stress (Canet-Aviles et al., 2004). Cells lacking DJ-1 have been shown to be more sensitive to hydrogen-induced oxidative stress, which could be rescued by overexpression of wild-type but not by the mutant L166P mutant (Yokata et al., 2003; Canet-Aviles et al., 2004), suggesting that DJ-1 could function as antioxidant. 11.2.1.4. PINK1 Mutations in a putative mitochondrial protein kinase called PINK1 (PTEN-induced kinase 1) have been associated with autosomal-recessive parkinsonism (Valente et al., 2004). The human gene is on chromosome 1p36, which contains the PARK6 linkage region, which has been previously linked to a rare form of familial PD (Valente et al., 2001). Two mutations were identified: a W437Stop mutation in two Italian families and a G309D mutation in a Spanish family. PINK1 has been cloned and named by Unoki and Nakamura (2001). The gene encodes a 581–cid protein with a predicted molecular mass of 62.8 kDa and a putative serine/ threonine protein kinase catalytic domain. The protein has all the required kinase sites, so it is highly likely to be a functional kinase (Manning et al., 2002). In addition the recombinant protein is capable of autophosphorylation (Nakajima et al., 2003). PINK1 has a mitochondrial targeting sequence at the N-terminus and is suggested to be a mitochondrial kinase. Both the wild-type and mutant PINK1 are mitochondrially located. With regard to the role of PINK1 in PD pathogenesis, it has been hypothesized that PINK1 may phosphorylate mitochondrial proteins in response to cellular stress, protecting against mitochondrial dysfunction. Further, this protective role is abrogated by the mutations, resulting in increased susceptibility to cellular stress (Valente et al., 2004). Interestingly, in a non-neuronal environment, PTEN (the protein associated with PINK1) has been shown to regulate the ubiquitin degradation of one of the cell cycle proteins through a ubiquitin E3 ligase (Mamillapalli et al., 2001). The discovery of PINK1 as a putative mitochondrial protein kinase and its association with familial PD pathogenesis further strengthen the role of mitochondrial impairment, along with oxidative stress and protein mishandling in PD (sporadic) pathogenesis (Greenamyre and Hastings, 2004). 11.2.2. Environmental toxins and Parkinson’s disease Epidemiological studies, including the results from the twin studies (Piccini et al., 1999; Tanner et al., 1999), have not only implicated ‘environmental exposure’ to

PD pathogenesis but also initiated the identification of environmental factors associated with the risk of developing PD. Case-control studies have suggested that: (1) rural living; (2) farming as an occupation; (3) drinking well-water; and (4) pesticide exposure are associated with an increased risk of PD (Uversky, 2004). For example, studies have linked the geographic distribution of pesticide usage with prevalence of PD. Surveys from several countries, including the USA, Canada, Australia, Hong Kong and Taiwan, have shown statistically significant associations between pesticide exposure and PD (Golbe et al., 1990; Hertzman et al., 1990; Liou et al., 1997; Chan et al., 1998; Gorell et al., 1998; Menegon et al., 1998). Experimental exposure of rodents to herbicides and pesticides further supports the involvement of environmental toxins in PD. Exposure of mice to the herbicides paraquat (Brooks et al., 1999) and maneb (Takahashi et al., 1989) caused a dose-dependent decrease in dopaminergic nigral neurons and striatal dopaminergic innervation, followed by reduced ambulatory movement. The mechanism of action of paraquat is believed to involve oxidative stress. The observation that combined effects of parquat and maneb (Thiruchelvam et al., 2000) have greater effects on the dopaminergic system than either of the chemicals alone suggests that exposure to a mixture of toxins may be relevant etiologically. The extent to which the mechanisms of action of environmental factors/toxins are related or independent is not clear. Interestingly, many pesticides and herbicides share the common mechanism of causing mitochondrial dysfunction by inhibiting complex I (Table 11.1). Many of these pesticides are used on a broad scale in commercial agriculture (Degli Esposti, 1998). Whether these compounds are capable of causing PD is yet to be determined. In addition to synthetic compounds, there exist many natural substances that potently inhibit complex I (Table 11.2) and therefore have a potential role in PD pathogenesis (Degli Esposti, 1998). Thus Table 11.1 Pesticides known to inhibit complex I Benzimidazole Bullactacin 6-Chlorobenzothiadiazole Cyhalothrin Fenazaquin Fenpyroximate

Hoe 110779 Pyridaben Pyrimidifen Sandoz 547A Tebufenpyrad Thiangazole

Reproduced from Betarbet et al. (2002) with permission from Brain Pathology. Original sources: Degli Esposti (1998) and Lummen (1998).

PARKINSON’S DISEASE: ANIMAL MODELS Table 11.2 Natural compounds known to inhibit complex I Compounds

Source

Rotenoids Piericidins Acetogenins

Leguminosae plants Streptomyces strains Annonacae plants (custard apple, paw-paw) Myxobacteria Rhubarb

Antibiotics Rhein

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depletion of striatal dopamine, which is known to be responsible for the clinical manifestation of PD. The reserpine model and the methamphetamine (METH) model are primarily based on mimicking the striatal dopamine loss observed in PD, whereas the 6-hydroxydopamine (6-OHDA) and MPTP models have simulated the selective degeneration of the nigrostriatal pathway. 11.2.4. The reserpine model

various environmental factors converging on similar mechanisms of action may eventually provide insights to PD pathogenesis. There is no specific environmental agent or ‘smoking gun’ that has been conclusively linked to PD pathogenesis to date. There are several explanations for this. Chronic, low-grade exposure to toxins over many years may be essential for developing progressive neurodegeneration but might be very hard to detect. There may be long latent periods between toxin exposure and neurodegeneration such that clinical symptoms develop many years after exposure. Furthermore, genetic differences in the ability to metabolize causative environmental agents may explain the occurrence of PD in only some individuals exposed to a toxin (Barbeau et al., 1985; Menegon et al., 1998). It is also important to recognize that environmental toxins need not be synthetic. As mentioned above, many potential toxins are naturally occurring plant or fungal products to which one may be exposed through water or food. It is therefore likely that an individual’s cumulative lifetime exposure to a combination of environmental factors in association with genetic susceptibility or resistance determines disease risk. No single animal model for PD today mimics all of the above-mentioned PD pathology and biochemical characteristics. However, each animal model developed so far is uniquely valuable to the extent to which they accurately simulate the pathogenic, histological, biochemical or clinical features of PD that an investigator wants to examine.

Systemic administration of reserpine causes depletion of brain catecholamines, leading to an akinetic state in rabbits (Carlsson et al., 1957). Furthermore, it has been shown that levodopa administration alleviated the reserpine-induced akinetic state, indicating that behavioral recovery is dopamine-dependent. This led to the major hypothesis, later confirmed in humans, that the motor symptoms of PD result from striatal dopamine depletion (Bernheimer et al., 1973). The discovery that striatal dopamine deficiency resulted in PD-like symptoms prompted the development of the reserpine animal model. Systemic reserpine administration depletes dopamine at the nerve terminals (Fig. 11.4) and induces a hypokinetic state in rodents. These movement deficits are due to loss of dopamine storage capacity in intracellular vesicles (Hornykiewicz, 1966). The precise pharmacological mechanisms are not clearly defined but it has been shown that at high doses reserpine depletes the intraneuronal vesicular storage of dopamine and other neurotransmitters (Gerlach and Riederer, 1996). The principal drawback of this model is that reserpine-induced changes are temporary and striatal reserpine administration does not induce morphologic changes in the dopaminergic neurons of the substantia nigra. Also, reserpine administration induces the release of other neurotransmitters that may not be directly implicated in PD. Nevertheless, this model has been successfully used to investigate the therapeutic effects of striatal dopamine replacement agents, including levodopa and dopamine receptor agonists (Gossel et al., 1995). On the other hand, the predictive value of symptomatic drug-testing in the reserpine model is imperfect, since some drugs that reverse reserpine-induced locomotor deficits are ineffective in PD.

11.2.3. Toxicant-induced animal models

11.2.5. Methamphetamine model

The cardinal characteristic of PD pathology is massive retrograde degeneration of the nigrostriatal pathway resulting in an initial loss of striatal dopaminergic fibers followed by degeneration of the nigral dopaminergic neurons. As a consequence, there is a dramatic

The psychostimulatory drugs, amphetamines, are similar to reserpine in that their activity is primarily associated with their dopamine-releasing mechanism (Seiden et al., 1975; McMillen, 1983). Like reserpine, METH administration results in dopamine depletion at

Reproduced from Betarbet et al. (2002) with permission from Brain Pathology. Original source: Degli Esposti (1998).

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the level of dopaminergic nerve terminals (striatum; Fig. 11.4) with minimal effect in the nigral cell bodies (Fibiger and Mogeer, 1971). At very high doses, METH has neurotoxic effects on rodents and non-human primates (Seiden et al., 1975; Wagner et al., 1979, 1980). Also, like reserpine, the mechanism of METH action is unclear. Indirect evidence suggests that METH acts through the dopamine receptor and transporter since selective antagonists are able to block its toxicity (Schmidt et al., 1985; Sonsalla et al., 1986, 1989). Antagonists of the N-methyl-D-aspartate receptor, such as MK-801, are also capable of inhibiting METHinduced toxicity (Sonsalla et al., 1991; Marshall et al., 1993). The neuroprotective effects of glutamate receptor antagonists on the METH model may be related to glutamate receptor-regulated dopamine release (Boireau et al., 1995). In vitro studies have suggested oxidative stress, via dopamine autoxidation, and excitotoxicity (Lafon-Cazal et al., 1993), as a result of perturbations in energy metabolism (Beal, 1992), as some of the causative factors in the neurotoxic actions of METH. The major drawback of the METH model is that the histological changes of PD, including degeneration of dopaminergic neurons and the presence of intracellular inclusions, have not been documented. Furthermore, it is an acute model of striatal dopamine depletion. However, the METH model has been used extensively for biochemical and physiological studies of the dopamine-depleted striatum to understand better such changes in the PD brain. 11.2.6. The 6-OHDA model The hydroxylated analog of dopamine, 6-OHDA (Blum et al., 2001), was the first chemical agent discovered that had specific neurotoxic effects on catecholaminergic pathways (Ungerstedt, 1968; Sachs and Jonsson, 1975). 6-OHDA uses the same catecholamine transport system as dopamine and norepinephrine, and produces specific degeneration of catecholaminergic neurons. Systemically administered 6-OHDA is unable to cross the blood–brain barrier. To target the nigrostriatal dopaminergic pathway specifically, 6-OHDA must be injected stereotactically (Fig. 11.4) into the substantia nigra, the nigrostriatal tract or the striatum (Perese et al., 1989; Przedborski et al., 1995). Following 6-OHDA (Przedborski et al., 1995; Schwarting and Huston, 1996) injections into substantia nigra or the nigrostriatal tract, dopaminergic neurons start degenerating within 24 h, and striatal dopamine is depleted 2–3 days later (Faull and Laverty, 1969). The magnitude of the lesion is dependent on the amount of 6-OHDA injected, the site of

injection and inherent differences in sensitivity between animal species. Extensive striatal dopamine loss (80–90%) is achieved in most studies and corresponds to specific behavioral changes. When injected into the striatum, 6-OHDA produces a slow, retrograde degeneration of the nigrostriatal system over a period of weeks (Przedborski et al., 1995). The studies with 6-OHDA are unique because usually 6-OHDA is injected in one hemisphere while the other hemisphere serves as an internal control. Unilateral injections lead to asymmetric circling motor behavior after administration of dopaminergic drugs, due to physiologic imbalance between the lesioned and the unlesioned striatum. Moreover this turning behavior can be quantified and correlates with degree of lesion (Ungerstedt, 1968). Although 6-OHDA-induced lesions have been described in mice, cats, dogs and monkeys, rats are most commonly used because of established stereotactic techniques and relatively low maintenance costs. Oxidative stress appears to be the main mechanism involved in 6-OHDA-induced neurotoxicity. It has been reported that 6-OHDA-induced degeneration involves the generation of hydrogen peroxide and hydroxyl radicals in the presence of iron (Sachs and Jonsson, 1975). The fact that intranigral injection of iron produces similar neurotoxic effects as 6-OHDA may suggest a role for iron in 6-OHDA-induced degeneration (Ben-Shachar and Youdim, 1991). In addition, studies have demonstrated that 6-OHDA leads to a reduction in glutathione (GSH) and superoxide dismutase activity (Perumal et al., 1992) and an increase in malondialdehyde (Kumar et al., 1995) levels in the striatum. It has also been shown that 6OHDA inhibits mitochondrial complex I, resulting in the production of superoxide free radicals (Hasegawa et al., 1990; Cleeter et al., 1992). The partial, or even complete, prevention of neurotoxic effects of 6-OHDA and iron by prior administration of iron chelating agents (Ben-Shachar et al., 1991), vitamin E (Cadet et al., 1989; Perumal et al., 1992) and the MAO-B inhibitor, selegiline (Knoll, 1986), may also be regarded as indirect evidence for the formation of free radicals and involvement of oxidative stress. The 6-OHDA model does not mimic all the clinical and pathological features characteristic of PD. 6-OHDA does not affect other brain regions, such as locus ceruleus, nor does it result in formation of cytoplasmic inclusions (LBs) like those seen in PD. Furthermore, the acute nature of the experimental model differs from the progressive degeneration of the dopaminergic nigral neurons in PD. Despite these limitations, the 6-OHDA model has been used to ascertain the efficacy of various therapeutic

PARKINSON’S DISEASE: ANIMAL MODELS interventions. The turning behavior following unilateral 6-OHDA administration, that correlates well with the degree of lesion, is very useful and provides a quantitative assay to asses the neuroprotective properties of various therapeutic strategies, including the efficacy of cell transplantation and testing of neurotrophic factors and compounds that promote survival of the degenerating dopaminergic nigral neurons in PD (Dunnett et al., 1981) as well as antiparkinsonian compounds (Schwarting and Huston, 1996). 11.2.7. The MPTP model MPTP, an analog of the narcotic meperidine (Demerol) was inadvertently discovered in the early 1980s by Langston and colleagues (1983). Injections of 1-methyl4-phenyl-propion-oxypiperidine (MPPP) or ‘synthetic heroin’ resulted in clinical symptoms remarkably similar to sporadic PD in young drug addicts (Langston et al., 1999). MPTP was identified to be the neurotoxin responsible for the parkinsonian effects observed. Data from postmortem MPTP human cases and monkeys exposed to MPTP have shown that, as in sporadic PD pathology, there is selective degeneration of the nigrostriatal pathway (Fig. 11.5). In the striatum MPTP exposure resulted in preferential degeneration of putamenal

Fig. 11.5. Photomicrographs of brain sections from a unilaterally 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey. Sections through the striatum (A) and the substantia nigra (B) are stained for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Note the markedly reduced TH-immunoreactivity in the lesioned striatum (top right) and lesioned substantia nigra (bottom right) versus the control striatum (top left) and control substantia nigra (bottom left).

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dopaminergic terminals as opposed to caudate nucleus. In the substantia nigra there is greater cell loss in the lateral and ventral segments whereas the ventral tegmental area, the adjoining dopaminergic region, is relatively spared. Also, the neuromelanin-containing nigral dopaminergic neurons were more susceptible to MPTP-induced degeneration, just like in PD. Researchers have capitalized on this discovery of MPTP to develop an animal model of PD. After administration, MPTP crosses the blood–brain barrier and is metabolized in astrocytes to its active metabolite, MPPþ, by MAO-B. MPPþ is selectively taken up into dopaminergic neurons via its affinity for the dopamine transporter (Fig. 11.4), and is thus selectively toxic to dopamine neurons (Javitch et al., 1985). MPPþ toxicity is believed to result from inhibition of complex I of the mitochondrial ETC (Fig. 11.3). Consequences of complex I inhibition are impairment of oxidative phosphorylation, ATP production and an increase in oxidative stress (Nicklas et al., 1985; Tipton and Singer, 1993), all of which are suggested to have a role in neurodegeneration (Chan et al., 1991; Fabre et al., 1999). This mechanism of action of MPPþ suggested a role for mitochondrial dysfunction in typical PD. Subsequently, PD patients were found to express systemic reductions in complex I activity (Bindoff et al., 1989; Parker et al., 1989; Shoffner et al., 1991). MPTP administration is one of the commonest animal models used to study PD. Exposure to MPTP results in nigrostriatal dopaminergic degeneration in a number of species (Zigmond and Stricker, 1989; Tipton and Singer, 1993), including mice, cats and primates. Susceptibility to MPTP varies across species and strains of animals. For unknown reasons, rats are resistant to MPTP toxicity and mouse strains vary widely in their sensitivity to the toxin. MPTP is usually systemically administered (subcutaneous, intraperitoneal, intravenous or intramuscular). Maintaining bilaterally lesioned animals, especially primates, can be difficult, as these animals may need to be maintained on levodopa or other dopaminergic drugs to enable them to eat and drink adequately (Petzinger and Langston, 1998). Unilateral intracarotid infusion of MPTP is another method employed in non-human primates wherein the symptoms are expressed mainly on one side, which enables the monkey to maintain normal nutrition and hydration without medication (Przedborski et al., 1991). Various doses and regimens of MPTP administration (acute versus chronic) are used by different labs (Przedborski et al., 2001). Acute MPTP exposure results in specific degeneration of the nigrostriatal dopaminergic pathway, with 50–93% cell loss in the substantia nigra pars compacta

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and more than 99% loss of dopamine in the striatum (Hantraye et al., 1993). However, there is substantial interanimal variability in terms of effective doses and reversibility of clinical symptoms. In primates, MPTP exposure mimics the behavioral characteristics of PD, including bradykinesia and rigidity (Hantraye et al., 1993); however, development of tremor is speciesdependent. Neurochemical changes following MPTP exposure include decreased levels of dopamine and its metabolites in the striatum (Russ et al., 1991), increased oxidative damage as evidenced by increased lipid peroxidation (Rios and Tapia, 1987), increased 3-nitrotyrosine levels, and diminished concentrations of antioxidants, such as GSH (Sriram et al., 1997). Cytoplasmic inclusions have rarely been observed in MPTP-treated non-human primates, except for one instance, where a-synuclein-positive aggregation in nigral cells of baboons has been reported following MPTP exposure (Kowall et al., 2000). The aggregates, however, were unlike the LBs characteristic of PD pathology. There are some additional limitations of the MPTP model of PD. Most protocols of MPTP administration utilize acute drug treatments and fail to mimic the progressive nature of PD. Repeated administration of low doses of MPTP treatment may overcome this limitation (Albanese et al., 1993; Bezard et al., 1997). However, long-term administration of MPTP, in smaller doses, has resulted in the recovery of motor behavior deficits in marmosets once the treatment is stopped (Russ et al., 1991). Moreover, Fornai et al. (2005) have recently reported that continuous MPTP administration to mice with an osmotic minipump mimics many features of PD, such as progressive behavioral changes, and formation of nigral inclusions immunoreactive for ubiquitin and a-synuclein in addition to severe striatal dopamine depletion and nigral cell loss, suggesting that continuous low-level MPTP exposure can mimic PD-like symptoms more accurately. Still, the MPTP model does not directly address the involvement of systemic mitochondrial impairment in PD. MPPþ inhibits complex I activity solely in cells expressing the dopamine transporter, i.e. dopaminergic cells. Thus, this model only tests the hypothesis that complex I dysfunction, limited to dopaminergic neurons, is toxic to dopaminergic neurons. Nevertheless, the MPTP model of PD has been invaluable in studying the mechanisms of PD pathogenesis. For example, this model suggested a role of mitochondrial dysfunction and environmental exposures in the etiology of PD (Le Couteur et al., 1999). MPTP has also lent support to the oxidative stress model of PD, and has provided clues to the mechanism of cell death in PD. Because monkeys have a motor repertoire similar to humans, the clinical

features of MPTP-induced parkinsonism are strikingly similar to human PD. As such, MPTP-treated monkeys have provided an important way to test new symptomatic therapeutic strategies, including drugs and dietary alterations, transplants, surgical interventions and gene therapy. Currently there is no better or more predictive model for this purpose (Dauer and Przedborski, 2003; Schober, 2004). 11.2.8. Pesticide-based models 11.2.8.1. Paraquat and maneb Epidemiological and experimental studies have indicated that exposure to environmental toxins, including agriculture chemicals, can contribute to PD pathogenesis (Uversky, 2004). Since animal models are important tools for studying human diseases, especially diseases like PD that are not spontaneously found in animals, environmental toxins have been administered to rodents in the hope of reproducing features of PD for further investigation. The herbicide paraquat, or 1,10 -dimethyl-4,40 -bipyridinium, has emerged as a putative risk factor for PD on the basis of its structural similarity to MPPþ, the active metabolite of MPTP (Fig. 11.4). Paraquat does cross the blood–brain barrier, although slowly, and to a limited extent. When injected systemically into mice it caused a dose-dependent decrease in dopaminergic nigral neurons and striatal dopaminergic innervation, followed by reduced ambulatory movement (Brooks et al., 1999; Fig. 11.6). The loss of dopaminergic nigral neurons, following paraquat exposure, later confirmed by Di Monte (2001), also resulted in significant increases in a-synuclein levels and accumulation of a-synuclein within neurons of substantia nigra pars compacta (Manning-Bog et al., 2002). Paraquat, however is only one of the many agricultural chemicals known to impact the dopamine systems adversely. Manganese ethylenebisdithiocarbamate, or maneb, has been shown to decrease locomotor activity and potentiate MPTP effects (Takahashi et al., 1989). Furthermore, the major active fungicidal component of maneb, manganese ethylene-bis-dithiocarbamate (Mn-EBDC), when administered directly into the lateral ventricles in rats, was selectively toxic to the dopaminergic system, induced extensive striatal dopamine efflux and preferentially inhibited mitochondrial complex III (Zhang et al., 2003). Maneb is used in overlapping geographical areas with paraquat, suggesting that exposures to mixtures of chemicals may also be relevant etiologically. Indeed, combined paraquat and maneb exposures produced greater effects on the dopaminergic system then either of the chemicals alone (Thiruchelvam et al., 2000), including reduced motor

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Fig. 11.6. Paraquat-induced neurodegeneration in mouse substantia nigra. Coronal sections through the substantia nigra of saline-treated (A) and paraquat-exposed (B) mice were stained for tyrosine hydroxylase (A, B; scale 150 mm) and silver (insets; scale 10 mm) for degeneration. Note fewer tyrosine hydroxylase-immunoreactive cells (B) and a degenerating neuron following 7 days of paraquat exposure (arrow, B inset). Mice received three consecutive weekly injections of saline or 10 mg/kg paraquat. Courtesy of Alison McCormack and Dr. Donato A. Di Monte.

activity and increased degeneration of striatal dopaminergic terminals and nigral cell bodies. The evidence that combined exposure to paraquat and maneb targets the nigrostriatal dopamine systems and induces motor impairment gives credence to the theory that environmental toxins and pesticides may have a role in PD pathogenesis. Further investigations using these pesticide models will help to determine the involvement of environmental exposures in the pathological, biochemical and clinical symptoms of PD. 11.2.8.2. Rotenone model Systemic complex I inhibition (and not selective, as with MPTP) is one of the key biochemical features of PD that has been virtually ignored, especially in

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terms of developing an animal model. We proposed that if ‘systemic complex I inhibition’ has a central role in PD pathogenesis, then systemic low levels of chronic complex I inhibition would induce selective degeneration of the nigrostriatal pathway. In our study we targeted ‘two birds with our stone’ – complex I inhibition and commonly used environmental toxin; we used rotenone, a pesticide and potent inhibitor of complex I (Betarbet et al., 2000). A naturally occurring compound derived from roots of a plant called Lonchocarpus species, rotenone is commonly used as an ‘organic’ insecticide and to kill nuisance fish in lakes. Rotenone is also a classic, high-affinity complex I inhibitor and is typically used to define the specific activity of complex I (Nicolaou et al., 2000; Schuler and Casida, 2001). Additionally, rotenone is a lipophilic compound that easily crosses the blood–brain barrier. Unlike MPPþ, rotenone does not require the help of transporters (Uversky, 2004) to cross cellular membranes. Once inside the cell rotenone accumulates in the mitochondria (Talpade et al., 2000), where it impairs oxidative phosphorylation by inhibiting complex I (Schuler and Casida, 2001). Rats were systemically and chronically exposed to low levels of rotenone via intrajugular or subcutaneous infusion (Betarbet et al., 2000; Sherer et al., 2003c). Chronic exposure to low doses of rotenone resulted in uniform inhibition of complex I throughout the rat brain, unlike MPTP, which selectively inhibits complex I in dopaminergic neurons due to its dependence on the dopamine transporter (Fig. 11.7). Despite this uniform complex I inhibition, rotenone caused selective degeneration of the nigrostriatal dopaminergic pathway, whereas striatal neurons and neurons of other brain regions, including globus pallidus and subthalamic nucleus, remained intact (Betarbet et al., 2000; Sherer et al., 2003c). Formation of ubiquitin and a-synuclein positive inclusions in nigral cells, which were morphologically similar to the LBs of PD, was also detected in rotenone-infused rats. Selective microglial activation in the striatum and nigral brain regions was also detected in rotenone-infused rats (Sherer et al., 2003a). Behaviorally, the rotenone-exposed rats were hypokinetic with a flexed posture similar to the stooped posture of PD patients. Some developed severe rigidity and a few had spontaneously shaking paws that were reminiscent of resting tremor in PD. Rotenone-induced complex I inhibition resulted in increased oxidative stress, both in vivo in rats (Sherer et al., 2003b) and invitro (Sherer et al., 2002) in neuroblastoma cells, as implicated by increased levels of protein carbonyls, a marker for oxidative stress. A dysfunctional UPS was also a consequence of rotenone-induced complex I inhibition. 20S proteasomal enzymatic activities were significantly

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Fig. 11.7. Photomicrographs of rat brain sections from control and following rotenone administration. Sections through the striatum (A, B) and the substantia nigra (C, D) stained for tyrosine hydroxylase (TH). Note the markedly reduced THimmunoreactivity in the rotenone-exposed lesioned striatum (B) and rotenone-exposed lesioned substantia nigra (D) versus the control striatum (A) and control substantia nigra (C).

and selectively reduced in the ventral midbrain regions in rotenone-infused rats. Furthermore, ubiquitin conjugated proteins, an indicator of proteins marked for degradation, were markedly increased in ventral midbrain, suggesting impairment of the 26S proteasome degradation pathway (Betarbet et al., 2006). Thus systemic, chronic, low doses of complex I inhibition with rotenone in rats reproduced numerous features of PD, including selective nigrostriatal degeneration, formation of synuclein-positive cytoplasmic inclusions, microglial activation, increased oxidative stress and a dysfunctional UPS. Since the initial studies with rotenone, numerous reports have either confirmed (Alam and Schmidt, 2002; Zhu et al., 2004) or questioned (Hoglinger et al., 2003; Lapointe et al., 2004) the selectivity of rotenoneinduced degeneration of the nigrostriatal dopaminergic pathway. These differences could be due to a ‘small window’ for rotenone’s action that results in selective neurodegeneration. There exists a threshold for every drug beyond which they have non-specific or ‘sideeffects’. For rotenone this threshold appears to be very small – some animals have an acute response whereas some are not affected by rotenone at all, and yet there are some rats that develop very characteristic features of

PD. At high doses, as shown by Ferrante et al. (1997), rotenone can have non-specific effects. The variability observed in all the studies to date, demonstrating that the severity of striatal dopaminergic degeneration can range from none to nearly complete lesions (Betarbet et al., 2000; Hoglinger et al., 2003; Sherer et al., 2003c; Lapointe et al., 2004; Zhu et al., 2004), is very interesting too. This variability clearly demonstrates the individual susceptibility to complex I inhibition in rats; this could be due to genetic differences and/or differences in the ability to metabolize environmental toxins (Uversky, 2004), similar to individual differences that may determine one’s susceptibility to develop PD. The rotenone model shows that the features of PD can be produced by systemic complex I inhibition. This indicates that the nigrostriatal pathway is intrinsically and selectively sensitive to complex I dysfunction. The previously described occurrence of complex I dysfunction in PD may further link environmental toxins to the pathogenesis of PD. Many other environmental agents, in addition to MPTP and rotenone (Fig. 11.4), affect mitochondrial function at complex I (Degli Esposti, 1998). Furthermore, complex I impairment may predispose neurons to excitotoxicity and oxidative damage, both of which have been implicated in PD (Greene and Greenamyre, 1996; Hensley et al., 1998). Interestingly, many PD features have been recapitulated in other species, including flies, Drosophila melanogaster (Coulom and Birman, 2004), and Caenorhabditis elegans (Wolozin et al., 2004) following rotenone exposure. Following several days of sublethal doses of rotenone exposure, flies developed locomotor impairments and selective loss of dopaminergic neurons in the brain clusters. Levodopa in the feeding medium rescued the behavioral deficits, implying that locomotor deficits are due to loss of dopaminergic neurons. In contrast, the antioxidant melatonin alleviated both behavioral deficits and neuronal loss, suggesting a major role for oxidative stress in neuronal degeneration. These studies also demonstrate how these models can be used for screening other complex I inhibitors, and therapeutic drugs (Wolozin et al., 2004). The rotenone model appears to be an accurate model in that systemic complex I inhibition results in specific, progressive and chronic degeneration of the nigrostriatal pathway similar to that observed in human PD. It also reproduces the neuronal inclusions and oxidative damage seen in PD. Thus, the rotenone model recapitulates most of the mechanisms thought to be important in PD pathogenesis. For this reason, neuroprotective drug treatment trials in this model may be more relevant to PD than other, more acute model systems. The major disadvantages of this model

PARKINSON’S DISEASE: ANIMAL MODELS are its labor-intensive nature and its variability, with some animals showing lesions and others not. In addition the sick, bilaterally lesioned animals are difficult to maintain, as with animals treated bilaterally with 6-OHDA or MPTP. 11.2.9. The 3-nitrotyrosine model A recent animal model was developed to understand further the role of oxidative stress in PD pathogenesis (Mihm et al., 2001). As mentioned earlier, oxidative DNA and protein damage and lipid peroxidation are observed in brains from PD patients (Yoritaka et al., 1996). Antioxidants and free radical spin traps attenuate MPPþ toxicity in animal models (Schulz et al., 1995; Matthews et al., 1999), suggesting the involvement of free radicals in neuronal degeneration. Recent evidence has implicated peroxynitrite formation in PD pathogenesis. Peroxynitrite is a highly reactive oxidant formed by the reaction of nitric oxide with superoxide anion. Reaction of proteins with peroxynitrite results in the modification of proteins at tyrosine residues (3-nitrotyrosines) (Beckman and Koppenol, 1996) and nitrated a-synuclein is more prone to aggregation than unmodified protein (Giasson et al., 2000). Furthermore, brains from PD patients show elevated 3-nitrotyrosine (Good et al., 1998), suggesting protein nitration may also play a role in the neurodegeneration in PD. This novel animal model of PD was designed to test directly the involvement of oxidative stress, specifically due to peroxynitrite, in the etiology of PD. Injection of free 3-nitrotyrosine into the striatum (Fig. 11.4) of mice resulted in loss of striatal tyrosine hydroxylasepositive terminals, loss of dopaminergic neurons in substantia nigra and motor abnormalities (Mihm et al., 2001). Thus, these experiments demonstrated that free 3-nitrotyrosine caused neurodegeneration in an animal model. There are some limitations to the 3-nitrotyrosine model of PD, however. Acute exposure to 3-nitrotyrosine fails to mimic the progressive nature of sporadic PD. Additionally, it is still not known whether intrastriatal injection of free 3-nitrotyrosine induces the protein aggregation and cellular inclusions associated with PD. Despite some limitations, this novel model of PD, based on oxidative stress, is useful for understanding mechanisms of PD etiology and has the potential for use in screening putative antioxidant therapies. 11.2.10. Inhibition of ubiquitin-proteasome system model As mentioned earlier, evidence from both familial and sporadic cases of PD has suggested a role for the UPS in PD pathogenesis. To confirm the role of UPS, two

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independent groups (Fornai et al., 2003; McNaught et al., 2004) have examined the possibility that inhibition of proteasomal function and protein degradation via the UPS might induce a model of PD. Indeed, Fornai et al. (2003) and McNaught et al. (2004) have demonstrated that UPS impairment could reproduce features similar to PD. A week after microinfusions of proteasome inhibitors, lactacystin and epoxomicin, directly into the striatum, loss of TH and DAT immunostaining with no apparent loss of GAD67 (glutamic acid decarboxylase) immunostaining was observed, suggesting the selective loss of striatal dopaminergic terminals. In addition, striatal dopamine and its metabolite DOPAC levels were reduced, whereas the levels of 5-HT were unchanged, confirming the selective toxicity for nigrostriatal dopaminergic pathway following striatal UPS inhibition. Striatal UPS inhibition also resulted in retrograde degeneration of nigral neurons and formation of cytoplasmic inclusions in the spared nigral neurons (Fornai et al., 2003). Interestingly, McNaught et al. (2004), using a different paradigm, such as systemic administration of proteasome inhibitors, also demonstrated that UPS impairment could produce features similar to PD. Proteasome inhibitors, both naturally occurring epoximicin and synthetic carbobenzoxy–L-isoleucyl-gamma-t-butyl-L-glutamyl-Lalanyl-L-leucinal (PSI), when administered systemically over a period of 2 weeks, resulted in progressive parkinsonism (over a period of 17–19 weeks) with bradykinesia, rigidity, tremor and abnormal posture that improved with apomorphine treatment. Positron emission tomography demonstrated reduced carbon-11labeled 2b-carbomethoxy-3b-(4-fluorophenyl) tropane (CFT) binding to dopaminergic nerve terminals in the striatum, indicative of degeneration of the nigrostriatal pathway. Histological analyses showed depletion of striatal dopamine, apoptotic cell death and inflammation in the substantia nigra pars compacta. Neurodegeneration was also observed in the locus ceruleus, dorsal motor nucleus of the vagus and the nucleus basalis of Meynert. At neurodegenerative sites, intracytoplasmic, eosinophilic, a-synuclein/ubiquitin-containing inclusions resembling LBs were present in the surviving neurons (McNaught et al., 2004). Thus proteasome inhibition produced certain key features of PD, including parkinsonian motor deficits, selective degeneration of the nigrostriatal pathway and the presence of cytoplasmic inclusions (Fornai et al., 2003; McNaught et al., 2004). Since these are recently developed models it is yet to be seen, however, if proteasome inhibition results in increased oxidative stress and inhibition of mitochondrial complex I of the ETC. Although it has been reported that low doses of chronic proteasomal inhibition, in SH-SY5Y neuroblastoma cells,

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can dramatically alter mitochondrial homeostasis by increasing free radical production and reducing complex I and II activity (Sullivan et al., 2004), these alterations could contribute to oxidative stress, one of the cardinal biochemical features of sporadic PD. Thus UPS inhibition may be able to reproduce salient features of PD remarkably well, thereby confirming the involvement of impaired UPS in PD pathogenesis. However this model too does not explain why VTA dopaminergic neurons are not affected. It is possible that proteasomal subunits are differentially expressed in nigral and VTA neurons and/or those steady-state levels of proteasomal functions are different in the two regions.

11.3. Genetic models of Parkinson’s disease 11.3.1. a-Synuclein a-Synuclein, a presynaptic protein, is heterogeneously expressed throughout the brain. a-Synuclein’s association with PD followed the identification of mutations in a-synuclein gene in some rare cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998; Singleton et al., 2003) as well as its presence in LBs (Spillantini et al., 1997), the cytoplasmic inclusions which are the pathological hallmark of PD. However the role of a-synuclein in neurodegeneration and PD pathogenesis remains an enigma. Therefore animal models have been developed to investigate the role of a-synuclein in the etiology of PD. These model systems have focused on the use of transgenic mice (Masliah et al., 2000; van der Putten et al., 2000; Giasson et al., 2002; Lee et al., 2002) or Drosophilia or fruit flies (Feany and Bender, 2000; Auluck and Bonini, 2002; Pendleton et al., 2002), and Caenorhabditis elegans (Lakso et al., 2003) overexpressing wild-type or mutated a-synuclein. Genetically manipulated mice have been extensively used as models, initially for PD and later for synucleopathies. Transgenic mice overexpressing human a-synuclein demonstrate a number of features of PD, including loss of nigrostriatal dopaminergic terminals in the striatum, development of a-synuclein and ubiquitin-positive cytoplasmic inclusions, and motor impairments (Masliah et al., 2000). The inclusions observed in these animals, however, lacked fibrillar organization, which is characteristic of the LBs observed in PD. Some inclusions were also present in the nucleus, a feature not seen in PD. Dopaminergic and behavioral defects were only observed in the high expressing line of transgenic mice, suggesting that a critical threshold of a-synuclein expression may be required for the dopaminergic and behavioral

abnormalities. Other transgenic mice with mutations at A53T had a-synuclein-positive inclusions and motor deficits, but there was no evidence of nigrostriatal dopaminergic degeneration. In fact, in these mice, neurons of the brainstem and motor neurons were most vulnerable. Similar pathology was observed in mice expressing wild-type and mutated forms of asynuclein (van der Putten et al., 2000; Giasson et al., 2002; Lee et al., 2002). Interestingly, the A53T transgenic mice were more vulnerable to neurotoxins, including MPTP (Song et al., 2004). The MPTPtreated human a-synuclein transgenic mice showed extensive mitochondrial alterations, increased mitochondrial size, filamentous neuritic aggregations, axonal degeneration and formation of electron-dense perinuclear cytoplasmic inclusions in substantia nigra (Song et al., 2004). Another interesting genetic approach to studying PD involves the expression of normal and mutated a-synuclein in Drosophila. These flies demonstrated many features of PD, including dopaminergic cell loss, filamentous intraneuronal inclusions and motor defects (Feany and Bender, 2000). Because of the well-characterized Drospohila genetics and the short lifespan of flies, this model offers a valuable opportunity to uncover novel proteins involved in PD pathogenesis. For example, this approach may uncover suppressor genes that prevent dopaminergic degeneration or susceptibility genes that exacerbate the effects of asynuclein expression. Animal models based on the transgenic expression of wild-type and mutated a-synuclein provide an important opportunity to study the involvement of a-synuclein in PD pathogenesis. However, there are some limitations to the use of transgenic a-synuclein models. Not all transgenic mouse models demonstrate key features of PD, such as nigrostriatal dopaminergic degeneration. Furthermore, it should be kept in mind that one of the mutations associated with human PD is normally expressed in mice (Trojanowski and Lee, 1999). Despite these limitations, transgenic a-synuclein mice provide an excellent model system for studying the formation of a-synuclein-positive protein aggregates. This issue warrants detailed investigation since protein aggregation is associated with a number of neurodegenerative disorders. Additionally, these transgenic mice provide accurate models for examining the interplay between genetic mutations and environmental exposures in the etiology of PD. For example, transgenic a-synuclein mice can be used to demonstrate sensitivity to various environmental toxins (Song et al., 2004). Such studies may uncover important contributions of genetic and environmental interactions to PD.

PARKINSON’S DISEASE: ANIMAL MODELS 11.3.2. Targeted a-synuclein overexpression One of the most striking drawbacks of a-synuclein transgenic mice has been the absence of neurodegeneration in the nigrostriatal pathway. Therefore the next approach was selectively to overexpress a-synuclein in different regions of the brain and more specifically in the striatum and substantia nigra. Recombinant adeno-associated viral vectors (Kirik et al., 2002) and lentiviral vectors (Lauwers et al., 2003) have been used to target the dopaminergic nigral neurons selectively. Overexpression of a-synuclein in the substantia nigra following stereotactic injections of lentiviral vectors encoding wild-type and A30P mutant human a-synuclein induced progressive neuropathological changes, including accumulation of a-synuclein in cell bodies and neurites, a-synuclein-positive neuritic varicosities and cytoplasmic inclusions that are also positive for ubiquitin. A year later a-synuclein-positive neurons displayed degenerative morphology and significant cell loss was observed. a-Synuclein overexpression however induced changes in both dopaminergic and non-dopaminergic neurons (Lauwers et al., 2003). In a slightly different approach, recombinant adenoassociated viral vectors were used specifically to express wild-type and A53T mutant human a-synuclein in the nigral dopaminergic neurons, in both rats (Kirik et al., 2002) and marmosets (Kirik et al., 2003), that induced a-synuclein-positive inclusions and swollen, dystrophic neurites similar to that observed in PD patients. The pathological changes occurred preferentially in the nigral dopamine neurons and were accompanied by 30–80% dopaminergic nigral cell loss and 40–50% reduction in striatal dopamine and tyrosine hydroxylase levels at 8 weeks. Motor impairment was observed in animals that showed more than 50– 60% cell loss. At 6 months, in rats, the neuropathological changes had subsided even though a-synuclein levels were maintained at high levels, suggesting that a-synuclein overexpression resulted in transient changes (Kirik et al., 2002). These models can be used to study a-synuclein-induced pathogenic mechanisms and subsequently therapeutic targets relevant to PD.

11.3.3. Parkin and UCH-L1 PD has also been associated with parkin and UCH-L1 mutations (Kitada et al., 1998; Leroy et al., 1998; Lucking et al., 1998; Shimura et al., 2000), indicating that the ubiquitin and proteasome pathways deserve intensive investigation. Development of good

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transgenic models would facilitate this line of investigation. 11.3.3.1. Parkin AR-JP, one of the most common familial forms of PD, was initially described in a series of Japanese kindreds (Kitada et al., 1998). The patients showed typical symptoms of PD, including bradykinesia, rigidity and resting tremor associated with: (1) early onset, typically before the age of 40; (2) foot dystonia at onset; (3) hyperflexia of the lower limbs; (4) diurnal fluctuations with a marked sleep benefit; (5) responsive to levodopa therapy; and (6) early onset of levodopainduced dyskinesias, and slow disease progression (von Coelln et al., 2004a). Pathologically, the disease is characterized by degeneration of dopamine neurons in the substantia nigra and locus cerulus with varying degrees of astrocytic gliosis and the absence of LBs. Furthermore, parkin, which is normally expressed diffusedly in neurons throughout the brain (Solano et al., 2000), is absent in the brain of patients with AR-JP (Shimura et al., 1999). Various deletions and point mutations in parkin have been found in ~50% of patients with AR-JP. Parkin is a 465-amino-acid residue, ~52 kDa protein with a UBL domain at the amino-terminal region and two RING-finger motifs at the carboxyterminal region. Most of the point mutations identified so far reside in the RING-IBR-RING domains of parkin, suggesting that this region may have a key role in parkin function. Parkin has been identified as a ubiquitin-protein ligase (E3) that acts along with the ubiquitin-conjugating enzymes (E2s) UbcH7 and UbcH8 (Imai et al., 2000; Shimura et al., 2001). It has been suggested that the RING-finger domain is involved in the recruitment of the E2 component of the ubiquitination machinery whereas the UBL serves as a proteasome-modifying motif (Upadhya and Hegde, 2003) that facilitates the transfer of polyubiquitinated substrates to the UPS. Familial-associated mutations in parkin impair its binding to UbcH7 and UbcH8 and are defective in E3 ligase activity of parkin, which suggests that disruption of E3 ubiquitin-protein ligase activity of parkin may cause AR-JP. It appears that decrease in enzyme activity rather than complete loss of function may underlie AR-JP pathogenesis. Mutations could either reduce the enzymatic activity of parkin, or its interactions with other proteins such as CHIP, carboxy-terminus of the Hsc70-interacting protein (Imai et al., 2002). With evidence suggesting a ‘decrease/loss in function’ of parkin as the mechanism underlying AR-JP pathogenesis, it was presumed that genetic

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manipulations in animal models would provide a better understanding of the pathogenic mechanism by which decreased parkin function could cause PD. Surprisingly, studies using parkin null mutant mice (Goldberg et al., 2003) and Drosophila (Greene et al., 2003), although providing more insight into parkin function, have not been able to explain fully the role of parkin in PD pathogenesis. The first set of parkin-deficient mice was generated by targeted deletion of exon 3 (Goldberg et al., 2003). These mice were viable and exhibited normal brain morphology without loss of dopaminergic neurons in the substantia nigra. However striatal extracellular dopamine levels were increased and synaptic excitability was reduced in the striatal target neurons, suggesting a role of parkin in dopamine regulation. Another study showed that inactivation of parkin gene (targeted deletion of exon 3) in mice (Itier et al., 2003) resulted in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. Although there was no evidence for loss of nigral dopaminergic neurons in these parkin mutant mice, the level of dopamine transporter protein was reduced whereas glutathione levels were increased in the striatum, suggesting compensatory changes in the nigrostriatal dopamine system. In the third parkin mutant mice (von Coelln et al., 2004b), generated by targeted deletion of exon 7, loss of catecholaminergic neurons of the locus cerulus was accompanied by loss of norepinephrine in some regions of the central nervous system. In addition there was a reduction of the norepinephrine-dependent startle response. However, as in the other parkin mutant mice, the nigrostriatal dopaminergic system did not show any signs of degeneration. Drosophila parkin null mutants exhibited an interesting phenotype with reduced lifespan, locomotor defects in terms of climbing and flying and male sterility. Interestingly, defects in mitochondrial pathology appeared to be the earliest manifestations and the underlying cause of muscle degeneration and defect in spermatids (Greene et al., 2003). Thus, although the underlying mechanism appears to be similar, aberration in mitochondrial function, parkin mutant flies/mice and PD patients appear to have distinct symptoms and pathology. It was therefore important to identify the protein substrates of parkin, assuming that defect in parkin (mutant parkin) would result in accumulation of its substrate(s) which would be toxic to dopaminergic neurons. Numerous substrates that are ubiquitinated by parkin have been identified. One of the substrates is cell division control-related protein (CDCrel-1), a ~44 kDa synaptic vesicle-associated protein (Zhang

et al., 2000) belonging to the septin family of proteins that includes GTPases required for cytokinesis. CDCrel-1 has been suggested to regulate synaptic vesicle release; however, its role in dopamine release is not known. Parkin mutations could affect CDCrel-1 modulation of dopamine release, which may ultimately contribute to the parkinsonian state (Dawson and Dawson, 2003). Interestingly, CDCrel-1 overexpression in substantia nigra neurons by adeno-associated virusmediated gene transfer induced dopamine-dependent neurodegeneration (Dong et al., 2003). Furthermore, CDCrel-1 accumulations were detected in brains of AR-JP patients (Choi et al., 2003), providing additional evidence for a potential role for CDCrel-1 in PD pathogenesis. A second substrate of parkin is the parkinassociated endothelial-like (Pael) receptor, a putative G-protein-coupled transmenbrane polypeptide (Imai et al., 2001). This receptor becomes misfolded when overexpressed in cells. It then aggregates and the insoluble protein elicits cell death via the unfolded protein response (UPR). UPR is a mechanism that involves stress response in the endoplasmic reticulum (ER), including increased biosynthesis of chaperones, in response to misfolded/mutated proteins in this organelle. Parkin ubiquitinates and promotes the degradation of insoluble Pael receptor with the help of two E2s, Ubc6 and Ubc7, located in the ER. Interestingly, Pael receptor is present in exceptionally high levels in tyrosine hydroxylase-containing neurons and the insoluble Pael receptor accumulates in the brains of AR-JP patients (Dawson and Dawson, 2003). Furthermore, overexpression of parkin can rescue cells from UPR elicited by a variety of stresses, including H2O2 and heat shock (Imai et al., 2000). Parkin has also been shown to protect dopaminergic cells in D. melanogaster from neurotoxicity induced by overexpression of Pael receptor (Yang et al., 2003). Surprisingly, a-synuclein, which has been linked to PD pathogenesis and is a major constituent of LBs (Spillantini et al., 1998), has not been associated with parkin-linked AR-JP, nor has it been linked to parkin-associated ubiquitination and degradation to date. Interestingly, however, a novel 22 kDa form of O-glycosylated a-synuclein (aSp22) and synphilin-1, a a-synuclein-associated protein, have been shown to be parkin substrates (Chung et al., 2001; Shimura et al., 2001). In addition, parkin overexpression can protect against a-synuclein-induced proteasomal dysfunction and toxicity (Petrucelli et al., 2002; Yang et al., 2003). Additional parkin substrates have also been identified, such as cyclin E (Staropoli et al., 2003) and p38 subunit of the aminoacyl-tRNA synthetase complex (Corti et al., 2003). However, parkin substrates have yet to be linked to PD pathogenesis (Ciechanover and Brundin, 2003; Goldberg et al., 2003; Greene et al., 2003; Itier et al., 2003; von Coelln et al., 2004b); none of the parkin null

PARKINSON’S DISEASE: ANIMAL MODELS mutants have shown accumulation of parkin substrates to date. Nevertheless, parkin’s neuroprotective role makes it a prime target for further investigation into its association with UPS and PD pathogenesis. 11.3.3.2. Ubiquitin carboxy hydrolase L A missense mutation (lle93M) in the gene coding for UCH-L1 has been identified in two siblings of a German family with autosomal-dominant familial PD that is characterized by levodopa-responsive motor symptoms (Leroy et al., 1998). However the neuropathology of this disease is yet to be confirmed, since postmortem tissue from these patients is not available. Moreover, there is just circumstantial evidence suggesting this mutation to be causal of disease. The mode of transmission of this Ile93M substitution is autosomal dominant, since only one UCH-L1 allele is altered. However the parents of the affected siblings are unaffected, indicating that this mutation is a rare polymorphism that segregates with disease or that it is a mutation with incomplete penetrance (Liu et al., 2002b). In sporadic PD, as recently reported, UCH-L1 is downregulated and oxidized in cerebral cortex (Choi et al., 2004). The implication of this finding is as yet unknown. UCH-L1 is a ubiquitous protein making up to 2% of all proteins in the brain. It belongs to a family of de-ubiquitinating enzymes that are responsible for hydrolysis of polyubiquitin chains into monomeric ubiquitin (Pickart, 2000). Mutations in the UCH-L1 gene result in 50% decrease of catalytic activity, implying that loss of UCH-L1 activity in PD might lead to reduced ubiquitination and therefore impaired clearance of abnormal proteins. It is suggested that accumulation of certain proteins may be toxic to neurons, leading to neurodegeneration. Genetic manipulation in mice has shown that autosomal-recessive UCH-L1 mutations did not result in dopaminergic neuronal death but in gracile axonal dystrophy (GAD) syndrome. The GAD mice are characterized pathologically by axonal degeneration in the gracile tract of the spinal cord and medulla oblongata and in terms of behavior by sensory ataxia at an early stage and motor ataxia at a later stage (Saigoh et al., 1999). The absence of parkinsonian characteristics, behavioral or histopathological, in GAD mice deficient in UCH-L1 suggests that partial loss of hydrolytic activity following Ile93M mutation may not be the only factor involved in the pathogenic process in this disease. Studies by Liu et al. (2002b) indicate that in vitro UCH-L1 may have an additional ubiquityl ligase-like activity that acts to increase polyubiquitination of mono- or diubiquitinated a-synuclein. Although the monomeric form of UCH-L1 catalyzes deubiquitination, the dimers display a ubiquitin ligase activity that

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generates ubiquitin-K63 bonds. Interestingly, Ser18Tyr mutation in UCH-L1 displays a significant reduction of ubiquityl ligase activity in vitro with no change in the hydrolase activity. The Ile93M mutation resulted in partially reduced ligase activity. However, it is not clear whether or not UCH-L1 ubiquityl ligase activity occurs in vivo under physiological conditions.

11.4. Conclusions Numerous animal models have been developed to understand PD pathogenesis, as well as to test potential therapeutics. Each model system has advantages and disadvantages, as discussed above. Many models of PD use acute toxin exposure to induce destruction of the nigrostriatal neurons. The relevance of these acute models to PD pathogenesis is uncertain since PD develops gradually over a long period of time until typical symptoms come to their full expression. On the other hand, these models can be used to screen drugs for symptomatic treatment of the disease. Chronic treatment (e.g. MPTP, rotenone) appears to simulate PD pathology more accurately. Furthermore, transgenic models are useful for evaluating the role of genetics in PD pathogenesis. The choice of model to be used depends upon the goals of the particular experimental paradigm and the questions being asked.

Acknowledgments This work was supported by National Institutes of Health grants NS38899 and ES012068 to JTG.

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Section 3 Clinical aspects

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 12

Scales to measure parkinsonism PABLO MARTI´NEZ-MARTI´N* AND ESTHER CUBO Unit of Neuroepidemiology, National Centre for Epidemiology, Carlos III Institute of Health, Madrid, Spain

12.1. Introduction For over 40 years, neurologists have applied methods that translate the results of observation into numbers to enable them to assess their patients. Compared to narrative records and opinion, quantification by means of appropriate measures brings relevant advantages. Moreover, ease of filing and sharing information, and the possibility of statistical data management, are additional important reasons for measurement. Parkinsonism is defined as the akinetic-rigid syndrome that mimics Parkinson’s disease (PD). Apart from PD itself, the most representative diseases of this group are progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration and dementia with Lewy bodies. PD has been known longer and is better characterized than these other illnesses, and is also more prevalent and susceptible to treatment. Accordingly, most of the specific instruments available to measure parkinsonism are scales that were originally designed for PD. This reflects the motivation and effort invested in fighting a given disease (Masur, 2004). On the whole, measurement of health status has really only developed as a formal discipline in recent decades, yet over this period rating scales have proliferated to the point where they have become instruments of common use, not merely for research but also for daily practice. Although this field has been characterized by a wide variety of design, content and metric quality, a tendency towards systematic application of standardized methods for development and analysis of these types of measures has nevertheless been imposed in recent years. This chapter will review the scientific background in support of the use of scales as instruments for

measurement, as well as the most relevant scales specifically designed for parkinsonism. Available data on the metric properties of each measure and recognized standards for comparison will also be shown.

12.2. Basic principles Measurement is a fundamental attribute of science. Every aspect related to science develops and applies appropriate measures to the conceptual context in which it is embedded. To measure is ‘the assignment of numerals to objects or events according to rules’ (Stevens, 1946). This definition may be adapted to the field of health measurement as ‘the assignment of the corresponding quantitative level to a condition or event, according to rules’ (Martinez-Martin, 2000). To measure entails ascertaining the extent or quantity of something by comparison with another fixed magnitude of the same species taken as the unit. This action is easy to understand and implement when the attribute (‘a characteristic inherent in a person or object’) is directly observable, is expressed in a univocal manner and has a unit of measurement available. However, measurement of many attributes is complicated by the fact that they are not observable, are expressed in varying ways or lack a unit of measurement. These conceptual or abstract objects (e.g. intelligence, emotions, pain) are called ‘constructs’. Such constructs typically lack a gold standard and may be interpreted in different ways by different observers. The use of scales for assessment in neurology arises from the need to quantify disorders and states for which ‘real’ physical measures do not exist (constructs such as disability or health-related quality of life (HRQoL), for example) or to obtain practical and comprehensive information that cannot be

*Correspondence to: Dr. P. Martı´nez-Martı´n, MD, PhD, Seccio´n de Neuroepidemiologı´a, Instituto de Salud Carlos III, C/. Sinesio Delgado, 6, 28029 Madrid, Spain. E-mail: [email protected], Tel: þ34-91-822-2643, Fax: þ34-91-387-7815.

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deduced from existing measures due to their limitations (costs, need for expert personnel, conditions of application). Biological analyses and apparatus-based tests yield objective results in real numerical values but require stereotyped test conditions, often call for expensive equipment and afford information on a single aspect at one point in time. In contrast, rating scales and self-evaluations are relatively quick and simple to apply, and provide global information over a wide timeframe. Consequently, these qualitative evaluations have been imposed through practice and are widely used. Nevertheless, this type of evaluation is subjective and the level of measurement is ordinal. Ordinal variables have a limited range of values, represented by numbers assigned in a fixed, e.g. descending, order. Hence, the numbers are only a symbol of rank. For example, in a scale from 0 (normal) to 4 (severe impairment), bradykinesia ¼ 4 cannot be assumed to be twice as severe as bradykinesia ¼ 2: all that these figures mean is that 4 is more severe than 3, and even more so than 2. In principle, ordinal variables only permit mathematical operations that preserve order. Median, mode and range are appropriate for descriptive purposes; for group comparison and correlation, non-parametric statistics (such as Wilcoxon–Mann–Whitney test, Spearman rank correlation coefficient, respectively) are used because parametric tests (such as t-test, analysis of variance (ANOVA), Pearson r) rest on the assumption of equality of intervals (Altman, 1991; Nunnally and Bernstein, 1994; Streiner and Norman, 2003; Heyen, 2004). The Likert model is the most frequently used scale model. It provides composite scores, drawn from the sum of the individual items, to represent the construct. From a pragmatic viewpoint, the total score may be statistically managed as an interval-level variable, albeit with limitations. This model is based on the following assumptions: (1) the score for any given item is a monotonic function (a function that is either always increasing or always decreasing) of the underlying construct; (2) there is a linear relationship between the total scores and the construct; and (3) the scale has internal consistency (LaRocca, 1989; Nunnally and Bernstein, 1994; Bowling, 2002; Streiner and Norman, 2003).

12.3. Conceptual framework In the mid-1970s, the World Health Organization proposed a model of illness assessment based on four fundamental aspects: (1) pathology (injury to or destruction of an organ or system); (2) impairment

(loss or alteration of an anatomical, physiological or psychological structure or function); (3) disability (objective consequences of the impairment that are expressed as functional limitation and restriction of activities); and (4) handicap (social disadvantage resulting from impairments and disabilities) (World Health Organization, 1980). For two decades, this model has guided the design and application of clinical and health–social evaluations, covering the entire spectrum from injury to the socioeconomic consequences of any given disorder, and representing the change in interest across the disease process, i.e. a shift in focus from pathology to consequences (disability and handicap) (Fig. 12.1A). This scheme suffers from two important problems, however: (1) the unidirectional nature of the model; and (2) the exclusion of decisive personal and environmental factors. It is self-evident that the same injury in two individuals will lead to a similar impairment (e.g. a spinal cord section at level T4 will produce paraplegia), but the precise degree of disability and social consequences will be quite different, depending on personal and environmental factors (e.g. capacity for coping and adaptation, existence of supportive familial and social networks, architectural barriers, policy of employment for the disabled, and so on). The new World Health Organization-sponsored International Classification of Functioning, Disability and Health (ICF) (World Health Organization, 2001), approved by the World Health Assembly in 2001, seeks to offset the above flaws, by taking into account these determining factors and the interactions among them. Fig. 12.1B outlines the conceptual content of and interaction among the components of the ICF. The application of this new classification is still in the early stages. Scales used to assess parkinsonism may be classified into two categories: disease-centered and patientcentered measures. In the main, disease-centered scales reflect aspects of interest to clinicians, and assess the severity of disease in terms of evolutionary stage, declared symptoms, signs obtained by means of examination by physicians or technicians, inability to perform activities of daily living (ADL) and complications. Patient-centered measures, on the other hand, assess the impact of the disease and its consequences from patients’ point of view, in terms of aspects that are of interest to them and are linked to quality of life and psychosocial adjustment. This latter type of assessment has emerged on to the scene of evaluation of parkinsonian syndromes in the last 10 years (Fitzsimmons and Bunting, 1993; Jenkinson et al., 1995; Peto et al., 1995; Martinez-Martin, 1998).

SCALES TO MEASURE PARKINSONISM

293

Pathology

Impairment

Disability

Handicap

A International classification of impairment, disability, and handicap (WHO, 1980)

Health condition (illness, disorder)

Body function and structure

Activities

Environmental factors

Participation

Personal factors

B International classification of functioning, disability and health (WHO, 2001)

Fig. 12.1. (A) International Classification of Impairment, Disability, and Handicap (World Health Organization, 1980); (B) International Classification of Functioning, Disability and Health (World Health Organization, 2001).

12.4. Design and validation of scales The creation and validation of a measuring instrument, such as a rating scale, is a complex task that should be performed in line with the following general principles: inclusion of areas most relevant to the goal being pursued; incorporation of components specifically related to such areas; production of valid scores that can be statistically analyzed; and achievement of the maximum simplicity possible. The first step consists of defining goals, that is to say, deciding what the scale is intended to measure, in which population and for what purpose. Discriminative measures are designed to draw distinctions between groups, evaluative measures determine changes in subjects across time, and predictive scales are, as the name implies, intended to predict future outcomes. In the case of discriminative scales, stability and sensitivity (precision) are paramount, whereas for evaluative and predictive instruments, responsiveness is the key feature (Kirshner and Guyatt, 1985; Juniper et al., 1996). An important aspect to settle is the method to be used to apply the scale (e.g. face-to-face interview, selfadministration, examination by physician or nurse). The next step is to identify and select the potential components of the instrument (items and dimensions) and establish and define the type of examination question (whether aimed at assessing presence, frequency, duration or severity), answer (yes/no, placing a mark on

a line, marking the answer that fits best) and strategy (signs to be assessed, standardized maneuvers). The score range per item (e.g. 0–4) and, where necessary, a precise definition for each scoring rank should be drawn up. Painstaking care must be taken over the wording to ensure that it is both simple and precise (Streiner and Norman, 2003). The first version of the scale or questionnaire (usually very extensive) is applied to a relatively small number of individuals belonging to the target population. These subjects are informed that they are participating in a pilot study. Instructions may be given to participants (and a semistructured questionnaire used) in order to elicit additional information about aspects such as difficulty in comprehending the questions, embarrassment about responding, appropriateness of the examination tasks, suggestions and so on. Pilot studies allow for flaws to be identified and ambiguities amended. Moreover, the results of such studies provide preliminary data on acceptability and reliability, along with the chance to avoid redundancy and shorten the scale to a reasonable length, if need be. Following appropriate revision, correction and item reduction, the definitive format of the scale is now ready for use. This version is applied to a widely representative sample of the target population in a new study. The ensuing data are then collected, entered into a database and subjected to statistical analysis to determine the precise characteristics and metric quality of the scale.

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The psychometric model of scale design and validation based on the classical test theory tends to predominate. This model establishes that the construct possesses a theoretical value (V) that can be indirectly measured through observable components related to the construct. It also assumes that individuals are able to differentiate between grades of intensity to which a numeric valuation is assigned. The answers, suitably transformed into scores and combined, furnish a final score that, provided the measure is valid, will differ from V solely as a consequence of random error. Classical test theory has some weaknesses and problems inherent in assumptions, such as the supposed error independency of the true value, equal contribution of each item to the final score or circular dependency (the interrelationship between the score in a sample and the norms of the scale) (Streiner and Norman, 2003). Another psychometric method, known as item response theory, is gaining interest in some fields. This model is centered on the item per se and is based on two assumptions: firstly, that the scale is unidimensional (only one trait is assessed); and secondly, that the probability of answering a given item positively is independent of the probability of answering any other item positively. The item characteristic curve, a fundamental concept for item reponse theory, is S-shaped, monotonic and links the likelihood of a positive response to the level of the latent variable. If the prior assumptions are fulfilled, it is then possible to calculate the probability of a positive response for each level of the latent variable, according to the capacity of the individual (observable performance) and level of difficulty of the item (Nunnally and Bernstein, 1994; Fayers and Machin, 2000; Streiner and Norman, 2003). Psychometric scales seek to measure a single attribute by means of several items. In view of the fact that all items are indicators of the latent variable (indicator variables are related to but exert no influence on the construct), psychometric methods may not be appropriate for building scales that contain symptoms and other causal variables (causal variables affect the construct because there is a causal relationship between the two) (Fayers and Machin, 2000; Fayers and Hand, 2002). This argument underlies the proposal for a different concept of measures, the so-called clinimetric scales (Feinstein, 1982, 1987; Wright and Feinstein, 1992). Clinimetric scales combine indicator and causal variables and can perform in a way that is different to psychometric scales. Clinimetric scales seek to measure a complex phenomenon, composed of several attributes, by means of a single index (a typical example is the Apgar index). Although some authors view psychometric and clinimetric instruments as complementary (Marx et al., 1999) or similar (Streiner, 2003), there are other, diame-

trically opposed proponents of one or the other approach (de Vet et al., 2003; Fava et al., 2004).

12.5. Metric characteristics Before applying a new scale to any clinical study, a set of properties should be demonstrated. This process is called validation. The following attributes should be checked to ascertain whether a scale is an effective instrument of measurement (LaRocca, 1989; Nunnally and Bernstein, 1994; Fayers and Machin, 2000; Scientific Advisory Committee of the Medical Outcomes Trust, 2002; Streiner and Norman, 2003):

Conceptual model: rationale for and description of the concept and populations that a measure is intended to assess, and the relationship between such concepts. Acceptability: extent to which scores adequately represent the true distribution of health status in the sample, as reflected by the distribution of scores. Rejection by the subject to the instrument’s use, missing data and loss of computable scores (quality of data) may be related to this concept. Scaling assumptions: equivalence of the items in distribution of response options, mean and standard deviation, variance, standard error of the mean, 95% confidence interval and preferential location of each item in a subscale or factor. Reliability: extent to which the scale is free of random error. Two well-characterized aspects are distinguishable in this section: internal consistency (interrelation among scale components) and repeatability or stability of scores among different raters (interrater reliability) and at different moments of time (intrarater or test–retest reliability). Validity: ability of the scale to measure the concept it purports to measure. There are several types of validity. Content validity refers to the extent to which the domain of interest is comprehensively sampled by the scale components (items, questions). Criterion-related validity refers to the relationship between scale scores and an independent gold standard (the criterion), and embodies two concepts: concurrent validity (agreement between the gold standard and the scale score) and predictive validity (ability of the scale to predict future status). Construct validity is the property that supports a proposed interpretation of scores based on the theoretical framework related to the construct being measured. Within this kind of validity, convergent validity refers to the relationship of the scale with other measures of the same construct, whereas discriminant (or divergent) validity represents the absence

SCALES TO MEASURE PARKINSONISM

of relationship between the scale and measures for constructs that are unrelated to the one being measured. Convergent and discriminant validity may be simultaneously explored by multitrait–multimethod analysis. Dimensionality (grouping of items in domains or latent variables) and discriminative validity (known groups or extreme groups validity that represents the measure’s ability to detect differences among specific groups in a single observation) are also part of construct validity. There is no gold standard available for most of the attributes measured in the fields of neurology or movement disorders. Construct validity is thus a relevant aspect that is usually checked in the scale validation process. Precision (or sensitivity) of the scale is the ability to detect small differences. Responsiveness is closely related to precision, and refers to the capacity to detect intrasubject changes over time.

295

Other characteristics of note are: (1) interpretability or degree to which a comprehensible meaning can be assigned to the scores; (2) respondent and administrative burden; (3) alternative forms (metric properties of different modes of administration, such as face-to-face interview, phone interview, self-evaluation); and (4) cross-cultural adaptation.

Most of these metric properties are analyzed by statistical methods. For example, acceptability is ascertained by the difference between the observed and possible range of scores, proximity between the mean and median (the middle point of the scale) and floor and ceiling effects. The three most frequently investigated attributes in clinical scales are reliability, validity and responsiveness (Ramaker et al., 2002). Standards of metric quality have been proposed for most of the aforementioned attributes. The most relevant are shown in Table 12.1. Before a scale can be used in clinical practice or research, it is essential that most of these criteria be verified.

Table 12.1 Standards for basic attributes of scales Attributes Acceptability Floor and ceiling effects Internal consistency Cronbach’s alpha Item–total correlation Reliability Interobserver – Nominal or ordinal data Continuous data Test–retest

– Nominal or ordinal data Continuous data

Convergent validity Responsiveness – Effect size

Values

Reference

1–15%

1

> 0.70 (group) 0.90–0.95 (individual) r > 0.20 or r > 0.40

2* 2 3* 4

kw> 0.60 ICC > 0.70 or ICC > 0.80 kw > 0.60 ICC > 0.70 or ICC > 0.90 r 0.40 r 0.60 > 0.20

ICC: Intraclass correlation coefficient. *Minimal criteria to fit (see Tables 12.3 and 12.4). 1. McHorney C, Tarlov A (1995). Qual Life Res 4: 293–307. 2. Scientific Advisory Committee of the Medical Outcomes Trust (2002). Qual Life Res 11: 193–205. 3. Streiner and Norman (2003). Health Measurement Scales, p. 70 4. Ware JE, Gandek B (1998). J Clin Epidemiol 51: 945–952. 5. Landis JR, Koch GG (1977). Biometrics 33: 159–174. 6. Fayers PM, Machin D (2000). Quality of Life. Wiley, Chichester, p. 63. 7. Bowling A (2002). Research Methods in Health, p. 148. 8. Fayers PM, Machin D (2000). Quality of Life. Wiley, Chichester, p. 79. 9. Fitzpatrick et al. (1998). Health Technol Assessm 2: 26. 10. Samsa et al. (1999). Pharmacoeconomics 15: 141–155.

5* 6* 7 5* 6* 1 8* 9 10

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12.6. Rating scales for Parkinson’s disease Aside from being the most prevalent of the parkinsonian syndromes, PD is also a very complex disorder to assess. Moreover, many clinical trials have been performed on PD to determine the effect of interventions with drugs, surgical procedures and rehabilitation. PD is consequently the parkinsonian syndrome for which most scales are available and on which most reviews on the topic have centered (Lang and Fahn, 1989; Martinez-Martin, 1993, 2000; Mitchell et al., 2000; Tison, 2000; Ramaker et al., 2002). PD is characterized by motor manifestations (bradykinesia, rigidity, rest tremor, and gait-and-balance disorder) and non-motor manifestations (cognitive dysfunction, sleep disturbances, autonomic disorder and depression). Furthermore, over the course of the disease, so-called complications (motor and nonmotor) linked to treatment appear in a large proportion of patients in the more advanced stages of the disease. Dyskinesia and fluctuations are capable of modifying the patient’s condition, at times abruptly, from one moment to the next, several times a day. Bearing in mind the degree to which the disease varies from one patient to another, it follows that, where PD is concerned, variability is the norm (Lang and Fahn, 1989) and that assessment is therefore a really complex task. 12.6.1. Brief history of the Parkinson’s disease rating scales Since 1960, a variety of PD evaluation scales have been published (Lang and Fahn, 1989; MartinezMartin, 1993). Initially, the goal was to assess the most salient manifestations of disease (symptoms and signs), their relationship with disease severity and any ensuing disability (Schwab, 1960; Canter et al., 1961; Hoehn and Yahr, 1967; Webster, 1968). Scales were also used to check the efficacy of available surgical and pharmacological treatments (Petrinovich and Hardyck, 1964; Klawans and Garvin, 1969; Schwab and England, 1969). In the latter half of the 1970s, the relevance of motor (fluctuations, dyskinesias) and mental complications was highlighted (Fahn, 1974; Lieberman, 1974; Kartzinel and Calne, 1976; Lhermitte et al., 1978) and items or sections for assessment of these complications were included in new scales over the course of the next 10 years (Lieberman et al., 1980; Larsen et al., 1984; Fahn et al., 1987). Occasionally, distinctive aspects of the disease, such as depression, cognitive impairment, pain and sleep disturbances, were also included for appraisal (McDowell et al., 1970;

Parkes et al., 1970; Lieberman, 1974; Fahn et al., 1987; Martinez-Martin et al., 1987). In 1987, both the Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn et al., 1987) and the Intermediate Scale for Assessment of Parkinson’s Disease (ISAPD) (Martinez-Martin, 1988) appeared with the aim of achieving a uniform, valid measure for the evaluation of PD. Somewhat surprisingly, publication of relevant validation data on both scales came some years after the original studies (Martinez-Martin et al., 1994, 1995; Richards et al., 1994; van Hilten et al., 1994). Since then, new PD rating scales have been subjected to a psychometric or clinimetric process of validation prior to their use for practice or research purposes (Rabey et al., 1997; Marinus et al., 2004). A non-comprehensive list of PD scales mainly intended to assess motor aspects is shown in Table 12.2. Although they are generally applied to determine the severity of impairments (symptoms and signs), functional impact and intensity of motor complications, these scales evince a wide variety of designs and are very variable in their features, each reflecting the concept held by their respective authors as to the theoretical construct to be measured and how it should be measured. Not only is there a huge diversity of modified (and non-validated) versions of original scales, but separate scales have also been developed to evaluate specific impairments, such as cognitive impairment, sleep and gait (Waxman et al., 1990; Martinez-Martin et al., 1997; Friedberg et al., 1998; Chaudhuri et al., 2002; Marinus et al., 2003b, c; Thomas et al., 2004; Visser et al., 2004a). Problems stemming from the profusion of PD rating scales and their modified versions include: (1) lack of validation of many scales means that their metric quality is unknown; (2) results yielded by studies using different scales for outcome measurement are difficult to compare; and (3) interpretation of results is uncertain in cases where several scales are used simultaneously and provide mutually contradictory results (Martinez-Martin, 1993). To avoid these sorts of problems, it was proposed that a valid and widely accepted scale be used as a common instrument of evaluation. It was with this intention, albeit from different perspectives, that the UPDRS and ISAPD were developed (Fahn et al., 1987; Martinez-Martin, 1988, 1993; Lang and Fahn, 1989). Whereas the UPDRS was designed as an extensive and comprehensive scale for application as a standalone instrument, the ISAPD sought to be a ‘common nucleus’ of assessment through use of a scale which, though brief, was informative and valid, and was simultaneously applicable to practice and research. As a rule,

SCALES TO MEASURE PARKINSONISM

297

Table 12.2 Rating scales for Parkinson’s disease

Progression and Prognosis Scale (Schwab, 1960) Northwestern University Disability Scale (Canter et al., 1961) Evaluation of Behavioral Changes (Petrinovich and Hardyck, 1964) PD Disability Rating Scale (Alba et al., 1968) Webster’s Scale (Webster, 1968) Columbia University Rating Scale (Yahr et al., 1969) Physical Findings Rating Scale (Klawans and Garvin, 1969) Schwab and England Scale (Schwab and England, 1969) PD Assessment Scale (Ande´n et al., 1970) PD Information Center Scale (Cotzias et al., 1970) Cornell–UCLA Disability Scale (McDowell et al., 1970) King’s College Hospital Rating Scale (Parkes et al., 1970) Disability Score (Birkmayer and Neumayer, 1972) Evaluation of PD (Walker et al., 1972) PD Evaluation Scale (Lieberman, 1974) Parameters for Evaluation of PD (Korten, 1977) New York University PD Evaluation (Lieberman et al., 1980) Assessment of Parkinson’s Disease (Larsen et al., 1984) Unified Parkinson’s Disease Rating Scale (Fahn et al., 1987) Intermediate Scale for Assessment of PD (Martinez-Martin et al., 1988) Short Parkinson’s Evaluation Scale (Rabey et al., 1997) Scales for Outcomes in PD – Motor (Marinus et al., 2004)

I

D

C

þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ

þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ

þ þ þ þ þ

These scales assess impairments (I þ), disability (D þ) and motor complications (C þ).

long scales require time for application and are burdensome to patients, whereas scales that are too short can be uninformative and insensitive. On the other hand, the wider the range of possible scores for each item, the greater the sensitivity of the scale, yet this is an advantage that works to the detriment of reliability (both interrater and test–retest). PD patient evaluation by means of scales is an issue that has not been definitively resolved. Consequently, new measures will continue to be designed and existing instruments improved. From a conceptual point of view, the most relevant contribution to this field in the past decade has been the development and use of specific HRQoL measures, an approach that complements clinical assessment relying on ‘classic’ scales. The most widely used and best studied scales are briefly described and reviewed below. The basic criteria that can be used as a standard of metric quality are shown in Table 12.1. The results of studies exploring metric characteristics of PD rating scales are summarized in Table 12.3. In order to rate the features examined and the compliance with such metric quality criteria for each scale simultaneously,

the following formula has been applied to the data displayed in Table 12.3: Q ¼ number of explored attributes/number of computable attributes (number of attributes explored fitting the criterion 2) where the number of computable attributes is 5 (alpha, item–total correlation, interrater reliability, test–retest reliability and convergent validity). For instance, if only Cronbach’s alpha (0.85), test– retest reliability (items and total >0.80) and convergent validity (r < 0.35) have been investigated in a given scale, the rating will be (3 attributes explored/5) (2 attributes over the criterion value 2) ¼ (3/5) 4 ¼ 2.4 points. The criteria applied appear marked with an asterisk in Table 12.1. The scale assessment score ranges from 0 to 10, meaning that the higher the score, the better the scale. The scores awarded are shown in Table 12.4. 12.6.2. The Hoehn and Yahr Staging Scale The Hoehn and Yahr staging scale (HY) (Hoehn and Yahr, 1967) is an easy-to-administer scale developed

298

Table 12.3 Psychometric characteristics of Parkinson’s disease rating scales

Scale

No. of items

Mode of administration

Coefficient alpha (Cronbach)

Item–total correlation (correlation coefficient)

HY

1

Examination

NA

NA

Interrater reliability

Test–retest reliability

Convergent validity (correlation coefficient)

k ¼ 0.44–0.71

_

UPDRS Total ¼ 0.71 Sect. II ¼ 0.26–0.84 Sect. III ¼ 0.75–0.87 SPES (items) Section II 0.15–0.62 Section III 0.09–0.65 Section IV 0.08–0.23 RSGE ¼ 0.78–0.83 FOGQ ¼ 0.66 SCOPA-Cog ¼ 0.66 SCOPA-Aut ¼ 0.60

SE

1

Patient interview

NA

NA

_

_

UPDRS Total ¼ 0.60 to 0.96 Sect. II ¼ 0.60 to 0.75 ISAPD 0.81– 0.98 RSGE ¼ 0.76 to 0.83

UPDRS

Sect. I 4

Section I patient interview self-administered by proxy

UPDRS total 0.90–0.96

Section II 0.02 to 0.65

Section II k items ¼ 0.31–0.88 Kendall’s W items 0.91–0.94 ICC items 0.61–0.91 ICC total ¼ 0.93

UPDRS total ICC ¼ 0.90–0.93

HY Total ¼ 0.71 Sect. II ¼ 0.26–0.84 Sect. III ¼ 0.06–0.87

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ISAPD ¼ 0.65–0.87

Sect. II 13 Sect. III 14 Sect. IV 11

Section II patient interview self-administered by proxy video Section III motor exam video Section IV patient interview

13 (þ4 for complic)

Patient interview þ motor exam

Section III 0.03–0.65

Section I k ¼ 0.49–0.65 ICC ¼ 0.71–0.75

Section III 0.88–0.95 Section IV

Section III

Dyskinesias a ¼ 0.58 Fluctuations a ¼ 0.74

k items ¼ 0.15–0.90 Kendall’s W items 0.42–0.89 ICC items ¼ 0.00–0.83 ICC total ¼ 0.90 Section IV Kendall’s W items 0.44–0.96 ICC items ¼ 0.39–0.96 ICC dyskinesias total ¼ 0.94 ICC fluctuations total ¼ 0.75

0.97

0.61–0.90

k ¼ 0.74–0.89

Section II k ¼ 0.53–0.81 ICC ¼ 0.82–0.87

Section III k ¼ 0.49–0.75 ICC ¼ 0.87–0.92

SE Total ¼ 0.60–0.96 Sect. II ¼ 0.60–0.75 ISAPD (total) Total ¼ 0.91–0.92 Sect. I ¼ 0.34 Sect. II ¼ 0.92 Sect. III ¼ 0.84 Sect. IV ¼ 0.43 SPES Sect. II ¼ 0.71–0.96 Sect. III ¼ 0.65–0.92 Sect. IV ¼ 0.36–0.89

SPES/SCOPA Sect. I ¼ 0.88 Sect. II ¼ 0.86 Sect. III ¼ 0.86 Dyskinesias ¼ 0.86 Fluctuations ¼ 0.95 RSGE Total ¼ 0.87–0.90 FOGQ Total ¼ 0.48 Section II ¼ 0.43 Section III ¼ 0.40 –

SCALES TO MEASURE PARKINSONISM

ISAPD

Section II 0.85–0.91

HY 0.65–0.87 UPDRS Total ¼ 0.91–0.92 Sect. I ¼ 0.34 Sect. II ¼ 0.92 Sect. III ¼ 0.84 Sect. IV ¼ 0.43

299

(Continued)

300

Table 12.3 (Continued)

Scale

No. of items

Mode of administration

Coefficient alpha (Cronbach)

Item–total correlation (correlation coefficient)

Interrater reliability

Test–retest reliability

Convergent validity (correlation coefficient)

SPES

Sect. I 3

Patient inteview þ motor exam

Sect. II 8

Section II 0.60

Section II >0.60

Section III 0.91

Section III 0.20–0.57

Sect. III 8

Sect. I 10

Patient inteview þ motor exam

Sect. II

1

Section III Kendall’s W 0.79–0.95

Self-administered

HY (items) Sect. II ¼ 0.15–0.62 Sect. III ¼ 0.09–0.65 Sect. IV ¼ 0.08–0.23 UPDRS (items) Sect. II ¼ 0.71–0.96 Sect. III ¼ 0.65–0.92 Sect. IV ¼ 0.36–0.89

Section I

Section I

Section I

Section I

UPDRS

0.74

0.15–0.65

ICC ¼ 0.86

ICC ¼ 0.81–0.95

Section II 0.81

Section II 0.38–0.72

Section II ICC ¼ 0.89

Section I ¼ 0.88 Section II ¼ 0.86 Section III Dyskinesias ¼ 0.86 Fluctuations ¼ 0.95

k ¼ 0.89

Webster ¼ 0.65 CAMCOG ¼ 0.41 Geriatric Depression scale(15 it.) ¼ 0.43

Section III Dyskinesias a ¼ 0.92 Fluctuations a ¼ 0.95

7 Sect. III 4

PDADLS

_

Section IV Kendall’s W 0.85–0.98

Sect. IV 5 SPES/SCOPA

Section II Kendall’s W 0.88–0.94

_

Section IV Dyskinesias ICC ¼ 0.89 Fluctuations ICC ¼ 0.72 _

_

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SE 0.81 to –0.98 MMSE ¼ 0.59 HADS ¼ 0.53

RSGE

GABS

6

28

Patient inteview þ motor exam

0.94

Patient interview/ self-administered

0.94

Patient interview

þ motor exam þ posturography

_

0.25–0.84

k ¼ 0.30–1

_

Barthel index 0.74 to 0.80 Nortwestern Univ. Disability scale 0.75–0.84 UPDRS Total ¼ 0.87–0.90 HY 0.78–0.83 SE 0.76 to 0.83

_

_

_

UPDRS Total ¼ 0.48 Section II ¼ 0.43 Section III ¼ 0.40 HY ¼ 0.66

_

k ¼ 0.31–0.83

Force platforms r ¼ 0.46–1

PPRS

6

Patient interview

0.76–0.80

_

_

r ¼ 0.77–0.78

BPRS ¼ 0.92 NOSIE psychotic 0.48 NOSIE irritative 0.55 MMSE no correlation

SCOPA-COG

10

Cognitive exam

0.83

r ¼ 0.34– 0.66

_

ICC ¼ 0.78

CAMCOG ¼ 0.83 MMSE ¼ 0.72 HY ¼ 0.39

PDSS

15

Self-administered By proxy

0.77

r ¼ 0.07– 0.66

_

Total ICC ¼ 0.94 Items ICC ¼ 0.61–0.99

Epworth (with PDSS item 15) 0.23 to 0.59 Hamilton ¼ 0.55 UPDRS Section IV ¼ 0.22 PDQ-39 ¼ 0.26 No correlation with HY, UPDRS-Sect. I & III, MMSE

301

(Continued)

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FOGQ

21

302

Table 12.3 (Continued)

No. of items

SCOPA-Sleep

Nocturnal Sleep (5) Daytime Sleepin. (6)

Mode of administration

Coefficient alpha (Cronbach)

Self-administered

NS – a ¼ 0.88 DS – a ¼ 0.91

NS ¼ 0.48– 0.85 DS¼ 0.55– 0.85

Interrater reliability

Test–retest reliability

Convergent validity (correlation coefficient)

_

Total NS ¼ 0.94

NS-PSQI ¼ 0.83

Total DS ¼ 0.89

PSQI subscales (r ¼ 0.38–0.73) DS-EPSS ¼ 0.81

Items NS k ¼ 0.82–0.90 Items DS k ¼ 0.49–0.82

SCOPA-AUT

25

Self-administered

_

_

_

ICC total ¼ 0.87 ICC subscales 0.65–0.90 k items 0.45–0.90

HY ¼ 0.60

RDRS

4

Exam/Video

_

_

Severity Kendall’s W 0.71–0.89

Severity rs ¼ 0.82–0.90

_

Type Kendall’s W 0.34–0.42 Disability Kendall’s W 0.28–0.48

Type Coef Crame´r ¼ 0.69–0.73 Disability Coef Crame´r 0.83–0.84

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Scale

Item–total correlation (correlation coefficient)

14

Exam

_

_

Hyperkinesia Kendall’s W 0.86–0.91 Dystonia Kendall’s W 0.31–0.47

Hyperkinesia Kendall’s tau 0.64–0.90 Dystonia Kendall’s tau 0.31–0.91

_ _

LFADLDS

5

Patient’s interview

_

_

_

_

RDRS ¼ 0.02–0.36 Diary ¼ 0.08–0.56

NA, not applicable. HY Hoehn and Yahr Staging Scale (Hoehn and Yahr, 1967) UPDRS Unified Parkinson’s Disease Rating Scale (Fahn et al., 1987) SE Schwab and England Scale (Schwab and England, 1969) ISAPD Intermediate Scale for Assessment of Parkinson’s Disease (Martinez-Martin et al., 1995) SPES Short Parkinson’s Evaluation Scale (Rabey et al., 1997) SPES/SCOPA SPES/SCales for Outcomes in Parkinson’s Disease Motor (Marinus et al., 2004) PDADLS Parkinson’s Disease Activities of Daily Living Scale (Hobson et al., 2001) RSGE Rating Scale for Gait Evaluation (Martinez-Martin et al., 1997) FOGQ Freezing of Gait Questionnaire (Giladi et al., 2000) GABS Clinical Gait and Balance Scale (Thomas et al., 2004) PPRS Parkinson Psychosis Rating Scale (Friedberg et al., 1998) SCOPA-COG SCales for Outcomes in Parkinson’s Disease – Cognition (Marinus et al., 2003c) PDSSParkinson’s Disease Sleep Scale (Chaudhuri et al., 2002) SCOPA-Sleep SCales for Outcomes in Parkinson’s Disease – Sleep (Marinus et al., 2003b) SCOPA-AUT SCales for Outcomes in Parkinson’s Disease – Autonomic (Visser et al., 2004a) RDRS Rush Dyskinesia Rating Scale (Goetz et al., 1994) CDRS Clinical Dyskinesia Rating Scale (Hagell and Widner, 1999) LFADLS Lang–Fahn Activities of Daily Living Dyskinesia Scale (Parkinson Study Group, 2001)

SCALES TO MEASURE PARKINSONISM

CDRS

303

304

P. MARTI´NEZ-MARTI´N AND E. CUBO

Table 12.4 Ranking of rating scales for Parkinson’s disease based on their psychometric attributes* Q index Global assessment SPES/SCales for Outcomes in Parkinson’s Disease Motor Intermediate Scale for Assessment of Parkinson’s Disease Unified Parkinson’s Disease Rating Scale Short Parkinson’s Evaluation Scale Parkinson’s Disease Activities of Daily Living Scale Hoehn and Yahr Staging Scale Schwab and England Scale Gait Rating Scale for Gait Evaluation Freezing of Gait Questionnaire Clinical Gait and Balance Scale Sleep SCales for Outcomes in Parkinson’s Disease Sleep Parkinson’s Disease Sleep Scale Dyskinesia Clinical Dyskinesia Rating Scale (Hyperkin.) (Dystonia) Rush Dyskinesia Rating Scale LangFahn Activities of Daily Living Dyskinesia Scale Other SCales for Outcomes in Parkinson’s Disease Cognition Parkinson Psychosis Rating Scale SCales for Outcomes in Parkinson’s Disease Autonomic

8.0 6.4 6.0 4.8 1.6 1.3 0.6 4.8 1.6 0.8 6.4 3.6 1.6 0.4 0.8 0.2 6.4 3.6 1.6

*Taking into account the minimal criteria shown in Table 12.1 and the psychometric attributes displayed in Table 12.3, an index (Q) combining availability of data about explored attributes and criteria fulfilling was calculated: Q ¼ (number of explored attributes/number of computable attributes) (number of attributes explored fitting the criterion 2), where the number of computable attributes ¼ 5.

to classify PD patients according to severity. It indicates the overall level of severity based on laterality of involvement, impairment of mobility and postural response, and disability. Despite having been developed over 30 years ago in the pre-levodopa era, the scale is nevertheless still widely used in clinical and research settings. The HY has been adapted to many different uses and even applied to disorders other than PD (Goetz et al., 2004). Although originally designed as a five-point scale (1 ¼ unilateral disease; 2 ¼ bilateral mild disease, with or without axial involvement; 3 ¼ mild to moderate bilateral disease, with first signs of deteriorating balance; 4 ¼ severe disease requiring considerable assistance; 5 ¼ confined to wheelchair or bed unless aided), during the 1990s, 0.5 increments were introduced for some clinical tests, thereby resulting in an seven-point scale with the addition of stages 1.5 and 2.5 (1.5 ¼ unilateral plus axial involvement; 2.5 ¼ mild bilateral disease, with recovery on pull test). This version of the HY scale

was included, but never validated, as a complementary assessment, in the UPDRS battery (Fahn et al., 1987), in the Core Assessment Program for Intracerebral Transplantations (CAPIT) (Langston et al., 1991, 1992), and in the Core Assessment Program for Surgical Interventional Therapies in PD (CAPSIT-PD) (Defer et al., 1999). The HY scale is a simple, descriptive, ordinal scale that provides a general estimate of clinical aspects in PD, combining functional deficits (disability) and objective signs (impairment). Although HY scores are frequently quoted in terms of means and standard deviations, they should properly be reported as medians and interquartile ranges, because of assumptions underlying the statistical analysis of non-continuous variables. Likewise, analysis of differences between groups or changes in scores should involve the use of non-parametric methods (Nunnally and Bernstein, 1994; Streiner and Norman, 2003). The HY scale may be used as

SCALES TO MEASURE PARKINSONISM an index of clinical progression in survival analysis (Goetz et al., 2004). Interrater reliability has been assessed by using non-weighted and weighted kappa statistics, resulting in moderate to satisfactory levels of agreement (0.44–0.71) (Ginanneschi et al., 1988, 1991; Geminiani et al., 1991). The intrarater reliability has never been assessed. The HY scale which has been used as the benchmark against the validity of other scales has been assessed. In this setting, a significant correlation has been observed between the HY scale and the UPDRS, ISAPD, Columbia and Sidney scales (correlation coefficients (Spearman, Pearson, other coefficients) ¼ 0.55– 0.91) (Hely et al., 1993; Martinez-Martin et al., 1994, 1995; van Hilten et al., 1994; Stebbins and Goetz, 1998; Stebbins et al., 1999). HY staging also correlated significantly with imaging measures representative of PD pathology, such as ß-CIT (123I-labeled 2b-carboxy3b-(4-iodophenyl)trophane) single photon emission computed tomography (SPECT) scanning and [18F] fluorodopa positron emission tomography (PET) scanning (Eidelberg et al., 1995; Staffen et al., 2000). In contrast, Henderson et al. (1991) reported a poor degree of correlation between the HY scale and other PDspecific measures of motor impairment and disability. 12.6.3. Schwab and England Scale This is a rapid scale, used to grade patients’ perception of overall functional capacity and dependence (Schwab and England, 1969). Despite being frequently used in PD-related studies and forming part of the UPDRS battery, this scale has not been included in the CAPIT (Langston et al., 1991, 1992) or in the CAPSIT-PD (Defer et al., 1999). Schwab and England scoring is expressed in terms of percentage, in 10 steps from 100 to 0, where 100% denotes normal state and 0% denotes bed-ridden with vegetative dysfunction. In spite of their appearance, these scores represent an ordinal level of measurement. Although this scale has been extensively used, it has been never formally tested and standardized, so that there is some uncertainty as to its reliability (McRae et al., 2000). Convergent validity has been indirectly assessed when Schwab and England was used to validate scales, such as the ISAPD, UPDRS and modified versions of the latter (Ramaker et al., 2002). In these studies, correlation coefficients were > 0.40, taken as criterion value (r (Spearman, Pearson) ¼ –0.60 to –0.98) (Martinez-Martin et al., 1994, 1995, 2000, 2003). Visser et al. (2004b) failed to find any correlation between a comorbidity index (Cumulative Illness Rating Scale – Geriatric: CIRS-G) (Miller et al., 1992) and the Schwab and England scale.

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12.6.4. The Unified Parkinson’s Disease Rating Scale The UPDRS was developed in an effort to incorporate elements from existing scales so as to provide a comprehensive means of monitoring PD-related disability and impairment. The development of this scale involved multiple trial versions, and the final published scale is officially known as UPDRS version 3.0 (Fahn et al., 1987). To date, the UPDRS has been the most widely used clinical rating scale for PD (Mitchell et al., 2000; Ramaker et al., 2002). This scale seeks to cover the clinical spectrum of PD and usually takes an average of 16–17 minutes to complete. The UPDRS consists of the following four subscales: (1) part I (four items), mental status, behaviour and mood; (2) part II (13 items), ADL, which may be scored in ‘on’ or ‘off’ states; (3) part III (14 items), motor examination (this section produces 27 scores due to assessment of several signs in different parts of the body); and (4) part IV (11 items), complications, comprising four items for dyskinesias, four items for fluctuations and three items for other complications. UPDRS subscales are used at different frequencies, with those most often used being sections II and III (Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease, 2003). Scoring of items in parts I, II and III ranges from 0 to 4 (0 ¼ normal, 4 ¼ severe), whereas scoring of part IV is irregular (with some items scoring from 0 to 4, and others 0 ¼ no and 1 ¼ yes). Total subscale scores are 16 for section I , 52 for section II , 108 for section III and 23 for section IV. The HY and Schwab and England Scales have been added to the UPDRS, thereby constituting a genuine evaluation battery. The UPDRS can be administered in several ways. Traditionally, parts I, II and IV are administered by interview and part III by performing a structured neurological examination. As alternative forms of administration, parts I and II can be self-administered or assessed by proxy (care-giver) with satisfactory overall results (Louis et al., 1996; Martinez-Martin et al., 2003). There is also a purpose-adapted scale for use by nurses (Bennett et al., 1997). An important feature of the UPDRS is the availability of a teaching tape for parts II and III (Goetz et al., 1995, 2003; Goetz and Stebbins, 2004), intended to enhance practical application of the scale and so greatly help improve interrater reliability. Of all available PD rating scales, the UPDRS is the most thoroughly tested instrument from a clinimetric point of view. Nonetheless, some relevant limitations exist, such as several ambiguities in the written text,

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inadequate instructions for raters and a number of metric flaws. In this connection, an ad hoc task force has recommended that the Movement Disorder Society sponsor the development of a new version of the UPDRS (Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease, 2003). The UPDRS has shown itself to have a satisfactory global internal consistency coefficient (Cronbach’s alpha ¼ 0.96) (Martinez-Martin et al., 1994). Yet, this determination suffers from two weaknesses: (1) as the UPDRS is a multidimensional scale, internal consistency should properly be determined for each domain; and (2) this high degree of internal consistency may be artificially increased due to redundancy among the large number of items in sections II and III (Cronbach, 1951; Martinez-Martin et al., 1994; Fitzpatrick et al., 1998; Ramaker et al., 2002). Alpha values exceeding 0.70 have been attained by parts II and III, even where part II is applied by patients themselves or their care-givers (van Hilten et al., 1994; Stebbins and Goetz, 1998; Martignoni et al., 2003; Martinez-Martin et al., 2003; Marinus et al., 2004). With regard to item–total correlation, some items, such as tremor, salivation, swallowing and sensory symptoms, have been shown to have poor item–total correlation (van Hilten et al., 1994; Martignoni et al., 2003; Marinus et al., 2004). Overall, sections II and III items display acceptable or satisfactory stability (kappa > 0.40), with part II items tending to be the most reliable (Martinez-Martin et al., 1994; Rabey et al., 1997; Marinus et al., 2004). Louis et al. (1996) have shown that interrater reliability is satisfactory for self-assessed parts I and II. In a study focusing on section 2 , concordance was higher between patients and care-givers (kappa ¼ 0.57– 0.88) than between patients and neurologists (kappa ¼ 0.31–0.88) (Martinez-Martin et al., 2003). In contrast, some section III items (language, facial expression, tremor, rigidity, bradykinesia and repetitive movements) have shown moderate or poor interrater reliability among neurologists (Martinez-Martin et al., 1994; Richards et al., 1994; Prochazka et al., 1997; Rabey et al., 1997), technicians (Bennett et al., 1997) and both categories of raters (Bennett et al., 1997; Camicioli et al., 2001). When section III has been rated through video recording, agreement among neurologists proved higher than between neurologists and research technicians (Goetz et al., 1995; Camicioli et al., 2001). Interrater reliability for part IV has proved quite satisfactory, except for the items, ‘off’ periods that come on suddenly (Kendall’s W ¼ 0.44) (Rabey et al., 1997), early-morning dystonia and unpredictable ‘off’ periods (ICC ¼ 0.39 and 0.41, respectively) (Marinus et al., 2004). Intrarater (test–retest)

reliability has proved satisfactory for part I, II and III total scores (ICC ¼ 0.74–0.90) and most of their respective items (kappa ¼ 0.42–0.81; 73% of the items yielded kappa values > 0.60) (Siderowf et al., 2002). In a study by Camicioli et al (2001), part III items, evaluated by a trained technician using videotaped assessment (only 30% of items had kappa >0.40), were found to have poor stability. Use of the nurseadapted version of this part resulted in intermediate agreement (low-to-moderate reliability values) (Bennett et al., 1997). Studies conducted to ascertain the convergent validity of the UPDRS vis-a`-vis other PD scales (HY, Schwab and England, ISAPD and Short Scale for Assessment of Motor Impairments and Disabilities in Parkinson’s disease (SPES/SCOPA – Motor)) and timed motor tests have furnished satisfactory results (correlation coefficients (Spearman et al.) ¼ 0.55– 0.96) (Martinez-Martin et al., 1994, 1997; Stebbins and Goetz, 1998; Stebbins et al., 1999; Martignoni et al., 2003; Marinus et al., 2004). Exploratory factor analysis has demonstrated the multidimensional assessment format of the UPDRS (Martinez-Martin et al., 1994), with part III being found to contain three to six factors that account for 60–80% of total scale variance (van Hilten et al., 1994; Stebbins and Goetz, 1998; Stebbins et al., 1999). This factor structure has been shown to be stable across both ‘on’ and ‘off’ states (Stebbins et al., 1999). A disability index, derived from UPDRS section II and designed as an illustrative model for interpretability of results yielded by this section, has displayed appropriate psychometric properties (reliability, convergent validity and known-groups validity) (Martinez-Martin et al., 2000). Nonetheless, the selection of items included in this index has been criticized because swallowing is viewed as an impairment rather than a disability (Hariz et al., 2002). Although this argument is valid, the model was originally created as a predictive and interpretative clinimetric index of patients’ functional status. From this stance, the item in question – swallowing – was therefore retained in the model because it provides prognostic information (inasmuch as this sign does not usually appear until patients reach moderate or advanced stages of the disease). 12.6.5. Intermediate Scale for Assessment of Parkinson’s Disease The ISAPD was designed using a statistical procedure for item selection, based on the Northwestern University Disability Scale, UCLA-Cornell scale, Webster

SCALES TO MEASURE PARKINSONISM scale and a five-item complementary scale (MartinezMartin et al., 1987, 1995; Martinez-Martin, 1988). The purpose was to obtain a relatively short, valid, functional scale to form a standard nucleus for clinical trials and daily clinical practice. It is composed of 13 items (11 for interview and two for examination purposes) related to ADL and general mobility, as well as sections for assessment of dyskinesias and fluctuations. The score range for each item is uniform, going from 0 (normal) to 3 (severe). The average time spent on administering it is 7 minutes. The original scale has been improved, the currently recommended version being ISAPD-2.1 (Martinez-Martin et al., 1998b, 2006). According to the original study and unpublished data, internal consistency has been satisfactory, with an alpha coefficient > 0.90, interitem correlation of 0.41–0.91, and item–total correlation of 0.61–0.90. Interrater reliability proved satisfactory for all items (kappa ¼ 0.74–0.89). Correlation with other scales, such as HY, UPDRS and Schwab and England (rS ¼ 0.65–0.98), showed the ISAPD as having satisfactory convergent validity with these measures. Factor analysis revealed the existence of three factors that explained 76.5% of the variance (factor I: basic ADL; factor II: mobility dependent on the lower limbs; and factor III: symptoms linked to the pharyngolaryngeal area, such as speech and eating) (Martinez-Martin et al., 1995).

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account for 61.5% of the total variance (Rabey et al., 1997). An independent study found two factors for each section (ADL and motor examination), which explained 70% and 79% of the total variance respectively (Martignoni et al., 2003). Item–total correlation proved satisfactory for all items in the ADL (rS > 0.60) and motor examination (rS > 0.57) sections, except for the rest and action tremor items in the latter (rS < 0.20) (Martignoni et al., 2003), a finding shared with the UPDRS (Rabey et al., 1997; Martignoni et al., 2003; Reichmann et al., 2003). Interrater reliability has been explored for the ADL, motor examination and motor complications sections and been pronounced satisfactory (mean Kendall’s W ¼ 0.88–0.94, 0.78–0.95, 0.85–0.94, respectively) (Rabey et al., 1997). Correlation between the respective items in the SPES and the HY scale has been found to surpass the criterion (rS ¼ > 0.40), except for eating (ADL section), rigidity, rest tremor and postural tremor (motor examination section) (Rabey et al., 1997; Martignoni et al., 2003). Significant correlations were also found between the UPDRS and SPES (ADL and motor sections) (rS ¼ 0.88–0.90) (Martignoni et al., 2003). The SPES has been specifically studied for sensitivity, registering a significant effect size (ES) in the motor examination section (ES ¼ 0.89) and moderate ES in the ADL section (ES ¼ 0.47) (Reichmann et al., 2003). SPES responsiveness has proved comparable to that of the UPDRS (Rabey et al., 2002).

12.6.6. Short Parkinson’s Evaluation Scale (SPES) In 1994, a European group initiated an international collaborative effort to overcome problems reportedly affecting the UPDRS (Martinez-Martin et al., 1994; Richards et al., 1994; van Hilten et al., 1994). In contrast to the UPDRS, the SPES represents a four-point scale (0 ¼ normal, 3 ¼ severe), endowed with less redundancy and more clearly defined ranks than the UPDRS, in order to improve interrater reliability without a significant loss of sensitivity. The SPES is made up of four sections: (1) mental state (three items); (2) ADL (eight items); (3) motor examination (eight items); and (4) treatment complications (five items) (Rabey et al., 1997). It usually takes 7–10 minutes to administer and instructions for use are available. The SPES is accompanied by the HY scale and an axial description of motor complications. With the exception of the mental state section, internal consistency has been found to be acceptable on the whole. Cronbach’s alpha ranged from 0.60 to 0.91 (Martignoni et al., 2003; Reichmann et al., 2003). Factor analysis identified four factors that

12.6.7. Short Scale for Assessment of Motor Impairments and Disabilities in Parkinson’s Disease (SPES/SCOPA) The SPES/SCOPA was designed to improve some clinimetric shortcomings of the SPES, particularly its internal consistency (Marinus et al., 2004). The development of this scale is part of a larger research project, known as SCales for Outcomes in Parkinson’s Disease (SCOPA). The SPES/SCOPA is composed of three sections: (1) motor impairment, containing two subscales, namely, motor examination (eight items) and historical information (two items); (2) ADL (seven items); and (3) motor complications (four items). There is a choice of four possible responses per item, ranging from 0 (normal) to 3 (severe). The mental section was removed from the SPES altogether because the authors felt that such complex functions could not be reliably and validly assessed by a single question. The mean time needed to complete the scale is 8.1 1.9 minutes.

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Although coefficient alpha for the different sections of the scale exceeded the criterion value for groups (Cronbach’s alpha ¼ 0.74 – 0.95), some components of the motor section, such as right-hand tremor and swallowing, displayed low item–total correlation (r < 0.20). Interrater reliability of the motor section proved fair for 50% of the items (ICC < 0.60, especially for postural tremor and right-side rigidity). In contrast, the reliability of the ADL and motor complication sections was satisfactory (save for changing positions, ADL section) (ICC ¼ 0.61–0.92). Interrater reliability and test–retest of the motor section, assessed by video by an international panel of experts, was also satisfactory (kappa and ICC > 0.70). The correlation between related sections of the SPES/SCOPA and the UPDRS (motor, ADL and motor complications) was high (r > 0.86). In all cases, correlations between these sections and the HY and Schwab and England scales were similar to those with the UPDRS, according to the scale’s authors (coefficients not specified) (Marinus et al., 2004). Known-groups validity was satisfactory. Statistically significant differences appeared when patients with different disease severity, based on HY staging, were compared. A significant trend was present in both sections of the scales (motor examination and ADL), with higher scores for patients among whom the disease was more advanced (ANOVA, P < 0.001). 12.6.8. The Parkinson’s Disease Activities of Daily Living Scale This is a short unidimensional scale, designed to evaluate a construct composed of heterogeneous components (dependency, effect of treatment, etc.) by means of a single number. Response options involve up to five possible answers referring to the difficulty experienced by the patient in performing ADL (1 ¼ without difficulty, 5 ¼ severe difficulties) (Hobson et al., 2001). Each response option describes PD-related interference with patients’ functioning in terms of limitations, need of assistance and effect of medication. The scale is designed to be selfadministered. Based on the original description, this scale possesses a satisfactory test–retest reliability, determined by a non-specified correlation coefficient (r ¼ 0.89) without any additional analysis to discard random agreement. Convergent validity with the Webster scale (Webster, 1968) proved satisfactory (Hobson et al., 2001).

12.6.9. Scales for assessment of specific aspects 12.6.9.1. Gait evaluation scales in Parkinson’s disease 12.6.9.1.1. The Rating Scale for Gait Evaluation (RSGE) This scale was specifically designed to evaluate gait disorder in PD. Whereas the first version consisted of 23 items (Martinez-Martin et al., 1997), version 2.0 consists of 21 items scored on a four-option scale (0 ¼ normal, 3 ¼ severe), embedded in the following four subscales: (1) socioeconomic (four items; maximum score 12 points); (2) functional ability/ADL (seven items; maximum, 21 points); examination (eight items; maximum, 24 points); and complications (two items; maximum, 6 points) (Badı´a et al., 1999). Aside from the examination section, the scores for the remaining subscales are obtained through interviews, and the timeframe is the previous week. If fluctuations are present, the functional ability section is scored in both ‘on’ and ‘off’ states. Internal consistency, as measured by coefficient alpha, was satisfactory (Cronbach’s alpha ¼ 0.94). Overall, item–total correlation surpassed the criterion (rS ¼ 0.47–0.84), except for the following items: falls, dyskinesias and axial rigidity (rS ¼ 0.25–0.39). Factor analysis identified four factors (mobility/gait, socioeconomic aspects, rigidity and complications) accounting for 68% of total variance. Interrater reliability was acceptable, with the exception of the ‘axial rigidity’ item (kappa ¼ 0.30). Six items in the examination section attained kappa values of close on 0.60 (kappa ¼ 0.54–0.58). Convergent validity with the Northwestern University Disability Scale, Schwab and England HY, total UPDRS and relevant UPDRS sections, Barthel index and timed tests (timed Up and Go test, cadence of step) was satisfactory (rS ¼ 0.68–0.90). 12.6.9.1.2. Freezing Of Gait Questionnaire (FOGQ) The definitive version of this questionnaire can be used for self-assessment. It comprises six items describing patients’ gait difficulties during ‘off’ periods, impact on the ADL, freezing-related circumstances and duration of the episodes. Answers are given on a five-point scale, where 0 indicates absence of the symptom and 4 represents the most severe disability or duration (Giladi et al., 2000). In the original study, Cronbach’s alpha proved high for the total score (alpha ¼ 0.94). Correlation with UPDRS sections II and III (complications were not analyzed) displayed a moderate association

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(r ¼ 0.40–0.43) and convergent validity with the HY scale was found to be satisfactory (r ¼ 0.66).

logical treatment, a finding indicative of adequate PPRS responsiveness (Friedberg et al., 1998).

12.6.9.1.3. Clinical Gait and Balance Scale (GABS)

12.6.9.2.2. SCales for Outcomes in Parkinson’s Disease – COGnitive scale (SCOPA-COG)

In effect, the GABS is a battery-type instrument designed to assess gait, freezing of gait, gait cycle, balance and posture. It consists of two parts: (1) historical information; and (2) evaluation of 14 gait parameters by examination of patients. These parameters include UPDRS items, full and half turn, Romberg test, tandem gait, one-limb stance, provocative tests for freezing, a modified Performance Oriented Assessment of Gait (POAG) scale, posturography on unstable surface (foam), the functional reach test, timed tests to assess gait speed, and the Up and Go test (Thomas et al., 2004). GABS items are scored as follows: items 1–17 on a scale of 0 (normal) to 4 (the most severe); and items 18–24 on a scale of 0 (normal) to 1 or 2 (1 and 2 being abnormal). Historical information consists of questions relating to walking, ADL, falls and freezing. Of the 18 items studied, intrarater reliability was moderate (kappa ¼ 0.40–0.60) for 10, substantial (kappa > 0.60) for 7 and poor (kappa ¼ 0.31) for 1. Correlation with objective tests (force platforms) was moderate (r > 0.42). Some components of the scale are potentially capable of differentiating between ‘on’ and ‘off’ states to a significant degree. 12.6.9.2. Mental state 12.6.9.2.1. The Parkinson Psychosis Rating Scale (PPRS) The PPRS is an easily administered rating instrument for quantitative evaluation of PD psychosis severity. It contains six items rated on a rank-order scale of 1 (normal) to 4 (severe), assessing the content and frequency of visual hallucinations, illusions and misidentification of persons, paranoid ideation, sleep disturbances, confusion and sexual concern. Definitions of the respective items and answers accompany the scale (Friedberg et al., 1998). In repeated application (6 weeks later), the internal consistency of the PPRS was satisfactory (Cronbach’s alpha ¼ 0.76–0.80), as was the intrarater reliability for the total scale, determined by statistical correlation (rS ¼ 0.77–0.78). Convergent validity between the PPRS and the Brief Psychiatric Rating Scale (BPRS), NOSIE-Psychotic and NOSIE-Irritative scales was satisfactory (NOSIE: Nurses’ Observation Scale for In-patient Evaluation), particularly in the case of the BPRS (r ¼ 0.92). There was no significant correlation between the PPRS and the Mini-Mental State Examination (MMSE). Like the BPRS, the PPRS showed significant changes after intervention with pharmaco-

This scale was developed to evaluate the specific cognitive disorder associated with PD. Although the SCOPA-COG was intended to be used for comparing groups in research situations, it may also be applied in clinical settings (Marinus et al., 2003c). Following a functional classification, this scale assesses four domains: (1) attention (direct and inverse series); (2) memory and learning (visual and verbal recall, digit span backward, short-term and delayed recall); (3) executive functions (semantic fluency, set shifting and motor execution); and (4) visuospatial functions (assembling figures) (Mahieux et al., 1998; Dubois and Pillon, 1999). It consists of 10 items having a maximum score of 43, with the higher scores reflecting better performance. The maximum domain scores are 4 points for attention, 22 for memory, 12 for executive functions and 5 for visuospatial function. The SCOPA-COG is administered by a rater and completed in 10–15 minutes. Mean scores were 13.3 4.0 points for PD patients with dementia, 28.8 5.8 for non-demented PD patients, and 30.7 5.6 for controls (Marinus et al., 2003c). Insofar as clinimetric issues are concerned, the internal consistency of this scale proved satisfactory (Cronbach alpha ¼ 0.83; item–total correlation ranged from 0.34 to 0.66). Test–retest showed moderate to substantial reliability for individual items (weighted kappa ¼ 0.40–0.75) and was satisfactory for the total scale (ICC ¼ 0.78). Convergent validity was supported by the SCOPA-COG’s correlation with other cognitive scales, such as the Cambridge Cognitive Examination (CAMCOG) (r ¼ 0.83) and the MMSE (r ¼ 0.72). Correlation with the HY scale bordered on the threshold of the criterion (rS ¼ –0.39) (the higher the severity of the disease, the lower the SCOPA-COG score). This scale is potentially more sensitive than the MMSE and CAMCOG because its coefficient of variation (CV) is higher (MMSE CV ¼ 0.14, CAMCOG CV ¼ 0.13, SCOPA-COG CV ¼ 0.29). 12.6.9.3. Sleep 12.6.9.3.1. Parkinson’s Disease Sleep Scale (PDSS) The PDSS is a scale addressing 15 items that explore the following aspects over the preceding week: overall quality of nocturnal sleep; sleep onset and maintenance; insomnia; nocturnal restlessness and psychosis; nocturia; nocturnal motor symptoms; sleep refreshment;

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and daytime dozing. Patients or care-givers indicate the severity of the symptoms for each item on a visual analog scale that goes from always (0) to never (10), except for the item, ‘overall quality of night’s sleep’ (very bad ¼ 0, to excellent ¼ 10). The total PDSS score is calculated by adding the item scores, and ranges from 0 to 150, so that the higher the score, the better the quality of nocturnal sleep (Chaudhuri et al., 2002). Coefficient alpha rose to 0.77 (Martinez-Martin et al., 2004). Interitem correlation ranged from – 0.007 to 0.70 (the lowest value of the criterion being 0.20). Item–total correlation was satisfactory (rS > 0.20), except for four items (presence of distressing hallucinations, nocturia, tremor on waking, unexpectedly falling asleep during the day), which did not correlate with the total scale. Factor analysis identified a principal factor that accounts for 65% of the variance and seems to be linked to the overall quality of nocturnal sleep. PDSS items loading on this factor were: overall quality of nocturnal sleep; staying asleep at night; and tired after waking (Martinez-Martin et al., 2004). Test–retest reliability proved satisfactory (ICC ¼ 0.61–0.99 for items, 0.94 for the total score) (Chaudhuri et al., 2002; Martinez-Martin et al., 2004). Correlation of the PDSS was moderate with respect to the Hamilton Depression scale (rS ¼ 0.55), weak with respect to UPDRS section IV (rS ¼ 0.22) and the PDQ-39 (rS ¼ 0.26) and non-significant with respect to the HY scale, UPDRS sections I and III, the MMSE and Epworth Sleepiness Scale (Martinez-Martin et al., 2004). The PDSS is able to differentiate between PD patients and controls, and between patients who are and are not suffering from sleep disturbances, as defined by UPDRS item 41. Nevertheless, there was no association between disease severity, based on HY staging, and PDSS scores (Chaudhuri et al., 2002; Martinez-Martin et al., 2004). Item 15 (unexpectedly falling asleep during the day) was significantly associated with the Epworth Sleepiness Scale (r ¼ –0.59) in one study (Chaudhuri et al., 2002) but not in another (Martinez-Martin et al., 2004). The standard error of measurement, based on the reliability index for a longitudinal observation (ICC) drawn from both studies, was 5.01–5.31 (MartinezMartin et al., 2004). 12.6.9.3.2. SCales for Outcomes in Parkinson’s Diseases – Sleep (SCOPA-Sleep) This scale consists of two sections (nocturnal sleep (NS) and daytime sleepiness (DS)). The first part

includes five items (sleep initiation, sleep fragmentation, sleep efficiency, sleep duration and early wakening). Scoring options per item range from 0 (not at all) to 3 (a lot). NS addresses nocturnal sleep problems in the past month, and the maximum score is 15. The DS section evaluates the presence of abnormal daytime sleep in the past month and includes six items with four response options, ranging from 0 (never) to 3 (often). Subjects indicate how often they fell asleep unexpectedly, and fell asleep in particular situations (while sitting peacefully, watching TV or reading, or while talking to someone). The maximum score in this section is 18 (Marinus et al., 2003b). The internal consistency of both subscales was satisfactory (Cronbach’s alpha for NS ¼ 0.88; for DS ¼ 0.91; item–total correlation coefficients, 0.48–0.85 for SN, and 0.55–0.88 for DS). Both subscales showed moderate to excellent test–retest reliability in the original study (kappa ¼ 0.49–0.90; values higher than 0.80 in 8 out of 11). ICC was satisfactory for both the NS and DS sections (ICC > 0.90). Factor analysis identified one factor in the NS section accounting for 68.1% of the variance, and one factor in the DS section accounting for 69.1% of the variance (Marinus et al., 2003b). The correlation between the NS section and the Pittsburgh Sleep Quality Index (PSQI) was high (r ¼ 0.83), and moderate to high with the PSQI subscales (r ¼ 0.38–0.73). The correlation between the DS section and the Epworth Sleepiness Scale was also high (r ¼ 0.81). A cut-off value of 6/7 for the NS section displayed high sensitivity and acceptable specificity when it came to distinguishing good from bad sleepers. In addition, a cut-off value of 4/5 for the DS section discriminated between patients with and those without excessive daytime sleepiness. The SCOPA – Sleep successfully differentiated PD patients from control subjects, except for the ‘difficulty falling asleep’ item (Marinus et al., 2003b). 12.6.9.4. Autonomic disorder 12.6.9.4.1. Scales for Outcomes in Parkinson’s Diseases – AUTonomic (SCOPA-AUT) This self-administered scale was designed to evaluate the presence and frequency of autonomic symptoms in PD. The SCOPA-AUT consists of 25 items assessing the following regions: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1) and sexual dysfunction (2 items for men and 2 items for women) (Visser et al., 2004a). Item scoring includes four response options ranging from 0 (never) to 3 (often), with a total score of 69 (higher scores reflecting worse autonomic functioning). The

SCALES TO MEASURE PARKINSONISM urinary and sexual regions have additional response options, designed to indicate, respectively, whether or not subjects have used a catheter or been sexually active during the preceding month. Test–retest reliability proved satisfactory (ICC for the total score 0.87 and for the different regions ranged from 0.68 to 0.90). Stability for most of the items ranged from moderate to excellent (kappa ¼ 0.65–0.87). Total SCOPA-AUT scores correlated significantly with the HY scale (rS ¼ 0.60), whereas coefficients for the regions ranged from 0.20 to 0.70. Knowngroups validity (control subjects and three groups of patients with different stages of severity) was satisfactory, except for sexuality-related domains. 12.6.9.5. Scales for dyskinesias in Parkinson’s disease 12.6.9.5.1. Obeso’s Dyskinesia Rating Scale This scale combines the patient’s historical assessments and the examiner’s rating of dyskinesias (Obeso et al., 1989). Disability is assessed using two categories of information: severity and duration. These scores are handled arithmetically to provide a single score based on the mean of the two subscores. The intensity score combines two clinical issues: patient awareness of movements and the actual observed intensity of such movements. The duration score, akin to the UPDRS part IV question on duration, divides the waking day into four segments. Though included in the CAPIT protocol for evaluation of patients who undergo neurosurgical intervention for PD (Langston et al., 1991, 1992; Anonymous, 1999), this scale has not been explored from a clinimetric point of view. 12.6.9.5.2. Rush Dyskinesia Rating Scale This scale represents a modified version of Obeso’s dyskinesia rating scale. It was designed as an objective scale to capture the impact of dyskinesia on ADL (Goetz et al., 1994). In this scale, three activities are evaluated: (1) walking; (2) putting on a coat and buttoning it; and (3) drinking from a cup. The most severe dyskinesias observed during any of three tasks must be rated from 0 (none) to 4 (violent). The rating is entirely based on objective observation with no interviewing of patient perceptions, and the score is tied directly to ADL and their successful completion. In addition to the intensity rating, the most pronounced types of dyskinesia associated with disability are identified (chorea, dystonia, myoclonus, and so forth). The Rush Dyskinesia Rating Scale, which can be scored live or by video tape, takes about 15 minutes to administer. To standardize its use, a

311

video record and the administration protocol were included in the original article, illustrating cases across the entire gamut of scores, severities and types of dyskinesia. Kendall’s coefficient of concordance between medical practitioners and research coordinators yielded satisfactory values for severity of dyskinesia (W ¼ 0.71– 0.89), and moderate values for type (W ¼ 0.34–0.42) and identification of the most disabling dyskinesias (W ¼ 0.28–0.48). There were no statistically significant differences between both groups of raters, although reliability was higher among the practitioners. Test–retest reliability was shown to be satisfactory for all evaluated aspects (correlation coefficients (Spearman, Crame´r) > 0.70) (Goetz et al., 1994). 12.6.9.5.3. Clinical Dyskinesia Rating Scale This scale was designed with the aim of fulfilling the following criteria: ease of use and application to any situation (e.g. for multiple assessments during a drug cycle, while performing standardized motor tests for parkinsonism); separate ratings for different body parts, including lateralization; separate rating for dystonia and hyperkinesias; and no estimate of disability (Hagell and Widner, 1999). It is composed of independent evaluations of hyperkynesias and dystonic postures separately observed in different body regions (face, neck, trunk, right and left upper extremities, right and left lower extremities). The score range is from 0 (none observed) to 4 (extreme), permitting the use of 0.5scoring intervals. The maximum total score for each subscale (dyskinesias and dystonia) is 28. Ratings are based on observations of the patient at rest and during activity. In the original study, the interrater reliability was explored for different groups of raters (neurologists, neurosurgeons and nurses specialized in PD), proving excellent for hyperkinesias (W ¼ 0.88) and moderate for dystonia (W ¼ 0.44). Overall test–retest reliability was satisfactory (Kendall’s tau ¼ 0.74). Dystonia ratings revealed a lesser degree of concordance (with some Kendall tau coefficients as low as 0.31). 12.6.9.5.4. Lang–Fahn Activities of Daily Living Dyskinesia Scale This scale is a modification of UPDRS section II. It consists of historical information on the way in which maximum dyskinesia severity influences the capacity to perform basic ADL tasks, such as writing, eating, dressing, maintaining personal hygiene and walking (Parkinson Study Group, 2001). Patients evaluate dyskinesias on preceding days, retrospectively. The

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scoring system for each of the five items comprising this scale runs from 0 (none) to 4 (maximum interference), with explicit definitions for the respective options. There was no relevant correlation with the Rush Dyskinesia Rating Scale or patients’ dyskinesia diary.

