Handbook of Parkinson's Disease 4th Edition (Neurological Disease and Therapy)

HANDBOOK OF

Parkinson’s Disease fourth edition

Edited by

Rajesh Pahwa University of Kansas Medical Center Kansas City, Kansas, U.S.A.

Kelly E. Lyons University of Kansas Medical Center Kansas City, Kansas, U.S.A.

New York London

Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2007 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid‑free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number‑10: 0‑8493‑7621‑1 (Hardcover) International Standard Book Number‑13: 978‑0‑8493‑7621‑4 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright. com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978‑750‑8400. CCC is a not‑for‑profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging‑in‑Publication Data Handbook of Parkinson’s disease / edited by Rajesh Pahwa, Kelly E. Lyons. ‑‑ 4th ed. p. cm. ‑‑ (Neurological disease and therapy ; 92) Includes bibliographical references and index. ISBN‑13: 978‑0‑8493‑7621‑4 (alk. paper) ISBN‑10: 0‑8493‑7621‑1 (alk. paper) 1. Parkinson’s disease‑‑Handbooks, manuals, etc. I. Pahwa, Rajesh. II. Lyons, Kelly E. RC382.H36 2007 616.8’33‑dc22 Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

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Foreword

Parkinson’s disease is one of the most common neurodegenerative diseases with a higher prevalence in older adults. It is a slowly progressive condition and has set the standard for research in neurodegeneration throughout the history of medicine. It was the first neurodegenerative disease for which the pathology was discovered, when I. Tretjakov first described the degenerated substantia nigra in 1919. The biochemistry was first described by A. Carlsson, and the transmitter deficit by O. Hornykiewicz. The accidental discovery of the selective neurotoxin 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for neurones of the substantia nigra in the 1980s has been of a similar importance, as it subsequently became possible to study Parkinson’s disease in animal models. All these basic research achievements were the basis for groundbreaking progress in the field of therapy. Parkinson’s disease was the first neurodegenerative disease for which transmitter replacement therapy was developed; it was the first condition in medical history for which cellreplacement therapy or neurotransplantation was attempted; and it was one of the first conditions for which therapy using electrical brain stimulation was shown to be beneficial. As we benefit from research advances, the beginner, the experienced neurologist, and the movement disorder specialist need continuous updates. New possibilities for treatment offer new choices for patients and expand the skill set and knowledge base of physicians. This new edition of the Handbook of Parkinson’s Disease covers all new aspects of the condition and fills the need for an authoritative and recent update. The editors have put together an excellent group of authors, each of whom is a well-known specialist in their field, and the chapters are scholarly and easy to read. William Koller, MD, PhD, who was among the editors of the previous editions of this handbook, was one of the founders of the research field of movement disorders in the United States. He was specifically dedicated to excellent clinical research and patient care. Kelly Lyons and Rajesh Pahwa, co-workers of Bill Koller for many years, have edited this handbook in his spirit and have succeeded in maintaining the quality of the previous editions with this fourth edition. The book will serve as an ideal reference for all those who care for patients as well as those who want to enter the field. Günther Deuschl, MD Professor of Neurology Chairman of the Department of Neurology Christian-Albrechts-University Kiel Universiätsklinikum Schleswig-Holstein Germany

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Preface

Parkinson’s disease is a progressive neurodegenerative condition with often devastating symptoms. Our knowledge of Parkinson’s disease has increased tremendously in recent years. We have achieved a greater understanding of the neurochemistry, neurophysiology, and neuropathology of Parkinson’s disease. Genes have been identified that are involved in the pathogenesis of some forms of familial autosomal dominant and recessive Parkinson’s disease. Advancements in neuropsychological and neuroimaging techniques have led to improvements in diagnostic accuracy, and therapeutic options have been expanded. In addition, new medications have been approved, new compounds and therapeutic approaches are under investigation, and new surgical procedures and therapies are being explored. In spite of these advances, there continue to be many complications associated with the long-term management of both motor and non-motor symptoms of Parkinson’s disease, and treatment remains a challenge. We present in this edition of the Handbook of Parkinson’s Disease the most up-todate information on the scientific and therapeutic aspects of Parkinson’s disease. This fourth edition offers a more integrated approach to managing parkinsonian symptoms and has been expanded to include more in-depth coverage of neuropsychiatric aspects of Parkinson’s disease, sleep issues, and non-pharmacological and nontraditional therapies. There is comprehensive coverage of the latest pharmacologic and surgical therapeutics as well as the newest basic research. It is our hope that this volume, in the tradition of the first three editions, will serve as a reference source for physicians, researchers, and other health care professionals seeking answers to the many questions related to understanding and treating Parkinson’s disease. We would like to thank each of the authors for their time and commitment in preparing state-of-the-art reviews of the most pertinent aspects of Parkinson’s disease. Rajesh Pahwa Kelly E. Lyons

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Contents

Foreword Günther Deuschl Preface . . . . v Contributors . . . . ix

. . . . iii

1. Early Iconography of Parkinson’s Disease 1 Christopher G. Goetz 2. Epidemiology 19 Michele Rajput, Alex Rajput, and Ali H. Rajput 3. Differential Diagnosis 29 John Morgan and Kapil D. Sethi 4. Pathophysiology and Clinical Assessment 49 Joseph Jankovic 5. Autonomic Dysfunction and Management 77 Richard B. Dewey, Jr. 6. Sleep Dysfunction 91 Laura Nieder and K. Ray Chaudhuri 7. Neuropsychological Aspects 109 Alexander I. Tröster and Steven Paul Woods 8. Management of Anxiety and Depression Jack J. Chen

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9. Management of Psychosis and Dementia 155 Kelvin L. Chou and Hubert H. Fernandez 10. Neuroimaging 177 Kenneth Marek, Danna Jennings, and John Seibyl 11. Neuropathology 195 Dennis W. Dickson 12. Neurochemistry of Nigral Degeneration 209 Jayaraman Rao 13. Neurophysiology and Neurocircuitry 223 Erwin B. Montgomery and John T. Gale 14. Animal Models 239 Giselle M. Petzinger and Michael W. Jakowec vii

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15. Genetics 269 Akiko Imamura, Matthew J. Farrer, and Zbigniew K. Wszolek 16. Environmental Risk Factors 279 Brad A. Racette 17. Amantadine and Anticholinergics 293 Khashayar Dashtipour, Joseph S. Chung, Allan D. Wu, and Mark F. Lew 18. Levodopa 309 Stewart A. Factor 19. Dopamine Agonists 335 Valerie Street and Mark Stacy 20. Monoamine Oxidase Inhibitors 349 Alex Rajput, Theresa A. Zesiewicz, and Robert A. Hauser 21. Catechol-O-Methyltransferase Inhibitors 365 Ronald F. Pfeiffer 22. Investigational Pharmacological Treatments 379 William G. Ondo 23. Lesion Surgeries 391 Michael Samuel, Keyoumars Ashkan, and Anthony E. Lang 24. Deep Brain Stimulation 409 Kelly E. Lyons and Rajesh Pahwa 25. Investigational Surgical Therapies 423 Joseph S. Neimat, Parag G. Patil, and Andres M. Lozano 26. Physical and Occupational Therapy 441 Atul T. Patel and Sean Shire 27. Voice, Speech, and Swallowing Disorders 451 Shimon Sapir, Lorraine Olson Ramig, and Cynthia Fox 28. Alternative Therapies 475 Jill Marjama-Lyons Index

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Contributors

Keyoumars Ashkan Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, Queen Square, London, U.K. K. Ray Chaudhuri Movement Disorders Unit, Kings College Hospital, University Hospital Lewisham and Guy’s King’s and St. Thomas’ School of Medicine, London, U.K. Jack J. Chen Department of Neurology, Schools of Medicine and Pharmacy, Movement Disorders Center, Loma Linda University, Loma Linda, California, U.S.A. Kelvin L. Chou Department of Clinical Neurosciences, Brown Medical School and NeuroHealth Parkinson’s Disease and Movement Disorders Center, Warwick, Rhode Island, U.S.A. Joseph S. Chung Department of Neurology, Movement Disorders Specialist, Southern California Kaiser Permanente, Los Angeles, California, U.S.A. Khashayar Dashtipour Division of Movement Disorders, Department of Neurology, Loma Linda University School of Medicine, Loma Linda, California, U.S.A. Richard B. Dewey, Jr. Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. Dennis W. Dickson Department of Pathology, Mayo Clinic College of Medicine, Jacksonville, Florida, U.S.A. Stewart A. Factor Emory University School of Medicine, Department of Neurology, Wesley Woods Health Center, Atlanta, Georgia, U.S.A. Matthew J. Farrer Mayo Clinic, Jacksonville, Florida, and Mayo School of Graduate Medical Education, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A. Hubert H. Fernandez Movement Disorders Center and Department of Neurology, University of Florida/McKnight Brain Institute, Gainesville, Florida, U.S.A. Cynthia Fox Tucson, Arizona, National Center for Voice and Speech, Denver, Colorado, U.S.A. John T. Gale Department of Neurosurgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, U.S.A. Christopher G. Goetz Department of Neurological Sciences, Rush University, Chicago, Illinois, U.S.A. Robert A. Hauser Parkinson’s Disease and Movement Disorders Center, University of South Florida, NPF Center of Excellence, Tampa, Florida, U.S.A. Akiko Imamura Mayo Clinic, Jacksonville, Florida, and Mayo School of Graduate Medical Education, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A. Michael W. Jakowec Department of Neurology, University of Southern California, Los Angeles, California, U.S.A. ix

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Joseph Jankovic Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, U.S.A. Danna Jennings Department of Neurology, The Institute for Neurodegenerative Disorders, New Haven, Connecticut, U.S.A. Anthony E. Lang Department of Medicine, Division of Neurology, The Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada Mark F. Lew Division of Movement Disorders, Keck/USC School of Medicine, Los Angeles, California, U.S.A. Andres M. Lozano Ontario, Canada

Division of Neurosurgery, Toronto Western Hospital, Toronto,

Kelly E. Lyons Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A. Kenneth Marek Department of Neurology, The Institute for Neurodegenerative Disorders, New Haven, Connecticut, U.S.A. Jill Marjama-Lyons Albuquerque, New Mexico, U.S.A. Erwin B. Montgomery Department of Neurology, National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A. John Morgan Department of Neurology, Medical College of Georgia, Augusta, Georgia, U.S.A. Joseph S. Neimat Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A. Laura Nieder Neurology Department, Guy’s King’s and St. Thomas’ School of Medicine, London, U.K. William G. Ondo Department of Neurology, Baylor College of Medicine, Houston, Texas, U.S.A. Atul T. Patel Department of Rehabilitation, Research Medical Center, Kansas City Bone and Joint Clinic, Overland Park, Kansas, U.S.A. Parag G. Patil Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, U.S.A. Rajesh Pahwa Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A. Giselle M. Petzinger Department of Neurology, University of Southern California, Los Angeles, California, U.S.A. Ronald F. Pfeiffer Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, U.S.A. Brad A. Racette Department of Neurology and American Parkinson Disease Association Advanced Center for Parkinson Research, Washington University School of Medicine, St. Louis, Missouri, U.S.A. Alex Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

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Ali H. Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Michele Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Lorraine Olson Ramig Department of Speech, Language, Hearing Sciences, University of Colorado, Boulder, and National Center for Voice and Speech, Denver, Colorado, U.S.A. Jayaraman Rao Department of Neurology, Parkinson’s Disease and Movement Disorders Center, Ochsner Foundation Clinic, New Orleans, Louisiana, U.S.A. Michael Samuel London, U.K.

Department of Neurology, King’s College Hospital, Denmark Hill,

Shimon Sapir Department of Communication Sciences and Disorders, University of Haifa, Haifa, Israel John Seibyl Department of Neurology, The Institute for Neurodegenerative Disorders, New Haven, Connecticut, U.S.A. Kapil D. Sethi Department of Neurology, Medical College of Georgia, Augusta, Georgia, U.S.A. Sean Shire Department of Rehabilitation, Research Medical Center, RMC-Brookeside, Kansas City, Missouri, U.S.A. Mark Stacy Division of Neurology, Duke University Medical School, Durham, North Carolina, U.S.A. Valerie Street Division of Neurology, Duke University Medical School, Durham, North Carolina, U.S.A. Alexander I. Tröster Department of Neurology, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, North Carolina, U.S.A. Steven Paul Woods Department of Psychiatry, University of California at San Diego, San Diego, California, U.S.A. Zbigniew K. Wszolek Mayo Clinic, Jacksonville, Florida, and Mayo School of Graduate Medical Education, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A. Allan D. Wu Division of Movement Disorders, Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, U.S.A. Theresa A. Zesiewicz Parkinson’s Disease and Movement Disorders Center, University of South Florida, NPF Center of Excellence, Tampa, Florida, U.S.A.

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Early Iconography of Parkinson’s Disease

Christopher G. Goetz Department of Neurological Sciences, Rush University, Chicago, Illinois, U.S.A.

Parkinson’s disease was first described in a medical context in 1817 by James Parkinson, a general practitioner in London. Numerous essays have been written about Parkinson himself and the early history of Parkinson’s disease (Paralysis agitans), or the shaking palsy. Rather than repeat or resynthesize such prior studies, this introductory chapter focuses on a number of historical visual documents with descriptive legends. Some of these are available in prior publications, but the entire collection has not been presented before. As a group, they present materials from the 19th century and will serve as a base, on which the subsequent chapters that cover progress of the twentieth and budding twenty-first centuries are built. In 2005, as part of the Movement Disorder Society annual international congress, an extensive history exhibit was developed. Interested readers can access the core of this exhibit (1).

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HISTORICAL AND LITERARY PRECEDENTS

FIGURE 1 Franciscus de le Böe (1614–1672). Also known as Sylvius de le Böe, and Franciscus Sylvius, this early physician was a Professor of Leiden and a celebrated anatomist. In his medical writings, he also described tremors and he may be among the very earliest writers on involuntary movement disorders (2).

FIGURE 2 François Boissier de Sauvages de la Croix (1706–1767). Sauvages was cited by Parkinson himself and described patients with “running disturbances of the limbs,” scelotyrbe festinans. Such subjects had difficulty in walking, moving with short and hasty steps. He considered the problem to be due to diminished flexibility of muscle fibers—possibly his manner of describing rigidity (2,3).

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FIGURE 3 William Shakespeare. A brilliant medical observer and writer, Shakespeare, described many neurological conditions, including epilepsy, somnambulism, and dementia. In Henry VI, first produced in 1590, the character, Dick, notices that Say is trembling: “Why dost thou quiver, man,” he asks, and Say responds, “The palsy and not fear provokes me” (2). Jean-Martin Charcot frequently cited Shakespeare in his medical lectures and classroom presentations and disputed the concept that tremor was a natural accompaniment of normal aging. He rejected “senile tremor” as a separate nosographic entity. After reviewing his data from the Salpêtrière service where 2000 elderly inpatients lived, he turned to Shakespeare’s renditions of elderly figures: “Do not commit the error that many others do and misrepresent tremor as a natural accompaniment of old age. Remember that our venerated Dean, Dr. Chevreul, today 102 years old, has no tremor whatsoever. And you must remember in his marvelous descriptions of old age (Henry IV and As You Like It), the master observer, Shakespeare, never speaks of tremor” (4,5).

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FIGURE 4 Wilhelm von Humboldt (1767–1835). The celebrated academic reformer and writer, von Humboldt, lived in the era of Parkinson and described his own neurological condition in a series of letters, analyzed by Horowski (6). The statue by Friedrich Drake shown in the figure captures the hunched, flexed posture of Parkinson’s disease, but von Humboldt’s own words capture the tremor and bradykinesia of the disease:

Trembling of the hands . . . occurs only when both or one of them is inactive; at this very moment, for example, only the left one is trembling but not the right one that I am using to write . . . . If I am using my hands this strange clumsiness starts which is hard to describe. It is obviously weakness as I am unable to carry heavy objects as I did earlier on, but it appears with tasks that do not need strength but consist of quite fine movements, and especially with these. In addition to writing, I can mention rapid opening of books, dividing of fine pages, unbuttoning and buttoning up of clothes. All of these as well as writing proceed with intolerable slowness and clumsiness (7).

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JAMES PARKINSON

FIGURE 5 Front piece of James Parkinson’s An Essay on the Shaking Palsy. This short monograph is extremely difficult to find in its original 1817 version, but has been reproduced many times. In the essay, Parkinson describes a small series of subjects with a distinctive constellation of features. Although he had the opportunity to examine a few of the subjects, some of his reflections were based solely on observation (8).

FIGURE 6 St. Leonard’s Church. The Shoreditch parish church was closely associated with James Parkinson’s life, as he was baptized, married, and buried there (9).

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FIGURE 7 John Hunter. The celebrated physician, Hunter [painted by J. Reynolds (10)], was admired by Parkinson, who transcribed the surgeon’s lectures in his 1833 publication called Hunterian Reminiscences (11). In these lectures, Hunter offered observations on tremor. The last sentence of Parkinson’s Essay reads:

. . . but how few can estimate the benefits bestowed on mankind by the labours of Morgagni, Hunter or Baillie (8). Currier has posited that Parkinson’s own interest in tremor was first developed under the direct influence of Hunter (12).

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FIGURE 8 James Parkinson’s home. No. 1 Hoxton Square, London, formerly Shoreditch, today carries a plaque, honoring the birthplace of James Parkinson (13). The plaque that hangs by the entrance is shown close-up.

FIGURE 9 James Parkinson as paleontologist. An avid geologist and paleontologist, Parkinson, published numerous works on fossils, rocks, and minerals (14). He was an honorary member of the Wernerian Society of Natural History of Edinburgh and the Imperial Society of Naturalists of Moscow.

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FIGURE 10 Counterfeit portrait of James Parkinson. To date, no portrait is known to exist of James Parkinson. This photograph of a dentist by the same name was erroneously published and widely circulated in 1938, as part of a Medical Classics edition of Parkinson’s Essay (15). Because Parkinson died prior to the first daguerreotypes, if a portrait is found, it will be a line drawing, painting, or print. A written description does however exist. The paleontologist, Mantell wrote:

Mr. Parkinson was rather below middle stature, with an energetic intellect, and pleasing expression of countenance and of mild and courteous manners; readily imparting information, either on his favourite science or on professional subjects (9).

FIGURE 11 One of Parkinson’s medical pamphlets. As an avid writer, Parkinson compiled many books and brochures that were widely circulated on basic hygiene and health. His Medical Admonitions to Families and The Villager’s Friend and Physician were among the most successful, although he also wrote a children’s book on safety entitled Dangerous Sports, in which he traced the mishaps of a careless child and lessons he learns through injury (13).

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JEAN-MARTIN CHARCOT AND THE SALPÊTRIÈRE SCHOOL

FIGURE 12 Jean-Martin Charcot. Working in Paris, in the second half of the 19th century, Charcot knew of Parkinson’s description and studied the disorder in the large Salpêtrière hospital that housed elderly and destitute women. He identified the cardinal features of Parkinson’s disease and specifically separated bradykinesia from rigidity (5,16):

Long before rigidity actually develops, patients have significant difficulty performing ordinary activities: this problem relates to another cause. In some of the various patients I showed you, you can easily recognize how difficult it is for them to do things even though rigidity or tremor is not the limiting features. Instead, even a cursory exam demonstrates that their problem relates more to slowness in execution of movement rather than to real weakness. In spite of tremor, a patient is still able to do most things, but he performs them with remarkable slowness. Between the thought and the action there is a considerable time lapse. One would think neural activity can only be affected after remarkable effort.

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FIGURE 13 Statue of a parkinsonian woman by Paul Richer. Richer worked with Charcot, and, as an artist and sculptor, produced several works that depicted the habitus, joint deformities and postural abnormalities of patients with Parkinson’s disease (14,17).

FIGURE 14 Evolution of parkinsonian disability. These figures, drawn by Charcot’s student, Paul Richer, capture the deforming posture and progression of untreated Parkinson’s disease over a decade (15,18).

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FIGURE 15 Parkinson’s disease and its variants. Charcot’s teaching method involved the sideby-side comparisons of patients with various neurological disorders. In one of his presentations on Parkinson’s disease, he showed two subjects, one with the typical or archetypal form of the disorder with hunched posture and flexion (left), and another case with atypical parkinsonism, showing an extended posture (right).The latter habitus is more characteristic of the entity progressive supranuclear palsy, although this disorder was not specifically recognized or labeled by Charcot outside of the term “parkinsonism without tremor” (5).

FIGURE 16 Charcot’s early tremor recordings. Charcot adapted the sphygmograph, an instrument originally used for recording arterial pulsation, to record tremors and movements of the wrist. His resultant tremor recordings (lower right), conducted at rest (A–B) and during activity (B–C), differentiated multiple sclerosis (top recording) from the pure rest tremor (lower recording) or mixed tremor (middle recording) of Parkinson’s disease (19).

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FIGURE 17 Charcot’s sketch of parkinsonian subject. Pencil sketch of a man with Parkinson’s disease drawn by Charcot during a trip to Morocco in 1889 (20). Referring to the highly stereotyped clinical presentation of Parkinson’s disease patients, Charcot told his students:

I have seen such patients everywhere, in Rome, Amsterdam, Spain, always the same picture. They can be identified from afar. You do not need a medical history (4,5). Charcot’s medical drawings form a large collection, which is housed at the Bibliothèque Charcot at the Hôpital de la Salpêtrière, Paris.

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FIGURE 18 Treatment of Parkinson’s disease. Prescription dated 1877 (21). In treating Parkinson’s disease, Charcot used belladonna alkaloids (agents with potent anticholinergic properties) as well as rye-based products that had ergot activity, a feature of some currently available dopamine agonists (21). Charcot’s advice was empiric and preceded the recognition of the well-known dopaminergic/cholinergic balance that is implicit to normal striatal neurochemical activity.

FIGURE 19 Vibratory therapy. Charcot observed that patients with Parkinson’s disease experienced a reduction in their rest tremor, after taking a carriage ride or after horseback riding. He developed a therapeutic vibratory chair that simulated the rhythmic shaking of a carriage (18). A vibratory helmet to shake the head and brain was later developed. Such therapies were not utilized widely and have not been studied in modern times.

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OTHER NINETEENTH CENTURY CONTRIBUTIONS

FIGURE 20 Dysautonomia in Parkinson’s disease. This drawing by Daniel Vierge (1851–1904) shows the Salpêtrière inpatient wards with a single central furnace for heat (18). In this context, Charcot recognized the distinctive dysautonomia of Parkinson’s disease, noting how patients experienced a sense of hyperthermia even in the drafty, cold wards of the French hospitals:

In the midst of winter (everyone on my service will substantiate this), you can see the parkinsonian patients with no blankets covering them and with only the lightest of clothes on . . . they feel hot especially around the epigastrium and back, although the face and extremities can also be the focus of their discomfort. When this heated sensation occurs, it is often accompanied by such severe sweating that the sheets and pajamas may need changing. I assure you that regardless of how hot these patients feel or how much they shake, their temperature remains normal (18).

FIGURE 21 Micrographia and tremorous handwriting. Charcot recognized that one characteristic feature of Parkinson’s disease was the handwriting impairment that included tremorous and tiny script. Charcot collected handwriting samples in his patients’ charts and used them as part of his diagnostic criteria, thereby separating the large and sloppy script of patients with action tremor from the micrographia of Parkinson’s disease (16).

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FIGURE 22 William Gowers’ work. William Gowers’ A Manual of Diseases of the Nervous System shows sketches of patients with Parkinson’s disease (left) and diagrams of joint deformities (right) (22). More known for written descriptions than visual images, Gowers offered one of the most memorable similes regarding parkinsonian tremor:

the movement of the fingers at the metacarpal-phalangeal joints is similar to that by which Orientals beat their small drums (22).

FIGURE 23 William Osler. Osler published his celebrated Principles and Practice of Medicine in 1982, one year before Charcot’s death. As an internist always resistant to the concept of medical specialization, Osler was influential in propagating information to generalists on many neurological conditions, including Parkinson’s disease. Osler was less forthcoming than Charcot in appreciating the distinction between bradykinesia and weakness, and sided with Parkinson in maintaining that mental function was unaltered. Osler was particularly interested in pathological studies and alluded to the concept of Parkinson’s disease as a state of accelerated aging (23).

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FIGURE 24 Eduard Brissaud. Brissaud was a close associate of Charcot and contributed several important clinical observations on Parkinson’s disease in the late 19th century. Most importantly, however, he brought neuropathological attention to the substantia nigra as the potential cite of disease origin. In discussing a case of a tuberculoma that destroyed the substantia nigra and in association with contralateral hemiparkinsonism, he considered the currently vague knowledge of the nucleus and its putative involvement in volitional and reflex motor control. Extending his thoughts, he hypothesized that, “a lesion of the locus niger could reasonably be the anatomic basis of Parkinson’s disease” (24).

REFERENCES 1. www.movementdisorders.org 2. Finger S. Origins of Neuroscience. New York, Oxford University Press, 1994. 3. Sauvages de la Croix FB. Nosologia methodica. Amstelodami: Sumptibus Fratrum de Tournes, 1763. 4. Charcot J-M. Leçons du Mardi: Policlinique: 1887–1888. Paris: Bureaux du Progrès Médical, 1888. 5. Goetz CG. Charcot, the Clinician: The Tuesday Lessons. New York: Raven Press, 1987. 6. Horowski R, Horowski L, Vogel S, Poewe W, Kielhorn F-W. An essay on Wilhelm von Humboldt and the shaking palsy. Neurology 1995; 45:565–568. 7. Leitzmann A. Briefe von Wilhelm von Humboldt an Eine Freundin. Leipzig: Inselverlag, 1909. 8. Parkinson J. Essay on the Shaking Palsy. London: Whittingham and Rowland for Sherwood, Neeley and Jones. 1817. 9. Morris AD, Rose FC. James Parkinson: His Life and Times. Boston: Birkhauser, 1989.

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10. Allen E, Turk JL, Murley R. The Case Books of John Hunter FRS. London: Royal Society of Medicine, 1993. 11. Parkinson J. Hunterian Reminiscences. London: Sherwood, Gilbert and Piper, 1833. 12. Currier RD. Did John Hunter give James Parkinson an idea? Arch Neurol 1996; 53:377–378. 13. Robert D. Currier Parkinson Archives legged to Christopher G. Goetz. 14. Parkinson, J. Organic Remains of a Former World (three volumes). London: Whittingham and Rowland for Sherwood, Neeley and Jones, 1804–1811. 15. Kelly EC. Annotated reprinting: Essay on the Shaking Palsy by James Parkinson. Medical Classics 1938; 2:957–998. 16. Charcot J-M. De la paralysie agitante (leçon 5). Oeuvres Complètes 1869; 1:161–188 (Paris, Bureaux du Progrès Médical). In English: On paralysis agitans (Lecture 5). Lectures on the Diseases of the Nervous System. Translated by G. Sigurson. Philadelphia: HC Lea and Company, 1879:105–107. 17. Historical art and document collection, Christopher G. Goetz. 18. Goetz CG, Bonduelle M, Gelfand T. Charcot: Constructing Neurology. New York: Oxford University Press, 1995. 19. Charcot J-M. Tremblements et mouvements choreiforms (leçon 15). Oeuvres Complètes 1888; 9:215–228 (Paris, Bureaux du Progrès Médical). In English: Choreiform Movements and Tremblings. Clinical Lectures on Diseases of the Nervous System. Translated by EF Hurd. Detroit: GS Davis, 1888:208–221. 20. Meige H. Charcot Artiste. Nouvelle Iconographie de la Salpêtrière 1898; 11:489–516. 21. Philadelphia College of Physicians, Original manuscript and document collection, Philadelphia, PA. 22. Gowers WR. A Manual of Diseases of the Nervous System. London: Churchill, 1886–1888. 23. Osler W. The Principles and Practice of Medicine. New York: Appleton and Company, 1892. 24. Brissaud E. Nature et pathogénie de la maladie de Parkinson (leçon 23:488–501). Leçons sur les maladies nerveuses: la Salpêtrière, 1893–1894; Paris: Masson, 1895.

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Epidemiology Michele Rajput, Alex Rajput, and Ali H. Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Epidemiology is “the study of distribution and determinants of health-related states in specified populations”(1). This chapter will focus on the distribution of parkinsonism. Unlike laboratory studies where the experimental conditions can be controlled, epidemiology examines natural events occurring in human populations that are influenced by characteristics of the individuals studied as well as by outside forces including medical, economic, and social factors. For these reasons, care must be taken when conducting and reviewing epidemiological studies. No two epidemiological studies are identical. For many reasons, the methods utilized at one location or at one time may not be possible at another and populations vary by time and place. Two primary factors must be considered in studying the epidemiology of parkinsonism, the case definitions used and the population studied.

INCLUSION CRITERIA FOR PARKINSON EPIDEMIOLOGY The two major considerations for inclusion in parkinsonism epidemiology are: 1. Does this individual have parkinsonism, normal aging, or another disorder? 2. Does this person have idiopathic Parkinson’s disease (PD) or another variant of parkinsonism? Primitive reflexes, slowed motor functions, flexed posture, and impaired postural reflexes characteristic of parkinsonism are also a part of normal aging (2). In general, age-related abnormalities are symmetrical while parkinsonism is often asymmetrical. Rest tremor, a common early feature of parkinsonism, is not part of normal aging and hence is the single most reliable feature of this disorder (3). The most common tremor disorder misdiagnosed as PD is essential tremor (ET). Typically, ET is present on positioning a limb against gravity and during activity. ET is usually restricted to the upper limbs and/or head. By contrast, resting tremor is characteristic of parkinsonism and may involve the upper and lower limbs. Nearly one-third of ET patients may develop rest tremor after many years and may be mistaken as having parkinsonism; however, the risk of PD does not appear to be greater in patients with ET (4). For epidemiological surveys, the diagnostic criteria should be simple, consistent through the study interval, and easy to apply. For example, after careful consideration of different diagnostic criteria utilized in epidemiological studies, de Rijk et al. (5) concluded that the most suitable for PD is the presence of two of at least three criteria—bradykinesia, rigidity, and resting tremor. In individuals with preexisting ET, the additional diagnosis of parkinsonism should be made only when all three criteria are present (6). The second major consideration is to classify parkinsonism cases into different variants. Most neurologists use the term PD for Lewy body disease but this diagnosis 19

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cannot be made definitively before death (7,8). Distinction between different parkinsonism variants is difficult, especially during the early stages of disease. Even in a clinical setting where patients are repeatedly evaluated by experts, accurate clinical diagnosis may not be possible as the telltale features that distinguish other variants from PD may evolve late or never (8–10). Classification into possible, probable, and definite PD has limited value in epidemiological studies that are primarily aimed at measuring the magnitude of the disorder in the population. Response to levodopa, though valuable, does not always distinguish between different variants of parkinsonism (12). The classification of parkinsonism has been evolving with time. Following the first description in 1817 by James Parkinson (13) and the discovery of the substantia nigra neuronal loss and Lewy body inclusions, parkinsonism was regarded as a single clinicopathological entity. This concept changed in the 1920s and 1930s after von Economo encephalitis from which an estimated 60% of the patients developed postencephalitic parkinsonism (14). At one time, these patients constituted a large proportion of the parkinsonism cases in the general population, but no new postencephalitic parkinsonism cases have been reported since the mid-1950s. Arteriosclerosis was once reported as a common cause of parkinsonism (15,16), but this diagnosis is now rare (17,18). This change in diagnostic classification reflects changes in autopsy studies and the determination of underlying pathology rather than a dramatic decline in arteriosclerosis in the general population. Neuroleptic induced parkinsonism was first recognized in the late 1950s and is now a common parkinsonism variant ranging between 7% (17) and 20% of all cases (18,19). Drug-induced parkinsonism is now second only to PD and is more common in women than men (18). Large clinicopathological studies of Shy–Drager syndrome (SDS) (20), striatonigral degeneration (SND) (21), and progressive supranuclear palsy (PSP) (22) were first reported in the 1960s. The current classification includes SND, SDS, and olivopontocerebellar atrophy under the common heading of multiple system atrophy (MSA). Prominent dysautonomia in SDS and akinetic rigid parkinsonian features in SND were not fully recognized until 1960 and 1964, respectively, and in all likelihood, such cases prior to that were classified as postencephalitic or atypical parkinsonism, as they occurred at a relatively young age and had widespread nervous system involvement. In spite of the improved understanding of these uncommon parkinsonism variants, the diagnosis is not always possible clinically. Autopsy series may be biased as the families of those suffering from the unusual variants may have heightened interest in finding out the nature of the disease and therefore consent to autopsy. The accurate frequency of these variants in the general population is, therefore, not possible to determine. In one epidemiological study, 2.5% of all parkinsonian patients were classified as MSAand 4.3% as PSP (18). Aprevious study from the same community reported a diagnosis of PSP in 1.4% and MSA in 2.1% of parkinsonian cases (17). Thus MSA and PSP each represent less than 5% of the contemporary parkinsonian cases in North America. The most common parkinsonism in epidemiological studies is idiopathic PD. The proportion of those with PD, however, varies widely in different studies from 42% (18) to 85% (17). Preponderance of PD is also noted in autopsy studies of unselected parkinsonian cases (12,23,24). The clinical and pathological classification of different parkinsonism variants continues to evolve. Classification into different variants is valuable, but it should be recognized that this only provides approximate estimates. Autopsy studies to confirm the diagnosis are not possible in epidemiological surveys; therefore, for

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descriptive epidemiological studies, all parkinsonian variants should be considered. Further classification may then be made based on the best clinical evidence. INCIDENCE OF PARKINSONISM Incidence is defined as the number of new cases per year and is usually described per 100,000 people. Conducting an incidence study requires not only defining cases but also determining which are the new cases. Some new onset cases that ought to be included may not be recognized until sometime later. As well, the number of new cases in a community may vary from one year to the next. Consequently, incidence studies require a long period of observations in the same community using consistent case finding methods and case definitions. The reported incidence rates of PD vary widely. The lowest PD incidence in Western countries was reported from Sardinia at 4.9/105 (25). A systematic review of 25 European studies identified five well-designed, similar studies of PD incidence (26). Four studies reported similar incidence of 16 to 19/105 but one Italian study reported a much lower incidence of 8.4/105, and age-adjusted PD incidence in Taiwan (Republic of China) is 10.4/105 (27). In the Western countries, some of the most reliable incidence studies are those from Rochester Minnesota using the record system of the Mayo Clinic, which combines case ascertainment with diagnosis by neurologists. Four different incidence reports based on the Rochester population have been published (15–18). Since druginduced parkinsonism was not recognized until the early 1960s (28), we excluded drug-induced parkinsonism from each study for the purpose of comparison. The rates for 1945–1954 (15), 1935–1966 (16), 1967–1979 (17), and 1976–1990 (18) were 20.5, 18.5, 18.2, and 20.5/105, respectively. There was no significant change in incidence over 55 years. The latest study (18) revealed overall incidence of parkinsonism of 25.6/105, including drug-induced parkinsonism. Incidence increases with increasing age. The incidence of parkinsonism was 0.8/105 in those aged 0 to 29 years, 25.6/105 in those 50 to 59 years and, more than 11 times higher (304.8/105) in the 80- to 99-year age group (18). There has been no significant change in the age-specific incidence rates during the 55-year interval of these studies (29). Slightly higher overall incidence of parkinsonism in recent reports likely reflects longer life expectancy in the general population, more frequent use of neuroleptics and improved diagnosis (18,29). Pathological studies (30,31) show a progressive increase in the rate of incidental Lewy body inclusions with advancing age. These cases are regarded as having preclinical PD. With every decade of life, there is a doubling of incidental Lewy bodies (31). The decline of parkinsonism and PD specifically, in the very old observed in some studies, is attributed to difficulty in ascertaining cases in the presence of comorbid disorders (18). Age remains the single most important risk factor for parkinsonism. An Italian study noted a 9% increase in risk for every increasing year of age (i.e., a 60-year-old has a 90% greater risk than a 50-year-old), and men had higher risk than women (19). The current lifetime risk of parkinsonism from birth is estimated at 4.4% for men and 3.7% for women (32). LIFE EXPECTANCY IN PARKINSONISM All of the parkinsonism variants limit mobility, and the increased tendency for falls and dysphagia predisposes these patients to life-threatening complications (33,34). Life expectancy prior to the widespread use of levodopa was significantly reduced.

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In one hospital based parkinsonism series during the 1950s and 1960s, the mean survival after onset was 10.8 years (35). Excluding postencephalitic parkinsonism, the mean survival was 9.42 years, which is frequently cited as the yardstick for the prelevodopa era life expectancy (35). Mean survival in the contemporary parkinsonism cases cannot be compared with that study. There have been significant social and health care advances leading to longer life in the general population, and one would expect that parkinsonism patients would share these survival gains. Comparisons for survival should be made matching for year of birth, gender, and region/country. Kurtzke et al. (36) noted that patients in the 1980s were, on an average, five years older at death than those who died in the 1970s—implying that life expectancy since the widespread use of levodopa has increased by five years. Several other studies (37–40) have also reported longer life expectancy, but it is still lower than expected. At the other extreme are studies (41,42) that suggest that current parkinsonism cases survive longer than the general population. It is difficult to reconcile that individuals suffering from a progressively disabling disorder would live longer than the matched general population. The most common error in the better than expected survival studies is measuring survival from the date of onset assigned several years retrospectively. During that period, the general population would have suffered some death. That gives the parkinsonism group an artificial advantage since they survived at least to diagnosis (41). When we assessed our patients using the date of onset, the parkinsonian patients had greater survival than the general population (40). The other reason for this error is inclusion of only the levodopa-treated cases (42). For any number of reasons, some patients may not be treated with levodopa, and those destined for longer survival may be treated with levodopa introducing significant bias. Researchers noted that survival is greater if only the levodopa-treated cases were considered (17). Restricting a study to only clinically diagnosed PD and excluding other variants introduces another source of bias as the inaccuracy of clinical diagnosis is well known (8,9) and survival is shorter in non-PD variants (10,43,44). Ablinded study withholding modern drugs from one group of matched patients is unethical and therefore not possible. In our clinic-based study of 934 parkinsonian cases seen between 1968 and 1990, survival measured from the date of first assessment was significantly reduced (P< 0.0001) (45). As of 1974, patients in this clinic had widespread and easy access to levodopa. Prelevodopa era reduction in survival was even more pronounced. Taken together, these indicate that widespread use of levodopa has improved survival. The timing of treatment with levodopa indicates that survival benefit is achieved only when the patients are treated prior to the loss of postural reflexes—Hoehn and Yahr stage III (35). Others reported similar observations of longer survival in patients with early levodopa treatment (38). It is evident that the survival gap between the current parkinsonian cases and the general population has narrowed. This gain in life expectancy is attributable exclusively to the better symptomatic control with levodopa that reduces disability and life-threatening complications (33,34). We estimate that an average patient with PD onset at age 62 now lives for approximately 20 years. PREVALENCE OF PARKINSONISM The prevalence rate is defined as the number of patients in the population at a given time. This can be difficult to ascertain, as approximately 15% of people in the community self-reporting a PD diagnosis do not actually have PD and 20% of people with PD have not been diagnosed (46). The two main factors that determine the

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prevalence rate are the incidence of new cases and life expectancy. Crude prevalence rates are greatly affected by the age distribution of the source population; ageadjusted rates are one way to permit comparisons between different populations but crude rates are most often reported. Prevalence rates can be estimated by multiplying incidence rate and the mean survival. Most observers regard Rochester, Minnesota, incidence rates as representative for North America. The latest annual incidence of parkinsonism in Rochester is 25.6/105 (18). The survival in parkinsonism has increased substantially during the last three decades. A conservative estimate of mean survival in contemporary parkinsonism is 15 years, though an average PD case would survive longer. Thus, the minimum prevalence rate in the North American general population is estimated at 384/105. Other methods have been used to determine prevalence rates for parkinsonism. A state registry in Nebraska reported a prevalence of 329.3/105 (47). Some studies have used consumption of antiparkinsonian drugs as a surrogate for a diagnosis of parkinsonism (48,49), but these underestimate prevalence since many people with parkinsonism are untreated and the medications can be used for other diagnoses. In the Caucasian population, the crude prevalence ratios vary from 84/105 to 775/105 population (50,51). Prevalence rates based on door-to-door surveys include 57/105 in China (People’s Republic of China) (52), 371.5/105 in Sicily (53), and 775/105 in Australia (51). In a Parsi community from Mumbai, India, the prevalence rate was 328/105 (54). In a U.S. community-based study of Copiah County residents that included only persons over the age of 40 years, the prevalence rate was 347/105 (55). A Dutch study in the early 1990s found a prevalence rate of 1400/105 in those aged 55 to 64 years and 4300/105 in the 85 to 94 years age group (56). In two Canadian studies using representative samples of residents aged 65 years and older, the prevalence rate in community residents was 3% (57) while in institutionalized persons the rate was 9% (58). Somewhat comparable figures were reported from Australia (51). Including only PD cases in persons aged 55 years and older, the prevalence rate of PD was 3600/105 in the community and 4900/105 in institutionalized persons. As discussed previously, incidence has remained relatively constant but life expectancy has increased; one would then expect overall crude prevalence rates to have increased over time. GENDER AND PARKINSONISM The available evidence indicates that men have a slightly higher risk of parkinsonism than women, with the exception of drug-induced parkinsonism (59,60). According to a meta-analysis, relative risk of parkinsonism for men compared to women is 1.5% (61). Suggested reasons for this risk included differential exposure to external risk factors, an X-linked genetic factor, and mitochondrial dysfunction. The lifetime risk of parkinsonism is greater in men than in women (4.4% vs. 3.7%) (32). In older patients, 65 to 84 years, the male to female incidence ratio was 1.66 for parkinsonism and 2.13 for PD (19). Interestingly, although women have a longer life expectancy than men, women with PD have the same mortality rates as men with PD (60). GEOGRAPHY, ETHNICITY, RACE, AND PARKINSONISM Parkinsonism has been reported in all countries and in all races. In most countries, geography, ethnicity, and race are intertwined. Comparing immigrants to residents of their homeland is one way to evaluate the associations with the risk of parkinsonism.

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The only reported large geographic cluster of well-documented parkinsonism is the Parkinson-dementia-amyotrophic lateral sclerosis (ALS) complex of Guam, and this may be related to consumption of Cycad sp. seeds (62). Although several studies have suggested that those with darker skin have a reduced risk of PD compared to lighter skin individuals (25,63), a review of 20 studies of PD in African-Americans found no consistent evidence to support this theory (64). The authors believed that ascertainment bias compromised the studies they reviewed. Studies that included communities with a mixed population did not observe any racial differences (55,65). Two studies conducted by the same investigator using similar methodology showed that the prevalence rate in AfricanAmericans was five times higher than in the Nigerians who presumably share a common genetic background (55,66). This difference remained significant when the life expectancy in the general population in the two countries was taken into account. There is no evidence that darker-skinned persons have larger numbers of substantia nigra-pigmented neurons nor is the vulnerability of these neurons different in different races. In one dopa-responsive dystonia autopsied case, we discovered markedly hypopigmented substantia nigra, but the skin color and tendency to tan were similar to her other siblings (67). Thus, skin color by itself does not appear to be related to the risk of parkinsonism or PD. A rural population in Taiwan (Republic of China) had prevalence rates similar to Western studies but greater than that in mainland China (People’s Republic of China), which is an evidence of environment playing a greater role than race (27). Chinese, Malays, and East Indians in Singapore had equal PD prevalence of approximately 300/105 (68). A California study (69) did find differences in incidence rates associated with race with Hispanics having the highest rate followed by non-Hispanic whites, Asians, and blacks. Incidence and prevalence rates do vary between and within countries. The lowest reported PD prevalence rate is 57/105 population in China (People’s Republic of China) (52), followed by 65.6/105 in Sardinia (25), 67/105 in Nigeria (66), 80.6/105 in Japan (70), and the highest reported rate of 775/105 in Australia (51). Geographic differences between different Western Canadian provinces have been reported (71), and a north–south gradient in the United States has been suggested in one study (72), but not confirmed by others (73). Difference in incidence of parkinsonism based on the population density in Saskatchewan revealed that those born and raised in smaller communities (with population 200 or less) had an increased risk of early onset parkinsonism (74). Several other North American and European reports (75–78) noted higher risk of PD with rural residence during early age, but others (79,80) failed to substantiate this finding. One Canadian study (81) noted no increase in the risk of PD in those who had previously lived in the rural areas or had worked on the farm. In summary, geographic differences for PD risk are attributable to shared geography, which points to a shared environmental exposure and are not linked to skin color or ethnic background.

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56. Schoenberg BS, Anderson DW, Haerer AF. Prevalence of Parkinson’s disease in the biracial population of Copiah County, Mississippi. Neurology 1985; 35(6):841–845. 57. Moghal S, Rajput AH, D’Arcy C, Rajput R. Prevalence of movement disorders in elderly community residents. Neuroepidemiology 1994; 13:175–178. 58. Moghal S, Rajput AH, Meleth R, D’Arcy C, Rajput R. Prevalence of movement disorders in institutionalized elderly. Neuroepidemiology 1995; 14:297–300. 59. Vanacore N, Bonifati V, Bellatreccia A, Edito F, Meco G. Mortality rates for Parkinson’s disease and Parkinsonism in Italy (l969–l987). Neuroepidemiology 1992; 11:65–73. 60. Diamond SG, Markham CH, Hoehn MM, McDowell FH, Muenter MD. An examination of male–female differences in progression and mortality of Parkinson’s disease. Neurology 1990; 40:763–766. 61. Wooten GF, Currie LJ, Bovbjerg VE, Lee JK, Patrie J. Are men at greater risk for Parkinson’s disease than women? J Neurol Neurosurg Psychiatry 2004; 75:637–739. 62. Spencer PS, Palmer VS, Ludolph AC. On the decline and etiology of high-incidence motor system disease in West Papua (Southwest New Guinea). Mov Disord 2005; 20(suppl 12):S199–S126. 63. Lerner MR, Goldman RS. Skin colour, MPTP, and Parkinson’s disease. Lancet 1987; 2:212. 64. McInerney-Leo A, Gwinn-Hardy K, Nussbaum RL. Prevalence of Parkinson’s disease in populations of African ancestry: a review. J Natl Med Assoc 2004; 96(7):974–979. 65. Mayeux R, Marder K, Cote LJ, et al. The frequency of idiopathic Parkinson’s disease by age, ethnic group, and sex in Northern Manhattan, 1988–1993. Am J Epidemiol 1995; 142:820–827. 66. Schoenberg BS, Osuntokun BO, Adejua AOG, et al. Comparison of the prevalence of Parkinson’s disease in black populations in the rural United States and in rural Nigeria: door-to-door community studies. Neurology 1988; 38:645–646. 67. Rajput AH, Gibb WRG, Zhong XH, et al. Dopa-responsive dystonia: pathological and biochemical observations in a case. Ann Neurol 1994; 35:396–402. 68. Tan LC, Venketasubramanian N, Hong CY, et al. Prevalence of Parkinson disease in Singapore: Chinese vs Malays vs Indians. Neurology 2004; 62(11):1999–2004. 69. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 2003; 157:1015–1022. 70. Harada H, Nishikawa S, Takahashi K. Epidemiology of Parkinson’s disease in a Japanese city. Arch Neurol 1983; 40:151–154. 71. Svenson LW. Regional disparities in the annual prevalence rates of Parkinson’s disease in Canada. Neuroepidemiology 1991; 10:205–210. 72. Lux WE, Kurtzke JF. Is Parkinson’s disease acquired? Evidence from a geographic comparison with multiple sclerosis. Neurology 1987; 37:467–471. 73. Lilienfeld DE, Sekkor D, Simpson S, et al. Parkinsonism death rates by race, sex and geography: a 1980’s update. Neuroepidemiology 1990; 9:243–247. 74. Rajput AH, Uitti RJ, Stern W, Laverty W. Early onset Parkinson’s disease in Saskatchewan. Can J Neurol Sci 1986; 13:312–316. 75. Hertzman C, Wiens M, Bowering D, Snow B, Calne D. Parkinson’s disease: a case-control study of occupational and environmental risk factors. Amer J Industrial Med 1990; 17: 349–355. 76. Koller W, Vetere-Overfield B, Gray C, et al. Environmental risk factors in Parkinson’s disease. Neurology 1990; 40:1218–1221. 77. Tanner CM, Chen B, Wang W, et al. Environmental factors in the etiology of Parkinson’s disease. Can J Neurol Sci 1987; 14:419–423. 78. Hubble JP, Cao T, Hassanein RES, Neuberger JS, Koller WC. Risk factors for Parkinson’s disease. Neurology 1993; 43:1693–1697. 79. Seidler A, Hellenbrand W, Robra B-P, Vieregge P. Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: a case-control study in Germany. Neurology 1996; 46:1275–1284. 80. Tanner CM, Chen B, Wang W, Peng M. Environmental factors and Parkinson’s disease: a case-control study in China. Neurology 1989; 39(5):660–664. 81. Semchuk KM, Love EJ, Lee RG. Parkinson’s disease and exposure to agricultural work and pesticide chemicals. Neurology 1992; 42:13281335.

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Differential Diagnosis John Morgan and Kapil D. Sethi Department of Neurology, Medical College of Georgia, Augusta, Georgia, U.S.A.

Parkinsonism refers to a clinical syndrome characterized by a variable combination of rest tremor, bradykinesia or akinesia, cogwheel rigidity, and postural instability. In general, two of these four features must be present to make a diagnosis of parkinsonism. However, the situation is complicated by rare cases of pure akinesia in the absence of tremor and rigidity that have the classic pathology of Parkinson’s disease (PD) (1). Within the rubric of parkinsonism there are a myriad of disorders, some yet unclassified (Table 1). The most common cause of parkinsonism is PD. Pathologically, PD is characterized by cell loss in the substantia nigra and other pigmented nuclei of the brainstem. Characteristic inclusions called Lewy bodies are found in the remaining neurons and the term “Lewy body parkinsonism” is sometimes used synonymously with PD. Some researchers consider it most appropriate to refer to even the clinical picture of PD as “Parkinson’s syndrome” on the premise that PD may not be one disease. Whereas the purists demand the presence of Lewy bodies at autopsy to diagnose PD, these inclusions may not be present in some inherited forms of otherwise classic PD. Currently, one such condition, parkin, has been mapped to chromosome 6 (2). This autosomal recessive parkinsonism of young onset differs pathologically from sporadic disease as Lewy bodies are usually absent. The clinical picture can be similar to idiopathic PD including the presence of tremor (3). There are other forms of inherited parkinsonism including LRRK2 mutation, where typical Lewy body pathology is found (4,5). In the absence of a known biological marker, the challenge facing the clinician is to make an accurate diagnosis of PD and differentiate it from other similar conditions. This review will give a practical approach to the differential diagnosis of parkinsonism and examine the diagnostic accuracy of a clinical diagnosis of PD.