12.7. Rating scales for other parkinsonisms 12.7.1. Unified Multiple System Atrophy Rating Scale (UMSARS) This scale is made up of the following four sections: (1) historical (12 items); (2) motor examination (14 items); (3) autonomic evaluation (four cardiovascular parameters); and (4) global disability (Wenning et al., 2004). The historical section includes information furnished by the patient or care-giver about speech, swallowing, hand-writing, cutting food and handling utensils, dressing, hygiene, walking, falling, orthostatic symptoms and urinary, sexual and bowel functions. The motor examination section includes facial expression, speech, ocular motor dysfunction, tremor at rest, action tremor, increased tone, rapid alternating movements of hands, finger-tapping, leg agility, dysmetria, arising from chair, posture, body sway and gait. In both sections, the item scoring system goes from 0 (normal) to 4 (maximal severe). The autonomic examination section captures blood pressure and heart rate (supine and standing up, or unable to record), and the presence of orthostatism (yes or no). The global disability scale measures patients’ dependence and capacity for ADL (one item with five answer options: l ¼ totally independent, minimal difficulty in doing all chores, to 5 ¼ totally dependent, bed-ridden). Internal consistency was satisfactory for sections I and II: Cronbach’s alpha ¼ 0.84 and 0.90, respectively; item–total correlation exceeded the criterion threshold for most of the items (rS > 0.50 for nine items of section I and 11 items of section II). Two items of section I and three of section II showed poor or null association with their corresponding total scores. The average index kappa for the participant centers was satisfactory (kappa > 0.70) for eight items in the historical section. Orthostatic hypotension was the item with the worst interrater reliability (kappa ¼ 0.52). Except for oculomotor dysfunction, hypertonia and finger-tapping items, satisfactory agreement was found for section II (kappa < 0.70), and substantial or excellent agreement for section IV (kappa ¼ 0.75– 0.94). Total scores displayed a similar level of interrater concordance (ICC ¼ 0.88, for section I; 0.93 for section II).

Section I correlated significantly with the HY, UPDRS section II (ADL) and Schwab and England scales (rS ¼ 0.76–0.90). Section II correlated with the HY, UPDRS section III (Motor Examination) and the International Co-operative Ataxia Rating Scale (ICARS) (Trouillas et al., 1997) (rS ¼ 0.80–0.93). Section IV also yielded significant correlation coefficients with the HY, UPDRS sections II and III and ICARS (rS ¼ 0.72–0.94), as well as with UMSARS sections I and II. On the whole, correlation between the total scores for UMSARS sections I and II and timed tests was moderate (rS ¼ 0.42–0.57). UMSARS sections I, II and IV proved adequate to the task of differentiating between patients at different levels of disease severity.

12.8. Health-related quality of life Quality of life is a popular term that allows for very different interpretations. As this concept embraces a wide range of topics and disciplines, there is no single universal or widely accepted theoretical framework, definition or measurement instrument for quality of life. Quality of life has been approached from both macro and micro perspectives. The former involves environment-related societal and objective factors (such as housing, social support, economy, safety and education); the latter depends on individual and subjective components (e.g. health, relationships, emotional status, spirituality and attitudes). HRQoL is a more restricted concept, linked to experiences and expectations associated with health status and health care. Despite the apparent simplicity of the term, however, controversy has surrounded its conceptual delineation (Leple`ge and Hunt, 1997). From a pragmatic point of view and with respect to the topic addressed by this chapter, HRQoL may be defined (following Schipper et al., 1996) as: ‘the perception and evaluation, by patients themselves, of the impact caused on their lives by the disease and its consequences’ (Martinez-Martin, 1998). It is an individual, subjective, self-controlled, multidimensional judgment, the components of which (along with their relative importance) change over time. These modifications may be caused by factors that depend on the subject (such as adaptation, new expectations, change in priorities) or, alternatively, on the environment (e.g. familial, societal). The very multiplicity of the potential components of the concept of HRQoL means that there is a tendency to consider only those that are in line with the official World Health Organization (1952) definition

SCALES TO MEASURE PARKINSONISM

313

35,000 30,000

29,261

25,000 20,000 15,000 10,000 5000 0

<1974

1978

1983

1988

1993

1998

2003

Fig. 12.2. Number of articles about ‘quality of life’ referred in Medline, on January 1, 2004.

of health: ‘a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity’. Another consideration that can influence a dimension’s inclusion as an HRQoL component is susceptibility to be modified by therapeutic interventions. Hence, those aspects that are not properly a part of an individual’s health status or are not closely related to health are excluded. The domains most frequently included in HRQoL measures are symptoms, physical function, mental status, social well-being, role activities, global judgments of health and personal constructs (Berzon et al., 1993; Schipper et al., 1996; Fitzpatrick et al., 1998; Fitzpatrick and Alonso, 1999).

12.9. Measurement of health-related quality of life Interest in quality of life has risen sharply over the last decade. Fig. 12.2. depicts the number of papers cited by Medline as containing the term ‘quality of life’ for the period 1974–2004. Approximately half were published in the previous 5 years (1999–2003). Reasons for the growing interest in quality of life reside in the ability to measure subjective perception of health by means of reliable instruments, the special information supplied by this kind of measure, the relationship between perceived health and use of resources, and the concept’s usefulness for evaluation of outcomes and decision-making. HRQoL measurement, a genuine ‘patient-centered’ type of evaluation, may prove important in order to identify problems that go undetected by other methods.

Adaptation, coping and personal response to the same disease or condition may be quite different between one person and another. HRQoL measures can help to capture the difference, and so enable tailor-made management strategies to be drawn up for the individual. Data derived from HRQoL measures rule out a simplistic approach. Variability in expectations, experience, time and environmental factors render HRQoL measurement unstable. Limited ability to distinguish individual determinants influencing scores and response bias makes interpretation of results that much more complex. Aspects, such as determination of the impact of HRQoL measurement on quality of care, development of appropriate measures for standard use in clinical practice, or adoption of an approach via ‘individualized’ rather than ‘standardized’ instruments, are still pending issues. HRQoL measures can be classified as generic or specific. Generic instruments are, in turn, classified as health profiles and utility measures. These measures may be applied to assessing the health status and/or illnesses of a variety of population samples, including the general population. Health profiles usually cover a wide range of basic HRQoL domains, including aspects of physical, mental and social functioning. Instances of the most frequently used health profiles are the Sickness Impact Profile (SIP) (Bergner et al., 1976), the Nottingham Health Profile (NHP) (Hunt et al., 1981) and the Medical Outcomes Study (MOS) Short Form Survey (SF-36) (Ware and Sherbourne, 1992). These instruments are suitable for general population and community health status surveys, studies on health care

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programs, assessment of HRQoL where specific measures are unavailable and for comparison between patients with different conditions. Generic profiles have some drawbacks, such as failure to include aspects of interest for specific conditions, lack of sensitivity and low responsiveness. Utility measures are derived from application of the economic theory of cost–utility analysis to assessment of health outcomes. These measures explore preferences with reference to different health states, across the spectrum from full health to death. A numerical score – the utility – is assigned to HRQoL status, with values ranging from 0.0 (death) to 1.0 (full health). The Quality of Well Being Scale (Kaplan, 1976), EuroQoL (EuroQoL Group, 1990) and Health Utilities Index (Feeny et al., 1995) are examples of this type of scale. They are relatively insensitive to change and provide no information about the domains involved in the health status. A combination of utility and survival data is used to obtain outcome measures such as quality-adjusted life years (QALYs). Specific HRQoL measures focus on those aspects of health status most relevant to the condition to be assessed. They may be developed for evaluation of a specific population group (e.g. children or the elderly), function (e.g. vision or sexual functioning), symptom (e.g. pain or insomnia) or disease (e.g. asthma or cancer). Compared to generic instruments, specific measures display higher acceptability (due to the prevalence of items that are important to the patient), improved precision and higher responsiveness. However, they do not allow for comparisons between diseases, nor may they be applied to conditions other than that for which they were created. The situation of HRQoL assessment in parkinsonian syndromes is on a parallel with that of clinical rating scales, inasmuch as there is a wide variety of specific measures, most of which were originally developed for the evaluation of PD. An important difference in the field of HRQoL measures, however, is that, in general, the validation work is not only far more complete but was also concluded at an early stage. A short review of the most representative instruments is given in Table 12.5 and a summary of studies about their psychometric properties is displayed in Table 12.6.

12.10. Specific health-related quality of life measures for Parkinson’s disease 12.10.1. Parkinson’s Disease Questionnaire (PDQ-39) This questionnaire was the first HRQoL-specific instrument for PD (Peto et al., 1995; Jenkinson et al., 1995). The PDQ-39 includes 39 items in the following

Table 12.5 Specific health-related quality of life instruments for Parkinson’s disease Parkinson’s Disease Questionnaire (PDQ-39 and PDQ-8) (Jenkinson et al., 1995; Peto et al., 1995) Parkinson’s Disease Quality of Life Questionnaire (PDQL) (de Boer et al., 1996) Parkinson’s Impact Scale (PIMS) (Calne et al., 1996) Parkinson’s Problem Schedule (PPS) (Brod et al., 1998) Parkinson-Life-Quality Questionnaire (Fragebogens PLQ) (van den Berg, 1998) SCOPA Psychosocial (SCOPA-PS) (Marinus et al., 2003a) Belastungsfragebogen Parkinson kurzversion (BELA-P-k) (Ellgring at al., 1993; Spliethoff-Kamminga et al., 2003) Parkinson’s Disease Quality of Life Instrument (PDQUALIF) (Welsh et al., 1997, 2003)

eight domains: (1) mobility (10 items); (2) ADL (six items); (3) emotional well-being (six items); (4) stigma (four items); (5) social support (three items); (6) cognition (four items); (7) communication (three items); and (8) bodily pain (three items). The timeframe is the preceding month. Each item is scored from 0 (no problem) to 4 (continuous problem/ unable to do it). Scoring for each dimension is calculated by dividing the sum total of the constituent item scores by the maximum possible score for the dimension as a whole, expressed as a percentage. The PDQ-39 Summary Index (PDQ-39 SI) is calculated by dividing the sum total of the dimension scores by the number of domains (Jenkinson et al., 1997a), so that the lower the index, the better the HRQoL. The PDQ-8 is a short-form questionnaire composed of eight items, each of which represents one PDQ-39 domain (Jenkinson et al., 1997b). The PDQ-39 is the most extensively studied HRQoL-specific instrument for PD from the standpoint of metric quality. It has been adapted for use in many countries. The PDQ-39 SI floor and ceiling effects are usually within the accepted limits of 1–15%, though these proportions are variable for each dimension. Social support and, to a lesser degree, stigma and

Table 12.6 Psychometric characteristics of health-related quality of life Parkinson’s disease measures Number of items

Alpha coefficient

Item-total correlation

Test–retest

Convergent validity

Parkinson’s Disease Questionnaire (PDQ-39)

39 items in 8 dimensions

Subscales (different studies): a ¼ 0.13–0.96

0.12–0.92

r ¼ 0.68–0.96 Social support

SF-36 r ¼ 0.21 to 0.80 EuroQoL

r < 0.40

r ¼ 0.75 (summary index)

ICC ¼ 0.86–0.95

Hoehn & Yahr r ¼ 0.60 r ¼ 0.16–0.72 (subscales) Schwab & England r ¼ 0.66, 071 UPDRS Subscales r ¼ 0.42–0.62 (summary index) Columbia r ¼ 0.08–0.58 (subscales) Beck Depr.Invent r ¼ 0.68 (summary index) MMSE r ¼ 0.32

–

SF-24 related domains:

Social support a ¼ 0.13–0.72

Parkinson’s Disease Quality of Life (PDQL)

37 items in 4 dimensions

Total scale: a ¼ 0.92–0.95 Subscales: a ¼ 0.77–0.87

Dimension-total score: r ¼ 0.58–0.74 Inter-domain correlation: r ¼ 0.46–0.68

SCALES TO MEASURE PARKINSONISM

Scale

0.22 to 0.66 CES-D Emotion 0.79 Hoehn and Yahr Dimensions 0.25 to 0.64 Total: 0.62 UPDRS subscales 0.24 to 0.77

315

(Continued)

316

Table 12.6 (Continued) Scale

Number of items

Alpha coefficient

Item-total correlation

Test–retest

Convergent validity

Totals 0.48 to 0.76 HADS subscales 0.34 0.74 Total 0.55, 0.67 10 items

a ¼ 0.89

–

ICC ¼ 0.72 (4 weeks) ICC ¼ 0.82 (8 weeks)

Parkinson’s Problem Schedule (PPS)

39 items; 3 dimensions

a ¼ 0.82–0.88

–

Parkinson-Life-Quality Questionnaire (Fragebogens PLQ)

44 items; 9 dimensions

Total scale: a ¼ 0.95 Subscales: a ¼ 0.62–0.87

–

Total scale: r ¼ 0.87 Subscales: r ¼ 0.69–0.86 (14 days)

EORTC QLQ30 0.67 Hoehn and Yahr 0.27 Schwab & England 0.27 QoL VAS 0.28 ADL scale 0.73

Psychosocial questionnaire for patients with Parkinson’s disease (SCOPA-PS)

11 items

a ¼ 0.83

ICC ¼ 0.24–0.67

ICC ¼ 0.46–0.83

PDQ-39 0.82 PDQ-8 0.76 HADS 0.69 EuroQoL 0.61 VAS 0.60

UPDRS r ¼ 0.25–0.55 Patient-based global evaluation of severity 0.26 Hoehn and Yahr 0.45 (motoric)

P. MARTI´NEZ-MARTI´N AND E. CUBO

Parkinson’s Impact Scale (PIMS)

Belastungsfragebogen Parkinson kurzversion (BELA-P-k)

Quality of Life Satisfaction (QLS-MS and QLS-DBS)

Total score: a ¼ 0.90 (Bb) a ¼ 0.93 (NfH)

32 items in 7 domains þ 1 transition question

Total scale: a ¼ 0.89

–

Bb Subscales: a ¼ 0.61–0.83 NfH subscales: a ¼ 0.77–0.88

r ¼ 0.15–0.74

k < 0.40 for 4 items

Subscales: a ¼ 0.55–0.85 (4/7 domains < 0.70)

QLS-MS: 12 items

QLS-MS: a ¼ 0.87

QLS-DBS: 5 items

QLS-DBS: a ¼ 0.73

–

–

COOP/WONCA Bb total score 0.69 Bb subscales 0.43–0.69

Loneliness scale Bb total score 0.49 Bb subscales 0.47–0.49 SIP Bb total score 0.50–0.58 Bb subscales 0.37–0.54 UPDRS R ¼ 0.02–0.50; 4/21 coeff. 0.40 SF-36 components 0.48 to 0.52 SIP components 0.61 – 0.70 Total: 0.73 SF-36 QLS-MS 0.59–0.63 QLS-DBS 0.32–0.36 EuroQoL QLS-MS 0.49–0.68 QLS-DBS 0.34–0.46

SCALES TO MEASURE PARKINSONISM

Parkinson’s Disease Quality of Life Instrument (PDQUALIF)

19 items in 4 dimensions “Bothered by” (Bb) and “Need for help” (NfH) scores are calculated for each dimension and for the total scale.

See text for abbreviations.

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communication are the domains most prone to exceeding the 15% threshold for floor effect (Hagell et al., 2003; Jenkinson et al., 2003). Insofar as the internal consistency of PDQ-39 dimensions is concerned, social support has regularly registered coefficient alpha values of < 0.70 in a number of studies (0.13–0.72). Depending on the study, item-to-dimension total correlation has also shown a variable number of items with coefficients of < 0.40. Test–retest reliability was found to be acceptable, except for social support (Peto et al., 1995; Martinez-Martin et al., 1998a, 1999; Bushnell and Martin, 1999; Marinus et al., 2002; Jenkinson et al., 2003). The convergent validity of the PDQ-39 with generic HRQoL measures, such as the SF-36, Nottingham Health Profile and EuroQoL, has been calculated (Jenkinson et al., 1995; Martinez-Martin et al., 1999; Schrag et al., 2000; Hagell et al., 2003). Whereas the correlation between the mobility and ADL dimensions of the PDQ-39 and most of the subscores for these measures generally exceeded the criterion of 0.40, social support tended to correlate poorly. Emotional well-being and communication frequently yielded coefficients of > 0.40, and the other domains registered intermediate positions. Similar findings were obtained for the PDQ-39 vis-a`-vis standard rating scales for PD, such as Hoehn and Yahr Staging, the Schwab and England Scale, UPDRS subscales, Columbia Scale, Barthel Index, Hospital Anxiety and Depression Scale (HADS) and Beck Depression Inventory (Jenkinson et al., 1995; Martinez-Martin et al., 1999; Schrag et al., 2000; Marinus et al., 2002; Martinez-Martin, 2002). Due to the fact that reliability coefficient values are < 0.90 for dimensions, standard error of measurement is high for social support, as it is occasionally for other dimensions, such as stigma and bodily discomfort (Fitzpatrick et al., 2004; Martinez-Martin et al., 2005). One study has calculated PDQ-39 SI sensitivity and responsiveness (Guyatt index ¼ 1.03; ES ¼ 0.48) at 3 months postintervention (start or transfer of treatment to controlled-release levodopa) (Martinez-Martin, 2002). The standardized response mean ranged from 0.05 (stigma) to 0.55 (mobility) for PDQ-39 dimensions in an observational 4-month follow-up study (Fitzpatrick et al., 1997). Additional responsiveness data (paired and unpaired t-tests) (Fitzpatrick et al., 1997; Martinez-Martin, 2002) and minimally important difference of change (Peto et al., 2001; Fitzpatrick et al., 2004) have also been ascertained.

12.10.2. Parkinson’s Disease Quality of Life Questionnaire de Boer et al. (1996) reported on the Parkinson’s Disease Quality of Life (PDQL) questionnaire, a specific instrument for evaluation of HRQoL in PD patients. This questionnaire contains 37 items in the following four dimensions: parkinsonian symptoms (14 items); systemic symptoms (seven items); social function (seven items); and emotional function (nine items). Item scoring ranges from 1 (all the time) to 5 (never). The overall score is obtained from the sum of scores for all items; the lower the score, the poorer the quality of life. In the original study, the PDQL was shown to possess a high internal consistency (Cronbach’s alpha for dimensions ¼ 0.80–0.87, and 0.94 for the total score), known-groups validity (groups with higher disease severity had significantly lower scores), and moderate convergent validity with a generic HRQoL measure (MOS-24). Subsequent studies obtained Cronbach’s alpha values of 0.69–0.87 for dimensions (with the systemic symptoms domain in all cases registering the lowest value) and 0.92–0.95 for the total score (Hobson et al., 1999; Serrano-Duen˜as et al., 2004). Hobson et al. (1999) ascertained PDQL convergent validity with depression measures (Yesavage scale, 15 items) and modification of PDQL score according to severity level as per motor examination (Webster scale). In the study undertaken by Serrano-Duen˜as et al. (2004), using an Ecuadorian Spanish version of the PDQL, item-dimension total correlation was in all cases > 0.40, dimension–total score correlation was 0.58–0.74 and interdimension correlation was 0.46– 0.68. The standard error of measurement, taking alpha as the reliability coefficient for a single observation, was 6.31 (SD ¼ 22.85; alpha ¼ 0.92). Convergent validity of PDQL dimensions with PD rating scales (Hoehn and Yahr, Schwab and England, UPDRS subscales) and the HADS was satisfactory (rS ¼ 0.24–0.77; only seven coefficients were < 0.40, and six of these belonged to the emotional function dimension). Total PDQL registered correlations with these scales, ranging from 0.48 to 0.67. Known-groups validity for different severity levels derived from HY and Webster staging proved satisfactory (Hobson et al., 1999; Serrano-Duen˜as et al., 2004). 12.10.3. Parkinson’s Impact Scale (PIMS) The PIMS is a brief questionnaire that measures non-physical aspects of PD patients’ HRQoL. It is

SCALES TO MEASURE PARKINSONISM composed of 10 items, each of which covers a relevant area of PD patients’ lives. Items are self-rated on a four-point Likert-type scale, with higher ratings indicating lower HRQoL. Since the PIMS factor structure does not appear to be stable across studies (Calne et al., 1996; Schulzer et al., 2003), it is advisable to use the total score. This is obtained by adding the weighted item scores (Calne et al., 1996). The PIMS was first validated with a multisite sample of 167 PD patients (Calne et al., 1996) but provided insufficient information on validity (Marinus et al., 2002). A later study with 116 PD patients furnished further information on the psychometric properties of the PIMS (Schulzer et al., 2003). PIMS internal consistency (Cronbach’s alpha) was 0.89. Test–retest reliability yielded an ICC ¼ 0.72 at 4 weeks (Calne et al., 1996) and an ICC ¼ 0.82 at 8 weeks (Schulzer et al., 2003). Significant differences were found between stable and fluctuating patients during ‘off’ periods (Calne et al., 1996). Convergent validity with the UPDRS subscales was moderate to high (r ¼ 0.25–0.55) for all patient ratings (stable patients, patients in their best and worst states) (Schulzer et al., 2003). In the same study, PIMS displayed adequate sensitivity, registering an adjusted ES of 0.37 (comparing patients on different doses of tolcapone). The receiver-operating characteristic (ROC) curve indicates a sensitivity of 80% and a specificity of 62.5% for PIMS responsiveness. 12.10.4. Parkinson’s Problem Schedule (PPS) In 1998, Brod et al. published a study describing the development and validation of the PPS, an instrument that contained 39 items relating to ‘activities, behaviours and emotions that are potentially problematic for PD patients’. Items were selected from patients’ responses to surveys, previous studies on psychosocial aspects in PD and semistructured interviews with patients and their partners. Factor analysis identified three dimensions (psychological, cognitive and motor functioning) having high internal consistency (0.82–0.88). Correlation between the three scales was moderate to high (r ¼ 0.40–0.57). These scales were used for logistic regression analysis with respect to demographic variables, illness severity, functional ability and psychosocial variables, thereby demonstrating an important association with functional status and irregular potentiation on adding the psychosocial evaluation. The psychological and cognitive dimensions displayed only a modest association with a patient-based

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global evaluation of disease severity (r ¼ 0.26). The three dimensions were independent of the demographic variables and were partially (only the motor domain) related to disease stage as per the Hoehn and Yahr classification. 12.10.5. Parkinson-Life-Quality Questionnaire (Fragebogens PLQ) This instrument was validated and published by van den Berg in 1998. It comprises 44 items in nine subscales and generates a global score as an index of HRQoL. The reliability of the questionnaire (internal consistency and test–retest reliability) was quite high, though some subscales displayed a consistency inferior to the criterion value (Cronbach’s alpha < 0.70). Convergent validity and responsiveness were studied in a small sample of patients, using parametric statistics. These aspects of validation have been insufficiently demonstrated. 12.10.6. Psychosocial Questionnaire for Patients with Parkinson’s Disease (SCOPA-PS) This scale consists of 11 items that evaluate the severity of a particular problem during the preceding month on a scale from 0 (not at all) to 3 (very much). This scale includes information about psychosocial functioning in terms of the patient’s difficulties in ADL, recreational activities, relationships with friends and relatives, dependence, isolation and concerns about the future (Marinus et al., 2003a). Coefficient alpha proved satisfactory (Cronbach’s alpha ¼ 0.83). Item–total correlation ranged from 0.24 (problems with sexuality) to 0.67 (asking others for help too often). Test–retest reliability was satisfactory for the total scale (ICC ¼ 0.85). For individual items, the test–retest reliability ranged from moderate to satisfactory (kappa ¼ 0.46 for problems in getting along with partners, family or good friends, to 0.83 for problems with sexuality). Correlation between the SCOPA-PS and the PDQ-39 and PDQ-8 total scores were 0.82 and 0.76 respectively. In contrast, correlations between the SCOPA-PS and the HADS, EQ-5D total score and visual analog scale were somewhat lower (Spearman r ¼ 0.69 for HADS and < –0.61 for EQ-5D and visual analog scale). The SCOPA-PS summary index revealed a significant rise with increasing disease severity, higher anxiety/depression and longer disease duration, thereby showing satisfactory known-groups validity.

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12.10.7. Belastungsfragebogen Parkinson kurzversion (BELA-P-k) The BELA-P-k questionnaire, which was first developed in Germany (Ellgring et al., 1993), is aimed at measuring the specific psychosocial problems in PD patients along with their self-reported need for help. A validation study was conducted using Dutch patients (Spliethoff-Kamminga et al., 2003). The questionnaire contains 19 items, grouped into four dimensions: (1) achievement capability/physical symptoms; (2) fear/ emotional symptoms; (3) social functioning; and (4) partner-bonding/family. Each dimension includes four or five items, rated on two five-point Likert-type scales (0–4), one addressing the degree to which the patient feels bothered by the issue, and the other addressing the need for help. Dimension scores are obtained by adding together the scores for both aspects of the corresponding items. This means that each dimension generates two subscale scores, i.e. ‘Bothered by’ (Bb) and ‘Need for help’ (NfH). Depending on the number of items comprising each dimension (4 or 5), subscale scores range from 0 to 16 (fear/emotional functioning dimension) or from 0 to 20 (remaining dimensions). A total Bb and NfH score can also be calculated by adding the dimension scores. All dimensions are rated in the same direction, with lower scores representing a better HRQoL. Internal consistency was good for the total Bb and NfH scores (0.90 and 0.93, respectively), and all subscales (dimensions) yielded Cronbach’s alpha coefficients above 0.70, except for the Bb score for the partner/family subscale (0.61). Data on the validity of the BELA-P-k are still limited. With respect to convergent validity, Bb scale scores were appropriately correlated with other HRQoL measures, such as the Darmouth COOP Functional Health Assessment Charts/Wonca (COOP/WONCA) questionnaire, SIP and loneliness scale (r > 0.45 for the total Bb score). All Bb subscale scores registered correlation values close to or above 0.40, with the exception of the fear/emotional functioning Bb score, which showed a slightly lower correlation coefficient (0.37) with the comparable SIP domain. There was significant correlation between total Bb and NfH scores (r ¼ 0.74). 12.10.8. Parkinson’s Disease QUAlity of LIFe instrument (PDQUALIF) The first reference to this questionnaire appeared in an abstract (Welsh et al., 1997). It has recently been used in a clinical trial with pramipexole (Parkinson Study Group, 2000). The validation study was published in 2003 (Welsh et al., 2003).

The PDQUALIF consists of 32 items in seven domains, these being: (1) social/role function (nine items); (2) self-image/sexuality (seven items); (3) sleep (three items); (4) outlook (four items); (5) physical function (five items); (6) independence (two items); and (7) urinary function (two items). Scores for each subscale are created by transforming raw scores to a 0–100 scale (sum total of items score, divided by the maximum possible total score and multiplied by 100). The lower the score, the better the quality of life. Cronbach’s alpha ranged from 0.55 to 0.85 for dimensions (4/7 dimensions < 0.70) and was 0.89 for the total score. Item–total correlation ranged from 0.15 to 0.74. Test–retest reliability registered kappa values of < 0.40 for four items and an ICC for dimensions and total score of 0.68–0.88. Correlation coefficients with UPDRS subscales were 0.02 (outlook with UPDRS–motor examination) to 0.50 (social/role function with UPDRS – ADL); only four out of 21 coefficients were >0.40. Low to moderate association was in evidence between PDQL domains and physical and mental or psychosocial components of the SF-36 and SIP. In contrast, total PDQL correlated with these measures to a moderate to high degree (0.31–0.70). Discriminative validity with respect to HY stages, taken as severity levels, proved satisfactory (Welsh et al., 2003). A therapeutic intervention had a differential effect on PDQL dimensions, though ES was not calculated (Parkinson Study Group, 2000).

12.11. Other health-related quality of life measures 12.11.1. Quality of Life Satisfaction A two-module HRQoL measure, the Quality of Life Satisfaction questionnaire, was developed by Kuehler et al. (2003) in order to assess quality of life in ‘patients with movement disorders who had been or were to be treated with deep brain stimulation’. The Quality of Life Satisfaction – Movement Disorder (QLS-MD) module contains 12 domains, represented by 12 items. The Quality of Life Satisfaction – Deep Brain Stimulation (QLS-DBS) module is composed of five items. Calculation of weighted satisfaction and global life satisfaction is not direct and the use of a formula is needed. For QLS-MD, missing data ranged from 3.2 (controllability/fluency of movement) to 14.4% (sexual excitability). Floor and ceiling effects were 0 (for three items) to 6.4% (floor) and 7.6% (ceiling). Cronbach’s alpha for the summary index was 0.87.

SCALES TO MEASURE PARKINSONISM For QLS-DBS, missing data ranged from 9.3 (absence of bodily symptoms) to 12.0% (independent handling of stimulator and physician care). Floor effect was 0 for four out of the five items and the summary index; ceiling effect was 0 for one item and the summary index; and the highest values were 3.0 and 17.3% respectively. Cronbach’s alpha for the summary index was 0.73. Correlation between measures derived from both modules ranged from 0.50 to 0.75. Convergent validity with the SF-36 physical and mental components proved higher in the case of QLS-MD (0.59–0.63) than in that of QLS-DBS (0.32–0.36); corresponding values with respect to the EuroQoL were 0.49–0.68 for QLS-MD and 0.34–0.46 for QLS-DBS.

12.12. Conclusions and future prospects Scales are instruments for measurement. In medicine, they are often used in clinical settings and research to quantify health-related attributes. Quantification of symptoms, signs and behavior is necessary for designation of severity level, interpretation of outcomes and recording, comparing or making decisions from a scientific point of view. Before any scale can be applied, a check must be run on certain basic properties that determine to what extent it can be used as a valid measure. These basic metric properties are internal consistency, inter- and intrarater reliability, construct validity and responsiveness. Table 12.1 sets out a list of standard values that allow for comparison of results yielded by validation studies against the recommended levels for each metric attribute. In this way, the reader can ascertain the quality of an instrument and obtain relevant information as to its strengths and weaknesses. Although most new clinical scales undergo this kind of analysis before being used in clinical trials or other applications, very few have been subjected to complete clinimetric analysis. No scale should be seriously considered for use if information about its basic quality attributes is lacking. A very different situation prevails in the field of HRQoL measures. These instruments are only published when many or most of the validation issues have already been settled. In terms of tradition, HRQoL measures are different from clinical measures in other aspects as well: participation in the development of HRQoL measures includes not only ‘experts’ but also individuals belonging to the target population and other representatives of the subjects’

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immediate environment (e.g. care-givers), an approach rarely found in the field of clinical scales. Copyright protection of most of the HRQoL measures is another striking difference between the two types of scale. Easy access to information, progressive specialization of research, proliferation of interdisciplinary work and multicenter/international collaboration make for better designs and analysis of measures. In the near future, new trends (item response theory, clinimetric approach) could substantially influence the current panorama of design and development of new scales. At the same time, scale validation studies will become more complex and comprehensive. PD patient assessment is still awaiting a definitive solution: indeed, there are many who think that there is no such thing as an ideal scale. The UPDRS has been the scale of reference for the last 15 years but has recently been revised to improve some metric flaws (Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease, 2003), with the validation of a new 48-item UPDRS version currently under way. Due to the fact that lengthy scales entail a time burden, it is to be expected that in overloaded clinical settings and daily clinical practice partial application (some subscales only) or shorter scales will be resorted to. On the other hand, increasing interest is now surrounding the treatment of non-motor aspects of PD, and each of these will inevitably call for specific measures. A great deal of activity is currently being devoted to this matter. Lastly, HRQoL evaluation is already part and parcel of standard assessment in clinical research on PD (Martinez-Martin, 2001; Marinus et al., 2002). This type of assessment should be introduced in clinical practice too, an issue still beset by a number of limitations. Insofar as other parkinsonisms are concerned, a specific scale has only been developed for multiple system atrophy (UMSARS; Wenning et al., 2004). Although the UPDRS has been applied to evaluating patients with parkinsonian syndromes other than PD, such as progressive supranuclear palsy (Cubo et al., 2000), to our knowledge specific rating scales for other parkinsonisms have not yet been published. It is foreseeable, however, that these types of measure will be developed in the future, not merely to enhance existing knowledge on these diseases (in respect of aspects such as natural history and relationships with diverse factors), but also to monitor the effect of therapeutic interventions.

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Acknowledgments This study was partially funded by a grant from the Carlos III Institute of Health (Red CIEN Network of Excellence C03/06). MJ Forjaz, Ramon y Cajal Research Fellow (Ministry of Science and Technology), helped with comments and technical support.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 13

Motor symptoms in Parkinson’s disease JOOHI SHAHED AND JOSEPH JANKOVIC* Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA

13.1. Introduction In 1817, James Parkinson first described the syndrome that now bears his name. He published his findings based on observations of 6 patients, only 1 of whom he actually examined and followed for a period of time. The clinical syndrome he described included involuntary tremulousness occurring at rest, muscular weakness, a stooped posture and gait festination, with preservation of sensation and intellect. The disorder was long referred to as ‘paralysis agitans’, inferring characteristics of seeming difficulty with voluntary movement while shaking uncontrollably. In the late 1800s, Charcot recognized that rest tremor was not an absolute component to this syndrome, and suggested instead it be referred to as ‘Parkinson’s disease’ (PD) in honor of its first descriptor. Over time, our understanding of this disease process has grown exponentially. Major milestones occurred with the recognition of tremor, rigidity, bradykinesia and postural instability as the cardinal features of PD, the anatomic localization of the brunt of the pathology to the substantia nigra, the discovery of dopamine deficiency and the therapeutic impact of levodopa. The more recent elucidation of genetic mutations and other pathogenic mechanisms of cell death involving not only the dopaminergic but also non-dopaminergic systems have allowed for a greater understanding of the pathophysiology of PD. Although dopaminergic deficiency correlates best with the presence of motor features, involvement of the non-dopaminergic system appears to be responsible for the non-motor features of PD (Lang and Obeso, 2004). The primary goal of this review is to focus on the pathophysiological mechanisms and clinical features of motor manifestations of PD.

13.2. Cardinal manifestations 13.2.1. Tremor The most typical and easily recognized symptom of PD is unilateral, 4–6 Hz, rest tremor. This is differentiated from the typical 5–8 Hz postural tremor of essential tremor (ET), enhanced physiologic tremor (8–12 Hz) and cerebellar outflow tremor (2–5 Hz). The classic description of rest tremor in PD is a supination–pronation (‘pill-rolling’) tremor, with onset in one hand followed by spread to the contralateral hand. Rest tremor in patients with PD also frequently involves the lip, chin, jaw and legs, but, in contrast to ET, it almost never involves the neck/head or voice (see Ch. 17; Table 13.1). The rest tremor characteristically disappears with action (another feature differentiating it from ET) and during sleep. It often intensifies during synkinesis with the opposite limb, during walking and with stress or anxiety. The lower extremities may be involved, often ipsilateral to the upper limb in which tremor first appears. Tremor often remains asymmetric, though it may develop bilaterally as the disease progresses. Patients with PD may also complain of an ‘internal’ shaking without visible tremor (Shulman et al., 1996). In some patients, postural tremor may be the first manifestation of PD (Jankovic et al., 1999; Jankovic, 2002; Louis et al., 2003). This postural tremor can be differentiated from ET by the fact that it often presents with a delay of several seconds or even minutes after assuming an outstretched horizontal position. This PD tremor has been referred to as a ‘re-emergent tremor’ (Jankovic et al., 1999), indicating that it is a variant of the more typical rest tremor, since it occurs

*Correspondence to: Joseph Jankovic, M.D., Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Department of Neurology, 6550 Fannin, Suite 1801, Houston, TX 77030, USA. E-mail: [email protected], Tel: 713-798-5998, Fax: 713-798-6808.

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Table 13.1 Features differentiating Parkinson’s disease from essential tremor

Age at onset Family history Tremor frequency Tremor characteristics Influencing factors Rest Action Mental concentration Ambulation Alcohol Postural tremor Kinetic tremor Limb tremor Distribution other than limbs Neuropathology

Treatment

Parkinson’s disease

Essential tremor

55–75 years þ/ 4–6 Hz Flexion–extension

10–80 years þþ 5–8 Hz Supination–pronation

Increases Decreases Decreases Increases þ/ Re-emergent þ/ Asymmetric Face, jaw, lips, chin Nigrostriatal degeneration, Lewy bodies Anticholinergics, amantadine, dopaminergic drugs, surgery

Decreases Increases Increases Decreases Decreases Without latency Yes Symmetric Head, voice, trunk, tongue No discernible pathology

with the same frequency and responds similarly to dopaminergic therapy. In contrast to re-emergent tremor, the postural tremor of ET appears without latency, immediately after the arms assume the posture-holding position. There is a growing body of evidence supporting the notion that a subset of patients with lifelong history of ET progress to develop otherwise typical PD (Shahed and Jankovic, 2006) and families with ET and autopsy-proven PD have been described (Yahr et al., 2003). Furthermore, functional imaging studies have demonstrated impairment in the dopaminergic system in some patients with ET (Brooks et al., 1992; Piccini et al., 1997; Lee et al., 1999; Antonini et al., 2005). Although presence of rest tremor is likely to prompt further evaluation for PD, it is not uniformly present throughout the course of disease in all PD patients. In some series of patients with PD, 15% never had tremor (Martin et al., 1973), but in a group of prospectively followed patients with autopsy-proven PD (Rajput et al., 1991), 100% had tremor at some point during their clinical course. Hughes et al. (1993) found that 69% of PD patients had rest tremor at onset, 75% had tremor during the course of their disease and 9% lost their tremor late in the disease. Rest tremor in PD is a complex phenomenon, and its pathophysiology is not well understood. Functional

Alcohol, beta-blockers, primidone, topamax, gabapentin, botulinum toxin, surgery

neuroimaging studies and electrode recordings during brain surgery point to the contribution of several different brain structures. One imaging study implicated dysfunction in the putamen and cerebellar vermis (Lozza et al., 2002). The cerebellum likely plays a modulating role (Deiber et al., 1993), potentially explaining similar involvement of this structure in patients with ET. Deep brain stimulation of the thalamus may suppress PD tremor, possibly by inhibiting thalamocortical loops (Wielepp et al., 2001; Fukuda et al., 2004). Stimulation of the subthalamic nucleus (STN), which is typically hyperactive in PD, can also normalize the amplitude and frequency of PD tremor toward physiologic ranges (Sturman et al., 2004). Tremor cells with firing frequency that is similar to clinically observed PD tremor have been found in both the STN (Hamani et al., 2004) and thalamus (Lenz et al., 1994). It is generally accepted, however, that tremor in PD is a result of abnormal synchronous oscillating neuronal activity within the basal ganglia, although the actual physiological mechanisms are still not well understood (Bergman and Deuschl, 2002). 13.2.2. Rigidity Rigidity is defined as resistance throughout the range of passive movement of a limb, such as flexion, extension or rotation about a joint. It differs from spasticity

MOTOR SYMPTOMS IN PARKINSON’S DISEASE in that it is not velocity-dependent and is not variable (clasp-knife phenomenon), and from gegenhalten, in which resistance is intermittent and increases with the degree of force used. The electromyographic (EMG) findings of parkinsonian rigidity are similar to those of voluntary muscle contractions, whereas the EMG is electrically silent in spasticity (Hoefer and Putnam, 1940). Increased spinal interneuron excitability (Le Cavorzin et al., 2003) is thought to play a role in PD rigidity, but the exact mechanism of this cardinal sign is not well understood. In PD, the rigidity is usually accompanied by a ‘cogwheel’ phenomenon, probably a manifestation of underlying tremor. Rigidity often increases with reinforcing maneuvers such as voluntary movements of the contralateral limb. This examination technique can greatly assist in the diagnosis of early PD, as the rigidity is ipsilateral to the rest tremor, if present. Axial rigidity (i.e. in the neck and trunk) may also be observed and may contribute to abnormal axial postures such as anterocollis and scoliosis (see below). Rigidity may be a factor in the frequent painful sensations experienced by PD patients. A large number experience shoulder pain as one of their earliest symptoms of PD, but it is often wrongly diagnosed as bursitis, arthritis or rotator cuff injury (Riley et al., 1989). Patients may undergo shoulder surgery in an attempt to control this discomfort, which in reality is likely a manifestation of rigidity and/or reduced arm swing. One retrospective case-control study (Gonera et al., 1997) suggested that a ‘prodromal phase’ lasting 4–6 years may precede the onset of PD, consisting of various musculoskeletal, autonomic, psychiatric or neurologic symptoms. 13.2.3. Bradykinesia Bradykinesia refers to slowness of movement, and is a hallmark of basal ganglia disorders. It encompasses difficulties with planning movement, initiating and executing movement and performing sequential and simultaneous tasks (Berardelli et al., 2001). Bradykinesia is similar to akinesia (absence of movement) and hypokinesia (poverty of movement), which can manifest by decreasing amplitude of repetitive movements such as finger-tapping. All of these are closely related to dexterity, which is reduced early in the course of PD in many patients, who may complain of difficulty with tasks requiring fine motor control, including buttoning or using utensils. Bradykinesia is often also an easily recognizable symptom of PD, and may be apparent to the examiner before the formal neurologic evaluation is begun. Hypomimia (masking of the facies), decreased blink

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rate, slowness of movement and difficulty getting up from a chair are all readily observed signs. On examination, however, bradykinesia is best elicited by asking the patient to perform rapid alternating movements of the hand (such as finger taps, hand grips and hand pronation–supination) and heel taps. Patients with PD usually demonstrate decrementing amplitude of successive movements, motor breaks (also referred to as ‘blocks’ or ‘freezing’), dysrhythmia, undershooting of the target and difficulty performing two tasks at once. Micrographia is another manifestation of bradykinesia in which there is decrementing amplitude of letter size with continued handwriting. It may be a more complex phenomenon, however, as it can be modulated by visual feedback (Teulings et al., 2002). The pathophysiology of bradykinesia is poorly understood, but of all the cardinal features of PD, it seems to correlate best with dopamine deficiency (Vingerhoets et al., 1997). This is consistent with the finding that decreased density of substantia nigra neurons correlates with parkinsonism in the elderly, even without PD (Ross et al., 2004). One study using recordings of cortical neurons in rats after haloperidolinduced bradykinesia found a reduction in the firing rate and amplitudes, and decreased intensity of bursting while at rest when compared to recordings before haloperidol administration (Parr-Brownlie and Hyland, 2005). The authors conclude that diminished dopaminergic stimulation is associated with reduced cortical activation and suggest that these cortical influences on spinal cord pathways in turn contribute to bradykinesia. Functional neuroimaging studies also suggest there is impaired recruitment of cortical and subcortical systems that normally regulate kinematic parameters of movement such as velocity, and increased recruitment of various premotor areas, including those responsible for visuomotor control (Turner et al., 2003). The anatomic deficit appears to localize to the putamen and globus pallidus (Lozza et al., 2002), resulting in a net reduction in the muscle force produced at the initiation of movement that can be improved by external cues such as vision and sound (Berardelli et al., 2001). 13.2.4. Postural instability Postural instability does not usually develop until later in the course of PD, typically after the onset of other parkinsonian features. Postural stability can be tested by quickly pulling the patient backward by the shoulders (the ‘pull test’). An abnormal response is characterized by the patient taking more than two steps backward, or if there is an absence of any postural response. Postural instability is often one of the most

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debilitating symptoms, however, as it can be a major cause of falls. In a postmortem study of parkinsonian disorders, the relatively longer latency to onset of falls in PD patients differentiates it from progressive supranuclear palsy (PSP), multiple systems atrophy (MSA), corticobasal degeneration (CBD), or dementia with Lewy bodies (DLB) (Wenning et al., 1999). In one clinicopathologic study, it was found that PSP could be reliably differentiated from PD by the presence of falls within the first year of symptom onset and lack of response to levodopa (Litvan et al., 1997). In this study, PD patients were also more likely to have asymmetric symptoms and tremor. One study of PD patients demonstrated that many had markedly reduced or absent anticipatory muscle activity in the calf (triceps surae) in response to a small pull to the arm, whereas age-matched controls maintained an intact anticipatory response 80 ms after the pull (Traub et al., 1980). The anticipatory contraction arises before actual muscle movement in the legs, which usually occurs with a latency of 150 ms. Interestingly, patients with PSP retained intact anticipatory responses, suggesting that other factors may contribute to falls in these patients. Other parkinsonian symptoms, orthostatic hypotension and age-related sensory changes can play a role in the postural instability observed in PD (Bloem, 1992). Stability of posture is also dependent on the integration of visual, vestibular and proprioceptive sensory input, and patients with PD may have difficulty with organization of these stimuli (Bronte-Stewart et al., 2002), a phenomenon termed kinesthesia. Postural instability is enhanced by simultaneous performance of cognitive and motor tasks, and is more likely to occur in patients with prior falls (Marchese et al., 2003). Additionally, PD patients are more prone to development of fear of falling, which can further exacerbate their level of balance control (Adkin et al., 2003). In one study, falls occurred in 38% of PD patients, occurred more than once a week in 13% and the frequency correlated only with the severity of postural instability (Koller et al., 1989). Although dopaminergic therapy, pallidotomy and deep brain stimulation of the STN can improve axial signs, including unperturbed stance in PD patients (Roberts-Warrior et al., 2000), postural instability, as measured by platform tilt and visual tilt, unfortunately does not respond to treatment (Maurer et al., 2003). More recently, attention has turned to the pathophysiologic role of the pedunculopontine nucleus (PPN) in the development of postural instability and gait disturbance (Papahill and Lozano, 2000). The PPN has limbic, reticular and spinal cord connections that are closely involved in movement control. Deep brain stimulation of this structure in PD patients was found to significantly improve gait dysfunction and postural instability (Plaha and Gill, 2005).

13.2.5. Juvenile and young-onset PD Juvenile parkinsonism (JP) is defined as onset of parkinsonism before the age of 21 years, whereas young-onset PD (YOPD) denotes patients with symptoms beginning between 21 and 40 years of age. The motor manifestation of these two entities can differ from typical adult-onset idiopathic PD. In one series, 85% of JP and 100% of YOPD patients had rest tremor, whereas dystonia occurred in 43% of JP and 9% of YOPD (Muthane et al., 1994). JP can be a heterogeneous entity with a wide variety of pyramidal and extrapyramidal signs, and all cases may not clearly be related to idiopathic PD (Cardoso and Camargos, 2000). In cases of JP other than those associated with the parkin, LRRK2 or PINK1 gene mutations, or dopa-responsive dystonia, more widespread lesions outside the basal ganglia may account for the variable phenotypes (Paviour et al., 2004; Bonifati et al., 2005). Dystonia is often a presenting sign of YOPD, and motor symptoms may progress more slowly (Golbe, 1991). Postural control is preserved for a longer period of time in YOPD patients, though they are more likely to develop motor fluctuations and treatment-related dyskinesias (Schrag et al., 1998; Silver et al., 2004). 13.2.6. Progression and subtypes of Parkinson’s disease Decades of experience with PD have led to recognition of the marked clinical heterogeneity as compared to the first descriptions of the disease by James Parkinson. With recent advances in molecular biology, genetics and pathology, it has been suggested that PD be referred to as a ‘syndrome’. Hoehn and Yahr (HY) (1967) described the typical progression of PD, and devised a rating scale to characterize stages of the disease. The five HY stages are differentiated by unilateral versus bilateral disease, the presence of axial symptoms and gait difficulty and degree of functional impairment. Though various schemas for segregating the clinical phenotypes of PD have been proposed, Zetusky et al. (1985) were the first to recognize in a large cohort of patients two major subtypes based on motor characteristics of the disease: those with tremor-dominant disease, and those with postural instability and gait disturbance (PIGD). The tremordominant cases were characterized by prominent tremor, an earlier age at onset and a greater likelihood of positive family history of PD. The PIGD subtype was associated with more prominent dementia, bradykinesia, functional disability and a more malignant disease course. A baseline analysis of a large cohort of PD patients initially enrolled in the multicenter Deprenyl and Tocopherol Antioxidative Therapy of Parkinson’s disease (DATATOP) trial (Jankovic et al., 1990) suggested that

MOTOR SYMPTOMS IN PARKINSON’S DISEASE 333 PD with older age at onset, bradykinesia and PIGD PD cohort (Jankovic et al., 1990) and age-related subgroup are associated with more functional disability, indepenanalysis of patients from a single Movement Disorders dent of cognitive function. In a community-based study center (Jankovic and Kapadia, 2001). of patients with idiopathic PD over a mean duration of Age itself may influence the degree of motor 3.3 years, Louis et al. (1999) found that bradykinesia, disability among PD patients. Levy et al. (2005) invesrigidity and postural instability subscores progressed at tigated a cross-sectional population of heterogeneous similar rates, whereas tremor subscores remained relaPD patients to assess the degree of effect of aging on tively constant. It was later determined in a longitudinal motor symptoms. For symptoms typically attributed to assessment of 297 PD patients that those with PIGD PD dopaminergic cell loss (tremor, rigidity, bradykinesia had a more rapid annual rate of decline when compared and facial expression), only age was a significant to tremor-dominant PD cases, as determined by scores predictor of severity. For non-dopaminergic motor on the Unified Parkinson’s Disease Rating Scale symptoms (speech and axial impairment), both age (UPDRS) (Jankovic and Kapadia, 2001). In this study, and disease duration were significant determinants of handwriting was the only component that did not severity. These findings underscore the notion that significantly progress. older age is associated with more rapid decline in motor Goetz et al. (2000) evaluated PD patients in function in PD patients. However, the age effect was HY stages II and III. Both groups had similar disease more prominent with non-dopaminergic symptoms, duration. The stage II subjects, however, could be which the authors correlate with more widespread maintained at their current level (based on UPDRS involvement of subcortical structures, including the scores) with appropriate dopaminergic therapy for non-dopaminergic locus ceruleus, pedunculopontine about 4 years, but at the cost of a higher degree of nucleus and the nucleus basalis of Meynert. levodopa-induced dyskinesias and higher medication A final consideration in the clinical course of PD doses. In stage III subjects, on the other hand, motor symptoms is the asymmetry of findings that is conimpairment progressed despite medication adjustment. sidered a clinical hallmark of the disease. The pathoThese findings were independent of initial UPDRS genesis of asymmetry in PD symptoms is poorly motor scores and disease duration. Bradykinesia was understood. One large study demonstrated that 46% found to be the most significant determinant of motor of patients met defined criteria for asymmetric disease, impairment in these patients. and that risk factors for the discrepancy between sides More recent neuropathologic and neuroimaging included shorter disease duration, younger age at studies have validated the clinical experience in onset, asymmetric initial symptom onset, hand domdetermining the rate of progression of PD. Braak inance and a family history of neurodegenerative diset al. (2004) have synthesized the neuropathologic proorders (Uitti et al., 2005). Interestingly, this study gression of PD by categorizing it into six stages. In the noted that left-handed individuals tended to have more first two stages, patients remain presymptomatic, with severe left hemiparkinsonism, suggesting that handeddegenerative pathology confined to the medulla oblonness may somehow influence parkinsonian asymmetry. gata/pontine tegmentum and olfactory bulb/anterior Lee et al. (1995) studied a cross-sectional population olfactory nucleus. In stages 3–4, the substantia nigra of 198 patients with idiopathic PD, and found no and other midbrain and forebrain structures become significant change in the asymmetry or focality of progressively more involved, during which time PD symptoms in up to 15 years of follow-up. Although patients begin to manifest overt parkinsonian signs or symptoms progressed faster initially, they later appsymptoms. In stages 5–6, the full pathologic and roached the normal age-related rate of decline. The clinical spectrum is maximally attained. Hilker et al. authors propose that an inciting event initiates cell (2005) studied the progression of dopaminergic imdeath in specific dopaminergic areas with injury to pairment in 31 clinically heterogeneous PD patients adjacent cells, thus accounting for the distribution by serial [18F]fluorodopa positron emission tomograand progression of neurologic signs and symptoms. In a retrospective study of 613 PD patients, anomalous phy (PET) scans. Their data demonstrate a lower patterns of asymmetry in PD patients were analyzed progression rate in patients with tremor-dominant (Toth et al., 2004). The authors found four groups of PD, but further suggest that neurodegenerative such PD patients: (1) those with rest tremor in a lower processes in PD slow down with increasing symptom limb with contralateral upper-extremity tremor; (2) duration, regardless of PD subtype. Not all potential rest tremor with contralateral action tremor; (3) initial variables were controlled in this study, and it is not asymmetric symptoms followed by similar but more clear if such imaging biomarkers are adequate to meaprominent contralateral symptoms; and (4) those in sure non-dopaminergic dysfunction (Jankovic, 2005). whom a tremor-dominant phenotype evolved over Nonetheless, the results parallel those of the clinical time to an akinetic-rigid form, with resolution of information obtained from analysis of the DATATOP

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tremor. They concluded that this variability in onset and progression could be explained by the simultaneous involvement of different topographic regions at the onset of symptoms, and that the disease may progress at different rates on different sides. The causal event and factors determining subsequent evolution of PD symptoms remain unclear.

13.3. Other motor abnormalities 13.3.1. Primitive reflexes In addition to the cardinal features of the disease, PD patients may exhibit a wide variety of secondary motor symptoms that span the neurologic system. In one study of 41 PD patients, 12 with PSP, 7 with MSA and 40 controls, Brodsky et al. (2004) found that the primitive glabellar reflex was present in 80.5% of PD patients, and was a moderately sensitive indicator (83.3%) of a parkinsonian disorder, though not specific (47.5%) for PD. By contrast, the palmomental reflex was present in only 34.1% of PD patients, was not sensitive (33.3%) but was more specific (90.0%, positive predictive value 83.3%). The presence of either primitive reflex did not correlate with MiniMental State Examination score. Though it is not clear how the presence of these primitive reflexes is related to the dopaminergic system, the fact that some are more likely to occur in advanced PD suggests a pathophysiologic link (Huber and Paulson, 1989). 13.3.2. Neuro-ophthalmologic findings A variety of neuro-ophthalmologic abnormalities can be seen in PD. Biousse et al. (2004), in their review of ophthalmologic features of PD, noted that any of the following may contribute to the ocular and visual complaints in these patients: decreased blink rate, ocular surface irritation, altered tear film, visual hallucinations, blepharospasm, decreased blink rate and decreased convergence. Ocular pursuit movements in one study of 7 PD patients (Lekwuwa et al., 1999) were lower in magnitude and fatigued with stimulus repetition when compared to controls, suggesting that oculomotor irregularities are analogous to limb bradykinesia. Whereas vertical saccade amplitude may be markedly diminished in PSP and latency may be prolonged in CBD, these movements are typically normal in PD (Vidailhet et al., 1994), a finding that may help differentiate these disorders. Abnormalities of ocular pursuit and saccades may be more severe with advanced disease, and saccade latency may be more prolonged toward the hemiparkinsonian side (Rascol et al., 1989). These changes may improve with

dopaminergic therapy (Gibson et al., 1987; Rascol et al., 1989), but in one study of smooth pursuit in PD patients, no observed changes were noted with on–off motor fluctuations (Sharpe et al., 1987). The direct role of dopamine deficiency in producing oculomotor abnormalities is thus unclear. One study of 23 parkinsonian patients suggested that in disorders other than PSP, the brainstem burst neurons responsible for initiation of saccades are likely intact, but the inputs to these neurons that control the size and direction of movements may be abnormal (Rottach et al., 1996). Increased frequency of square-wave jerks (SWJ) is abnormal, though the exact pathophysiology is unknown. This finding may be present in PD patients, but it is more likely to occur in patients with PSP. Those PD patients demonstrating SWJ had more severe freezing of gait (FOG), falls and postural instability (Rascol et al., 1991). In one study of PD patients undergoing unilateral pallidotomy, the number and amplitude of SWJ were significantly increased following the procedure at 1-month follow-up, suggesting that loss of pallidal inhibition to thalamocortical loops induces cortical dysfunction, resulting in abnormal ocular fixation (O’Sullivan et al., 2003). Blepharospasm and apraxia of eyelid opening (AEO) are two conditions that may be difficult to differentiate on examination, but both can be present in PD patients (Zadikoff and Lang, 2005). Blepharospasm is a focal dystonia characterized by spontaneous sustained involuntary closure of the eyelids. AEO often coexists with blepharospasm, but is defined as difficulty opening the eyes, often in the absence of true eyelid spasm. In one study, 75% of AEO cases were associated with blepharospasm; this study further found that AEO occurs in 0.7% of PD patients compared to 33.3% of patients with PSP (Lamberti et al., 2002). EMG studies initially suggested that blepharospasm was related to irregular inhibition of the tonically active levator palpebrae superioris muscle (Esteban and Gimenez-Roldan, 1988), and that AEO resulted from abnormal persistent activity of the orbicularis oculi muscle (Tozlovanu et al., 2001). A study involving synchronous EMG measurements of both the levator palpebrae superioris and orbicularis oculi muscles demonstrated various combinations of inhibition, dystonia and motor impersistence in both muscle groups (Aramideh et al., 1994), suggesting implications for treatment with botulinum toxin, but supporting the view that blepharospasm and AEO are related phenomena. Though one study suggested that patients with idiopathic blepharospasm were more likely to develop PD (10 of 105 blepharospasm patients) than normal controls (2 of 105) (Micheli et al., 2004), the relationship between the two is still unclear.

MOTOR SYMPTOMS IN PARKINSON’S DISEASE Other, but relatively rare, neuro-ophthalmologic abnormalities seen in PD include supranuclear gaze palsy, oculogyric crises and convergence insufficiency. Though supranuclear gaze palsy and restriction of vertical eye movements are typical of PSP, they are not unique to this disorder. The exact frequency in PD is not known, but it typically occurs later in the disease course. Movements similar to oculogyric crises are rare, and are thought to relate to levodopa-induced dyskinesias since they occur at the same time as peak-dose choreoathetotic limb movements (LeWitt, 1998; Linazasoro et al., 2002). A case report of diplopia related to convergence insufficiency has been described in a PD patient during ‘off’ periods (Racette et al., 1999). 13.3.3. Bulbar dysfunction Bulbar symptoms, including dysarthria and hypophonia, dysphagia and sialorrhea, are frequently present in patients with PD, and may be a major cause of social disability. They may or may not be pathophysiologically related to the cardinal motor signs. Speech disorders in PD will be discussed elsewhere (see Ch. 17) but are typified by monotonous, soft and breathy speech with variable rate (Critchley, 1981). This often disabling symptom can be ameliorated through speech therapy (De Swart et al., 2003; Liotti et al., 2003). The Lee Silverman Voice Treatment is particularly effective (Ramig et al., 2004). In our study of 274 patients with PD followed for an average of 6.36 (3–17) years, dysarthria correlated with bradykinesia, PIGD type of PD and poor response to levodopa, and was inversely related to tremor. These findings suggest that, although dysarthria is at least in part due to dopaminergic dysfunction, non-dopaminergic mechanisms also play an important role in this troublesome symptom. Dysphagia is often subclinical in PD patients, and may be present early in the course. This symptom may be due to either dysfunction of initiating the swallowing reflex, or prolongation of laryngeal or esophageal movement. The deficits may be subclinical, especially early in the course of the disease (Potulska et al., 2003). Recent studies have shown that PD patients actually have less saliva production than normal controls (Proulx et al., 2005) and others have suggested that excessive drooling is due to decreased swallowing (Bagheri et al., 1999). 13.3.4. Respiratory disturbances Respiratory disturbances in PD can be a significant contributor to morbidity and mortality. In one study, pneumonia was one of several independent

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predictors of death among nursing-home PD patients, and aspiration pneumonia carried the highest mortality risk (Fernandez and Lapane, 2002). One study of 58 patients with PD identified both restrictive and obstructive patterns on spirometry (Sabate et al., 1996). The obstructive pattern could be central or peripheral, and could be related to rigidity, cervical arthrosis or restricted passive range of motion in the neck. Restrictive dysfunction was not related to bradykinesia, rigidity or tremor in this study, though others have suggested chest wall rigidity is a significant contributor (Shill and Stacy, 1998). In another study, 31 of 63 (49%) PD patients had abnormal pulmonary flow–volume curves; of these, 54% had a restrictive pattern that was attributed to incoordinated expiratory effort or low chest wall compliance (Izquierdo-Alonso et al., 1994). Obstructive patterns in this study were attributed to weakness of upper respiratory musculature. One study of 12 PD patients with on–off motor fluctuations determined that all had restrictive patterns while both on and off, but this worsened during off periods (De Pandis et al., 2002). Levodopa administration may produce respiratory dyskinesias as well (Rice et al., 2002). 13.3.5. Dystonia and skeletal abnormalities Dystonia in PD patients may be an early presenting sign in young patients, is more common in females and patients with long disease duration or may be a consequence of levodopa therapy (Jankovic and Tintner, 2001). Patients may also develop a ‘striatal hand’ deformity, consisting of flexion at the metacarpophalangeal joints, extension at the proximal interphalangeal joints and flexion of the distal interphalangeal joints (Fig. 13.1). This deformity appears similar to the ulnar deviation or ‘claw hand’ seen more commonly in arthritic disorders, but is in fact a dystonia that can improve with dopaminergic therapy. Lower-extremity ‘striatal’ deformities in PD can include an equinovarus foot positioning or toe extension, and may impair the ability to stand and walk or wear shoes (Ashour et al., 2005). The ‘dropped head’ sign may be seen in PD; in one patient this was due to neck extensor myopathy with typical myopathic features on EMG (Lava and Factor, 2001), but it is more likely associated with disproportionate anterior neck muscle rigidity (Yoshiyama et al., 1999). One study found that only 7 of 459 patients with parkinsonism had neck extensor weakness, all had myopathic EMG findings and a poor response to levodopa and 6 had dysautonomia, suggesting that the ‘dropped head’ sign may be an indicator for MSA (Askmark et al., 2001).

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J. SHAHED AND J. JANKOVIC In one study of 8 PD patients with camptocormia, the symptom emerged 4–14 years into the disease course and worsened during off periods (Djaldetti et al., 1999). Deep brain stimulation of the subthalamic nucleus has been shown to improve camptocormia in PD (Hellmann et al., 2006; Yamada et al., 2006). Some authors have suggested it is a form of axial dystonia and is more common in PIGD-PD (Bloch et al., 2006). Other investigators have found atrophy and fatty infiltration of the spinal extensor muscles (Lepoutre et al., 1996), and suggest that this is secondary to flexor rigidity. Secondary spinal malformations may also contribute to the abnormal posture. Scoliosis has long been recognized as part of the PD symptom complex (Duvoisin and Marsden, 1975). The scoliosis often occurs in the direction contralateral to the most prominent hemiparkinsonian signs. Although this has not been unequivocally shown (Grimes et al., 1987) in humans, rats with experimentally induced hemiparkinsonism had a greater degree of scoliosis-like skeletal deformity that correlated directly with the degree of dopamine depletion, and occurred ipsilateral to the side of the lesion (HerreraMarschitz et al., 1990). 13.3.6. Gait abnormalities

Fig. 13.1. Striatal hand deformity. Reproduced from Ashour et al. (2005) from the Lancet Neurology with permission from Elsevier.

Camptocormia is a dystonic posture characterized by marked flexion of the thoracolumbar spine which abates in the recumbent position and sometimes with sensory tricks (Figs. 13.2 and 13.3). Though it has long been considered a psychogenic disorder, in our study of 16 cases, 11 had PD (Azher and Jankovic, 2005).

The parkinsonian gait is characteristically slow, shuffling and narrow based, often associated with a stooped posture (Jankovic et al., 2001). Postural instability, discussed earlier, also contributes to the gait disturbance of PD. Disease processes other than PD may produce similar gait changes, including normal-pressure hydrocephalus, lower-body (vascular) parkinsonism and other Parkinson’s plus syndromes; these should be considered in the differential diagnosis if gait disturbance predominates the clinical picture, especially if early in the clinical course. In these other disorders, however, the other cardinal PD features may not be as prevalent. For example, in normal-pressure hydrocephalus, the gait is broad-based with outward rotation of the feet, and steps are short, typical of a frontal disorder (Stolze et al., 2001). In further contrast to PD, armswing is not reduced, and other extrapyramidal signs are typically absent (Kuba et al., 2002). Vascular parkinsonism manifests predominantly with lower-body involvement, postural instability, a history of falling, dementia, corticospinal findings, incontinence and pseudobulbar affect (Winikates and Jankovic, 1999). These patients often have risk factors for vascular disease, and are less likely to have tremor. FOG is another characteristic feature of the PD gait, though it may not occur universally (Bloem et al., 2004). It is commonly precipitated during turns, at

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Fig. 13.2. This man, who has camptocormia while standing, can adopt a normal posture while seated and when lying flat. Reproduced from Azher and Jankovic (2005) with permission from Lippincott Williams and Wilkins.

the initiation of gait, walking through narrow spaces and reaching destinations. Three subtypes of FOG have been characterized (Schaafsma et al., 2003): (1) moving forward with short shuffling steps; (2) akinesia or difficulty getting started; and (3) a ‘block’ in which the legs tremble in place as the patient tries to overcome the disturbance. Episodes typically last less than 10 seconds, are more severe in the ‘off’ state, and occur less frequently with levodopa therapy. In an analysis of the DATATOP cohort, Giladi et al. (2001) found that baseline factors associated with greater risk of developing FOG were higher rigidity, bradykinesia, speech and postural instability scores and longer disease duration (Giladi et al., 2001). Tremor at disease onset conferred a decreased risk of FOG. FOG is associated with multiple social and medical consequences for the patient, especially because it is another common cause of falls (Bloem et al., 2004). Subsequent studies have shown that FOG does not correlate with bradykinesia, rigidity or postural instabil-

ity (Bartels et al., 2003), and it has been suggested that it may represent a different underlying pathophysiology than these cardinal PD features. An EMG study of the tibialis anterior and gastrocnemius muscles during ambulation in PD patients with FOG showed a consistent pattern of premature muscle activity in the immediate period before freezing, suggesting a central disorder producing disturbance of the gait cycle (Nieuwboer et al., 2004). A study of stride length in PD patients with and without FOG found that FOG entailed difficulty regulating stride-to-stride variation, producing an ‘arrhythmia’ of steps (Hausdorff et al., 2003). In this study, levodopa produced reduction in stride variability. Though this may seem physiologically similar to bradykinesia, this study also found no correlation with that cardinal PD feature. N-isopropyl-p-123-I-iodoamphetamine SPECT scans in one series of PD patients with FOG revealed significantly decreased perfusion in Brodmann’s area 11 (orbitofrontal cortex; Matsui et al., 2005).

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Fig. 13.3. This patient with Parkinson’s disease has camptocormia that improves with a ‘sensory trick’ of climbing the hands up a vertical wall, reinforcing the fact that such postures may represent a dystonic phenomenon. Reproduced from Azher and Jankovic (2005) with permission from Lippincott Williams and Wilkins.

13.4. Diagnostic criteria and features suggesting atypical parkinsonism Other parkinsonian disorders such as PSP, MSA, CBD and vascular parkinsonism will be discussed in detail elsewhere. Early PD may be difficult to discern, especially as signs may be subtle (Koller and Montgomery, 1997). The diagnosis may be inferred by the presence of a combination of the cardinal motor features and associated symptoms (Rao et al., 2003), many of which are easily assessed by the UPDRS (Fahn et al., 1987; Goetz et al., 1995). Various criteria for the clinical diagnosis of PD have been proposed (Ward and Gibb, 1990; Calne et al., 1992; Hughes et al., 1992a; Koller, 1992; Gelb et al., 1999), encompassing the presence of cardinal disease features, asymmetry, levodopa response and various exclusionary symptoms. None of these has been tested for reliability or validity (Koller and Montgomery, 1997). Analysis of the 800 patients in the DATATOP cohort revealed that only 65 (8.1%) patients no longer met entry diagnostic criteria for PD, suggesting a high rate of clinical diagnostic accuracy amongst movement disorders specialists (Jankovic et al., 2000). In an autopsy series of 100 patients with a clinical diagnosis of PD, Hughes et al. (1992b) found that 76% had typical

PD pathology, but that when diagnostic criteria were retrospectively applied, the accuracy improved to 82%. Rajput et al. (1991) propose that any atypical features suggesting a diagnosis other than idiopathic PD are clinically obvious within 5 years of symptom onset. Some features suggesting atypical parkinsonism are listed in Table 13.2. No definitive diagnostic test for PD exists. In the past, pathologic confirmation of the hallmark Lewy body has typically been considered the ‘gold standard’ of PD diagnosis (Gibb and Lees, 1988). Functional neuroimaging techniques may greatly assist in the differential diagnosis of idiopathic PD (Piccini and Whone, 2004), especially when combined with neurologic assessment of the typical motor manifestations. However, the radiotracers that are conventionally used to assess dopaminergic pathways in PD do not measure the number or density of dopaminergic neurons, making such imaging studies poor surrogate markers of disease progression or as viable endpoints in clinical trials (Ravina et al., 2005). Finally, as genetic investigations into PD progress, the identification of novel mutations will likely lead to testing that will not only confirm the diagnosis in affected individuals, but also help identify family members or populations at risk for the disease (Funayama et al., 2002;

MOTOR SYMPTOMS IN PARKINSON’S DISEASE Table 13.2 Factors suggesting atypical parkinsonism Poor response to levodopa No dyskinesias despite high levodopa dose History of exposure to toxins or infections known to be associated with parkinsonism Unilateral atrophy Absence of rest tremor Unilateral rigidity (painful) Unilateral myoclonus (cortical) Asymmetrical apraxia Alien limb Fluctuations in cognition Early hallucinations or psychosis Psychotic symptoms with levodopa Extreme sensitivity to neuroleptics Impaired downgaze Deep facial folds Palilalia Early loss of postural reflexes and falls Pure freezing of gait Stiff gait with knees extended Levodopa-induced facial dystonia Anterocollis Contractures Laryngeal stridor Ataxia Dysautonomia Lower motor neuron and/or upper motor neuron signs Excessive snoring, inspiratory sighs

Wszolek et al., 2003; Uitti et al., 2004). This asymptomatic, at-risk population may be eventually targeted for neuroprotective therapy.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 14

Autonomic dysfunction in Parkinson’s disease HORACIO KAUFMANN1* AND DAVID S. GOLDSTEIN2 1

Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

2

14.1. Introduction Autonomic dysfunction occurs commonly in Parkinson’s disease (PD). Indeed, the original report by James Parkinson in 1817 noted prominent constipation and urinary incontinence. The well-known movement disorder usually dominates the clinical picture and has occupied the attention of clinicians and researchers. Nevertheless, a substantial minority of parkinsonian patients have severe and disabling symptoms of autonomic impairment, several of which are treatable. Autonomic disturbances in PD can manifest as dysphagia, constipation, urinary urgency, incontinence, erectile dysfunction, orthostatic hypotension (OH) and postprandial hypotension, dishidrosis and impaired thermoregulation. It has been difficult to quantify the prevalence of autonomic dysfunction in PD. First, antiparkinsonian medication with levodopa can worsen OH and delay gastric emptying. Anticholinergics further decrease gastrointestinal motility. Until relatively recently these abnormalities were incorrectly believed to reflect side-effects of the drugs, whereas we now know that the drugs interact importantly with the dysautonomia that is part of the disease process itself. Second, the parkinsonian form of multiple system atrophy (MSA-P), which always features signs and symptoms of autonomic dysfunction, can resemble PD clinically, so that studies can overestimate or understimate the frequency of autonomic dysfunction by misdiagnosis. In a retrospective study, almost one-third of patients with pathologically proven PD had autonomic dysfunction documented in the medical record (Rogers et al., 1980). This retrospective approach most likely underestimates the frequency of autonomic failure. Compared to age-matched control subjects, PD patients

have higher frequencies of constipation, erectile dysfunction, urinary urgency, incomplete bladder emptying, dysphagia and orthostatic light-headedness. Indeed, about 9 in 10 patients with PD have one or more of these autonomic symptoms (Singer et al., 1991). Autonomic problems increase significantly with increasing disease severity (Visser et al., 2004). Here we review components of the autonomic nervous system and clinical manifestations, diagnosis and treatment of autonomic abnormalities in PD. We also note similarities and differences between autonomic abnormalities in MSA and PD. MSA is covered elsewhere in this volume (see Ch. 46).

14.2. Components of the autonomic nervous system The autonomic nervous system has five components (Goldstein, 2001): (1) enteric; (2) parasympathetic cholinergic; (3) sympathetic cholinergic; (4) sympathetic noradrenergic; and (5) adrenomedullary hormonal. Langley, who introduced the term ‘autonomic nervous system’ about a century ago, referred to neurons in ganglia outside the brain and spinal cord that seemed to function independently, or autonomously, of the central nervous system. Now we know that the components of the autonomic nervous system do not function independently of the central nervous system, but the phraseology has stuck. Langley identified enteric, sympathetic and parasympathetic components. In the early 20th century, Cannon discovered and emphasized the adrenal hormonal component. The autonomic nervous system therefore is not only neuronal but also neurohormonal. One might instead refer to the components as ‘automatic’ neuroendocrine systems, along with the

*Correspondence to: Horacio Kaufmann, MD, Department of Neurology, Box 1052, 1 Gustave L. Levy Place, New York, NY 10029–6594, USA. E-mail: [email protected], Tel: þ212-241-7315, Fax: þ212-20-26042.

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H. KAUFMANN AND D. S. GOLDSTEIN sympathetic neurocirculatory function for humans to tolerate standing up, sympathetic noradrenergic failure presents as orthostatic intolerance and OH.

vasopressin system, renin–angiotensin–aldosterone system and hypothalamo–pituitary–adrenocortical system. Failure of a particular component of the autonomic nervous system produces characteristic clinical manifestations. Parasympathetic cholinergic failure presents as constipation, dry mouth, a constant pulse rate, urinary retention and erectile failure in men. Sweating, whether thermoregulatory, gustatory or emotional, depends on delivery of acetylcholine, not catecholamines, from sympathetic nerves. Sympathetic cholinergic failure therefore manifests as decreased sweating. Due to the absolute requirement of intact

14.3. Cardiovascular autonomic dysfunction 14.3.1. Orthostatic and postprandial hypotension The sympathetic nervous system is essential for maintaining blood pressure during orthostasis. OH is the cardinal manifestation of sympathetic neurocirculatory failure and occurs in about 40% of patients with PD (Table 14.1).

Table 14.1 Reported criteria and frequencies of orthostatic hypotension in Parkinson’s disease (PD) First author (ref. no.)

Prevalence

n

Notes

Allcock (1)

47%

89

Awerbuch (2)

10%

20

Bellon (3) Bhattacharya (4)

65% 49%

46 49

Bonuccelli (5)

14%

51

Briebach (6) Hillen (7)

40% 58%

250 36

Holmberg (8)

60%

47

Hubble (9)

100%

27

Korchounov (10)

30%

148

Krygowska-Wajs (11) Kujawa (12)

36% 47% 14%

20 15 29

Kuroiwa (13) Loew (14) Magalhaes (15) Micieli (16)

25% 20% 30% 54%

16 10 135 13

Papapetropoulos (17) Rajput (18) Sandyk (19)

10% 50% 31%

52 6 37

Community-based cohort 20 mmHg decrease in BPs or to < 90 Independent of PD duration Independent of PD severity Higher prevalence if older Untreated early PD 20 mmHg decrease in BPs >30 mmHg decrease in BPs 20 mmHg decrease in BPs and 10 mmHg decrease in BPd All on levodopa De novo untreated PD 20 mmHg decrease in BPs 20 mmHg decrease in BPs PD patients > 65 years old 15 mmHg decrease in BPs Decrease in MAP > 2 SD from normal Higher prevalence if older Higher prevalence if longer duration All had episodes of OH All on selegiline, none on levodopa 20 mmHg decrease in BPs at 10 20 mmHg decrease in BPs or 10 mmHg decrease in BPd, and <15 beats/min heart rate increment at 20 Early Advanced >25 mmHg decrease in BPs or >10 mmHg decrease in BPd >2 SD decrease in BPs from normal 20 mmHg decrease in BPs Pathology-proven PD 25 mmHg decrease in BPs and 10 mmHg decrease in BPd Untreated At disease presentation Autopsy study Untreated Related to PD severity

AUTONOMIC DYSFUNCTION IN PARKINSON’S DISEASE

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Table 14.1 (Continued) First author (ref. no.)

Prevalence

n

Notes

Senard (20)

58%

91

Thaisetthawatkul (21) Tranchant (22) Turkka (23) Wenning (24) Average Sum

5% 53% Unreported 78% 41%

20 19 52 11

20 mmHg decrease in BPs All on levodopa Independent of disease duration Related to PD severity 30 mmHg decrease in BPs >20 mmHg decrease in BPs Independent of disease duration Autopsy study

1237

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OH is often defined as a decrease in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 minutes of standing (Consensus, 1996). Symptoms include orthostatic light-headedness, blurred vision, generalized weakness, fatigue, cognitive impairment and pain in the shoulders and back of the neck. A related problem is postprandial hypotension, a fall in blood pressure after meals, which occurs even in the supine position and can be very pronounced. Postprandial hypotension is extremely commom in PD, even in patients who do not experience OH (Micieli et al., 1987; Hasegawa and Okamoto, 1992; Benarroch et al., 2000). Postprandial hypotension frequently underlies the apparent worsening of parkinsonian symptoms after meals. Patients appear dazed or ‘frozen’, suggesting an ‘off’ state related to fluctuating levodopa responses. The lack of a reliable method for the differential diagnosis between PD and MSA-P during life, and the widespread assumption that early severe OH is diagnostic of MSA, complicate estimating the frequency of OH in PD. Indeed, in small postmortem studies (Saito et al., 1992; Benarroch et al., 2000), 4 out of 5 patients with prominent OH and pathologically proven PD had carried a diagnosis of MSA during life. Meanwhile, one-third of patients with pathologically proven MSA have been reported to die misdiagnosed with PD (Magalhaes et al., 1995). As shown in Table 14.1, among 23 studies the reported frequency of OH in PD varied widely from 5 to 100%, but the variability decreased noticeably as the size of the study increased. All studies involving more than 80 patients reported an OH frequency between 20 and 60%. Across all studies, the mean percentage of PD patients with OH was 41%. In most clinical series, OH is believed to be a late complication of PD. Few studies have actually analyzed formally the timing of onset of OH in relation to the movement disorder. In an analysis of historical data from patients with PD and OH who were evaluated at the National Institutes of Health, about 65% of patients had evidence that OH had developed early in their disease (unpublished observations). OH was present in 14% of patients with early, newly diagnosed, untreated PD who were followed for 7 years to ascertain their diagnosis (Bonuccelli et al., 2003). In that study, 15% of the original cohort of patients turned out to have other types of parkinsonism during the follow-up period. The notion that OH can be an early finding in PD and even precede the movement disorder is confirmed by postmortem pathology reports of PD patients, with detailed historical data conclusively showing that

symptomatic OH had occurred before the onset of the motor abnormalities (Kaufmann et al., 2004). As shown in Table 14.1, studies have noted higher frequencies of OH in older patients, in patients with more severe disease or in patients with a longer duration of disease at the time of evaluation. Although no study has attempted to weight these likely intercorrelated factors, it appears that the frequency of OH increases with progression of the disease, rather than age. 14.3.2. The role of levodopa Contrary to a long-held notion, treatment with levodopa does not cause OH in PD (Hoehn, 1975). If levodopa did so, then a higher proportion of patients with than without OH would be on levodopa therapy, and this is not the case (Goldstein et al., 2002; Bhattacharya et al., 2003). Patients with PDþOH do not differ from those without OH in levodopa treatment or actual plasma levodopa concentrations. Even more convincingly, OH can occur in patients with PD who have never taken levodopa or discontinued levodopa treatment in the remote past (Martignoni et al., 1995). As discussed below, such patients have physiologic evidence of decreased cardiovascular innervation by sympathetic nerves, which at least partly explains the OH. It is important to consider, however, that even with concomitant carbidopa treatment, which attenuates conversion of levodopa to dopamine outside the central nervous system, levodopa increases plasma levels of both dopamine and its deaminated metabolite, dihydroxyphenylacetic acid (Kaakkola et al., 1985; Rose et al., 1988; Myllyla et al., 1993; Tohgi et al., 1995). Exogenously administered dopamine at relatively low doses produces vasodilation, by stimulating dopamine receptors on vascular smoothmuscle cells and possibly by inhibiting norepinephrine release from sympathetic nerves (Yeh et al., 1969; Lokhandwala, 1990; Durrieu et al., 1991). Dopamine also augments natriuresis and diuresis, which promotes depletion of extracellular fluid and blood volumes. In patients with PD and decreased cardiovascular sympathetic innervation and baroreflex abnormalities (see below), vasodilation and hypovolemia elicited by dopamine produced from levodopa could decrease blood pressure both during supine rest and during standing. Thus, orthostatic intolerance and OH may occur in patients with PD while taking levodopa/carbidopa or dopamine receptor agonists, not directly from the effects of these drugs alone but from interactions with baroreflex and sympathoneural pathophysiologic mechanisms occurring as part of the disease process.

AUTONOMIC DYSFUNCTION IN PARKINSON’S DISEASE 14.3.3. Cardiac sympathetic denervation More than 25 studies over the past several years have shown that virtually all patients with PD have loss of sympathetic innervation of the heart. This is indicated by low myocardial concentrations of radioactivity after injection of the sympathoneural imaging agents, 123 I-metaiodobenzylguanidine (Satoh et al., 1997, 1999; Braune et al., 1998, 1999; Yoshita et al., 1998; Orimo et al., 1999; Druschky et al., 2000; Ohmura, 2000; Reinhardt et al., 2000; Takatsu et al., 2000a, b) and 6-[18F] fluorodopamine (Goldstein et al., 1997, 2000, 2002), by neurochemical assessments during right heart catheterization (Goldstein et al., 2000), and by postmortem pathologic studies (Orimo, 2001, 2002; Amino et al., 2005). About half of the patients with PD without OH had a loss of 6-[18F]fluorodopamine-derived radioactivity diffusely in the left ventricular myocardium, and slightly less than half had loss localized to the lateral or inferior walls, with relative preservation in the septum or anterior wall. Only a very small minority had entirely normal cardiac 6-[18F]fluorodopaminederived radioactivity. Thus, virtually all patients with PD have had evidence for at least some loss of cardiac sympathetic innervation. Neuropathological data support this in vivo observation: Lewy bodies have been reported in the cardiac plexus of patients with PD (Iwanaga et al., 1999) and tyrosine hydroxylase immunoreactive axons had nearly disappeared in the left ventricular anterior wall from specimens with PD. Moreover, the numbers of neurofilament and S-100 protein immunoreactive axons were also drastically decreased. Triple immunofluorolabeling for neurofilament, tyrosine hydroxylase and myelin basic protein showed profound involvement of cardiac sympathetic axons in PD (Amino et al., 2005). Neuroimaging and neuropathological evidence of cardiac sympathetic denervation has also been shown in most patients with pure autonomic failure (PAF), a Lewy body disorder likely related to PD. PAF is a neurodegenerative disorder of peripheral autonomic neurons but no motor abnormalities (Consensus, 1996). Postmortem studies of patients with PAF have shown Lewy bodies in autonomic ganglia, distal sympathetic axons and epicardial nerves (Hague et al., 1997). However, despite the absence of clinical parkinsonism in PAF, Lewy bodies were also found in substantia nigra of these patients. As shown in Table 14.2, most patients with PD have Lewy bodies, not only in the substantia nigra but in sympathetic ganglia as well. The overlapping pathologic findings suggest that PAF and PD may lie along a spectrum of Lewy body

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disorders that affect peripheral autonomic neurons (Kaufmann and Biaggioni, 2003). 14.3.4. Absence of postganglionic lesion in multiple system atrophy Just as the literature is consistent about cardiac sympathetic denervation in PD, it is also consistent about intact cardiac sympathetic innervation in MSA, ascertained by neuroimaging (Yoshita et al., 1997; Braune et al., 1999; Druschky et al., 2000; Reinhardt et al., 2000), normal or even increased rates of entry of norepinephrine and other catechols into coronary sinus plasma (Goldstein et al., 2000) and postmortem pathology (Orimo, 2001, 2002). In contrast to PAF and PD, MSA does not involve Lewy bodies, either in the substantia nigra or sympathetic neurons. Glial and neuronal cells of MSA patients contain cytoplasmic inclusions that, similar to Lewy bodies, contain a-synuclein (Wakabayashi et al., 1998; Dickson et al., 1999; Kaufmann et al., 2001). Thus, these disorders may be considered a-synucleinopathies (Jellinger, 2003). In sum, compelling neuroimaging, neurochemical and postmortem pathological evidence indicates that PD features cardiac sympathetic denervation, whereas MSA features intact cardiac sympathetic innervation. This difference is consistent with a postganglionic sympathetic lesion in PD and PAF but not in MSA. Neuroimaging evidence of cardiac sympathetic denervation may become a useful tool for distinguishing PD from PD in difficult cases. 14.3.5. Vascular sympathetic denervation Whether sympathetic denervation in the peripheral vasculature might contribute to OH in PD has been unclear. The extent of loss of sympathetic innervation in PD seems to vary among organs. Normal tissue concentrations of 6-[18F]fluorodopamine-derived radioactivity have been noted in the liver, spleen, salivary glands and nasopharyngeal mucosa but decreased concentrations in the thyroid gland and renal cortex (Goldstein et al., 2002). Findings based on 123Imetaiodobenzylguanidine scanning have led to the view that in PD cardiac sympathetic denervation occurs independently of OH or other manifestations of autonomic failure and that the denervation is selective for the heart (Yoshita et al., 1998; Braune et al., 1999; Satoh et al., 1999; Takatsu et al., 2000a). Consistent with more generalized sympathetic denervation in PDþOH than in PD without OH, however, is the finding that patients with PDþOH

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Table 14.2 Postmortem findings in primary chronic autonomic failure or Parkinson’s disease (PD) First author

Ref. no.

Diagnosis

n

SN LB?

SNS LB?

Benarroch Kato Kaufmann (case 1) Orimo Schober (case 2) Vanderhaeghen (case 1) Saito Arai Evans Hague Johnson (case 1) Miura Orimo Roessman Terao Van Ingelghem Benarroch Graham Johnson (case 2) Kato Kluyskens (case 5) Nick Nishie Orimo Schober (case 1) Schwarz Shy (case 2) Thapedi Iwanaga Den Hartog Jager Rajput Takeda Wakabayashi

(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (4) (13) (14) (15) (1) (16) (11) (2) (17) (18) (19) (4) (5) (20) (21) (22) (23) (24) (25) (26) (27)

PDþOH PDþOH PDþOH PDþOH PDþOH PDþOH PDþOH PAF PAF PAF PAF PAF PAF PAF PAF PAF MSA MSA MSA MSA MSA MSA MSA MSA MSA MSA MSA MSA PD PD PD PD PD

3 3 1 3 1 1 1 1 1 1 1 1 1 1 1 1 6 1 1 7 1 1 8 3 1 1 1 1 11 6 6 1 10

Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes No No No No No (implied) No No No* No No No No No

Not reported Not reported Yes Yes Yes Yes ?** Yes No Yes No ?** Not reported Yes Yes Yes Not reported No No Not reported Not reported No No* No No* No No No* Yes (9/11) Yes (5/6) Yes (5/6) Yes Yes (9/10)

SN LB, substantia nigra Lewy bodies; SNS LB, sympathetic nervous system Lewy bodies; PDþOH, Parkinson’s disease with orthostatic hypotension; PAF, pure autonomic failure (previously called idiopathic orthostatic hypotension); MSA, multiple system atrophy (previously called Shy–Drager syndrome); *eosinophilic neuronal inclusions; **Japanese article with English abstract. References cited in Table 14.2: 1. Benarroch EE, Schmeichel AM, Parisi JE (2000). Involvement of the ventrolateral medulla in parkinsonism with autonomic failure. Neurology 54(4): 963–968. 2. Kato S, Oda M, Hayashi H et al. (1995). Decrease of medullary catecholaminergic neurons in multiple system atrophy and Parkinson’s disease and their preservation in amyotrophic lateral sclerosis. J Neurol Sci 132(2): 216–221. 3. Kaufmann H, Nahm K, Purohit D et al. (2004). Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 63: 1093–1095. 4. Orimo S, Oka T, Miura H et al. (2002). Sympathetic cardiac denervation in Parkinson’s disease and pure autonomic failure but not in multiple system atrophy. J Neurol Neurosurg Psychiatry 73: 776–777. 5. Schober R, Langston JW, Forno LS (1975). Idiopathic orthostatic hypotension. Biochemical and pathologic observations in 2 cases. Eur Neurol 13: 177–188. 6. Vanderhaeghen JJ, Perier O, Sternon JE (1970). Pathological findings in idiopathic orthostatic hypotension. Its relationship with Parkinson’s disease. Arch Neurol 22: 207–214. 7. Saito F, Tsuchiya K, Kotera M. (1992). An autopsied case of Parkinson’s disease manifesting Shy-Drager syndrome. Rinsho Shinkeigaku 32: 1238–1244. 8. Arai K, Kato N, Kashiwado K et al. (2000). Pure autonomic failure in association with human alpha-synucleinopathy. Neurosci Lett 296: 171–173.

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Table 14.2 (Continued) 9. Evans DJ, Lewis PD, Malhotra O et al. (1972). Idiopathic orthostatic hypotension. Report of an autopsied case with histochemical and ultrastructural studies of the neuronal inclusions. J Neurol Sci 17(2): 209–218. 10. Hague K, Lento P, Morgello S et al. (1997).The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature. Acta Neuropathol (Berl) 94: 192–196. 11. Johnson RH, Lee Gde J, Oppenheimer DR et al. (1966). Autonomic failure with orthostatic hypotension due to intermediolateral column degeneration. A report of two cases with autopsies. Q J Med 35(138): 276–292. 12. Miura H, Tsuchiya K, Kubodera T et al. (2001). An autopsy case of pure autonomic failure with pathological features of Parkinson’s disease. Rinsho Shinkeigaku 41: 40–44. 13. Roessmann U, Van den Noort S, McFarland DE (1971). Idiopathic orthostatic hypotension. Arch Neurol 24(6): 503–510. 14. Terao Y, Takeda K, Sakuta M et al. (1993). Pure progressive autonomic failure: a clinicopathological study. Eur Neurol 33: 409–415. 15. van Ingelghem E, van Zandijcke M, Lammens M (1994). Pure autonomic failure: a new case with clinical, biochemical, and necropsy data. J Neurol Neurosurg Psychiatry 57(6): 745–747. 16. Graham JG, Oppenheimer DR (1969). Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 32: 28–34. 17. Kluyskens Y, Bossaert L, Snoeck J et al. (1977). Idiopathic orthostatic hypotension and the Shy and Drager syndrome; Physiological studies in four cases; pathological report of one case. Acta Cardiol 32(5): 317–335. 18. Nick J, Contamin F, Escourolle R et al. (1967). [Idiopathic orthostatic hypotension with a complex neurological syndrome of extrapyramidal predominance]. Rev Neurol (Paris) 116(3): 213–227. 19. Nishie M, Mori F, Fujiwara H et al. (2004). Accumulation of phosphorylated alpha-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy. Acta Neuropathol (Berl) 107(4): 292–298. 20. Schwarz GA (1967). The orthostatic hypotension syndrome of Shy-Drager. A clinicopathologic report. Arch Neurol 16(2): 123–139. 21. Shy GM, Drager GA (1960). A neurological syndrome associated with orthostatic hypotension: a clinical-pathologic study. Arch Neurol 2: 511–527. 22. Thapedi IM, Ashenhurst EM, Rozdilsky B (1971). Shy-Drager syndrome. Report of an autopsied case. Neurology 21(1): 26–32. 23. Iwanaga K, Wakabayashi K, Yoshimoto M et al. (1999). Lewy body-type degeneration in cardiac plexus in Parkinson’s and incidental Lewy body diseases. Neurology 52: 1269–1271. 24. Den Hartog Jager W, Bethlem J (1960). The distribution of Lewy bodies in the central and autonomic nervous system in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry 23: 283–290. 25. Rajput AH, Rozdilsky B (1976). Dysautonomia in Parkinsonism: a clinicopathological study. J Neurol Neurosurg Psychiatry 39: 1092– 1100. 26. Takeda S, Yamazaki K, Miyakawa T et al. (1993). Parkinson’s disease with involvement of the parasympathetic ganglia. Acta Neuropathol (Berl) 86(4): 397–398. 27. Wakabayashi K, Takahashi H (1997). Neuropathology of autonomic nervous system in Parkinson’s disease. Eur Neurol 38 (Suppl 2): 2–7.

have lower mean plasma levels of norepinephrine, the sympathetic neurotransmitter, during supine rest, than do patients without OH (Senard et al., 1990, 1993; Niimi et al., 1999; Goldstein et al., 2002). 14.3.6. Plasma norepinephrine Concentrations of norepinephrine in antecubital venous plasma provide a means – albeit indirect – of detecting sympathetic denervation in the body as a whole. Thus, patients with OH from PAF have low plasma norepinephrine levels during supine rest (Ziegler et al., 1977; Goldstein et al., 1989). Patients with PDþOH have lower plasma norepinephrine concentrations than patients without OH (Senard et al., 1990, 1993). In patients with PDþOH, plasma norepinephrine levels, although significantly lower than in patients without OH, are not particularly low

for healthy people of similar age and are clearly higher than in patients with PAF. It is possible that partial loss of sympathetic fibers leads to augmented traffic in the remaining fibers, resulting in increased proportionate release of norepinephrine from the reduced vesicular stores. Moreover, because denervation would produce concurrent decreases in both release and reuptake of norepinephrine, plasma norepinephrine levels might fail to detect a real decrease in norepinephrine release. Levodopa/carbidopa treatment might also increase individual variability in plasma norepinephrine levels. 14.3.7. Baroreflex abnormalities A particular pattern of beat-to-beat blood pressure responses to the Valsalva maneuver can detect sympathetic neurocirculatory failure, including that in PDþOH

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(Goldstein and Tack, 2000). During phase II of the maneuver, the blood pressure decreases progressively, because reflex, sympathetically mediated, cardiovascular stimulation is deficient in response to reduced cardiac filling. During phase IV the pressure fails to exceed the baseline value. All patients with unequivocal PDþOH who are able to perform a technically adequate Valsalva maneuver show this abnormal pattern, regardless of levodopa/carbidopa treatment. Failure of baroreflex-mediated sympathetic cardiovascular stimulation, in response to acutely decreased venous return to the heart, therefore characterizes OH in PD. Similar abnormalities occur in MSA and PAF. Normally, plasma norepinephrine levels approximately double within 5 minutes of standing from the supine position (Lake et al., 1976). Most PDþOH patients have an attenuated increase in plasma norepinephrine levels during orthostasis. The finding that OH in PD is associated with failure to increase norepinephrine levels appropriately during orthostasis is consistent with decreased baroreflex–sympathoneural function. Studies have disagreed about whether baroreflex–sympathoneural gain changes as a function of aging (Shimada et al., 1985, 1986; Ebert et al., 1992; Matsukawa et al., 1996; Davy et al., 1997, 1998; Rudas et al., 1999; Tanaka et al., 1999; Niimi et al., 2000; O’Mahony et al., 2000; Seals et al., 2001; Ferrari, 2002). Some of this inconsistency may have resulted from the different types of measures used: direct indices, such as peroneal muscle sympathetic activity, or indirect indices, such as limb vascular resistance. When both direct and indirect measurements have been applied in the same subjects, cardiopulmonary baroreflex control of sympathetic outflow, assessed by exposure of subjects to lower-body negative pressure, has been found to be augmented, not impaired, with age in healthy humans; meanwhile reflexive limb vasoconstriction is attenuated (Davy et al., 1998). The ability to inhibit sympathetic outflow in response to increased cardiac filling, from head-down tilt, does not decrease either with normal human aging (Tanaka et al., 1999). Regulation of sympathetic outflow by arterial baroreceptors, measured by sympathetic microneurography after injection of vasoactive drugs, remains roughly unchanged (Rudas et al., 1999), even with lower-body negative pressure applied concurrently to keep central venous pressure constant (Davy et al., 1997). In contrast, studies have consistently found that baroreflex–cardiovagal gain decreases with normal human aging (Bristow et al., 1969; Matsukawa et al., 1996; Rudas et al., 1999; O’Mahony et al., 2000). Relatively few studies have assessed baroreflex–cardiovagal gain in PD (Szili-Torok et al., 2001), and none so far have

stratified patients in terms of the occurrence of OH. The extent of heart rate change with the Valsalva maneuver is blunted (Camerlingo et al., 1987), but this might reflect the advanced age of PD patients (van Dijk et al., 1993). When estimating baroreflex–cardiovagal gain from the slope of the relationship between interbeat interval and systolic blood pressure during phase II of the Valsalva maneuver, almost all patients with PDþOH have markedly decreased baroreflex–cardiovagal gain (unpublished observations). In PD lacking OH, baroreflex–cardiovagal gain may be statistically decreased from normal, but in PDþOH, baroreflex–cardiovagal gain is virtually always low. In our series so far, patients with PDþOH have had evidence for attenuation of both baroreflex–cardiovagal and baroreflex–sympathoneural function. This finding leads to the proposal that a combination of baroreflex failure and at least some loss of sympathetic nerves may be required for OH to become manifest in PD. It should be noted that baroreflex failure itself is not thought to produce OH (Robertson et al., 1993a, b). 14.3.8. Denervation supersensitivity Clinical and preclinical studies of chronic autonomic failure have consistently noted increased blood pressure or vasoconstrictor responses to exogenously administered adrenoceptor agonists in patients with PDþOH. This finding would be consistent with ‘denervation supersensitivity’, as described classically by Cannon (1939). At least part of this supersensitivity may result from increased expression of a- or b-adrenoceptors or increased intracellular signaling after receptor occupation (Davies et al., 1982; Vatner et al., 1985; Warner et al., 1993; Kurvers et al., 1998; Baser et al., 1991). Moreover, theoretically, cardiac sympathetic denervation supersensitivity might predispose to the development of arrhythmias (Inoue et al., 1987). Augmented cardiovascular responsiveness to adrenoceptor agonists can have other explanations, however, such as decreased baroreflex buffering of sympathetic outflows, which, as noted above, seems to characterize PDþOH. Structural adaptations of vascular walls, with increases in wall-to-lumen ratios, occur commonly in hypertension, and supine hypertension often seems to attend OH in patients with autonomic failure (Biaggioni and Robertson, 2002). Thus, although studies of PD patients have noted augmented pressor responses to exogenously administered norepinephrine, with the augmentation seen mainly or only in patients with PDþOH (Senard et al., 1990; Niimi et al., 1999), the results do not necessarily lead to the conclusion that PDþOH features denervation supersensitivity.

AUTONOMIC DYSFUNCTION IN PARKINSON’S DISEASE In summary, a combination of loss of sympathetic nerves and baroreflex failure can explain OH in PD and worsening of OH during treatment with levodopa/ carbidopa or dopamine receptor agonists. Cardiac sympathetic denervation characterizes most patients with PD and virtually all patients with PDþOH. These findings contrast with normal cardiac sympathetic innervation in MSA. The functional consequences of cardiac sympathetic denervation in PD, the relationship between central dopaminergic and peripheral noradrenergic pathologies and the bases for cardioselective sympathetic denervation in PD remain unknown. 14.3.9. Treatment of orthostatic hypotension The first step to avoid or minimize OH is to identify and eliminate drugs that can cause OH, such as antihypertensive agents and diuretics. Levodopa and dopamine receptor agonists may exacerbate OH, especially during the first weeks of treatment. Gradual dosage increases when initiating therapy or dose reductions in established patients can minimize this adverse effect. Sodium and water intake should be increased in these patients, with liberal use of table salt or administration of sodium tablets. Patients should also be instructed not to lie flat, even during the daytime. Lying flat results in accelerated sodium loss from the effects of increased cardiac filling and from pressure natriuresis, leading to loss of intravascular volume. Overnight volume depletion can explain the typical finding of worse OH in the morning in patients with autonomic failure. Elevating the head of the bed on blocks is often recommended. Patients and their families should be educated about the hypotensive effects of meal ingestion, exposure to environmental heat and prolonged physical exertion. Isotonic exercise produces less hypotension than does isometric exercise. Exercise in a pool prevents blood pressure reductions during the exercise; however, OH can be worse after exiting the pool. In patients with autonomic failure, eating a meal can significantly lower blood pressure, because vasoconstriction in other vascular beds fails to compensate adequately for splanchnic vasodilation induced by meal ingestion. In some patients, hypotension only occurs postprandially. Thus, patients should eat frequent, small meals with a low carbohydrate content and alcohol intake should be minimized. Caffeine taken with breakfast may be helpful. Hot baths should be avoided, and patients should be especially careful during warm weather. This is because heat-induced vasodilation and persipiration still occur, but sympathetic vasoconstriction is impaired. Straining at stool with a closed

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glottis (i.e. producing a Valsalva maneuver), playing wind instruments and singing can be particularly dangerous for patients with PDþOH. A high-fiber diet is encouraged to prevent constipation, and singing or playing wind instruments should be undertaken only when sitting. The use of knee-high compressive stockings is not effective, but waist-high stockings or abdominal binders may be an effective, albeit poorly tolerated, countermeasure for OH. OH should only be treated pharmacologically in patients who are symptomatic, because the treatments usually worsen supine hypertension. Perhaps because of adaptive cerebral autoregulatory changes, some patients with autonomic failure tolerate very low arterial pressures when standing without experiencing symptoms of cerebral hypoperfusion. Blood pressure levels change throughout the day and from one day to another (Vagaonescu et al., 2000). Thus, the patient’s normal cycle of blood pressure and orthostatic symptoms should be identified before treatment is initiated. The physiological mechanisms of OH, if identified, can guide its management. Measures include drugs to increase intravascular volume, increase peripheral vascular resistance and correct anemia, if present. Fludrocortisone, a synthetic mineralocorticoid, is widely used to increase intravascular volume in PD patients with symptomatic OH (Hickler, 1959). Therapy with fludrocortisone is initiated at a dose of 0.1 mg/day. The daily dose can be increased, but to no more than 0.5 mg/day. Maximal clinical response occurs after approximately a week; dosage adjustments should take into consideration this delayed onset. Pedal edema and weight gain of 2–3 kg (5–7 lb) are expected consequences of fludrocortisone therapy. For fludrocortisone to work effectively requires that the patient be on a high-salt diet. Because of the potential for potassium wasting, serum potassium should be monitored in patients during initiation of fludrocortisone treatment for OH. Desmopressin (DDAVP), a synthetic vasopressin analog that acts at V2-receptors on renal tubular function, enhances water reabsorption and thus would be expected to work adjunctively with fludrocortisone to expand intravascular volume. DDAVP is administered intranasally in doses of 5–40 mg at bedtime (Mathias et al., 1986). Since DDAVP can induce hyponatremia, careful monitoring of serum sodium, preferably during a brief inpatient stay, is necessary during the first 4–5 days of treatment and at monthly intervals thereafter. Indometacin, a prostaglandin inhibitor, has been used to treat OH, especially in combination with fludrocortisone, but the lack of rigorous clinical data supporting

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the efficacy of this combination precludes a recommendation for its use (Crook et al., 1981). Sympathomimetic agents increase peripheral vascular resistance and are useful in the treatment of symptomatic OH in PD. Midodrine is an orally active, selective a1-adrenoceptor agonist that does not cross the blood– brain barrier and does not cause central excitatory effects (Kaufmann et al., 1988; Wright et al., 1998). The pressor response to midodrine begins within about an hour, making this agent potentially useful in treating patients who benefit from on-demand increases in blood pressure (e.g. for postprandial and morning hypotension). Midodrine therapy is started with a dose of 2.5 mg and increased to no more than 10 mg t.i.d. A typical daily regimen includes a dose before breakfast, a dose before lunch and a third dose at mid-afternoon. Theoretically, routine administration of midodrine at high, fixed doses might down-regulate a-adrenoceptors and mitigate the pressor effect. Midodrine should not be administered before bedtime, as the blood pressure is typically high when the patient is lying down. Erythropoietin increases red blood cell mass and blood viscosity. In addition, it also increases plasma endothelin, inhibits nitric oxide and increases renal sodium reabsorption (Perera et al., 1994). Hypotensive parkinsonian patients with anemia may benefit from a 6-week course of subcutaneously administered recombinant erythropoietin (4000 units twice weekly; Perera et al., 1994). Other treatments for OH should be continued during erythropoietin therapy. A number of investigational agents are currently being studied. L-threo-DOPS (the biologically active stereoisomer of the amino acid 3,4-dihydroxyphenylserine) is a precursor of norepinephrine that has shown promise in the treatment of OH in small clinical trials (Kaufmann et al., 2003).

14.4. Gastrointestinal dysfunction James Parkinson’s 1817 description of gastrointestinal problems in the patients in his case series was lastingly accurate: ‘food is with difficulty retained in the mouth until masticated; and then as difficulty swallowed ... the saliva fails of being directed to the back part of the fauces, and hence is continually draining from the mouth ... the bowels which all along had been torpid, now in most cases, demand stimulating medicines of very considerable power: the expulsion of the faeces from the rectum sometimes requiring mechanical aid’ (Parkinson, 1955). Although dysphagia, drooling and constipation are the most common gastrointestinal abnormalities, early satiety, epigastrial distension and nausea caused by delayed gastric emptying are also very frequent in PD patients.

14.4.1. Neuropathology PD affects both the extrinsic and intrinsic innervation of the gut, which explains the prominent motility disturbances. Lewy bodies have been found in enteric neurons, in the Auerbach and Meissner plexuses along the entire gastrointestinal tract, including the esophagus, stomach, small intestine and colon, particularly in neurons of the Auerbach plexus in the lower esophagus (Wakabayashi et al., 1988). A study using histochemistry showed that Lewy bodies are mostly found in vasoactive intestinal peptide-containing neurons in the enteric plexus (Wakabayashi et al., 1990). The extrinsic parasympathetic innervation of the gut originates in neurons of the dorsal nucleus of the vagus in the medulla. These neurons innervate the entire gastrointestinal tract, with the exception of the proximal esophagus (innervated by the glossopharyngeal nerve) and the distal colon and rectum (innervated by the sacral parasympathetic nerves), and are severely affected early in PD. Vagal activity increases propulsive motility and relaxation of sphincters and stimulates secretions of the exocrine and endocrine glands of the stomach, intestine, pancreas and liver. Early involvement of vagal or enteric neurons may explain the finding that constipation is a predictor of later development of PD (Abbott et al., 2001). According to Braak and Braak (2000), PD develops in a sequence of six neuropathologic stages, with the earliest, presymptomatic change being in the dorsal nucleus of the vagus nerve. The vulnerability of these neurons may be related to their having long unmyelinated axons that project to postganglionic neurons of the enteric nervous system. Braak et al. (2003) have also proposed that a neurotoxic pathogen, gaining entry to the body via the gastrointestinal tract, might ascend via retrograde and transneuronal transport in vagal post- and then preganglionic fibers, to harm vulnerable neurons of the dorsal motor nucleus of the vagus nerve. Enteric neurons of PD patients have been reported to contain Lewy bodies, suggesting decreased motility from loss of neurons promoting perstalsis. No experimental evidence related to this novel hypothesis has appeared so far. In contrast to the involvement of dorsal vagal neurons, neurons in the nucleus ambiguus are not directly affected in PD. Nucleus ambiguus neurons innervate the muscles of the palate, pharynx and larynx through myelinated axons in the vagus nerve. The reason for abnormal swallowing in PD is likely to be abnormal supranuclear control of oropharyngeal muscles. This is suggested by the observation that many patients suffer severe dysphagia only when ‘off’ and improve as soon as a dose of levodopa becomes effective.

AUTONOMIC DYSFUNCTION IN PARKINSON’S DISEASE Sympathetic outflow to the gastrointestinal tract, which arises from preganglionic neurons at the T1–L1 segments of the spinal cord and relays, via the splanchnic nerves, in the celiac and mesenteric ganglia, is involved in reflexes that decrease gut motility. A substantial proportion of dopamine production in the body takes place in non-neuronal cells of the gut (Eisenhofer et al., 1997) that express tyrosine hydroxylase (Mezey et al., 1996, 1998, 1999). Whether PD involves altered non-neuronal dopamine production in the gut remains unknown. Singaram et al. (1995) reported decreased dopaminergic myenteric neurons in patients with PD and chronic constipation. The number of neurons containing immunoreactive tyrosine hydroxylase, however, was normal. PD patients also had decreased dopamine in the external muscular layer but not in the mucosa. No evidence has accrued for improvement in constipation by levodopa treatment. 14.4.2. Clinical gastrointestinal problems 14.4.2.1. Drooling Excessive drooling is a distressing and frequent problem in PD, but it is not due to excessive saliva production. On the contrary, salivation is reduced in PD (Bagheri et al., 1999; Proulx et al., 2005). Drooling is due to reduced swallowing frequency, allowing excess saliva to accumulate in the mouth. Treatment with oral anticholinergics is ineffective. Botulinum toxin injected in the parotid and submandibulary glands has been used successfully (Jost, 1999; Pal et al., 2000; Friedman and Potulska, 2001; Dogu et al., 2004), but dysphagia is a potential adverse effect of the diffusion of botulinum toxin into nearby muscles. 14.4.2.2. Dysphagia Dysphagia in patients with PD is related to the severity of the disease and may occur in up to 50% of patients (Bushmann et al., 1989; Edwards et al., 1992; Johnston et al., 1995). In general, abnormalities of swallowing are mild (Wintzen et al., 1994). PD patients who experience significant swallowing dysfunction should be evaluated by a speech and swallowing expert. Swallowing studies may help to define the nature of the dysphagia and the presence or absence of silent aspiration. The three phases of swallowing – buccal, pharyngeal and esophageal – may be disrupted in PD. Abnormal lingual control (lingual festination) can impair the ability to pass a bolus of food backward into the pharynx. The pharyngeal swallow reflex may be disturbed as well (Born et al., 1996). Normally,

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the soft palate moves to prevent the bolus from entering the nasal cavity, the hyoid bone rises; the larynx prevents the bolus from entering the trachea, the true and false vocal cords close and the epiglottis lowers; the cricopharyngeal sphincter opens and food or liquid moves to the esophagus. In PD patients, abnormalities in the pharyngeal phase can lead to silent aspiration. There have been reports of repetitive reflux of food from the vallecula and pyriform sinuses into the oral cavity (Wintzen et al., 1994). In the esophageal phase, the smooth muscles of the esophagus move the bolus in rhythmic, wave-like contractions into the stomach. Esophageal dysmotility occurs in as many as 70% of PD patients with non-peristaltic swallows, belching, segmental spasms, esophageal dilatation and gastroesophageal reflux (Ertekin et al., 2002). Repetitive, spontaneous contractions of the proximal esophagus have been described in patients with PD, a finding similar to that in acahalasia (Johnston et al., 2001). Vocal cord palsy is frequent in patients with MSA and may lead to aspiration (Simpson et al., 1992; Wu et al., 1996). 14.4.2.2.1. Treatment Soft diets help most types of dysphagia by making it easier to move food in the mouth and esophagus. Soft food also decreases aspiration by reducing the need for separate fluid intake, which is a potential source of aspiration. Patients with motor fluctuations should be instructed to eat only during ‘on’ times when dysphagia is less pronounced. Some patients suffer from achalasia, which can be treated with botulinum toxin injection into the cardia (Gui et al., 2003). Feeding gastrostomies or jejunostomies are a last resort and are rarely necessary for patients with PD. However, these procedures can provide the benefit of allowing more normal food and medication intake. 14.4.2.3. Delayed gastric emptying Gastric retention due to delayed gastric emptying is a common problem in PD and results in nausea, early satiety and abdominal distension. Levodopa, as a large neutral amino acid, is absorbed relatively little in the stomach and mainly in the small bowel, mostly the duodenum, by an active transport mechanism (Wade et al., 1973). Because of the high capacity of the transporter, competition between levodopa and other dietary neutral amino acids (e.g. valine, leucine and isolucine) is not common but may occur. Delayed gastric emptying retards delivery of levodopa to the absorptive sites in the duodenum. Reduced bioavailability of levodopa explains some of the response fluctuations that develop after long-term

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levodopa therapy (Kurlan et al., 1988a). Studies have shown higher gastric retention 1 hour after a meal in patients with PD who experience motor fluctuations, compared with patients without fluctuations (Djaldetti et al., 1996). Factors that slow gastric emptying also delay and blunt peak plasma levodopa levels and may cause a delay or a complete failure of the clinical response to the dose. With direct delivery of levodopa into the duodenum, motor fluctuations can improve markedly (Kurlan et al., 1988b). 14.4.2.3.1. Treatment Timing of gastric emptying is related to meal characteristics, such as bulk, tonicity and composition. Lipid and carbohydrates and excessive gastric acidity delay gastric emptying. Small frequent meals are recommended. Prokinetic drugs that accelerate gastric emptying include muscarinic agents, peripheral dopamine blockers and serotonin (5-HT)-4-receptor agonists. The muscarinic receptor agonists bethanechol and carbachol have long been used for the treatment of markedly delayed gastric emptying or paralytic ileus. These agents exert a prokinetic effect by stimulating muscarinic receptors in intestinal smooth muscle. Unfortunately, bethanechol increases the amplitude of gastric contractions in an uncoordinated manner, with little improvement in coordinated peristalsis. Additionally bethanechol can elicit nausea and vomiting. Other common side-effects are diaphoresis, flushing, salivation and abdominal cramping. The typical dosage is 25 mg orally four times daily or 2.5–5 mg subcutaneously q.i.d. Dopamine D2-receptor blockers stimulate gastric motility. Metoclopramide, the most effective, cannot be used in parkinsonian patients, because it blocks central dopamine receptors and worsens parkinsonism. Domperidone acts mostly on peripheral dopamine receptors and is an effective prokinetic agent (10–40 mg po q.i.d.) in PD (Soykan et al., 1997). It is not yet available in the USA. Agonists at 5-HT-4 receptors stimulate release of acetylcholine from enteric neurons, activating prokinetic pathways. The first available 5-HT-4 agonist was cisapride (Jost and Schimrigk, 1993; Katayama et al., 1995). Unfortunately, cisapride prolongs the cardiac QT interval, predisposing to the ventricular arrhythmia torsades de pointes, which may cause hypotension, syncope and sudden death. The agent was withdrawn from the market in the USA. The proarrhythmic action of cisapride is due to its ability to block the myocyte cell membrane potassium channel, an effect that is independent of its prokinetic action. Recently, 5-HT-4 gastrointestinal prokinetic drugs with very low affinity for the cardiac potassium channel have been developed, such as mosapride and

tegaserod. These drugs do not prolong the QT interval and are not arrhythmogenic (Potet et al., 2001). 14.4.2.4. Nausea and vomiting as a side-effect of levodopa and dopamine agonists The most prominent toxic effect of levodopa and dopamine agonists (particularly apomorphine) is nausea and vomiting. A proposed mechanism for this toxicity is increased occupation of dopamine receptors in the area postrema of the dorsal medulla. The area postrema lacks an efficient blood–brain barrier. Dopamine produced from levodopa outside the central nervous system could occupy area postrema receptors, evoking nausea and vomiting. Carbidopa inhibits the enzymatic conversion of levodopa to dopamine. As a catechol, carbidopa has little ability to penetrate the blood–brain barrier. The combination of levodopa with carbidopa therefore attenuates conversion of levodopa to dopamine outside the brain, augmenting entry of levodopa to the central nervous system, where enzymatic conversion to dopamine can proceed. The combination of levodopa with carbidopa decreases dopaminergic occupation of receptors in the area postrema, resulting in less nausea and vomiting. The brand name for levodopa/carbidopa, Sinemet, comes from the Latin words for ‘without vomiting’. Trimethobenzamide is a dopamine receptor blocker with some prokinetic effect commonly used for the prevention of nausea associated with the use of apomorphine (at a dose of 300 mg po t.i.d.) (Bowron, 2004). 14.4.2.5. Constipation Normal defecation requires two separate processes: movement of stool along the colon by peristaltic waves of contracting smooth muscle and then expulsion of feces through the anal canal by the coordinated action of voluntary and involuntary muscles. In patients with PD, stool transit time is prolonged, because colonic motility is reduced due to abnormal intrinsic and extrinsic vagal innervation. Degeneration of intrinsic enteric neurons and extrinsic parasympathetic efferent fibers that regulate contractility of colonic muscle underlie slow transit time, resulting in reduced frequency of defecation. Frequently, defecation is also abnormal due to pelvic floor dyssynergia. Defecography and anal sphincter electromyogram (EMG) in some PD patients showed paradoxical contraction of the puborectalis muscle (Mathers et al., 1988, 1989). The puborectalis muscle, which is one of the muscles that comprise the pelvic floor and plays an important role in both fecal continence and defecation, is

AUTONOMIC DYSFUNCTION IN PARKINSON’S DISEASE tonically contracted and maintains the anorectal angle at rest. Contraction of the internal and external anal sphincters contributes to continence. During defecation, the puborectalis muscle relaxes, opening the anorectal angle, the internal anal sphincter opens reflexively, and the external anal sphincter is voluntarily relaxed, thus allowing normal expulsion of rectal stools. In a patient with pelvic floor dyssynergia, the puborectalis muscle fails to relax, or contracts, increasing the anorectal angle. This accentuates its flap valve action. Moreover, anal sphincters paradoxically contract during attempted defecation. This results in outlet obstruction, dyschezia (straining to start or finish a bowel movement) and constipation. It has been suggested that this paradoxical contraction of the pelvic musculature is dystonic in nature (Stocchi et al., 2000). In support of this argument, apomorphine has been shown to alleviate this defecatory problem in some patients with PD. Similarly, injection of botulinum toxin in the puburectalis muscle or in the external anal sphincter has been reported as helpful. Other disorders associated with constipation in PD patients include megacolon (Kupsky et al., 1987) and sigmoid volvulus (Lewitan et al., 1951). 14.4.2.5.1. Treatment The management of constipation in PD consists of dietary changes, exercise and pharmacotherapy. Dietary modifications are aimed at increasing bulk and softening the stool. Patients should be encouraged to drink at least eight glasses of water each day and to increase the bulk and fiber content of their diet. Low-fiber foods such as many baked goods should be eaten infrequently and bananas should be avoided altogether. At least two meals per day should include high-fiber raw vegetables, to stimulate the gastrocolic reflex. Increasing physical activity can also be helpful. If stools remain hard, stool softeners (e.g. docusate) given with meals can be used. Lactulose in doses of 10–20 g/day may benefit some patients. Patients should be educated about the delayed onset of effect of stool softeners and encouraged to continue with fluids, increased bulk, high-fiber diet and exercise. Discontinuing anticholinergic agents may increase bowel motility. Milk of magnesia, other mild laxatives or enemas should be reserved for patients who do not respond to other interventions. Laxatives or enemas may be useful once weekly as part of an overall bowel regimen. 14.4.2.5.2. Prokinetic agents Mosapride citrate, a 5-HT-4 agonist and partial 5-HT-3 antagonist (Yoshida et al., 1993), an effect that makes it also antiemetic, blocking vagal 5-HT receptors in the

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chemoreceptor trigger zone, ameliorates constipation in parkinsonian patients. In a recent study of parkinsonian patients with constipation and difficulty in defecation, mosapride treatment for 3 months improved bowel frequency and difficult defecation (Liu et al., 2005). Mosapride shortened colonic transit time, augmented the amplitude of rectal contraction during defecation and lessened the volume of postdefecation residuals.

14.5. Bladder dysfunction Three types of neuronal outflow regulate urinary bladder function: (1) sacral parasympathetic; (2) lumbar sympathetic; and (3) somatic. The pelvic nerves carry the sacral parasympathetic (S2–S4) output to the bladder. Activation of muscarinic cholinergic receptors promotes bladder emptying (micturition) through contraction the detrusor muscle and relaxation of the bladder neck. The lumbar sympathetic (T11–L2) output, carried via the hypogastric nerves, relaxes the detrusor muscle via b-adrenoceptors and contracts the bladder neck via a-adrenoceptors, thus promoting urinary retention. The sacral somatomotor output arises from motor neurons of the nucleus of Onuf (S2–S4) and is carried by the pudendal nerve. Stimulation of the motor neurons augments contraction of the external sphincter via nicotinic cholinergic receptors and promotes storage of urine. Micturition involves a spino-ponto-spinal reflex that is initiated by bladder tension receptors and integrated in pontine micturition centers. Extensive research on central neural pathways underlying reflexive micturition has pointed to glutamic acid as the major excitatory transmitter, with other transmitters, including norepinephrine, dopamine, and GABA, modulating the glutamatergic transmission (de Groat, 1998). In the cat, four brainstem regions appear to regulate micturition: (1) Barrington’s nucleus (or the pontine micturition center) in the dorsomedial pons; (2) the periaqueductal gray; (3) the preoptic area of the hypothalamus; and (4) an area in the ventrolateral pons, called the L-region. It has been suggested that cells in Barrington’s nucleus directly excite bladder motor neurons and indirectly inhibit internal urethral sphincter motoe neurons, preoptic hypothalamic cells regulate initiation of micturition, L-region cells control motor neurons innervating the pelvic floor (including the external urethral sphincter) and periaqueductal gray cells receive afferent input about bladder filling (Blok, 2002). Studies using positron emission tomography and functional magnetic resonance imaging scanning in humans have indicated activation of the same regions associated with urination or the attempt to urinate (Kershen et al., 2003). Afferent information for the

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micturition reflex comes from bladder distension. A balance between cortical stimulation and supraspinal inhibition determines a set point for reflexive responses as the bladder fills (Hebjorn et al., 1976). In PD, cell loss in the substantia nigra, which normally has an inhibitory effect on the micturition reflex (Lewin et al., 1967; Yoshimura et al., 2003), leads to hyperreflexia of the detrusor muscle, with involuntary or uninhibited contractions and an urge to urinate (Fitzmaurice et al., 1985; Araki et al., 2000). The animal model produced by 1-methyl-4phenyl-1, 2,3,6-tetrahydropyridine (MPTP) suggests an inhibitory role of the substantia nigra on the micturition reflex (Albanese et al., 1988; Yoshimura et al., 1998). Further evidence that the basal ganglia affects the micturition reflex comes from a report in patients with PD receiving deep brain stimulation of the subthalamic nucleus (Seif et al., 2004). With the stimulator off, urodynamic parameters showed detrusor hyperreflexia. When turning the stimulator on, induction of the micturition reflex was delayed towards normalization, with the initial desire to void at higher bladder volumes and an increment of the maximal bladder capacity. During the voiding phase, deep brain stimulation subthalamic nucleus stimulation induced a small, non-significant increase in the pressure of the detrusor, maximum urinary flow and reduction in residual urine. Urinary problems are common and afflict both women and men with PD (Dmochowski, 1999). A comprehensive questionnaire and urodynamic evaluation in patients with PD and urinary symptoms revealed detrusor hyperreflexia in 79% of patients, whereas 16% had detrusor hyporeflexia (Araki et al., 2000). Impaired contractile function occurred in 9% of patients and detrusor–sphincter dyssynergia in 3%. Scores derived from questionnaires of irritative and obstructive symptom were fairly accurate in predicting urodynamic abnormalities. Bladder function deteriorated and postvoid residual urine volume increased with advancing disease severity. In another study, sphincter EMG revealed pseudodyssynergia or bradykinesia in 50% of female PD patients (Dmochowski, 1999). In MSA there is also degeneration of neurons in Onuf’s nucleus. In later stages of the disease there is neuronal loss affecting parasympathetic innervation of the detrusor, producing detrusor hypocontractility or arreflexia, with increased residual urine and overflow incontinence. 14.5.1. Prostate surgery In men with PD bladder outflow obstruction due to benign prostatic hyperplasia results in urinary hesitancy and low urine flow. Obstruction can cause detrusor

overactivity and urinary urgency as well. Therefore, surgery of the prostate is considered in PD patients in the hope that detrusor hyperactivity results from bladder outlet obstruction rather than PD. Unfortunately, surgery frequently worsens symptoms and results in overt urinary incontinence. Defreitas et al. (2003) found that bladder filling during urodynamic evaluation occurs earlier when detrusor hyperactivity is due to PD and that urge incontinence is rare in men with detrusor hyperactivity due to bladder outlet obstruction. Urological intervention is not contraindicated in men with PD, but patients should try anticholinergic medication first if urge incontinence is prominent. If conservative measures fail, a voiding cystometrogram to demonstrate obstructed voiding should be performed before transurethral resection of the prostate is considered (Chandiramani et al., 1997). It has been suggested that, in addition to detrusor hyperreflexia, patients with PD may have impaired relaxation or ‘bradykinesia’ of the urethral sphincter, resulting in bladder outflow obstruction and difficulty in micturition, with similar symptoms to prostatic hypertrophy. A study of subcutaneous apomorphine in patients with PD showed that apomorphine reduced bladder outflow resistance and improved voiding. It was proposed that this intervention be used to demonstrate the reversibility of outflow obstruction in men with PD before prostatic surgery is undertaken (Christmas et al., 1988; Aranda and Cramer, 1993). 14.5.2. Onset of urinary symptoms is earlier in multiple system atrophy In MSA urinary symptoms, like OH, are typically present before the onset of the motor symptoms. Urinary symptoms in PD tend to occur later. Also characteristic of MSA are early urinary incontinence due to Onuf’s nucleus involvement, postmicturition residual volume more than 100 ml, loss of the bulbocavernosus reflex and denervation indicated by sphincter EMG (Chandiramani et al., 1997). Worsening urinary control after transurethral resection of the prostate or anti-incontinence procedures in women is typical in men with MSA, immediately after or within a year of surgery (Beck et al., 1994). Since the anterior horn cells of Onuf’s nucleus are not affected in PD, sphincter EMG was proposed as a means of distinguishing between PD and MSA. Both the anal and urethral sphincters are innervated by the anterior horn cells in Onuf’s nucleus, leading to changes of chronic reinnervation, with prolongation of the mean duration of motor units in patients with MSA (Eardley et al., 1989; Fowler, 1996).

AUTONOMIC DYSFUNCTION IN PARKINSON’S DISEASE 14.5.3. Treatment Many patients can reduce nocturnal frequency by restricting fluid intake after the evening meal. In PD patients with autonomic dysfunction and supine hypertension, nocturia may also result from pressure natriuresis (see treatment of orthostatic hypotension, above) and improves by sleeping with the head and torso elevated. Pharmacologic treatments include peripherally acting anticholinergics, such as oxybutynin (5–10 mg at bedtime or three times daily), propantheline (7.5–15 mg at bedtime or three times daily) or tolterodine tartrate (1–2 mg twice daily based on individual response and tolerability). Anticholinergic agents reduce detrusor contractions and are useful in the treatment of detrusor hyperactivity but may worsen voiding problems and even produce urinary retention in patients with detrusor hypoactivity or outlet obstruction. Therefore, before starting treatment, it is important to measure postvoid residual volume with an ultrasound study or urodynamic evaluation. If postvoid residual volume is less than 100 ml, then treatment with anticholinergics may provide benefit (Fowler, 1999). It is important to re-evaluate the patient if there is no improvement after pharmacologic therapy. Increased residual urine can stimulate detrusor contractions. Anticholinergic drugs should also be administered with caution, as they may also aggravate gastrointestinal motility disorders and increase gastric retention. a1-Adrenoceptor antagonists can decrease tone in the bladder neck and may be helpful for patients with a hypoactive detrusor; however, these agents worsen OH. If the patient has residual volume more than 100 ml, then self-catheterization is indicated. This can also be combined with anticholinergic therapy to enhance continence between catheterizations. If the patient or relative cannot perform catheterization, surgical management of the problem may be needed. If daytime frequency or urgency precedes nocturia, mechanical outlet obstruction should be ruled out. Any deterioration in voiding pattern (even in the absence of dysuria) should raise concern about a urinary tract infection, and this should be treated promptly.

14.6. Sexual dysfunction Dopaminergic mechanisms seem to participate in libido and arousal-related vasodilation of penile erectile tissue. The cause of erectile dysfunction (ED: difficulty achieving or sustaining an erection) in PD is unknown but might reflect dopamine deficiency. About 60% of male PD patients have ED (Singer et al., 1992). Impaired sexual arousal, behavior,

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orgasm and drive are also frequent (Lake et al., 1976). Sexual fantasy, however, seems to remain normal in most patients (Yu et al., 2004). ED is almost invariably an early symptom in men with MSA and can precede other symptoms by several years. 14.6.1. Treatment Many drugs can cause male sexual dysfunction, and a thorough medication history often uncovers causative agents. Propranolol and other b-adrenergic blockers, which are sometimes used to treat tremor or hypertension in PD, should be discontinued if possible. Other drugs that may cause sexual dysfunction include a1-adrenoceptor blockers, guanethidine, thiazide diuretics, anxiolytics, digoxin, cimetidine and some antidepressants. Depression is a common cause of impotence and can respond to antidepressants, although some antidepressants themselves can cause impotence (e.g. selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors). Some patients with anxiety- or stress-associated sexual dysfunction may benefit from low-dose anxiolytics. If no medical or psychologic reason appears to be causing impotence, several options are available. Intracavernous injections or transurethral suppositories of alprostadil, a synthetic prostaglandin E1, induce penile erection, but their use is cumbersome. Sildenafil, an orally active inhibitor of the type V cyclic guanosine monophosphate-specific phosphodiesterase (the predominant isoenzyme in the human corpus cavernosum) has improved ED in small clinical trials of PD patients (Zesiewicz, 2000; Hussain et al., 2001). Patients with MSA, however, developed severe hypotension (Saadia et al., 2002). A report on men using subcutaneous injections of apomorphine to treat motor fluctuations in PD noted that the treatment benefited their sexual function and induced penile erection (O’Sullivan and Hughes, 1998). Drug trials to assess the effect of sublingual apomorphine to treat ED had promising results, although nausea occurs in a proportion of the patients (Dula et al., 2000; Perimenis et al., 2004). Some patients on high doses of antiparkinsonian therapy become hypersexual, even in the face of inability to perform.

14.7. Thermoregulation and sweating abnormalities Preoptic and hypothalamic neurons are important for thermoregulatory function and may be affected in PD. During normal human aging, the ability to tolerate swings of environmental temperature declines. Elderly

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healthy volunteers have a decreased set point for mounting sympathetic noradrenergic responses to core hypothermia (Frank et al., 1997). Thermoregulatory sweating is a sympathetic nervous system function where the effector neurotransmitter is acetylcholine, in contrast to noradrenergic mediation of sympathetic cardiovascular functions. Many studies assessing cutaneous sympathetic cholinergic function in PD have relied on measurements of skin humidity or electrical conductance as indices of sweat production; results have been variable (Wang et al., 1993; Jost et al., 1995; Denislic and Meh, 1996; Braune et al., 1997; De Marinis et al., 2000; Haapaniemi et al., 2000; Sharabi et al., 2003). PD patients can have increased, decreased or normal sweating. In PD patients with sympathetic neurocirculatory failure and cardiac sympathetic noradrenergic denervation, sympathetic cholinergic innervation of sweat glands appears to remain intact, since such patients have normal sweating during the quantitative sudomotor axon reflex test (Sharabi et al., 2003). Turkka and Myllyla (1987) reported increased sweating in PD patients, both before and after heat exposure; however, whether PD patients have appropriate thermoregulatory sweating responses in terms of maintaining core temperature is unknown. Abnormal sensations of heat or cold and hypothermia can occur in the PD patient. Excessive sweating of the head and neck in response to external heat has been associated with poor heat dissipation in the rest of the body. Some of these phenomena disappear with levodopa treatment. Severe drenching sweats can also occur as an end-of-dose ‘off’ phenomenon in patients with motor fluctuations (Sage and Mark, 1995). In contrast, some patients will experience sweating during ‘on’ responses following levodopa administration, frequently in association with dyskinesia (Swinn et al., 2003), although it is rarely as severe as that seen in the ‘off’ state. Severe hyperpyrexia after levodopa withdrawal can represent a form of neuroleptic malignant syndrome (Cao and Katz, 1999). Ethanol and aspirin in high doses can cause intermittent sweating. Thyrotoxicosis, chronic infections and the postmenopausal state should also be considered in the differential diagnosis.

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atrophy, and progressive supranuclear palsy.] Rinsho Shinkeigaku 37 (6): 476–482. Yoshita M, Hayashi M, Hirai S (1998). Decreased myocardial accumulation of 123I-meta-iodobenzyl guanidine in Parkinson’s disease. Nucl Med Commun 19 (2): 137–142. Yu M, Roane DM, Miner CR et al. (2004). Dimensions of sexual dysfunction in Parkinson disease. Am J Geriatr Psychiatry 12 (2): 221–226. Zesiewicz TA, Helal M, Hauser RA (2000). Sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men with Parkinson’s disease. Mov Disord 15 (2): 305–308. Ziegler MG, Lake CR, Kopin IJ (1977). The sympatheticnervous-system defect in primary orthostatic hypotension. N Engl J Med 296 (6): 293–297.

Further Reading Bradbury S, Egglestone C (1925). Postural hypotension: a report of three cases. Am Heart J I: 75–86. Gelb DJ, Oliver E, Gilman S (1999). Diagnostic criteria for Parkinson disease. Arch Neurol 56 (1): 33–39. Kaufmann H (2002). Treatment of patients with orthostatic hypotension and syncope. Clin Neuropharmacol 25 (3): 133–141. Nozaki S, Kang J, Miyai I et al. (1993). [Postprandial hypotension in Parkinson’s disease—the incidence and risk factor]. Rinsho Shinkeigaku 33 (11): 1135–1139. Rajput AH, Rozdilsky B (1976). Dysautonomia in parkinsonism: a clinicopathological study. J Neurol Neurosurg Psychiatry 39 (11): 1092–1100. Senard JM, Brefel-Courbon C, Rascol O et al. (2001). Orthostatic hypotension in patients with Parkinson’s disease: pathophysiology and management. Drugs Aging 18 (7): 495–505. Wakabayashi K (1989). [Parkinson’s disease: the distribution of Lewy bodies in the peripheral autonomic nervous system]. No To Shinkei 41 (10): 965–971.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 15

Sleep in Parkinson syndromes ¨ GL2 CLAUDIA TRENKWALDER1* AND BIRGIT HO 1

Paracelsus Elena-Klinik, Kassel and University of Go¨ttingen, Germany 2

Department of Neurology, Medical University of Innsbruck, Austria

15.1. Introduction and pathophysiology of sleep in Parkinson syndromes Sleep complaints are frequent and substantially impair quality of life in patients with Parkinson’s disease (PD). Listening to PD patients, it is soon revealed that fatigue and sleepiness are major complaints independent of any medication and motor disability. Although previous research on sleep and daytime sleepiness in PD primarily focused on nocturnal sleep disturbance and pharmacological therapy, recent neuropathological publications demonstrate that neurodegeneration involves sleep regulation and daytime alertness to a large degree (Braak et al., 2003). Severely disrupted sleep and rapid-eye movement (REM) sleep disturbances are early signs of neurodegeneration with involvement of the brainstem with Lewy bodies. First, the neurodegenerative process starts in the lower brainstem areas, according to the six progressive stages described by Braak and collaborators (Del Tredici et al., 2002; Braak et al., 2003). REM sleep behavior disorder (RBD) may be a preclinical and premotor sign of PD or other Parkinson syndromes. Therefore the observation of early changes in sleep may be of particular importance, especially if neuroprotective agents may be available in the future. Second, the behavioral, respiratory and motor system phenomena accompanying the disease may produce nocturnal symptoms. Third, the medications used as treatment may induce new symptoms, such as nightmares, nocturnal movements or increased wakefulness. In addition to the primary cause of PD, the loss of dopaminergic neurons in the substantia nigra, serotonergic neurons originating in the dorsal raphe nuclei

are reduced in number, as are noradrenergic neurons originating in the region of the locus ceruleus (Jellinger, 1986). Cholinergic neurons of the pedunculopontine nucleus, implicated in control of REM sleep, are also reduced in number (Zweig et al., 1989). Because the noradrenergic, serotonergic and cholinergic systems have all been implicated in the control and regulation of sleep, abnormalities in these systems may account for some of the sleep disturbances that occur in patients with parkinsonism. Abnormalities of the mesocorticolimbic dopamine system, as well as the mesostriatal system, are apparent in PD and may contribute to sleep–wake disturbances (Javoy-Agid and Agid, 1980). The administration of a dopamine D1-receptor agonist produces electroencephalographic (EEG) desynchronization and behavioral arousal (Ongini et al., 1985). High doses of dopamine D1- and D2-receptor agonists, such as apomorphine (Chianchetti, 1985), reduce total sleep time; the dopamine D1- and D2-agonist pergolide decreases the amount of slow-wave sleep (Tagaya et al., 2002). Very low doses, however, induce sleep and increase the amount of slow-wave sleep. Low doses of apomorphine also induce sleep when injected into the ventral tegmental area, an effect that is blocked by dopamine receptor autoantagonists, suggesting that dopamine D2 autoreceptors play a role in the mediation of sleep through autoinhibition of the firing rate of ventral tegmental dopaminergic neurons (Svensson et al., 1987; Bagetta et al., 1988). It is not surprising, therefore, that levodopa and dopamine agonists induce yawning, sleepiness or even irrestistible onset of sleep in some patients (Ho¨gl et al., 2001b). The arousing effects of higher doses of dopamine D2-receptor agonists may be due to effects at postsynaptic receptors. This may also explain the

*Correspondence to: Claudia Trenkwalder, MD, Paracelsus Elena-Klinik, Center of Parkinsonism and Movement Disorders, Klinikstr. 16, D-34128 Kassel, Germany. E-mail: [email protected], Tel: þ49/561-6009-200, Fax: þ49/561-6009-126.

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arousal effects that occur when high dosages of dopamine agonists are applied during the day. In normal individuals, levodopa reduces the amount of REM sleep, an effect that may be due to increased activity of dopamine, norepinephrine, or both. The effects of levodopa on sleep may be due in part to effects on serotonergic neurons. RBD is an important and characteristic sleep problem in PD, as it requires a neurodegenerative process, if it is not pharmacologically induced (Schenck et al., 1992). It differentiates sleep disturbance in PD from a severely disruptive sleep of any other origin, as RBD is not associated with any other sleep problems, such as periodic limb movements during sleep (PLMS), insomnia, restless-legs syndrome (RLS) or sleep with increased number of awakenings. RBD can be induced by antidepressants, such as mirtazapine or serotonine reuptake inhibitors (Onofrj et al., 2003; Winkelman and James, 2004).

15.2. Diagnosis of Parkinson syndrome sleep disorders To determine which factors are most important, the patient’s clinical history and that of partners or caregivers is used, as well as examination and polysomnographic evaluation. Sleep disturbance is rarely the presenting complaint in a patient with previously undiagnosed parkinsonism, with the exception of RBD, which presents with violent behavior in only a few cases. More commonly, the diagnosis of PD has been established, and the patient complains about nocturnal problems, i.e. insomnia, daytime sleepiness, or both. The history of sleep problems should include all the features the physician would obtain from any patient with a sleep complaint. It must include disease-specific questions on nocturnal akinesia, daytime fatigue in relation to medication intake and psychiatric symptoms. The use of a disease-specific questionnaire, such as the Parkinson Disease Sleep Scale (PDSS) may be helpful (Chaudhuri et al., 2002), as the Unified Parkinson’s Disease Rating Scale (UPDRS: see Ch. 13) comprises only one question related to sleep. A careful history given by the bed partner is essential to determine the occurrence of movements, sleeptalking, the frequency of awakenings and probable difficulties in getting up and moving at night. The medication schedule is significant. If dopaminergic medications are not prescribed in the evening, nocturnal rigidity may often contribute to the sleep disturbance; on the other hand, excessive evening doses of dopamine agonists may induce sleep-onset insomnia. For the majority of patients a history

of nocturnal problems is sufficient to establish a treatment regimen. Some patients, however, require a polysomnogram to diagnose the sleep disorder correctly. These patients may be characterized by severe daytime sleepiness and sudden onset of sleep during the daytime. They should be screened for sleep apnea syndrome or severe PLMS syndrome and may then require respiratory polysomnography. Patients who present with probable RBD or hallucinations may need a polysomnogram to evaluate whether both syndromes are present or either one, as the treatment options are different. Simultaneous closed-circuit television monitoring and surface electromyographic monitoring of all four extremities are often helpful to decide whether nocturnal myoclonic movements or the RBD is contributing to the sleep disturbance. If daytime sleepiness is a prominent complaint, or suspected from the care-giver’s reports, several tests or scales can be used, such as the Multiple Sleep Latency Test (MSLT) (Carskadon et al., 1986), the Maintenance of Wakefulness Test (MWT) (Mitler et al., 1982; Doghramji et al., 1997), the seven-point Stanford Sleepiness Scale (SSS) (Hoddes et al., 1973), the nine-point Karolinska Sleepiness Scale (KSS) (Gillberg et al., 1994) and the eight-question Epworth Sleepiness Scale (ESS) (Johns, 1991). Whereas the SSS and KSS are appropriate to assess momentaneous sleepiness at a single time point, the eight questions of the ESS cover a time span of 2 weeks. The best-established polygraphic test for daytime sleepiness is the MSLT (Richardson et al., 1978). In this test, the subject is put to bed in a sleep-conducive environment for 30 minutes on five occasions distributed throughout the day (usually 9 a.m.; recording time is 20 or 30 minutes). The latency to sleep onset is measured, as well as the latency to onset of REM sleep. Normative values are well established for the MSLT. Another possibility is the MWT (Mitler et al., 1982, 2000). In contrast to the MSLT, the instruction to the patient in the MWT is ‘not to fall asleep’. The MWT therefore measures the ability to maintain wakefulness in monotonous situations. Because the MWT trial is interrupted as soon as the patient falls asleep, the MWT does not measure REM latencies. Therefore, the MSLT is more appropriate to get wellestablished mean sleep latencies, and to evaluate sleep-onset REM periods. In contrast, the MWT is better able to assess the capacity to remain awake in monotonous situations, which may be relevant for everyday life such as driving. In both tests, the individual sleep latency at any given time point of the test will also permit information on the circadian variation of the patient’s sleepiness.

SLEEP IN PARKINSON SYNDROMES

15.3. Clinical features of sleep in Parkinson’s disease 15.3.1. Sleep fragmentation The most consistent abnormality in PD sleep is sleep fragmentation. Sleep studies show sleep disruption caused by many, often short, motor events, not even fulfilling the criteria for PLMS, tremor or dyskinesias. Sometimes arousals without any motor event may also induce an awakening that may lead to prolonged wakefulness (Kales et al., 1971; Bergonzi et al., 1975). Increased amount of stage 1 sleep and reduced amount of stage 3 and 4 sleep and REM sleep are also common; in some patients deep sleep is completely absent. The number of sleep spindles during slow-wave sleep is reduced (Bergonzi et al., 1975; Friedman, 1980). In de novo patients or milder cases, sleep architecture may still be normal (Ferini-Strambi, 1992). Untreated PD patients show a significant decrease of stage 3 and 4 sleep and increased periodic limb movements (Wetter et al., 2000). EEG alpha activity may be prominent during REM sleep (Mouret, 1975; Brunner et al., 2002). In other Parkinson syndromes, such as progressive supranuclear palsy (PSP), patients had a shorter total sleep time, lower sleep efficiency, a significant reduction in sleep spindles, an atonic slow-wave sleep, and a lower percentage of REM sleep, although the frequencies of REM sleep muscle tone abnormalities are controverse (Arnulf et al., 2005). 15.3.2. Characteristic parkinsonian motor signs: hyperkinesia and akinesia The predominant motor symptoms of PD – tremor and dyskinesias – mainly occur during wakefulness but may also arise during non-REM sleep stages. Parkinson rest tremor usually disappears with the onset of stage 1 sleep, in some cases before EEG alpha activity is entirely gone (April, 1966; Stern et al., 1968), stops in stage 3–4 sleep but may reappear in stages 1 and 2 and with awakenings, arousals and body movements (Fish et al., 1991). Tremor is not associated with spindles or K-complexes. Tremor may also appear, with various amplitudes, for a few seconds during sleep stage changes, during bursts of REM and shortly before or after a REM period (Stern et al., 1968). In contrast to the quiet sleep in normal persons, a variety of motor activity, short jerks or increased muscle tone, abnormal simple and complex movements are common and predominate in the picture of a Parkinson polysomnogram. Sometimes scoring following the system of Rechtschaffen and Kales (1968) is difficult as sleep stages cannot be defined unequivocally. One

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study examined the interrater reliability of sleep scoring in patients with Parkinson’s disease with three experienced scorers. A good interrater reliability was found for distinguishing REM from non-REM sleep, but a reliable differentiation of non-REM sleep stages was much more difficult (Bliwise et al., 2000). Patterns of simple motor activity during sleep include repeated blinking at the onset of sleep, blepharospasm at the onset of REM sleep and prolonged tonic contractions of limb extensor or flexor muscles during non-REM sleep (Mouret, 1975). Abnormal muscle tone in REM sleep has been described in early studies (Traczynska-Kubin et al., 1969; Mouret, 1975). Fragmentary myoclonus in surface EMG and jerks of the extremities may be recorded in stage 1 and 2 Parkinson sleep (Broughton and Tolentino, 1984). Painful dystonia in the limb primarily affected by the disease may result in an extension of the great toe (‘striatal toe’), as a sign for off dystonia. Early-morning foot dystonia may occur just before waking or soon thereafter and may reflect the low concentration of dopamine in the basal ganglia after the last intake of medication at night. It usually starts as a sign of motor response fluctuations that occur almost exclusively in idiopathic PD patients, but not in other Parkinson syndromes. Early-morning akinesia and painful off dystonia are frequent complaints of advanced PD patients and require adequate nocturnal treatment strategies (Lees et al., 1988). Nocturnal akinesia, the most frequent complaint of PD patients at night, is characterized by a lack of dopamine and disables PD patients significantly more than dyskinetic stages. Patients complain about being unable to turn in bed or stand up at night without help, and of painful muscle cramps. In the polysomnogram sleep fragmentation and increased muscle tone predominate during nocturnal akinesia. 15.3.3. Sleep-associated motor phenomena PLMS (Atlas Task Force of the American Sleep Disorders Association, 1993), previously known as ‘nocturnal myoclonus’, occur in sleep and are usually associated with a variety of sleep disorders, such as RLS, narcolepsy, Parkinson syndromes or sleep apnea. New criteria have been published for scoring PLMS more appropriately in research projects (Zucconi et al., 2006). Periodic limb movements are defined as at least four movements in a row with a defined intermovement interval and periodicity. An index of more than 5 PLM per hour of sleep (PLMS index >5) is estimated as a pathological value and occurs in up to one-third of patients with untreated PD, but is even more common in elderly controls (Wetter et al., 2000). PLMS may

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often be associated with arousals (Ondo et al., 2002) and therefore lead to sleep disruption. Some authors doubt that isolated PLMS have any pathological relevance for sleep disorders (Mendelson, 1996) and question if they should be treated at all (Leissner and Sandelin, 2002). The association of RLS in PD is still incompletely understood (Poewe and Ho¨gl, 2004). The frequency of RLS in PD is controversial (Ondo et al., 2002).

Reist et al., 1995), these results were not confirmed in a later study (Ho¨gl et al., 2001a). Baseline UPDRS motor score, tapping rates and motor function after the usual medication did not show a global difference after total or partial sleep deprivation compared to a night of normal sleep (Ho¨gl et al., 2001a).

15.4. Rapid-eye movement sleep behavior disorder

15.3.4. Sleep benefit The term ‘sleep benefit’ has been coined to describe the phenomenon of subjective fluent mobility on awakening from a night sleep (Marsden, 1980; Marsden et al., 1981), even prior to drug intake. Sleep benefit has been estimated or reported from questionnaires to occur in around one-third to one-half of patients with PD (Merello et al., 1997). It has been suggested that accumulation and storage of dopamine in remain dopaminergic nerve terminals underlie sleep benefit (Marsden, 1980; Marsden et al., 1981). About onethird of PD patients report a ‘sleep benefit’ (Currie et al., 1997). Only one study has investigated the phenomenon of sleep benefit using polysomnography (Ho¨gl et al., 1998). Ten patients with clear-cut sleep benefit were matched pairwise to 10 patients without sleep benefit. Patients with sleep benefit showed a distinctive response profile to levodopa, with more severe interdose ‘off’, indicating pharmacodynamic differences between patients with and without sleep benefit. However, polysomnography did not show any significant differences between both groups; there was even a non-significant trend towards more fragmented sleep in patients with sleep benefit (Ho¨gl et al., 1998). 15.3.5. Sleep deprivation in Parkinson’s disease An increased motor response to apomorphine has been found in normal rats after selective REM sleep deprivation (Tufik, 1981) and was also demonstrated in a parkinsonian rat model (Drucker-Colin et al., 1996). Selective REM sleep deprivation per se also produced a significant increase in ambulatory behavior and rearing in another parkinsonian rat model (Andrade et al., 1987). In humans, dopamine D2-receptor binding was modified after total sleep deprivation in patients with major depression (Ebert et al., 1994). The question whether sleep deprivation is able to improve motor performance in patients with PD was addressed by several authors (Bertolucci et al., 1987; Levin, 1991; Reist et al., 1995; Ho¨gl et al., 2001a). Whereas significant motor improvements were reported in the earlier studies (Bertolucci et al., 1987; Levin, 1991;

First described by Schenck and collaborators (1987, 1992), the criteria for RBD are now modified in the new International Classification of Sleep Disorders, ICSD-2 (American Sleep Disorders Association, 2005). To make a diagnosis of RBD, both polysomnographic abnormalities and abnormal behaviors are now required. The criteria require: (1) the presence of REM sleep without atonia in polysomnography; and (2) the presence of sleep-related (potentially) injurious behaviors by history and/or documented during PSG. In contrast to previous criteria, polysomnography is now obligatory to make the diagnosis of RBD (American Sleep Disorders Association, 2005) and includes complex behaviors during REM sleep with a loss of skeletal muscle atonia. Sleep-talking, screaming, dream mentation or nightmares are associated with a variety of movements that may disrupt sleep continuity. The motor activity in RBD may consist of small jerky movements of the extremities – finger or hand twitches – but can also lead to abrupt violent body movements; some patients commonly fall out of bed. Comella and coworkers (1998) found 15% clinically diagnosed RBD in a cohort of PD patients; other data show higher numbers (Gagnon et al., 2002). Our own group found abnormalities of REM sleep in 40% of 45 patients with PD; 24% had REM sleep without atonia, and 16% had full-blown RBD (Wetter et al., 2001). More than one-third of an unselected population of PD patients revealed RBD diagnosed in the sleep laboratory. Depending on the diagnostic criteria of RBD, the prevalence of RBD may vary substantially. When RBD is diagnosed polysomnographically without clinical criteria, those numbers may even increase to up to 60% of Parkinson syndrome patients (Fantini et al., 2005). In atypical Parkinson syndromes such as multiple system atrophy (MSA), RBD is detected polysomnographically in up to 100% of patients (Plazzi et al., 1997; Vetrugno et al., 2004), similar to up to 80% RBD in advanced PD patients (authors’ own observations). Only 50% of polysomnographically diagnosed patients would have been detected by history alone (Eisensehr et al., 2001; Gagnon et al., 2002). However, recent

SLEEP IN PARKINSON SYNDROMES questionnaires or interviews for diagnosing RBD according to ICSD criteria by sleep specialists still lack sufficient interrater reliability (Vignatelli et al., 2005). RBD most likely reflects dysfunction in the brainstem circuitry and the dorsolateral pontine tegmentum, where REM sleep without atonia can be induced in animal experiments. RBD may represent a preclinical marker of a neurodegenerative process in synucleinopathies such as PD and MSA and may precede motor symptoms by years (Schenck, et al., 1996; Iranzo et al., 2006). Neuroimaging studies of patients with characteristic complaints of RBD revealed a marked reduction of presynaptic dopamine transporter binding, indicating early PD or MSA (Eisensehr et al., 2000). Subclinical RBD correlates with the extent of presynaptic dopamine transporter binding in idiopathic RBD (Eisensehr et al., 2003). The duration of REM sleep correlated with fluorodopa uptake as measured by positron emission tomography (PET) in PD patients with RBD (Hilker et al., 2003). RBD as an early sign of PD could be confirmed in a recent study relating olfactory dysfunction to RBD as a possible indicator for a-synucleinopathy measured by dopamine transporter FP-CIT single photon emission computed tomography (SPECT) (Stiasny-Kolster et al., 2005). The distribution of cerebral metabolism assessed with whole brain function perfusion using (99m) Tc-ethylene cysteinate dimer (ECD) SPECT showed hypoperfusion in idiopathic RBD patients consistent with anatomic metabolic profile in PD (Mazza et al., 2006). Controversy exists, however, as to whether RBD and psychosis share a common pathway. Sleep disorders in general seem to be more frequent in PD patients with nocturnal hallucinations (Arnulf et al., 2000) and sometimes difficult to distinguish by clinical history alone. Other authors found that sleep disturbances in PD do not occur as early as olfactory deficits but during the first years of PD (Henderson et al., 2003). In the long term, sleep disorders and RBD are similarly frequent in the PD population with and without hallucinations. Sleep alterations are not necessarily harbingers of hallucinations (Goetz et al., 2005). Experimental studies point to the role of different regulatory centers in the brainstem responsible for either the duration of REM sleep or REM atonia. An excessive GABAergic output from the basal ganglia to the peduncolopontine tegmental nucleus in parkinsonian patients may induce sleep disturbances, including a reduction of REM sleep periods and RBD (REM without atonia) (Takakusaki et al., 2004). RBD may occur in treated or non-treated PD patients and may disturb the patient’s sleep by disagreeable dreams or awakenings, affecting sleep continuity.

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Features of violent or injurious behavior during sleep should be treated for the safety of both patient and bed partner. Some bed partners, however, are anxious and severely confused by the patient’s bizarre nocturnal behavior. RBD may disrupt the relationship between the patient and care-giver and may be the main reason for admittance to a nursing home (Comella et al., 1998). As RBD can be easily treated in most patients with small dosages of clonazepam (0.5–1 mg), the condition should be diagnosed and treated adequately and early (Schenck and Mahowald, 1990).

15.5. Respiratory disorders of sleep in parkinsonism Results of studies on respiration during sleep in PD patients have yielded inconsistent results. In 26 patients with untreated PD and short disease duration, respiration during sleep was found to be normal (Ferini-Strambi et al., 1992). ‘Disorganized’ respiration with frequent central and obstructive apneas was found in patients with parkinsonism and autonomic disturbance (Apps et al., 1985). Some authors reported that apneas were predominantly central (Emser et al., 1987), whereas others mainly observed obstructive apneas (Hardie et al., 1986). More recent studies have demonstrated that obstructive sleep-disordered breathing is present in around 20% of patients with PD (Arnulf et al., 2002). Another study found increased apnea/hypopnea indices mostly without significant oxygen desaturation in 43% of PD patients (Diederich et al., 2005). An abnormal tone of the muscles surrounding the upper airway has been suggested as contributing to sleep-disordered breathing in PD (Vincken et al., 1984). These patients are characterized with upper-airway obstruction during wakefulness and decreased effective muscle strength in pulmonary function testing (Hovestadt et al., 1989). In some patients, upper-airway endoscopy has shown intermittent airway closure due to dyskinetic movements of glottic and supraglottic structures caused by either the disease itself or dopaminergic medications (Vincken et al., 1984). A questionnaire survey found that severe snoring was associated with increased daytime sleepiness in PD, as it is in controls (Ho¨gl et al., 2003b). Upper-airway dysfunction has been reported to be partially responsive to levodopa treatment (Vincken et al., 1989). In patients with advanced parkinsonism, stridor was observed during off dystonia (Corbin and Williams, 1987). Stridor, however, is much more characteristic of MSA. It has been recognized as an adverse prognostic sign regarding survival (Silber and Levine, 2000).

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Stridor may occur during the nighttime only, or extend into daytime. In a study of 10 patients with MSA, all MSA patients displayed snoring, 42% stridor, and 37% obstructive sleep apnea. Breathing and motor abnormalities are often concomitant in the same patient, indicating a diffuse impairment of sleep homeostatic integration that should be included within the diagnostic features of MSA (Vetrugno et al., 2004). Pathophysiologically, a vocal cord paralysis (Isozaki et al., 1996; Kakitsuba et al., 1997; Maurer et al., 1999) which may be uni- or bilateral (Maurer et al., 1999; Silber and Levine, 2000), has been reported to underlie stridor. It has been recognized that mostly vocal cord abductor function is impaired (Blumin and Berke, 2002). In contrast, other authors found that not paralysis, but rather dystonia with persistent tonic EMG activity, is underlying stridor (Merlo et al., 2002). Stridor, which is produced by vibration of the vocal cords (Kakitsuba et al., 1997; Maurer et al., 1999), must be differentiated from ordinary palate snoring (Kakitsuba et al., 1997). Although stridor produces a very characteristic high-pitched sound, care-givers often cannot differentiate between snoring and stridor (Kakitsuba et al., 1997). In some of these patients, specifically in those with MSA, further respiratory abnormalities are present, including reduced ventilatory responses to hypercapnia and hypoxia (Chokroverty et al., 1978; McNicholas et al., 1983; Tsuda et al., 2002; Vetrugno et al., 2004). Tracheostomy (Munschauer et al., 1990) and nocturnal continuous positive-airways pressure (CPAP) therapy have been proposed for the treatment of stridor (Iranzo et al., 2000; Isono et al., 2001). Although positive results with long-term nocturnal CPAP therapy have been reported in MSA (Iranzo et al., 2004), adherence and practicability are still debated in these patients.

15.6. Daytime sleepiness in Parkinson’s disease Excessive daytime sleepiness, not resulting from respiratory problems in PD, is a well-known phenomenon in PD patients. Studies have described an increased risk for causing motor vehicle accidents by sudden sleep onset, so-called ‘sleep attacks’ (Frucht et al., 1999). Those episodes were primarily attributed to the intake of non-ergot dopamine agonists and therefore a variety of studies investigated the effect of dopaminergic drugs on daytime performance and sleepiness in PD patients, leading to controversial results. One study showed an association of daytime sleepiness with more advanced stages of PD, longer disease duration and male sex (Ondo et al., 2001). Other studies could not confirm these results: Higher daily levodopa dosages were predictors of sleep

episodes while driving, whereas gender, age, disease severity and individual dopaminergic agents were not (Brodsky et al., 2003). Patients with PD preselected for sleepiness, however, did not meet those criteria, and sleepiness did not result from pharmacotherapy or sleep abnormalities but was related to the pathology of disease (Arnulf et al., 2002). Dopaminomimetics may exacerbate sleepiness in a small subset of patients, but the primary pathology seems to contribute largely to the development of daytime sleepiness. These patients may benefit from wake-promoting agents such as bupropion, modafinil or traditional psychostimulants (Rye, 2003). An interesting observation reveals that PD patients are not aware of their sleepiness compared to elderly controls. Therefore the patient’s history or excessive daytime sleepiness (EDS) scores may not be helpful; only observation or objective measurements of sleepiness, such as PSG, may solve the question of sleepiness in individual PD patients (Merino-Andreu et al., 2003). The most serious consequence of daytime sleepiness in PD is whether PD patients are allowed to drive and if there should be special tests for sleepiness. As there are different laws in different countries, it is necessary to advise PD patients that sudden sleepiness may occur in the course of the disease and may be attributed to specific dopaminergic drugs. Finally, the patients themselves are responsible for their ability to drive and need to decide individually.

15.7. Treatment of disturbed sleep or impaired wakefulness in Parkinson’s disease Treatment of disturbed sleep and impaired wakefulness in PD principally aims to eradicate possible causes. For instance, if nocturnal akinesia, earlymorning dystonia or painful off periods are causing the sleep problem, optimizing the dopaminergic treatment during the night is the most important step. Optimizing the motor state in general has been shown to improve sleep (Askenasy and Yahr, 1985; Ho¨gl et al., 2003a). In mild cases, nocturnal motor symptoms may disappear with adequate dopaminergic treatment during the day (Askenasy and Yahr, 1985). A number of patients benefit from a bedtime dose of a controlled-release formulation containing 100–200 mg levodopa/25–50 mg dopamine decarboxylate inhibitor (DDCI) (Jansen and Meerwaldt, 1990; Koller et al., 1999). In this context, the advantage of long-acting dopamine agonists, such as cabergoline, become obvious (Ho¨gl et al., 2003a). However, higher dosages of dopamine agonists per se tend to disrupt sleep (Saletu et al., 2001; Happe et al., 2003; Ho¨gl et al., 2003a). Subjectively, this is

SLEEP IN PARKINSON SYNDROMES not necessarily associated with a subjective impairment of sleep because the benefit of dopaminergic treatment predominates over this effect (Ho¨gl et al., 2003a). If causal treatment of the sleep disturbance is not possible, i.e. because of side-effects of dopaminergic treatment or other reasons, treatment should at least be tailored to be as specific as possible (Askenasy, 2001). As has been discussed earlier, sleep-disordered breathing is very frequent in patients with PD. Basically, treatment modes are similar to those for patients without PD. In patients with obstructive apneas and hypopneas, nasal CPAP offers the best chance of success and can be used effectively by most patients with parkinsonism, until the advanced stages of the disease are reached (Askenasy, 2001). For patients with MSA and severe vocal cord dysfunction, tracheostomy is sometimes necessary. Patients with bilateral vocal fold paresis, a life threatening condition, should be treated for their glottic obstruction with CPAP at night or tracheotomy (Blumin and Berke, 2002). Appropriate nasal CPAP therapy may improve the condition of a PD patient substantially, also normalizing nocturnal blood pressure and neuropsychiatric symptoms. Although nasal CPAP therapy is first-line treatment for obstructive sleep apnea (Loube et al., 1999), handling of the CPAP device and the mask is sometimes complicated by impaired mobility and craniofacial dyskinesia. If sleep-disordered breathing is milder, or nasal CPAP cannot be used, intraoral mandibular advancement devices can be a useful alternative (Thorpy et al., 1995; Mohsenin et al., 2003). The improvement achieved with such devices (apnea– hypopnea index reduction) is usually smaller than with CPAP treatment. Some authors have noted that mild snoring or sleep-disordered breathing improves with levodopa therapy (Scha¨fer, 2001; Yoshida et al., 2003), but may not be sufficient to restore sleep in Parkinson syndromes. For REM sleep behavior disorder, clonazepam 0.5–2 mg has been reported to be the treatment of choice (Schenck and Mahowald, 1990). Treatment should be started to avoid these episodes of abnormal sleep behavior interfering with the relationship between patient and care-giver (Comella et al., 1998). If clonazepam is insufficient, melatonin can be tried as an alternative (Kunz and Bes, 1999). Some authors have reported improvement of RBD with dopaminergic therapy, e.g. levodopa (Tan et al., 1996) or pramipexole (Fantini et al., 2003). Quetiapin and clozapin may be useful alternatives, but this has not been formally evaluated. Importantly, RBD may worsen after

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subthalamic nucleus stimulation, possibly due to increased mobility, and may then require additional treatment (Arnulf et al., 2000). As in patients with idiopathic RLS, in PD RLS should first be treated by establishing full body iron stores, because this seems to be an important modulator of RLS severity, not only in the idiopathic form (Allen and Earley, 2001), but also in patients with RLS and PD (Ondo et al., 2002). Ferritin should be elevated above 45 mg/l in patients without inflammatory disease (Allen and Earley, 2001). Tricyclic antidepressants or serotonin reuptake inhibitors may manifest or worsen symptoms of RLS and eventually may have to be stopped in PD patients. Treatment of RLS includes dopaminergic substances, such as treatment of nocturnal akinesia in PD. Long-acting dopamine agonists such as cabergoline or transdermal application may be preferred. Treatment studies are not available. If a nocturnal dopaminergic treatment is not tolerable or insufficient, antiepileptics, such as gabapentin, clonazepam or opiates, are treatment options for RLS in Parkinson syndrome. It is unclear if augmentation, a well-known phenomenon of dopaminergic treatment in idiopathic RLS, occurs in PD patients with RLS. Augmentation is characterized by earlier onset of symptoms throughout the day, or an increase of RLS symptoms despite increase in the drug dose (Allen et al., 2003). Conceivably, these features are difficult to disentangle in patients with PD. Opiates can be used for treating RLS in PD, but the development of sleep apnea (Walters et al., 2001) needs to be closely monitored. Specifically in patients with PD or parkinsonian syndromes, constipation may be a contraindication for opiate treatment. Nocturia has been identified as another cause for sleep fragmentation in patients with PD. In cases of detrusor hyperreflexia, oxybutinin or tolterodine may be tried, but the anticholinergic side-effects must be kept in mind. Intranasal application of desmopressin has been recommended to combat nocturia (Suchowersky et al., 1995), but electrolytes need to be closely monitored to prevent low sodium and related seizures. High doses of dopaminergic treatment in advanced stages of PD may lead to insomnia and require further medication. Tricyclic antidepressants with sedating properties, such as amitryptiline (25–50 mg) or mirtazapine (15 mg) (Gordon et al., 2002), are frequently helpful for sleep-onset insomnia. The anticholinergic effects of tricyclic antidepressants may have therapeutic benefits for daytime parkinsonian symptoms in addition to depression, but they can induce nocturnal delirium in patients with cognitive impairment.

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Symptomatic treatment of sleep disorders in PD implies hypnotics and other sleep-promoting substances. Low-dose short-acting benzodiazepines or benzodiazepine receptor agonists such as low doses of triazolam, flunitrazepam or zolpidem may be tried. A possible worsening of pre-existing sleep-disordered breathing must be taken into account (Schuld et al., 1999). In patients with severe PD and insomnia, sleep fragmentation, akathisia and nocturnal hallucinations, clozapine has been found to improve sleep in general (Trosch et al., 1998). Quetiapin has also been reported to improve sleep, in both PD patients and care-givers (Gimenez-Roldan et al., 2003). Although insomnia complaints are extremely frequent (Tandberg et al., 1998) in patients with PD, there is a severe lack of controlled trials on the efficacy of hypnotics in these patients. The treatment of daytime sleepiness has long been neglected in patients with PD. This may relate to the fact that the increased daytime sleepiness is often unnoticed, even by patients themselves (MerinoAndreu et al., 2003). However, increased daytime sleepiness severely impairs quality of life assessed in patients with narcolepsy (Broughton et al., 1984). The capacity to remain awake is most important for social functioning, and increased daytime sleepiness is associated with increased risk for accidents in patients with PD (Comella, 2002; Hobson et al., 2002). Treatment of daytime sleepiness will first aim to identify causes that can be eliminated, such as sleep-disordered breathing, or sleepiness associated with a certain dopamine agonist. If those causes are absent or cannot be modified, symptomatic treatment comes into the discussion. First-line substance is modafinil, which has been demonstrated to improve subjective sleepiness in placebo-controlled studies (Ho¨gl et al., 2002; Adler et al., 2003). However, the improvements were small and data on long-term efficacy are not available. Methylphenidate is another stimulant which has been used for a long time in narcolepsy. It has been shown to improve apathia in an elderly patient with PD and cognitive impairment (Chatterjee and Fahn, 2002). Stimulants like amphetamines act on the dopamine system, and have previously been investigated for their effects on mobility in PD (Parkes et al., 1975), but possible motor side-effects must be taken into account. For instance, methylphenidate treatment in combination with levodopa has led to an increase in dyskinesia (Camicioli et al., 2001). Bupropion has also been recommended for the treatment of daytime sleepiness in PD (Rye, 2003), based on the reversal of daytime sleepiness in MPTP-lesioned primates (Rye, 2003). The effect of adenosine agonists such as caffeine has not been specifically investigated in PD but the

interaction between adenosine and the dopaminergic system is well recognized (Solinas et al., 2002). In clinical practice, however, the use of stimulants is not a relevant treatment option in PD patients, as the effects are small and side effects have to be considered. Dopaminergic medication may induce visual hallucinations, frequently starting at night, in up to 30% of PD patients (Sharf et al., 1978). PD patients with dementia are at high risk of developing psychiatric side-effects of dopaminergic therapy, and may require a reduced dopaminergic dosage in the afternoon or evening. Nocturnal hallucinations, mostly characterized by a reduction in sleep efficiency, slow-wave sleep and REM sleep, should be treated with low dosages of clozapine (Parkinson Study Group, 1999) that should be slowly increased until a complete remission is achieved. Patients who do not tolerate clozapine may be switched to low-dose quetiapine (12.5–50 mg) that is also appropriate for treatment of PD patients because of its side-effect profile (Fernandez et al., 1999; Reddy et al., 2002). Low dosages of benzodiazepines may be an alternative or additional treatment option in mild psychosis or nocturnal confusion, but no studies in patients with PD are yet available.

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Schenck CH, Bundlie SR, Mahowald MW (1996). Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 46: 388–393. (Erratum in Neurology (1996) 46: 1787.) Schuld A, Kraus T, Haack M et al. (1999). Obstructive sleep apnea syndrome induced by clonazepam in a narcotic patient with REM-sleep-behavior disorder. J Sleep Res 8: 321–322. Sharf B, Moskovitz C, Lupton MD et al. (1978). Dream phenomena induced by chronic levodopa therapy. J Neural Transm 43: 143–151. Silber MH, Levine S (2000). Stridor and death in multiple system atrophy. Mov Disord 15: 699–704. Solinas M, Ferre S, You ZB et al. (2002). Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J Neurosci 22: 6321–6324. Stern M, Roffwarg H, Duvoisin R (1968). The parkinsonian tremor in sleep. J Nerv Ment Dis 147: 202–210. Stiasny-Kolster K, Doerr Y, Moller JC et al. (2005). Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alphasynucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 128: 126–137. Suchowersky O, Furtado S, Rohs G (1995). Beneficial effect of intranasal desmopressin for nocturnal polyuria in Parkinson’s disease. Mov Disord 10: 337–340. Svensson K, Alfoldi P, Hajos M et al. (1987). Dopamine autoreceptor antagonists: effects of sleep–wake activity in the rat. Pharmacol Biochem Behav 26: 123–129. Tagaya H, Wetter TC, Winkelmann J et al. (2002). Pergolide restores sleep maintenance but impairs sleep EEG synchronization in patients with restless legs syndrome. Sleep Med 3: 49–54. Takakusaki K, Saitoh K, Harada H et al. (2004). Evidence for a role of basal ganglia in the regulation of rapid eye movement sleep by electrical and chemical stimulation for the pedunculopontine tegmental nucleus and the substantia nigra pars reticulata in decerebrate cats. Neuroscience 124: 207–220. Tan A, Salgado M, Fahn S (1996). Rapid eye movement sleep behaviour disorder preceding Parkinson’s disease with therapeutic response to levodopa. Mov Disord 11: 214–216. Tandberg E, Larsen JP, Karlsen K (1998). A communitybased study of sleep disorders in patients with Parkinson’s disease. Mov Disord 13: 895–899. Thorpy M, Chesson A, Derderian S et al. (1995). Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances. Sleep 18: 511–513. Traczynska-Kubin D, Atzef E, Petre-Quadens O (1969). Sleep in parkinsonism. Acta Neurol Psychiatr Belg 69: 727–733. Trosch RM, Friedman JH, Lannon MC et al. (1998). Clozapine use in Parkinson’s disease: a retrospective analysis of a large multicentered clinical experience. Mov Disord 13: 377–382. Tsuda T, Onodera H, Okabe S et al. (2002). Impaired chemosensitivity to hypoxia is a marker of multiple system atrophy. Ann Neurol 52: 367–371.

Tufik S (1981). Increased responsiveness to apomorphine after REM sleep deprivation: supersensitivity of dopamine receptors or increase in dopamine turnover? J Pharm Pharmacol 33: 732–733. Vetrugno R, Provini F, Cortelli P et al. (2004). Sleep disorders in multiple system atrophy: a correlative video-polysomnographic study. Sleep Med 5: 21–30. Vignatelli L, Bisulli F, Zaniboni A et al. (2005). Interobserver reliability of ICSD-R minimal diagnostic criteria for the parasomnias. J Neurol 252 (6), 712–717. Vincken WG, Gauthier SG, Dollfuss RE et al. (1984). Involvement of upper-airway muscles in extrapyramidal disorders. A cause of airflow limitation. N Engl J Med 311: 438–442. Vincken WG, Derauay CM, Cosio MG (1989). Reversibility of upper airway obstruction after levodopa therapy in Parkinson’s disease. Chest 96: 210–212. Walters AS, Winkelmann J, Trenkwalder C et al. (2001). Longterm follow-up on restless legs syndrome patients treated with opioids. Mov Disord 16: 1105–1109. Wetter TC, Collado-Seidel V, Pollmacher T et al. (2000). Sleep and periodic leg movement patterns in drug-free patients with Parkinson’s disease and multiple system atrophy. Sleep 23: 361–367. Wetter TC, Trenkwalder C, Gershanik O et al. (2001). Polysomnographic measures in Parkinson’s disease: a comparison between patients with and without REM sleep disturbances. Wien Klin Wochenschr 113: 249–253. Winkelman JW, James L (2004). Serotonergic antidepressants are associated with REM sleep without atonia. Sleep 27: 317–321. Yoshida T, Kono I, Yoshikawa K et al. (2003). Improvement of sleep hypopnea by antiparkinsonian drugs in a patient with Parkinson’s disease: a polysomnographic study. Intern Med 42: 1135–1138. Zucconi M, Ferri R, Allen R et al. (2006). The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med 7: 175–183. Zweig RM, Jankel WR, Hedreen JC et al. (1989). The pedunculopontine nucleus in Parkinson’s disease. Ann Neurol 26: 41–46.

Further Reading Kumru H, Santamaria J, Tolosa E et al. (2004). Rapid eye movement sleep behavior disorder in parkinsonism with parkin mutations. Ann Neurol 56: 599–603. Montplaisir J, Petit D, Decary A et al. (1997). Sleep and quantitative EEG in patients with progressive supranuclear palsy. Neurology 49: 999–1003. Olson EJ, Boeve BF, Silber MH (2000). Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 123: 331–339. Schenck CH, Milner DM, Hurwitz, TD et al. (1989). A polysomnographic and clinical report on sleep-related injury in 100 adult patients. Am J Psychiatry 146: 1166–1173.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 16

Sensory symptoms in Parkinson’s disease RUTH DJALDETTI* AND ELDAD MELAMED Department of Neurology, Rabin Medical Center, Beilinson Campus, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

16.1. Introduction The clinical diagnosis of Parkinson’s disease (PD) is straightforward when the visible motor signs are present. However, at this stage, already more than 30–50% of the dopaminergic neurons are lost (Brooks, 1991; Emami-Avedon et al., 2000; Heiss and Hilker, 2004). Clinical studies have shown that sensory symptoms, such as pain, anosmia and depression, may precede the development of parkinsonism, sometimes by many years, and that they are an integral part of the disease (Witjas et al., 2002). These observations are in line with the pathological finding that the formation of Lewy bodies may begin in the dorsal glossopharyngeal vagus complex in the brainstem and in the olfactory area, even before any change occurs in the substantia nigra pars compacta (Braak et al., 2002, 2003; Del Tredici et al., 2002). Furthermore, using fluorodopa positron emission tomography (PET) and beta-carbomethoxy-3 beta(4-iodophenyl)tropane (ß-CIT) single photon emission computed tomography (SPECT) with dopamine transporter ligands, researchers clearly demonstrated reduced uptake of these ligands in the preclinical stage of the disease. Therefore, directing more attention to the sensory symptoms of PD may help clinicians to make an earlier diagnosis of the disease, with earlier introduction of treatment. This chapter will focus on pain and disturbances in smell and vision, and general sensations in PD.

16.2. Pain 16.2.1. Basal ganglia and nociception The sensory discriminative dimension of pain depends on the intensity, duration, quality and location of the nociceptive stimulus. Other pain dimensions include

the motor, behavioral, affective and cognitive reactions to the stimulus. The involvement of the basal ganglia in motor control, motor processing and execution is well established (Chudler and Dong, 1995). Although less intensively studied, their role in somatosensory processing as well is becoming clearer. Cumulative evidence shows that central pain is usually associated with lesions in the thalamus and that the intralaminar nuclei of the thalamus, which participate in the perception of pain, have major input to the basal ganglia (Berendse and Groenewegen, 1990). Other nociceptive information reaches the basal ganglia through multiple parallel pathways from the sensory areas of the cortex, amygdalae and cingulated cortex (Malach and Graybiel, 1986). Stimulation of the substantia nigra activates neurons in lamina V of the spinal cord, thereby inhibiting the response to nociceptive stimuli (Barnes et al., 1979). The presence of efferent fibers from the basal ganglia to the ventral anterior and ventrolateral complex of the thalamus is well documented. Researchers theorize that the dopamine in the accumbens and striatum modulates the ability of the neocortical and limbic areas involved in sensory, associative and affective processes to influence complex aspects of motor function (Kemel et al., 1988). The explanation for the change in pain perception in patients with PD is based on anatomophysiological studies showing that the basal ganglia contain neurons with somatosensory function (Chudler and Dong, 1995). In rats, nigral neurons have been shown to respond to lowintensity mechanical stimulation, and striat al neurons to noxious stimulation. These neurons have large bilateral cutaneous receptive fields. Increased pain sensitivity has also been reported after injections of 6-hydroxydopamine into the substantia nigra. Furthermore, neuroimaging SPECT studies demonstrated changes in uptake

*Correspondence to: R. Djaldetti, MD, Department of Neurology, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49 100, Israel. E-mail: [email protected], Tel: þ972-3-937-6358, Fax: þ972-3-922-3352.

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of dopaminergic ligands in association with exogenous pain stimuli and in chronic pain syndromes, and human functional magnetic resonance imaging (fMRI) studies showed bilateral activation of the basal ganglia and thalamus in response to hot and cold noxious stimulation (Tracey et al., 2000; Hagelberg et al., 2002). Interestingly, several pain syndromes are also associated with abnormalities in brain dopamine metabolism. PET studies in patients with burning-mouth syndrome, which sometimes coexists with PD, revealed decreased uptake of 6-[18F]fluorodopa in the putamen (Jaaskelainen et al., 2001) and higher D1- and D2-receptor binding in the striatum (Hagelberg et al., 2003). 16.2.2. Clinical syndromes of pain In the 18th century, Gaubius characterized pain as ‘a feeling that the soul will prefer not to experience’. Although naive, this definition reflects the universal attempt to avoid pain, once it has been felt. Today, pain is defined as an unpleasant or distressing sensory experience. Pain is the most common of the sensory symptoms in PD. Despite the lack of objective sensory loss in PD, as many as half of all patients experience pain related to the condition. In 1817, James Parkinson himself described a patient ‘violently affected with rheumatic pain to the finger ends’. Initially, painful sensations were attributed to rigidity and bradykinesia or to side-effects of antiparkinsonian treatment. It was only in the second half of the 20th century that pain and abnormal sensations were recognized as primary symptoms of PD. The secondary pain syndromes in PD are caused by limb rigidity, dystonia, sleep disorders, gastrointestinal problems and neck and back pain. Frozen shoulder (accompanied by pain) due to limb rigidity is one of the presenting symptoms of the disease. Patients are usually first referred to orthopedic specialists for pain relief. Careful examination reveals that the pain is secondary to limitation of limb movement, causing stiffness of the shoulder joint. Painful dystonia is a less common presenting symptom of PD, but is a frequent problem in more advanced stages. Low back pain is also very common in patients with PD, but data on its prevalence and severity compared to the general population are limited. It is possible that low back pain is aggravated by reduced mobility or abnormal gait. The primary pain in PD has different characteristics from the secondary pain syndromes. Patients describe the primary pain as a vague overall sensation of tension, discomfort or paresthesia that is little affected by motion (Snider et al., 1976; Koller, 1984; Quinn et al., 1986; Ford, 1998). In some cases, it is not localized to one anatomic area and may be difficult to pinpoint; in

others, pain occurs in peculiar anatomic areas, such as the genitals, intraoral region (burning-mouth syndrome) and throat (Ford et al., 1996). Other sensations include burning paresthesia, occasionally aggravated by levodopa therapy, and tingling and numbness in the fingers and toes. In a minority of patients, pain is restricted to the limbs. The pain may be episodic, lasting from a few minutes to several hours, or continuous. It is usually unilateral, almost always occurring on the more affected side. If pain is the initial symptom of the disease (10% of patients), the side it is on will predict the side on which the motor symptoms will emerge. Sometimes the pain is so severe that treatment or hospitalization is required. Quantitative clinical studies have indicated that the heat pain threshold is lower in patients with PD compared with healthy subjects. It is also lower in PD patients who experience pain than in patients who do not, and lower on the side with more severe tremor or rigidity. In patients with motor fluctuations, there are no differences in heat pain threshold between ‘on’ and ‘off’ periods, suggesting that neurotransmitters other than dopamine are involved in pain encoding (Djaldetti et al., 2004). Although there is no evidence for the involvement of the spinothalamic system in PD, somatic and tactile hallucinations do occur, albeit very rarely (Fe´nelon et al., 2002). The tactile hallucinations are usually combined with visual hallucinations. Typically, patients sense that the skin is infested by parasites or worms; they feel the worms crawling or biting, and occasionally, they can see the insects. Sometimes, patients feel and see other persons hugging them. The hallucinations respond to a reduction in dopaminergic medications or to neuroleptic agents. It has been suggested that tactile hallucinations result from a narcoleptic-like rapid-eye movement (REM) disorder (Arnulf et al., 2000). As such, hallucinations may be generated by brainstem structures controlling REM sleep. 16.2.3. Therapeutic options for pain The therapeutic approach to pain begins with a thorough inquiry into the nature of the pain and its relation to dopaminergic medications. In the initial stages of disease, levodopa may alleviate pain in some, but not all, patients (Waseem and Gwinn-Hardy, 2001; Gilbert, 2004). The proposed underlying mechanism involves a levodopa-induced increase in heat pain threshold and pain tolerance (Battista and Wolff, 1973). Patients with response fluctuations frequently report pain in the ‘off’ state. In some patients, pain is constant, with no correlation to the ‘off’ or ‘on’ state. If the painful sensations are associated with low doses of levodopa (wearing-off, early-morning dystonia), the best strategy is to increase the dose in order to

SENSORY SYMPTOMS IN PARKINSON’S DISEASE prevent motor fluctuations (Waseem and GwinnHardy, 2001). Apomorphine is useful in patients with severe ‘off’ periods, in whom pain does not respond to analgesic agents (Factor, 2004). If pain is associated with high doses of levodopa (dyskinesias, dystonia), the dopaminergic medications should be reduced. Dopamine is probably not the only neurotransmitter involved in pain modulation. Findings of high levels of morphine-like factors, namely, Met-enkephalin, substance P and dynorphin (Shu et al., 1988, 1990), and upregulation of opiate receptors in the striatum point to their possible role in somatosensory responses (Simantov et al., 1976). In cases in which pain is unrelated to levodopa therapy, the approach used in neuropathic central pain may be effective, namely, a combination of serotonin reuptake inhibitors, anticholinergic agents, opioid receptor-mediating agents, and new-generation antiepileptic medications, especially gabapentin (Fox et al., 2003; Bischofs et al., 2004). Thus far, there are no controlled studies examining this issue. Some researchers propose that a decrease in opioid peptide function in PD may disrupt the ‘finetuning’ of the pain-modulatory function of melatonin and facilitate the emergence of sensory symptoms. This line of treatment should be explored as well. Deep brain stimulation seems to be effective when medication adjustments fail to control the motor symptoms and pain. Several studies have shown that unilateral or bilateral pallidal or subthalamic stimulation can alleviate pain and dysesthesias in more than 40% of patients (Loher et al., 2002; Lozano and Hamani, 2004). The specific target area still needs to elucidated. Alternative treatments, such as acupuncture, although not beneficial for the motor symptoms, might relieve pain and other sensory symptoms (Shulman et al., 2002). We expect such complementary therapies eventually to take on a larger analgesic role in PD, though controlled studies are still needed to evaluate their efficacy.

16.3. Disorders of olfaction Olfactory loss is prevalent in PD and was first documented in 1975 (Ansari and Johnson, 1975). The dysfunction involves perceptual and semantic processes, such that patients fail to detect, discriminate and identify different odor categories (Quinn et al., 1987; Sobel et al., 2001; Tissingh et al., 2001). It can also indirectly affect other symptoms, such as weight loss, because it diminishes the pleasure of eating, which triggers appetite. The olfactory deficits occur in the preclinical stages of the disease, and have also been found in asymptomatic family members (Berendse et al., 2001; Ponsen et al., 2004). Pathological studies show that

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the neurodegenerative process in PD slowly rises via the postganglionic autonomic fibers to the vagus nerve in the brainstem, and then spreads to the olfactory neurons (Braak et al., 2002, 2003; Del Tredici et al., 2002). This evidence suggested that there is a widespread extranigral pathology in PD, and that one of the earliest sites affected is the olfactory bulb and related portions of the anterior olfactory region, which contain packed dopaminergic neurons. The formation of Lewy bodies in these areas precedes the involvement of the substantia nigra. As dopamine is known to inhibit olfactory transmission, the degeneration of these areas may be responsible for the early hyposmia in PD. Interestingly, patients with PD have been found to possess twice as many dopaminergic cells in the olfactory bulb as healthy individuals (Huisman et al., 2004). The pattern of smell loss appears to be specific to idiopathic PD, as opposed to other parkinsonian syndromes, and is not present even in PD patients with the parkin mutation (Muller et al., 2002; Katzenschlager and Lees, 2004; Khan et al., 2004). The latter observation suggests that different pathogenetic mechanisms are involved in the neurodegenerative process. It is still unclear if the degree of dysfunction in odor discrimination is associated with disease duration and severity, which might make at least some aspects of olfactory dysfunction in PD a secondary degenerative effect. Although the extent of nigral degeneration in PD can be visualized years before the clinical diagnosis by PET and SPECT imaging of the brain with dopaminergic ligands, these methods are costly and difficult to apply. Several researchers have therefore suggested that clinical smell tests, such as the University of Pennsylvania Smell Identification Test (UPSIT), may be useful as an early marker of PD onset, with confirmation in positive cases by ß-CIT SPECT. Smell tests and CIT SPECT with the dopamine transporter ligand detected a group of hyposmic asymptomatic firstdegree relatives of patients with PD with reduced ß-CIT binding. After 2 years, 10% of these patients had developed clinical PD. The rate of decline in dopamine transporter binding in the hyposomic patients was significantly greater than in the relatives with normal olfaction (Ponsen et al., 2004). The same holds for individuals with REM sleep behavior disorder and hyposmia (Stiasny-Kolster et al., 2005). These findings hold promise for the effectiveness of neuroprotective therapy, when it becomes available. Despite loss of olfactory function, olfactory hallucinations are rare in PD. The odors reported are burning rubber or grass and decaying fish (Tousi and Frankel, 2004). The involvement of the olfactory system in the pathogenesis of PD also has therapeutic implications

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for the symptomatic clinical stage. Studies using a 6-hydroxydopamine-induced rat model of PD have shown that transplantation of olfactory ensheathing cells (cultured from the olfactory bulb), which express a high level of growth factors, into the striatum can restore the chemical and functional abilities of this region (Agrawal et al., 2004).

16.4. Visual disorders Visual disturbances, though not common in PD, were reported as early as the 1980s. They have since been confirmed by clinical, psychophysiological and neurophysiological investigations (Haug et al., 1994; BodisWollner, 1997; Rodnitzky, 1998). The presence of visual disturbances is not surprising, as dopamine is a major retinal neurotransmitter and has been identified in the amacrine and interplexiform retinal cells, lateral geniculate nucleus and visual cortex (Kramer, 1971; Harnois and Di Paolo, 1990). The most frequent vision-related abnormalities in PD are loss of color discrimination, spatiotemporal contrast sensitivity and color contour perception (Bodis-Wollner et al., 1987; Price et al., 1992; Buttner et al., 1995a). Studies with the Farnsworth-Munsell 100-hue test have demonstrated a significant elevation in total and partial error scores for color discrimination ability in PD. The relation between impaired color discrimination and disease severity and duration remains unclear because of the small size of most of the study samples and because the patients were already being treated with antiparkinsonian medications at the time of the test, which could have affected the results. No correlation was found using [123]ß-CIT SPECT, suggesting that the color vision dysfunction is not directly related to the dopaminergic nigrostriatal degeneration and perhaps involves an extranigral lesion (Muller et al., 1998). The average latency of visual evoked potentials in patients with PD exceeds that of age-matched subjects, and over two-thirds of all patients have abnormal latency (Bodis-Wollner and Yahr, 1978; Bhaskar et al., 1986). The phase shifts in the non-linear visual evoked potentials components indicate a dysfunction in temporal processing. As the dysfunction is at times transient, researchers believe there may be an ‘input’ temporal frequency-dependent abnormality in the foveal pathway. Color fusion time is used to evaluate the acuity of the perception of monochromatic contours. Measurements are performed with a computer-aided method. Patients with PD have been found to have a shortened fusion time, especially for dark green, light blue and dark red stimuli (Buttner et al., 1995a).

Neuropsychological tests of basic visual perception, complex perceptual discrimination and spatial orientation demonstrate decreased spatial orientation functioning (Bodis-Wollner and Paulus, 1999; Bodis-Wollner, 2003). Visuospatial working memory and attentional set-shifting seem to be selectively impaired in the early stages of the disease. Electrophysiological studies also demonstrate dysfunction of higher-level visuocognitive information processing, reflecting an impairment in neural assemblies involving the basal ganglia, dorsal visual stream and frontal–prefrontal circuits. Age may also affect the visuocognitive responses in PD: studies of visuocognitive event-related potentials in young and older patients showed a greater central processing time in the younger group (Lieb et al., 1999). At the retinal level, patients with PD show reductions in photopic, scotopic and pattern-derived electroretinograms, all correlated with the clinical stage of the disease (Sartucci et al., 2003). The significant error in chromatic discrimination and other vision dysfunctions in PD may be due to altered intraretinal dopaminergic synaptic activity (Peppe et al., 1998) as a consequence of systemic dopaminergic deficiency. Optical coherence tomography studies reveal loss of the circumpapillary retinal nerve fiber layer, especially in the inferior quadrant (Inzelberg et al., 2004). Some of the deficits, which are consistent with physiological studies, suggest that the dopaminergic deficiency may affect the center–surround interaction of the neurons. The visuospatial deficits, however, are not simply passive reflections of retinal deficiency. Additional pathology beyond the retina may also play a role in visual responses. This is supported by the finding that saccadic eye movements are affected in PD (Rascol et al., 1989). Whether these changes contribute directly to the visuospatial dysfunction is still unknown, although recent fMRI and electroencephalogram studies have pointed to an essential role of the occipital cortex in saccadic eye movements (Elbel et al., 2002; Rogers, 2003). Accordingly, visual and eye movement studies suggest that certain neuropsychiatric and cognitive deficits in PD are linked to the visual system. The hallucinations in PD may reflect the increased dopaminergic transmission, or they may be part of the visual dysfunction. Visual hallucinations are by far the most common type of hallucinations in PD; with an estimated frequency of almost 40% of patients. Risk factors are age and dementia. Visual perception in demented PD patients with hallucinations is worse than in demented patients without hallucinations (Mosimann et al., 2004). The visual hallucinations are characterized by benign, non-threatening figures of people, animals, insects or stereotypic, brightly colored moving images.

SENSORY SYMPTOMS IN PARKINSON’S DISEASE There is indirect evidence suggesting the presence of inclusions in the outer plexiform layer of the retina in a patient with Lewy body dementia (Maurage et al., 2003), implying involvement of the retina in the pathogenesis of visual hallucinations. An fMRI study identified cortical activation patterns associated with visual hallucinations (Stebbins et al., 2004). In hallucinating patients, external visual stimuli did not activate regions of the posterior cortex, as seen in nonhallucinating patients, but they hyperactivated anterior cortical regions (frontal cortex, caudate nucleus). This finding is in line with the decreased cerebral blood flow to the temporal lobe and temporo-occipital regions (Okada et al., 1999) and the presence of Lewy bodies in the temporal lobe, specifically the amygdala and parahippocampus (Harding et al., 2002) documented in PD patients. This type of activation can predispose individuals to hallucinations, as the decreased responsiveness to external perceptions (monitored by the posterior cortex) and the increased frontal activation give rise to a sensory visual experience. The combination of aberrant visual perception, decreased retinal dopamine level and disruption of the occipitofrontal circuits provides the pathogenetic mechanism for visual hallucinations. Both visual hallucinations and color discrimination disability significantly influence contour perception of certain stimuli (Buttner et al., 1996; Diederich et al., 1998). These data, combined with the finding that disease stage, duration and severity do not seem to have a significant effect on chromatic contour perception (Muller et al., 1998), suggest that the distorted contour perception is due to impairment at a central stage of visual processing in PD and an imbalance of the serotonergic system. There are only a few studies on the effect of medications on the visual abnormalities in PD. One group reported that abnormal delays in visual evoked potentials were normalized with levodopa/carbidopa therapy in 9 of 14 previously untreated parkinsonian patients (Bhaskar et al., 1986). Levodopa also improved contrast sensitivity (Bulens et al., 1987; Hutton et al., 1993; Mestre et al., 1996) and color vision in PD patients (Buttner et al., 1994). The role of amantadine in the treatment of vision abnormalities is unclear. Amantadine produced a significant shortening in the latency of the event-related potential (P300) in a visual discrimination paradigm, but the effect on the timing of the primary visual evoked potentials was minimal or absent (Bandini et al., 2002). In another study, there was no difference in the total error scores of the Farnsworth-Munsell 100-hue test before and after amantadine sulfate infusion (Buttner et al., 1995b).

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Apomorphine has the potential to reverse vision abnormalities in cases of retinal dopamine depletion. Systemic administration of apomorphine in toads increased the discharge rates of retinal class R2 and R3 ganglion cell fibers in response to visual objects traversing their excitatory receptive fields (Glagow and Ewert, 1997). In PD patients, there was a significant improvement of achromatic static contrast sensitivity, but the effects on color discrimination were marginal (Buttner et al., 2000). We can conclude from these data that dopamine deficiency in the basal ganglia and the visual system plays a role in the underlying pathophysiology of the distorted color vision in PD. However, the minor response to dopaminergic treatment implies that other anatomical structures and neurotransmitters are involved as well.

16.5. Disorders of other senses Hearing and taste are apparently not involved in PD, although they may not yet have been sufficiently studied to reach definitive conclusions. The only reference to the possible involvement of the auditory system is the rare report of auditory hallucinations. Auditory hallucinations in PD, if present, are usually unformed; the voices the patients hear are indistinct and incomprehensible, and do not contain any commands (Inzelberg et al., 1998). There are only a few case reports of PD patients with well-formed and threatening auditory hallucinations, similar to those in schizophrenia (Factor, 2004). The mechanism underlying the development of auditory hallucinations is a genetic mutation that increases susceptibility in both PD and schizophrenia, or the presence of Lewy bodies in the temporal lobe (Harding et al., 2002).

16.6. Conclusions Although described more than 20 years ago, the nonmotor complications of PD, especially the sensory symptoms, have attracted less attention than the motor complications, and data on their prevalence remain sparse. Nevertheless, in some patients, pain may cause greater distress than motor symptoms. In addition, the sensory symptoms, such as abdominal or chest pain, may mimic respiratory, gastrointestinal or cardiac emergencies, and their better recognition could spare patients unnecessary investigations and useless treatments. The recognition of other sensory impairments in PD would help physicians to diagnose the disease earlier, long before the motor symptoms emerge. When neuroprotective agents become a more important part of the armamentarium of PD, sensory symptoms will serve to

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identify the patients at risk who require more expensive and accurate diagnostic procedures. Finally, further research of these symptoms will reveal other anatomic sites affected and clarify the pathogenesis of PD.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 17

Speech disorders in Parkinson’s disease and the effects of pharmacological, surgical and speech treatment with emphasis on Lee Silverman voice treatment (LSVTÒ) LORRAINE OLSON RAMIG1,2,3*, CYNTHIA FOX3 AND SHIMON SAPIR4 1

Department of Speech, Language and Hearing Sciences, University of Colorado-Boulder Department of Speech, Denver, CO, USA 2

Columbia University, New York, NY, USA

3

National Center for Voice and Speech, Denver, CO, USA

4

Department of Communication Sciences and Disorder, Faculty of Social Welfare and Health Studies, University of Haifa, Haifa, Israel

17.1. Introduction The reduced ability to speak is considered to be one of the most difficult aspects of Parkinson’s disease (PD) by many patients and their families. Nearly 9 out of 10 people with PD have a speech or voice disorder. The common perceptual features of reduced loudness (hypophonia), reduced pitch variation (monotone), breathy and hoarse voice quality and imprecise articulation, (Darley et al., 1969a, b; Logemann et al., 1978; Scott and Caird, 1981), together with lessened facial expression (masked facies), contribute to limitations in communication in the vast majority of these individuals (Pitcairn et al., 1990a, b; Adams, 1997). People with PD are much less likely to participate in conversations or have confidence in communication, compared with healthy aging adults (Fox and Ramig, 1997). Successful treatment of the speech disorder in PD has been challenging. In fact, historically, it has been concluded that speech treatment does not work for people with PD (Sarno, 1968; Allan, 1970; Greene, 1980; Weiner and Singer, 1989). Most recent statistics report that, although 89% of individuals with PD have a speech and voice disorder, only 3–4% receive speech treatment (Oxtoby, 1982; Hartelius and Svensson, 1994).

There are a number of explanations for this discrepancy. One factor is that, because speech treatment has previously not been successful for PD, physicians do not refer patients for speech treatment. In addition, early in the disease, the patient often successfully compensates for the problems (performs to external cue in the physician’s office) and is unaware of a speech problem. A common scenario is that ‘a soft-speaking, monotone’ individual with PD arrives at the physician’s office and denies any problem with speech. The physician is able to understand the person with PD since they are talking in a quiet examination room and so no referral for speech treatment is made. At each annual visit, this scenario is repeated. Many years pass and the communication abilities of the person with PD continue to decline; he or she reduces activities (talks on the phone less, limits social events and may retire from employment or volunteer activities). By the time the speech disorder is obvious in the physician’s quiet examination room, the disorder has had a major negative impact on the person with PD’s quality of life for years. When the referral for speech treatment is finally made, the treatment may be more challenging and the outcome less positive due to the severity of the speech disorder and the likely progression of other symptoms of PD which make focusing on speech treatment difficult.

*Correspondence to: Lorraine Olson Ramig, PhD, CCC-SLP, Department of Speech, Language and Hearing Science, University of Colorado-Boulder and National Center for Voice and Speech, Denver, Campus Box 409, Boulder, CO 80305, USA. E-mail: [email protected], Tel: þ1-303-492-3023; Cell: 917-541-3291.

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Medical treatments, including neuropharmacological as well as neurosurgical methods, may be effective in improving limb symptoms; however, their impact on speech production remains unclear (Rigrodsky and Morrison, 1970; Wolfe et al., 1975; Larson et al., 1994; Baker et al., 1997; Ghika et al., 1999; Kompoliti et al., 2000; Wang et al., 2002). In addition, previous speech treatment approaches for people with PD, focusing on articulation and rate, have limited efficacy data and limited evidence of long-term success. Recently, however, a speech treatment approach called Lee Silverman voice treatment (LSVT) has generated the first high-quality level I efficacy data for successfully treating voice and speech disorders in this population. This chapter will: (1) briefly review speech and voice characteristics associated with PD; (2) discuss medical, surgical and behavioral speech treatment approaches for PD; (3) provide an overview of the LSVT speech treatment approach and efficacy data; and (4) highlight future directions in speech treatment for PD.

17.2. Speech and voice characteristics in Parkinson’s disease Disorders of laryngeal, respiratory and articulatory function have been documented across a number of perceptual, acoustic and physiological studies in people with PD (Leanderson et al., 1971, 1972; Beukelman, 1989; Moore and Scudder, 1989; Yorkston, 1996; Yorkston et al., 1997; Baker et al., 1998). Although the neural mechanisms underlying these voice and speech disorders are unclear (Hanson and Metter, 1983; Estenne et al., 1984; Hoodin and Gilbert, 1989a, b; Ackermann and Ziegler, 1991; Ackermann et al., 1997), they have traditionally been attributed to the motor signs of the disease (rigidity, bradykinesia, hypokinesia and tremor). An additional explanation for the speech and voice impairment in PD is a deficit in the sensory processing related to speech (Ho et al., 1999a, 2001; Sapir et al., 2002). This section will review characteristics of speech and voice impairment in people with PD, including laryngeal and respiratory disorders, articulatory disorders and deficits in sensory processing related to speech. 17.2.1. Laryngeal and respiratory disorders Darley et al. (1975) described perceptual characteristics of speech and voice in people with PD (Darley et al., 1969a, b). They identified reduced loudness, monopitch, monoloudness, reduced stress, breathy, hoarse voice quality, imprecise articulation and short rushes of speech as the classic features of speech and

voice in people with PD. Collectively these speech symptoms are called hypokinetic dysarthria (Darley et al., 1975). Logemann and colleagues (1978) conducted a study with 200 people with PD to examine vocal tract control and to quantify and describe features of the disorder. In the study 89% of the people with PD presented with laryngeal disorders, comprising breathiness, hoarseness, roughness and tremulousness. Ho et al. (1998) and Sapir and colleagues (2002) both reported that voice problems were first to occur in people with PD; other speech problems (prosody, articulation and fluency) gradually appeared later and accompanied more severe motor signs. Acoustic descriptions of voice characteristics of people with PD have also been documented. Vocal sound pressure level (SPL) has been measured. Early studies varied in reporting a reduction in vocal SPL in these people (Canter, 1963, 1965a, b; Ludlow and Bassich, 1983, 1984; Metter and Hanson, 1986). However, Fox and Ramig (1997) compared 29 people with PD with an age- and gender-matched control group and found that vocal SPL was 2–4 dB (at 30 cm) lower across a number of speech tasks in people. A 2–4 dB change is equal to a 40% perceptual change in loudness (Fox and Ramig, 1997). Furthermore, Ho and colleagues (2001) found that the voice intensity of people with PD decayed much faster than that observed in a healthy comparison group during various speech tasks. Results related to fundamental frequency (acoustic correlate of pitch) in the speech of people with PD have consistently reported reduced frequency (Canter, 1963, 1965a, b; Ludlow and Bassich, 1984; Metter and Hanson, 1986; Fraile and Cohen, 1995). Fundamental frequency variability has been reported to be consistently lower in people with PD as compared to healthy aging people (Canter, 1965a, b; Ludlow and Bassich, 1984). These findings support the perceptual characteristics of monopitch or monotonous speech typically observed in this patient population (Darley et al., 1969a, b; Logemann et al., 1973). Disordered laryngeal function has been documented through a number of imaging studies of the vocal folds (videoendoscopic studies). Hansen et al. (1984) reported vocal fold bowing (lack of medial vocal fold closure) in 30 out of 32 people with PD. Smith and colleagues (1995) documented that 12 of 21 people with PD in their study demonstrated a form of glottal incompetence (bowing, anterior or posterior chink) on flexible fiberoptic views. Perez et al. (1996) studied 29 people with PD and observed that 50% of them demonstrated difficulties with phase closure of the vocal folds, 46% demonstrated an asymmetrical vibratory pattern and 55% had laryngeal tremor (with vertical laryngeal tremor being the most common).

SPEECH DISORDERS IN PARKINSON’S DISEASE Additional data to support laryngeal closure problems in people with PD come from the work of Luschei et al. (1999), who studied single motor unit activity in the thyroarytenoid (TA) muscle in people with PD and suggested that the firing rate of the TA motor units was decreased in males with PD in the study. The investigation reported that this finding, as well as those in past studies, suggests that PD affects rate and variability in motor unit firing in the laryngeal musculature. Baker et al. (1998) found that absolute TA amplitudes during a known loudness level task in people with PD were lowest for the group of people with PD when compared to young normal adults and normal aging adults. Relative TA amplitudes were also decreased in both the aging and PD groups when compared to the young normal adults. The authors concluded that reduced levels of TA muscle activity may contribute to the reduced vocal loudness that is observed in people with PD and aging populations. A number of studies have documented evidence of disordered respiratory function in people with PD. Researchers reported reduced vital capacity (Cramer, 1940; Laszewski, 1956; De La Torre et al., 1960), a reduction in the total amount of air expended during maximum phonation tasks (Mueller, 1971), reduced intraoral air pressure during consonant/vowel productions (Mueller, 1971; Marquardt, 1973; Solomon and Hixon, 1993) and abnormal airflow patterns (Vincken et al., 1984; Schiffman, 1985). The origin of these respiratory abnormalities may be related to variations in airflow resistance resulting from abnormal movements of the vocal folds and supralaryngeal area (Vincken et al., 1984) or abnormal chest wall movements and respiratory muscle activation patterns (Estenne et al., 1984; Murdoch et al., 1989; Solomon and Hixon, 1993). 17.2.2. Articulatory disorders Imprecise consonants have been observed in people with PD (Cramer, 1940; Logemann et al., 1973, 1978). Logemann et al. (1973, 1978) reported articulation problems in 45% of the 200 unmedicated people with PD they studied. Sapir et al. (2001) found abnormal articulation in 50% of 42 medically treated people with PD. Disordered rate of speech has also been reported in some people with PD. Whereas rapid rates, or short rushes of speech, have been described in 6–13% of people with PD (Canter, 1965a, b; Hansen et al., 1984; Hammen et al., 1989; Adams, 1997), Canter (1965a) found slower than normal rates. Pallilalia or stutteringlike speech dysfluencies have been observed in some people with PD (Darley et al., 1969a; Sapir et al., 2001).

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Acoustic correlates of disordered articulation have been studied and include problems with timing of vocal onsets and offsets (voicing during normally voiceless closure intervals of voiceless stops) and spirantization (presence of fricative-like, aperiodic noise during stop closures) (Uziel et al., 1975; Weismer, 1984; Ackermann and Ziegler, 1991). In another study (Forrest et al., 1989), dysarthric speakers with PD showed longer voice onset times (VOTs) than normal. Such abnormal VOTs may reflect a problem with movement initiation (Forrest et al., 1989), which may be related to deficits in internal cueing, timing and/or sensory gating (Ackermann and Ziegler, 1991; Sapir et al., 2001). Disordered articulatory movements have been documented in people with PD through kinematic analysis of jaw movements (Hirose et al., 1981; Caligiuri, 1987, 1989a, b; Conner et al., 1989; Conner and Abbs, 1991). Researchers consistently report that people with PD show a significant reduction in the size and peak velocity of jaw movements during speech when compared to healthy people with normal speech (Conner et al., 1989; Forrest et al., 1989; Dromey, 2001). The reduction in range of movement has been attributed to rigidity of the articulatory muscles (Gath and Yair, 1988; Rosenfeld, 1991); however, this may be related to a problem with sensorimotor perception and/or scaling of speech and non-speech movements (Ackermann and Ziegler, 1991; Ho et al., 1998, 1999a, b, 2000). Electromyographic (EMG) studies of the lip and jaw muscles in people with and without PD have provided some evidence for increased levels of tonic resting and background activity (Leanderson et al., 1971, 1972; Netsell et al., 1975; Hunker and Abbs, 1984; Moore and Scudder, 1989) as well as for loss of reciprocity between agonist and antagonistic muscle groups (Leanderson et al., 1971, 1972; Hirose et al., 1981; Hunker and Abbs, 1984; Hirose, 1986). These findings are consistent with evidence for abnormal sensorimotor gating in the orofacial and limb systems, which are presumably related to basal ganglia dysfunction (Schneider et al., 1986; Caligiuri and Abbs, 1987; Schneider and Lidsky, 1987). Whether or not these abnormal sensorimotor findings are indicative of excess stiffness or rigidity in the speech musculature is not clear (Caligiuri, 1987; Caligiuri and Abbs, 1987; Conner et al., 1989; Conner and Abbs, 1991). 17.2.3. Sensory observations Although the speech problems associated with PD are considered to be related to the motor dysfunctions of the disease, sensory problems in these people have

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been recognized for years (Barbeau et al., 1962; Koller, 1984; Schneider and Lidsky, 1987). Numerous investigators documented sensorimotor deficits in the orofacial system (Schneider et al., 1986; Caligiuri and Abbs, 1987; Diamond et al., 1987; Schneider and Lidsky, 1987) and abnormal auditory, temporal and perceptual processing of voice and speech (Schneider et al., 1986; Schneider and Lidsky, 1987; Ackermann and Ziegler, 1991; Solomon et al., 1994; Ho et al., 1999a, b, 2000; Graber et al., 2002), and they have been implicated as important etiologic factors in speech and voice abnormalities secondary to PD (Fox et al., 2002). Behavioral evidence from limb and speech motor systems for sensory-processing disorders in PD include errors on tasks of kinesthesia (Demirci et al., 1997; Jobst et al., 1997; Klockgether et al., 1997); difficulties with orofacial perception, including decreased jaw proprioception, tactile localization on tongue, gums and teeth, and targeted and tracking head movements to perioral stimulation (Schneider et al., 1986); problems utilizing proprioceptive information for normal movement (Schneider et al., 1986; Jobst et al., 1997); and abnormal higher-order processing of afferent information, as demonstrated by abnormal reflex and voluntary motor responses to proprioceptive input (Rickards and Cody, 1997). Overall, the basal ganglia may be an area in the brain where sensory information related to movement is filtered (Schneider et al., 1986), in that it ‘gates out’ sensory information when it is not relevant for a motor action, or when it is overly familiar. Thus one aspect of PD might include complex deficits in the utilization of specific sensory inputs to organize and guide movements. Problems in sensory perception of effort have been identified as an important focus of successful speech and voice treatment (Ramig et al., 1995b). Specifically, it is often observed that soft-speaking people with PD report that their voices are not reduced in loudness, but rather, their spouse, ‘needs a hearing aid’ (Marsden, 1982; Fox and Ramig, 1997). When these same people are asked to speak in a louder voice, they often comment, ‘I feel like I am shouting‘, despite the fact that listeners judge the louder voice to be within normal range. If persons with PD hear a tape recording of themselves using increased loudness, they can easily recognize that their voice sounds within normal limits, despite the fact they feel they are talking too loud. This suggests that the breakdown may be in online feedback (auditory and proprioceptive) while speaking. Two areas of research have begun exploring evidence of a sensory component to the speech disorder in PD. Liotti et al. (2000) examined neuroimaging data (positron emission tomography (PET)) in people with

PD during voice and speech tasks. Preliminary data documented that people with PD, as compared to non-PD control people, demonstrated an overactivation of auditory cortex during overt speech motor activity, suggesting impaired audiovocal gating. This finding may be relevant to the phenomenological observation that people with PD complain that they are ‘too loud’ when they try to increase their loudness to a normal level. Another area of work examined sensory (auditory) feedback control on speech of a person with PD using behavioral perturbations of both amplitude (loudness) and pitch (frequency) during voicing tasks pre/ postspeech treatment (LSVT; Houde et al., 2004). Pre-LSVT the person with PD demonstrated a lack of vocal response to perturbations in amplitude and pitch feedback while sustaining the vowel ‘ah’, consistent with impaired audiovocal gating. Post-LSVT, behavioral responses (as measured by audio recordings) to perturbations in speech feedback revealed that this individual developed a faster, more automatic to perturbations as a result of LSVT response. Thus, preliminary data suggest that people with PD may have altered cortical responses to pitch and amplitude perturbations, which are modified immediately post-LSVT training. Future research into the nature of this apparent impaired audiovocal gating in people with PD and its role in speech disorders is needed. 17.2.4. Summary of Parkinson-related speech dysfunction In summary, perceptual, acoustic, physiological and sensory processing data have documented varying degrees of dysfunction in different aspects of speech in people with PD. The most common perceptual speech characteristics are reduced loudness, monopitch, hoarse voice and imprecise articulation. Acoustic studies of speech of people with PD appear to parallel perceptual studies and have shown evidence of reduced vocal SPL, reduced vocal SPL range, reduced fundamental frequency range and abnormal articulatory acoustics, such as spirantization. Physiological studies of articulatory muscles have revealed reduced amplitude and speed of movements from a kinematic analysis, EMG activity and abnormal vocal fold closure patterns. Finally, sensory studies have revealed sensorimotor deficits that include errors on tasks of kinesthesia, difficulties with oral facial perception, including decreased jaw proprioception, tactile localization on tongue, gums and teeth, and targeted and tracking head movements to perioral stimulation. The neurophysiological mechanisms underlying speech and voice disorders in PD are still

SPEECH DISORDERS IN PARKINSON’S DISEASE poorly understood at this time, particularly in regard to deficits in sensory processing.

17.3. Treatment for speech and voice disorders Management of speech and voice disorders in people with PD has been challenging for both medical and rehabilitation practitioners. Current treatments for speech and voice disorders in people with PD consist of medical therapies, surgical procedures, behavioral speech therapy or a combination thereof (Schultz et al., 1999; Schultz and Grant, 2000). Medical therapies alone are not as effective for treating speech symptoms as they are for limb motor symptoms. Thus, speech symptoms are often grouped with other axial symptoms (e.g. balance, gait, posture) that are also considered less responsive to traditional medical therapies. At this time, a combination of medical therapy (e.g. optimal medication) with behavioral speech therapy appears to offer the greatest improvement for speech dysfunction (Schultz et al., 1999). There are a number of papers that have reviewed the literature related to speech treatment in PD, including medical, surgical and behavioral interventions for this population (Schultz and Grant, 2000; Anon., 2002; Yorkston et al., 2003; Pinto et al., 2004). The following review of treatment options will help guide physician choices for recommendations for speech treatment. 17.3.1. Medical treatments Neuropharmacological approaches for the treatment of PD have had positive outcomes on motor function. However, the impact of these treatments on speech, voice and swallowing production is highly variable across published reports. Although some studies have reported general positive effects of levodopa on limb function (Rigrodsky and Morrison, 1970; Mawdsley and Gamsu, 1971; Wolfe et al., 1975; Mawdsley, 1973; Nakano et al., 1973; Critchley, 1981), the magnitude and consistency of improvement in speech tend to be less impressive (Rigrodsky and Morrison, 1970; Wolfe et al., 1975). More recent studies reported little variation in speech, voice and respiratory characteristics at different points in the drug treatment cycle (Solomon and Hixon, 1993; Larson et al., 1994). In a review of speech treatment options, Pinto et al. (2004) reported that pharmacological methods of treatment alone do not appear to improve voice and speech function in PD people significantly. The actions of pharmacological therapies on speech and voice functioning in people with PD are not well

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understood. Reports in the literature cite variable responses to medication, with no report documenting a consistent and significant impact of functional communication abilities in people with PD. This may explain the nearly identical prevalence of voice and articulation abnormalities in medicated (85.7%; Sapir et al., 2001) and unmedicated (89%; Logemann et al., 1978) people with PD. Studies by Kompoliti et al. (2000) and Wang et al. (2002) proposed that laryngeal and articulatory speech components, like gait, postural instability and cognitive impairment that are also not responsive to dopaminergic therapy, are in fact caused by non-dopaminergic lesions. These studies are important in that they emphasize the need for speech impairments to be treated primarily via non-pharmacologic methods. At this time, pharmacological treatment alone is not sufficient for managing the symptoms of hypokinetic dysarthria in people with PD. 17.3.2. Surgical treatments Recently, much attention has been paid to the effects of neurosurgery, in particular deep brain stimulation procedures, on speech and voice of people with PD. The results of studies looking at speech outcomes postsurgery are variable (Pinto et al., 2004). Ablative surgeries, including pallidotomy and thalamotomy, had significant negative effects on speech, voice and swallowing following bilateral surgery and variable results following unilateral surgery (Countryman and Ramig, 1993; Ghika et al., 1999). Pinto et al. (2004) summarized published studies looking at the effects of deep brain stimulation on speech and reported that thalamic stimulation, although it improved some motor components of speech, had a worsening effect on perceptual assessment and electrophysiological measurements of speech postsurgery. Pallidal stimulation was observed as having both beneficial and worsening effects for perceptual assessment of speech postsurgery. Similarly, studies examining speech following deep brain stimulation of the subthalamic nucleus (DBS-STN) reported variable outcomes for perceptual assessment of speech and electrophysiological measurements (Pinto et al., 2004). Pinto et al. (2004) concluded that, of the surgical therapies, DBS-STN had some efficacy for improving subcomponents of speech (e.g. lip movements). However, there was an overall worsening of speech intelligibility when it was clinically assessed. In a 5-year follow-up study of bilateral DBS-STN in advanced PD, significant postoperative improvements occurred in all parkinsonian motor signs except speech when the people were off dopaminergic medication (Krack et al., 2003).

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At this time, speech and voice disorders appear to be less responsive to deep brain stimulation surgeries than global limb motor functioning. This outcome may be predictable given that DBS-STN should improve levodopa-responsive symptoms. Since speech disorders in PD do not respond well to levodopa, it can be predicted that they will not respond well to DBSSTN. This does not account for the appearance of speech symptoms postsurgery when there were no presurgery speech problems or the worsening of speech symptoms after surgery. One hypothesis for these unpredictable outcomes is that there is a spread of voltage to surrounding structures that negatively impacts speech (Pinto et al., 2004). Based upon stimulation site within the STN, speech outcomes may vary in a predictable manner. If the voltage spread is in proximity to the internal capsule, the result in speech may be characterized by hesitations and face muscle tightness, whereas proximity to cerebellothalamic fibers may result in speech characterized by slurred articulation and stuttering. It has also been suggested that speech functioning may be susceptible to micro lesioning as a result of electrode placement resulting in worsening of speech postsurgery, particularly when the placement is in the dominant hemisphere (Wang et al., 2003). Further research into the effects of DBS-STN is needed to understand fully its impact on speech in people with PD. Another surgical intervention that has been reported in the literature is fetal cell transplantation in people with PD. Baker and colleagues (1997) observed the limited effect of fetal dopaminergic cell transplant on speech functioning of people with PD. Similar to DBS-STN, the people with PD who had fetal cell transplantation surgery improved limb motor functioning, but not speech. Other surgical procedures include augmentation of vocal folds with collagen. Hill et al. (2003) augmented the vocal folds of 12 people with collagen injections and achieved temporary improvement in hypophonia, with an average benefit lasting 7.8–8.5 weeks. Although augmentation of vocal folds will help with the laryngeal aspect of speech disorders in people with PD, it does not address the sensory aspect of the speech disorder. It may be that, for people with PD who have moderate to severe degrees of incomplete vocal fold closure, a combination of vocal fold augmentation and behavioral speech therapy will offer the greatest improvements. Current data reveal that neuropharmacological and neurosurgical approaches alone do not improve speech and voice consistently and significantly (Schultz et al., 1999; Pinto et al., 2004). Behavioral speech therapy should be considered as an adjunct for improving speech and voice, even for optimally medicated

people with PD and for those who have undergone neurosurgical procedures. 17.3.3. Behavioral speech and voice therapy for PD For many years, speech and voice disorders in people with PD were considered resistant to traditional behavioral speech therapy (Sarno, 1968; Allan, 1970; Greene, 1980; Weiner and Lang, 1989; Aronson, 1990). Although changes in speech may be achieved in the treatment room, the challenge of carry-over and long-term treatment outcomes has been encountered consistently over a wide range of speech therapies that have been applied to this population (Adams, 1997). These approaches have included training in control of speech rate, prosody, loudness, articulation and respiration (Yaryura-Tobias et al., 1971). Speech therapy with assistive instruments, such as delayed auditory feedback, voice amplification devices and pacing boards, have also shown limited long-term success (Helm, 1979; Downie et al., 1981; Adams, 1997). Reviews of evidence-based practice for behavioral speech therapy for people with PD have been reported in the literature (Anon., 2002) and will be summarized here (Yorkston et al., 2003; Deane et al., 2004a, b). The Evidence Based Medical Review for the Treatments of Parkinson’s Disease, sponsored by the Movement Disorder Society, published a review of speech therapy for PD in 2002. This review reported that there were a varied number of speech therapies reported in the literature, but very few clinical trials. This report critiqued four level I randomized controlled studies with the following inclusion criteria: randomized controlled studies, treatments with a duration of at least 2 weeks, a minimum of 10 people with idiopathic PD, and objective assessments of speech functioning before and after the speech therapy protocol. One of the four critiqued studies was a combination of two published articles on the same group of people with PD (Ramig et al., 1995a, 1996). The Johnson and Pring (1990) and Robertson and Thompson (1984) studies compared a speech therapy protocol to no therapy in people with PD. The Ramig et al. (1995a, 1996) and Scott and Caird (1983) studies compared two forms of speech therapy in people with PD. Summary findings from this review concluded that there was insufficient evidence to conclude on the efficacy of speech therapy in the following areas: (1) prevention of disease progression in PD; (2) as a sole treatment in any indication of PD; (3) as an adjunct treatment to medication and/or surgery; (4) in preventing motor complications in PD; and (5) on motor and non-motor complications of PD.

SPEECH DISORDERS IN PARKINSON’S DISEASE The authors recommended that future clinical research should include larger, randomized, prospective and controlled studies. In addition, the use of functional neural imaging studies to examine people with PD before and after speech therapy to determine the functional and anatomic changes related to speech treatment was suggested. Furthermore, the authors proposed that behavioral speech therapies should be intensive and focus on loudness or prosody based on the evidence reviewed (Scott and Caird, 1983; Johnson and Pring, 1990; Ramig et al., 1996). Since the publication of the Movement Disorders review, other level I studies for speech therapy in PD have been published. One study by Ramig and colleagues (2001a) was independently reviewed by the primary author of the section responsible for speech therapy and it was concluded to be of high-quality level I evidence (Goetz, personal communication). Deane and colleagues in a Cochrane Review (2004a, b) also examined behavioral speech therapy studies. These authors included only randomized controlled studies and analyzed quality of the studies based on Consolidated Standard of Reporting Trials (CONSORT) guidelines. In two publications, the results of studies comparing speech therapy to a placebo or no intervention and studies comparing two forms of speech therapy were analyzed. In the first publication three randomized controlled trials totaling 63 people comparing speech and language therapy with placebo or no intervention for speech disorders in PD were examined. These studies included Johnson and Pring (1990), Roberston and Thompson (1984) and Ramig et al. (unpublished data). The authors concluded that there was insufficient evidence to prove or disprove the benefit of speech and language therapy for speech disorders in people with PD due to the methodological flaws, the small number of people examined and the possibility of publication bias. In the second publication two randomized controlled trials totaling 71 people with PD comparing two different forms of speech therapy were analyzed. These studies included Scott and Cairn (1983) and Ramig et al. (1995a). Again, the authors concluded there was insufficient evidence to support or refute the efficacy of one form of speech therapy over another. Both of the Cochrane Review publications were based upon studies published before February 2001. Currently, an update of information from the Cochrane Review for speech therapy and PD is taking place. The updated Cochrane Review will include and analyze randomized controlled studies that have been published or are in progress from 2001 to the present. Members of the Academy of Neurologic Communications Disorders and Sciences reviewed the evidence for behavioral management of respiratory and

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phonatory dysfunction from dysarthria, including studies of speech therapy for people with PD (Yorkston et al., 2003). These authors did not limit their review to randomized controlled trials; rather they included case, single subject and group designs. The strength of evidence was based upon the following factors: type of study (e.g. case, single subject, group), primary focus of treatment (e.g. biofeedback, LSVT), number of people, medical diagnosis, replicability, psychometric adequacy (e.g. reliability), evidence for control, measures of impairment, measures of activity or participation and study conclusions. For speech therapy related to PD, this review included three studies of biofeedback devices totaling 39 people; five studies with devices (e.g. delayed auditory feedback) totaling 16 people; 14 studies of LSVT totaling 90 people; and three miscellaneous studies of group treatment (Yorkston et al., 2003). Conclusions from the review reported that LSVT has the greatest number of outcome measures associated with any speech treatment examined. Furthermore the authors summarized that for the most part outcomes were positive and can be interpreted with confidence (Yorkston et al., 2003). Recommendations for future research for biofeedback, devices and group treatment approaches included having a larger number of people in studies, well-controlled replicable and reliable studies of well-defined populations and control or comparison group studies (randomized controlled studies). Recommendations for future research in LSVT included additional documentation of longterm maintenance effects, large multisite effectiveness studies (clinical trials), alternative modes of administration (e.g. different dosages of intensity) and further study of treated people with PD to define better predictors of success or failure with the treatment.

17.4. Intensive voice treatment for Parkinson’s disease The newest and generally perceived state-of-the-art treatment for PD is the LSVT (Yorkston et al., 2003; Pinto et al., 2004). The fundamentals of LSVT are based upon the hypothesized features underlying the voice disorder in people with PD (Fox et al., 2002). These features include: (1) an overall amplitude scale-down of the speech mechanism (reduced amplitude of neural drive to the muscles of the speech mechanism) that may result in a ‘soft voice that is monotone’ (Barbeau et al., 1962; Penny and Young, 1983; Albin et al., 1989); (2) problem in sensory perception of effort that prevents a person with PD from accurately monitoring his/her vocal output (Barbeau et al., 1962; Berardelli et al., 1986); resulting

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in (3) the individual’s difficulty in independently generating (internal cueing/scaling) the right amount of effort to produce adequate loudness (Stelmach, 1991; Demirci et al., 1995). Key elements of LSVT and details on outcome measures that range across perceptual, acoustic and physiological levels are summarized. LSVT is based upon elements derived from neurology, physiology, motor learning, muscle training and neuropsychology. LSVT integrates clinical concepts and techniques from literature in the areas of motor speech and voice in a manner specifically designed for people with PD. In addition, LSVT is administered in a manner consistent with principles of exercise science (Frontera et al., 1988; Brown et al., 1990), skill acquisition (Verdolini, 1997) and motor learning (Schmidt and Lee, 1999) (e.g. high effort, multiple repetitions, intensive, simple), together with a focus on sensory awareness. Furthermore, LSVT adheres to rules of experience-dependent neuroplasticity (Kleim and Jones, 2005). These elements have previously not been systematically combined in a speech treatment program for people with PD (Yorkston, 1996) and may contribute to the success of LSVT as compared to previous speech treatment approaches (Fox et al., 2002). The five essential concepts of the LSVT include: (1) focus on voice (increased amplitude of movement/increased vocal loudness); (2) improve sensory perception of effort, i.e. ‘calibration’; (3) administer treatment in a high-effort style; (4) intensity (four times a week for 16 sessions in 1 month); and (5) quantify treatment-related changes. The LSVT approach centers on a specific therapeutic target: increasing vocal loudness (increasing amplitude of movement). This key target acts as a trigger to increase effort and coordination across the speech production system. By incorporating sensory awareness training with motor exercises, LSVT facilitates acceptance and comfort with increased loudness, and the ability to self-monitor vocal loudness. Addressing this apparent sensory challenge in people with PD may facilitate generalization and maintenance of treatment effects. Furthermore, a simple, redundant and intensive treatment may help accommodate the processing speed, memory and executive function deficits observed in some individuals with PD, and promote overlearning and internalization of the vocal effort required for normal loudness (Fox et al., 2002). Incorporation of systematic education, homework exercises and carry-over tasks (e.g. assignments to use new loud voice outside the treatment room) further assist in generalization of therapeutic gains to daily living situations. Findings from initial treatment studies on 45 people with PD documented posttreatment SPL increases

ranging from 8 to 13 dB SPL (at 30 cm, across a variety of speech tasks) for those treated with LSVT compared to an alternative treatment group (respiratory treatment; changes from 1 to 2 dB) (Ramig et al., 1995a). Follow-up studies documented that these SPL increases were maintained for the LSVT group to 1 year (Ramig et al., 1996) and 2 years posttreatment (Ramig et al., 2001a). An additional 44 people (15 treated PD, 15 untreated PD and 14 healthy age-matched control group) were studied over 6 months and findings were similar (Ramig et al., 2001b). The data from these combined studies (Ramig et al., 1995a, 1996, 2001a, b) offer strong support for the short- and long-term efficacy of voice treatment for PD. People who had intensive voice treatment (LSVT) had significant improvements in vocal fold closure, as measured by videostroboscopy as well as electroglottography (Smith et al., 1995; Garren et al., 2000), subglottal air pressure (2–3 cm H2O) and maximum flow declination rate (200–300 l/l per s) (Ramig and Dromey, 1996). An alternative treatment group (respiratory) did not improve on these measures. Increased vocal effort in the LSVT-treated group improved vocal fold valving to contribute to increased vocal SPL and improved speech production. There was no evidence of increased vocal hyperfunction (unwanted strain or excessive vocal fold closure) posttreatment in any person with PD (Ramig et al., 1995a; Smith et al., 1995; Garren et al., 2000). These findings are further supported by perceptual reports (Baumgartner et al., 2001; Sapir et al., 2002) documenting increased loudness and improved voice quality accompanying LSVT. Taken together, these findings support the positive impact of voice treatment for people with PD. These studies have also provided important information about mechanisms underlying speech and voice disorders in PD and have identified fundamental elements of treatment-related change. Data have documented that successful speech treatment generates other important effects across the vocal tract, encompassing positive changes in articulation, swallowing and facial expression (Dromey et al., 1995; El Sharkawi et al., 2002; Spielman et al., 2003). Preliminary imaging results with PET have identified posttreatment changes consistent with improved neural functioning in two studies (Liotti et al., 1998, 2003; Narayana et al., 2005). Specifically, pre-LSVT, loud phonation in people with PD activated cortical premotor areas, particularly supplementary motor area. In the same people with PD post-LSVT, cortical premotor activity during spontaneously loud voicing (LSVTinduced) normalized hyperactivity in the supplementary motor area and increased activity in the basal

SPEECH DISORDERS IN PARKINSON’S DISEASE ganglia (right putamen), suggesting a shift from abnormal cortical motor activation to more normal subcortical organization of speech motor output. Furthermore, post-LSVT changes in people with PD demonstrated an increase in activity in right anterior insula and right dorsolateral prefrontal cortex. Right insula activation has been associated with nonlinguistic vocalization (singing, emotional expressive prosody) and emotional expression. This suggests, along with right hemisphere lateralization of postLSVT effects in people with PD, that LSVT may recruit a phylogenetically old, preverbal communication system involved in vocalization and emotional communication. Challenges that diminish treatment outcomes with LSVT include people with PD who have severe depression, moderate to severe dementia, atypical parkinsonism (e.g. multiple system atrophy, progressive supranuclear palsy) or people who have had neurosurgery for their PD (e.g. deep brain stimulation). These people are more challenging to treat during therapy due to factors such as difficulty working to maximum effort, more difficulty staying on task, easily confused or on/off drug effects. Frequently the ultimate treatment outcomes are adjusted for these people with advanced PD or those who have had surgical intervention. Instead of striving for self-generated improved loudness in daily conversation, the end treatment goal may be self-generated loudness in 10 functional phrases and cued loudness during conversational speech. Although treatment outcomes are adjusted in these individuals, they can, and do, make significant gains in communication abilities that are important to both the person with PD and his or her family members. The documentation of level I evidence for the efficacy of behavioral speech therapy for speech and voice disorders associated with PD is ongoing. To date, LSVT appears to be the most promising form of behavior therapy to address the type of speech impairments experienced by people with PD.

17.5. Summary and future directions Positive gains have been made over the years towards recognizing key variables for successful speech treatment outcomes in people with PD. Ongoing and future investigations have the potential to clarify further underlying mechanisms of speech disorders in PD while addressing key variables for improving speech treatment outcomes. Some areas of ongoing research include: (1) increasing accessibility/feasibility to intensive speech therapy (e.g. LSVT) through use of technology; (2) applying principles of successful

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speech therapy (LSVT) to limb motor systems and creating a combined amplitude-based speech and physical therapy program (Big and Loud); and (3) evaluating the potential neurorestorative impact of exercise-based speech therapies in individuals with PD. 17.5.1. Increasing accessibility to speech therapy An area of continued research is addressing the practical challenges of delivering speech treatment intensively (four individual sessions a week for 4 weeks). Halpern et al. (2004, 2005) reported on the use of a personal digital assistant, as an assistive device for delivering LSVT to people with PD. This personal digital assistant, named the LSVT companion (LSVTC), was designed to meet the challenges of treatment accessibility and frequency that people with PD often encounter. The LSVTC is specially programmed to collect data and provide feedback as it guides people through the LSVT exercises, enabling them to participate in therapy sessions at home. Fifteen people with PD participated in this study, during which nine voice treatment sessions were completed with a speech therapist and seven sessions were completed independently at home utilizing the LSVTC. Acoustic data collected in a sound-treated booth before and after the 16 treatment sessions demonstrated that, following treatment, the people with PD made significant gains in vocal loudness across a variety of voice and speech tasks. These results were similar to previously published data on 16 face-to-face sessions both immediately posttreatment and at 6-month follow-up (Halpern et al., 2004, 2005). These pilot findings support the feasibility of the LSVTC and further development of technology-based approaches to enhance treatment accessibility. An evolution of the LSVTC has been the development of an LSVT virtual speech therapist (LSVTVT). This is a perceptive animated character, modeled after expert LSVT speech therapists, that delivers LSVT in a computer-based program. This work builds upon the well-established foundation of experimental efficacy data (Ramig et al., 1995a, 1996, 2001a, b) and state-of-the-art learning tools, incorporating intelligent animated agents (Cole et al., 1998, 1999, 2003; Stone, 1999; Barker, 2003; COLIT03; LLOUD03). A prototype of the LSVTVT has been developed and clinical testing has begun. In addition, research into the effectiveness of delivering intensive speech therapy via telehealth systems or other web-enabled speech therapy systems will continue to enhance accessibility to the intensive sensorimotor training that is important for successful speech outcomes.

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17.5.2. Principles of speech therapy applied to limbs Recently, principles of LSVT/Loud were applied to limb movement in people with PD (Training Big) and have been documented to be effective in the short term (Farley et al., 2004). Specifically, trainingincreased amplitude of limb and body movement (Bigness) in people with PD has documented improvements in amplitude (trunk rotation/gait) that generalized to improved speed (upper/lower limbs), balance and quality of life (Farley et al., 2004; Farley and Koshland, 2005). In addition, people were able to maintain these improvements when challenged with a dual task. The extension of this work to a novel integrated treatment program that simultaneously targets speech and limb motor disorders in people with PD (Training Big and Loud) has been proposed. Results from pilot work in 3 people with PD who received Big and Loud treatment revealed that they all improved amplitude of speech (SPL/loudness) and limb movements (reaching or gait) posttreatment. The gains in speech and limb movement were comparable to previously published data from independently training Loud or Big, respectively (Fox and Farley, 2004). Furthermore, these gains were maintained for most measures up to 6 months posttreatment (Fox et al., 2005). There is a great need to simplify rehabilitation approaches for people with PD due to the progressive nature of the disorder, cognitive challenges that make motor learning difficult and logistical and financial burdens that intensive speech and physical therapies present. A whole-body, amplitude-based treatment program may be one possible solution. 17.5.3. Neurorestorative/neuroprotective effects of exercise in Parkinson’s disease

functional recovery (neurorestorative) and increased levels of dopamine in the striatum (Fisher et al., 2004). Key elements of exercise in animal models that promoted neuroprotection or neurorestoration included intensive training of motor tasks, increased practice of motor tasks, active engagement in tasks and the sensory experience of the motor task (Uziel et al., 1975; Fisher et al., 2004). A behavioral speech therapy (LSVT/Loud) that targets sensorimotor deficits in people with PD and incorporates elements such as single focus (increased loudness/amplitude), intensive training (4 days/week for 4 weeks), multiple repetitions and sensory retraining (Fox et al., 2002) has been documented (Ramig et al., 2001a, b). These principles are consistent with literature citing key elements of exercise that contribute to neuroplasticity and brain reorganization in animal models of PD (Fisher et al., 2004) and human stroke-related hemiparesis (Liepert et al., 1998). We need future studies to evaluate specifically the impact of intensive behavioral speech therapy on neuroplasticity and the potential for neuroprotection, as measured by dopamine-related changes in imaging studies over time. Preliminary studies of PET-related changes pre/post-LSVT have already documented treatment-dependent functional reorganization in people with PD. These findings include recruitment of the right hemisphere, and activation of motor regions in the left hemisphere, such as the thalamus and presupplementary motor area (Liotti et al., 2003; Narayana et al., 2005). These data suggest that speech therapy may go beyond treating the symptoms of PD and may have the potential to impact progression of speech disorders associated with the disease over time.

17.6. Conclusion Recent advances in neuroscience have brought exercise to the forefront of therapeutic options for people with PD. The potential neuroprotective effects of exercise in animal models of PD, and key aspects of exercise that contribute to neuroplasticity, compel the need for well-defined exercise-based behavioral speech treatments in individuals with PD (Tillerson et al., 2001; Kleim et al., 2003; Taub, 2004). Increased physical activity has been shown in animal models of PD to be neuroprotective (reversal of symptoms, attenuation of dopamine loss) if initiated at the time of exposure to a toxin (Tillerson et al., 2001, 2003). A more recent study has shown that, in animal models where dopamine cells are allowed to degenerate to levels equivalent to humans at the time of diagnosis of PD, progressive exercise promoted

The majority of people with PD experience speech and voice disorders at some point during the disease course and these deficits impair their quality of life. Medical and surgical treatments alone have not sufficiently alleviated speech disorders for people with PD. Thus a combination of behavioral speech therapy, specifically the LSVT approach, in medically managed people with PD appears at present to be the most effective type of speech intervention, though more level I studies are needed. There are many exciting avenues of ongoing and future speech research that will clarify our understanding of the underlying mechanism of speech disorders in PD and impact development of rehabilitation strategies over the next decade.

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Acknowledgments This chapter has been supported in part by NIHNIDCD grants R01 DC-01150, R21 DC05583, and R21 DC006078; select portions of this chapter have been published previously.

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Further Reading Connor NP, Abbs JH, Cole KJ et al. (1989). Parkinsonian deficits in serial multiarticulate movements for speech. Brain 112: 997–1009. Logemann JA (1998). Evaluation and Treatment of Swallowing Disorders 1st edn Austin, Texas. Pro-Ed Publisher; Pro-Ed Publisher, Austin, Texas. Riecker A, Mathiak K, Wildgruber D et al. (2005). MRI reveals two distinct cerebral networks subserving speech motor control. Neurology 64 (4): 700–706.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 18

Clinical features, pathophysiology and treatment of dementia associated with Parkinson’s disease MURAT EMRE* Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul, Turkey

18.1. Introduction Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease (AD), has been considered to be the prototypical disease of movement, whereas AD represented the prototypical disease of cognition. The cognitive aspects of PD have been largely ignored for many years. However, as the life expectancy of patients with PD became longer, cognitive dysfunction and dementia associated with the disease, which tend to emerge more in advanced age, became more apparent. In fact, it was recently described that 36% of those in an incident cohort of PD patients had evidence of cognitive impairment, suggesting that cognitive dysfunction is an inherent feature of the disease (Foltynie et al., 2004). Dementia associated with PD (Parkinson’s disease dementia, PDD) has thus been increasingly more recognized and there has been extensive research into its epidemiology, clinical characteristics, underlying neurochemical deficits and neuropathology. These efforts yielded a number of results, revealing that PD is frequently associated with a characteristic dementia, which differs from AD in many ways. This chapter will be devoted to the description of epidemiology, clinical features, associated biochemical and neuropathological changes, diagnostic aspects and management of PDD.

18.2. Epidemiology There have been a number of cross-sectional, populationbased as well as prospective cohort studies to investigate the frequency of dementia among patients with PD.

These studies all revealed that both prevalence and incidence of dementia are significantly higher in patients with PD, as compared to demographically comparable controls. Other features of the disease associated with, and the risk factors predictive of, dementia in PD were also identified. 18.2.1. Prevalence of dementia in Parkinson’s disease The prevalence figures for PDD differ substantially across studies depending on the populations included, assessment methods used, diagnostic tools and possibly also how dementia was defined. A meta-analysis of 27 earlier studies suggested a prevalence rate of 40% (Cummings, 1988). Results from several crosssectional, population-based studies revealed comparable figures. An older study including all identifiable patients in southern Finland reported a prevalence rate of 29% (Marttila and Rinne, 1976). In a study in the New York area, covering 180 000 inhabitants, Mayeux et al. (1992) found a prevalence rate of 41%, and in a comparable study in Norway covering a population of 220 000, a prevalence rate of 28% was reported (Aarsland et al., 1996). 18.2.2. Incidence of dementia in Parkinson’s disease It was questioned if demented patients with PD are accurately reflected in prevalence studies, because they may not survive as long as those who are not demented (Marder et al., 1991). In this respect incidence figures usually provide a more reliable estimate

*Correspondence to: Murat Emre, MD, Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, 34390 C¸apa Istanbul, Turkey. E-mail: [email protected], Tel/Fax: 90-212533-8575.