IDIOPATHIC PARKINSON’S DISEASE The onset of PD is gradual and the course slowly progressive albeit at different rates in different individuals. In most series, 65% to 70% of the patients present with an asymmetric tremor especially of the upper extremity (6). After a variable delay, the disorder progresses to the other side with bilateral bradykinesia and gait difficulty that takes the form of festination and, in advanced cases, freezing. Postural instability and falls tend to be a late feature. Eye movements may show saccadic pursuit and upgaze may be limited in the elderly. Downgaze is normal. Autonomic disturbances may occur but are not severe in early disease. Depression may occur early in the disease but dementia, as a presenting manifestation, is not a feature of PD. Several signs should ring alarm bells when considering a diagnosis of PD. These include early dementia, early autonomic dysfunction, gaze difficulty (especially looking down), signs of upper motor neuron lesion or cerebellar signs in addition to parkinsonism, stepwise deterioration, and apraxia (Table 2). 29

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TABLE 1 Classification of Parkinsonism Primary Parkinson’s disease Sporadic Familial Secondary parkinsonism Drug-induced parkinsonism (DIP) Toxin-induced parkinsonism Infectious Creutzfeld-Jakob disease (CJD) Metabolic Structural Tumor Subdural hematoma Vascular

Other Degenerative Disorders Corticobasal degeneration (CBD) Dementia with Lewy bodies (DLB) Multiple-system atrophy (MSA) Progressive supranuclear palsy (PSP) Spinocerebellar ataxias (SCA) Hallervorden-Spatz disease Huntington’s disease (HD) Neuroacanthocytosis Wilson’s disease X-linked dystonia-parkinsonism (Lubag)

Conditions Mimicking Parkinsonism Essential tremor (ET) is more common than PD and results in tremor that affects primarily the upper extremities, head, and voice (7). The tremor is absent at rest, except in most severe cases, and is increased by maintained posture and voluntary movement. Mild cogwheeling may be present but bradykinesia is not a feature (Table 3). The confusion occurs when a patient with a long history of ET begins to develop signs of parkinsonism. Patients with PD may have a prominent action tremor adding to the diagnostic uncertainty. In addition, there are elderly patients with ET who exhibit mild bradykinesia on detailed testing (8). It is debatable if patients with ET

TABLE 2 Features Indicating an Alternate Diagnosis to Parkinson’s Disease Early or predominant feature Young onset Minimal or absent tremor Atypical tremor Postural instability Ataxia Pyramidal signs Amyotrophy Symmetric onset Myoclonus Dementia Apraxia, cortical sensory loss Alien limb sign Gaze palsies Dysautonomia Hallucinations (nondrug related) Acute onset Stepwise deterioration

Disease Drug or toxin-induced parkinsonism, Wilson’s disease, Hallervorden-Spatz disease PSP, vascular parkinsonism CBD, MSA PSP, MSA MSA MSA, vascular parkinsonism MSA, parkinsonism dementia of Guam PSP, SND CBD, CJD, MSA DLB CBD CBD PSP, OPCA, CBD, DLB, PSG MSA DLB Vascular parkinsonism, toxin-induced, psychogenic Vascular parkinsonism

Abbreviations: CBD, cortiobasal degeneration; CJD, Creutzfeld–Jakob disease; DLB, dementia with Lewy bodies; MSA, multiple system atrophy; OPCA, olivopontocerebellar atrophy; PSG, progressive subcortical gliosis; PSP, progressive supranuclear palsy; SND, striatonigral degeneration.

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Differential Diagnosis TABLE 3 Differentiating Essential Tremor from Parkinson’s Disease

Body parts Rest tremor Postural tremor Kinetic tremor Frequency Bradykinesia Rigidity Family history Response to beta blockers Response to levodopa Postural instability

Essential tremor

Parkinson’s disease

Arms > Head > Voice > Legs

Arms > Jaw > Legs

− +++ +++ 7–12 Hz − ± ++ + − −

+++ + ± 4–6 Hz ++ ++ ± − ++ +

are at an increased risk to develop PD (9). Psychomotor slowing in a severely depressed individual may resemble PD but there is no tremor and patients improve with antidepressant therapy. OTHER CAUSES OF PARKINSONISM Drug-Induced Parkinsonism Drug-induced parkinsonism is a common complication of antipsychotic drug use with a reported prevalence of 15% to 60% (10). In one study, 51% of 95 patients referred for evaluation to a geriatric medicine service had neuroleptic-induced parkinsonism (11). Frequently, these patients are misdiagnosed as PD and treated with dopaminergic drugs without any benefit. In a community study, 18% of all cases initially thought to be PD were subsequently diagnosed as drug-induced parkinsonism (12). The symptoms of drug-induced parkinsonism may be indistinguishable from PD. Drug-induced parkinsonism is often described as symmetrical whereas PD is often asymmetrical. However, one series found asymmetry of signs and symptoms in 30% of drug-induced patients (13). Patients with drug-induced parkinsonism are as varied in their clinical manifestations as patients with PD. Some patients have predominant bradykinesia, whereas others are tremor predominant. Postural reflexes may be impaired, festination is uncommon, and freezing is rare (13,14). When the patient is on a dopamine-blocking agent, it is difficult to distinguish underlying PD from drug-induced parkinsonism. If possible, the typical dopamineblocking agents should be stopped or substituted with atypical antipsychotics and the symptoms and signs of parkinsonism should resolve within a few weeks to a few months, but it could take up to six months or more for signs and symptoms to resolve completely (15). Cerebrospinal fluid (CSF) dopamine metabolites have been studied in drug-induced parkinsonism. These may be low in untreated PD but are relatively normal or increased in drug-induced parkinsonism. However, the Deprenyl and Tocopherol Antioxidative Therapy of Parkinson’s Disease (DATATOP) cohort CSF study showed that there is a significant overlap between PD and normals, making this test of doubtful clinical value (16). One study utilizing 6-flurodopa positron emission tomography (PET) scanning showed that a normal PET scan predicted good recovery from drug-induced parkinsonism upon cessation of the dopamine-blocking

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Morgan and Sethi TABLE 4 Drugs Known to Cause Parkinsonism Generic Name

Trademark

Chlorpromazine Thiordazine Mesoridazine Chlorprothixine Triflupromazine hydrochloride Carphenazine maleate Acetophenazine maleate Prochlorperazine Piperacetazine Butaperazine maleate Perphenazine Molindone hydrochloride Thiothixene Trifluoperazine hydrochloride Haloperidol Fluphenazine hydrochloride Amoxapine Loxapine Metoclopramide Promazine Promethazine Thiethylperazine Trimeprazine Risperidone Olanzapine Ziprasidone Combination drugs

Thorazine Mellaril Serentil Taractan Vesprin Proketazine Tindal Compazine Quide Repoise maleate Tilafon Moban Navane Stelazine Haldol Prolixin, 5 mg Asendin Loxitane, Daxolin Reglan Sparine Phenergan Torecan Temaril Risperdala Zyprexaa Zeodona Etrafon, Triavil

a

In high dosages.

agent and an abnormal PET scan was associated with persistence of signs in some but not in all patients (17). Drug-induced parkinsonism should be considered and inquiry should be made about intake of antipsychotic drugs and other dopamine-blocking agents like metoclopramide (Table 4). Once drug-induced parkinsonism has been considered and ruled out, the most common conditions confused with PD include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and frontotemporal dementia (FTD) with parkinsonism. Together these entities are referred to as atypical forms of parkinsonism. Progressive Supranuclear Palsy PSP also known as Steele Richardson Olszewski syndrome is easy to diagnose in advanced stages (18). However, diagnostic confusion may occur early in the disease and in cases that have atypical features. Typically, the disorder presents with a gait disturbance with resultant falls in over half the cases (19). Measurable bradykinesia in the upper extremity may not be present at the initial presentation. The clinical features of PSP consist of supranuclear gaze palsy, especially involving the downgaze with nuchal extension and predominant truncal extensor rigidity. Varying degrees of bradykinesia, dysphagia, personality changes, and other behavioral disturbances

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coexist. Patients often exhibit a motor recklessness and get up abruptly out of a chair (Rocket sign) even if this results in a fall. Another sign is the “applause sign” where the patient is unable to stop clapping after given directions to clap the hands three times (20). Extraocular movement (EOM) abnormalities are very characteristic but may not be present at the onset of the illness or for several years (21). These abnormalities consist of square wave jerks, instability of fixation, slow or hypometric saccades, and predominantly a downgaze abnormality (22,23). Asking the patient to generate a saccade in the direction opposite to a stimulus (antisaccade test) is frequently abnormal in PSP (23). The oculocephalic responses are present in early disease, but may be lost with advancing disease suggesting a nuclear element to the gaze palsy. Bell’s phenomenon may be lost in advanced cases. Some patients with PSP have a limb dystonia that can be asymmetric, which can cause confusion with CBD (24). Rest tremor is rare but has been reported in pathologically confirmed PSP (25). Radiologically, PSP differs from PD in that in advanced cases there is atrophy of the midbrain tectum and tegmentum with resultant diminution of the anteroposterior (AP) diameter of the midbrain (26,27). There may be dilatation of the third ventricle and sometimes a signal alteration may be seen in the tegmentum of the midbrain (28). PET scanning utilizing 6-flurodopa may distinguish PSP from PD in that the uptake is diminished equally in both the caudate and putamen in PSP, whereas in PD the abnormalities are largely confined to the putamen (29). PET scans using raclopride binding show that the T2 receptor sites are diminished in PSP, whereas in PD, these are normal (30). Clinically, CBD, DLB, MSA, progressive subcortical gliosis (PSG), and even prion diseases have been misdiagnosed as PSP because of the presence of supranuclear gaze palsies (31–34). PSP also needs to be distinguished from other causes of supranuclear gaze palsy, including cerebral Whipple’s disease, adult onset Niemann–Pick type C, and multiple cerebral infarcts (35–37). The presence of prominent early cerebellar symptoms or early, unexplained dysautonomia would favor MSA over PSP (38), and the presence of alien limb syndrome, cortical sensory deficits, and focal cortical atrophy on magnetic resonance imaging (MRI) would favor CBD (39). The clinical diagnostic criteria proposed by Litvan et al. (40,41) may be helpful. Multiple System Atrophy MSA, originally coined by Graham and Oppenheimer (42), refers to a variable combination of parkinsonism, autonomic, pyramidal, or cerebellar symptoms and signs. MSA can be subdivided into three types: striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and Shy–Drager syndrome (SDS) (43). All subtypes of MSA may have parkinsonian features. It is especially difficult to differentiate SND and PD. SND was originally described by Van Eecken et al. (44). The parkinsonian features of MSA consist of progressive bradykinesia, rigidity, and postural instability (43). However, in a clinicopathological report, one of four patients had a rest tremor characteristic of PD (45). Although symptoms are usually bilateral, unilateral presentations have been described (46). The autonomic failure is more severe than that seen in idiopathic PD and occurs early in MSA. Other useful clinical clues for the diagnosis of MSA include disproportionate anterocollis and the presence of cold blue hands. The response to levodopa is usually incomplete in MSA (47). However, patients with MSA may initially respond to levodopa, but the benefit usually declines within one or two years of treatment (48). Levodopa induced dyskinesia may occur in MSA.

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Dyskinesia typically involves the face and neck but may also involve the extremities (49). Therefore, the presence of levodopa-induced dyskinesia cannot be used to make a definite diagnosis of PD. The situation is further complicated by the fact that PD patients may develop autonomic dysfunction, including postural hypotension, urinary problems, constipation, impotence, and sweating disturbances. The autonomic dysfunction in PD may be worsened by dopaminergic therapy. Autonomic dysfunction tends to be severe in MSA and occurs early (50). Stridor can also occur early in MSA but not in PD (51). Urinary symptoms are very common in MSA. On urodynamic testing, there is a combination of detrusor hyperreflexia and urethral sphincter weakness (52). In addition, neurogenic anal and urethral sphincter abnormalities are very common in MSA (53). However, this finding is not diagnostic and may occur in other conditions like PSP (54). Neuroimaging may show nonspecific abnormalities like diffuse hypointensity involving the putamen, but more specific findings include a strip of lateral putaminal hyperintensity or pontine atrophy with an abnormal cross sign in the pons (55). Cardiac autonomic innervation may be tested using 123I metaiodobenzylguanidine (MIBG) scintigraphy. There is growing evidence that the MIBG scintigraphy is abnormal in PD and DLB due to postsynaptic sympathetic denervation (56). In contrast, in MSA, the uptake in the heart is normal due to the presynaptic nature of the pathology. There is some overlap between normal individuals and patients with parkinsonism, which decreases the sensitivity and specificity of this technique. Dementia with Lewy Bodies In DLB, Lewy bodies are found in the neocortex as well as brainstem and diencephalic neurons (57). Some of these patients may have associated neurofibrillary tangles. The parkinsonian syndrome of DLB may be indistinguishable from PD. However, these patients have early onset dementia and may have hallucinations, delusions, and even psychosis in the absence of dopaminergic therapy (58,59). Another characteristic feature is wide fluctuations in cognitive status. It may be difficult to distinguish PD dementia (PDD) from DLB. As a rule, if the dementia precedes or appears within one year of motor symptoms, the diagnosis of DLB is made (57). Rarely, patients with DLB may develop supranuclear gaze palsy, resulting in confusion with PSP (31,32). Some patients respond partially and temporarily to dopaminergic therapy; however, occasionally the response to levodopa is robust. Corticobasal Degeneration Rebeiz et al. (60) initially described this disorder as corticodentatonigral degeneration with neuronal achromasia. CBD typically presents in the sixth or seventh decade with slowly progressive unilateral, tremulous, apraxic, and rigid upper limb (61). The disorder tends to be gradually progressive with progressive gait disturbances, cortical sensory loss, and stimulus sensitive myoclonus, resulting in a “jerky useless hand” (62–64). Jerky useless lower extremity is uncommon but may occur. Rarely, these patients may develop Babinski signs and supranuclear gaze palsy. When typical, the clinical picture is distinct and easily recognizable. However, atypical cases may be confused with PSP and the myoclonic jerking may be confused with the rest tremor of PD. The gait disturbance typically consists of slightly wide based apraxic gait rather than the typical festinating gait of PD. Fixed limb dystonia

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Differential Diagnosis TABLE 5 Differential Diagnosis of Parkinson’s Disease

Symmetry of deficit Axial rigidity Limb dystonia Postural instability Vertical gaze palsy Dysautonomia L-dopa response Asymmetric cortical atrophy Hallucinations

PD

PSP

MSA

CBD

DLB

+ + + ++ + + +++

+++ +++ + +++ +++ − −

+++ ++ + ++ + ++ +

− + +++ + ++ − −

+ + + ++ + + ++

− +

− −

− −

++ −

− ++

Abbreviations: CBD, corticobasal degeneration; DLB, dementia with Lewy bodies; MSA, multiple system atrophy; PD, Parkinson’s disease; PSP, progressive supranuclear palsy.

may be prominent and strongly suggests CBD, however, some patients with PSP may also have asymmetric limb dystonia (24). Patients with CBD do not benefit from levodopa and the course is relentlessly progressive. Rare cases of a parietal form of Pick’s disease may be confused with CBD (65). The clinical spectrum of CBD has recently been expanded to include early onset dementia and aphasia (66); however, in general, these patients have a conspicuous absence of cognitive deficits. MRI in CBD shows focal atrophy, especially in the parietal areas (67), and PET scans show asymmetric decrease of regional cerebral metabolic rates for glucose utilization (68). Tables 5 and 6 summarize some of the differential diagnostic features. Frontotemporal Dementia with Parkinsonism FTD is characterized by profound behavioral changes and an alteration in personality and social conduct with relative preservation of memory (69–70). Extrapyramidal symptoms are common, and parkinsonism occurs in 40% of patients (71). Akinesia, rigidity, and a shuffling gait are the most common with typical tremor being rare (72). The PET scan reveals an equal decrease in the beta CFT uptake in the caudate and the putamen, as opposed to PD where putamen is preferentially involved (72). This disorder is generally easy to distinguish from PD, but may be confused with DLB and other disorders causing dementia and parkinsonism.

TABLE 6 Magnetic Resonance Imaging Features of Some Cases of Parkinsonism

Cortical atrophy Putaminal atrophy Pontine atrophy Midbrain atrophy Cerebellar atrophy High putaminal iron

PSP

PD

MSA (OPCA)

MSA (SND)

CBD

+ − + ++ − −

+ − − − − −

± − +++ + ++ +

+ ++ − − − +

++ − − − − −

Abbreviations: CBD, corticobasal degeneration; DLB, dementia with Lewy bodies; MSA, multiple system atrophy; OPCA, olivopontocerebellar atrophy; PD, Parkinson’s disease; PSP, progressive supranuclear palsy; SND, striatonigral degeneration.

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Toxin-Induced Parkinsonism In general, these disorders are uncommon and may pose less of a differential diagnostic problem. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism is distinct from the dopamine-blocking agent induced parkinsonism in that it is irreversible and is due to the destruction of the substantia nigra neurons (73). The clinical features have some similarities to PD except that the onset is abrupt and the affected individuals are younger than typical PD (74,75). These patients respond to levodopa with early levodopa-induced fluctuations (76). The patients may worsen gradually even in the absence of continued exposure to the toxin (77). In manganese poisoning, patients may superficially resemble PD, their symptoms including soft speech, clumsiness, and impaired dexterity; however, they have a peculiar cockwalk gait in which they swagger on their toes (78,79). The typical rest tremor is absent. They may also have limb and truncal dystonia that is very unusual in untreated PD. Dementia and psychosis may occur, and these patients do not respond well to dopaminergic drugs. Manganese is a component of welding rods, and welders have been said to develop typical PD at an earlier age of onset as compared to controls (80). However, many studies fail to show a relationship between welding and PD (81). Parkinsonism as a result of carbon monoxide intoxication has been well described (82). The parkinsonism may be delayed after the acute episode. These patients often show a slow shuffling gait, loss of arm swing, retropulsion, bradykinesia, rigidity and, occasionally, a rest tremor. The pull test tends to be markedly abnormal. A CT scan or MRI may show necrotic lesions of the globus pallidus (83,84). There may also be associated white matter lesions that may progress without further exposure to carbon monoxide (85). Other toxins that have been reported to cause parkinsonism include carbon disulfide (86), cyanide (87,88), and methanol (89,90). These patients often have an acute onset and, in some cases, show basal ganglia lesions on neuroimaging. Post-hypoxic parkinsonism has an acute evolution following a bout of severe prolonged hypoxia. Variable degrees of intellectual deterioration often accompany post-hypoxic parkinsonism, and the patients usually do not have rest tremor. Post-Traumatic Parkinsonism Isolated head trauma is rarely a cause of parkinsonism (91). Parkinsonism may be seen in the setting of diffuse severe cerebral damage after severe brain injury (92). However, repeated minor trauma to the head as in boxers (dementia pugilistica) may be complicated by the late onset of dementia, parkinsonism, and other clinical features (93,94). Boxers are not immune to developing typical PD; however, the onset of parkinsonism and dementia in a boxer would be suggestive of dementia pugulistica. Imaging studies may show a cavum septum pellucidum and cerebral atrophy. A PET study using 6-fluorodopa showed damage to the caudate and the putamen in post-traumatic parkinsonism, whereas in PD the putamen is more severely involved. Multi-Infarct Parkinsonism Arteriosclerotic or multi-infarct parkinsonism is a debatable entity (95). However, patients who have predominant gait disturbance with slightly wide-based gait with some features of gait apraxia and frequent freezing are seen (96). These patients are labeled lower-half parkinsonism, and they usually lack the typical rest tremor or other signs in the upper extremities (97). The gait disorder may not be distinct from

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senile gait, and a similar gait disorder may also be seen in patients with Binswanger’s disease (98,99). Levodopa responsiveness is uncommon but has been demonstrated occasionally in patients with pathologically confirmed multi-infarct parkinsonism. The proposed criteria for the diagnosis of vascular parkinsonism include acute or subacute onset with a stepwise evolution of akinesia and rigidity along with vascular risk factors (100). This should be supplemented by at least two or more infarcts in the basal ganglia on neuroimaging. In some cases, there may be more widespread MRI white matter abnormalities. Spontaneous improvement in symptoms and signs without dopaminergic therapy is suggestive of vascular parkinsonism. Some patients with multiple cerebral infarction have a clinical picture characterized by gaze palsies, akinesia, and balance difficulties consistent with PSP. In fact, one study found that 19 out of 58 patients with a clinical diagnosis of PSP had radiographic evidence of multiple small infarcts in the deep white matter and the brainstem (35). Parkinsonism with Hydrocephalus Varying degrees of hypomimia, bradykinesia, and rigidity in the absence of tremor may occur in high pressure as well as in normal pressure hydrocephalus (NPH) (101). High-pressure hydrocephalus rarely poses any diagnostic difficulties because of the relatively acute onset in the presence of signs of raised intracranial pressure. However, NPH may be more difficult to distinguish from PD. The classic triad of NPH includes a subacute onset of dementia, gait difficulty, and urinary incontinence (102). The gait is slightly wide-based, with features of gait apraxia or slight ataxia. Rarely, levodopa responsiveness has been demonstrated (103). In some patients, the gait might improve for a few hours to days by the removal of CSF (104). Parkinsonism Due to Structural Lesions of the Brain Blocq and Marinesco were the first to report a clinicopathological correlation of midbrain tuberculoma, involving the nigra and contralateral parkinsonism (105,106). In most cases, the responsible lesions have been tumors, chiefly gliomas and meningiomas. Interestingly, these are uncommon in the striatum and have usually involved the frontal or parietal lobes. Subdural hematoma may present with subacute onset of parkinsonism with some pyramidal signs (107). Other rare causes of parkinsonism and structural lesions have included striatal abscesses (108) and vascular malformations. However, the structural lesions are easily confirmed by neuroimaging. Occasionally, parkinsonism has been reported in patients with basal ganglia calcifications that usually occur in the setting of primary hypoparathyroidism. The calcification should be obvious on neuroimaging (109). Infectious and Postinfectious Causes of Parkinsonism The classic postencephalitic parkinsonism is not seen currently. It was characterized by a combination of parkinsonism and other movement disorders. Particularly, characteristics were “oculogyric crises”, which resulted in forceful and painful ocular deviation lasting minutes to hours. Other causes of oculogyric crises are Tourette’s syndrome, neuroleptic-induced acute dystonia, paroxysmal attacks in multiple sclerosis, and possibly conversion reaction. The parkinsonism may improve with levodopa but response deteriorates quickly. Parkinsonism rarely occurs as a sequelae of

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other sporadic encephalitides. Human immunodeficiency virus dementia has also been reported with parkinsonian features. Other infectious causes include striatal abscesses and neurosyphilis. Psychogenic Parkinsonism As compared to other psychogenic movement disorders such as tremor, psychogenic parkinsonism is uncommon (110). A tremor of varying rates with marked distractibility along with inconsistent slowness and the presence of feigned weakness and numbness might lead to the correct diagnosis. PARKINSONISM IN YOUNG ADULTS The onset of parkinsonism under the age of 40 is usually called young onset parkinsonism. When symptoms begin under the age of 20, the term “juvenile parkinsonism” is sometimes used (111). Under the age of 20, parkinsonism typically occurs as a component of a more widespread degenerative disorder. However, parkin mutations have been described in some young patients (2). Dopa Responsive Dystonia There is a significant overlap in young patients with dystonia and parkinsonism. Patients with young onset parkinsonism manifest dystonia that may be responsive to dopaminergic drugs (112). However, the response may deteriorate upon long-term followup. Patients with hereditary dopa responsive dystonia have an excellent and sustained response to low doses of levodopa (113). In addition, PET scans show markedly reduced 6-fluorodopa uptake in patients with young onset PD, whereas the fluorodopa uptake is normal in patients with dopa responsive dystonia (114). Patients with dopa responsive dystonia have a guanosine triphosphate-cyclohydrolase deficiency that is not a feature of PD in young adults. Wilson’s Disease Wilson’s disease usually presents primarily with neuropsychiatric impairment. It should be considered in every case of young onset parkinsonism, because it is eminently treatable and the consequences of nonrecognition can be grievous. The most common neurological manifestations are tremor, dystonia, rigidity, dysarthria, drooling, and ataxia. A combination of parkinsonism and ataxia is particularly indicative of neurological Wilson’s disease (115). Parkinsonism is the most prevalent motor dysfunction, whereas about 25% of patients present with disabling cerebellar ataxia, tremor, or dysarthria (116). Typically, the tremor involves the upper limbs and the head and rarely the lower limbs. It can be present at rest with postural maintenance and may persist with voluntary movements. The classic tremor is coarse and irregular and present during action. Holding the arms forward and flexed horizontally can emphasize that the proximal muscles are active (wing-beating tremor). Less commonly, tremor may affect just the tongue and the orofacial area (117). Dystonia is also quite common in Wilson’s disease. The characteristic feature is an empty smile due to facial dystonia. Dysarthria is very common and may take the form of a dystonic or scanning dysarthria. Approximately 30% of patients present with behavioral and mental status changes (118). The psychiatric disorder may take the form of paranoid symptoms, sometimes accompanied by delusional thinking and hallucinations.

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Early presentation may be a decline in memory and school performance. Patients may develop anxiety, moodiness, disinhibited behavior, and loss of insight. A characteristic feature is inappropriate laughter. Although eye movements are typically normal, some cases of Wilson’s disease may show a saccadic pursuit, gaze distractibility, or difficulty in fixation (119). Kayser–Fleischer rings (KF rings) due to copper deposition in the cornea may be easy to recognize in patients with a light colored iris; however, in patients with brown irides, these rings may be very difficult to see. Usually, the ring is goldenbrown in color and involves the whole circumference of the cornea. However, in the early stages, the ring may be more apparent in the upper than the lower pole. Rarely, these rings can be unilateral. KF rings are best appreciated by a slit-lamp examination done by a neurophthalmologist. Typically, the absence of KF rings on the slit-lamp examination rules out neurological Wilson’s disease. However, there are reports of patients with typical neurological Wilson’s disease without any KF rings (120,121). Radiologically, advanced cases of Wilson’s disease may have cavitation of the putamen (122). However, putaminal lesions are not specific to Wilson’s disease. Other causes of putaminal cavitation or lesions include hypoxic ischemic damage, methanol poisoning, mitochondrial encephalomyopathy, and wasp-sting encephalopathy. Nearly half the patients of established neurological Wilson’s disease have hypodensities of the putamina on CT scans in contrast to patients with hepatic disease who frequently have normal CT scans (123). MRI is more sensitive, and almost all patients with neurological features have some disturbance on T2-weighted images in the basal ganglia with a pattern of symmetric, bilateral, concentric-laminar T2 hyperintensity and the involvement of the pars compacta of the substantia nigra, periaqueductal gray matter, pontine tegmentum, and thalamus (124). The hepatic component of Wilson’s disease may cause increased T1 signal intensity in the globus pallidus (125). In the adult age group, the basal ganglia lesions may be different from those in the pediatric group. Putaminal lesions may not be present, and the globus pallidus and substantia nigra may show increased hypointensity on T2-weighted images. Cortical and subcortical lesions may also be present with a predilection to the frontal lobe. However, rare cases of neurological Wilson’s disease may have a normal MRI (126). PET scans of Wilson’s disease may show a reduction of 6-fluorodopa uptake (127). The most useful diagnostic test is serum ceruloplasmin, and a 24-hour urinary copper excretion supplemented by a slit-lamp examination for KF rings. Unfortunately, not all patients with Wilson’s disease have a low ceruloplasmin level (128). Measurement of liver copper concentration makes a definitive diagnosis. In heterozygotes, it is between 50 and 100 µg/g of tissue, and in patients with Wilson’s disease, it may be over 200 µg/g (129). Pantothenate Kinase-Associated Neurodegeneration (Hallervorden–Spatz Disease) Previously known as Hallervorden–Spatz Disease (HSD), pantothenate kinaseassociated neurodegeneration is usually a disease of children but young adults may be affected. Typically, the disease occurs before the age of 20. Facial dystonia tends to be prominent, coupled with gait difficulty and postural instability. Patients may have night blindness progressing to visual loss secondary to retinitis pigmentosa. Other extrapyramidal signs include choreoathetosis and a tremor that has been

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poorly characterized. Cognitive problems include impairment of frontal tasks and memory disturbances, and psychiatric manifestations have been reported. CT scans are often normal; however, low-density lesions have been described in the globus pallidus. MRI, especially using a high field strength magnet, shows decreased signal intensity in the globus pallidus with a central hyperintensity. This has been called the “eye of the tiger sign” (130). Genetic testing for PANK 2 mutation is now commercially available and may be performed in doubtful cases (131). Juvenile Huntington’s Disease This autosomal dominant neurodegenerative disorder typically presents with chorea, difficulty with gait, and cognitive problems. However, the “Westphal variant” of the disease affecting the young may manifest bradykinesia, tremulousness, myoclonic jerks and, occasionally, seizures and cognitive disturbances (132). Eye movement abnormalities including apraxia can be remarkable. When coupled with a lack of family history, these young patients may be confused with young onset PD; however, neuroimaging and genetic testing should easily distinguish the two. Hemiparkinsonism Hemiatrophy Syndrome These patients have a long-standing hemiatrophy of the body and develop a progressive bradykinesia and dystonic movements around the age of 40 (133). Ipsilateral corticospinal tract signs may be found, which are not a feature of PD. Neuroimaging reveals brain asymmetry with atrophy of the contralateral hemisphere with compensatory ventricular dilatation. Regional cerebral metabolic rates are diminished in the hemisphere contralateral to the clinical hemiatrophy in the putamen and the medial frontal cortex, whereas in PD the regional cerebral metabolic rates are normal or increased contralateral to the clinically affected side (134). X-linked Dystonia Parkinsonism (Lubag) This inherited disorder usually occurs in the Philippines. However, rare cases are seen in other parts of the world (135). Typical age of presentation is around the age of 30 to 40 years. Focal dystonia or tremor is the initial finding followed by other parkinsonian features. Rarely, parkinsonian features may precede dystonia. Clinically, this disorder is differentiated from idiopathic PD by the presence of marked dystonia and the pattern of inheritance. Neuroacanthocytosis This is a rare cause of parkinsonism and typically presents with a hyperkinetic movement disorder, including chorea, tic-like features, and polyneuropathy. MRI shows a characteristic atrophy of the caudate and a hyperintensity in the putamen on T2weighted images and acanthocytes are revealed on a fresh blood smear (136). DIAGNOSTIC CRITERIA FOR PARKINSON’S DISEASE From the preceding discussion, it is obvious that there are a large number of disorders that can be confused with PD. In an effort to improve diagnostic accuracy, several sets of clinical diagnostic criteria for PD have been proposed (137–141). Table 7 lists the United Kingdom Parkinson’s Disease Society Brain Bank clinical diagnostic criteria.

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Differential Diagnosis TABLE 7 United Kingdom Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria Inclusion criteria

Exclusion criteria

Supportive criteria

Bradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions) and at least one of the following: ■ muscular rigidity ■ 4–6 Hz rest tremor ■ postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction

—History of repeated strokes with stepwise progression of parkinsonian features —History of repeated head injury —History of definite encephalitis —Oculogyric crises —Neuroleptic treatment at onset of symptoms —More than one affected relative —Sustained remission —Strictly unilateral features after 3 yr —Supranuclear gaze palsy —Cerebellar signs —Early severe autonomic involvement —Early severe dementia with disturbances of memory, language, and praxis —Babinski sign —Presence of cerebral tumor or communicating hydrocephalus on CT scan —Negative response to large doses of levodopa (if malabsorption excluded) —MPTP exposure

(Three or more required for diagnosis of definite PD) —Unilateral onset —Rest tremor present —Progressive disorder —Persistent asymmetry affecting side of onset most —Excellent response (70–100%) to levodopa —Severe levodopainduced chorea —Levodopa response for 5 yr or more —Clinical course of 10 yr or more

Abbreviations: CT, computed tomography; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson’s disease.

The first clinicopathological study found that only 69% to 75% of the patients with an autopsy-confirmed diagnosis of PD had at least two of the three cardinal manifestations of PD: tremor, rigidity, and bradykinesia (141). Furthermore, 20% to 25% of patients who showed two of these cardinal features had a pathological diagnosis other than PD. Even more concerning, 13% to 19% of patients who demonstrated all the three cardinal features typically associated with a clinical diagnosis of PD had another pathological diagnosis. Rajput et al. (142) reported autopsy results in 59 patients with parkinsonian syndromes. After a long-term followup period, the clinical diagnosis of PD was retained in 41 of 59 patients. However, only 31 of 41 (75%) patients with clinically determined PD showed histopathological signs of PD at autopsy examination. A third series (143) comprised 100 patients with a clinical diagnosis of PD, who had been examined during their life by different neurologists using poorly defined diagnostic criteria. When autopsies were performed (mean interval between symptom-onset and autopsy 11.9 years), PD was found in 76 patients. The authors reviewed the charts of these patients and applied the United Kingdom Parkinson’s Disease Society Brain Bank clinical criteria for PD requiring bradykinesia and at least

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one other feature, including rigidity, resting tremor, or postural instability, and focusing on clinical progression, asymmetry of onset, and levodopa response. Sixteen additional exclusion criteria were also applied (Table 7). With the application of these diagnostic criteria, 89 of the original 100 patients were considered to have PD, but again only 73 (82%) were confirmed to have PD at autopsy. When the authors reexamined the patients with all the three cardinal features (excluding the postural instability), only 65% of patients with an autopsy diagnosis of PD fit this clinical category. These authors (144) studied another 100 patients with a clinical diagnosis of PD that came to neuropathological examination. Ninety fulfilled pathologic criteria for PD. Ten were misdiagnosed: MSA (six), PSP (two), postencephalitic parkinsonism (one), and vascular parkinsonism (one). They next examined the accuracy of diagnosis of parkinsonian disorders in a specialist movement disorders service (145). They reviewed the clinical and pathological features of 143 cases of parkinsonism, likely including many of the patients previously reported (144). They found a surprisingly high positive predictive value (98.6%) of clinical diagnosis of PD among the specialists. In fact, only 1 of 73 patients diagnosed with PD during life was found to have an alternate diagnosis. This study demonstrated that the clinical diagnostic accuracy of PD may be improved by utilizing stringent criteria and a prolonged followup. A retrospective study (146) showed that the hallucinations are very predictive of Lewy body pathology, either PD or DLB. Further refinements in neuroimaging are likely to improve the clinical accuracy of early PD in the future. REFERENCES 1. Quinn NP, Luthert P, Hanover M, Marsden CD. Pure akinesia due to Lewy body. Parkinson’s disease: a case with pathology. Mov Disord 1989; 4:885–892. 2. Rajput AH. Pathologic and biochemical studies of juvenile parkinsonism linked tochromosome 6q. Neurology1999; 53(6):1375. 3. Klein C, Pramstaller PP, Kis B, et al. Parkin deletions in a family with adult-onset, tremordominant parkinsonism: expanding the phenotype. Ann Neurol 2000; 48(1):65–71. 4. Polymeropoulos MH. Autosomal dominant Parkinson’s disease and alpha-synuclein. Ann Neurol 1998; 44(3 suppl 1):S63–S64. 5. Ross OA, Toft M, Whittle AJ, et al. Lrrk2 and Lewy body disease. Ann Neurol 2006; 59(2):388–393. 6. Paulson HL, Stern MB. Clinical manifestations of Parkinson’s disease. In: Watts RL, Koller WC, eds. Movement Disorders: Neurological Principles and Practice. New York: McGraw-Hill, 1997:183–199. 7. Findley LJ, Koller WC. Essential tremor. Clin Neuropharm 1989; 12:453–482. 8. Montgomery EB, Baker KB, Lyons K, Koller WC. Motor initiation and execution in essential tremor and Parkinson’s disease Mov Disord 2000; 15(3):511–515. 9. Pahwa R, Koller WC. Is there a relationship between Parkinson’s disease and essential tremor? Clin Neuropharm 1993; 16:30–35. 10. Hardie RJ, Lees AJ. Neuroleptic induced Parkinson’s syndrome: clinical features and results of treatment with levodopa. Neurology 1987; 37:850–854. 11. Stephen PJ, Williams J. Drug-induced Parkinsonism in the elderly. Lancet 1987; 2:1082. 12. Mutch WJ, Dingwall-Fordyce I, Downie AW, et al. Parkinson’s disease in a Scottish city. Br Med J 1986; 292:534–536. 13. Sethi KD, Zamrini EY. Asymmetry in clinical features of drug-induced parkinsonism. J Neuropsych Clin Neurosci 1990; 2:64–66. 14. Giladi N, Kao R, Fahn S. Freezing phenomenon in patients with Parkinsonian syndromes.Mov Disord 1997; 12(3):302–305. 15. Klawans HL, Bergan D, Bruyn GW. Prolonged drug induced parkinsonism. Confin Neurol 1973; 35:368–377.

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120. Weilleit J, Kiechl SG. Wilson’s disease with neurological impairment but no KayserFleischer rings. Lancet 1991; 337:1426. 121. Demirkiran M, Jankovic J, Lewis RA, Cox DW. Neurologic presentation of Wilson disease without Kayser-Fleischer rings. Neurology 1996; 46(4):1040–1043. 122. Nelson RF, Guzman DA, Grahovaac Z, Howse DCN. Computerized tomography in Wilson’s disease. Neurology 1979; 29:866–868. 123. Dettori P, Rochelle MB, Demalia L, et al. Computerized cranial tomography in presymptomatic and hepatic form of Wilson’s disease. Eur Neurol 1984;23:56–63. 124. King AD, Walshe JM, Kendall BE, et al. Cranial MR imaging in Wilson’s disease. Am J Roentgenol 1996;167(6):1579–1584. 125. Steindl P, Ferenci P, Dienes HP, et al. Wilson’s disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997; 113(1):212–218. 126. Saatci I, Topcu M, Baltaoglu FF, et al. Cranial MR findings in Wilson’s disease. Acta Radiologica 1997; 38(2):250–258. 127. Snow BJ, Bhatt M, Martin WR, et al. The nigrostriatal dopaminergic pathway in Wilson’s disease studied with positron emission tomography. J Neurol Neurosurg Psychiatry 1991; 54:12–17. 128. Scheinberg IH, Sternlieb I. Wilson’s disease: Major Problems in Internal Medicine. Vol 3. Philadelphia: W.B. Saunders, 1984. 129. Brewer GJ, Yuzbasiyan-Gurkan V. Wilson’s disease. Medicine 1992; 71:139–164. 130. Sethi KD, Adams RJ, Loring DW, EL Gammal T. Hallervorden-Spatz syndrome: clinical and magnetic resonance imaging correlations. Ann Neurol 1988; 24:692–694. 131. Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003; 348(1):33–40. 132. Adams P, Falek A, Arnold J. Huntington’s disease in Georgia: Age at onset. Am J Hum Genet 1988; 43:695–704. 133. Klawans HL. Hemiparkinsonism as a late complication of hemiatrophy: A new syndrome. Neurology 1981; 31:625–628. 134. Przedborski S, Giladi N, Takikawa S, et al. Metabolic topography of the hemiparkinsonism-hemiatrophy syndrome. Neurology 1994; 44:1622–1628. 135. Waters CH, Faust PL, Powers J, et al. Neuropathology of lubag (X-linked dystoniaParkinsonism). Mov Disord 1993; 8:387–390. 136. Spitz MC, Jankovic J, Killian JM. Familial tic disorder, Parkinsonism, motor neuron disease and acanthocytosis: A new syndrome. Neurology 1985; 35:366–370. 137. Litvan I, Bhatia KP, Burn DJ, et al. Movement Disorder Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 2003; 18(5):467–468. 138. Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study. Neurology 1992; 42:1142–1146. 139. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999; 56:33–39. 140. Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988; 51:745–752. 141. Ward CD, Gibb WR. Research diagnostic criteria for Parkinson’s disease. Adv Neurol 1990; 53:245–249. 142. Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism prospective study. Can J Neurol Sci 1991; 18:275–278. 143. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55:181–184. 144. Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinson’s disease. Neurology 2001; 57:1497–1499. 145. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002; 125:861–870. 146. Williams DR, Lees AJ. Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study. Lancet Neurol 2005; 4(10):605–610.

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Pathophysiology and Clinical Assessment Joseph Jankovic Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, U.S.A.

INTRODUCTION In his 1817 An Essay on the Shaking Palsy, Parkinson (1) recorded many features of the condition that now bears his name. Parkinson emphasized the tremor at rest, flexed posture, festinating gait (Fig. 1), dysarthria, dysphagia, and constipation. Charcot and others later pointed out that the term paralysis agitans used by Parkinson was inappropriate, because in Parkinson’s disease (PD), strength was usually well preserved and many patients did not shake. Although traditionally regarded as a motor system disorder, PD is now considered to be a much more complex syndrome involving motor as well as nonmotor systems (2,3). For example, oily skin, seborrhea, pedal edema, fatigability, and weight loss are recognized as nonspecific but typical parkinsonian features. The autonomic involvement is responsible for orthostatic hypotension, paroxysmal flushing, diaphoresis, problems with thermal regulation, constipation, and bladder, sphincter, and sexual disturbances. The involvement of the thalamus and the spinal dopaminergic pathway may explain some of the sensory complaints such as pains, aches, and burning–tingling paresthesias (4). The special sensory organs may also be involved in PD and cause visual, olfactory, and vestibular dysfunction (5). A number of studies have drawn attention to the protean neurobehavioral abnormalities in PD, such as apathy, fearfulness, anxiety, emotional lability, social withdrawal, increasing dependency, depression, dementia, bradyphrenia, a type of anomia termed the “tip-of-the-tongue phenomenon,” visual–spatial impairment, sleep disturbance, psychosis, and other psychiatric problems (6). The rich and variable expression of PD often causes diagnostic confusion and a delay in treatment (7). In the early stages, parkinsonian symptoms are often mistaken for simple arthritis or bursitis, depression, normal aging, Alzheimer’s disease, or stroke (Fig. 2). PD often begins on one side of the body, but usually becomes bilateral. However, parkinsonism may remain unilateral, particularly when it is a late sequelae of post-traumatic hemiatrophy, or when it is due to a structural lesion in the basal ganglia (8). In a survey of 181 treated PD patients, Bulpitt et al. (9) found at least 45 different symptoms attributable to PD. However, only nine of these symptoms were reported by the patients in more than five-fold excess when compared with those of a control population of patients randomly selected from a general practice. These common symptoms included being frozen or rooted to a spot, grimacing, jerking of the arms and legs, shaking hands, clumsy hands, salivation, poor concentration, severe apprehension, and hallucinations. However, even these frequent symptoms are relatively nonspecific and do not clearly differentiate PD patients from diseased controls. In many cases, a follow-up for several years is needed before the diagnosis becomes apparent. Gonera et al. (10) found that four to six years prior to the onset of classic PD symptoms patients experience a prodromal phase char49

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FIGURE 1 A 74-year-old man with nine years of bilateral parkinsonism demonstrated by hypomimia, hand tremor and posturing, stooped posture, and a shuffling gait.

FIGURE 2 (A) A 74-year-old woman with facial asymmetry and right hemiatrophy for five years associated with right hemiparkinsonism. (B) Voluntary facial contraction reveals no evidence of right facial weakness.

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acterized by more frequent visits to general practitioners and specialists as compared to normal controls. During this period, PD patients, compared with normal controls, had a higher frequency of mood disorder, “fibromyalgia,” and shoulder pain. Different diagnostic criteria for PD, based on clinical and pathological findings, have been proposed but their reliability has not been vigorously tested. In one study of 800 patients diagnosed with PD and prospectively followed by trained parkinsonologists from early, untreated stages, the final diagnosis after a mean of 7.6 years of followup was considered to be other than PD in 8.1% of cases (11). In a study of 143 cases of parkinsonism who came to autopsy and had a clinical diagnosis made by neurologists specializing in movement disorders, the positive predictive value of the clinical diagnosis of PD was 98.6% and for the other parkinsonian syndromes, it was 71.4% (12). Although the emphasis in PD research has been on dopaminergic deficiency underlying motor dysfunction, there is growing body of evidence that the caudal brainstem nuclei (e.g., dorsal motor nucleus of the glossopharyngeal and vagal nerves), anterior olfactory nucleus, and other nondopaminergic neurons may be affected long before the classic loss of dopaminergic neurons in the substantia nigra (13). According to the Braak staging, during the presymptomatic stages 1 and 2, the PD-related inclusion body pathology remains confined to the medulla oblongata and olfactory bulb. In stages 3 and 4, the substantia nigra and other nuclear grays of the midbrain and basal forebrain are the focus of initially subtle and then severe changes, and the illness reaches its symptomatic phase. In the end-stages 5 and 6, the pathological process encroaches upon the telencephalic cortex. This staging proposal has been challenged, as there have been no cell counts to correlate with the described synuclein pathology and there was no observed asymmetry in the pathological findings that would correlate with the asymmetry of clinical findings. In addition, there is controversy as to the classification of dementia with Lewy bodies, viewed by Braak as part of stage 6, but others suggest that it is a separate entity since these patients often have behavioral and psychiatric problems before or at the same time as the onset of motor or other signs of PD. Although systemic, mental, sensory, and other nonmotor symptoms of PD are often quite disabling, PD patients are usually most concerned about the motor symptoms (14). Several studies have demonstrated that patients who predominantly manifest “axial” symptoms such as dysarthria, dysphagia, loss of equilibrium, and freezing are particularly disabled by their disease as compared to those who have predominantly limb manifestations (15). The poor prognosis of patients in whom axial symptoms predominate is partly due to a lack of response of these symptoms to dopaminergic drugs. The specific mechanisms underlying PD symptoms are poorly understood. An accurate assessment of the disorder’s motor signs should help to differentiate them from the motor changes associated with normal aging. Normal elderly subjects may have mild extrapyramidal impairment, including slow movement and a shuffling gait as well as disinhibition of the nuchocephalic reflex, glabellar blink reflex, snout reflex, head-retraction reflex, and the presence of paratonia, impaired vertical glaze, and cogwheel visual pursuit (16). Although these signs occur more frequently in parkinsonian patients than other aged individuals, they are not specific to PD. They may indicate an age-dependent loss of striatal dopamine and dopamine receptors (17). Receptor loss may explain why these age-related motor signs do not improve with levodopa treatment (18). This chapter will focus on the pathophysiology and clinical assessment of the cardinal signs of PD: bradykinesia, tremor, rigidity, and postural instability (Table 1).

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TABLE 1 Motor Features of Parkinsonism Tremor at resta Rigiditya Bradykinesiaa Loss of postural reflexesa Hypomimia (masked facies) Speech disturbance (hypokinetic dysarthria) Hypophonia Dysphagia Sialorrhea Respiratory difficulties Loss of associated movements Shuffling, short-step gait Festination Freezing Micrographia Difficulty turning in bed Slowness in activities of daily living Stooped posture, kyphosis, and scoliosis, Dystonia, myoclonus, orofacial dyskinesia Neuro-ophthalmologic findings Impaired visual contrast sensitivity Visuospatial impairment Impaired upward gaze, convergence, and smooth pursuit Impaired vestibuloocular reflex Hypometric saccades Decreased blink rate Spontaneous and reflex blepharospasm (glabellar or Myerson’s sign) Lid apraxia (opening or closure) Motor findings related to dopaminergic therapy Levodopa-induced dyskinesia (chorea, dystonia, myoclonus, tic) a

Cardinal signs.

BRADYKINESIA Bradykinesia, or slowness of movement, is often used interchangeably with hypokinesia (poverty of movement) and akinesia (absence of movement). Bradykinesia is the most characteristic symptom of basal ganglia dysfunction in PD (19). It may be manifested by a delay in the initiation and slowness of execution of a movement. Other aspects of bradykinesia include a delay in arresting movement, decrementing amplitude and speed of repetitive movement, and an inability to execute simultaneous or sequential actions. In addition to whole body slowness and impairment of fine motor movement, other manifestations of bradykinesia include drooling due to impaired swallowing of saliva (20), monotonous (hypokinetic) dysarthria, loss of facial expression (hypomimia), and reduced arm swing when walking (loss of automatic movement). Micrographia has been postulated to result from an abnormal response due to reduced motor output or weakness of agonist force coupled with distortions in visual feedback (21). Bradyphrenia is slowness of thought and does not always correlate with bradykinesia. Therefore, different biochemical mechanisms may underlie these two parkinsonian disturbances (22). After recording electromyographic (EMG) patterns in the antagonistic muscles of parkinsonian patients during a brief ballistic elbow flexion, Hallett and Khoshbin

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(23) concluded that the most characteristic feature of bradykinesia was the inability to “energize” the appropriate muscles to provide a sufficient rate of force required for the initiation and the maintenance of a large, fast (ballistic) movement. Therefore, PD patients need a series of multiple agonist bursts to accomplish a larger movement. Micrographia, a typical PD symptom, is an example of a muscle-energizing defect (23). The impaired generation and velocity of ballistic movement can be ameliorated with levodopa (24,25). Bradykinesia, more than any other cardinal sign of PD, correlates well with striatal dopamine deficiency. Measuring brain dopamine metabolism of rats running on straight and circular treadmills, Freed and Yamamoto (26) found that dopamine metabolism in the caudate nucleus was more affected by posture and direction of movement. Dopamine metabolism in the nucleus accumbens was more linked to the speed and direction of the antagonists, appears to be normal in PD, and is probably more under cerebellar than basal ganglia control (23). In other words, in PD, the simple motor program to execute a fast ballistic movement is intact, but it fails because the initial agonist burst is insufficient. The degree of bradykinesia correlates with a reduction in the striatal fluorodopa uptake measured by positron emission tomography (PET) scans and with nigral damage (27). Studies performed in monkeys made parkinsonian with the toxin 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) (28), and in patients with PD provide evidence that bradykinesia results from excessive activity in the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) (29). Thus, there are both functional and biochemical evidence of increased activity in the outflow nuclei, particularly STN and GPi, in patients with PD. As a result of the abnormal neuronal activity at the level of the GPi, the muscle discharge in patients with PD changes from the normal high (40 Hz) to pulsatile (10 Hz) contractions. These muscle discharges can be auscultated with a stethoscope (30). More recent studies suggest that the observed 15 to 30 Hz oscillations of the STN may reflect synchronization with cortical beta oscillation via the cortico-subthalamic pathway and may relate to mechanisms of bradykinesia. Stimulation at the 15 Hz rate worsens bradykinesia, and dopaminergic drugs promote faster oscillations (about 70 Hz) and improve bradykinesia—similar to the high frequency stimulation associated with deep brain stimulation (31,32). Bradykinesia, like other parkinsonian symptoms, is dependent on the emotional state of the patient. With a sudden surge of emotional energy, the immobile patient may catch a ball or make other fast movements. This curious phenomenon, called “kinesia paradoxica,” demonstrates that the motor programs are intact in PD, but that patients have difficulty in utilizing or accessing the programs without the help of an external trigger (33). Therefore, parkinsonian patients are able to make use of prior information to perform an automatic or a preprogrammed movement, but they cannot use this information to initiate or select a movement. Another fundamental defect in PD is the inability to execute learned sequential motor plans automatically (34). This impairment of normal sequencing of motor programs probably results from a disconnection between the basal ganglia and the supplementary motor cortex, an area that subserves planning function for movement. The supplementary motor cortex receives projections from the motor basal ganglia (via the GPi and ventrolateral thalamus) and, in turn, projects to the motor cortex. In PD, the early component of the premovement potential (Bereitschaftspotential) is reduced, probably reflecting inadequate basal ganglia activation of the supplementary motor area (35,36). Recording from the motor cortex of MPTP monkeys, Tatton

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et al. (37) showed markedly increased gain of the long-latency (M2) segments of the mechanoreceptor-evoked responses. This and other findings indicate that PD patients have an abnormal processing of sensory input necessary for the generation and execution of movement. Most neurophysiologic and neurobehavioral studies in PD have concluded that the basal ganglia (and possibly the supplementary motor cortex) play a critical role in planning and sequencing voluntary movements (38). For example, when a patient arises from a chair, he/she may “forget” any one of the sequential steps involved in such a seemingly simple task: to flex forward, place hands on the arm rests, place feet under the chair, and then push out of the chair into an erect posture. Similar difficulties may be encountered when sitting down, squatting, kneeling, turning in bed, and walking. Lakke (33) suggests that since the patient can readily perform these activities under certain circumstances, such as when emotionally stressed, the intrinsic program is not disturbed, and, therefore, these axial motor abnormalities are a result of apraxia. Thus, the PD patient has an ability to “call up” the axial motor program on command. The inability to combine motor programs into complex sequences seems to be a fundamental motor deficit in PD. The study of reaction time and velocity of movement provides some insight into the mechanisms of the motor deficits at an elementary level. Evarts et al. (39) showed that both reaction and movement times are independently impaired in PD. In patients with asymmetrical findings, reaction time is slower on the more affected side (40). Reaction time is influenced not only by the degree of motor impairment but also by the interaction between cognitive processing and motor response. This is particularly evident when choice reaction time is used and compared to simple reaction time (22). Bradykinetic patients with PD have more specific impairment in choice reaction time, which involves a stimulus categorization and a response selection, and reflects disturbance at more complex levels of cognitive processing (41). Reduced dopaminergic function has been hypothesized to disrupt normal motor cortex activity leading to bradykinesia. While recording from single cortical neurons in free-moving rats, a decrease in firing rate correlated with haloperidol-induced bradykinesia, demonstrating that reduced dopamine action impairs the ability to generate movement and causes bradykinesia (42). Bereitschaftspotential, a premovement potential, has been found to be abnormal in PD patients and to normalize with levodopa (43). The movement time, particularly when measured for proximal muscles, is less variable than the reaction time and more consistent with the clinical assessment of bradykinesia. Both movement and reaction times are better indicators of bradykinesia than the speed of rapid alternating movements. Ward et al. (44) attempted to correlate the median movement and reaction times with tremor, rigidity, and manual dexterity in 10 patients. The only positive correlations were found between movement time and rigidity and between reaction time and manual dexterity. Of the various objective assessments of bradykinesia, movement time correlated best with the total clinical score, but it was not as sensitive an indicator of the overall motor deficit as the clinical rating. Ward et al. (44) concluded that although movement time was a useful measurement, it alone did not justify the use of elaborate and expensive technology. The clinical rating scale probably more accurately reflects the patient’s disability, because it includes more relevant observations.