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of frequency as they are prospective and thus relatively free of survival bias. In earlier studies, with relatively short duration and smaller number of patients, the incidence figures were reported to be four times higher than controls (Mindham et al., 1982; Rajput et al., 1987). In a larger study with a 5-year followup, the incidence rate was reported to be six times higher than in controls (Aarsland et al., 2001a), whereas in another study with follow-up for 5 years, the incidence rate was 69 per 1000 person-years; by the age of 85 the risk of dementia was 65% (Mayeux et al., 1990). The cumulative incidence of dementia in patients with PD was assessed in several prospective studies with a sizeable number of patients and long follow-up times. In most of these studies patients free of dementia at baseline were included and the occurrence of newly emerging dementia was assessed after variable lengths of time. In one of these studies, conducted in Australia, after 5 years of follow-up, dementia was diagnosed in 62% of patients with PD who were free of this condition at baseline, as compared to 17% of controls (Reid et al., 1996). In a similar study conducted in the UK, the cumulative incidence of dementia was 38% after 10 years and 53% after 14 years (Hughes et al., 2000; Read et al., 2001). Finally, in a prospective study in Norway, 8-year follow-up of patients, of whom 26% already had dementia at baseline, revealed a cumulative incidence of 78% (Aarsland et al., 2003a). 18.2.3. Risk factors Risk factors for dementia in PD have been described in both cross-sectional studies as associated features, as well as in studies involving prospective follow-up of patient cohorts free of dementia at baseline as features predictive of incident dementia. In cross-sectional studies age at onset, age at the time of evaluation, duration of the disease, presence of depression and atypical neurological features such as early occurrence of autonomic failure, symmetrical disease presentation and unsatisfactory response to dopaminergic treatment have been described to be associated with dementia (Mayeux et al., 1988, 1992; Aarsland et al., 1996). It was also suggested that left body involvement may represent a risk factor for PDD (Tomer et al., 1993). In prospective studies similar features were described to be predictive; in addition several baseline characteristics were found to be predictive of incident dementia. These included age at onset and at the entry to the study, severity of the motor disability, cognitive scores at baseline, confusion or psychosis while being treated with levodopa, early occurrence of drug-related halluci-

nations, axial involvement such as speech impairment and postural imbalance, presence of depression, smoking and excessive daytime sleepiness (Mayeux et al., 1990; Starkstein et al., 1992, Stern et al., 1993; Marder et al., 1995, Goetz et al., 1998; Levy et al., 2000; Aarsland et al., 2001a; Read et al., 2001; Gjerstad et al., 2002; Levy et al., 2002a). With regard to behavioral symptoms, the presence of psychosis at baseline seems to be a predictor of poor prognosis: in a longitudinal study of 59 psychotic patients dementia was diagnosed in 68% 26 months later (Factor et al., 2003). Among cognitive features, poor verbal fluency at baseline was found to be significantly and independently associated with incident dementia (Jacobs et al., 1995). Similarly, poor performance on verbal memory (Levy et al., 2002a) and the presence of subtle involvement of executive functions at baseline were reported to predict the emergence of dementia at follow-up (Woods and Troster, 2003). Advanced age emerges as one of the most significant risk factors in both cross-sectional and prospective studies: In the population-based study reported by Mayeux et al. (1992), the prevalence was zero in patients below the age of 50 but 69% above the age of 80. Similarly, in a group of 91 patients who were entered in a prospective observational study, the prevalence was 37% versus 9% in patients whose disease had begun after or before the age of 70, respectively; after 5 years’ follow-up the prevalence of dementia had risen to 62% and 17% respectively (Reid et al., 1996). It seems that the combination of old age and severe motor symptoms is particularly detrimental: patients with old age and severe disease had 9.7-fold increased risk for incident dementia as compared to young patients with mild disease (Levy et al., 2002b). As younger patients with high severity and older patients with low severity of motor symptoms did not show a significantly increased risk, a combined effect of age and disease severity was assumed. Rapid-eye movement (REM) sleep behavior disorder is frequently seen in patients with PD; this may be even more the case in patients who eventually develop dementia. A close correlation between synuclein pathology and REM sleep behavior disorder (RBD) has been described; a striking observation was that RBD preceded dementia or parkinsonism by a median of 10 (range 2–29) years. The authors suggested that in the setting of degenerative dementia or parkinsonism, RBD often reflects an underlying synucleinopathy (Boeve et al., 1998, 2003).

18.3. Clinical features Patients with PD are usually elderly individuals and they are prone to develop disorders of old age as much

CLINICAL FEATURES, PATHOPHYSIOLOGY AND TREATMENT as their peers without PD. Therefore, they can theoretically be affected by all types of etiologies which can cause dementia in the population at large, including symptomatic forms, such as vascular dementia, or other degenerative dementias, such as AD. The clinical profile of dementia in such cases will be compatible with the underlying etiology. Dementia is, however, highly prevalent in PD, suggesting that the disease process itself is responsible for the dementia syndrome encountered in PD. This dementia syndrome associated with PD has characteristic clinical features, which can be best subsumed as a dysexecutive syndrome with prominent impairment of attention, visuospatial dysfunction, moderately impaired memory and accompanying behavioral symptoms such as apathy and psychosis (Emre, 2003a). The cognitive, behavioral and other associated features of PDD are summarized in Table 18.1.

Table 18.1 Cognitive features of dementia associated with Parkinson’s disease as compared to Alzheimer’s disease

Cognitive domaine Attention

Memory

Executive functions Language

18.3.1. Cognitive features 18.3.1.1. Attention and psychomotor speed Impaired attention is an early and prominent feature of patients with PDD (Litvan et al., 1991). Impairments in reaction time, vigilance and fluctuating attention were found to be comparable to those seen in patients with a similar condition, dementia with Lewy bodies (DLB) (Ballard et al., 2002). Patients with PDD have longer response times in both measures of simple and choice reaction time, suggesting that their central processing time is also prolonged in addition to motor slowing. Compared to patients with AD, PDD patients were found to be more apathetic and to have more prominent cognitive slowing (bradyphrenia) (CahnWeiner et al., 2002); the magnitude of cognitive slowing was found to be disproportionate to the general level of cognitive performance (Pate and Margolin, 1994). 18.3.1.2. Executive functions Executive functions are defined as the ability to plan, organize and perform goal-directed behavior; by that virtue they also include skills such as insight and foresight. Impairment in executive functions is the core feature of dementia syndrome associated with PD. Deficits in executive functions have been demonstrated in tasks measuring rule-finding, problem-solving, planning, set elaboration, set shifting and set maintenance (Pillon et al., 2001). In structured scales of cognitive functions PDD patients were found to have lower initiation, perseverance and construction subscores, but higher memory subscores (Aarsland et al., 2003b). Patients have more difficulties with internally cued behavior, i.e. when they have to develop their own strategies or pace them-

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Visuospatial functions

Dementia associated with Parkinson’s disease Prominent impairment with fluctuations Less impaired, retrieval deficits

Early and prominent impairment as the core feature Impaired verbal fluency, no impairment in core language functions Early, disproportionate and prominent impairment

Alzheimer’s disease Less impaired, fluctuations not usual Severely impaired, prominent storage deficits as the core feature Impairment only in later stages Early impairment, becomes more prominent with progression Less impaired, becomes prominent only with disease progression

selves; their performance improves substantially when external cues are provided. Patients with frontal cortical damage have comparable deficits; it was suggested that difficulties in patients with PDD may have a different mechanism, being rather due to inability in shifting attention to novel stimuli than perseverative errors due to lack of suppression of inadequate responses, which are typically seen in patients with frontal lobe damage (Owen et al., 1993). Abnormalities in executive functions occur early in the course of PDD and are prominent throughout the course (Pillon et al., 1986, 2001; Huber et al., 1989a; Litvan et al., 1991; Cahn-Weiner et al., 2002). One exception is insight – insight is usually preserved in patients with PDD as opposed to those with AD (Galvin et al., 2003). 18.3.1.3. Memory All memory functions are impaired in PDD, including working memory, explicit memory, involving both verbal and visual modalities and implicit memory, such as procedural learning. Deficits in working memory can be found already early in the disease course (Kensinger et al., 2003). The relative severity of amnesia as compared to other cognitive deficits, and the profile of impairment in different memory functions, differ from those seen in AD. In explicit memory

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patients with PDD have been consistently reported to have deficits in learning new material; these deficits are however less severe than those seen in patients with AD (Helkala et al., 1989; Pillon et al., 1991; Stern et al., 1993). In PDD the memory impairment is characterized by a deficit in free recall with preserved recognition, indicating that information storage is achieved, but memory traces are not readily accessed and the timely recall is compromised; when structured cues or multiple choices are provided, retrieval is facilitated (Helkala et al., 1988; Pillon et al., 1993; Noe et al., 2004). In fact, memory scores in patients with PDD were found to be correlated with performance in executive function tests (Pillon et al., 1993). Based on this observation it was suggested that impairment of memory in PDD may rather be due to difficulties in accessing of memory traces because of deficiency in internally cued search strategies, as part of the dysexecutive syndrome (Pillon et al., 2001). This is in contrast to the ‘limbic’ or ‘hippocampal’ type of amnesia with abnormalities of storage and consequent deficits of recall as well as recognition as the key neuropsychological feature in AD. 18.3.1.4. Visuospatial functions Early and prominent deficit in visuospatial function is another characteristic feature of PDD (Girotti et al., 1988; Huber et al., 1989a; Stern et al., 1993). Compared to AD patients with a similar severity of dementia, impairment in visuospatial functions was found to be more severe in PDD (Huber et al., 1989a; Stern et al., 1993); these deficits seem to appear early and to be disproportionately severe in patients with PDD (Levin et al., 1991). Visual perception is globally more impaired as compared to controls; compared to patients with AD, PDD patients perform worse in all perceptual scores, and patients with visual hallucinations tend to have worse visual perception than those without (Mosimann et al., 2004). Visuospatial abstraction and reasoning were found to be more impaired in patients with PDD as compared to AD, whereas visuospatial memory tasks were worse in patients with AD (Mohr et al., 1990). Tasks that require visuospatial analysis and orientation were the most affected, suggesting that impairment in visual perception may be the core of the problem (Girotti et al., 1988). Impairment becomes especially evident in more complex tasks that require planning and sequencing of response or selfgeneration of strategies so that deficits in visuomotor tasks may be partly due to problems in sequential organization of behavior (Stern et al., 1983) or deficits

in executive functions (Bondi et al., 1993; Crucian and Okun, 2003). 18.3.1.5. Language Core language functions are largely preserved in patients with PDD as compared to those with AD (Cummings et al., 1988; Huber et al., 1989a). Language changes in PDD usually consist of mild anomia, as opposed to prominent aphasic-type language abnormalities early on in patients with AD, which increase throughout the course of the illness. Impaired verbal fluency, the main finding in the language domain, was found to be more severe than that seen in patients with AD (Huber et al., 1989a; Stern et al., 1993). Recently it was demonstrated in PD patients without dementia, that verb generation is more impaired than generation of nouns suggesting that deficits may affect more representation of actions as opposed to grammatical representation (Peran et al., 2003). Other deficits include decreased information content of spontaneous speech and impaired comprehension of complex sentences, but these are to a significantly lesser extent than in patients with AD (Matison et al., 1982; Cummings et al., 1988; Grossman et al., 1991, 1992). Ideomotor apraxia is also not a common feature of PDD (Huber et al., 1989a). As for impairments in memory, it was suggested that most of the language deficits, such as impaired verbal fluency and word finding difficulties, may not reflect a true involvement of language functions, but may rather be related to the dysexecutive syndrome, such as impairment of self-generated search strategies (Grossman et al., 1991; Pillon et al., 2001). 18.3.1.6. Comparison of cognitive features of Parkinson’s disease dementia with Alzheimer’s disease and Dementia with Lewy Bodies Several recent studies compared cognitive profiles in patients with PDD, DLB and AD. The results confirmed the similarities between PDD and DLB, and differences between these two as compared to AD. (Cahn-Weiner et al., 2002; Aarsland et al., 2003b; Galvin et al., 2003; Mosimann et al., 2004; Noe et al., 2004). Patients with AD performed significantly worse on memory sub-scale whereas those with PDD were found to have more apathy (Cahn-Weiner et al., 2002). Compared with AD, patients with PDD and DLB had higher memory subscores, but lower initiation, perseverance and construction subscores indicating less impaired memory, but more impaired executive and visuospatial functions (Aarsland et al., 2003b). Patients with PDD were characterized by preserved insight, preserved language skills and

CLINICAL FEATURES, PATHOPHYSIOLOGY AND TREATMENT fluctuations as compared to patients with AD (Galvin et al., 2003). Similarly patients with PDD and DLB performed significantly worse on attentional tasks but better on memory tests than patients with AD, no significant differences were found between the PDD and DLB patients on any of the neuropsychological tests, the sole difference was that psychoses associated with cognitive impairment at the beginning of the disease was more frequent in DLB patients (Noe et al., 2004). Compared to AD patients with a similar severity of dementia impairment in visuospatial functions was found to be more severe in patients with PDD, the profound visuoperceptual impairments were similar to those in patients with DLB (Mosimann et al., 2004). Thus, the principal differences between PDD and AD are the presence of a retrieval deficit type memory abnormality in PDD as compared to ‘limbic’ type amnesia in AD, the relative lack of language abnormalities in PDD as compared to AD, and the predominance of executive and visuospatial deficits in PDD as compared to AD. 18.3.2. Behavioral features PDD is associated with prominent behavioral symptoms and changes in personality (Girotti et al., 1988). The most common neuropsychiatric symptoms are depression, hallucinations, delusions, apathy and anxiety. Hallucinations and delusions commonly follow treatment with dopaminergic agents, but occur disproportionately frequently in patients with dementia (Aarsland et al., 2001b). When minor forms such as feeling of presence were included visual hallucinations were found in 70% of patients with PDD as opposed to 25% of those with AD (Fenelon et al., 2000). Likewise depressive features were found to be more common in patients with PDD than in those with AD (Huber et al., 1989a; Litvan et al., 1991). A comparison of patients with PDD and AD revealed that 83% of those with PDD as opposed to 95% with AD had at least one psychiatric symptom: hallucinations were more severe in PDD, whereas increased psychomotor activity such as aberrant motor behavior, agitation, disinhibition and irritability were more common in AD. In PDD apathy was more common in mild stages while delusions increased with more severe motor and cognitive dysfunction (Aarsland et al., 2001b). Patients with PDD were discriminated by presence of visual and auditory hallucinations and sleep disturbance as compared to patients with AD (Galvin et al., 2003). The characteristic neuropsychiatric pattern of PDD, i.e. the combination of visual hallucinations, frequently accompanied by delusion, and REM sleep

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behavior disorder, is similar to other synucleinopathies such as DLB and partly to multiple system atrophy, but differs from other degenerative diseases such as AD and progressive supranuclear palsy. 18.3.3. Motor, autonomic and other associated features Many PD patients who develop dementia have predominance of certain motor symptoms or pattern of motor impairment. In PDD patients motor symptoms were described to be more symmetrical with predominance of bradykinesia, rigidity and postural instability, such features have also been correlated with more rapid cognitive decline (Mortimer et al., 1982; Zetusky et al., 1985; Huber et al., 1988; Pillon et al., 1989; Ebmeier et al., 1990; Hershey et al., 1991; Foltynie et al., 2002), whereas tremor dominance has been associated with relative preservation of mental status (Foltynie et al., 2002). In a cross-sectional study of motor features in PD it was found that the ‘postural imbalance gait difficulty’ subtype was over-represented with 88% in patients with PDD in contrast to 38% in non-demented patients (Burn et al., 2003). PD patients with falls were found to be more likely to have lower MMSE scores than those without falls and were also more likely to have frank dementia (Wood et al., 2002). Levodopa-responsiveness was suggested to diminish as cognitive impairment emerges, although this was largely based on retrospective assessments (Caparros-Lefebvre et al., 1995; Apaydin et al., 2002; Joyce et al., 2002). Proposed mechanisms for emergence of L-dopa refractoriness as dementia develops include a-synuclein pathology in striatum (Duda et al., 2002), and loss of striatal dopamine D2- and D3-receptors (Piggott et al., 1999; Joyce et al., 2002). Alternatively, an apparently reduced response to dopaminergic medication might reflect emergence or predominance of non-dopaminergic features, such as postural instability (Levy et al., 2000; Burn et al., 2003). Symptoms due to autonomic dysfunction such as orthostatic and postprandial hypotension resulting in syncope and falls, bowel and bladder disturbances, reduced heart rate variability predisposing to ventricular arrhythmias, and sexual dysfunction are rather frequent and may be disabling in patients with PDD (Kaufmann and Biaggioni, 2003). Life-threatening neuroleptic sensitivity, akin to that seen in DLB, was reported in patients with PDD (Aarsland et al., 2003c). REM sleep behavior disorder is common as a concomitant feature in PDD, in some patients it can be a harbinger of incipient dementia, sometimes antedating the onset of dementia for many years (Boeve et al., 2003).

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18.4. Neurochemical deficits associated with Parkinson’s disease dementia Deficits in several ascending modulatory pathways, including monoaminergic and cholinergic systems, have been suggested to underlie cognitive and affective symptoms in PDD. As the predominant neurochemical impairment in PD is the nigrostriatal dopaminergic deficit, it was initially assumed that this deficit could also underlie cognitive impairment. Many, especially young patients with PD, however, may not show any apparent cognitive impairment despite considerable motor dysfunction. Although some cognitive deficits benefit from levodopa in experimental studies, the clinical experience that dementia does not improve under levodopa treatment, and that levodopa may even worsen behavioral and cognitive functions, especially in demented patients (Hietanen and Teravainen, 1988), suggests that dopaminergic deficit is unlikely to be the main impairment underlying dementia in PD. This does not exclude, however, that some cognitive deficits may be due to impairment in dopaminergic modulation of frontal subcortical circuits involved in cognition. Striatal dopamine concentrations were shown to be decreased to the same extent in demented and non-demented patients (Ruberg and Agid, 1988), whereas the decrease in dopamine levels in neocortical areas was found to be greater in demented than in non-demented PD patients (Scatton et al., 1983), suggesting a role for the degeneration of mesocortical dopaminergic system in dementia. In line with these findings, reduced 18F-dopa uptake in the caudate nucleus and frontal cortex correlated with impairment in neuropsychological tests measuring verbal fluency, working memory and attentional functioning (Rinne et al., 2000), indicating that ascending dopaminergic projections may play a role in cognitive dysfunction in PD. In another positron emission tomography (PET) study using 18F-dopa as a marker of dopaminergic function, patients with PDD showed reduced 18F-dopa uptake bilaterally in the striatum, midbrain and anterior cingulate area compared to normal controls. A relative difference in 18F-dopa uptake between patients with and without dementia was a bilateral decline in the anterior cingulate area and ventral striatum and in the right caudate nucleus in the PDD group, suggesting that dementia in PD may be associated with impaired mesolimbic and caudate dopaminergic function (Ito et al., 2002). These seemingly conflicting results on the role of dopaminergic deficits in cognitive dysfunction were reconciled by a hypothesis that some cognitive deficits may be due to dopaminergic deficits and improve through dopaminergic stimulation

early in the disease process, whereas undue dopaminergic stimulation may be detrimental in later stages (Kuliseversusky, 2000). Involvement of other ascending monoaminergic systems, namely noradrenergic and serotoninergic pathways, was also suggested to underlie cognitive impairment and to contribute to dementia in PD. Locus ceruleus was found to be severely damaged in patients with PD. In a few studies both neuronal loss and norepinephrine depletion in locus ceruleus were described as being significantly more severe in demented PD patients (Mann et al., 1983; Cash et al., 1987; Zweig et al., 1993). In a larger study the concentration of norepinephrine was also found to be reduced in cortex and hippocampus; nevertheless there was no difference between demented and non-demented patients (Scatton et al., 1983). Likewise, neuronal loss in raphe nuclei and reduced serotonin concentrations in the striatopallidal complex and in various cortical areas, notably in frontal cortex as well as in hippocampus, was also described in patients with PD. There was, however, no difference between demented and non-demented patients (Scatton et al., 1983). The strongest evidence with regard to biochemical impairments underlying dementia in PD exists for cholinergic deficits. A number of structural, biochemical and functional studies suggest that cholinergic deficits due to degeneration of the ascending cholinergic pathways significantly contribute to cognitive impairment and dementia in patients with PD. Loss of cholinergic cells in the nucleus basalis of Meynert (nbM) was described early on in patients with PDD (Whitehouse et al., 1983). This neuronal loss in nbM was found to be greater in patients with PD than in those with AD (Candy et al., 1983). The significant depletion of large neurons in nbM in patients with PD was found not to be associated with AD-type pathology in the cerebral cortex (Nakano and Hirano, 1984). These morphological findings were reflected by biochemical deficits in nbM and in cerebral cortex: cholinacetyltransferase (ChAT) activity was found to be decreased in the frontal cortex and nbM of patients with PD, the decrease in the frontal cortex was greater in PD patients with dementia (Dubois et al., 1983). Extensive reductions of ChAT and acetylcholinesterase (AchE) in all examined cortical areas were described: ChAT reductions in temporal neocortex correlated with the degree of mental impairment, but not with the extent of plaque or tangle formation. In addition in PD, but not in AD, the decrease in neocortical ChAT correlated with the number of neurons in nbM, suggesting that primary degeneration of these cholinergic neurones may be related to declining cognitive function in PD (Perry et al., 1985). Amongst the various pathological and

CLINICAL FEATURES, PATHOPHYSIOLOGY AND TREATMENT chemical indices examined, only presynaptic cholinergic markers (including the number of neurons in nbM) and serotonin S1 receptor binding were related to dementia in PD (Perry et al., 1987). Reductions in ChAT activity were found to be more extensive in the neocortical (especially temporal) as opposed to archicortical areas (Perry et al., 1993). An important finding of potential clinical relevance was that nicotinic receptor binding was reduced in striatum in patients with PDD, suggesting that the risk of worsening in motor symptoms under cholinergic treatment, through undue stimulation of striatal cholinergic receptors, may be low (Pimlott et al., 2004). Recently, in a comparative study of patients with AD, DLB and PD, mean midfrontal ChAT activity was found to be markedly reduced in PD and DLB as compared to normal controls and AD: the activity was reduced to almost 20% of controls in DLB and PD, whereas in AD the reduction was close to 50% of that seen in normal individuals (Tiraboschi et al., 2000). These findings were confirmed in vivo, by imaging cortical cholinergic function using PET: compared with controls, mean cortical AChE activity was lowest in patients with PDD (–20%), followed by patients with PD without dementia (–13%) and AD (–9%). Thus, reduced cortical AChE activity seemed to be more characteristic of patients with PDD than of AD patients with similar severity of dementia (Bohnen et al., 2003). In contrast to AD, PDD is also associated with neuronal loss in the pediculopontine cholinergic nuclei which project to structures such as thalamus (Rub et al., 2002). Although the bulk of evidence points to cholinergic impairment as the main neurotransmitter deficit associated with dementia in PD, it was proposed that deficits in other, ascending monoaminergic pathways, which are described above, may also contribute to behavioral and cognitive symptoms. Based on experimental findings and known role of these pathways in various cognitive, affective and behavioral functions, it was suggested that dopaminergic deficits may be partly responsible for impairment in executive functions; cholinergic deficits may be responsible for impairments in memory, attention and executive functions; whereas noradrenergic deficits may contribute to impaired attention and serotoninergic deficit to depressive mood (Pillon et al., 2001)

18.5. Neuropathological changes associated with dementia in Parkinson’s disease There have been a large number of clinicopathological correlation studies investigating the nature of pathology underlying dementia in PD. The results have been

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somewhat controversial, with regard to both the type and the site of pathology. The differences are probably due to the patient populations examined, differences in pathological assessments, especially the staining methods used and brain areas examined, and if and how extensive different pathologies were concomitantly assessed. Based on their outcomes these studies can be broadly categorized into three groups: (1) those suggesting a predominant role for the degeneration in subcortical nuclei; (2) those suggesting AD-type pathology being closely associated with dementia; and (3) those indicating that it is the Lewy body-type degeneration that correlates best with dementia in PD (Emre, 2003b). As described above, cell loss in several nuclear grays was suggested to underlie dementia in various studies, without implicating the nature of pathology leading to this loss. In accordance with the predominant pathology in PD, loss of dopaminergic neurons was suggested also to underlie dementia by several authors. Rinne et al. (1989) found that cellular loss in substantia nigra medial part correlated with dementia: this correlation was still significant after accounting for amyloid burden. Similar findings were reported by Jellinger and Paulus (1992), who described that patients with PDD had more cell loss in the medial substantia nigra, but they also had more severe AD pathology in isocortex and hippocampus as compared to patients without dementia. In another study, however, a comparison of neuronal loss in the substantia nigra of demented and non-demented patients showed no difference and no correlation with dementia (Gaspar and Gray, 1984). The role of cell loss in cholinergic nuclei, locus ceruleus and raphe nuclei has been extensively discussed above. Recently components of thalamus assigned to the limbic loop were found to be most severely affected by PD-related pathology (Lewy bodies and Lewy neurites), as opposed to a mild pathology in other thalamic nuclei. Based on these findings it was suggested that damage to the thalamic components of the limbic loop nuclei may contribute to cognitive, emotional and autonomic symptoms in patients with PD (Rub et al., 2002). Coincident Alzheimer-type pathology has been suggested to correlate with dementia in PD in a number of studies (Boller et al., 1980; Mann and Jones, 1990; de Vos et al., 1995; Braak et al., 1996; Jellinger, 1997; SantaCruz et al., 1999; Jellinger et al., 2002). For example, in a study of 36 autopsy-confirmed cases, AD-type pathology in cortex was found in all severely and in half of the mildly demented patients, but also in 3 of 13 non-demented cases (Boller et al., 1980). In another study, AD-type pathology was found to be the major determinant of cognitive decline in most

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patients. Cortical Lewy bodies were reported to be present in all patients independent of the presence or absence of dementia (de Vos et al., 1995). Braak and coworkers (1996) suggested that ‘concurrent incipient AD with fully developed PD is likely to cause impaired cognition and AD pathology; stage III or more is the most common cause of intellectual decline in PD’. Similarly, in a study conducted in 200 consecutive autopsy cases of PD patients, of whom 33% had had dementia, the vast majority of patients with dementia had AD-type changes in cortex and the presence of dementia significantly correlated with AD pathology (Jellinger et al., 2002). In most of these studies, however, the severity of AD-type pathology was not quantified. It was not described whether these changes would be sufficient for a pathological diagnosis of AD, and in some, the extent and severity of concomitant Lewy body-type pathology was not investigated. Later studies suggested that senile plaques seem to be present in most cases with advanced dementia and thus demonstrate high specificity, but are absent in many cases with cognitive impairment and have low sensitivity (Hurtig et al., 2000). There have also been suggestions that the cause of dementia may differ from patient to patient. In a large study with 100 histologically confirmed PD cases, dementia was diagnosed during life in 44%. Among the 31 cases with well-documented dementia, 29% were found to have pathological criteria for AD, 10% had numerous cortical Lewy bodies, ‘satisfying the criteria for diagnosis of diffuse Lewy body disease’, 6% had a possible vascular cause and 55% were found to have no definite pathologic cause; cortical Lewy bodies were identified in all cases, whether demented or not (Hughes et al., 1993). The third group of studies suggests Lewy body-type degeneration in cortical, limbic or both areas as the main pathology underlying dementia in PD. Association of cortical Lewy bodies with dementia in PD was first suggested by Kosaka et al. (1988). Subsequently, this association was questioned in several studies which reported low specificity of Lewy bodies or poor correlation with dementia. The advent of stains more specific for Lewy body-type pathology has facilitated investigation of the contribution of Lewy-type pathology to PDD. In four recent studies in which, instead of ubiquitin staining, a-synuclein antibodies (a more sensitive marker of Lewy bodies) were used to identify Lewy body pathology, dementia was reported to correlate best with Lewy bodies in limbic and cortical areas in all (Hurtig et al., 2000; Mattila et al., 2000; Apaydin et al., 2002; Kovari et al., 2003). a-Synuclein-positive cortical (especially frontal) Lewy bodies were found to be significantly associated with cognitive impair-

ment, independent of AD-type pathology, although AD-type pathology was frequently coexistent. The abundance of Lewy neurites in the CA2 region of the hippocampus also seemed to show a strong correlation with the severity of cognitive impairment (Churchyard and Lees, 1997). An interesting finding is the significant correlation between neocortical Lewy bodies, senile plaques and neurofibrillary tangles (NFTs), suggesting common origins for these pathologies or that one may trigger the other (Apaydin et al., 2002). This close spatial association may also explain why AD-type pathology can be found to correlate with dementia in some studies and Lewy-type pathology in others, even if the patient populations would be the same. A study by Kovari et al. (2003) added another dimension to the interpretation of discrepancies, suggesting that the specific pattern of Lewy body distribution is also important for dementia to develop. In 22 patients with PDD, postmortem quantitative assessment of Lewy bodies, NFT and senile plaques revealed a highly significant correlation between clinical dementia-rating scores and regional Lewy body scores in the entorhinal cortex and area 24. There was some correlation with senile plaque density in the entorhinal cortex, but NFT densities did not predict cognitive status. In multivariate models only Lewy body densities in the entorhinal cortex and anterior cingulate cortex were significantly associated with clinical scores, indicating that Lewy body formation in limbic areas may be crucial for the development of PD dementia. Another recent clinicopathological correlation study extended these findings, suggesting that the presence of limbic or cortical Lewy body may not always be associated with dementia in PD: 9 out of 17 patients with a clinical diagnosis of PD and no history of cognitive impairment showed a neuropathological picture consistent with limbic (or transitional) category of DLB and in 8 a pathology consistent with neocortical DLB was observed (Colosimo et al., 2003). The authors suggested that important factors other than the absolute number of Lewy bodies in the neocortex and limbic system may influence the development of cognitive impairment in PD. These findings may imply that it is not only the number but also the topography of Lewy bodies that is crucial for the development of dementia. Finally, evidence from recent genetic studies involving patients with the familial form of dementia with PD revealed that a-synuclein (which is the main constituent of Lewy bodies) pathology alone is capable of inducing dementia. Interestingly, families with an a-synuclein gene mutation which leads to a triplication of gene locus seem to develop dementia, whereas those with duplication do not (Singleton et al., 2003; Chartier-Harlin et al., 2004; Farrer et al., 2004; Ibanez et al., 2004). Thus, the

CLINICAL FEATURES, PATHOPHYSIOLOGY AND TREATMENT type and severity of the neurodegenerative phenotype may be related to the dose of the a-synuclein gene and consequent quantitative variation in the levels of the a-synuclein protein. As a consequence, not only the presence, but also the topography and burden of Lewy bodies may be crucial for the development of dementia. Dementia in PD usually develops later in the disease course. The temporal and spatial pattern of disease pathology may provide insight as to why. Recently, an ascending order of pathological changes was proposed to occur in PD: lesions initially commencing in certain brainstem nuclei and anterior olfactory nucleus, less vulnerable nuclear grays and cortical areas were subsequently becoming affected. The disease process in the brainstem seems to pursue an ascending course: the ensuing cortical involvement begins with the anteromedial temporal mesocortex and spreads to neocortex involving high-order sensory association and prefrontal regions, areas involved in cognitive functions (Braak et al., 2003). This pattern of ascending pathology from initial changes in the brainstem, which gradually spreads to involve limbic and neocortical areas, may explain why dementia develops, and why cognitive changes usually appear relatively late, in classic PD.

18.6. Genetics Genetic risk factors for PDD have not been exhaustively studied. The best investigated is the association with ApoE genotype. ApoE 4 genotype has been associated with an increased risk for AD; however, such an association was not found between ApoE4 and PDD (Inzelberg et al., 1998). In a systematic review and meta-analysis of 22 eligible case-control studies, which assessed ApoE genotypes in PD, the ApoE2, but not the ApoE4 allele, was shown to be positively associated with sporadic PD (Huang et al., 2004). This is in contrast to AD, for which the ApoE2 is protective. The same association with ApoE2 and sporadic PD was also found in a population-based study: the presence of at least one ApoE2 allele significantly increased the risk of PD. Both ApoE2 and ApoE4 alleles appeared to increase the risk of PDD; the risk of dementia for ApoE4 carriers was, however, not significantly different for subjects with or without PD, whereas ApoE2 strongly increased the risk of dementia in patients with PD (Harhangi et al., 2000), indicating that the presence of ApoE4 allele by itself does not predispose to Lewy body-type degeneration. The disparate risks caused by ApoE genotypes in PD versus AD also suggest that AD and PDD do not have a common genetic predisposition. This assumption is supported by the fact that there is no excess of AD

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among probands with PD (Levy et al., 2004), which would be anticipated if there were any major shared genetic background. Familial forms of dementia associated with PD are rare. Such cases have mostly been associated with mutations in the a-synuclein gene, the protein which is the major component of Lewy bodies. Altered expression of, or missense mutations in, the a-synuclein gene have been linked to early-onset familial PD, sometimes associated with dementia (Singleton et al., 2003; Farrer et al., 2004; Singleton and Gwinn-Hardy, 2004). It seems that the age of onset of PD and the likelihood of dementia increase as the additional copies of the gene increase: dementia has not been reported in families with duplication of the gene whereas triplication has been associated with dementia (Singleton et al., 2003; Chartier-Harlin et al., 2004; Farrer et al., 2004; Ibanez et al., 2004). The additional copies of the gene result in an excess of wild-type a-synuclein protein; triplication leads to a doubling of a-synuclein expression (Farrer et al., 2004; Miller et al., 2004). Taken together, this evidence indicates that increased expression of a-synuclein alone can induce dementia, whereby the type, site and severity of the neurodegeneration may be related to the dose of a-synuclein gene and thus quantitative variation in the levels of the protein.

18.7. Neuroimaging A number of structural and functional imaging studies have been conducted in patients with PDD. Despite some variance in results, several features have been reported to be consistently associated with PDD in most of these studies. Nevertheless, none of these features are specific and sensitive enough to be used in routine clinical practice; rather they are supportive and may be useful when there is diagnostic doubt on clinical grounds. 18.7.1. Structural imaging The presence and pattern of atrophy in PDD have been somewhat controversial. For example, Huber et al. (1989b) reported that the presence of dementia in patients with PD was not associated with any specific pattern of structural magnetic resonance imaging (MRI) abnormalities; in contrast, hippocampal atrophy on MRI, more severe than that found in patients with AD, was claimed to be present in PDD patients in another study (Laakso et al., 1996). In a volumetric study with MRI there were no significant differences in whole-brain or caudate volumes between controls, PD and PDD patients, and there were no significant

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correlations between caudate volume and global cognitive function, executive performance or processing speed, suggesting that structural changes in the caudate do not contribute to the cognitive impairment in patients with PD (Almeida et al., 2003). A specific pattern of atrophy was suggested in a recent MRI study: whereas temporal lobe atrophy, including the hippocampus and parahippocampal gyrus, was found to be more severe in AD patients, there was more severe atrophy of the thalamus and occipital lobe in patients with PDD (Burton et al., 2004). 18.7.2. Functional imaging Functional imaging studies in PDD have been conducted using single photon emission computed tomography (SPECT), PET and MRI. SPECT and PET studies utilized markers of cerebral metabolism as well as markers of different neurotransmitter systems. These studies and the value of functional imaging in the diagnosis of patients with parkinsonism and dementia have been reviewed by Burn and O’Brien (2003). In SPECT perfusion deficits have been reported in a number of studies, with somewhat varying pattern. The most consistent findings have been perfusion deficits in temporoparietal cortex, and in some studies in frontal and occipital areas in patients with, as opposed to those without, dementia (Kawabata et al., 1991; Spampinato et al., 1991; Sawada et al., 1992; Tachibana et al., 1993; Antonini et al., 2001). A review of SPECT studies performed in PD revealed that, in PDD, regional cerebral blood flow assessments often demonstrate frontal hypoperfusion or bilateral temporoparietal deficits (Bissessur et al., 1997). Perfusion deficits in precuneus and inferior lateral parietal regions, areas asociated with visual processing, have been described in patients with PDD, whereas patients with AD showed a perfusion deficit in a more anterior and inferior location (Firbank et al., 2003). Results obtained in PET studies using metabolic markers were in line with those from SPECT studies. More severe abnormalities in temporoparietal regions of PD patients with dementia as opposed to those without were also observed in FDG-PET studies (FDG, fluorodeoxyglucose) (Peppard et al., 1992). In some studies regions of hypometabolism included frontal association and posterior cingulate cortices; greater hypometabolism was also observed in the visual cortex (van der Borght et al., 1997). SPECT and PET studies using markers of discrete neurotransmitter systems also revealed specific patterns of impairment. In a study using 18F-dopa as a

marker of dopaminergic function, patients with PDD showed reduced 18F-dopa uptake bilaterally in the striatum, midbrain and anterior cingulate area compared to normal controls and a bilateral decline in the anterior cingulate area, ventral striatum and the right caudate nucleus, as opposed to PD patients without dementia (Ito et al., 2002). Using a marker of vesicular acetylcholine transporter, [123I] iodobenzovesamicol (IBVM) and SPECT, significant differences between AD patients and controls, as well as between PD patients with and without dementia, have been demonstrated (Kuhl et al., 1996). In PD patients without dementia, reduction in IBVM binding was restricted to the parietal and occipital cortex, whereas demented PD cases have an extensive decrease in cortical binding, similar to patients with early-onset AD. Recently a potentially useful diagnostic imaging method was described to differentiate patients with PDD/DLB from others. Using a marker of presynaptically located dopamine transporter, FP-CIT and SPECT, patients with PD, PDD and DLB were found to have significant reductions in FP-CIT binding in the caudate as well as anterior and posterior putamens compared with patients with AD and controls. Transporter loss in DLB was of similar magnitude to that seen in PD; the greatest loss in all three areas was seen in patients with PDD (O’Brien et al., 2004). Iodine-123 meta-iodobenzylguanidine (123I-MIBG) is an analog of norepinephrine and may be used in conjunction with SPECT imaging to quantify postganglionic sympathetic cardiac innervation. The heart-to-mediastinum ratio was found to be lower in PD as compared to normal controls and also lower than in other akinetic-rigid syndromes such as multiple system atrophy and progressive supranuclear palsy (Yoshita, 1998). This ratio was also found to be lower in patients with DLB. Thus cardiac 123I-MIBG can be used to distinguish between DLB, PDD and AD: in common with DLB, PD patients will have reduced heart-to-mediastinum ratios, whereas in AD, tracer uptake is expected to be normal (Yoshita et al., 2001). Functional MRI (fMRI) was also used to detect sites of abnormal activity in PD patients with cognitive impairment. Using event-related fMRI, significant signal intensity reductions were found in bilateral caudate and right putamen as well as bilateral dorsolateral and ventrolateral prefrontal cortex during a working-memory paradigm in PD patients with cognitive impairment compared with those who were cognitively unimpaired (Lewis et al., 2003). Likewise, proton magnetic resonance spectroscopy was used for the same purpose, N-acetyl aspartate levels were found to be significantly reduced in the occipital

CLINICAL FEATURES, PATHOPHYSIOLOGY AND TREATMENT cortex of demented versus non-demented PD patients, and the amount of reduction correlated with measures of neuropsychological performance (Summerfield et al., 2002).

18.8. Diagnosis 18.8.1. Diagnostic process Diagnosis of dementia in patients with PD can sometimes be difficult. This is because of several confounding factors such as severe motor and speech impairment, comorbidities such as depression or systemic disorders and adverse events of drugs. The onset, course and pattern of behavioral and neuropsychological impairment and the clinical context within which these symptoms occur are of paramount importance to differentiate whether the patient is suffering from a dementia syndrome or from its imposters, such as confusion or depression. Once these are excluded and a dementia syndrome is diagnosed, other disorders with combined motor and mental dysfunction should be considered in the differential diagnosis. These include other degenerative disorders, notably those leading to ‘Parkinson-plus’ syndromes, such as progressive supranuclear palsy, vascular subcortical dementia and normal-pressure hydrocephalus, among others. Appropriate neuropsychological tests, including those which assess executive functions, a detailed history, including a deliberate screening for features known to be associated with PDD, and a review of current treatment are the essential diagnostic tools (Table 18.2).

Table 18.2 Management of Parkinson’s disease patients with dementia Assessment of suspected dementia Detailed history with emphasis on onset, course and chronology of symptoms Assessment of cognitive functions, behavioral and other associated symptoms Screening for systemic diseases and adverse effects of drugs Optimization of antiparkinson medication, cessation of drugs with high risk If dementia associated with Parkinson’s disease is diagnosed, evaluation of need for treatment Substitutive treatment Use of cholinesterase inhibitors such as rivastigmine Symptomatic treatment Use of atypical antipsychotics such as clozapine and quetiapine; caution: increased risk of vascular events Use of antidepressants (avoid tricyclics)

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18.8.2. Relation to Dementia with Lewy Bodies DLB and PDD share many pathological and clinical features. In fact, these features are almost indistinguishable when both conditions are fully developed. It is the time course of the symptoms and presenting features that differentiates these two disorders. Obviously there are some differences when groups of patients with these two conditions are compared, which are due to definitions per se and the chronology of certain symptoms included therein. Thus, in any given study comparing cohorts of patients, patients with DLB may not have as severe motor symptoms, as this is not a precondition for the diagnosis, whereas all patients with PDD must have motor symptoms, as this is part of the diagnostic criteria. The clinical and pathological overlap between these two conditions has led to the assumption that they represent the same pathological condition with different temporal and spatial sequence of events, and hence different chronology of clinical symptoms. There is no sound clinical or pathological basis to determine a fixed time interval between the development of motor symptoms versus onset of dementia symptoms in differentiation of PDD from DLB. In fact, it is very difficult to determine retrospectively, based on historical data, when exactly cognitive or behavioral changes emerged or when they became extensive and severe enough to justify the diagnosis of dementia. Therefore, based on an empirical and practical approach it is suggested that the diagnosis of PDD should be entertained when dementia develops following the diagnosis of idiopathic PD, whereas the diagnosis of DLB should be warranted when the diagnosis of dementia precedes the development of motor symptoms.

18.9. Treatment Until recently no pharmacological interventions have been available for the treatment of patients with PDD. During the last 5–10 years results of clinical studies with two classes of interventions have been reported with variable degree of efficacy. These include substitution therapy, in an attempt to reduce cholinergic deficits associated with this condition, and non-specific treatment approaches to improve behavioral symptoms. As a general rule, before a treatment is initiated with one of the agents described below, other intrinsic and extrinsic factors which can trigger or aggravate mental dysfunction, such as systemic diseases or adverse events of drugs, should be assessed and treated. Antiparkinson medication and treatment for concomitant diseases should be

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optimized, avoiding those agents which are known to be associated with cognitive impairment or behavioral symptoms, such as anticholinergics, tricyclic antidepressants and benzodiazepines. The effects of dopaminergic treatment on cognitive symptoms have been assessed in several studies. Withdrawal of dopaminergic treatment was reported to be associated with a worsening of performance on tests sensitive to frontal lobe function (Lange et al., 1992); in another study, however, dopaminergic treatment was reported to improve some cognitive deficits but to worsen others (Cools et al., 2001). The latter observation may be due to the fact that there is an optimal level of dopaminergic stimulation needed in prefrontal cortex for normal cognitive functioning (Kulisevsky, 2000). The width of therapeutic window for improvement of cognitive function, as compared to that needed to improve motor symptoms, may vary, and there may be a mismatch between the two, depending on the disease stage and the consequent amount of dopaminergic deficit. The general clinical experience indicates that dopaminergic medication does not improve symptoms of PDD; in fact, psychotic features can worsen under dopaminergic treatment, especially in patients with dementia. The lack of efficacy of dopaminergic treatment on mental dysfunction has led to a search for alternative treatment approaches. Prompted by the substantial cholinergic deficits found in patients with PDD, cholinergic treatment strategy was investigated in these patients, after cholinesterase inhibitors (ChE-I) became available for the treatment of AD. As anticholinergic agents have been used for decades to treat the motor symptoms of PD, there was some skepticism about using procholinergic treatment, because of the fear that motor functions may worsen. A small, open study with tacrine in PD patients with cognitive impairment, which described rather dramatic improvements and no worsening of motor functions, delivered the first signal that this may not happen (Hutchinson and Fazzini, 1996). Since then a number of mostly open and small studies have been reported with all commercially available ChE-I, and a large, randomized, placebo-controlled study with rivastigmine has been published. These studies are shown in Table 18.3 and summarized below. The effects of donepezil, the first ChE-I to become available after tacrine, were described in seven reports, either in patients with PDD or in PD patients with psychotic symptoms. These included a small case series, three open and three small, randomized, placebo-controlled studies. In the open-label studies, which included 6–15 patients and lasted 6–20 weeks, psychotic features, including visual hallucinations, improved in all and cognitive function, as measured

with the Mini-Mental State Examination (MMSE), was reported to improve in one study and remained unchanged in the other two. Motor symptoms seemed to be unaffected in two studies, but worsening was reported in 2 out of 8 patients in the third study (Bergman and Lerner, 2002; Fabbrini et al., 2002; Minett et al., 2003). In one study hallucinations improved on treatment and worsened after withdrawal; the authors recommended avoiding an abrupt withdrawal of medication which may produce acute cognitive and behavioral decline (Minett et al., 2003). The three randomized controlled studies involved 14–23 patients with treatment durations between 10 and 18 weeks, one of them also included a 33-week open-label extension period (Aarsland et al., 2002; Brashear et al., 2004; Leroi et al., 2004). In all three studies there was an improvement in cognitive functions, mostly on MMSE; visual hallucinations were assessed in only one study and were not improved. Motor symptoms did not worsen in two and in the double-blind phase of the third study, but during the open-label extension of the latter there seemed to be a deterioration of motor function and Unified Parkinson’s Disease Rating Scale (UPDRS) total and subscores were worse than baseline in half of the 15 patients remaining in the extension phase (Brashear et al., 2004). In a single open-label study, 16 patients were treated with galantamine over 8 weeks. Global evaluation of mental functions showed improvement in 8 and worsening in 4 patients; tests such as MMSE, clockdrawing and verbal fluency favored galantamine. Hallucinations improved in 7 out of 9 patients who had hallucinations at baseline. Parkinsonism, as assessed clinically, was reported to be improved in 6 patients; however, a mild worsening of tremor was observed in 3 patients (Aarsland et al., 2003d). The most robust data with regard to the efficacy and safety of ChE-I in patients with PPD exist for rivastigmine, an inhibitor of both AchE and butrylcholinesterase. There have been three earlier reports of rivastigmine treatment in PDD, one case series and two open-label studies. The two open-label studies included 15 and 28 patients and the duration of treatment was 14 and 26 weeks, respectively. In both studies cognitive functions, as measured by MMSE in one and in addition with Alzheimer’s Disease Assessment Scale – cognitive section (ADAS-cog) and Clinical Global Impression of Change (CGIC) in the other, significantly improved from baseline. Visual hallucinations were assessed in one of them and showed significant improvement. In both studies there was no worsening of motor symptoms (Reading et al., 2001; Giladi et al., 2003). Recently the first large, randomized, controlled, multicenter study ever conducted with a ChE-I in PDD was reported (Emre

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Table 18.3 Clinical studies with cholinesterase inhibitors in patients with dementia associated with Parkinson’s disease

Drugs and authors Tacrine Hutchinson and Fazzini (1996) Donepezil Werber and Rabey (2001) Aarsland et al. (2002)

Number of patients

Design of the study

Treatment duration (weeks)

7

Open

8

11 14

Open Randomized controlled trial: double-blind, placebo-controlled, cross-over Open Open Open treatment/withdrawal/retreatment Chart review Randomized controlled trial: double-blind, placebo-controlled, parallel groups Randomized controlled trial: double-blind, placebo-controlled, parallel groups; open-label extension

26 10 þ 10

Bergman and Lerner (2002) Fabbrini et al. (2002) Minett et al. (2003) Kurita et al. (2003) Leroi et al. (2004)

6 8 15 3 16

Brashear et al. (2004)

20

Rivastigmine Reading et al. (2001) Bullock and Cameron (2002) Giladi et al. (2003) Emre et al. (2004)

15 5 28 541

Open/washout phase Chart review Open/washout phase Randomized controlled trial: double-blind, placebo-controlled, parallel groups

14/3 20–52 26 þ 8 26

Galantamine Aarsland et al. (2003d)

16

Open

8

et al., 2004). This study included 541 patients with a diagnosis of dementia due to PD according to Diagnostic and Statistical Manual, IVth version (DSM-IV) criteria, treated over 24 weeks. Both primary efficacy endpoints (ADAS-cog to assess cognitive functions and CGIC for clinical, global assessment of change) showed statistically highly significant improvements in favor of rivastigmine. On ADAS-cog, patients on rivastigmine showed a mean 2.1-point improvement at the end of the study, whereas those on placebo deteriorated by 0.7 points (P < 0.001). On CGIC more patients on rivastigmine improved (41% versus 30% on placebo) and more patients on placebo deteriorated (43% on placebo versus 34% on rivastigmine) (P ¼ 0.007). On all secondary efficacy parameters there were statistically significant differences in favor of rivastigmine: neuropsychiatric symptoms as measured with neuropsychiatric inventory showed an improvement on rivastigmine and no change from baseline on placebo; measures of attention improved on rivastigmine and worsened on placebo; improvement from baseline was also seen on Ten-Point

6 8 20/6/12 2–52 18 12þ33 (open-label)

Clock-Drawing test, verbal fluency and MMSE on rivastigmine, whereas patients on placebo worsened as compared to baseline scores. On a scale of activities of daily living, patients on rivastigmine showed a minimal worsening whereas those on placebo had significantly more deterioration. Adverse events were significantly more frequent on rivastigmine; the main adverse events were those related to the gastrointestinal system, and nausea and vomiting were the most frequent ones. Worsening of parkinsonian symptoms was reported more frequently as an adverse event on rivastigmine (27% versus 16% on placebo), mainly driven by worsening of tremor (10% on rivastigmine versus 4% on placebo). The objective measures of motor symptoms, however, as assessed by UPDRS part III, did not reveal any significant differences between rivastigmine and placebo groups. PDD is frequently associated with behavioral symptoms such as depression and psychosis. There have been no randomized controlled studies of antidepressants in patients with PDD and magnitude of response or potential differences between different drugs are not known. As a

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general rule tricyclic antidepressants should be avoided because of their anticholinergic effects. As described above, psychotic symptoms, notably hallucinations, can improve under treatment with ChE-I, but sometimes treatment with neuroleptics may become necessary. Classic neuroleptics are contraindicated as they may worsen motor function and some patients may be particularly prone to adverse effects of dopaminergic receptor blockade, developing life-threatening neuroleptic hypersensitivity. There have been attempts to treat psychosis in PD with atypical neuroleptics. Randomized, placebocontrolled studies showing significant improvement of psychosis without worsening of motor symptoms exist only for clozapine (French Clozapine Parkinson Study Group, 2000; Parkinson Study Group, 1999). Placebocontrolled, randomized trials with olanzapine revealed that it did not significantly improve psychosis, but significantly worsened motor function (Breier et al., 2002; Ondo et al., 2002). Although not investigated in placebo-controlled trials – and the results of open studies are mixed, reporting both improvement in psychosis and deterioration in motor symptoms – clinical experience indicates that risperidone also worsens motor function in patients with PD (Ellis et al., 2000; Friedman and Fernandez, 2002). Large, randomized, placebocontrolled studies are also lacking for quetiapine: a comparative trial against clozapine revealed that it may improve psychosis in patients with PD without worsening parkinsonism (Morgante et al., 2004). In a retrospective analysis of all PD patients receiving quetiapine, with a mean treatment duration of 15 months and average dose of 60 mg/day, 82% were reported to have partial or complete resolution of their psychosis. Motor worsening was noted in 32%, although it was not usually severe enough to warrant discontinuation. It was of note that more quetiapine non-responders were those who had dementia, and motor worsening while on quetiapine also tended to occur more frequently in demented patients (Fernandez et al., 2003). A systematic review of atypical neuroleptics for the treatment of psychosis in PD emphasized that clozapine is the only drug with proven efficacy. Olanzapine was not recommended because of its potential to worsen motor function, whereas evidence for risperidone and quetiapine was considered to be inconclusive (Goetz et al., 2002). Although not yet tested in PD patients with dementia, another medication with potential use in these patients is modafinil, an agent that promotes wakefulness. Daytime sleepiness is a frequent problem encountered in patients with PDD. In randomized, controlled studies modafinil was shown to ameliorate excess daytime sleepiness in patients with PD (Hogl et al., 2002; Adler et al., 2003).

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 19

Disorders of mood and affect in Parkinson’s disease DANIEL WEINTRAUB1-3* AND MATTHEW B. STERN2,4{ 1

Departments of Psychiatry and Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA 2

Parkinson’s Disease Research, Education and Clinical Center (PADRECC), Philadelphia Veterans Affairs Medical Center, PA, USA

3

Mental Illness Research, Education and Clinical Center (MIRECC), Philadelphia Veterans Affairs Medical Center, PA, USA 4

Department of Neurology, University of Pennsylvania School of Medicine, PA, USA

19.1. Introduction Although Parkinson’s disease (PD) is primarily considered a movement disorder, the high prevalence of psychiatric complications suggests that it could more accurately be conceptualized as a neuropsychiatric disease. Disorders of mood and affect, though receiving less attention than motor aspects of the disease, have long been recognized as a part of PD. In first describing the clinical profile of PD in his 1817 monograph, James Parkinson acknowledged depression as a cardinal feature of the illness, stating of one patient, ‘A more melancholy object I never beheld’. Although depression is common in PD, occurring in up to one-half of patients (Dooneief et al., 1992), reports on its frequency have varied depending on the research setting, the type of depression being studied and the diagnostic criteria used. Depression frequently co-occurs with other non-motor symptoms, including psychosis and cognitive impairment. Other disorders of mood and affect can occur in PD. Anxiety disorders may be as common as depression, and the two are frequently comorbid. Apathy, a common syndrome in neurodegenerative diseases, is a disorder of affect that may overlap with, but is usually distinct from, depression. Finally, pseudobulbar affect (PBA), also called emotional lability, is a syndrome of emotional dysregulation characterized by spells of crying and/or laughing. The hallmark neuropathophysiological changes that occur in PD plus the association between

exposure to dopaminergic medications and certain psychiatric disorders suggest a neurobiological basis for most psychiatric symptoms, though psychological factors are likely involved in the development of mood disorders. Although antidepressants and anxiolytics are commonly prescribed in PD, controlled studies demonstrating efficacy and tolerability are lacking. Psychiatric complications in PD are associated with excess disability, worse quality of life, poorer outcomes and care-giver distress. Yet in spite of this and their frequent occurrence, there is incomplete understanding of the epidemiology, phenomenology, risk factors, neuropathophysiology and optimal treatment strategies for these disorders. Psychiatric complications are typically multimorbid, and there is great intra- and interindividual variability in presentation. Not surprisingly, there is evidence that psychiatric disorders in PD are underrecognized and undertreated (Shulman et al., 2002; Weintraub et al., 2003). This chapter is an overview of the prevalence of disorders of mood and affect in PD, and their impact on disability, quality of life and outcomes. The etiology and pathophysiology of the various disorders will be reviewed, focusing primarily on the contribution of disease-specific neurobiological changes. Clinical correlates and comorbid non-motor symptoms will be covered, as well as a review of existing knowledge on clinical management and treatment.

*Correspondence to: Daniel Weintraub, M.D., Departments of Psychiatry and Neurology, University of Pennsylvania School of Medicine, 3535 Market Street, Room 3003, Philadelphia, PA 19104, USA. E-mail: [email protected], Tel: þ1-215-349-8207, Fax: þ1-215-348-8389. { Parker Family Professor of Neurology at the University of Pennsylvania Health System.

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19.2. Depression 19.2.1. Epidemiology The majority of epidemiological studies on depression in PD (dPD) report prevalence rates between 20 and 40%, with estimates varying from less than 5% to as high as 75% (Starkstein et al., 1990a; Cummings, 1992; Hantz et al., 1994; Allain et al., 2000). This variation reflects methodological differences between the studies, including sampling methods, survey sites and assessment tools both to define depression and to quantify the severity of depressive symptoms. More recent studies using community samples and formal diagnostic criteria (e.g. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria; First et al., 1996) have reported that major depression may occur in 5–10% of PD patients, with an additional 10–30% experiencing either minor or subsyndromal depression (Hantz et al., 1994; Cole et al., 1996; Tandberg et al., 1996; Liu et al., 1997; Starkstein et al., 1998). Although recent research suggests that the typical depression case may be non-severe, the evidence in total is that dPD is common. 19.2.2. Impact and course of depression in Parkinson’s disease The presence of dPD is associated with excess disability (Liu et al., 1997; Weintraub et al., 2004), worse quality of life (Schrag et al., 2000) and increased care-giver distress (Aarsland et al., 2000), exacerbating the physical and emotional burden that PD places on patients and their significant others. In a survey of PD patients, care-givers and clinicians in six countries, depressive symptoms were the single most important factor in patient quality of life ratings, even ranking ahead of disease severity (Global Parkinson’s Disease Study Steering Committee, 2002). Preliminary longitudinal research indicates that dPD is associated with impairment in fine motor skills (Kuhn et al., 1996), more rapid progression of motor impairment and disability (Starkstein et al., 1992a) and the development of psychosis (Giladi et al., 2000). Depression may also be a risk factor for global cognitive impairment (Starkstein et al., 1992a; Tro¨ster et al., 1995; Tandberg et al., 1997) or dementia (Stern et al., 1993; Marder et al., 1995). Future studies need to determine whether successful treatment of depression can ameliorate such secondary impairments. Little is known about the long-term course of dPD. It has been reported to be a chronic illness (Starkstein et al., 1992a) and one naturalistic study found that only one-third of patients with depression at baseline

showed an improvement in their symptoms over a 9-year period (Rojo et al., 2003). The risk of suicide as an outcome of dPD has not been studied, but data from a computerized death registry suggest that the rate of suicide is less in PD than in the general population (Myslobodsky et al., 2001), which is somewhat surprising given that suicide ideation occurs in up to 30% of PD patients (Gotham et al., 1986; Leentjens et al., 2003a). 19.2.3. Etiology and pathophysiology Theories related to the etiology of dPD argue that depression either is ‘reactive’ and secondary to the psychosocial stress of a chronic disease, or results from neuroanatomical and/or neurobiological changes that are part of the neurodegenerative process in PD. These two theories are not mutually exclusive, as is discussed below. It was once thought that depression occurred primarily in the early and late stages of PD, with patients in the middle stages typically unaffected. These findings supported the hypothesis that dPD could be subdivided into ‘psychological’ and ‘biological’ subtypes: the diagnosis of a chronic, progressive and disabling illness in early PD was presumed to effect a psychological depression secondary to the disorder itself, whereas advanced neurodegeneration (i.e. cell death, dysfunction in neural networks and neurotransmitter depletion) in late PD was said to induce a biological depression. PD patients and their families clearly have to adjust to managing a chronic illness that may result in significant impairment in physical, occupational, interpersonal, social, sexual and recreational domains. They are acutely aware that there is no cure for the disease and that existing treatments are palliative and lose effectiveness over time. In many patients symptoms of depression may develop at the time of initial diagnosis. Findings from studies that reported an association between depression and early-onset PD (Kostic et al., 1994; Cole et al., 1996) suggest that younger patients may experience more significant career, family and financial disruptions (Brown et al., 1988). However, the high rates of dPD cannot be completely explained as a reaction to the stress of the illness. Some researchers have found that PD patients have more depressive symptoms than patients with other chronic disabling diseases (Ehmann et al., 1989; Menza and Mark, 1994). In addition, recent research on the association between severity of depression and stage or severity of PD has been equivocal (Ehmann et al., 1989; Starkstein et al., 1990a; Menza and Mark, 1994; Tandberg et al., 1997).

DISORDERS OF MOOD AND AFFECT IN PARKINSON’S DISEASE Other research findings, from case-control studies and prospective studies using large case registries, suggest a biological basis for dPD. This research has found that PD patients have a higher lifetime prevalence of anxiety and depressive disorders (Shiba et al., 2000) and non-PD patients with depression are at higher risk of subsequently developing PD (Schuurman et al., 2002). These findings implicate depression as a potential risk factor for, or a prodromal symptom of, PD, similar to what has been reported for other non-motor symptoms, including rapid-eye movement sleep behavior disorder (Schenck et al., 1996; Olson et al., 2000). From a biological standpoint, the high frequency of dPD has been explained by dysfunction in the following brain regions, neural networks and neurotransmitters: (1) subcortical nuclei and the frontal lobes; (2) cortical-striatal-thalamo-cortical and basotemporal limbic neural networks; and (3) brainstem monoamine and indolamine systems (i.e. dopamine, serotonin and norepinephrine). One previous positron emission tomography study in PD found an association between depressive symptoms and altered basal ganglia metabolism (Mentis et al., 2002), and a single photon emission computed tomography study found an association between increasing severity of depression and anxiety symptoms and decreased striatal dopamine transporter availability in the left anterior putamen (Weintraub et al., 2005b). Another region implicated in depression is the limbic system, and patients with dPD were found to have reduced basal limbic system echogenicity using structural neuroimaging (Berg et al., 1999). Functional brain imaging studies have reported simultaneous frontal cortex and basal ganglia hypometabolism in PD patients with depression, changes that are presumed to reflect neurodegeneration of the cortical-striatal-thalamo-cortical circuits (Mayberg et al., 1990; Mentis et al., 2002). Regarding neurotransmitters, a disproportionate degeneration of dopamine neurons in the ventral tegmental area has been reported in patients with a history of dPD (Brown and Gershon, 1993). Other monoaminergic neurotransmitter systems (e.g. serotonin and norepinephrine) are also significantly affected in PD. Imaging studies have found both a decrease in signal intensity of the pontomesencephalic midline structures, which contain neural pathways originating in monoaminergic brainstem nuclei, in depressed PD patients (Berg et al., 1999) and a negative correlation between Unified Parkinson’s Disease Rating Scale (UPDRS) depression items and dorsal midbrain binding ratios, which reflect regional serotonin transporter densities (Murai et al., 2001). In addition, preliminary research

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has demonstrated associations between dPD and a functional polymorphism (the short allele) in the promoter region of the serotonin transporter (Menza et al., 1999; Mo¨ssner et al., 2001) and reduced cerebrospinal fluid levels of the serotonin metabolite 5-hydroxyindoleacetic acid (Mayeux et al., 1998). If the combination of pan-neurotransmitter deficits and disruption in neural networks contributes to the high prevalence of dPD, then this characteristic and perhaps unique combination of brain changes may dictate different depression treatment strategies than those commonly employed for depression in non-PD populations. For instance, depressed PD patients do not demonstrate the euphoric response to psychostimulant medication seen in non-PD depressed patients (Cantello et al., 1989), which raises questions about the efficacy of structurally related antidepressants (e.g. bupropion) in this population. 19.2.4. Clinical correlates Some epidemiological studies have found that dPD is associated with female sex (Tandberg et al., 1996), a personal history of depression (Starkstein et al., 1990a), early-onset PD (i.e. before age 55) (Kostic et al., 1994; Cole et al., 1996), right-sided (left-brain) predominant motor symptoms (Starkstein et al., 1990a) and ‘atypical’ parkinsonism (e.g. prominent akinesia-rigidity or extensive vascular disease) (Tandberg et al., 1997; Starkstein et al., 1998). However, extensive non-confirmatory results mean that consensus has not been reached on the demographic and clinical correlates of dPD. Patients with long-standing exposure to levodopa frequently develop motor fluctuations, including dyskinesias during ‘on’ periods and worsening parkinsonism during ‘off’ periods. In some patients, ‘off’ periods are associated with temporary dysphoria and anxiety (Menza et al., 1990) that may be relieved by levodopa administration (Maricle et al., 1995), but in others there does not appear to be an association between either ‘off’ states and worsening mood or ‘on’ states and improved mood (Richard et al., 2001). Although such mood changes may not meet criteria for existing affective disorders due to their brevity, they nonetheless can be debilitating and distressing to patients. In addition, patients with mood fluctuations in the context of motor fluctuations are more likely also to have dPD and other neuropsychiatric complications (Racette et al., 2002). Surgery has become increasingly common as a treatment for PD. Pallidotomy and thalamotomy are well-established ablative surgical treatments, and in general neither is thought to have significant cognitive

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or psychiatric sequelae (Green et al., 2002). Nonablative deep brain stimulation (DBS), usually of the bilateral subthalamic nucleus (STN), has become the most common surgical treatment for PD. However, the impact of DBS on psychiatric symptoms and cognition appears varied. A number of psychiatric side-effects have been reported with STN DBS, including depression and mania (Bejjani et al., 1999; Berney et al., 2002; Herzog et al., 2003), but there is research reporting both improvement and worsening in mental status post-DBS (Houeto et al., 2002). The STN has a heterogeneous organization that includes connections to limbic regions, which may explain the reported association with affective changes in some patients. 19.2.5. Common comorbid non-motor symptoms in depression Psychosis (Aarsland et al., 1999; Marsh et al., 2004), anxiety (Menza et al., 1993), apathy (Starkstein et al., 1992b), fatigue (Lou et al., 2001) and insomnia (Caap-Ahlgren and Dehlin, 2001) have all been associated with dPD. Research suggests not only a significant association between psychosis and depressive disorders, but that depressed patients non-responsive to antidepressant treatment are more likely to have comorbid psychosis (Weintraub et al., 2003). The majority of patients with a depression diagnosis also meet criteria for an anxiety disorder, and vice versa (Menza et al., 1993). Although apathy is thought to be a distinct psychiatric syndrome associated with frontal lobe impairment (Pluck and Brown, 2002), there is overlap between depression and apathy in PD (Starkstein et al., 1992b). It is unclear to what extent these comorbid psychiatric symptoms either lead to or are secondary to depression, or are associated with underlying cognitive impairment and not independently associated with depression. Although dPD is very common, mania (i.e. bipolar disorder) appears to be rare (Cannas et al., 2002). Some episodes of disinhibited behavior that have been labeled as mania are probably cases of impulse control disorders (e.g. gambling and hypersexuality) that may be induced by exposure to dopamine replacement therapies. Cognitive impairment is a common non-motor complication of PD that is made worse by depression (Tro¨ster et al., 1995; Norman et al., 2002). Depressive symptoms early in the course of PD are related to more rapid cognitive decline (Starkstein et al., 1992a) and an increased risk of developing dementia (Hughes et al., 2000). Conversely, cognitive impairment has been associated with an increased risk of developing

depression in some studies (Tandberg et al., 1997), and the combination of dementia and depression is correlated with lower levels of cerebrospinal fluid 5-hydroxyindoleacetic acid in PD than either dementia or depression alone (Sano et al., 1989). Interestingly, PD patients with major depression have significantly greater cognitive decline and decline in functional ability than patients with minor depression when followed over time (Starkstein et al., 1992a), suggesting qualitative differences between different types of depression in this population. Among the cognitive changes that occur in PD, executive impairment in particular has been associated with depression (Wertman et al., 1993; Kuzis et al., 1997; Anguenot et al., 2002). These frontal system deficits may be due to the additive effects of PD and depression (Tro¨ster et al., 1995). Non-PD elderly patients with major depression have been reported to demonstrate significant impairment in executive functioning compared with elderly controls, and non-responders to antidepressant treatment have more executive dysfunction than responders (Kalayam and Alexopolous, 1999). The exact nature of the association between executive dysfunction and dPD, its potential to confound depression by presenting with comorbid apathy, its impact on the outcome of antidepressant treatment and its reversibility with successful antidepressant treatment all remain in question. It has been argued that D2/D3 dopamine agonists (e.g. pramipexole and ropinirole) might be appropriate for the depression-executive dysfunction syndrome of late life (Alexopolous, 2001). 19.2.6. Relationship of comorbid medical disorders to depression Hypothyroidism, testosterone deficiency, elevated plasma homocysteine and vitamin B12 deficiency levels have all been associated with depression in non-PD populations, although research linking these disorders to dPD has been sparse. These disorders may go unrecognized, as their clinical symptoms overlap with those of PD, particularly PD complicated by depression. Homocysteine is a byproduct in the metabolic pathway of levodopa, and increased homocysteine levels are correlated with long-term treatment with levodopa/ carbidopa, a complication that can be managed with folic acid supplementation. A recent study found that PD patients with elevated homocysteine levels were more depressed than patients with normal homocysteine levels (O’Suilleabhain et al., 2004). Administration of 800–3600 mg/day of S-adenosylmethionine, which plays a role in the metabolism of homocysteine, improved dPD in a preliminary study (Di Rocco et al., 2000).

DISORDERS OF MOOD AND AFFECT IN PARKINSON’S DISEASE Depression is a common complication of hypothyroidism, and the incidence of hypothyroidism in PD is increased (Tandeter and Shvartzman, 1993). However, hypothyroidism may be difficult to diagnose clinically in this population because the symptoms of poor concentration, fatigue, flat affect and bradykinesia overlap with PD symptoms. In addition, certain PD medications (e.g. levodopa) may inhibit thyroidstimulating hormone release in patients with primary hypothyroidism and mask the laboratory diagnosis early in the disease (Tandeter and Shvartzman, 1993). Therefore, to screen for hypothyroidism in PD it is also necessary to check triiodothyronine and thyroxine levels. Testosterone levels decline progressively with age, and approximately 20–25% of males >60 years of age show signs of clinical hypogonadism. Many symptoms of testosterone deficiency are non-specific and overlap with non-motor symptoms of PD, including decreased enjoyment of life, lack of energy, sexual dysfunction and depression. In a preliminary openlabel study, testosterone-deficient men with PD who were administered testosterone replacement therapy showed a trend toward improvement in anxiety symptoms and on part I of the UPDRS, which covers psychosis, depression and cognitive impairment (Okun et al., 2002). Vitamin B12 deficiency is associated with a variety of neuropsychiatric symptoms, including depression (Lindenbaum et al., 1988), and is relatively common in older patients. Therefore, an evaluation of B12

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status should be included in the work-up of PD patients presenting with mood symptoms. 19.2.7. Presentation, assessment and diagnosis of depression Assessing dPD is challenging, partly as a result of symptom overlap with core PD symptoms (e.g. insomnia, psychomotor slowing, difficulty concentrating and fatigue). In addition, PD patients may withdraw from social activities not only as a result of depression, but also if they are uncomfortable being in public when experiencing tremors or dyskinesias. Even the appearance of a patient with PD (e.g. bradykinetic movements and flat facies) can be mistaken for that of someone with severe, melancholic depression. Non-somatic symptoms of depression (e.g. suicide ideation, anhedonia, feelings of guilt and psychic anxiety) more likely indicate the presence of a depressive disorder than do many somatic symptoms (e.g. loss of appetite, insomnia, low energy and psychomotor retardation) (Starkstein et al., 1990b; Leentjens et al., 2003a). There is also some evidence that depressed PD patients have a different symptom profile than depressed patients without PD. This profile includes higher rates of anxiety, pessimism, irrationality, suicide ideation without suicide behavior and less guilt and self-reproach (Cummings, 1992; Slaughter et al., 2001) (Table 19.1). Also complicating the diagnostic process for dPD is the common occurrence of other affective disturbances

Table 19.1 Clinical features of Parkinson’s disease (PD) depression Symptom

Comments

Depressed mood or sadness Anhedonia

Specific to PD depression, but variably present Diminished pleasure may be more specific to depression than diminished interest, which also occurs in apathy Daytime fatigue common in PD without depression and as a side-effect of treatment with dopaminergic agents Mental slowing common in PD without depression Changes in attention common in PD without depression Sleep changes almost universally present in PD, though early-morning wakening may be more specific to PD depression May be more specific to PD depression compared with other neurovegetative symptoms Specific to PD depression, but may not be as prevalent as in non-PD depression

Fatigue Psychomotor changes Decreased concentration Insomnia Diminished appetite Feelings of worthlessness and guilt Suicidality Anxiety

Suicide intent or attempts may not be as prevalent, though helplessness and hopelessness are common Overwhelming majority of depressed PD patients also have clinically significant anxiety

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(e.g. apathy and pseudobulbar affect) that can confound depression. In addition, since dPD is frequently comorbid with other non-motor symptoms (e.g. psychosis and cognitive impairment), it may be difficult to categorize disorders for which depressive symptoms are but one component. When depression is suspected, a clinician should begin with a careful history and physical examination. A past history of depression is a predictor of future depression. Recent changes in mood and behavior should be assessed within the context of the patient’s current PD treatment (e.g. potential on–off phenomena or recent surgery). Although DSM-IV recommends using an exclusive or disease-etiologic approach (i.e. not considering a specific criterion to be met if its presence is better explained by PD rather than depression) (Hoogendijk et al., 1998; Leentjens et al., 2000b), this approach has not been validated, and the current recommendation of experts is to use an inclusive scoring approach (i.e. counting all depressive symptoms toward a diagnosis of depression) when diagnosing depression or rating depression severity in PD. Another recommendation is that clinicians focus on symptoms of depressed mood and/or anhedonia (loss of interest and pleasure), questioning both the patient and available family members about changes from baseline (both pre- and post-PD onset). Some experts believe that anhedonia should focus on loss of ability to experience pleasure, not loss of interest, as the latter is also a core symptom of apathy. This change in the conceptualization of anhedonia is similar to what has been recommended in the drafting of provisional diagnostic criteria for depression of Alzheimer’s disease (Olin et al., 2002). If the clinician notes a significant change in mood, loss of interest or pleasure in activities, increased crying spells, guilt or a sense of despair or hopelessness, then a more focused interview on depressive symptoms should ensue. At this point, the clinician should inquire about the presence of vegetative symptoms (e.g. sleep, appetite, energy and concentration), without regard to etiology, in order to determine if the patient meets criteria for a major depressive disorder. Patients with PD can also have other clinically significant depressive disturbances that do not meet the severity criteria for major depression, including minor depression, dysthymia, subsyndromal depression and adjustment disorders. The high prevalence of dPD necessitates that all patients be screened for depression on a regular basis. Depression-screening tools can useful, though they have not been comprehensively evaluated in PD. One commonly used instrument, the Geriatric Depression Scale (GDS), uses a ‘yes/no’ format, can be self-administered

and emphasizes the cognitive symptoms of depression. There are 30- and 15-item versions of the GDS (Yesavage et al., 1983; Sheikh and Yesavage, 1986), and a cut-off score of 5 on the GDS-15 demonstrates high sensitivity and high specificity for a diagnosis of depression in a primary care setting (D’Ath et al., 1994). Thus, a more detailed evaluation for depression should occur with a score of 5 on the GDS-15 (or 10 on the GDS-30). The Beck Depression Inventory (BDI) (Beck et al., 1961) is another self-rated instrument that is also more strongly weighted to assess the cognitive symptoms of depression (e.g. guilt and loss of pleasure). Research with the BDI has determined two optimal cut-off points for the BDI: a score of 13/14 for differentiating PD patients with and without a depression diagnosis and a score of 8/9 for depression screening (Leentjens et al., 2000b). The Hamilton Depression Rating Scale (HDRS) (Hamilton, 1960) is used primarily in clinical research. The Montgomery Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979) is also used in research settings, but can be used in clinical practice to monitor the course of depression. Unlike the GDS and BDI, both the HDRS and MADRS are administered by a trained rater. A cut-off score of 14/15 on the MADRS was found to be optimal for both discriminating PD patients with and without a depression diagnosis and for depression screening (Leentjens et al., 2000a). It is important to involve a patient’s care-giver or significant other in the assessment and treatment process, even with non-demented patients, both to provide collateral information and to enhance treatment compliance. PD patients are often perceived as withdrawn and depressed by observers, even when they do not endorse depressed mood (Pitcairn et al., 1990). This suggests that others may be misinterpreting nondepressive symptoms in the patient with PD; however, this could also indicate that patients may lack insight into their mood disturbance. The impact of depression on care-giver well-being and health should also be considered. Addressing relevant psychosocial concerns (e.g. support in the home, cost of medications and assistive devices, transportation issues and changes in lifestyle) may help improve overall quality of life for both the care-giver and patient. Consultation with a geriatric psychiatrist or neuropsychiatrist should be considered in difficult cases. These cases would include patients in whom there is diagnostic uncertainty or those with treatment-resistant depression, suicide ideation and comorbid conditions, including panic disorder, psychosis and mania. Treatment-resistant depression is usually defined as a

DISORDERS OF MOOD AND AFFECT IN PARKINSON’S DISEASE patient who has failed three or more antidepressant trials when the trials were of sufficient length (e.g. at least 8 weeks) and dosage. In clinical practice, patients frequently do not tolerate medications, cannot afford them, or do not finish a course of medication because they are not convinced that they are depressed or have a depressive disturbance warranting specific treatment. Consultation with a psychiatrist and close follow-up and counseling may increase treatment adherence. ‘Watchful waiting’ with a follow-up appointment within 2–4 weeks to monitor the patient’s status can also be a useful strategy when the diagnosis or treatment is unclear. The presence of suicide ideation or a comorbid psychiatric disorder suggests a complex psychiatric problem and should also trigger a referral to a psychiatrist. Some PD patients describe having a plan to end their life if they became so disabled that they could no longer function. Active suicide ideation (i.e. current thoughts with intent or a plan) should prompt an immediate referral for further evaluation. When depression and either anxiety or psychosis are comorbid, it can be difficult to determine if depression is the primary disorder and should be the focus of treatment. Manic-depressive illness or bipolar disorder can also be very difficult to manage in PD. The anti-PD medications can exacerbate mania, and the medications used to treat mania (e.g. lithium, valproic acid and atypical antipsychotics) can worsen parkinsonism. A referral to a psychiatrist familiar with PD for the aforementioned clinical scenarios may help with the assessment, diagnosis and treatment of these patients. 19.2.8. Treatment of depression in Parkinson’s disease The results of numerous open-label trials using selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants in PD suggest a positive effect and reasonable tolerability for active treatment (Hauser and Zesiewicz, 1997; Ceravolo et al., 2000; Tesei et al., 2000; Dell’Agnello et al., 2001; Rampello et al., 2002). However, efficacy can only be established through the conduct of placebo-controlled studies, and at the time of this submission there have been only three published placebo-controlled antidepressant treatment studies for depression in PD (Andersen et al., 1980; Wermuth et al., 1998; Leentjens et al., 2003b). One study showed efficacy for a tricyclic antidepressant (TCA) (nortriptyline); however, TCAs can be difficult for PD patients to tolerate because they can aggravate PD-associated orthostatic hypotension, constipation, dry mouth and

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cognitive problems. The other two studies evaluated SSRIs and showed no difference between active and placebo treatment. A recent review and meta-analysis concluded that there was no evidence for the efficacy of newer antidepressants in PD, and in addition that they may be less effective for dPD than for depression in elderly, non-PD patients (Weintraub et al., 2005a). There is some concern about SSRIs worsening parkinsonism (Richard et al., 1997a; van de Vijver et al., 2003), perhaps secondary either to a direct dopamineblocking effect or to a serotonin-mediated decrease in dopamine turnover related to increased activity of raphe nuclei projections on nigral cells (Jimenez-Jimenez et al., 1994). However, clinical experience and the results of two placebo-controlled studies and numerous open-label studies suggest that most PD patients are able to tolerate SSRI treatment without clinically significant worsening of their parkinsonism (Hauser and Zesiewicz, 1997; Ceravolo et al., 2000; Tesei et al., 2000; Dell’Agnello et al., 2001; Rampello et al., 2002). Notwithstanding, it is important that the safety and tolerability of antidepressants in PD be tested in the context of placebo-controlled trials. Examining the experience of patients receiving routine clinical care, it was reported that half of PD patients currently taking an antidepressant at an adequate dosage (Alexopolous et al., 2001) still met DSM-IV criteria for a depressive disorder (Weintraub et al., 2003). This finding may partly have been due to undertreatment, as only 11% (1/9) of patients taking an antidepressant and still meeting criteria for depression were taking an antidepressant dosage within the highest recommended range, and only 33% (3/9) had received more than one antidepressant trial. This research also found that the overwhelming majority of PD patients in clinical practice are treated primarily and solely with an SSRI, and other classes of antidepressants were rarely used. Several PD medications have been used in the treatment of depression. Levodopa is not thought to have a consistent mood-elevating or depressing effect, although there have been case reports of patients using levodopa for its stimulating effects. Preliminary studies have reported the effectiveness of the dopamine agonist pramipexole as an antidepressant in both nonPD (Corrigan et al., 2000) and PD populations (Rektorova et al., 2003). It is important to determine whether the combination of a dopamine agonist and an antidepressant is superior to either alone, and if dopamine agonists offer prophylaxis against the development of dPD. In addition, selegiline, a selective monoamine oxidase B inhibitor at lower dosages, has been reported to have antidepressant properties, although it is not commonly used either

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as an antidepressant or a PD medication. There has also been concern that the combination of selegiline and SSRIs might lead to serotonin syndrome, although clinical experience suggests that the combination is safe (Richard et al., 1997b). Many questions remain concerning the pharmacologic treatment of dPD. For instance, it is unclear if the altered neural substrate (e.g. impairment of neural networks servicing the frontal lobe and multiple monoaminergic deficits) means PD patients will experience a more limited or variable response to standard antidepressant treatment than that reported in other populations. Also, the appropriate dosing titration schedules and final therapeutic ranges for antidepressant use in PD have yet to be established. Likewise, the duration of antidepressant treatment for PD patients is not clear, including as to whether chronic antidepressant therapy is indicated for general or for select patients. Concerning non-pharmacologic approaches, electroconvulsive therapy can successfully treat both depression and the motor symptoms associated with PD, although the motor benefits wear off once treatment is discontinued (Moellentine et al., 1998). Two open trials of transcranial magnetic stimulation for dPD reported a moderate improvement in both mood and motor symptoms (Dragasevic et al., 2004; Fregni et al., 2004). It is unclear whether there is a place for psychotherapy (e.g. cognitive-behavioral therapy or problem-solving therapy) in the treatment of dPD, either as an alternative first line treatment or as an approach to rehabilitation for those with partial medication response. Anecdotally, however, there are many PD patients who prefer psychotherapy, do not respond to pharmacotherapy, or are reluctant to take another medication (for fear of side-effects or to avoid adding to an already complex medication regimen), so psychotherapy may be an important alternative. When using psychotherapy in PD, we have often found it helpful to involve significant others in the psychotherapeutic process, particularly when cognitive impairment is present. Given the available evidence, it is reasonable to begin treatment of dPD with an SSRI. Although the safety and efficacy of this antidepressant class have not been firmly established, the potential risks and benefits of using these medications must be weighed against the risks of an untreated depressive episode. If an SSRI is not completely effective, there are very few data to guide clinical practice, though we would suggest using a second ‘newer’ antidepressant with a different pharmacological profile. These medications might include antidepressants that affect both serotonin

and norepinephrine (e.g. venlafaxine, duloxetine and mirtazapine) or a medication such as the unicyclic aminoketone, bupropion, a norepinephrine reuptake inhibitor and relatively weak dopamine reuptake inhibitor. If the patient has failed two adequate trials of antidepressant therapy, consultation with a psychiatrist may help resolve any diagnostic issues and provide additional guidance on appropriate somatic treatments. The addition or substitution of psychotherapy may be beneficial, especially in patients without significant cognitive impairment or psychosis. Although not a specific treatment for depression, it is believed that regular exercise optimizes both physical and mental health in PD. Other non-motor symptoms, such as insomnia, daytime fatigue and pain, may contribute to depression, so it is important to diagnose and treat these symptoms when they are present. Finally, assessment and treatment of any contributing comorbid medical conditions (e.g. hypothyroidism and B12 deficiency) are important.

19.3. Anxiety Up to 40% of PD patients experience anxiety symptoms or disorders, including generalized anxiety disorder, panic attacks and obsessive-compulsive disorder (Richard et al., 1996; Walsh and Bennett, 2001). Though patients often avoid public situations so that parkinsonian symptoms (e.g. tremor and dyskinesias) will not be noticed, such behavior does not meet DSM-IV diagnostic criteria for social phobia. Anecdotal experience indicates that anxiety symptoms are often more upsetting and disabling than depressive symptoms in PD, perhaps due to their intensity, accompanying somatic complaints and propensity to worsen parkinsonism. Increasing anxiety and discrete anxiety attacks have been associated with motor complications, particularly the onset of ‘off’ periods, although this relationship does not hold for all patients (Richard et al., 2001). When it does occur, patients often describe a sensation of feeling ‘trapped’ as they become increasingly immobilized, with symptoms resolving with improvement in motor symptoms. Similar to depression, studies have reported an increased prevalence of anxiety disorders up to 20 years before PD onset (Gonera et al., 1997; Shiba et al., 2000). This research underscores the biological underpinnings of anxiety in PD, and a neuropathophysiological link between the two disorders may be noradrenergic dysfunction (Richard et al., 1996). Regarding treatment of anxiety, there have been no controlled treatment studies in PD to inform clinical decision-making (Walsh and Bennett, 2001). For

DISORDERS OF MOOD AND AFFECT IN PARKINSON’S DISEASE patients who experience anxiety as part of an ‘off’ state, PD medication adjustments can be made in an attempt to decrease the duration and severity of these episodes. Anecdotally, newer antidepressants are commonly used for anxiety disorders, whether or not comorbid depression is present. However, anxiety in PD responds variably to antidepressants, and many patients require treatment with benzodiazepines (most commonly low-dose lorazepam, alprazolam or clonazepam). Given that these patients are frequently physically and cognitively impaired, benzodiazepines must be used cautiously.

19.4. Apathy Apathy, succinctly defined as a decrease in goaldirected behavior, thinking and mood, is reported to occur in approximately 40% of PD patients (Starkstein et al., 1992b; Isella et al., 2002). Although there is overlap between apathy and depression, delirium and dementia, apathy also occurs independently of these syndromes (Starkstein et al., 1992b). Similar to depression, it is associated with impaired function (Isella et al., 2002). Apathy is usually accompanied by diminished self-awareness, so changes are typically noticed and brought to the attention of clinicians by care-givers. A common assumption is that the patient is depressed, though a lack of endorsement of sad mood and the typical cognitive changes seen in depression (e.g. guilt, helplessness and hopelessness) suggest a diagnosis of apathy instead. It is also important to distinguish between apathy and PD-induced slowness. Goal-directed behavior is associated with dopaminergic and noradrenergic function, and with activation of the frontal cortex and basal ganglia (Duffy, 1997). Studies of apathy in PD have reported associations with executive deficits, verbal memory impairment and bradyphrenia (Starkstein et al., 1992b; Isella et al., 2002). There have been no treatment studies for apathy in PD. Comorbid psychiatric conditions (e.g. depression) should be treated initially. Anecdotally, psychostimulants (e.g. methylphenidate) and stimulant-related compounds (e.g. modafinil) are used in clinical practice, but their effectiveness for this condition is not known. Based on the proposed neuropathophysiology of apathy, antidepressants and other medications that increase dopamine or norepinephrine activity (e.g. dopamine agonists, TCAs, dual reuptake inhibitor antidepressants, bupropion and atomoxetine) may be beneficial (Marin et al., 1995). In addition to pharmacologic treatment, it is important to educate patients and families on the distinction between apathy and

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depression and to encourage steps that overcome patient inertia and may lead to improved functioning and quality of life (Shulman, 2000).

19.5. Pseudobulbar affect PBA, a specific form of emotional or affective lability, can occur in a variety of neurodegenerative diseases and neurological conditions, including PD (Schiffer and Pope, 2005). Clinically, PBA is characterized by repeated brief episodes of uncontrollable crying or laughing, with the expressed emotion typically incongruent with the patient’s underlying mood. If a stimulus is present, the emotional response is in excess of what would ordinarily be expected. For some patients, the episodes are embarrassing and distressing, and family members may mistakenly attribute crying episodes to an underlying depression. Regarding the neuropathophysiology of PBA, a final common pathway is likely disinhibition of the brainstem bulbar nuclei that control the motor expression of crying and laughing (Schiffer and Pope, 2005). PBA in PD probably results from impairment in neural networks connecting the cortex and brainstem (Green, 1998). Numerous small-scale studies have found both TCAs and SSRIs to be efficacious in the treatment of PBA, though none included PD patients (Arciniegas and Topkoff, 2000), and there is anecdotal evidence that mood-stabilizers (e.g. valproic acid) can be effective. The combination of dextromethorphan and quinidine has been found to be effective for this syndrome in amyotrophic lateral sclerosis (Brooks et al., 2004); perhaps its effects are related to its N-methyl-D-aspartate receptor antagonist or sigma-1 receptor agonist (i.e. antiglutamatergic) properties (Schiffer and Pope, 2005). In addition to somatic treatment, it is important to educate patients and family members on the differences between PBA (an affective syndrome) and depression (a mood disorder).

19.6. Conclusion Disorders of mood and affect occur commonly in PD, and their presence increases motor and cognitive disability and is a primary source of patient and caregiver distress. The high prevalence of these disorders cannot be explained solely as a reaction to psychosocial stress and is due in part to neurodegeneration affecting neurons in the basal ganglia, disruption in cortical-subcortical and basotemporal limbic neural networks, and pan-monoamine deficiencies. There is great interindividual variability in the presentation of mood and affective disorders in PD, and they are

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frequently comorbid. Although uncontrolled studies and clinical experience suggest that pharmacotherapy is well tolerated and beneficial to many patients, efficacy and tolerability have yet to be demonstrated for any of these disorders. There is a pressing need for additional research on disorders of mood and affect in PD to validate diagnostic criteria, to test further or develop rating instruments to establish those with good psychometric properties, to understand better the neurobiological underpinnings of these disorders and to establish efficacious and well-tolerated forms of treatment.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 20

Neurobehavioral disorders in Parkinson’s disease JOSE MARTIN RABEY* Department of Neurology, Assaf Harofeh Medical Center, Zerifin, Israel, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

20.1. Introduction Classical epistemology has provided a three-dimensional framework for conceptualizing the psychological components of behavior. Within this schema, the intellect is differentiated from two other, equally important categories: motivation and the emotions and the executive functions, which include capacities for initiating and carrying out self directed, goal-oriented activities effectively. This conceptual organization has facilitated the identification and classification of behavioral phenomena. Most of the studies described in the first 70 years of the 20th century were done by studying individual patients, or at most a small series of patients with similar disorders. The most common questions addressed by these studies concerned localization of function. Groups of patients with different lesion sites or behavioral syndromes were tested with standard protocols, looking for quantitative measures of performance, and these performances were compared across patient groups and with non-brain-damaged control groups. As a result of the neuropsychological research it has been shown that different aspects of behavior correspond to major cerebral structural systems (Shepherd, 1990; Kertesz, 1994). In addition to answering questions about localization, the experimental neuropsychology of the 1960s and 1970s also uncovered aspects of the functional organization of behavior (Luria, 1973). In the past two decades, neurobehavior and neuropsychology have been drastically transformed, not only by the influx of theoretical ideas from cognitive psychology, but also by the advent of powerful new methods for studying brain activity during cognition. In this respect, an important transformation in neurobehavioral

research occurred with the introduction of functional neuroimaging. After its introduction, positron emission tomography (PET) was quickly applied by researchers interested in brain–behavior relations. This technique provides images of regional glucose utilization, blood flow, oxygen consumption or receptor density in the brain of live humans. Moreover, with the use of radioactive ligands, abnormalities can be related to specific neurotransmitter systems as well as specific anatomic regions. PET was soon joined by other techniques for measuring regional brain activity, each of which has its own strengths and weaknesses. Single photon emission computed tomography (SPECT) was quickly adapted for some applications, since PET, although less expensive, was also a less quantifiable and less spatially accurate method for obtaining images of regional cerebral blood flow. Most recently, functional magnetic resonance imaging (fMRI) has provided good anatomic and temporal resolution, using non-invasive techniques (Feinberg and Farah, 1997). Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN) and to a lesser extent in the adjacent ventral tegmental area (VTA). The abnormal degeneration of the dopaminergic system leads to a progressive depletion of the neurotransmitter dopamine (DA) in the striatum, where the SN projects, as well as in the corticolimbic areas, receiving dopaminergic projections from the VTA. This causes a variety of motor and non-motor disturbances. The most important DA deficiency-related clinical motor manifestations in PD are bradykinesia, rigidity,

*Correspondence to: Professor J.M. Rabey, Department of Neurology, Assaf Harofeh Medical Center, Zerifin 70300, Israel. E-mail: [email protected], Tel: þ972-8-977-9180, Fax: þ972-8-977-9182.

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rest tremor and postural abnormalities. The non-motor abnormalities consist of cognitive deficits, depression, anxiety, apathy and psychosis, among others. This chapter reviews the non-cognitive neurobehavioral disturbances found in patients with PD. It is much more difficult to characterize and measure emotional behavior and executive functions than cognitive functions. Recognizing the fact that many emotional responses are both multidetermined and multidimensional makes it difficult, if not impossible, to delineate precisely the differences between the effects of a lesion, of personality predisposition and of situational reactions, particularly since most often the patient’s emotional behavior results from interactions between these factors. Thus, in comparison with the cognitive functions, both the understanding and assessment of the emotional disorders accompanying cerebral damage are less well developed (Lezak, 1997). In PD the situation is more complicated, considering that the ‘gold standard’ treatment for the disease consists of the administration of levodopa, which is converted into DA in the brain of patients. DA activates receptors located in the striatum, the limbic and frontal cortex (via the mesolimbic and mesocortical pathways). These two regions play a crucial role in the genesis of non-cognitive behavior. Therefore it is sometimes quite difficult to determine if the behavioral alterations observed in a PD patient are disease- or treatment-related.

20.2. Parkinson’s disease 20.2.1. General overview Since its original description (Parkinson, 1817), PD was considered mainly a motor disorder. This was based on the original description by James Parkinson, who did not note any psychiatric or behavioral change that might be associated with the disease as indicated by the definition, which states ‘senses and intellect being uninjured’ (Parkinson, 1817). It may be that this was his idea when assessing the early stages of the disease. Later, when discussing advanced disease patients, he used descriptive words such as ‘unhappy sufferer’, or ‘a more melancholy object I never beheld. The patient, a handsome middle-size, sanguine man, of a cheerful disposition and an active mind, appeared much emaciated, stooped and dejected’, suggesting the presence of depression. During the 19th century, Charcot and Vulpian (1861), referring to PD, concluded that ‘in general, psychic faculties are definitely impaired and at a given point, the mind becomes clouded and the memory is lost’.

Untreated PD was considered to be associated with mental and emotional abnormalities prior to the introduction of levodopa. Psychoanalytically oriented literature described a parkinsonian personality (Sands, 1942) and a detailed analysis attributed various unconscious explanations for the parkinsonian symptomatology (Booth, 1948; Flynn, 1962). These theoretical concepts were superseded by clinical observations oriented towards cognitive and affective changes inherent to the disease and the psychiatric side-effects caused by levodopa. The main motor symptoms in PD – rigidity, bradykinesia and rigidity – are exacerbated by neuropsychological problems that include depression, lack of motivation, bradyphrenia, lack of emotional expression, social anxiety and a stress-dependent increase of motor symptoms. Social anxiety and stress-induced increase in symptoms clearly result from an interaction of somatic and psychological factors. Social anxiety can be regarded as a secondary symptom that develops in PD as an indirect consequence of the motor symptoms. Patients are afraid of being negatively evaluated in public and of receiving negative comments. Social withdrawal increases as a result and the freedom provided by symptomatic control with medication is used far less than is possible (Ellgring et al., 1993). Today it is widely accepted that abnormalities of the mental state in PD are common, with more than 60% of patient reporting one or more psychiatric symptoms (Aarsland et al., 1999b). They constitute some of the most difficult challenges for treatment in advanced stages of the disease, producing increased disability and influencing the quality of life (QoL). Among different behavioral problems described, depression and anxiety are the most common disturbances in untreated PD (Aarsland et al., 1999b). They can also antedate motor symptoms by several years (Shiba et al., 2000). In addition, advanced PD is often associated with cognitive impairment, apathy and sexual or sleep disturbances. In advanced PD, several features related to antiparkinsonian medication complicate the management of the disease. These neuropsychiatric disorders include various symptoms which range from vivid dreams, nightmares and visual hallucinations with preserved insight to hallucinations without insight, delusions, mania, psychosis and delirium. Fluctuations in motor performance on antiparkinsonian treatment may also be associated with psychiatric symptoms, particularly anxiety and panic attacks. In addition, depression, suicidal ideation, pain, hallucinations and delusions may be found (Nissembaum et al., 1987; Witjas et al., 2002).

NEUROBEHAVIORAL DISORDERS IN PARKINSON’S DISEASE Levodopa administration to PD patients has been demonstrated to induce depression (Jenkins and Groh, 1970), euphoria (Celesia and Barr, 1970), mania (Muenter, 1970), hypersexuality (Uitti et al., 1989), delusions (Jenkins and Groh, 1970), confusion (Celesia and Barr, 1970; Jenkins and Groh, 1970; Mindham, 1970), night terrors (Sharf et al., 1978), vivid dreams (Sharf et al., 1978), visual hallucinations (Goetz et al., 1982) and paranoid psychosis (Hurwitz et al., 1988; Friedman and Lannon, 1989). However, it must be kept in mind that PD patients may have psychosis unrelated to their medications (Crowe et al., 1976; Klawans, 1988). Although the differentiation between psychiatric symptoms related to ‘off’ states and those independent of motor fluctuations can be difficult, a proper diagnosis has important treatment implications. Anxiolytic, antidepressant or analgesic medications are usually ineffective for such off-related events, but they typically resolve when ‘off’ periods are terminated by antiparkinsonian medication. In particular, apomorphine rescue injections have been shown to provide rapid improvement of psychiatric symptoms (Maricle et al., 1995). 20.2.2. Evaluation of behavioral disorders in Parkinson’s disease PD patients have a myriad of psychiatric symptoms. Usually, most published studies focused on one or few psychiatric symptoms such as depression, anxiety and psychosis (Cummings, 1992; Aarsland et al., 1999b). In these studies, behavior (non-cognitive) was usually studied by screening psychiatric symptoms in a PD population and scoring its prevalence and intensity or comparing the symptoms with data collected from a matched-age healthy group or a group of patients with another chronic disease (rheumatoid arthritis, for example). Considering the evaluation of mental features, it is important to mention that very few questionnaires have been validated for clinical use in the analysis of behavior disorders in PD. Among them, the most popular in use are the Neuropsychiatric Inventory (NPI) (Cummings et al., 1994), the Neurobehavioral Rating Scale (NRS) (Sultzer et al., 1992) and the Brief Psychiatric Rating Scale (BPRS) (Overhall and Gorham, 1962). The NPI consists of a care-giver-based, structured interview which assesses the severity and frequency of 10 psychiatric symptoms occurring during the last month (before the date of the evaluation). The fields covered by the inventory are: delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy,

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disinhibition, irritability and abnormal motor output. The NPI has proved validity and reliability in patients with dementia. Aarsland et al. (1999b) utilized the NPI successfully to evaluate 139 PD patients in Norway. According to the results presented, the most common behavior disorders found were depression (38%) and hallucinations (27%) and the least common symptoms were euphoria and disinhibition. The highest mean scores were found for depression, apathy and hallucinations. Psychiatric symptoms correlated with the stages of the disease and cognitive impairment. In addition, they did not find any relation with left- or right-sided parkinsonism. In addition to the utilization of validated questionnaires, some groups have also created new scoring scales for the evaluations of behavioral symptoms. Among those publications it is important to mention two studies. One is the work performed by Witjas et al. (2002). In this study the authors tried to assess the frequency and disability caused by non-motor fluctuations (NMF) in PD. For this purpose they created a structured questionnaire, which was applied to 50 PD patients. NMFs were evaluated by scoring 54 symptoms classified into three subgroups: (1) 26 dysautonomic; (2) 21 cognitive and psychiatric; and (3) 7 pain/ sensory. Patients were asked to rate their disability from 0 (no disability) to 4 (maximum discomfort) and to specify which kind of fluctuation subgroup (motor or non-motor) was the most incapacitating. The most frequent psychic fluctuations were anxiety (66%), slowing of thinking (58%), fatigue (56%), irritability (52%) and hallucinations (52%), whereas slowness of thinking (58%) was the most common cognitive symptom. In addition, they found that anxiety correlated highly with a greater level of disability. Surprisingly, 28% of patients stated that NMFs involved a greater degree of disability than motor fluctuations. Patients who reported a large number of psychic fluctuations had severe motor complications (‘on–off’ fluctuations or early-morning dystonia) (P < 0.05). The number of psychic manifestations correlated with the duration of levodopa treatment, but not with the daily dose of the drug (P < 0.001). In addition, it is important to mention that the psychic symptoms did not correlate with the Mattis Dementia Rating Scale or the Beck Depression Inventory (Witjas et al., 2002). Martinez-Martin et al. (2004) created a new questionnaire based on the NPI, the NRS and the BPRS. In addition to the motor tests, they evaluated 86 PD patients with the Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983). According to the prevalence data obtained in their study, the four most frequent features found were bradyphrenia,

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bradypsychia, depression and anxiety (present in more than 50% of patients examined). Other quite common symptoms were insomnia and parasomnia, somatic preoccupation, fatigue, apathy and agitation (present in nearly 40% of patients). In this study, the researchers also found that depression, verbal communication and cognitive-behavioral mental status were the domains that most significantly affected the QoL of the care-givers. 20.2.3. Quality-of-life questionnaires in Parkinson’s disease In the last years, in addition to measurements of motor, cognitive and emotional functions, a new item has received attention: QoL measurements. From a pragmatic point of view, QoL refers to the patient’s own perception and self-evaluation regarding the effects of an illness and its consequences on her or his life. The most relevant aspects to be considered in QoL are physical status, social interactions, economic and vocational status and religious and spiritual status. Both generic and disease-specific instruments that assess health-related QoL are being used in crosssectional and longitudinal PD research, such as clinical drug trials and studies that ascertain the economic burden and QoL deficits associated with PD. Longitudinal studies measure change in patient status over time, whereas cross-sectional studies can evaluate concurrent patient symptoms from a single disease or from multiple chronic conditions. The disease-specific instruments can be more sensitive to change in patient health status. PD patients have many reasons for a decrease in QoL, such as restrictions in mobility, falls, emotional disorders, social embarrassment, isolation, sleep disturbances, dyskinesias and fluctuations. Many aspects of these disorders go unnoticed and only QoL assessments help to rate them. Specific questionnaires recently developed, like the PDQ-39 (Jenkinson et al., 1995) and PDQL-37 (De Boer et al., 1996), have been designed and validated for the screening of mental and motor symptoms in PD. Several studies recently published have shown that PD patients’ well-being, general health perception and health satisfaction are strongly influenced by the impact of psychological and emotional factors and more weakly by physical symptoms of the disease (Calne et al., 1996; Schrag et al., 2000; Chrischilles et al., 2002). QoL assessment in PD is an important and expanding area that will probably play a key role in the management of future clinical trials and pharma-

coeconomics (Martinez-Martin, 1998). Considering the publications of the last years, it is quite clear that in the future clinical evaluation of PD patients should include mental health and self-reported QoL assessments. 20.2.4. Depression and Parkinson’s disease 20.2.4.1. Prevalence studies Depression may occur at any stage of PD (Allain et al., 2000). Its prevalence rates vary greatly, from 3 to 90%, depending on definitions and ascertainment methods. The measurement of depression using questionnaires is difficult as most standardized questionnaires contain questions that overlap with features of PD. Nevertheless, it is clear that depression and anxiety occur more commonly in patients with PD than in an age-matched population. Although in one study depression in PD subjects was no more common than in subjects with arthritis (Gotham et al., 1986), more recent larger studies found depression to be significantly more frequent in patients with PD than in patients with ostheoarthritis or diabetes (Nilsson et al., 2002). Gotham et al. (1986) reviewed 14 studies with a total of 1500 PD patients and estimated a mean depression prevalence of 46% (range 20–90%). Approximately half of depressed patients with PD do not meet the criteria for major depressive disorder, but do meet the criteria for dysthymia (Cummings, 1992). Dysthymia typically has an insidious onset. Chronic long-term stress and female gender appear to be risk factors. Moreover, patients with dysthymia are at increased risk for developing a major depressive episode in the future. Hantz et al. (1994) reported that only 2.7% of PD patients met Diagnostic and Statistical Manual (American Psychiatric Association, 2000; DSM-IV) criteria for major depression, suggesting that this psychiatric disorder may occur at an equal frequency in PD and non-PD individuals. Tandberg et al. (1996) reported, in a community survey in Norway, that among 245 patients with PD, 7.7% had major depression and 45.5% had mild depressive symptoms. These two studies strongly suggest that the prevalence of major depression in PD is low, but a significant proportion of PD patients have mild depressive symptoms. Mood alterations, even in mild forms, contribute to impairments in daily functioning among PD patients. Fine motor skills and cognitive function in PD patients decline when depression superimposes (Troster et al., 1995; Kuhn et al., 1996). Moreover, depression is the strongest and most consistent factor that negatively affects health-related QoL measures in PD (Phillips, 1999; Kuopio et al., 2000). This negative impact

NEUROBEHAVIORAL DISORDERS IN PARKINSON’S DISEASE extends to care-giver burden (Aarsland et al., 1999a; Meara et al., 1999). 20.2.4.2. The problem of diagnosis of depression in Parkinson’s disease The diagnosis of depression in PD can be confounded by an overlap of the motor features of PD and the clinical features of depression. Masked facies, bradyphrenia, fatigue, insomnia or hypersomnia, akathisia or bradykinesia and weight loss, all features of PD, may suggest depression in a euthymic PD patient. Sleep disturbances, including sleep fragmentation, early awakening, vivid dreams and rapid-eye movement (REM) behavioral disorder commonly occur in PD patients who are not depressed, so that classic screening tools may be inaccurate for PD patients. Researchers have therefore looked for discriminatory symptoms. Starkstein et al. (1990) reported that anorexia, pain, loss of libido and sleep disturbances were very characteristic in depressed PD patients and uncommon in non-depressed PD subjects. Feelings of worthlessness, pathological guilt and suicidal ideation are possibly the best useful discriminatory elements to diagnose major depression in a PD patient. Due to these diagnostic difficulties, screening tests and clinical judgment often correlate poorly (Mayeux et al., 1981; Hantz et al., 1994). Shulman et al. (1997) submitted 103 PD patients without dementia to a neurological examination, asking physicians to report their immediate impression of depression. These patients were then administered the Beck Depression Inventory to determine whether depressive criteria were met. The two assessments agreed in only 35%. 20.2.4.3. Risk factors predisposing Parkinson’s disease patients to depression The risk factors for major depression in PD remain debatable. PD patients with akinetic-rigid parkinsonism, cognitive dysfunction, early onset of disease or right-sided motor symptoms appear to be at increased risk for depression (Starkstein et al., 1990; Cummings, 1992; Cole et al., 1996). Other reports do not support those findings. Moreover, age at PD onset, gender, current age, disease duration and motor severity have all been reported to influence the risk for depression in some reports, but not in others. Few consistent findings emerge from these reports. Most studies reveal no relationship between depression and patient age at assessment, duration of PD symptoms or onset of symptoms (Gotham et al., 1986; Barclay et al., 1997). In fact, depression often antedates parkinsonism, suggesting that the affective illness may be an early, premotor sign of PD (Santamaria et al., 1986).

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20.2.4.4. Cognitive decline and depression in Parkinson’s disease A difficult problem to solve is the relationship between intellectual impairment and depression in PD. This question is difficult considering that depressive patients may show inattention, lack of interest and dysphoria. Some researchers suggested that depression occurs independently from dementia and Mayeux et al. (1981) found a significant negative correlation between the severity of depression and cognitive impairment. In another study, the same group (Mayeux et al., 1990) examined the clinical characteristics of 250 nondemented PD patients and evaluated their association with the incidence of dementia during a 5-year period. The odds ratio for incident dementia with PD in this group was significantly increased in the setting of depression. Starkstein et al. (1989) applied a neuropsychological battery to PD patients and found that severity of depression was the single most important factor associated with the severity of cognitive impairment. PD patients with major depression performed significantly worse than non-depressed PD patients on all cognitive studies, with most severe impairments on frontal lobe tasks. In addition to disease severity, other factors that play a role in the prevalence of depression are older age and lower cognitive score (Tandberg et al., 1996; Cubo et al., 2000; Giladi et al., 2000). Troster et al. (1995) found that PD patients with and without dementia demonstrated impairment in immediate and delayed verbal recall, semantic fluency and problem-solving. Yet, when matched for demographic and disease variables, only the depressed PD groups demonstrated impairment relative to the normal controls in the areas of visual confronting, naming and lexical and semantic fluency. Moreover, pronounced impairment in immediate recall and semantic fluency was present only in the depressed group. 20.2.4.5. Antiparkinsonian drugs and depression Considering the large number of medications with which PD patients are treated, the risk of drug-induced depression has been studied. No antiparkinsonian drug has been associated with the induction or aggravation of depression (Cummings, 1992). Moreover, anticholinergic drugs have been considered to have a mild euphoric effect. Selegiline has been reported to have mood-elevating properties and some DA-receptor agonists have been associated with improvement in affective functions. However, although selegiline, amantadine and levodopa have minimal antidepressant effects, there are no clinical data supporting their use as a substitute for classic antidepressants.

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Corrigan et al. (2000) conducted an 8-week doubleblind, randomized trial of fluoxetine (20 mg) versus pramipexole (0.375, 1.0 or 5.0 mg) versus placebo. Patients receiving pramipexole had a statistically significant improvement on the Hamilton Psychiatric Rating Scale for Depression, the Montgomery-Ashberg Depression Rating Scale and the Clinician’s Global Impression – Severity of Illness scale. However, the greatest benefit was seen with high doses of pramipexole (5 mg/day) and side-effects were relatively common at this dosage (Corrigan et al., 2000). 20.2.4.6. Pathogenesis of depression in Parkinson’s disease The precise pathophysiology of depression in PD has not been completely elucidated. Decreased cerebrospinal fluid 5-hydroxyindoleacetic acid levels, a serotonin metabolite, have been found in depressed PD patients (Mayeux et al., 1986, 1988; Asberg et al., 1984). The role of DA and norepinephrine in mediating depression in patients with PD is not fully understood. It is probable that depression is mediated by neuronal loss in dopaminergic, serotonergic and adrenergic pathways. Alterations of brainstem raphe–basal limbic systems may play a role in the pathogenesis of depression. Becker et al. (1997) described significantly reduced raphe echogenicity via transcranial sonography in depressed PD patients versus age- and sex-adjusted non-depressed controls. Over the last 25 years, evidence has accumulated to suggest that a derangement of the hypothalamic– pituitary–adrenal axis occurs in patients with major depression (Carroll, 1982). With the overnight lowdose dexamethasone suppression test, many depressed patients show adrenal cortisol hypersecretion, as well as flattened cortisol circadian periodicity and failure to suppress plasma cortisol concentrations. Carroll (1982) reported a 67% sensitivity and 96% specificity in the diagnosis of melancholia (or major depression) with the dexamethasone suppression test in hospitalized patients. In 1990, our research group submitted 32 PD patients (14 with dementia), all of them non-depressed, and 20 matched-age healthy controls to a dexamethasone oral test (1 mg) and measured cortisol, adrenocorticotropic hormone and beta-endorphin (Rabey et al., 1990). We found that about 50% of the patients were (as in a population with major depression) non-suppressors of cortisol plasma levels. As a consequence of these findings, we suggested that it was possible that non-depressed PD patients may share some pathophysiological features at the hypothalamic–hypophyseal–adrenal level with patients with major depression. The hypothesis to explain

those findings is that patients with depression may have higher levels of corticotropin-releasing factor as a result of a disturbance in the balance of neurotransmitters in the tuberoinfundibular pathway, which influence the release of the hormone (Eisler et al., 1981). If this is the case, considering that DA and norepinephrine are two neurotransmitters that may exert an inhibitory effect on the release of corticotropin-releasing factor at hypothalamic levels (and both are diminished in the brain of PD patients) (Hornykiewicz and Kish, 1986), we suggested that the decrement of these two neurotransmitters may induce high levels of corticotropin-releasing factor, resistant to exogenic dexamethasone. These alterations occur in both PD patients and patients with major depression. A study performed by Serra-Mestres and Ring (2002) may support this hypothesis. These authors found that non-depressed PD patients had a greater response to ‘sad’ words on the Emotional Stroop task than non-depressed healthy controls, suggesting that non-depressed PD patients ‘may be more sensitive to negative stimuli which may predispose them to develop depression’. 20.2.4.7. Antidepressant therapy and Parkinson’s disease Antidepressant therapy should be started without reservation if depression is interfering with the patient’s daily function and QoL. Although evidence-based clinical trials are lacking regarding the use of selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) in the treatment of depression in PD, their use is widespread in clinical practice and generally they are effective. In a recent paper Chung et al. (2004) performed a systematic review of antidepressant therapies in PD and found only three randomized controlled trials performed in 106 patients with PD. One was the study my group performed in the mid-1990s (Rabey et al., 1996). In this study, we randomly submitted 47 patients with PD and depression to fluvoxamine (mean daily dose 78 mg) versus amitriptyline (mean daily dose 69 mg) in a single-blind study. A 50% reduction in the Hamilton Depression Score was considered a good response for analysis. After 16 months, 55% of the amitriptyline group (15/27) and after 17 months, 60% of the fluvoxamine group (12/20) showed a 50% decrease in the Hamilton Score. We did not find any therapeutic advantage of one drug compared to the other. In addition, the rate of dropouts was relatively high (around 40%) in both arms of the treatment. Clinicians may be concerned that SSRIs may worsen the PD patient motor performance by decreasing DA

NEUROBEHAVIORAL DISORDERS IN PARKINSON’S DISEASE release in nigrostriatal pathways. However, clinical trial data and clinical experience do not support this concept. In fact, a large database study conducted in 199 PD patients by Gony et al. (2003) failed to identify any significant difference in the frequency of extrapyramidal symptoms between the different antidepressant classes utilized. Supporting this concept, Dell’Agnello et al. (2001) treated in an open way 62 depressed (nondemented) PD patients with four different types of SSRI (citalopram, fluoxetine, fluvoxamine or sertraline) for 6 months. They also did not detect a significant change in the motor performances measured with the Unified Parkinson’s Disease Rating Scale. At the same time, a good therapeutic response was measured with the Beck and Hamilton Depression Scales. Patients concomitantly receiving monoamine oxidase (MAO) inhibitors and SSRIs may be at increased risk for developing serotonin syndrome. MAO-B inhibitors may interfere with serotonin metabolism, resulting in excessive stimulation of 5-HT1A receptors. Selegiline and rasagiline are selective inhibitors of MAO-B and, at the doses recommended for PD (10 mg/day selegiline; 1 mg/day rasagiline) there is minimal inhibition of MAO-A. In a review of 4568 PD patients treated with selegiline and an antidepressant, only 11 patients (0.24%) reported symptoms that were probably consistent with a serotonin syndrome (Richard et al., 1997). Concerning the use of TCA in PD patients, it is important to mention that these types of antidepressants also have an anticholinergic (antimuscarinic) effect, which makes them especially useful for the treatment of rest tremor frequently found in these patients. However, this pharmacodynamic property also constitutes its limitation. Clomipramine, amitriptyline, doxepin, imipramine and protryptiline have the highest risk of producing undesirable ‘atropinelike’ side-effects: dry mouth, confusion, constipation and orthostatic hypotension. As a consequence, it is advised that treatment with TCA should be started at the lowest possible dose. Further titration should be performed under medical surveillance. In addition, TCA should be avoided in patients with significant cardiac disease as they may produce arrhythmias (Roose and Dalack, 1992). A baseline electrocardiogram is recommended before initiating TCA treatment, especially in elderly patients. Aggravation of cognitive functions in aged PD patients is also a serious limitation in the use of TCA. 20.2.5. Mania Mania, hypomania and euphoria do not occur in untreated PD patients (Mayeux, 1990), but have all

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been reported as side-effects of dopaminergic medication (Lang et al., 1982; Boyson, 1991). In this respect, Goodwin et al. (1971) reported that the incidence of hypomania was 1.5% in 908 patients treated with levodopa. In another study, the same group (Goodwin, 1972) treated 11 depressed non-PD patients with levodopa and 6 of them (50%) with a previous history of mania or hypomania developed acute mania or hypomania while treated with 4–10 g/day. The main hypothesis to explain this feature is to assume that increased synthesis of DA in the VTA (V10) in the midbrain may overstimulate the limbic system, producing the symptomatology. O’Brien et al. (1971) reported an interesting case of a man who developed episodes of inappropriate laughter and grandiosity that occurred in cycles 90 minutes after each 6 g of levodopa. Jouvent et al. (1983) reported 2 of 10 PD patients who developed hypomania after receiving high doses of bromocriptine. Acute mania was also described in PD patients receiving selegiline (Boyson, 1991; Kurlan and Dimitsopulos, 1992). Some researchers (Suchowersky and deVries, 1990; Kurlan and Dimitsopulos, 1992) also warned against the concomitant use of selegiline and antidepressants (mainly fluoxetine) because of the possibility of precipitating mania. As a consequence of the information available today, it is advised that PD patients with a previous history of mania and hypomania should be treated cautiously with dopaminergic therapy with periodic monitoring of their mental performance to avoid the reappearance of this symptomatology. 20.2.6. Hypersexuality Hypersexuality seems to be a rare complication related to the treatment of PD. It is estimated to occur in 0.9–3% of patients (Goodwin, 1971, Lesser et al., 1979). It is more common in men and has been described with all dopaminergic medications, including apomorphine (Courty et al., 1997), pramipexole and ropinirole. Increased libido and return of penile erection after years of impotence have been reported in patients treated with levodopa (O’Brien et al., 1971). In these cases, aberrant behavior was not described. Other researchers described an increased preoccupation of PD patients with sexual activities after being exposed to dopaminergic treatment, out of proportion with their interest before this treatment (Uitti et al., 1989). Some patients become more voyeuristic or showed disinhibition, involving indecent exposure in public places or sadomasochism (Quinn et al., 1983). In many of these patients, the increased sexual desire and preoccupation

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were not accompanied by a return of sexual function. Goodwin (1971) reported an association between psychosis and hypersexuality in PD. Low doses of classic antipsychotics may overcome these features. However, these medications should be used with caution considering their possible motor complications. Low doses of atypical antipsychotics may be used in cases of hypersexuality with good results. It is interesting to mention that Fernandez and Durso (1998) reported a case of zoophilia (sexual contact with a domestic dog) in a PD patient, who responded to clozapine therapy. Also it is useful to remember that a diminution of the offending drug (levodopa or DA agonists) may help to abate the syndrome of hypersexuality. Impotence has been reported in 40–60% of male PD patients. Sildenafil has been reported to be useful in 22 PD patients with impotence (Brewer and Stacy, 1998). It has been reported that patients with PD may suffer from depression, anhedonia and sexual impotence due to low levels of testosterone. In these cases, substitutive therapy should be used (Okun et al., 2002). 20.2.7. Anxiety Anxiety is an unpleasant emotional state consisting of psychophysiological responses to the anticipation of unreal or imagined danger, ostensibly resulting from unrecognized intrapsychic conflict. Autonomic concomitants include tachycardia, altered respiration rate, sweating, trembling, weakness and fatigue. Psychological concomitants include feelings of impending danger, powerlessness, apprehension and tension. Panic attacks are discrete periods of intense fear or discomfort that are accompanied by at least four of 13 cognitive symptoms (according to DSM-IV criteria: American Psychiatric Association, 2000): (1) palpitations, accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath, (5) feelings of choking, (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady or faint; (9) derealization or depersonalization; (10) fear of losing control or going crazy; (11) fear of dying; (12) paresthesias; (13) chills or hot flushes. It is well known that, in psychiatric populations, anxiety and depressive disorders commonly coexist. Lydiard (1991) reported that up to 60% of patients with depression also have anxiety and 20–30% of patients with major depression suffer from panic attacks. Anxiety is common in PD. Some publications suggest that the proportion of patients with PD experiencing clinically significant anxiety is greater than that of the general population, clinic attenders or

persons with other chronic medical conditions (Richard et al., 1997). Considering that depression is the most common behavioral disorder that accompanies PD, it is clear that anxiety will be the second most common behavioral disturbance. Cummings (1991) noted that depression in PD is distinguished from other depressive disorders by greater anxiety and less self-punitive ideation. Menza et al. (1993b) reported that 92% of PD patients who suffered an anxiety disorder also had a depressive disorder and that 67% of those with a depressive disorder also presented an anxiety syndrome. Although other studies have also found a close correlation between depression and anxiety (Fleminger, 1991; Vazquez et al., 1993), anxiety can occur in the absence of depression. A study by Liu et al. (1997) showed that, although in the cohort studied, general depression correlated with anxiety, 14 of 58 PD patients free of depressive symptoms suffered from general anxiety disorders (GAD) (applying DSM-IV criteria: American Psychiatric Association, 2000). Reviewing the epidemiology and comorbidity of anxiety disorders in the elderly, Flint (1994) concluded that GAD and phobias account for most anxiety in late life and that panic disorders are rare. This finding contrasts with what has been described in patients with PD. Moreover, it was noted that when panic disorders did occur in elderly patients, females accounted for all the cases. In contrast to elderly subjects, in PD the occurrence of panic disorder involved both males and females. Virtually all types of anxiety disorder have been described in PD, but GAD panic disorder and social phobia appear to be the ones most commonly encountered. The relation between anxiety and dementia is not clear. Depression seems to be equally frequent in PD patients with and without dementia (Cummings, 1992). Lauterbach (1993) studied 38 patients with familial parkinsonism and found no relationship between anxiety and cognitive decline. Similar conclusions were reported by Vazquez et al. (1993) and Fleminger (1991). 20.2.7.1. Pathogenesis of anxiety The main neurotransmitters implicated in the pathogenesis of anxiety include norepinephrine, serotonin and gamma-aminobutyric acid (GABA). There is convincing evidence implicating noradrenergic dysfunction in the development of primary anxiety disorders, especially panic attacks (Charney et al., 1987; Nutt and Lawson, 1992). Interestingly, many abnormalities of the noradrenergic system have been described in PD brains (Agid et al., 1989). Studies have demonstrated a catecholaminergic cell

NEUROBEHAVIORAL DISORDERS IN PARKINSON’S DISEASE loss in the locus ceruleus in PD (German et al., 1992; Patt and Gerhard, 1993). In addition to the derangement of the nucleus ceruleus in PD patients, changes have been described in both central and peripheral adrenergic receptors. Studies have shown a decrease of a2-adrenoreceptors in the cortex of PD patients (Cash et al., 1984). Other studies also demonstrated a decrease in a2-adrenergic binding in platelets from PD patients (Villeneuve et al., 1985). Berlan et al. (1989) suggested that untreated PD is associated with a significant reduction in a2-adrenergic sensitivity. It has been suggested that PD patients are more vulnerable to panic attacks because they have an alteration of a2-adrenergic receptors. Probably the locus ceruleus is disinhibited in PD secondary to an alteration in other neurotransmitters. Lauterbach (1993) and Vazquez et al. (1993) provided data suggesting that locus ceruleus disinhibition in PD may lead to secondary panic attacks, whereas locus ceruleus degeneration and subsequent incompetence might explain attenuation of primary panic attacks. Supporting a possible link of norepinephrine and anxiety, it is important to mention that PD patients with a history of anxiety developed panic attacks at frequencies comparable with psychiatric patients with panic disorders when they were challenged with yohimbine (an a2-antagonist) (Richard et al., 1999). Serotonin is another neurotransmitter that has been postulated to play a role in the production of anxiety disorders, particularly obsessive-compulsive disorder and social phobias, GAD and perhaps panic disorders (Charney et al., 1990). Selective abnormalities in the serotonergic system have been described in PD (Jellinger, 1987; Halliday et al., 1990). In the basal ganglia (putamen, caudate, globus pallidus), SN, hypothalamus and frontal cortex there is a selective decrease of serotonin (Jellinger, 1987). It is possible that interactions between noradrenergic and serotonergic systems are important for the manifestation of certain anxiety disorders, since serotonin can decrease locus ceruleus firing by 5-HT2 serotonin receptors (Charney et al., 1990). The potential role of GABA in the genesis of anxiety symptomatology is suggested by the fact that benzodiazepines are very effective for its treatment. These drugs work by activation of GABA receptors in the brain (Charney et al., 1990). In addition, in the brains of PD patients an increased concentration of GABA has been measured in the putamen and pallidus and a decreased concentration in cortical areas (Agid et al., 1989). There are some data to suggest that DA may be involved in the development of anxiety, social phobias

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and panic disorders (Pitchot et al., 1992; Potts and Davidson, 1992). If a derangement of DA is related to anxiety, this will explain why patients with PD show a high frequency of anxiety. Maricle et al. (1995) performed a study in which they administered levodopa in an infusion to PD patients and demonstrated a relationship between dopaminergic deficiency and anxiety, at least associated with motor fluctuations. In addition to the findings just mentioned, it has also been noted that DA decreases the firing rate of the locus ceruleus (Cederbaum and Aghajanian, 1977). Other researchers have also suggested that DA deficiency may result in an alteration of the noradrenergic system, which would explain its relationship with certain anxiety disorders (Iruela et al., 1992; Lauterbach, 1993; Vazquez et al., 1993). Concerning the relationship between cerebral lateralization and anxiety, some studies have shown that PD patients with predominant left-side symptoms (which imply a lesion in the right-brain hemisphere) suffer from more anxiety disorders than patients with right motor features (Rubin et al., 1986; Fleminger, 1991; Tomer et al., 1993). 20.2.7.2. Treatment of anxiety in Parkinson’s disease The drugs commonly used for treating anxiety in PD include benzodiazepines, TCA, SSRI, atypical cyclic antidepressants (trazodone), non-selective MAO inhibitors and buspirone. There are no controlled studies on medication for anxiety syndromes in PD. Stein et al. (1990) suggested that PD patients with anxiety may respond to benzodiazepines and antidepressants. Lauterbach and Duvoisisn (1992) cautioned that benzodiazepines may at times worsen PD symptomatology. Alprazolam (Small, 1997) was shown to be effective for anxiety symptoms in an elderly population after cardiac surgery. In my experience, alprazolam is a very useful drug for the management of GAD and other types of anxiety in PD patients. It is especially useful for the management of anxiety and discomfort related to ‘off’ episodes. Elderly PD patients may be more sensitive to anxiolytic medications due to their altered liver metabolism, low kidney filtration rate, injuries resulting from a tendency to fall if oversedated and their underlying medical conditions (Small, 1997). Higginson et al. (2001) examined which symptoms of anxiety diminish after surgical intervention for PD. Thirty-nine PD patients were screened using the Beck Anxiety Inventory (BAI) 1 month before and 4 months after surgery (24 underwent pallidotomy, 10 underwent deep brain-stimulating electrode implantation in the internal segment of the globus pallidus, 4 underwent

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thalamic brain stimulation and 1 underwent left thalamotomy). According to the results obtained, the surgical procedures produced a significant reduction in terms of BAI total score as well as neurophysiologic autonomic and subjective factors from the BAI. These factors were distinct from the motor symptoms of PD. In other words, the amelioration in anxiety was not an epiphenomenon of parkinsonian symptoms improved by the surgical procedure. The explanation for a change in anxiety symptoms after basal ganglia surgery may be related to activation of neural loops (with secondary changes in blood flow in the limbic and frontal regions) obtained secondary to surgical procedures (Miyakawi et al., 2000). 20.2.8. Pathological repetitive behavior Patients with PD may suffer from stereotypies and perseverations in the course of their disease. Stereotypies consist of the persistent repetition of senseless acts or words. This may be a persisting maintenance of a bodily attitude (stereotypy of attitude), repetition of senseless movements (stereotypy of movement, echopraxia) or a constant repetition of certain words or phrases (stereotypy of speech, echolalia, verbigeration). Perseveration means the persistence or repetition of a response after the causative stimulus has ceased or in response to different stimuli (for example, the patient correctly answers a question, but later gives the same answer to succeeding questions) (Ridley, 1994). This condition has been studied in a variety of conditions (Ridley and Baker, 1982). It has been associated with dysfunction in the regulation–inhibition activity of frontal lobes, particularly in patients with subcortical pathologies. The terms stereotypies and perseverations are sometimes used interchangeably in the literature or with the implication that stereotypies are more severe than perseveration, or considering that stereotypy refers to motor acts whereas perseveration refers to the behavioral consequence of mental states (Ridley, 1994). The main neurochemical change found in PD consists of a derangement of DA in the nigrostriatal, mesolimbic and mesocortical pathways. As a consequence, the symptoms of PD may be explained as secondary to an underactivation and increased inhibition of behavioral sets (frontal region) with difficulties in changing responses according to external signals resulting in reduced behavioral output. In addition to these motor effects, there are also marked mental effects consisting mainly of perseverations of attentional sets. Bowen et al. (1975) were the first to show that some patients

with PD perform poorly on the Wisconsin Card Sorting Test (WCST). Subsequently, Flowers and Robertson (1985) showed that PD patients were also impaired on a simplified version of the same task in which they were required to make choices according to alternating rules. Sometimes only stimulus-bound behavior remains. A PD patient may make a rapid and skillful movement in order to avoid some perceived mishap, but may be unable to make the same movement under normal voluntary control. In patients with PD, perseverations usually occur in intellectual tasks and may be seen as difficulty in suppressing ongoing attention to prior stimulation and as the unrestrained perpetuation of a response beyond its proper point of completion. The difficulty in suppressing response tendencies may interfere with performance on tasks requiring delayed responses (Milner, 1971). In these cases perseverations are often associated with the intrusion of previous memory traces. Most commonly these features are found in patients with PD and early dementia. Gasparini et al. (2001) studied the role of frontal lobes in the production of perseverations in PD, by evaluating 32 patients with PD treated with levodopa in a visuospatial memory task to assess the effect of perseverations in visuospatial recall. They also performed the WCST in order to evaluate their shifting capabilities. The results of the study showed that there is a strong correlation between an increase in recurrent perseverations and a decrease in mnemonic retrieval in the Rey Complex Figure, as well as between an increase of stuck-in-set perseverations and a decrease in the number of categories achieved on the WCST. The results obtained suggested that perseverations interfere in the storage of mnemonic input, probably linked with an abnormal recall of memory traces. The phenomenon was similar at different stages of the illness. Chronic ingestion of large doses of amphetamines (which increases the release of DA and norepinephrine in the brain) produces psychosis and a special form of stereotype behavior termed ‘punding’ (Rylander, 1972). In this situation, the patient engages in long complex and repetitive behaviors such as sorting collections of small items or dismantling pieces of mechanical equipment. The behavior is ‘compulsive’ in the sense that the patient becomes distressed if prevented from pursuing the chosen activity. Although it is usually uncommon to note bursts of stereotyped behaviors in PD patients, obsessive-compulsive traits have been commonly observed in these patients more than in normal controls (Alegret et al., 2001). An excesive dopaminergic activity has been postulated to play a relevant role in the pathophysiology

NEUROBEHAVIORAL DISORDERS IN PARKINSON’S DISEASE of the punding phenomenon. Indeed, punding is known to appear occasionally in levodopa-treated PD patients and ‘behavior improves with a reduction in the dose of antiparkinsonian drugs’ (Fernandez and Friedman, 1999). Punding behavior has also been described in PD patients treated with quetiapine (Miwa et al., 2004). Quetiapine is an atypical antipsychotic, which interacts with multiple transmitter receptors in the brain, with a higher affinity for serotonin 5-HT2 than for DA D1 or D2. In addition, it has been suggested that quetiapine may have a glutamatergic action in the brain (Oh et al., 2002). It is clear from these studies that further research is needed to elucidate the pathophysiological mechanisms of punding behavior and serotonin. 20.2.9. Psychosis and Parkinson’s disease Intrinsic psychiatric disorders characterized by mood and cognitive dysfunction in PD were known in the pre-levodopa era, but the incidence of psychosis was low (Schwab et al., 1950). Psychotic symptoms have become much more common since the introduction of levodopa and other dopaminergic agents (Fischer et al., 1990; Cummings, 1991). Among the problems observed in PD patients, one of the most difficult to handle is the development of psychosis. It can be manifested by various symptoms, ranging from visual hallucinations, paranoid delusions (including agitation, aggression, accusations and sexual preoccupation) to confusion and delirium. Usually it occurs in the advanced stages of the disease and in older patients and is causally linked to treatment with levodopa, but also to all other antiparkinsonian drugs. In fact, psychiatric complications are a major risk factor for nursing-home placement of PD patients (Goetz and Stebbins, 1993). The psychiatric symptoms most commonly found are visual hallucinations and delusions. It is estimated that the prevalence of the syndrome varies between 10 and 50% (Goodwin et al., 1971; Cummings, 1991). In PD, hallucinations usually occur on a background of a clear sensorium; however, a concomitant confusional state is common in older or demented patients. Hallucinations are usually fully formed, non-threatening images of people or animals and tend to be nocturnal, recurrent and stereotyped for each patient (Cummings, 1991). Occasionally, especially in men, there will be an erotic content to the visions (Sanchez-Ramos et al., 1996) and about 28% of the time hallucinations may have a frightening or threatening characteristic (Moskovitz et al., 1978). Quite frequently, the patients when asked will recognize that the images seen are not real (hallucinosis).

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However, in the same interview patients may change their opinion and a few minutes later they may claim that they are ‘real’ (personal experience). Pure auditory hallucinations are extremely rare in patients with PD, but a secondary auditory component has been described in 26–40% of patients with visual hallucinations (Moskovitz et al., 1978; Graham et al., 1997). Another group (Inzelberg et al., 1998) reported that 8% of patients with visual hallucinations also suffered from auditory ones. In this report, patients described human voices that were non-threatening and often incomprehensible. True illusions, which are distortions of actual visual stimuli, are also uncommon, but do occur in some patients (Moskovitz et al., 1978; Graham et al., 1997). Typically, patients may report seeing faces in patterned fabric or misinterpret a curtain blown by the wind as a person moving. Although difficult to interpret as true hallucinations or illusions, some patients may report the sensation that ‘someone is standing beside or behind them’ (Sanchez-Ramos et al., 1996). Delusions are not as common as hallucinations in PD, but they usually constitute a more serious therapeutic problem. In PD they are usually paranoid in nature and most often occur on a background of a clear sensorium without any other element of a thought disorder (which differs from delusions found in schizophrenic patients). It has been estimated that they occur in 7–8% of PD patients (Factor and Friedman, 1997). However, other reports mention a prevalence of 17% (Cummings, 1991). Some examples include fear of being injured, poisoned and filmed (Serby et al., 1978). Delusions of conjugal infidelity and elaborate conspiring on the part of the family are also relatively common. Less commonly observed, sometimes PD patients believe that family members ‘have been replaced by identical-appearing imposters’ (the Capgras phenomenon). Related to this symptom there are also beliefs of reduplication, where persons or places are ‘duplicated or replaced’ (Roane et al., 1998). These features are classified as delusional mistaken identification syndrome. 20.2.9.1. Pathogenesis of psychosis in Parkinson’s disease The pathogenesis of the psychotic syndrome in PD patients is poorly understood. An unsolved question is why the appearance of psychosis is a relatively late complication of chronic levodopa treatment. Chronic levodopa administration to PD patients induces higher levels of DA synthesis, not only in the SN (area A9) where it is missing, ‘normalizing the reservoir of DA’, but also in the VTA (area A10) in the midbrain, where its accumulation produces an ‘inundation’ of

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DA into the limbic and frontal areas (nucleus accumbens, amygdala, olfactory bulbe, septum, prefrontal areas). Chronic loading of DA into those areas related to the control of emotions and feelings may play a role in the occurrence of psychosis. However, considering the fact that, from the beginning of treatment, PD patients are administered levodopa for years, it appears that chronic overloading of DA into the limbic and frontal region is not enough. Therefore, in addition it is necessary to receive another disturbance within time, which will play a part in the genesis of psychosis. One of the suggested possibilities is to consider that, with aging, the brains of PD patients suffer from a progressive loss of acetylcholine, an important neurotransmitter essential for normal cognitive functions. In this respect, it is important to remember that eosinophilic intracytoplasmatic bodies (considered the pathological hallmark for the diagnosis of PD) were first described by Lewy in cholinergic neurons in the forebrain (nucleus basalis of Meynert) in a patient who suffered from paralysis agitans (PD) (Lewy, 1912). This means that PD patients may suffer from a progressive loss of cholinergic input into the cortex, even when they are not yet clinically demented (Nakano and Hirano, 1984). Supporting this hypothesis, it is important to mention that Whitehouse et al. (1983) described loss of cholineacetyl transferase in the nucleus basalis of Meynert in the brain of PD patients without dementia. Kosaka (1990) was the first to describe cases of patients with dementia and an increasing number of atypical Lewy bodies in the cortex and suggested that this was probably a new entity. Years later, when Lewy bodies were easily identified in the cortex with monoclonal antibodies for ubiquitine, a list of symptoms which characterize the diagnosis of Lewy body dementia was established (McKeith et al., 1999). The diagnosis includes the presence of fluctuative cognition, parkinsonism and psychotic features (mainly visual hallucinations). Klawans (1978) suggested (according to animal studies) that some populations of cells may develop receptor hypersensitivity under chronic levodopa stimulation. In their laboratory experiment, they showed that chronic stimulation of DA receptors may cause dopaminergic-induced stereotyped behavior, which appears at subthreshold doses and with a shorter latency than in animals not chronically exposed to dopaminergic stimulation. Thus, chronic exposure to DA agonists causes hypersensitivity of DA receptors rather than the expected results of downregulation. Applying this model, Moskovitz et al. (1978) proposed that there may be two populations of sensitive neurons in the limbic cortex. They suggested that a

population of DA-facilitated neurons might predominate and thus be responsible for the psychotic symptoms observed with chronic levodopa treatment. In this case, they proposed that chronic levodopa therapy might result in dopaminergic kindling and supported the hypothesis that DA may play a role in the development of some types of psychosis via such a kindling mechanism. Another proposed mechanism by which levodopa may produce visual hallucinations and psychosis is by interfering with serotonin metabolism. Postmortem studies have shown that patients with psychosis have low brainstem levels of serotonin (Nausieda et al., 1982). In addition, it is known that acute administration of levodopa reduces brain serotonin levels (Goodwin, 1971; Nausieda et al., 1982). L-tryptophan treatment normalizes serotonin content in serotonergic neurons. This effect may explain the beneficial effect reported by our group (Rabey et al., 1977) of the addition of l-tryptophan to treat levodopa-induced hallucinations in elderly PD patients. Melamed et al. (1993) have also shown that stimulation of 5-HT2 receptors may overcome psychosis in PD-treated patients. Dysfunction of serotonergic systems has also been suggested by the frequent association of dopaminergic psychosis with sleep disturbances and altered dreaming, both of which seem to have a serotonergic basis (Nausieda et al., 1982; Sanchez-Ramos et al., 1996). 20.2.9.2. Treatment of psychosis Psychosis may first emerge after a levodopa dose increases or after the introduction of a new antiparkinsonian agent. It can occur after infection, emotional or physical trauma, surgery or stroke. Decrease or discontinuation of levodopa can improve the syndrome, but at the expense of rapid worsening of the motor signs of the illness. If the psychosis persists, there is a treatment algorithm that should be applied to overcome the condition. First anticholinergics and selegiline should be stopped. Then amantadine, DA agonists and entacapone should be discontinued in the order just mentioned. Finally, levodopa may be reduced. It is not advised to stop levodopa quickly as its interruption may lead to the development of a neuroleptic malignant syndrome (Henderson and Wooten, 1981). The syndrome is manifested by altered mentation, fever, increased rigidity with leukocytosis and increased blood creatine phosphokinase. One of the most common mistakes in the emergency room is to confound this syndrome with sepsis. The syndrome is considered a medical emergency, which

NEUROBEHAVIORAL DISORDERS IN PARKINSON’S DISEASE requires hospitalization in an intensive care unit. Usually the condition is treated with good hydration, bromocriptine orally and amantadine intravenously. Dantrolene has also been used. Takubo et al. (2003) reviewed 99 episodes of neuroleptic malignant syndrome (or malignant syndrome), which occurred in 93 patients in Japan. The most frequent precipitating event was discontinuation or dose reduction of antiparkinsonian drugs, particularly levodopa. Intercurrent infection was the next most common precipitating event. Although the first approach in treating a PD patient with psychosis is the diminution of antiparkinsonian treatment, these patients frequently require specific treatment. It is important to stress that classical antipsychotics should be avoided, except in cases of acute emergencies (butirophenon intramuscularly, for example), as they may worsen the motor condition of the patients. These PD patients, as a consequence of classical antipsychotic exposure, may also develop the malignant syndrome. Among the new class of atypical antypsychotics, isperidone and olanzapine are quite problematic as they may worsen extrapyramidal features due to their D2-receptor-blocking properties. Clozapine at low doses has been proven to be an excellent medication (Rabey et al., 1995; Klein et al., 2003) as an antipsychotic. However, its use requires periodic monitoring of blood white cell counts to avoid the occurrence of neutropenia. Quetiapine is another atypical antipsychotic that has been introduced in the treatment of psychosis in PD. It has a strong sedative effect, even at low doses (Juncos et al., 2004). However its antipsychotic therapeutic effect may be limited in PD. Recently (Rabey et al., 2005), we conducted a double-blind study for 6 months comparing quetiapine with placebo in 58 PD patients with and without dementia. The BPRS was utilized to evaluate patients. The study did not show a statistical difference between patients submitted to quetiapine or placebo in the intention to treat analysis. In this study we had a dropout rate in the quetiapine-treated group of about 40% (mainly due to lack of benefit of quetiapine). Juncos et al. (2004) reported a positive result in treating PD patients with psychosis. However, the patients we treated (Rabey et al., 2005) suffered from more severe symptomatology than the patients treated by Juncos et al. (2004). These results suggest that quetiapine is probably effective in patients with mild symptomatology, but the drug should be used with caution in psychotic patients with more severe symptoms. Whereas PD patients with serious cognitive or psychiatric impairments are generally not considered good

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candidates for brain surgery (Hallet and Litvan, 1999; Limousine-Dowsey et al., 1999; Lai et al., 2000), 19 PD patients with ‘mild’ psychosis were submitted to pallidotomy (Yamada et al., 2003). Their conclusions were that drug-induced psychosis (DIP), even if its degree is not severe, may also be a limiting factor of the therapeutic potential of pallidotomy. Another surgical approach for the treatment of PD is deep brain stimulation (DBS) in the subthalamic nucleus. Although ‘a priori’ it was considered that surgery could be considered more appropriate for DIP (considering that after surgery a substantial reduction in the dose of dopaminergic agents is possible), the available information does not support this presumption as, on the contrary, psychiatric symptoms like mania, depression, anxiety and cognitive disturbances developed after surgery (Hallet and Litvan, 1999; Limousine-Dowsey et al., 1999; Pillon et al., 2002; Trepanier et al., 2000; Krack et al., 2002; Romito et al., 2002; Daniele et al., 2003). 20.2.10. Apathy and amotivation Motivation is a state of being that produces a tendency toward action. The state may be deprivation (e.g. hunger), a value system or a strongly held belief (e.g. religion). In the process of learning and perception, biological mechanisms play an important role in motivating behavior (Kaplan and Sadock, 2003). Apathy means lack of motivation. Sometimes the concept is used instead of the concept of amotivation. Apathy may contribute to disability in several organic and psychiatric conditions and may also affect healthy adults. The failure to recognize the existence of apathy commonly leads to the misdiagnosis of the patient’s behavior as lazy, self-centered or as evidence of the existence of cognitive impairment (Campbell and Duffy, 1997). Physicians usually find the care of apathetic patients unrewarding since the patients are likely to be more passive, less interested in their condition and less compliant. Family members may become resentful and angry as the patient becomes increasingly withdrawn. Amotivation is more likely to be observed associated with other behavioral symptoms. Covington (1991) considered a feedback loop in which behavioral and organic symptoms together with inactivity and loss act synergically to increase suffering and disability. Motivational behavior is an important factor of successful adjustment to stressful life events and illness. Patients with self-determination and motivation are more likely to deal with health problems in a more constructive manner. In this respect, it is important to apply

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detailed health quality scorings to PD patients with and without apathy syndromes. Patients with motivation are more likely to be active, looking for current information about medical and surgical interventions as well as new clinical research opportunities. They like to be consulted about treatment strategies and will often provide detailed medical information. They also provide better feedback regarding their response to therapy. In contrast, the consequences of amotivation on self-management, lifestyle, family interaction, socialization and participation in community activities are likely to result in a greater loss of functional status and a consequent deterioration of self-esteem (Webster and Grossberg, 1996). Marin (1990) and Marin et al. (1991) elaborated a scale to measure apathy in two versions, one self-administered and one scored by the clinician. Apathy has been considered by some researchers to be a feature of depression. Criteria for the diagnosis of depression include, in addition to poor concentration, difficulty making decisions, feelings of fatigue and also loss of motivation (applying DSM-IV criteria: American Psychiatric Association, 2000). In contrast to depression, apathy and abulia are not characterized by anhedonia, hopelessness or low mood, but rather by isolated lack of motivation and initiative. Starkstein et al. (1992) administered a modified version of Marin’s Apathy Evaluation Scale (Marin, 1990) together with scales measuring depression, anxiety, cognitive functions and parkinsonian severity in 50 patients with PD: 42% of patients had significant apathy, 12% of those with apathy were not depressed and 30% had both apathy and depression. An additional 26% had depression but not apathy and 32% had neither apathy nor depression. PD patients with and without depression suffered from the same amount of apathy. Apathetic patients (with and without depression) showed a poorer performance on tests of verbal memory and time-dependent tasks. Basic clinical data (age, gender, PD duration, education, severity of akinesia or rigidity) were similar in PD patients with and without apathy. Moreover, the poor performance of PD patients with apathy in time-dependent cognitive tasks suggested a relationship between bradyphrenia and apathy. Levy et al. (1998) applied the NPI to study the discriminability of apathy and depression in 154 patients with PD, Alzheimer’s disease, frontotemporal dementia, Huntington’s disease and progressive supranuclear palsy. PD patients showed apathy in 33% of cases. In this group, PD patients had a relatively higher functional status and relatively less cognitive impairment that the other patient subgroups that showed higher preva-

lence rates of apathy (varying from 59% in Huntington to 91% in progressive supranuclear palsy). There was no correlation between the presence of apathy and depression in the total sample and the authors concluded that apathy is a behavioral syndrome that is distinct from depression. Levels of insight may help to differentiate between apathy and depression. Ott et al. (1996) studied apathy and loss of insight in Alzheimer’s patients. In their study, apathy was highly correlated with loss of insight (P < 0.005), but not with general cognitive impairment. Behavioral difficulties correlated highly with apathy (P < 0.005), but not with level of insight or level of cognitive impairment. Patients suffering from severe apathy are particularly unlikely to report this feature spontaneously to their physician. On the other hand, physician training has emphasized disorders of emotions over disorders of motivation (Marin, 1997). Apathy, as an independent symptom unrelated to depression, is not usually easily diagnosed without awareness of its existence. 20.2.10.1. Pathogenesis of apathy The limbic system has been viewed as essential for the expression of emotions and motivation. The amygdala in particular is thought to play the role of a ‘motivational rheostat’ filtering environmental stimuli and influencing goal-directed behavior (Duffy, 1997). Duffy proposed four different neuronal circuits, all with limbic input, that are involved in generating motivational valence and translating motivation into behavior. This system makes contact with the basal ganglia. Important structures of the motivational circuits are considered to be the nucleus accumbens, the ventral pallidum and the VTA. Levy et al. (1998) suggested that apathy occurs when the cortex is functionally disconnected from key limbic imput and Mayeux et al. (1987) proposed that bradyphrenia results from neuronal depletion of the locus ceruleus. Apathy has been observed in different diseases that affect basal ganglia, such as Wilson’s disease, progressive supranuclear palsy, Huntington’s disease, dementia pugilistica and lacunar stroke (Duffy and Kant, 1997). Diminished motivation arises from prefrontal syndromes following lesions of the mesiofrontal cortex and its connections to the anterior cingulated cortex (this syndrome may be due to trauma, hydrocephalus, aneurysm or stroke affecting the anterior cerebral circulation). Starkstein et al. (1993) described neural pathways between the internal pallidum and the pedunculopontine nucleus with relays in the posterior limb of the posterior capsule and the SN that may cause bradyphrenia and apathy.

NEUROBEHAVIORAL DISORDERS IN PARKINSON’S DISEASE The prefrontal cortex is fundamental to real-life decision-making. Individuals with damage to the prefrontal cortex fail to act according to their understanding of the consequences of their acts and thus appear oblivious to their future (Nakano and Hirano, 1984). The left prefrontal cortex may play a role in setting positive goals and when this region is affected, apathy may occur. Functional imaging demonstrates an association between positive goal attainment and activity in the left prefrontal cortex. The left prefrontal cortex has been associated with positive, optimistic emotions, whereas the right prefrontal cortex is associated with withdrawn behavior (Davidson et al., 1999). Supporting this hypothesis, in a study performed in Alzheimer’s patients applying SPECT, apathy was correlated with decreased left temporoparietal perfusion, whereas loss of insight was correlated with decreased right temporo-occipital perfusion (Ott et al., 1996). DA is the main neurotransmitter of goal-directed behavior, modulating motivation, arousal and motor response (Duffy, 1997). There is abundant evidence of the action of dopaminergic input on goal-directed behavior, including the effects of amphetamines that initially produce enhanced focus and motivation, but with chronic use later result in stereotype behaviors. In contrast, chronic neuroleptic exposure is often associated with apathetic behavior. Other neurotransmitters have been implicated to interact with the DA effect in motivation, such as a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), neurotensin, substance P, N-methyl-Daspartate (NMDA), as well as agonists of nicotinic and opioid receptors. Cholinergic and serotonergic pathways also play a role in the modulation of motivational circuits (Hooks and Kalivas, 1994; Duffy, 1997). Another approach to the topic of motivation and apathy has been presented by Cloninger (1987). Cloninger’s theory of personality describes three heritable major dimensions of personality: (1) novelty-seeking; (2) harm avoidance; and (3) reward dependence. Novelty-seeking has been associated with DA and includes behavior activation, exploratory behavior and avoidance of monotony. The other two behaviors have been related to serotonin and norepinephrine respectively. Evidence of DA’s role in novelty-seeking behavior includes the reduction of spontaneous investigatory behavior in animals following DA-depleting lesions (Stellar and Stellar, 1985), increased novelty-induced motor activity following DA microinjection in the ventral pallidum and nucleus accumbens (Hooks and Kalivas, 1994) and the appearance of self-stimulation

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behavior after electrode placement in the dopaminergic pathways (Fray et al., 1983). PD patients submitted to Cloninger’s Tridimensional Personality Questionnaire (TPQ) have shown reduced novelty-seeking behavior as compared with a group of age- and disability-matched rheumatologic and orthopedic patients (Menza et al., 1990, 1993). Concerning harm-avoidance and reward-dependence ratings, there were no differences among the groups compared. The results obtained confirm the concept that PD patients have personality traits which are quite characteristic, like rigidity, seriousness, introversion (Todes and Lees, 1985; Eatough et al., 1990). Considering that these personality traits probably precede the diagnosis of PD led Menza et al. (1990) to repeat a questionnaire asking the PD patients and spouses to complete the questions as they would have been answered 20 years ago. PD patients persisted in scoring lower on novelty-seeking behavior based on the premorbid ratings. Novelty-seeking behaviors were negatively correlated with advanced age, in agreement with previous normative data received with the TPQ questionnaire (Cloninger et al., 1991). This finding is consistent with the common observation of increased passivity and amotivation among the elderly. 20.2.10.2. Treatment of apathy Most antidepressants are not effective in apathy or abulia and may cause unnecessary side-effects. Improvement of these disorders has been reported when treating patients with DA agonists (Barrett, 1991) and methylphenidate (Chatterjee and Fahn, 2002). Apathy scores improved in levodopa-induced ‘on’ states (Czernecki et al, 2002). Better control of parkinsonian motor symptoms may also improve apathy. Diagnosis and education of patients and carers regarding apathy and abulia as symptoms of PD different from depression or laziness are often helpful in improving patient and care-giver distress. 20.2.11. Sleep and behavior disorders in Parkinson’s disease REM sleep behavior disorder is a relatively common disorder (15–47%) in PD patients and may predate the onset of clinical features by several years (Schenck et al., 1996; Comella et al., 1998; Gagnon et al., 2002). The disorder is defined as the presence of muscle tone during REM sleep, associated with a history of active and complex sleep behavior in the absence of epileptiform activity (Thorpy, 1990). About 87% of patients with this disorder are male, with a reported mean age between 52.4 and 60.9 years (Schenck et al., 1996; Olson et al., 2000).

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The most common behavior reported was an actual assault on the spouse, but other behavior included flailing, kicking, punching and vocalization. Sometimes patients showed jumping out of bed and sleep-walking. This behavior is unusual during daytime naps. The pathophysiology of this disorder may be related to visual hallucinations (Nomura et al., 2003), although the individual hallucinations do not reflect REM intrusions such as hypnogogic or hypnopompic hallucinations.

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NEUROBEHAVIORAL DISORDERS IN PARKINSON’S DISEASE Takubo H, Shimoda-Matsubayashi S, Mizuno Y (2003). Serum creatine kinase is elevated in patients with Parkinson’s disease: a case controlled study. Parkinsonism Relat Disord 9: S43–S46. Tandberg E, Larsen JP, Aarsland D et al. (1996). The occurrence of depression in Parkinson’s disease. A communitybased study. Arch Neurol 53: 175–179. Thorpy MJ (1990). International Classification of Sleep Disorders: Diagnostic and Coding Manual. American Sleep Disorders Association, Rochester MN. Todes CJ, Lees AJ (1985). The pre-morbid personality of patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 48: 97–100. Tomer R, Levin BE, Weiner WJ (1993). Side of onset of motor symptoms influences cognition in Parkinson’s disease. Ann Neurol 34: 579–584. Trepanier LL, Kumar R, Lozano AM et al. (2000). Neuropsychological outcome of GPi pallidotomy and GPi or STN deep brain stimulation in Parkinson’s disease. Brain Cogn 42: 324–347. Troster AI, Stalp LD, Paolo AM et al. (1995). Neuropsychological impairment in Parkinson’s disease with and without depression. Arch Neurol 52: 1164–1169. Uitti RJ, Tanner CM, Rajput AH et al. (1989). Hypersexuality with antiparkinson therapy. Clin Neuropharmacol 12: 375–383. Vazquez A, Jimenez-Jimenez FJ, Garcia-Ruiz P et al. (1993). “Panic attacks” in Parkinson’s disease: a long-term complication of levodopa therapy. Acta Neurol Scand 87: 14–18. Villeneuve A, Berlan M, Lafontan M et al. (1985). Platelet alpha-2-adrenoreceptors in Parkinson’s disease: decreased number in untreated patients and recovery after treatment. Eur J Clin Invest 15: 403–407. Webster J, Grossberg G (1996). Disinhibition, apathy, indifference, fatigability, complaining and negativism. Int Psychogeriatr 8 (Suppl 3): 403–408.

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Whitehouse PJ, Hedreen JC, White CL et al. (1983). Basal forebrain neurons in the dementia of Parkinson’s disease. Ann Neurol 13: 243–248. Witjas T, Kaplan E, Azulay JP et al. (2002). Non-motor fluctuations in Parkinson’s disease: frequent and disabling. Neurology 59: 408–413. Yamada K, Goto S, Ushio Y (2003). GPi pallidotomy for Parkinson’s disease with drug induced psychosis. Parkinsonism Relat Disord 10: 35–40. Zigmond AS, Smith RP (1983). The hospital anxiety and depression scale. Acta Psychiatr Scand 67: 361–370.

Further Reading Bechara A, Tranel D, Damasio H et al. (1996). Failure to respond autonomically to anticipated future outcomes following damage to prefrontal cortex. Cereb Cortex 6: 215–225. Mayeux R (1992). The mental status in Parkinson’s disease. In: WC Koller (Ed.), Handbook of Parkinson’s Disease, 2nd edn. Marcel Dekker Inc, New York, pp. 159–184. Molho ES (2002). Psychosis and related problems. In: SA Factor, WJ Weiner (Eds.), Parkinson’s Disease. Diagnosis and Clinical Management. Demos Medical Publishing, New York, pp. 465–480. Schenck CH, Hurwitz TD, Mahowald MW (1993). REM sleep behavior disorder: an updated on a series of 96 patients and a review of the world literature. J Sleep Res 2: 224–231. Schiffer RB, Kurlan R, Rubin A et al. (1988). Evidence for atypical depression in Parkinson’s disease. Am J Psychiatry 145: 1020–1022. Starkstein SE, Petracca G, Chemerinski E et al. (1998). Depression in classic versus akinetic-rigid Parkinson’s disease. Mov Disord 13: 29–33.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 21

Early detection of Parkinson’s disease CATHERINE GALLAGHER1* AND ERWIN B. MONTGOMERY JR1,2 1

Department of Neurology, University of Wisconsin School of Medicine and Public Health, and 2

National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA

21.1. Introduction The hope that effective neuroprotective or neurorestorative therapies for Parkinson’s disease (PD) are ‘just around the corner’ has generated interest in detecting the disease at its earliest stages, when institution of these therapies is most likely to be beneficial. The development of valid early detection methods has proved a challenge. At the time of publication there were no prospectively validated tests to quantify the risk of developing PD in asymptomatic individuals. Only one detection battery, based on a select population of those with some symptom possibly suggestive of PD but insufficient to warrant a clinical diagnosis, has been prospectively validated (Montgomery et al., 2000a, b). The importance of developing predictive tests is clear but underappreciated in the science community. In the absence of a compelling marketable product, it will probably be up to governmental organizations and private foundations to support this type of research. There are reasonable concerns that governmental organizations, such as the National Institutes of Health, have bias against this research. Although this bias may not be evident in written policy, it may nonetheless exist in the study sections dominated by basic scientists who do not feel the daily press of caring for patients (personal observation). The following plea in the request for grant applications by the Michael J. Fox Foundation may be prescient: We appreciate that non-human animal and/or cell-based model systems may be necessary for identification and development of potential biomarkers [italics by Michael J. Fox Foundation]. Although we agree that understanding the biological function of an identified biomarker and its

possible contribution to disease are additional avenues that can arise from biomarker research, we imagine that successful proposals will be those that remain focused on biomarker development, refinement and/or validation. The purpose of this chapter is to consider what is required for the development of predictive tests in medicine and for PD specifically and to review the most promising current approaches. The lack of validated early diagnostic and predictive markers is not due to lack of past efforts and therefore, it is important to understand why these may have failed. Indeed, in the day-to-day activities of diagnosing and treating, the critical issues related to appropriate diagnostic or predictive assessments are seldom consciously realized, let alone actively considered.

21.2. Considerations in the development of predictive tests The development of predictive tests requires approaches unlike those typically used for testing hypotheses in basic and clinical research. Typical approaches in these disciplines might involve comparing a group with preclinical parkinsonism to a control group not at risk. Tests would then be developed to distinguish between the two groups. The first problem with this approach is that there is currently no way to identify the test group (patients with presymptomatic or preclinical parkinsonism). Consequently, most efforts begin by comparing those with clinically diagnosable PD to normal controls. This approach requires the assumption that the features studied in those with recognizable disease are relevant to those at risk. However, we know that a measure that

*Correspondence to: Catherine Gallagher, MD, Department of Neurology, H6/574 CSC, 600 Highland Ave., Madison, WI 53792, USA. E-mail: [email protected], Tel: þ1-608-263-0755, Fax: þ1-608-263-0412.

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is abnormal at one stage of a disease process may be less abnormal at another stage of disease. For example, elevations in serum liver enzymes in patients with cirrhosis diminish with progressive loss of functioning liver cells. In the case of PD, one assumes that patients with clinically diagnosable PD have a high probability of reduced substantia nigra neurons; however, we know from pathologic studies that substantia nigra neurons are probably not affected at presymptomatic stages of the disease (Braak et al., 2003). Furthermore, there is suspicion that biomarkers for dopamine neurons may lack specificity and sensitivity, even in established PD. One study that examined the progression of dopamine loss inferred by [18F]fluorodopa positron emission tomography (PET) scanning found that 11% of subjects, although meeting the clinical criteria for PD, did not have attrition of dopamine terminals by imaging measures (Whone et al., 2003). 21.2.1. Defining disease From the above discussion, it would appear that studies to develop predictive tests would benefit from selecting subjects at the earliest possible identifiable stages of disease. At extremes of the continuum lie healthy individuals and those who meet clinical criteria for a diagnosis of PD. Intermediate to these extremes are those who will develop disease but who have no symptoms (presymptomatic) and subjects with some symptoms of insufficient degree to warrant a clinical diagnosis (preclinical disease). These definitions could be criticized because in some sense the presence of any degenerative process that will progress to result in clinical diagnosis constitutes disease. This is more than a semantic argument. On one hand, those diagnosable with preclinical parkinsonism already have ‘damage’ to the nervous system that cannot be compensated by normal mechanisms (otherwise they would not have any symptoms of any degree), whereas presymptomatic patients may not. This leads to the assumption that presymptomatic detection is inherently better than preclinical detection. However, if disease progression could be stopped at the preclinical level, with prevention of further disability, would this not also be considered a victory? When developing a diagnostic test it is important to define the ‘gold standard’ by which outcomes are to be evaluated. The dilemma is that in the case of PD there are no methods, other than prolonged observation, to distinguish those with some symptoms of PD who will go on to develop disease from those who will not. To date, the gold standard for PD is pathological confirmation; however, this is unfeasible for most developmental efforts due to the variability in the duration

between testing and obtaining postmortem tissue and the availability of that tissue. For PD, defining a presymptomatic population and following it until a pathologic diagnosis can be established may require prohibitive study duration. Alternatively, the gold standard could be considered a clinical diagnosis of PD based on clinical criteria, although the specificity and sensitivity of clinical diagnosis when compared in retrospective autopsy controlled studies are problematic (Hughes et al., 1992). A scheme commonly used for the clinical diagnosis of PD is that the presence of three of four cardinal signs (bradykinesia/akinesia, rigidity, tremor and postural/ gait abnormalities) constitutes clinically definite and two out of the four clinically probable PD (Calne et al., 1992). However, these are dichotomous assessments – that is, a symptom was either present or absent – the degree to which each symptom or sign was present and the thresholds were not addressed. Using clinical diagnosis as the gold standard, duration of follow-up would presumably be shorter using subjects in the preclinical population. However, in one study of 205 preclinical subjects followed for 2 years, only 59 became diagnosable as having PD and 40 subjects were found not to have PD with any confidence. The remainder either had some other neurological disorder or there was not sufficient confidence of either having or not having PD (Montgomery et al., 2000b). In a retrospective survey, 22% of patients stated they had to wait over 1 year between the time they first noted a problem and when the diagnosis was made. Eight percent had to wait over 2 years (Montgomery et al., 2000a). 21.2.2. Using biomarkers Any biomarker used for the prediction of disease will be, by definition, a surrogate outcome measure. Biomarkers are generally defined as ‘all detectable biologic parameters, whether biochemical, genetic, histological, anatomic, physical, functional, or metabolic’ (Smith et al., 2003). A surrogate outcome is defined as ‘a laboratory measurement or a physical sign used as a substitute for a clinically meaningful end point that measures directly how the patient feels, functions, or survives’ (Gotzsche et al., 1996). A surrogate marker may be a link in a causal pathway, or simply an epiphenomenon of disease that reflects disease severity, in this case the presymptomatic disease process. Here, we distinguish the notion of a surrogate or biomarker for the prediction of disease as opposed to surrogate markers for therapeutic interventions that captured considerable recent interest. The surrogate should accurately and reproducibly reflect disease progression, should be sensitive for any effect of treatment and should

EARLY DETECTION OF PARKINSON’S DISEASE not be influenced by treatment, independent of the treatment’s effect on the disease. Three stages of surrogate marker development have been described: (1) type 0, natural history marker; (2) type I, biologic activity marker; and (3) type II, surrogate marker of therapeutic efficacy (Holloway and Dick, 2002). The Food and Drug Administration accepts type II surrogate markers as ‘validated’ (Katz, 2004). Although the use of surrogate markers allows for shorter clinical trials, there are multiple examples in the literature of non-beneficial or even harmful interventions made on the basis of surrogate outcomes (Fleming and DeMets, 1996). None of the surrogate outcomes used in the study of PD (SPECT findings, time to levodopa therapy, time to motor fluctuations or improvement in Unified Parkinson’s Disease Rating Scale (UPDRS) scores) have been clearly validated as reflecting outcomes with ‘clear and convincing value to patients’ (Holloway and Dick, 2002). 21.2.3. Developing clinical prediction rules Clinical measures that are used to estimate the probability of a diagnostic outcome, such as the probability that a patient with chest pain is having a myocardial infarction, have been called clinical prediction rules: 1. In the development of clinical tests, both the results of the test and the outcome (target of prediction) should be clearly defined. 2. The patient population and sampling methods should be clearly defined. 3. An estimate of the error rate, or proportion of patients who are misclassified using the testing method, should be made. This should be done by prospectively comparing the sensitivity and specificity of the test derived from the group of patients initially studied (training set) with a new group of patients (test set) (Wasson et al., 1985). The study by Montgomery and colleagues (2000a) developed a battery of tests to predict PD using a mixed population. This population included some who were recently diagnosed with PD (clinical population) and those who were preclinical, as described above. The preclinical population contained a mixture of subjects, some of whom would develop parkinsonism and others who would not. A mixed population was selected so that subjects with recently diagnosed PD would help ensure specificity whereas the preclinical subjects would help ensure sensitivity. It was recognized that this approach could result in a tautology. In other words, statistical analyses use optimization procedures that are designed to determine if any correlation exists between data sets; the consequence is that any correlation that is discovered could

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be spurious. Spurious correlations limit the generalizability (utility) of the study results (see discussion below). Consequently, the PD battery was prospectively applied to a new preclinical population. This group included subjects with preclinical parkinsonism who eventually developed the disease (study subjects were followed for 2 years). Statistical analysis using this new (test set) showed that the PD battery had 92% specificity and 68% sensitivity in predicting those in the preclinical population who would ultimately be diagnosed as having or not having PD (Montgomery et al., 2000b). Even after the study populations have been defined and tested, the statistical validation of diagnostic and predictive value is complex. The effects of inaccuracies, both for identifying those at risk (sensitivity) and distinguishing those not at risk (specificity), can be greatly magnified by the prevalence of those at risk. Thus, specificity and sensitivity are only part of the solution to developing diagnostic and predictive tests, as will be discussed below. 21.2.4. Statistical methods Statistical analysis helps us to quantify uncertainty so that we can make the best possible decision with limited information. Essential features of all predictive tests are sensitivity, specificity, positive and negative predictive value and generalizability. Sensitivity, or true-positive rate, is the proportion of patients with disease who will have a positive test result and can be expressed as: P(test positive/disease) where P is a symbol for probability and P(test positive/disease) is read as the probability of having a positive test if one has the disease. Specificity or true negative rate is the probability of a negative test in a person who does not have disease, or P(test negative/no disease) read as the probability of having a negative test if the person does not have the disease. 21.2.4.1. Specificity/sensitivity trade-off and the receiver operator characteristic curve Frequently the outcome measure of a diagnostic or predictive test is a continuous variable, such as the degree of slowed movement velocity and therefore some threshold separating a normal from an abnormal test result must be selected. The specificity and sensitivity will be influenced by where the threshold is determined. Changing the threshold in one direction may increase the truepositive rate and therefore improve sensitivity, but at the same time would increase the risks of a false-positive rate, therefore worsening specificity. A receiver operator characteristics (ROC) curve relates the specificity and sensitivity to the threshold for abnormality by plotting

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Fig. 21.1. Demonstration of a receiver operator characteristics curve. Typically in developing diagnostic or predictive tests, there is an overlap in the test results between those with the condition of interest (filled bars) and those without the condition of interest (open bars). The question then becomes where to select a cut-off (top figure). The numbers of false positives and false negatives will vary depending on where the cut-off is selected. The receiver operator characteristics curve (bottom figure) relates the specificity (true negatives) to the sensitivity (true positives) for different cut-offs (arrows running between the two figures). Reproduced from Montgomery (2005), with permission from Taylor and Francis.

the sensitivity and (1 – specificity) for each possible value of the threshold (Fig. 21.1). A test with no diagnostic or predictive value would lie along the diagonal of the ROC curve and the area under the curve would be 0.5. The greater the departure from the diagonal,the greater the diagnostic or predictive value and the greater the area under the curve. Thus, a decision of where to establish a cut-off can be drawn from examination of the ROC curve by determining the consequences of false positives and false negatives. Further, the area under the curve (Fig. 21.2) also indicates the diagnostic value of t (Montgomery, 2005). 21.2.4.2. Methods to improve specificity and sensitivity As will be demonstrated, the diagnostic and predictive value are greatly affected by the prior probabilities or prevalence of the disease or risk. Low prevalence requires greater specificity, which may come at the cost of sensitivity. One method of improving the situation is to have a hierarchy of tests such that the population that continues on to the next test has successively greater prevalence of the disease or risk. However, this often comes at the cost

of a significant reduction in sensitivity because more persons with disease or risk are lost with each successive test. An alternative is to create a test battery such that the combined results increase the specificity and sensitivity. There are several caveats. First, the individual tests should reflect different domains of the disease. For example, in one predictive battery, tests of motor function were combined with tests of olfaction and a mood inventory (Montgomery et al., 2000a). Multiple tests that relate to the same domain can actually worsen the predictive value (Stevens, 2002). However, there is a trade-off in the fact that the ratio of variables to subjects greatly increases and increases the risk for spurious correlations (see Generalizability, below). A number of variable reduction techniques are available, such as principal components analysis. Montgomery et al. (2000a, b) used a nested logistic regression analysis to reduce the number of variables. 21.2.4.3. Positive and negative predictive value Sensitivity and specificity are readily determined using data from clinical trials. However, much more meaningful value from the point of view of an individual

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Fig. 21.2. Demonstration of the effects of different overlaps on the receiver operator characteristic curves. A, C, the interval histograms of hypothetical test results for a group at risk and a group not at risk. There is greater overlap in A compared to C, suggesting that the test developed to distinguish subgroups in A will function better than that developed for C. This is reflected in their corresponding receiver operator characteristic curves, shown in B and D, respectively. As can be seen, the area under the receiver operator characteristic curve is greater in B than in D. Reproduced from Montgomery (2005), with permission from Taylor and Francis.

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test subject is the predictive value of the test. The positive predictive value is the likelihood that a person who has just received a positive test result actually has the disease (rather than the test result being a false positive). Predictive value depends on the prior probability of disease, or prevalence of disease in the population (which can be determined from epidemiological studies). If the condition is rare, the majority of positive test results will be ‘false-positive’ results; conversely, most negative tests will be true negatives because there are only a few cases of disease in the population. The likelihood that the patient has disease (prior probability) given additional information such as a positive test result (posterior probability) can be estimated using an extension of Bayes theorem: PðDjTÞ ¼ PðDÞPðTjDÞ= ½PðDÞPðTjDÞ þ PðHÞPðTjHÞ where P(D|T) is the positive predictive value, or probability of having the disease (or risk) given a positive test; P(D) is the prevalence, or probability of having the disease or risk within the population selected; P(T|D) is the probability of having a positive test if you have the disease (sensitivity); P(H) is the probability of not having the disease or risk (which ¼ 1 – P(D) and therefore determinable from epidemiological studies); P(T|H) is the probability of having a positive test if you do not have the disease or risk (falsepositive rate, which ¼ 1 – specificity and determinable by clinical studies) (Pegano and Gauvreau, 1993; Bernardo and Smith, 1994). P(D|T) is not directly calculable from specificity and sensitivity, but is modified by P(D) or disease prevalence, sometimes referred to as prior probability. The same considerations apply to the negative predictive value, meaning the test’s ability to predict the absence of disease or risk. Therefore, characterization of a test’s specificity and sensitivity is not a sufficient measure of its diagnostic or predictive value. Consider, for example, the influence of different disease prevalence rates on the predictive value of mammography for a surgical diagnosis of breast cancer. Depending on the study, the sensitivity of mammography alone is 85% (higher in some studies) and specificity about 96% (Thurfjell et al., 1997, 2000; Banks et al., 2004). The false-positive rate has been estimated at 6–8% in the USA, where 1/10 mammograms gives a false-positive result (Elmore et al., 1998). From this information, we can determine the positive predictive value of mammography for two different scenarios; when the prevalence of breast cancer in the population is 0.3%, the positive predictive value of mammography is calculated as P(D/T) ¼ (0.003)

(0.85)/[(0.003)(0.85)þ(0.997)(0.06)] ¼ 0.040, or about 4%. This means that a woman with a positive screening mammogram has a 4% chance of having breast cancer. This is quite similar to actual estimates; breast cancer is found in about 3% of women who have an abnormal mammogram (0.3% of all mammograms) (Elmore et al., 1998). However, assume for a moment that disease prevalence is 1%; then the positive predictive value of mammography is P(D/T) ¼ (0.01)(0.85)/ [(0.01)(0.85) þ 0.99(0.06)] ¼ 0.125, or 12.5%. This improvement in the positive predictive value of the test is a result of an approximately threefold increase in disease prevalence. In the first scenario (disease prevalence 0.3%), 6237 out of 100 000 patients will have further diagnostic testing to detect 255 cases of cancer and in the second scenario (disease prevalence 1%), 6790 patients will have further testing to detect 850 cases of cancer. In the USA, about 11% of mammograms are read as abnormal (but in Sweden only 2–5%) and the likelihood of a false-positive mammogram after 10 mammograms is nearly 50% – 18% of these women will eventually undergo negative biopsies and for every $100 spent for screening, $33 is spent in the evaluation of false-positive results (Elmore et al., 1998). This undoubtedly reflects societal choices about the cost of prevention and to an extent is driven by litigation. 21.2.4.4. Generalizability Whether a test remains accurate when generalized to new situations is called external validity. The test outcomes should be reproducible in a similar population and, ideally, transportable to new populations. Many characteristics of patient selection and sampling methods used in the initial study can influence transportability, including historical, geographic and methodological issues, disease stage and follow-up interval. The most heavily validated tests will be reproducible and transportable in all of these realms (Justice et al., 1999). The issue of generalizability becomes even more problematic when developing predictive tests. In this case, the ‘population that can be studied’, patients affected by the disease, is not equivalent to the ‘population of concern’, those who have not yet expressed the disease. Because most tests that have been advanced as predictive tests for PD were developed as tests to detect disease, it is assumed that these data can be extrapolated to the population of concern. Complicating this, the pattern of change in currently available biomarkers does not appear to be linear (Hilker et al., 2005). Typically, testing methodologies look for correlations between the results of the test and the presence of disease. In mathematical optimizing procedures such as linear regression models, lines of

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different slopes and intercepts are ‘fitted’ to the data and the line whose slope and intercept results in the leastsquared error is selected. The danger in this approach is that due to idiosyncracies (sampling issues), the population from which the test is developed will show a correlation that is spurious and cannot be generalized to the population of concern. Many test result outcomes are continuous data, so the cut-off used to predict disease using these data is expected to be different for preclinical stages of disease. New cut-offs will need to be restudied prospectively in new populations to determine their sensitivity, specificity and predictive value of tests for preclinical disease.

nomic impact of detection and prevention of PD in a hypothetical manner because as yet there are no neuroprotective or restorative therapies whose costs can be projected.

21.2.4.5. Social, economic and political considerations The ultimate measure of a clinical prediction rule is its effect on patient care. Instead of trying to minimize the number of misclassified patients, one should try to minimize the chance of a serious error in patient care. For example, it may be better to have 10 false-positive mammograms for each case of breast cancer detected than to miss one case of early breast cancer. Certainly, many of the same issues will confront the use of any diagnostic or predictive test for PD. It is amazing that in the vast majority of articles published on diagnostic or predictive tests, there is little mention of the social, economic, moral, ethical or political ramifications. An initial question is whether the availability of a predictive test is a benefit or detriment to the individual. For untreatable disease, little benefit (aside from genetic counseling) can be offered to those found to be at high risk. Possible detriments to the individual include being denied insurance based on the results of a predictive test as a ‘preexisting’ condition (Godard et al., 2003) and personal/ interpersonal conflict regarding sharing of test results with family members who may also be affected by the results of test (Doukas and Berg, 2001). Other issues are economic and societal: What if tomorrow a scientist discovers a preventive treatment for PD and its annual cost to the individual is 20% of the median household income? Who would be treated? Would society default to whomever is able to pay the cost? Could the health care system afford to pay for everyone at risk, especially in view of the fact that we currently have no predictors and everyone must be considered at risk? Would there be a lottery? These are not simple questions, as witnessed by past actions related to banning tobacco use, requiring motorcycle helmet use and removing carcinogens from the environment. The cost-effectiveness of screening for presymptomatic PD depends on the efficacy of neuroprotective therapies. Dorsey and Siderowf (2005) have presented varying scenarios on the eco-

21.3.1. Disease prodrome

21.3. What in the neurobiology of Parkinson’s disease can be used to develop predictive tests? Clinical, neuroimaging and pathologic studies suggest that the disease process of PD is initiated several to many years before clinical signs appear and provide hope that treatments that modify the course of this process will soon be developed.

It is generally held that a significant portion of the degenerative process occurs before PD is diagnosed. Indeed, the brains of individuals who have no recorded clinical symptoms of parkinsonism may contain immunoreactive inclusions suggestive of early-stage disease. The assumption that degeneration of the substantia nigra pars compacta (SNpc) is the cause of PD has made the loss of this neuronal group a target for developing diagnostic tests. However, degeneration of the SNpc could be a relatively late development in the pathogenesis of PD. Braak et al. (2003) have postulated, based on cross-sectional pathologic studies, that pathologic changes of PD advance in a topographically predictable caudal-to-rostral pattern. At (pathologic) stage 1, involved regions include the dorsal motor nucleus of the vagus and olfactory bulb; at stage 2 these structures and the caudal raphe nuclei, gigantocellular reticular nucleus and locus ceruleus complex; at stage 3 all of the preceding structures and the midbrain, including pars compacta of substantia nigra. Brains of patients with a clinical diagnosis of PD typically corresponded to pathologic stages 4–6, during which the SNpc and temporal allocortex and mesocortex, followed by regions of neocortex, are involved. Most of the brains of PD patients obtained for this study were from Hoehn and Yahr stages III–IV, raising the question of whether some patients with (pathologic) stages I–III did have some clinical signs or symptoms of PD that had not been investigated. This topographic pattern of degeneration would fit well with the observation that olfactory degeneration, rapid-eye movement (REM) sleep behavior disorder, depression and autonomic nervous system dysfunction can significantly precede motor symptoms in patients who develop PD. Pathologic analyses are snapshots in time that strongly suggest that incidental brains with ‘incidental Lewy bodies’

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would develop PD if they continued living. Validation of this assumption requires prospective analysis. Some evidence for preclinical motor symptoms comes from retrospective clinical-type assessments. For example, Tetrud (1991) examined canceled checks written by a Parkinson patient over years prior to his diagnosis of PD. Abnormalities in the signature were noted 5 years before the diagnosis. Similarly, review of videotapes of soccer-playing showed symptoms 14 years before diagnosis in a professional soccerplayer (Lees, 1992). Calne and Snow (1993) reported a young man who volunteered as a normal control but was found to have reduced [18F]fluorodopa (18F-dopa) uptake on positron emission tomography (PET) and subsequently developed signs of clinically probable PD. Most investigators have estimated a preclinical period for PD of 5–7 years based on imaging and pathological studies (Morrish, 1997; Marek et al., 2003). However, there is variation in rate of disease progression between individuals with sporadic PD (Hoehn and Yahr, 1967; Zetusky et al., 1985; Morrish et al., 1996). In individuals at risk for PD based on genetic background and functional imaging of the dopaminergic system, latency to onset of PD may be as long as 20 years (Piccini et al., 1999). On the other hand, for patients with some degree of (preclinical) parkinsonism on initial screening measures, approximately one-half will develop PD within 3 years (Montgomery et al., 2000b). 21.3.2. What is the potential of developing neuroprotective or neurorestorative therapies? Rapid advances in our understanding of the neurobiology of PD gives confidence that neuroprotective (preventing or slowing further degeneration) and neurorestorative (restoring the organism to a former state of health) treatments are within reach (Dawson and Dawson, 2002). A number of clinical trials of candidate neuroprotective agents, some of which have proved promising, have been extensively reviewed (Halbig et al., 2004). The primary targets thus far include oxidative stress, inflammation and apoptosis and abnormal intracellular protein trafficking. Intracerebral administration of glial-derived nerve growth factor (GDNF) has improved parkinsonian features in laboratory animal models (Grondin and Gash, 1998) and one open-label study of intraparenchymal injections of GDNF in humans has had encouraging results (Patel et al., 2005; Slevin et al., 2005). Further clinical trials failed to show a significant change in the clinical end point but preserved F-dopa influx into the posterior putamen in the treatment group (Lang et al., 2006).

Viral vector delivery of GDNF has shown promise in primate models and may some day be applied to humans (Palfi et al., 2002).

21.4. Disease biomarkers: Previous efforts Potential biomarkers come from any number of domains that reflect the pathogenesis of PD. 21.4.1. Clinical biomarkers A number of clinical symptoms may precede motor symptoms of PD, but taken individually are non-specific. These include anosmia, mood and personality changes, sleep disturbances, subtle cognitive disturbance, micrographia and dysautonomia. 21.4.1.1. Olfaction Olfactory function is frequently abnormal in PD (Doty et al., 1992), Alzheimer’s disease, parkinsonism– dementia complex of Guam (Doty et al., 1988, 1991) and motor neuron disease (Elian, 1991), but generally unimpaired in essential tremor (Busenbark et al., 1992), restless-legs syndrome (Adler et al., 1998) and vascular parkinsonism (Katzenschlager et al., 2004). Smell is less severely impaired in other degenerative parkinsonian syndromes than in PD (Doty et al., 1993). Hyposmia was detected in 10% of relatives of patients with PD and was associated with reduced striatal dopamine transporter binding in 4 of 25 hyposmic relatives – 2 subsequently developed parkinsonism (Berendse et al., 2001). 21.4.1.2. Motor abnormalities Patients with early PD and unilateral symptoms have abnormal performance on visuomotor tracking tasks even when using the clinically unaffected limb (Hocherman and Giladi, 1998). Ocular smooth pursuits are initiated normally in PD but peak velocity and displacement are reduced and progressively decline with repetition, as found with limb movements (Lekwuwa et al., 1999). Simple reaction time is delayed (Heilman et al., 1976; Hallett, 1990). Speech and handwriting analysis have been proposed as possible screening tools for preclinical detection of motor changes (Tetrud, 1991). 21.4.1.3. Autonomic symptoms Older individuals with infrequent bowel movements (less than one per day) may be at higher risk for PD than those with more frequent movements (Abbott et al., 2001).

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21.4.1.4. Psychiatric symptoms

21.4.2.3. Electromyogram silent period

Depression is common in PD and may even be associated with an increased risk of developing the disease (Schuurman et al., 2002). The evaluation of depression in PD is somewhat complex because the vegetative symptoms of PD resemble symptoms of depression assessed by most screening instruments (Leentjens et al., 2000; Wolters et al., 2000).

During voluntary muscle contraction, transcranial cortical magnetic stimulation induces a silent period in electromyogram activity. The duration of this silent period is reduced in patients with PD, significantly more so on the rigid side in patients with unilateral symptoms. This is felt to represent an alteration in cortical-cortical inhibition (Valls-Sole, 2000).

21.4.1.5. Rapid-eye movement sleep behavior disorder

21.4.2.4. Evoked potentials More than half of PD patients have delayed P300 visual evoked potentials (Wang et al., 2000); however, absence of this wave on visual evoked potential can also be a normal finding. Short-latency somatosensory evoked potentials showed reduced N30 amplitude in about 50% of PD patients but also patients with other neurological diseases (Rossini et al., 1989).

Idiopathic REM sleep behavior disorder appears to be a risk factor for the development of PD; Schenck et al. (1996) reported that 38% of older male patients presenting with REM sleep behavior disorder (RBD) developed parkinsonism 3.7 1.4 (SD) years after the diagnosis of RBD and at a mean interval of 12.7 7.3 years after the onset of RBD. Some have suggested that patients with synucleinopathies (PD, multiple system atrophy and dementia with Lewy bodies) are particularly predisposed to the development of RBD (Boeve et al., 2003). 21.4.2. Neurophysiological studies A number of electrophysiological correlates of clinical abnormalities have been described in patients with PD. Currently, the sensitivity and specificity of these measures for PD and their usefulness as predictive measures have not been evaluated (Valls-Sole and Valldeoriola, 2002). Many of these neurophysiological measures are felt to reflect the integrity of inhibitory systems, e.g. the reflex amplitude is increased when normal inhibitory controls are disrupted. 21.4.2.1. Auditory startle reaction The auditory startle reaction to an unexpected loud stimulus is regarded as a brainstem reflex; auditory startle reactions are absent or reduced in progressive supranuclear palsy, may be delayed in PD and are normal or exaggerated in multiple system atrophy (Kofler et al., 2001). Audiospinal facilitation using the soleus H-reflex is reduced bilaterally, even in patients with a hemiparkinsonism, and is corrected by levodopa (Delwaide et al., 1993). 21.4.2.2. Long latency reflexes Electrical or mechanical stimulation of a mixed nerve can give rise to reflex responses in relatively distant muscles, known as ‘long latency reflexes’. These responses are elicited more easily during tonic contraction of the muscle. Long latency reflexes are abnormally enhanced in PD (Valls-Sole, 2000).

21.4.2.5. Sympathetic skin response Sympathetic skin response is reported as abnormal (of prolonged latency, reduced amplitude, or both) in 35– 59% patients with PD (Choi et al., 1998; ZakrzewskaPniewska and Jamrozik, 2003). Abnormal sympathetic skin response is even more common in multiple system atrophy (Bordet et al., 1996). In hemiparkinson patients, the sympathetic skin response is of lower amplitude on the motor affected side (Fusina et al., 1999). Skin wrinkling in response to prolonged water immersion, probably mediated by sympathetic effects on the sweat glands, is reported as showing greater abnormality on the motor unaffected side (Djaldetti et al., 2001).

21.4.2.6. Clinical batteries One method that can be employed to help improve the sensitivity and specificity of diagnostic and predictive tests is to use a battery of sequential tests. The result of each test changes the prior probability of the following test. This method works well as long as the component tests are not highly correlated. A battery of tests, consisting of the Beck Depression inventory, University of Pennsylvania Smell Identification Test and speed of wrist movement task can be used to generate a PD score that distinguishes PD from normal with about 69% sensitivity and 88% specificity (Montgomery et al., 2000a). Prospective application of this test battery to a self-selected group of 208 patients (test set) with some degree of parkinsonism yielded 68% sensitivity and 92% specificity for the development of PD within 3 years (Montgomery et al., 2000b). Another group of investigators found that a battery consisting of finger-tapping rate combined with either olfactory assessment or measurement of visual contrast

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sensitivity discriminated mild PD patients from controls with 90% accuracy (Camicioli et al., 2001). 21.4.3. Biochemical markers Scientific observations of Parkinson disease have led to several interrelated theories of pathogenesis: (1) cellular energy deficiency; (2) oxidative stress; (3) glutamatemediated excitotoxicity; (4) inflammation; and (5) apoptosis (programmed cell death) as well as necrosis as pathways of cell death. Biochemical evidence of these processes has been found and in some cases investigated as a marker for early disease. To what extent these biochemical abnormalities are unique to PD with respect to other central nervous system neurodegenerative disorders is not clear. Mitochondrial complex I activity is deficient in PD in both substantia nigra and muscle (Schapira, 1994). Commensurate with this, the reduced form of coenzyme Q10 is deficient in platelets of patients with de novo PD, an abnormality that is partially reversed by selegiline treatment (Gotz et al., 2000). Platelets take up glutamate through an energy-dependent mechanism; platelet glutamate uptake rates can be measured as an indirect measure of impaired cellular energy metabolism. In PD, platelet glutamate uptake rates are 50% lower than in controls and patients with other parkinsonian syndromes; however, these changes can also be found in Down’s syndrome (Begni et al., 2003), Alzheimer disease (Ferrarese et al., 2000) and amyotrophic lateral sclerosis (Ferrarese et al., 2001). Cytogenetic analysis shows that patients with PD have a higher frequency of markers of chromosomal damage, including single strand breaks, than controls (Migliore et al., 2001). Again these findings are not unique to PD (Petrozzi et al., 2002) The cerebrospinal fluid concentration of 8-hydroxyguanosine, a marker of oxidative RNA damage, is three times that of controls in early PD, but is also elevated in other neurodegenerative disorders (Abe et al., 2003). Levels of urinary isatin, an endogenous monoamine oxidase inhibitor, are increased in patients with PD and decrease with pharmacotherapy (Hamaue et al., 2000). Glutathione has several functions in the brain as an antioxidant and regulator of mitochondrial complex I activity; abnormal levels of reduced glutathione have been observed in the brains of patients with PD in numerous postmortem studies; however, cerebrospinal fluid glutathione levels have not proven a useful peripheral marker (Konings et al., 1999). Concentrations of regulators of apoptosis such as caspase-3 and Bcl-2 are altered in lymphocytes of PD patients (Blandini et al., 2004). Increased levels of inflammatory cytokines, such as tumor necrosis fac-

tor (TNF)-a, interleukin (IL)-1b, IL-6, transforming growth factor (TFG)-a, TGF-b and decreased levels of neurotrophins, such as brain-derived neurotrophic factor and nerve growth factor, are present in the ventricular and lumbar cerebrospinal fluid of PD patients (Nagatsu et al., 2000). Evidence of impaired dopamine metabolism can be found in peripheral blood lymphocytes of patients with PD (Caronti et al., 1999); dopamine content, tyrosine hydroxylase immunoreactivity and dopamine transporter immunoreactivity are reduced and dopamine receptor expression is increased (Barbanti et al., 1999). 21.4.3.1. Genetic prediction Genetic testing could be considered a special case of biochemical markers. At least nine single genetic defects have been identified in kindreds with familial PD (Dawson and Dawson, 2003) and a search for polygenetic factors and susceptibility genes is under way (Momose et al., 2002). Many of the forms of parkinsonism associated with known genetic abnormalities differ clinically from those with the usual disorder, such as earlier age of onset and multiple affected family members. Lucking et al. (2000) found that, of 100 patients with isolated PD, 77% of those with symptoms beginning before 20 years of age, 26% of patients with symptoms beginning between 21 and 30 years of age and 2–7% of patients with symptoms beginning between 31 and 45 years carried a mutation in the parkin gene. Autosomal-recessive juvenile parkinsonism related to mutations in the parkin gene is highly penetrant; few patients have disease onset later than age 50. Therefore, the positive predictive value of the test (the likelihood of developing disease in a person who carries two parkin Whether heterozygous carriers of parkin mutation are at higher risk of developing late-onset disease has been debated; the incidence of late-onset PD in these carriers and in the general population is similar (Gasser, 2005). Patients with (sporadic) PD are more likely to have a first-degree family member with the disease (16%) whereas those without PD are less likely to have a family member with PD (4%) (Payami et al., 1994). Thus, it would seem reasonable to conclude that having a first-degree relative with PD is an identifiable risk factor and therefore indicative of a prodromal period. However, what these studies demonstrate is the probability of having a first-degree relative with PD if you have PD, or P(FH|PD), where FH is having a positive family history and PD is having PD. The real question is positive predictive value of a positive family history, or the probability of having PD if you have a positive family history, denoted by P (PD|FH). This latter probability is unknown but can be estimated using Bayes theorem (Bernardo and Smith, 1994). This requires knowing the disease prevalence,

EARLY DETECTION OF PARKINSON’S DISEASE or probability of having PD in the general community, denoted by P(PD) and the probability of having a family history, denoted by P(FH). These latter probabilities can be estimated from epidemiological studies. PðPDjFH Þ ¼ PðFH jPDÞ PðPDÞ=PðFH Þ PðPDÞ Using an age-specific prevalence for the sixth decade (the age of greatest risk for a PD diagnosis) of 118.6 per 100 000 (average for P(PD) from values cited by Korell and Tanner (2005)), the P(PD|FH) is 0.47%. A person at this age of relatively highest risk is highly unlikely to get PD, even if he or she has a first-degree family member with PD. 21.4.4. Neurotransmitter receptor and transporterbased imaging biomarkers: positron emission tomography and single photon emission tomography Neuroimaging allows us to evaluate non-invasively a number of surrogate markers of PD: health and function of the dopamine neuron, morphology of the substantia nigra, changes in neuronal and muscular bioenergetics and even alterations in brain networks. There are several groups of dopamine-producing cells in the brain: the SNpc, ventral tegmental area, arcuate and periventricular hypothalamic nuclei, plexiform cells of the retina, zona incerta of posterior hypothalamus, dorsal motor nucleus of the vagus, nucleus tractus solitarius (Kline et al., 2002), periaqueductal and periventricular gray and periglomerular cells of olfactory bulb (Moore and Bloom, 1978). Nigrostratal projections are implicated in PD motor impairment and mesocortical projections in non-motor and dysexecutive symptoms. Peripheral nerves are also frequently involved, particularly those of the sympathetic nervous system and olfactory bulb. In dopaminergic neurons, dopamine is synthesized from tyrosine via tyrosine hydroxylase and dopa decarboxylase; additional biosynthetic enzymes in epinephrine and norepinephrine neurons produce these transmitters from dopamine. Many radiopharmaceutical agents imaged via PET and SPECT have been developed as markers of dopamine uptake, metabolism, and receptor binding. Animal studies have shown that 18F-dopa, a fluorinated analog of levodopa, administered as a PET tracer is transported into the central nervous system through the high-affinity large neutral amino acid carrier, taken up into neurons by dopamine transporter, decarboxylated to F-dopamine (Brooks, 2000), vesicularized in presynaptic terminals and degraded via monoamine oxidase and catecholamine-O-methyltransferase (COMT)

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to form circulating metabolites that are excreted in the urine (Brown et al., 1999). Therefore, 18F-dopa uptake in the brain is a function of dopaminergic nerve terminal density, dopamine transporter function and dopamine metabolism (Pirker, 2003). Neurotransmitter transporters are classified into two categories: plasma membrane transporters such as dopamine transporter that are responsible for high-affinity uptake of the transmitter from the extracellular space into the neuronal cytoplasm and vesicular transporters such as the vesicular monoamine transporter (VMAT) that take up neurotransmitter from the cytoplasm into secretory vesicles. Tropane-based PET and SPECT tracers such as 123I-b-CIT and 99mTc-TRO-DAT-1 have a high affinity for the dopamine transporter but also for serotonin transporters. (þ)-alpha-[11C]Dihydrotetrabenazine (DTBZ) binds to the vesicular monoamine transporter (VMAT2) located in presynaptic vesicles. Raclopride binds to D2-type dopamine receptors. 21.4.4.1. Image analysis/quantitation Because background activity and radiopharmaceutical dose vary from one study to another, radioactivity in specific regions of interest (ROIs) selected from PET or SPECT images is normalized by comparison with a region low in dopaminergic projections, usually the occipital cortex or cerebellum. Tracer uptake is expressed as a ratio: net striatal ROI counts-to-neutral ROI counts (for example, striatum-cerebellum/cerebellum). 18F-dopa uptake can be expressed as a striatalto-occipital ratio (SOR), but most research studies have used a multiple-time graphical analysis (MTGA) approach. MTGA generates a time–activity curve from dynamic images; a constant that represents rate of tracer uptake, Ki, is calculated using the Patlak equation (Patlak and Blasberg, 1985). Some investigators have suggested that the ratio method and MTGA approach perform equally well when using 18F-dopa PET for the detection of PD (Dhawan et al., 2002). 18F-dopa studies have varied in the method of ROI selection (and co-registration with magnetic resonance to assure anatomic specificity), techniques of data analysis (e.g. MTGA versus ratio method) and the way results are reported (as ratios of normal, ratios of baseline or absolute values). Percentage change (in Ki) from baseline will amplify tracer loss in PD patients, for whom ‘baseline’ tracer uptake is smaller than normal to begin with; therefore a consensus conference of experts suggested that investigators report both the absolute change and the percentage change (Brooks et al., 2003). In patients with PD, loss of 18F-dopa uptake in the posterior putamen is most sensitive to disease progression (Morrish

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et al., 1998). Comparison of a number of studies using this tracer shows that 95% confidence intervals (and, where available, range) for putamen Ki overlap between PD patients and controls. This is also the case for most types of dopamine transporter imaging (Brooks, 2000). For this reason, studies using 18F-dopa PET have relied on the application of several principles by experienced investigators to distinguish patients with PD from controls: (1) absolute Ki, particularly of the total striatum and putamen, is greatly reduced in PD; (2) in PD there is loss of tracer activity in the posterior putamen with relative preservation of tracer activity in the caudate head (Sawle et al., 1994); and (3) asymmetry of 18F-dopa uptake in the striatum suggests PD. 21.4.4.2. Sensitivity of radioligand imaging for Parkinson’s disease Note that the discussion below addresses the issue of sensitivity and specificity of radioligand imaging for the detection of diagnosable PD and not presymptomatic or preclinical parkinsonism. However, this review is helpful because the same issues that arise relative to these investigations with subjects diagnosed with PD will apply to studies hoping to detect presymptomatic and preclinical disease. The sensitivity and specificity of PET and SPECT imaging depend on both technical and biological factors. PET radiopharmaceuticals reliably produce two simultaneous orthogonally oriented annihilation photons – an inherent advantage in calculating detailed positional information from decay events. Therefore, PET generally has a higher sensitivity and spatial resolution than does SPECT (Palmer et al., 1992). PET radiopharmaceuticals require a cyclotron for production and decay rapidly; therefore imaging is performed shortly after tracer injection. Tropane-based agents accumulate slowly in the striatum, requiring a 24-hour delay between tracer injection and imaging. A critical factor that influences signal-to-noise ratio is the specificity of radiotracer binding or trapping. Particularly in the case of 18F-dopa PET, a large proportion of the radioactivity present at the time of scan acquisition represents circulating metabolite. Use of COMT inhibitor to prevent 18F-dopa metabolism and three-dimensional imaging can improve signal-to-noise ratio significantly (Brooks, 2000). Adaptations of the dopamine neuron to aging, external factors and disease state can also influence tracer uptake. In normal individuals, both number of dopamine neurons and dopamine transporter levels decline with age; smoking and female gender are associated with an increase in dopamine transporter binding (Piccini, 2003). 18F-dopa PET has been used to show that dopamine turnover increases in early PD and may be a more

sensitive marker for early PD than is plasma uptake rate constant Ki (Sossi et al., 2002). Consecutive C11-dopa and 11C-CIT-FE (a fluoroethyl analog of B-CIT) PET scans done on patients with PD and normal controls showed a greater reduction in 11C-CIT-FE activity in the striatum in comparison to L-C11dopa Ki, consistent with downregulation of dopamine transporter or increased dopa decarboxylase activity. Dopaminergic medications also present a potential confounding variable. Levodopa therapy produces slight downregulation of striatal dopamine transporter levels during treatment that resolves following wash-out (Innis et al., 1999). Results regarding the effects of dopamine agonist treatment are not consistent for pramipexole and pergolide, but it appears that these agents can cause alterations in dopamine transporter binding (Ahlskog et al., 1999, Guttman et al., 2001). 21.4.4.3. Specificity for Parkinson’s disease Discriminant function analysis emphasizing a pattern of reduced, asymmetrical 18F-dopa uptake in the putamen is able to assign probabilities of disease with high accuracy (Sawle et al., 1994; Berendse et al., 2001). However, other studies have revealed a significant misclassification rate using similar principles (Whone et al., 2003). Weng et al. (2004) found 99mTc-TRO-DAT-1 SPECT imaging distinguished 100% of 78 patients with early PD from 40 age-matched controls. Although techniques differ, some small studies suggest that radiotracer imaging distinguishes PD from parkinsonian syndromes (Otsuka et al., 1997; Pirker et al., 2000), essential tremor (Asenbaum et al., 1998) and dystonia (Jeon et al., 1998). 21.4.4.4. Misclassification rate The Requip as early therapy versus L-dopa-PET (REAL-PET) study found that approximately 11% of patients suspected clinically as having PD had normal 18 F-dopa PET studies; all of the patients in this group had normal scans at 2-year follow-up (Whone et al., 2003). Whether the PET scan results were false negatives and these patients will eventually progress as clinically probable PD is yet to be seen. The Parkinson study group found that, of 69 patients with essential tremor studied with 123Ib-CIT, 5 patients were misclassified by blinded readers and quantitative analysis as having PD. They considered various explanations for this, especially that ‘ET [essential tremor] may be an overlap syndrome with PD in a subset of cases’. Subsequent network analyses and follow-up shows that these subjects do not have PD (Eckert et al., 2007). In terms of the false-positive rate, estimates are hard to come by. In spite of the cumulative numbers of

EARLY DETECTION OF PARKINSON’S DISEASE patients used as controls in these functional imaging studies, cases of abnormal studies in patients without a diagnosis of PD are rare (Snow et al., 1991). 21.4.4.5. Symptom threshold Establishing the threshold for imaging at which the disease is first established is important for presymptomatic detection. The difference between the imaging levels for controls and that which is associated with clinical diagnosis constitutes the range for presymptomatic and preclinical detection. 18F-dopa PET studies have shown that symptom onset appears to occur when putamen Ki is about 70% of normal and caudate Ki about 90% of normal on 18F-dopa PET (Morrish et al., 1998; Rakshi et al., 1999). In early hemi-PD, dopamine transporter activity is about 50% of normal contralateral to the affected limb (Marek et al., 1996). Pathologic studies have estimated that symptom onset corresponds to 68% cell loss in the lateral ventral substantia nigra and a 48% loss in the caudal nigra (Fearnley and Lees, 1991). These observations explain to some extent the differing estimates, based on functional imaging and pathologic studies, of the threshold for symptom onset; they are studying different parameters (aromatic amino acid decarboxylase activity, dopamine transporter density and cell number). 21.4.4.6. Sensitivity to progression The ability to measure the progression of imaging changes is important to the development of predictive tests. Forward analysis of the correlation with clinical progression and imaging measures can then be used to extrapolate backwards to determine the duration of the prodromal phase. In an issue of Experimental Neurology, Brooks et al. (2003) published an assessment of neuroimaging techniques as biomarkers of progression of PD. The criteria they considered were that: (1) a progression indicator should describe a biological process that changes with progression of PD; (2) it should correlate with clinical deterioration; (3) the biomarker should be objective, (4) reproducible and (5) sensitive for progression of disease; (6) the signal-to-noise ratio should be low; (7) it should be safe, tolerable and (8) relatively inexpensive; (9) it could be used repeatedly on individual patients; and (10) longitudinal data should be available on a sufficient number of patients to allow an informative assessment of the distributional properties (mean and variance) of the progression measure (Brooks et al., 2003). Based on these criteria, the researchers concluded that b-CIT SPECT, 18F-dopa PET and 11C-dihydrotetrabenazine PET performed well as biomarkers of pro-

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gression of PD. In studies of disease progression, striatal 18F-dopa and 18F b-CIFT have correlated well with UPDRS scores and with nigral cell density (Rinne et al., 1999; Brooks et al., 2003). Functional imaging has shown an average annual loss of 4–13% of 18Fdopa, b-CIT and 18F-CFT or 123I- b-CIT uptake in comparison to a 0–2.5% change in healthy controls (Marek et al., 2003). However, Morrish (2003) estimated that the sensitivity of dopamine transporter imaging to a 10-point change in the UPDRS score (clinically defined off) would range from 5 to 16%. Since patients recruited at symptom onset progress at average of 4–7 UPDRS points per year, this amount of change in the imaging data is expected to less reliable than clinical measures if reproducibility of the test is not perfect. Mean scan-to-scan variability for dopamine transporter PET and SPECT techniques ranged from 1.5 to 17%; Morrish points out that an average error of 17%, with a standard deviation of 13% allows a ‘normal range’ in error of 43%. 21.4.4.7. Predictive value of PET and SPECT Sensitivity and specificity of a test for disease do not necessarily translate to its sensitivity and specificity for transitional stages between health and disease, i.e. its predictive value. To determine how radionuclide imaging performs as a predictive test, one would need to image a cohort of persons at risk for the disease and then follow them forward in time to determine the accuracy of the initial test. A few groups of patients at risk for PD have been imaged, as described below. 21.4.4.7.1. Asymptomatic individuals with genetic risk factors for Parkinson’s disease 21.4.4.7.1.1. Parkin (PARK2) mutation carriers Khan et al. (2002) obtained serial 18F-dopa PET scans, separated by an average of 10 years, on 5 members of a family afflicted by early-onset PD. Four individuals carried at least one parkin mutation; 3/4 had extrapyramidal signs that worsened over 10 years; one individual who carried the parkin mutation remained asymptomatic. Each of the parkin carriers had reduced putamen 18F-dopa Ki in comparison to controls and the annual rate of loss of 18F-dopa Ki was significantly slower in parkin carriers than in PD. Kruger et al. (2001) studied a family with relatively mild phenotype due to mutations in the a-synuclein gene and found presynaptic dopaminergic alterations consistent with sporadic PD in two affected family members but normal 18F-dopa and 11C-raclopride PET in one presymptomatic mutation carrier. Hilker et al. (2001) used 18Fdopa and 11C-raclopride PET to investigate an Italian

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kindred that included asymptomatic carriers of the parkin mutation; asymptomatic carriers had posterior putamen Ki values between normal and sporadic PD values, many within the normal range. 21.4.4.7.1.2. Relatives of Parkinson’s disease patients Piccini et al. (1997) used 18F-dopa PET in asymptomatic members of 7 unrelated kindreds in which at least 2 members had parkinsonism. Eight (25%) of the 32 asymptomatic relatives showed abnormal putamen 18F-dopa uptake (2.5 sd below the normal mean). Berendse et al. (2001) screened relatives of PD patients for hyposmia and then performed 123Ib-CIT on 23 hyposmic individuals: 4 of these individuals had abnormal 123Ib-CIT binding and 2/4 developed signs of PD within 1 year. Several other studies suggest that subclinical central dopamine deficiency is present in some first-degree relatives of patients with PD but the predictive value of the finding has not yet been investigated (Piccini et al., 1997; Maraganore et al., 1999). 21.4.4.7.1.3. Twin studies Piccini et al. (1999) studied 18 monozygotic and 16 dizygotic twins discordant for PD with 18F-dopa PET and found that that the rate of subclinical striatal dopaminergic dysfunction was significantly higher in 18 monozygotic than in 16 dizygotic twin pairs (55% versus 18%, respectively). Four monozygotic twin pairs became clinically concordant for PD with a latency of 2–20 years. 21.4.4.7.2. MPTP-exposed patients Vingerhoets et al. obtained two 18F-dopa PET scans separated by 7 years on 10 patients who had been exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the early 1980s; 5 patients were asymptomatic at the time of the first scan. They found that the (striatum-background)/background ratio in all MPTPexposed subjects decreased with an average slope of 2.3% per year, ‘significantly faster than controls’. Two patients remained normal during this interval. For 1 patient there was little change in fluorodopa accumulation between scans; for the other, there was a significant decline from a ratio of 0.77–0.61. In this study, fluorodopa accumulation ratios for subjects and controls overlap and the control group is not well matched in terms of age. The subjects selected for the study were at higher risk than the general population for the development of PD; therefore, it would be difficult to use this data to evaluate the predictive value of 18F-dopa PET. 21.4.5. Alternative imaging studies There are a number of imaging techniques that do not depend on imaging neurotransmitter receptors or trans-

porters. These depend on changes in anatomy; other aspects of the SNpc, such as iron content; or physiological/metabolic changes, such as glucose utilization. 21.4.5.1. Anatomic changes in Parkinson’s disease: ultrasound, magnetic resonance imaging Pathologic studies have shown that, in PD, there is exponential loss of pigmented substantia nigra neurons with greatest loss in the lateral ventral nigra, a pattern opposite to that of normal aging (Fearnley and Lees, 1991). Hutchinson and Raff (2000) found that T1-weighted magnetic resonance images (MRI) sensitive to cell volume showed loss of signal in a lateral-to-medial gradient in cases of PD, corresponding to the known neuropathologic pattern of degeneration. Severity of changes correlated with UPDRS scores. Other authors have described changes in volume of putamen (Lisanby et al., 1993; Vymazal et al., 1999; O’Neill et al., 2002), globus pallidus and prefrontal cortical gray matter and connections (Lisanby et al., 1993; O’Neill et al., 2002). Decreased volumes of striatal structures have not been reproduced in all studies (Schulz et al., 1999). Morphometric studies in normal patients have shown a non-linear decrease in volume of basal nuclei with age (Brabec et al., 2003). Furthermore, one fairly consistent finding from the psychiatric literature is that the volume of the basal nuclei seems to increase over time in schizophrenics treated with typical neuroleptics (Keshavan et al., 1994, Corson et al., 1999). This suggests that both age and pharmacotherapy with levodopa and dopa agonists are potential confounding factors that should be more closely controlled in future volumetric studies. 21.4.5.2. Substantia nigra iron content Several late-onset neurodegenerative diseases, Alzheimer’s disease, PD and Huntington’s disease, have a higher accumulation of iron in affected brain regions as compared to age-matched controls (Connor et al., 1995; Moos and Morgan, 2004). In these disorders, regional changes in iron content exceed the increase in brain iron that occurs with normal aging (Bartzokis et al., 2004). Genetic conditions that cause excess iron accumulation in the nervous system (for example, pantothenate kinase-associated neurodegeneration, formerly Hallervorden–Spatz disease, Friedreich ataxia) are also associated with neurodegeneration. The bulk of brain iron is stored in ferritin molecules. Absence of ferritin iron-binding protein in dopaminergic neurons of the substantia nigra (in which 10– 20% of free iron is bound to neuromelanin) may make these neurons particularly vulnerable to excess free iron accumulation (Bartzokis et al., 2004). Many studies have used MRI to show decreased T2 relaxation

EARLY DETECTION OF PARKINSON’S DISEASE time in the pars compacta of the substantia nigra and other subcortical structures in PD, probably due to increased iron content (Antonini et al., 1993; Gorell et al., 1995; Ryvlin et al., 1995; Bartzokis et al., 1999, 2004; Vymazal et al., 1999). Male subjects with early-onset PD had increased ferritin-bound iron levels in several basal ganglia regions, suggesting that ferritin iron may be a risk factor for earlier-onset PD (Bartzokis et al., 2004). Substantia nigra iron content has been criticized as a biomarker of PD because in one large study T2 values in the substantia nigra did not correlate with disease duration or with clinical severity (Antonini et al., 1993). Another morphologic finding possibly related to increased substantia nigra iron content is increased echogenicity of the substantia nigra on ultrasound. An echogenic area of 0.25 cm or more in the substantia nigra in young individuals correlates with reduced putamenal and caudate 18F-dopa Ki on PET (Berg et al., 2002). Increased substantia nigra echogenicity correlates with extrapyramidal signs in ‘healthy’ elderly individuals (Berg et al., 2001). The prevalence of substantia nigra hyperechogenicity increases only slightly with age and correlates with increased substantia nigra iron content in postmortem studies (Berg et al., 2002). The authors postulate that increased substantia nigra iron content, through increased generation of hydroxyl and superoxide radicals, causes oxidative stress that will predispose these individuals to developing parkinsonism. Although substantia nigra hyperechogenicity is found in PD and 9% of ‘healthy’ individuals (Becker et al., 1995), a prospective study linking this finding to the development of PD has not yet been done. 21.4.5.3. Metabolic alterations: hydrogen magnetic resonance spectroscopy 1

H magnetic resonance spectroscopy (MRS) can be used to evaluate the concentration of several cerebral metabolites: standard measurements are of Nacetylaspartate (NAA), a marker of viable adult neurons, creatine and phosphocreatine (Cr), indicators of energy metabolism, choline (Cho), a marker of cell (especially neuronal) membranes and myoinositol (mI). MRS is susceptible to misinterpretation mainly due to the complexity of calibrating results from spectra: ratio methods are susceptible to misinterpretation if reference metabolite (especially Cho or Cr) concentration varies (Dudek, 2004); furthermore, in the study of PD, voxel inhomogeneity is expected to be an issue in the brainstem and alterations in substantia nigra iron content may affect the results of spectroscopy (Jenkins et al., 1999). Results from MRS studies have varied; NAA/Cr ratios in the SN have been reported to be both

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increased and decreased in PD. Several studies found significant differences between PD and controls in the NAA/Cho or NAA/Cr ratios in the globus pallidus and putamen and cerebral cortex, whereas other studies have not found significant differences between PD and controls in these regions (O’Neill et al., 2002). A quantitative 1H MRS study of 10 PD patients and 13 age- and sex-matched controls showed significantly lower Cr in the substantia nigra of PD patients; there were no significant differences in NAA, Cho, or mI (O’Neill et al., 2002). 21.4.5.4. Phosphate and carbon spectroscopy Phosphorous MRS has also been used to investigate PD and parkinsonian syndromes. Metabolites that can be imaged using MRS include phosphocreatine (PCr), inorganic phosphate (Pi) and cytosolic free Mg2þ and pH. Preliminary studies have shown alterations in the concentrations of some of these metabolites in the occipital lobe of patients with PD in comparison to patients with multiple system atrophy (Barbiroli et al., 1999) and progressive supranuclear palsy (Martinelli et al., 2000). Regional high-energy phosphate and phospholipid metabolism may also be altered in the basal ganglia of patients with PD (Kudo et al., 1997). Penn et al. (1995) studied metabolite levels in skeletal muscle and found a significant difference in inorganic phosphate/ phosphocreatine (Pi/PCr) ratio between PD patients and controls. Other researchers have not found any significant difference in muscular energy metabolism between patients with PD and controls (Taylor et al., 1994). 21.4.5.5. Sympathetic failure in Parkinson’s disease: cardiac imaging 123

I-metaiodobenzylguanadine (MIBG), a physiological analog of norepinephrine, is taken up and vesicularized by presynaptic sympathetic nerve terminals. Cardiac MIBG uptake is reduced in PD and other disorders associated with autonomic failure. Patients with PD and symptomatic orthostatic hypotension display increased end-organ sensitivity to norepinephrine and severely decreased myocardial and lower-extremity MIBG uptake. However, patients with PD and decreased myocardial MIBG uptake do not invariably have clinical signs or symptoms of orthostatic hypotension (Takatsu et al., 2000). Heart/mediastinum MIBG uptake is significantly reduced in PD patients, even those in early stages of disease, in comparison to controls (Iwasa et al., 1998, Satoh et al., 1999) and is more severely reduced at advanced stages of disease (Hamada et al., 2003). Range of tracer uptake does overlap somewhat between young PD patients

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and controls but it is not clear if these results were normalized for age (Hamada et al., 2003). Reduced cardiac MIBG uptake in synucleinopathies (Lewy body disease, PD, multiple system atropy and pure autonomic failure) in contrast to tauopathies has led to the suggestion that MIBG scintigraphy be used and a diagnostic test undertaken to distinguish between these disorders (Taki et al., 2004). Of interest, cardiac MIBG uptake is also less severely reduced in multiple system atrophy than in PD, probably because the autonomic defect is postganglionic in PD but preganglionic/central in multiple system atrophy. Some investigators have proposed that cardiac MIBG uptake be used to distinguish PD from multiple system atrophy (Braune et al., 1999; Druschky et al., 2000). 21.4.5.6. Changes in network dynamics One intriguing concept that becomes more evident as we try to understand the effectiveness of lesions and deep brain stimulation for the treatment of PD is that motor and cognitive symptoms of the disease result from abnormal activity within different interconnected networks or subcortical nuclei and brain regions (Lozza et al., 2004). 18F fluorodeoxyglucose studies of PD have shown increased metabolic activity in the lentiform nucleus and thalamus associated with decreased activity in the lateral frontal, paracentral, inferior parietal and parieto-occipital areas correlated with degree of bradykinesia and rigidity in PD (Eidelberg et al., 1994). Lentiform nucleus hypermetabolism is improved following pallidotomy (Dogali et al., 1994). Subthalamotomy reduces basal ganglia output through internal globus pallidus/substantia nigra pars reticularis and also influences downstream neural activity in the pons and ventral thalamus (Su et al., 2001). Other investigators have suggested that patterns of alteration in regional glucose metabolism can be used to discriminate patients with suspected atypical parkinsonian syndromes from their counterparts with classic PD (Antonini et al., 1998). Diffusion tensor MRI uses preferential diffusion of water molecules along white-matter tracts to image neuronal connections. It has been used to show decreased fractional anisotropy in the region of interest between the substantia nigra and the lower part of the putamen/caudate complex (Yoshikawa, 2004), suggesting alteration in the connections between these structures. To what extent any of these observations could be used as specific or sensitive markers for preclinical PD remains to be seen.

21.5. Summary A number of techniques (clinical, electophysiological, biochemical, imaging and genetic) have been

used to detect or quantify pathophysiology of PD. These tests are candidates to be used singularly or as part of a test battery for the preclinical detection of PD. However, a number of questions need to be answered: 1. Assuming that a predictive test is applied at time X, what outcome will be accepted at time Y as indicating accuracy of the test? Establishing a gold standard that is accurate and feasible to use in validation trials remains an issue. 2. What is the required time duration between X and Y to determine if the primary outcome (e.g. clinical diagnosis of PD) has occurred? 3. Who should be screened for PD – patients known to carry genetic mutations correlated with PD, family members of patients with PD, the general population past a certain age? Prior probability of disease will vary significantly between these groups. 4. Although many techniques seem to perform well as diagnostic tests for PD, in many cases the sensitivity, specificity, positive and negative predictive value and generalizability have not been assessed. Even tests that are well validated as distinguishing between PD and controls are expected to perform less well as predictive tests (due to greater overlap between normal and control groups) and can only be conscientiously used in patient care if prospectively validated.

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Section 4 Etiology

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 22

Mitochondria in the etiology of Parkinson’s disease ANTHONY H. V. SCHAPIRA* University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London and Institute of Neurology, University College London, London, UK

22.1. Introduction The identification to date of six different gene mutations and another five chromosomal loci linked to familial Parkinson’s disease (PD) indicates the etiological heterogeneity of this disorder. At the pathogenetic level, several biochemical abnormalities, including mitochondrial complex I deficiency and free radicalmediated damage, have been demonstrated in the substantia nigra of sporadic PD patients. Again, there is heterogeneity amongst these, with some patients exhibiting one defect and others multiple abnormalities. The role of mitochondrial dysfunction in PD now extends beyond that of a respiratory chain defect; mutations in two nuclear genes (PINK1 and DJ-1) encoding mitochondrial proteins have been described in familial PD. This chapter reviews the role of mitochondria in PD etiology and pathogenesis.

22.2. Mitochondrial DNA structure, function and inheritance Mitochondrial DNA (mtDNA) is a small circular double-stranded molecule 16 493 bases long encoding two ribosomal RNAs, 22 transfer RNAs and 13 proteins (Fig. 22.1). These 13 proteins are all part of the oxidative phosphorylation (OXPHOS) system for generating energy by aerobic metabolism (Table 22.1). MtDNA remains dependent on the nucleus for the production of proteins involved in its transcription, translation, replication and repair. Mutations in nuclear genes encoding proteins involved in mtDNA maintenance, e.g. mtDNA polymerase gamma (POLG), can cause a variety of human disorders, including late-onset PD (see below).

MtDNA-encoded proteins are translated on mitochondrial ribosomes and incorporated directly into complexes I, III, IV and V on the inner membrane. Nuclear-encoded proteins are translated on cytosolic ribosomes and are imported into the mitochondrion through a complex receptor and transport system. For many proteins, this involves an N-terminal amino-targeting sequence that interacts with membrane receptors and signals the carrier protein’s import into the mitochondrion. The signaling sequence is then cleaved and the protein trafficked to the appropriate mitochondrial compartment. Some proteins are incorporated into the outer mitochondrial membrane and others directly into the intermembranous space. The vast majority of mitochondrial proteins are encoded by the nucleus and they have a wide range of functions. Many are involved in the metabolic pathways for which the mitochondrion is responsible, e.g. OXPHOS, beta-oxidation, urea cycle, apoptotic pathways. The OXPHOS system comprises the four respiratory chain complexes (I–IV) and adenosine triphosphatase (ATPase: complex V). These proteins are embedded in the inner mitochondrial membrane and consist of a total of approximately 85 subunits, 72 being encoded by nuclear DNA and 13 by mtDNA. The OXPHOS system is not only responsible for adenosine triphosphate (ATP) production, but is also an important source of superoxide radicals. Thus defects of the OXPHOS system have the potential not only to cause a failure of energy metabolism, but also increased free radical-mediated damage. MtDNA continuously replicates and this involves the nuclear-encoded enzymes mtDNA POLG, thymidine kinase 2 and deoxyguanosine kinase. MtDNA is inherited through the female line, although there has

*Correspondence to: Professor A. Schapira, University Department of Clinical Neurosciences, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK. E-mail: [email protected], Tel: þ44-207830-2012, Fax: þ44-20-7472-6829.

482

A. H. V. SCHAPIRA D-Loop

1601 1671 V

(MELAS, CPEO 3243 A→G)

O H

15887

(LHON 15257 G→A)

TAS T 14747

12s rRNA

(LHON 14484 T→C)

Cyt b

0/16569P

14673

LSP

16s rRNA

(MiMyCa 3260 A→G) (MELAS 3271 T→C)

648 HSP F

E

14148 14149

ND6

Complex I NADH Dehydrogenase Genes

L

3307

Complex IV Cytochrome C Oxidase Genes

ND5

(LHON 3460 G→A) (LHON 4160 T→C)

ND1 4262

I Q

4470

M

L S H

ND2 A 5511

W

N OL C Y

Complex III Ubiquinol: Cytochrome C Oxidoreductase genes

Complex V ATP Synthase Genes

12337 12137

Ribosomal RNA

ND4 (LHON 11778 G→A) G

10766/10760

ND3

5904 COI

S

K COII

COIII ATPase6

D-Loop Region

R ND4L

10470 10404 10059 9990

Transfer RNA

D 7444

A

B

Complex I

ATPase8 9207 7586 8262 8366 8527/8527 (NARP 8993 T→G) (MERRF 8344 A→G) (MERRF 8356 A→G)

II

III

IV

V

Fig. 22.1. For full color figure, see plate section. Schematic representation of human mitochondrial DNA (mtDNA) and the respiratory chain. (A) Included are the color-coded genes for respiratory chain proteins, ribosomal and transfer RNAs. The OH and OL are the origins of heavy- and light-strand replication respectively. The location of the more common mtDNA mutations is indicated. (B) The oxidative phosphorylation system. Each hexagon is the product of a single gene: white, nuclear; others color-coded to the mtDNA molecule in (A).

been one report of paternal inheritance of a mtDNA microdeletion in a complex I gene (Schwartz and Vissing, 2002). Over 100 mtDNA mutations have been associated with human disease. The majority of these result in a spectrum of encephalomyopathies. These include a variety of ocular and limb myopathies in addition to disorders such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and myoclonic epilepsy with ragged red fibers (MERRF). MtDNA mutations responsible for mitochondrial diseases include point mutations of tRNAs or protein-coding genes and genomic rearran-

gements, including deletions and duplications. mtDNA mutations may be somatic, such as occur with senescence, or inherited. However, about 40% of patients with proven mtDNA mutations have no family history. Interestingly, patients with mitochondrial myopathies have an increased incidence of movement disorders over and above that expected in controls (Truong et al., 1990). Also, certain families with point mutations in complex I coding genes have Leber’s hereditary optic neuropathy (LHON), particularly associated with dystonia (Jun et al., 1994; De Vries et al., 1996). Furthermore, mitochondrial complex I deficiency has been identified

MITOCHONDRIA IN THE ETIOLOGY OF PARKINSON’S DISEASE Table 22.1 The respiratory chain and oxidative phosphorylation system

Complex Complex I

Complex II

Complex III

Complex IV Complex V

Enzyme activity

No. of subunits

Mitochondrial DNA-encoded subunits

NADH ubiquinone reductase Succinate ubiquinone reductase Ubiquinol cytochrome c reductase Cytochrome c oxidase Adenosine triphosphate synthase

43

7

4

–

11

1

13

3

14

2

in platelet mitochondria from patients with dystonia (Benecke et al., 1992; Schapira et al., 1997). mtDNA mutations are often present in heteroplasmic form, i.e. coexisting with normal wild-type mtDNA. The proportion of mutant to wild-type may vary between individuals and between tissues of the same individual. There is a relationship between the mutant load and the degree of biochemical defect, although this is both tissue-dependent and recessive: from studies undertaken so far, 5–20% of wild-type mtDNA can compensate at the biochemical level.

22.3. Mitochondrial complex I deficiency in Parkinson’s disease A mitochondrial defect in PD was first identified in 1989 in substantia nigra from patients with PD (Schapira et al., 1989a, b). This study has been expanded over the years and results to date show that there is a specific 35% complex I deficiency in PD nigra (Mann et al., 1994). This defect in complex I activity does not affect any other part of the respiratory chain. In addition, no defect in mitochondrial activity has been identifiable in any other part of PD brain, including caudate putamen, globus pallidus, tegmentum, cortex, cerebellum or substantia innominata (Schapira et al., 1990b). The discovery of complex I deficiency in PD raised many questions, specifically regarding its primary or secondary role in etiology/pathogenesis. As virtually

483

all the brains taken from PD patients had been exposed to levodopa, an important question related to whether levodopa caused the complex I deficiency. However, there is no deficiency of complex I activity in PD striatum which one might expect from the rat model (Cooper et al., 1995). Levodopa does not appear to cause any deficiency of complex I activity in platelet mitochondria, which again might be expected given the relatively high circulating levels of levodopa in the periphery. Most importantly, it has been shown that patients with multiple system atrophy (MSA) who have taken levodopa in quantities and for duration comparable to patients with PD have no defect of mitochondrial activity in their substantia nigra (Gu et al., 1997). Furthermore, cell loss in the nigra is at least as severe in MSA as it is in PD and so one would expect that, if the mitochondrial defect in PD were simply a reflection of this degeneration, the same abnormality should be present in MSA. Its absence in MSA therefore suggests that its presence in PD is the result of a more specific cause than simple cell loss. Following the report of complex I deficiency in PD substantia nigra, respiratory chain abnormalities were described in skeletal muscle mitochondria from PD patients. This particular area has proved very contentious, with several groups describing either similar defects, or no abnormality whatsoever (Schapira, 1994). Two magnetic resonance spectroscopy studies on skeletal muscle mitochondrial function in PD have shown conflicting results (Taylor et al., 1994; Penn et al., 1995). Finally, mitochondrial complex I deficiency was also identified in platelet mitochondria of PD patients (Parker et al., 1989; Krige et al., 1992; Haas et al., 1995). In contrast to skeletal muscle there is a consensus amongst several laboratories that complex I deficiency does exist in PD platelet mitochondria. The majority of studies, however, suggest that this deficiency, at least based on a group-to-group analysis, is modest (circa 20–25% Schapira, 1994). The complex I deficiency in PD lacks the sensitivity to allow its use as a biomarker of PD.

22.4. Mitochondrial DNA mutations in Parkinson’s disease Several studies have investigated the structure of mtDNA in tissues from PD patients to determine whether the complex I defect is associated with an underlying mtDNA mutation. An early study suggested increased levels of the common deletion in PD brain (Ikebe et al., 1990). However, this study did not use age-matched controls and the increase in the common deletion was in fact no greater than would

484

A. H. V. SCHAPIRA

be expected from the aging process. Other studies using properly matched controls found no increase in this mitochondrial mutation in PD substantia nigra (Schapira et al., 1990a; Lestienne et al., 1991). Several studies have sequenced mtDNA in PD but these have all used unselected patients in terms of their complex I activity (Ozawa et al., 1991; Ikebe et al., 1995). Although some reports have suggested an increased frequency of certain mtDNA polymorphisms in PD, this has not been replicated in all studies (Shoffner et al., 1993; Lucking et al., 1995; Kosel et al., 2000; Richter et al., 2002; Vives-Bauza et al., 2002). Certain mtDNA haplotypes influence PD expression and haplotype J was associated with a significant decrease in risk for PD, which in turn is strongly associated with the presence of a single nucleotide polymorphism at A10398G (van der Walt et al., 2003). A second study showed a 22% decrease in PD in those with the UKJT haplotype cluster (Pyle et al., 2005). In contrast, a smaller study reported an increased risk for PD with haplotypes J and T (Ross et al., 2003). It is possible to use a cell complementation system to assess whether mitochondrial or nuclear DNA determines a respiratory chain deficiency. This system makes use of rho-zero cells in which mtDNA has been eradicated by ethidium bromide, but which are still capable of surviving in medium supplemented with uridine and pyridine. These cells have a nucleus but no functioning respiratory chain. mtDNA taken from donor cells may then be fused into these rho-zero cells. The production of a respiratory chain defect in the recipient cells will indicate that this is derived from the donor mtDNA. This system has been used to show that the respiratory chain defects of LHON 3460 (Cock et al., 1998) and mtDNA depletion syndrome (Bodnar et al., 1993) have a nuclear component. Others have shown that the biochemical deficiency associated with mtDNA deletions and the 3243-basepair tRNALeu (UUR) mutation associated with the MELAS phenotype follow the transfer of mtDNA from donor to recipient rho-zero cells (Dunbar et al., 1996). Two studies have used genetic transplantation to investigate the potential for PD mtDNA to determine the complex I defect. In one, unselected PD platelets were fused and grown in mixed culture (Swerdlow et al., 1996). In another, PD patients were selected on the basis of demonstrating a peripheral complex I deficiency. These patients’ cells were then fused with rho-zero cells and grown in both mixed and clonal culture (Gu et al., 1998). In both, mtDNA transferred from the PD patients induced a complex I defect in the recipient cybrid cells. These results indicate that the mtDNA in these patients caused the complex I

deficiency through either inherited or somatic mutations. Further experiments suggested that the recipient cells also developed abnormal calcium handling and a lower mitochondrial membrane potential. A mutation in the mtDNA 12S RNA was found in a patient with maternally inherited early-onset PD, deafness and neuropathy (Thyagarajan et al., 2000), but this has not been found in other cases of PD. In summary, at the time of writing, no specific mtDNA abnormality has been consistently found in PD patients to explain the complex I deficiency.

22.5. Nuclear mitochondrial mutations causing Parkinson’s disease As explained above, nuclear DNA encodes approximately 97% of mitochondrial proteins. Several gene mutations causing familial PD have been described. These include POLG mutations and mutations in PINK1 and DJ-1, all of which code for mitochondrial proteins. POLG mutations have been demonstrated in patients with progressive external ophthalmoplegia (PEO) and parkinsonism. Autosomal-dominant or recessive inheritance of PEO with age of onset ranging from 10 to 54 years was followed some years later (range 6–40 years) by the development of an asymmetric, levodopa-responsive bradykinetic rigid syndrome together with resting tremor in some patients. Additional features included variable limb, pharyngeal or facial weakness, cataracts, ataxia, peripheral neuropathy and premature ovarian failure (Luoma et al., 2004). Muscle biopsy demonstrated ragged red, cytochrome oxidase-negative fibers in all patients with multiple mtDNA deletions on Southern blotting. Symmetrically reduced striatal [18F]b-CFT was seen in 2 patients. Brain histology was available on a further 2 patients; both showed severe loss of substantia nigral dopaminergic neurons but without the development of Lewy bodies or other synuclein aggregates. Four families had the same A2864G mutation, inherited in autosomal fashion in three and with a founder effect in the fourth. Mutations in the exonuclease or polymerase portions of the gene were identified in the autosomalrecessive families. A further patient with autosomaldominant PEO-parkinsonism and an A2492G mutation has been reported (Mancuso et al., 2004). Recently, recessive mutations in PINK1 were found to be responsible for a familial form of early-onset parkinsonism, previously mapped to chromosome 1p36 (the PARK6 locus; Valente et al., 2004a). The PINK1 gene is ubiquitously transcribed and encodes a mitochondrial kinase (Unoki and Nakamura, 2001; Valente et al., 2004a). Preliminary data have suggested that

MITOCHONDRIA IN THE ETIOLOGY OF PARKINSON’S DISEASE PINK1 may play a role in protecting cells against stress conditions that affect mitochondrial membrane potential (Valente et al., 2004a), but the downstream targets through which PINK1 mediates its protection have not been identified. As 11 out of the 14 reported mutations fall into the kinase domain of PINK1 (Hatano et al., 2004; Rohe et al., 2004; Valente et al., 2004a, b), altered phosphorylation of target proteins probably represents a key pathogenic mechanism, leading to abnormal stress response and neurodegeneration. How phosphorylation of these target proteins affects mitochondrial function is not known. The reversible phosphorylation of proteins is an important method of regulating cellular activities (Hunter, 2000). Up to 30% of eukaryotic proteins are phosphorylated (Cohen, 2002) and there are more that 500 human genes encoding protein kinases (Manning et al., 2002). The phosphorylation of mitochondrial proteins is considered pivotal to the regulation of respiratory activity in the cell and to signaling pathways leading to apoptosis, as well as for other vital mitochondrial processes. Recent investigations demonstrated that a number of the subunits of the respiratory chain enzyme complexes are phosphorylated, including several subunits of complex I (Bykova et al., 2003; Hojlund et al., 2003; Schulenberg et al., 2003, 2004; Chen et al., 2004; Murray et al., 2004). As PINK1 protects cells against stress conditions that affect the mitochondrial membrane potential, which is maintained by the respiratory chain enzymes, it is tempting to speculate that PINK1 mediates its protective role through phosphorylation of certain respiratory chain enzyme subunits. Even though PINK1 provides the first direct genetic link between a mitochondrial defect and parkinsonism, several earlier observations have implicated mitochondrial dysfunction in the pathogenesis of other forms of familial PD. A parkin knockout mouse model has been described (Goldberg et al., 2003). This showed an increase in striatal extracellular dopamine, a reduction in synaptic excitability and a mild non-progressive motor deficit at 2–4 months. There was no loss of dopaminergic neurons and no inclusion formation. Dopamine receptor-binding affinities and parkin E3 ligase substrate levels were normal. Interestingly, these mice had decreased striatal mitochondrial respiratory chain function and reductions in specific respiratory chain and antioxidant proteins (Palacino et al., 2004). Parkin knockout flies developed muscle pathology, mitochondrial abnormalities and apoptotic cell death (Greene et al., 2003). Overexpression of parkin in PC12 cells indicated that it is associated with the mitochondrial outer membrane (Darios et al., 2003; Shen and Cookson, 2004). Parkin-positive patients have

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decreased lymphocyte complex I activity (Shen and Cookson, 2004).

22.6. Mitochondrial toxins and Parkinson’s disease The neurotoxin 1-methyl 4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) causes dopaminergic cell loss in the nigrostriatum and induces parkinsonism in humans, other primates and rodents. This is achieved via specific uptake and conversion pathways. MPTP is converted to 1-methyl 4-phenylpyridinium (MPP) via the intermediate 2,3-dihydropyridinium (MPDP) by monoamine oxidase (MAO) A and B, preferentially by MAO-B (Singer et al., 1986). This conversion probably occurs in glia, as MAO-B is predominantly located in astrocytes and serotinergic neurons in the central nervous system, where it is located on the mitochondrial outer membrane (Levitt et al., 1982). Inhibition of MAO can prevent MPTP toxicity. MPDP is capable of passing across cell membranes and so the conversion of MPDP to MPPþ probably occurs in the extracellular space by autooxidation (Di Monte et al., 1992). MPPþ is a substrate for the dopamine reuptake system (Javitch et al., 1984; Chiba et al., 1985). Blockade of MPPþ uptake by, for instance, nomifensine can prevent MPTP toxicity (Melamed et al., 1985; Schultz et al., 1989). Thus MPPþ is actively concentrated into dopaminergic neurons. Although taken up via the nerve terminals in the striatum, MPPþ may be concentrated in the cell body through its affinity with neuromelanin (Lyden et al., 1983; D’Amato et al., 1987). Thus neuromelanin, which is an autooxidation product of levodopa, may act as a toxic sink in the cell body. Once inside the cell, MPPþ is concentrated to millimolar proportions by an energy-dependent mitochondrial ion-concentrating system. Within mitochondria, MPPþ inhibits complex I. There is also evidence that MPPþ generates free radicals and recent evidence that the nitric oxide synthase inhibitor, 7-nitroindozole, can prevent MPPþ toxicity in monkeys (Hantraye et al., 1996). The current assumption is that MPPþ induces cell death through a combination of inhibition of ATP synthesis and free radical generation. The emergence of the neurotoxin MPTP as an experimental tool to produce a model of PD has provided some insight into the etiology and pathogenesis of idiopathic PD. MPTP was originally synthesized as a meperidine analog ‘designer drug’ and sold as an injectable narcotic on the streets of northern California (Davis et al., 1979; Langston et al., 1983). It is likely that hundreds of people injected MPTP but a few individuals who repeatedly used this drug developed an akinetic rigid syndrome with or without

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resting tremor within 7–14 days. These patients responded well to levodopa, although subsequently went on to develop fluctuations and dyskinesias in response to treatment (Langston and Ballard, 1984). 18 F-dopa positron emission tomography (PET) scans of some of these patients showed reduced uptake. Interestingly, a less severe reduction of 18F-dopa uptake was also seen in individuals exposed to the drug who had not developed clinical features of parkinsonism (Calne et al., 1985; Martin et al., 1986) and subsequent repeat scans have shown further progressive loss of the nigrostriatal system as determined by 18F-dopa uptake over time. Although MPTP-induced parkinsonism has clinical, pharmacological and 18F-dopa uptake parallels with idiopathic PD, in the few cases that have come to postmortem the pathological changes are similar but not identical to PD. Severe loss of nigral neurons in the substantia nigra is seen, but without evidence of classic Lewy bodies (Langston et al., 1983). Systemic injection of MPTP into non-human primates also produces parkinsonism with bradykinesia, rigidity and freezing. Tremor may also develop but it is not the typical resting tremor of parkinsonism, usually being a postural or action tremor (Martin et al., 1986; Tetrud and Langston, 1992). Like humans, MPTP-treated monkeys develop severe dopamine depletion in the striatum with marked nigrostriatal neuronal loss. There is also cell loss in the locus ceruleus in MPTP-treated monkeys similar to that seen in idiopathic PD. In MPTP-treated monkeys eosinophilic intraneuronal inclusions have been observed but they lack the structure typical of Lewy bodies (Forno et al., 1988). Other complex I inhibitors have also been shown to induce dopaminergic cell death. Rotenone is a potent and specific complex I inhibitor and is commonly used in the USA as a pesticide. Infusion of low doses of rotenone over 1 month into rodents induced nigrostriatal cell death and Lewy-like inclusions (Betarbet et al., 2000). Subsequent studies have indicated that the damage induced by rotenone is also related to free radical generation and is more widely distributed than in PD (Hoglinger et al., 2003b). Annonacin is a complex I inhibitor and is found in sour-sop, a drink used in the Caribbean, and when injected into rats this compound induces nigral degeneration (Champy et al., 2004). Acute carbon monoxide poisoning results in complexing of carbon monoxide with the ferrous iron, protophorphyrin IX, and this prevents the carriage of oxygen. In addition carbon monoxide is a potent inhibitor of cytochrome oxidase (complex IV) of the mitochondrial respiratory chain. Survivors of carbon monoxide poisoning have developed parkinsonism

within a few days or weeks of exposure (Grinker, 1926; Gordon, 1965; Klawans et al., 1982). The affected patients show necrosis of the globus pallidus on computed tomography and magnetic resonance imaging scanning. The effects of this toxin therefore contrast with MPTP; carbon monoxide induces a postsynaptic defect whereas MPTP produces a presynaptic lesion more in keeping with PD. A postsynaptic pallidal lesion may similarly be produced by manganese. There have been numerous reports of manganism developing amongst individuals exposed to manganese dioxide ore, usually by inhalation of manganese dust. Exposure is typically chronic over 6 months to 16 years and the onset of manganism is slow, beginning with apathy, muscle weakness and cramps and general irritability. Progression occurs and is characterized by dysarthria and psychosis followed by severe rigidity, anarthria and dystonia with little or no tremor (Huang et al., 1993). Manganese predominantly appears to affect the globus pallidus with relative sparing of the substantia nigra (Kish et al., 1985).

22.7. Mitochondria, oxidative stress and the proteasomal system There are several lines of evidence which indicate the presence of free radical-mediated oxidative stress and damage to biomolecules in PD substantia nigra. Glutathione (GSH) in its reduced form is an important compound in antioxidant defense and in the repair of oxidized proteins. It is oxidized to its disulfide, GSSG. High GSH/GSSG ratios are maintained by glutathione reductase (GSSG), which converts GSSG to GSH. One study reported a decrease in the activity of glutathione peroxidase in PD nigra, putamen and globus pallidus (Mena, 1979), but this has not been reproduced by others (Riederer and Wuketich, 1976). However, there is evidence that GSH levels are decreased in PD substantia nigra (Perry et al., 1982; Sian et al., 1994). Total GSH levels appear to be slightly lower in PD substantia nigra. This combination suggests enhanced free radical generation in the PD nigra. Superoxide dismutase (SOD) exists in cytosolic (copper/zinc, Cu/Zn) SOD and mitochondrial manganese (Mn) SOD forms and is important in dismutating superoxide ions. Thus levels of this enzyme are indicative of superoxide generation. Both copper/zinc and manganese SOD appear to be increased in PD substantia nigra (Marttila et al., 1988; Saggu et al., 1989). High levels of copper/zinc SOD are expressed at the mRNA level in control and PD nigral pigmented neurons (Hirsch et al., 1989; Ceballos et al., 1990). Taken

MITOCHONDRIA IN THE ETIOLOGY OF PARKINSON’S DISEASE together these observations suggest that PD nigral neurons in particular are exposed to increased superoxide generation. Levels of polyunsaturated fatty acids (Dexter et al., 1986), malondialdehyde and hydroperoxides (Jenner, 1991) are increased in PD substantia nigra. These are the products of free radical damage to lipid membranes and imply oxidative damage in PD. Free radical damage to DNA produces intracellular 8-hydroxydeoxyguanosine. Elevated concentrations of this product are seen in PD in the nuclear DNA and particularly in the mtDNA fractions from patients with PD (Sanchez-Ramos et al., 1994). Levels of these products are also particularly high in control brains in the substantia nigra and striatum, confirming that, even in controls, this area of the brain is a site of high oxidative stress. Animal studies have implicated nitric oxide (NO.) in the nigrostriatal neuronal loss in PD. Nitric oxide synthase (NOS) activity is at its highest in the nigrostriatal system in non-human primates and humans. Inhibition of NOS protects against MPTP toxicity in primates (Hantraye et al., 1996) and in the methamphetamine animal model of PD (Itzhak and Ali, 1996). Attempts to demonstrate altered levels of NO. in the brains of PD patients have been inconclusive, with both decreased and increased levels of cerebrospinal fluid nitrate, a marker of NOS activity, being seen (Kuiper et al., 1994; Molina et al., 1994; Qureshi et al., 1995). Nitrotyrosine residues have been identified in Lewy bodies, implying NO-mediated damage to proteins (Good et al., 1998; Giasson et al., 2000). The ubiquitin proteasomal system (UPS) is the primary mechanism responsible for the elimination of mutant, damaged and misfolded intracellular proteins and for regulating the levels of short-lived proteins that mediate cellular activities such as gene transcription and neurotransmission (Pickart, 2001; Sherman and Goldberg, 2001). Polyubiquitin-protein conjugates and free (non-ubiquitinated) proteins/peptides are respectively degraded by 26S and 20S proteasomes, which are multicatalytic proteases found in the cytoplasm, endoplasmic reticulum, perinuclear region and nucleus of eukaryotic cells. Proteasomal degradation of proteins is achieved by a series of ATP-dependent peptidases (Voges et al., 1999). A defect of mitochondrial respiratory chain activity results in impaired oxidative phosphorylation and an increase in free radical generation (Benaroudj et al., 2003) and thus will affect UPS function by both limiting activity and increasing the substrate load of oxidized protein. This interaction has been elegantly demonstrated in primary mesencephalic cultures (Hoglinger et al., 2003a).

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The activities of the UPS are normally upregulated to clear unwanted proteins but failure of this process to occur normally results in the accumulation of abnormal proteins; their aggregation forms insoluble inclusion bodies, disruption of cellular homeostasis and integrity. Such defects often lead to cell death via an apoptotic mechanism (McNaught and Olanow, 2003). However, UPS activity is reduced in the PD brain (McNaught et al., 2003) and this may promote or contribute to abnormal protein aggregation, cell dysfunction and death. Mutant and damaged proteins are known to saturate and inhibit activity of the UPS, leading to the accumulation of a wide range of poorly degraded intracellular proteins (Bence et al., 2001). Parenteral administration of proteasomal inhibitors to rodents has been reported to induce neuronal cell loss in a pattern comparable to PD and motor abnormalities that respond to dopaminergic therapy (McNaught et al., 2004). Epoxomicin or Z-Ile-Glu (OtBu)-Ala-Leu-al) (PSI) was injected intraperitoneally (epoxomicin) or subcutaneously (PSI) six times over 14 days. After a latency of 2 weeks, rats developed a progressive motor deficit with rigidity and bradykinesia that was responsive to apomorphine and a bilaterally and symmetrically reduced striatal fluorodopa PET signal at 17 weeks. The loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the presence of microglial activation were confirmed by tyrosine hydroxylase (TH) and OX-42 staining respectively. There was a 53% loss of THþ cells at 2 weeks and a 72% loss at 6 weeks with a corresponding fall in striatal dopamine levels. Neuronal degeneration also occurred in the locus ceruleus, dorsal motor vagal nucleus and nucleus basalis of Meynert. Ubiquitin-rich intracytoplasmic protein aggregations with structural similarities to Lewy bodies were observed in neurons of the SNc, locus ceruleus and dorsal motor vagal nucleus. This model appears, therefore, to have many clinical, morphological and pharmacological parallels to PD.