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TREMOR Tremor, although less specific than bradykinesia, is one of the most recognizable symptoms of PD. However, only half of all patients present with tremor as the initial manifestation of PD, and 15% never have tremor (45). Although tremor at rest (4–6 Hz) is the typical parkinsonian tremor, most patients also have tremor during activity, and this postural tremor (5–8 Hz) may be more disabling than the resting tremor. Postural tremor without parkinsonian features and without any other known etiology is often diagnosed as essential tremor (ET) (Table 2). However, isolated postural tremor clinically identical to ET may be the initial presentation of PD and may be found with higher-than-expected frequency in relatives of patients with PD (46,47). The two forms of postural tremors can be differentiated by a delay in the onset of tremor when arms assume an outstretched position. Although most patients with PD have a latency of a few seconds (up to a minute) before the tremor reemerges during postural holding, hence reemergent tremor, postural tremor of ET usually appears immediately after arms assume a horizontal posture (48). Since the reemergent tremor has similar frequency to that of rest tremor and both tremors generally respond to dopaminergic drugs, it is postulated that the reemergent tremor represents a variant of the more typical rest tremor. It has been postulated that the typical tremor at rest results from nigrostriatal degeneration and consequent disinhibition of the pacemaker cells in the thalamus (49). These thalamic neurons discharge rhythmically at 5 to 6 Hz, a frequency similar to the typical parkinsonian tremor at rest (50,51). Some support for the thalamic pacemaker theory of PD tremor also comes from the studies of Lee and Stein (52), which show that the resting 5 Hz tremor is remarkably constant and relatively resistant to resetting by mechanical perturbations. Furthermore, during stereotactic thalamotomy, 5 Hz discharges are usually recorded in the nucleus ventralis intermedius of the thalamus in parkinsonian subjects, even in the absence of visible tremor (53). This rhythmic bursting is not abolished by deafferentation or paralysis. Because the frequency (6 Hz) of the postural (action) tremor is the same as the frequency of the cogwheel phenomenon elicited TABLE 2 Differential Diagnosis of Parkinsonian and Essential Tremor

Age at onset (years) Sex Family history Site of involvement Characteristics Influencing factors Rest Action Mental concentration, walking Frequency (Hz) Electromyography Associated features Neuropathology Treatment

Parkinsonian tremor

Essential tremor

55–75 M>F − Hands, legs, jaw, chin, tongue Supination-pronation

10–80 M
↑ ↓ ↑

↓ ↑ ↓

4–7 Alternating contractions Cogwheel rigidity (±)

8–12 Simultaneous contractions Dystonia, Charcot-Marie-Tooth disease No discernible pathology

Nigrostriatal degeneration, Lewy bodies Anticholinergics, amantadine, dopaminergic drugs

Alcohol, beta-blockers, primidone, botulinum toxin

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FIGURE 3 Parkinsonian cogwheel rigidity elicited by passive rotation of the wrist is enhanced by voluntary repetitive movement of the contralateral hand.

during passive movement, some authors have suggested that the postural tremor and cogwheel phenomenon have similar pathophysiologies (Fig. 3) (54). The biochemical defect underlying either resting or postural parkinsonian tremor is unknown. Bernheimer et al. (55) showed that the severity of tremor paralleled the degree of homovanillic acid reduction in the pallidum. In contrast, bradykinesia correlated with dopamine depletion in the caudate nucleus. In an experimental monkey model of parkinsonian tremor, a pure lesion in the ascending dopaminergic nigrostriatal pathway is not sufficient to produce the alternating rest tremor (56). Experimental parkinsonian tremor requires nigrostriatal disconnection combined with a lesion involving the rubrotegmentospinal and the dentatorubrothalamic pathways. A typical PD tremor is observed in humans and animals exposed to MPTP, which presumably affects, rather selectively, the nigrostriatal dopaminergic system (57,58). However, the cerebellorubrothalamic system has not been examined in detail in this MPTP model. Furthermore, in MPTP subjects, a prominent action tremor was more typically seen than a tremor at rest. In early studies, mechanical and optic devices were used to record tremor (59). EMG recordings and accelerometers, assisted by computer analysis, have been utilized to measure the characteristics of tremor. However, most accelerometers record tremor in a single plane. By using computed triaxial accelerometry, the distortion of the normal motion characteristics in patients with PD and ET during voluntary arm abduction–adduction movement was recorded (24). There was a good correlation between the reduction in the distortion and the clinical improvement in response to medications. However, the quantitative recordings of tremor, although accurate, are time-consuming, costly, and influenced by the emotional state of the patient. Moreover, it is questionable whether such recordings provide a reliable index of a meaningful therapeutic response. RIGIDITY AND POSTURAL ABNORMALITIES Rigidity is less variable than tremor, and it probably better reflects the patient’s functional disability. Rigidity may contribute to subjective stiffness and tightness,

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a common complaint in patients with PD. However, there is relatively poor correlation between the sensory complaints experienced by most patients and the degree of rigidity (60,61). In mild cases, cogwheel rigidity can be brought out by a passive rotation of the wrist or flexion–extension of the forearm while the patient performs a repetitive voluntary movement in the contralateral arm (Fig. 3) (62). Rigidity may occur proximally (e.g., neck, shoulders, and hips) and distally (e.g., wrists and ankles). At times, it can cause discomfort and actual pain. Painful shoulder, probably due to rigidity but frequently misdiagnosed as arthritis, bursitis, or rotator cuff, is one of the most frequent initial manifestations of PD (63). Rigidity is often associated with postural deformity, resulting in flexed neck and trunk posture and flexed elbows and knees. Some patients develop ulnar deviation of hands (striatal hand), which can be confused with arthritis (64,65). Other skeletal abnormalities include neck flexion (dropped head or bent spine) (66) and truncal flexion (camptocormia) (Figs. 4 and 5) (67,68). Duvoisin and Marsden (69) studied 20 PD patients with scoliosis and found that 16 of the patients tilted away from the side with predominant parkinsonian symptoms but subsequent studies could not confirm this observation (70). The neurophysiologic mechanisms of rigidity are poorly understood. Spinal monosynaptic reflexes are usually normal in PD. Recordings from muscle spindle afferents revealed an activity in rigid parkinsonian patients, not seen in normal controls. This suggested an increased fusimotor drive due to hyperactivity of both alpha and gamma motor neurons. However, this fusimotor overactivity probably is an epiphenomenon, reflecting the inability of PD patients to relax fully. Passive shortening of a rigid muscle, due to PD or seen in tense subjects, produces an involuntary contraction called the Westphal phenomenon. Although the mechanism of this sign

FIGURE 4 A 63-year-old woman with progressive scoliosis to the right side for 20 years and left hemiparkinsonism manifested by hand and leg tremor, rigidity, and bradykinesia. (A) Front view. (B) Back view.

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FIGURE 5 A 44-year-old woman with Parkinson’s disease showing typical dystonic (“striatal”) hand with flexion at the metacarpophalengeal joints, extension at the proximal interphalangeal joints, and flexion of the distal interphalangeal joints. The dystonia completely resolved with levodopa. Source: From Ref. 64.

is unknown, it probably is the result of excessive supraspinal drive on normal spinal mechanism. This shortening reaction may be abolished by procaine infiltration of the muscle. Thus, there is no convincing evidence of a primary defect of fusimotor function in parkinsonian rigidity (71). The measurement of torque or resistance during passive flexion–extension movement has been used most extensively as an index of rigidity. It has been demonstrated that rigidity correlated with increased amplitude of the long-latency (transcerebral) responses to sudden stretch. These long-latency stretch reflexes represent a positive (release) phenomenon, mediated by motor pathways that do not traverse the basal ganglia. The earlier techniques of passively flexing and extending the limbs were later refined by Mortimer and Webster (72), who designed a servo-controlled electronic device to move the limb at a constant angular velocity. They and others (73–75) demonstrated a close relationship between the enhanced long-latency stretch reflexes and the degree of activated rigidity. Using measurements of the tonic stretch reflex as an index of rigidity, Meyer and Adorjani (76) found an inverse correlation between the “dynamic sensitivity” (ratio between the increase in reflex EMG at a high vs. low angular velocity) and the severity of parkinsonian rigidity. In contrast, the “static” component of the tonic stretch reflex (the maximum reflex activity at greatest stretch or at sustained stretch) positively correlated with the severity of rigidity. Both the dynamic and the static components of the tonic stretch reflex may be reduced by antiparkinson drugs (76). Although Lee and Tatton (74) showed diminution of the

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amplitude of the reflex after treatment, correlating it with improvement in rigidity, the measurement of long-latency responses is quite cumbersome, time-consuming, and possibly unreliable (77). Moreover, a marked overlap in the long-latency response between PD and normal subjects has been noted (78). POSTURAL INSTABILITY The loss of balance associated with propulsion and retropulsion is probably the least specific, but most disabling, of all parkinsonian symptoms. Purdon-Martin (79), after studying nine brains of patients with postencephalitic parkinsonism, concluded that globus pallidum degeneration was most responsible for the loss of righting reflexes and postural instability in parkinsonian patients. Reichert et al. (5) correlated postural instability in PD patients with reduced or absent vestibular responses. Traub et al. (80) studied postural reflexes in 29 PD patients by recording anticipatory postural responses in the legs (triceps surae) in response to perturbations of one of the arms. In normal subjects, a burst of activity can be recorded from the calf muscles at a latency of 80 msec after the perturbation. This postural adjustment occurs even before any movement can be recorded in the legs (latency, 150 msec). Therefore, this reflex adjustment is anticipatory and centrally generated. In PD, the anticipatory postural reflexes are absent or markedly diminished. Such abnormalities were present in 10 of the 18 patients with moderately severe PD and in two of 11 PD patients without obvious postural instability. Since some patients with normal anticipatory reflexes can still fall, it is likely that other mechanisms contribute to the falls of parkinsonian patients (14,81). Furthermore, patients with progressive supranuclear palsy (PSP), who are much more prone to falling than PD patients, have normal anticipatory postural responses (80). Weiner et al. (82) found moderate or severe loss of balance in response to a standing postural perturbation in 68% of 34 patients in a geriatric care facility. They suggested that a postural reflex dysfunction was largely responsible for the unexplained falls in the elderly. Loss of postural reflexes usually occurs in more advanced stages of PD and, along with freezing, is the most common cause of falls, often resulting in hip fractures. The loss of protective reactions further contributes to fall-related injuries. Many patients with postural instability, particularly when associated with flexed truncal posture, have festination, manifested by faster and faster walking in order to prevent falling. When combined with axial rigidity and bradykinesia, loss of postural reflexes causes the patient to collapse into the chair when attempting to sit down. The “pull test” (pulling the patient by the shoulders) is commonly used to determine the degree of retropulsion or propulsion. FREEZING AND OTHER GAIT ABNORMALITIES A slow, shuffling, narrow-based gait is one of the most characteristic features of PD (83). The parkinsonian gait reveals certain features that overlap with the gait disturbance associated with normal pressure hydrocephalus (84,85). In a study of 50 subjects older than 70 years, Sudarsky and Ronthal (86) established a principal cause of the gait disorder in all but seven subjects (“essential gait disorder”). They, but not others (87), suggested that this senile gait is related to normal pressure hydrocephalus. The gait and postural problems associated with PD probably result from a combination of bradykinesia, rigidity, loss of anticipatory proprioceptive reflexes, loss of protective reaction to a fall, gait and axial apraxia, ataxia, vestibular dysfunction, and

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orthostatic hypotension. When gait disorder, with or without freezing and postural instability, is the dominant motor dysfunction, “lower body” parkinsonism should be considered in the differential diagnosis (88). This syndrome is thought to represent a form of “vascular” parkinsonism associated with a multi-infarct state. Furthermore, gait disorder and postural instability are typically associated with PSP (89,90). One of the most disabling symptoms of PD is freezing or motor blocks, a form of akinesia (91,92). The observation that some patients even with severe bradykinesia have no freezing and other patients have a great deal of freezing but minimal or no bradykinesia suggests that the two signs have different pathophysiologies. Furthermore, that bradykinesia usually responds well to levodopa and freezing does not indicates that freezing may be a manifestation of a nondopaminergic disturbance. Freezing consists of a sudden, transient (a few seconds) inability to move. It typically causes “start hesitation” when initiating walking and the sudden inability to move the feet (as if “glued to the ground”) when turning or walking through narrow passages (such as the door or the elevator), when crossing streets with heavy traffic, or when approaching a destination (target hesitation). Patients often learn a variety of tricks to overcome freezing, such as marching to command (“left, right, left, right”), visual cues such as stepping over objects (end of a walking stick, pavement stone, cracks in the floor, etc.), walking to music or metronome, shifting body weight, rocking movements, and others (88,93,94). When freezing occurs early in the course of the disease or is the predominant symptom, a diagnosis other than PD should be considered. Disorders associated with prominent freezing include PSP, multiple system atrophy (MSA), and vascular parkinsonism (88,95). OTHER MOTOR MANIFESTATIONS There are many other motor findings in PD (Table 1), most of which are directly related to one of the cardinal signs. For example, the loss of facial expression (hypomimia, masked facies) and the bulbar symptoms (dysarthria, hypophonia, dysphagia, and sialorrhea) result from orofacial-laryngeal bradykinesia and rigidity (96). Respiratory difficulties result from a variety of mechanisms, including a restrictive component due to rigid respiratory muscles and levodopa-induced respiratory dyskinesia (97,98). Of the various oculomotor problems characteristically seen in PD, the following are most common: impaired saccadic and smooth pursuit, limitation of upward gaze and convergence, oculogyric crises, spontaneous and reflex blepharospasm, apraxia of lid opening (involuntary levator inhibition), and apraxia of eyelid closure (99,100). Although supranuclear ophthalmoplegia is often used to differentiate PSP from PD, this oculomotor abnormality has also been described in otherwise typical parkinsonism (101). Some patients exhibit the reemergence of primitive reflexes attributed to a breakdown of the frontal lobe inhibitory mechanisms normally present in infancy and early childhood, hence the term “release signs.” The glabellar tap reflex, also known as Meyerson’s sign, has often been associated with PD. Its diagnostic accuracy, however, has not been subjected to rigorous studies. We examined the glabellar reflex and the palmomental reflex in 100 subjects, which included patients with PD (n=41), PSP (n=12), MSA (n=7), and healthy, age-matched, controls (n=40). Although relatively sensitive signs of parkinsonian disorders, particularly PD, these primitive reflexes lack specificity, as they do not differentiate between the three most common parkinsonian disorders (102). In one study, 24 of 27 patients with asymmetric PD

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exhibited mirror movements on the less affected side, the mechanism of which is unknown (103). ASSESSMENT OF DISABILITY The assessment of PD is difficult, because it is expressed variably in an individual patient at different times and it is influenced by emotional state, response to medication, and other variables. Moreover, there is a marked interpatient variability of symptoms and signs. To study this heterogeneity and to determine possible patterns of clinical associations, we analyzed the clinical findings in 334 patients with PD and identified at least two distinct clinical populations of parkinsonian patients (104). One subtype was characterized by a prominent tremor, an early age at onset, and a greater familial tendency. Another subtype was dominated by postural instability and gait difficulty (PIGD) and was associated with a greater degree of dementia, bradykinesia, functional disability, and a less favorable long-term prognosis. These findings are supported by the results of an analysis of 800 patients with untreated PD included in the multicenter trial Deprenyl and Tocopherol Antioxidative Therapy of Parkinson’s Disease (DATATOP). The PIGD group had greater occupational disability and more intellectual impairment, depression, lack of motivation, and impairment in activities of daily living than a corresponding group of patients with tremor-dominant PD (15). The investigators concluded that patients with older age of onset and a presentation with PIGD and with bradykinesia are more likely to have a more aggressive course than those with early symptoms dominated by tremor (105). In order to determine the overall rate of functional decline and to assess the progression of different signs of PD, we prospectively followed 297 patients (181 males) with PD for at least three years (105). Data from 1731 visits, over a period of an average of 6.36 years (range = 3–17 years), were analyzed. The annual rate of decline in the total Unified Parkinson’s Disease Rating Scale (UPDRS) scores was 1.34 units in the on state and 1.58 units in the off state. Patients with older age at onset had a more rapid progression of disease than those with younger age at onset. Furthermore, the older onset group had significantly more progression in mentation, freezing, and UPDRS activities of daily living subscores. Handwriting was the only component of the UPDRS that did not significantly deteriorate during the observation period. Regression analysis of 108 patients, whose symptoms were rated during the off state, showed a faster rate of cognitive decline as age at onset increased. The slopes of progression in UPDRS scores, when adjusted for age at initial visit, were steeper for the PIGD group of patients as compared to the tremor-dominant group. These findings, based on longitudinal follow-up data, provide evidence for a variable course of progression of the different PD symptoms, thus implying different biochemical or degenerative mechanisms for the various clinical features associated with PD. Hence, PD should be considered a syndrome with characteristic patterns of symptoms, course, response to therapy, and different etiologies. The different subsets of PD may have a different pathogenesis and even a different genetic predisposition. Longitudinal studies of PD progression utilizing imaging ligands targeting both dopamine metabolism ([18F]DOPA) and dopamine transporter density (β-CIT) using both PET and single photon emission CT (SPECT), respectively, have demonstrated an annualized rate of reduction in striatal [18F]DOPA or [123I]β-CIT uptake of about 6% to 13% in PD patients compared with a 0% to 2.5% change in healthy controls (106). With improved methodology of β-CIT SPECT scans, the annualized rate

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of decline is now estimated to be 4% to 8% (107). These functional imaging studies are consistent with pathological studies, showing that the rate of nigral degeneration in PD is 8- to 10-fold higher than that of healthy age-matched controls. Several studies have suggested that the rate of progression of PD may not be linear and that the disease progresses more rapidly initially and the rate of deterioration slows with more advanced disease, arguing against the “long-latency” hypothesis for a presymptomatic period in PD (108,109). The accurate and reliable evaluation of motor dysfunction is essential for an objective assessment of the efficacy of potentially useful drugs. Various mechanical, electrophysiologic, and clinical methods have been utilized to measure the motor findings in PD objectively. Some of the techniques are designed to measure the frequency, amplitude, force, velocity, acceleration of contraction, and other quantitative parameters of the abnormal movement. However, such measurements may have little relevance to the actual functional disability of the patient. In assessing the motor symptoms and signs of PD, two approaches have been used, both of which strive to quantify the motor findings (77). One method utilizes neurologic history and an examination with subjective rating of symptoms, signs, and functional disability, and the other method utilizes timing of specific tasks or neurophysiologic tests of particular motor disturbances. Although the latter method is considered to be more objective and scientific, it is not necessarily more accurate, reliable, or relevant than the clinical rating. However, both approaches have certain advantages and disadvantages and, when combined, may provide a useful method of assessing the severity of the disability and the response to therapy. Most of the subjective methods of assessment of parkinsonian disability utilize rating scales of various symptoms and disabilities. The most widely used method of staging PD is the Hoehn and Yahr scale (110). Although this staging scale is useful in comparing populations of PD patients, it is relatively insensitive to changes in the clinical state. Therefore, the Hoehn and Yahr scale is not useful in monitoring the response of individual patients to therapy. Thus, it is important that the severity of the disease is objectively assessed in the context of the individual’s goals and needs. Although a variety of neurophysiologic- and computer-based methods have been proposed to quantify the severity of the various parkinsonian symptoms and signs, most studies rely on clinical rating scales, particularly the UPDRS (111–114; see Appendix 1). In some studies, the UPDRS is supplemented by more objective timed tests such as the Purdue Pegboard or movement and reaction times (19). There are also many scales, such as the Parkinson’s Disease Questionnaire-39 and the Parkinson’s Disease Quality of Life Questionnaire, which assess quality of life (115). When a particular aspect of parkinsonism requires more detailed study, separate scales should be employed, such as tremor scales or the Gait and Balance Scale (116). Also, it is important that when performing the UPDRS, the instructions are followed exactly. For example, one study of 66 pull tests, part of the UPDRS used to assess postural instability (117), performed by 25 examiners showed marked variability in the technique among the examiners and only 9% of the examinations were rated as error-free (118). REFERENCES 1. Parkinson J. An Essay on the Shaking Palsy. London: Sherwood, Neely, and Jones, 1817. 2. Lang AE, Obeso JA. Challenges in Parkinson’s disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol 2004; 3:309–16.

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82. Weiner WJ, Nora LM, Glantz RH. Elderly inpatients: postural reflex impairment. Neurology 1984; 34:945–947. 83. Jankovic J, Nutt JG, Sudarsky L. Classification, diagnosis and etiology of gait disorders. Adv Neurol 2001; 87:119–133. 84. Fisher CM. Hydrocephalus as a cause of disturbance of gait in the elderly. Neurology 1982; 32:1358–1363. 85. Knutsson E, Lying-Tunell M. Gait apraxia in manual-pressure hydrocephalus: problems of movement and muscle activation. Neurology 1985; 35:155–160. 86. Sudarsky L, Ronthal M. Gait disorders among elderly patients. A survey study of 50 patients. Arch Neurol 1983; 40:740–743. 87. Koller WC, Glatt SL, Fox JH. Senile gait. A distinct neurologic entity. Clin Geriatr Med 1985; 1:661–669. 88. FitzGerald PM, Jankovic J. Lower body parkinsonism: Evidence for vascular etiology. Mov Disord 1989; 4(3):249–260. 89. Jankovic J, Friedman D, Pirozzolo FJ, McCrary JA. Progressive supranuclear palsy: Clinical, neurobehavioral, and neuro-ophthalmic findings. Adv Neurol 1990; 53:293–304. 90. Winikates J, Jankovic J. Clinical correlates of vascular parkinsonism. Arch Neurol 1999; 56:98–102. 91. Giladi N, Kao R, Fahn S. Freezing phenomenon in patients with parkinsonian syndromes. Mov Disord 1997; 12:302–305. 92. Giladi N, McDermott MP, Fahn S, et al. Freezing of gait in PD. Prospective assessment of the DATATOP cohort. Neurology 2001; 56:1712–1721. 93. Dietz MA.Goetz CG, Stebbins GT. Evaluation of a modified inverted walking stick as a treatment for parkinsonian freezing episodes. Mov Disord 1990; 5:243–247. 94. Marchese R, Diverio M, Zucchi F, et al. The role of sensory cues in the rehabilitation of parkinsonian patients: A comparison of two physical therapy protocols. Mov Disord 2001; 15:879–883. 95. Elble RJ, Cousins R, Leffler K, Hughes L. Gait initiation by patients with lower-half parkinsonism. Brain 1996; 119:1705–1716. 96. Hunker CJ, Abbs JH, Barlow SM. The relationship between parkinsonian rigidity and hypokinesia in the orofacial system: a quantitative analysis. Neurology 1982; 32: 749–755. 97. Jankovic J. Respiratory dyskinesia in Parkinson’s disease. Neurology 1986; 36:303–304. 98. Rice JE, Antic R, Thompson PD. Disordered respiration as a levodopa-induced dyskinesia in Parkinson’s disease. Mov Disord 2002; 17:524–527. 99. Leport FE, Duvoisin RC. Apraxia of eyelid opening: An involuntary levator inhibition. Neurology 1985; 35:423–427. 100. Jankovic J. Apraxia of lid opening. Mov Disord 1995; 10:686–687. 101. Guiloff RJ. George RJ. Marsden CD. Reversible supranuclear ophthalmoplegia associated with parkinsonism. J Neurol Neurosurg Psychiatry l980; 43:552–554. 102. Brodsky H, Dat Vuong K, Thomas M, Jankovic J. Glabellar and palmomental reflexes in parkinsonian disorders. Neurology 2004; 63:1096–8. 103. Espay AJ, Li JY, Johnston L, Chen R, Lang AE. Mirror movements in parkinsonism: evaluation of a new clinical sign. J Neurol Neurosurg Psychiatry 2005; 76:1355–1358. 104. Zetusky WJ, Jankovic J, Pirozzolo FJ. The heterogeneity of Parkinson’s disease: Clinical and prognostic implications. Neurology 1985; 35:522–526. 105. Jankovic J, Kapadia AS. Functional decline in Parkinson’s disease. Arch Neurol 2001; 58:1611–1615. 106. Marek K, Innis R, van Dyck C, et al. [123I]β-CIT/SPECT imaging assessment of the rate of Parkinson’s disease progression. Neurology 2001; 57:2089–2094. 107. Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287:1653–1661. 108. Hilker R, Schweitzer K, Coburger S, et al. Progression of Parkinson’s disease is nonlinear as determined by serial PET imaging of striatal [18]Fluorodopa activity. Arch Neurol 2005; 62:378–382. 109. Jankovic J. Progression of Parkinson’s disease: Are we making progress in charting the course? Arch Neurol 2005; 62:351–352.

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110. Hoehn MM, Yahr MD. Parkinsonism: Onset, progression and mortality. Neurology 1967;17:427–442. 111. Fahn S, Elton RL. Members of the UPDRS Development Committee: Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, CaIne DB, Lieberman A, eds. Recent Developments in Parkinson’s Disease. Vol. II. Florham Park, New Jersey: Macmillan Health Care Information, 1987:153–163. 112. Goetz CG, Stebbins GT, Shale HM, et al. Utility of an objective dyskinesia rating scale for Parkinson’s disease: inter- and intrarater reliability assessment. Mov Disord 1994; 9: 390–394. 113. Goetz CG, Stebbins GT, Chmura TA, et al. Teaching tape for the motor section of the Unified Parkinson’s Disease Rating Scale. Mov Disord 1995; 10:263–266. 114. Goetz CG, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale: (MDS-UPDRS): Process, format and clinimetric testing plan. Mov Disord 2007 (in press). 115. Marinus J, Ramaker C, van Hilten JJ, Stiggelbout AM. Health related quality of life in Parkinson’s disease: a systematic review of disease specific instruments. J Neurol Neurosurg Psychiatry 2002; 72:241–248. 116. Thomas M, Jankovic J, Suteerawattananon M, et al. Clinical gait and balance scale (GABS): validation and utilization. J Neurol Sci 2004; 217:89–99. 117. Hunt AL, Sethi KD. The pull test: A history. Mov Disord 2006; 21:894–899. 118. Munhoz RP, Li JY, Kurtinecz M, et al. Evaluation of the pull test technique in assessing postural instability in Parkinson’s disease. Neurology 2004; 62:125–127.

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Appendix 1 Unified Parkinson’s Disease Rating Scale MENTATION, BEHAVIOR, AND MOOD (HISTORY) 1. Mentation 0 = None 1 = Mild. Consistent forgetfulness with partial recollection of events and no other difficulties. 2 = Moderate memory loss, with disorientation and moderate difficulty handling complex problems. Mild but definite impairment of function at home with need of occasional prompting. 3 = Severe memory loss with disorientation for time and often to place. Severe impairment in handling problems. 4 = Severe memory loss with orientation preserved to person only. Unable to make judgments or solve problems. Requires much help with personal care. Cannot be left alone at all. 2. Thought disorder (due to dementia or drug intoxication). 0 = None 1 = Vivid dreaming 2 = “Benign” hallucinations with insight retained. 3 = Occasional to frequent hallucinations or delusions, without insight, could interfere with daily activities. 4 = Persistent hallucinations, delusions, or florid psychosis. Not able to care for self. 3. Depression 0 = Not present. 1 = Periods of sadness or guilt greater than normal, never sustained for days or weeks. 2 = Sustained depression (one week or more). 3 = Sustained depression with vegetative symptoms (insomnia, anorexia, weight loss, loss of interest). 4 = Sustained depression with vegetative symptoms and suicidal thoughts or intent. 4. Motivation/initiative 0 = Normal 1 = Less assertive than usual; more passive. 2 = Loss of initiative or disinterest in elective (nonroutine) activities. 3 = Loss of initiative or disinterest in day-to-day (routine) activities. 4 = Withdrawn, complete loss of motivation.

Source: From Ref. (111).

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ACTIVITIES OF DAILY LIVING (HISTORY) 6. Speech 0 = Normal 1 = Mildly affected. No difficulty being understood. 2 = Moderately affected. Sometimes asked to repeat statements. 3 = Severely affected. Frequently asked to repeat statements. 4 = Unintelligible most of the time. 7. Salivation 0 = Normal 1 = Slight but definite excess of saliva in mouth; may have nighttime drooling. 2 = Moderately excessive saliva with some drooling. 3 = Marked excess of saliva with some drooling. 4 = Marked drooling, requires constant tissue or handkerchief. 8. Swallowing 0 = Normal 1 = Rare choking 2 = Occasional choking 3 = Requires soft food 4 = Requires nasogastric tube or gastrotomy feeding. 9. Handwriting 0 = Normal 1 = Slightly slow or small 2 = Moderately slow or small; all words are legible. 3 = Severely affected; not all words are legible. 4 = The majority of words are not legible. 10. Cutting food 0 = Normal 1 = Somewhat slow and clumsy, but no help needed. 2 = Can cut most food, although clumsy and slow, some help needed. 3 = Food must be cut by someone, but can still feed slowly. 4 = Needs to be fed. 11. Dressing 0 = Normal 1 = Somewhat slow, but no help needed. 2 = Occasional assistance with buttoning, getting arms in sleeves. 3 = Considerable help required but can do some things alone. 4 = Helpless 12. Hygiene 0 = Normal 1 = Somewhat slow, but no help needed. 2 = Needs help to shower or bathe; or very slow in hygienic care. 3 = Requires assistance for washing, brushing teeth, combing hair, and going to bath room. 4 = Foley catheter or other mechanical aids.

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13. Turning in Bed 0 = Normal 1 = Somewhat slow and clumsy, but no help needed. 2 = Can turn alone or adjust sheets, but with great difficulty. 3 = Can initiate, but not turn or adjust sheets alone. 4 = Helpless 14. Falling 0 = Normal 1 = Rare falling. 2 = Occasionally falls, less than once per day. 3 = Falls an average of once daily. 4 = Falls more than once daily. 15. Freezing 0 = None 1 = Rare freezing when walking; may have start-hesitation. 2 = Occasional freezing when walking. 3 = Frequent freezing; occasionally falls from freezing. 4 = Frequent falls from freezing. 16. Walking 0 = Normal 1 = Mild difficulty. May not swing arms or may tend to drag leg. 2 = Moderate difficulty, but requires little or no assistance. 3 = Severe disturbance of walking, requiring assistance. 4 = Cannot walk at all, even with assistance. 17. Tremor (rated for right and left sides separately) 0 = Absent 1 = Slight and infrequently present. 2 = Moderate; bothersome to patient. 3 = Severe; interferes with many activities. 4 = Marked, interferes with most activities. 18. Sensory symptoms 0 = None 1 = Occasionally has numbness, tingling, or mild aching. 2 = Frequently has numbness, tingling, or aching, not distressing. 3 = Frequent painful sensations. 4 = Excruciating pain. MOTOR EXAMINATION (single point in time) 20. Speech 0 = Normal 1 = Slight loss of expression, diction, and/or volume. 2 = Monotone, slurred but understandable; moderately impaired. 3 = Marked impairment, difficult to understand. 4 = Unintelligible

Jankovic

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21. Facial expression 0 = Normal 1 = Minimal hypomimia, could be normal, “poker face”. 2 = Slight but definitely abnormal diminution of facial expression. 3 = Moderate hypomimia, lips parted some of the time. 4 = Masked or fixed facies with severe or complete loss of facial expression, lips parted 1/4 inch or more. 22. Tremor at rest (rated separately for jaw, right and left upper and lower extremities) 0 = Absent 1 = Slight and infrequently present. 2 = Mild in amplitude and persistent. Or moderate in amplitude, but only intermittently present. 3 = Moderate in amplitude and present most of the time. 4 = Marked in amplitude and present most of the time. 23. Action or postural tremor of hands (rated for right and left separately) 0 = Absent 1 = Slight; present with action. 2 = Moderate in amplitude; present with action. 3 = Moderate in amplitude, with posture holding as well as action. 4 = Marked in amplitude, interferes with feeding. 24. Rigidity ( judged on passive movement of major points with patient relaxed in sitting position; cogwheeling to be ignored; rated separately for neck, right and left upper and lower extremities) 0 = Absent 1 = Slight or detectable only when activated by mirror or other movements. 2 = Mild to moderate. 3 = Marked, but full range of motion easily achieved. 4 = Severe, range of motion achieved with difficulty. 25. Finger taps (patient taps thumb with index finger in rapid succession with widest amplitude possible, each hand evaluated and scored separately). 0 = Normal 1 = Mild slowing and/or reduction in amplitude. 2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement. 3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 4 = Can barely perform the task. 26. Hand movements (patient opens and closes hands in rapid succession with widest amplitude possible, each hand evaluated and scored separately). 0 = Normal 1 = Mild slowing and/or reduction in amplitude. 2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement.

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3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 4 = Can barely perform the task. 27. Hand pronation–supination (pronation–supination movements of hands, vertically or horizontally, with as large as amplitude as possible, both hands evaluated simultaneously and scored separately) 0 = Normal 1 = Mild slowing and/or reduction in amplitude. 2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement. 3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 4 = Can barely perform the task. 28. Leg agility (patient taps heel on ground in rapid succession, picking up entire leg. Amplitude should be about three inches; rated separately for each side). 0 = Normal 1 = Mild slowing and/or reduction in amplitude. 2 = Moderately impaired. Definite and early fatiguing. May have occasional arrests in movement. 3 = Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement. 4 = Can barely perform the task. 29. Arising from chair (patient attempts to arise from a straight-back wood or metal chair with arms folded across chest). 0 = Normal 1 = Slow, or may need more than one attempt. 2 = Pushes self up from arms of seat. 3 = Tends to fall back and may have to try more than one time, but can get up without help. 4 = Unable to arise without help. 30. Posture 0 = Normal 1 = Not quite erect, slightly stooped posture; could be normal for older person. 2 = Moderately stooped posture, definitely abnormal; can be slightly leaning to one side. 3 = Severely stooped posture with kyphosis; can be moderately leaning to one side. 4 = Marked flexion with extreme abnormality of posture. 31. Removed 32. Gait 0 = Normal 1 = Walks slowly, may shuffle with short steps, but no festination or propulsion. 2 = Walks with difficulty, but requires little or no assistance; may have some festination, short steps, or propulsion.

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3 = Severe disturbance of gait, requiring assistance. 4 = Cannot walk at all, even with assistance. 33. Postural stability (response to sudden posterior displacement produced by pull on shoulders while patient erect with eyes open and feet slightly apart. Patient is prepared.) 0 = Normal 1 = Retropulsion, but recovers unaided. 2 = Absence of postural response, would fall if not caught by examiner. 3 = Very unstable, tends to loose balance spontaneously. 4 = Unable to stand without assistance. 34. Body bradykinesia (combining slowness, hesitancy, decreased armswing, small amplitude, and poverty of movement in general). 0 = None 1 = Minimal slowness, giving movement a deliberate character; could be normal for s ome persons. Possibly reduced amplitude. 2 = Mild degree of slowness, poverty of movement that is definitely abnormal. Alternatively, some reduced amplitude. 3 = Moderate slowness, poverty or small amplitude of movement. 4 = Marked slowness, poverty or small amplitude movement. COMPLICATIONS OF THERAPY (score these items to represent the status of the patient in the week prior to the examination) Dyskinesias 36. Duration—What proportion of the waking day are dyskinesias present? (historical information) 0 = None 1 = 1–25% of day 2 = 26–50% of day 3 = 51–75% of day 4 = 76–100% of day 37. Disability—How disabling are the dyskinesias? (historical information; may be modified by office examination) 0 = Not disabling 1 = Mildly disabling 2 = Moderately disabling 3 = Severely disabling 4 = Completely disabling 38. Pain—How painful are the dyskinesias? 0 = No painful dyskinesia 1 = Slight 2 = Moderate 3 = Severe 4 = Marked

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39. Presence of early morning dystonia (historical information) 0 = No 1 = Yes CLINICAL FLUCTUATIONS 40. “Off ” predictable—Are any “off ” periods predictable as to timing after a dose of medication? 0 = No 1 = Yes 41. “Off ” unpredictable—Are any “off ” periods unpredictable as to timing after a dose of medication? 0 = No 1 = Yes 42. “Off ” sudden—Do any of the “off ” periods come on suddenly, for example, over a few seconds? 0 = No 1 = Yes 43. “Off ” duration—What proportion of the waking day is the patient “off ” on average? 0 = None 1 = 1–25% of day 2 = 26–50% of day 3 = 51–75% of day 4 = 76–100% of day OTHER COMPLICATIONS 44. Does the patient have anorexia, nausea, or vomiting? 0 = No 1 = Yes 45. Does the patient have any sleep disturbances, for example, insomnia or hypersomnolence? 0 = No 1 = Yes 46. Does the patient have symptomatic orthostasis? 0 = No 1 = Yes MODIFIED HOEHN AND YAHR STAGING Stage 0 = No signs of disease Stage I = Unilateral disease Stage I.5 = Unilateral disease plus axial involvement Stage II = Bilateral disease, without impairment of balance

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Stage II.5 = Mild bilateral disease, with recovery on pull test Stage III = Mild to moderate bilateral disease; some postural instability; physically independent Stage IV = Severe disability; still able to walk or stand unassisted Stage V = Wheel chair bound or bedridden unless aided MODIFIED SCHWAB AND ENGLAND ACTIVITIES OF DAILY LIVING SCALE 100%—Completely independent. Able to do all chores without slowness, difficulty, or impairment. Essentially normal. Unaware of any difficulty. 90%—Completely independent. Able to do all chores with some degree of slowness, difficulty, and impairment. Might take twice as long. Beginning to be aware of difficulty. 80%—Completely independent in most chores. Takes twice as long. Conscious of difficulty and slowness. 70%—Not completely independent. More difficultly some chores. Three to four times as long in some. Must spend a large part of the day with chores. 60%—Some dependency. Can do most chores, but exceeding slowly and with much effort. Errors; some impossible. 50%—More dependent. Help with half, slower, etc. Difficulty with everything. 40%—Very dependent. Can assist with all chores, but few alone. 30%—With effort, now and then does a few chores alone or begins alone. Much help needed. 20%—Nothing alone. Can be a slight help with some chores. Severe invalid. 10%—Totally dependent, helpless. Complete invalid. 0%—Vegetative functions such as swallowing, bladder, and bowel functions do not function. Bed-ridden.

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Autonomic Dysfunction and Management Richard B. Dewey, Jr. Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.

Although Parkinson’s disease (PD) is commonly regarded as a disorder of dopamine deficiency, it is actually a multisystem degenerative disorder. As nondopaminergic brain pathways are involved in the genesis of many symptoms, these cannot be successfully treated by merely increasing brain dopaminergic stimulation. The autonomic symptoms fall into this category, and thus management is often challenging. The autonomic features of PD affect cardiovascular function, gastrointestinal (GI) motility, urinary bladder function, sexual ability, and thermal regulation. A list of the common symptoms and signs of autonomic dysfunction is shown in Table 1. Although symptoms of autonomic failure typically present later in the course of the disease, rare case reports exist of autonomic abnormalities as the presenting feature (1). This chapter will outline the common autonomic features of PD and discuss treatment approaches for each. FREQUENCY OF AUTONOMIC DYSFUNCTION IN PARKINSON’S DISEASE Although the focus of routine follow-up visits between PD patients and neurologists is typically on motor symptoms of the disease, autonomic problems are frequently present and can be identified if patients are specifically asked. In one study of 48 men with PD, 89% had at least one autonomic symptom compared with 43% of elderly control subjects (2). Autonomic symptoms seen in these men with PD included erectile dysfunction (60%), urinary urgency (46%), constipation (44%), dysphagia (23%), and orthostatism (22%), and each of these symptoms was more common in PD patients than controls. Siddiqui et al. (3) performed a comprehensive symptom survey of autonomic symptoms in 44 patients with PD, comparing the frequency and severity of these symptoms with 24 aged-matched controls. Using a five point scale to rate symptom severity, the authors tabulated the severity of symptoms in each of five areas: GI, urinary, sexual dysfunction, cardiovascular, and thermoregulatory. They found that PD patients exhibited autonomic symptoms more frequently than controls. Significant differences were seen in the following areas: increased salivation (52% vs. 13%), dysphagia (30% vs. 8%), constipation (20% vs. 0%), and orthostatism (66% vs. 29%). DIAGNOSTIC TESTING FOR AUTONOMIC DYSFUNCTION IN PARKINSON’S DISEASE Although simple questioning can identify the presence of autonomic symptoms and lead to initiation of treatment, diagnostic testing may be helpful in confirming the presence of autonomic involvement. Certain studies can also be useful for discriminating PD from multiple system atrophy (MSA), whereas other studies are not useful in this differential diagnosis. 77

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Dewey TABLE 1 Autonomic Features of Parkinson’s Disease Cardiovascular Orthostatic hypotension Decreased heart rate variability Decreased MIBG cardiac scintigraphy Cardiac arrhythmias Gastrointestinal Impaired swallowing Drooling Constipation Delayed gastric emptying Urinary bladder Frequency Urgency Urge incontinence Nocturia Sexual dysfunction Decreased desire Decreased arousal Reduced attainment of orgasm Erectile dysfunction Sexual dissatisfaction Sweating abnormalities Hyperhidrosis Anhydrosis Abbreviation: MIBG, [123I]metaiodobenzylguanidine.

[123I]Metaiodobenzylguanidine Scintigraphy [123I]Metaiodobenzylguanidine (MIBG) is a norepinephrine analog, which is transported into and stored in the terminals of sympathetic nerve endings. MIBG uptake is expressed as a ratio of single photon emission computed tomography signal in heart to that of the upper mediastinum. The lower the ratio, the fewer are the functioning sympathetic nerve terminals in the heart. A number of studies have looked at the sympathetic innervation of cardiac muscle in PD patients using this technique, and all have shown that MIBG uptake in myocardium is significantly less in PD than in matched controls (4). Courbon et al. (5) compared MIBG uptake in two groups of patients with PD: those with normal autonomic function tests and those with overt dysautonomia. They found that patients without dysautonomia had impaired MIBG uptake, just like patients with overt autonomic symptoms. They concluded that MIBG scintigraphy is a sensitive marker of PD, even in patients without autonomic symptoms. Orimo et al. (6) used this technique to compare MIBG uptake in PD patients, normal controls, neurological controls (essential tremor, vascular parkinsonism), and in patients with MSA. They found that the ratio of MIBG uptake in heart to mediastinum was decreased in 84% of PD patients, compared with normal controls. This uptake ratio was lower in more advanced compared with earlier stage PD patients, a finding which has been replicated using fluorodopa positron emission tomography (PET) scanning (7). The MIBG uptake ratio was not significantly different from controls in patients with essential tremor, vascular parkinsonism, or MSA (6). Thus, although MSA can be difficult to differentiate from PD with autonomic failure on clinical grounds, a number of studies have suggested that MIBG scintigraphy may be useful in making this distinction; PD patients have decreased uptake with MSA patients having relatively normal uptake.