22.8. Conclusions There are several different causes of PD, which include, at the time of writing, 11 separate loci associated with familial PD. Environmental risk factors have been defined but no single environmental agent has been identified as causing idiopathic PD. It is clear that mitochondria play an important role in PD pathogenesis. However, rather than necessarily contributing directly, it seems more likely that mitochondrial dysfunction operates as part of a complex network which includes oxidative stress and abnormal protein handling.

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Schapira AH, Cooper JM, Dexter D et al. (1989a). Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1 (8649): 1269. Schapira AHV, Cooper JM, Dexter D (1989b). Mitochondrial complex I deficiency in Parkinson’s disease. Ann Neurol 26: 122–123. Schapira AH, Holt IJ, Sweeney M et al. (1990a). Mitochondrial DNA analysis in Parkinson’s disease. Mov Disord 5 (4): 294–297. Schapira AH, Mann VM, Cooper JM et al. (1990b). Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. J Neurochem 55 (6): 2142–2145. Schapira AH, Warner T, Gash MT et al. (1997). Complex I function in familial and sporadic dystonia. Ann Neurol 41 (4): 556–559. Schulenberg B, Aggeler R, Beechem JM et al. (2003). Analysis of steady-state protein phosphorylation in mitochondria using a novel fluorescent phosphosensor dye. J Biol Chem 278 (29): 27251–27255. Schulenberg B, Goodman TN, Aggeler R et al. (2004). Characterization of dynamic and steady-state protein phosphorylation using a fluorescent phosphoprotein gel stain and mass spectrometry. Electrophoresis 25 (15): 2526–2532. Schultz W, Scarnati E, Sundstrom E et al. (1989). Protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism by the catecholamine uptake inhibitor nomifensine: behavioral analysis in monkeys with partial striatal dopamine depletions. Neuroscience 31 (1): 219–230. Schwartz M, Vissing J (2002). Paternal inheritance of mitochondrial DNA. N Engl J Med 347 (8): 576–580. Shen J, Cookson MR (2004). Mitochondria and dopamine: new insights into recessive parkinsonism. Neuron 43 (3): 301–304. Sherman MY, Goldberg AL (2001). Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29 (1): 15–32. Shoffner JM, Brown MD, Torroni A et al. (1993). Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics 17 (1): 171–184. Sian J, Dexter DT, Lees AJ et al. (1994). Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 36 (3): 348–355. Singer TP, Salach JI, Castagnoli N Jr et al. (1986). Interactions of the neurotoxic amine 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine with monoamine oxidases. Biochem J 235 (3): 785–789. Swerdlow RH, Parks JK, Miller SW et al. (1996). Origin and functional consequences of the complex I defect in Parkinson’s disease. Ann Neurol 40 (4): 663–671. Taylor DJ, Krige D, Barnes PR et al. (1994). A 31P magnetic resonance spectroscopy study of mitochondrial function in skeletal muscle of patients with Parkinson’s disease. J Neurol Sci 125 (1): 77–81. Tetrud JW, Langston JW (1992). Tremor in MPTP-induced parkinsonism. Neurology 42 (2): 407–410.

MITOCHONDRIA IN THE ETIOLOGY OF PARKINSON’S DISEASE Thyagarajan D, Bressman S, Bruno C et al. (2000). A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy. Ann Neurol 48 (5): 730–736. Truong DD, Harding AE, Scaravilli F et al. (1990). Movement disorders in mitochondrial myopathies. A study of nine cases with two autopsy studies. Mov Disord 5 (2): 109–117. Unoki M, Nakamura Y (2001). Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene 20 (33): 4457–4465. Valente EM, Abou-Sleiman PM, Caputo V et al. (2004a). Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304 (5674): 1158–1160.

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Valente EM, Salvi S, Ialongo T et al. (2004b). PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol 56 (3): 336–341. van der Walt JM, Nicodemus KK, Martin ER et al. (2003). Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet 72 (4): 804–811. Vives-Bauza C, Andreu AL, Manfredi G et al. (2002). Sequence analysis of the entire mitochondrial genome in Parkinson’s disease. Biochem Biophys Res Commun 290 (5): 1593–1601. Voges D, Zwickl P, Baumeister W (1999). The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem 68: 1015–1068.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 23

Iron as a trigger of neurodegeneration in Parkinson’s disease ANDRZEJ FRIEDMAN1*, JOLANTA GALAZKA-FRIEDMAN2 AND ERIKA R. BAUMINGER3 1

Department of Neurology, Medical University in Warsaw, Poland 2

Faculty of Physics, Warsaw University of Technology, Poland

3

Racah Institute of Physics, Hebrew University, Jerusalem, Israel

23.1. Introduction Iron plays an important role in all living cells and is essential for many metabolic functions in the central nervous system (Sipe et al., 2002). The concentration of iron in human substantia nigra (SN) increases with aging up to the third decade and then levels off (Hallgren and Sourander, 1958; Zecca et al., 2004). Under normal conditions iron in SN, as in other organs, catalyzes various reactions. It constitutes an essential component of enzymes in the oxidative metabolism, yet it is a double-edged sword and may also be deleterious by triggering oxidative stress. In oxidative reactions in the central nervous system, as in any other tissue, iron generates free radicals via the Fenton reaction: Fe2þ þ H2 O2 ! Fe3þ þOH þOH Free radicals, produced in this process, are neutralized under normal conditions by free radical scavengers. It is the excess of free radicals, caused either by an increase in production of free radicals or by decreased abilities to neutralize them, which may become a starting point for oxidative stress (Halliwell, 1992). Broken iron homeostasis in SN may therefore be the trigger for neurodegeneration, leading to Parkinson’s disease. The causes of this broken iron homeostasis may be related to a change in iron concentration, a change in the iron redox state or a change in the forms of iron binding. This chapter will present and discuss the results of investigations dealing with these items. Presenting the problem of the change in the concentration of iron in parkinsonian SN, we will discuss

results of studies performed on postmortem specimens by various techniques and studies on living subjects using non-invasive methods – magnetic resonance imaging (MRI) and transcranial sonography (TCS). Though the correlations between signals obtained by these last two techniques and iron concentration are not completely solved, such studies have attempted to compare the amount of iron in different tissues. A review of the results reported for MRI and TCS dealing with the comparison between iron concentration in parkinsonian and control SN will be presented. The redox state of iron, as well as the forms of iron binding, can only be assessed in postmortem tissues, though MRI and TCS may be able to show iron inside ferritin. There is a wide range of published results dealing with the concentration of iron in SN and its redox state. The differences in the obtained values may be due to artifacts in the experiments or may also reflect, to some extent, the wide range of iron concentrations in individual cases, both in disease and control. Though in some papers large differences in iron concentrations between normal and PD SN were reported, in others only non-significant changes could be detected. It has to be emphasized, however, that biological processes are not linear, and even small changes may lead to a process destroying nervous tissue in SN (Galazka-Friedman and Friedman, 1997). At the end of this chapter we will present various speculations about the scenario of broken iron homeostasis in Parkinson’s disease.

*Correspondence to: Andrzej Friedman, Department of Neurology, Medical University, ul. Kondratowicza 8, 03-242 Warsaw, Poland. E-mail: [email protected], Tel: þ48-22-3265815, Fax: þ48-22-3265815.

494

A. FRIEDMAN ET AL. measurement, the amount of tissue needed for the measurement and the sensitivity of the method. With some techniques additional information, like the iron valence and/or the identification of iron-binding compounds or the concentration of other elements in the tissues, can be obtained. The iron concentrations measured by different techniques yield very different results – ranging from 48 to 480 mg/g for wet control tissues and from 85 to 280 mg/g for wet PD tissues (Table 23.1 and Fig. 23.1). The lowest concentrations were measured by spectrophotometry. Spectrophotometry requires homogenization of samples in hydrochloric acid and pepsin (Sofic et al., 1988, 1991) and much of the iron may be lost during this procedure. On the other hand total reflection X-ray fluorescence (TXRF), measured in 5 samples of control SN, gave a very high iron concentration, though with a comparatively large standard deviation (410 223 mg/g). This result may therefore be due to large differences between concentrations measured in each of the samples. The results cited in the tables give the concentration of iron in mg/g tissue. In two papers, one applying inductively coupled plasma spectroscopy (Mann et al., 1994) and the other colorimetry (Loeffler et al., 1995), the results are given in ng/mg protein. It is difficult to compare these results for iron concentrations with all others, yet the results of these two experiments are inconsistent with each other (1159 379 and 5600 400 ng/mg protein respectively).

23.2. Iron concentration in normal and parkinsonian substantia nigra 23.2.1 Postmortem studies SN has been known for its high iron concentration since 1958, when Hallgren and Sourander published the results of a quantitative assessment by colorimetry of iron concentration in normal human brains. These authors measured 52 samples of SN. The average iron concentration in SN calculated from these measurements was 184.6 65.2 mg/g wet tissue, which was higher than that measured by these authors in human liver (134.4 93.6 mg/g). Since the late 1960s many researchers tried to assess the iron concentration in parkinsonian and normal SN. The normal SNs were usually obtained from control subjects, who died without any clinical or pathological signs of neurodegenerative disease. The results obtained in these measurements on postmortem SN are summarized in Tables 23.1 and 23.2 and Figs. 23.1 and 23.2. The data presented are based on all available papers published up to the end of 2004 and only include references to papers in which data obtained from certain experiments were described for the first time. As shown in these tables and figures, iron concentrations were assessed in postmortem tissue by different techniques. Each technique has its advantages and disadvantages depending on several factors, such as the tissue preparation necessary for carrying out the

Table 23.1 Iron concentration in substantia nigra in control (C) and Parkinson’s disease (PD) measured in wet tissues Method

Sample weight (mg)

No. of C samples

Iron concentration (mg/g)

Col

?

81

184.6 65.2

XRF SPH TXRF AA

? 50–80 ? 50

? 8 5 6

? 48 8 410 223 140 13

NAA MS

10–30 237–1125

? 20

154 45 171 17

ICP

10

22

Col

50

8

1159 379 ng/ mg protein 5600 400 ng/ mg protein

No. of PD samples

Iron concentration (mg/g)

11 8

? 85 11

6

281 22

9

174 21

18

1813 846 ng/ mg protein 4600 300 ng/ mg protein

14

Reference Hallgren and Sourander (1958) Earle (1968) Sofic et al. (1988) Zecca and Swartz (1993) Griffiths and Crossman (1993) Zecca et al. (2001) Galazka-Friedman et al. (unpublished)a Mann et al. (1994) Loeffler et al. (1995)

Col, colorimetry; XRF, X-ray fluorescence; SPH, spectrophotometry; TXRF, total reflection X-ray fluorescence; AA, atomic absorption; NAA, neutron activation analysis; MS, Mo¨ssbauer spectroscopy; ICP, inductively coupled plasma spectroscopy. a These numbers are based on data from Galazka-Friedman et al. (1996) and data obtained from additional samples.

IRON AS A TRIGGER OF NEURODEGENERATION IN PARKINSON’S DISEASE

495

Table 23.2 Iron concentration in substantia nigra in control (C) and Parkinson’s disease (PD) measured in lyophilized tissues Method

Sample weight (mg)

No. of C samples

Iron concentration (mg/mg)

No. of PD samples

Iron (mg/mg)

ICP AAE MS

100–250 50–500 90–150

9 12 1

580 60 613 56 890 70

7 9 1

780 60 653 55 644 60

Reference Dexter et al. (1989) Uitti et al. (1989) Galazka-Friedman et al. (1996)

ICP, inductively coupled plasma spectroscopy; AAE, atomic absorption and emission; MS, Mo¨ssbauer spectroscopy.

700 Iron concentration in control 600

Iron concentration in PD

500

µg/g

400 300 200 100 0 COL

SPH

TXRF

AA

NAA

MS

SPH pc

SPH pr

Fig. 23.1. Concentrations of iron (in mg/g) in wet tissue as measured by various techniques. COL, colorimetry (Hallgren and Sourander, 1958); SPH, spectrophotometry (Sofic et al., 1989); TXRF, total reflection X-ray fluorescence (Zecca and Swartz 1993); AA, atomic absorption (Griffiths and Crossman, 1993); NAA, neutron activation analysis (Zecca et al., 2001); MS, Mo¨ssbauer spectroscopy (Galazka-Friedman et al., unpublished); pc, pars compacta; pr, pars reticulata (Sofic et al., 1991).

1200 Iron concentration in control 1000

Iron concentration in PD

µg/g

800 600 400 200 0 ICP

AAE

MS

AA oral

AA caudal

Fig. 23.2. Concentrations of iron (in mg/g) in lyophilized tissue as measured by various techniques. ICP, inductively coupled plasma spectroscopy (Dexter et al., 1989); AAE, atomic absorption and emission (Uitti et al., 1989); MS, Mo¨ssbauer spectroscopy (Galazka-Friedman et al., 1996); AA, atomic absorption separately for oral and caudal substantia nigra (Riederer et al., 1989).

496

A. FRIEDMAN ET AL.

As seen from the tables, TXRF and neutron activation analysis were only applied for control SN. All other methods mentioned above were used to measure iron concentrations in both control and PD SN. As in the control samples, the low concentration for SN iron measured by spectrophotometry is also notable for PD samples. Most methods used need chemical pretreatment of the samples. In some this pretreatment may affect the estimate of the amount of iron in the samples. Mo¨ssbauer spectroscopy – recoil-free resonance absorption – is the only method used on postmortem samples that does not need any pretreatment of the samples once they are removed from the brain. In this respect it is the most reliable, though not the most sensitive method used. It requires about 15 mg Fe (which always contains 0.3 mg (2.1%) of the Mo¨ssbauer-sensitive isotope Fe57) in a sample in order to give a signal. It will detect any iron in the sample that is present in an amount higher than that, irrespective of its valence or spin state (Galazka-Friedman et al., 1996). This method, which is able to assess not only the iron concentration but also the iron redox state (divalent versus trivalent iron) and iron-binding compound, was used by Bauminger et al. (1994), Gerlach et al. (1995) and Galazka-Friedman et al. (1996, 2004), but the concentration of iron in SN in PD and controls was assessed in only two experiments (Bauminger et al., 1994; Galazka-Friedman et al., 1996). As seen in Tables 23.1 and 23.2, the concentrations of iron in SN obtained with this method are similar to those obtained by colorimetry, atomic absorption and neutron activation analysis in wet tissues for control SNs and by atomic absorption and emission and inductively coupled plasma spectroscopy in lyophilized tissues. Among all methods mentioned, neutron activation analysis is the most sensitive for determining the iron concentration. This method was used to measure iron concentration in control samples of various ages (Zecca et al., 2001a). Only two samples in this study were obtained from subjects of age typical for PD. The results obtained for these two cases differ significantly from each other (109 and 199 mg/g). Even with this very sensitive method, results so different from each other were obtained. This probably points to a wide variability in iron concentration from case to case. The gaps between the results cited in Tables 23.1 and 23.2 may be due to a wide range of iron concentrations in different individuals and to a non-homogeneous distribution of iron within SN. The size of investigated samples ranged from 10 mg (Mann et al., 1994) up to 1125 mg for pooled samples (Galazka-Friedman et al., unpublished). The high sensitivity of some methods, requiring only small sizes of samples, may make

it possible to estimate the concentration of iron in specific regions of SN. However, due to the non-homogeneous distribution of iron in SN, these results may not represent the amount of iron in whole SN per unit weight. The large range of concentrations of iron obtained in PD SN may be further magnified by problems with the diagnosis of PD. The paper by Sofic et al. (1991) compares the iron concentrations in SN between controls and patients with severe parkinsonism and dementia (referred to in this paper as PD plus) and patients with dementia of Alzheimer type. It is not obvious that patients with parkinsonian symptoms and dementia do represent typical Lewy body Parkinson’s disease (Litvan et al., 2003). Nevertheless, as can be seen in Fig. 23.1, with the exception of spectrophotometry studies (Sofic et al., 1988), there is general agreement concerning the total concentration of iron in SN measured by the different methods. The smaller concentrations measured by spectrophotometry in both parkinsonian and control SNs, as well as in measurements on pars compacta and pars reticulata of SNs, may, as discussed earlier, probably be due to an artifact of the method. The results of measurements performed on lyophilized samples (Fig. 23.2) do not show such discrepancies, except for those made separately for the oral and caudal part of SN (Riederer et al., 1989). There were several experiments comparing the iron concentration in PD SN with that in control SN. The paper by Jean Lhermitte et al. (1924) is often cited as the first description of an increased iron concentration in Parkinson’s disease (Go¨tz et al., 2004), sometimes even as a first description of increased iron in parkinsonian SN (Kaur and Andersen, 2004). However Lhermitte et al. (1924), who used Perls and Turnbull staining, showed only abnormal iron deposits in the globus pallidus of 1 patient who died with the clinical diagnosis of PD. In effect, the authors mentioned explicitly that ‘[iron] in the substantia nigra was present in normal amounts’ (Lhermitte et al., 1924). In nine studies the concentrations of iron in SN were assessed for PD and control. X-ray fluorescent spectroscopy was used in one study to determine the iron content in 11 parkinsonian SNs and the results were compared with an unknown number of measurements of control samples (Earle, 1968). In this study a twofold increase of total iron content in parkinsonian SN versus control was found. No error of this calculation was given. These measurements were performed on samples kept in formalin for a long time. Some of the samples were stored for more than 70 years in formalin, and control brains were stored for longer than PD. It was shown that this type of storage

IRON AS A TRIGGER OF NEURODEGENERATION IN PARKINSON’S DISEASE promotes a leak of iron from the tissue (Bauminger et al., 1994; Chua-anusorn et al., 1997) and it is possible that this leak is different in control and PD tissue. The same may also be true for experiments applying spectrophotometry, where iron is lost during sample preparation. Table 23.3 demonstrates the ratios of iron concentrations in PD versus control with their errors, as calculated for each of the nine studies. As can be seen from the table, five of the obtained ratios show an increase in iron in PD SN, whereas three results show

497

no significant change and one even shows a decrease. It seems that it is hard at this point to confirm the oftencited statement, that there is a substantial increase in the total concentration of iron in parkinsonian SN compared to control. In some experiments a comparison of nigral iron between PD and controls was made separately on pars compacta and pars reticulata or the oral and caudal part of SN. These results are presented in Table 23.4. A higher concentration of iron in pars reticulata than in pars compacta in control brains was found by Sofic

Table 23.3 Ratio of iron concentrations between Parkinson’s disease (PD) and control (C) substantia nigra as obtained by different methods Method

No. of PD samples

No. of C samples

Ratio Fe(PD)/Fe(C)

Reference

XRF SPH AA MS ICP COL ICP AAE MS

11 8 6 9 18 14 7 9 1

? 8 6 20 22 8 9 12 1

2.0 ? 1.77 0.37 2.01 0.24 1.02 0.16 1.56 0.23 0.82 0.08 1.34 0.17 1.07 0.13 0.93 0.18

Earle (1968) Sofic et al. (1988) Griffiths and Crossman (1993) Galazka-Friedman et al., unpublisheda Mann et al. (1994) Loeffler et al. (1995) Dexter et al. (1989) Uitti et al. (1989) Galazka-Friedman et al. (1996)

XRF, X-ray fluorescence; SPH, spectrophotometry; AA, atomic absorption; MS, Mo¨ssbauer spectroscopy; ICP, inductively coupled plasma spectroscopy; COL, colorimetry; AAE, atomic absorption and emission. The first six studies were made on wet tissue, whereas the remaining three were done on lyophilized tissue. a These numbers are based on data from Galazka-Friedman et al. (1996) and data obtained from additional samples.

Table 23.4 Iron concentrations assessed in parts of substantia nigra (SN) (pars compacta versus pars reticulata or oral versus caudal) Method and part of SN

Sample W or L

Sample weight (mg)

No. of control samples

Iron amount (mg/g)

No. of PD samples

Iron amount (mg/g)

PD/C ratio

Reference

SPH pc

W

?

9

62 7

7

89 9

1.44 0.22

SPH pr

W

?

9

91 15

7

89 9

0.92 0.18

AA oral

L

50–80

4

340 100

11

430 100

1.26 0.47

AA caudal

L

50–80

4

230 100

11

280 100

1.22 0.59

ICP pc

L

100–250

3

740 60

8

960 60

1.30 0.13

Sofic et al. (1991) Sofic et al. (1991) Riederer et al. (1989) Riederer et al. (1989) Dexter et al. (1989)

PD, Parkinson’s disease; C, control; W, wet tissue; L, lyophilized tissue; SPH, spectrophotometry; AA, atomic absorption; ICP, inductively coupled plasma spectroscopy; pc, pars compacta; pr, pars reticulata.

498

A. FRIEDMAN ET AL.

et al. (1991), and also in a semiquantitative assessment by Jellinger et al. (1990). On the other hand the study by Dexter et al. (1989) suggests a higher concentration of iron in pars compacta. Comparison of the total amount of iron in parkinsonian and control SN was also made semiquantitatively with the use of Perl’s and Turnbull staining (Jellinger et al., 1990). In these measurements a twofold increase in the iron concentration in parkinsonian SN in pars compacta was found, whereas no such increase was found in pars reticulata of SN. The same method of Perl’s staining, modified by Smith et al. (1997), has been used by Faucheux et al. (2002), who compared the iron content in parkinsonian and control SN. These authors found a large increase of about 10 times in the amount of iron in parkinsonian pars compacta of SN compared to control. This staining method is, however, only sensitive to redox active iron and only a small percentage of the tissue-bound iron is available for redox activity (Smith et al., 1997). The very large difference in the amount of this redox active iron found by Faucheux et al. (2002) may be due to iron, which is safely stored in neuromelanin or ferritin in control tissue, but is present outside these storage compounds as redox active iron in pathological tissues in Parkinson’s disease. 23.2.2. Magnetic resonance imaging studies The observation by Drayer et al. (1986) that the brain areas known for high concentration of iron display a characteristic form of contrast in magnetic resonance images became a starting point for MRI investigations of iron in human brain. The iron-rich regions appear darker than the surrounding areas with low iron concentration. This iron-related contrast is fielddependent. Higher magnetic fields make it visible, whereas at magnetic fields of 1.0 T or below it disappears (Schenck et al., 1990). The nuclear magnetic resonance signal is proportional to the degree of proton magnetization and to the rate of Larmor precession. Attempts to relate the MRI signal with the concentration of iron were presented by Schenck et al. (1990), but no unequivocal conclusions were reached. The aim of the studies reviewed below was to obtain a semiquantitative comparison between the iron content in various brain areas in control and PD patients and/or to find which of the parameters obtained by MRI relate best to the iron concentration in tissues. As in the postmortem studies reviewed above, the conclusions of MRI in vivo studies, concerning the difference of iron concentrations between control and PD SN, are not conclusive. Although some

authors found an increase of iron concentration in SN of PD patients (Gorell et al., 1995; Ryvlin et al., 1995; Graham et al., 2000), in one of the first assessments of the concentration of iron by MRI a decrease of iron was found in parkinsonian SN (Rutledge et al., 1987). Other authors found only non-significant changes (Vymazal et al., 1999). Several MRI studies aimed to assess iron in other basal ganglia, showing an increase of iron in PD caudate, pallidum and putamen (Ye et al., 1996). These findings are at odds with the results on postmortem studies, in which either no increase in the iron concentration in PD in these structures was found (Riederer et al., 1989) or even a significant decrease in PD was reported (Dexter et al., 1989). Assessment of brain iron has typically involved the measurements of proton transverse relaxation rates, R2 (1/T2) or R2’ (1/T2’). Transverse relaxation rates are assumed to depend on inhomogeneities in the local magnetic field. Such inhomogeneities may be caused by the presence of iron, which is mainly stored in ferritin (Gelman et al., 1999). In earlier studies R2 was believed to be a good indicator of iron levels (Drayer et al., 1986; Vymazal et al., 1999). Some authors even claimed they could distinguish with this method iron in pars compacta and pars reticulata of SN (Drayer et al., 1986; Ryvlin et al., 1995). Others however, doubted the possibility of a precise separation of these two parts of SN by MRI (Antonini et al., 1993; Gelman et al., 1999). Doubts also arose whether T2 (or R2) is the right parameter to assess iron concentrations. Brooks et al. (1989) and Chen et al. (1989) independently compared the results of MRI assessment of iron and ferritin concentrations, based on T2 measurements in whole postmortem brains or excised specimen, with the concentrations of iron and ferritin determined by atomic absorption or neutron activation analysis (for iron) and radioimmune assay (for ferritin) in the same samples. Both studies failed to show any correlation between MRI findings and iron or ferritin concentrations in specific brain areas as determined by the other methods. It was also suggested by others that low signal intensity on T2-weighted images is only a non-specific marker of a neurodegenerative process (Stern et al., 1989). According to Gelman et al. (1999), the only possibility of assessing the amount of iron in a small-size structure like SN by MRI is in high-field-strength (3.0 T) measurements of R20 (R20 ¼ R2* – R2). These authors compared the results obtained by their R20 measurements on healthy volunteers with data from the literature on postmortem samples from various brain areas. The highest iron concentration was found

IRON AS A TRIGGER OF NEURODEGENERATION IN PARKINSON’S DISEASE by this method in globus pallidus, followed by SN. These results are in agreement with those found in control human brain samples by Hallgren and Sourander (1958). In this MRI study the authors did not evaluate the amount of iron in PD patients. Another method of MRI assessment of iron content in SN, partially refocused interleaved multiple echo (PRIME), was used by Graham et al. (2000). These authors compared their MRI (in vivo) data with brain iron concentrations published in the literature on postmortem tissues by Hallgren and Sourander (1958) for controls and by Griffiths and Crossman (1993) for PD. In this study the R2* and R20 relaxation rates were higher in SN of PD patients than in controls. No correlation with the disease duration or severity was found in this study. Bartzokis et al. (1999, 2004) proposed another method of increasing the specificity of MRI iron measurements. This method, field-dependent relaxation rate increase (FDRI), measures the difference of R2 obtained with two different field-strength MRI instruments. These authors state that FDRI is a specific measure of the total iron contained in ferric oxyhydroxide particles within the iron core of ferritin. In this study no significant differences in FDRI between PD patients and controls were found. They did, however, find a tendency in SN, and especially in pars reticulata, for a higher FDRI, corresponding, according to them, to higher amounts of iron in young PD patients compared to age-matched young controls. This difference, though, was reversed with higher FDRI for controls in the old age groups of PD and controls. Two more MRI comparisons of nigral iron between PD patients and controls have since been published (Mondino et al., 2002; Atasoy et al., 2004). In both studies the authors compared T2-weighted images using 1.5 T systems. In the first one no difference was found between PD and controls (Mondino et al., 2002). In the second one PD patients had lower T2 intensities in SN compared to controls (Atasoy et al., 2004). In that study this decrease correlated with severity of PD as measured by Unified Parkinson’s Disease Rating Scale. The results obtained by MRI for the change of iron concentration in SN between PD patients and controls are summarized in Table 23.5. Six out of nine studies suggested a somewhat higher concentration of iron in parkinsonian SN and two found only non-significant differences. In the first MRI experiment a lower concentration of iron in parkinsonian SN was found. These results show that so far MRI data have not solved the dispute over iron increase in PD SN. Though this method is surely promising, the interpretation of MRI data regarding iron concentrations seams still not completely solved.

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23.2.3. Transcranial sonography Ultrasound technique was introduced 10 years ago to the study of Parkinson’s disease (Becker et al., 1995). Becker et al. presented the results of a transcranial color-coded real-time sonography of patients with PD compared to controls. This study, although only a semiquantitative assessment, demonstrated a substantial increase in SN echogenicity in PD (70% of patients), whereas in controls hyperechogenicity was only seen in a minority of subjects (<7%). As revealed by further studies, this hyperechogenicity correlated with the reduction of [18F]-dopa uptake in a PET study (Berg et al., 2002). Although, as stated by these authors, the reason for the increase in SN hyperechogenicity is unknown, the authors suggest that it may reflect a higher concentration of iron in the tissue (Becker and Berg, 2001). However, iron as an element is not directly involved in changing the ultrasound signal. Ultrasound patterns depend on tissue impedance and on velocity propagation of ultrasound in tissue. It also depends on the temporal bone window (Bogdahn et al., 1990). Not only higher iron concentration but also changes in iron-binding compounds may influence echo-brightness. In a study comparing echogenicity of SN in postmortem brains with metal concentrations assessed by atomic absorption, the only correlation found was between iron concentration and the area of hyperechogenicity of SN (Berg et al., 2002). The concentrations of other metals, like copper, manganese, zinc and calcium, did not show any correlation with echogenicity. As findings of the ultrasound technique depend on the density of tissues, other causes for increased echogenicity of SN, e.g. gliosis, should also be considered. This is especially so as brain structures known for high levels of iron, such as globus pallidus (Hallgren and Sourander, 1958), do not show high echogenicity (Berg et al., 2002). On the other hand, high echogenicity of SN was also found in newborns and young children (Iova et al., 2004). This also sheds doubts on the dependence of ultrasound on the iron content in the tissue, as at a young age only small amounts of iron were found in SN (Hallgren and Sourander, 1958). In a recent study, a 5-year follow-up of ultrasound measurements of SN in PD patients was presented (Berg et al., 2005). During this period only a small increase in the intensity of the ultrasound signals of SN was detected, although the disease progression during these 5 years was much more severe. Taking into account the study by Riederer et al. (1989), where higher iron content in SN was only found in the more severe cases of PD, the question of what exactly is reflected by hyperechogenicity remains open.

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Table 23.5 Results of magnetic resonance imaging studies comparing substantia nigra in Parkinson’s disease (PD) and controls Method

Field intensity

No of subjects PD/controls

Result

Reference

Restoration of T2 signal

1.5 T

12/30

Lower amount of iron in PD

T2 relaxation time (ms)

1.5 T

30/33

T2 relaxation time (ms) plus additional T2* measurements

3.0 T

13/10

T2 relaxation time (ms)

2.0 T

45/45

FDRI

1.5 T and 0.5 T

12/14

T2 relaxation time (ms)

1.5 T

23/18

PRIME R2*, R20

1.5 T

20/13

T2 relaxation time (ms)

1.5 T

25/27

T2 relaxation time (ms)

1.5 T

20/16

T2 in PD 67.5 2.9 T2 in control 70.6 3.7 P <0.02 0.02 Higher amount of iron in PD Lower values of R2 (P < 0.05) and higher values of R2* (P ¼ 0.001) and R2’ (P < 0.001) in PD than in controls T2 in PD 61 4.7 T2 in controls 63.8 4.3 P < 0.01 No overall difference Increased FDRI in young PD Decreased FDRI in old PD T2 in PD 82.4 6.0 T2 in controls 85.1 5.3 Not significant R2* in PD 0.0237 0.0035 R2* in controls 0.0212 0.0026 R20 in PD 0.0092 0.0034 R20 in controls 0.0069 0.0021 P < 0.05 No numerical data given No difference between PD and controls Decrease of T2 in parkinsonian patients No numerical data given

Rutledge et al. (1987) Antonini et al. (1993)

Gorell et al. (1995)

Ryvlin et al. (1995) Bartzokis et al. (1999) Vymazal et al. (1999) Graham et al. (2000)

Mondini et al. (2002) Atasoy et al. (2004)

FDRI, field-dependent relaxation rate increase; PRIME, partially refocused interleaved multiple echo.

The differences in echogenicity of SN between Parkinson’s disease and control seem to be beyond any discussion. However it is not obvious that this higher echogenicity is related to a higher total iron concentration.

23.3. Redox state of iron in substantia nigra A high concentration of divalent iron was found only by spectrophotometry (Sofic et al., 1988; results repeated by Riederer et al., 1989). These authors described a shift of the Fe2þ/Fe3þ ratio from 2.45 0.54 in control SN to 1.06 0.57 in parkinsonian SN. The authors suggested that this increase in trivalent iron is related to the pathomechanism of neurodegeneration in Parkinson’s disease. However, as discussed earlier, in the procedure used by Sofic et al. (1988), the homogenization of samples in hydrochloric acid

and pepsin leads to release of iron from ferritin and to its reduction to divalent iron. The presence of ascorbic acid within SN (Riederer et al., 1989) makes it even more plausible. Neither Turnbull staining (Jellinger et al., 1990) nor Mo¨ssbauer spectroscopy (Bauminger et al., 1994; Galazka-Friedman et al., 1996, 2004; Gerlach et al., 1995) was able to detect divalent iron in samples studied. In a study in which Mo¨ssbauer spectroscopy was used to assess the highest possible amount of divalent iron in a sample of SN (Galazka-Friedman et al., 1996), computer simulations showed that divalent iron can be only less than 5% of the total iron in this tissue. Recently divalent iron was found in a postmortem study of a patient with parkinsonism–dementia complex of Guam (Ide-Ektessabi et al., 2004) and in the MPTP monkey model of PD by synchrotron radiation micro beams (Ide-Ektessabi et al., 2004). However,

IRON AS A TRIGGER OF NEURODEGENERATION IN PARKINSON’S DISEASE the synchrotron radiation micro beams measurements reflect the situation in one cell or one neuromelanin granule and can, therefore, not assess the total amount of divalent iron in SN. Furthermore, the MPTP model does not correspond ideally to the situation in PD.

23.4. Iron bindings and iron location in substantia nigra The identity of the iron-binding compounds in SN is another issue largely discussed in the literature. Hallgren and Sourander (1958), using colorimetry, assessed that only 30% of brain iron is bound to ferritin. According to Mo¨ssbauer spectroscopy and MRI, most of the iron in SN is ferritin-like, oxyhydroxide iron (Bauminger et al., 1994; Bartzokis et al., 1999). Although it is generally believed that most of this iron is stored in ferritin, some authors suggest that the ironbinding compound may be neuromelanin, as ferritinlike iron was detected by Mo¨ssbauer spectroscopy in neuromelanin isolated from SN (Gerlach et al., 1995). It is however not established whether this oxyhydroxide iron is not attached to neuromelanin during the isolation procedure. Ferritin is the main iron storage protein in all living species. Ferritins are composed of a protein shell with an outer diameter of about 12 nm and an inner diameter of about 8 nm. The protein is composed of 24 subunits. Mammalian ferritins are composed of two types of subunits, L (light) and H (heavy) chains, which have different functions. In iron storage organs like the liver, L chains are dominant (L-rich ferritin), whereas H chains are the dominant subunits in the heart and in the brain (H-rich ferritin) (Harrison and Arosio, 1996). H chains contain ferroxidase centers and rapidly convert divalent to trivalent iron, which is then stored within the ferritin molecule. H-ferritin is dominant in organs, which require little iron storage. L chains lack the ferroxidase center and are slow in sequestering iron, yet promote the building of the iron core for long-term storage (Chasteen and Harrison, 1999). Iron can be stored within the protein shell, forming a hydrous iron (III)-oxide-mineral core similar to ferrihydrite. It can contain between 0 and 4800 iron atoms. The mineral core also contains varying amounts of inorganic phosphate. The cores differ somewhat in different species and organs, and vary in composition, crystallinity and size (Chasteen and Harrison, 1999). Ferrihydrite itself is a poorly ordered hydrous iron oxide with the approximate formula (5Fe2O39H2O) (Eggleton and Fitzpatrick, 1988). Neuromelanin, a black pigment present in neurons of SN, may also bind iron (Zecca et al., 2001a).

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According to X-ray diffraction studies, neuromelanin has a multilayer, graphite-like, three-dimensional structure (Zecca et al., 2001b). It is highly capable of attracting iron and other metals and may therefore protect tissues from damage caused by free iron. It was shown that the very procedure of isolation of neuromelanin causes the attraction of iron from the surrounding tissue, making the assessments of iron concentrations in neuromelanin in whole tissues even more difficult (Zecca et al., 2004). Mo¨ssbauer effect measurements showed that most of the iron in neuromelanin isolated from SN is ferritin-like iron, arranged as polynuclear hydrous iron oxide aggregates (Gerlach et al., 1995, and our own unpublished data). Electron paramagnetic resonance (EPR) measurements showed that, in addition to such aggregates, isolated Fe3þ ions are present in purified neuromelanin of SN (Aime et al., 1997). According to Zecca et al. (2001a), iron bound to neuromelanin may constitute 10–20% of the total iron in SN of healthy elderly subjects; the rest is mainly stored in ferritin of glial cells, outside neurons. The presence of iron in neuromelanin was also checked by energy-dispersive X-ray microanalysis (Hirsch et al., 1991; Jellinger et al., 1992) and by laser microprobe analysis – LAMMA (Good et al., 1992). These experiments gave contradictory results, as in one of them no iron was detected in neuromelanin (Hirsch et al., 1991), whereas in the two others the presence of iron in neuromelanin in SN was confirmed (Good et al., 1992; Jellinger et al., 1992). Mo¨ssbauer spectra observed for isolated neuromelanin are similar, yet not identical, to spectra obtained from ferritin. Taking into consideration these small differences, we tried to estimate the amount of neuromelanin iron that could be present in the sample and not be detected by Mo¨ssbauer spectroscopy. To accomplish this, a simulated neuromelanin iron spectrum with parameters obtained from the spectra of neuromelanin isolated from control SN (Gerlach et al., 1995, and our own unpublished data) was included in the theoretical spectra that were computer-fitted to the experimentally observed spectra in whole tissues of SN (Galazka-Friedman et al., 2004). The quality of the computer fits, as measured by the chi-square of the fit between the simulated and experimental spectra, did not change significantly if a neuromelanin iron subspectrum, whose intensity was up to 15% of the overall spectral area, was included in the fitted spectra. Mo¨ssbauer measurements therefore indicate that less than 15% of the iron in SN may be bound to neuromelanin (Galazka-Friedman et al., 2004), with most of the rest being bound to ferritin. Electron microscopy shows clearly ferritin in SN (Galazka-Friedman et al., 1998).

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As mentioned above, iron is not distributed homogeneously in SN. Another important issue is therefore in which part of human SN the main iron pool is located and whether ferritin is present within nervous cells. In some studies no ferritin in human SN neurons was detected (Moos, 2000), whereas recently H-rich ferritin was detected within melanized nervous cells of human SN (Connor et al., 2003). Except in the semiquantitative assessment by Jellinger et al. (1990), it was not possible to separate nervous from glial cells in all experiments measuring iron concentrations in postmortem samples of SN. It must be assumed therefore that iron may be located in both compartments. Glial cells contain mostly L-rich ferritin, whereas neurons contain H-rich ferritin (Connor et al., 2003). Two independent studies have shown a decrease of L-rich ferritin in parkinsonian SN compared to controls (Connor et al., 1995; Galazka-Friedman et al., 2004). Therefore this decrease in L-ferritin level may represent changes in glial cells. Glial cells were implicated in the pathogenesis of PD in 1988, when it was shown that PD is an active inflammatory process (McGeer et al., 1988). The proliferation of microglial cells in PD promotes the destruction of nervous tissue. Microglial cells contain large amounts of ferritin, mostly L-ferritin. The ways in which microglial cells produce the destructive inflammatory process include an induction of oxidative stress (McGeer and McGeer, 2004). A decrease of L-ferritin in microglial cells could be the starting point for this process, leading to an efflux of iron from the ferritin shell, and making it available for the Fenton reaction. Recently a decrease of L-ferritin was also found in human SN with incidental Lewy bodies (Koziorowski et al., 2006).

23.5. Broken homeostasis of iron as a cause of Parkinson’s disease A detailed description of the homeostasis of iron within cells was given by Harrison and Arosio (1996). Here we present only the most important elements of this equilibrium. Iron enters the cells carried by a transport protein, transferrin, through specific receptors located at the cell’s surface. Inside the cells, iron is released to the cytoplasm and most of it is then sequestered by the iron storage protein, ferritin. Only a small percentage of iron is left in the form of a labile iron pool. If the cells lack iron, the number of transferrin receptors on their surface is increased. In this situation the synthesis of ferritin is downregulated. When there is an excess of iron in the cell, a reverse mechanism downregulates the transferrin receptors and upregulates the synthesis of ferritin. Two iron-regulatory proteins, IRP1 and IRP2, maintain the equilibrium of intracellu-

lar iron. In PD the broken homeostasis of iron should be seen as the disequilibrium of iron within the whole system, involving nervous and glial cells of SN. Broken homeostasis of iron was postulated as a cause of neurodegeneration in Parkinson’s disease by many researchers (for review, see Youdim et al., 1989; Thompson et al., 2001; Go¨tz et al., 2004; Kaur and Andersen, 2004). Youdim and coworkers were the first to suggest that broken homeostasis of iron in the brain may be the starting point for PD. They proposed that Parkinson’s disease is a progressive siderosis of SN, in which the mechanism of the deleterious role of iron is related to an increase of its total amount and the shift of the Fe2þ/Fe3þ ratio from 3:1 to 1:1. This 1:1 ratio, according to these authors, is optimal for maximal rapid formation of OH free radicals, but, as mentioned above, the Fe(II) detected in this experiment is probably due to an artifact caused by the sample preparation. As these authors could not find any ferritin or hemosiderin-bound iron in SN, they suggested neuromelanin as the iron-binding substance. Neuromelanin could be involved in the promotion of the oxidative stress by reducing increased amounts of ferric iron into ferrous one (Youdim et al., 1989). Thompson et al. (2001) point to the possible role of iron transport, intracellular iron turnover and iron storage proteins in initiating oxidative stress in various neurological diseases. Discussing the possible role of iron in the pathogenesis of PD, these authors cite the results of experimental studies in which an increase in the concentration of iron in parkinsonian SN compared to control was found. They also report studies in which an overproduction of lactoferritin receptors within neuronal cells in PD was shown and studies demonstrating a change in the ferritin structure in parkinsonian SN. According to Thompson et al. (2001), another factor related to iron metabolism that may influence iron homeostasis in parkinsonian SN is an overproduction of lactoferritin receptors. Lactoferritin is an iron transport protein with an affinity for iron that is 300 times greater than that of the other iron transport protein, transferrin. The overproduction of lactoferritin receptors may lead to an increase of iron within neurons, which could start neurodegeneration. Another factor that may affect iron homeostasis in PD, suggested by Thompson et al. (2001), is a decrease in the concentration of L-ferritin in parkinsonian SN. As mentioned above, this decrease, originally demonstrated by Connor et al. (1995), may cause a defect in the iron storage abilities of ferritin, and as these authors stress, the maintenance of iron in a safe form is crucial for iron homeostasis in the brain (Thompson et al., 2001).

IRON AS A TRIGGER OF NEURODEGENERATION IN PARKINSON’S DISEASE According to Kaur and Andersen (2004), iron misregulation in Parkinson’s disease is related to several factors. They cite experimental data suggesting an increase in the total amount of iron in parkinsonian SN, a disturbed ferritin synthesis, and a malfunction of iron regulatory proteins, particularly IRP-1. These authors, discussing the large range of published results concerning iron concentration in SN, in both controls and PD, support an earlier presented opinion that even marginal changes in iron availability may lead to a disruption of iron homeostasis in PD (Galazka-Friedman and Friedman, 1997). According to Kaur and Andersen (2004), iron availability for redox reactions depends on the equilibrium between iron uptake and iron storage. The disturbed synthesis of ferritin leads to formation of iron deposits in the basal ganglia and a clinical picture similar to PD (Crompton et al., 2005). The third factor, which may be implicated in iron deregulation in PD, is related, according to Kaur and Andersen (2004), to the iron-regulatory proteins IRP1 and IRP2, which protect cells from the oxidative stress caused by an increase in the labile iron pool. They suggest, citing the data from the paper by Faucheux et al. (2002), that there may be changes in these iron-regulatory proteins in Parkinson’s disease, which might enhance the mismanagement of iron, leading to neuronal death. In a review Go¨tz et al. (2004) present the increase in the total amount of iron in SN as a main cause for degeneration in PD. This excess of iron stored in glial cells in ferritin and hemosiderin and in nervous cells in neuromelanin is released, forming the low-molecularweight chelatable iron complexes. This low-molecularweight iron pool may trigger redox reactions leading to damage. The authors do not suggest any mechanism of this increase in iron concentration and they do not exclude the possibility that this is only a phenomenon secondary to neurodegeneration and reactive proliferation of glial cells. Go¨tz et al. (2004) also largely discuss the interactions between iron and neuromelanin, suggesting that neuromelanin plays a dominant role in the oxidative stress injury in PD. As presented by these authors, neuromelanin may act as both a toxifying and detoxifying component in PD, depending on the intracellular environment and the stage of the disease. Recent Mo¨ssbauer spectroscopy studies have shown slight, though significant, differences between Mo¨ssbauer spectra obtained from parkinsonian SN and control SN (Galazka-Friedman et al., 2004). This slight difference may be due to a small amount of non-ferritin iron in PD SN samples, which could correspond to the redox active iron found by Faucheux et al. (2002). These results can be related to the finding of a decrease of L-ferritin in parkinsonian SN (Connor

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et al., 1995; Galazka-Friedman et al., 2004). With the lack of L chains, iron core formation is slowed down and the H chains may not be able to empty their ferroxidase centers in order to take up more iron. This may lead to an excess of non-ferritin iron in SN, which may eventually be bound to neuromelanin. Degradation of neuromelanin in Parkinson’s disease may release this iron, which could then initiate the Fenton reaction. Based on these results, we suggest that the starting point for non ferritin iron in PD SN may be related to a decrease in L-rich ferritin in PD (Galazka-Friedman et al., 2004). This hypothesis is also supported by the finding of a mutation in the gene encoding L-ferritin, which causes an adult onset of basal ganglia disease (Curtis et al., 2001). This mutation caused a great number of iron inclusions in several brain areas, especially in globus pallidus, as shown at the autopsy of one case (Curtis et al., 2001). This mutation can cause a variety of clinical symptoms of movement disorders from chorea and dystonia to akinetic-rigid syndrome, typical of Parkinson’s disease (Crompton et al., 2005). In all cases described by these authors increased signal intensities were found in the SN on T2-weighted MRI (Crompton et al., 2005). This increased signal was detected in the brains of patients with apparently decreased L-ferritin. As a decrease of L-ferritin leads to a decreased ability of iron storage within the ferritin shell, it may be that the signal corresponds to increased non-ferritin iron deposits. The genetic mutation in neuroferritinopathy causes a dramatic decrease of L-ferritin. According to enzymelinked immunosorbent assay studies, in Parkinson’s disease the decrease of L-ferritin in SN is less than in neuroferritinopathy, but it may be sufficient for a small increase of non-ferritin iron, available for Fenton chemistry (Connor et al., 1995; Galazka-Friedman et al., 2004). The neurodegenerative process may therefore start by a small amount of non-ferritin mobile iron without any substantial increase in total iron in SN.

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Bartzokis G, Tishler TA, Shin I-S et al. (2004). Brain ferritin iron as a risk for age at onset in neurodegenerative diseases. Ann NY Acad Sci 1012: 224–236. Becker G, Berg D (2001). Neuroimaging in basal ganglia disorders: perspectives for transcranial ultrasound. Mov Disord 16: 23–32. Becker G, Seufert J, Bogdahn U et al. (1995). Degeneration of substantia nigra in chronic Parkinson’s disease visualized by transcranial color-coded real time sonography. Neurology 45: 182–184. Berg D, Roggendorf W, Schroeder U et al. (2002). Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol 59: 999–1005. Berg D, Merz B, Reiners K et al. (2005). Five-year follow-up study of hyperechogenicity of the substantia nigra in Parkinson’s disease. Mov Disord 20 (3): 383–385 [Epub ahead of print, DOI 10.1002/mds.20311]. Bogdahn U, Becker G, Winkler J et al. (1990). Transcranial color-coded real-time sonography in adults. Stroke 21: 1680–1688. Brooks DJ, Luthert P, Gadian D et al. (1989). Does signalattenuation on high-field T2-weighted MRI of the brain reflect regional cerebral iron deposition? Observations on the relationship between regional cerebral water proton T2 values and iron levels. J Neurol Neurosurg Psychiatry 52: 108–111. Chasteen ND, Harrison PM (1999). Mineralization in ferritin: an efficient means of iron storage. J Struct Biol 126: 182–194. Chen JC, Hardy PA, Clauberg M et al. (1989). T2 values in the human brain: comparison with quantitative assays of iron and ferritin. Radiology 173: 521–526. Chua-anusorn W, Webb J, Macey DJ et al. (1997). The effect of histological processing on the form of iron-loaded human tissues. Biochim Biophys Acta 1360: 255–261. Connor JR, Snyder BS, Arosio P et al. (1995). A quantitative analysis of isoferritins in select regions of aged, parkinsonian, and Alzheimer’s diseased brains. J Neurochem 65: 717–724. Connor JR, Boyer PJ, Menzies SL et al. (2003). Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 61: 304–309. Crompton DE, Chinnery PF, Bates D et al. (2005). Spectrum of movement disorders in neuroferritinopathy. Mov Disord 20: 95–99. Curtis ARJ, Fey C, Morris CM et al. (2001). Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28: 350–354. Dexter DT, Wells FR, Lees AJ et al. (1989). Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem 52: 1830–1836. Drayer BP, Olanow W, Burger CA et al. (1986). Parkinson plus syndrome: diagnosis using high field MR imaging of brain iron. Radiology 159: 493–498. Earle KM (1968). Studies on Parkinson’s disease including X-ray fluorescent spectroscopy of formalin fixed brain tissue. J Neuropathol Exp Neurol 27: 1–13. Eggleton RA, Fitzpatrick RW (1988). New data and a revised structural model for ferrihydrite. Clays Clay Miner 36: 111–114.

Faucheux BA, Martin ME, Beaumont C et al. (2002). Lack of upregulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson’s disease. J Neurochem 83: 320–330. Galazka-Friedman J, Friedman A (1997). Controversies about iron in parkinsonian and control substantia nigra. Acta Neurobiol Exp (Wars) 57: 217–225. Galazka-Friedman J, Bauminger ER, Friedman A et al. (1996). Iron in parkinsonian and control substantia nigra—a Mo¨ssbauer spectroscopy study. Mov Disord 11: 8–16. Galazka-Friedman J, Bauminger ER, Tymosz T et al. (1998). Mo¨ssbauer spectroscopy, electron microscopy and electron diffraction studies of ferritin-like iron in human heart, liver and brain. Hyperfine Interactions (C) 3: 49–52. Galazka-Friedman J, Bauminger ER, Koziorowski D et al. (2004). Mo¨ssbauer spectroscopy and ELISA studies reveal differences between Parkinson’s disease and control substantia nigra. Biochim Biophys Acta 1688: 130–136. Gelman N, Gorell JM, Barker PB et al. (1999). MR imaging of human brain at 3.0 T: preliminary report on transverse relaxation rates and relation to estimated iron content. Radiology 210: 759–767. Gerlach M, Trautwein AX, Zecca L et al. (1995). Mo¨ssbauer spectroscopic studies of purified human neuromelanin isolated from the substantia nigra. J Neurochem 65: 923–926. Good PF, Olanow CW, Perl DP (1992). Neuromelanincontaining neurons of the substantia nigra accumulate iron and aluminium in Parkinson’s disease: a LAMMA study. Brain Res 593: 343–346. Gorell JM, Ordidge RJ, Brown GG et al. (1995). Increased iron-related MRI contrast in the substantia nigra in Parkinson’s disease. Neurology 45: 1138–1143. Go¨tz ME, Double K, Gerlach M et al. (2004). The relevance of iron in the pathogenesis of Parkinson’s disease. Ann N Y Acad Sci 1012: 193–208. Graham JM, Paley MNJ, Gruenewald RA et al. (2000). Brain iron deposition in Parkinson’s disease imaged using the PRIME magnetic resonance sequence. Brain 123: 2423–2431. Griffiths PD, Crossman AR (1993). Distribution of iron in the basal ganglia and neocortex in postmortem tissue in Parkinson’s disease and Alzheimer’s disease. Dementia 4: 61–65. Hallgren B, Sourander P (1958). The effect of age on the non-haemin iron the human brain. J Neurochem 3: 41–51. Halliwell B (1992). Oxygen radicals as key mediators in neurological disease: fact or fiction. Ann Neurol 32: S10–S15. Harrison PM, Arosio P (1996). The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta 1275: 161–203. Hirsch EC, Brandel JP, Galle P et al. (1991). Iron and aluminium increase in the substantia nigra of patients with Parkinson’s disease: an X-ray microanalysis. J Neurochem 56: 446–451. Ide-Ektessabi A, Kawakami T, Watt F (2004). Distribution and chemical state analysis of iron in the parkinsonian substantia nigra using synchrotron radiation micro beams. Nucl Instrum Methods Phys Res B 213: 590–594.

IRON AS A TRIGGER OF NEURODEGENERATION IN PARKINSON’S DISEASE Iova A, Garmashov A, Andruchtchenko N et al. (2004). Postnatal decrease in substantia nigra echogenicity. Implications for the pathogenesis of Parkinson’s disease. J Neurol 251: 1451–1454. Jellinger K, Paulus W, Grundke-Iqbal I et al. (1990). Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases. J Neural Transm Park Dis Dement Sect 2: 327–340. Jellinger K, Kienzl E, Rumpelmair G et al. (1992). Iron-melanin complex in substantia nigra of parkinsonian brains: an X-ray microanalysis. J Neurochem 59 (3): 1168–1171. Kaur D, Andersen J (2004). Does cellular iron dysregulation play a causative role in Parkinson’s disease? Ageing Res Rev 3: 327–343. Koziorowski D, Friedman A, Arosio P et al. (2006). ELISA reveals a difference in the structure of substantia nigra ferritin in Parkinson’s disease and Incidental Lewy Body compared to control. Park Rel Disord [Epub ahead of print, DOI 10.1016/j.parreldis.2006.10.002]. Lhermitte J, Krauss WM, McAlpine D (1924). On the occurrence of abnormal deposits of iron in the brain in parkinsonism with special reference to its localisation. J Neurol Psychopathol 5: 195–208. Loeffler DA, Connor JR, Juneau PI et al. (1995). Transferrin and iron in normal, Alzheimer’s disease, and Parkinson’s disease brain regions. J Neurochem 65: 710–716. Litvan I, Bhatia KP, Burn DJ et al. (2003). SIC Task Force appraisal of clinical diagnostic criteria for parkinsonian disorders. Mov Disord 18: 467–486. Mann VM, Cooper JM, Daniel SE et al. (1994). Complex I, iron, and ferritin in Parkinson’s disease substantia nigra. Ann Neurol 36: 876–881. McGeer PL, McGeer EG (2004). Inflammation and the degenerative diseases of aging. Ann N Y Acad Sci 1035: 104–116. McGeer PL, Itagaki S, Akiyama H et al. (1988). Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 24: 574–576. Mondini F, Filippi P, Magliola U et al. (2002). Magnetic resonance relaxometry in Parkinson’s disease. Neurol Sci 23: S87–S88. Moos T (2000). Absence of ferritin protein in substantia nigra pars compacta neuron. A reappraisal to the role of iron in Parkinson disease pathogenesis. Mov Disord 15 (Suppl 3): 319A. Riederer P, Sofic E, Rausch W-D et al. (1989). Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52: 515–520. Rutledge JN, Hilal SK, Silver AJ et al. (1987). Study of movement disorders and brain iron by MR. AJR Am J Roentgenol 149: 365–379. Ryvlin P, Broussolle E, Piollet H et al. (1995). Magnetic resonance imaging evidence of decreased putamenal iron content in idiopathic Parkinson’s disease. Arch Neurol 52: 583–588. Schenck JF, Mueller OM, Souza SP et al. (1990). Magnetic resonance imaging of brain using a 4 Tesla whole-body scanner. In: RB Frankel and RP Blakemore, (Eds.), Iron Biominerals. Plenum Press, New York, pp. 373–383. Sipe JC, Lee P, Beutler E (2002). Brain iron metabolism and neurodegenerative disorders. Dev Neurosci 24: 188–196.

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Smith MA, Harris PLR, Sayre LM et al. (1997). Iron accumulation in Alzheimer disease is a source of redox generated free radicals. Proc Natl Acad Sci USA 94: 9866–9868. Sofic E, Riederer P, Heinsen H et al. (1988). Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74: 199–205. Sofic E, Paulus W, Jellinger K et al. (1991). Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 56: 978–982. Stern MB, Braffman BH, Skolnick BE et al. (1989). Magnetic resonance imaging in Parkinson’s disease and parkinsonian syndromes. Neurology 39: 1524–1526. Thompson K, Shoham S, Connor JR (2001). Iron and neurodegenerative disorders. Brain Res Bull 55: 155–164. Uitti RJ, Rajput AH, Rozdilsky B et al. (1989). Regional metal concentrations in Parkinson’s disease, other chronic neurological disease, and control brains. Can J Neurol Sci 16: 310–314. Vymazal J, Righini A, Brooks RA et al. (1999). T1 and T2 in the brain of healthy subjects, patients with Parkinson’s disease, and patients with multiple system atrophy: relation to iron content. Radiology 211: 489–495. Ye FQ, Allen PS, Martin WRW (1996). Basal ganglia iron content in Parkinson’s disease measured with magnetic resonance. Mov Disord 11: 243–249. Youdim MBH, Ben-Shachar D, Riederer P (1989). Is Parkinson’s disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration? Acta Neurol Scand 126: 47–54. Zecca L, Swartz HM (1993). Total and paramagnetic metals in human substantia nigra and its neuromelanin. J Neural Transm Park Dis Dement Sect 5: 203–213. Zecca L, Gallorini M, Schuenemann V et al. (2001a). Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes. J Neurochem 76: 1766–1773. Zecca L, Tampellini D, Gerlach M et al. (2001b). Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour. J Clin Pathol: Mol Pathol 54: 414–418. Zecca L, Stroppolo A, Gatti A et al. (2004). The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci USA 101: 9843–9848.

Further Reading Ben-Shachar D, Youdim MBH (1992). Brain iron and nigrostriatal dopamine neurons in Parkinson’s disease. In: RB Lauffer (Ed.), Iron and Human Disease. CRC Press Inc. Boca Raton, pp. 349–363. Castellani RJ, Siedlak SL, Perry G et al. (2002). Sequestration of iron by Lewy bodies in Parkinson’s disease. Acta Neuropathol (Berl) 100: 111–114. Griffiths PD, Dobson BR, Jones GR et al. (1999). Iron in the basal ganglia in Parkinson’s disease. An in vitro study using extended X-ray absorption fine structure and cryoelectron microscopy. Brain 122: 667–673. Levi S, Santambrogio P, Cozzi A et al. (1994). The role of Lchain in ferritin iron incorporation. J Mol Biol 238: 649–654.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 24

Oxidative stress and Parkinson’s disease PETER JENNER* Neurodegenerative Disease Research Centre, School of Health and Biomedical Sciences, King’s College, London, UK

24.1. Introduction The formation of reactive oxygen and nitrogen species is a normal physiological event essential for the functioning of the nervous system in healthy individuals (Halliwell and Gutteridge, 1999). In contrast, the excess formation of such species induces oxidative or nitrative stress leading to cellular damage and contributes significantly to the pathogenesis of neurodegenerative diseases, such as Parkinson’s disease. The fact that oxidative and nitrative stress occur in Parkinson’s disease is not in question. As will be detailed below, there is a wealth of evidence to support their involvement in the mechanisms associated with nigral dopaminergic cell degeneration (Jenner, 1991, 1994, 1996, 1998, 2003; Jenner et al., 1992; Jenner and Olanow, 1996, 1998). Why oxidative stress occurs and how it contributes to the overall pathological picture in Parkinson’s disease, in contrast, remains unanswered. The relationship to a range of other potentially pathogenic processes also occurring in the brain in Parkinson’s disease is a keen area of debate and one which is also addressed in a number of other chapters in this volume. The intention of this chapter is to examine the role that oxidative stress contributes to the neurodegenerative process in Parkinson’s disease but more importantly how it forms part of a broader sprectrum of disease-related events that may have commonality with other degenerative disorders. The concept of oxidative stress in Parkinson’s disease arose from the metabolism of dopamine in basal ganglia by chemical and enzymatic mechanisms (Cohen, 1987; Spina and Cohen, 1988, 1989; Cohen and Spina, 1989). Chemically, dopamine is degraded to produce reactive semiquinone derivatives on the

pathway to polymerization and melanin formation (Graham, 1978, 1979; Graham et al., 1978; Sulzer and Zecca, 2000). Indeed, the pigmentation of dopaminergic neurons in the zona compacta of substantia nigra by neuromelanin and their degeneration in Parkinson’s disease was a pivotal component of the hypothesis based on dopamine degradation. Enzymatically, dopamine is metabolized by monoamine oxidase to produce hydrogen peroxide which can be converted by iron-mediated Fenton reactions to form the highly reactive hydroxyl radical (Olanow, 1990, 1992). Since the substantia nigra is enriched in iron compared to other brain regions, this process was used to propagate the concept of dopamine’s involvement in oxidative stress (Enochs et al., 1994). From this beginning, extensive investigations took place into the occurrence of oxidative stress in substantia nigra in Parkinson’s disease. The ideas that prevailed were fueled by findings that toxins such as 6-hydroxydopamine, generating free radicals either directly or indirectly, could destroy dopaminergic neurons both in vitro and in vivo (Heikkila and Cohen, 1972; Cohen and Heikkila, 1974; Ferger et al., 2001). Both levodopa and dopamine were shown to exert toxic actions against a variety of cell types in culture (Michel and Hefti, 1990; Mena et al., 1992). However, although the occurrence of oxidative stress in substantia nigra in Parkinson’s disease was never in doubt, the role played by dopamine became highly questionable (see Ahlskog (2005) for recent review). Specifically, not all dopaminergic cells in the substantia nigra die in Parkinson’s disease, and dopaminergic neurons in other areas of the brain are not affected by the disease process (Fearnley and Lees, 1991). There is an inverse relationship between the extent of melanization of

*Correspondence to: Professor Peter Jenner, NDRC, School of Health and Biomedical Sciences, King’s College, London SE1 1UL, UK. E-mail: [email protected], Tel: þ44-20-7848-6011, Fax: þ44-20-7848-6034.

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catecholamine-containing cells and cell death in Parkinson’s disease such that less melanized cells are more vulnerable to the disease process (Hirsch et al., 1988, 1989; Gibb et al., 1990; Kastner et al., 1992). Pathological change also occurs in non-dopamine, non-catecholamine-containing areas of the nervous system (Jellinger, 1990) and may not start in the substantia nigra (Braak et al., 2004). Even the toxicity of dopamine to cells in culture may be artefactual and related to its conversion to hydrogen peroxide in the culture medium due to the presence of iron and non-physiological levels of antioxidants (Clement et al., 2002). Early evidence had also suggested that dopamine turnover in nigrostriatal neurons was enhanced as an early compensatory mechanism in Parkinson’s disease (see Agid et al. (1986) for review). Although the dopamine content of the striatum is far higher than that of the substantia nigra, if this does occur, it explains how increased amounts of hydrogen peroxide might be generated in substantia nigra. However, the increase in dopamine turnover appears to occur later in the course of the illness than previously thought and early compensation may be non-dopaminergic in origin (Bezard et al., 2003). In addition, supportive experimental studies showing that haloperidol-induced increases in striatal dopamine turnover depleted antioxidant defenses in mice (Cohen and Spina, 1989) were not reproduced (Cohen, personal communication). Indeed, in Parkinson’s disease it would be necessary to explain how increased dopamine turnover produces oxidative stress in an area of the brain that is high in antioxidant defenses. A final nail in the coffin of dopamine-mediated oxidative stress in Parkinson’s disease comes from the consensus that the administration of levodopa to normal individuals or patients with Parkinson’s disease does not initiate or hasten nigral cell degeneration (see Olanow et al. (2004) for review). So, oxidative stress occurring in Parkinson’s disease must have major contributions from sources other than dopamine degradation. Neurons in the substantia nigra and the other pigmented and non-pigmented nuclei of the brain that degenerate in Parkinson’s disease may be exquisitely sensitive to oxidative stress. Alternatively, there may be alterations in free radical-generating pathways that render them prone to oxidative damage and cellular destruction. Consequently, it is necessary to examine briefly the evidence that suggests oxidative stress occurs in Parkinson’s disease, how this is generated and how it forms part of the cell death process.

24.2. A brief history of oxidative stress The study of postmortem tissue from patients dying with Parkinson’s disease has been primarily responsible for generating the evidence that oxidative stress

occurs (see the following reviews for relevant bibliography: Jenner (1991, 1994, 1996, 1998, 2003); Jenner et al. (1992); Jenner and Olanow (1996, 1998)). Studies have focused on the substantia nigra and little has been done in other brain areas affected by pathological change in Parkinson’s disease (see later). Useful comparisons have been made with biochemical changes occurring in other neurodegenerative disorders affecting the substantia nigra, notably parkinson plus syndromes, such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) (Dexter et al., 1991; Sian et al., 1994a). From the outset, it should be borne in mind that data from such studies are subject to all the caveats associated with the use of postmortem tissues and the changes that might occur during brain removal and storage. Invariably, the brain material comes from individuals treated with a range of antiparkinsonian medications up to the time of death and they potentially might also affect subsequent biochemical analysis. The evidence for the occurrence of oxidative stress in the substantia nigra in Parkinson’s disease has been extensively reviewed previously. It is not the object of this chapter to revisit the topic but rather to draw on the key information required to establish the manner in which oxidative stress may contribute to the pathogenesis of Parkinson’s disease (Jenner and Olanow, 1998; Jenner, 2003). The potential for iron-mediated free radical formation initiated a range of assessments of the iron content of substantia nigra in Parkinson’s disease (Dexter et al., 1987, 1989b; Sofic et al., 1988; Riederer et al., 1989; Good et al., 1992; Zecca et al., 2004). Overall there is agreement that iron levels are increased in the zona compacta of substantia nigra and this area has been reviewed extensively in Chapter 23 in this volume. However, there does not seem to be agreement about the state of ionization of iron, whether it is present in a free or reactive form or whether it is inactivated by binding to proteins such as ferritin (Sofic et al., 1988; Riederer et al., 1989; Dexter et al., 1990; Mann et al., 1994; Gu et al., 1998b; Faucheux et al., 2002, 2003). The question of the origin of excess iron remains unresolved and whether it has a glial or neuronal origin (see later). There is also some evidence for alterations in proteins associated with the transport of iron, and their receptors in brain and in the periphery, but again this is an area that lacks consensus (Faucheux et al., 1993, 1995, 1997, 2002; Leveugle et al., 1996; Logroscino et al., 1997; Qian and Wang, 1998; Grau et al., 2001). It is clear, however, that changes in iron levels in the substantia nigra are not specific to Parkinson’s disease since they occur in other neurodegenerative diseases affecting this brain region, such as MSA or

OXIDATIVE STRESS AND PARKINSON’S DISEASE PSP, and also in neurodegenerative diseases affecting other areas of the brain, such as Huntington’s chorea and Alzheimer’s disease (Dexter et al., 1991; Zecca et al., 2004). In Parkinson’s disease, changes in iron levels do not appear to be an early component of the pathogenic process since they are not measurable in substantia nigra in incidental Lewy body disease, which may represent a preclinical stage of Parkinson’s disease (Jenner, 1993). Even so, they may contribute significantly to the progression of Parkinson’s disease if iron is present in a reactive form. An oxidative stress hypothesis of Parkinson’s disease requires an explanation as to why antioxidant cellular defenses do not prevent cell death. One factor could be loss of reduced glutathione (GSH) in the substantia nigra but the reason for this is not clear (Riederer et al., 1989; Sian et al., 1994a). There is no evidence for alterations in the redox state of glutathione since no corresponding increase in the level of the oxidized glutathione (GSSG) was found. The oxidative-reductive cycle of GSH invokes a number of enzyme activities and potentially one of these, namely glutathione reductase, may be impaired in Parkinson’s disease as a result of nitrative stress (Barker et al., 1996). GSH deficiency does not appear to be related to reduced activity of the rate-limiting synthetic enzyme, g-glutamyl-cysteine synthetase, although changes do occur in g-glutamyltranspeptidase, an enzyme important in the conservation of the precursor peptides of GSH (Sian et al., 1994b). The change in GSH levels was thought to be specific to substantia nigra and to Parkinson’s disease but has also been shown to occur in the substantia nigra in MSA and PSP (Fitzmaurice et al., 2003). However, alterations in GSH may represent one of the earliest biochemical changes so far recognized in Parkinson’s disease. This is because it occurs to the same extent in incidental Lewy body disease, where dopaminergic cell loss is small, as is found in advanced Parkinson’s disease (Jenner, 1993). Changes in other major antioxidant systems in substantia nigra in Parkinson’s disease have not been consistently reported. Alterations in the level of catalase and glutathione peroxidase were shown to occur in early studies (Ambani et al., 1975; Kish et al., 1985). Subsequent investigations failed to confirm the decrease in glutathione peroxidase and confirmation of the change in catalase does not appear to have been undertaken (Marttila et al., 1988). Alterations in superoxide dismutase activity are also confounded by conflicting reports. An initial study suggested that Cu, Zn-dependent superoxide dismutase, the cytosolic form of the enzyme, was increased (Marttila et al., 1988). In subsequent studies, this could not be shown

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but in contrast an increase was found in the mitochondrial Mn-dependent form of superoxide dismutase, largely localized to mitochondrial membranes (Saggu et al., 1989; Yoritaka et al., 1997). The change in Mn-dependent superoxide dismutase would be consistent with the alterations in mitochondrial function known to occur in Parkinson’s disease (see Ch. 22 and subsequent discussion). Levels of vitamin E and vitamin C are reported to be unaltered in Parkinson’s disease, although cycling between reduced and oxidized forms has not been measured (Riederer et al., 1989; Dexter et al., 1992). Alterations in mitrochondrial electron chain transport may also contribute to the oxidative stress that occurs in Parkinson’s disease (Mizuno et al., 1989; Schapira et al., 1989, 1990). As reported in Chapter 22 in this volume, there is inhibition of complex I of the respiratory chain which in turn may lead to excessive formation of superoxide radicals. A decrease also occurs in another key Krebs cycle enzyme, a-ketoglutarate dehydrogenase (Mizuno et al., 1994; Gibson et al., 2000, 2003), although this is often overlooked. However, this too may lead to an increase in free radical production either directly or by enhancing the effects of complex I inhibition (Tretter and dam-Vizi, 2004; dam-Vizi, 2005). The importance of the alterations in complex I activity is shown by the construction of cybrids using platelet mitochondrial DNA from patients with Parkinson’s disease (Swerdlow et al., 1996; Gu et al., 1998a; Trimmer et al., 2004). These cells divide and continue to exhibit complex I deficiency, suggesting a genetic origin, and this is associated with an increase in markers of oxidative stress. Another major thread to the involvement of oxidative stress as a cause of dopaminergic cell death in Parkinson’s disease originates from the actions of selective toxins. The best-known example is that of 6-hydroxydopamine, which through the formation of reactive oxygen species can destroy catecholaminecontaining neurons (Heikkila and Cohen, 1972; Cohen and Heikkila, 1974; Graham et al., 1978; Ferger et al., 2001). More recently, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium ion (MPPþ), rotenone and paraquat have all been associated with dopaminergic cell death and in each case there is some evidence to support a mechanism based at least partially on free radical formation (Heikkila et al., 1984; Di Monte et al., 1986; Cleeter et al., 1992; Betarbet et al., 2000; McCormack et al., 2002, 2005; Testa et al., 2005). Rotenone and MPPþ both impair complex I of the mitochondrial respiratory chain, as occurs in Parkinson’s disease, so increasing the formation of superoxide (Ramsay et al., 1987;

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Panov et al., 2005). MPPþ may also disrupt the vesicular storage of dopamine in presynaptic nerve terminals, leading to its enhanced breakdown and to free radical formation (Lotharius and O’Malley, 2000; Nakamura et al., 2000). Paraquat undergoes redox cycling, as a result of which free radical formation is also increased (Bonneh-Barkay et al., 2005). The action of these toxins in experimental models of Parkinson’s disease both in vitro and in vivo has served to strengthen the view that oxidative stress is a key mechanism underlying neurodegeneration. However, the systemic administration of rotenone not only results in dopaminergic cell death, but it also induces destruction in a range of other brain areas, resulting in pathology that more closely resembles MSA than Parkinson’s disease (Hoglinger et al., 2003). This is important since it demonstrates that it is not only dopaminergic neurons in the substantia nigra that are vulnerable to oxidative stress. The data discussed so far only indirectly show that oxidative stress occurs in substantia nigra in Parkinson’s disease but free radical-mediated toxicity to biomolecules can be detected in tissues from patients dying with the illness.

24.3. Clues from oxidative damage Oxidative damage occurs in the substantia nigra in Parkinson’s disease, as judged by alterations in markers of lipid, protein and DNA oxidation in postmortem tissues. Increased lipid peroxidation was initially demonstrated through measurement of increased levels of polyunsaturated fatty acids (Dexter et al., 1986, 1989a). However, because of the increased iron content of the tissue in Parkinson’s disease, it is feasible that this occurred during the assay procedure. Subsequently however, an increase in lipid hydroperoxides was also demonstrated, confirming that free radical attack on lipid membranes is enhanced in Parkinson’s disease (Dexter et al., 1994). Subsequently, an immunohistochemical study demonstrated increased reactivity to 4-hydroxynonenal (HNE) in dopaminergic cells in substantia nigra (Yoritaka et al., 1996). This latter change, which is often ignored, is highly important since HNE is a highly reactive product of lipid peroxidation that in turn may be able to interact with a variety of protein molecules. Indeed, HNE adducts are present in Lewy bodies in Parkinson’s disease (Castellani et al., 2002). Recently, we have shown in cell culture that HNE can cause cell death associated with increased oxidative or nitrative stress, impaired mitochondrial function and decreased proteasomal activity (Hyun et al., 2002b). The latter may be due to a direct toxic action

since proteasome-HNE adducts were detected. Recently, the levels of isoflurans, another marker of lipid peroxidation, were also shown to be elevated in substantia nigra in Parkinson’s disease (Fessel et al., 2003). Increased protein oxidation occurs in substantia nigra in Parkinson’s disease, as demonstrated by enhanced levels of reactive protein carbonyls (Alam et al., 1997a). However, higher amounts were also found in all other areas of the brain examined both within and outside the basal ganglia. The interpretation of these data is difficult but there are two potential explanations. The tissues studied were from patients receiving levodopa up to the time of death and so the effects observed may be a reflection of drug treatment rather than pathogenesis. However, since no increase in protein carbonyls was found in the brain of primates treated with very high doses of levodopa over a 3-month period, this appears unlikely (Lyras et al., 2002). An alternative explanation is that the pathogenic process involved in Parkinson’s disease is more extensive than currently thought and extends to many different brain areas, but only the substantia nigra and some other brain regions are sensitive to the alterations that occur. This might involve differences in the ability to remove oxidized or other damaged proteins by proteasomal activity. Alterations in DNA oxidation are suggested to occur in Parkinson’s disease as measured by increased levels of 8-hydroxyguanine or 8-hydroxy-deoxyguanosine (Sanchez-Ramos et al., 1994; Alam et al., 1997b; Zhang et al., 1999). Alterations in DNA repair enzymes and other DNA-related enzymes have also been reported (Shimura-Miura et al., 1999; Fukae et al., 2005). A detailed study of alterations in a range of DNA bases and products of oxidation in Parkinson’s disease showed only guanine was affected (Alam et al., 1997b). However, whereas the levels of 8-hydroxyguanine were increased, these were balanced by a decrease in the levels of Fapy-guanine, another product of oxidative damage to guanine. 8-Hydroxyguanine and Fapy-guanine are alternative products arising from the initial oxidation product of hydroxyl radical attack on guanine bases. Since the subsequent formation of 8-hydroxyguanine or Fapy-guanine is determined by pH, these findings may reflect an alteration in the redox potential of nigral cells rather than an increase in overall DNA damage. Altered redox potential may itself enhance free radical production through a variety of mechanisms (see later). It should also be borne in mind that levodopa may contribute to oxidative damage to DNA, particularly in the presence of divalent metal ions (Spencer et al., 1994).

OXIDATIVE STRESS AND PARKINSON’S DISEASE

24.4. When and where does oxidative stress occur? Oxidative stress induces the acute death of nigral dopaminergic cells in model systems but its relationship to the time course of the pathogenesis of Parkinson’s disease remains unclear. There is relatively little evidence to analyze when examining cell death mechanisms in relation to the staging of the illness. An obvious reason is that little brain tissue becomes available for biochemical examination in the earlier stages of the disease. Instead, reliance has been put on the use of tissue from individuals dying with incidental Lewy body disease (Jenner et al., 1992). In these tissues at least, some markers of oxidative stress, such as the reduction in the levels of GSH, are already changed. In contrast, the levels of iron and mitochondrial function appear to be normal, suggesting that oxidative stressrelated changes cannot be viewed as a single ongoing process but rather part of a sequence of events that occurs during pathogensis. The source of the increased levels of reactive oxygen species in Parkinson’s disease is uncertain (see later) and so it is difficult to know which components of the oxidative stress cycle should be investigated in relation to disease progression. It is usually presumed that oxidative stress affecting dopaminergic neurons in the substantia nigra originates from within those nerve cells. Part of the reason relates to the original hypothesis that oxidative stress is due to alterations in the metabolism of dopamine. However, most parameters associated with oxidative stress alter in a downward manner by approximately 30–40%, including the loss of GSH and the impairment of mitochondrial function as well as decreased proteasomal activity (Schapira et al., 1989; Sian et al., 1994a; McNaught and Jenner, 2001). However, dopaminergic cells account for only 1–2% of all cells present within the substantia nigra. So, biochemical analysis of homogenates of this tissue must include changes occurring in cell types other than neurons to account for alterations of the extent reported. The most likely explanation is the involvement of glial cells. Glial cell proliferation in the form of a reactive microlgiosis, and to a lesser extent astrocytosis, is a key pathological feature of Parkinson’s disease (McGeer et al., 1988; Banati et al., 1998). Postmortem tissues have indicated that alterations in iron and glutathione content can be detected in glial cells in substantia nigra in Parkinson’s disease as well as in dopaminergic neurons (Morris and Edwardson, 1994; Pearce et al., 1997). So, the role of the glial cell may be critical to the pathogenic process in Parkinson’s disease and indeed it may be a source of both oxidative and nitrative stress, as discussed later.

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As hinted above, the source of reactive oxygen species causing oxidative stress in Parkinson’s disease needs to be determined. In contrast to measures of alterations in oxidative stress and oxidative damage, there is much less information available as to the origin of free radicals. The concept of altered dopamine metabolism may apply to events within dopaminergic neurons of the substantia nigra but it is unlikely to be relevant to other brain areas pathologically affected in Parkinson’s disease (Ahlskog, 2005). Alterations in both complex I and a-ketoglutarate dehydrogenase may account for the formation of superoxide as the mitochondrial electron transport chain is a major source of free radical production in Parkinson’s disease (see Schapira (1994) for review of the role of mitochondria in Parkinson’s disease). However, changes may occur in other enzymes whose actions could lead to oxygen radical formation in both neurons and glial cells in Parkinson’s disease, including NADPH oxidase and cyclooxygenase 2 (Teismann et al., 2003; Tieu et al., 2003). But at this time, it is impossible to pinpoint the source of the reactive oxygen species or indeed their nature. Variously, hydrogen peroxide, superoxide and hydroxyl radical formation are used to explain the concept of oxidative stress in Parkinson’s disease. However, inevitably the data which underlie these concepts are based on the use of experimental systems and it is not possible to determine which species exists in the human parkinsonian brain except by indirect measure at postmortem.

24.5. Oxidative stress as a primary or secondary event Although oxidative stress clearly occurs in the substantia nigra in Parkinson’s disease, so do a variety of other events that may contribute to pathogenesis, including mitochondrial dysfunction and abnormal protein handling (Schapira et al., 1989; McNaught et al., 2002a, 2003). Excitotoxicity has also been proposed as contributing to neuronal cell death on the basis of experimental data (Blandini et al., 1996; Beal, 1998; Rodriguez et al., 1998) but there is no direct evidence in Parkinson’s disease to show that this occurs. All of these are reviewed in other chapters in this volume and they put into context the fact that multiple biochemical events are occurring in a cascade or cycle of biochemical change leading to cell death. This beggars the question as to whether these events are individually primary or secondary components of that process. This has proved almost impossible to unravel because of the complexity of the interactions between the events that take place. For example, impairment of mitochondrial

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function can cause the formation of reactive oxygen species and the occurrence of excitotoxicity (Cleeter et al., 1992). Excitotoxicity can impair mitochondrial function and cause the formation of reactive oxygen species (Almeida et al., 1998). Inhibition of proteasomal function leads to oxidative and nitrative stress and impairment of mitochondrial function (Lee et al., 2001b). Multiple examples exist of how initiating this sequence of events at one point inevitably leads to the involvement of other processes proposed to be key to dopaminergic cell death (Jenner, 2003). Indeed, it may turn out that none of the processes so far described is the primary cause of cell death in Parkinson’s disease; rather they form parts of a sequence of events that can be triggered by a variety of insults. This is reflected in the fact that similar cascades of biochemical change occur in a range of neurodegenerative illnesses affecting various parts of the nervous system, suggesting that they merely form part of the cells’ response to a primary toxic insult. Crucial to this understanding is determining the relationship of oxidative stress to neuronal cell death and glial cell activation and the way in which this contributes to the initiation as opposed to the progression of Parkinson’s disease.

24.6. Oxidative or nitrative stress or both? One key event occurring in Parkinson’s disease is the potential for interaction between oxidative and nitrative stress (see Jenner (2003) for review). As reviewed elsewhere in this volume, a key component of glial cell activation is the upregulation of inducible nitric oxide synthase (iNOS) and the subsequent production of nitric oxide. Nitric oxide is weakly neurotoxic but its reaction with superoxide to form peroxynitrite gives rise to the formation of a powerful oxidizing species (Beckman and Koppenol, 1996). Peroxynitrite can in turn be converted to the highly toxic hydroxyl radical. In fact, the evidence for nitrative stress in Parkinson’s disease is stronger than for the occurrence of oxidative stress, with clear evidence for the source of nitric oxide, for the formation of peroxynitrite and for peroxynitrite attack on proteins and other biomolecules. The use of 3-nitrotyrosine immunoreactivity to detect attack by peroxynitrite has shown nitration to occur in nigral tissue in Parkinson’s disease as well as in a variety of experimental models of the disorder (Ferrante et al., 1999; Pennathur et al., 1999; Iravani et al., 2005). In particular, the presence of 3-nitrotyrosine immunoreactivity in Lewy bodies suggests a pathogenic role and nitrated forms of both a-synuclein and parkin have been detected (Good et al., 1998; Giasson et al., 2000; Chung et al., 2004). So maybe

oxidative stress should not be considered in isolation. Indeed, the combination of oxidative and nitrative stress originating from both neurons and glial cells may be a more powerful mechanism for explaining the pathogenesis of Parkinson’s disease compared to either process alone (Jenner, 2003).

24.7. Oxidative stress and individual patients with Parkinson’s disease An important question is the relevance of oxidative stress to pathogenic events occurring in individual patients with Parkinson’s disease. There is no doubt that studies of postmortem tissues overall show alterations in markers of oxidative stress as well as altered mitochondrial function and proteasomal activity (Schapira, 1994; Jenner and Olanow, 1998; McNaught et al., 2001). However, it is clear that, when interpreting alterations in markers of oxidative stress and indeed other biochemical processes that occur in Parkinson’s disease, nothing is absolute. In reality, many patients with Parkinson’s disease have levels of markers of oxidative stress that fall within the normal range. Indeed, studies of mitochondrial function, the only area where large numbers of postmortem samples have been studied, show that only 30% of individuals with Parkinson’s disease have alterations in complex I activity that lie outside the normal range (Mann et al., 1992). There is also no correlation in individual patients between having altered mitochondrial function and increased oxidative stress (Mann et al., 1994). This means that, despite the common acceptance that processes such as oxidative stress form part of the pathogenic cascade process, in individual patients this may not be the case. Perhaps one major error in trying to understand the pathogenesis of Parkinson’s disease is the presumption that the events that occur in one patient or in one group of patients are relevant to the population as a whole. If this is not the case, it might explain why the majority of the mechanistically based agents developed for neuroprotection in Parkinson’s disease have failed in clinical trials (Bezard, 2003; Diguet et al., 2004; Schapira and Olanow, 2004; Olanow and Jankovic, 2005). It also implies that there is a need to find a readily measurable biomarker of oxidative stress and of the other components of pathogenesis in Parkinson’s disease (Michell et al., 2004). Only then will assessment of events occurring in an individual patient be possible. This may allow the subdivision of the patient population into those undergoing cell death for one cause compared to those where pathogenic events are occurring for other reasons.

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24.8. Moving outside the substantia nigra Whereas events occurring in the substantia nigra have been studied extensively in relation to oxidative stress, the same is not true of the other brain areas affected by pathology in Parkinson’s disease. Even within the substantia nigra, oxidative changes have not been assessed in relation to surviving dopaminergic neurons in the zona compacta. There has been little or no study of changes occurring in the adjacent ventral tegmental area that contains the cell bodies, giving rise to the mesolimbic and mesocortical dopaminergic systems which appear less damaged than nigral cells (Agid et al., 1986). For non-dopaminergic areas of the brain that die in Parkinson’s disease, there is virtually no information on alterations in oxidative stress that occur in the locus ceruleus, the raphe nuclei, the pedunculopontine nucleus, the dorsal motor nucleus of the vagus or substantia innominata (but see Riederer et al., 1989, 1992 for some investigation). These encompass a variety of pigmented and non-pigmented cells that are catecholamine-containing or non-catecholaminecontaining but that are linked by pathological change with the presence of Lewy bodies (Jellinger, 1987). There has been some study of other pathological states where Lewy bodies are found, notably in cortical brain regions and elsewhere, particularly incidental Lewy body disease and dementia of the Lewy body type. But these have not shown alterations in markers of oxidative stress or mitochondrial function in cortical regions that mimic those in the substantia nigra in Parkinson’s disease (Gu et al., 1998b; Jenner et al., 1992). This would imply that Lewy body formation may be initiated for a variety of reasons and that their presence cannot be used to presume how pathogenesis occurs. Indeed, it may be that the composition of Lewy bodies differs in different brain regions in Parkinson’s disease (Jellinger, 1987), although involving a disruption of proteolysis (McNaught et al., 2002b). So current views are confined by a lack of investigation and it is merely presumed that oxidative stress and other pathogenic events occur in these areas to the same extent as they do in the substantia nigra. Indeed, this is unlikely to be the case as the substantia nigra appears unique with metabolic activity and alterations in protein oxidation that are higher than found in surrounding brain regions (Floor and Wetzel, 1998). Indeed, another view is that this group of cells is exquisitely prone to oxidative stress and there is nothing to suggest that this is true of other brain nuclei that degenerate in Parkinson’s disease. This is an important concept in relation to the course of pathogenesis in Parkinson’s disease. A recent controversial suggestion is that the degenerative

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process does not start in the substantia nigra but rather in areas of the brainstem (Braak et al., 2004). It subsequently sweeps forward to involve nigral dopaminergic cells and to induce motor symptoms, at which point a diagnosis of Parkinson’s disease is made. This issue is crucial since it affects all current concepts of pathogenesis and how neuroprotection might be achieved in Parkinson’s disease. Unfortunately, current concepts tend to be restricted to models of dopaminergic cell death and this may be incorrect. The other presumption is that Parkinson’s disease is restricted to specific nuclei of the brain, but this is now contested by evidence suggesting a systemic disease process. Even in the brain, the finding of increased protein oxidation in all regions suggests a widespread pathogenic process (Alam et al., 1997a). In peripheral tissues, mitochondrial dysfunction is found in platelets and muscle, although this is disputed, as discussed elsewhere in this volume (Parker et al., 1989; Bindoff et al., 1991; Mann et al., 1992; Yoshino et al., 1992; Schapira, 1994). Aterations in iron metabolism, markers of DNA oxidation and DNA-related enzymes have been detected in the periphery in Parkinson’s disease (Logroscino et al., 1997; Kikuchi et al., 2002; Migliore et al., 2002). Similarly, alterations in the level of oxidation products of DNA are found in urine (Sato et al., 2005). There is also evidence for peripheral alterations in the redox status of coenzyme Q10 (Gotz et al., 2000; Sohmiya et al., 2004). The origin of these changes is not clear but strongly suggests that systemic oxidative stress occurs in Parkinson’s disease. This may relate to other evidence which suggests that Parkinson’s disease involves a peripheral inflammatory process that subsequently affects brain through a weakening or opening of the blood–brain barrier (Gotz et al., 2000; Barcia et al., 2005; Kortekaas et al., 2005). Perhaps this should not be a surprise as Lewy bodies can be detected in the myenteric plexus, supporting the idea that whatever process leads to their formation occurs not only in the brain but also in peripheral tissues. This suggestion again serves to separate pathogenic events in Parkinson’s disease from altered dopamine oxidation as the source of reactive oxygen species formation and pathogenesis.

24.9. Familial versus sporadic Parkinson’s disease The concept of oxidative stress in Parkinson’s disease has been almost entirely related to the sporadic form of the illness. However, the recent discovery of a range of gene defects and mutant products in familial Parkinson’s disease makes it necessary to extend the

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understanding of pathogenesis to encompass inherited disease (Cookson, 2005; Gandhi and Wood, 2005; Moore et al., 2005a). Indeed, links can be made between mutant gene products and oxidative stress and other components of the pathogenic cascade. For example, a-synyclein is intimately associated with the vesicular storage of dopamine and so alterations in its function could change the formation of reactive oxygen species (Maguire-Zeiss et al., 2005). In addition, oxidation or nitration of a-synuclein enhances its aggregation and the formation of inclusion bodies (Paxinou et al., 2001). In our own studies, overexpression of a-synuclein in cell lines leads to an increase in oxidative stress and loss of GSH and to changes in mitochondrial function (Lee et al., 2001a). Nitrative stress also occurred leading to peroxynitrite formation, as assessed by increased 3-nitrotyrosine immunoreactivity. Similarly, wild-type parkin, but not mutant, protects against oxidative insult, so reducing markers of oxidative and nitrative stress and preventing alterations in mitochondrial function (Hyun et al., 2002a). Parkin is an E3 ubiquitin-protein ligase and is able to alter the degradation of oxidized or damaged proteins (Shimura et al., 2000). There is a loss of function on mutation, resulting in altered proteolysis as well as an increase in oxidative and nitrative stress (Jiang et al., 2004; Palacino et al., 2004; Greene et al., 2005; Sriram et al., 2005). Nitrative stress also removes parkin’s E3 ligase activity and its protective effects (Chung et al., 2004; Yao et al., 2004). Another gene mutation affects DJ-1, which appears to be a protective transcriptional coactivator that blocks oxidative stress-induced apoptosis (Bonifati et al., 2003; Xu et al., 2005). DJ-1 is responsive to oxidative stress produced by paraquat or hydrogen peroxide and functions as an antioxidant (Mitsumoto and Nakagawa, 2001; Mitsumoto et al., 2001). The downregulation of DJ-1 by gene deletion or siRNA sensitizes cells to oxidative stress (Xu et al., 2005). DJ-1 may participate in the oxidative stress response by directly buffering cytosolic redox changes. This may be important since alterations in the products of guanine oxidation in Parkinson’s disease appear due to altered cellular redox potential (see earlier). The role of DJ-1 in oxidative stress is related to effects at the mitochondrial level as it is relocated to mitochondria after overexpression in cell lines (Xu et al., 2005; Canet-Aviles et al., 2004, although this is disputed; see Zhang et al., 2005). DJ-1-deficient mice exhibit a hypersensitivity to MPTP and to oxidative stress and there is also an association between DJ-1 and parkin that is promoted by oxidative stress (Kim et al., 2005; Moore et al., 2005b). The recent description of PINK-1 also correlates with an activity at the mitochondrial level since it is a mitochondrial protein

with kinase activity that protects against oxidative stress and mitochondrial dysfunction (Valente et al., 2004). Whether the recently described LRRK2 (dardarin) mutation functions as a mediator or modulator of oxidative stress is unknown but it appears to be a cytoplasmic kinase (Paisan-Ruiz et al., 2004; Zimprich et al., 2004; West et al., 2005; Gloeckner et al., 2006). This is an important issue since LRRK2 mutations appear to be commonly associated with late-onset sporadic Parkinson’s disease (Gilks et al., 2005; Goldwurm et al., 2005; Hernandez et al., 2005).

24.10. Selectivity of oxidative stress to Parkinson’s disease Many papers are written about oxidative stress in Parkinson’s disease as though it is a phenomenon which is restricted to this illness. As already emphasized, it may not be a process that is related to pathogenic change in non-nigral non-dopaminergic brain areas in Parkinson’s disease or to the formation of Lewy bodies as the same changes do not occur in incidental Lewy body disease or dementia of the Lewy body type (see above). Oxidative stress (or rather changes in markers of this process) also occurs in PSP and MSA, where cell death occurs in the substantia nigra but presumably by different pathogenic mechanisms, leading to the formation of inclusions other than Lewy bodies (Giasson et al., 2000; Cantuti-Castelvetri et al., 2002; Gomez-Tortosa et al., 2002; Kikuchi et al., 2002; Fitzmaurice et al., 2003; Fukae et al., 2005; Rampello et al., 2005; Stefanova et al., 2005; Aoyama et al., 2006). In Huntington’s chorea, affecting the striatum and globus pallidus (Mariani et al., 2005; Stoy et al., 2005), in Alzheimer’s disease, affecting cortical regions (Migliore et al., 2005; Wang et al., 2005; Schipper et al., 2006), in motor neurone disease, affecting upper and lower motor neurons (Carri et al., 2003; Ihara et al., 2005) and in a range of other neurodegenerative illness, including mild cognitive impairment (Keller et al., 2005; Wang et al., 2006), prion diseases (Budka, 2003; Unterberger et al., 2005) and Friedreich’s ataxia (Calabrese et al., 2005), oxidative stress has been shown to occur. Vascular degenerative diseases, such as ischemia and stroke, are similarly associated with oxidative damage in the brain (Warner et al., 2004; Margaill et al., 2005; Mariani et al., 2005; Schaller, 2005). So oxidative stress appears to be a generalized response to cellular distress shown both by a range of different neuronal cell types in different parts of the nervous system and in a range of degenerative illnesses. As such, it would appear unlikely that it forms part of the primary pathogenesis of Parkinson’s disease but rather is a component of the cascade of intertwined biochemical

OXIDATIVE STRESS AND PARKINSON’S DISEASE changes that arise as a result of the initiation of cell death occurring for a variety of different reasons.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 25

Neurotrophic factors and Parkinson’s disease DON M. GASH*, YAN CHEN AND GREG GERHARDT Morris K. Udall Parkinson’s Disease Research Center of Excellence, University of Kentucky College of Medicine, Lexington, KY, USA

25.1. Introduction Neurotrophic factors are endogenous proteins that modulate cell-signaling pathways regulating stem cell proliferation, neuronal differentiation, differentiation, growth and regeneration (Barde, 1989; Gotz and Schartl, 1994; Goldman, 1998). They are generally small, soluble proteins with molecular weights between 13 and 24 kDa and often function as homodimers. Here, we review neurotrophic factors for midbrain dopamine neurons, the principal neuronal population affected in the pathogenesis of Parkinson’s disease. Like most signaling molecules, neurotrophic factors can be divided into families of closely related molecules. They are produced by both glial cells and neurons. Trophic factor interactions with receptors can be complex. The prototypic neurotrophic factor, nerve growth factor (NGF), is a target-derived molecule that can bind to two different types of transmembrane cell surface receptors, a tyrosine kinase receptor (TrkA) and a pan neurotrophic receptor p75NTR (Lad et al., 2003a, b). After NGF-TrkA binding, the receptor dimerizes and is activated by transphosphorylation of the catalytic intracellular domain, which initiates a complex intracellular signaling cascade leading to immediate, early and late transcriptional changes in the target cell promoting neuronal survival, neuritogenesis and synaptogenesis (Campenot and MacInnis, 2004). In contrast, NGF binding to p75NTR activates different cell programs, including those leading to downregulation or death (Barrett, 2000; Mamidipudi and Wooten, 2002). Whereas target-derived neurotrophic factors are carried by retrograde axonal transport to neuronal perikarya in other central nervous system sites, some neurotrophic

factors like ciliary neurotrophic factor function in an autocrine or paracrine fashion, affecting nearby neuronal cells (Vergara and Ramirez, 2004). Many neurotrophic factors are both neuroprotective (protect neurons from injury) and neurorestorative (promote structural and functional regeneration). The best-defined protective functions are seen during neural development. During development, excessive numbers of neurons are generated in many brain regions. Developing neurons that fail to make connections with appropriate trophic factor-producing target cells will be deprived of necessary neurotrophic factors and die. Those neurons that establish connections survive and function properly (e.g. NGF; see Campenot and MacInnis, 2004). Neurotrophic factors are also capable of promoting the regrowth of damaged neurons and their processes both in vitro and in animal models (Lad et al., 2003a, b). Clearly, identifying neurotrophic factors with the right combination of protective and restorative actions and developing effective strategies for drug delivery have profound therapeutic implications for Parkinson’s disease.

25.2. Dopaminergic trophic factors 25.2.1. In vitro studies At least 28 trophic factors have been reported to exert trophic effects on dopamine neurons in culture (Table 25.1). Culture systems offer the opportunity for screening large numbers of candidate molecules and tracking trophic proteins during purification procedures. The bioassay used to discover and characterize glial cell line-derived neurotrophic factor (GDNF) illustrates one of the methodologies followed in these

*Correspondence to: Don M. Gash, Department of Anatomy and Neurobiology, University of Kentucky Medical Center, 317 Whitney-Hendrickson Bldg, Lexington, KY 40536–0098, USA. E-mail: [email protected], Tel: þ1-859-2575036, Fax: þ1-859-257-3625.

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Table 25.1 Dopaminergic trophic factors: in vitro studies Family/factor

Actions

Selected references

Neurotrophins BDNF

S, D/G, NP

NT-3 NT-4/5 EGF family EGF

D/G S, D/G, NP

TGF-a BMP family BMP-2 BMP-2, BMP-4 and BMP-6

S, D/G

Hyman et al. (1991); Knusel et al. (1991); Beck et al. (1992); Spina et al. (1992) Hyman et al. (1994); Studer et al. (1995) Hynes et al. (1994); Lingor et al. (2000) Hadjiconstantinou Casper et al. (1991); Ferrari et al. (1991); Park and Mytilineou (1992) Alexi and Hefti (1993)

S, D/G D/G

Espejo et al. (1999); Reiriz et al. (1999) Stull et al. (2001)

S

Jordan et al. (1997)

S, NP

Krieglstein et al. (1995b); Lingor et al. (1999); Strelau et al. (2000b); Krieglstein et al. (2002) Strelau et al., 2000a

BMP-6, BMP-7 and BMP-12 GDF family GDF-5 GDF-15 GDNF family Artemin GDNF

S, D/G, NP, NR

S, NP S S, D/G, NP, NR

Baloh et al. (1998) Lin et al. (1993); Hou et al. (1996); Burke et al. (1998); Eggert et al. (1999) Horger et al. (1998); Akerud et al. (1999) Milbrandt et al. (1998)

Neurturin Persephin TGF-b family TGF-b1

S S

TGF-b2, TGF-b3 IGF family Insulin, IGF-1 and IGF-2 Other trophic factors Activin A CNTF aFGF bFGF

S D/G

Knusel et al. (1990); Liu and Lauder (1992)

S, NP S S S, NP

GGF-2 PDGF-BB VEGF

S, NP S, D/G, NP S, D/G

Krieglstein et al. (1995a) Magal et al. (1993) Engele and Bohn (1991) Ferrari et al. (1989, 1991); Engele and Bohn (1991); Otto and Unsicker (1993); Casper and Blum (1995) Zhang et al. (2004) Othberg et al. (1995); Pietz et al. (1996) Silverman et al. (1999); Pitzer et al. (2003)

S, NP

Krieglstein and Unsicker (1994); Krieglstein et al. (1995a); Poulsen et al. (1994)

The trophic factors reported to affect dopamine neurons in culture are listed here. The trophic effects reported fell into four different categories: S, survival; D/G, differentiation/growth (e.g. neuritogenesis, increased expression of DA markers); NP, neuroprotective; NR, neurorestorative. BDNF, brain-derived neurotrophic factor; NT-3, neurotrophin-3; EGF, epidermal growth factor; TGF, transforming growth factor; BMP, bone morphogenetic protein; GDF, growth/differentiation factor; GDNF, glial cell line-derived neurotrophic factor; IGF, insulin-like growth factor; CNTF, ciliary neurotrophic factor; aFGF, acidic fibroblast growth factor; bFGF, basic fibroblast growth factor; GGF, glial growth factor; PDGF-BB, platelet-derived growth factor, (B polypeptide chain homodimer); VEGF, vascular endothelial growth factor.

studies. Dissected blocks of fetal rat midbrain tissue, containing developing substantia nigra dopamine neurons, are disassociated and maintained in defined media (Lin et al., 1994). Dopamine neurons represent only a small subpopulation of the cultured cells and gradually

atrophy and die under the culture conditions employed over a period of several weeks. Molecules added to the media that prolong the maintenance of dopamine neurons are termed survival factors. Although the endpoint is readily quantifiable, sufficient information

NEUROTROPHIC FACTORS AND PARKINSON’S DISEASE is not obtained to assess fully the specificity and efficacy of the test compound. False positives are generated by compounds that generically increase cell viability or stimulate other cell populations to produce survival factors. 25.2.2. In vivo studies Better indications of specificity and efficacy come from in vivo studies. Sixteen of the 28 trophic factors with in vitro dopaminergic activities have also been demonstrated to exert trophic actions in rodent model systems of Parkinson’s disease (Table 25.2). One strong indication of efficacy with in vivo studies is replication by different laboratories using different animal models and different modes of trophic factor delivery. Rankings based on the number of papers

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published linking each trophic factor to dopaminergic responses (Table 25.2) identify GDNF (358 papers) and brain-derived neurotrophic factor (BDNF: 225 papers) as the two most extensively studied factors for dopamine neurons. Given the propensity for primarily publishing positive data, the number of reports suggests both trophic factors exert strong and reproducible dopaminergic actions. However, farther analysis suggests that BDNF may have only a limited therapeutic role for Parkinson’s disease. Although BDNF promotes behavioral changes and increases electrical activity in dopamine neurons in the rat (Altar et al., 1994; Shen et al., 1994), only a subpopulation of dopamine neurons appear to respond to BDNF (Mufson et al., 1994). In addition, the trophic factor does not promote survival of injured dopamine neurons in the 6-hydroxydopamine lesion model of parkinsonism

Table 25.2 Dopaminergic trophic factors: rodent Parkinson’s disease (PD) models

Family/factor Neurotrophins BDNF NGF NT-3 NT-4/5 EGF family EGF BMP family BMP-7 GDF family GDF-5 GDF-15 GDNF family Artemin GDNF

Papers on dopaminergic effects

Anti-PD effects

Selected references

225 147 27 17

NP, NR NR NP, NR NP, NR

Altar et al. (1994); Frim et al. (1994); Hagg (1998) Garcia et al. (1992) Hagg (1998) Hagg (1998)

42

NR

Hadjiconstantinou et al. (1991); Pezzoli et al. (1991)

4

NP

Harvey et al. (2004)

9 3

S, NP, NR NP

Sullivan et al. (1997, 1998, 1999) Strelau et al. (2000b)

6 358

NP S, NP, NR

Rosenblad et al. (2000) Hoffer et al. (1994); Kearns and Gash (1995); Tomac et al. (1995); Granholm et al. (1997); Cass et al. (2000); Kirik et al. (2000, 2001)

Neurturin 26 Persephin 9 Other trophic factors CNTF 20 aFGF 20 bFGF 103 VEGF 125

NP, NR NR

Horger et al. (1998); Akerud et al. (1999), Milbrandt et al. (1998)

NP, NR NR S, NP, NR NR

Hagg and Varon (1993) Date et al. (1990) Otto and Unsicker (1990); Zeng et al. (1996); Tornqvist et al. (2000) Pitzer et al. (2003)

Trophic factors that have been reported to promote recovery in rodent models of Parkinson’s disease are cross-listed with the total number of papers reporting dopaminergic effects for each factor (National Library Medicine, Medline – Biomedical Journal Literature Search 5/6/06). The trophic actions reported are: S, survival; NP, neuroprotective; NR, neurorestorative. BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; NT-3, neurotrophin-3; EGF, epidermal growth factor; BMP, bone morphogenetic protein; GDF, growth/differentiation factor; GDNF, glial cell line-derived neurotrophic factor; CNTF, ciliary neurotrophic factor; aFGF, acidic fibroblast growth factor; bFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor.

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D. M. GASH ET AL. eration of the injured nigrostriatal dopaminergic neural circuitry (Tables 25.2 and 25.3). The safety and efficacy of GDNF therapy for Parkinson’s disease have been evaluated in four clinical trials (Table 25.4). The results have been mixed: significant indications of efficacy were found in the two phase I trials, whereas the phase II studies failed to achieve their primary endpoints (Table 25.4). Also, although the safety profile of GDNF delivered by direct infusion into the putamen (i.e. intraputamenal) has been excellent, several risk factors have recently emerged that need to be fully evaluated (Slevin et al., 2005b; Sherer et al., 2006). Screening studies found that some patients have developed antibodies to the recombinant human GDNF used in therapy. In a toxicology study using rhesus monkeys, focal cerebellar lesions were

(Klein et al., 1999). This raises concerns over the ability of BDNF to protect adequately the population of dopamine neurons at risk in Parkinson’s disease and slow degenerative processes. In contrast, GDNF has consistently been shown to be both neurorestorative and neuroprotective. Thus, based on the consistent positive results reported by numerous research groups over the past decade, the most potent trophic factor for treating Parkinson’s disease appears to be GDNF. GDNF was the first of a group of four related proteins to be purified, sequenced and cloned (Lin et al., 1993). In adult rodents and nonhuman primates, the central nervous system administration of GDNF has been demonstrated to promote dopamine neuronal survival, to confer protection against dopaminergic neurotoxins and stimulate regen-

Table 25.3 Dopaminergic trophic factors – primate Parkinson’s disease models Family/factor Neurotrophins BDNF GDNF family GDNF

Neurturin

Delivery method

Actions

References

IT infusion

NP

Tsukahara et al. (1995)

ICV, IPu, IN Injections and infusions

NR

IPu, IC, and IN Viral vector ICV Injections Viral vector

S, NP NP

Gash et al. (1996); Zhang et al. (1997); Gerhardt et al. (1999); Grondin et al. (2002); Palfi et al. (2002); Gash et al. (2005) Kordower et al. (2000) Li et al. (2003)

Three trophic factors have been reported to protect and/or restore the nigrostriatal dopaminergic system in non-human primate models of Parkinson’s disease. Various methods of delivery have been used: intrathecal (IT) infusion, injections, infusions and viral vector transfections into the lateral ventricle (intracerebroventricular, ICV), putamen (intraputamenal, IPu), caudate nucleus (intracaudate, IC) and substantia nigra (intranigral, IN).

Table 25.4 Dopaminergic trophic factors – Parkinson’s disease patients Family/factor GDNF family GDNF

Delivery site

Actions

References

ICV – phase 1 and 2 IPu – Bristol phase 1 IPu – Kentucky phase 1 IPu – Phase 2

NE FI FI NE

Nutt et al. (2003) Gill et al. (2003); Patel et al. (2005); Slevin et al. (2005a,b) Lang et al. (2006)

Four clinical trials have been conducted in patients testing the safety and efficacy of GDNF in treating Parkinson’s disease. The first trial examined the effects of monthly bolus injections of GDNF into the lateral ventricle (Nutt et al., 2003). The other three studies used evaluate the effects of continuous intraputamenal infusion of the trophic factor for periods ranging from 6 months to several years. Various methods of delivery have been used: intrathecal (IT) infusion, injections, infusions and viral vector transfections into the lateral ventricle (intracerebroventricular, ICV), putamen (intraputamenal, IPu), caudate nucleus (intracaudate, IC) and substantia nigra (intranigral, IN). NE, not efficacious; FI, significant functional improvements; GDNF, glial cell line-derived neurotrophic factor.

NEUROTROPHIC FACTORS AND PARKINSON’S DISEASE identified in some animals receiving very high intraputamenal doses of GDNF. While these safety issues are being investigated, intensive efforts are continuing by a number of research groups to develop effective therapeutic approaches using GDNF and related proteins to treat Parkinson’s disease. As these preclinical and clinical studies are further advanced than those on other trophic factors and likely to lead to additional clinical trials, the remainder of this chapter will focus on GDNF and related proteins.

25.3. The GDNF family: proteins, receptors and actions GDNF (Lin et al., 1993) and the related proteins neurturin (Kotzbauer et al., 1996), persephin (Milbrandt et al., 1998) and artemin (Baloh et al., 1998) define a novel family of neurotrophic factors (Table 25.5) composing a subgroup of the transforming growth factor-b (TGF-b) superfamily. The first member of this family, GDNF, is a glycosylated and disulfide-bound homodimer. The biologically active form of GDNF is composed of two 134-amino-acid monomers that migrate in gels with an apparent molecular weight in the 33–45 kDa range. Neurturin is a closely related protein with a 92% amino acid homology with GDNF. The expression of neurturin overlaps with GDNF in substantia nigra, striatum and other brain areas (Golden et al., 1998; Cho et al., 2004; Oo et al., 2005). Although GDNF family receptor alpha-1 (GFRa-1) is the preferred receptor for GDNF and GFRa-2, the preferred receptor for neurturin, both trophic factors are functional ligands for the other’s receptor (Sariola and Saarma, 2003). This raises questions about redundancy. Is it possible for two trophic factors to serve

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the same functions in the brain, or are their biological actions different? The data to date do not provide a clear answer, but suggest a strong overlap in functions. Redundancy is an effective biological strategy to assure the maintenance of essential molecular functions, which may explain the functional overlap of GDNF and neurturin in the brain. The homologies of artemin and persephin with GDNF are much lower, 28% and 40% respectively. Much less is known about the normal biological actions of these two factors. GFRa-3, the primary receptor for artemin, is predominantly expressed in peripheral neurons (Orozco et al., 2001). Artemin is also a functional ligand for GFRa1, but persephin does not bind to either GFRa-1 or GFRa-2. Indeed, the mechanisms responsible for persephin’s actions in promoting dopamine neuron survival in culture are not known. Unlike other members of the TGF-b superfamily, which signal through the receptor serine-threonine kinases, GDNF family ligands activate intracellular signaling cascades via receptor tyrosine kinase. The receptors of the GDNF family ligands have multiple components. They include a signaling unit, the membrane-spanning receptor tyrosine kinase RET (Durbec et al. 1996; Trupp et al., 1996), and a high-affinity GFR (see above) ligand-binding protein. GDNF family ligands first bind to the glycosylphosphatidylinositol (GPI)-anchored GFRa. Then, the GDNF family ligand– GFRa complex binds to and stimulates autophosphorylation of RET (Trupp et al., 1998; Rosenthal, 1999). Alternatively, a pre-associated complex between GFRa and RET could form the binding site for the GDNF family ligand (Eketjall et al., 1999). Evidence has emerged for another multicomponent receptor complex consisting of GFRa-1 and neural cell adhesion molecule (NCAM: Paratcha et al., 2003), that

Table 25.5 Receptors and nigrostriatal expression of glial cell line-derived neurotrophic factor (GDNF) family trophic factors GDNF family trophic factors

GFR-a receptors

Nigrostriatal expression

Homology with GDNF

GDNF

GFRa-1 GFRa-2 GFRa-2 GFRa-1 GFRa-3 GFRa-1 GFRa-4

Yes Yes Yes Yes Low levels?

100%

28%

Lin et al. (1993); Golden et al. (1998); Oo et al. (2005) Kotzbauer et al. (1996); Golden et al. (1998); Cho et al. (2004) Baloh et al. (1998); Rosenblad et al. (2000)

Low levels?

40%

Milbrandt et al. (1998)

Neurturin Artemin Persephin

92%

Selected references

The four known members of the GDNF family are listed together with their GDNF family receptors (GFR). GDNF and neurturin function as ligands for GFRa-1 and GFRa-2, which are expressed in the nigrostriatal pathway.

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D. M. GASH ET AL.

could be activated by GDNF and neurturin. NCAM is abundantly expressed in Schwann cells and hippocampal and cortical neurons (Crossin and Krushel, 2000). NCAM-deficient mice display structural abnormalities in the rostral migratory bulb, the olfactory bulb and the hippocampus, as well as the functional deficits in learning and memory (Tomasiewicz et al., 1993; Cremer et al., 1994, 1997; Chazal et al., 2000). This suggests that GDNF may utilize NCAM signaling pathways to promote axonal growth in hippocampal and cortical neurons in an RET-independent way. A publication by Enomoto et al. (2004) challenged this idea with the use of specific transgenic mice that express GFRa-1 under an RET promoter on a GFRa-1 null background. Although these mice lack all RETindependent GFRa-1 expression, no structural abnormalities in the olfactory bulb and the hippocampus were detected. However these data are not conclusive given the overlap of GFRa-1 and GFRa-2 expression and activities. Moving from the molecular to the systems level, GDNF exerts the type of effects on dopamine neurons that might slow the process of Parkinson’s disease and even reverse some of the degenerative changes. If this therapeutic potential is realized, it would represent a new approach directed toward the disease process and disease progression. In contrast, the current goldstandard treatment, levodopa, is palliative and does not prevent the relentless progression of Parkinson’s degeneration. Preclinical studies conducted to date suggest that GDNF exerts at least three general trophic actions on dopamine neurons in the substantia nigra: pharmacological upregulation, restoration and neuroprotection. 25.3.1. Pharmacological GDNF upregulates dopaminergic functions, such as increasing the evoked release of dopamine (Gerhardt et al., 1999; Grondin et al., 2003). It also appears to modulate the phosphorylation of tyrosine hydroxylase (Salvatore et al., 2004). 25.3.2. Restoration GDNF increases the number of neurons expressing the dopamine markers tyrosine hydroxylase and dopamine transporter in the substantia nigra (Gash et al., 1996; Kordower et al., 2000; Grondin et al., 2002). This suggests that one trophic action is to stimulate recovery of injured/quiescent nigral neurons. Supporting this interpretation is the consistent observation that GDNF promotes increases in dopamine neuron perikaryal size and the number of neurites.

25.3.3. Neuroprotection Nigrostriatal administration of GDNF either shortly before or following a neurotoxic challenge (e.g. 6-hydroxydopamine, methylamphetamine or 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)) protects dopamine neurons from injury in rodents and non-human primates (Kordower et al., 2000; Fox et al., 2001).

25.4. GDNF therapy for Parkinson’s disease While all four known GDNF family trophic factors promote the survival of dopamine neurons in culture and both neurturin and artemin can functionally activate GDNF’s preferred receptor GFRa-1, most studies to date have focused on using GDNF for the clinical treatment of Parkinson’s disease. GDNF has undergone extensive preclinical testing in rodent and non-human primate models of parkinsonism (Tables 25.2 and 25.3), with strong protective and restorative effects found consistently for the nigrostriatal dopamine system. Based on the preclinical results, four clinical trials have been conducted to evaluate the safety and efficacy of GDNF in Parkinson’s disease patients (Table 25.4). GDNF has been safely administered in all four trials, with the most pronounced side-effects seen from monthly bolus injections into the lateral ventricle (Nutt et al., 2003). The safety profile using implanted catheters to infuse GDNF directly into the putamen has been excellent in two phase I trials involving 15 patients (Gill et al., 2003; Patel et al., 2005; Slevin et al., 2005a, b). There have not been serious side-effects; the most consistent negative symptom has been occasional brief episodes of mild electrical ‘shocks’ in the neck and back (Lhermitte’s symptoms). The safety profile in patients in a multicenter, double-blinded phase II trial was similar, even though two significant safety concerns arose while this study was in progress (Lang et al., 2006; Sherer et al., 2006). One concern was the identification of both binding and neutralizing antibodies in the blood of some patients receiving GDNF therapy in all three clinical trials testing intraputamenal GDNF delivery. Although clinical manifestations from the GDNF antibodies have not emerged, the long-term effects of circulating antibodies to GDNF in adults are not known. The second concern came from lesions in the cerebellum of four monkeys receiving very high doses of intraputamenal GDNF in a toxicology study. As with the antibodies, clinical manifestations of cerebellar injury have not been seen in patients treated with GDNF. Indeed, in the studies conducted to date in patients (Chebrolu et al., 2006) and from the one reported autopsy of a long-term intraputamenal GDNF recipient who died from a myocardial infarct (Love et al., 2005), no evidence of cerebellar injury from GDNF therapy has been found.

NEUROTROPHIC FACTORS AND PARKINSON’S DISEASE Both phase I intraputamenal delivery studies have shown significant indications of efficacy with improvements in the 30% range on the total Unified Parkinson’s Disease Rating Scale (UPDRS) after 6 months of treatment, both on and off medication (Gill et al., 2003; Slevin et al., 2005a, b). Improvements on the UPDRS motor component in the off state, considered to be the gold standard for judging efficacy, were also in the 30% range for both studies. Recently, Gill and colleagues (Patel et al., 2005) have demonstrated that these improvements were maintained for 2 years in their 5 patients. However, neither of the two phase II trials achieved significant improvements on total or motor UPDRS scores (Lang et al., 2006). Although a placebo component to the striking differences between the phase I and phase II trials cannot be ruled out, methodological differences between the successful and unsuccessful studies (Sherer et al., 2006) along with preclinical data analysis suggest that at least two factors are critical for efficacious GDNF therapy: site-specific delivery and target tissue distribution. 25.4.1. Site-specific delivery of GDNF into the nigrostriatal system Although cerebroventricular delivery is an effective route for GDNF delivery in animal models, it does not appear to be efficacious in Parkinson’s disease patients! No clinical benefits were found in a double-blind, randomized trial involving 50 Parkinson’s disease patients receiving monthly bolus injections of up to 4000 mg GDNF into the lateral ventricle (Nutt et al., 2003). Why? The best evidence to date indicates that GDNF does not diffuse far enough from the ventricle into the basal ganglia to affect the nigrostriatal dopaminergic system in the human brain. In rhesus monkeys receiving chronic lateral ventricle infusions of GDNF, immunocytochemical staining for the trophic factor reveals staining only 2 mm deep in the periventricular region of the septum, caudate nucleus and nucleus accumbens (Fig. 25.1A). In a Parkinson’s patient receiving 300 mg monthly bolus injections of GDNF into the lateral ventricle, who died from other causes 3 weeks after the last trophic factor administration, GDNF immunoreactivity could not be identified in the brain (Kordower et al., 1999). Although the several millimeters penetration of GDNF into the brain parenchyma adjacent to the lateral ventricle and third ventricle was sufficient in rhesus monkeys to upregulate nigrostriatal dopamine neurons and improve motor functions (Grondin et al., 2002, 2003), this diffusion distance evidently is not sufficient in the human brain, which is more than 12 times larger. In contrast, site-specific infusion of GDNF into the putamen was effective in both parkinsonian rhesus monkeys and in Parkinson’s patients in two phase I studies. In

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GDNF: Intraventricular R Cd

LV

Cd

LV

ic

ic

Pu Pu Acb

Acb

A GDNF: Intraputamenal R Cd

LV

Cd

LV

ic

ic

Pu

Pu

Acb

Acb

B Fig. 25.1. (A) Using nickel-enhanced black imunocytochemical staining for GDNF, there was limited penetration of GDNF infused into the lateral ventricle (LV) of rhesus monkeys into adjacent brain tissue. (B) In contrast, much of the putamen (Pu), intenal capsule (ic) and portions of caudate nucleus (Cd) were included in the volume of GDNF distributed by direct striatal infusion. Some tissue surrounding the catheter tract (*) was lost in processing. Acb ¼ nucleus accumbens; scale bar ¼ 2 mm in A & B. From Ari et al. (2003) with permission from Wiley.

rhesus monkeys, there is an approximately 11–14 mm radius of diffusion of immunoreactive GDNF in the rhesus monkey putamen and caudate nucleus following chronic intraputamenal GDNF infusion (Fig. 25.1B; Ai et al., 2003). Continuous intraputamenal GDNF infusion promotes both structural and functional recovery in advanced parkinsonian monkeys (Grondin et al., 2002). Similar results have been reported in 15 advanced PD patients receiving continuous intraputamenal GDNF infusion for 6 months and longer (Gill et al., 2003; Slevin et al., 2005a). Evidence for concomitant structural recovery came from positron emission tomography (PET) scans in 5 of the patients, which showed a significant 28% increase in [18F]dopamine uptake in the putamen after 18 months of GDNF therapy (Gill et al., 2003; Patel et al., 2005). The autopsy findings in the one long-term phase I patient who died from a heart attack have shown neuronal sprouting of dopamine fibers (i.e. tyrosine hydroxylase-positive neurites) in the putamen adjacent to the GDNF infusion site (Love et al., 2005). 25.4.2. Convection-enhanced delivery (CED) and GDNF target tissue distribution CED is likely to prove essential for achieving efficacy in trophic factor treatments for Parkinson’s disease.