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In addition to being helpful at differentiating PD from mimicking conditions, autonomic involvement of the heart appears to be an early finding in PD. Spiegel et al. (8) performed MIBG scintigraphy in 18 PD patients with Hoehn and Yahr stage I disease, who were demonstrated to be levodopa-responsive. They found that 13 patients (72%) had significantly reduced cardiac tracer accumulation indicating that in most PD patients, autonomic involvement of the myocardium is an early finding and might be useful in helping to differentiate PD from other conditions. Several authors have performed pathologic studies on postmortem cardiac tissue in an effort to visualize the sympathetic denervation associated with PD. These studies have shown a near complete loss of sympathetic axons in nerve fascicles of the epicardium (9,10), with Lewy bodies being found in the cardiac plexus (11,12). In one study, five of nine patients with Lewy bodies in the sinoatrial node had atrial cardiac arrhythmias during their life, suggesting that the sympathetic involvement of the heart in PD might predispose to cardiac arrhythmias (12). Autonomic Testing An exhaustive review of the various tests of autonomic function in PD is beyond the scope of this chapter. Briefly, the tests that have been commonly employed in the study of PD autonomic failure include heart rate variation (with deep breathing and valsalva), tilt table testing for orthostatism, sudomotor axon reflex testing, and thermoregulatory sweat testing. Abnormalities may be seen in one or more of these depending on the presenting symptoms. Several studies have suggested that as a group, autonomic failure is more severe in MSA than in PD, but these studies often use the severity of autonomic failure to help assign the diagnosis; the more severe the autonomic symptoms, the more likely the patient will be classified as having MSA. Riley and Chelimsky (13) have noted the circular nature of this reasoning and performed a comparative study of autonomic tests in patients with PD and MSA, in whom autonomic failure was not used for diagnosis. They found a high frequency of abnormal test results in patients with dysautonomia with both PD and MSA, and the severity of autonomic failure did not differ between the groups. They suggested that thermoregulatory sweat testing might be the most sensitive test for PD-related autonomic failure, since all patients with dysautonomia with either diagnosis who received this test had abnormal results. There is some controversy on whether quantitative sudomotor axon reflex testing (QSART) is helpful for detecting sympathetic dysfunction in PD. In one study (14), patients with abnormal blood pressure responses to valsalva and decreased cardiac fluorodopa PET scanning (indicating sympathetic dysfunction) had normal QSART test results. They interpreted this finding as indicating that the sympathetic dysfunction in PD involves the loss of noradrenergic but not cholinergic function. A number of studies (15–18) have confirmed that heart rate variability is decreased in patients with PD. SYMPTOMS AND MANAGEMENT OF AUTONOMIC DYSFUNCTION IN PARKINSON’S DISEASE Orthostatic Hypotension A significant drop in systolic blood pressure when moving from sitting or lying to the standing position is undoubtedly one of the most important symptoms of autonomic failure seen in PD. Orthostatism can be either symptomatic, in which patients complain of lightheadedness, dizziness or actual syncope, or asymptomatic in spite of

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significant drops in systolic blood pressure. When symptomatic, orthostatic hypotension can lead to significant disability including wheelchair or even bed confinement. Estimates of the frequency of orthostatic hypotension vary. A communitybased study conducted in U.K. found that 47% of a group of 89 patients enrolled had orthostatic hypotension, as defined by a drop of 20 mmHg when standing from a supine position or to a systolic pressure of less than 90 mmHg (19). They did not find an association between PD severity and the presence of orthostatic hypotension. In a study of early, untreated PD 14% of 51 patients met similar criteria for orthostatic hypotension (20). The strength of this study is that all patients were followed for at least seven years, and 9 of 60 patients were excluded from the analysis due to the development of other symptoms making the diagnosis of idiopathic PD insecure. Additionally, because all patients were evaluated before they began antiparkinsonian medications, the confounding effect of drugs was not a factor in this study. This is an important consideration, as dopaminergic therapy is believed to aggravate orthostatism in patients with parkinsonism and autonomic failure. On the other hand, a comparative study of orthostatic blood pressure measurements in PD patients in both “off ” and “on” states did not show a significant difference, indicating that blood pressure dysregulation is due mostly to neuropathologic changes rather than to the effect of dopaminergic drugs (21). The underlying mechanism of orthostatic hypotension in PD and MSA has been studied. Goldstein et al. (22) noted that since patients with PD and orthostatic hypotension have cardiac sympathetic denervation (as shown consistently in studies of MIBG uptake) while MSA patients do not, the mechanism producing orthostatic hypotension must be different. They measured venous catecholamines and metanephrines, finding low levels of normetanephrine and dihydroxyphenylglycol in patients with PD and orthostatic hypotension, whereas in patients with MSA and orthostatic hypotension, normal levels were found. They concluded that in MSA, there is dysregulation but not loss of catecholamine secreting cells in the adrenal medulla and sympathetic nervous system, whereas in PD, there is loss of sympathetic nervous system cells with relative sparing of the adrenal medullary system. Pathologically, studies have shown cell loss in the intermediolateral nucleus of the spinal cord in PD with Lewy bodies being found in the hypothalamus, sympathetic ganglia, sacral parasympathetic nuclei, and the GI tract. This widespread distribution of cell loss in structures important for autonomic function indicated that the dysautonomia seen in PD is due to both central and peripheral autonomic nervous system involvement (23,24). In addition to the hypotension seen in PD patients when in the upright position, the autonomic dysfunction in PD leads often to supine hypertension at night. Plaschke et al. (25) performed 24-hour ambulatory blood pressure monitoring in PD patients with and without dysautonomia. They found that nocturnal mean arterial pressure was significantly higher in PD patients with dysautonomia (and in MSA patients) than in PD patients without autonomic symptoms. They suggested that supine hypertension may increase the risk of stroke in such patients. Management of orthostatism begins with simple physical measures and progresses to drug therapy when severe. All patients with symptomatic orthostatic hypotension should be advised to raise the head of their bed by about 30 degrees. This maneuver activates the renin–angiotensin system and reduces salt excretion by the kidneys, thus increasing blood pressure. Patients should also consider liberalizing dietary salt, preferably by salting their food rather than by taking salt tablets, which may pass unabsorbed through the GI tract. Support hose are often recommended as

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well, but compliance with this measure is often poor, especially in men. When orthostatic hypotension is mild, these physical measures may be sufficient. For more severe orthostatic hypotension, fludrocortisone acetate is typically recommended at a dose of 0.1 to 0.2 mg daily. This drug promotes salt retention by the kidney, which in turn increases plasma volume and systemic blood pressure. Patients frequently develop mild ankle edema, which is evidence that this therapy is actually working. All patients taking fludrocortisone should receive periodic testing for serum potassium, as this ion is excreted from the kidney as sodium is retained. Potassium replacement therapy should be initiated if the levels fall outside the normal range. For those in whom physical measures and fludrocortisone are insufficient to eliminate symptomatic orthostatic hypotension, pressor agents should be considered. Examples of drugs in this class with efficacy in orthostatic hypotension include ergotamine/caffeine (26), ephedrine (27), and indomethacin (28). Midodrine hydrochloride, approved for orthostatic hypotension in 1996, has been specifically studied as a treatment for symptomatic neurogenic orthostatic hypotension in PD (29). This drug has been shown to exhibit a dose-related increase in mean systolic blood pressure with the effect peaking at 1 hour (30). Due to its short half-life, the drug may need to be given three times daily during the waking day at doses ranging from 2.5 to 10 mg per administration. Care should be given not to give the drug late in the day, since supine hypertension may result after the patient retires for the night. Some PD patients with milder degrees of autonomic failure may develop orthostatic hypotension only after meals, so-called postprandial hypotension. This is believed to be related to a shunting of blood flow to the myenteric region with resulting diminished blood flow to the brain. In this case, midodrine could be administered right before a large meal to counteract this effect. Some patients find that several cups of coffee (containing caffeine) taken before or with meals may also help with postprandial orthostatic hypotension. Dysphagia Swallowing difficulty is common in PD; in one small series of 13 patients, it was seen in 77% of patients (31). Potulska et al. (32) recruited 18 PD patients for detailed swallowing studies of which 13 had symptomatic dysphagia. All patients, including the five who had no swallowing complaints, had prolongation of esophageal bolus transport suggesting that autonomic impairment of swallowing may occur early. Patients who complained of dysphagia had abnormalities of the oral and pharyngeal stages of swallowing. Since the oral phase of swallowing is under voluntary control, some have suggested that oral phase dysphagia is due to bradykinesia of the swallowing musculature. Evidence supporting this idea comes from a study of dyskinetic and nondyskinetic patients showing that the dyskinetic ones had better swallowing efficiency, perhaps due to a more optimal dosage of levodopa (33). On the other hand, another study of 15 patients who had swallowing studies before and after a dose of levodopa showed minimal improvement following the drug, suggesting that the main problem is due to autonomic failure, not dopaminergic deficiency affecting skeletal muscle control (34). Management of dysphagia in PD is entirely empiric. A recent review by the Cochrane Collaboration (35) uncovered no randomized trials dealing with nonpharmacological treatments for dysphagia in PD, and thus no recommendations for therapy could be made. Sharkawi et al. (36) performed an uncontrolled pilot study of the Lee Silverman Voice Treatment (LSVT) for dysphagia in PD, in which

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a modified barium swallow was done before and one month after LSVT in a group of eight patients. They reported that abnormalities of swallowing improved by 51% after therapy, principally by improving tongue base function during the oral and pharyngeal phases of swallowing. As this was a small uncontrolled study, further work is necessary to establish whether speech therapy is helpful for dysphagia in PD. Anecdotally, it has been suggested that patients with dysphagia employ the “chin-down” posture when swallowing (37) and consider adding thickeners to liquids before drinking. Since dysphagia is a significant risk factor for aspiration pneumonia (the cause of death in many patients with advanced PD), when this problem becomes severe, patients should consider placement of a percutaneous gastrostomy tube. Sialorrhea The presence of excessive saliva in the mouth with resultant drooling is a common problem in PD with estimates of up to 77% of patients being affected (31). When severe, patients will often complain bitterly about the problem and may request drug treatment to deal with it. Although the clinical impression of the physician is often that the patient has too much saliva, this turns out not to be the case. Proulx et al. (38) studied 83 PD patients and 55 controls by collecting saliva secreted over a fiveminute period. They found that the PD patients secreted significantly less saliva than the normal controls and that levodopa use was a contributor to this reduced salivary output. It has also been demonstrated that de novo patients, not yet treated with dopaminergic drugs, have decreased salivary production (39). These studies suggest that although dopaminergic drugs may exacerbate the problem, decreased salivary production may be an early sign of autonomic involvement in PD. If PD patients secrete less saliva than normals, why do they drool and appear to have excess saliva? The most likely explanation is that PD patients exhibit a decreased frequency of automatic swallowing, and when combined with a forward tilt of the head (common particularly in advanced PD), drooling results (38). The treatment of drooling in PD has been attempted with anticholinergic drugs such as benztropine, scopolamine, and glycopyrrolate; the latter having been recommended as the agent with the fewest troublesome side effects (40). Most recently, several authors have reported results of botulinum toxin injections as a treatment for drooling in PD. Mancini et al. (41) injected 450 U of botulinum toxin type-A (Dysport®) into the parotid and submandibular glands using ultrasonographic guidance in PD and MSA patients with disabling sialorrhea. They reported a reduction of drooling within one week that lasted about a month and was unassociated with adverse effects such as dysphagia. Dogu et al. (42) compared ultrasound-guided botulinum toxin injections (Botox®) in the parotid gland with blind injections (using no guidance) and measured postinjection salivary output in the two groups. Although subjective sialorrhea improved in both groups, the group receiving ultrasound guidance experienced a significant reduction in salivary output, whereas the blind injection group did not. The authors concluded that ultrasound guidance is necessary to ensure success with botulinum toxin injections for this purpose. Ondo et al. (43) evaluated the effects of botulinum toxin type-B (Myobloc®) as a treatment for sialorrhea. In this study, ultrasound-guided injections with 2500 U of active drug was compared to placebo injections. Efficacy was evaluated by use of a visual-analog scale, questionnaires, and by salivary gland scintigraphy. The active drug group experienced significant improvement in all measures when compared with the placebo group. While there is

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considerable enthusiasm in the literature for various treatments for sialorrhea aimed at drying up saliva, it must be kept in mind that increased salivary production is not the problem in PD and that these patients already have reduced salivary output. Since saliva is an important component of oral health, drugs and procedures that reduce oral saliva may potentially lead to increased tooth decay (38). Although this has not yet been systematically studied, caution is required in the use of these agents. Constipation Constipation is a very common complaint among patients with PD and is probably multifactorial in origin. Frequency estimates vary, but in one study of 94 patients, 71% were constipated as defined by less than one bowel movement in three days (44). Although the neuropathology of PD itself is a major causative factor, these authors pointed out in addition that PD patients have a significantly reduced water intake per day when compared with controls. Further questioning of these constipated PD patients revealed that, in most, decreased water drinking preceded the onset of constipation. Braak et al. (45) observed that the neuropathology of PD begins in the glossopharyngeal and vagal nerves and then spreads caudally into the brainstem where the substantia nigra becomes affected. In accordance with this finding, Singaram et al. (46) counted neurons in the myenteric plexus of the colon and found that 9 of 11 PD patients had fewer intact dopaminergic neurons in the colon compared with controls. Since this is an early finding, one would expect constipation to precede the onset of motor symptoms of PD and, in fact, several careful studies have affirmed this supposition. Abbott et al. (47,48) reporting on the long-term follow-up of 6790 men in the Honolulu Heart Program observed that the incidence of PD was higher in those with constipation than in those without (18.9/10,000 person-years vs. 3.8/10,000 person-years). Patients whose constipation was resistant to treatment had the highest incidence of developing PD during the follow-up period (51.6/10,000 person-years). The main strength of this study was the elimination of recall bias through the study design, which asked patients about bowel habits an average of 12 years before they developed PD. In addition to slowed colonic motility due to dopaminergic denervation of the GI tract, anal sphincter dysfunction has been reported in PD patients, which may contribute to constipation. Mathers (49) described paradoxical anal sphincter muscle contraction during simulated defecation straining in five of six patients with PD studied with anal electromyography (EMG), and they suggested, based on this finding, that functional anal outlet obstruction may contribute to constipation. In four of these patients, they noted improvement in the defecatory mechanism following apomorphine, suggesting that this anal dyscoordination may occur on the basis of dopaminergic deficiency. Stocchi et al. (50) confirmed the finding of impaired anal relaxation during straining in PD and added that anal sphincter EMG was normal in PD patients; by comparison, sphincter EMG in MSA patients showed denervation and chronic neurogenic signs. Antiparkinsonian medication has been implicated as another factor contributing to constipation in PD. The literature is conflicting on whether drugs have a significant effect on colonic motility, and perhaps the most reasonable answer is that drug therapy is not the primary cause of constipation, but in some cases may aggravate the condition. This is probably most important for anticholinergic agents, which are known to reduce intestinal motility (51).

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As the cause of constipation in PD is multifactorial, its management requires a multimodality approach. All patients should be advised to increase daily water consumption and add bulking agents to the diet, such as psyllium preparations and high-fiber foods; however, rarely is this sufficient therapy. Cisapride, a prokinetic agent that directly stimulates acetylcholine release in the gut, has been shown to improve constipation and shorten colonic transit time in PD (52). However, this drug was withdrawn from the market in most countries due to QT prolongation and its proarrhythmic effect in some patients. Mosapride citrate is a newly synthesized agent with a similar mechanism of action as cisapride but without known cardiac toxicity. It was recently studied using an open-label design in 14 patients with PD and MSA, where it was well tolerated and effective in producing subjective improvement in bowel frequency and difficult defecation (53). The value of this agent remains to be validated by placebo-controlled trials. Of agents that are currently available for the treatment of constipation, the osmotic laxative polyethylene glycol (Miralax) has been shown to be safe and effective in randomized clinical trials, though none of these have been conducted specifically in PD patient populations (54–56). Although a 17- or 34-gm daily dose has been shown to improve bowel movement frequency within two weeks, a 68-gm dose has been more recently recommended to produce a bowel movement in most constipated patients within 24 hours. For the minority of constipated PD patients in whom anal outlet obstruction is the suspected cause (presumably due to paradoxical contraction of the puborectalis muscle during straining), botulinum toxin type-A injections of 100 U into this muscle under transrectal ultrasonographic guidance has been shown to be effective in a small open-label trial (57). The duration of benefit was not measured and this finding needs to be confirmed using controlled trials before it can be recommended. Urinary Bladder Dysfunction The most frequent urinary complaints in PD patients are frequency, urgency, urge incontinence, and nocturia. Hobson et al. (58) performed a community-based questionnaire survey in Wales, U.K., and found that bladder problems were reported in 51% of 123 PD patients returning the survey compared to 31% of 92 controls. The calculated relative risk of developing bladder symptoms in PD patients compared to controls was 2.4. Lemack et al. (59) performed a similar questionnaire-based assessment of bladder problems in PD patients, but selected early-stage patients (Hoehn and Yahr stage 2.5 or lower) to determine if bladder problems occur early in the disease. Men with early PD assessed using the American Urological Association Symptom Index had a mean score of 12 compared to the community sample of normal male volunteers whose mean score was 4.8. Significant differences were seen on questions for frequency, urgency, and weak urinary stream. Women completed the Urogenital Distress Inventory-6 where PD patients had a mean score of 4.8 compared to 2.1 for normal controls. There was no correlation between bladder dysfunction and any measure of motor severity of PD except for gait speed, which was significantly slower in patients with higher scores for bladder dysfunction. This observation suggests that neural pathways for gait and bladder control might be involved in parallel by the degenerative process of PD. Urodynamic studies have been conducted in small samples of PD patients with persistent bladder complaints to elucidate the nature of the problem. Berger et al. (60) studied 29 patients and found that detrusor hyperreflexia was present in 90% and that incomplete sphincter relaxation during involuntary detrusor contractions as shown

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by EMG was present in 61%. Winge et al. (61) conducted detailed urodynamic studies in 32 PD patients without regard to whether they had bladder symptoms. Using the Danish Prostate Symptom Score (Dan-PSS), they found that 43.8% of patients met criteria for symptomatic bladder dysfunction. Irritative bladder symptoms were more commonly seen in patients with greater severity of PD as assessed by motor scoring. On urodynamic testing, bladder capacity was lower in the group with high Dan-PSS scores, and capacity increased when dopaminergic drugs were administered. Detrusor overactivity was also seen in this group, but medication administration did not impact this feature. The authors suggested that since bladder capacity improved following dopaminergic drugs, dopamine deficiency may in part underlie the irritative bladder symptoms in PD. Whether this is due primarily to central or peripheral dopaminergic cell degeneration is unknown. The treatment of bladder dysfunction in PD is difficult due to its often multifactorial origin. For instance, in men with irritative bladder symptoms, prostatic hypertrophy may be a contributor to outlet obstruction. For this reason, patients with symptomatic bladder dysfunction should be referred to a urologist with experience in evaluating and managing the bladder problems of PD patients. Generally, treatment will be initiated only after appropriate urodynamic testing is completed. Once a significant obstructive component has been ruled out, treatment of patients with hyperactive detrusor can begin with drugs such as tolterodine (62), oxybutnin (63), or imipramine (64). Patients with nocturia should also be advised to avoid water intake in the evening. Sexual Dysfunction Though PD patients rarely complain of sexual difficulties, if specifically asked, dysfunction in this area is very common. Bronner et al. (65) performed a comprehensive assessment of sexuality in 75 patients (32 women, 43 men) with PD who did not complain of problems in this area. Using specific sexual function scales, they asked patients to rate their sexuality currently and retrospectively before the onset of their PD. They found that in men, 68% had erectile dysfunction, 65% were dissatisfied with their sexual life, and 40% had difficulty reaching orgasm. In women, the major problems were difficulty getting aroused (88%), difficulty reaching orgasm (75%), and decreased sexual desire (47%). Comparing scores before PD onset to the present, most patients reported a deterioration in sexual functioning with the progression of PD. Using stepwise regression, the authors found that in men, associated disease, medications, and severity of PD predicted sexual dysfunction, whereas in women, levodopa use appeared to decrease sexual desire. The underlying neuroanatomical substrate for sexual dysfunction in PD is complex and poorly understood. The central dopaminergic system is known to be important for sexual functioning, but conflicting data exist on whether dopaminergic drugs have a beneficial or harmful effect on sexual performance. Erectile dysfunction in men is probably due mainly to autonomic degeneration with the progression of PD. Treatment of the many facets of sexual dysfunction in PD is complex, and most recommend that special attention be given to ascertaining this problem (since patients will rarely volunteer it during a routine visit) and that sexual counseling be offered to those in whom problems are identified. Erectile dysfunction in men has received specific attention in the literature, and several drugs have been tested as therapeutic agents for this problem. Sublingual apomorphine, a potent D1- and

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D2-dopamine agonist, has been studied in a rigorous clinical trial and found to be effective at improving erectile dysfunction due to several different etiologies, although it has not been specifically studied in PD patients (66). Sublingual apomorphine is not available in the United States. The dopamine agonist pergolide has been found to improve sexual function in PD patients, presumably also via a central dopaminergic mechanism (67). Several studies have evaluated the effects of sildenafil in PD patients with erectile dysfunction. An open-label pilot study (68) showed that in 10 men, sildenafil improved sexual satisfaction, erectile function, and the ability to reach orgasm. In a larger open-label study (69) of 33 depressed male PD patients given a fixed dose of 50 mg of sildenafil one hour before sexual activity, 84.8% reported improved erections. A double-blind, placebo-controlled crossover study compared the efficacy and adverse effects of sildenafil in 12 patients with PD to 12 patients with MSA (70). Using the international index of erectile dysfunction as the primary efficacy parameter, they found that 9 of 10 PD patients completing the study had improved erectile function when assigned to active drug. There was a slight but asymptomatic decline in mean blood pressure measurements one hour after active drug ingestion in the PD patients. In contrast, although the MSA patients had improved erectile function on active drug, severe, symptomatic orthostatic declines in blood pressure were seen in three patients one hour after ingestion of the active drug, leading to discontinuation of recruitment of MSA patients into the study. Sweating Dysfunction Hyperhidrosis is a problem in some patients with PD, and when severe, this symptom can be severely disabling. Little is known about the problem due to a paucity of careful studies. A small study (71) demonstrated that PD patients generate more sweat when exposed to heat than control patients and that excessive sweating increases with disease severity. Swinn et al. (72) recruited 77 consecutive PD patients and 40 controls for a study of sweating. The authors designed their own questionnaire to evaluate sweating, which consisted of 41 questions. PD patients were much more likely than controls to report excess sweating, particularly episodes of whole body, drenching sweats (44% of PD patients vs. 10% of controls). Hypohidrosis was also reported, but the frequency in PD patients was not significantly different from controls. PD patients tended to experience sweating episodes when they were “off ” or “on” with dyskinesia and 70% of patients who had dyskinesia reported excessive sweating. Sweating problems did not appear to be related to disease duration or severity. Other autonomic symptoms (urinary frequency and sialorrhea) were correlated with excess sweating. Patients who experienced drenching sweats had an impaired quality of life. Treatment of sweating problems in PD is difficult, and no clear guidelines or evidence-based recommendations exist. Since some episodes are associated with off periods and others with dyskinesia, efforts should be made to reduce off time as much as possible while avoiding dyskinesia by adjusting antiparkinsonian medications. Although some have suggested treatment with L-dihydroxyphenylalanine or beta blockers, no studies have been published which evaluate these treatments in PD (73). Although there is a growing literature on the treatment of focal hyperhidrosis with botulinum toxin injections (74–78), this therapy has not been studied in PD-related sweating disorders and would not be expected to be applicable to those patients with whole-body drenching sweats due to the practical problem of administering the drug to the target tissue. Beyond attempted pharmacological

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treatments, Swinn et al. (72) suggest that PD patients with hyperhidrosis be counseled to avoid hot environments, overactivity, or poorly ventilated clothing. SUMMARY Autonomic symptoms are common in patients with PD, though often under-recognized. As in the case of constipation, evidence for autonomic dysfunction may precede the onset of motor features by years; however, most autonomic symptoms increase in severity with the progression of motor disability. Careful attention by treating physicians to the autonomic features of PD is necessary in order to recognize these problems early and begin treatment in a timely fashion. In most areas of autonomic dysfunction in PD, the field remains in its infancy with many additional studies being needed to better understand the pathophysiology of the problem and to discover more effective treatments. REFERENCES 1. Kaufmann H, Nahm K, Purohit D, Wolfe D. Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 2004; 63:1093–1095. 2. Singer C, Weiner WJ, Sanchez-Ramos JR. Autonomic dysfunction in men with Parkinson’s disease. Eur Neurol 1992; 32:134–140. 3. Siddiqui MF, Rast S, Lynn MJ, Auchus AP, Pfeiffer RF. Autonomic dysfunction in Parkinson’s disease: a comprehensive symptom survey. Parkinsonism Relat Disord 2002; 8:277–284. 4. Taki J, Yoshita M, Yamada M, Tonami N. Significance of 123I-MIBG scintigraphy as a pathophysiological indicator in the assessment of Parkinson’s disease and related disorders: it can be a specific marker for Lewy body disease. Ann Nucl Med 2004; 18:453–461. 5. Courbon F, Brefel-Courbon C, Thalamas C, et al. Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson’s disease. Mov Disord 2003; 18:890–897. 6. Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H. (123)I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999; 67:189–194. 7. Li ST, Dendi R, Holmes C, Goldstein DS. Progressive loss of cardiac sympathetic innervation in Parkinson’s disease. Ann Neurol 2002; 52:220–223. 8. Spiegel J, Mollers MO, Jost WH, et al. FP-CIT and MIBG scintigraphy in early Parkinson’s disease. Mov Disord 2005; 20:552–561. 9. Amino T, Orimo S, Itoh Y, Takahashi A, Uchihara T, Mizusawa H. Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol 2005; 15:29–34. 10. Orimo S, Oka T, Miura H, et al. Sympathetic cardiac denervation in Parkinson’s disease and pure autonomic failure but not in multiple system atrophy. J Neurol Neurosurg Psychiatry 2002; 73:776–777. 11. Iwanaga K, Wakabayashi K, Yoshimoto M, et al. Lewy body-type degeneration in cardiac plexus in Parkinson’s and incidental Lewy body diseases. Neurology 1999; 52:1269–1271. 12. Okada Y, Ito Y, Aida J, Yasuhara M, Ohkawa S, Hirokawa K. Lewy bodies in the sinoatrial nodal ganglion: clinicopathological studies. Pathol Int 2004; 54:682–687. 13. Riley DE, Chelimsky TC. Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson’s disease. J Neurol Neurosurg Psychiatry 2003; 74: 56–60. 14. Sharabi Y, Li ST, Dendi R, Holmes C, Goldstein DS. Neurotransmitter specificity of sympathetic denervation in Parkinson’s disease. Neurology 2003; 60:1036–1039. 15. Devos D, Kroumova M, Bordet R, et al. Heart rate variability and Parkinson’s disease severity. J Neural Transm 2003; 110:997–1011. 16. Gurevich TY, Groozman GB, Giladi N, Drory VE, Hausdorff JM, Korczyn AD. R-R interval variation in Parkinson’s disease and multiple system atrophy. Acta Neurol Scand 2004; 109:276–279.

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42. Dogu O, Apaydin D, Sevim S, Talas DU, Aral M. Ultrasound-guided versus ‘blind’ intraparotid injections of botulinum toxin-A for the treatment of sialorrhoea in patients with Parkinson’s disease. Clin Neurol Neurosurg 2004; 106:93–96. 43. Ondo WG, Hunter C, Moore W. A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson’s disease. Neurology 2004; 62:37–40. 44. Ueki A, Otsuka M. Life style risks of Parkinson’s disease: association between decreased water intake and constipation. J Neurol 2004; 251(suppl 7):VII18–VII23. 45. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24:197–211. 46. Singaram C, Ashraf W, Gaumnitz EA, et al. Dopaminergic defect of enteric nervous system in Parkinson’s disease patients with chronic constipation. Lancet 1995; 346:861–864. 47. Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology 2001; 57:456–462. 48. Abbott RD, Ross GW, White LR, et al. Environmental, life-style, and physical precursors of clinical Parkinson’s disease: recent findings from the Honolulu-Asia Aging Study. J Neurol 2003; 250(suppl 3):III30–III39. 49. Mathers SE, Kempster PA, Law PJ, et al. Anal sphincter dysfunction in Parkinson’s disease. Arch Neurol 1989; 46:1061–1064. 50. Stocchi F, Badiali D, Vacca L, et al. Anorectal function in multiple system atrophy and Parkinson’s disease. Mov Disord 2000; 15:71–76. 51. Jost WH, Eckardt VF. Constipation in idiopathic Parkinson’s disease. Scand J Gastroenterol 2003; 38:681–686. 52. Jost WH, Schimrigk K. Cisapride treatment of constipation in Parkinson’s disease. Mov Disord 1993; 8:339–343. 53. Liu Z, Sakakibara R, Odaka T, et al. Mosapride citrate, a novel 5-HT4 agonist and partial 5-HT3 antagonist, ameliorates constipation in parkinsonian patients. Mov Disord 2005; 20:680–686. 54. Cleveland MV, Flavin DP, Ruben RA, Epstein RM, Clark GE. New polyethylene glycol laxative for treatment of constipation in adults: a randomized, double-blind, placebocontrolled study. South Med J 2001; 94:478–481. 55. Di Palma JA, Smith JR, Cleveland M. Overnight efficacy of polyethylene glycol laxative. Am J Gastroenterol 2002; 97:1776–1779. 56. DiPalma JA, DeRidder PH, Orlando RC, Kolts BE, Cleveland MB. A randomized, placebocontrolled, multicenter study of the safety and efficacy of a new polyethylene glycol laxative. Am J Gastroenterol 2000; 95:446–450. 57. Albanese A, Brisinda G, Bentivoglio AR, Maria G. Treatment of outlet obstruction constipation in Parkinson’s disease with botulinum neurotoxin A. Am J Gastroenterol 2003; 98:1439–1440. 58. Hobson P, Islam W, Roberts S, Adhiyman V, Meara J. The risk of bladder and autonomic dysfunction in a community cohort of Parkinson’s disease patients and normal controls. Parkinsonism Relat Disord 2003; 10:67–71. 59. Lemack GE, Dewey RB Jr, Roehrborn CG, O’Suilleabhain PE, Zimmern PE. Questionnairebased assessment of bladder dysfunction in patients with mild to moderate Parkinson’s disease. Urology 2000; 56:250–254. 60. Berger Y, Blaivas JG, DeLaRocha ER, Salinas JM. Urodynamic findings in Parkinson’s disease. J Urol 1987; 138:836–838. 61. Winge K, Werdelin LM, Nielsen KK, Stimpel H. Effects of dopaminergic treatment on bladder function in Parkinson’s disease. Neurourol Urodyn 2004; 23:689–696. 62. Serels SR, Appell RA. Tolterodine: a new antimuscarinic agent for the treatment of the overactive bladder. Expert Opin Investig Drugs 1999; 8:1073–1078. 63. Diokno AC, Appell RA, Sand PK, et al. Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc 2003; 78: 687–695. 64. Clarke B. Anticholinergic medication for the unstable bladder: prospective trials of imipramine/propantheline versus penthienate and oxybutynin versus penthienate. Int Urogynecol J Pelvic Floor Dysfunct 1996; 7:191–195.

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65. Bronner G, Royter V, Korczyn AD, Giladi N. Sexual dysfunction in Parkinson’s disease. J Sex Marital Ther 2004; 30:95–105. 66. Von Keitz AT, Stroberg P, Bukofzer S, Mallard N, Hibberd M. A European multicentre study to evaluate the tolerability of apomorphine sublingual administered in a forced dose-escalation regimen in patients with erectile dysfunction. BJU Int 2002; 89:409–415. 67. Pohanka M, Kanovsky P, Bares M, Pulkrabek J, Rektor I. Pergolide mesylate can improve sexual dysfunction in patients with Parkinson’s disease: the results of an open, prospective, 6-month follow-up. Eur J Neurol 2004; 11:483–488. 68. Zesiewicz TA, Helal M, Hauser RA. Sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men with Parkinson’s disease. Mov Disord 2000; 15:305–308. 69. Raffaele R, Vecchio I, Giammusso B, Morgia G, Brunetto MB, Rampello L. Efficacy and safety of fixed-dose oral sildenafil in the treatment of sexual dysfunction in depressed patients with idiopathic Parkinson’s disease. Eur Urol 2002; 41:382–386. 70. Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ. Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson’s disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatry 2001; 71:371–374. 71. Turkka JT, Myllyla VV. Sweating dysfunction in Parkinson’s disease. Eur Neurol 1987; 26:1–7. 72. Swinn L, Schrag A, Viswanathan R, Bloem BR, Lees A, Quinn N. Sweating dysfunction in Parkinson’s disease. Mov Disord 2003; 18:1459–1463. 73. Feddersen B, Klopstock T, Noachtar S. Hyperhidrosis in Parkinson disease. Neurology 2005; 64:571. 74. Baumann L, Slezinger A, Halem M, et al. Pilot study of the safety and efficacy of Myobloc (botulinum toxin type B) for treatment of axillary hyperhidrosis. Int J Dermatol 2005; 44:418–424. 75. Glaser DA. Treatment of axillary hyperhidrosis by chemodenervation of sweat glands using botulinum toxin type A. J Drugs Dermatol 2004; 3:627–631. 76. Nelson L, Bachoo P, Holmes J. Botulinum toxin type B: a new therapy for axillary hyperhidrosis. Br J Plast Surg 2005; 58:228–232. 77. Solish N, Benohanian A, Kowalski JW. Prospective open-label study of botulinum toxin type A in patients with axillary hyperhidrosis: effects on functional impairment and quality of life. Dermatol Surg 2005; 31:405–413. 78. Vadoud-Seyedi J, Simonart T, Heenen M. Treatment of plantar hyperhidrosis with dermojet injections of botulinum toxin. Dermatology 2000; 201:179.

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Sleep Dysfunction Laura Nieder Neurology Department, Guy’s King’s and St Thomas’ School of Medicine, London, U.K.

K. Ray Chaudhuri Movement Disorders Unit, Kings College Hospital, University Hospital Lewisham and Guy’s King’s and St. Thomas’ School of Medicine, London, U.K.

INTRODUCTION The earliest description of sleep problems of Parkinson’s disease (PD) dates back to the original description of PD by James Parkinson. In his original monograph, he stated that “His attendants observed, that of late the trembling would sometimes begin in his sleep, and increase until it awakened him: when he always was in a state of agitation and alarm” (1). This may have been the first description of nocturnal akinesia, tremor and, perhaps, rapid eye movement (REM) behavior disorder (RBD) that complicate sleep of people with PD. In spite of sleep dysfunction being a key aspect of the nonmotor symptom complex of PD, it is only recently that sleep disturbances related to PD have received diagnostic and therapeutic attention (2–8). The issue of sleep dysfunction and its treatment has also become relevant, as evidence suggests that sleep problems are a key determinant of quality of life and effective treatment may improve overall quality of life (9,10). “Poor nights” for people with PD may occur not only in advanced PD, but also in early untreated PD or even prior to motor symptoms. Such morbidity may have a significant adverse effect on daytime functioning and functional capacity (such as driving), as well as quality of life (9–12). Certain sleep disorders may provide useful diagnostic information in differentiating between parkinsonian syndromes and may be important prognostic indicators of neuropsychiatric disturbance and dementia (13). EPIDEMIOLOGY AND SYMPTOMS Sleep dysfunction in PD is multifactorial, and as many as 98% of patients with PD may suffer at some time from nocturnal symptoms that can disturb their sleep (2). Overall prevalence figures range from 25% to 98% (2–4). A community-based study reported 60% of PD patients with sleep problems, compared with 33% of age- and sex-matched healthy controls (4). The NMSQuest study in 123 PD patients across all age groups and 96 age-matched controls, using a validated nonmotor symptom questionnaire in an international multicenter setting, identified high rates for a range of sleep-related disorders (14). Although some complaints such as nocturia (67%) were common in controls, other complaints such as insomnia (41%), intense/vivid dreams (31%), acting out during dreams (33%), restless legs (37%), and daytime sleepiness (28%) were more prevalent in PD and may reflect more fundamental dysfunction of sleep-related mechanisms. In another observational study, Hely et al. (15) evaluated PD patients for a period of 15 to 18 years after being recruited to a 91

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TABLE 1 Causes of Nighttime Sleep Disruption and Daytime Sleepiness in Parkinson’s Disease Patients Disease-related Insomnia Motor function

Urinary difficulties Neuropsychiatric/parasomnias

Treatment-related Motor

Urinary Neuropsychiatric

Sleep-altering medications

Fragmentation of sleep (sleep maintenance insomnia) Sleep-onset insomnia Akinesia (difficulty in turning) Restless legs/Akathisia Periodic limb movements of sleep Sensory problems (pain, paresthesia) Nocturia Nocturia with secondary postural hypotension Depression-related insomnia Vivid dreams Nightmares Sleep talking Nocturnal vocalizations Somnambulism Hallucinations Panic attacks REM behavior disorder Confusional awakenings Nocturnal off-period-related tremor Dystonia Dyskinesia Off-period-related pain/paresthesia/muscle cramps Off-period-related incontinence Hallucinations Vivid dreaming ? Off-period-related panic attacks ? REM behavior disorder Akathisia Alerting effect, nocturnal agitation

Abbreviation: REM, rapid eye movement;?, possible clinical phenomenon. Source: From Ref. 6.

bromocriptine versus levodopa trial. One-third of the original cohort was evaluated, and most had significant nonmotor symptoms including sleep disorders, which were more troublesome and disabling than the motor symptoms or levodopainduced dyskinesia. A study by Shulman et al. (16) reported that nonmotor symptoms of PD are frequently overlooked, even in movement disorder centers. Sleep disturbances of PD may be grouped into four broad categories: insomnia, motor, urinary, and neuropsychiatric (Table 1). Daytime somnolence or excessive daytime sleepiness (EDS) is also an important issue. Sleep architecture studies in PD show variable results but, on the whole, common features are reduced total sleep time and sleep efficiency, multiple sleep arousals, and fragmentation of sleep (7,8,17,18). A circadian variation of symptoms has been identified and, as such, patients can be classified into a “morning better,” “morning worse”, and a nonaffected group (7). EDS is an important aspect of sleep-related morbidity of PD and may be caused by the underlying dopaminergic denervation, dopaminergic medications, or may be due to poor nocturnal sleep (17). In the following section, we will review some key aspects of the pathophysiology of sleep dysfunction in PD and related sleep disorders.

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PATHOPHYSIOLOGY Sleep disorders related to PD are multifactorial, and the causation is complex and largely unknown. Degeneration of central sleep regulatory neurons either due to a direct or an indirect effect of dopaminergic cell loss in the brainstem and related thalamo-cortical pathways, is implicated (17,19,20). A preclinical pathological staging of PD has been proposed by Braak (21). It has been traditionally believed that the pathological process of degeneration of dopaminergic neurons starts in the substantia nigra; however, Braak (21) proposed an alternative, as he has introduced the concept of a six-stage pathological process, beginning at clearly designated “induction sites.” In Braak stage 1 of PD, there is degeneration of the olfactory bulb and the anterior olfactory nucleus, which may clinically manifest as olfactory dysfunction. Progression of the pathological process to the lower brainstem occurs in Braak stage 2, which are key areas mediating nonmotor symptoms such as olfaction, sleep homeostasis, and other autonomic features. The brainstem areas, particularly the raphe nucleus (serotonin), locus ceruleus (norepinephrine), and pedunculopontine nucleus (PPN), play a major role in the sleep–wake cycle and mediate the so-called flip-flop switch that mediates thalamo-cortical arousal (22). The clinico-pathological correlations are becoming increasingly evident. There is strong evidence that symptoms such as olfactory dysfunction and sleep disturbances such as RBD or EDS may precede the development of motor symptoms in PD, thus correlating with Braak stages 1 and 2 (2,23–25). Degeneration of brainstem nuclei, such as the locus ceruleus, raphe nuclei, and the PPN, plays a critical role in thalamo-cortical arousal and the sleep–wake cycle and leads to dysregulation of basic REM and non-REM sleep architecture (19,20,26,27). Clinically, the manifestations are insomnia, parasomnias, and EDS. The latter may be dependent on dysfunction of the flip-flop switch proposed by Saper et al. (22,28), suggesting that the brain can be either “off” [promoting sleep by activating the ventrolateral preoptic area (VLPO) thought to be a sleeppromoting center] or “on” [promoting wakefulness by activation of the tuberomamillary nucleus (TMN), which is the wake-promoting area along with locus ceruleus and the raphe nuclei] (22). Regulators of the internal rhythm between the two switches are via the suprachiasmatic nucleus and also possibly, hypocretin 1 (orexin), a hypothalamic peptide (28,29). Hypocretin 1 is virtually undetectable in narcolepsy and may have a complex relationship with the dopaminergic systems in the basal ganglia (17). The hypocretin neurons, for instance, project to the dopaminergic neurons in the substantia nigra (17). Hypocretin-1 could function as an external regulator of the flip-flop switch promoting wakefulness, and dopaminergic dysfunction caused by neuronal degeneration can destabilize this switch and its regulators, promoting rapid transitions to sleep intruding on wakefulness. Although hypocretin-1 insufficiency has not been confirmed by studies of cerebrospinal fluid in three patients with PD and EDS associated with the use of dopamine agonists, one study reported low hypocretin-1 levels in the ventricular fluid of advanced PD patients (30,31). Other nocturnal disabilities in PD arise from causes secondary to progression of disease, causing “destructuring of sleep” and motor complications generated by dopaminergic treatment (32). Examples of the latter include nocturnal akinesia, early morning dystonia, and EDS. The cause of restless legs syndrome (RLS) in PD is unknown. Sleep-disordered breathing is being increasingly recognized in PD and may reflect a combination of central and peripheral mechanisms (7,18).

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SYMPTOMS Nocturnal Akinesia Nighttime akinesia is perhaps the clinically most relevant symptom of PD patients. Nocturnal akinesia usually results from a relatively “drug free” period, as many regimens have the last dopaminergic treatment well before bedtime. Theoretically, this would mean that a “wearing off” period would occur before the next morning dose. There is some support of this observation, as some studies have reported a significant reduction in symptoms of nocturnal akinesia such as pain, spasm, and stiffness, after nocturnal dosing of a long-acting dopamine agonist such as cabergoline or sustained infusion of apomorphine through the night (33,34). Nocturnal akinesia presents as a complex of symptoms that range from difficulty in turning in bed to emergence of tremor (Table 2). The Parasomnias Rapid Eye Movement Sleep Behavior Disorder REM sleep behavior disorder (RBD) was first reported by Schenck et al. in 1986 and is a parasomnia, which is typically characterized by vivid and usually frightening dreams or nightmares associated with a paradoxical simple or complex movement during REM sleep when muscles are usually atonic (13,23). RBD is thought to have a population prevalence of 0.5%. During REM sleep, patients enact their dreams, which can be vivid or unpleasant, and partners report vocalizations (talking, shouting, vocal threats) and abnormal movements (arm/leg jerks, falling out of bed, violent assaults) (35–40). Typical clinical features of RBD are summarized in Table 3. Although clinical history may suggest a diagnosis, in some situations such as when there is a high risk of physical injury or loud snoring suggestive of obstructive sleep apnea, confirmation of diagnosis should be obtained by a single night of polysomnography (PSG) with video telemetry. PSG would show an increased electromyographic (EMG) activity during REM sleep. Symptoms of RBD may predate the diagnosis of PD. Schenck et al. (37) reported that in 11 of 29 men (38%), 50 years or older in whom idiopathic RBD was diagnosed, a parkinsonian disorder was identified after a mean interval of 3.7 years following the diagnosis of RBD and 12.7 years after the onset of RBD. One study (41) suggested an increased risk of developing PD in individuals who have RBD and olfactory disturbance. This concept is consistent with the recent hypothesis of Braak et al. (21) who suggest that the preclinical stages 1 and 2 of PD start at the olfactory and medullary area of the brainstem. Although the pathological basis of RBD is unknown, speculation is that RBD is related to the

TABLE 2 Symptoms and Signs of Nocturnal Akinesia and Nighttime Wearing Off Difficulty in turning Muscle spasm/cramps Pain Early morning dystonia Restless legs syndrome Periodic limb movements Nocturia Tremor Panic attacks

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TABLE 3 Clinical Features Characterizing Rapid Eye Movement Behavior Disorder Predilection for male gender Mean age of onset 50–65 yr (wide age range reported varying from 20–80 yr) REM associated vocalizations, shouting, swearing, screaming, groaning (catathrenia) Simple and complex motor movements Muscle twitching Arm/leg jerking Kicking Fighting (boxing or trying to hit/strangulate partner) Falling out of bed Self and partner injury Dreams associated with attacks by animals or humans or insects Behaviors are indicative of content of dream Occurs during the later half of sleep period (early morning) Abbreviation: REM, rapid eye movement. Source: From Ref. 13.

degeneration of lower brainstem nuclei like the PPN and periceruleal nucleus. Specifically, on the basis of the studies in cats, several brainstem areas such as laterodorsal tegmental nucleus (LDTN), perilocus ceruleus region (peri-LC), nucleus reticularis magnocellularis, and the ventrolateral reticulospinal tracts, in addition to the PPN, have been implicated (13). Lesions in the peri-LC regions lead to REM sleep without atonia and, in one of the first cases of RBD to come to autopsy, there was a marked reduction in the number of neurons in LC, whereas an increased number of neurons in the PPN and LDTN were observed (42). The authors suggested that RBD could have been caused by decreased cholinergic activity of the LC and reduced disinhibition of the PPN and LTDN. However, this is controversial, as others have noted depletion of neuro-melanin neurons in LC and depleted choline-acetyl transferase neurons in the LDTN and PPN in multiple system atrophy cases (43). Furthermore, why clonazepam remains the most effective drug for treatment of RBD cannot be explained by these possible pathophysiological mechanisms. REM Sleep Behavior Disorder: Differential Diagnosis A list of differential diagnoses of RBD is provided in Table 4. Somnambulism usually complicates early non-REM sleep and exhibits purposeful movements such as walking away from the bed not necessarily associated with violent dreams or abrupt

TABLE 4 Possible Differential Diagnosis of Rapid Eye Movement Behavior Disorder Parasomnias of non-REM sleep Somnambulism Confusional arousal Night terrors Nocturnal panic attacks Nightmares Nocturnal seizures Severe periodic limb movements of sleep Obstructive sleep apnea Abbreviation: REM, rapid eye movement.

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movements such as kicking, fighting, or jumping. Night terrors and confusional episodes occur early in sleep unlike RBD and may involve screaming or incoherent speech but there is no recall of the dream. Nocturnal panic attacks in PD may complicate nocturnal akinesia with dysautonomia such as palpitations, hyperhydrosis, and immediate full awareness without dream enactment, whereas seizures may be associated with tonic-clonic posturing, tongue biting, incontinence, and postictal confusion. Excessive Daytime Sleepiness and Sudden Onset of Sleep EDS is a common complaint of PD patients. One study (4) reported a prevalence of 15.5% in PD patients compared with only 1% in healthy age-matched controls. Gjerstad et al. (44) examined the occurrence of EDS in 142 patients, 7% had EDS, and after follow-up of four years this had risen to 29%. The authors concluded that EDS occurs at a rate of 6% in new PD patients per year. The causation is complex and may represent a destabilization of the flip–flop switch of wakefulness due to dopaminergic denervation (22,28). In addition, the effect of poor nocturnal sleep and antiparkinsonian or other drugs may be causative (Table 5). EDS may manifest as some patients feel sleepy and drift off slowly to sleep, whereas others may experience fatigue. A controversial notion is the concept of sudden onset of sleep without any preceding drowsiness, resembling narcolepsy in some patients (17,45,46). Some had originally suggested the term “sleep attacks” linked to use of nonergot dopamine agonists (47). However, recent reviews suggest that “sleep attacks” are not drug-specific but rather a class effect of all dopamine agonists used to treat PD as well as dopaminergic agents such as levodopa and, furthermore, use of the term “sleep attack” is discouraged (47–49). Like RBD, EDS can occur early in PD and may predate the diagnosis in some cases (50,51). However, based on a study in 15 untreated PD patients, Kaynak et al. (52) reported that there is no evidence of EDS in untreated PD, and EDS occurs after treatment with dopaminergic agents. Arnulf et al. (53) performed a PSG and multiple sleep latency test (MSLT) in PD patients with and without hallucinations. EDS was present in 50% of each group, whereas sleep onset REM periods and sleep latency below 10 minutes characteristic of narcolepsy were present mainly in the hallucinating group (53). This would suggest that a subset of PD patients may have an intrinsic susceptibility to sudden onset of sleep, which may be unmasked by the use

TABLE 5 Possible Causes of Excessive Daytime Sleepiness in Parkinson’s Disease Nonmedication-related Advancing disease Nocturnal sleep disruption Parasomnias Depression Medication-related Dopaminergic treatment Antihistamines Hypnotics Anxiolytics Selective serotonin reuptake inhibitors Source: From Ref. 6.

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of some dopaminergic drugs. Tan et al. (54) reported that irresistible sleepiness not preceded by obvious somnolence or warning was present in 14% of a Chinese PD population compared to less than 2% in controls (54). Such subjects may, therefore, be susceptible to falling asleep while driving or operating machinery. EDS needs to be differentiated from fatigue. Also, postprandial hypotension in PD may unmask sleepiness and akinesia (55). Fatigue may be present in up to 43% of PD patients and is usually associated with sleepiness, although tiredness is a key feature (56). Driving, Excessive Daytime Sleepiness, and Sudden Onset of Sleep The combination of motor dysfunction of PD, the propensity to EDS, and fatigue may pose a particular problem in relation to driving. After a survey of 6620 patients and 361 phone interviews, Meindorfner et al. (57) found that 60% of this PD population was still driving and 11% had caused at least one traffic accident in the preceding five years (57). The risk factors identified for accidents included a high Epworth Sleepiness Scale (ESS) score, moderately severe motor disability of PD, and a previous history of sudden onset of sleep while driving. Restless Legs Syndrome and Periodic Limb Movements RLS and periodic leg movements (PLM) commonly occur together and both can be effectively treated by dopaminergic drugs, raising speculation that there may be an underlying dopaminergic dysfunction and a link with PD. An observational study by Ondo et al. (58) reported RLS to occur in PD at a rate twice that of the general population. A comparative study by Lussi et al. (59) suggested a prevalence rate of RLS of 24% in PD. RLS may occur across all stages of PD and even in untreated PD (60). Wetter (60) examined sleep and PLM patterns in de novo PD and multiple system atrophy using two nights of PSG (60). They reported frequent problems with sleep disruption and an increased PLM index in de novo PD. These observations are in agreement with recent clinical findings in a study of untreated PD versus controls and advanced PD using a bedside sleep scale (61). However, a confusing issue is that, in some cases (more than 65% of PD patients in the study reported by Ondo et al.), RLS may emerge after the diagnosis of PD, when patients are already on dopaminergic therapy, which is thought to be first-line treatment for RLS. Furthermore, in PD, RLS may be confused with akathisia, which may be related to dopaminergic dyskinesia. Sleep-Disordered Breathing EDS may overlap with daytime somnolence due to sleep-disordered breathing. Obstructive sleep apnea causing sleep-disordered breathing may be suggested by a history of loud crescendo snoring and irregular snoring with snorting, gasping, and gaps, particularly in an overweight subject. Partner corroborated history of apnea, daytime fatigue, and somnolence also suggest sleep apnea. Formal PSG will identify sleep apnea, which may occur in up to 50% of patients with PD with resultant daytime sleepiness (18,62). Sleep apnea may coexist with RLS, PLM, or RBD, and it is important to diagnose the apnea as treatment for RBD with clonazepam, for instance, may aggravate sleep apnea. Nocturia Nocturia has been consistently shown to be one of the most common problems causing sleep disruption in PD. A survey by Stocchi et al. (63) reported nocturia in 43% of 200 PD patients. An overall prevalence of nocturia in PD of 30% to 80% has been

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reported (6,64). A validation study of the Parkinson’s Disease Sleep Scale (PDSS) and an independent Spanish validation of the PDSS both reported nocturia as the most prevalent nocturnal symptom of PD (65,66). The causation is unclear. Nocturia may reflect a symptom of nocturnal wearing off while an underlying striatal dopamine D1-receptor-related dysfunction has also been implicated (67,68). Nocturia associated with nocturnal off periods may lead to incontinence and bed soiling. Nocturia also appears to be a problem of advancing PD rather than early or untreated PD, as indicated in a study using the PDSS in untreated and advanced PD patients compared to controls (61). Neuropsychiatric Comorbidites Complicating Sleep Depression is common in PD and affects sleep quality, causing insomnia (6,7). Dementia will also lead to sleep dysfunction with evidence of RBD, insomnia, and nocturnal hallucinations. Hallucinations may complicate nocturnal sleep and some have suggested an overlap with RBD (39,53). An eight-year follow-up study of cases with RBD and PD suggested a high rate of development of visual hallucinations in those with RBD (69). Sinforiani et al. (70) have reported that RBD could be a risk factor for future development of hallucinations and cognitive failure, based on neuropsychiatric evaluations in 110 patients. Drug-Induced Sleep Disruption Insomnia and nighttime agitation may be caused by late dosing of selegiline, probably as a result of its amphetamine metabolites, whereas other drugs, such as amantadine and anticholinergics, may also produce an alerting effect. The effect of rasagiline on sleep is unclear and needs to be ascertained. Selective serotonin reuptake inhibitors (SSRIs) may need to be avoided at bedtime, as they may impair sleep onset (7). Dopamine agonists and levodopa have a variable and dose-dependent effect on sleep, either promoting or disrupting sleep, although studies suggest that overnight sustained dopaminergic stimulation improves sleep in PD, by reducing nocturnal akinesia, RLS, and PLM (6,7). MEASURING SLEEP DISORDERS Until 2002, there were no specific instruments to clinically assess sleep problems of PD in a comprehensive and holistic fashion. Existing sleep scales for other disorders, such as the Pittsburgh Sleep Quality Index (PSQI), Stanford Sleepiness Scale, or the Karolinska Sleepiness Scale, are not specific for PD and have problems related to scale clinimetrics in relation to complexity and face validity when these are used in PD (66, 71–73). For instance, the PSQI, although quantifiable, does not specifically address sleep disturbances of PD, such as restlessness of legs, painful posturing of arms or legs, tremors, or fidgeting. The Stanford Sleepiness Scale and the Karolinska Sleepiness Scale appear too short for a comprehensive assessment of sleep problems. The gold standards for measurement of physiological aspects of sleep architecture are PSG and MSLT. However, these are tests of sleep structure, need specialized sleep laboratories, and can be expensive. In the United Kingdom, for instance, facilities for sleep studies are scarce and not readily available. Furthermore, these studies do not provide any information on aspects of sleep dysfunction in PD, such as nocturnal tremor, akinesia, nocturia, or hallucinations. The Unified Parkinson’s Disease Rating Scale is widely used for motor assessments in PD and contains only one sleep-related inquiry: “Does the patient have any

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sleep disturbances, for example, insomnia or hypersomnolence?” (74). As such, this is inadequate for sleep assessment of PD and a proposed revision of the scale may have more sleep related items incorporated (74,75). The ESS is a self-administered questionnaire, aimed toward assessment of EDS in eight situations of daily life (76). The ESS is widely used in PD and correlates well with the relevant question (question 15) on the PDSS. The study by Meindorfner et al. (57) suggested that a high ESS score in a patient with moderately advanced PD may predict a risk for sudden onset of sleep and road traffic accidents. However, the ESS does not quantify the types of sleep disturbances that occur in PD. Furthermore, the interpretation of the ESS suffers from cross-cultural differences and uncertain test–retest reliability. The first bedside scale for a comprehensive assessment of sleep problems was validated and published in 2002 and is the PDSS, which has now been translated globally and used across the world for a bedside assessment of clinical aspects of sleep disabilities of PD (65,66). The PDSS is a 15-question visual analog scale, which can be easily administered at the bedside and has also undergone formal linguistic validation in Italy, Spain, and Japan (66,77). The PDSS has robust test–retest reliability and good discriminatory power between patients with PD and healthy controls. Patients and caregivers respond to individual questions on the basis of their experiences in the past week, and scores for each item range from 0 (symptom severe and always experienced) to 10 (symptom free). The maximum cumulative score for the PDSS is 150 (patient is free of all symptoms). The PDSS aims to distinguish between sleep onset and sleep maintenance insomnia (questions 2 and 3); nocturnal motor symptoms (questions 10 to 13); nocturnal restlessness, dystonia, and pain (questions 4, 5, 10, 11); neuropsychiatric symptoms (questions 6 and 7); and nocturia (questions 8 and 9). EDS is addressed by question 15, whereas question 14 addresses sleep refreshment. A total score below 90 or an individual item score below 6 is likely to indicate significant sleep disturbance. One criticism is that PDSS does not specifically address the issue of sleep-disordered breathing and RBD, and a modification has been suggested (78). As part of a program for development of scales to address various aspects of PD (SCOPA), Marinus et al. (79) have also developed and validated the SCOPA-Sleep Scale. This is a short, two-part scale that assesses nocturnal sleep and daytime sleepiness, and contains nondisease-specific items. The SCOPA-Sleep Scale has been validated in PD and is reliable, but unlike the PDSS, it is not a visual analog scale and does not address some problems specific to PD, such as nocturnal hallucinations, pain, dystonia, tremor, and nocturia, which can be quantified in the PDSS. Sleep architecture can be studied using PSG, and MSLT provides measures of alertness. These studies are not routinely required for the assessment of sleep in PD. However, in cases where obstructive sleep apnea or severe PLM is suspected, PSG is essential. In cases of severe RBD or other parasomnias, PSG is useful for confirmation of diagnosis. A pathological MSLT result (sleep latency <10 minutes) in a PD patient may also suggest a propensity to sudden onset of sleep. TREATMENT There is a poor evidence base for the treatment of sleep problems in PD, and the issue is complicated by the fact that treatment of sleep problems in PD needs to take into account the multifactorial nature of sleep disturbances in PD. A review by the Movement Disorder Society Task Force reported that there were no robust trials of dopaminergic agents for the treatment of nonmotor symptoms in PD, including

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sleep (80). Only modafinil (for EDS) and melatonin (for insomnia) have been studied in randomized, double-blind trials in a small number of patients with PD (Table 6). Other published reports consist of case series and open-label trials with limited and inadequate evidence for treatment.