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Macromolecules like GDNF diffuse slowly in brain parenchyma and usually over short distances (Bobo et al., 1994). CED entails increasing the bulk flow rate of large molecules to increase tissue penetration and promote distribution over larger volumes of the brain (Bobo et al., 1994; Hamilton et al., 2001; Nguyen et al., 2003). The importance of CED can be seen in a recent study where intranigral infusion in parkinsonian monkeys was facilitated by brief pulses of GDNF at the convection enhancement rate of 22 ml/min (Gash et al., 2005). GDNF distribution in the brain predicted the extent of dopaminergic restoration and functional recovery (r2 ¼ 0.82). The fatal flaw in the failed Amgen multicenter phase II study (Sherer et al., 2006) may have been the catheter used, which tends to concentrate the drug at the catheter tip (Salvatore et al., 2006). Combined with the low dose and infusion rate employed in the trial, it is likely that distribution of the GDNF in the putamen was severely limited. In contrast, the Kentucky phase I trial used a catheter designed to promote CED and the protocol included short-duration pulsed infusions at a CED rate of over 10 ml/min every 6 hours to supplement the low basal infusion rate (Slevin et al., 2005a). The non-human primate data upon which this clinical protocol was based indicate that reasonable putamenal distribution is achieved by appropriate catheter design and periodic pulsed CED (Ai et al., 2003; Fig. 25.1). The Bristol phase I catheter design also differed from that used in the Amgen phase II trial. Its features should have facilitated CED. In addition, the Bristol study utilized monthlong periods of GDNF infusion at dose levels three times higher than those employed in the phase II trial. Dose along with a CED-compatible catheter design may have combined to produce the benefits reported in the Bristol study.

25.5. Effective therapy: the challenge is delivery All evidence to date supports the concept that successful trophic factor therapy requires site-specific delivery. The blood–brain barrier effectively blocks entry from bloodborne proteins, including trophic factors. Infusions into the cerebrospinal fluid are not effective in humans because of brain size and may produce unwanted side-effects by stimulating other trophic factor-responsive populations such as sensory neurons. In addition to focal delivery into the appropriate site, it can be posited that the delivery must be tightly regulated. Regardless of the method used to deliver GDNF – direct infusion, stem cells, encapsulated cells, gene therapy – prolonged elevated levels of GDNF in

the brain are likely to produce adverse side-effects. Circulating antibodies to GDNF are one possible outcome and it is quite typical to find antibodies to endogenous proteins used therapeutically (e.g. beta-interferon and insulin; see Stoever and Palmer, 2002; Durelli and Ricci, 2004). The effects of circulating GDNF antibodies are not known. Focal Purkinje cell lesions have been reported in some monkeys receiving high levels of GDNF in a toxicology study (Sherer et al., 2006). Another possible side-effect is aberrant sprouting and tyrosine hydroxylase downregulation of the nigrostriatal dopaminergic pathway, which has been reported by Georgievska et al. (2002) in rats exposed to high GDNF levels from viral vector gene transfer. Also, increased neuronal death has been reported in rats with elevated GDNF from viral vector gene transfer in a stroke model (Arvidsson et al., 2003). The one methodology that allows controlled, sitespecific delivery of GDNF in patients today utilizes subcutaneously implanted programmable pumps attached to catheters implanted into the brain (Grondin et al., 2002; Gill et al., 2003; Slevin et al., 2005a). Although cumbersome in some aspects, the entire system is self-contained other than requiring periodic pump refills on an outpatient basis every month or so. A number of other procedures for site-specific trophic factor therapy are in development, including gene therapy, stem cells and encapsulated cells (Kordower et al., 2000; Bensadoun et al., 2003; D’Costa et al., 2003; Svendsen and Langston, 2004). With both implanted cells and genes, maintaining control of trophic factor release has proven to be a difficult technical challenge. Creative approaches are currently in preclinical testing, such as tetracyclinedependent regulatory systems to induce transit gene expression under clinical control (Markusic et al., 2005). One important milestone is to achieve sufficient reliability for the regulatory systems to be used in clinical applications. In summary, trophic factor therapy has long held the promise to revolutionize the treatment of Parkinson’s disease and other neurodegenerative disorders. Realizing the promise has proven to be surprisingly elusive. The field is now in a challenging era, where several small phase I clinical trials have yielded encouraging results, although phase II studies have been disappointing. Analysis of the differences between the successful and unsuccessful trials strongly suggests that efficacious therapeutic approaches require controlled, site-specific delivery of trophic factors using methodology to optimize target tissue distribution. In addition, several safety issues have arisen that need to be addressed: the effects of antibodies generated to trophic factors being used in therapy and possible cerebellar toxicology from continuous exposure to high drug levels. The next

NEUROTROPHIC FACTORS AND PARKINSON’S DISEASE generation of preclinical studies is under way to understand and build upon the hard-won lesions from the four clinical trials on GDNF conducted to date. New clinical trials will depend upon progress being made in optimizing trophic factor delivery and understanding/managing the safety concerns.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 26

Neuroinflammation and Parkinson’s disease SERGE PRZEDBORSKI* Departments of Neurology, Pathology and Cell Biology, Columbia University, New York, NY, USA

Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder of the aging brain after Alzheimer’s dementia. Its clinical hallmarks include resting tremor, slowness of movement, rigidity and postural instability (Fahn and Przedborski, 2000), all of which have been attributed to a profound deficit in brain dopamine (Hornykiewicz and Kish, 1987). Given this fact, it is not surprising to notice that the lion’s share of attention with respect to PD neuropathology has been paid to the dopaminergic systems of the central nervous system (CNS) and more particularly to the nigrostriatal pathway. Yet, it is now well established that degenerative changes in PD are not restricted to the nigrostriatal pathway or to other dopaminergic systems. Abnormal histological features can also be found in many non-dopaminergic cell groups, including the locus ceruleus, raphe nuclei and nucleus basalis of Meynert (Braak et al., 1995). Affected brain areas in PD are not only depleted of specific types of neurons, but also exhibit intraneuronal proteinaceous inclusions named Lewy bodies (Galvin et al., 1999) and inflammatory changes such as morphological and functional alterations in glial cells (McGeer et al., 1988b; Forno et al., 1992). For decades, gliosis has been a well-recognized neuropathological feature of PD, thought of as secondary and insignificant, as far as the pathogenesis of this illness is concerned. More recently, however, human epidemiological studies have suggested that inflammation increases the risk of developing PD (Chen et al., 2003) and investigations in experimental models of PD have shown that inflammatory response can modulate nigrostriatal dopaminergic neuronal death (Liberatore et al., 1999; Gao et al., 2002; Wu et al., 2002, 2003). These facts prompt many investigators to

regard inflammation as a noxious factor in the neurodegenerative process in PD and related conditions. Nguyen and collaborators (2002), however, remind us that the inflammatory response is not always injurious and that it can provide beneficial effects in an otherwise compromised system, such as by stimulating the production of neurotrophic factors and some repair and remyelination mechanisms. Based on the aforementioned premises, this chapter will review the topic of inflammation in PD. To achieve this goal, the notion of inflammation in neurodegenerative disorders will first be discussed to define the key players and to set the stage for the rest of the discussion. Then, the issue of how inflammation is triggered in PD and which place it occupies in the sequence of events that ultimately leads to the demise of dopaminergic neurons will be approached. A description of the composition of the inflammatory response in various parkinsonian syndromes including PD per se as well as in animal models of PD will follow. Minimal changes have occurred vis-a`-vis the anatomical description of inflammation in all these different PD-related settings and thus they primarily represent a reiteration of previous publications I have written on this subject. And, finally, a discussion about the potential beneficial and deleterious role of inflammation in PD and how it can be targeted for therapeutic purposes will be offered.

26.1. Inflammation in neurodegenerative disorders Inflammation can involve any part of the body, including the brain. The inflammatory reaction of the CNS is a complex phenomenon which should not just be equated with the infiltration of the diseased brain

*Correspondence to: Dr. Serge Przedborski, Departments of Neurology, Pathology and Cell Biology, Columbia University, 650 West 168th Street, Black Building Rm 302, New York, NY 10032, USA. E-mail: [email protected], Tel: (212)-342-4119, Fax: (212)-342-3663.

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parenchyma by blood-derived immune cells, since such infiltration only represents one particular type of inflammatory response, often called exudative inflammation. Although exudative inflammation can be observed in a host of acute insults of the CNS accompanied by a rupture of the blood–brain barrier, it is not the one expected to be found in chronic neurodegenerative diseases. Indeed, in these types of chronic brain disorders, rather than seeing infiltration of circulating macrophages and other bloodborne cells, the diseased brain tissue is populated with resident inflammatory cells such as microglia and astrocytes. In many neurodegenerative diseases, those innate immune cells are activated and produce a variety of inflammatory mediators (Eddleston and Mucke, 1993; Mennicken et al., 1999; Nguyen et al., 2002). In addition to the glial response, T-lymphocyte infiltration has also been identified in several neurodegenerative diseases, including PD (Bas et al., 2001; Hisanaga et al., 2001), suggesting an involvement of the adaptive immune system in the inflammatory process seen in these illnesses. In the context of this chapter, it is also important to discuss briefly the widespread misconception that necrosis, but not other forms of cell death such as apoptosis, elicits inflammation. This view likely finds its basis in the principle that, contrary to necrosis, non-necrotic forms of cell death (Clarke, 1990; Yaginuma et al., 1996) are not associated with a gross spillage of the intracellular content from degenerating cells, which is perceived by many as a determining factor in triggering inflammation. Although the inflammatory reaction is generally stronger in brain areas of necrosis than, for example, in areas of apoptosis, this may simply reflect the greater number of cells dying in necrotic areas. Moreover, authors who claim that non-necrotic forms of cell death such as apoptosis do not elicit inflammation are referring to exudative inflammation, as defined above (Wyllie et al., 1980). However, in the CNS, even in experimental situations associated with necrosis, the inflammatory response is largely local, i.e. mainly made of resident microglia and astrocytes, as seen in experimental situations associated with apoptosis. Therefore, whereas the intensity of the glial reaction may vary among the distinct forms of cell death detailed by Peter Clarke (1999), the occurrence of gliosis should not be regarded as a characteristic of necrosis only. The occurrence of inflammation in neurodegenerative diseases such as PD cannot and should not imply that dopaminergic neurons are dying by necrosis. As previously stressed (Przedborski and Goldman, 2004), prior to embarking on the discussion of inflammation in PD, the meaning of gliosis, which is some-

time also called reactive astrocytosis, must be addressed. Gliosis, in neurological diseases, normally refers to scarring produced by astrocytes; however, it is often loosely used to define simply increased immunoreactivity for the intermediate filament, glial fibrillary acid protein (GFAP). The extensive use of this term, especially in landmark studies, makes the interpretation of glial pathology difficult, as the limited range of techniques employed does not always allow an appropriate interpretation of the data. For instance, it is often unclear whether gliosis, evidenced by increased GFAP immunostaining, meant increased stainability of the tissue, increased numbers of astrocytes, increased size of astrocytes or a combination of all of these. It is also not always possible to comment on the status of other glial cells such as oligodendrocytes and microglia or T cells. Consequently, all efforts will be made to spell out what those studies actually show. Nonetheless, a more accurate and comprehensive analysis of the inflammatory reaction in PD may have to wait for this topic to be revisited using more modern techniques. Even though the description of glial cells in normal and PD brain has already been discussed elsewhere (Przedborski and Goldman, 2004), it is essential that this aspect be revisited here. It must be remembered that astrocytes play an important role in the normal, undamaged adult brain for the homeostatic control of the neuronal extracellular environment. Contrasting with the large body of information about astrocytes, only scattered information is available regarding the role of microglia and T cells in the immature brain and even less in the normal adult brain. Following an injury to the brain, both astrocytes and microglial cells can undergo dramatic phenotypic changes that enable them to respond to and play a role in the pathological processes (Eddleston and Mucke, 1993; Gehrmann et al., 1995). For example, microglial activation is characterized by a series of alterations including proliferation; increased or de novo expression of marker molecules such as major histocompatibility complex antigens; migration; and eventually transformation into a macrophage-like appearance (Banati et al., 1993). As indicated by Przedborski and Goldman (2004), in neurodegenerative diseases both microglia and astrocytes can become activated, producing an array of inflammatory factors and taking on phagocytic functions. Although some glial factors are specifically produced by reactive astrocytes or activated microglia, others, such as interleukin-1ß (IL-1ß), can apparently be produced by both (Rothwell, 1999). Also, it is believed that microglia are responsible for more generalized phagocytosis involving activation of the complement cascade, whereas astrocytes are implicated in

NEUROINFLAMMATION AND PARKINSON’S DISEASE circumscribed phagocytic processes, such as the removal of individual synapses (Wyss-Coray and Mucke, 2002). The most efficient and aggressive phagocytes in the CNS are likely the round or ameboid microglia, which express high levels of macrophage markers, whereas ramified microglia have little phagocytic activity (Kreutzberg, 1996). In neurodegenerative diseases many microglia cells show a ramified morphology, although they express activation markers (Dickson et al., 1993), suggesting that they might be non-phagocytic (DeWitt et al., 1998). Astrocytes may also participate in phagocytosis, either directly (Shaffer et al., 1995) or by regulating microglial activities (DeWitt et al., 1998). As indicted above, there is often T-cell infiltration in affected brain areas in neurodegenerative diseases. Yet, the prevailing theory about the pathogenesis of neurodegenerative diseases, except for multiple sclerosis and related conditions, is that the observed inflammation results from a glial reaction and T-cell infiltration secondary to the loss of neurons; hence neurodegenerative diseases such as PD are not to be considered as autoimmune diseases in which a peripheral immune reaction directed against the CNS is the primary event. However, the identification of T cells in the diseased brain parenchyma raises intriguing questions, such as: How do T cells enter the brain? What subtypes are they? How are they recruited within diseased areas? What could be their role in the disease process? The CNS is an immune-privileged site due to the complexities of the blood–brain barrier and its lack of lymphatic drainage (Becher et al., 2000). The latter results in an ineffective dialog between the CNS and the immune system and is one mechanism preventing the exchange of CNS antigens with the peripheral immune system (Becher et al., 2000). It is proposed that such complications in this dialog result in the failure of the immune system to protect and to promote regeneration within the damaged CNS, in contrast to its role in such maintenance within the peripheral nervous system (Moalem et al., 1999). Despite these obstacles, compelling evidence indicates that activated, but not naive T cells, can enter the CNS regardless of whether the blood–brain barrier is inflamed (Hickey et al., 1991). It seems that activated T cells circulate peripherally until they are arrested by adhesive interactions with the endothelium (Hauzenberger et al., 1995). Adhesive molecules, such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, which are instrumental in the extravasation of T cells, are minimally expressed in the normal brain but can be markedly upregulated in the diseased brain (McCluskey and Lampson, 2000). Once in the CNS, activated T cells must recognize their antigen in order

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to perform their effector functions (e.g. release of cytokines) and participate in the recruitment of additional T cells through the secretion of chemokines (McCluskey and Lampson, 2000). The basic requirement for antigen recognition by T cell is that the antigen be processed into a peptide, be complexed to major histocompatibility complex-encoded proteins and be translocated to the cell surface (McCluskey and Lampson, 2000). Whether infiltrating T cells correspond to specific antigen-activated T cells that can exert effector functions contributing to the disease process in neurodegenerative disorders, or merely to nonspecific antigen-activated T cells which patrol the CNS, remains to be clarified.

26.2. How inflammation arises in Parkinson’s disease and related conditions Most data available to date are consistent with the view that inflammation in PD results from the detection by defense mechanisms of ongoing neuronal perturbations. This implies that, as already alluded to above, microglial and astrocytic activation and T-cell infiltration within injured areas are not primary events but rather the consequence of the neuronal pathology. If inflammation in PD is a secondary event, i.e. rises after the demise of dopaminergic neurons has already started, does this fact preclude a role for inflammation in the neurodegenerative process? Prior to answering this question it is important to remember that neuronal death in diseases such as PD proceeds in an asynchronous fashion – not all dopaminergic neurons within the substantia nigra pars compacta die simultaneously. This implies that at any given time, only a small number of dopaminergic neurons are actually dying and among these many, if not all, are at various stages along the cell death process. Consequently, the very first neurons that succumb to the disease process are responsible for initiating inflammatory events. From then on, all compromised, but still living, neighboring neurons will now also be subjected to the effects of inflammation, which will intensify as more neurons die and the glial response grows. Assuming that inflammation exerts deleterious effects on dopaminergic neurons (see below), it can thus be easily understood how inflammation may amplify the neurodegenerative process and stimulate its progression. Even if this scenario is correct, the nature of the signal that triggers inflammation and which emanates from the dysfunctional or dying neurons remains enigmatic. Because glial cells entertain intimate contacts with neurons, it is tempting to imagine that the initiation of the inflammatory response could derive from

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a defect in the nature or quality of the neuronal contact with glia cells. Indeed, early on in the process of apoptosis, cells including neurons harbor plasma membrane alterations, which lead to the cell surface exposure of phosphatidylserine, as evidenced by the binding of annexin V (van den Eijnde et al., 1998). It can thus be hypothesized that such alterations of the neuronal membrane could be readily perceived by glial cells as a pathological signal, leading to their activation. Although not mutually exclusive, several cell culture studies show that inflammation can be triggered by soluble factors, either secreted by or leaking from ‘sick’ neurons. One such molecule is chromogranin A, a glycoprotein widely distributed in the CNS, which accumulates in areas with neuronal degeneration and in Lewy bodies (Nishimura et al., 1994). Upon its release or leakage from neurons, chromogranin A can activate microglia and promote neurodegeneration by a microglial-dependent mechanism (Ciesielski-Treska et al., 1998). In addition, stressed neurons in both PD and experimental models of PD expressed high amounts of the prostaglandin-synthesizing enzyme, cyclooxygenase-2 (Cox-2). Once produced by the neurons, prostaglandins can presumably reach the extracellular space and activated glial cells. Finally, the idea that misfolded neuronal proteins and protein aggregates could also trigger glial activation is particularly appealing in the context of PD, given the fact that mutations in the genes encoding for parkin and ubiquitin C-terminal hydrolase L1 (two enzymes of the ubiquitin/proteasome pathway) and for a-synuclein (a main component of the intraneuronal proteinaceous inclusions, Lewy bodies) lead to familial PD (Vila and Przedborski, 2004). There is no shortage of ideas about how glial cells may be activated in response to neuronal perturbations, but we still do not know with certainty how this occurs. Most data support the hypothesis that inflammation in neurodegenerative diseases such as PD is likely not a non-specific response to dysfunctional and dying neurons. Instead, it is more probable that the inflammatory response is related to the ligation of specific transmembrane receptors, such as toll-like receptors (TLRs), which are present on glial cells (Bowman et al., 2003; Zuany-Amorim et al., 2002). A critical aspect of the TLR machinery is the fact that, among the 10 different TLRs, each is activated by a specific ligand (Iwasaki and Medzhitov, 2004). Although activation of TLRs has been studied mainly in the context of pathogens, one may hypothesize that the development of inflammation in PD could also arise from the activation of the TLRs by specific structural molecules originating from dysfunctional and dying neurons such as, for example, truncated or oligomeric species of a-synuclein.

26.3. Description of the inflammatory response in Parkinson’s disease In the normal adult brain, microglia, which constitute roughly 10% of all glial cells, appear not to be evenly distributed (Lawson et al., 1990) and for the most part they harbor a morphology of resting state: elongated, almost bipolar cell bodies with spine-like processes that often branch perpendicularly. With respect to the main areas of the brain affected in PD, the density of these cells seems much higher in the substantia nigra compared to any other brain regions (Kim et al., 2000). This observation, together with the demonstration that substantia nigra neurons are more susceptible to activated microglial-mediated injury (Kim et al., 2000), supports the idea that inflammation plays a meaningful role in the PD neurodegenerative process. In contrast with microglia, astrocytes in the normal adult brain display a rather homogeneous distribution except in midbrain, where the estimated density of GFAP-positive cells varies among the different catecholaminergic groups (Damier et al., 1993). For instance, the density of GFAP-positive cells is moderate in the midbrain areas known to be most severely affected in PD, such as substantia nigra pars compactam, and high in those least affected, such as the gray substance (Damier et al., 1993). Furthermore, as pointed out by Hirsch and collaborators (1999), within the substantia nigra pars compacta the density of GFAP-positive cells is lowest in the calbindin-D28Kpoor areas, where the loss of dopaminergic neurons is presumably the most severe (Damier et al., 1999). Although the neuropathology of PD goes well beyond the degeneration of dopaminergic systems (Braak et al., 1995), most attention has been paid to the nigrostriatal dopaminergic neurons, whose cell bodies are located in the substantia nigra pars compacta and their projecting nerve terminals in the striatum. It is thus not surprising that most data available about inflammation in PD pertain to the substantia nigra and the striatum. In keeping with this, several studies have reported that the loss of dopaminergic neurons in postmortem PD brains is associated with microglial and astrocytic alterations (McGeer et al., 1988b; Forno et al., 1992; Banati et al., 1998; Mirza et al., 2000). It also appears that the described changes in microglia and astrocytes are consistently more important in the substantia nigra pars compacta than in the striatum (McGeer et al., 1988b). This contrasts with the fact that the loss of dopaminergic elements is consistently more severe in the striatum than in the substantia nigra pars compacta. Although the explanation for this divergence is unknown, it may be due to the fact that the dopaminergic structures, which are

NEUROINFLAMMATION AND PARKINSON’S DISEASE degenerating, represent a larger fraction of the total pool of cellular elements in the substantia nigra pars compacta, but only a small one in the striatum; dopaminergic synapses represent less than 15% of the entire pool of synapses in the striatum (Pickel et al., 1981). It is thus possible that the pathological signal emanating from dysfunctional and degenerating dopaminergic elements is dampened to a greater extent in the striatum by the larger number of intact structures that surround them. In addition to these topographical differences, the magnitudes of the microglial and astrocytic changes in PD brains also appear quite different. The substantia nigra pars compacta of postmortem PD brains exhibits, at best, slightly more astrocytes based on counts of GFAP- and metallothionein I/II-positive cells (Mirza et al., 2000). These data, however, do not indicate whether the finding results from glial hyperplasia (i.e. proliferation of astrocytes) or simply more stained astrocytes. Indeed, without having to invoke any change in number of astrocytes, it is well recognized that reactive astrocytes, by upregulating proteins such as GFAP, become readily visible by immunostaining. Remarkably, the majority of immunostained astrocytes in PD exhibit rather a resting-like morphology, with thin and elongated processes, and only few exhibit a true reactive morphology with hypertrophic cell body and short processes (Forno et al., 1992; Mirza et al., 2000). Thus, whether gliosis in PD results from astrocytic proliferation, increased stainability, or both, remains to be ascertained. Among other astrocytic pathologic features seen in PD is the intriguing finding of argyrophilic, tau-negative, a-synuclein-positive glial inclusions (Wakabayashi et al., 2000). These were only found in the brainstem: 40% of the PD samples studied showed these glial inclusions in the substantia nigra and 80% in other brainstem regions (Wakabayashi et al., 2000). Of note, in these tissue samples oligodendrocytes also contained these proteinaceous inclusions (Wakabayashi et al., 2000). More importantly, the number of such inclusions in astrocytes were presumably proportional to the severity of nigral neuronal loss (Wakabayashi et al., 2000). Unlike astrocyte alterations, the microglial changes in PD are consistently more severe (McGeer et al., 1988b; Banati et al., 1998; Mirza et al., 2000; Imamura et al., 2003), but also less frequently addressed. Despite this caveat, the handful of studies cited above provides a rather similar picture about the status of microglial cells in PD tissues, at both the level of the midbrain and the striatum. Microglial cells can be readily evidenced in PD samples by immunostaining for various microglial markers such as, usually, human leukocyte antigen-DR (HLA-DR) and major histocom-

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patibility complex class II (MHC-II) antigens and, less often, intercellular adhesion molecule-1 and leukocyte functional antigen-1 (McGeer et al., 1988b; Banati et al., 1998; Mirza et al., 2000; Imamura et al., 2003). Many of these markers, however, are not specific for activated microglia; hence positive cellular immunoreactivity due to the labeling of resting microglia is to be expected in normal control tissues. Thus, the assessment of the microglial response in pathological samples such as PD generally sits on the comparison of the morphology and the number of labeled cells between PD and controls. So, morphologically, microglial cells in PD tissues, unlike in control tissues, typically exhibit thick, elongated processes (McGeer et al., 1988b; Banati et al., 1998; Mirza et al., 2000); less often microglial cells in PD tissues also exhibit a round cell body devoid of processes, a morphology reminiscent of ameboid macrophages. Quantitative analysis shows that the number of activated microglia in the substantia nigra pars compacta, as evidenced by HLA-DR or ferritin immunostaining, is much higher in PD than in controls (Mirza et al., 2000; Imamura et al., 2003). Activated microglia in PD are predominantly found in close proximity to free neuromelanin in the neuropil and to remaining neurons in the substantia nigra, which they often surround or cover, realizing an image of neuronophagia (McGeer et al., 1988b). Similar microglial activation is also found in the putamen (Imamura et al., 2003).

26.4. Description of the neuroinflammatory response in Parkinsonian syndromes Although PD is the commonest cause of parkinsonism, more than 30 different neurological syndromes share PD clinical features (Dauer and Przedborski, 2003) and among these, PD does not have a monopoly on the association of nigrostriatal neurodegeneration and glial alterations (Oppenheimer and Esiri, 1997). Many of these non-PD parkinsonian syndromes exhibit both clinical features (e.g. ocular movement or upper motor neuron abnormalities) and loci of neurodegeneration in brain regions not typically seen in PD (striatum or corticospinal track pathology). Despite this, all of these syndromes show nigrostriatal dopaminergic neuronal loss, whose magnitude can vary greatly, and sometimes brainstem Lewy bodies. In addition, in most publications authors mention the presence of gliosis, usually to denote increased small non-neuronal cells, visualized by hematoxylin-and-eosin stain, or more GFAP-positive cells. When present these changes are found at the level of the nigrostriatal pathway, as well as at the level of the other affected regions of the brain not normally affected in PD. Even in the initial reports

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on progressive supranuclear palsy (Steel et al., 1964) and striatonigral degeneration (Adams and SalamAdams, 1986), gliosis, as just defined, was already recognized as a prominent feature of the pathological changes seen in these syndromes. Over the last decade, several familial forms of parkinsonism have been identified (Vila and Przedborski, 2004). Like in sporadic PD, histological examination revealed similar glial alterations in most of the familial forms of parkinsonian syndromes, whether they are linked to unknown (Dwork et al., 1993) or known gene defects (Vila and Przedborski, 2004). In this vein, the situation reported for the autosomal-dominant form of PD linked to leucine-rich repeat kinase 2 (LRRK2)/dardarin mutations is particularly fascinating (Zimprich et al., 2004). Indeed, in the 6 patients carrying a LRRK2/dardarin mutation who came to autopsy there was neuronal loss and gliosis in the substantia nigra in all (Zimprich et al., 2004). Yet, although all 6 had parkinsonism, some cases only had dopaminergic neuronal loss and gliosis without Lewy bodies, whereas others had dopaminergic neuronal loss and gliosis associated with Lewy bodies (Zimprich et al., 2004). In the latter cases, Lewy bodies were restricted to the brainstem, or widespread in brainstem and cortex. In one case, there were also tau-immunoreactive lesions not only in neurons, but also in glial cells (Zimprich et al., 2004). These data support the view that inflammation is a generic phenomenon that arises from neuronal death irrespective of the type of parkinsonian syndrome or neuropathological picture. It also suggests that the presence of Lewy bodies is not a prerequisite for the occurrence of inflammation in PD and related conditions. This view is also consistent with parkin mutation-linked parkinsonism, which is a recessive form of PD with a loss of dopaminergic neurons, typically not associated with Lewy bodies, but with gliosis (Hayashi et al., 2000). To date, however, although the occurrence of gliosis in all of these conditions is clearly indicated, unlike in PD, no comprehensive qualitative or quantitative analysis of these alterations has been published and simple information such as whether the reported gliosis refers to astrocytes, microglia, or to both is in most instances lacking.

26.5. Description of the neuroinflammatory response in experimental models of Parkinson’s disease Experimental models of PD are multiple and can be genetic or toxic (Dauer and Przedborski, 2003). The neuropathological picture found in these models is often very similar to that found in PD itself. In almost

all of the PD models, some indications can be found about the fact that the demise of nigrostriatal dopaminergic neurons is associated with a glial response. However the amount of data regarding inflammation in these different models is quite disparate. For instance, if some data on inflammation are available for the herbicide paraquat (McCormack et al., 2002) and mitochondrial poison rotenone (Sherer et al., 2003) and even for transgenic mice expressing mutant a-synuclein (Gomez-Isla et al., 2003), it is incomparable to the wealth of information readily available for the 6-hydroxydopamine (6-OHDA) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxic models of PD. Of note, the type and magnitude of glial alterations in rodents following the administration of 6-OHDA (Stromberg et al., 1986; Akiyama and McGeer, 1989; Sheng et al., 1993; Przedborski et al., 1995; He et al., 1999; Nomura et al., 2000; Rodrigues et al., 2001) appear very similar to those seen following the administration of MPTP (see below). Thus, to avoid unnecessary repetitions, the description of the glial response in experimental models of PD will be limited to those reported in the MPTP model. The beauty of the latter resides in the fact that data on the glial response are available from MPTP-intoxicated humans, to monkeys, to rodents. In the few MPTP-intoxicated individuals who came to autopsy, postmortem examination revealed a paucity of nigrostriatal dopaminergic neurons accompanied by the presence of numerous small cells intensely immunoreactive for either the astrocytic marker GFAP or for the microglial marker HLA-DR (Langston et al., 1999). Almost all of the stained cells did show morphological characteristics of reactive astrocytes and activated microglia (Langston et al., 1999). Images of neuronophagia were also often seen in these nigrostriatal specimens (Langston et al., 1999). Although no formal quantification has been performed, it appears that the greater the abundance of GFAP- and HLA-DR-positive cells, the more profound the loss of dopaminergic neurons (Langston et al., 1999). Based on these neuropathological data (Langston et al., 1999), it also appears that more astrocytes adopted a reactive morphology in the postmortem samples from MPTP-intoxicated individuals than from PD. A comparable observation was made in 6 monkeys who survived 5–14 years after exposure to MPTP (McGeer et al., 2003) in that evidence of extracellular neuromelanin and activated microglia in the substantia nigra was documented (Table 26.1). From a neuropathological standpoint, microglial activation and neuronophagia are indicative of an active, ongoing inflammatory process. Although this assertion is consistent with the fact that PD is a progressive condition,

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Table 26.1 Dopaminergic neurodegeneration and microglial activation in eight elderly rhesus monkeys (Macaca mulatta) treated with MPTP Activated microgliaa Age Years after Type of Monkey (years) treatment treatment

M1

17

11

M2

15.5

10

M3

11

5.5

M4

18

14

M5

18

14

M6 M7 M8

20 18 16

11 Control Control

Right ICA, 0.95 mg/kg Bilateral, IV, 2 mg/kg Right ICA, 1.5 mg/kg Bilateral, IV, 2 mg/kg Right ICA, 0.7 mg/kg Right ICA, 0.51 mg/kg No treatment No treatment

SN cell lossb

Free melaninc

Ipsilateral Contralateral Ipsilateral Contralateral Ipsilateral Contralateral

3

2

4

1

3

3

3

3

3

3

4

4

2

2

2

0

3

3

4

4

3

3

3

3

3

1

2

0

3

2

1 0 0

0 0 0

2 0 0

1 0 0

4 1 1

4 1 1

a

Microglial activation: 4, very strong; 3, strong; 2, moderate; 1, weak; 0, none. Degree of nigral TH-positive neuronal loss: 4, complete depletion; 3, very severe depletion; 2, severe depletion; 1, moderate depletion; 0, no depletion (normal). c Amount of free melanin: 4, very large; 3, large; 2, moderate; 1, weak; 0, none. SN, substantia nigra; ICA, intracarotid administration. Reproduced from McGeer et al. (2003), with permission from the American Neurological Association. b

it challenges, as stated by McGeer and collaborators (2003), the tenet that MPTP would ‘produce an acute loss of cells, followed by healing and long-term stabilization of surviving neurons’. Instead, both the human and monkey neuropathological data suggest that a single acute MPTP insult can set in motion a selfsustained cascade of cellular and molecular events with long-lasting detrimental effects on dopaminergic neurons. Supporting this interpretation is the positron emission tomography demonstration, performed twice, 7 years apart, on 10 individuals exposed acutely to MPTP, which revealed a worsening of striatal [18F] fluorodopa uptake in these patients (Vingerhoets et al., 1994). Furthermore, among the MPTP-intoxicated individuals who participated in this study, 3 apparently developed parkinsonism between the first and the second scan (Vingerhoets et al., 1994). Mice injected with MPTP and killed at different time points after the last injection show that the appearance of reactive astrocytes parallels the destruction of dopaminergic structure in both the striatum and the substantia nigra (Fig. 26.1) and that GFAP expression remains high even after the main wave of neuronal death has passed (Czlonkowska et al., 1996; Kohutnicka et al., 1998; Liberatore

et al., 1999). Remarkably, the blockage of the uptake of the active metabolite of MPTP, 1-methyl-4-phenylperydinium (MPPþ), into dopaminergic neurons not only completely prevents substantia nigra dopaminergic neuronal death, but also GFAP upregulation (O’Callaghan et al., 1990). Collectively, these findings are consistent with the view that in the MPTP model, as in PD, the astrocytic reaction is consequent to the death of neurons and not the reverse. As for the activation of microglial cells (Fig. 26.1), which is well documented in the MPTP mouse model (Czlonkowska et al., 1996; Kohutnicka et al., 1998; Liberatore et al., 1999; Dehmer et al., 2000), it occurs earlier than that of astrocytes and, more importantly, it peaks before that of dopaminergic neurodegeneration (Liberatore et al., 1999). In light of the MPTP data presented above and illustrated in Fig. 26.1, it can thus be surmised that the response of both astrocytes and microglial cells to the demise of substantia nigra dopaminergic neurons clearly occurs within a timeframe allowing these glial cells to participate in the neurodegeneration of the nigrostriatal pathway in the MPTP mouse model. There have also been some descriptive data from Czlonkowska and collaborators (Kurkowska-Jastrzebska

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S. PRZEDBORSKI Days after MPTP s

0 0.5 1

2

4

7

21

MAC-1

- 165 kDa

GFAP

- 45 kDa

β-actin

- 42 kDa

120

** **

80

*

60 30 0 s0

B

Ratio GFAP/β-actin 100

Ratio MAC-1/β-actin 100

A

3

6

9

60

**

*

30

* 15 s

12 15 18 21

Days after MPTP

** *

45

s0

3

C

6

9

12 15 18 21

Days after MPTP

D

E

F

G

H

I

Fig. 26.1. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced glial reaction. (A–C) Ventral midbrain MAC-1 (A and B; Mac-1 is also knowm as CD11b/CD18) and glial fibrillary acid protein (GFAP: A and C) expression is minimal in salineinjected mice (S), but increases in a time-dependent manner after MPTP injection. Data represent mean sem (n ¼ 4–5). **P < 0.01; *P < 0.05, compared with saline, Newman–Keuls post-hoc test. (D–I) There is a robust MAC-1 (D) and GFAP (G) immunostaining in the substantia nigra pars compacta of MPTP-treated mice compared with that in saline-treated control mice (F and I) at 24 hours after injection. (E and H) Magnification of the boxed areas in D and G shows that the MAC-1- and GFAP-immunoreactive cells in the MPTP-treated mice seem to have a morphology typical of activated microglia cells (E) and of reactive astrocytes (H). Scale bars represent 200 mm (D, F, G, I; shown in D) and 15 mm (E, H; shown in E). From Liberatore GT, Jackson-Lewis V, Vukosavic S et al. (1999). Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5: 1403–1409, with permission from Nature Publishing Group.

et al., 1999a, b) about the response of the adaptive immune system. For instance these authors have found in mice a marked increase of MHC-II antigen expression by microglia as well as a recruitment of T cells in both ventral midbrain and striatum after the administration of MPTP. Conversely, these researchers failed to identify any B cells in these tissue samples. Based on these studies, it appears that the infiltrating T cells were mainly of the CD8þ type, but some CD4þ were present too and more than 50% of the observed lymphocytes expressed the CD44 antigen.

26.6. What role does neuroinflammation play in Parkinson’s disease? In the context of neurodegeneration, the inflammatory and in particular the glial response has typically been regarded as triggered by the death of neurons and whose sole role was to eliminate the cellular debris. It is only recently that the idea has gained recognition that both innate and adaptive immune cells, such as microglia and T cells, could influence the fate of compromised neurons. One significant correlate of this assertion is that the death of specific neurons in a

NEUROINFLAMMATION AND PARKINSON’S DISEASE given neurodegenerative disease might not be as cellautonomous as initially thought. Relevant to this concept is the study performed in chimeric mice that are mixtures of normal- and mutant superoxide dismutase-1 (SOD1)-expressing cells (Clement et al., 2003). In this work it appears that toxicity to motor neurons in this model of amyotrophic lateral sclerosis does require damage from mutant SOD1 acting within non-neuronal cells and non-neuronal cells that do not express mutant SOD1 delay degeneration of mutantexpressing motor neurons. Regarding the role that glial cells could play within the neurodegenerative process, Streit (2002) points out that for the last decade there have been intense discussions on whether inflammation and especially activated microglia are beneficial or harmful to neurons. In PD, as in other pathological situations, the dispute emanates from the fact that studies in cell culture and to a lesser extent in animal models of PD have demonstrated both neuroprotective and neurotoxic effects of inflammation. One example that kindles the controversy is the demonstration that the blockade of the microglial activation by minocycline has been associated with either reduction or augmentation of dopaminergic neurodegeneration after MPTP administration (Du et al., 2001; Wu et al., 2002; Yang et al., 2003; Diguet et al., 2004). Perhaps the divergence of opinion regarding the role of inflammation in PD and related conditions could be resolved by accepting the idea that inflammation in general and microglia in particular are capable of performing both neuroprotective and neurodestructive functions and that, depending on local factors, extent of the degenerative process and even possibly the etiology of the disease in question, inflammation can give rise to quite distinct outcomes. 26.6.1. Neuroinflammation is neuroprotective Although not performed in PD or in PD models per se, several in vivo observations strongly support a neuroprotective and neuroregenerative role of inflammation and microglia in the injured CNS. One of the most prototypical examples of such beneficial effects of inflammation is the facial nerve axotomy paradigm in newborn rats and rabbits in which axotomized motor neurons exhibit signs of recovery that coincide with the development of a glial response (Moran and Graeber, 2004). It has also been shown that 2–5 weeks after implantation of microglia cells into a small mechanically produced cavity in the rat spinal cord, prominent neuritic growth was observed in microglial grafts (Rabchevsky and Streit, 1997). These results agree with Streit’s position (2002), which is that under both normal and pathological conditions, neuronal

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well-being and proper functioning are highly dependent on the presence of large numbers of glial cells that sustain an abundance of neuron-supporting functions. In keeping with this latter view, it should be remember that various types of glia and T cells in mature and, to a greater extent, in immature tissues can indeed provide a host of trophic factors that are essential for the survival of dopaminergic neurons. Among these, glial-derived neurotrophic factor (GDNF), which is released by reactive astrocytes (Schaar et al., 1993) and by activated microglia following a mechanical lesion of the striatum (Batchelor et al., 2000), seems to be the most potent factor supporting nigrostriatal dopaminergic neurons during their period of natural, developmental death in postnatal ventral midbrain cultures (Burke et al., 1998). It is also worth emphasizing that GDNF induces dopaminergic nerve fiber sprouting in the injured rodent striatum (Batchelor et al., 1999) and that this effect is markedly decreased when GDNF expression is inhibited by intrastriatal infusion of antisense oligonucleotides (Batchelor et al., 2000). Brain-derived neurotrophic factor (BDNF) is another trophic factor that can also be released by reactive astrocytes (Rubio, 1997; Stadelmann et al., 2002), by activated microglia (Batchelor et al., 1999; Stadelmann et al., 2002) and that can support the survival and outgrowth of dopaminergic structures in the striatum (Batchelor et al., 1999). It should also be emphasized that oligodendrocytes have emerged as a source of potent trophic factors (Du and Dreyfus, 2002). For instance, it was shown that striatal oligodendrocytes greatly improve the survival and phenotype expression of mesencephalic dopaminergic neurons in culture, while simultaneously decreasing the apoptotic demise of these cells (Sortwell et al., 2000). Aside from the fact that glial cells are pivotal to neuronal well-being, by maintaining ion and pH homeostasis and extracellular volume, they can also protect these cells against damage by scavenging toxic molecules released by the dysfunctional and dying neurons. With respect to the dopaminergic neurons, dopamine can produce reactive oxygen species (ROS) through different routes (Przedborski and Jackson-Lewis, 2000). Along this line, glial cells may protect remaining neurons against the resulting oxidative stress by metabolizing dopamine via monoamine oxidase-B and catecholO-methyl transferase present in astrocytes and by detoxifying ROS through the enzyme glutathione peroxidase, which is detected almost exclusively in astrocytes (Hirsch et al., 1999). In contrast to glial cells, neurons lack the uptake system for cysteine (Pow, 2001) and thus rely heavily on astrocytes for

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their synthesis of glutathione (Dringen, 2000), which is a tripeptide of great importance in the protection of the brain against ROS. Up to now, however, how astrocytes assist neurons in their production of glutathione remains incompletely understood. It is hypothesized (Dringen, 2000) that astrocytes achieve this goal by using various extracellular substrates as precursors for glutathione. The latter, once released from astroglial cells, would then become a substrate for the astroglial ectoenzyme gamma-glutamyltranspeptidase and the generated dipeptide CysGly would serve as a precursor of neuronal glutathione. It is also proposed (Dringen, 2000) that glutamine, which is released from astrocytes, would be used by neurons as a precursor for the glutamate necessary for glutathione synthesis. Finally, astrocytes, which can avidly take up extracellular glutamate via the glutamate transporters GLT1 and GLAST, may mitigate the presumed harmful effects of the subthalamic excitotoxic input to the substantia nigra (Benazzouz et al., 2000), which is hyperactive in PD (DeLong, 1990). Taken together, the data reviewed here support the contention that glial cells and especially astrocytes could play neuroprotective roles in PD. Whether any of those dampen the neurodegenerative process in parkinsonian patients remains to be demonstrated. 26.6.2. Neuroinflammation and neurodegeneration If, as advocated by Streit (2002), the primary purpose of glial cells is to support neuronal function, it may be challenging to put forth a pathological scenario that transforms these cells into harmful effectors. Nevertheless, one cannot ignore the rapidly growing number of observations consistent with the point of view that activation of the innate immune system and especially of microglia exacerbates pre-existing or concomitant neuronal dysfunction and degeneration. The importance of activated microglial cells in the neurodegenerative process is underscored by the demonstration that the stereotaxic injection of bacterial endotoxin lipopolysaccharide (LPS) into the substantia nigra pars compacta of adult rats is associated with a local activation of microglia and an ensuing degeneration of dopaminergic neurons (Liu et al., 2000b), presumably mediated by IL-1b and caspase-11 (Arai et al., 2004). Similarly, LPS-induced microglial activation led to neurodegeneration of dopaminergic MES23.5 cells or primary ventral midbrain neurons only when co-cultured with purified microglia (Le et al., 2001). (Hybridoma cell line MES23.5: rat/mouse mesencephalon mouse neuroblastoma N18TG2 cells.) In an attempt to reconcile the inherent supportive role of glial cells with their observed detrimental actions, Streit (2004) has pioneered the concept of

glial cell senescence. According to this author, glial cells, such as microglia, would become progressively disabled during normal aging or in pathological situations, thus losing their functional capacity to support neurons and hence neurons would slowly degenerate. Although this idea is appealing, there is thus far no compelling data to support such a scenario in neurodegenerative diseases such as PD and investigations performed in animal models of PD rather suggest a more direct noxious role of inflammation in the demise of dopaminergic neurons. It has been proposed that perhaps the apparent detrimental actions of glial cells result from a phenomenon of facilitative neurotoxicity (Streit, 2002). Based on this model, glial cells will only eliminate neurons that have been compromised beyond viability and functionality by the primary pathological event. Here, glial cells would take on an active role in the demise of neurons that are destined to die and whose continued presence would not be beneficial in promoting neuronal recovery. Finally, as dubious as some experts believe this to be, one cannot exclude the fact that, upon activation, glial cells in brain parenchyma would exert indiscriminate neurotoxicity, which can significantly stimulate neurodegeneration and promote both the progression and propagation of a disease such as PD. This last scenario is not so unrealistic since it is well established that activated microglial cells can produce a variety of noxious compounds, including ROS, reactive nitrogen species, proinflammatory prostaglandins and cytokines. Among the array of reactive species produced by glial cells, lately significant attention has been given to reactive nitrogen species due to the prevalent idea that nitric oxide (NO)-mediated nitrating stress could be pivotal in the pathogenesis of PD (Przedborski et al., 1996, 2001; Ara et al., 1998; Pennathur et al., 1999; Giasson et al., 2000). It is particularly relevant to mention that numerous astrocytes in the substantia nigra pars compacta of PD patients (Hunot et al., 1996) and microglia in the substantia nigra pars compacta of MPTP-intoxicated mice (Liberatore et al., 1999; Dehmer et al., 2000), but not of controls, are immunoreactive for inducible NO synthase (iNOS). Upon its induction, this NOS isoform produces high amounts of NO (Nathan and Xie, 1994) as well as superoxide radicals (Xia and Zweier, 1997) – two reactive species that can either directly or indirectly promote neuronal death by inflicting oxidative damage. It should also be mentioned that a main source of glial-derived ROS emanates from the microglial enzymatic complex NADPH-oxidase, which upon its induction and activation can produce large amounts of superoxide radicals (Colton et al., 1996). This parti-

NEUROINFLAMMATION AND PARKINSON’S DISEASE cular multiunit enzymatic complex has been reported to be activated in the substantia nigra pars compacta of both PD patients and mice intoxicated with MPTP (Wu et al., 2002, 2003) and the genetic inactivation of NADPH-oxidase has been shown to mitigate MPTP-induced neurodegeneration in mice (Wu et al., 2003). Prostaglandins and their synthesizing enzymes, such as Cox-2, constitute a second group of potential culprits. Indeed, Cox-2 has emerged as an important determinant of cytotoxicity associated with inflammation (O’Banion, 1999). In the normal basal ganglia, Cox-2 is minimally expressed (Teismann et al., 2003). However, in both PD and MPTP mouse tissues, Cox-2 expression in the brain can increase significantly, as do the levels of its products such as prostaglandin E2 (Mattammal et al., 1995; Teismann et al., 2003). In the MPTP mouse model of PD, it was shown that Cox-2 was induced via a c-Jun N-terminal kinasedependent mechanism (Teismann et al., 2003; Hunot et al., 2004), whose blockade, like that of Cox-2 itself, attenuates neurodegeneration (Teismann et al., 2003; Hunot et al., 2004). Of note, although Cox-2 does modulate MPTP-induced dopaminergic neurotoxicity, its isoenzyme Cox-1 was ineffective in doing so (Teismann et al., 2003). A third group of glial-derived compounds that can inflict damage in PD is the proinflammatory cytokines. Several among these, including tumor necrosis factora (TNF-a) and IL-1b, are increased in both substantia nigra pars compacta tissues and cerebrospinal fluid of PD patients (Mogi et al., 1994, 1996, 2000), although some of the reported alterations may be related to the chronic use of the anti-PD therapy levodopa (Bessler et al., 1999). Nevertheless, at autopsy convincing immunostaining for TNF-a, IL-1b and interferongamma (IFN-g) is observed in substantia nigra pars compacta astrocytes from PD patients (Hunot et al., 1999). These cytokines may act in PD on at least two levels. First, although they are produced by reactive astrocytes, they can stimulate other astrocytes and even microglia not yet activated, amplifying the inflammatory response and consequently the glialrelated injury to neurons. Relevant to this view is the demonstration that astrocyte-derived TNF-a, IL-1b and IFN-g stimulate the expression of the cell surface receptor Fc-e-R11/CD23 by microglia (Hunot et al., 1999). Then, upon ligation of Fc-e-R11/CD23, activated microglia induce iNOS expression, leading to NO production which, in turn, can amplify the production of cytokines by astrocytes and diffuse to neighboring neurons. Second, astrocytic and microglial-derived cytokines may also act directly on dopaminergic neurons by binding to specific cell surface cytokine recep-

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tors such as TNF-a receptor and FAS receptor. In connection with these, it must be stressed that investigations on TNF-a have generated confusing results in the MPTP mouse model in that ablation of both TNF-a receptor-1 and -2 did not impact MPTPinduced dopaminergic neurodegeneration (Rousselet et al., 2002), whereas ablation of TNF-a and the pharmacological inhibition of its synthesis did attenuate MPTP toxicity in mice (Ferger et al., 2004). As for FAS, its expression appears increased in mouse ventral midbrain after MPTP injection and mice deficient in this plasma membrane receptor were found more resistant to MPTP injections compared to their wild-type littermates (Hayley et al., 2004). Once activated, these cytokine receptors trigger intracellular death-related signaling pathways, whose molecular correlates include translocation of the transcription nuclear factor-k-B (NF-k-B) from the cytoplasm to the nucleus and activation of the apoptotic machinery, whose implication in the overall mechanism of dopaminergic neuronal death seems quite significant (Vila and Przedborski, 2003). PD patients exhibit a 70-fold increase in the proportion of dopaminergic neurons with NF-k-B immunoreactivity in their nuclei compared to control subjects (Hunot et al., 1997). Despite the robust recruitment of NF-k-B, it is not clear whether this transcriptional factor is instrumental in PD pathogenesis, as mice deficient in one of NF-k-B main polypeptides, p50, had their nigrostriatal pathway as severely damaged by MPTP as that in their wild-type counterparts (Hunot et al., 2004).

26.7. Conclusion and therapeutic perspective It seem clear from the above discussion that several lines of evidence indicate that both morphological and functional indices of inflammation are encountered in the diseased areas of the PD brain, other prominent sporadic and familial parkinsonian syndromes, as well as experimental models of PD. Thus far, most attention has been given to the innate immune response, involving the resident inflammatory cells such as astrocytes and microglia. In striking contrast is the limited amount of information currently available about the adaptive immune response in PD and related conditions. This discrepancy may be explained by the fact that brain inflammation in neurodegenerative disorders, as stressed by McGeer and McGeer (2004), is thought to be primarily a local immune reaction that occurs without significant involvement of adaptive immune cells. However, there are some descriptive studies, performed in both PD autopsy material and in the MPTP mouse model, that have begun to examine the status of T cells in damaged

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brain areas (McGeer et al., 1988a; Kurkowska-Jastrzebska et al., 1999a, b). As for, B cells and immunoglobulin, it has been reported by several groups that antibodies to dopaminergic neurons are found in the cerebrospinal fluid of PD patients (Emile et al., 1980; Defazio et al., 1994; Rowe et al., 1998) and that the stereotaxic injection of PD immunoglobulin G into the mouse substantia nigra provokes the degeneration of dopaminergic neurons (Chen et al., 1998). Collectively, these data support the idea that if the innate immune response is the chief cellular component of brain inflammation seen in PD and related conditions, there is unmistakable evidence supporting the involvement of the adaptive immune system as well. Given this fact, additional studies geared toward better characterizing the adaptive immune system in PD and related conditions are certainly warranted. Popular experimental models of PD, such as that generated by the neurotoxin MPTP, produce a more severe and acute degenerative event accompanied with a more robust inflammatory reaction than that occurring in PD. Despite these striking departures from PD neuropathology, the experimental models of PD discussed in this chapter have been and continue to be critical in our ability to ascertain the role of inflammation in the degeneration of the nigrostriatal pathway. Based on the large body of literature discussed above, the current belief that emerged about inflammatory reaction in PD is that it appears more often endowed with deleterious properties, capable of exacerbating dopaminergic neuronal death, rather than with beneficial effects, capable of mitigating neurodegeneration or even promoting repair of the nigrostriatal pathway. Should this view be correct, targeting cellular and molecular aspects of brain inflammation may have far-reaching implications for the treatment of neurodegenerative disorders such as PD. Along this line, three very different strategies of treatment may be envisioned. First, attempts to prevent the glial reaction and more specifically the microglial activation may be foreseen. Several preclinical studies have successfully prevented microglial activation, especially in the MPTP and 6-OHDA models of PD with a variety of agents, whose molecular basis of their anti-inflammatory actions often remains enigmatic. These agents include, for example, the antibiotic minocycline (Du et al., 2001; He et al., 2001; Wu et al., 2002), the peroxisome proliferator-activated receptor-gamma agonist pioglitazone (Breidert et al., 2002), the vasoactive intestinal peptide (Delgado and Ganea, 2003) and some opiate receptor antagonists (Liu et al., 2000a). Because we begin to acquire a deeper understanding of the microglial molecular pathways responsible for

their activation (Bhat et al., 1998; Pyo et al., 1998; Taylor et al., 2005), more specific agents to prevent microglial activation are likely to emerge in the near future. Second, therapeutic strategies can also be aimed at blocking the effects of specific proinflammatory mediators without searching to mitigate glial response per se. As discussed above, factors such as iNOS-derived NO (Liberatore et al., 1999), NADPH-oxidase-derived ROS (Gao et al., 2003; Wu et al., 2003) or caspase-11 (Furuya et al., 2004) could all be considered as suitable therapeutic targets. With no exception, preclinical studies, especially performed in the MPTP mouse model of PD, have shown that these kinds of proinflammatory factors are capable of causing neurotoxic phenotypes and that their ablation attenuates neurodegeneration. In all of these studies, however, the beneficial effects provided by the blockade of one of these proinflammatory factors provided only mild protection. This fact should not preclude the significance of these findings, but argues that multiple such factors may have to be inhibited simultaneously before any substantial neuroprotection is observed and that improvement in the quality of life of PD patients can be expected. Third, immunization strategies with CNS antigens expressed at the lesion site have been shown to induce T cells to enter inflamed CNS tissue, attenuate innate glial immunity and increase local neurotrophic factor production. For instance, in the MPTP mouse model of PD, vaccination with glatiramer acetate, a random amino acid polymer that generates non-encephalitic T cells, which cross-react with myelin basic protein, did confer protection against dopaminergic neurodegeneration (Benner et al., 2004). In this work, glatiramer acetate-immune cells administered to MPTPintoxicated mice by adoptive transfer entered inflamed brain regions, suppressed microglial responses and increased expression of GDNF (Benner et al., 2004). These preclinical data suggest that vaccination strategies with antigens derived from prominent proteins residing in the site of neurodegeneration deserve to be tested further for their potential in mitigating inflammation and ensuing demise of dopaminergic neurons in PD and related conditions.

Acknowledgments The author thanks Mr. Matthew Lucas for his assistance in preparing this manuscript and is supported by National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) Grants (R01 NS42269, R01 NS38370 and P01 NS11766), NIH National Institute on Aging Grant (R01AG 21617),

NEUROINFLAMMATION AND PARKINSON’S DISEASE National Institute of Environmental Health Sciences (NIEHS) Grant (R21 ES013177), U.S. Department of Defense (DAMD) Grant (17-03-1), Parkinson’s Disease Foundation (New York, USA) and the Muscular Dystrophy Association/Wings-over-Wall Street.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 27

Excitotoxicity CLAIRE HENCHCLIFFE* AND M. FLINT BEAL Weill Medical College of Cornell University, Department of Neurology and Neuroscience, New York, NY, USA

27.1. Introduction Major strides have been made over the last decade in understanding the underlying pathophysiology of Parkinson’s disease (PD). In particular, studies of proteins identified via genetic approaches in heritable PD, such as parkin and a-synuclein, have been pivotal in developing current models of dopaminergic cell loss. However, it is increasingly recognized that multiple other factors may contribute to propagation of the neurodegenerative process. Identifying the culprits will open new avenues to develop novel therapies (Koller and Cersosimo, 2004). Excitotoxicity is neuronal cell death resulting from excitatory amino acid receptor activation. The term was coined by Olney in 1969, but Lucas and Newhouse (1957) had previously demonstrated neurotoxicity in murine retina as a consequence of administration of the excitatory amino acid, glutamate. A large body of evidence implicates excitotoxicity in neurologic diseases in both the acute setting (acute cerebral ischemia, epilepsy, trauma) by necrosis and in neurodegenerative processes resulting from milder injury, possibly by apoptosis. Excitotoxic neuronal damage is suggested to contribute to PD, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and Alzheimer’s disease (AD). The excitatory neurotransmitter, glutamate, causes neuronal damage through excitotoxic mechanisms (Schwartz et al., 2003; Bruijn et al., 2004) and the N-methyl-D-aspartate (NMDA) receptor pathway has been extensively studied in this regard. Changes in glutamatergic neurotransmission are a feature of several neurodegenerative disorders, including PD, and a number of findings have served to highlight the importance of glutamate in PD, in particular its

enhanced activity in the basal ganglia. Interventions that modulate glutamate activity are both in use and under testing in PD, with the aim of alleviating parkinsonian signs and symptoms. Whether these same agents could also provide a means of neuroprotection remains controversial. This chapter will review current understanding of how excitotoxic cell damage and death occur, will describe the role altered glutamatergic neurotransmission is thought to play in PD and will review evidence for excitotoxicity in neuronal cell loss in PD and its in vitro and animal models.

27.2. Mechanisms of excitotoxicity 27.2.1. The glutamate-NMDA receptor pathway Glutamate’s excitotoxic effects are primarily via its NMDA receptor and calcium influx is crucial to delayed excitotoxic cell death from this neurotransmitter (Choi, 1987). Glutamate is the primary excitatory amino acid neurotransmitter in the central nervous system and brain tissue contains high levels of glutamate (10 mmol/kg). Glutamate receptors are widespread: approximately 70% of excitatory synapses are stimulated by glutamate and glial cells also express glutamate receptors. Its function is vital to the workings of neuronal circuitry in the brain and spinal cord. However, under certain conditions, neuronal cell death can result from activation of glutamate receptors. The level of glutamate in the extracellular milieu is therefore tightly controlled under normal circumstances. Glutamate is released presynaptically in vesicles via several mechanisms, including a calcium-dependent mechanism involving N- and P/Q-type calcium channels. Glutamate release is counterbalanced by uptake

*Correspondence to: Claire Henchcliffe, Weill Medical College of Cornell University, Department of Neurology and Neuroscience, 428 East 72nd Street, Suite 400, New York, NY 10021, USA. E-mail: [email protected], Tel: þ1-212746-2584, Fax: þ1-212-746-8296.

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mediated by a variety of transporters (Danbolt, 2001). The glutamate transporter family, or Naþ/Kþ-coupled excitatory amino acid transporters (EAAT1–EAAT5), plays a major role in clearing extracellular glutamate. Glutamate receptors are categorized in two groups: ionotropic and metabotropic (Fig. 27.1). The ionotropic receptors are directly coupled to cationic channels, while metabotropic receptors (mGluR) are coupled to G-proteins, mediating subsequent activation of intracellular signaling cascades. 27.2.1.1. Ionotropic glutamate receptors Development of glutamate analogs, as well as identification of naturally occurring excitotoxins, has facilitated indepth characterization of the different ionotropic glutamate receptors. They are classified into: (1) NMDA; (2) a-amino-3-hydroxy-5-methylisoxazole propionate (AMPA); and (3) kainate receptors. Each is composed of multiple subunits, with characteristic pharmacologic and physiologic properties depending upon which particular combination of subunits is present. Splice variants of some subunits further contribute to diversity (Dingledine et al., 1999). NMDA receptors are composed of subunits NMDAR1 in combination with NMDAR2 (with splice

variants A–D for the R2 subtype). A less common R3 is sometimes present. The NMDAR2 subunit confers the particular kinetic properties of channel opening and the effect of the different antagonists depends on the exact structure of NMDAR2. Activation of the NMDA receptor is complex, as glycine is required as a co-agonist. Each receptor has two sites for glutamate binding and two for glycine binding, with both required for channel opening. In addition, Mg2þ may block NMDA receptors in a voltage-dependent fashion. These receptors are mainly present in neurons and when activated allow calcium influx. AMPA and kainate receptors are also comprised of multiple subunits. AMPA receptor subunits Glu1–4 have been characterized and during RNA processing are subject to alternative splicing. Kainate receptors are formed of multimeric assemblies of GLUK5–7 and GLUK1 and 2 subunits. AMPA and kainate receptors are present in both neurons and glia. Activation of AMPA receptors postsynaptically, by allowing Naþ influx and Kþ efflux, can lead to membrane depolarization that releases the voltage-dependent Mg2þ NMDA blockade of NMDA receptors. This can therefore result in calcium influx via the NMDA receptor-coupled ion channel. This depolarization

Fig. 27.1. Three classes of glutamate (GLU) receptors regulate glutamate signaling. The ionotropic receptors comprise the N-methyl-D-aspartate (NMDA) receptor and the more closely related a-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) and kainate receptors. All are comprised of multiple subunits. The NMDA receptor, which has been best studied in excitotoxic processes, regulates a channel allowing influx of Ca2þ, necessary for excitotoxicity. It is gated by Mg2þ and requires glycine (GLY) as a co-agonist. The AMPA and kainate receptors regulate a channel allowing influx of Naþ and efflux of Kþ. Some AMPA receptors allow permeability to Ca2þ. Metabotropic receptors, designated mGluR1 to mGluR5, activate second-messenger systems. The receptors are linked to G-proteins (G) and activate phospholipase C (PLC), thus triggering a signaling cascade involving second messengers, including inositol 1,4,5-triphosphate (IP3).

EXCITOTOXICITY may also allow further calcium influx by activation of voltage-dependent Ca2þ channels. 27.2.1.2. Metabotropic glutamate receptors The metabotropic glutamate receptors fall into three groups, based on agonist selectivity, the particular second-messenger systems activated and by sequence homologies. Each group comprises receptors that are distinguished by their exact protein sequence, designated mGluR1–mGluR5. Their expression is more limited than that of the ionotropic receptors. Although all subtypes are detected in the striatum (Testa et al., 1994), mGluR1 and mGluR5 are highly expressed by cholinergic and GABAergic interneurons (TallaksenGreene et al., 1998; Pisani et al., 2001). These two subtypes, in addition to mGluR4, are also found in GABAergic neurons within the striatopallidal and striatonigral tracts (Testa et al., 1995, 1998; Bradley et al., 1999; Hanson and Smith, 1999). In contrast, mGluR2/3 receptors are found at the termini of corticostriatal neurons, that use glutamate as a neurotransmitter (Testa et al., 1998). Within the substantia nigra (SN), mGlu1 (and some mGlu5) are present in the pars compacta (SNpc) (Testa et al., 1994, 1998; Kosinski et al., 1998; Hubert et al., 2001), with mGluR3 also expressed in the pars reticulata (SNpr). Neurons within the subthalamic nucleus (STN) possess mGluR5 localized within the postsynaptic membrane and mGluR2 presynaptically (Testa et al., 1994; Awad et al., 2000; Bradley et al., 2000). 27.2.2. Calcium influx mediates excitotoxicity Calcium influx is required for delayed excitotoxic cell death mediated by glutamate (Choi, 1987). Neuronal degeneration in cortical cell cultures correlates with calcium load, but not intracellular concentration (Hartley et al., 1993; Eimerl and Schramm, 1994) and it is thought that the calcium load induced is actually sequestered in the mitochondria, effectively buffered by Naþ/Ca2þ exchange (Tymianski et al., 1993a; Wang et al., 1994; White and Reynolds, 1995). Excitotoxicity can be blocked by preventing mitochondrial calcium uptake, despite increased intracellular calcium (Stout et al., 1998; Nicholls and Budd, 2000), as well as by calcium chelators (Tymianski et al., 1993b). Release from the mitochondrial compartment likely also contributes to cellular demise (Frandsen and Schousboe, 1991; Lei et al., 1992). Mitochondrial calcium sequestration results in opening of the permeability transition pore complex, with resulting release of cytochrome c and other factors important in mediating apoptosis. A role for Naþ influx, in addition to calcium, has also been suggested (Hasbani et al., 1998; Ikegaya et al., 2001).

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In cultured hippocampal neurons, there are three phases of change in intracellular calcium (Randall and Thayer, 1992). In the first 5–10 minutes, intracellular calcium increases. This is followed by a latent phase of approximately 2 hours, during which calcium levels return to normal. Next, there is a gradual sustained rise in intracellular calcium with a plateau associated with cell death. Several mechanisms likely interplay in a complex series of intersecting cascades which bring about neuronal cell damage and death subsequent to increased calcium load (Fig. 27.2). NMDA receptor activation triggers intracellular signaling pathways in a specific pattern, dependent upon receptor coupling to the scaffolding protein PSD-95 (postsynaptic density-95) (Sattler et al., 1999; Aarts and Tymianski, 2004). Phosphatidyl-inositol 3-kinase (PI 3-kinase) plays a central role in signaling and blocking its activation by wortmannin or LY294002 prevents NMDA-induced mitogen-activated protein (MAP) kinase activation (Perkinton et al., 2002). Furthermore, PI 3-kinase directs activation of the serine-threonine kinase Akt, that acts upon multiple substrates, including transcription factors (Perkinton et al., 2002). However, not all downstream effects of NMDA receptor activation are blocked by PI 3-kinase inhibitors and there are likely multiple intersecting pathways involved (Crossthwaite et al., 2004). Other processes implicated as part of the downstream cascade include activation of nitric oxide synthase (NOS) (Mungrue and Bredt, 2004), proteases, endonucleases, inhibition of protein synthesis, mitochondrial damage (Nicholls, 2004) and free radical generation. These have profound consequences for cellular function as well as structure; for example, NMDA activation was shown to lead to phosphorylation of tau cytoskeletal proteins and structural changes (Couratier et al., 1996a, b). 27.2.3. Free radical generation in excitotoxic cell death Several avenues of evidence serve to demonstrate a link between free radicals and the excitotoxic process. In cultured cerebellar neurons, an NMDA dose-dependent increase in superoxides is detected by electron paramagnetic resonance (Lafon-Cazal et al., 1993) and this can be blocked by removing extracellular calcium or by adding NMDA antagonists. NMDA, AMPA and kainic acid induce free radical generation (Sun et al., 1992; Bondy and Lee, 1993). Dykens and colleagues (1987) originally showed that kainate-induced toxicity could be reduced by superoxide dismutase (SOD) and hydroxy radical scavengers, such as mannitol, in cerebellar neurons. Indeed, overexpression of SOD in cultured cortical neurons reduces susceptibility to toxicity induced by

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Fig. 27.2. Glutamate binds to ionotropic receptors (N-methyl-D-aspartate receptor (NMDA-R), a-amino-3-hydroxy-5-methylisoxazole propionic acid receptor (AMPA-R)/kainate-R), allowing Ca2þ influx. The NMDA receptor is linked to postsynaptic density protein PSD-95 and this mediates activation of nitric oxide synthase, leading to formation of nitric oxide and superoxide radicals, leading to inhibition of mitochondrial respiration and neurotoxicity. Mitochondria buffer calcium, but mitochondrial Ca2þ uptake is associated with neuronal cell loss. NMDA receptor activation also leads to a protein kinase signaling cascade, including phosphatidylinositol 3-kinase and the serine-threonine kinase Akt, which act upon multiple substrates. In addition, non-NMDA glutamate receptors (AMPA/kainate), when activated, lead to Naþ influx and Kþ efflux, affecting membrane potential. This, in turn, affects Mg2þ binding to the NMDA receptor and so NMDA receptor activity. A different mechanism has been postulated in chronic neurodegenerative diseases, in which ‘slow excitotoxicity’ results from impaired mitochondrial metabolism, leading to depletion of intracellular adenosine triphosphate stores, with subsequent membrane depolarization lowering the threshold for NMDA receptor activation.

glutamate or ischemia (Chan et al., 1990). Excitotoxic injury can likewise be attenuated by the free radical scavengers ubiquinone and ascorbic acid (Majewska and Bell, 1990; Favit et al., 1992). Striatal injections of NMDA, AMPA or kainate result in excitotoxic lesions that are attenuated by the free radical spin trap N-tertbutyl-a (2-sulfophenyl)-nitrone (S-PBN) (Schulz et al., 1995a). This same compound also reduces hydroxy radical generation and toxicity due to malonate lesions. Mitochondria play a key role in the production of reactive oxygen species, linked to increased intracellular calcium (Dugan et al., 1995; Reynolds and Hastings, 1995). Reynolds and Hastings exploited properties of an oxidation-sensitive dye, dichlorohydrofluorescein, observing localized areas of fluorescence at the margins of neuronal cell bodies in culture in response to excitotoxic levels of glutamate. Dye activation could be blocked by uncoupling mitochondrial electron transport and was dependent upon both calcium entry and NMDA receptor function.

27.2.4. Nitric oxide in excitotoxic cell death Excitotoxicity may increase oxidative stress and a key contributor to this pathway is NOS (Dawson et al., 1991; Lafon-Cazal et al., 1993; Beal, 1998; Mungrue and Bredt, 2004). A downstream role of nitric oxide (NO) is supported by several lines of evidence. Calcium influx via the activated NMDA channel activates NOS (Garthwaite, 1995), with resulting elevated NO leading to direct neurotoxicity but also to inhibition of mitochondrial respiration (Dawson et al., 1993; Nicholls, 2004). NOS produces NO and superoxide radicals, which react to form peroxynitrite. This breaks down to highly reactive hydroxyl radicals, leading to protein, lipid and DNA damage (Beckman and Crow, 1993; Ciccone, 1998). The NMDA receptor is coupled to NO production by PSD-95, a scaffolding protein (Sattler et al., 1999). If this interaction is disrupted, excitotoxicity in vitro is blocked and acute ischemic injury in vivo is reduced (Aarts et al., 2002). Glutamate

EXCITOTOXICITY neurotoxicity can be blocked in vitro either by NOS inhibitors, or by hemoglobin, which scavenges NO (Dawson et al., 1991). In NOS knockout mice, focal ischemic lesions are attenuated (Huang et al., 1994). Studies using enzyme inhibitors are limited due to lack of specificity, confounding results because of potential effects on endothelial NOS (therefore adding a vascular effect) as well as the neuronal isoform. However, 7nitroindazole is an inhibitor without effects on blood pressure or acetylcholine-induced vasorelaxation and this more specific means of inhibiting NOS activity was found to attenuate NMDA excitotoxicity (Schulz et al., 1995b). Finally, the role for NO, as expected, is likely considerably more subtle and complex. Redoxmodulatory sites, cysteine residues, are also present on the NMDA receptor–ion channel complex. Redoxrelated forms of NO react with these residues by Snitrosylation, resulting in blockade of the ion channel, and this is protective against excitotoxic damage to neuronal cells (Kim et al., 1999; Choi et al., 2000). 27.2.5. Protease activation in the excitotoxic process Neurotoxicity resulting from kainic acid administration in vivo is associated with calpain activation (Siman and Noszek, 1988). Calpain inhibitors are not effective against glutamate neurotoxicity in cultured cerebellar neurons (Manev et al., 1991), but they do reduce AMPA-induced toxicity in vitro, as well as in models of cerebral ischemia (Lee et al., 1991; Caner et al., 1993; Bartus et al., 1994; Hong et al., 1994). Expression of human calpastatin in transgenic mice prevents calpain activation that is normally seen after hippocampal kainic acid injections. In addition, the cytoskeletal disruption usually observed following kainate injection is prevented (Higuchi et al., 2005). In a mouse model of PD, adenovirus-mediated overexpression of calpastatin in striatal neurons leads to protection against N-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated cell death. Efforts to implicate caspases in this process have been disappointing: use of a broad caspase inhibitor, z-VAD-fmk, did not have any effect on the level of LPS-activated microglia-induced excitotoxic cell death in primary rat cortical neuron cultures (Takeuchi et al., 2005). 27.2.6. Are other glutamate receptors involved in excitotoxic cell death? There is abundant evidence that the mGluRs play a regulatory role in basal ganglia function, by either inhibiting or increasing dopamine release (Golembiowska et al., 2002). Might they also play a role in excitotoxicity? Activation of group I receptors increases

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glutamate release, whereas corresponding group II and group III receptor activation inhibit glutamate release, likely via an autoreceptor function (Glaum and Miller, 1994). One would therefore predict that selective group II mGluR agonists might attenuate excitotoxicity. Indeed, in some models this has been the case. Selective agonists LY354740, LY3389795 and LY379268, as well as DCG-IV, which is less selective, reduce the degree of glutamate toxicity in cortical neurons in vitro and in cerebral ischemia of rat hippocampus (Allen et al., 1999; Bond et al., 1999, 2000; Kingston et al., 1999). (R,S)-4-phosphonophenylglycine and L-2-amino4-phosphonobutyrate both activate group III receptors. In experimental hypoxic/hypoglycemic injury in rat hippocampus, as well as NMDA-mediated excitotoxicity in cultured rat cerebellar granule neurons, these two compounds afford a neuroprotective effect (Lafon-Cazal et al., 1999; Sabelhaus et al., 2000). Moreover, group I mGluR antagonists, 1-aminoindan-1, 5-dicarboxylic acid and (S)-(þ)-2-(30 -carboxybicyclo[1.1.1]pentyl)-glycine, protect against neuronal cell loss after experimental hypoxia/hypoglycemia in rats and in global ischemia affecting gerbil hippocampus (Pellegrini-Giampietro et al., 1999). The mGluR1 antagonist (þ)-2-methyl-4carboxyphenylglycine attenuates neuronal loss in global ischemia in gerbils, as well as NMDA-induced toxicity in rat hippocampus and striatum (Bruno et al., 1999). A selective mGluR5 antagonist, 6-methyl-2-(phenylethynyl)-pyridine (MPEP) protects cultured cortical neurons in vitro from NMDA-induced cell death (Bruno et al., 2000; O’Leary et al., 2000; Movsesyan et al., 2001) and protects rat striatum from NMDAinduced cell death (Bruno et al., 2000). In conclusion, the role of receptors other than the NMDA type deserves further investigation, as they may provide valuable opportunities for novel therapeutic interventions.

27.3. Slow excitotoxicity and mitochondrial dysfunction in neurodegenerative disease Several lines of evidence support a complex interplay between excitotoxicity and mitochondrial function. In contrast to the classic excitotoxic mechanisms discussed above, a related mechanism of slow excitotoxicity, that would be more important in chronic progressive neurodegenerative processes, has been proposed by Beal (1992; Beal et al., 1993) and supported by other investigators (Albin and Greenamyre, 1992; Greene and Greenamyre, 1996). As described in section 27.2.1.1, magnesium blocks calcium influx through NMDA receptor channels at normal resting potential. However, energy is required to maintain this resting potential. Therefore, impaired mitochondrial metabolism may lead to reduced membrane potential.

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In this condition, voltage-dependent magnesium blockade is lost and calcium influx may occur through the NMDA receptor-linked channel despite near-physiologic levels of glutamate. If sufficient, the elevated intracellular calcium concentration would induce free radical formation by mitochondria, activate NOS and thereby cause oxidative damage to proteins, lipids and DNA. Mitochondrial damage sustained would then further compromise energy metabolism and could potentially lead to a cycle of increasing excitotoxic damage and metabolic compromise. In cultured rat cerebellar neurons, energy depletion caused by absence of oxygen, glucose, inhibitors of oxidative phosphorylation or sodium potassium ATPase activity results in a lowered threshold for excitotoxic damage due to elevated glutamate levels (Novelli et al., 1988). This is consistent with the model of slow excitotoxicity discussed above. Inhibition of glycolysis by iodoacetate, or of oxidative phosphorylation by cyanide, a complex IV inhibitor, in cultured chick retina likewise results in excitotoxicity without increased extracellular glutamate concentration, via NMDA receptor activation (Zeevalk and Nicklas, 1991). Cultured hippocampal or cortical neurons are more susceptible to excitotoxicity following cyanide treatment (Dubinsky and Rothman, 1991). Moreover, hyperpolarizing the cell membrane by using potassium channel activators is protective against excitotoxicity in cultured cells (Abele and Miller, 1990).

27.4. Glutamate in motor pathways and in Parkinson’s disease The striatum plays a pivotal role in motor control and influences efferent output from the globus pallidus interna (GPi) and SNpr, via the direct and indirect pathways. The direct pathway consists of a GABAergic projection from striatum to GPi and SNpr. The indirect pathway comprises striatal output via GABAergic projections to the globus pallidus externa (GPe), that in turn sends GABAergic projections to the STN. The STN in turn has glutamatergic output on to the GPi and SNpr (Yelnik, 2002), as well as SNpc and the pedunculopontine nucleus (PPN), which might be responsible for some non-dopaminergic symptoms of PD. Stimulation of the STN induces bursting activity in the SNpc dopaminergic neurons (Rodriguez et al., 1998), raising the question of whether changes in STN output in PD could have direct consequences for further degeneration of the SNpc. Additionally a subthalamostriatal pathway exists, as well as sparse projections to the frontal cortex, dorsal raphe nucleus and the reticular formation (Kita and Kitai, 1987), presenting the possibility of effects on a diverse array of

structures. Although an oversimplified model, some aspects of motor control can be viewed as a balance between direct and indirect pathways, leading to opposite effects on thalamic relay to the motor cortex. According to classical models of basal ganglia organization, motor cortical areas connect with dorsolateral putamen in the motor circuit. Cortical projections to medium spiny striatopallidal (GABAergic) and large aspiny striatal interneurons (cholinergic) utilize glutamate as their major neurotransmitter. The dopaminergic nigrostriatal tract arising from the SNpc serves to modulate excitatory effects of this cortical input on striatal neurons. During the course of PD, complex changes occur in signaling pathways involving the basal ganglia and changes in glutamate neurotransmission are integral to this process (Fig. 27.3) (Bergman et al., 1990, 1994; Wichmann et al., 1994; Raz et al., 2000). With progressive loss of the modulatory influence of the SNpc in PD, the net effect is overinhibition of GPe neurons due to overactive D2 striatal projection neurons, resulting in STN hyperactivity (Obeso et al., 2000). However, changes are actually more complex: both the mean rate of activity and the pattern of STN projection neuron firing are altered in PD and experimental models of parkinsonism. STN neurons normally fire irregular patterns, but in PD firing is more synchronous and rhythmic (Bevan et al., 2002). This is thought in turn to result in some of the abnormalities in coding motor processes, as increased GPi and SNpr output inhibits thalamocortical projections, resulting in impaired movement initiation and execution. Although much attention has focused on changes in STN activity in PD, glutamatergic neurotransmission is altered in other structures in models of PD. The STN projects to the PPN, which sends excitatory glutamatergic (as well as cholinergic) projections to the SNpc. The PPN is hyperactive in a 6-hydroxydopamine (6-OHDA) model of PD in rodent (Breit et al., 2001). In addition, the cortex has glutamatergic projections onto the striatum and these also are more active in PD than under normal conditions (Calabresi et al., 1993, 2000; Picconi et al., 2002). The direct and indirect pathways are modulated in opposite directions not only by glutamate, but also by adenosine, and are further modulated by mGluR5 activation. It has been proposed that adenosine A2A and mGluR5 receptor activity may modulate glutamate release. These receptors are abundantly co-localized with glutamatergic nerve endings: in purified nerve termini from glutamatergic rat striatum, almost half of the glutamatergic terminals contain A2A and mGluR5 receptors (Rodrigues et al., 2005). Striatal glutamate levels are increased by activation of mGluR5 receptors

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Fig. 27.3. Glutamatergic pathways (black arrows) in the normal basal ganglia (A) compared to altered pathways in Parkinson’s disease (PD) (B). This is a highly simplified model of direct and indirect pathways (denoted by arrows, with black representing use of the neurotransmitter glutamate) and shows changes occurring with progressive loss of dopaminergic cells of the subtantia nigra (SN). Other anatomic structures are abbreviated as follows: STN, subthalamic nucleus; GPe, globus pallidus external segment; GPi, globus pallidus internal segment; Th, thalamus, with nuclei ventral anterior and ventral lateral (VA/VL). Loss of nigral dopaminergic cells results in decreased output to the globus pallidus in both direct and indirect pathways, denoted by a dashed line. The result of this change is STN hyperactivity, a pathophysiologic hallmark of PD and increased glutamatergic (Glu) output from the STN in PD is denoted by thick arrows. The net effect of these changes is decreased thalamic output to the motor cortex.

(Pintor et al., 2000) and striatal glutamate outflow is modulated by A2A receptor ligands, as measured by microdialysis (Corsi et al., 2000, 2003). Antagonists of A2A (Fredholm et al., 2003) and mGluR5 (Bruno et al., 2000, Battaglia et al., 2002) are neuroprotective in models of glutamate excitotoxicity. Dopaminergic denervation enhances striatal spiny neuron NMDA receptor sensitivity (Oh et al., 1998, 1999). NMDAR1 and NMDAR2B subunits are reduced in membrane fractions of 6-OHDA-lesioned rats, whereas NR2A subunit abundance is unaltered (Dunah et al., 2000). The authors suggested this results from redistribution of a subset of receptors to the intracellular compartment and changes are normalized by chronic administration of levodopa. Moreover, this study found that phosphorylation states of receptor subunits are altered in lesioned animals and chronic administration of levodopa leads to hyperphosphorylation of each of these three subunits. It is conceivable that these changes alter NMDA receptor activity in such a way as to contribute to the development of motor complications observed in PD patients. There has been considerable clinical interest in the use of NMDA antagonists to treat motor complications in PD. NMDA blockade decreases motor fluctuations in a levodopa-treated rat model of PD (Papa et al., 1995). NMDA receptor antagonists also reduce development of levodopa-associated motor fluctuations in MPTP-treated primates (Blanchet et al., 1998). Motor fluctuations and dyskinesias are ameliorated by aman-

tadine, dextrorphan and dextromethorphan (Verhagen Metman et al., 1998; Luginger et al., 2000; Rascol, 2000; Thomas et al., 2004). Riluzole improved dyskinesias in a small series of patients with PD (Merims et al., 1999): 100 mg/day led to a 24% decrease in mean daily waking hours with dyskinesias. This was suggested to be related to the finding that riluzole restores a physiologic firing rate and pattern in the GPi of MPTP monkeys treated with levodopa (Boraud et al., 2000). Unfortunately, findings were not reproduced in a study investigating the effects of 50 mg riluzole, administered twice per day, on apomorphine-induced dyskinesias in PD (Braz et al., 2004). Could other glutamate receptors play a role in the development of motor complications? AMPA receptors have been proposed as a possible candidate (Konitsiotis et al., 2000), but their role in PD is controversial and requires more study (Silverdale et al., 2002).

27.5. Excitotoxicity in Parkinson’s disease There is no direct evidence for a role for excitotoxicity in PD, but there exist several lines of evidence suggesting a toxic effect of glutamate in neurodegeneration of dopaminergic neurons in the SNpc (Klockgether and Turski, 1993; Greene and Greenamyre, 1996; Beal, 1998; Greenamyre, 2001; Simon and Beal, 2002). As described above, glutamatergic projections from the STN stimulate cells of the GP, SN and PPN. Since the STN is overactive in PD, this raises the possibility

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that these targets are at risk of excitotoxic damage, secondary to increased glutamate release. Furthermore, with progressive loss of nigral neurons, there is increased disinhibition of the STN, thus potentially leading to more nigral damage (Rodriguez et al., 1998). Impaired energy metabolism could lead to enhanced susceptibility to excitotoxicity. The importance of mitochondrial dysfunction in PD has been emphasized by many studies (see Ch. 22) and mitochondria in PD cybrids have impaired calcium buffering capacity, highlighting a possible role for excitotoxic mechanisms (Sheehan et al., 1997). 27.5.1. Evidence for excitotoxicity in animal models of Parkinson’s disease Despite lack of evidence of excitotoxicity in PD itself, in various animal models of PD there is evidence of altered glutamate activity and multiple avenues of research have shown that antiexcitotoxic agents and glutamate antagonists are neuroprotective for dopaminergic neurons. The selective NMDA antagonists 2-amino-7-phosphonoheptanoic acid (AP7), (6)-3-(2carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and dizocilpine (MK801) protect from dopaminergic neuronal cell death induced by intranigral injection of 1-methyl-4-phenylpyridinium ion (MPPþ) (Turski et al., 1991). Co-administration directly into the SN of these NMDA antagonists with MPPþ into the SN afforded protection against MPPþ-induced cell death for up to 24 hours. Systemic MK801 or CPP afforded protection against MPPþ-induced cell death up to 4 hours, which could be prolonged by repeated systemic administration of antagonists. If repeated intranigral injections were made for at least 24 hours, the protective effect was still detectable at 7 days. In the MPTP model of PD, the selective NMDA antagonist MK801 provides neuroprotection in primates (Zuddas et al., 1992) and mice (Tabatabaei et al., 1992). In mice, systemic administration of the non-competitive NMDA antagonist MK801, or of the competitive antagonists CGP39551 and LY274614 for 24 hours, leads to a partial but significant reduction in MPTP-induced loss of striatal dopamine levels at 24 hours and 1 week (Brouillet and Beal, 1993). CPP, a competitive NMDA antagonist, is also protective for dopamine neurons in MPTP-treated primates (Lange et al., 1993). Infusion over a 4-week period of MK-801 into rat STN significantly reduced nigral (SNpc) cell loss evaluated by Nissl staining after unilateral 6-OHDA lesions (Blandini et al., 2001). Behavioral changes were also prevented, as measured by turning behavior after amphetamine administration. Protective effects were not observed in this model with 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-

sulfonamide disodium (NBQX), a selective AMPA antagonist. An intermediary role in this process for NO is supported by the finding that NOS inhibitors are neuroprotective in the MPTP model of PD in rodents (Schulz et al., 1995b) and primates (Hantraye et al., 1996). Other authors, however, have found less encouraging results. In MPTP-treated mice, administration of MK801 or the competitive NMDA antagonist CGP40116 did not lead to improvement in loss of striatal dopamine content up to 96 hours, or at 20 days. There was a slight and non-significant 10% improvement in loss of tyrosine hydroxylase immunoreactive cells counted in the SN (Kupsch et al., 1992). Using systemic or intranigral MPTP administration in rodents, Sonsalla and colleagues (1992) did not find evidence that MK801 effectively reduced dopamine cell loss. Furthermore, MK801 failed to protect against MPPþ-induced cell death in dissociated mesencephalic cultures from rat (Michel and Agid, 1992). Since increased STN output leads to greater glutamatergic stimulation at downstream synapses and therefore the possibility of excitotoxic damage in the SNpc, several researchers have proposed that intervening at this step holds the potential for neuroprotection (Rodriguez et al., 1998). Antiexcitotoxic agents and/ or glutamate antagonists have been considered as candidates to provide a neuroprotective effect (Halbig et al., 2004). A number of glutamate antagonists are available for the treatment of neurologic disease (see section 27.4). Amantadine, an NMDA receptor antagonist, has been suggested to increase survival in PD in a non-blinded, retrospective study (Uitti et al., 1996), but there have been no controlled trials to study this possibility. Memantine is a non-competitive NMDA receptor antagonist, with strong voltage-dependency and rapid-offset kinetics (Parsons et al., 1999): this could theoretically allow blockade during sustained receptor activation associated with a pathological condition, such as mitochondrial dysfunction, and then rapid release under transient stimulation by glutamate in physiological conditions. There is no evidence that memantine alters the course of disease in PD. Riluzole is a sodium channel blocker that prevents glutamate release in overactive glutamatergic neurons by sodium channel inhibition and is a non-competitive blocker at the NMDA receptor, although its precise mechanism of action is unclear (Doble, 1996; Wokke, 1996). It is approved in the treatment of ALS, where it modestly extends survival time (Gurney et al., 1996; Lacomblez et al., 1996). A neuroprotective role in ischemia and trauma has also been suggested (Siniscalchi et al., 1999; Wahl and Stutzmann, 1999). Riluzole attenuates MPPþ-mediated cell death in dopaminergic cell cultures (Storch et al., 2000). In MPTP-treated

EXCITOTOXICITY rodents and primates, riluzole protects against dopaminergic neuron loss (Boireau et al., 1994a, b; Bezard et al., 1998; Araki et al., 2001; Obinu et al., 2002). Injecting riluzole before MPTP in rhesus monkeys can prevent parkinsonian symptoms, particularly bradykinesia and rigidity (Benazzouz et al., 1995). Twenty patients with PD have been treated with riluzole in an open-label study, over a 6-month period. At doses of 100 mg/day the drug was well tolerated. However, despite a trend for benefit in those having taken riluzole, the effect was not statistically significant (Jankovic and Hunter, 2002). A 2-year prospective, placebocontrolled, double-blind multicenter trial, involving 1084 PD patients, assigned to take placebo, 50 or 100 mg of riluzole twice per day, was terminated early. The authors reported that, at interim analysis, 711 of the 1084 patients had started dopaminergic therapy, with no significant difference between placebo and riluzole groups. Using the primary endpoint of need for supplemental dopaminergic therapy, predefined criteria for futility were met and, with a probability of starting levodopa or dopamine agonists during the first 18 months of 0.69 on placebo, versus 0.71 on riluzole, the data did not demonstrate benefit for those receiving riluzole (Rascol et al., 2002). 27.5.2. The parkin gene and excitotoxic cell death Mutations in the parkin gene account for cases of autosomal-recessive inherited PD and are also found in some cases of sporadic PD (see Ch. 9). The protein parkin is an E3 ubiquitin ligase, crucial in the ubiquitin/ proteasomal protein degradation pathway. Overexpression of parkin protein actually protects cultured cerebellar granule cells and midbrain dopaminergic neurons from excitotoxicity induced by kainate (Staropoli et al., 2003). This protection is accompanied by decreased accumulation of cyclin E. Moreover, parkin RNAi rendered these cells more sensitive to kainate toxicity. It has been suggested that disrupted cell cycle-related kinase activity plays a key role in kainate-induced cell death in postmitotic neurons (Copani et al., 2001). It is therefore intriguing that cyclin E, which together with cyclin-dependent kinase 2 regulates the G1/S-cell cycle transition, has now been identified as a substrate for ubiquitination by parkin (Staropoli et al., 2003). 27.5.3. Glial cells may modulate excitotoxicity in Parkinson’s disease Microglial activation may contribute to neurotoxicity in several neurodegenerative processes, including PD (see Ch. 26), as well as ALS and AD (Kreutzberg,

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1996; Eikelenboom et al., 2002; Koutsilieri et al., 2002; McGeer and McGeer, 2002; Orr et al., 2002; Turner et al., 2004). Loss of SNpc neurons is associated with a glial response: activated microglial cells are the major contributors, although reactive astrocytes are also present in both PD and experimental models of PD (Teismann et al., 2003). SN neurons are highly susceptible to injury by activated microglia (Kim et al., 2000) and NMDA directly injected into rat striatum leads to microglial activation with subsequent NOS induction (Iravani et al., 2004). Activated microglia release cytokines that mediate glutamate release (McNaught and Jenner, 2000). In an animal model of PD, MPTP induces increased glutamate release and decreases glutamate uptake by glial cells (Carboni et al., 1990; Hazell et al., 1997). However, the role of glial cells is likely complex and there are reasons to believe they have both protective and deleterious effects. These cells scavenge neurotoxic agents: glia can avidly take up glutamate from the extracellular milieu and could theoretically reduce possible excitotoxic effects of increased glutamate levels, for example arising from overactive STN glutamatergic output. This is in addition to a possible protective effect arising from neurotrophic factor release (see Ch. 25), including glial-derived neurotrophic factor, with potent activity in promoting dopaminergic neuron survival, induction of dopaminergic nerve fiber sprouting and attenuation of dopamine neuronal death in MPTP-treated monkeys (Burke et al., 1998; Batchelor et al., 1999; Kordower et al., 2000). Brain-derived neurotrophic factor (BDNF) protects striatal neurons against NMDA-induced excitotoxic damage in an animal model of HD (Perez-Navarro et al., 2000). Moreover, striatal grafting of a BDNF-secreting cell line in mice prevents excitotoxin-associated changes in Akt, Bcl-2 family members and in caspase-3 activation (Perez-Navarro et al., 2005). Lipopolysaccharide (LPS)-induced microglia activation by direct LPS injection into the SNpc leads to dopamine neuron loss and inhibiting microglial activation in this model reduces such cell loss (Liu et al., 2000). LPS-activated microglia lead to neuritic beading, that is, focal bead-like swellings in axons and dentritic processes, in rat primary cortical neuron cultures (Takeuchi et al., 2005), that is followed by cell death. These neuritic beads are comprised of collapsed cytoskeletal proteins, which form secondary to impaired neuronal transport as mitochondrial dysfunction leads to decline in intracellular adenosine triphosphate. Neuritic beading has been observed in PD (Mattila et al., 1999) and may be induced experimentally by a number of stimuli, including glutamate, NO and oxidative stress (Park et al., 1996; Faddis et al., 1997;

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Hasbani et al., 1998, 2001; Ikegaya et al., 2001; Oliva et al., 2002; Roediger and Armati, 2003). Blockade of the NMDA receptor by MK801 almost completely attenuates mitochondrial dysfunction, morphologic changes and neuronal cell loss in murine embryonic primary cortical neuron culture induced by LPS activation of primary mixed glial cells (Takeuchi et al., 2005).

27.6. Surgical modulation of glutamate neurotransmission in Parkinson’s disease Since a hyperactive STN could potentially lead to excitotoxicity, could normalizing the STN’s efferent activity prevent further damage to dopaminergic cells of the SN? The notion is consistent with observed effects of NMDA antagonists in animal models of PD described in section 27.5 above. It is important to determine whether such an effect exists, as this would raise major implications over when to intervene with surgical treatment and would point to considering surgery in early and moderate PD. There is, as yet, no evidence to support neuroprotection from surgical intervention in PD itself, but STN lesions and STN deep brain stimulation (DBS) do afford protection against cell death for SNpc neurons in animal models of PD. In 6-OHDA-lesioned rats, kainic acid-mediated ablation of the STN 1 week prior diminishes loss of SN dopaminergic neurons, as measured by cell counts of tyrosine hydroxylase-positive cells in the SNpc. STN ablation also supports nigral neurons after nigrostriatal lesioning induced by 3-nitroproprionic acid, a mitochondrial toxin (Nakao et al., 1999). In a series of staged interventions, kainate-induced STN ablation in rats was followed by 6-OHDA lesions of the nigrostriatal tract 1 week later, or else 6-OHDA was administered 1 hour, 2 hours, 3 days or 7 days prior to kainate injection of the STN. Four weeks after the 6-OHDA lesion, in those animals who had received a kainic acid STN ablation 1 week prior, 97% of tyrosine hydroxylase immunoreactive cells survived. There was less survival when 6-OHDA lesions were made prior to the STN, with cell survival decreasing as the STN lesion was further in time from the 6-OHDA insult (Chen et al., 2000). Likewise, Carvalho and Nikkhah (2001) found that STN lesions were protective in the 6-OHDA model of PD, as evaluated by numbers of tyrosine hydroxylase immunoreactive cells counted. However, simply counting tyrosine hydroxylase-positive cells leaves some uncertainty as to whether this reflects exactly the number of dopaminergic neurons. In a similar experimental model, using ibotenic acid to lesion rat STN followed by 6-OHDA injection 2 weeks later,

surviving neurons were measured both by counts of cells positive for the retrograde tracer fluorogold, injected bilaterally at the same time as the STN lesion and also by tyrosine hydroxylase immunoreactivity. By fluorogold tracer counts, there was 70% cell loss at 2 weeks and 85% loss at 6 weeks. However, tyrosine hydroxylase immunoreactive cell counts were significantly less in control animals than in those with STN lesions prior to 6-OHDA. Amphetamine-turning behavior was also better in STN-lesioned animals than controls. This suggests that STN ablation led to improved nigral cell function, possibly by rescuing a dopaminergic phenotype, rather than by preventing neuronal excitotoxic cell death (Paul et al., 2004). DBS of the STN is approved for the treatment of advanced PD, yet despite multiple trials verifying clinical efficacy, detailed understanding of its mechanism of action is still lacking. DBS has been proposed to inactivate target STN cells by high-frequency stimulation (discussed in Ch. 43). However, its action now seems considerably more complex and in rodents, high-frequency stimulation of the STN may result in an increase, rather than decrease, in glutamate release on STN targets (Windels et al., 2000). Stefani and colleagues (2005) measured GPi levels of extracellular glutamate and cyclic guanosine monophosphate (cGMP) by microdialysis, followed by high-performance liquid chromatography and radioimmunoassay, in 14 patients undergoing STN DBS treatment of PD. Extracellular glutamate levels did not change, although this does not necessarily reflect synaptic concentrations. However, in 5 patients in whom basal cGMP levels could be measured, STN DBS did result in significantly increased extracellular cGMP levels in the GPi, in parallel with clinical symptom improvement. Extracellular cGMP reflects accurately its intracellular levels and the authors suggested this resulted from an increase in excitatory signaling, due to glutamate. However, without demonstrating this directly, it remains possible that other neurotransmitters could have been responsible for the observed effect. Long-term follow-up for patients with PD undergoing STN DBS has now been reported (Krack et al., 2003). Clinical effectiveness is well maintained in many domains of PD symptoms, but we have no evidence as yet of neuroprotection in humans. To address these issues further and to ask whether STN high-frequency stimulation could provide neuroprotection, investigators have turned to animal models of PD. Maesawa and colleagues (2004) placed a right STN microelectrode, under guidance by extracellular recording combined with stereotaxy, in 13 out of 25 ratsand then all 25 underwent 6-OHDA lesions of the right striatum. One group received continuous electrode

EXCITOTOXICITY stimulation at 130 Hz, 80–100 mA, for 2 weeks, a second group received the electrode but no electrode stimulation and the third group had no electrodes implanted. After 2 weeks, ipsilateral amphetamineinduced rotation was reduced in those with stimulation (their gait was described as ambling), whereas those without stimulation had typical circling behavior. Of note, in those animals receiving STN stimulation, SNpc tyrosine hydroxylase immunoreactive cell loss secondary to striatal 6-OHDA injury was partially attenuated. However, the animal models provide only limited conclusions with regard to PD and it has been suggested that results could be confounded by STN lesions, possibly reducing uptake by nigrostriatal neuron termini of 6-OHDA, so limiting its toxicity. The PPN is a major source of glutamatergic afferents to the dopaminergic nigrostriatal pathway (Scarnati and Florio, 1997). It receives inhibitory GABAergic signals from the GPi and SNpr and has excitatory glutamatergic projections to the SNpc and the STN (as well as cholinergic projections to the SNpc). Unilateral kainic acid lesions of the PPN in macaques, followed by MPTP administered systemically over 1–3 months, afforded protection from MPTP treatment in terms of nigral cell loss as well as parkinsonian motor deficits (Takada et al., 2000). However, in PD itself, the relevance of this finding is unclear. In fact, neurons of the PPN are lost in PD, with Lewy bodies detected in this structure (Zweig et al., 1989). A novel approach to modifying glutamatergic neurotransmission is that of gene therapy. Luo and colleagues (2002) exploited a technique using adenoassociated viral vector-mediated somatic cell gene transfer, to express the glutamic acid decarboxylase (GAD) gene in excitatory glutamatergic neurons of rat STN. GAD catalyzes synthesis of the neurotransmitter GABA. Rats receiving gene therapy were subjected to 6-OHDA lesions 4–5 months after GAD gene introduction and an ipsilateral STN stimulator was placed. GABA and glutamate levels were measured in the SNpr by microdialysis. In the presence of the GAD gene, STN stimulation resulted in an increase of approximately fourfold in GABA levels detected by microdialysis and in control animals no significant change was observed. Moreover, singleunit recordings from a subset of animals revealed an altered ratio of excitatory to inhibitory responses, with 78% inhibitory responses in the GAD rats, compared to 5–10% inhibitory responses in control animals. Whether this approach might modify the disease process itself was investigated by subjecting GADinjected rats to medial forebrain bundle lesions by 6-OHDA 3 weeks later. Using stereology to count SN dopaminergic neurons revealed massive loss of

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dopaminergic neurons in control animals, whereas in GAD-injected rats, 35% (14%) of dopaminergic neurons in the SN and 80% (11%) in the ventral tegmental area survived. A small clinical trial exploiting this approach is now underway in patients with PD to evaluate safety (During et al., 2001).

27.7. Conclusions Although selective loss of dopaminergic neurons fundamental to the development of PD is unlikely to result primarily from excitotoxicity, the excitotoxic process could well be a secondary factor in cell dysfunction and death in this disease. Excitotoxicity as classically described is more likely to play a direct role in acute neuronal damage, rather than chronic progressive diseases such as PD. However, multiple avenues of evidence emphasize a complex interplay of processes and chronic activation of the pathways described above might be favored by mitochondrial dysfunction in PD. Certainly, pharmacologic or surgical manipulation of glutamatergic neurotransmission represents a valuable approach for symptomatic therapy in PD. It remains to be seen how effective these therapeutic interventions could be in retarding the progress of PD and whether they have a place as part of a multidrug regimen, addressing interconnecting cellular processes important in neurodegeneration.

Acknowledgments Thanks to Patricia M. White and Penelope Schumacher for editorial assistance and Trevor Winterbottom PhD for critical reading of the manuscript.

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Roediger B, Armati PJ (2003). Oxidative stress induces axonal beading in cultured human brain tissue. Neurobiol Dis 13: 222–229. Sabelhaus CF, Schroder UH, Breder J et al. (2000). Neuroprotection against hypoxic/hypoglycaemic injury after the insult by the group III metabotropic glutamate receptor agonist (R, S)-4-phosphonophenylglycine. Br J Pharmacol 131: 655–658. Sattler R, Xiong Z, Lu WY et al. (1999). Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284: 1845–1848. Scarnati E, Florio T (1997). The pedunculopontine nucleus and related structures: functional organization. In: JA Obeso MR DeLong, C Ohye, CD Marsden (Eds.), The Basal Ganglia and New Surgical Approaches for Parkinson’s Disease. Lipincott-Raven, Philadelphia, PA, pp. 97–110. Schulz JB, Henshaw DR, Siwek D et al. (1995a). Involvement of free radicals in excitotoxicity in vivo. J Neurochem 64: 2239–2247. Schulz JB, Matthews RT, Jenkins BG et al. (1995b). Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J Neurosci 15: 8419–8429. Schwartz M, Shaked I, Fisher J et al. (2003). Protective autoimmunity against the enemy within: fighting glutamate toxicity. Trends Neurosci 26: 297–302. Sheehan JP, Swerdlow RH, Parker WD et al. (1997). Altered calcium homeostasis in cells transformed by mitochondria from individuals with Parkinson’s disease. J Neurochem 68: 1221–1233. Silverdale MA, Crossman AR, Brotchie JM (2002). Striatal AMPA receptor binding is unaltered in the MPTPlesioned macaque model of Parkinson’s disease and dyskinesia. Exp Neurol 174: 21–28. Siman R, Noszek JC (1988). Excitatory amino acids activate calpain I and induce structural protein breakdown in vivo. Neuron 1: 279–287. Simon DK, Beal MF (2002). Pathogenesis: oxidative stress, mitochondrial dysfunction, and excitotoxicity. In: SA Factor, WJ Weiner (Eds.), Parkinson’s Disease: Diagnosis and Clinical Management. Demos Medical Publishing, New York, NY, pp. 281–290. Siniscalchi A, Zona C, Sancesario G et al. (1999). Neuroprotective effects of riluzole: an electrophysiological and histological analysis in an in vitro model of ischemia. Synapse 32: 147–152. Sonsalla PK, Zeevalk GD, Manzino L et al. (1992). MK-801 fails to protect against the dopaminergic neuropathology produced by systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice or intranigral 1-methyl-4-phenylpyridinium in rats. J Neurochem 58: 1979–1982. Staropoli JF, McDermott C, Martinat C et al. (2003). Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 37: 735–749. Stefani A, Fedele E, Galati S et al. (2005). Subthalamic stimulation activates internal pallidus: evidence from cGMP microdialysis in PD patients. Ann Neurol 57: 448–452.

EXCITOTOXICITY Storch A, Burkhardt K, Ludolph AC et al. (2000). Protective effects of riluzole on dopamine neurons: involvement of oxidative stress and cellular energy metabolism. J Neurochem 75: 2259–2269. Stout AK, Raphael HM, Kanterewicz BI et al. (1998). Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci 1: 366–373. Sun AY, Cheng Y, Bu Q et al. (1992). The biochemical mechanisms of the excitotoxicity of kainic acid. Free radical formation. Mol Chem Neuropathol 17: 51–63. Tabatabaei A, Perry TL, Hansen S et al. (1992). Partial protective effect of MK-801 on MPTP-induced reduction of striatal dopamine in mice. Neurosci Lett 141: 192–194. Takada M, Matsumura M, Kojima J et al. (2000). Protection against dopaminergic nigrostriatal cell death by excitatory input ablation. Eur J Neurosci 12: 1771–1780. Takeuchi H, Mizuno T, Zhang G et al. (2005). Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J Biol Chem 280: 10444–10454. Tallaksen-Greene SJ, Kaatz KW, Romano C et al. (1998). Localization of mGluR1a-like immunoreactivity and mGluR5-like immunoreactivity in identified populations of striatal neurons. Brain Res 780: 210–217. Teismann P, Tieu K, Cohen O et al. (2003). Pathogenic role of glial cells in Parkinson’s disease. Mov Disord 18: 121–129. Testa CM, Catania MV, Young AB (1994). Anatomical distribution of metabotropic glutamate receptors in mammalian brain, In: PJ Conn, J Patel (Eds.), The Metabotropic Glutamate Receptors. Humana Press, Totowa, NJ, pp. 99–123. Testa CM, Standaert DG, Landwehrmeyer GB et al. (1995). Differential expression of mGluR5 metabotropic glutamate receptor mRNA by rat striatal neurons. J Comp Neurol 354: 241–252. Testa CM, Friberg IK, Weiss SW et al. (1998). Immunohistochemical localization of metabotropic glutamate receptors mGluR1a and mGluR2/3 in the rat basal ganglia. J Comp Neurol 390: 5–19. Thomas A, Iacono D, Luciano AL et al. (2004). Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry 75: 141–143. Turner MR, Cagnin A, Turkheimer FE et al. (2004). Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15: 601–609. Turski L, Bressler K, Rettig KJ et al. (1991). Protection of substantia nigra from MPPþ neurotoxicity by N-methylD-aspartate antagonists. Nature 349: 414–418.

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Tymianski M, Charlton MP, Carlen PL et al. (1993a). Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci 13: 2085–2104. Tymianski M, Wallace MC, Spigelman I et al. (1993b). Cellpermeant Ca2þ chelators reduce early excitotoxic and ischemic neuronal injury in vitro and in vivo. Neuron 11: 221–235. Uitti RJ, Rajput AH, Ahlskog JE et al. (1996). Amantadine treatment is an independent predictor of improved survival in Parkinson’s disease. Neurology 46: 1551–1556. Verhagen Metman L, Del Dotto P, Natte R et al. (1998). Dextromethorphan improves levodopa-induced dyskinesias in Parkinson’s disease. Neurology 51: 203–206. Wahl F, Stutzmann JM (1999). Neuroprotective effects of riluzole in neurotrauma models: a review. Acta Neurochir Suppl 73: 103–110. Wang GJ, Randall RD, Thayer SA (1994). Glutamateinduced intracellular acidification of cultured hippocampal neurons demonstrates altered energy metabolism resulting from Ca2þ loads. J Neurophysiol 72: 2563–2569. White RJ, Reynolds IJ (1995). Mitochondria and Naþ/Ca2þ exchange buffer glutamate-induced calcium loads in cultured cortical neurons. J Neurosci 15: 1318–1328. Wichmann T, Bergman H, DeLong MR (1994). The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism. J Neurophysiol 72: 521–530. Windels F, Bruet N, Poupard A et al. (2000). Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat. Eur J Neurosci 12: 4141–4146. Wokke J (1996). Riluzole. Lancet 348: 795–799. Yelnik J (2002). Functional anatomy of the basal ganglia. Mov Disord 17 (Suppl 3): S15–S21. Zeevalk GD, Nicklas WJ (1991). Mechanisms underlying initiation of excitotoxicity associated with metabolic inhibition. J Pharmacol Exp Ther 257: 870–878. Zuddas A, Oberto G, Vaglini F et al. (1992). MK-801 prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in primates. J Neurochem 59: 733–739. Zweig RM, Jankel WR, Hedreen JC et al. (1989). The pedunculopontine nucleus in Parkinson’s disease. Ann Neurol 26: 41–46.

Further Reading Benazzouz A, Piallat B, Ni ZG et al. (2000). Implication of the subthalamic nucleus in the pathophysiology and pathogenesis of Parkinson’s disease. Cell Transplant 9: 215–221.

Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 28

Protein-handling dysfunction in Parkinson’s disease KEVIN ST. P. MCNAUGHT* Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA

28.1. Introduction Parkinson’s disease (PD) is a slowly progressive, agerelated, neurodegenerative disorder and is characterized clinically by motor dysfunction, with bradykinesia, rigidity, tremor, postural instability and gait dysfunction being the cardinal symptoms (Lang and Lozano, 1998a,b). However, non-motor features (e.g. autonomic dysfunction and dementia) often develop in PD patients, especially during the advanced stages of the illness (Lang and Lozano, 1998a, b). The pathological hallmark of PD is degeneration of the neuromelanin-pigmented neurons in the substantia nigra pars compacta (SNpc), leading to destruction of the nigrostriatal pathway and consequently reduction of dopamine levels in the striatum (Forno, 1996). Notably, prominent neuronal death and depletion of respective neurotransmitters also occur in other areas of the central nervous system (CNS), in particular the locus ceruleus (LC), dorsal motor nucleus (DMN) of the vagus, nucleus basalis of Meynert (NBM) and the olfactory system (Forno, 1996; Braak et al., 2003; Zarow et al., 2003). Further, pathology can occur in some regions of the peripheral nervous system (PNS), such as autonomic ganglia (e.g. superior cervical ganglion) and the mesenteric plexus in the wall of the gut (Wakabayashi and Takahashi, 1997). Neurodegeneration in the extranigral regions likely plays a role in the development of both motor and non-motor dysfunction that occur in patients with PD. Characteristically, neurodegeneration at the various pathological sites is accompanied by protein accumulation, aggregation and the formation of Lewy body inclusions in PD (Fig. 28.1) (Forno, 1996; Braak et al., 2003). The etiology of PD remains elusive in the majority (90%) of cases. Reports of incidence and prevalence

rates of the illness vary, but most studies show that occurrence of the disorder increases with aging in both sexes, in diverse racial/ethnic groups and in all countries where studies have been performed (Van Den Eeden et al., 2003; Marras and Tanner, 2004). For example, Van Den Eeden and colleagues (2003) found an overall population incidence rate of PD annually to be 13.4 per 100 000 individuals, but this rate increases to 38.8 and 107.2 per 100 000 individuals in the age range of 60–69 and 70–99 years, respectively. Thus, advancing age is an important risk factor for the development of PD. An increasingly supported hypothesis relating to the cause of PD suggests that exposure to environmental toxins leads to the development of the illness in individuals who are rendered susceptible due to their genetic profile, poor ability to metabolize toxins and/or advancing age (Tanner, 2003). The pathogenic process has been linked to a variety of factors, including oxidative stress (Jenner, 2003), mitochondrial dysfunction (Orth and Schapira, 2002), inflammation (McGeer and McGeer, 2004), excitotoxicity (Beal, 1998) and apoptosis (Tatton et al., 2003). It remains unclear as to how these cellular, biochemical and molecular changes relate to each other and neuronal degeneration in PD. In recent years, a growing body of genetic, postmortem and experimental evidence has shown that protein aggregation plays a major role in the etiopathogenesis of common sporadic as well as in rare familial forms of PD (McNaught and Olanow, 2003; Hattori and Mizuno, 2004; Moore et al., 2005a). In this chapter, we review the pathways that mediate the degradation and clearance of intracellular proteins; how these mechanisms are altered, leading to protein aggregation in the different forms of PD; and the relationship between protein aggregation and other cellular,

*Correspondence to: Kevin St. P. McNaught, Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-73, One Gustave L. Levy Place, New York, NY 10029, USA. E-mail:[email protected], Tel: þ1-212-241-4251, Fax: þ1-212-987-0348.

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Fig. 28.1. For full color figure, see plate section. Lewy bodies in substantia nigra pars compacta dopaminergic neurons in sporadic Parkinson’s disease. (A) Histological staining with hematoxylin for nuclei and eosin for cytoplasm shows a spherical Lewy body with an intensely stained central core and a lightly stained peripheral halo in a neuromelanin-pigmented dopaminergic neuron. Eosin is a protein-binding dye and so the intense staining of Lewy bodies (eosinophilic) demonstrates the accumulation of proteins in these inclusions. (B–D) Standard immunohistochemistry with a brown chromogen and blue hematoxylin counterstain for nuclei shows that protein aggregates and Lewy bodies contain ubiquitinated proteins (B) and a-synuclein (C, D) in the soma and processes of neuromelanin-pigmented dopaminergic neurons. Note that neurons may contain diffuse accumulation of proteins, small protein aggregates and/or Lewy bodies (one or more) in their cytoplasm.

biochemical and molecular changes and the neurodegenerative process, in PD.

28.2. Cellular control of proteins Cellular processes often lead to the generation of proteins that are abnormal, such as incomplete, mutant, misfolded, denatured, oxidized and otherwise damaged proteins (Sherman and Goldberg, 2001; Goldberg, 2003). This is particularly notable in the CNS due to the relatively high utilization of oxygen and elevated rate of metabolism, and the enzymatic- and auto-oxidation of neurotransmitters such as dopamine, all of which facilitate the production of reactive oxygen species and other free radicals that can induce protein damage (Tse et al., 1976; Keller et al., 2004). Abnormal proteins have a tendency to misfold, aggregate, interfere with intracellular processes and induce cytotoxicity (Kopito, 2000; Bence et al., 2001; Grune et al., 2004; Bennett et al., 2005). Thus, their production must be limited and/or rapidly cleared so as to maintain the integrity and viability of cells (Sherman and Goldberg, 2001; Goldberg, 2003). Indeed, in the CNS, a balance between the generation of abnormal proteins and their

clearance is crucial since these neurons have a limited ability for repair/regeneration and their long lifespan is associated with alterations in a variety of intracellular process, such as oxidative stress and mitochondrial dysfunction, that cause protein damage and accumulation (Keller et al., 2004). Further, in the aging CNS, there is a marked increase in oxidatively damaged proteins and so there needs to be a compensatory increase in protein clearance to maintain some degree of structural and function integrity of the neuronal populations (Floor and Wetzel, 1998; Keller et al., 2000, 2004). There are two systems that mediate the majority of protein degradation and clearance within cells (Ciechanover, 2005). An autophagic process involving cathepsins (cysteine proteases) is responsible for the degradation of membrane and extracellular components following endocytosis into the lysosome (Ciechanover, 2005). The ubiquitin-proteasome system (UPS) is primarily responsible for the clearance of abnormal and cytoplasmic proteins and this process occurs in the cytoplasm, nucleus and endoplasmic reticulum (ER) (Figs. 28.2 and 28.3) (Pickart, 2001a; Goldberg, 2003; Pickart and Cohen, 2004;

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Fig. 28.2. For full color figure, see plate section. Protein handling within cells. In cells, the synthesis, use and abuse of proteins inevitably lead to the generation of unwanted proteins, such as incomplete, mutant, misfolded, denatured, oxidized and otherwise damaged proteins and peptides. Because these products have a high tendency to aggregate, interfere with cellular processes and induce cytotoxicity, they must be removed to maintain cell viability. The ubiquitin-proteasome system (UPS) is the primary pathway responsible for the degradation and clearance of unwanted proteins. This involves the adenosine triphosphate (ATP)dependent identification and labeling of abnormal proteins with multiple ubiquitin molecules in the ubiquitination pathway. This pathway is mediated by the sequential action of three enzymes: a ubiquitin activating enzyme (E1) which activates ubiquitin by forming a thioester, followed by a ubiquitin conjugating enzyme (E2) that carries activated ubiquitin as a thioester and finally a ubiquitin ligase (E3) which transfers activated ubiquitin to the substrate protein. Polyubiquitination of proteins serves as a signal for ATP-dependent recognition, unfolding and degradation by the 26S proteasome complex to produce short peptide fragments that are further hydrolyzed by peptidases to yield constituent amino acids. Following identification but before entry into the proteasome, polyubiquitin chains are separated from unwanted protein then disassembled by deubiquitination enzymes (ubiquitin C-terminal hydrolases) into monomeric ubiquitin which can be reused in the ubiquitination cycle. Other processes and components, such as phosphorylation by protein kinases and refolding by heat shock proteins (HSPs), serve to promote the recognition and degradation of unwanted proteins by the UPS (Hartl and Hayer-Hartl, 2002; Goldberg, 2003; Muchowski and Wacker, 2005).

Ciechanover, 2005). This pathway also plays a significant role in the turnover of short-lived regulatory/ functional proteins and is therefore intimately linked with many inter-/intracellular processes (Pickart, 2001a; Goldberg, 2003; Pickart and Cohen, 2004; Ciechanover, 2005). The UPS comprises two processes that occur consecutively to degrade unwanted proteins (Pickart, 2001a; Goldberg, 2003; Pickart and Cohen, 2004; Ciechanover, 2005). In the first step, a ubiquitin molecule (a 76-amino-acid, 8.5 kDA polypeptide) is conjugated to unwanted proteins via a covalent isopeptide bond between the C-terminal Gly residue of ubiquitin and

an internal Lys residue of the substrate protein (Fig. 28.1). Thereafter, additional ubiquitin molecules are attached to the previously conjugated ubiquitin (at a Lys residue) in a sequential manner to form a polyubiquitin chain. Ubiquitination is adenosine triphosphate (ATP)-dependent and is mediated by three different enzymes acting in sequence, namely a ubiquitin activating enzyme (E1) which activates ubiquitin by forming a thioester, followed by a ubiquitin conjugating enzyme (E2) that carries activated ubiquitin as a thioester and finally an ubiquitin ligase (E3) which transfers activated ubiquitin to the substrate protein. In mammalian cells, it appears that only one E1

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Fig. 28.3. Proteasomes. (A) Electron micrograph of a 26S proteasome complex from yeast (Saccharomyces cerevisiae). Reproduced from Glickman et al. (1998) with permission from Elsevier. (B) Subunit composition and organization of the 26S proteasome. The 26S proteasome is comprised of a 28-subunit catalytic core, 20S proteasome (670 kDa), which is an assembly of two outer and two inner heptameric rings stacked axially to form a hollow cylindrical structure in which proteolysis occurs. Each of the two inner rings of the 20S proteasome is composed of seven different b-subunits, three of which host the three different catalytic sites on the inner surface of the complex. These proteolytically active sites mediate the hydrolysis of proteins at the C-terminus of hydrophobic, basic and acidic residues and are referred to as the chymotrypsin-, trypsin- and peptidylglutamyl-peptide hydrolytic activities, respectively. The outer rings comprise seven different a-subunits, none of which contains catalytic activity, but together serve as an anchor for the multi-subunit PA700/19S regulator (700 kDa) that binds to either or both ends to form the 26S proteasome complex. PA700 is assembled from two subcomplexes: a base that contains six ATPase plus two non-ATPase subunits and an attached lid that comprises several non-ATPase subunits. PA700 performs several functions and these require adenosine triphosphate (ATP): it opens the channel through the 20S proteasome, which is normally gated by the N-termini of the a-subunits; recognizes polyubiquitinated proteins (via the Rpn10/S5a and Rpt5/S60 ); and unfolds proteins to allow entry to the catalytic core (Lam et al., 2002; Pickart and Cohen, 2004). Indeed, proteins that reach the 26S proteasome and cannot be unfolded or degraded have the potential to block the chamber and inhibit proteasomal function. The PA28/11S regulatory complex (200 kDa), which is a hetero- or homoheptameric ring of PA28a-, PA28b- or PA28g-subunits, may also bind to 20S proteasome and open the channel through the complex (not shown). This process is ATP-independent and mediates the degradation of non-ubiquitinated proteins or peptides, particularly for antigen presentation in the immune system (Goldberg et al., 2002).

enzyme exists, whereas 20 – 40 E2 enzymes have been identified and there are 500 –1000 E3 enzymes which can be grouped into distinct families (e.g. HECT domain and RING finger domain E3s). The selectivity of protein ubiquitination is assured by the fact that each E3 enzyme is specific for one or a limited number of different proteins. Additionally, some proteins require posttranslational modification (e.g. phosphorylation of IkB) before they can undergo ubiquitination and this provides a further degree of selectivity in the process (DiDonato et al., 1996). In the second step of the UPS, unwanted proteins previously tagged by ubiquitin are unfolded by PA700 to permit entry into the inner chamber of the 26S proteasome complex, where they are degraded in an ATP-dependent manner. The degradation products of 26/20S proteasomes are 2–25-residue peptide fragments that are further hydrolyzed by peptidases to produce their constituent amino

acids which are reused in protein synthesis (Saric et al., 2004). Following recognition but before entry into the proteasome, polyubiquitin chains are separated from protein conjugates, then disassembled by deubiquitination enzymes (ubiquitin C-terminal hydrolases) into monomeric ubiquitin, which is reused in the ubiquitination cycle. It has been found that a chain of at least four ubiquitin molecules linked through lysine at 48 (K48) is required for targeting proteins to the 26S proteasome, whereas monoubiquitination (and polyubiquitination linked through lysine 63, K63) preferentially targets proteins to participate in various cellular functions (e.g. gene expression and transport) (Thrower et al., 2000; Pickart, 2001b). In the immune response, proteasome-derived peptides are transferred into the endoplasmic reticulum, bind to major histocompatibility complex class I molecules, then transported to the

PROTEIN-HANDLING DYSFUNCTION IN PARKINSON’S DISEASE cell’s surface for presentation to cytotoxic T cells (Goldberg et al., 2002). Short peptides and some proteins (e.g. oxidatively damaged proteins) can be degraded by the 20S proteasome (the catalytic core of the 26S proteasome) without prior ubiquitination (Grune et al., 2004). In addition, some proteins that are targeted to the 26S proteasome can resist degradation and interfere with the proteasome and possibly block the inner chamber, resulting in proteasomal inhibition (Holmberg et al., 2004; Venkatraman et al., 2004). Molecular chaperones or heat shock proteins (HSPs), such as HSP70 and HSP90, are a highly conserved class of proteins that contribute to protein handling within cells (Hartl and Hayer-Hartl, 2002; Muchowski and Wacker, 2005). HSPs act to facilitate the proper folding and localization of proteins and serve to prevent inappropriate interactions within and between proteins that can otherwise lead to misfolding and aggregation. Additionally, HSPs promote the refolding of proteins that become abnormal. Importantly, HSPs function synergistically with the UPS in several ways, notably in their ability to alter the folding pattern of abnormal proteins to facilitate their recognition and entry into 26/20S proteasomes for degradation (Conconi et al., 1998; Luders et al., 2000; Imai et al., 2003b; Muchowski and Wacker, 2005). HSPs also play a role in the assembly of the 26S proteasome complex (Imai et al., 2003a). Under normal circumstances, cells maintain a dynamic balance between the production of abnormal proteins and their clearance by the UPS, other proteolytic pathways and HSPs. Disturbance of this equilibrium, either by the excess production of abnormal proteins or reduced degradation, leads to an adverse state called proteolytic stress (McNaught et al., 2002a; McNaught and Olanow, 2003). During proteolytic stress, poorly degraded or undegraded proteins tend to accumulate and aggregate with each other and with normal proteins through covalent cross-linking and interactions at exposed hydrophobic regions (Rajan et al., 2001; Goldberg, 2003; Grune et al., 2004). Such protein aggregates can disrupt intracellular processes and induce cytotoxicity (Kopito, 2000; Bence et al., 2001; Grune et al., 2004; Bennett et al., 2005). In recent years, several studies have shown that when UPS-mediated degradation fails, cells can activate a secondary response. This is the transport, sequestration and compartmentalization of poorly degraded/undegraded proteins and aggregates to form inclusion bodies (Johnston et al., 1998, 2002; Kopito, 2000; Kawaguchi et al., 2003; Arrasate et al., 2004). In neurodegenerative disorders, where proteolytic stress is a key factor, protein aggregates and inclusion

575

bodies can be seen within different compartments of the cell (Ciechanover and Brundin, 2003). In PD, these proteinaceous inclusions are known as Lewy bodies and they are typically seen in the cytoplasm of neurons at the various pathological sites (McNaught et al., 2002a; Olanow et al., 2004).