TABLE 6 Management Strategies for Symptoms Contributing to Nocturnal Disturbance in Parkinson’s Disease Insomnia-related symptoms Fragmented sleep with difficulty in sleep onset and sleep maintenance Nonpharmacologic measures Avoidance of nighttime alcohol, caffeine, tobacco Increase in daytime physical activity and ensuring exposure to daylight Psychological therapies: relaxation training, cognitive therapies, biofeedback training Pharmacologic strategies Short-acting benzodiazepines: clonazepam, temazepam, diazepam Nonbenzodiazepine hypnotics: zopiclone Tricyclic antidepressants: amitriptyline (may help nocturia but may aggravate RLS) Motor symptoms Fidgeting, painful cramps and posturing, tremor, sleep akinesia, RLS-type symptoms Nonpharmacologic measures Use of satin bed sheets and bed straps to help moving in bed Bed rails Pharmacologic strategies (based on case series and open label trials) Sustained dopaminergic stimulation (nighttime dosing of ) Sustained release levodopa ± COMT inhibitor, Stalevo Long-acting dopamine agonists, e.g., cabergoline Nocturnal apomorphine infusion (severe RLS/PLM/dystonia/cramps) Combination of daytime apomorphine and evening cabergoline (dual agonist therapy) Practical measures to aid bioavailability of dopaminergic medications Avoidance of high-protein meals at night Domperidone if delayed gastric emptying REM behavior disorder Clonazepam (usually first choice) Pramipexole Melatonin (in double blind trial) Carbamazepine Donepezil Levodopa Neuropsychiatric symptoms Distressing dreams, hallucinations, depression Nonpharmacologic measures Consider alternative diagnosis: MSA, LBD, PSP Pharmacologic strategies Hallucinations If Drug-induced: optimize therapy Atypical neuroleptics: quetiapine, clozapine Depression Amitriptyline; noradrenaline reuptake inhibitors; dopamine agonists, e.g., pramipexole Panic attacks During “on” periods: alprazolam, lorazepam During “off” periods: sustained release levodopa ± COMT inhibitor; cabergoline; apomorphine infusion Any time: sertraline, fluoxetine, paroxetine (Continued)

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TABLE 6 Management Strategies for Symptoms Contributing to Nocturnal Disturbance in Parkinson’s Disease (Continued) Urinary symptoms Nocturia Incontinence because of inability to move during “off” phase Nonpharmacologic measures Reduction of evening fluid intake Emptying bladder before bed Use of condom catheters/bedside commode If associated with postural hypotension, head-up tilt of bed Pharmacologic strategies Low-dose amitriptyline Possible role for D1/D2 agonists, e.g., cabergoline, pergolide, apomorphine If associated with detrusor instability: oxybutinin, tolterodine If associated with morning hypotension: desmopressin nasal spray, avoidance of evening diuretics, antihypertensives, vasodilators Abbreviations: COMT, catechol O-methyl-transferase; CR, controlled-release; MSA, multiple system atrophy; LBD, Lewy body dementia; PLM, periodic limb movement; PSP, progressive supranuclear palsy; RLS, restless legs syndrome. Source: From Refs. 6,7.

The use of the PDSS enables the clinician to adopt a systematic and pragmatic approach to treatment of nighttime symptoms. An example would be patients with PDSS scores, indicating nocturnal motor disabilities due to wearing off, might benefit from extending the action of levodopa, by combining levodopa with a catechol O-methyl-transferase inhibitor such as entacapone or tolcapone, or using a nighttime dose of a dopamine agonist. Scores indicating hallucinations might warrant withdrawal of nighttime dopamine agonists or treatment with clonazepam if RBD is suspected. A summary of management strategies for sleep disturbances related to PD is outlined in Table 6.

Sleep Benefit and Sleep Hygiene Sleep benefit is a common phenomenon of variable duration ranging from 30 minutes to 3 hours in PD and implies improvement in mobility and motor state in the morning and after drug intake at night (98). The mechanism of sleep benefit is unknown, and possible causes include (i) recovery of dopaminergic function and storage during sleep, (ii) a circadian rhythm-related phenomenon, or (iii) a pharmacological response to dopaminergic drugs (7,30). Good sleep hygiene is also useful. Activities such as a hot bath a couple of hours before bedtime, maximizing daytime activity, ensuring bright light exposure, having a hot sweet drink or a light snack at bedtime, use of handrails in bed and/or satin sheets to enable easier turning in bed, flexible bed times, a reclining armchair for some, and avoiding stimulants such as tea or coffee at bedtime are part of good sleep hygiene (81). Nocturia remains one of the most common causes of sleep disruption in PD and can be reduced by avoiding diuretics, tea, or coffee at bedtime. The use of desmopressin nasal spray may also be helpful in some patients (64). Some have suggested the use of combined D2–D1 receptor dopamine agonists such as pergolide, but this has not been established in clinical trials (82). In cases with risk of urinary incontinence, condom catheters or a bedside urinal are essential to ensure a good quality sleep with minimal interruption.

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Nocturnal Akinesia Nocturnal akinesia is usually caused by nighttime wearing off, and strategies promoting overnight dopaminergic stimulation may be helpful. Sustained-release levodopa/benserazide significantly (P < 0.016) improved ability to turn in bed and total time awake (decreased from 2.13 to 0.67 hours, P = 0.046) in a 12-month open-label, noncomparative trial of 15 PD patients with distressing nocturnal symptoms (83). Open-label comparative observational reports in PD patients with severe sleep disruption due to nocturnal motor symptoms suggest that cabergoline, a long-acting once a day dopamine agonist, may be superior to levodopa or pergolide (84,85,95). Overnight apomorphine infusion also has been reported to be beneficial for nocturnal motor and nonmotor symptoms of PD (86). Studies are investigating the efficacy of prolonged release formulations of agents such as ropinirole and the rotigotine transdermal patch on nocturnal akinesia. Excessive Daytime Sleepiness In PD, severe EDS needs treatment, and first concurrent medications that may be sedating should be eliminated or reduced (Table 5). Modafinil (100–400 mg/day), a nonaddictive sleep–wake cycle activator, is nonstimulating and the only drug that has shown efficacy in improving EDS in double-blind, placebo-controlled trials (87,88). A seven-week, double-blind, placebo-crossover study of modafinil (200 mg) followed by a four-week open-label extension (200 and 400 mg) study by Adler et al. (88) showed significant improvement in ESS with modafinil and improvement in clinical global impression scores for wakefulness in the open-label arm. Those with high ESS scores and a history of sudden onset of sleep should be advised not to drive alone or long distances. Dopamine agonists when initiated should be titrated up slowly, especially in older patients. Neuropsychiatric Problems Depression affects approximately 40% of patients with PD and may contribute to sleep disturbances, necessitating active treatment with sedating antidepressants (e.g., trazodone) or SSRIs (Table 6). Panic attacks can occur in both on and off periods, and off-related panic can be overcome by sustained dopaminergic stimulation. Successful treatment of the neuropsychiatric problems often leads to improvement of sleep quality in PD. Rapid Eye Movement Behavior Disorder and Restless Legs Syndrome The treatment of choice for RBD is clonazepam, a benzodiazepine, although the mechanism is unknown and there are no controlled trials (13). Other drugs thought to be helpful for RBD include pramipexole, levodopa, carbamazepine, donepezil, and melatonin (64,89–91). Caution needs to be exercised with the use of clonazepam, as in some cases, RBD may be confused with sleep apnea, which can be worsened by clonazepam. Nighttime dosing with drugs such as selegiline may aggravate RBD. Others have reported a paradoxical worsening of RBD with deep brain stimulation (DBS) of the subthalamic nucleus (STN) (92). RLS may complicate PD and cause significant sleep disruption, and there are no trials investigating treatment of RLS in PD. In some cases, targeted treatment with a long-acting dopamine agonist such as cabergoline, given at nighttime, may be effective (84,85). The role of drugs, such as the rotigotine transdermal patch or the

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prolonged release formulation of ropinirole, is being investigated. In severe cases, hospital admission with overnight apomorphine infusion may be required (86). Deep Brain Stimulation of the Subthalamic Nucleus STN DBS may improve sleep quality through increased nocturnal mobility and reduction of sleep fragmentation (92,93). Therefore, STN DBS is an effective therapeutic option for the treatment of advanced PD, as it improves the cardinal symptoms of PD and also seems to improve sleep architecture. CONCLUSION Sleep disorders in patients with PD are common (94). They are a key component of the nonmotor symptom complex of PD and remain under-diagnosed and undertreated. Sleep problems may arise from uncontrolled motor symptoms, degeneration of the neuroanatomical substrates responsible for the sleep–wake cycle or unwanted medication side effects. Routine assessment of patients with PD should include inquiry regarding the quality of sleep and sleep-related symptoms. Use of validated bedside clinical tools such as the PDSS, SCOPA-Sleep, and ESS offer a robust way to assess the presence or absence of sleep disruption. Uncontrolled nocturnal motor symptoms may be ameliorated by long-acting dopaminergic agents, whereas other sleep disruptions such as hallucinations or RBD require a different approach. In resistant cases, patients may need to undergo a formal sleep study with PSG and/or MSLT. Targeted nighttime treatment should result in improved sleep for patients with PD. REFERENCES 1. Parkinson J. An essay on the shaking palsy [reprint of monograph published by Sherwood, Neely, and Jones, London, 1817]. J Neuropsychiatry Clin Neurosci 2002; 14:223–236. 2. Chaudhuri KR, Healy D, Schapira AH. The nonmotor symptoms of Parkinson’s disease. Diagnosis and management. Lancet Neurology 2006; 5(3):235–245. 3. Lees AJ, Blackburn NA, Campbell VL. The nighttime problems of Parkinson’s disease. Clin Neuropharmacol 1988; 11:512–519. 4. Tandberg E, Larsen JP, Karlsen K. A community-based study of sleep disorders in patients with Parkinson’s disease. Mov Disord 1998; 13:895–899. 5. Karlsen K, Larsen JP, Tandberg E, et al. Fatigue in patients with Parkinson’s disease. Mov Disord 1999; 14:237–241. 6. Chaudhuri KR. Nocturnal symptom complex in PD and its management. Neurology 2003; 61(suppl 3):S17–S23. 7. Garcia-Borreguero D, Larosa O, Bravo M. Parkinson’s disease and sleep. Sleep Med Rev 2003; 7:115–129. 8. Adler CH, Thorpy MJ. Sleep issues in Parkinson’s disease. Neurology 2005; 64(suppl 3): S12–S20. 9. Karlsen KH, Larsen JP, Tandberg E, et al. Influence of clinical and demographic variables on quality of life in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999; 66:431–435. 10. Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson’s disease: a population-based, prospective study. J Am Geriatr Soc 2000; 48(8):938–942. 11. Findley L, Aujla MA, Bain PG, et al. Direct economic impact of Parkinson’s disease: a research survey in the United Kingdom. Mov Disord 2003; 18(10):1139–1145. 12. Bosanquet N, May J, Johnson N. Alzheimer’s Disease in the United Kingdom. Burden of Disease and Future Care. Health Policy Review Paper No. 12. London: Health Policy Unit, Imperial College School of Medicine, 1998.

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86. Reuter I, Ellis CM, Chaudhuri KR. Nocturnal subcutaneous apomorphine infusion in Parkinson’s disease and restless legs syndrome. Acta Neurol Scand 1999; 100:163–167. 87. Hogl B, Saletu B, Brandauer E, et al. Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a double blind, randomised, crossover, placebo controlled, polygraphic trial. Sleep 2002; 25(8):905–909. 88. Adler CH, Caviness JN, Hentz JG, et al. Randomised trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord 2003; 18:287–293. 89. Fantini ML, Gagnon J-F, Filipini D, et al. The effects of pramipexole in REM sleep behavior disorder. Neurology 2003; 61:1418–1420. 90. Tan A, Salgado M, Fahn S. Rapid eye movement sleep behavior disorder preceding Parkinson’s disease with therapeutic response to levodopa. Mov Disord 1996; 11:214–216. 91. Dowling GA, Mastick J, Colling E. Carter JH, Singer CM, Aminoff MJ. Melatonin for sleep disturbances in Parkinson’s disease. Sleep Med 2005; 6:459–466. 92. Krack P, Van Blercom N, Chabardes S, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003; 349: 1925–1934. 93. Hjort N, Ostergaard K, Dupont E. Improvement of sleep quality in patients with advanced Parkinson’s disease treated with deep brain stimulation of the subthalamic nucleus. Mov Disord 2004; 19:196–199. 94. Factor SA, McAlarney T, Sanchez Ramos JR, Weiner WJ. Sleep disorders and sleep effect in Parkinson’s disease. Mov Disord 1990; 5:280–285. 95. Nausieda PA, Weiner WJ, Kaplan LR, Weber S, Klawans HL. Sleep disruption in the course of chronic levodopa therapy: an early feature of levodopa psychosis. Clin Neuropharmacol 1982; 5:183–194. 96. Smith MC, Ellgring H, Oertel WH. Sleep disturbances in Parkinson’s patients and spouses. J Am Geriatr Soc 1997; 45:194–199. 97. Gillberg M, Kecklund G, Akerstedt T. Relations between performance and subjective ratings of sleepiness during a night awake. Sleep 1994; 17:236–241 98. Comella CL, Stebbins GT, Bohmer J. Sleep benefit in Parkinson’s disease. Neurology 1995; 45(suppl 4):A286.

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Neuropsychological Aspects Alexander I. Tröster Department of Neurology, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, North Carolina, U.S.A.

Steven Paul Woods Department of Psychiatry, University of California at San Diego, San Diego, California, U.S.A.

INTRODUCTION This chapter first acquaints the reader with basic distinctions between the clinical “brain–behavior” disciplines, namely neuropsychology, behavioral neurology, and neuropsychiatry. After describing the most common approaches to neuropsychological evaluation and the goals of neuropsychological evaluation in Parkinson’s disease (PD), the chapter highlights the cognitive alterations that most frequently accompany PD and those that occur in and differentiate dementias seen in PD from other neurodegenerative conditions. A discussion of the impact of emotional comorbidity on cognition makes clear the importance of treating anxiety, depression, and other psychiatric symptoms, in optimizing the afflicted person’s functioning and quality of life. Both medical and surgical treatments have the potential to impact cognition. Only a sparse literature devotes itself to treatment-related neurobehavioral complications, and less frequent improvements. The chapter concludes with a brief comparison of the most common cognitive alterations, accompanying parkinsonian and related syndromes such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and essential tremor. Although the neuropsychological features in parkinsonian syndromes probably lack the specificity and sensitivity to be of differential diagnostic utility, the neurobehavioral differences observed among groups of patients with various disorders can guide diagnostic hypotheses, treatment planning, and inform about the plural neurobehavioral roles of the basal ganglia.

NEUROPSYCHOLOGY, BEHAVIORAL NEUROLOGY, AND NEUROPSYCHIATRY Sir William Osler first used the term neuropsychology in 1913; however, neuropsychology, at least as a clinical endeavor, did not emerge as a subdiscipline of psychology until the 1940s, largely in response to demands for the assessment and rehabilitation of brain-injured soldiers in World War II (1). The likely first published use of a clinical neuropsychological test with persons having parkinsonian syndrome is Shaskin et al.’s (2) administration of the Wechsler Bellevue Scale, an intelligence scale, to postencephalitic parkinsonians. Neuropsychology shares with behavioral neurology and neuropsychiatry the goal of relating behavior to underlying brain structure and function (3). However, neuropsychology’s principal clinical method, namely its standardized, quantitative, norm-referenced approach to the evaluation 109

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of cognition and behavior, is perhaps the characteristic that most clearly distinguishes it from behavioral neurology and neuropsychiatry. COMMON APPROACHES TO NEUROPSYCHOLOGICAL EVALUATION Neuropsychological assessment approaches fall broadly into three categories: (i) the fixed battery (or cognitive-metric) approach; (ii) the process (or hypothesis-testing) approach; and (iii) the flexible battery approach. These approaches can readily be conceptualized as differing along two dimensions: test selection and administration/interpretation. Test selection may be fixed or flexible; administration and interpretation are characterized, respectively, as standardized and actuarial at one extreme, and as nonstandardized and qualitative at the other extreme. Each approach has strengths and weaknesses (Table 1). The fixed battery approach falls at the extremes of fixed test selection, standardized administration, and actuarial interpretation. It is best exemplified by the Halstead–Reitan Battery (4). The process, or hypothesis-testing, approach emphasizes qualitative aspects of neuropsychological functions, which are found in developmental and cognitive psychology. Champions of the process approach promote “testing the limits” with patients and assessing the component processes of cognition, rather than relying exclusively upon summary scores. In other words, the process approach views critically how a task is solved and how the solution unfolds over time, rather than the achievement score quantifying the quality of the end product. Although the fixed battery and process approaches dominated neuropsychology, initially, the flexible battery has recently emerged as the most commonly used approach to neuropsychological evaluation (5). Flexible batteries benefit from the strengths of the fixed battery and process approaches by striving to quantify the qualitative aspects of cognition and task performance (6). In this way, the flexible battery approach capitalizes on advances in cognitive neuroscience while remaining firmly grounded in psychometric theory. In addition, the flexible battery approach incorporates a standard battery of tests from which the clinician can tailor the evaluation to address particular patients’ needs and/or explore given domains of function in

TABLE 1 Advantages and Disadvantages of the Three Major Approaches to Neuropsychological Assessment

Comprehensiveness Ease of administration Compatibility with research database Ease of training technical personnel Cost Time required Information about cognitive mechanisms underlying impairment Normative data Ease of incorporating new technical developments Information redundancy Comparability of scores across tests

Fixed

Flexible

Process

− + + + − −

± − ± − + +

+ − − − ± ±

− ±

+ ±

+ ±

− + ±

+ − ±

+ − −

Abbreviations: +, advantage/strength; −, disadvantage/weakness; ±, test battery dependent.

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Neuropsychological Aspects TABLE 2 Commonly Used Neuropsychological Tests by Cognitive Domain Assessed Cognitive domain Premorbid estimates

Neuropsychological screening Intelligence

Attention and working memory

Executive function

Memory

Language

Visuoperception Motor and sensory-perception Mood state and personality

Quality of life, coping, and stressors

Test Barona Demographic Equations; North American Adult Reading Test; Wechsler Test of Adult Reading; Wide Range Achievement Test Mattis Dementia Rating Scale; Repeatable Battery for the Assessment of Neuropsychological Status Kaufman Brief Intelligence Test; Raven’s Progressive Matrices; Wechsler Abbreviated Scale of Intelligence; Wechsler Adult Intelligence Scale Auditory Consonant Trigrams; Brief Test of Attention; Continuous Performance Tests; Digit and Visual Spans; Paced Auditory Serial Addition Test; Stroop Testa Cognitive Estimation Test; Delis–Kaplan Executive Function System; Halstead Category Test; Trailmaking Testa; Tower of London; Wisconsin Card Sorting Test Benton Visual Retention Test; California Verbal Learning Test; Rey Auditory Verbal Learning Test; Rey Complex Figure Testa; Wechsler Memory Scalea; Hopkins Verbal Learning Test Boston Naming Test; Controlled Oral Word Association Test; Sentence Repetition; Token Test; Complex Ideational Material Benton Facial Recognition Test; Benton Judgment of Line Orientation; Hooper Visual Organization Test Finger Tappinga; Grooved Pegboarda; Hand Dynamometera; Sensory-Perceptual Examination Beck Anxiety Inventory; Beck Depression Inventory; Hamilton Depression Scale; Minnesota Multiphasic Personality Inventory; Profile of Mood States; State-Trait Anxiety Inventory Parkinson’s Disease Questionnaire; Coping Responses Inventory; Ways of Coping Questionnaire; Life Stressors and Social Resources Inventory

a

Tests may not be appropriate for patients with marked motor impairment. Source: From Ref. 30.

greater detail as desired. Many clinicians utilize a small fixed battery and then elaborate this battery depending upon the referral question, the patient’s ability to cooperate with certain tasks, patient and family concerns, and presenting diagnoses. The particular components and length of a neuropsychological evaluation will vary across clinical settings, but typically include the following: ■

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A clinical interview and review of records to ascertain relevant biopsychosocial background information; Informal observations regarding patient behavior, sensorimotor functions, cognition, and affect; The administration of psychometric tests to measure intelligence, attention and executive functions, language, learning and memory, visuospatial perception, praxis, motor and sensory-perception, mood state, quality of life, and personality/coping variables (Table 2 lists a sample of tests and the domains of functioning they evaluate); An integration of findings and recommendations into oral and/or written feedback that is provided to the patient, family, and healthcare providers.

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THE ROLE OF NEUROPSYCHOLOGY IN THE MANAGEMENT OF PARKINSON’S DISEASE Neuropsychology provides an important contribution to the management of patients with PD. Neuropsychological evaluation delineates the nature and extent of cognitive changes, if any, and a profile of relative neuropsychological strengths and weaknesses. Such knowledge is helpful in: ■

■

■

■

■ ■

the determination of the most probable etiology of mild- and new-onset cognitive changes; development and formulation of strategies or treatments to ameliorate the impact of cognitive deficits on functioning; guidance of the patient and family in making and requesting adaptive changes in the patient’s home, leisure, and work environments, which enhance functioning and minimize handicap; decision making about the appropriateness of medical and neurosurgical interventions for a patient; assessment of competence to consent to treatment; financial, legal, placement planning.

Given the prevalence of cognitive and behavioral changes in PD, every patient would, in ideal circumstances, receive a baseline evaluation when first diagnosed with PD. Such a baseline neuropsychological evaluation would facilitate the accurate detection and diagnosis of subsequent neurobehavioral changes and permit the evaluation of treatment effects. This, however, occurs rarely and probably reflects costeffectiveness issues in a managed care environment and the reluctance of many patients to contemplate in the early disease stages the threat of later, possibly significant, cognitive compromise. In the absence of an early baseline evaluation, a neuropsychological evaluation in the context of cognitive morbidity relies on a less accurate, probabilistic estimation of premorbid functioning to detect and estimate the extent of impairments. Accordingly, if a full evaluation is not indicated or cannot be achieved soon after diagnosis, a cognitive screening should be contemplated as an alternative. Such screening can be readily achieved in the neurologist’s office using the Mattis Dementia Rating Scale (7), or comparable instruments. Likewise, the administration of brief self-report measures of mood state and quality of life [e.g., the Beck Depression (8) and Anxiety Inventories (9), and Parkinson’s Disease Questionnaire 8-item short-form (10)] are invaluable, in screening for mood disturbance and the extent to which treatments are impacting quality of life. Affective disturbances are crucial to screen for on a regular basis, considering the high prevalence of anxiety and depression in patients with PD (11), and the high likelihood of these entities going undiagnosed (12) or undertreated (13) in routine neurologic practice. The optimization of quality of life, from the patient’s perspective, facilitates a patient–physician collaboration and treatment adherence. A more comprehensive neuropsychological evaluation that supplements screening should be strongly considered under the following circumstances: ■

■

if the patient, caregiver, and/or clinician suspect changes in the patient’s ability to carry out fundamental and/or instrumental activities of daily living, which are unlikely to be related to motor dysfunction; if there is concern regarding a possible evolving dementia related to depression, PD, Alzheimer’s disease (AD), or any other medical and/or psychiatric condition;

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if the neurologist suspects that brief cognitive screening tests [e.g., the Mini Mental State Exam (14)] are not sufficiently sensitive to detect possible changes in cognitive functions; indeed, screening measures designed to detect cognitive decline in AD are typically poorly sensitive to mild subcortical dementias as often seen in PD (15). if the patient is being considered for surgical treatment of PD. In fact, recently published guidelines emphasize the need for neuropsychological evaluation in this regard (16,17). Such evaluation facilitates patient selection and provides a baseline against evaluating potential postsurgical neurobehavioral changes and their implications. if a patient experiences difficulties at work likely unrelated to motor symptoms and signs; when issues and questions arise regarding a person’s competence to: manage financial affairs, prepare an advanced directive or living will, or consent to treatment (18); when questions arise about the most appropriate environment for the continued care of the patient; when the patient and/or family report that the patient experiences emotional changes and/or is withdrawing from social roles; once a patient has experienced delirium or hallucinations, given that such phenomena may be harbingers of dementia (19).

Prior to making a referral for neuropsychological evaluation, it is important to determine whether neuropsychological evaluation is appropriate to address the specific question the clinician or patient might have. Of equal importance is that the referring clinician carefully articulates the referral question, which allows the neuropsychologist to tailor evaluative procedures accordingly, and that the neuropsychologist clearly communicates the findings and their possible implications to the referring clinician, patient, and family, while specifically addressing the referral question. NEUROPSYCHOLOGICAL FINDINGS IN PARKINSON’S DISEASE Parkinson (20) contended that patients with shaking palsy did not exhibit significant intellectual changes; however, by the late 1800s, investigators had begun to recognize the presence of cognitive deficits in patients with PD (21). Mild neuropsychological changes are widely accepted to occur in early PD. Increasingly, it is recognized that cognitive alterations, especially in executive functions and/or memory, may already be present at the time of disease diagnosis. Recent studies estimate that one-quarter to one-third of patients may have deficits detectable on careful neuropsychological testing at the time of disease diagnosis (22,23). Cognitive declines early in the disease most often include deficient information processing speed, visuospatial abilities, verbal fluency, recall, and executive functions (24,25). The neuropsychological dysfunction associated with early PD is hypothesized to reflect nigrostriatal dopamine depletion and disruption of mesocortical and mesolimbic pathways. More pronounced cognitive dysfunction is evident only later in the disease, and is probably attributable to neurochemical changes extending beyond the dopaminergic system (26–28), in addition to structural neuropathology. The dementia (prevalence of about 30%), or perhaps more accurately dementias, observed in PD probably reflect diverse neuropathological entities. At autopsy, dementia in clinically diagnosed PD most

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often reveals AD or Lewy body dementia (LBD) pathology, or some combination of pathologies associated with these two conditions. Consequently, although dementia in PD generally conforms neurobehaviorally to a “subcortical dementia” profile early in its course, it is neuropsychologically heterogeneous across individuals and, almost invariably, later in its course has both cortical and subcortical features. Nonetheless, many cognitive features of early dementia in PD represent a more severe form of the cognitive changes observable in PD without dementia. Neuropsychological Dysfunction in Parkinson’s Disease Without Dementia In reviewing the PD literature, Lieberman (29) reported that 17% to 53% of treated and untreated PD patients without dementia demonstrate cognitive dysfunction. Unfortunately, few of the studies reported formal criteria for determining what did or did not constitute dementia, thus making it difficult to determine whether patients were in the early stages of dementia. As noted earlier, more recent studies suggest that formal neuropsychological testing may uncover mild cognitive deficits in 25% to 36% of PD patients at the time of diagnosis (22,23). When present in early PD, cognitive dysfunction is typically mild and most commonly involves bradyphrenia (a slowness of thought) and subtle deficits in executive functions, recall, and/or visuoperceptual/spatial functions (30). Attention and Executive Functions Attention and executive deficits in PD are most often ascribed to frontal lobe dysfunction secondary to striatofrontal deafferentation and, in particular, pathophysiological alterations in the basal ganglionic-dorsolateral frontal loops with medial nigral dopamine depletion impacting the caudate and its frontal projections (31). Performance on simple tasks of attention, for example, forward digit span, is most often preserved in patients with PD (32). On the other hand, deficits on tasks, requiring complex attention, planning, reasoning, abstraction, conceptualization, and cognitive flexibility, are more readily identified in PD. Deficits are most apparent on tasks that require spontaneous, self-directed information, processing strategy formulation and deployment (33). Executive dysfunction may account for some of the deficits observed on recall, verbal fluency, and visuoperceptual tasks (34), but it is unlikely that executive deficits alone can explain the range of cognitive changes observable in PD (35,36). Observations of executive dysfunction in PD are increasingly accompanied by functional neuroimaging data that permit a clearer understanding of these deficits’ neural correlates. Positron emission tomography studies have shown reduced blood flow in the globus pallidus (37), the caudate, and the dorsolateral frontal cortex of PD patients compared with controls in response to activation with the Tower of London task (38). Performance on the Tower of London task is improved by levodopa administration, and this improvement is accompanied by normalization of dorsolateral frontal cortex blood flow relative to healthy elderly. Given recent concern about pathological gambling among patients taking dopamine agonists (39), studies of decision making during a gambling task may provide important insights into this phenomenon. One gambling task evaluating decision making, judgment, and impulsivity is that of Bechara et al. (40). Examinees are instructed to maximize their gambling winnings by choosing cards from different

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decks, which yield either a high payoff (coupled with high risk), or low payoff at low risk. The low payoff, low-risk decks are designed to yield net winnings in the long term, whereas the high payoff, high-risk decks yield losses. Czernecki et al. (41) found that PD patients’ performance on the gambling task did not improve across assessments, suggesting a failure to benefit from experience. Consistent with the clinical association between dopaminergic treatment and pathological gambling, another study (42) found that deficits on the gambling task may only be observable when patients are on dopaminomimetic medications. Language Hypophonia and dysarthria sometimes characterize speech in patients with PD. As compared to patients with AD, aphasia and paraphasic errors are rarely observed in PD, although production and comprehension of complex syntax may be reduced on occasion (43–45). Comprehension of written material and writing (limited by motor impairments) is also relatively preserved in PD. Visual confrontation naming tasks, requiring naming of pictured or actual objects, is preserved in PD without dementia (46), although rare studies report subtle naming impairments in early PD (47). More common are deficits on verbal fluency tasks requiring, within time constraints, the oral generation of words belonging to semantic categories or beginning with certain letters of the alphabet (46,48). Verbal fluency decrements are not universally observed in PD, but, when present, probably reflect deficient use of word retrieval strategies such as clustering and/or switching (48), meaning grouping of words by component sound or category, and moving efficiently between sounds and categories. Learning and Memory Deficits in memory are not a characteristic of PD. Patients with PD display difficulty in retrieving newly learned information from memory stores, as indicated by mild impairments in free recall, but relatively intact recognition and cued recall (49). Patients with PD may also show an increased reliance on serial encoding (recalling words in the order they are presented) and reduced semantic encoding (indexed by recall of groups of words according to semantic category) (50,51). Although retrieval and semantic encoding deficits are evident in group studies of PD, there is diversity in memory profiles of individual patients with PD (52). Remote memory is generally preserved in early PD (53). Prospective memory, or memory for intended, future actions, may be compromised in PD (54,55). Findings regarding performance on measures of nondeclarative memory, which refers to “knowing how” and is a form of remembering that can be expressed only through the performance of task operations, appear to be task-dependent (56). Thus, impairments in the learning of new motor, perceptual, and cognitive skills may or may not be evident (57–60) while priming is typically intact (58,61). Visuospatial Perception Visuoperceptual impairments are thought to occur in early PD, even when motoric task demands are minimized (62,63); however, some argue that visuoperceptual impairments are secondary to deficits in set-shifting, spatial memory, bradyphrenia, and dexterity (34,64). Visuospatial impairments do not appear to improve with dopamine replacement and do not reliably vary with motor “on” and “off ” periods. Thus, if dopamine impacts visuoperceptual abnormalities in PD, it is probably in conjunction with other neurochemical or pathophysiological processes (65).

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Neuropsychological Dysfunction in Parkinson’s Disease with Dementia The annual incidence of clinically diagnosed dementia in PD (PDD) is about 3% for individuals younger than 60 years and 15% or less for those 80 years and older (66,67). Estimates of dementia prevalence in patients with PD vary between 9% and 93%, depending on which diagnostic criteria, ascertainment methods, and sampling methods are implemented (24). The methodologically soundest studies yield prevalence estimates of about 25% (68). Dementia is very rarely present early in the disease course; moreover, dementia that precedes or accompanies the evolution of motor symptoms should raise concern that the dementia might be related to factors other than PD, for example, AD, LBD, or depression. Recently revised diagnostic criteria for LBD (69) propose that the clinical diagnostic term “PD with dementia” be reserved for individuals who have a clinical diagnosis of PD and have had only motor symptoms for at least 12 months before developing fluctuating cognition and other neuropsychiatric symptoms such as hallucinations. When the neuropsychiatric presentation precedes any extrapyramidal signs, the differential diagnoses include LBD, AD, and vascular dementia. Whether PDD and LBD turn out to be neuropathologically distinct entities remains to be resolved, though neuropsychological studies have generally failed to distinguish between these two putative entities (30). Dementia in PD, like other dementias, involves multiple cognitive impairments and a related decline in day-to-day functioning. Cummings’ (70) categorization of dementia as “cortical” and “subcortical” on the basis of neurobehavioral features has been criticized on neuroanatomical grounds, but nevertheless remains a useful clinical heuristic. While recent work suggests that the cognitive profile of dementia in PD is likely heterogeneous (perhaps reflecting variability in neuropathological findings) at the group level, the neuropsychological deficits evident in PDD most often resemble those of the “subcortical” dementias (71). Perhaps the most striking features of the “subcortical” dementias, including PDD, are bradyphrenia, memory retrieval deficits, executive dysfunction, diminished spontaneity, and depression. Features of the “cortical” dementias such as AD (e.g., aphasia, agnosia, and apraxia) are typically absent in PDD, even later in the course of dementia. Recently published “practice parameters” concerning diagnosis of dementia (72) provide little guidance in the evaluation of patients with PD and dementia, and fail to address neuropsychological evaluation methods. Attention and Executive Functions Performance on more complex attentional tasks, those that require the self-allocation of attentional resources, divided attention, and selective attention, is impaired in PDD (73,74). As the disease progresses, patients with PDD may show difficulty even on those attention tasks in which external cues are provided (75). Executive functions are tied to frontal–striatal–thalamic circuit integrity, especially to the dorsolateral circuit (76). Frontal lobe dysfunction in PDD most likely stems from nigrostriatal dopaminergic deficits, resulting in a striatocortical deafferentation effect (77). However, cholinergic dysfunction secondary to neuronal loss in the septal and basal nuclei likely also plays a role in executive dysfunction (78). Executive deficits are particularly evident on tasks that require patients to develop, deploy, and maintain efficient information processing strategies. It has been hypothesized that the basal ganglia and frontal-subcortical circuits function as a subcognitive, internal navigational system that limit PDD patients’ available options for efficient problem solving (77,79).

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Poor performance on tasks that require coordination of complex mental and motor functions (e.g., operation of an automobile) may be conditioned by visuospatial deficits, leading to the defective planning and execution of strategies to accomplish a task (e.g., turning a corner while walking or driving) (80). Language Verbal fluency findings in PDD are inconsistent. In general, patients with PDD are comparably impaired to patients with AD on lexical and semantic verbal fluency tasks (81) and, in some cases, verbal fluency deficits may be even more severe in PDD (28). Demented PD patients may perform especially poorly on a task that requires the examinee to rapidly generate as many verbs (i.e., “things that people do”) as possible (82). Impairment in visual confrontation naming, most often measured by the Boston Naming Test, is less pronounced in PDD than in AD, if present at all (83). Memory Memory deficits are evident in PDD, although the profile of memory impairment in PDD is both qualitatively and quantitatively different than is observed in patients with AD. As in patients with PD, the memory deficit in early PDD is typically characterized by deficits in retrieval, rather than consolidation. That is, patients with early PDD are sufficiently able to retain information over time, but show deficits in retrieving the information from memory in free recall trials, in other words, without the aid of recognition or cueing. As the dementia becomes more severe, patients with PDD display broader memory deficits, including deficient encoding and consolidation, which is comparable with patients with AD (19). Although remote memory is typically intact early in PDD, deficits in this area become increasingly evident as the dementia progresses (63,84). However, the remote memory impairment is milder in PDD than AD. Also, in contrast to AD in which more remote memories are relatively preserved, PDD affects recall of the various decades of a patient’s life similarly (85). In contrast to nondemented patients with PD, patients with PDD typically perform poorly on most nondeclarative memory tasks (58). Visuoperceptual Functions Impaired visuospatial and visuoconstructive functions have been found consistently in PDD relative to nondemented patients and healthy controls, even when tasks minimize or eliminate motor demands (47,86,87). Findings from studies comparing the visuoperceptual abilities of PD and AD groups are not conclusive. However, it appears that patients with LBD show more prominent visuoconstructional and visuospatial deficits than do patients with AD (88,89). Affect and Emotion In contrast to AD, depression is much more frequently seen in PDD. In fact, the presence of depression is oftentimes considered an important distinguishing feature between subcortical and cortical dementia syndromes. Depression has been found to exacerbate cognitive dysfunction in PD. Patients with PDD, and LBD in particular, experience hallucinations more commonly than do patients with AD (90). Risk Factors for Dementia in Parkinson’s Disease Various demographic and disease variables predict PDD (Table 3). More recent work suggests that neuropsychological evaluation may also facilitate early identification of PDD. Jacobs et al. (91) and Mahieux et al. (92) noted that poorer performance by

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TABLE 3 Risk Factors for Dementia in Parkinson’s Disease Demographic variables

Disease variables

Neurobehavioral variables

Greater age Lower education

Later onset Disease duration

Lower socioeconomic status Family history of Parkinson’s dementia

Disease severity Susceptibility to levodopainduced psychosis or confusion

Depression Diminished cognitive test performance: Executive/Attention Verbal fluency Visuoperceptual List learning

patients with PD on verbal fluency, attentional, and visuospatial tasks was associated with subsequent development of dementia. Woods and Tröster (93) found that nondemented PD patients who met criteria for dementia at one-year follow-up evaluation demonstrated poorer baseline performance on measures of word-list learning and recognition, complex auditory attention, and executive function. IMPACT OF DEPRESSION AND ANXIETY ON COGNITION IN PARKINSON’S DISEASE Depression Symptoms of depression are commonly observed in patients with PD. Prevalence rates for depression in PD range from 7% to 90%, although 40% is the most frequently cited estimate. Approximately one-half of PD patients become depressed at some point during the disease course (94), with about half of these patients developing minor depression, whereas the other half develops major depression. Depression is a known risk factor for PD and PDD (66,95), and has been shown to adversely impact functional ability (96,97) and accelerate the progression of cognitive decline in PD (98,99). Depression in PD is unique in that, unlike in other neurodegenerative conditions such as AD, it significantly affects cognition (100). Executive functions and memory are foremost among the neuropsychological abilities impaired by depression (101–103). The negative impact of depression on cognition is more readily evident in the later stages of PD, and depression must be of at least moderate severity before it markedly impacts cognition (104,105). In light of depression’s detrimental effect on cognition, an important clinical question with treatment implications is whether cognitive and/or functional decline in PD is a dementia due to neurodegeneration or due to depression. Little literature addresses the incidence and prevalence of dementia due to depression in PD, and whether dementia in patients with comorbid depression improves with treatment and resolution of depressive symptomatology (106). Etiologic inferences about an individual PD patient’s dementia, when the dementia is accompanied by marked depression, should probably be deferred until such time as the depression has been adequately treated and neuropsychological reevaluation has been performed. Recent attention has also been drawn to the need to distinguish depression from apathy in PD (107). Apathy may occur in as many as 45% of patients with PD and, like depression, may be associated with executive deficits (108). Anxiety Anxiety disorders are seen in approximately 40% of patients with PD (109). Despite their frequent occurrence and contribution to morbidity and caregiver burden (11),

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anxiety symptoms in PD have received relatively little attention, perhaps because they overlap with symptoms of depression, PD, and medication effects, and are thus difficult to measure (110). The relationship between anxiety and cognition in PD has received virtually no attention. Ryder et al. (111) found that self-reported symptoms of anxiety, but not depression, were related to cognitive functioning in a small sample of male patients with PD. Self-reported trait anxiety was negatively related to performance on a neuropsychological screening battery, accounting for approximately 70% of the variance. The authors posit that anxiety may partly explain the association between depression and cognition in PD, although replication of their findings and additional large-scale studies are needed. EFFECT OF PHARMACOLOGIC AND SURGICAL TREATMENTS ON COGNITIVE FUNCTIONS IN PARKINSON’S DISEASE Modern treatment algorithms for patients with PD consist of both pharmacological and surgical intervention strategies (112). Neuropsychological evaluation can facilitate objective measurement of cognitive, neurobehavioral, emotional, and quality of life outcomes associated with treatment, as well as aid determinations regarding treatment (113). Pharmacologic Treatments Anticholinergics and Cholinesterase Inhibitors Anticholinergic medications used to treat motor symptoms in PD potentially produce adverse effects on memory, executive functions, and global cognitive abilities. In placebo-controlled studies, Bedard et al. (114,115) found anticholinergics to induce executive deficits in PD, but not in control participants. Although anticholinergicinduced memory decrements are observable even in patients without preexisting cognitive impairments (116), Saint-Cyr (117) found that confusional states are more likely to be induced by anticholinergics in patients with preexisting cognitive impairment. Thus, anticholinergics should be avoided in elderly patients who are susceptible to developing confusional states (118). Cholinesterase inhibitors were initially used sparingly and rarely in PDD and LBD. There is increasing recognition that cholinesterase inhibitors such as rivastigmine, donepezil, and galantamine may improve not only cognition, but also neuropsychiatric symptoms in both conditions, and that these agents are well tolerated by patients with PD (119–123). Levodopa and Dopamine Agonists Findings concerning the impact of levodopa on cognitive functions are inconsistent, with studies showing improvement, decrements, and an absence of significant cognitive changes associated with levodopa therapy or its withdrawal (124). Despite these inconsistent findings, evidence is accumulating that levodopa has short-term effects on certain aspects of memory and executive functions, perhaps as mediated by disease stage. Kulisevsky et al. (125) reported that short-term improvements in learning and memory, visuoperception, and certain executive functions were associated with dopamine replacement therapies, but stated that these cognitive improvements were not maintained over time. Owen et al. (126) found that only certain aspects of executive functioning (i.e., planning accuracy) were improved with levodopa therapy early in the disease, whereas other aspects (response latency)

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remained relatively unaffected. That levodopa affects only certain components of cognitive functions is consistent with the findings of Fournet et al. (127), who reported poorer performance only on working memory tasks in patients with PD after withdrawal from levodopa, and of Lange et al. (128), who also found that levodopa withdrawal impacted performance on only a minority of executive function measures. Levodopa’s rather selective effects on working memory and certain executive functions may be related to its mediation of dorsolateral frontal cortex blood flow in response to executive task activation (129). Dopamine agonists such as pergolide (130,131) and bromocriptine (132–134) have limited, if any, cognitive effects at therapeutic doses, acutely or after chronic administration. However, pramipexole may have negative effects on attention, verbal memory, and verbal fluency (135). Catechol-O-methyl-transferase (COMT) inhibitors are used to reduce peripheral breakdown of levodopa and thereby increase the amount of levodopa reaching the brain. One study found that after six months of treatment with the COMT-inhibitor tolcapone patients demonstrated improved attention, memory, and constructional skills (136). Selegiline and Rasagiline Selegiline and rasagiline, selective monoamine oxidase-B (MAO-B) inhibitors, have been hypothesized to exert a neuroprotective effect in PD by way of reducing physiologic stress associated with MAO-B oxidation of dopamine. Along with improvement in motor functions, several small, uncontrolled studies have found selegiline to be associated with improved global cognitive functioning, P300 latencies, and/or memory in patients with PD (137–140). In contrast, selegiline was reported not to significantly impact cognition in a large sample of untreated patients with early PD (141). The potential cognitive effects of rasagiline in PD patients have not been evaluated. Surgical Interventions Ablative Surgeries Ablative surgical interventions for PD involve stereotactic lesions in the globus pallidus, thalamus, or subthalamic nucleus to reduce motor symptoms. Cognitive and emotional outcomes after ablative procedures for PD in the 1950s and 1960s are sparsely documented. Wilkinson and Tröster (142) pointed out that outcomes from early and more recent studies are difficult to compare for a variety of reasons. In general, however, modern studies reveal that ablative procedures such as pallidotomy, thalamotomy, and subthalamotomy (especially unilateral) are relatively safe from a cognitive perspective. With regard to unilateral pallidotomy, declines in verbal fluency performance have been reported in approximately 75% of outcome studies that included a measure of verbal fluency (62,143–145). Postoperative decrements on measures of attention, memory, and executive functions (typically mild and transient) have been reported more occasionally, and significant cognitive complications even more rarely (146,147). Preexisting cognitive impairment, advanced age, and dominant hemisphere surgery have been proposed to increase the risk for postoperative cognitive decline. Few formal neuropsychological studies of bilateral pallidotomy have been undertaken, despite the observation that the most frequent adverse events among such patients are declines in speech and cognition (147). Despite their small number,

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these studies yield inconsistent findings. Some suggest that cognitive declines after bilateral pallidotomy may be limited in scope and severity (148,149), or that some gains in memory might be observed (150), but others report marked morbidity (151,152). Although early studies examining outcomes after thalamotomy reported decrements in language and memory with regularity (113), modern thalamotomy is associated with minimal risk of cognitive morbidity (153,154). Initial reports of the apparent cognitive safety of subthalamotomy (155,156) remain to be confirmed by larger, controlled studies. Deep Brain Stimulation Nonablative surgical procedures for treatment of PD involve either unilateral or bilateral implantation of high-frequency stimulation electrodes into deep brain nuclei. Studies detailing neuropsychological outcomes after unilateral globus pallidus (GPi) deep brain stimulation (DBS) have supported the neurobehavioral safety of this technique (113,157), although a few studies have demonstrated minor postoperative declines in verbal fluency (158–160). The majority of studies indicate that even bilateral GPi stimulation is cognitively well tolerated (161–163), although in isolated cases, cognitive declines can occur (152,164). There are few studies evaluating cognitive outcomes after thalamic DBS, but preliminary findings suggest that this procedure is associated with minimal cognitive morbidity up to one year after surgery (165–167). Indeed, subtle and limited cognitive improvements might be witnessed after thalamic DBS. The majority of DBS procedures now target the subthalamic nucleus (STN). Modest decrements in verbal fluency are the most commonly reported adverse cognitive sequelae associated with STN DBS (16,17,168). Findings regarding possible postoperative declines and/or improvements in global cognitive abilities, memory, attention, and executive functions are less consistent (113,169). When considered in the context of the important benefits of surgery on motor functions, mood state, and quality of life (170), the cost of possible minor and/or transient cognitive declines in a minority of well-selected patients seems to be overshadowed by the benefits. Preliminary evidence indicates that elderly patients (older than 69 years), as well as those patients displaying presurgical cognitive deficits, might be at greater risk for neurobehavioral morbidity after STN DBS. Transplantation Fetal mesencephalic tissue transplantation studies have indicated variability in neurocognitive outcomes among individual patients, but, given small sample sizes, the source of variability is difficult to identify (113). A recent double-blind study comparing patients, having undergone sham surgery and embryonic tissue implantation, failed to find significant differences in cognitive functioning between the groups (171). NEUROPSYCHOLOGICAL ASPECTS OF PARKINSON-PLUS SYNDROMES AND ESSENTIAL TREMOR “Parkinson-plus syndromes” traditionally include PSP, MSA, and corticobasal degeneration (CBD). Although sparse, preliminary neuropsychological studies indicate that the cognitive impairment profiles likely differ across the parkinson-plus syndromes (172). A summary of key differences is presented in Table 4.

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TABLE 4 Comparison of Neurobehavioral Features of Parkinson’s Disease with Dementia, Lewy Body Dementia, Corticobasal Degeneration, Progressive Supranuclear Palsy, and Multiple System Atrophy PDD Attention Executive (e.g., problem-solving, conceptualization, planning, flexibility) Language Letter fluency Category fluency Visual confrontation naming Memory for new information Recall Recognition Memory for old information Praxis Alien-hand sign Visuoperceptual/constructional functions Depression Apathy Fluctuating cognition

LBD

CBD

PSP

MSA

-

--

-

-

--

--

--

-

--

0/-

--0/-

---/--

0/-

-/-0

0

-0/0/0

-/-? 0/0

0/0 ? --/--

0/0 0 0/0

0/0 0 0 0

-0/-

----

0

0/-0

0/-0

Abbreviations: 0, impairment absent; -, mild to moderate impairment; --, moderate to severe impairment;?, questionable; PDD, Parkinson’s disease with dementia; LBD, Lewy body dementia; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy; MSA, multiple system atrophy.

Progressive Supranuclear Palsy Prevalence rates of dementia in PSP range from 50% to 80%, but some authors contend that these numbers reflect over-diagnosis due to bradyphrenia, emotional problems, and visual dysfunction that accompany PSP. Cognitive deficits are seen in approximately 50% of patients with PSP (172), with the neuropsychological profile being typical of diseases with subcortical involvement, including slowed information processing, executive dysfunction, and information retrieval deficits (173). As compared to patients with PD, cognitive slowing and executive dysfunction in PSP emerges earlier in the disease course, is more severe, and progresses more rapidly (174–177), and this differential executive dysfunction may reflect radiographically demonstrated differences in frontal atrophy between the two conditions (178). Executive dysfunction in PSP may also differ qualitatively from that in PD (179). Memory and attention are relatively intact in PSP, although retrieval deficits and accelerated rates of forgetting may be present (180,181). The early presence of cognitive impairment distinguishes PSP from MSA (182). Multiple System Atrophies The MSA nomenclature subsumes several different diseases, including olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), and Shy–Drager syndrome (SDS). Cognitive deficits are relatively mild in most forms of MSA, and dementia is not a common feature of these conditions (183), except perhaps in OPCA, in which 40% to 60% of patients may develop dementia, which is more prevalent in familial forms of the disease (184). Mild executive and memory deficits have been reported in MSA (SND and SDS) (185), but are considered to be of similar severity

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to those observed in nondemented patients with PD (176,186). Patients with MSA may show more pronounced attentional impairments and longer reaction times relative to patients with PD (186,187). Corticobasal Degeneration The prevalence of cognitive impairment and/or dementia in CBD is not established. Neuropsychological functions appear to be relatively preserved in the early stages of CBD, at least within an average of five years of diagnosis (188), with dementia emerging as a more common feature later in the disease course (189). Although the neuropsychological profile of CBD reveals both cortical and subcortical features (190), it is possible to differentiate CBD from AD and PSP (176,191). The neuropsychological profile associated with CBD is marked by significant executive dysfunction, which is comparable in severity to PSP, but relatively milder than is observed in patients with AD. Also evident in CBD is asymmetric apraxia (not evident in PSP or AD), alienhand sign (not reported in PSP or AD), impairment in motor programming and speed (similar to PSP but unlike AD), attentional dysfunction, and deficits in verbal fluency (comparable to AD). When aphasia is present it is most often of the nonfluent type (192). Memory impairment in CBD is characterized by deficient retrieval and encoding, but qualitatively and quantitatively different from AD, which is more likely to be marked by deficient consolidation and retention of information over time. Recall on remote memory tests is impaired, but unlike in AD, recognition is intact (193). REFERENCES 1. Lezak MD. Neuropsychological Assessment. 3rd ed. New York: Oxford University Press, 1995. 2. Shaskin D, Yarnell H, Alper K. Physical, psychiatric, and psychometric studies of postencephalitic parkinsonism. J Nerv Ment Dis 1942; 96:652–662. 3. Mendez MF, VanGorp W, Cummings JL. Neuropsychiatry, neuropsychology, and behavioral neurology—a critical comparison. Neuropsychiatry Neuropsychol Behav Neurol 1995; 8(4):297–302. 4. Reitan RM, Wolfson D. The Halstead-Reitan Neuropsychological Test Battery. Tucson: Neuropsychology Press, 1985. 5. Sweet JJ, Moberg PJ, Suchy Y. Ten-year follow-up survey of clinical neuropsychologists: part I. Practices and beliefs. Clin Neuropsychol 2000; 14(1):18–37. 6. Poreh AM. The quantified process approach: an emerging methodology to neuropsychological assessment. Clin Neuropsychol 2000; 14(2):212–222. 7. Mattis S. Dementia Rating Scale. Odessa, FL: Psychological Assessment Resources, 1988. 8. Beck AT, Steer RA. Beck Depression Inventory. San Antonio: The Psychological Corporation, 1987. 9. Beck AT, Steer RA. Beck Anxiety Inventory. San Antonio: The Psychological Corporation, 1993. 10. Jenkinson C, Fitzpatrick R, Peto V. The Parkinson’s Disease Questionnaire: User Manual for the PDQ-39, PDQ-8 and PDQ Summary Index. Oxford: Health Services Research Unit, Department of Public Health, University of Oxford, 1998. 11. Marsh L. Anxiety disorders in Parkinson’s disease. Int Rev Psychiatry 2000; 12:307–318. 12. Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2002; 8:193–197. 13. Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. Recognition and treatment of depression in Parkinson’s disease. J Geriatr Psychiatry Neurol 2003; 16(3):178–183. 14. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3):189–198.

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Management of Anxiety and Depression Jack J. Chen Department of Neurology, Schools of Medicine and Pharmacy, Movement Disorders Center, Loma Linda University, Loma Linda, California, U.S.A.

INTRODUCTION Anxiety and depression have become recognized as common nonmotor, psychiatric comorbidities in idiopathic Parkinson’s disease (PD), which contribute to additional disability such as significant impairments of cognitive, functional, motor, and social performance. This leads to reductions in quality of life and increased caregiver distress (1–8). Preliminary data suggest that depression may be an independent predictor of mortality in patients with PD (9). However, these affective disorders are under-recognized and under-treated in patients with PD due to symptom overlap with motor and cognitive features of PD (10–12). In the presence of other comorbid psychiatric conditions (e.g., anxiety), depressive symptoms, quality of life, and functional domains are further worsened. Specifically, the presence of anxiety with depression has been found to increase the severity of depressive symptoms and to delay the response to psychotropic treatment (13). Therefore, effective detection and treatment of anxiety and depression are important aspects of PD management. This chapter will discuss the epidemiology, possible mechanisms, recognition, and management of these affective disorders in idiopathic PD. ANXIETY Epidemiology In James Parkinson’s original monograph, An Essay on the Shaking Palsy, little mention was made of the nonmotor symptoms of anxiety and depression (14). However, it is now known that clinically significant anxiety symptoms occur in 20% to 52% of PD patients, a frequency greater than that found in community dwelling agematched controls (1,15–17). Menza et al. (18) reported a depressive disorder in 92% of PD patients diagnosed with an anxiety disorder, and an anxiety disorder was present in 67% of depressed PD patients. This is consistent with results by Starkstein et al. (16), reporting depression in 76% of patients with PD and anxiety. In addition to generalized anxiety disorder (GAD), patients with PD regardless of sex also experience panic disorders and social phobias with a prevalence of approximately 30%. (17,19,20). The presence of anxiety not only contributes to mental and somatic discomfort, but may also contribute to existing motor symptoms or fluctuations (7). For example, patients will report that episodic states of anxiety will aggravate preexisting tremor or dyskinesia, and fear of falling has been associated with impaired postural stability (21). Additionally, an “internal tremor” is frequently associated with anxiety (22). Consequently, in patients with high levels of anxiety or significant episodic anxiety, the initiation of appropriate anxiolytic therapy may improve motor symptoms as well as mental and psychosocial functioning. 133

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Mechanisms Little is known about the etiology of anxiety disorders in PD, and they may be attributed to a combination of medical, neurochemical, and psychosocial phenomena. In a subset of patients, anxiety disorders are a “reactive” response secondary to the diagnosis of PD. However, when compared with non-PD patients with chronic illnesses and similar disability, patients with PD have significantly more severe anxiety (23). Epidemiologic observations indicate that patients with PD are at greater risk of developing anxiety disorders before the diagnosis of PD (24,25). These findings suggest that anxiety may be an early nonmotor phenotype of PD and that disability, although it may contribute to anxiety, is not the sole etiologic determinant. Anxiety has been associated with motor fluctuations (20,26–28). During “off ” phases, patients may experience feelings of despair, hopelessness, and panic that dissipate during the “on” phases (20). Frequency of freezing is also highly correlated with the presence of panic disorders and secondary panic attacks (29). However, emotional fluctuations do not always correlate temporally with motor state (30–31). In a study of 87 patients with PD, 29% had fluctuations in anxiety, 24% in motor, and 21% in mood (30). Of the patients with motor fluctuations, 75% had mood and/or anxiety fluctuations that did not necessarily correlate with motor state. Although the pattern of anxiety or mood fluctuations can be heterogeneous, adjustment of antiparkinson medications to minimize the motor fluctuations can be beneficial. Neurochemically, degeneration of subcortical nuclei and ascending dopamine, norepinephrine, and serotonin (5-HT) pathways within the basal ganglia–frontal circuits may be responsible for symptoms of anxiety (32–35). Remy et al. (35) utilized [11C]RTI-32 positron emission tomography (PET), an in vivo marker of both dopamine and norepinephrine transporter binding, to localize differences between 8 depressed and 12 nondepressed patients with PD matched for age, disease duration, and antiparkinsonian medication. Exploratory analyses revealed that the severity of anxiety in the PD patients was inversely correlated with binding of [11C]RTI-32 in the amygdala, locus coeruleus, and thalamus. These results suggest that anxiety in PD might be associated with a specific loss of dopaminergic and noradrenergic innervation in the locus coeruleus and the limbic system. Detection and Recognition No standardized tool or method has been specifically developed to detect and assess anxiety in the PD population. Detection may be problematic, because several symptoms of anxiety overlap with mental and somatic symptoms commonly associated with PD. The Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition (DSM-IV) criteria for GAD in the general population includes a period of at least six months with prominent tension, worry, and feelings of apprehension about everyday events and problems, along with the presence of at least four of 22 accompanying autonomic, psychic, and somatic symptoms (36). However, several of these accompanying symptoms, such as tremor, concentration difficulties, dizziness, muscle aches, and numbness or tingling, are also commonly attributed to PD and may not be recognized as components of an anxiety disorder. Given that anxiety appears to be common over the course of PD, periodic assessment would significantly enhance detection. In the absence of cliniciandirected questioning or screening, anxiety in PD often goes unrecognized (15). In a clinic-based study, Shulman et al. (15) reported that recognition of anxiety more than doubled (from 19–39%) when patients were screened with the Beck Anxiety Inventory

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(BAI). In addition to the BAI, the Hospital Anxiety and Depression Scale (HADS) has demonstrated satisfactory psychometric performance in the PD population (37–39). Because anxiety and depressive symptoms are frequently comorbid in PD, a finding of anxiety should also prompt a screening for depression. Treatment Agents that possess anxiolytic properties include benzodiazepines, buspirone, mirtazapine, nefazodone, selective serotonin reuptake inhibitors (SSRIs), trazodone, tricyclic antidepressants (TCAs), and venlafaxine. Five agents, bromazepam, buspirone, citalopram, paroxetine, and sertraline, have been evaluated for the treatment of anxiety in PD (40–44). Benzodiazepines Although benzodiazepines are commonly used in the management of anxiety, only one randomized controlled trial addressed this in the PD population (40). Bromazepam, a long-acting benzodiazepine, was reported to improve psychic and somatic (i.e., tremor) symptoms of anxiety. Anecdotally, other benzodiazepines have also been noted to be effective. Clonazepam was reported to be effective in a patient with anxiety and panic attacks that were refractory to alprazolam, lorazepam, and numerous antidepressants (45). Although benzodiazepines may be effective, its long-term use, especially in the elderly or frail patient, may be associated with unfavorable effects on alertness, cognition, and gait, and an increased risk of falls (46–48). Therefore, benzodiazepines should be used judiciously with careful evaluation of potential risks and benefits. Selective Serotonin Reuptake Inhibitors Results from uncontrolled studies suggest that SSRIs are effective for anxiety in PD (42–44). In an open-label study (n = 10), Menza et al. (42) reported that citalopram (mean dose 19 mg/d) improved anxiety in depressed PD patients. In a study of 30 patients, paroxetine (20 mg twice daily) reduced psychic and somatic anxiety symptoms, as well as depressive symptoms after six weeks (43). Sertraline was also found to have anxiolytic effects in PD patients (44). Although these data are derived from uncontrolled studies, many specialists prefer to use SSRIs for managing anxiety and depression in PD (49). The SSRIs are relatively well tolerated, although acute, treatment-emergent side effects such as agitation, diarrhea/loose stools, insomnia, nausea, and sedation may occur. Occasionally, SSRIs may worsen tremor, and chronic use is associated with an increased risk of developing endocrinologic and metabolic adverse effects, such as hyponatremia, sexual dysfunction, and weight gain (Table 1) (50–52). The concomitant use of amantadine has been reported to reduce the risk of SSRI-induced sexual dysfunction (53). Reversible SSRI-induced worsening of parkinsonism has also been reported, but data are conflicting regarding the magnitude of this risk (54–56). Pharmacodynamic studies have not detected any significant reduction of motor function in patients with PD treated with SSRIs (57–58). Patients on a concomitant monoamine oxidase-B (MAO-B) inhibitor (e.g., rasagiline, selegiline) may be at increased risk of developing 5-HT syndrome; however, the overall risk appears to be minimal. In one survey-based study, the frequency of 5-HT syndrome in patients on concomitant selegiline was 0.24%, with 0.04% of patients experiencing serious symptoms (59). Data for the safety of SSRIs in combination with rasagiline are limited. In a study of rasagiline in PD, among those taking SSRIs (n = 77), there

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TABLE 1 Comparison of Selected Antidepressant Side Effects Sedation TCAs Amitriptyline Doxepin Imipramine Desipramine Nortriptyline SSRIs Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Other Bupropion Duloxetine Mirtazapine Nefazodone Venlafaxine

Antimuscarinic

Hypotension

Weight gain

Sexual dysfunction

+++ ++ ++ + +

+++ +++ ++ + +

++ ++ +++ + +

+++ ++ ++ + +

+ + + 0 0

+ + 0 0 + 0

+ + 0 0 + 0

0 0 0 0 0 0

+ + + ++ ++ +

++ ++ +++ ++ +++ ++

0 + ++a ++ +

+ ++ + 0 +

0 0 ++ ++ 0

0 0 +++a 0 +

0 ++ ++ + +++

a

At low doses. Abbreviations: +, minor; ++, moderate; +++, major; 0, nonsignificant; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants. Source: From Refs. 50–52.

were no significant differences in adverse events with rasagiline compared to placebo (60). Abrupt discontinuation of SSRIs after extended treatment may precipitate a withdrawal or discontinuation syndrome, characterized by somatic and psychological symptoms that resemble anxiety (61). Therefore, if discontinuation is required, a gradual tapering of the dosage is recommended, particularly with short half-life agents such as paroxetine. Miscellaneous Agents Buspirone, an anxiolytic with partial 5-HT agonism and low sedative potential, has not been evaluated in a controlled manner for the management of anxiety in PD. However, in a 12-week randomized, controlled study (n = 16) evaluating the effect of buspirone on PD motor symptoms, moderate doses (10–40 mg/d) of buspirone were associated with a modest beneficial effect on anxiety (41). Higher daily doses (i.e., 100 mg) of buspirone significantly enhanced anxiety and worsened parkinsonism. In a three-week randomized, controlled study (n = 10) evaluating the effect of low-dose buspirone on levodopa-induced dyskinesia, no significant effect on anxiety was noted (62). However, since the therapeutic onset of buspirone requires up to six weeks, the short duration of this study may not have been sufficient to detect any significant anxiolytic effect. DEPRESSION Epidemiology Depressive symptomatology may occur at any stage of PD and is a major factor related to poor quality of life for both patients and caregivers, with caregiver distress highly correlated with the patient’s severity of depression (8,12,63,64). Depressive

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disorders are common in PD. In a community-based study, the prevalence of depressive symptomatology in PD patients was six times that of healthy age- and sexmatched controls (2). In a registry-based study of 211,245 patients, Nilsson et al. (65) compared the incidence of depression in PD patients (n = 11,698) with non-PD patients with diabetes (n = 91,318) and non-PD patients with osteoarthritis (n = 10,822) who were matched for degree of disability. An increased probability of developing a depressive episode was found for patients with PD when compared with the diabetes and osteoarthritis groups. Nilsson et al. (66) also showed that patients with an affective disorder (depression or mania) had an increased risk of being diagnosed with PD (odds ratio 2.2) when compared to patients with osteoarthritis or diabetes. In an analysis of 10 studies that used DSM-III criteria to define depression, an aggregate prevalence of 42% was reported for depressive disorders in PD (67). The prevalence rates of dysthymia, minor depression, and major depression in PD patients were 22.5%, 36.6%, and 24.8%, respectively. Studies using DSM-IV criteria and a structured clinical interview reported similar results, with the prevalence of major depression ranging from 20% to 25% in PD (11,68–70). Additionally, depression appears to occur more frequently in the presence of advanced disease, anxiety, cognitive impairment, and psychosis (2,71–74). In an international survey of over 1000 PD patients, more than 50% of patients displayed clinically significant depressive symptomatology (8). In a clinic-based study of over 350 patients with PD, clinically significant depressive symptomatology was present in 57% of patients, with 40.2% considered mildly to moderately depressed and 16.7% classified as moderately to severely depressed (71). Patients with PD may also suffer from depressive symptoms that do not meet criteria for major depression, minor depression, or dysthymic disorder, but nonetheless seem to have clinical relevance. Subsyndromal depression is defined as the presence of two or more depressive symptoms at subthreshold levels (i.e., short duration or not present most of the day or nearly every day) (75). Patients with depressive symptoms only during “off ” states may be classified as having subsyndromal depression. With the inclusion of clinically important subsyndromal depressive disorders, the prevalence of clinically significant depressive symptomatology is present in 40% to 64% of patients with PD (2,8,11,12,15,71). Mechanisms The underlying mechanism for depression in PD remains poorly understood, but the phenotypic expression of depressive disorders has been attributed to a combination of medical, neurochemical, and psychosocial phenomena. Depression may be a “reactive” response or demoralization phenomenon associated with the diagnosis of PD and its relative disability. However, when compared with patients with other chronic disabling conditions matched for functional disability, patients with PD exhibit greater depressive symptomatology (76). Additionally, in patients with PD, depression often precedes the onset of motor symptoms (25,77,78), and the natural history of depression in PD does not parallel the progression of physical symptoms, suggesting that it is an independent process (79,80). In comparison with control subjects, patients with PD are approximately twice as likely to experience a mood disorder (anxiety, depression, nervousness, overstrain) in the 10 years preceding onset of motor symptoms (77). These findings suggest that, in a subset of patients, depression may be an early nonmotor phenotype of PD and that disability, although it may contribute to depressive symptoms in PD, is not the sole etiologic determinant. As

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with anxiety, mood fluctuations are sometimes associated with medication “on” and “off ” states (28). Affective and behavioral changes (e.g., aggression, depression, mania) have also been reported as complications of deep brain stimulation (DBS), especially subthalamic nucleus (STN) DBS (81). Interestingly, depression has been infrequently reported to develop, as a result of thalamic and pallidal DBS (82). In a review of 23 articles reporting on the effect of STN DBS on mood state in PD, nine studies reported a mood elevating or antidepressant effect in 16.7% to 76% of patients, 13 studies reported a depressant effect in 2% to 33.3% of patients, and eight studies reported a mania-inducing effect in 4.2% to 8.1% of patients (83). In one series of 24 consecutive patients undergoing STN DBS, six patients (25%) experienced significant worsening of mood and three were transiently suicidal despite motor improvement (84). In a series of 137 patients who underwent STN DBS, 16 (12%) developed depression (85). Mood disturbances induced by STN DBS could be the result of stimulation spreading to adjacent nonmotor circuits, aberrant electrode placement, or activation of inappropriate contacts, resulting in stimulation of adjacent cells or fiber tracts. In some cases, alteration of the contact selection reverses the depression (86,87) Additionally, anxiety or depressive symptoms may be due to exacerbation or unmasking of previously existing disorders (88). It is also possible that depressive or anxiety symptoms may be a reactive response if the procedure was less successful than anticipated and, in some cases, depressive symptoms may be part of a “dopaminergic withdrawal syndrome” that occurs secondary to postprocedure dose-reduction of dopamimetic agents (81). Pathologic degeneration of mesolimbic dopamine, norepinephrine, and 5-HT pathways in conjunction with degeneration of orbital–frontal circuits and subcortical structures, such as the locus coeruleus, dorsal raphe nuclei, and ventral tegemental area, are also postulated to be associated with the expression of depressive symptoms (33,35,89,90). Imaging utilizing PET with 18fluorodeoxyglucose demonstrates increased hypometabolism in the caudate and orbital inferior frontal lobe of depressed PD patients as compared with nondepressed PD patients and with nonPD controls (91). Additionally, a significant inverse correlation between orbital inferior frontal lobe metabolic activity and severity of depressive symptoms was observed (91). Serotonergic fibers originating in the dorsal raphe project heavily toward frontal dorsal areas and serotonergic abnormalities may further disrupt activity in the dorsal frontal areas. An in vivo single photon emission computed tomography study with [123I] β-carboxymethoxy-iodophenyl tropane (β-CIT) demonstrated that in patients with PD, disruption of the brainstem raphe 5-HT system is highly correlated with mood and mentation (90). Abnormalities in dopaminergic and noradrenergic innervation to subcortical structures have also been demonstrated. Depressed PD patients have lower [11C]RTI32 binding (i.e., loss of dopaminergic and noradrenergic innervation) than nondepressed PD patients in the locus coeruleus and in several regions of the limbic system, including the amygdala, anterior cingulate cortex, the thalamus, and the left ventral striatum (35). Remy et al. (35) reported that binding of [11C]RTI-32 in the left ventral striatum was inversely correlated with the degree of apathy and the intensity of depression in the patients. This finding of laterality is consistent with other studies, reporting a link between depression and right-sided symptoms (72,92). A significant reduction in dopamine transporter availability in the left anterior putamen has also been found to be correlated with increasing severity of anxiety and depression symptoms in patients with PD (93). Abnormalities of dopamine innervation

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may produce mood fluctuations via effects on the posterior cingulate cortex (PCC), an area strongly linked to mood and anxiety and with known regional cerebral blood flow (rCBF) responsiveness to dopamimetic drugs. Abnormal activity in the medial frontal gyrus and PCC was demonstrated in a study of eight patients with PD, and clinically significant levodopa-related mood fluctuations (mania, depression, or anxiety) were compared to 13 patients with similarly severe PD and fluctuations of motor state but not of mood (94). The rCBF response to levodopa in the medial frontal gyrus and PCC was significantly different between mood fluctuators and control patients, with controls exhibiting a normal response after levodopa administration, whereas the mood fluctuators did not exhibit a response. The implication is that mood fluctuations may arise in PD patients who have abnormal dopaminergic modulation within the caudate nucleus, anterior cingulate cortex, or orbital frontal cortex, all of which innervate the PCC. Overall, the studies on the functional anatomy of depression in PD demonstrate that deficits in serotoninergic and catecholaminergic innervations to cortical and subcortical components are involved. Cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid, a 5HT metabolite, have been reported to be lower in PD patients with major depression as compared with nondepressed PD patients and PD patients with minor depression (95). However, some studies have detected no differences in CSF biogenic amine concentrations between depressed and nondepressed PD patients (96). The effect of elevated homocysteine levels on mood and cognition has also been investigated. Levodopa-induced elevations in plasma homocysteine levels in patients with PD were associated with greater depressive symptomatology, as well as impaired performance on a battery of cognitive tests (97). The association between elevated homocysteine levels and psychiatric symptomatology requires further investigation. A search for specific susceptibility genes for depression in PD has focused on genes associated with the actions of 5-HT. Some studies have been linked to allelic variation in the 5-HT transporter gene to anxiety and depression in PD (98,99), whereas others have found no association (100). Preliminary data also demonstrate that in patients with PD, the presence of two long alleles in the CNR1 gene, which codes for CB1 cannabinoid receptors, is associated with a reduced prevalence of depression. This suggests that pharmacological manipulation of cannabinoid neurotransmission could be a novel therapeutic approach for treatment of depression in PD (101). Detection and Assessment There are no reliable and empirically derived criteria for recognition of depression in PD. Therefore, it is not surprising that depression remains under-detected and under-treated in the PD population (15,71). In a clinic-based study, nearly two-thirds of patients with clinically significant depressive symptomatology were not receiving antidepressant therapy (11). Older individuals often underreport depressive symptoms and are likely to focus on somatic or vegetative complaints (e.g., fatigue or loss of energy, reduced sexual desire or functioning, pain, sleep changes, or appetite changes), which are the prominent features of mood disorders as well as PD (102). Patients may simply attribute any mood symptoms to their PD, even when their PD has been relatively stable and the mood changes are relatively acute. In one study, over half the patients who had clinically significant depressive symptoms did not consider themselves depressed (11).

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In a clinic-based study, the detection of depressive symptomatology in patients with PD more than doubled (21–44%) when patients were screened using the Beck Depression Inventory (BDI) (15). The assessment and recognition of depression has been ranked highly as an indicator for improving care of PD patients (103). All PD patients should be screened periodically to detect clinically significant depressive symptomatology. If self-reported disability is out of proportion to findings on the neurologic exam, depression should be suspected (73). Caregivers or family members are often valuable sources of information about the patient’s psychological wellbeing, especially when self-report may be unreliable (104). The DSM-IV diagnostic criteria for major depression includes the persistent presence of five of the following nine symptoms: anhedonia, depressed mood, diminished ability to think or concentrate, fatigue or loss of energy, feelings of worthlessness or inappropriate guilt, insomnia or hypersomnia, psychomotor agitation or retardation, recurrent thoughts of death, and significant weight gain or loss (36). However, because several of these symptoms overlap with features of PD, the assessment of depression in patients with PD is not always straightforward. This is highlighted by a study demonstrating that anergy, early morning awakening, and psychomotor retardation are common and similarly frequent in both depressed and nondepressed patients with PD (105). Clinician-completed symptom rating scales can be used as a screening tool to provide a measure of symptom severity or response to treatment. Examples include the Hamilton Depression Rating Scale (HAMD) and the Montgomery–Asberg Depression Rating Scale that have been validated for use in the PD population (70,106–108). Despite the issue of separating out the somatic complaints of depression from underlying medical illnesses or consequence of aging, key psychological symptoms of depression, such as sad mood or frequent tearfulness, decreased interest in normally pleasurable activities or social avoidance, difficulty in making decisions or planning daily activities, feelings of worthlessness or hopelessness, and recurrent thoughts of death or suicide, are less affected by age or comorbid medical conditions and may be more helpful in reaching an accurate diagnosis. The United States Preventive Services Task Force (USPST) has recommended screening for depression in all adults, regardless of medical comorbidities (109). For routine clinical purposes, the USPST recommends asking the patient two questions: “Over the past two weeks, have you felt down or hopeless?” and “Over the past two weeks, have you felt little interest in doing things?” A “yes” to either question is a positive screen and warrants additional investigation. Patients may also complete standardized, self-report instruments that are easily and rapidly administered in the outpatient setting and can be scored by physicians or allied health professionals. Several instruments are available, such as the BDI, Geriatric Depression Scale (GDS), HADS, Zung Self-Rating Scale, and the Center for Epidemiologic Studies Depression Scale (38,110–113). Although the 21-item BDI contains several somatic items, it has been determined to be a valid and internally consistent instrument for screening depression in the PD population if the cutoff score is modified. A cutoff score of 13/14 or 14/15 has been suggested for maximum discrimination between depressed and nondepressed patients with PD (114–116). Instruments that are free of somatic items include the 30-item GDS (GDS-30) (111), the 15-item GDS (GDS-15) (117), and the 7-item depression component of the HADS (38). The GDS-30 and GDS-15 have also been found to be reliable and valid for use in the PD population (108,118). In one study, sensitivity and specificity analyses showed that GDS-30

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cutoff scores of 8/9 or 9/10 could be useful for screening of depression and 14/15 or 15/16 for diagnostic purposes in patients with PD (118). For the GDS-15, a cutoff score of 4/5 is associated with high discriminant validity for distinguishing depressed from nondepressed patients in PD. Its test characteristics were found to be comparable to that of the HAMD (108). The HADS has also been validated for use in the PD population (39). A 12-item short-form BDI, which excludes somatic items, has also been used to assess depression in PD but has not been psychometrically validated for PD (119). Overall, self-report instruments may be an effective means of screening for depressive symptomatology in patients with PD. A physical examination and laboratory screening (e.g., complete blood count, liver function, serum testosterone level, serum vitamin B12, thyroid function) may be performed to exclude potential systemic causes of depressive symptomatology. Testosterone deficiency associated with depressive symptomatology (e.g., anhedonia, fatigue, and sexual dysfunction) has been described in males with PD and may possibly be managed with testosterone replacement therapy (120). Likewise, symptoms of hypothyroidism (e.g., anxiety, difficulty with concentration, dysphoria, fatigue, irritability, and motor retardation) resemble depressive symptomatology and are treatable with thyroid replacement. It is also important to ensure that patients are on optimal doses of antiparkinson drugs to minimize motor fluctuations that may contribute to mood fluctuations. Treatment Patients with PD and untreated depression experience reduced quality of life compared with those who are depressed and taking antidepressant medications (62). Additionally, depression in PD patients often persists or worsens longitudinally, and untreated minor depression commonly progresses to major depression. Therefore, even mild depressive disturbances should be considered clinically significant and should warrant monitoring if not definitive treatment. The efficacy and safety of various antidepressants in the management of depression in patients with PD has been addressed in numerous uncontrolled studies (42,56,121–138) and a few controlled studies (139–150). Pharmacologic Tricyclic antidepressants The TCAs inhibit synaptosomal reuptake of dopamine, norepinephrine and, to a lesser extent, 5-HT. The TCAs also possess antimuscarinic and antihistaminic properties. Amitriptyline (139,144,147), desipramine (149), imipramine (150), and nortriptyline (148) have demonstrated antidepressive effects in randomized, controlled trials involving parkinsonian patients. Although these studies have methodologic limitations, all study agents were found to be effective. In two studies conducted in the prelevodopa era, desipramine and imipramine improved parkinsonian motor symptoms, as well as symptoms of anxiety and depression (149,150). Uncontrolled studies have reported favorably on the efficacy of imipramine in treating PD depression (137,138). There are no published data on doxepin for the management of depression in PD. The tertiary amine TCAs (e.g., amitriptyline and imipramine) are associated with clinically significant central and peripheral side effects (e.g., antimuscarinic effects, confusion, hallucinations, hypotension, sedation, sexual dysfunction, and weight gain) that are often undesirable and/or intolerable for patients (Table 1),

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especially the elderly. However, in a subset of patients, such as those with bladder hyperactivity or drooling, the antimuscarinic activity of TCAs may be of added benefit. Sedating TCAs (e.g., amitriptyline) are also often selected for patients with insomnia (49). The secondary amine TCAs (e.g., desipramine and nortriptyline) are associated with a milder degree of side effects and are preferable if potent antimuscarinic effects are not desired. Lastly, the TCAs rarely have been associated with treatment-emergent extrapyramidal symptoms (151,152). Selective serotonin reuptake inhibitors The SSRIs inhibit the synaptosomal reuptake of 5-HT and are generally preferred over the TCAs because of better overall tolerability (11) (Table 1). For the management of depression in patients with PD, all currently available SSRIs have been studied; albeit the numbers of patients in the trials have been small. Results from uncontrolled retrospective and prospective studies suggest that citalopram (42,56,127,128,131), escitalopram (123), fluoxetine (56,136), fluvoxamine (56), paroxetine (43,129,132,134), and sertraline (56,124,125,133) are effective for the treatment of depression in PD, with the majority of studies investigating citalopram or sertraline. In a prospective, open-label study (n = 62) examining the efficacy of four SSRIs (citalopram, fluoxetine, fluvoxamine, and sertraline) for the treatment of PD depression, all agents were similarly effective (56). Taken together, the data from these uncontrolled studies in depressed PD patients suggest that the efficacy of SSRIs may be a class effect. However, outcomes from controlled studies of SSRIs for depression in PD have been mixed and have also included small numbers of patients (139,140,142–145,147). In one study (n = 32), sertraline and amitriptyline were found to be equally efficacious (139). Fluoxetine has been found to be efficacious (140,142) and, in one study involving 16 patients, efficacy was similar to nefazadone (142). In another study (n = 47), fluvoxamine (mean dose = 78 mg) and amitriptyline (mean dose = 69 mg) were similarly efficacious (147). However, approximately 40% to 45% of patients in each group dropped out due to adverse effects, predominantly confusion and hallucinations. On the other hand, some studies have found no significant difference between sertraline or citalopram and placebo (143,145). In a 10-week controlled study of 12 patients, Leentjens et al. (143) reported a clear treatment effect with sertraline and placebo, but without a significant betweengroup difference. In a 6-week controlled study (n = 37), Wermuth et al. (145) also reported a significant treatment effect with citalopram and placebo, but a significant between-group difference was not observed. Due to the small sample size, it is possible that these studies were not adequately powered to detect significant differences between study drug and placebo. Thus, based solely on the available scientific evidence, the efficacy of SSRIs for the management of depression in PD appears favorable yet remains unclear. Furthermore, many PD patients remain depressed despite long-term treatment with an SSRI (11). This may be related to use of an inadequate antidepressant dosage, limited efficacy, or poor adherence to medication. Miscellaneous agents In addition to SSRIs and TCAs, several other antidepressants are available, including bupropion, duloxetine, milnacipran, mirtazapine, moclobemide, nefazodone, reboxetine, selegiline, trazodone, and venlafaxine. Of these agents, only mirtazapine, moclobemide, and nefazodone have been evaluated in a controlled manner for the management of depression in PD (141,142,146). In terms of natural products, high-dose S-adenosyl-methionine was found to be effective for PD depression in a 10-week, open-label, pilot study involving 13 patients (153).

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Bupropion, a dopamine reuptake inhibitor, may be effective in PD depression (130). Common side effects include agitation, constipation, dry mouth, excessive sweating, tremor, and weight loss. Uncommon side effects include psychosis and seizures at high dosages. Mirtazapine is a dual-action antidepressant that augments noradrenergic and serotonergic transmission via antagonism of central α2-autoreceptors. The drug also has antihistaminic properties. In a randomized, double-blind, placebo-controlled study involving 20 depressed PD patients, mirtazapine 30 mg/d in combination with brief psychotherapy was superior to placebo in reducing depression (141). Common side effects include constipation, dry mouth, orthostasis, sedation, and weight gain. The incidence of sedation was inversely correlated with dosage. Additionally, uncontrolled data suggest that mirtazapine attenuates parkinsonian tremor and levodopa-induced dyskinesia (154,155). Uncommon side effects include agranulocytosis, hypercholesterolemia, hepatic impairment, hallucinations/psychosis, and rapid eye movement sleep behavior disorder (156,157). Moclobemide (not available in the United States) is a reversible inhibitor of monoamine oxidase type A (MAO-A), and selegiline is an irreversible, selective inhibitor of monoamine oxidase type B (MAO-B). Inhibition of brain MAO-A activity increases norepinephrine and serotonin concentrations. One small controlled trial (n = 10) compared moclobemide to moclobemide plus selegiline in PD patients with major depression and found a greater benefit with combination of moclobemide– selegiline treatment (146). In non-PD patients, transdermally administered selegiline is effective and safe for the treatment of major depression (158,159). Through transdermal delivery, selegiline is directly and continuously absorbed into the bloodstream. As a result, initial exposure of the drug to the digestive tract is minimized and lower therapeutic doses allow for levels of selegiline, inhibiting both MAO-A and MAO-B isoforms in the brain to produce an antidepressant effect while sufficiently preserving MAOA in the digestive tract to break down tyramine. However, at higher therapeutic doses, dietary tyramine modification is required to reduce the risk of hypertensive crisis. To date, no published data are available on the efficacy and safety of transdermal selegiline for the treatment of depression in patients with PD. Nefazodone and trazodone possess antidepressive and anxiolytic properties. Both agents antagonize 5-HT receptors and modestly inhibit the reuptake of norepinephrine and 5-HT. In a controlled comparative study (n = 16), nefazodone and fluoxetine were similarly effective at improving depression, with nefazodone also producing a notable improvement in motor symptoms (142). However, the use of nefazodone may be limited by reports of hepatoxicity and significant hepatic CYP450 3A4-mediated drug–drug interactions. Trazodone has not been studied in PD depression; however, low-dose trazodone is commonly used as a sedative/hypnotic. Of note, a metabolite of trazodone, m-chlorophenylpiperazine, is anxiogenic and a subset of patients may experience irritability and enhanced anxiety, especially if trazodone is used in the presence of a potent CYP450 2D6 isoenzyme inhibitor (e.g., fluoxetine and paroxetine) (160). Common side effects of both nefazodone and trazodone include dizziness, orthostatic hypotension, and sedation. Duloxetine, milnacipran, and venlafaxine are dual-action antidepressants that selectively inhibit norepinephrine and 5-HT reuptake, and reboxetine is a selective norepinephrine reuptake inhibitor. To date, there are no published reports on the use of duloxetine for managing depression in PD. Preliminary reports on milnacipran and reboxetine (neither available in the United States) suggest that these antidepressants

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may be effective in PD patients (121,122,126). With venlafaxine, open-label data (n = 14) suggest that at 75 mg/d, it is well tolerated and improves depressive symptoms in patients with PD (125). At low doses, the pharmacologic activity of venlafaxine resembles that of an SSRI and, therefore, an anxiolytic effect can also be expected. At higher doses, norepinephrine reuptake activity becomes more pronounced and an activating effect can be expected. Venlafaxine-induced hypertension has also been observed at higher dosages; therefore, blood pressure should be monitored periodically. Dopamine agonists Pramipexole and ropinirole have been reported to have antidepressant properties (161–165). In an 8-month, prospective, randomized study (n = 41) comparing the antidepressant effects of pramipexole and pergolide, as an add-on to levodopa in depressed patients with PD, a significant improvement in depressive symptoms was only observed in the pramipexole-treated patients (162). In a prospective, observational study of 657 pramipexole-treated patients with PD, the frequency of anhedonia and depression was significantly reduced during treatment with pramipexole (166). In an open-label study with ropinirole and pramipexole, both were shown to improve depression in PD patients (165). In a study enrolling non-PD patients with treatment-resistant depression, ropinirole was added to a TCA or SSRI and demonstrated modest benefit (167). Additional studies on the effect of dopamine agonists on depressive symptoms in PD are warranted. Assessment of Efficacy Overall, based on clinical experience and the available scientific data, SSRIs and TCAs may be considered useful for the treatment of depression in PD, and the agent that provides the best overall clinical benefit-to-risk profile should be selected (168). Amoxapine and lithium should be avoided, given the propensity of these agents to worsen motor symptoms and the availability of safer agents (169,170). Additionally, the nonselective MAO inhibitors (e.g., isocarboxazid, phenelzine, and tranylcypromine) should be avoided in levodopa-treated patients due to the risk of hypertensive crisis. Several antidepressants, such as bupropion, fluoxetine, fluvoxamine, nefazodone, and paroxetine, are potent in vivo inhibitors of various cytochrome P450 (CYP450) drug-metabolizing isoenzymes (171,172). These antidepressants may increase the risk for drug interactions. The first step in treating a patient who fails to respond to treatment is to increase the dosage of the antidepressant. If a patient fails to respond to a maximal, tolerated therapeutic dosage, then the antidepressant should be discontinued and replaced by another from a different pharmacologic class. For example, if a patient fails to respond to an SSRI, a switch to a dual action antidepressant (e.g., duloxetine, venlafaxine) should be made. When anxiety is present with depression, there may initially be a slowed response to antidepressant therapy (13,173). Since depression is a potentially recurrent disorder, once depressive symptoms have improved or recovery has been achieved, it is recommended that maintaining treatment at the effective dose should continue for at least six months to reduce the risk for relapse. Persisting symptoms of concurrent anxiety have been found to increase the risk for relapse of depression (174). Nonpharmacologic Cognitive behavior therapy (CBT) is based on the construct that depressed people hold distorted cognitions. The aim of CBT is to provide a structured approach to help

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people to identify maladaptive thoughts contributing to emotional discomfort and to replace them with more enabling alternatives. Some evidence suggests that CBT is effective for reducing depressive symptoms in people with chronic neurological conditions (175). The use of CBT in the PD population has been described in a few case reports and small studies (176–178). In a pilot study, 12 PD patients with either major depressive disorder or dysthymia received 10 sessions of modified individual CBT, and their caregivers attended four psychoeducational sessions (176). All patients had a history of poor tolerance or lack of efficacy to antidepressants. Results indicated that patients’ depression, negative inferences, and perception of social support significantly improved over the course of the study. Additionally, caregivers’ knowledge and provision of appropriate types of support and subjective feelings of caregiver burden were improved. In another study of nine young PD patients, CBT was associated with improvement in some psychological indices (178). However, in the study, CBT was not specifically targeted for depression. In a case series report, home-based CBT resulted in a clinically meaningful reduction of depressive symptoms (177). These preliminary results indicate that individual CBT in patients with PD, along with psychoeducational support to caregivers, is effective for reducing depressive symptoms and caregiver burden. Additionally, reports in elderly patients without PD suggest that a multimodal treatment approach (i.e., psychotherapy and antidepressant treatment) may be more effective than a single treatment approach (179). In cases of severe pharmacologically refractory major depression, serial electroconvulsive therapy (ECT) may be effective for improving depressive symptoms and may also provide transient improvement in motor symptoms (180). However, common adverse effects of ECT include delirium and cognitive impairment, and its long-term utility is limited. Preliminary data suggest that repetitive transcranial magnetic stimulation (rTMS), a less invasive physical intervention than ECT, may improve depressive symptoms as well as cognitive and motor symptoms in PD patients (122,181,182). The role of rTMS in management of depression in PD warrants further evaluation. Lastly, application of a structured physical therapy program may also improve depressive symptomatology in patients with PD (183). CONCLUSION Anxiety and depression are prevalent nonmotor psychiatric features in patients with PD and should be considered as areas for therapeutic intervention. These affective disorders contribute to the accelerated disability and functional morbidity in patients with PD, and are correlated with poor quality of life and increased caregiver distress. Despite the high prevalence of anxiety and depression in PD, these conditions are often unrecognized and untreated in a large portion of PD patients. Various instruments may be utilized to diagnose and assess anxiety and depression. However, despite attempts to improve the sensitivity and specificity of these instruments for use in the PD population, uncertainties remain. The best approach may be to remain vigilant for the presence of anxiety or depression, to have a low threshold for intervention, and to utilize an individualized approach. The scientific data on the efficacy of nonpharmacologic and pharmacologic treatments for the treatment of anxiety and depression in the PD population are relatively sparse, and derived from studies enrolling small numbers of patients. However, the data suggest that available interventions may be efficacious for the PD population. Nevertheless, clinicians

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143. Leentjens AF, Vreeling FW, Luijckx GJ, et al. SSRIs in the treatment of depression in Parkinson’s disease. Int J Geriatr Psychiatry 2003; 18(6):552–554. 144. Serrano-Duenas M. A comparison between low doses of amitriptyline and low doses of fluoxetin used in the control of depression in patients suffering from Parkinson’s disease [in Spanish]. Rev Neurol 2002; 35(11):1010–1014. 145. Wermuth L, Sorensen PS, Timm B, et al. Depression in idiopathic Parkinson’s disease treated with citalopram:a placebo-controlled trial. Nordic J Psychiatry 1998; 52(2): 163–169. 146. Steur EN, Ballering LA. Moclobemide and selegeline in the treatment of depression in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; 63(4):547. 147. Rabey JM, Orlov E, Korczyn AD. Comparison of fluvoxamine versus amitriptyline for treatment of depression in Parkinson’s disease [abstr]. Neurology 1996; 46:A374. 148. Andersen J, Aabro E, Gulmann N, et al. Antidepressive treatment in Parkinson’s disease:a controlled trial of the effect of nortriptyline in patients with Parkinson’s disease treated with L-dopa. Acta Neurol Scand 1980; 62(4):210–219. 149. Laitinen L. Desipramine in treatment of Parkinson’s disease. Acta Neurol Scand 1969; 45(1):109–113. 150. Strang RR. Imipramine in treatment of Parkinson’s disease: a double-blind placebo study. BMJ 1965; 2:33–34. 151. Gill HS, DeVane CL, Risch SC. Extrapyramidal symptoms associated with cyclic antidepressant treatment: a review of the literature and consolidating hypothesis. J Clin Psychopharmacol 1997; 17(5):377–389. 152. Vandel P, Bonin B, Leveque E, et al. Tricyclic antidepressant-induced extrapyramidal side effects. Eur Neuropsychopharmacol 1997; 7(3):207–212. 153. Di Rocco A, Rogers JD, Brown R, et al. S-Adenosyl-methionine improves depression in patients with Parkinson’s disease in an open-label clinical trial. Mov Disord 2000; 15(6): 1225–1229. 154. Gordon PH, Pullman SL, Louis ED, et al. Mirtazapine in parkinsonian tremor. Parkinsonism Relat Disord 2002; 9(2):125–126. 155. Meco G, Fabrizio E, Di Rezze S, et al. Mirtazapine in L-dopa-induced dyskinesias. Clin Neuropharmacol 2003; 26(4):179–181. 156. Normann C, Hesslinger B, Frauenknecht M, et al. Psychosis during chronic levodopa therapy triggered by the new antidepressive drug mirtazapine. Pharmacopsychiatry 1997; 30(6):263–265. 157. Onofrj M, Luciano AL, Thomas A, et al. Mirtazapine induces REM sleep behavior disorder (RBD) in parkinsonism. Neurology 2003; 60(1):113–115. 158. Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry 2003; 64(2):208–214. 159. Bodkin JA, Amsterdam JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry 2002; 159(11): 1869–1875. 160. Bagdy G, Graf M, Anheuer ZE, et al. Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635. Int J Neuropsychopharmacol 2001; 4(4):399–408. 161. Reichmann H, Brecht MH, Koster J, et al. Pramipexole in routine clinical practice: a prospective observational trial in Parkinson’s disease. CNS Drugs 2003; 17(13): 965–973. 162. Rektorova I, Rektor I, Bares M, et al. Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomized study. Eur J Neurol 2003; 10(4):399–406. 163. Lattanzi L, Dell’Osso L, Cassano P, et al. Pramipexole in treatment-resistant depression: a 16-week naturalistic study. Bipolar Disord 2002; 4(5):307–314. 164. Corrigan MH, Denahan AQ, Wright CE, et al. Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 2000; 11(2):58–65. 165. Perugi G, Toni C, Ruffolo G, et al. Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series. Pharmacopsychiatry 2001; 34:137–141.

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166. Lemke MR, Brecht HM, Koester J, et al. Anhedonia, depression, and motor functioningin Parkinson’s disease during treatment with pramipexole. J Neuropsychiatry Clin Neurosci 2005; 17(2):214–220. 167. Cassano P, Lattanzi L, Fava M, et al. Ropinirole in treatment-resistant depression: a 16week pilot study. Can J Psychiatry 2005; 50:357–360. 168. Goetz CG, Koller WC, Poewe W, Rascol O, Sampaio C. Treatment of depression in idiopathic Parkinson’s disease. Mov Disord 2002; 17(suppl 4):S112–S119. 169. Sa DS, Kapur S, Lang AE. Amoxapine shows an antipsychotic effect but worsens motor function in patients with Parkinson’s disease and psychosis. Clin Neuropharmacol 2001; 24(4):242–243. 170. Coffey CE, Ross DR, Massey EW, et al. Dyskinesias associated with lithium therapy in parkinsonism. Clin Neuropharmacol 1984; 7(3):223–229. 171. Spina E, Scordo MG. Clinically significant drug interactions with antidepressants in the elderly. Drugs Aging 2002; 19(4):299–320. 172. Richelson E. Pharmacokinetic interactions of antidepressants. J Clin Psychiatry 1998; 59(suppl 10):22–26. 173. Flint AJ, Rifat SL Anxious depression in elderly patients. Response to antidepressant treatment. Am J Geriatr Psychiatry 1997; 5(2):107–115. 174. Alexopoulos GS, Myers BS, Young RC, et al. Recovery in geriatric depression. Arch Gen Psychiatry 1996; 53(4):305–312. 175. Mohr DC, Boudewynn C, Goodkin DE, et al. Comparative outcomes for individual CBT, supportive-expressive group psychotherapy and sertraline for the treatment of depression in multiple sclerosis. J Consult Clin Psychol 2001; 69:942–949. 176. Dobkin RD, Allen La, Menza M. Treating depression in Parkinson’s disease: a cognitivebehavioral approach (abstract). Mov Disord 2006; 21(suppl 13):S129. 177. Cole K, Vaughan F. Brief cognitive behavioural therapy for depression associated with Parkinson’s disease. A single case series. Behav Cogn Psychother 2005; 33:89–102. 178. Dreisig H, Beckmann JM, Wermuth L, et al. Psychological effects of structure cognitive psychotherapy in young patients with Parkinson disease: a pilot study. Nordic J Psychiatry 1999; 53:217-221. 179. Miller MD, Cornes C, Frank E, et al. Interpersonal psychotherapy for late-life depression: past, present, and future. J Psychother Pract Res 2001; 10(4):231–238. 180. Moellentine C, Rummans T, Ahlskog JE, et al. Effectiveness of ECT in patients with parkinsonism. J Neuropsychiatry Clin Neurosci 1998; 10(2):187–193. 181. Boggio PS, Fregni F, Bermpohl F, et al. Effect of repetitive TMS and fluoxetine on cognitive function inpatients with Parkinson’s disease and concurrent depression. Mov Disord 2005; 20(9):1178–1184. 182. Dragasevic N, Potrebic A, Damjanovic A, et al. Therapeutic efficacy of bilateral prefrontal slow repetitive transcranial magnetic stimulation in depressed patients with Parkinson’s disease: an open study. Mov Disord 2002; 17(3):528–532. 183. Pellecchia MT, Grasso A, Biancardi LG, et al. Physical therapy in Parkinson’s disease: an open long-term rehabilitation trial. J Neurol 2004; 251(5):595–598.

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Management of Psychosis and Dementia Kelvin L. Chou Department of Clinical Neurosciences, Brown Medical School and NeuroHealth Parkinson’s Disease and Movement Disorders Center, Warwick, Rhode Island, U.S.A.

Hubert H. Fernandez Movement Disorders Center and Department of Neurology, University of Florida/McKnight Brain Institute, Gainesville, Florida, U.S.A.