28.3. Protein-handling dysfunction in familial Parkinson’s disease During the past 10 years, there have been numerous discoveries of gene mutations that cause rare familial forms of PD (McNaught and Olanow, 2003; Hattori and Mizuno, 2004; Petrucelli and Dawson, 2004). Although the clinical spectrum and pathology of these illnesses often differ significantly from each other and from typical sporadic PD, it appears that they share similar pathogenic mechanisms, namely protein mishandling and aggregation (McNaught and Olanow, 2003; Hattori and Mizuno, 2004; Petrucelli and Dawson, 2004). This concept relates to the observation that these mutations affect proteins that have a high propensity to misfold and aggregate, or impair the activity of UPS enzymes and related proteolytic systems (McNaught and Olanow, 2003; Hattori and Mizuno, 2004; Petrucelli and Dawson, 2004). Specifically, mutations in a-synuclein, parkin, ubiquitin Cterminal hydrolase L1 (UCH-L1), DJ-1, PTEN (phosphatase and tensin homolog deleted on chromosome 10)-induced kinase 1 (PINK1) and dardarin/leucinerich repeat kinase 2 (LRRK2), evidently alter protein handling and this defect appears to play a key role in the pathogenesis of familial PD. 28.3.1. a-Synuclein In the 1990s, autosomal-dominant PD in several European families was linked to chromosome 4q21q23 (PARK 1) (Polymeropoulos et al., 1996, 1997; Kruger et al., 1998). Subsequent genetic analyses revealed that the defects were A53T and A30P point mutations in the gene that encodes for a previously discovered protein known as a-synuclein (Polymeropoulos et al., 1997; Kruger et al., 1998). More recently, an E46K mutation in a-synuclein was reported in another European family with autosomaldominant PD (plus features of dementia with Lewy bodies) (Zarranz et al., 2004), but no other point mutation has been found. However, in recent years, several studies have discovered duplication in the normal asynuclein gene in European families (Chartier-Harlin et al., 2004; Ibanez et al., 2004) and triplication of the normal a-synuclein gene in European and American families (Muenter et al., 1998; Singleton et al.,

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K. ST. P. MCNAUGHT

2003; Farrer et al., 2004; Miller et al., 2004) with autosomal-dominant PD. Patients with a-synuclein-linked familial PD share features of individuals with typical sporadic PD, but there are also significant differences, in particular the relatively early age of onset (mean in the 40s) and high occurrence of dementia in patients with a-synuclein mutations. Further, patients with duplication/triplication of the a-synuclein gene tend to have dementia with Lewy bodies in addition to or instead of parkinsonism (Muenter et al., 1998; Singleton et al., 2003; Chartier-Harlin et al., 2004; Farrer et al., 2004; Ibanez et al., 2004; Miller et al., 2004). Pathologically, patients with the A53T mutation or multiplication mutation of the a-synuclein gene show a marked increase in a-synuclein levels with protein aggregation in various brain regions (Muenter et al., 1998; Duda et al., 2002; Kotzbauer et al., 2004). However, in patients with the A53T mutation, Lewy bodies are scarcely present and there is a marked accumulation of a-synuclein and tau in the cerebral cortex and striatum (Duda et al., 2002; Kotzbauer et al., 2004). In addition, patients with triplication of the a-synuclein gene have vacuoles in the cortex, neuronal death in the hippocampus and inclusion bodies in the glial cells (Muenter et al., 1998). Thus, there are significant differences between the pathology in a-synuclein-linked familial and typical sporadic PD. a-Synuclein is a 140-amino-acid, 14 kDa protein and belongs to a family of related proteins that also include b- and g-synucleins (Goedert, 2001). a-Synuclein, so called because of its intracellular localization to synapses and nuclear envelope when first discovered (Maroteaux et al., 1988; Jakes et al., 1994), is expressed throughout the CNS (Solano et al., 2000). It is enriched in presynaptic nerve terminals and associates with lipid membranes and vesicles (Goedert, 2001). The normal function of a-synuclein is unknown, but there is some evidence that it plays a role in synaptic neurotransmission (Abeliovich et al., 2000; Goedert, 2001). The process by which alterations in the a-synuclein gene induce pathogenesis in PD appears to involve a gain of function of the mutant protein, which is consistent with the dominant inheritance pattern of transmission. However, the precise mechanisms by which mutant or excess asynuclein induces neuronal death are unclear. Normal a-synuclein is monomeric and is intrinsically unstructured or natively unfolded at low concentrations (Weinreb et al., 1996; Conway et al., 1998). PDrelated mutations in the protein induce misfolding, oligomerization and aggregation (Conway et al., 1998, 2000; Li et al., 2001; Lashuel et al., 2002; Caughey and Lansbury, 2003). Also, high concentrations of a-

synuclein cause the protein to oligomerize into bpleated sheets (Conway et al., 1998). During the fibrilization of a-synuclein, intermediary oligomeric species (called protofibrils) are formed and convert to annular structures with pore-like properties that can permeabilize/damage membranes (Conway et al., 2000; Li et al., 2001; Lashuel et al., 2002). It has been suggested that protofibrils are the toxic a-synuclein species responsible for neurodegeneration in familial PD (Caughey and Lansbury, 2003). However, these concepts relating to the biophysical properties of asynuclein are largely based on the in vitro conformational changes of the protein and their relevance in the normal and PD brain remain to be determined. The cytotoxicity of mutant/excess a-synuclein might also involve interference with proteolysis. Normal a-synuclein is a substrate for the UPS and might be preferentially degraded in a ubiquitin-independent manner (Bennett et al., 1999; Tofaris et al., 2001; Liu et al., 2003). In vitro and in vivo studies have demonstrated that mutant a-synuclein, which misfolds, oligomerizes and aggregates, is resistant to UPSmediated degradation and also inhibits this pathway (Stefanis et al., 2001; Tanaka et al., 2001; Snyder et al., 2003). As a result, there is accumulation of a wide range of proteins in addition to a-synuclein in cells expressing mutant a-synuclein (Stefanis et al., 2001; Tanaka et al., 2001; Snyder et al., 2003). As previously discussed, high levels of undegraded or poorly degraded proteins have a tendency to aggregate with each other and other proteins, form inclusion bodies, disrupt intracellular processes and cause cell death (Bence et al., 2001). In this respect, it is reasonable to suggest that alterations in the a-synuclein gene cause the UPS to fail and this defect underlies protein aggregation, Lewy body formation and neurodegeneration in hereditary PD. Many studies, employing a variety of procedures, have examined the effects of expressing familial PD-related mutant (and wild-type) a-synuclein in transgenic animals (Fernagut and Chesselet, 2004). Most of these investigations found that the overexpression of A53T, A30P or wild-type a-synuclein causes inclusion body formation but does not cause neurodegeneration in transgenic mice (Fernagut and Chesselet, 2004). However, the expression of mutant (A53T, A30P) or wildtype a-synuclein in transgenic Drosophila (Feany and Bender, 2000) or the adenoviral-mediated expression of A53T mutant or wild-type a-synuclein in the SNpc of adult non-human primates (common marmosets) (Kirik et al., 2003) causes dopamine cell degeneration. These observations raise the possibility that additional factors, such as environmental toxins, might be required to trigger the development of PD in individuals carrying

PROTEIN-HANDLING DYSFUNCTION IN PARKINSON’S DISEASE mutations in a-synuclein. This is a relevant concept since not all carriers of point mutations in a-synuclein develop PD. 28.3.2. Parkin In 1997, it was found that autosomal-recessive juvenile parkinsonism (AR-JP), first discovered in Japanese families, was linked to chromosome 6q25.2-q27 (PARK 2) (Yamamura et al., 1973; Matsumine et al., 1997). Soon thereafter, this locus was found to code for a gene called parkin (Kitada et al., 1998; Mizuno et al., 2001). Subsequently, it was shown that many deletions, multiplications and point mutations resulting in missense and nonsense changes spanning the entire parkin gene cause familial PD (Hattori and Mizuno, 2004). It is estimated the parkin mutations account for half of early-onset familial cases of PD or 1 in 10 of all early-onset occurrences of PD (Lucking et al., 2000). It is noteworthy that parkin mutations have also been associated with late-onset (¼ 60 years old) hereditary PD (Foroud et al., 2003). Clinically, AR-JP varies significantly from typical sporadic PD. AR-JP can have a very early age of onset, ranging from 7 to 58 years (average 26.1 years) and demonstrate a benign rate of progression (Lucking et al., 2000). These patients also demonstrate foot dystonia at disease onset, less frequent rest tremor, diurnal fluctuations, hyperreflexia, transient improvement of motor disability after sleep or rest and severe dyskinesias tend to develop with levodopa therapy (Lucking et al., 2000). Neuropathologically, AR-JP also differs from typical PD. In AR-JP, neuronal death is restricted to the SNpc and LC. Lewy bodies or other protein aggregates are absent in patients with AR-JP (Mori et al., 1998). However, Lewy bodies have been found in a patient with parkin-linked autosomal-dominant parkinsonism and clinical features more typical of sporadic PD (Farrer et al., 2001). The parkin gene encodes parkin protein which has 465 amino acids/52 kDa and expressed in the cytoplasm, nucleus, Golgi apparatus and processes of neurons throughout the CNS (Horowitz et al., 2001). Recent studies have shown that parkin is an E3 ubiquitin ligase (Imai et al., 2000, 2001; Shimura et al., 2000, 2001; Zhang et al., 2000). As with other E3 ubiquitin ligases, parkin contains a ubiquitin-like (UBL) domain at the N-terminal, a central linker region and a RING finger domain (comprising two RING finger motifs separated by an in-between-RING domain) at the C-terminal. Parkin acts in concert with the E2 enzymes Ubc6, UbcH7 and UbcH8, to ubiquitinate a variety of substrates. These include synphilin-1, CDCrel-1, parkin-associated endothelin receptor-like

577

receptor (Pael-R), an O-glycosylated isoform of asynuclein (aSp22), cyclin E a/b-tubulin, p38 subunit of the aminoacyl-tRNA synthetase complex and synaptotagmin X1 (Imai et al., 2000, 2001; Shimura et al., 2000; Hattori and Mizuno, 2004). Parkin, through its UBL domain, has been shown to interact with the 26S proteasome Rpn10/S5a subunit which, along with Rpt5/S60 , plays a role in the recognition of ubiquitinated substrates by the PA700 proteasome activator (Sakata et al., 2003; Pickart and Cohen, 2004). Parkin also interacts with a protein complex containing CHIP/HSP70 (CHIP, carboxy terminus of Hsp70-binding protein) and which promotes the activity of parkin (Cyr et al., 2002; Imai et al., 2002). The mechanism by which mutations in parkin induce pathology is unclear, but could relate to a loss of E3 ubiquitin ligase activity in familial PD. Parkin protein and enzymatic activity are markedly reduced in the SNpc and LC which degenerate in the disorder (Mori et al., 1998; Shimura et al., 1999, 2000, 2001). Consequently, there is an accumulation of undegraded parkin substrates, including Pael-R and aSp22, in these brain areas (Imai et al., 2001; Shimura et al., 2001). It has been shown that normal parkin prevents ER dysfunction and unfolded protein-induced cell death following overexpression of Pael-R in cultured cells and Drosophila (Imai et al., 2000, 2001; Yang et al., 2003). Thus, it is possible that the accumulation of undegraded substrate proteins disrupts intracellular processes, leading to neurodegeneration in familial PD. Interestingly, mutation of parkin in transgenic mice does not induce nigrostriatal degeneration as in AR-JP (Goldberg et al., 2003; Itier et al., 2003; Von Coelln et al., 2004; Perez and Palmiter, 2005). In addition, it has been shown that the frequency of point mutations, deletions and duplications of parkin is similar in AR-JP (3.8%) and normal control (3.1%) subjects (Lincoln et al., 2003). These observations raise the possibility that additional agents, perhaps exposure to environmental substances, may be necessary to trigger the development of parkinsonism in some individuals carrying mutations in parkin. 28.3.3. UCH-L1 In 1998, it was discovered that an I93M missense mutation in the gene (4p14; PARK 5) encoding UCH-L1, a deubiquitinating enzyme, was responsible for autosomal-dominant PD in a European family (Leroy et al., 1998). Since the parents were asymptomatic, this suggests that the mutation causes disease with incomplete penetrance. The patients had clinical features that resemble sporadic PD, including a good response to levodopa, although the age (49 and 51

578

K. ST. P. MCNAUGHT

years) of onset was relatively early. Genetic screening studies have failed to detect additional UCH-L1 mutations in patients with familial PD (Wintermeyer et al., 2000). So, mutations in UCH-L1 appear to be a very rare cause of PD. Interestingly, several studies have found that the UCH-L1 gene is a susceptibility locus in sporadic PD and that polymorphisms, such as the S18Y substitution, confer some degree of protection against developing the illness (Maraganore et al., 2004). Thus, genetic variability in UCH-L1 may play a role in the pathogenesis of the more common sporadic PD. The mechanism by which alterations in the UCHL1 gene cause PD is unknown. The encoded 230amino-acid/26 kDa protein is expressed exclusively in neurons in many areas of the CNS (Solano et al., 2000) and constitutes 1–2% of the soluble proteins in the brain (Wilkinson et al., 1989, 1992; Solano et al., 2000). Brain samples from subjects with UCH-L1linked PD are not available and so it is not known how the UPS, proteolysis and protein levels are altered in this illness. It has been shown that a mutation in UCH-L1 causes a reduction in deubiquitinating activity in vitro and in the brain of transgenic mice with the neurological disorder gracile axonal dystrophy (GAD) (Leroy et al., 1998; Nishikawa et al., 2003; Osaka et al., 2003). Further, toxin- or mutationinduced inhibition of UCH-L1’s activity leads to a marked decrease in the levels of ubiquitin in cultured cells and in the brain of GAD mice (McNaught et al., 2002c; Osaka et al., 2003). Also, impairment of ubiquitin C-terminal hydrolases leads to degeneration of dopaminergic neurons with protein accumulation and formation of Lewy body-like inclusions in rat ventral midbrain cell cultures (McNaught et al., 2002c). Interestingly, a recent study showed that UCH-L1 has E3 ubiquitin ligase activity, but it remains unclear if and how the PD-related mutation alters this function of the protein (Liu et al., 2002). Thus, it is reasonable to suspect that a mutation in UCH-L1 causes the UPS to fail, leading to altered proteolysis and ultimately cell death. However, further studies are required to decipher the pathogenic mechanism of UCH-L1 alterations in PD. 28.3.4. DJ-1 In 2001, genetic studies of several European families with autosomal-recessive early-onset parkinsonism found linkage to chromosome 1p36 (PARK 7) (van Duijn et al., 2001). Later, these families were found to have deletion, truncating and missense mutations in the gene that encodes a previously known protein, called DJ-1 (Nagakubo et al., 1997; Bonifati et al.,

2003, 2004). So far, no additional mutation in DJ-1 has been reported and it is thought that this defect could account for only 1–2% of early-onset cases of the illness (Abou-Sleiman et al., 2003). The clinical expression of DJ-1-linked PD is similar to parkin-related PD, namely early onset (mid-30s) of symptoms, slow progression, presence of dystonia, levodopa-responsiveness and the occurrence of psychiatric disturbance (Bonifati et al., 2003, 2004). There is at present no report on the neuropathology in DJ-1 PD subjects. DJ-1 is a 189-amino-acid/20 kDa protein, is widely found in the CNS, is more prominent in astrocytes compared to neurons and is present in the cytosol and nucleus of cells (Bandopadhyay et al., 2004; Shang et al., 2004). The normal function of DJ-1 is unknown. There is evidence to suggest that it acts as an antioxidant or a sensor of oxidative stress (Yokota et al., 2003; Taira et al., 2004). In addition, the molecular structure and in vitro properties of DJ-1 indicate that it might function as a molecular chaperone and a protease (Lee et al., 2003; Olzmann et al., 2004; Wilson et al., 2004). Recently, DJ-1 was found to interact with parkin, CHIP and HSP70, suggesting a link to these proteolytic systems (Moore et al., 2005b). The pathogenic mechanism of mutant DJ-1 is unknown. The recessive pattern of inheritance raises the possibility that the mutations induce a loss of function of the protein in familial PD. The DJ-1 mutations (e.g. L166P) that occur in PD destabilize and inactivate the protein, impair its proteolytic activity and promote its rapid degradation by the proteasome (Moore et al., 2003; Olzmann et al., 2004). Overexpression of DJ-1 protects cultured cells from oxidative stress, but knockdown of DJ-1 increases susceptibility to oxidative stress, ER stress and proteasomal inhibition (Yokota et al., 2003; Taira et al., 2004). In addition, mutations in DJ-1 reduce its ability to inhibit the aggregation of a-synuclein both in vitro and in vivo (Shendelman et al., 2004). Interestingly, a recent study has shown that deletion of DJ-1 in transgenic mice does not induce neurodegeneration (Goldberg et al., 2005), suggesting that other factors may be involved in the pathogenic process in PD. Thus, one may speculate that mutations in DJ-1 lead to a loss of its putative antioxidant, chaperone and proteolytic activity. Such defects, if proven to be the case in future studies, would indicate that altered protein handling also plays a role in the pathogenesis of this familial form of PD. 28.3.5. PINK1 Autosomal-recessive early-onset PD in several European families was found to result from missense

PROTEIN-HANDLING DYSFUNCTION IN PARKINSON’S DISEASE and truncating mutations in a gene located at chromosome 1p35 (PARK 6) and codes for a protein designated PINK1 (Valente et al., 2001, 2002, 2004). This mutation has since been found in additional families (Healy et al., 2004b). Clinically, this form of PD is characterized by early onset (32–48) of symptoms, slow progression and good response to levodopa (Valente et al., 2001; Healy et al., 2004b). PINK1 is a 581-amino-acid/62.8 kDa protein and, although it has been localized to the mitochondrion, further studies are required to determine its cellular and anatomical distribution (Valente et al., 2004). The normal function of PINK1 is unknown. It appears to be a serine/threonine protein kinase which phosphorylates proteins involved in signal transduction pathways (Valente et al., 2004). In cell cultures, wild-type PINK1 prevents proteasome inhibitor-induced mitochondrial dysfunction and apoptosis, but this protection is lost with familial PD-related mutations (Valente et al., 2004). Interestingly, familial PD-related mutations in PINK1 have been found in normal control subjects without parkinsonism (Rogaeva et al., 2004). These findings raise the possibility that mutations in PINK1 could render neurons susceptible to agents, such as abnormal proteins and toxins, that act on proteasomes to induce cell death. Thus, the pathogenic process in PINK1-related familial PD might involve alterations in protein handling. 28.3.6. Dardarin/LRRK2 In 2002, a large Japanese family having autosomaldominant PD with incomplete penetrance was linked to a mutation on chromosome 12p11.2-q13.1 (PARK 8) (Funayama et al., 2002). Subsequently, this linkage was found in several families from different countries and it is estimated that the mutation could account for 5% of familial cases of PD (Nichols et al., 2005). More recently, two papers published simultaneously reported that the defects in these patients were several missense mutations in the gene encoding a protein called dardarin or LRRK2 (Paisan-Ruiz et al., 2004; Zimprich et al., 2004). Interestingly, not all individuals with these mutations develop parkinsonism, suggesting the possible requirement of other etiological factors to act as a trigger for the illness (Di Fonzo et al., 2005). PD patients with mutations in dardarin/LRRK2 have a clinical spectrum similar to sporadic PD with an age of onset ranging from 35 to 78 years. However, there are important pathological differences (Funayama et al., 2002; Wszolek et al., 2004; Zimprich et al., 2004). All subjects had nigrostriatal degeneration, some had Lewy bodies and some did not have these inclusions; others had extensive cortical Lewy bodies

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consistent with dementia with Lewy bodies and some had tau-immunoreactive glial and neuronal inclusions consistent with tauopathies such as progressive supranuclear palsy. Dardarin/LRRK2 is predicted to encode a 2482/ 2527-amino-acid protein which is expressed throughout the brain (Paisan-Ruiz et al., 2004). The normal function of this protein is not yet known. Based on its similarity with other proteins, it has been suggested that dardarin/LRRK2 might be a cytoplasmic kinase (Paisan-Ruiz et al., 2004; Zimprich et al., 2004). It remains to be determined how mutations in dardarin/ LRRK2 alter the structure and function of the protein. Some proteins, such as IkB, require phosphorylation as a prerequisite to their ubiquitination and proteasomal degradation (DiDonato et al., 1996). It will therefore be interesting to determine if dardarin/LRRK2 acts to phosphorylate proteins and if mutations alter the ability of substrates to undergo ubiquitin-dependent degradation by the UPS.

28.4. Protein-handling dysfunction in sporadic Parkinson’s disease The majority of PD cases occur sporadically with insidious onset and unknown cause. At present, there is no convincing evidence to suggest that a defect in parkin, UCH-L1, a-synuclein, DJ-1, PINK1 or dardarin/ LRRK2 is responsible for sporadic PD. However, these or other genes could be involved as a susceptibility factor in this form of the illness. It is widely believed that gene and/or aging related-susceptibility coupled with exposure to environmental toxins underlies the etiology of sporadic PD (Tanner, 2003). Thus, it is interesting that variability in the genes encoding a-synuclein (Mellick et al., 2005), parkin (Oliveira et al., 2003), UCH-L1 (Maraganore et al., 2004) but not PINK1 (Healy et al., 2004a) or DJ-1 (Morris et al., 2003), has been associated with an increased risk of developing sporadic PD. Several etiopathogenic factors have been linked with the neurodegenerative process. Most recently, inadequate UPS-mediated proteolysis has been implicated in the etiopathogenesis of sporadic PD (McNaught and Olanow, 2003) (Table 28.1). 28.4.1. Altered proteasomal function There has been indirect, but nevertheless significant, findings to suggest that proteasomal dysfunction plays a role in the vulnerability and degeneration of the SNpc and perhaps other regions in PD. mRNA level and enzymatic activity of 26/20S proteasomes and proteasome activators decrease with advancing age in the

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Table 28.1 Gene mutations which implicate altered protein handling in familial Parkinson’s disease

Locus PARK 1 and 4

Chromosome location

Gene product and properties

4q21-q23

a-Synuclein 140 amino acids/14 kDa protein Localized to synaptic terminals

PARK 5

6q25.2-q27

4p14

Point mutations (A53T, A30P and E46K) Duplication

Inheritance pattern

Age of onset (years)

Autosomaldominant

Range: 30–60 Mean: 45

Function: unknown. Possibly play a role in synaptic activity

Triplication

Parkin 465 amino acids/52 kDa protein Expressed in cytoplasm, Golgi complex, nuclei and processes Function: E3 ubiquitin ligase Ubiquitin C-terminal hydrolase L1 230 amino acids/26 kDa protein Neuron-specific protein Function: deubiquitinating enzyme (possible E3 activity also)

Deletions Point mutations Multiplications

Autosomalrecessive

Missense mutation (I93M)

Autosomaldominant

Range: 7–58 Mean: 26.1

Rarely autosomaldominant

49 and 50

Clinical spectrum

Pathological features

Levodopa-responsive; rapid progression; prominent dementia E46K and multiplication cases demonstrate overlap with dementia with Lewy bodies

Neuronal loss in the SNpc, LC and DMN

Levodopa-responsive but with severe dyskinesias; slow progression; foot dystonia; diurnal fluctuations; and hyperreflexia

Typical Parkinson’s disease

Lewy bodies are rare and tau accumulation occurs in some A53T cases. Extensive Lewy bodies in E46K and multiplication cases Triplication cases demonstrate degeneration in the hippocampus, vacuolation in the cortex and glial cytoplasmic inclusions Selective and severe destruction of the SNpc and LC Generally Lewy body-negative

Neuropathology not yet determined

K. ST. P. MCNAUGHT

PARK 2

Mutations

1p35–1p36

PARK 7

PARK 8

Missense Truncating

Autosomalrecessive

Range: 32–48

Levodopa-responsive; slow progression

Neuropathology not yet determined

1p36

PINK 1 581 amino acids/62.8 kDa protein Localized to mitochondria Function: unknown. May be a protein kinase DJ-1

Deletion

Autosomalrecessive

Truncating

Levodopa-responsive; slow progression; dystonia; psychiatric disturbance

Neuropathology not yet determined

12p11.2– 12q31.1

189 amino acids/20 kDa protein More prominent in the cytoplasm and nucleus of astrocytes compared to neurons Function: unknown. Possible antioxidant, molecular chaperone and protease Dardarin/LRRK2 2482/2527 amino acids

Range: 20–40s Mean: mid-30s

Autosomaldominant

Range: 35–79 Mean: 57.4

Typical Parkinson’s disease features; slow progression; dementia present; features of motor neuron disease reported

SNc degeneration Some cases show extensive Lewy bodies; some do not have Lewy bodies Also, intranuclear inclusions, tau-immunoreactive inclusions and neurofibrillary tangles are present

Missense

Missense

Function: unknown. May be a protein kinase

SNpc, substantia nigra pars compacta; LC, locus ceruleus; DMN, dorsal motor nucleus.

PROTEIN-HANDLING DYSFUNCTION IN PARKINSON’S DISEASE

PARK 6

581

582

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midbrain and other areas of the CNS (El-Khodor et al., 2001; Gaczynska et al., 2001). The SNpc, in comparison with other brain areas, has a higher level of basal protein oxidation and oxidative stress and these processes are elevated in parallel with aging (Floor and Wetzel, 1998). Therefore, declining proteasomal activity coupled with increasing oxidative protein damage with advancing age could underlie the age-related increase in the propensity of the SNpc to undergo degeneration. Indeed, mild neuronal loss with Lewy bodies is found in the SNpc of 10 –15% of individuals who die over the age of 65 years without clinical evidence of neurological disorder (Gibb and Lees, 1988; Braak et al., 2003). This condition, referred to as incidental Lewy body disease, occurs with 10 times the frequency of PD and is thought to represent the presymptomatic phase of sporadic PD (Gibb and Lees, 1988). There is a marked increase in the levels of a-synuclein and oxidatively damaged, 4-hydroxynonenal-conjugated, nitrated, phosphorylated and ubiquitinated proteins in the SNpc and other brain areas in PD (Olanow et al., 2004). Indeed, protein aggregates and Lewy body inclusions containing a wide variety of proteins, including a-synuclein and ubiquitin, can be seen at the various pathological sites in patients with PD (Olanow et al., 2004). Taken together, these observations suggest that the UPS may be inhibited and/or saturated, resulting in protein accumulation and aggregation in the disorder. The accumulation of both ubiquitinated and non-ubiquitinated proteins (e.g. oxidized proteins and a-synuclein) (Bennett et al., 1999; Tofaris et al., 2001; Liu et al., 2003; Grune et al., 2004) in the brain indicates that a defect in proteolysis at a central and common point, i.e. the 20S proteasome core, is likely since both groups of proteins accumulate in the illness. These observations provided the stimulus for studying the structure and function of 26/20S proteasomes in sporadic PD. It was shown that the chymotrypsin-like, trypsin-like and peptidylglutamyl peptide hydrolytic (PGPH) enzymatic activities of the proteasome were reduced by approximately 44–55% in the SNpc in PD compared to age-matched controls (McNaught and Jenner, 2001; McNaught and Olanow, 2003; Furukawa et al., 2002; Tofaris et al., 2003). In contrast, the three proteolytic activities of the proteasome were unchanged in regions that do not degenerate in PD, namely the frontal cortex, striatum, hippocampus, pons and cerebellum (McNaught and Jenner, 2001; McNaught and Olanow, 2003; Tofaris et al., 2003). Interestingly, Tofaris and colleagues examined PD cases with relatively mild neuropathology, suggesting that altered proteasomal function occurs early in the pathogenic process (Tofaris et al., 2003). There is a 40% reduction in the

content of proteasome a-subunits, but not b-subunits, in the SNpc in PD compared to age-matched controls (McNaught et al., 2003). In contrast, the levels of asubunits were increased by 9% in the cerebral cortex and by 29% in the striatum in PD. Immunohistochemical staining demonstrated reduced levels of 26/20S proteasomal a-subunits, but not b-subunits, within dopaminergic neurons in the SNpc of PD subjects compared to age-matched controls (McNaught et al., 2003). As discussed previously, the PA700 proteasome activator is a complex of over 20 different subunits with varying molecular weights (Pickart and Cohen, 2004). In PD, there was either no change (42 kDa, 46 kDa and 95 kDa bands) or up to a 33% loss (52.5 kDa, 75 kDa and 81 kDa bands) of PA700 subunits in the SNpc (McNaught et al., 2003). In contrast, there was a marked increase in the levels of subunits at the 81 kDa, 75 kDa, 52.5 kDa and 42 kDa bands in the frontal cortex and/or the striatum of PD subjects compared to controls. In normal control subjects, the levels of the PA28 proteasome activator were very low in the SNpc compared to the frontal cortex and striatum (McNaught et al., 2003). In PD brains, PA28 immunoreactivity was almost undetectable in the SNpc and levels were reduced in the frontal cortex (24%) and striatum (16%) in comparison to controls (McNaught et al., 2003). These findings indicate that, in sporadic PD, there is inhibition of proteasomal function in regions that degenerate whereas there is upregulation in areas that are speared from the pathogenic process. 28.4.2. Role of proteasomal dysfunction to the neurodegenerative process A role for inhibition of proteasomal function in the pathogenesis in PD is supported by several observations. Proteasomes not only play a critical role in the degradation and clearance of unwanted proteins, but they also play a major role in controlling the levels of short-lived regulatory/function proteins and are intimately linked with a variety of cellular processes (Table 28.2). Indeed, proteasomes are linked with antioxidant defense mechanisms (Jha et al., 2002; Atlante et al., 2003), mitochondrial activity (Lee et al., 2001; Hoglinger et al., 2003), inflammatory responses (Li et al., 2003) and antiapoptotic pathways (Jesenberger and Jentsch, 2002) (Table 28.2). Consistently, inhibition of proteasomal function disrupts these processes and causes oxidative stress (Kikuchi et al., 2003), mitochondrial dysfunction (Kikuchi et al., 2003), proinflammatory reactions (Rockwell et al., 2000) and apoptotic cell death (Hoglinger et al., 2003). Most of these proteasome-linked cellular processes have been found to be altered in PD, further supporting the role of

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Table 28.2 Alterations in ubiquitin-proteasome system (UPS)-linked cellular processes in Parkinson’s disease Cellular processes linked to the UPS

Alterations in Parkinson’s disease

Degradation and clearance of abnormal proteins (Goldberg, 2003) Antioxidant defense mechanisms (Jha et al., 2002; Kikuchi et al., 2003) Mitochondrial function (Hendil et al., 2002; Hoglinger et al., 2003; Shamoto-Nagai et al., 2003; Sullivan et al., 2004) Inflammatory response (Rockwell et al., 2000; Li et al., 2003)

Yes: failure of the UPS and protein aggregation Yes: oxidative stress (Jenner, 2003)

Immune processes (Goldberg et al., 2002) Apoptotic signaling (Jesenberger and Jentsch, 2002; Hoglinger et al., 2003) Synaptic function and neurotransmission (Hegde and DiAntonio, 2002) Signal transduction (Wilkinson, 1999) Protein transport/trafficking (Aguilar and Wendland, 2003) Gene transcription (Muratani and Tansey, 2003) Development and differentiation (Hegde and DiAntonio, 2002) Regulation of cell cycle and division (Adams, 2004)

Yes: complex I activity impaired (Orth and Schapira, 2002) Yes: microglial activation and gliosis (Hunot and Hirsch, 2003; McGeer and McGeer, 2004) Yes: complement activation (McGeer and McGeer, 2004) Yes: apoptotic cell death (Tatton et al., 2003) Yes: altered basal ganglia function (Bezard et al., 2003; Obeso et al., 2004) Yes: altered neuronal activity (Bezard et al., 2003; Obeso et al., 2004) Yes: inclusion body formation (Olanow et al., 2004) Yes: altered expression of a variety of proteins (Grunblatt et al., 2004) – –

The UPS controls the levels of short-lived regulatory/functional proteins that mediate a wide variety of cellular processes. Thus, failure of the UPS to degrade proteins not only causes protein accumulation and aggregation, but it also alters cellular functions. Many of these cellular and biochemical defects occur in Parkinson’s disease and likely play a role in the neurodegenerative process.

proteasomal dysfunction in the pathogenic process (Table 28.2). Typically, inhibition of proteasomal function causes protein accumulation and the formation of aggresomes, which are intracytoplasmic proteinaceous inclusions formed at the centrosome in response to inadequate protein degradation (Johnston et al., 1998; Kopito, 2000; Junn et al., 2002). The demonstration that Lewy bodies contain the centrosome-related maker g-tubulin, UPS components and HSP and share other compositional and organization features of aggresomes further supports the role of proteasomal dysfunction in the pathogenic process in PD (McNaught et al., 2002a; Olanow et al., 2004). Impairment of proteasomal function usually induces cell death and this often occurs via an apoptotic mechanism. It has been shown that application of proteasome inhibitors in cultured cells, or injection of these agents into the brain of rats, induces preferential degeneration of dopaminergic neurons in the SNpc (McNaught et al., 2002b, c; Petrucelli et al., 2002; Fornai et al., 2003). Neurodegeneration is accompanied by protein accumulation and the formation of a-synuclein /ubiquitin-immunoreactive inclusions in these models (McNaught et al., 2002b, c; Petrucelli et al., 2002).

Recently, it was shown that systemic exposure of rats to PSI (Z-Ile-Glu (OtBu)-Ala-Leu-al, a peptide aldehyde) or epoxomicin (Ac (Me)-Ile-Ile-Thr-Leu-EX, a peptide a0 ,b0 -epoxyketone), which are synthetic and bacterial proteasome inhibitors respectively, induces a model that closely recapitulated many features of PD (McNaught et al., 2004). Proteasome inhibitortreated rats developed progressive, PD-like, motor dysfunctions that could be improved with levodopa and apomorphine administration. Positron emission tomography (PET) demonstrated a gradual loss of dopaminergic nerve terminals in the striatum and postmortem analyses showed striatal dopamine depletion and progressive neurodegeneration with apoptosis and inflammation in the SNpc (Fig. 28.4). Also, neuronal death occurred in the LC, DMN and NMB. At the various pathological sites in the rats treated with proteasome inhibitors, there was a 43–82% inhibition of proteasomal function, accumulation of proteins and the formation of intraneuronal a-synuclein/ubiquitinpositive inclusion bodies. Thus, this model, based on inhibition of proteasomal function, more closely recapitulates the behavioral, pathological and biochemical features of sporadic PD than every other model of the disorder described to date. Taken together, these

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Fig. 28.4. For full color figure, see plate section. Parkinson’s disease-like neuropathology in the brain of living rats treated with proteasome inhibitors. Rats were administered the proteasome inhibitor PSI (Z-Ile-Glu (OtBu)-Ala-Leu-al, 3.0 mg/kg) or vehicle (controls) by six subcutaneous injections spaced over a period of 2 weeks. Seventeen weeks later, the animals underwent positron emission tomography imaging to visualize dopaminergic nerve terminals in the striatum using the specific dopamine transporter ligand carbon-11-labeled 2b-carbomethoxy-3b-(4-fluorophenyl)tropane (11C-CFT). Color bar: Max (red) and Min (black) represent a maximum binding ratio of 3.5 and a minimum binding ratio of 0 for 11C-CFT, respectively. The other colors represent intermediate binding levels. Note the marked reduction of 11C-CFT binding in the striatum, indicative of nigrostriatal degeneration, in proteasome-inhibited rats.

findings suggest that altered proteasomal function could be the key factor in the etiopathogenesis of sporadic PD. 28.4.3. The cause of proteasomal dysfunction An important question therefore is what causes proteasomal dysfunction in sporadic PD. There are several possibilities, including so far undiscovered gene mutations and defects induced by other factors which occur in the disease process, such as oxidative stress or mitochondrial dysfunction (Jenner and Olanow, 1998; Bulteau et al., 1999; Hendil et al., 2002). Alternatively, the actions of environmental toxins could be responsible for proteasomal dysfunction in PD. Inhibitors of the proteasome are widely distributed in the environment (Kisselev and Goldberg, 2001). They are produced by bacteria (e.g. actinomycetes which infect the below-ground portion of crops) (Fenteany and Schreiber, 1998; Sin et al., 1999), fungi (e.g.

Apiospora montagne, which infests wheat/flour) (Koguchi et al., 2000), plants (Nam et al., 2001; Kazi et al., 2003; Jana et al., 2004) and the chemical/pharmaceutical industry (Kisselev and Goldberg, 2001; Zhou et al., 2004). Indeed, lactacystin and epoxomicin, which are among the most potent proteasome inhibitors known, are naturally produced by actinomycetes (Streptomyces) bacteria (Cross, 1981; Ensign et al., 1993). These microbes are found globally in the soil and aquatic habitats of garden and farmland and are well known for infecting root vegetables and potatoes (causing ‘scab’ formation) (Cross, 1981; Ensign et al., 1993). Also, structurally related analogs and the active pharmacophore of natural and synthetic compounds known to inhibit the proteasome potently, such as PSI, are also present in the environment (Kisselev and Goldberg, 2001). Notably, agrochemicals such as the fungicide maneb (specifically its active metabolite) (Zhou et al., 2004) and pesticides, including rotenone, have been shown to impair proteasomal function (Hoglinger et al., 2003; Shamoto-Nagai et al., 2003; Wang and Li, 2004). Thus, proteasome inhibitors are likely to enter the food chain and significant levels of these toxins may be present in rural areas and well water. These factors could play a role in the finding that rural living and drinking well water are both associated with a high risk of developing PD (Priyadarshi et al., 2001).

28.5. Conclusion Since the discovery of PD, there have been multifaceted approaches aimed at determining the cause and mechanism of neurodegeneration in the illness. Several etiopathogenic concepts have been implicated. In recent years, accumulating evidence points to proteinhandling dysfunction as a major factor in the etiopathogenesis of familial and sporadic forms of PD. In the years ahead, more discoveries implicating protein mishandling are likely and these will provide further insights into the pathogenic process in PD. Elucidating the mechanism of neurodegeneration is not merely an academic pursuit as this is likely to reveal novel targets that can be exploited to develop better medicines, such as neuroprotective drugs, for treating patients with the illness. Further, understanding the role of protein mishandling in the neurodegenerative process may even lead to the development of a biomarker for PD.

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Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved

Chapter 29

Programmed cell death in Parkinson’s disease ROBERT E. BURKE* Departments of Neurology and Pathology, Columbia University, The College of Physicians and Surgeons, New York, NY, USA

29.1. The concept and mechanisms of programmed cell death 29.1.1. Programmed cell death: history of the concept Programmed cell death (PCD) is a form of death in which genetic programs intrinsic to the cell bring about its demise through orderly molecular pathways. It is to be distinguished from necrotic cell death in which a harsh physical or biological injury destroys the cell in the absence of any mechanistic participation by the cell. Generally, necrotic cell death is characterized morphologically by the disruption of cellular and nuclear membranes and intracellular organelles. The molecular pathways of PCD are highly conserved evolutionarily and they can be universally identified in diverse contexts of cell death. In addition, common morphologies of PCD are identified in diverse contexts as well, the most common being that of apoptosis, as described below. This universality and molecularly ordered nature of PCD brought a new outlook for approaches to neuroprotection in Parkinson’s disease (PD). Prior to the introduction of the PCD concept, it was widely believed that in order to forestall neuron death in the disease, it would be necessary to identify its specific proximate causes, whether they be environmental toxins or other agents. However, with the introduction of the concept of PCD, it became apparent that without knowing the proximate causes, or even in the presence of diverse possible proximate causes, it would still be possible to abrogate neuron death by inhibiting the common pathways of PCD. As shall be reviewed herein, this approach to neuroprotection has proven to be widely effective in numerous animal models of parkinsonism

and these studies provide a firm scientific basis for the hope that similar approaches may in the future prove effective for the human disease. The concept of PCD had its origins in the field of developmental biology when it was demonstrated that cell death is a normal and important feature of the ontogeny of the organism (Ernst, 1926; Glucksmann, 1951). In developmental neurobiology, the first demonstration of PCD was made by Victor Hamburger and Rita Levi-Montalcini, when they observed naturally occurring cell death in dorsal root ganglia during normal development of the chick embryo (Hamburger and Levi-Montalcini, 1949; Hamburger, 1992). These investigators also made the critical observation in this and related studies that the magnitude of the naturally occurring cell death event was regulated by the targets of the developing structures. They proposed that targets provide limiting amounts of trophic molecules, for which the developing neurons must compete. Their observations thus provided the basis for neurotrophic theory (Clarke, 1985; Barde, 1989) and ultimately led to the discovery of nerve growth factor (Levi-Montalcini, 1987). Another key milestone in the evolution of the PCD concept was the definitive description and definition of apoptosis, the most widely observed morphologic form of PCD, by Kerr et al. in 1972. These investigators recognized that the morphology of apoptosis is widely observed in the naturally occurring cell death during development, as originally reported by Glucksmann (1951), including that which occurs during the development of the central nervous system. Thus, these investigators were the first to recognize apoptosis as the most prevalent morphology of naturally occurring cell death in the nervous system. In

*Correspondence to: Robert E. Burke, Department of Neurology, Room 308, Black Building, Columbia University, 650 West 168th Street, New York, NY 10032, USA. E-mail; [email protected], Tel: þ1-212-305-7374, Fax: þ1-212-305-5450.

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addition, on the basis of the universality in appearance of the features of apoptosis, they perspicaciously proposed that apoptosis is ‘an active, inherently programmed phenomenon’. The field of PCD entered the molecular era with the ground-breaking studies of H. Robert Horvitz in the nematode Caenorhabditis elegans, for which he was the co-recipient of the Nobel Prize in Physiology or Medicine in 2002. In C. elegans, 131 cells undergo developmental cell death; of these, 105 are neurons. By characterizing the nature of mutations which affect the loss of these cells, Horvitz and his colleagues identified critical molecular mediators of PCD, many of which were the founding members of gene families which play critical roles in PCD in higher organisms (Ellis et al., 1991; Putcha and Johnson, 2004). For example, ced-3, a critical mediator of PCD in C. elegans, was found to be homologous to interleukin1ß-converting enzyme (Yuan et al., 1993), now known as caspase-1. Caspase-1 was the first identified member of the caspase family of proteases, which now includes 14 members in mammals and which are critical effectors of PCD (Strasser et al., 2000), as presented in more detail below. Horvitz and his colleagues also determined that a dominant mutation in the ced-9 gene prevented all cells from dying (Ellis et al., 1991). This promotion of survival was similar to the effect of the Bcl-2 oncogene, which had been shown to promote cell survival, rather than cell proliferation (Vaux et al., 1988) and which also had been shown to rescue some of the developmental cell deaths in C. elegans (Vaux et al., 1992). Hengartner and Horvitz (1994) demonstrated that ced-9 shares homology with Bcl-2. Bcl-2 and ced-9 were thus the founding members of a large family of related molecules with antiapoptotic and proapoptotic functions (Merry and Korsmeyer, 1997; Adams and Cory, 1998), presented in further detail below. A critical additional milestone in the evolution of the PCD concept was the direct demonstration in several models that gene transcription is required in order for death to occur (Martin et al., 1988; Oppenheim et al., 1990; White et al., 1994). Although this requirement depends on cellular context (Rukenstein et al., 1991), it nevertheless supports the mechanistic nature of PCD. 29.1.2. Apoptosis and other morphologies of PCD The initial and complete morphologic characterization of apoptosis was achieved by Kerr and his colleagues (1972) by ultrastructural examination of a variety of tissues. They identified what is perhaps the best known feature, because it can also be observed at the light

Fig. 29.1. The morphologic features of apoptosis.

microscope level – which is condensation of the nuclear chromatin. The condensed chromatin may appear as masses subjacent to the nuclear membrane (Kerr et al., 1995) or as distinct, rounded masses (which can be multiple) within the nucleus (Fig. 29.1). On electron microscopy, the condensed chromatin is markedly electron-dense; it is homogeneous in appearance and it has very distinct, well-demarcated boundaries. Some of these features can also be observed in brain tissue by the light microscope and they are so characteristic as to permit identification of apoptosis at that level. On histologic strain with basophilic dyes (thionin, cresyl violet, toluidine blue), apoptotic chromatin clumps are intensely and homogeneously stained, rounded and with precisely demarcated boundaries. Additional features observed by Kerr and colleagues at the ultrastructural level included preservation of cellular organelles, such as mitochondria and both nuclear and plasma membranes (Fig. 29.1). As the cells die, they form membrane blebs, which break off, forming apoptotic bodies. These may encompass cytoplasm, cellular organelles and chromatin fragments. The apoptotic bodies are phagocytosed by adjacent, intact cells. In their initial description of apoptosis, Kerr et al. (1995) made the additional important observations that apoptosis occurs rapidly, usually within 24 hours for a given cell, and that it does not elicit an inflammatory response.

PROGRAMMED CELL DEATH IN PARKINSON’S DISEASE Although apoptosis is clearly the most prevalent morphology of PCD, it is important to recognize that other morphologies exist. Clarke (1990) has identified three other forms. For the purposes of this review, we will comment on only two: autophagy (Clarke’s type 2) and ‘cytoplasmic’ (type 3b). In his review, Clarke confined his description of autophagy to what is now termed ‘macroautophagy’. It should be distinguished from the related processes of microautophagy and chaperone-mediated autophagy (Klionsky and Emr, 2000). Macroautophagy is a process in which intracellular contents are enveloped by an intracellular isolation membrane. This enclosed structure, an autophagosome, subsequently merges with a lysosome, forming an autophagolysosome (Shintani and Klionsky, 2004). Its contents are proteolyzed and the constituents are recycled by the cell. It is important to recognize that autophagy does not always lead to the destruction of the cell; on the contrary, in some contexts, by recycling essential molecules, it can sustain the life of the cell and the organism (Kuma et al., 2004; Lum et al., 2005). Nevertheless, autophagy has also been identified as a mediator of cellular degeneration and in that context, it is reasonably considered as a form of PCD for two reasons. First, it leads to the elimination of cells in normal, developmental processes (Clarke, 1990). In fact, autophagy has been identified within the cells that degenerate in C. elegans (Ellis et al., 1991). Second, autophagy is mediated by orderly molecular pathways (Klionsky and Emr, 2000; Mizushima et al., 2003). Far less

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is known about the molecular pathways mediating autophagy than apoptotic PCD and they will not be discussed further here. Ultimately, however, these pathways may prove relevant to human PD, because autophagy has been identified in vitro in models of dopamine neuron degeneration (Stefanis et al., 2001; Larsen et al., 2002) and features suggestive of autophagy have been reported in postmortem PD substantia nigra (SN) (Anglade et al., 1997). Clarke’s ‘cytoplasmic’ (type 3b) form of death is characterized by cytoplasmic changes, particularly dilatation of the endoplasmic reticulum (ER) (Clarke, 1990), in the absence of nuclear chromatin condensation. To date it has not been identified in models of parkinsonism or human postmortem material, but a similar morphology has been described in weaver mouse, in which there is postnatal degeneration of SN dopamine neurons (Oo et al., 1996) due to a mutation in a potassium channel, GIRK2 (G-protein-coupled inward rectifier potassium channel) (Slesinger et al., 1996). 29.1.3. The molecular pathways of PCD There are three principal pathways by which the molecular events of PCD can be initiated: the intrinsic and extrinsic pathways and ER stress (Fig. 29.2). The schematic depicted in Fig. 29.2 is certainly an oversimplification, as many possible interactions between these three pathways are not shown, but it serves as a useful organizational framework. The main focus of attention

Fig. 29.2. The three principal pathways for the activation of programmed cell death. DD, death domain; DED, death effector domain.

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in this review will be on the intrinsic pathway, which has been more extensively investigated in PD and models thereof, but some observations relevant to the extrinsic pathway and ER stress will be touched upon briefly. The extrinsic pathway of cell death has an important role in killing lymphocytes, cancerous cells and virus-infected cells (Ashkenazi and Dixit, 1998). In the extrinsic pathway, PCD is initiated by the binding of an extracellular ligand to a cell surface receptor (a ‘death receptor’). Examples include the binding of Fas ligand (FasL or CD95L) to the Fas (or CD95) receptor and the binding of tumor necrosis factor (TNF) to the TNF receptor (TNF-R1). These death receptors all contain cytoplasmic death domains (DD). Following ligand binding, these intracellular DDs interact with homologous DDs on adapter proteins, which also contain death effector domains (DED). The inactive, zymogen form of caspase-8 also contains a homologous DED, which, upon interaction with the DEDs of the adaptor proteins, permits close association (‘induced proximity’) of several procaspase-8 molecules (Fig. 29.2). The low intrinsic proteolytic activity of the procaspase-8 molecules then achieves autocleavage, resulting in the fully active, cleaved form of caspase-8. Caspase-8 then mediates cleavage and activation of caspase-3, which, as an effector caspase, cleaves numerous cellular proteins. Caspase-8 also cleaves and activates Bid, a proapoptotic member of the Bcl-2 family. Astrocytes and microglia are important sources of cytokines which activate the extrinsic pathway of cell death, such as TNF-a (Dong and Benveniste, 2001) and the role of these inflammatory mediators is presented in further detail in Chapter 26 of this volume. In the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of dopamine neuron degeneration, there is evidence that TNF-a plays a role in striatal dopaminergic terminal degeneration. Following MPTP administration, TNF-a mRNA is increased in the striatum (Ferger et al., 2004). Mice homozygous null for TNF-a show relative preservation of striatal dopaminergic fibers and dopamine levels following MPTP, but this protection is not observed for dopaminergic neuron cell bodies in the nigra (Ferger et al., 2004). The extrinsic pathway mediator Fas has also been implicated in the mouse MPTP model. Hayley et al. (2004) observed increased protein expression in dopamine neurons and glia of the SN pars compacta (SNpc) following MPTP injection. Fas null mice showed the opposite pattern of protection from MPTP from that observed in the TNF-a studies; SN dopamine neuron cell bodies were protected, but their striatal fibers were not (Hayley et al., 2004). Thus it may be

the case that different mediators of the extrinsic pathway play different roles in neurodegeneration in different cellular compartments. A possible role for the extrinsic pathway in mediating dopamine neuron degeneration in the MPTP model is further supported by the observations of Viswanath et al. (2001), who detected increased caspase-8 activity in SN following MPTP, accompanied by cleavage of Bid. There is also evidence for a role for activators of the extrinsic pathway of PCD in postmortem studies of PD brain. Mogi and coworkers (1994) demonstrated by immunoassay an approximately fourfold increase in TNF-a in the caudate putamen of PD patients in comparison to age-matched controls. They observed a similar degree of increase in lumbar cerebrospinal fluid. At a cellular level, Boka and colleagues (1994) observed TNF-a-positive glia in the SN of PD patients, but not in controls. In keeping with a possible functional role for TNF-a signaling in human brain, they observed positive immunostaining for TNF-R (the p55 form) in neuromelanized neurons of the SNpc in both PD patients and controls. Studies by Mogi and colleagues (1996) have also suggested a role for Fas in PD pathogenesis. They have demonstrated increases in the soluble form of Fas in the PD caudate putamen. In relation to Fas signaling, Hartmann et al. (2002) have observed that the adaptor protein for the Fas receptor (Fas-associated death domain, or FADD) is expressed in melanized dopaminergic neurons of the midbrain and its relative abundance of expression correlates with greater degree of vulnerability among dopamine neurons to degeneration in PD. The SNpc, the most vulnerable region, showed a higher percentage of FADD-positive profiles than ventral tegmental area and central gray substance, which showed few. These observations, suggesting that TNF-a and Fas may play roles in the neurodegeneration of PD, are supported by the finding that there is an increase in the number of melanized SN neurons expressing the activated form of caspase-8, demonstrated with an antibody specific for the cleaved form, in PD brains as compared to age-matched controls (Hartmann et al., 2001b). Viswanath et al. (2001) made a similar observation without quantification. In conclusion, there are many observations, particularly in the MPTP model and human postmortem material, to suggest a role for the extrinsic PCD pathway in the pathogenesis of PD. Another pathway for the activation of PCD is the ER stress pathway (Fig. 29.2). The ER provides a cellular compartment for the posttranslational modification and folding of membrane and secretory proteins. If the ER becomes unable to achieve prompt protein folding, due to protein mutations, or cellular stresses (such as ER Ca2þ depletion or inhibition of glycosyla-

PROGRAMMED CELL DEATH IN PARKINSON’S DISEASE tion), or due to protein overload, it will result in the prolonged exposure of internal protein hydrophobic domains, with potential toxicity to the cell. The cell has developed multiple mechanisms to deal with this problem, including increased production of proteinfolding chaperones, suppression of protein translation and ER-associated protein degeneration by the proteasome (Mori, 2000). If, however, these efforts to maintain cellular homeostasis fail, the ER transmits molecular signals to initiate PCD. Two transcription factors, ATF4 and ATF6, induce expression of another transcription factor, CHOP/GADD153, which, in turn, mediates PCD (Zinszner et al., 1998), in part by increasing oxidation within the ER (Marciniak et al., 2004). ER stress also leads to PCD by the activation of caspase-12 (Nakagawa et al., 2000; Rao et al., 2001) which is localized to the ER. The downstream effects of caspase-12 activation are not fully known, but may result in a cytochrome c-independent activation of caspase-9 (Momoi, 2004). Although caspase12 has been clearly demonstrated to be a mediator of ER stress-induced apoptosis in rodent cells, it is questionable whether it plays such a role in human cells, because the human gene contains a frame shift mutation with a premature stop codon (Fischer et al., 2002). However, recent evidence suggests that human caspase-4 may function like rodent caspase-12 to mediate ER stress-related apoptosis (Hitomi et al., 2004). A possible role for ER stress has been suggested for inherited PD due to loss of function mutations in the parkin gene (Ishikawa and Tsuji, 1996; Kitada et al., 1998). These mutations indicate that protein processing may play an important pathogenetic role because parkin is an E3 ubiquitin ligase (Shimura et al., 2000) and as such it plays a role in targeting proteins for degradation by the proteasome (Ciechanover, 1998). One target of parkin is Pael-R, a difficult-to-fold protein (Imai et al., 2000, 2001). It has been postulated that loss of parkin function results in Pael-R accumulation, ER stress and neuronal death (Imai et al., 2001). The possibility that ER stress may play a role in other forms of PD has been supported by gene expression studies which have shown that the neurotoxins used in tissue culture models to injure dopamine neurons induce the expression of many genes which participate in the ER stress response, particularly CHOP/GADD153 (Ryu et al., 2002; Holtz and O’Malley, 2003). We have shown that in living animal models of parkinsonism induced by the neurotoxins 6hydroxydopamine (6-OHDA) and MPTP, there is increased protein expression of CHOP/GADD153 and it appears to play a functional role in mediating apoptotic death, because mice with a homozygous CHOP null mutation are protected from 6-OHDA-

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induced death (Silva et al., 2005b). Thus, apoptosis due to ER stress will be an important avenue for future investigations in the pathogenesis of PD. 29.1.4. The intrinsic pathway of PCD In the intrinsic pathway of PCD, the pivotal event that commits the cell to death is the release of cytochrome c and other protein mediators of PCD from the mitochondrion (Figs. 29.2 and 29.3). This event is controlled by members of the Bcl-2 family, of which there are now over 20 members identified (Scorrano and Korsmeyer, 2003). Among the members of the Bcl-2 family, there are competing relationships among anti-and proapoptotic members and the fate of the cell is determined by which is predominant. All members of the Bcl-2 family contain at least one of four conserved domains called Bcl-2 homology (BH) domains (Adams and Cory, 1998). Most antiapoptotic Bcl-2 proteins contain at least BH1 and BH2; the two prototypic examples, Bcl-2 and Bcl-XL, contain all four. There are two classes of proapoptotic Bcl-2 family members. The ‘multidomain’ members, such as Bax and Bak, contain BH1, 2 and 3 domains. The ‘BH3-only’ members, such as Bid, Bim and Bad, contain only BH3. The antiapoptotic proteins Bcl-2 and Bcl-XL both contain C-terminal membrane anchor domains, which localize them to the outer mitochondrial membrane as well as the ER and the nuclear membrane. At the mitochondrial outer membrane, these proteins protect against cytochrome c release and the initiation of the downstream cell death cascade. This protective effect of the antiapoptotic Bcl-2 proteins is antagonized by interaction with Bax or Bak (Fig. 29.3). This interaction allows the release of

Fig. 29.3. The intrinsic pathway of programmed cell death.

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cytochrome c and other proapoptotic proteins from the mitochondrion and initiation of the cell death cascade. Bax is normally located in the cytoplasm; with the onset of apoptotic stimulation it translocates to the mitochondrion to initiate cytochrome c release. Bak is normally expressed on the outer membrane of the mitochondrion. Activation of Bax or Bak is absolutely required for apoptosis to occur, because cells which carry a double homozygous deletion of both are resistant to a wide variety of inducers of apoptosis (Wei et al., 2001), Bax and Bak are activated by BH3-only proapoptotic members of the Bcl-2 family. These proteins are, in turn, activated by death-inducing signals by a variety of posttranslational modifications. Bid, for example, is activated by cleavage by caspase-8, as previously described. Bad is activated by alteration of its phosphorylation status (Datta et al., 2000). Activation of Bax or Bak by BH3-only proteins results in their homo-oligomerization and by mechanisms which are not completely understood, permeabilization of the outer mitochondrial membrane (Scorrano and Korsmeyer, 2003). Two hypothesized mechanisms are opening of the mitochondrial permeability transition pore and the formation of pores directly by Bax or Bak (Scorrano and Korsmeyer, 2003). In the intrinsic pathway, the release of cytochrome c results in the activation of a caspase cascade (Fig. 29.3). In mammalian cells, there are now 14 identified caspases (Thornberry and Lazebnik, 1998). All of these proteases contain a cysteine at their active site and they all cleave on the carboxyl side of an aspartate (thus, ‘caspases’). Among the caspases which play a role in PCD, there are two groups; ‘initiator’ caspases (-2, -8, -9 and -10) and ‘effector’ caspases (-3, -6, -7). These two groups are distinguished by their N-terminals. Initiator caspases contain long Nterminal regions which are involved in the regulation of their activation; for example, the death effector domain in caspase-8 (Fig. 29.2). The effector caspases contain only short (20–30 amino acids) N-terminal prodomains. All caspases are produced by cells as inactive zymogens. All caspases are activated by proteolytic cleavage (by an initiator caspase) to produce a large (20 kDa) and a small (10 kDa) subunit, which then associate to form a heterodimer. These heterodimers, in turn, associate to form a heterotetramer consisting of two p20/p10 heterodimers, which comprises the active form of the enzyme. Until recently, it was believed that the initiator caspases were activated by a similar process, but there is now evidence that dimerization of zymogen monomers may be sufficient for activation (Boatright and Salvesen, 2003). Caspases cleave at a preferred tetrapeptide sequence of X4-glutamate-X2-aspartate. The specificity of each

caspase is determined by the amino acids at the X4 and X2 positions; for example, for caspase-3 the preferred sequence is aspartate-glutamate-valineaspartate. Whatever the precise mechanism for caspase-9 activation, it becomes activated upon association with a cytoplasmic protein Apaf-1 (apoptosis-protease-activating factor-1) and the cytochrome c released from the mitochondrion, in the presence of deoxynucleoside adenosine triphosphate (dATP), to form a 1.4 MDa complex called ‘the apoptosome’ (Riedl and Shi, 2004) (Fig. 29.3). Activated caspase-9 then cleaves and activates caspase-3 and other effector caspases. Effector caspases then systematically cleave select cellular proteins either to eliminate their function or, alternatively, to activate proteins which then become proapoptotic. An example of the former is the cleavage of nuclear lamina (Thornberry and Lazebnik, 1998). An example of the latter is the cleavage of an inhibitor of caspase-activated deoxyribonuclease (CAD), permitting CAD to act as a nuclease (Thornberry and Lazebnik, 1998). A second example of activation of a proapoptotic protein by caspase-3 cleavage is gelsolin, which, after caspase cleavage, becomes able to sever actin filaments (Kothakota et al., 1997). The activity of caspases is regulated by inhibitorof-apoptosis proteins (IAPs), of which there are eight known in mammalian cells (Riedl and Shi, 2004) (Fig. 29.3). These proteins all contain regions (baculoviral IAP repeat or BIR) which bind to and inhibit select caspases. In mammalian cells, caspase-3, -7 and -9 are all subject to IAP inhibition. This inhibition of IAPs can, in turn, be blocked by a family of proteins that contain a tetrapetide motif which binds to, and blocks, the BIRs of IAPs. In mammals, the founding member of this family was found to be released by mitochondria and termed the second mitochondriaderived activator of caspases (SMAC) or direct IAPbinding protein (DIABLO) (Chai et al., 2000; Shi, 2002) (Fig. 29.3). In addition to cytochrome c and SMAC/DIABLO, mitochondria release a protein apoptosis-inducing factor (AIF) in response to cell death stimuli (Susin et al., 1999). When first identified, it was shown that this protein is capable of causing nuclear condensation and DNA fragmentation, as occurs in apoptosis, and that none of these effects is blocked by caspase inhibitors (Susin et al., 1999). More recently, it has been shown that, by a mechanism not yet understood, AIF release from the mitochondrion is mediated by the DNA repair enzyme poly (ADP-ribose) polymerase I (PARP-1); PARP inhibition or genetic deletion prevents mitochondrial AIF release, translocation to the nucleus and cell death (Yu et al., 2002). The demonstration of

PROGRAMMED CELL DEATH IN PARKINSON’S DISEASE this pathway indicates that there are important non-caspase-dependent pathways to cell death. Although there are likely to be multiple upstream pathways acting upon the proapoptotic BH3-only proteins to initiate mitochondrial release of death mediators, one such pathway which has been the focus of extensive investigation involves the activation of the transcription factor c-jun by phosphorylation (reviewed in Silva et al., 2005a). Phosphorylation and activation of c-jun are mediated by c-jun Nterminal kinase (JNK), which, in turn, is activated by phosphorylation by a complex kinase cascade including the mixed-lineage kinases (MLK) (Silva et al., 2005a). There is abundant evidence from studies in tissue culture and animal models that this kinase cascade plays an important role in initiating PCD (Wang et al., 2004). In relation to PD specifically there are now numerous experiments utilizing either pharmacologic or genetic approaches to blocking the JNK/c-jun kinase cascade which have demonstrated efficacy in preventing dopamine neuron death in animal models of parkinsonism (Silva et al., 2005a). This signaling pathway acts upon BH3-only mediators in multiple ways to initiate death. There is evidence that c-jun induces the expression of Bim (Putcha et al., 2001; Whitfield et al., 2001). In addition, JNK not only phosphorylates and activates c-jun, but also phosphorylates and activates Bim directly (Lei and Davis, 2003). In addition, JNK phosphorylates and directly activates Bad (Donovan et al., 2002). These observations, coupled with direct evidence for activation of c-jun in human PD brain, has led to a trial of a MLK inhibitor for neuroprotection in PD (Silva et al., 2005a).

29.2. PCD in dopamine neurons of the substantia nigra during development and in animal models of parkinsonism 29.2.1. Naturally occurring cell death in substantia nigra dopamine neurons Like most developing neural systems, the dopamine neurons of the SN undergo a naturally occurring PCD event (Janec and Burke, 1993; Oo and Burke, 1997), which morphologically is characterized by the exclusive appearance of apoptosis. In rodents, the cell death event is largely postnatal, ending by the fourth postnatal week. As envisioned by classic neurotrophic theory, the magnitude of this death event is regulated by interactions with the striatal target, because experimental manipulations which disrupt such interactions result in increased cell death (reviewed in Burke, 2004). This cell death is mediated, at least in part, by the caspases. The activated forms of caspase-9

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(Ganguly et al., 2004) and -3 (Jeon et al., 1999) can be demonstrated by immunohistochemistry with specific antibodies, as can specific caspase-3 protein cleavage products (Oo et al., 2002). This activation of caspases is likely to be mediated by the intrinsic pathway of PCD. Overexpression of Bcl-2 within dopaminergic neurons, under the control of the tyrosine hydroxylase promoter, results in suppression of natural cell death and a 30% increase in the surviving number of SN dopamine neurons (Jackson-Lewis et al., 2000). Homozygous Bax null mice show a trend towards diminished levels of apoptotic death, but they do not demonstrate a lasting increase in the adult number of SN dopamine neurons (Vila et al., 2001), suggesting that other proapoptotic proteins (such as Bak) may compensate for the null mutation. There is no evidence that the ER stress pathway of PCD plays a role in the naturally occurring cell death of dopamine neurons, because expression of CHOP/GADD153 is not observed and the homozygous CHOP null mutation has no effect (Silva et al., 2005a). Whether the extrinsic pathway of PCD plays a role is unknown. 29.2.2. Programmed cell death in animal models of parkinsonism An important step forward in establishing the possible relevance of PCD to neurodegeneration in human PD was the demonstration that PCD occurs in dopamine neurons of the SN, not only during normal naturally occurring cell death in the developmental period, but also in settings of pathologic death, for example, that induced by toxins and in the adult brain. There is now evidence that the processes of PCD occur in SN dopamine neurons in the major current animal models of parkinsonism, including in adulthood, depending on the dose, timing and route of administration of the neurotoxin. The evidence in these models is both correlative, in which activation of PCD mediators has been demonstrated in conjunction with the occurrence of death, and functional, in which disruption of cell death pathways by pharmacologic or genetic means has led to improved dopamine neuron survival in the model. For the purposes of this review, we will consider primarily studies that have been conducted in living animals. One of the first established models of parkinsonism utilized the selective catecholaminergic neurotoxin 6OHDA to destroy SN dopamine neurons (Ungerstedt, 1968; Kostrzewa and Jacobowitz, 1974). This model is considered to be potentially relevant to human PD because 6-OHDA is an endogenous oxidative metabolite of dopamine (Kostrzewa and Jacobowitz, 1974) and it has been demonstrated in human caudate (Curtius et al., 1974). We demonstrated that, during the

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naturally occurring cell death period, intrastriatal injection of 6-OHDA induces apoptosis in SN dopamine neurons (Marti et al., 1997). Although we initially attributed this induction of apoptosis to a destruction of intrastriatal dopaminergic terminals by the toxin and a resulting loss of developmental target-derived trophic support, more recent studies have suggested that this is likely to be true only in part; some of the death is likely to be due to a direct effect of the toxin. Recent studies have shown that, in dopamine neuron apoptosis due to naturally occurring cell death, or its augmentation by axotomy, there is a characteristic pattern of immunostaining for activated caspase-3 and its cleavage products which is strictly perinuclear (Jeon et al., 1999; Oo et al., 2002). In the developmental intrastriatal 6-OHDA model, however, in addition to this pattern, there is a pattern of cytoplasmic staining observed in the immunostaining for activated caspase-3 and its cleavage products (Jeon et al., 1999; Oo et al., 2002). Apoptosis occurs in SN dopamine neurons following intrastriatal 6-OHDA not only in immature animals, but in adults as well (Marti et al., 2002), confirmed by electron microscopy. The activation of caspase-3 in the intrastriatal 6OHDA model is likely to be mediated, at least in part, by activation of the intrinsic pathway of PCD, because it is accompanied by activation of caspase-9, indicated by immunostaining with antibodies specific for the activated form (Ganguly et al., 2004). As previously mentioned, the ER stress pathway is also involved in this model, because CHOP/GADD153 expression is induced and, in the adult model, a homozygous CHOP null mutation is protective (Silva et al., 2005b). The ability of 6-OHDA to induce apoptosis in SN in animal models depends on the site of injection and the dose. We observed that direct injection of 6OHDA (8 mg) into the SN, as in the classic Ungerstedt model, did not induce apoptotic morphology (Jeon et al., 1995). Other investigators have found, however, that injection of a similar or lower dose into the adjacent medial forebrain bundle does induce morphologic and DNA nick end-labeling evidence of apoptosis (He et al., 2000; Zuch et al., 2000). As for 6-OHDA models, the occurrence of apoptosis and the participation of pathways of PCD in MPTP models depend on how the toxin is administered. In the most widely used regimen, the acute model of MPTP toxicity, multiple doses of the toxin are administered to mice every 2 hours. In a morphologic assessment of three different doses of MPTP administered according to this regimen, Jackson-Lewis and colleagues (1995) were unable to detect apoptotic morphology or DNA in situ end-labeling in the SN at any

of the three time points following injection. Even in the absence of apoptotic morphology, some investigations have suggested a possible role for the molecular mediators of PCD. Hassouna et al. (1996) noted increased Bax mRNA and protein expression following acute MPTP, but this was not a quantitative analysis. Yang and collaborators (1998) clearly demonstrated the ability of Bcl-2, overexpressed in transgenic mice, to protect from striatal dopamine and dopamine transporter loss in the acute MPTP model; in fact, the transgene was more effective in the acute model, where apoptosis is not observed, than in the chronic model, where it is (see below). As these investigators pointed out, however, Bcl-2 can protect not only from apoptotic death, but also necrotic death (for example, see Kane et al., 1993), so protection from neural death by Bcl-2 cannot be taken as direct evidence that the pathways of PCD as delineated above are involved. In the acute MPTP model, Viswanath and colleagues (2001) demonstrated the ability of the general caspase inhibitor protein p35, expressed as a transgene, to protect from dopamine neuron loss. However, the protection was slight. They also demonstrated, by tissue assays, increases in the activity of caspases in the SN after MPTP injection. However, these assays were performed at the tissue level, not the cellular level, so it is not known that the changes occurred in dopamine neurons; they may instead have occurred in non-neural cells. Indeed, Furuya et al. (2004) clearly demonstrated a role for caspase-11, an inflammatory caspase (Thornberry and Lazebnik, 1998; Strasser et al., 2000), in the acute MPTP model in non-dopaminergic, inflammatory cells. A caspase-11 null mutation protected from acute MPTP-induced SN neuron loss. However, most of the caspase-11 was expressed in microglia, not dopamine neurons. The caspase-11 null mutation was not protective in the chronic MPTP model, in which apoptosis is observed and, on the other hand, a dominant negative form of Apaf-1 was protective in the chronic model (see below) but not in the acute model (Furuya et al., 2004). These authors concluded that the acute model is characterized by an inflammatory process in which the role for caspase-11 is non-cell-autonomous to dopamine neurons. We conclude that there is little evidence to date for apoptosis or the activation of PCD pathways intrinsic to dopamine neurons in the acute MPTP model. The chronic model of MPTP toxicity is induced by administering a single dose each day (30 mg/kg) for 5 days (Tatton and Kish, 1997). In their original description of this model, Tatton and Kish (1997) clearly identified apoptotic nuclear chromatin clumps within phenotypically defined SN dopamine neurons and DNA nick end-labeling. Like Yang et al., Offen and

PROGRAMMED CELL DEATH IN PARKINSON’S DISEASE colleagues (1998) demonstrated that overexpression of Bcl-2 in transgenic mice protects from loss of striatal dopamine in this model. As discussed above, given the spectrum of Bcl-2 effects, this finding does not provide direct evidence for a role of the intrinsic pathway of PCD. More convincing evidence for a role for this pathway comes from the demonstration by Vila and colleagues (2001) that mice deficient in Bax are protected from the induction of apoptosis and loss of SN dopamine neurons in the chronic model. In keeping with a role for the intrinsic pathway of PCD, Mochizuki et al. (2001) have demonstrated that transduction of SN dopamine neurons with a dominant negative form of Apaf-1 also protects from the loss of dopamine neurons. These authors conclude that the intrinsic pathway is likely to be activated in the chronic MPTP model. This activation is likely to be responsible for the activation of caspase-3, as reported by Turmel et al. (2001) 29.2.3. The c-jun signaling cascade in animal models of parkinsonism Initial studies of c-jun expression in the central nervous system of living animals in models of injury were difficult to interpret in relation to cell death, because early studies in peripheral systems had shown that expression could be upregulated by regenerative processes (Jenkins and Hunt, 1991). The earliest studies specifically within the SN in models of death induced by 6-OHDA (Jenkins et al., 1993) and by axotomy (Leah et al., 1993) noted substantial and sustained increases in c-jun expression but these changes were interpreted largely in relation to a possible role in regenerative responses. In the 6-OHDA model, however, the maximal expression of c-jun, at 4–8 days postlesion (Jenkins et al., 1993) is when other investigators subsequently showed that cell death is maximal (Sauer and Oertel, 1994). With increased awareness of apoptosis as a distinct morphology of PCD (Kerr et al., 1995) and the ability to detect it by nuclear staining, it became clear that cjun expression could be correlated at the cellular level with this form of cell death in living animals. This was true in the context of natural cell death in the peripheral (Messina et al., 1996) and central (Ferrer et al., 1996b) nervous systems and in models of induced natural cell death (Ferrer et al., 1996a). Similarly, in the SN, close correlations could be made between c-jun expression and markers of apoptosis. Herdegen et al. (1998) demonstrated in the adult axotomy model a close regional and temporal association between prolonged c-jun expression and DNA nick end-labeling for apoptosis (Gavrieli et al., 1992). Oo et al. (1999)

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demonstrated in a postnatal model of apoptosis in the SNpc, induced by early target deprivation, that c-jun and JNK expression could be correlated at a cellular level with apoptotic morphology. Thus, these early morphologic studies of apoptotic cell death suggested a clear correlation with c-jun expression. The first principal evidence for a functional role for JNK/c-jun signaling in cell death in living animals derived from studies in JNK null animals. Yang and co-investigators (1997) showed that mice null for the JNK3 isoform are resistant to kainic acid-induced seizures and associated hippocampal neuron apoptosis. Further evidence for a role for c-jun in neuronal apoptosis came from studies of mice in which the endogenous c-jun gene was replaced by an altered gene in which the serines at positions 63 and 73 were replaced by alanines, which cannot be phosphorylated (Behrens et al., 1999). Mice homozygous for this mutant, non-phosphorylatable form of c-jun were also resistant to seizures and hippocampal neuron apoptosis induced by kainate. A functional role for c-jun in mediating death specifically within dopamine neurons has been supported by studies using viral vector gene transfer approaches. Crocker et al. (2001) have demonstrated in an axotomy model that adenovirus-mediated expression of a c-jun dominant-negative construct prevents the loss of dopamine neurons in the SN and the loss of dopaminergic fibers in the striatum. A functional role for JNK/c-jun signaling in dopamine neuron death is also supported by the demonstration that gene transfer of the JNK binding domain of JIP-1 (which inhibits JNK activation) protects dopamine neurons from chronic MPTP toxicity (Xia et al., 2001). Again, this approach not only prevented the loss of SN dopamine neurons, but also their striatal terminals, as assessed by catecholamine levels. In view of this evidence that phosphorylation of cjun plays a role in the mediation of cell death in dopamine neurons and given that JNK is the dominant kinase for c-jun (Kyriakis and Avruch, 2001), it would be predicted that JNK isoforms also play a role in the death of these neurons. Hunot and co-investigators (2004) have shown in the acute model of MPTP toxicity that both JNK2 and JNK3 homozygous null animals are resistant. JNK1 null animals were not protected. Compound mutant JNK2 and 3 homozygous nulls were even more protected; they showed only a 15% loss of neurons. Thus both JNK2 and JNK3 play a role in cell death in this model. The compound null mutation also protected dopaminergic fibers in the striatum. These investigators postulated that increased transcriptional activity mediated by JNK phosphorylation of c-jun may mediate cell death and they found that the immune mediator cyclooxgenase-2 is upregulated. JNK was

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shown to be necessary for this upregulation, as it was abolished in the compound JNK mutants. Thus, JNK may ultimately act, at least in part, in the inflammation of the acute MPTP model by upregulation of cycloogenase-2, which has been implicated as a death mediator in this model (Teismann et al., 2003) (see Ch. 26). As discussed earlier in relation to caspase-11 in this model, these results should not be interpreted as direct evidence for a role for JNK as a mediator of apoptotic death intrinsic to dopamine neurons. The principal reason is that apoptosis does not occur in the acute MPTP model (Jackson-Lewis et al., 1995), as discussed. These studies, based on genetic techniques using either gene transfer or transgenesis in mice, indicating a functional role for c-jun signaling in the mediation of neuron death in living animals, have received much support from pharmacologic studies using the specific MLK inhibitors CEP1347 and its analog CEP11004 (Murakata et al., 2002). These MLK inhibitors have also been shown to be protective in animal models of parkinsonism. In a single-dose model of MPTP toxicity, Saporito and co-investigators (1999) demonstrated that CEP1347 attenuated the loss of dopaminergic terminal markers and cell bodies in SN, demonstrated by immunostaining. In the MPTP single-dose model, there is increased phosphorylation of JNK and this increase is attenuated by CEP1347 (Saporito et al., 2000). In the intrastriatal injection of the 6-OHDA model in postnatal rats, CEP11004 diminished the number of dopaminergic apoptotic profiles (Ganguly et al., 2004) and the number of activated caspase-9-positive profiles in proportion to overall protection from cell death (Ganguly et al., 2004). In this study there was almost complete protection of striatal tyrosine hydroxylase-positive fibers; this was especially remarkable considering that the toxin was injected directly into striatum. Overall, these genetic and pharmacologic studies demonstrate a clear role for the JNK/c-jun signaling pathway in initiating PCD in a variety of living animal models of parkinsonism.

29.3. Evidence for programmed cell death in human postmortem Parkinson’s disease brain Initial reports of apoptotic morphology or positive DNA nick end-labeling in human PD brains generated controversy which remains unresolved. Mochizuki and colleagues (1996) reported the presence of DNA nick end-labeling in the SN of PD brains and suggested that it was due to apoptosis. However, it was subsequently realized that positive DNA nick end-labeling alone (in the absence of apoptotic morphology) cannot be taken as specific evidence for apoptosis, because such labeling can also be observed in necrotic cell death (Grasl-

Kraupp et al., 1995). Anglade et al. (1997) reported ultrastructural evidence for both autophagy and apoptosis in the brains of a few PD patients. The apoptotic features, however, were not sufficiently well defined and the phenotype of the cells as dopaminergic was not certain. Additional investigations, however, have provided more support for the possibility of apoptotic death in dopamine neurons of the PD brain. Tompkins and co-workers (1997) used a nuclear dye (propidium iodide) to demonstrate clear examples of apoptotic chromatin clumps with co-labeling for DNA nick end-labeling in neuromelanin-containing SN neurons of patients with PD and diffuse Lewy body disease. Additional examples of such co-labeling of apoptotic nuclear chromatin clumps for DNA nick end-labeling in neuromelanin-containing neurons in the SN of PD patients were provided by Tatton (Tatton et al., 1998; Tatton, 2000). Other investigators, however, have been unable to confirm these observations (Kosel et al., 1997; Wullner et al., 1999). There are many possible reasons for these mixed results. Apoptosis is a short-lived process and it is likely to be exceedingly difficult to identify in chronic neurologic diseases in which neuron death occurs gradually over years. In addition, as discussed earlier, apoptosis is only one of the known morphologies of PCD (Clarke, 1990) and its absence in tissue does not exclude a possible role for PCD mechanisms. Ultrastructural analysis is required to identify these cell death morphologies and it is exceedingly difficult to achieve a high-quality analysis in postmortem material. Thus, controversies and mixed results from studies of human postmortem material, based on purely morphologic assessment, are not unexpected. Assessment of the possible role of PCD in human PD has been assisted by the development of antibodies for immunohistochemical demonstration of the components of PCD pathways in postmortem tissue sections, particularly the activated forms of the caspases. Using an antibody specific for the activated form of caspase3, Hartmann et al. (2000) demonstrated staining in the neuromelanin-containing neurons of the SN in PD brain. Interpretation of this result was somewhat complicated, however, by the appearance of similar staining in non-diseased controls, which was attributed to premortem agonal hypoxia. These investigators noted, however, a higher percentage of activated caspase-3positive profiles in the PD brain when normalized for the number of remaining melanized (i.e., dopaminergic) neurons. These observations receive support form those of Tatton (2000), who identified activated caspase-3 staining in neuromelanin-containing cells in PD SN and virtually none in controls. In relation to other

PROGRAMMED CELL DEATH IN PARKINSON’S DISEASE caspases, we have previously discussed reports of the activated form of caspase-8 in PD brains by Hartmann et al. (2001b) and Viswanath and colleagues (2001). In addition to these observations on the activated forms of these caspases, investigators have demonstrated alterations in the cellular expression of the proapoptotic protein Bax in PD brains. Hartmann and colleagues (2001a) demonstrated that, although there was no change in the percentage of Bax-positive profiles among neuromelanin-containing SN neurons of PD patients in comparison to controls, there was about a 3.5-fold increase in the percentage of Bax-positive profiles among Lewy body-containing neurons in comparison to non-Lewy body-containing neuromelaninpigmented neurons. These observations suggest that Bax may be more highly expressed in ‘sick’ Lewy body-positive dopamine neurons. Unlike Hartmann et al., Tatton (2000) did observe a greater number of Bax-positive profiles in PD SN. An observation supporting a possible role for JNK/ c-jun signaling in human PD was made by Hunot et al. (2004), who noted that nuclear translocation of c-jun could be identified in neuromelanin-containing SN neurons of PD patients and not in controls.

29.4. Conclusions In summary, there is much evidence from human postmortem studies and neurotoxin models of dopamine neuron death to suggest that the molecular pathways of PCD play a role in human PD. Nevertheless, the evidence cannot be considered definitive or complete. The case for a role for PCD pathways in human PD will be strengthened by the development of animal models that are firmly based on certain causes of the disease in humans, such as genetic causes. Although neurotoxin models have been highly useful in identifying the PCD pathways that may play a role in the disease, they remain of uncertain direct relevance to the human condition. In addition, the case for PCD in human PD will be strengthened by broader studies by independent investigators with reagents for known upstream mediators of PCD. And finally, perhaps the most compelling and gratifying support for the PCD hypothesis in PD will derive from clinical therapeutic trials with specific inhibitors of PCD pathways, should they prove to be neuroprotective and prevent the progression of the disease.

Acknowledgments The author is supported by the NIH (NS26836, NS38370), DAMD17-03-1-0492, The Parkinson’s Disease Foundation and the Michael J Fox Foundation.

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Index Page numbers in italic, e.g. 91, refer to figures. Page numbers in bold, e.g. 411, denote tables. A-77636, 91, 92 A-86929, 91, 92 acetylcholine biosynthesis, 33, 34 degradation, 34 motor behavior generation and, 48–9 receptors muscarinic, 27, 35–6, 44 nicotinic, 33–5 release, 34, 35, 82, 93 transport, 33, 34, 410 uptake, 33 acetylcholinesterase, 19, 33, 34, 55, 162, 164, 183, 357, 406, 411, 412, 413 acetylcoenyzme A, 33, 34 adenosine basal ganglia and, 22, 41–3 degradation, 41 motor behavior generation and, 48–9 receptors, 41, 42–3 signal transduction, 41 synthesis, 41 transport, 41 adenosine triphosphate, 41, 221, 236, 245, 267, 481, 483, 556, 561, 573, 574 Alzheimer’s disease, 9, 124, 140, 182, 209–14, 246, 255, 256, 401, 403, 404, 407, 426, 448–9, 466, 496, 509, 514 angiotensin, 22, 40, 343 animal models, see Parkinson’s disease: animal models apomorphine, 84–5, 89, 90–1, 91, 354–7, 379, 381, 441, 487, 559, 583 apoptosis, see programmed cell death autonomic nervous system bladder dysfunction in Parkinson’s disease, 355–7 cardiovascular dysfunction in Parkinson’s disease baroreflex abnormalities, 349–50 denervation, 347, 350–1 hypotension, 344, 344, 246 plasma norepinephrine insufficiency, 349

autonomic nervous system (Continued ) cardiovascular dysfunction in Parkinson’s disease (Continued ) role of levodopa, 346 components, 343–4 gastrointestinal dysfunction in Parkinson’s disease constipation, 115, 134, 143, 222, 344, 351–5, 371, 427, 441 delayed gastric emptying, 353–4 drooling, 123, 352–3 dysphagia, 335, 343, 352–4 nausea and vomiting, 78, 90, 119, 352, 354, 357, 413, 442 postmortem analysis, 348 sexual dysfunction in Parkinson’s disease, 357 sweating dysfunction in Parkinson’s disease, 357 see also Parkinson’s disease: sensory symptom(s) basal ganglia acetylcholine, 32–6, see also acetylcholine anatomy and physiology, 5–6, 3–13 cannabinoids in, see cannabinoid(s) carbon monoxide as neurotransmitter in, 47 cholecystokin, 22, 40–1, 164 circuitry history, 122, 123 models, 3–7, 4, 19–20 cytokines as neurotransmitters in, 47, 49 discharge, 3–4, 10–12, 66 diseases 67–72, see also specific diseases endocannabinoids, 43–6 focusing hypothesis and, 8 function assessment, 7–8 glutamate receptors, see glutamate: receptors

basal ganglia (Continued ) growth factors as neurotransmitters in, 47, 49 histological organization, 3–4 inputs, 4–5 internally generated movement and, 8–9 neurochemistry in Parkinson’s disease, 176–7 cerebellum, 183–4 Ch1–Ch3 groups, 183 cholinergic systems, 182 globus pallidus, 171, 177–8, 180–1 hypothalamus, 184 locus ceruleus, 183 mRNA expression for receptors in, 172–5 nucleus basalis of Meynert, 182 olfactory system, 184–5 pedunculopontine nucleus, 182 raphe nucleus, 183 retinal amacrine cells, 184 spinal cord, 181–2 striatum, 162–7, 169–71 substantia nigra pas compacta (SNc or SNpc), 153–62 subthalamic nucleus, 178–9 ventral tegmental area (VTA), 153–5, 159–62 neuromodulators, 22 neuropeptides, 37–41, see also endorphins; neurokinins; neurotensin neurotransmitters, 20–1, 22, 47, 49–50, see also specific neurotransmitters nitric oxide as neurotransmitter in, 46–7 nociception and, 377–8 opioids, 22 oscillatory activity, 9–10 receptors, 24–5 scaling hypothesis and, 8 serotonin 36–7, see also serotonin signal transduction, 24–5 see also globus pallidus bladder dysfunction and Parkinson’s disease, 355–7

608 bromocriptine, 84–5, 89, 90, 92, 122, 171, 441, 447

camptocormia, 336, 337–8 cannabinoid(s) agonist, 44–5 in basal ganglia, 22 receptors, 43–5, 158, 169, 174 carbon monoxide, 47, 212, 486 cardiovascular dysfunction in Parkinson’s disease, see autonomic nervous system: cardiovascular dysfunction in Parkinson’s disease catecholamines, 36, 121, 159, 344, 406 brain, 271 early research, 119–20 5-HT, 21, 22, 36–8, 153, 157, 161–4, 169, 176, 178, 180–5, 277, 354–5, see also serotonin cholecystokinin, 40–1, 155 in basal ganglia, 22, 40–1, 164 in Parkinson’s disease, 187 receptors, 158 striatal afferents and, 164 choline acetyltransferase, 33, 34, 82, 179, 182–3 coenzyme A, 33, 34 corticobasal degeneration, 260 cytokines, 47, 250, 280, 466, 537, 544–5, 561, 549 see also growth factors

dementia and Parkinson’s disease brain activation, 255–6 cholinesterase inhibitors and, 413 clinical features behavioral, 405 cognitive, 403, 403–5 motor and autonomic, 405 diagnosis Lewy bodies and, 411 process, 411, 411 diffuse Lewy body (DLB), 256, see also Lewy bodies: diffuse dopaminergic function and, 255 epidemiology incidence, 401–2 prevalance, 401 risk factors, 402 genetics, 409 incidence, 401–2 neurochemical deficits and, 176–7, 406–7 neuroimaging and, 407–9 functional, 410–11

INDEX dementia and Parkinson’s disease (Continued ) neuroimaging and (Continued ) structural, 409–10 resting brain metabolism and, 255 treatment, 411–14, 413 dihydrexidine, 90–1, 91, 93 dinapsoline, 91 DJ-1 mutation, 136, 233, 234, 268, 269–70, 481, 484, 514, 578–9 Parkinson’s disease and, 135, 217, 218, 233–4, 575, 578, 581 protein handling dysfunction and, 578 dopamine agonists, 6, 37, 68, 78–9, 83, 89, 89–92, 91, 122–5, 168, 170, 250, 251, 344, 365–6, 370–2, 424, 427, 429, 468, 561, see also dopaminergic: drugs and medications biosynthesis, 22, 23, 154–5, 162, 254, 273 degradation, 23, 507–8 early research, 120–1 motor behavior generation and, 48–9 receptor(s) activation, 24 agonists, 90, 271, 346, 351 cognition and, 93 D2 dogma and, 89–90 function, 77–8, 84–5 isoforms, 81 localization, 79–83 molecular biology, 78–83, 88–9 peripheral, 83, 354 pharmacology, 77–93 signaling, 24, 85–8, 86, 89, 91 release, 6, 11, 21, 23, 33–5, 37, 40, 88, 157, 165, 253–4, 272, 280, 557 reuptake, 22, 428, 485 striatal cholinergic neurons and, 82 transport and transporters, 22–3, 23, 34, 37, 84, 88, 123, 143, 154, 246, 247, 251, 254, 260, 268, 273–5, 280, 369, 377, 379, 410, 423, 466–9, 526, 584, 598 working memory and, 82 see also dopaminergic dopaminergic cell death 84, 159, 165, 486, 509–10, 512–13, see also dopaminergic: dysfunction denervation, 28, 42, 559 drugs and medications, 11, 32, 122, 125, 167, 169, 251, 272–3,

330, 366, 369–70, 378, 405, 421, 425, 441, 445, 468 dysfunction, 249, 260, 333, 335, 470, see also dopaminergic: cell death neurons, 21, 24, 32, 35, 40, 43, 47, 139, 141, 153, 155–9, 161–2, 179, 182–6, 188, 220, 230, 234, 265, 266, 267, 268, 271–81, 338, 365, 377, 407, 435, 467, 484–5, 507, 510–11, 524, 524, 535–41, 543–6, 558–63, 572, 578, 582, 594, 597, 600 nigrostriatal pathways, 10, 21, 23, 31, 33, 40, 43, 49, 83, 157, 247, 255, 265, 266, 268, 270–80, 380, 406, 484, 507, 511, 513, 527–8, 535, 538–40, 543, 558, 559, 563 receptors, 164–5, 173, 414 system, 23, 28, 33, 40, 130, 154, 162, 169, 183, 185, 246, 258, 270, 274, 280, 329, 330, 334, 372, 406, 435, 464, 513, 524, 527, 535, 538 terminals, 28, 33–4, 157, 162, 184, 266, 273, 275, 277–8, 594, 598, 600 therapies, 83, 330, 332–5, 371–2, 389, 441, 487, 561 see also dopamine dyskinesia dopamine receptor pharmacology and, 91–3, 169 genesis D1-receptors and, 92–3 D2-receptors and, 92–3 pulsatile dopamine delivery and, 92–3 incidence, 92, 102, 124, 171, 221, 251, 482 levodopa-induced, 46, 91, 142, 169–71, 186, 221–2, 233, 251, 253–5, 254, 358 mRNA expression and, 166 rating scales for, 303–4, 311–12 severe, 169 dystonia forms, 69–72, 222, 334, 367 levodopa and, 339, 578 neurophysiology, 67, 69–71 pain syndromes, 378–9 in PARK2, 222, 580 in PARK7, 581 rating scales, 303–4, 311 skeletal abnormalities and, 335 supranuclear palsy and, 211

INDEX encephalitis lethargica, 117, 119, 139, 209 endocannabinoids, 43–6, 44 endorphins, 39, 161, 166, 180, 440 environmental toxins, 270–1, 270–1 excitotoxicity mechanisms calcium influx, 28, 555 free radical generation and cell death, 555–6, 556 glutamate-NMDA receptor pathway, 156, 160, 466, 553–5, 554, 556 mitochondrial impairment, 512 nitric oxide, 556–7 protease activation, 557 mitochondrial function and, 557–8 neuronal cell death and, 511 in Parkinson’s disease, 559–62, 571 protection against, 46 slow, 557–8

GABA in basal ganglia, 22, 28–9 biosynthesis, 29–30, 30, 165 degradation, 29–30, 30 interneurons, 93, 164–5, 180 receptors, 30–2, 156, 168, 173, 179, 181, 443 release, 5, 35, 37, 45, 178, 254 signal transduction, 30–1 transaminase, 29, 30 transport, 29–30, 30 uptake, 29 see also GABAA; GABAB; GABAC GABAA, 22, 28, 30–2, 88, 156–7, 168, 171, 178, 181 binding, 157, 171, 181 receptors, 28, 30–2, 156–7, 168, 178 see also GABA GABAB, 22, 27–8, 30–2, 156–7, 168, 178–9, 181 binding, 168, 178–9 receptors, 27–8, 30–2, 157, 178–9 see also GABA GABAC, 22, 30, 156, see also GABA gamma-aminobutyric acid, see GABA; GABAA; GABAB; GABAC gastrointestinal dysfunction due to Parkinson’s disease, see autonomic nervous system: gastrointestinal dysfunction in Parkinson’s disease GDNF, see glial cell line-derived neurotrophic factor genes, Parkinson’s disease and, 135–6, 136, see also specific genes

glial cell line-derived neurotrophic factor (GDNF) proteins, receptors and actions, 525, 525–6 therapy, 526–7, 527, 528 glial cell(s) activation, 249, 259, 275–6, 487, 512, 538–40, 544, 561, 583 dopamine metabolism and, 23 excitoxicity and, 561–2 ferritin storage, 501–2 5-HT uptake, 37 functions, 543–4 GABA metabolism and, 30 glutamate metabolism and, 25, 25–6, 163, 553 inflammation, 535–7 micro-, 123, 139, 249–50, 250, 252–3, 275–6, 487, 502, 537–41, 543–4, 546, 561, 583 neurodegeneration and, 543–4 neuroprotection, 543–4 neurotrophic cell production, 521, 522–5 oligodendro-, 211, 213 proliferation, 502, 511 senescence, 544 transport proteins in, 44 globus pallidus activity changes in, 12, 19, 21 externus, 12–13, 171, 558, 559 GABA receptors and, 31 glutamatergic pathways, 559 gross morphology, 205, 247 internus, 12, 13, 69, 180, 247, 558, 559 neurochemistry, 170–5, 171, 177–8, 180 neuronal loss in, 211 neurons, 189 see also basal ganglia glutamate antagonists, 272, 560 biosynthesis, 25, 25–6 degradation, 25 motor behavior generation and, 48–9 pathways and, 558–9, 559 neurotransmission, 280, 558, 562–3 receptors, 22, 27–8, 35, 49, 89, 156, 163, 168, 172, 178–81, 553–5, 556, 557–8 classification, 26 ionotropic, 26–7, 156 metabotropic, 27, 47, 88, 156 signaling, 49, 163 release, 25, 272 toxicity, 553–4, 557, 559

609 glutamate (Continued ) transport and transporters, 25–6, 25, 29, 45, 163, 544 uptake, 25–6, 43, 466, 561 see also glutamatergic glutamaterigic denervation, 58 neurons, 26, 41, 160, 560, 563 terminals, 25, 27–8, 32–4, 160, 181, 558 transmission (neuron), 28, 41, 43, 45–6, 355, 553, 558, 563 see also glutamate growth factors as basal ganglia neurotransmitter, 47, 49 cigarette smoking and, 141 in Parkinson’s disease treatment, 252 platelet-derived, 47 production of, 35, 252, 380 see also cytokines Guam, parkinsonism-dementia complex of, 212–13, 464, 500

health-related quality of life, 312–13, 213 BELA-P-k, 320 measurement, 313–14, 314 Parkinson’s disease questionnaire, 314, 314–17, 318 Parkinson’s impact scale (PIMS), 318–19 Parkinson’s problem schedule (PPS), 319 PDQUALIF, 320 psychosocial questionnaire, 319 quality of life satisfaction, 320–1 publications, 313 questionnaires, 438 hippocampus atrophy, 213, 410, 576, 582 catecholamines in, 406 D receptors in, 79–82 neuromorphology, 19 NMDA-induced toxicity, 557 PARK and, 580 parkinsonism and, 210, 213, 407 Huntington’s disease, 67, 71–2, 121–2, 259, 448, 470, 509, 514, 553 6-hydroxydopamine lesions, 83, 380, 523 hypotension orthostatic, 90, 210, 218, 222, 312, 332, 343–4, 344–5, 346, 351–2, 357, 427, 441, 471

610 hypotension (Continued ) postprandial, 343–4, 405 hypothyroidism, 424–5, 428

imaging alternative, 470–2 approaches, 245 magnetic resonance, 212, 245, 257, 258, 355, 378, 409–10, 435, 467, 470–1, 483, 486, 493, 498–9, 500, 555 for monitoring neuroprotection in Parkinson’s disease, 251–2 pathologic considerations, 245–6 positron emission tomography (PET), 8, 47, 69, 169, 223, 245, 247–8, 250, 259, 277, 305, 333, 355, 369, 377, 388, 406, 423, 435, 464, 467, 486, 527, 541, 583, 584 for preclinical detection, 249 presynaptic dopaminergic system MRI, 246, 470 PET, 246, 467–70 SPECT, 246–8, 247, 256, 469 transcranial sonography, 246 proton magnetic resonance spectroscopy (MRS), 245, 257, 410 single photon emission computed tomography (SPECT), 130, 224, 245–51, 247, 253, 255, 258–60, 305, 377, 379–80, 410, 435, 449, 458–9, 467–9 transcranial sonography, 499–500 ultrasound, 130, 357, 470–1, 499–500 immediate early gene (IEG), 5, 48–9, 86 inflammation, see neuroinflammation iron binding and location in substantia nigra, 501–2 concentration in substantia nigra postmortem studies, 494–5, 496–8, 497 magnetic resonance imaging studies, 498–9, 500 neuromelanin and, see neuromelanin oxidative stress and, 493, 508–13 Parkinson’s disease and, 134, 137, 493–503 in substantia nigra, 470, 500–1, 508

late onset gene (LOG), 48–9

INDEX learning, 9–10 procedural, 9 reward-based, 9 levodopa dyskinesia induction by, 39, 46, 91–2, 170, 221, 233, 333, 335, 339, 387, 446, 449 therapy, 39, 90, 121–2, 142, 211–13, 279, 335, 337, 346, 354, 371, 378–9, 446, 459, 468, 577 treatment, 10, 26, 34, 90, 122, 135, 163, 167, 169–71, 180, 184, 346, 353, 358, 369, 406, 437, 445–6 and carbidopa, 122–3, 346, 349–51, 354, 381, 424 see also dopamine; dopaminergic Lewy bodies caffeine exposure and, 141 cortical, 208, 218, 230, 235, 246, 255, 408, 579 dementia and, 403–5, 407–9, 411, 446, 465, 513–14, 575–6, 580 disease, 218–19, 230, 235, 246, 249, 255, 347, 408, 472, 509, 511, 513–14, 582, 600 diffuse (DLB), 218, 220, 230, 235, 249, 255–6, 408, 600 formation, 124, 182, 185, 206–9, 214, 220, 223, 230, 234, 377, 379, 408, 513–14, 571, 576, 578 history, 118, 118, 446 incidental, 131, 141, 208, 463, 502, 509, 511, 513–14, 582 neuropathology, 119, 207–8, 209, 209, 255, 256, 266, 347, 348, 365, 381, 510, 408–9, 513, 538, 563, 572, 580 parkin protein and, 218, 223, 369 Parkinson’s disease and, 182, 184–5, 205, 207, 207–8, 209, 214, 217–18, 221, 230, 234, 246, 256, 266, 291, 330, 332, 338, 407, 496, 510, 572, 575 pure autonomic failure and, 347, 348, 349–50, 472 structural components, 219, 408, 487, 513, 583, see also a-synuclein: -positive inclusions a-synuclein in, see a-synuclein locus ceruleus neurons, 159, 183–4, 181, 443, 463, 486–7, 531, 571, 580 neuropathology, 182, 205–7, 210–13, 217–23, 235, 276, 333, 365, 406–7 pharmacology, 181, 186, 246, 272

lymphocytes, 185, 188, 466, 485, 536, 542, 594

maneb, 270, 274–5, 584 manganese, 159–60, 486 neuromelanin and, 160 parkinsonism induction by, 121, 124, 137–8, 212, 486, 499 methanol induction of parkinsonism, 212 1-methyl-4phenyl-1,2,3,6tetrahydropyridine (MPTP), see MPTP motor behavior neurotransmitters, 48–9 glutamate pathways, 558–9, 559, see also glutamate; glutamatergic MPTP (1-methyl-4phenyl-1,2,3,6tetrahydropyridine), 122–3, 135 -induced parkinsonism, 135, 139, 274, 486 models of parkinsonism, 84, 157, 159–60, 162, 164, 166–8, 170, 177, 187, 271, 273–4, 501, 540–1, 542, 594 mouse, 161, 542, 560, 594, 598, 600 primate, 10–11, 31–2, 46, 84, 90, 92, 155, 157, 161, 166, 168, 179–80, 274, 486, 500, 559–61, see also Parkinson’s disease: animal models toxicity, 135, 212, 273, 485, 487, 540, 545, 598–600 multiple system atrophy (MSA), 143, 161, 210, 210–11, 211, 236, 246, 257–9, 258, 291, 312, 321, 343, 347, 348, 356, 368, 393, 405, 410, 465, 471–2, 508

neostriatum, 3, 38, 85, 165, 168 neurochemistry of Parkinson’s disease, see basal ganglia: neurochemistry in Parkinson’s disease neuroinflammation in neurodegenerative disorders, 535–7, 544–5 neuroprotection and, 543–4 in parkinsonian syndromes, 539–40 in Parkinson’s disease animal models, 540–2, 541, 542 inflammatory response, 538–9 origin, 537–8 role, 542–5

INDEX neuroinflammation (Continued ) therapy, 545–6 neurokinins, 22, 38–9, 158, 166 neuromelanin iron accumulation and, 159, 470, 498, 501 levodopa and, 485 manganese storage in, 160 neural locations for, 184, 206, 207, 223, 273, 501, 539, 572, 600–1 Parkinson’s disease and, 502–3, 507, 571 structure, 501 neuropeptide Y (NPY), 3, 22, 29, 40, 164 neuroprotection, 27, 35, 38, 43, 50, 78, 113, 125–6, 231, 269, 394, 512–13, 526, 546, 553, 560, 562, 591, 597 neurotensin, 22, 40, 88, 155, 158, 161–2, 167, 170, 172–5, 178, 187, 181 neurotransmitters, see specific neurotransmitters nitric oxide, 266, 277, 352, 487, 512, 556 as basal ganglia neurotransmitter, 46–7, 164, 230 synthase, 3, 29, 164, 230, 485, 487–9, 512, 542, 555, 556 3-nitrotyrosine, 230, 268, 274, 277, 512, 514

6-OHDA degeneration induction by, 272 lesion induction by, 45, 47, 83, 177, 179, 272, 559–60, 562–3 models for Parkinson’s disease, 83–4, 163, 272, 546, 558, 562, 598–600 neurotoxicity, 272 opioids, 22, 48–49 oxidative stress brain locations for, 511, 513 excitotoxicity and, 556 history, 508–10 iron and, 493, 508–13 markers, 275 mechanism of action, 486–7, 582 neural degeneration and, 276, 572 neuromelanin and, 502–3 obesity and, 138 6-OHDA-induced neurotoxicity and, 272 proteosomal dysfunction and, 584 role in Parkinson’s disease, see Parkinson’s disease: oxidative stress and vs. nitrative stress, 512

palsy progressive supranuclear, 162, 165, 211, 211, 234, 236, 259, 259–60, 291, 321, 332, 367, 405, 410–11, 448, 465, 471, 508, 540, 579 shaking, 109–10, 112–14, 126 paralysis agitans, see Parkinson’s disease paraquat, 124, 135, 137, 159, 234, 268, 270, 274–5, 275, 509–10, 514, 540 PARK forms of Parkinson’s disease, see Parkinson’s disease: autosomaldominant familial; Parkinson’s disease: autosomal-recessive familial; Parkinson’s disease: chromosome: 1 and; Parkinson’s disease: chromosome: 2 and parkin -deficient mice, 230, 280 in excitotoxic cell death, 561 as genetic model for Parkinson’s disease, 279–81 gene, 221–2, 246, 249, 280, 466, 561, 577, 595 -interacting proteins, 228–30 mutations, 124, 221, 223, 225, 226, 269, 379, 446, 469–70, 540 protein handling dysfunction and, 577 Parkinson, James birth, 109 career, 111–12 description of ‘paralysis agitans’, 129 Essay on the Shaking Palsy, 109, 112, 112–15, 124, 205 goal, 214 observations, 126, 265, 329, 332, 343, 352, 378, 421, 436 Parkinson’s disease, 265–9 age and, 133 animal models, 23, 28, 34, 39–40, 42, 50, 83–4, 122–4, 135–6, 139, 153–4, 161–2, 170–1, 178, 265–81, 356, 394, 487, 527, 535, 544, 560–3, 591, 595, 597–601 primate, 10, 31, 83–4, 90, 156–7, 162, 166, 171–8, 180–1, 185, 253, 524, 541, 526 rodent, 83, 166, 231, 275, 523, 523, 542 atypical, 338–9, 339 autonomic dysfunction in, see autonomic nervous system autosomal-dominant familial (PARK1), 217–21, 218, 219, 221

611 Parkinson’s disease (Continued ) autosomal-dominant familial (Continued ) (PARK3), 230 (PARK4), 230–1 (PARK5), 231, 231 (PARK8), 234–6, 236 autosomal-recessive familial (PARK2), 221–2, 221, 224, 224–30, 224–7, 229 (PARK6), 231–3, 232 (PARK7), 233, 233–4 (PARK9), 236 bladder dysfunction in, see autonomic nervous system: bladder dysfunction in Parkinson’s disease carbon monoxide induction of, 212 cardiovascular dysfunction in, see autonomic nervous system: cardiovascular dysfunction in Parkinson’s disease cholinergic function and, 248–9, see also acetylcholine circuit models, 10–13 chromosome 1 and, 236–7 2 and, 230, 237 dementia in, see dementia and Parkinson’s disease demographics, 130–4 dopamine D1-agonists in, 90–1 early detection anatomic changes and, 470 biochemical markers and, 466–70 clinical biomarkers and, 464–5 history of, 464–72 neurobiological characters and, 463–4 neurophysiological studies and, 465–6 test development and, 457–63, 460–1 epidemiology, 129, 130, 134 etiology environmental toxins, 270–1, 270–1 genetic mutations, 269–70, 482–3, 483–7 excitoxicity, 559–62, 571, see also excitoxicity gastrointestinal dysfunction in, see autonomic nervous system: gastrointestinal dysfunction in Parkinson’s disease gender and, 133

612 Parkinson’s disease (Continued ) genes and Parkinson’s disease, 135–6, 136, see also specific genes genes causing, 135–6, 136 DJ-1, see DJ-1: Parkinson’s disease and genetic forms, 209 initial discoveries in, 124–5 glutamate neurotransmission and, see glutamate history basal ganglia circuitry and, 122 Charcot, Jean-Martin and, 115–16, 116, 117, 124 clinical trials, 125 dopamine research, 120–2 early descriptions, 109–11 early neuropathological findings, 117–18, 118 encephalitis lethargica and, 119 environmental risk factors, 124 genetic discoveries, 124–5 MPTP role, 122–3 observations of paralysis agitans, 109, 114–19, 329 treatments, 125 imaging, see imaging incidence, 129, 131–4, 133, 142–3, 466, 535, 571 iron and, 134, 137, 493–503 levodopa responses, 253–5, 254 Lewy bodies in, see Lewy bodies: Parkinson’s disease and measurement, 313–14, 314, see also parkinsonism: measurement microglial activation, 250, 250–1 molecular mechanisms, 268 6-hydroxydopamine, 83 MPTP, 84, 273, 273–4, see also MPTP 6-OHDA, 272–3, see also 6-OHDA reserpine, 28, 36, 93, 120, 159, 166, 268, 271–2 ubiquitin protease inhibitors, 84, see also ubiquitin mood disorders anxiety, 428–9, 442–4 apathy, 429, 447–9 clinical correlates, 423–4 comorbid non-motor symptoms, 424–5 depression, 422, 425, 425–7, 430, 438–441 etiology and pathophysiology, 422–3 mania, 441 pseudobulbar affect (PBA), 429

INDEX Parkinson’s disease (Continued ) mood disorders (Continued ) psychosis, 445–7 treatment, 427–8 motor symptoms bulbar dysfunction, 335 bradykinesia, 331 dystonia skeletal deformities, 335–6, 336 gait abnormalities, 337–8, 338–9 neuron-ophthalmologic abnormalities, 334–5 postural instability, 332–4 primitive reflexes, 334 in respiratory muscle, 335 rigidity, 330–1 tremor, 329–30, 330 multiple system atrophy, see multiple system atrophy neurobehavioral disorders anxiety, 428–9, 442–4 apathy, 429, 447–9 evaluation, 437–8 depression, 422, 425, 425–7, 430, 438–441 hypersexuality, 441 mania, 441 pathological repetitive behavior, 444–5 psychosis, 445–7 sleep, see sleep in Parkinson syndromes neuroinflammation and, see neuroinflammation: in Parkinson’s disease neuropathology gross morphologic abnormalities, 205–6, 206 of Lewy bodies, see Lewy bodies: neuropathology of locus ceruleus, 206–7 of substantia nigra pars compacta, 206, 206–8 neuropeptide levels, 187 neurophysiology, 67–9, see also specific neurotransmitters neuroprotective agents, 251–2 neurotrophic factors dopaminergic trophic factors, 521, 522, 522–3, 523–4, 524–5 GDNF proteins, receptors and actions, 525, 525–6 GDNF therapy, 526–7, 527, 528 nigrostriatal dopaminergic pathway, 266 noradrenergic function, 248–9, see also catecholamines

Parkinson’s disease (Continued ) 6-OHDA models, 83–4, 163, 272, 546, 558, 562, 598–600 oxidative stress and, 122, 136, 221, 510–14, 266–7, 268, 274, 277–8, 466, 486–7, 571, 583 parkin as genetic model for 279–81, see also parkin pesticide models maneb, 270, 274–5, 584 3-nitrotyrosine, 230, 268, 274, 277, 512, 514 paraquat, 124, 135, 137, 159, 234, 268, 270, 274–5, 275, 509–10, 514, 540 rotenone, 84, 124, 135, 159, 161, 165, 183, 266, 267–8, 275–8, 276, 486, 509–10, 540, 584 preclinical detection, 249 programmed cell death and, see programmed cell death progressive supranuclear palsy and, see palsy: progressive supranuclear protein-handling dysfunction in, 571–84 race and, 133 rating scales, 296, see also healthrelated quality of life: measurement history, 296–7, 297 metric characteristics, 294–5, 295 ranking, 304 restorative approaches fetal cell implantation, 252–3 intraputaminal glial-derived neurotrophic factor infusions, 253 risk factors, 134 alcohol, 142 coffee and caffeine, 141–2 diet, 138 epidemiologic clues, 135 farming, 136 gender, 142–3 gene-environment interactions and, 143 head trauma, 140 infection, 139 inflammation, 139 metals, 137 obesity, 138–9 occupation, 137–8 pesticide exposure, 136 physical inactivity, 139 polychlorinated biphenyls (PCBs), 137

INDEX Parkinson’s disease (Continued ) risk factors (Continued ) rural living, 136 single genes as, 135–6, 136 smoking, 140–1, 141 well water, 136 sensory symptom(s) olfaction disruption, 379–80 pain, 377–9 visual disorders, 380–1 seratogenergic function, 248, 248–9 sexual dysfunction, 357 sleep disorders, see sleep in Parkinson syndromes speech disorders, see speech in Parkinson’s disease sporadic, 83, 124, 134, 135, 160, 209, 214, 219, 221, 223–4, 226–8, 230–7, 249, 251, 269–70, 273, 277–8, 281, 409, 464, 466, 469, 481, 513–14, 540, 545, 561, 571, 572, 575–9, 582–4 subthalamic nucleus (STN) and, 12 sweating dysfunction, 357 a-synuclein and, see a-synuclein therapy antidepressant, 428, 440 challenges, 528 CPAP, 370–1 dopaminergic, 330, 332–5, 371–2, 389, 441, 487, 561 GDNF, 524, 526–7 gene, 84, 239, 274, 528, 563 growth factor, 252 levodopa, see levodopa: therapy; levodopa: treatment pharmaco-, 90, 355, 370, 428, 430, 466, 470 psycho-, 428 speech, 335, 389–91, 393–4 ubiquitin carboxy terminal hydrolase L as genetic model for, 281, see also ubiquitin: carboxyterminal hydrolase ubiquitin-proteosome inhibition model for, 277–8, see also ubiquitin: -proteosome system parkinsonism basal ganglia nuclei and, see basal ganglia chromosome 17 and, 213 -dementia complex of Guam, 212–13, 213 definition, 291 frontotemporal dementia and, 213

parkinsonism (Continued ) measurement, see also healthrelated quality of life; parkinsonism: measurement scale(s) basic principles, 291–2 conceptual framework, 292 health related quality of life, see health-related quality of life WHO international classification, 293 measurement scale(s) autonomic disorder, 310–11 design and validation, 293–4 for dyskinesia, 311–12 freezing of gain questionnaire (FOGQ), 308–9 gait evaluation, 308 Hoehn and Yahr (HY) staging, 297, 304–5 intermediate scale for assessment of Parkinson’s disease (ISAPD), 306–7 mental state, 309 metric characteristics, 294–5, 295 Parkinson’s disease activities of daily living scale, 308 psychometric characteristics, 298–303 ranking, 304 Schwab and England, 305 short Parkinson’s evaluation (SPES), 307 sleep, 309–10 SPES/SCOPA, 307–8 UMSARS, 312, 321 unified Parkinson’s disease rating scale (UPDRS), 91, 125, 251–3, 296, 298–301, 304–12, 315–17, 318–21, 333, 338, 366, 368, 412–13, 423, 425, 469–70, 527 neurotoxin-induced, 212 postencephalitic, 209–10 see also Parkinson’s disease pergolide, 84–5, 89, 122, 365, 468 Pink 1 mutation, 270, 514, 581 pramipexole (Mirapex), 87, 89, 90, 92, 122, 171, 251, 320, 371, 424, 427, 440–1, 468 programmed cell death apoptosis in, 221, 592, 592–3 history of concept, 591–2 molecular pathways, 593, 593–7 in Parkinson’s disease substantia nigra dopamine neurons and, 597

613 programmed cell death (Continued ) in Parkinson’s disease (Continued ) animal models of, 597–9 c-jun signaling cascade and, 599–600 human postmortem evidence for, 600–1 protein cellular control of, 572–5, 573–4 handling in cells, 573 familial Parkinson’s disease and, 575–9, 580–1 sporadic Parkinson’s disease and, 579–84 ubiquitin-proteasome system and, 582–4, 583, 584 proteosomal system, 486–7, 574 dysfunction of, 582–3, 583, 584, 584 see also protein: handling in cells pure autonomic failure (PAF), 347, 348, 349–50, 472

quinpirole, 44, 80, 89, 90, 92

reserpine, 28, 36, 93, 120, 159, 166, 268, 271–2 respiratory chain and oxidative phosphorylation system, 483 ropinirole (Requip), 78, 87, 89, 90, 122, 171, 251, 424, 441 rotenone, 84, 124, 135, 159, 161, 165, 183, 267–8, 275–6, 281, 486, 509–10, 540, 584 rotigotine, 89

scrotinin, in basal ganglia, 22 serotonin anxiety and, 442–3 in basal ganglia, 19, 21, 36–7 biosynthesis, 36–7, 446 degradation, 36–7, 163 in globus pallidus, 177, 180 in median raphe, 248 in Parkinson’s disease, 187, 248, 354, 423 receptors, 37, 178, 180–1, 407 release, 36–7 reuptake inhibitors, 357, 366, 371, 379 signal transduction, 37 in striatopallidal, 406 syndrome, 428, 441 transport, 36–7, 247, 423, 467 turnover, 169

614 serotonin (Continued ) see also catecholamines: 5-HT sexual dysfunction in Parkinson’s disease, 357 SKF39393, 91 SKF82958, 91 sleep in Parkinson syndromes clinical features daytime sleepiness, 370 hyperkinesia and akinesia, 367 sleep-associated motor phenomena, 367–8 sleep benefit, 368 sleep deprivation, 368 sleep fragmentation, 367 diagnosis, 366 pathophysiology, 365–6, 449–50 REM sleep behavior disorder, 368–9 respiratory disorders, 369 treatment, 370–2 somatostatin (SOM), 3, 22, 25, 29, 38, 40, 88, 164, 170, 175, 187 speech in Parkinson’s disease characteristics, 386–9 disorders articulatory, 387 laryngeal, 386–7 respiratory, 386–7 treatment, 389–91 sensory observations, 387–8 voice treatment, 391–3

INDEX speech in Parkinson’s disease (Continued ) therapy, 335, 389–91, 393–4 substantia nigra pars compacta (SNc or SNpc), 6, 206, 206–8, 213, 572 subthalamic nucleus (STN), 3–6, 4, 8–11, 12–13, 19, 21, 25, 27–9, 32, 42–3, 46, 123, 160–1, 163, 165, 171, 172–5, 178–80, 183, 185–6, 187, 330, 332, 389–90, 424, 555, 558, 559, 560–3 sweating dysfunction in Parkinson’s disease, 357 a-synuclein aggregation, 135, 221, 274 antibodies, 208, 408 expression, 219–21, 230, 278–9, 409 gene, 124, 209, 217–20, 230–1, 269, 278–9, 409, 469, 575–6 mutation, 209, 218, 408 immunostaining, 208, 208 oligomers, 219–20, 221 -opathy, 348, 369, 402, 405 -positive inclusions, 185, 223, 242, 246, 257, 274–6, 278–9, 539 protein handling dysfunction and, 575–7 toxicity, 220–1, 237

tremor, essential, 23, 130, 171, 248, 329, 330, 464, 468

ubiquitin -activating enzyme, 228, 267 carboxy-terminal hydrolase, 124, 136, 217, 231, 269, 281, 538, 573, 574, 578, 580 -conjugating enzyme, 228, 267, 269, 279 inhibition model for Parkinson’s disease, 277–8 monomers, 124 -proteosome system, 124–5, 207, 214, 220, 228, 229, 268, 268–9, 277, 279, 487, 514, 538, 561, 572, 573, 582–4, 583, 584 UCHL-1, 26, 269, 77–8

ventral striatum, 3–4, 19, 21, 24, 80, 162, 249, 406, 410 vesicular aceylcholine transporter, 34

working memory, 67, 82, 93, 380, 403, 406, 410

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