INTRODUCTION James Parkinson in his original observations on Parkinson’s disease (PD) commented mainly on tremor and gait abnormality (1); however, it has become increasingly evident that PD patients can have cognitive and behavioral changes, and that these changes, most notably psychosis and dementia, can affect motor function. Furthermore, pharmacotherapy of psychosis and dementia can limit optimal treatment of the motor symptoms through dopamine antagonism and can even contribute to cognitive and behavioral dysfunction in PD. This makes it complicated to differentiate which features are medication side effects and which are intrinsic to PD. It is essential to identify both psychosis and dementia in PD. Those with concomitant dementia are more prone to the development of dopamine-induced confusion, agitation, and psychosis, limiting treatment of the motor symptoms. Psychosis in PD is a risk factor for nursing home placement (2,3) and is associated with a higher mortality rate (4,5). Moreover, psychosis is the single greatest stress for caregivers. Dementia in PD also contributes to caregiver stress (6) and leads to a more rapid motor and functional decline (7,8), early institutionalization (2,9), and increased mortality (10–12). As the manifestations of psychosis and dementia are potentially treatable, recognition and treatment may enable the PD patient to live at home for a longer period and decrease caregiver stress. PSYCHOSIS Psychosis is a disorder characterized by hallucinations, delusions, or disorganized thinking (13), and is estimated to occur in 20 to 40% of PD patients (14,15). The most common manifestations of psychosis in PD are visual hallucinations (14,16–18). Although visual hallucinations are a common feature of patients with dementia with Lewy bodies (DLB), and may occasionally occur in demented PD patients who are not taking medications, the vast majority of PD patients who develop psychotic symptoms do so on antiparkinsonian therapy, and may return to their nonpsychotic baseline if the PD medications are discontinued (19–21). All antiparkinsonian drugs, not just dopaminergic agents, have been demonstrated to cause psychosis (22–25). Visual hallucinations in PD may occur at any time, and may be vivid and realistic, or out of focus. Patients may experience “presence” hallucinations (the sensation that someone or something is in the room) or “passage” hallucinations (brief visions seen in the peripheral field of vision) (14). Auditory hallucinations are the second 155

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most common, with tactile and olfactory hallucinations occurring less commonly (18). Nonvisual hallucinations mainly occur in people who already suffer from visual ones (14,18,26,27). Delusions, or beliefs that do not have a foundation in reality, occur less frequently in PD. The phenomenology of delusions in PD overlaps with those seen in other dementias (28) and usually carries a paranoid theme. However, most types of delusions occur with relatively equal frequency (18). Thought broadcasting, ideas of reference, loosened associations, and “negative” symptoms are generally uncommon in PD. There is no gold standard rating scale for the severity of psychosis in PD. Many different scales have been used to assess psychosis in PD studies, including the Neuropsychiatric Inventory (NPI) (29), Brief Psychiatric Rating Scale (BPRS) (30), Behave-AD (31), Positive and Negative Symptom Scale (PANSS) (32), Scale for the Assessment of Positive Symptoms (33), Clinical Global Impression Scale (34), and the Parkinson Psychosis Rating Scale (PPRS) (35). Many of these scales were developed for use in Alzheimer’s disease (AD) or schizophrenia. As psychosis in PD manifests generally as “positive” symptoms such as hallucinations and delusions (18), and “negative” symptoms such as conceptual disorganization are not present, scales such as the BPRS and the PANSS assess many nonrelevant items. Only one scale, the PPRS, has been validated in the PD population. However, some items on the PPRS, such as sexual preoccupation, may not be that prominent in PD psychosis. There is only one item each on hallucinations, delusions, and illusions, which may not fully explore and track the phenomenology of PD psychosis. It has also not been tested in a longitudinal fashion, and its ability to track changes due to treatment has not been studied. A scale to adequately assess psychosis in PD is warranted. Pathophysiology of Psychosis and Risk Factors The pathophysiology of psychosis in PD is poorly understood, but dopaminergic and serotonergic mechanisms have been proposed. One theory is that chronic excessive stimulation of dopamine receptors, particularly in the mesolimbic/mesocortical pathways, causes hypersensitization, resulting in psychosis when patients are treated with dopaminergic agents (36). However, exogenous dopamine supplementation by itself is not the only factor in the development of psychosis since all PD medications (anticholinergics, dopaminergics, and amantadine) can induce similar hallucinations despite their different mechanisms of action (25), and PD psychosis was described prior to the use of levodopa (37). Serotonin has been implicated because the atypical antipsychotic drugs are purported to work through their high affinity for 5-HT2 compared to D2 receptors. However, PD patients with psychosis have decreased serotonin content in the brainstem at autopsy (38). Potential explanations for this finding include postsynaptic serotonergic hypersensitivity as a result of decreased central serotonin activity (39) and/or increases in serotonin activity from levodopa administration (40). The precise anatomic substrate of hallucinations and psychosis is unknown, but may be due in part to visual dysfunction. PD patients who hallucinate perform slightly worse on visual acuity testing (mean visual acuity 20/45) than nonhallucinators (20/33) (17) and have greater impairment in color vision and contrast sensitivity (41). Furthermore, visual evoked potentials are abnormal in PD patients with visual hallucinations (42). Other structures in the brain may also be involved. One reported patient experienced formed visual hallucinations after bilateral subthalamic

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nucleus (STN) deep brain stimulation (DBS) surgery only when the stimulators were turned on (43), leading the authors to hypothesize that this resulted from stimulation of limbic fibers near the STN. Finally, a functional MRI study demonstrated greater activation in the frontal lobe in PD patients with chronic visual hallucinations compared to nonhallucinators (44). The exact contribution of these neurotransmitters and structures to the genesis of psychosis is unclear. The presence of dementia, advancing age, impaired vision, depression, sleep disorders, and longer disease duration have all been associated with the development of drug-induced psychosis (15,45–48). Although psychosis has been reported to occur with all of the antiparkinsonian medications (22–25), the dopamine agonists are more likely to cause psychosis than levodopa (49,50). The duration or dose of antiparkinsonian drug therapy, however, has not been found to be associated with an increased risk for psychosis (45,51,52). General Treatment of Psychosis The management of the psychotic PD patient begins by searching for correctable causes, including infection, metabolic derangements, social stress, and drug toxicity. Infections may not always cause fevers in the geriatric population, so a search for urinary tract infections or pneumonias is warranted. Some PD patients who did not manifest psychotic symptoms at home may decompensate upon moving into the hospital environment. In many of these cases, moving the patient into a secure familiar environment or treating the underlying medical illness may ameliorate psychotic symptoms (19). Finally, medications with CNS effects may cause or exacerbate psychosis in PD and are often overlooked. These medications include pain or sleeping medications such as narcotics, anxiolytics, hypnotics, and antidepressants. If psychotic symptoms persist despite identification and correction of the above factors, antiparkinsonian medications are slowly reduced and if possible discontinued. Antiparkinsonian drugs should be reduced and discontinued in the following order: anticholinergic agents, selegiline, amantadine, dopamine agonists, catechol-Omethyltransferase inhibitors and, finally, levodopa (53). If psychosis improves, the patient is then maintained on the lowest possible dose of antiparkinsonian medications. If psychosis persists, and further reductions in antiparkinsonian medications cause intolerable motor function, the use of an atypical antipsychotic agent is warranted. Specific Treatments for Psychosis Atypical Antipsychotics Atypical antipsychotics are typically used to treat psychosis in PD. Table 1 provides a summary of atypical antipsychotic studies in PD. The United States Food and Drug Administration (FDA) recently asked all atypical antipsychotic manufacturers to add a boxed warning to their product labels, saying that atypical antipsychotics, when used in elderly patients with dementia, were associated with a higher risk of mortality (54). However, since the deaths were primarily due to cardiovascular or infectious causes, it is unclear how the atypical antipsychotics cause increased mortality. Since psychosis can be difficult to treat in PD, it is likely that these agents will continue to be utilized until a direct cause and effect relationship is uncovered. Clozapine Clozapine was the first atypical antipsychotic approved by the FDA, and is the only atypical antipsychotic that has been demonstrated to have better efficacy than typical

8 14

Open-label Open-label

12.8 mg/d 1–5 mg/d

54 mg/d 60.8 mg/d

119.2 mg/d

75–200 mg/d

4.6 mg/d

4.1 mg/d

4.2 mg/d

0.67 mg/d 1.5 mg/d 0.5–4 mg/d 1.9 mg/d 0.73 mg/d 1.1 mg/d 1.1 mg/d

24.7 mg/d 36 mg/d

75–250 mg/d

Dosage

4 6

No significant improvement in BPRS scores No difference compared to placebo 32 84

Improved total BPRS, NPI, and CGIS psychosis scores Improved total BPRS, NPI, and CGIS psychosis scores No significant improvement overall

6 6 4 9 9 33 16

Improved mean BPRS Improved mean CGIS, positive subscore of PANSS

3

Number of psychosis improved

3 5

No significant worsening of UPDRS scores No difference compared to placebo 5 13

Worsening of total and motor UPDRS scores Worsening of total and motor UPDRS scores Worsened UPDRS motor

0 6 5 0 3 6 1

0

0

3

Number of PD worsened

158

Abbreviations: BPRS, Brief Psychosis Rating Scale; CGIS, Clinical Global Impression of Severity; NPI, Neuropsychiatric Inventory; PANSS, Positive and Negative Syndrome Scale; PD, Parkinson’s disease; UPDRS, Unified Parkinson’s Disease Rating Scale.

43 103

21

Double-blind

Retrospective Retrospective

16

Double-blind

Reddy et al. (85) Fernandez et al. (86) Aripiprazole Fernandez et al. (95) Friedman et al. (96)

49

Double-blind

30

41

Double-blind

Double-blind

6 6 6 9 10 39 17

60 60

Double-blind Double-blind with open- label follow up Open-label Open-label Open-label Open-label Open-label Open-label Open-label

6

Number of patients

Double-blind

Design

Rabey et al. (89)

Risperidone Meco et al. (68) Ford et al. (71) Rich et al. (72) Workman et al. (67) Meco et al. (73) Leopold (74) Mohr et al. (75) Olanzapine US Olanzapine trial (82) European Olanzapine trial (82) Ondo et al. (81) scores Quetiapine Ondo et al. (88)

Clozapine Wolters et al. (58) Parkinson Study Group (56) Pollak et al. (57)

Agent

TABLE 1 Double-Blind and Selected Open-Label Reports of Atypical Antipsychotics in Parkinson’s Disease

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neuroleptics (55). Double-blind placebo-controlled and open-label studies with clozapine have shown that the drug effectively treats psychosis in PD without worsening motor function (53,56,57). The first double-blind, placebo-controlled trial of clozapine in PD resulted in the only negative study (58). It was a small study of six patients at a single site. Three patients completed the study and three had worsened parkinsonism. However, the authors titrated clozapine using a schizophrenia titration schedule and went as high as 250 mg/d. This resulted in subjects complaining of severe sedation, which may have partly manifested as worsened parkinsonism. We now know that doses as small as 6.25 mg daily can result in improvement of psychosis in PD patients. Two randomized, double-blind, placebo-controlled trials of low-dose clozapine have been published (56,59). One trial was conducted in the United States and one in France. In the U.S. trial, clozapine, at a mean dose of 25 mg/d, resulted in a significant benefit on four measures of psychosis. Motor function did not decline, and tremor improved significantly. Only one subject suffered a decline in white blood cell (WBC) count requiring termination, which was reversed within one week after stopping clozapine. The most commonly used dose was 6.25 mg/d. The French study reported similar results, with patients taking a mean dose of 35 mg/d. In terms of long-term efficacy and safety, a retrospective analysis of 39 parkinsonian patients on a mean dose of 47 mg/d of clozapine for 60 months showed that 85% had continued response to the medication, whereas 13% had complete resolution of psychosis (60). A second study reported a five-year follow-up of 32 patients with PD and psychosis, 14 of whom had dementia (61). Nineteen of these patients were still taking clozapine at a mean dose of 20 mg/d. Nine subjects had stopped clozapine because of improvement in their psychosis, but three patients discontinued the drug due to somnolence. Unfortunately, with clozapine, there is concern about agranulocytosis. Therefore, weekly WBC monitoring for six months, biweekly monitoring for the next six months, and monthly monitoring thereafter is mandated. This complication is not dose-related, so monitoring must be performed in all patients on clozapine. Although agranulocytosis had been thought to occur in 1% to 1.5% of patients, the actual incidence of agranulocytosis was only 0.38% in a recent analysis of over 99,000 U.S. patients with schizophrenia (62). Sedation, orthostatic hypotension, and sialorrhea are other common side effects of clozapine (57), but anticholinergic side effects have not been a major problem in PD (56). More recently, the use of atypical antipsychotics has been associated with a “metabolic syndrome” (insulin resistance, weight gain, dyslipidemia, and abnormal glucose metabolism) in schizophrenic patients (63). This has not been shown to occur in PD patients. The prevalence of diabetes in 44 parkinsonian subjects was similar to that of an age-matched group in the general population (60). This may be because subjects in this study were on a smaller dose of clozapine (50.6 mg/d) when compared to doses used in schizophrenic patients (300–900 mg/d). In summary, low dose clozapine is safe and effective for psychosis in PD patients. However, due to stringent monitoring, the search for a more practical and “low-maintenance” treatment for psychosis in PD remains an important goal. Risperidone Risperidone is chemically distinct from clozapine and was found to behave more like “typical” neuroleptics, with a dose-dependent incidence of extrapyramidal side effects (64,65). In PD, all but one report of risperidone were open-label (Table 1).

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Although risperidone was effective for psychosis in general, some reports describe the complete absence of motor side effects (67–69), whereas others report severe motor worsening in each patient who took the drug (70,71). The few studies that reported no worsening of parkinsonism followed small numbers of patients for a short period of time. Five open-label studies of risperidone reported 78 PD patients on doses ranging from 0.5 to 4.0 mg/d, with 21 having worsening of motor features (71–75), although in the largest open-label study (39 patients), five of the six patients that worsened were thought to have DLB, rather than PD (74). In the only double-blind study of risperidone (66), the efficacy and safety of risperidone and clozapine were compared. Ten subjects with PD psychosis were enrolled. The mean motor Unified Parkinson’s Disease Rating Scale (UPDRS) score worsened in the risperidone group and improved in the clozapine group, though this difference did not reach statistical significance. On the contrary, risperidone improved psychosis and clozapine did not. It is unclear why the results of risperidone studies in PD are so mixed, but multiple factors may be responsible. Most of the studies were open-label and differ in terms of speed of medication titration and duration of the observations. However, given the results in the PD population thus far, it is unlikely that a double-blind placebo-controlled trial will be performed, and many movement disorder specialists are reluctant to place patients on this agent. Olanzapine Olanzapine has a chemical structure similar to clozapine. It offered more promise than risperidone, because it induced catalepsy at higher doses than would be used in humans (76) and did not cause significant prolactin secretion, a feature seen with risperidone (77). The first open-label study of olanzapine in PD showed that it was effective for drug-induced psychosis in 15 nondemented patients, at a mean dose of 6.5 mg/d, without worsening motor function (78). However, all subsequent openlabel studies of olanzapine in PD showed that approximately 40% of subjects had motor decline (79). Four double-blind trials of olanzapine have been published, three of which were placebo-controlled and one which compared olanzapine to clozapine (80–82). The clozapine trial was prematurely stopped because six of seven olanzapine treated subjects had significant motor decline (80). All three of the placebocontrolled trials reported that olanzapine had no effect on psychosis in PD and exacerbated parkinsonism (81, 82). In addition, sedation and weight gain were common undesirable side effects. An evidence-based review of the treatment of psychosis in PD concluded that “there is insufficient evidence to demonstrate efficacy of olanzapine” and “olanzapine carries an unacceptable risk of motor deterioration” at low doses (83). Quetiapine Of all the atypical antipsychotics, quetiapine has the closest structural resemblance to clozapine. It has a strong affinity for the serotonin 5-HT2 receptor and moderate affinity for the dopamine D2 receptor (84). It also has low affinity for the muscarinic receptor, and thus anticholinergic effects are not seen. Agranulocytosis has not been reported with quetiapine. There have been multiple open-label studies of quetiapine for drug-induced psychosis in PD—the two largest reports have been retrospective analyses. Reddy et al. (85) found that 35 of 43 PD patients treated with quetiapine had improved psychosis. Five patients (13%), all of whom were demented, experienced mild worsening of

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motor symptoms but not significant enough to discontinue treatment. Fernandez et al. (86) reported 106 parkinsonian patients treated with quetiapine. Seventy-eight out of 106 (74%) remained on quetiapine for a mean duration of 15 months at an average dose of 60 mg/d. Eighty-seven (82%) patients had partial or complete resolution of their psychosis, whereas 19 (18%) patients had no improvement. Motor decline was noted in 34 (32%) patients, but rarely warranted quetiapine discontinuation. Demented subjects had a 12-fold increased risk of nonresponse. A double-blind, randomized, comparison trial of 40 PD patients placed on either quetiapine or clozapine found that both medications improved psychosis (87). There was no difference between the two groups in any parameters, either behaviorally or motorically, and the investigators concluded that both medications were equally efficacious. However, in two double-blind, placebo-controlled trials, quetiapine was not found to be efficacious for PD psychosis (88,89). In one trial (88), 31 subjects with PD psychosis were randomized in a 2:1 double-blind fashion to quetiapine or placebo. The final dose of quetiapine ranged from 75 to 200 mg/d, but the trial may not have been adequately powered to detect an effect. The second doubleblind, placebo-controlled trial randomized 30 patients to quetiapine (mean dose 119 mg/d) and 28 patients to placebo (89). Fifteen patients in the quetiapine group discontinued the medication, 10 of them because of lack of efficacy. The authors postulated that the large dropout rate might have influenced their results. The results of these two trials are surprising, given that the available open-label studies of over 400 patients suggest that quetiapine appears to be well tolerated and effective. Future double-blind studies with larger numbers of subjects are needed. Ziprasidone Ziprasidone has a much higher affinity for serotonin 5-HT2 than dopamine D2 receptors and other atypical agents (90). Ziprasidone prolongs the QT interval, which has limited its use. However, there have been no cases of ziprasidone causing torsades de pointes (91). There have been only two case series reported on ziprasidone in PD. The first was a small open-label, 12-week trial in 12 PD patients (mean age 72.1 years) with psychosis (92). Mean doses of ziprasidone were 24 mg at one month and 32 mg at 12 weeks, with an improvement in psychosis of 58% after one month and 72% at 12 weeks. Although two patients had a slight worsening of motor symptoms, the UPDRS motor scores did not significantly worsen over the course of the trial. Two patients had to withdraw from the study, one because of sedation and the other due to gait deterioration. The second open-label report investigated an intramuscular preparation of ziprasidone for the emergency treatment of psychosis in PD (93). Five patients were given gluteal intramuscular injections of either 10 or 20 mg of ziprasidone. The mean BPRS score before injection was 72 and improved to 48 two hours after injection. During the 24 hours following the injections, there was no worsening of parkinsonian symptoms. On the basis of these studies, it appears that ziprasidone may be helpful for psychotic symptoms in PD without worsening parkinsonism. However, on the basis of a review of the available data on ziprasidone in schizophrenia, it was concluded that its extrapyramidal symptom profile is “the same as olanzapine but not quite as good as quetiapine or clozapine” (94). Aripiprazole Aripiprazole differs from the other agents in that it is a partial agonist at the D2 and 5HT1 receptors and an antagonist at the 5HT2a receptors. Aripiprazole also has a high 5HT/D2 affinity ratio, which theoretically makes it less likely to cause extrapyramidal

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symptoms. The data on aripiprazole in PD are scarce. An initial open-label study showed that aripiprazole improved psychosis completely in two out of eight subjects with PD, whereas the other six subjects discontinued the medication: two due to lack of efficacy, two due to motor worsening, one due to lack of motor improvement, and one due to intolerable restlessness and confusion (95). Another study of 14 PD subjects with drug-induced psychosis showed that aripiprazole (dose range 1–5 mg/d) improved psychosis in six patients, worsened psychosis in four, and caused no significant change in four (96). Eight subjects in this study withdrew: three because of worsened parkinsonism, two because of increased psychosis, two due to both worsened parkinsonism and psychosis, and one because of lack of efficacy. Although these studies were open-label and preliminary, they suggest that aripiprazole has a variable effect on psychotic symptoms, causes a high dropout rate due to adverse effects, and therefore should be used with caution in the PD population. Odansetron Odansetron is a selective 5HT-3 receptor antagonist. Although odansetron was ineffective for psychosis in schizophrenic patients (97), there have been reports of its success in the PD population. Zoldan et al. (98,99) reported two open-label trials with improvement of psychosis in a total of 40 PD patients. One patient had headache and seven had constipation. These positive findings have not been reproduced by others (100). Cholinesterase Inhibitors In multiple AD trials, cholinesterase inhibitors had mild-to-moderate benefits in both cognition and psychosis (101,102). Cholinesterase inhibitors are also effective for psychosis in DLB patients and are a potential alternative to the atypical antipsychotics for PD psychosis. An early open-label study with tacrine showed that five of seven demented PD patients had complete resolution of psychotic symptoms (103); however, the use of this drug has been limited because of hepatic toxicity. Fabbrini et al. (104) administered donepezil (5 mg qhs) to eight nondemented PD patients with visual hallucinations, with or without delusions. At the end of two months, subjects had decreased PPRS scores with hallucinations and paranoid ideation, being the most responsive. However, two patients experienced clinically significant motor decline. Another small open-label study enrolled six patients with PD, dementia, and psychotic symptoms and treated them with 10 mg/d of donepezil (105). Five patients showed moderate-to-significant improvement in psychosis and one showed minimal improvement. None had worsening of motor symptoms. Finally, Kurita et al. (106) reported three PD patients who had improvement of visual hallucinations with 5 mg/d of donepezil without worsening of motor function, but one patient had treatment emergent delusions that resolved, after donepezil was discontinued. Only one placebo-controlled trial of donepezil has been reported for PD psychosis (107). This was a randomized, crossover trial in 22 subjects with PD and dementia. There was no difference in BPRS scores between patients on donepezil and patients on placebo; however, the trial excluded patients with severe psychosis. Rivastigmine can also improve hallucinations in PD patients (108,109). In a 24week, double-blind, placebo-controlled, randomized trial of 541 PD patients with dementia (110), patients on rivastigmine showed a mean improvement of 2.0 on the NPI, from a baseline mean score of 12.7. There is one open-label study of galantamine on psychosis in PD (111). Seven of the nine patients in this study with hallucinations improved, three of whom had

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complete amelioration of psychosis. However, three patients experienced increased tremor. Electroconvulsive Therapy Electroconvulsive therapy (ECT) is an effective treatment for primary psychiatric disorders, especially treatment-resistant depression. Experience with ECT for PD psychosis, however, is limited to case studies. ECT has been demonstrated to be beneficial in PD patients with psychosis (112–114), and can transiently improve parkinsonian motor symptoms, but may require a period of hospitalization, and result in significant confusion. ECT should only be considered when patients are resistant to pharmacological therapies. Long-Term Outcome of Treatment for Psychosis Goetz and Stebbins (5) described 11 PD patients in a nursing home with hallucinations, all of whom were never discharged from the nursing home and died within two years. In an open-label extension of the U.S. double-blind clozapine trial, only 25% of completers died over a 26-month observational period. Forty-two percent were in nursing homes, 68% were demented, and 69% were still psychotic (4). A separate study of 39 parkinsonian patients, treated with clozapine for psychosis, found that only 15% had died over a span of five years and 33% had been admitted to nursing homes (115). There are few studies looking at whether or not patients can be weaned off their antipsychotic medications. Fernandez et al. tried to wean off clozapine or quetiapine in psychiatrically stable PD patients with a history of drug-induced psychosis. The study had to be aborted after enrolling only six patients, who had all been on their antipsychotics for an average of 20 months (116). Five experienced worsened psychosis, where three of these patients had a more severe psychosis than at baseline, suggesting the possibility of a “rebound psychosis.” In contrast, a five-year follow-up of 32 PD patients with psychosis on clozapine found that nine were able to discontinue the clozapine without recurrence of psychosis (61). More research in this area is needed, but a recent six-year longitudinal study of PD patients with hallucinations found that hallucinators at baseline continued to have hallucinations at the end of study observation (16). Therefore, once patients start antipsychotic medications, it is likely that they will require treatment indefinitely. DEMENTIA Cognitive impairment is common in PD, especially in the domain of executive function (28). Such deficits are usually the earliest cognitive signs in PD (117). Patients or caregivers often report difficulties with decision making, planning, and completion of goal-directed behaviors. When these cognitive deficits worsen, and patients have impairment of occupational or social functioning, a diagnosis of dementia is made (13). At this point, it is unclear whether the presence of early cognitive deficits leads to dementia. The rate of cognitive decline in PD can be variable depending upon the population subset. A recent community-based study estimated that the mean overall annual rate of cognitive decline in PD patients was one point on the Mini-Mental State Examination (MMSE) (118). However, patients with PD and dementia declined faster, at a rate of 2.3 points, whereas PD patients who did not develop dementia progressed at the same rate as age-matched controls.

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Complicating the picture of dementia in PD is the clinical entity of DLB, a dementing illness characterized by parkinsonism, visual hallucinations, and fluctuating cognition (119). There are multiple clinical (parkinsonism, visual hallucinations, attention deficits, executive dysfunction) and pathological similarities (Lewy bodies in the limbic and neocortex) between the two disorders, leading to the hypothesis that the two conditions could be considered as opposite ends of the spectrum of one illness (120,121). The clinical criteria for making a diagnosis of DLB and PD dementia have been updated (120). Patients whose disease begins with cognitive impairment are diagnosed with DLB, whereas patients who first develop parkinsonism and meet the criteria for a diagnosis of idiopathic PD are diagnosed with PD dementia when dementia occurs. Previously, a clinical diagnosis of DLB was made only if the dementia developed before or within a year of the onset of parkinsonian symptoms (122). However, long-term studies with neuropathological follow-up will be essential in determining whether this clinical distinction correlates with the underlying pathological substrate. Incidence, Prevalence, and Risk Factors Estimates of incidence and prevalence of dementia in PD vary widely because of different definitions, methods of ascertainment, and study designs. Prevalence rates of dementia in hospital- or clinic-based cohort studies range from 11% to 22% (123–125), whereas population-based estimates are somewhat higher, ranging from 18% to 44% (9,126–129), perhaps reflecting referral bias. A recent systematic review of the literature estimated that the prevalence of dementia in PD ranges from 25% to 31% (130). This review also found that dementia in PD accounted for 3% to 4% of the total dementia population. Incidence rates for PD dementia range from 4% to 11% per year, with a relative risk for the development of dementia in PD of 2 to 6 (12,129,131–133). Age and severity of extrapyramidal symptoms were associated with an overall risk of developing dementia. One study demonstrated that age and severity of disease by themselves were not associated with a greater risk of dementia, but the combination of these two features resulted in an almost 10-fold greater risk (134), suggesting a combined effect. Later age of onset of PD, longer duration of PD symptoms, the presence of hallucinations, depressive symptoms, and a family history of dementia have also been reported to be risk factors for dementia, although less consistently. Although dementia in PD has been traditionally thought of as occurring in the “latter half ” of the disease, it may actually parallel motor progression from its onset and is simply recognized much later than the motor symptoms. Fernandez et al. correlated the neuropsychological profiles of 106 random PD patients to the total motor UPDRS “off ” scores and found a significant correlation with MMSE and Dementia Rating Scale (DRS) scores (r = −0.34, P < 0 .001; r = −0.34 , P < 0.001, respectively). Moreover, certain motor aspects correlated better: bradykinesia and postural/gait dysfunction were most correlated with cognitive function but tremor was not, axial signs also correlated more than appendicular signs, and parkinsonism on the right side correlated more than on the left side (135). Some common risk factors for the development of AD, including head injury, hypertension, and diabetes mellitus, are not predictors for the development of dementia in PD (136). However, the epsilon 4 isoform of the apolipoprotein E gene (APO-E4), an established risk factor for AD, has been shown to correlate with an

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increased risk of dementia in PD (12,137,138). Furthermore, the epsilon 2 allele (APO-E2) is also associated with the development of dementia in PD patients (12,137), whereas it is considered protective in AD. Pathophysiology of Dementia There is controversy regarding which features are the primary contributors to dementia in PD. PD is characterized by cell loss in the substantia nigra pars compacta (SNc), resulting in loss of dopaminergic input into the striatum. Several pathological and functional imaging studies have shown that in PD, there is greater depletion in the lateral compartment of the SNc, which projects to the putamen, than in the medial compartment, which projects to the caudate (139–141). Cognitive impairment is associated with loss of dopaminergic projections to the caudate (142). This functional division of the striatum is, perhaps, the main reason for the predominance of motor, over cognitive symptoms in PD and is likely why dopaminergic agents do not markedly improve cognition in PD (143). A relationship between cholinergic deficiency and dementia in PD has also been reported (144). Striking cell loss is seen in the nucleus basalis of Meynert, which provides projections to the amygdala and neocortex (144,145). Additionally, choline acetyltransferase activity has consistently been reported to be decreased to approximately 40% to 60% of control values in frontal, temporal, and hippocampal cortex (146–148), and correlates with cognitive impairment. Loss of neurons in the locus ceruleus and corresponding noradrenergic deficiency may also be associated with cognitive impairment in PD, but this has not been consistently shown (149,150). Multiple autopsy series have shown that the presence of AD pathology correlates with dementia in PD (151–153). However, because some demented PD patients can have minimal numbers of plaques and neurofibrillary tangles, the assertion that AD pathology is responsible for PD dementia remains controversial (154,155). Recently, much of the literature has focused on the presence of Lewy bodies in the cortex and limbic system, and their association with cognitive impairment. Hurtig et al. (154), in a clinicopathologic study of 22 demented and 20 nondemented PD patients, discovered that cortical Lewy bodies were highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD. In contrast, the presence of AD pathology (senile plaques and neurofibrillary tangles) was only 64% sensitive and between 70% and 75% specific for dementia. In another study, Apaydin et al. (156) looked at the brains of 13 PD patients with dementia compared to nine PD patients without dementia. The authors found that 12 of the 13 demented PD patients had a 10-fold increase in Lewy body counts compared to the nondemented group. In seven of these patients, Lewy bodies were primarily present in the limbic areas, whereas in the other five, the Lewy bodies were widespread. General Treatment of Dementia Similar to the guidelines governing the general treatment of psychosis, any sudden change in cognition or behavior is most likely due to a medical cause. Therefore, infections, metabolic and endocrine derangements, and hypoperfusion states should be considered and treated if present. A switch to an unfamiliar environment may also precipitate an acute deterioration in cognitive status, and can be helped to a small degree with reassurance and frequent orientation. Substance abuse, including reliance on over-the-counter preparations containing antihistamines, is another factor that may be commonly overlooked. A review of the medication list is necessary

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and medications with CNS effects (sedatives, narcotics, antidepressants, anxiolytics, and antihistamines) should be discontinued, or used sparingly. The clinician should also be aware that other commonly prescribed medications, including antiemetics, antispasmodics for the bladder, H2 receptor antagonists, antiarrhythmic agents, antihypertensive agents, and nonsteroidal anti-inflammatory agents, may also cause cognitive impairment. Treatment for Dementia Cholinesterase Inhibitors Four cholinesterase inhibitors have been approved by the FDA for the treatment of AD: tacrine (1993), donepezil (1995), rivastigmine (2000), and galantamine (2001), but only rivastigmine has been approved for PD dementia (2006). They are all postulated to help correct the cholinergic deficit seen in PD dementia by increasing the amount of acetylcholine (ACh) available for binding to cholinergic receptors in the synaptic cleft. For all the cholinesterase inhibitors, the most common side effects are gastrointestinal distress (nausea, diarrhea, vomiting), fatigue, insomnia, and muscle cramps (157). Rivastigmine tends to also be associated with weight loss and dizziness. Although all these medications inhibit the action of acetylcholinesterase (AChE), there are subtle differences between these agents, especially with regard to butyrylcholinesterase (BuChE) inhibition and effect on the nicotinic receptors (Table 2). BuChE also breaks down ACh in the synaptic cleft, so inhibition of both BuChE and AChE may theoretically have greater clinical effect in dementia than inhibition of AChE alone. Both tacrine and rivastigmine inhibit BuChE. Cholinergic nicotinic receptor binding is reduced in PD and directly parallels the degree of dementia (158). Galantamine is also an allosteric modulator of presynaptic nicotinic cholinergic receptors. Therefore, by potentiating cholinergic nicotinic transmission, galantamine may be more suited for patients with PD dementia. However, despite these differences between the cholinesterase inhibitors, there have been no comparison trials to suggest that one is superior over another for PD dementia. Hutchinson and Fazzini (103) reported an open-label trial of tacrine in seven patients with PD dementia. All patients had improvement in hallucinations: five with complete resolution and two with partial improvement. They also had a 7.1-point improvement in mean MMSE scores and an improvement in motor scores. These

TABLE 2 Properties of the Cholinesterase Inhibitors Property Chemical class Cholinesterase selectivity Nicotinic ACh receptor action Type of cholinesterase inhibition

Tacrine Acridine AChE and BuChE modulator

Donepezil Piperidine AChE

Noncompetitive reversible

Noncompetitive reversible

Dose range Dosing frequency

5–160 mg qid

2.5–10 mg qd

–

Rivastigmine Carbamate AChE and BuChE –

Galantamine Phenanthrene alkaloid AChE

Noncompetitive reversible; most potent 1.5–12 mg bid

Competitive reversible; least potent

Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; BuChE, butyrylcholinesterase.

allosteric modulation

4–32 mg Bid or qd with sustained release preparation

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results suggested that cholinesterase inhibitors could improve neuropsychiatric features in PD without motor deterioration. However, in other studies, tacrine was associated with fulminant hepatotoxicity, which has limited its use. The accumulation of evidence that cholinesterase inhibitors were effective for the cognitive and behavioral sequelae of DLB without significant motor side effects rejuvenated interest in these compounds for treating dementia in PD (159–163). Subsequently, multiple open-label reports in PD dementia emerged and are summarized in Table 3 (103,105–106,108–109,111,164–166). Unfortunately, variability in the trial designs, inclusion criteria, and assessment measures make it difficult to compare studies. Overall, however, it appears that the cholinesterase inhibitors result in mild improvements in cognition without change in parkinsonian features. The few studies that reported motor deterioration noticed an effect mainly on tremor. In a randomized, double-blind, placebo-controlled trial (167), 14 individuals with PD and cognitive impairment received either donepezil (5 or 10 mg/d) or placebo in a cross-over design of two sequential periods lasting 10 weeks each. Patients had a history of cognitive decline at least one year after the onset of parkinsonism (3.0 ± 2.6 years) to decrease the likelihood of enrolling patients with DLB. The entire cohort had a mean age of 71 years, average duration of PD 10.8 years, and a mean levodopa dose of 485 mg/day. Patients had to have a MMSE score between 16 and 26. In addition, all patients had to have a decline in memory and at least one other category of cognitive function. After 10 weeks of treatment, donepezil improved the MMSE score by 2.1, but the placebo group did not improve (0.3). Furthermore, the clinician’s interview based impression of change (CIBIC) was greater for the donepezil group when compared to placebo. Motor function did not worsen during donepezil treatment, and no carry-over effect was noted. There have been two other double-blind, placebo-controlled trials of donepezil in PD patients. Leroi et al. (168) randomized 16 patients to donepezil (2.5–10 mg/d) or placebo. Patients had to meet DSM-IV criteria for either dementia or cognitive impairment secondary to PD. Seven patients were placed on donepezil therapy for a mean duration of 15.2 weeks. There was no difference between the two groups at the final visit in terms of MMSE or DRS scores, but the donepezil group had a 60% improvement in the DRS memory subscore, compared to a 12.5% improvement in the placebo arm. Four of the donepezil treated patients withdrew from the study, one from worsening parkinsonism. However, there were no significant group differences in the UPDRS scores from baseline to the final visit. The second trial used a crossover design in 22 PD subjects with dementia (107). Patients had to have a MMSE score between 17 and 26, and meet DSM-IV criteria for dementia in order to be included in the study. Each treatment period was 10 weeks with a six-week washout between the two periods. Patients on donepezil had a nonsignificant improvement in their ADAS-cog scores (primary outcome measure), but had a two-point improvement on their MMSE score and on overall clinical impression. There are no placebo-controlled trials reported for galantamine at this time. However, a large double-blind, placebo-controlled trial of rivastigmine for dementia in PD has been reported (110). This study enrolled 541 patients with mild-tomoderate dementia and PD, and randomized them to rivastigmine (mean dose 8.6 mg/d) or placebo for 24 weeks. About 410 subjects completed the study with dropouts primarily due to nausea, vomiting, and tremor. There was a significant improvement in the primary outcome measures for the rivastigmine group: ADAScog score at 24 weeks (2.1 ± 8.2) and the overall clinical impression. Secondary efficacy variables, Alzheimer’s Disease Cooperative Study–Activities of Daily Living

16

28 76

75

75

71

ND

70

69

75

74

Age

13

7

ND

12

ND

12

5

10

8

Length PD

Cognitive outcome

Cognition improved in 2 and stabilized in 2. 1 patient did not have dementia Improved ADAS-cog scores, but not MMSE Global cognitive improvement in 8 patients, worse in 4

Improved NPI and MMSE

MMSE improved in 1 patient 16 to 21 Improved MMSE in both groups, no significant change in NPI

Improvement on SAPS (5/6)

ADAS-cog improved, MMSE nonsignificant improvement

Improved MMSE, VH reduced

Motor response

6 patients improved, 4 had no change, 3 had worsened tremor

Not formally tested. 2 patients worsened, 1 improved slightly UPDRS mildly improved

Unchanged in 2 patients, tremor worsened in 1 No change in mean UPDRS motor scores, 7 patients reported tremor UPDRS unchanged

SPES unchanged overall but 5 patients had motor improvement SAS unchanged

UPDRS markedly improved

168

Abbreviations: ADAS-cog, Alzheimer’s Diseases Assessment scale-cognitive subscale; DLB, dementia with Lewy bodies; MMSE, Mini-Mental State Examination; ND, not described; PDD, Parkinson’s disease with dementia; SAPS, Scale for the Assessment of Positive Symptoms; SAS, Simpson–Angus Scale; UPDRS, Unified Parkinson’s Disease Rating Scale; VH, visual hallucinations; SPES, Short Parkinson Evaluation Scale.

Galantamine

Rivastigmine

Aarsland et al. (111)

5

Rivastigmine

Reading et al. (109) Bullock & Cameron (108) Rivastigmine

12

Donepezil

Minett et al. (165)

Giladi et al. (164)

3

Donepezil 11 (PDD) 8 (DLB)

6

Donepezil

7/4

Tacrine/Donepezil

N 7

Drug Tacrine

Bergman & Lerner (105) Kurita et al. (106)

Hutchinson & Fazzini (103) Werber & Rabey (166)

Study

TABLE 3 Summary of Open-label studies of Cholinesterase Inhibitors for Dementia in Parkinson’s Disease

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Scale, NPI-10, MMSE, verbal fluency, Cognitive Drug Research Computerized Assessment System power of attention tests, and the Clock-Drawing test also improved in the rivastigmine group. In a 24-week open extension of this trial (169), patients on rivastigmine in the original trial maintained their improvement at week 48 of treatment, whereas patients who were previously taking placebo and placed on rivastigmine (mean 7.7 mg/day) experienced a 2.8 improvement in ADAS-cog scores at the end of 24 weeks. In summary, there is emerging data that cholinesterase inhibitors produce a mild-to-moderate benefit on cognition in PD dementia. Although direct comparison between the different drugs is difficult, rivastigmine is the only approved medication for PD dementia. Other possible approaches to improving cholinergic function in the brain, such as dietary supplementation with cholinergic precursors (lecithin) and administration of cholinergic receptor agonists (bethanechol, milameline, tasaclidine), have not been found to be useful in AD and are unlikely to be tried in patients with PD dementia. Other Pharmacologic Agents Few other pharmacologic strategies for specifically treating dementia in PD have even been reported. Because noradrenergic depletion could contribute to executive dysfunction in PD, Bedard et al. (170) conducted a trial of naphtoxazine (SDZ-NVI085), a selective noradrenergic alpha 1 agonist, versus placebo in nondemented patients with PD. The results of the study demonstrated improved performance on tasks of set-shifting and cognitive flexibility, such as the Stroop and Odd-Man-Out tests. Furthermore, specific evoked potentials (Nd1 and Nd2 curves), thought to reflect attentional processes and known to be affected in PD, were improved with naphtoxazine. Memantine, an N-methyl-D-aspartate antagonist, has been approved for AD but to date there are no published studies of memantine for PD dementia. Estrogen replacement therapy (ERT) may be a reasonable protective strategy for the development of dementia in women who have PD. The effect of ERT on the risk of development of dementia was investigated in 87 women with PD without dementia, 80 women with PD with dementia, and 989 nondemented healthy women. ERT did not affect the risk of PD, but appeared to be protective for the development of dementia, arising within the setting of PD (OR 0.22, 95%CI 0.05–1.0) (171). Furthermore, a survey of PD patients residing in nursing homes in five U.S. states demonstrated that female residents on ERT were less cognitively impaired than patients not taking ERT (172). REFERENCES 1. Parkinson J. An Essay on the Shaking Palsy. London: Sherwood, Neely, & Jones, 1817. 2. Aarsland D, Larsen JP, Tandberg E, et al. Predictors of nursing home placement in Parkinson’s disease: a population-based, prospective study. J Am Geriatr Soc 2000; 48(8): 938–942. 3. Goetz CG, Stebbins GT. Risk factors for nursing home placement in advanced Parkinson’s disease. Neurology 1993; 43(11):2227–2229. 4. Factor SA, Feustel PJ, Friedman JH, et al. Longitudinal outcome of Parkinson’s disease patients with psychosis. Neurology 2003; 60(11):1756–1761. 5. Goetz CG, Stebbins GT. Mortality and hallucinations in nursing home patients with advanced Parkinson’s disease. Neurology 1995; 45(4):669–671. 6. Aarsland D, Larsen JP, Karlsen K, et al. Mental symptoms in Parkinson’s disease are important contributors to caregiver distress. Int J Geriatr Psychiatry 1999; 14(10):866–874.

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Neuroimaging Kenneth Marek, Danna Jennings, and John Seibyl Department of Neurology, The Institute for Neurodegenerative Disorders, New Haven, Connecticut, U.S.A.

Neuroimaging has provided insight into the pathophysiology and natural history of Parkinson’s disease (PD) and has emerged as a tool to monitor disease progression and to assess new potentially neuroprotective or neurorestorative therapies for PD. Diverse imaging methods have been successfully applied to neurological disorders. Although technology such as functional magnetic resonance imaging or magnetic resonance spectroscopy has been especially useful in assessing stroke, multiple sclerosis, and epilepsy (1–3), in vivo neuroreceptor imaging using single photon emission tomography (SPECT) and positron emission tomogrpahy (PET) have so far been most valuable in assessing PD. SPECT and PET use specific radioactively labeled ligands to neurochemically tag or mark normal or abnormal brain chemistry. Recent advances in radiopharmaceutical development, imaging detector technologies, and image analysis software have expanded and accelerated the role of imaging in clinical research in PD, in general, and neurotherapeutics, in particular. In this overview, we will focus on developments in neuroreceptor imaging in PD.

IMAGING TECHNOLOGY Both PET, also called dual photon emission tomography, and SPECT are sensitive methods of measuring in vivo neurochemistry (4,5). The choice of imaging modality is ultimately determined by the specific study questions and study design. Generally, PET cameras have better resolution than SPECT cameras; however, SPECT studies may be technologically and clinically more feasible, particularly for large clinical studies and in clinical practice. PET studies may benefit from greater flexibility in the range of radiopharmaceuticals that can be tested, but SPECT studies have the advantage of longer half-life radiopharmaceuticals necessary for some studies. The strengths and limitations of in vivo neuroreceptor imaging studies depend on the imaging technology utilized to measure brain neurochemistry and the ligand or biochemical marker used to tag a specific brain neurochemical system. The properties of the radiopharmaceutical are the most crucial issue in developing a useful imaging tool for PD. Some of the key steps in development of a potential radioligand include assessment of its brain penetration, its selectivity for the target site, its binding properties to the site, and its metabolic fate. These properties help to determine the signal-to-noise ratio of the ligand and the ease of quantitation of the imaging signal. Although ligands targeting neuronal metabolism have been used successfully to study PD patients, this review will focus on dopaminergic ligands (6). Specific markers for the dopaminergic system, including 18F-DOPA (7–12), 11C-VMAT2 (13–15), and dopamine transporter (DAT) ligands (16–22), have been widely used to evaluate patients with PD. Dopamine ligands are useful to assess PD insofar as they reflect the ongoing dopaminergic degeneration in PD. In the study most directly correlating changes in 177

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TABLE 1 Comparison of Dopamine Presynaptic Ligands in Parkinson’s Disease Studies [123I]β-CIT Target Bilateral reduction in hemi-PD Correlates with UPDRS in cross section Annual reduction change with aging (% loss from baseline) Annual progression (% loss from baseline)

11

C-VMAT2

18

F-DOPA

DA transporter

Vesicular transporter

DA turnover

Yes

Yes

Yes

Yes

Yes

Yes

0.8–1.4

0.5

No change

6–13

10

7–12

Abbreviations: DA, dopamine; PD, Parkinson’s disease; UPDRS, Unified Parkinson’s Disease Rating Scale.

dopamine neuronal numbers and imaging outcomes, there is good correlation between dopamine neuron loss and 18F-DOPA uptake, although conclusions are limited by a very small sample size of only five subjects (12). Numerous other studies have shown that the vesicular transporter and dopamine transporter are reduced in the striatum in postmortem brain from PD patients (23–25). In turn, numerous clinical imaging studies have shown reductions in 18F-DOPA, 11C-VMAT2, and DAT ligand uptake in PD patients and aging healthy subjects, consistent with the expected pathology of PD and of normal aging. Specifically, these imaging studies demonstrate progressive, asymmetric, putamen greater than caudate—loss of dopaminergic uptake (26–28) (Table 1). In addition, both 11C-VMAT2 and DAT ligands demonstrate reductions in activity with normal aging (13,29). Imaging with 18F-DOPA, 11C-VMAT2, and DAT ligands target different components of the presynaptic nigrostriatal neuron. The mechanism of each of these ligands has been elucidated in preclinical studies. Imaging with 18F-DOPA depends on conversion of 18F-DOPA by aromatic amino acid decarboxylase and uptake and trapping of 18F-dopamine into synaptic vesicles. Studies in 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-treated monkeys have shown a correlation between the 18 F-DOPA uptake and both dopaminergic neurons in the substantia nigra and dopamine levels in the striatum (30). The vesicular monoamine transporter acts to sequester newly synthesized or recovered monoamines (dopamine, serotonin, norepinephrine, and histamine) from the cytosol into the synaptic vesicles, thereby protecting the neurotransmitters from catabolism by cytosolic enzymes and packaging them for subsequent exocytotic release (31). VMAT2 ligand uptake is reduced in two commonly used rodent models of PD: the 6-hydroxydopamine-treated rat and the MPTP-treated mouse (32,33). DAT, a protein on the nerve terminal, is responsible for reuptake of dopamine from the synaptic cleft. In MPTP-treated monkeys, the loss of DAT paralleled that of dopamine in the striatum, and in MPTP monkeys treated with nigral implants, recovery of behavioral function was correlated with changes in DAT imaging (34,35). Several DAT ligands have been developed and used to assess PD and related disorders. Table 2 provides a detailed comparison of the properties of these ligands. This comparison both illustrates the increasing choice of radioligands available and underscores the distinction of those ligands that enable easy quantification of the imaging signal. DAT imaging agents are cocaine analogs with nanomolar affinity at the DAT (36–41). These ligands are chemically modified to alter the rapid metabolism

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Neuroimaging TABLE 2 Characteristics of Single Photon Emission Computed Tomography Dopamine Transporter Radioligands SPECT tracer

[123I]β-CIT

[123I]FP-CIT

99mTc-TRODAT

[123I]Altropane

Time to peak uptake

Protracted 8–18 hr Prolonged 1.4 nM Ki 1.7:1

Rapid 2–3 hr

Rapid 2–3 hr

Rapid 0.5–1 hr

Prolonged 3.5 nM Ki 2.8:1

Intermediate 9.7 nm Ki 26:1

Rapid 6.62 nM IC50 28:1

High

High

Low

Low

Washout phase DAT binding affinity DAT:SERT selectivity SPECT target:background tissue ratio

Abbreviations: DAT, dopamine transporter; SERT, serotonin transporter; SPECT, single photon emission computed tomography.

of cocaine at the ester linkage to provide more in vivo stability of the parent compound. Nonetheless, the kinetic properties of DAT radiotracers are quite different with regard to plasma protein binding, permeability across the blood–brain barrier, binding affinity, selectivity, and elimination. These differences are crucial to the applications of the DAT ligand for imaging (42). For example, although a given DAT tracer may distinguish PD from healthy controls based on the qualitative appearance of striatal uptake, the ability to distinguish the longitudinal changes in severity of PD may be more difficult for tracers with relatively poorer signal-to-noise properties (lower specific to nonspecific brain uptake) (Table 2). The quantitative properties of the radiotracer must be well understood to assess disease progression. Specifically, does the imaging signal provide a measure that is related to Bmax, the density of DAT, and/or the integrity of dopamine neurons? For some tracers, absolute quantitation of the DAT signal may require invasive methods involving full kinetic modeling, whereas other DAT tracers have a pharmacokinetic profile, which simplifies the methods for signal quantification. For example, the unusual binding kinetics of [123I]β-carboxymethoxy-iodophenyl tropane (CIT), with a protracted period of stable specific radiotracer uptake in the brain and extremely slow elimination from the DAT sites in striatum, permit reproducible quantitative determination of DAT density using a simple tissue ratio method (19,43). For DAT tracers with faster washout from specific binding sites, this simple ratio technique overestimates the density of binding sites in healthy striatum relative to PD (44), although these tracers may permit better visual discrimination of the diseased from control cases. Of the DAT SPECT tracers in development, [123I]β-CIT, [123I]FP-CIT, [123I]altropane, and [99mTc]-TRODAT have been the most widely evaluated agents for SPECT imaging (18,20,45) and [18F]-CFT (WIN 35,428) for PET (46,47). None of these tracers is commercially available as yet in North America, although one tropane derivative of cocaine (FP-CIT, DATSCAN®) is available as a [123I]-labeled tracer in Europe. PARKINSON’S DISEASE DIAGNOSIS ACCURACY The diagnosis of PD is currently based primarily on clinical judgment. However, the variability of disease presentation, progression, and response to medications often makes the diagnosis uncertain. In a population-based study, at least 15% of patients with a diagnosis of PD did not meet strict diagnostic criteria, and approximately 20% of patients with PD who had medical attention had not been diagnosed with PD (48).

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Prevalence studies of parkinsonism suggest a diagnostic accuracy of 80% after examination and application of clinical diagnostic criteria (49–51). Long-term clinicopathologic studies evaluating the diagnostic accuracy of PD demonstrate that the diagnoses most commonly mistaken for PD are progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) (52,53). However, early in the course of PD, the most common misdiagnoses include essential tremor, vascular parkinsonism, drug-induced parkinsonism, and Alzheimer’s disease (54,55). It has been estimated that the diagnosis is incorrect in as many as 35% of those initially diagnosed as PD by generalists (56). In addition, symptoms of parkinsonism are relatively common in elderly subjects, making the diagnosis most challenging in this population. Subtle extrapyramidal signs on neurological evaluation are common in the elderly with recorded prevalences of 32% (57) and 35% (58). Prevalence estimates for clinically evident parkinsonism in similarly aged subjects are much lower at around 3%. Neurologists with specialized training in parkinsonism are able to make the diagnosis of PD with a higher accuracy than generalists. In a six-year follow-up study of the Deprenyl and Tocopherol Antioxidative Therapy of Parkinson’s Disease (DATA TOP) cohort, the diagnosis of PD was changed in only 8% of subjects. Similarly, in a study of movement disorder specialists, sensitivity was 91% for the diagnosis of PD compared to a diagnosis based on pathology (59,60). In vivo imaging holds the promise of improving diagnostic accuracy by providing an assessment of the nigrostriatal dopaminergic system early in disease or at the threshold of diagnosis. The reduction in DAT density in PD is region-specific (putamen > caudate) and asymmetric, consistent with both pathologic assessment of DAT loss and clinical presentation of PD. Although comparisons of imaging and pathology help to confirm the validity of the imaging studies, they also highlight questions for which imaging studies may provide unique and otherwise unobtainable data. For example, in vivo imaging studies with either 18F-DOPA/PET or [123I]βCIT/SPECT demonstrate a reduction in ligand uptake of approximately 50% to 70% in the putamen in PD subjects (20,61). The reduction in dopamine terminal function or DAT density and the pattern of striatal degeneration is consistent with the reduction in substantia nigra pars compacta neurons of greater than 80% and of putamenal dopamine content of 95% in PD brains (62–64). However, these imaging studies also have shown at or near the threshold of diagnosis, patients with symptoms of PD show a reduction in putamenal 18F-DOPA or DAT activity of 40% to 60% rather than 80% to 90%, as suggested by pathology studies (65–67). Difficulty in accurately diagnosing individuals early in the course of PD clearly impacts the clinical care of individuals and may also have implications when recruiting subjects for early PD clinical trials. Two recent studies involving early, untreated parkinsonian subjects suggest that imaging may identify individuals without typical PD at the time of enrollment. In the REAL-PET study, comparing ropinirole and levodopa as initial treatments in untreated patients, 11% (21/193) of enrolled subjects had scans without evidence of reduction in 18F-DOPA uptake at baseline and after two years (68). In the Early versus Late LevoDOPA (ELLDOPA)-CIT study (69), comparing initial levodopa therapy to placebo in recently diagnosed patients, 14% (21/142) of enrolled subjects had scans without evidence of reduction in [123I]β-CIT uptake at baseline and again at nine months (19/19, 2 terminated). The uncertainty of the clinical diagnosis is an important factor in the design and critical analysis of clinical therapeutic trials. Inclusion of subjects who do not have PD increases estimates of disease frequency and confounds efficacy studies of agents that may alter the rate of progression of disease. Data from these studies underscores the difficulty

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in accurately diagnosing parkinsonian patients in the early stages, based solely on clinical evaluation. DAT imaging offers an objective measure of the density of the presynaptic dopaminergic neurons. Several studies have shown that DAT ligand uptake is already reduced by about 50% when compared to age-corrected controls, indicating a role for DAT and SPECT in confirming a diagnosis of PD in patients with early symptoms (70,71). In a blinded study, 35 patients with suspected early parkinsonian syndrome (PS) were referred for DAT imaging, using [123I]β-CIT and SPECT, by community neurologists who were unsure of their diagnosis (71). In this study, PS was defined as any condition expected to have a reduction in DAT density, including PD, PSP, MSA, diffuse Lewy body disease (DLBD), striatonigral degeneration (SND), or cortiobasal degeneration (CBD). To evaluate the accuracy of DAT imaging as a diagnostic tool, patients were followed clinically over a six-month period. Two movement disorder experts assigned a clinical diagnosis at the time of referral. One movement disorder expert remained masked to the imaging data and assigned a clinical diagnosis at the six-month interval. The six-month clinical diagnosis served as the “gold standard” diagnosis for the study. Based on this study, the sensitivity of the [123I]β-CIT and SPECT imaging diagnosis was 92% whereas the specificity of the imaging was 100% when compared to the clinical “gold standard” diagnosis at sixmonth follow-up. Two subjects referred with a questionable diagnosis of PS had a diagnosis of PS by the clinical “gold standard,” whereas their imaging showed no deficit of DAT uptake. [123I]FP-CIT and SPECT was performed, and subjects were followed over a two- to four-year period. In this study, the clinicians were aware of the imaging results and utilized this information in making a final diagnosis. In 9 of 33 subjects, dopaminergic neuronal degeneration was found and, in all cases, a diagnosis of PS was confirmed clinically. In 24 subjects, there was no evidence of dopaminergic neuronal degeneration, and other non-PS diagnoses were assigned in 19 of these subjects at follow-up (70). Both studies suggest that the positive predictive value of DAT imaging in the diagnosis of PS is high; however, the negative predictive value is lower. Combining data from DAT with the clinical evaluation improves the diagnostic accuracy of PS in difficult to diagnose cases. These imaging data acquired from early PD patients at the threshold of illness have clarified the natural history of the disease, providing a means to improve our diagnostic accuracy earlier in the disease process and providing further impetus to develop therapies to protect the remaining 50% of dopaminergic neurons not yet affected at disease onset. PARKINSON’S DISEASE DIFFERENTIAL DIAGNOSIS AND SEVERITY The initial questions of an imaging ligand are whether it reliably distinguishes between subjects with and without a known pathology (a marker for disease trait) and whether the changes in the imaging outcomes correlate with disease severity (a marker for disease state). In several studies, dopamine and vesicular transporter ligands and 18F-DOPA discriminated between individuals with PD and healthy subjects, with a sensitivity greater than 95% (11,13,20,72–74). These studies take advantage of the relatively greater dopaminergic loss in the putamen to enhance the discriminant function. Furthermore, the reduction in both dopamine and vesicular transporter and 18F-DOPA imaging activity correlated with well-defined clinical rating scales of PD severity (16,20,28,75). Interestingly, when specific PD symptoms were compared, the loss of dopaminergic activity measured by imaging correlated with bradykinesia but not with tremor (20,76). Cross-sectional studies show that

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severity of bradykinesia measured by clinical scales reflects the severity of the nigrostriatal dopamine neuron loss. Therefore, in vivo dopaminergic imaging provides a biomarker for the presence of disease and for the severity of the pathologic process. In clinical practice, the diagnosis is most difficult at the onset of symptoms. In studies focused on early PD patients, in vivo imaging demonstrated a 40% to 60% reduction in DAT or F-DOPA activity in the putamen contralateral to the symptomatic side. PD generally presents as a unilateral motor disorder and progresses during a variable period of three to six years to affect both sides, although frequently remaining asymmetric (77). The unilateral motor presentation reflects the asymmetric dopaminergic pathology, which is, in turn, demonstrated by in vivo dopaminergic imaging (11,66,67). DAT imaging has also been shown to be useful in special diagnostic situations such as psychogenic, drug-induced, traumatic or vascular parkinsonism, in distinguishing these syndromes without a presynaptic dopamine deficit from PD and other related disorders (78,79). A more difficult diagnostic problem is the distinction between the more specific diagnosis of PD and other related neurodegenerative disorders categorized as parkinsonism. The more common etiologies, such as PSP, MSA, CBD, and DLBD, may account for about 15% to 20% of patients with apparent PD. Parkinsonism is characterized by significant nigrostriatal neuronal loss demonstrated by a reduction in in vivo presynaptic dopaminergic imaging. Although the severity of DAT or 18F-DOPA loss does not discriminate between PD and other causes of parkinsonism, the pattern of loss in parkinsonism is less regionspecific (putamen and caudate equally affected) and more symmetric than PD. This strategy discriminates between PD and other causes of parkinsonism with a sensitivity of about 75% to 80% (80–82). In addition, the more widespread pathology associated with parkinsonism may be reflected in abnormalities in postsynaptic dopamine receptor imaging and in metabolic imaging, which are not seen in PD. Therefore, the pattern of presynaptic dopaminergic loss may be coupled with postsynaptic dopamine receptor imaging or metabolic imaging to distinguish PD from other parkinsonisms (83,84). PARKINSON’S DISEASE PROGRESSION The rate of clinical progression of PD is highly variable and unpredictable (77). In clinical studies, several clinical endpoints for progressive functional decline in PD have been used, including the Unified Parkinson’s Disease Rating Scale (UPDRS) in the “defined off ” state or after drug washout up to two weeks, time to need for dopaminergic therapy, or time to development of motor fluctuations (85–89). Clinical rating scales are extremely useful, but ratings may be investigator-dependent and are frequently confounded by changes in symptomatic treatment. Pathological studies investigating rate of progression have been limited and rely entirely on crosssectional data (63,64). These studies have in general considered patients with severe illness of long duration. In vivo imaging studies provide the opportunity to evaluate patients longitudinally from early to late disease using an objective biomarker for dopaminergic degeneration. In several studies, neuroreceptor imaging of the nigrostriatal dopaminergic system has been used as a research tool to monitor progressive dopaminergic neuron loss in PD. In longitudinal studies of PD progression both 18F-DOPA and DAT imaging [β CIT(2β-carboxymethoxy-3β(4-iodophenyl)tropane) and CFT] using both

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FIGURE 1 Single photon emission computed tomography (SPECT) [123I]β-CIT images from a patient with PD two years after diagnosis and 46 months later. Note the asymmetric reduction in [123I]β-CIT uptake more marked in the putamen than in the caudate of the patient, and the progressive loss of activity. Levels of SPECT activity are color-encoded from low (black) to high (white).

PET and SPECT have demonstrated an annualized rate of reduction in striatal [18F]DOPA, [18F]CFT, or [123I]β-CIT uptake of about 6% to 13% in PD patients, compared with 0% to 2.5% change in healthy controls (90–94). Similar findings have been reported for VMAT2 imaging (K. Frey, personal communication, 2002) (Fig. 1). Evidence from studies of hemi-PD subjects provides further insight into the rate of disease progression. In early hemi-PD, there is a reduction in 18F-DOPA and DAT uptake of about 50% in the affected putamen and of 25% to 30% in the unaffected putamen. Since most patients progress clinically from unilateral to bilateral in three to six years, it is likely that the loss of these in vivo imaging markers of dopaminergic degeneration in the previously unaffected putamen will progress at about 5% to 10% per annum (11,66). Imaging has also been used to monitor progression of PD in patients receiving fetal substantia nigral transplants for PD. Several studies have shown an increase in 18 F-DOPA uptake six months to six years post-transplant (95,96). The change in 18 F-DOPA uptake has been correlated with postmortem survival of grafted dopaminergic nigral cells (97). The most important role of longitudinal imaging studies is to provide a tool to assess objectively potential neuroprotective and restorative therapies for PD. Several candidate drugs, including coenzyme Q10, a mitochondrial agent; monoamine oxidase-B inhibitors; neuroimmunophilin, a nerve growth factor; riluzole, a glutamatergic drug; CEP 1347, an antiapoptotic agent; and dopamine agonists, have been or are in ongoing clinical studies of neuroprotection (85–87,89,98–100). Imaging studies assessing progression of disease have provided data to estimate sample sizes required to detect slowing of disease progression due to study drug treatment. The sample size required depends on the effect size of the disease modifying drug and the duration of exposure to the drug. The effect of the drug is generally expressed as the percent reduction in rate of loss of the imaging marker in the group treated with the study drug versus the control group. More specifically, imaging studies have sought a reduction of between 25% and 50% in the rate of loss of 18F-DOPA or [123I]β-CIT uptake (i.e., a reduction from 10%/yr to 5–7.5%/yr). The sample size needed to detect a 25% to 50% reduction in the rate of loss of F-DOPA or β-CIT uptake during a 24-month interval ranges from approximately 30 to 120 research subjects in each study arm (90,101).

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Two similar studies compared the effect of initial treatment with a dopamine agonist [pramipexole (CALM-PD CIT) or ropinirole (REAL-PET)] or levodopa on the progression of PD, as measured by [123I]β-CIT or 18F-DOPA imaging. These two clinical imaging studies targeting dopamine function with different imaging ligands and technology both demonstrated slowing in the rate of loss of [123I]β-CIT or 18F-DOPA uptake, in early PD patients treated with dopamine agonists compared to levodopa. These studies evaluated two related, predominantly D2 dopamine receptor agonists, suggesting that the results may indicate a class effect. The relative reduction in the percent loss from baseline of [123I]β-CIT uptake in the pramipexole versus the levodopa group was 47% at 22 months, 44% at 34 months, and 37% at 46 months, after initiating treatment. The relative reduction of 18F-DOPA uptake in the ropinirole group versus the levodopa group was 35% at 24 months. These data suggest that treatment with the dopamine agonists, pramipexole and ropinirole with or without levodopa may either slow or accelerate the dopaminergic degeneration of PD. Furthermore, these studies demonstrated that in vivo imaging can be used effectively to assess potential disease modifying drugs in well controlled, blinded clinical studies (68,102) In the CALM-PD CIT and REAL-PET studies, there was no correlation between the percent change from baseline in the imaging outcome and the change from baseline in UPDRS at 22 to 24 months. There are several explanations for the lack of correlation between [123I]β-CIT or 18F-DOPA uptake and UPDRS in longitudinal studies. First, the UPDRS is confounded by the effects of the patient’s antiparkinson medications, both acutely after initiating therapy and with ongoing treatment. Even evaluation of the UPDRS in the “defined off ” state or after prolonged washout does not eliminate the long duration symptomatic effects of these treatments (88,103). Second, in early PD, the temporal patterns for rate of loss of dopamine transporter or 18 F-DOPA and the change in UPDRS may not be congruent. This is most evident in the preclinical period when the imaging outcomes are reduced by 40% to 60% prior to diagnosis. In the CALM-PD study, the loss of striatal [123I]β-CIT uptake from baseline was significantly correlated (r = −0.40, P = 0.001) with the change in UPDRS from baseline at the 46-month evaluation, suggesting that the correlation between clinical and imaging outcomes begins to emerge with longer monitoring (102). These data suggest that particularly in early PD, clinical and imaging outcomes provide complementary data and that long-term follow-up will be required to correlate changes in clinical and imaging outcomes. Slowing the loss of imaging outcomes in PD is relevant only if these imaging changes ultimately result in meaningful, measurable, and persistent changes in clinical function in PD patients. Concerns that levodopa may accelerate PD progression led to the design of the ELLDOPA (Early Versus Late Levodopa) study. The purpose of the study was to determine if levodopa alters the natural rate of progression of PD. The ELLDOPA study was a randomized, double-blind, placebo-controlled, parallel-group, multisite clinical trial involving subjects with early, untreated PD (69). Three hundred and sixty subjects were enrolled and randomized to four treatment arms: levodopa 150 mg/day, 300 mg/day, 600 mg/day, and a placebo arm. The active treatment groups were titrated during a course of nine weeks to their respective doses followed by a 40-week maintenance period. Subjects were titrated off active treatment and underwent a twoweek washout period. A subset of 135 subjects had DAT imaging using β-CIT and SPECT at baseline and at 40 weeks, prior to the washout period. The primary outcome measure was the change in severity as measured by the total UPDRS scores from baseline to week 42 (two weeks following washout). The percent change in the striatal DAT uptake between baseline and week 40 was the primary imaging outcome.

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The results of the ELLDOPA clinical study revealed an improvement in the UPDRS in the treated arms in a dose-response pattern. Comparing baseline and 42week UPDRS, the scores worsened by 7.8 ± 9.0 points in the placebo group, 1.9 ± 6.0 points in the levodopa 150 mg/day group, 1.9 ± 6.9 points in the 300 mg/day group, and improved by 1.4 ± 7.7 points in the 600 mg/day group. The clinical outcome of the study was suggestive of a protective effect of levodopa at the 600-mg/day dose; however, a short washout period from levodopa could explain these results. In the neuroimaging substudy, 21 of 142 (14.7%) subjects had β-CIT uptake in the range expected for healthy controls. These subjects without evidence of dopaminergic deficit (SWEDD’s) had no decrease in uptake from baseline to week 40, and did not improve clinically with levodopa therapy making their diagnosis unlikely to be PD. Comparing the baseline and 40-week imaging, the percent decline in β-CIT uptake was more pronounced in the levodopa groups than the placebo group (−7.2%, −4%, −6%, and −1.4% for the 600-, 300-, 150-mg/day, and placebo groups, respectively). These imaging data are suggestive of an increase in the loss of uptake with increasing doses of levodopa, and thus contradicted the clinical findings. A potential pharmacologic effect of levodopa on the imaging outcome measure was entertained as a possible explanation for the decrease in uptake. The clinical outcomes showed that levodopa may have slowed the rate of progression, but in contrast, the imaging substudy suggested that levodopa caused a more rapid decline in the nigrostriatal nerve terminals. These contradictory results from the clinical and neuroimaging studies, involving dopamine agonists and levodopa, led to the review of existing data regarding potential pharmacologic effects of dopaminergic medications on the imaging outcome measures. There are limited data available concerning the direct effects of medications on the DAT or dopamine turnover (32,104). Preclinical studies have shown inconsistent results (105). Human studies have been limited by small sample sizes, but have failed to show a direct drug effect on the DAT or dopamine turnover (106–109). Given the paucity of data, the INSPECT study was designed to directly address the question of whether dopaminergic medications have a pharmacologic effect on the DAT imaging outcome measure. In this study, subjects are imaged with β-CIT and SPECT at baseline and randomized to one of the three arms: no treatment, treatment with levodopa 600 mg/day, or treatment with pramipexole 3 mg/day. After 12 weeks of treatment (eight weeks titration and four weeks maintenance), a second β-CIT and SPECT scan is obtained. Data from the first 67 subjects completing the two scans show no short-term change in DAT uptake with either levodopa (n = 24) or pramipexole (n = 23) compared to the untreated group (n = 20). The mean percent change for those treated with levodopa was 2.2 ± 9.9, for pramipexole −2.8 ± 8.3, and for the untreated group 2.5 ± 7.7 (110). These small changes are consistent with that of test–retest evaluations using β-CIT and SPECT. Other studies have also shown no remarkable change in the activity of DAT ligands or 18F-DOPA uptake by levodopa or dopamine agonists. In the CALM-PD CIT study there was no significant change in β-CIT uptake after 10 weeks of treatment with either pramipexole (1.5–4.5 mg) or levodopa (300–600 mg), consistent with previous studies evaluating levodopa and selegiline effects after 6 to 12 weeks (102,106,107). In a similar study, treatment with pergolide for six weeks also showed no significant changes in [123I]β-CIT striatal, putamen, or caudate uptake, but there was an insignificant trend toward increased [123I]β-CIT uptake (108). Data assessing RTI-32, another DAT ligand, demonstrated significant reductions from baseline in striatal DAT after six weeks treatment with both levodopa and pramipexole, but also

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with placebo, and this pilot study could not detect differences between the treatment and placebo (109). Although these clinical studies are not conclusive, there does not appear to be a short-term change in DAT uptake with exposure to levodopa or pramipexole. Given that there is no change in DAT uptake after short-term exposure to pramipexole or levodopa, the increased loss of β-CIT uptake in the levodopa-treated group compared to the pramipexole group in the CALM-CIT study is unlikely explained by a pharmacologic effect on the DAT. Likewise, the increased loss in β-CIT uptake in the levodopa 600-mg/day group compared to placebo in the ELLDOPA trial does not appear to be explained by an effect of levodopa on the DAT. Although data from these studies do not address the possibility that pharmacologic effects may emerge in longer-term studies, an effect, if one existed, would be expected to occur within weeks of the initiation of therapy. PRECLINICAL PARKINSON’S DISEASE Estimates based on postmortem studies suggest that for every patient who presents with PD, there may be up to 15 cases of preclinical PD (development of Lewy body pathology without clinical signs of PD) (111). Neuroreceptor imaging studies provide a window into this preclinical period of PD, the time during which neurodegeneration has begun, but symptoms have not yet become manifest. Preclinical identification of affected subjects is particularly important if intervention exists, which may prevent progression of disease. The most extensive preclinical imaging data is from studies imaging patients with hemi-PD. In several imaging studies, there is a significant reduction in putamen DAT or 18F-DOPA uptake of about 25% to 30% in the “presymptomatic” striatum in these patients who are known to progress to bilateral disease (11,66,67). Progression studies also elucidate the preclinical period of PD. For example, given the assumption that progression is linear, it is possible to back extrapolate from sequential imaging data and reported symptom duration to estimate the level of reduction in dopaminergic activity at symptom onset and the duration of the preclinical phase of PD (Fig. 2). Data from longitudinal imaging studies using both

FIGURE 2 Presymptomatic loss of 18F-Dopa in the asymptomatic co-twin of a PD patient. Note that the asymptomatic co-twin shows mild reduction in 18F-Dopa at baseline, which has worsened abnormality at five-year follow-up associated with onset of symptoms. Source: Courtesy of D Brooks, London, U.K.

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18 F-DOPA and DAT imaging have been remarkably consistent with estimated disease onset at 70% to 75% of normal dopaminergic activity and a preclinical phase of four to eight years (102,112). Interestingly, these data are consistent with estimates of duration of the preclinical phase from pathology studies of 4.7 years derived from cross-sectional data (111). Although the data available to calculate estimates of preclinical phase must be viewed as preliminary, data acquired using different imaging methods measuring different components of the dopaminergic system and data from an independent pathology study suggest a relatively brief preclinical phase of less than a decade for PD. These data influence our understanding of disease etiology and developing strategies for disease screening and treatment. For example, if preclinical disease is relatively short, repetitive screening might be required to identify affected individuals in an at risk population. Furthermore, as potential preventive or restorative therapies are developed, these treatments might be directed to the time period from onset of degeneration to onset of symptoms. Most studies of the preclinical period have focused on potential “at risk” individuals for PD, such as family members or unaffected twins of PD patients. In a study of hyposmic first-degree relatives of PD patients, it was shown that four of 40 (10%) hyposmic relatives with no parkinsonian signs converted to PD over a twoyear period (113). Of the 40 subjects, seven showed a reduction in [123I] β-CIT uptake and the four with the lowest uptake were those converting to PD. Findings from this study suggest that [123I] β-CIT and SPECT have the capacity to detect changes in DAT prior to the onset of symptoms. In studies of familial PD in several well-characterized kindreds, 11 of 32 asymptomatic relatives were found to have reduced 18F-DOPA uptake and three of these subjects have subsequently developed symptomatic PD (114). Several asymptomatic cotwins who also showed a reduction in 18F-DOPA activity later developed symptoms of PD (Fig. 2), although the concordance rate for monozygotic and dyzygotic twins remains uncertain (115). Sporadic cases also have been reported of individuals imaged as presumed healthy subjects with mildly abnormal 18F-DOPA uptake, who later developed definite PD (116). Preclinical identification of subjects with PD forces us to reexamine our clinical definitions of disease. The recent identification of genes, which confer the PD phenotype in familial PD, will provide an opportunity to evaluate an “at risk” population both clinically and with sequential imaging studies (117,118). As additional genetic markers are discovered, imaging will play an essential role in assessing neurodegeneration and possibly in redefining clinical disease onset.

FUTURE DIRECTIONS Neuroimaging has provided key insights into the natural history of PD and has become a necessary if not sufficient test to assess potential new disease modifying therapies for PD. Although this review has focused on presynaptic dopamine ligands, several additional directions for imaging in PD have emerged or are under active study. Several postsynaptic dopamine imaging ligands have been used to study the postsynaptic dopaminergic receptors in PD (119–121), although quantitative information has been limited by relatively low sensitivity of the ligands available and has been complicated by uncertainty regarding endogenous dopamine binding to the receptor target. Postsynaptic dopamine receptor imaging studying dopamine release is a novel approach to using imaging to assess function, particularly in studies involving cell replacement therapy (122).

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Although dopamine degeneration is a crucial feature of PD, it is clear that there is widespread degeneration in the brain in PD and that many clinical manifestations of PD are likely not due to dopamine deficiency. Ligands for nondopaminergic targets have been and are being developed to investigate nondopaminergic manifestations of PD and to better understand the cause of PD and of dyskinesia. The role of brain imaging in PD will continue to expand, as new imaging targets emerge and additional disease modifying drugs are developed. As simpler tools to identify preclinical “at risk” individuals become available, neuroreceptor imaging will be widely used to establish and monitor the onset and progression of disease. As treatments become available that target both the mechanisms that initiate and subsequently promote the course of disease progression, precise information about an individual’s neurochemical status will be essential to optimize clinical management.

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Neuropathology Dennis W. Dickson Department of Pathology, Mayo Clinic College of Medicine, Jacksonville, Florida, U.S.A.

INTRODUCTION The common denominator of virtually all disorders associated with clinical parkinsonism is neuronal loss in the substantia nigra, particularly of dopaminergic neurons in the pars compacta that project to the striatum (Fig. 1). The ventrolateral tier of neurons appears to be the most vulnerable in many parkinsonian disorders and these tend to project heavily to the putamen (1). The more medial groups of neurons send projections to the forebrain and the medial temporal lobe and are less affected. The dorsal tier of neurons may be most vulnerable to neuronal loss associated with aging (1). PARKINSON’S DISEASE The clinical features of Parkinson’s disease (PD) include bradykinesia, rigidity, tremor, postural instability, autonomic dysfunction, and bradyphrenia. The most frequent pathologic substrate for PD is Lewy body disease (2). Some cases of otherwise clinically typical PD have other disorders, such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) or vascular disease, but these are uncommon, especially when the clinical diagnosis is made after several years of clinical followup (3,4). The diagnostic accuracy rate has approached 90% in some series (5). The brain is usually grossly normal when viewed from the outer surface. There may be mild frontal atrophy is some cases, but this is variable. The most obvious morphologic change in PD is only visible after the brainstem is sectioned. The loss of neuromelanin pigmentation in the substantia nigra and locus ceruleus is usually grossly apparent and may be associated with a rust color in the pars reticulata, which correlates with increased iron deposition in the tissue. Histologically, there is neuronal loss in the substantia nigra pars compacta along with compensatory astrocytic and microglial proliferation. Although biochemically there is loss of dopaminergic termini in the striatum, the striatum is histologically unremarkable. In the substantia nigra and locus ceruleus, neuromelanin pigment may be found in the cytoplasm of macrophages. Less common are neurons undergoing neuronophagia (i.e., phagocytosis by macrophages). Hyaline cytoplasmic inclusions or Lewy bodies and less welldefined “pale bodies” are found in some of the residual neurons in the substantia nigra (Fig. 2). Similar pathology is found in the locus ceruleus, the dorsal motor nucleus of the vagus, as well as the basal forebrain (especially the basal nucleus of Meynert). The convexity neocortex usually does not have Lewy bodies, but the limbic cortex and the amygdala may be affected. Depending upon the age of the individual, varying degrees of Alzheimer-type pathology may be detected, but if the person is not demented, this usually falls within the limits for that age. Some cases may have abundant senile plaques, but few or no neurofibrillary tangles (NFTs). Lewy bodies are proteinaceous neuronal cytoplasmic inclusions (6,7). In some regions of the brain, such as the dorsal motor nucleus of the vagus, Lewy bodies tend to form within neuronal processes and are sometimes referred to as intra-neuritic 195

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FIGURE 1 Midbrain sections from a variety of disorders associated with parkinsonism, including Parkinson’s disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and a disorder not associated with parkinsonism, Alzheimer’s disease (AD). Note loss of pigment in the substantia nigra in all disorders, except AD.

Lewy bodies. In most cases, Lewy bodies are accompanied by a variable number of abnormal neuritic profiles, referred to as Lewy neurites. Lewy neurites were first described in the hippocampus (8), but are also found in other regions of the brain, including the amygdala, cingulate gyrus, and temporal cortex. At the electron microscopic level, Lewy bodies are composed of densely aggregated filaments (9) and Lewy neurites also are filamentous, but they are usually not as densely packed (8). Neurons that are most vulnerable to Lewy bodies include the monoaminergic neurons of the substantia nigra, locus ceruleus, and dorsal motor nucleus of the vagus,

FIGURE 2 Parkinson’s disease: Lewy bodies are hyaline inclusions visible with routine histologic methods in pigmented neurons of the substantia nigra (arrow in A). They are immunostained with antibodies to synuclein (arrow in B).

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as well as cholinergic neurons in the basal forebrain. Lewy bodies are rarely detected in the basal ganglia or thalamus, but are common in the hypothalamus, especially the posterior and lateral hypothalamus, and the brainstem reticular formation. The oculomotor nuclear complex is also vulnerable. In the pons, the dorsal raphe and subpeduncular nuclei are often affected, but neurons of the pontine base are not. Lewy bodies have not been described in the cerebellar cortex. In the spinal cord, the neurons of the intermediolateral cell column are most vulnerable. Lewy bodies can be found in the autonomic ganglia, including submucosal ganglia of the esophagus (10). Although not usually numerous in typical PD, Lewy bodies can be found in cortical neurons, especially in the limbic lobe. Cortical Lewy bodies can be difficult to detect with routine histology, but are visible with special staining techniques and are usually most numerous in small nonpyramidal neurons in lower cortical layers. Similar lesions in the substantia nigra are referred to as “pale bodies” or as “preLewy bodies.” Ultrastructural studies of cortical Lewy bodies demonstrate poorly organized filamentous structures similar to Lewy neurites. The distribution of Lewy bodies in PD has been placed in a six-stage scheme that hypothesizes the earliest changes are in the lower brainstem and the olfactory bulb, with “spread” of the disease process to progressively higher levels of the neuraxis (11). In this scheme, the locus ceruleus is involved at stage 2, the substantia nigra is involved at stage 3, the basal forebrain and limbic lobe at stage 4, the multimodal association neocortex at stage 5, and the primary neocortex at stage 6. The hypothesis predicts that preparkinsonian manifestations would be nonmotor (e.g., autonomic dysfunction and anosmia) and that the late stage would be associated with cortical Lewy body dementia. The scheme remains to be confirmed, but there is intriguing evidence that would suggest that sleep disorders, constipation, and anosmia may precede overt parkinsonism in some cases by many years (12–14). The chemical composition of Lewy bodies has been inferred from immunohistochemical studies. While antibodies to neurofilament were first shown to label Lewy bodies (15), ubiquitin (16) and more recently α-synuclein (17) (Fig. 2) antibodies are better markers for Lewy bodies, and α-synuclein appears to be the most specific marker currently available. Lewy neurites have the same immunoreactivity profile as Lewy bodies (18). Biochemical studies of purified Lewy bodies have not been accomplished, but evidence suggests that they may contain a mixture of proteins, including neurofilament and α-synuclein (19–21). PARKINSON’S DISEASE DEMENTIA Pathological findings considered to account for dementia in PD include severe pathology in monoaminergic and cholinergic nuclei that project to the cortex producing a “subcortical dementia” (39%), coexistent Alzheimer’s disease (AD) (29%), and diffuse cortical Lewy bodies (26%) (22). The basal forebrain cholinergic system is the subcortical region most often implicated in dementia, and neurons in this region are damaged in both AD and Lewy body dementia. Neuronal loss in the basal nucleus is consistently found in PD, especially PD with dementia (23). Cholinergic deficits are common in PD (24) and they may contribute to dementia in PD in those cases that do not have concurrent AD or cortical Lewy bodies. While virtually all PD brains have a few cortical Lewy bodies (22), they are usually neither widespread nor numerous in PD patients who were not demented. Several studies have shown, however, that cortical Lewy bodies are numerous and widespread in PD with dementia (25–27) and that the density of cortical Lewy bodies

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and Lewy neurites, especially in the medial temporal lobe (28), correlates with the severity of dementia (29). There are exceptions to this rule with occasional reports of patients with many Lewy bodies who were clinically normal (30). MULTIPLE SYSTEM ATROPHY MSA refers to a neurodegenerative disease characterized by parkinsonism, cerebellar ataxia, and orthostatic hypotension (31). There is no known genetic risk factor or genetic locus in MSA. The MSA brain shows varying degrees of atrophy of the cerebellum, cerebellar peduncles, pons and medulla, as well as atrophy and discoloration of the posterolateral putamen and pigment loss in the substantia nigra. The histopathological findings include neuronal loss, gliosis, and microvacuolation, involving the putamen, substantia nigra, cerebellum, olivary nucleus, pontine base, and intermediolateral cell column of the spinal cord. White matter inevitably shows demyelination, with the brunt of the changes affecting white matter tracts in the cerebellum and pons (Fig. 3). Lantos et al. (32) first described oligodendroglial inclusions in MSA and named them glial cytoplasmic inclusions (GCIs). GCIs can be detected with silver stains, such as the Gallyas silver stain, but are best seen with antibodies to synuclein, where they appear as flame- or sickle-shaped inclusions in oligodendrocytes (Fig. 3). Like Lewy bodies, GCIs are also immunostained with antibodies to ubiquitin (32). At the ultrastructural level, they are nonmembrane-bound cytoplasmic inclusions composed of filaments (7 to 10 nm) and granular material that often coats the filaments making precise measurements difficult (33). GCIs are specific for MSA and have not been found in other neurodegenerative diseases. In addition to GCIs, synuclein immunoreactive lesions are also detected in some neurons in MSA. Biochemical studies of synuclein in MSA have shown changes in its solubility (34).

FIGURE 3 Multiple system atrophy (MSA): Substantia nigra neuronal loss in MSA is obvious in the cluster of pigment-laden macrophages (arrow in A), but neuronal inclusions are not present. Synuclein immunostaining of the substantia nigra shows many small inclusions in oligodendroglial cells (B). The white matter in the cerebellum shows marked myelin loss (Luxol fast blue stain for myelin) (C) and in the affected areas there are many synuclein-immunoreactive glial inclusions (arrows) (D).

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PROGRESSIVE SUPRANUCLEAR PALSY PSP is an atypical parkinsonian disorder associated with progressive axial rigidity, vertical gaze palsy, dysarthria and dysphagia first described by Steele–Richardson–Olszewski (35). Frontal lobe syndrome and subcortical dementia are present in some cases. In contrast to PD, gross examination of the brain often has distinctive features. Most cases have varying degrees of frontal atrophy that may involve the precentral gyrus. The midbrain, especially the midbrain tectum, and to a lesser extent the pons, shows atrophy. The third ventricle and aqueduct of Sylvius may be dilated. The substantia nigra shows loss of pigment, whereas the locus ceruleus is often better preserved. The subthalamic nucleus is smaller than expected and may have a gray discoloration. The superior cerebellar peduncle and the hilus of the cerebellar dentate nucleus are usually atrophic and have a gray color due to myelinated fiber loss (36). Microscopic findings include neuronal loss, gliosis and NFTs affecting the basal ganglia, diencephalons, and brainstem (Fig. 4). The nuclei most affected are the globus pallidus, subthalamic nucleus, and substantia nigra. The cerebral cortex is relatively spared, but lesions are common in the peri-Rolandic region. Recent studies suggest that cortical pathology may be more widespread in cases of PSP with atypical features, such as dementia (37). The limbic lobe is preserved in PSP. The striatum and thalamus often have some degree of neuronal loss and gliosis, especially the ventral anterior and lateral thalamic nuclei. The basal nucleus of Meyn-

FIGURE 4 Progressive supranuclear palsy: The basal ganglia have neurofibrillary tangles (NFTs) and threads (A) and tufted astrocytes (B) with tau immunostains. There is severe neuronal loss and gliosis in the subthalamic nucleus (C) and many NFTs and glial lesions in the subthalamic nucleus (D). The substantia nigra has neuronal loss and NFTs in pigmented neurons (arrow) (E). The neurons in the substantia nigra have tau-immunoreactive NFTs (F).

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ert usually has mild cell loss. The brainstem regions that are affected include the superior colliculus, periaqueductal gray matter, oculomotor nuclei, locus ceruleus, pontine nuclei, pontine tegmentum, vestibular nuclei, medullary tegmentum, and inferior olives. The cerebellar dentate nucleus is frequently affected and may show grumose degeneration, a type of neuronal degeneration associated with clusters of degenerating presynaptic terminals around dentate neurons (38). The dentatorubrothalamic pathway consistently shows fiber loss. The cerebellar cortex is preserved, but there may be mild Purkinje loss with scattered axonal torpedoes. The spinal cord is often affected, where neuronal inclusions can be found in anterior horn and intermediolateral cells. Silver stains (e.g., Gallyas stain) or immunostaining for tau reveal NFTs in residual neurons in the basal ganglia, diencephalon, brainstem, and spinal cord. In addition to NFTs, special stains demonstrate argyrophilic, tau-positive inclusions in both astrocytes and oligodendrocytes. Tufted astrocytes are increasingly recognized as a characteristic feature of PSP (39) and are commonly found in the motor cortex and striatum (40) (Fig. 4). They are fibrillary lesions within astrocytes based upon double immunolabeling of tau and glial fibrillary acidic protein. Oligodendroglial lesions appear as argyrophilic and tau-positive perinuclear fibers or “coiled bodies,” and they are often accompanied by thread-like processes in the white matter, especially in the diencephalon and cerebellar white matter. NFTs in PSP are composed of 15-nm straight filaments (41). The abnormal filaments in glial cells in PSP also contain straight filaments. Biochemical studies also show differences between tau in AD and PSP. In AD, the abnormal insoluble tau migrates as three major bands (68, 64, and 60 kDa) on Western blots, whereas in PSP, it migrates as two bands (68 and 64 kDa) (42). CORTICOBASAL DEGENERATION Corticobasal degeneration (CBD) is only rarely mistaken for PD due to characteristic focal cortical signs that are the clinical hallmark of this disorder. Common clinical presentations include progressive asymmetrical rigidity and apraxia, progressive aphasia, and progressive frontal lobe dementia (43). Most cases also have some degree of parkinsonism, with bradykinesia, rigidity, and dystonia more common than tremor. Given the prominent cortical findings on clinical evaluations, it is not surprising that gross examination of the brain often reveals focal cortical atrophy. The atrophy may be severe and “knife-edge” in some cases or subtle and hardly noticeable in others and it may be asymmetrical. Atrophy is often most marked in the medial superior frontal gyrus, parasagittal pre and postcentral gyri and the superior parietal lobule. The temporal and occipital lobes are usually preserved. The brainstem does not have gross atrophy as in PSP, but pigment loss is common in the substantia nigra. In contrast to PSP, the superior cerebellar peduncle and the subthalamic nucleus are grossly normal. The cerebral white matter in affected areas is often attenuated and may have a gray discoloration. The corpus callosum is sometimes thinned, the frontal horn of the lateral ventricle is frequently dilated, the caudate head may have flattening, and the thalamus may be smaller than usual. Microscopic examination of atrophic cortical sections shows neuronal loss with superficial spongiosis, gliosis, and usually many achromatic or ballooned neurons (44). Ballooned neurons are swollen and vacuolated neurons found in middle and lower cortical layers. They are variably positive with silver stains and tau immunohistochemistry, but intensely stained with immunohistochemistry for α-B-crystallin, a small heat shock protein, and for neurofilament (Fig. 5).

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FIGURE 5 Corticobasal degeneration (CBD): The hallmark lesion in CBD is the astrocytic plaque (asterix), which is a cluster of irregular tau processes around a central astrocyte (A). The white matter and gray matter in CBD has numerous tau-immunoreactive thread-like processes (B). Cortical neurons have swelling characteristic of ballooning degeneration (C) and the ballooned neurons have intense immunoreactivity with the stress protein α-B-crystallin (D). Neurons in the substantia nigra have round inclusions called corticobasal bodies (arrow in E) that are positive for tau (arrow in F). Note also the many thread-like processes in (F).

Cortical neurons in atrophic areas also have tau-immunoreactive lesions. In some neurons, tau is densely packed into a small inclusion body somewhat reminiscent of a Pick body or a small NFT. In other neurons, the filamentous inclusions are more dispersed and diffuse. As in PSP, neurofibrillary lesions in CBD are not detected well with most diagnostic silver stains and thioflavin fluorescent microscopy. Neurofibrillary lesions in brainstem monoaminergic nuclei, such as the locus ceruleus and substantia nigra, sometimes resemble globose NFTs. In addition to fibrillary lesions in the perikarya of neurons, the neuropil of CBD invariably contains a large number of thread-like tau-immunoreactive processes. They are usually profuse in both gray and white matter, and this latter feature is an important attribute of CBD and a useful feature in differentiating it from other disorders (44). The most characteristic tau-immunoreactive lesion in the cortex in CBD is an annular cluster of short, stubby processes with fuzzy outlines that may be highly suggestive of a neuritic plaque of AD (45) (Fig. 5). In contrast to Alzheimer plaques,

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they do not contain amyloid, but rather tau-positive astrocytes and have been referred to as “astrocytic plaques.” Astrocytic plaques differ from the tufted astrocytes seen in PSP, and the two lesions do not co-exist in the same brain (39). The astrocytic plaque may be the most specific histopathologic lesion of CBD (46). In addition to cortical pathology, deep gray matter is consistently affected in CBD. The globus pallidus and putamen show mild neuronal loss with gliosis. Thalamic nuclei may also be affected. In the basal ganglia, thread-like processes are often extensive, often in the pencil fibers of the striatum. Tau-positive neurons, but not NFTs, are common in the striatum and globus pallidus. The internal capsule and thalamic fasciculus often have many thread-like processes. The subthalamic nucleus usually has a normal neuronal population, but neurons may have tau inclusions, and there may be many thread-like lesions in the nucleus. Fibrillary gliosis typical of PSP is not seen in the subthalamic nucleus in CBD. The substantia nigra usually shows moderate-to-severe neuronal loss with extraneuronal neuromelanin and gliosis. Many of the remaining neurons contain NFTs, which have also been termed “corticobasal bodies” (47) (Fig. 5). The locus ceruleus and raphe nuclei have similar inclusions. In contrast to PSP where neurons in the pontine base almost always have at least a few NFTs, the pontine base is largely free of NFTs in CBD. In contrast, tau inclusions in glia and thread-like lesions are frequent in the pontine base. The cerebellum has mild Purkinje cell loss and axonal torpedoes. There is also mild neuronal loss in the dentate nucleus, but grumose degeneration is much less common than in PSP. In CBD, the filaments have a paired helical appearance at the electron microscopic level, but the diameter is wider and the periodicity is longer than the paired helical filaments of AD (45). These structures have been referred to as twisted ribbons. Similar to PSP, abnormal insoluble tau in CBD migrates as two prominent bands (68 and 64 kDa) on western blots (42). POSTENCEPHALITIC PARKINSONISM Parkinsonism following encephalitis lethargica during the influenza pandemic between 1916 and 1926 is known as postencephalitic parkinsonism (PEP). During the recovery phase of the acute viral encephalitis, parkinsonian rigidity developed with the most characteristic clinical features being oculogyric crises. The PEP brain has NFTs in the cortex, basal ganglia, thalamus, hypothalamus, substantia nigra, brainstem tegmentum, and cerebellar dentate nucleus (48). The distribution of the pathology overlaps with PSP and, in some studies, it has not been possible to distinguish the two disorders by histopathologic analysis alone (48). Biochemical studies of abnormal insoluble tau in PEP have features similar to AD with three major bands (68, 64 and 60 kDa) on western blot studies, and electron microscopy shows paired helical filaments similar to those in AD (49). GUAM PARKINSON-DEMENTIA COMPLEX A characteristic parkinsonism with dementia [Parkinson dementia complex (PDC)] with a number of features that overlap with PSP (50) has been reported in the native Chamorro population of Guam since the 1950s (51). The frequency of PDC is declining in recent years for unknown reasons, and the etiology is unknown. The gross findings in PDC are notable for cortical atrophy affecting frontal and temporal lobes, as well as atrophy of the hippocampus and the tegmentum of the rostral brainstem (52). These areas typically have neuronal loss and gliosis with many NFTs in residual neurons.

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Extracellular NFTs are also numerous. In the cortex, NFTs show a different laminar distribution from AD, with more NFTs in superficial cortical layers in Guam PDC and in lower cortical layers in AD (53). The hippocampus has numerous NFTs. The substantia nigra and locus ceruleus also have marked neuronal loss and many NFTs. The basal nucleus and large neurons in the striatum are also vulnerable to NFTs. Biochemically and morphologically, NFTs in Guam PDC are indistinguishable from those in AD (54). DEMENTIA PUGILISTICA An akinetic-rigid syndrome with dysarthria and dementia is sometimes a long-term outcome of repeated closed-head trauma, as seen in professional boxers. The pathology on gross examination, other than lesions that can be attributed to trauma, for example, subdural membranes and cortical contusions, is nonspecific. The substantia nigra may also show pigment loss. Microscopically, there are NFTs similar to those in AD in the brainstem monoaminergic nuclei, cortex and hippocampus and some cases also have amyloid plaques (55,56). At the electron microscopic level, they are composed of paired helical filaments and biochemically composed of 68, 64, and 60 kDa forms (57). FAMILIAL PARKINSONISM While most parkinsonian disorders are sporadic, rare familial forms have been described and mutations have been found or genetic linkage analyses have suggested a strong genetic factor in their etiology (58). Perhaps the most common cause of early onset familial PD is autosomal recessive juvenile PD (ARJP). The clinical features are somewhat atypical in that dystonia is common in ARJP (59). The pathology of ARJP is based upon only a few autopsy reports. Initial studies emphasized severe neuronal loss in the substantia nigra with no Lewy bodies, but a more recent report of an individual who died prematurely of an automobile accident had Lewy bodies in the substantia nigra and other vulnerable regions (60,61). Even in sporadic PD there is an inverse relationship between the disease duration and the number of Lewy bodies in the substantia nigra. When the disease is very severe, there are very few residual neurons. Since Lewy bodies are intraneuronal inclusions that are phagocytosed after the neuron dies, it is not surprising that there are few Lewy bodies in cases of long duration. Less common than ARJP are autosomal dominant forms of early onset PD. The best characterized is the Contursi kindred, a familial PD due to a mutation in the αsynuclein gene (62). The pathology of the Contursi kindred is typical Lewy body PD; however, given the young age of onset, by the time the individual dies, Lewy body pathology is typically widespread in the brain. Lewy neurites are also prominent in many cortical areas. Some young onset autosomal dominant PD kindreds, such as the Iowa kindred, have atypical clinical presentations and include family members with dementia and psychosis. The Iowa kindred has a multiplication of the αsynuclein gene (63). Families with duplications have a milder phenotype than those with a triplication of the α-synuclein gene, suggesting a role for overexpression of α-synuclein in the pathogenesis of even sporadic PD (64). The pathology in cases with gene triplication is associated with severe Lewy body-related pathology in the cortex, hippocampus, and amygdala, in addition to the substantia nigra and other brainstem nuclei and, in some cases, glial inclusions similar to those found in MSA are present (65) (Fig. 6). Late onset familial PD, such as Family C, has clinical characteristics and pathology that is virtually indistinguishable from sporadic PD (66). This kindred is linked to chromosome 2, but the gene has yet to be discovered.

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FIGURE 6 Familial Parkinson’s disease (PD): Many Lewy bodies are detected in early onset familial cases and some of the inclusions have unusual morphologies (A, B). Like multiple system atrophy, synuclein-immunoreactive glial inclusions are also detected in some cases of familial early onset PD.

The most common cause of autosomal dominant late onset PD is mutation in the LRRK2 gene on chromosome 12 (67,68). The pathology in most cases is characterized by Lewy bodies (69), but in some individuals, other types of pathology, including neurofibrillary pathology or ubiquitin immunoreactive inclusions, are detected (67,70). The genetic influence of LRRK2 to seemingly sporadic PD continues to expand (71–73), with problems in interpretation of genetic results related to the incomplete penetrance of the mutations, reaching more than 80% only after 70 years of age (74). ACKNOWLEDGMENTS Supported by NIH AG16574, AG17216, AG14449, AG03949, NS40256, Mayo Foundation, State of Florida Alzheimer Disease Initiative and the Society for Progressive Supranuclear Palsy. REFERENCES 1. Gibb WR, Lees AJ. Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1991; 54:388–396. 2. Forno LS. Concentric hyalin intraneuronal inclusions of Lewy type in the brains of elderly persons (50 incidental cases): relationship to parkinsonism. J Am Geriatr Soc 1969; 17: 557–575. 3. Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism—a prospective study. Can J Neurol Sci 1991; 18:275–278. 4. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55:181–184.

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Neurochemistry of Nigral Degeneration Jayaraman Rao Department of Neurology, Parkinson’s Disease and Movement Disorders Center, Ochsner Foundation Clinic, New Orleans, Louisiana, U.S.A.

INTRODUCTION Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. Molecular biological studies have suggested that PD may be caused by multiple etiologies. Mutations of several different genes have been identified to be responsible for the different inherited forms of PD. In many of these instances, the clinical, neurochemical, neuropathological, and pharmacological characteristics bear significant similarities to that of idiopathic PD. With some mutations, the patients also exhibit cerebellar and cortical dysfunctions along with the well-established clinical features commonly noted in idiopathic PD (1). Although the inherited forms of PD have provided insights into the pathological process underlying PD, they represent only a small fraction of PD cases. Animal models and epidemiological studies point to the possibility that mitochondrial toxicity induced by environmental toxins could be one cause of PD. One study in a large number of patients who had been exposed to several types of occupational chemicals and pesticides suggested that those patients who have been exposed to pesticides and herbicides had a 70% higher incidence of PD, 10 to 20 years after the original time of exposure, than those who were exposed to most other occupational chemicals (2). Although there may be multiple causes of PD, the most common denominator among experimentally induced animal models of PD, inherited forms of PD as well as idiopathic PD is the profound degeneration of the dopaminergic neurons of substantia nigra pars compacta (SNpc). The striatum contains 80% of all the dopamine in the brain (3,4). The A9 group of dopaminergic neurons, consisting of densely packed cells in the SNpc, and the A10 group located in the ventral tegmental area of Tsai (VTA) are the major source of dopamine in the brain and, more specifically, the basal ganglia (5,6). The VTA and SNpc dopamine neurons have unique neurophysiological and neurochemical properties, as well as a unique pattern of ontogenesis (7). Recognizing the neurochemical and molecular factors that are unique to the ventral tier of the SNpc, the site of maximum degeneration in PD, is crucial to the understanding of the pathogenesis of PD. MELANIZED MIDBRAIN DOPAMINE NEURONS The midbrain dopaminergic neurons are characterized by the presence of neuromelanin. Neuromelanin is distributed mostly in cells that synthesize dopamine, norepinephrine, but not epinephrine, and it is derived from dopamine, dopaquinone, and their oxidized products as well as catecholamines that are not stored in the vesicles (8). Tetrabenazine and reserpine, drugs that block incorporation of dopamine in the presynaptic vesicles, increase accumulation of neuromelanin and over-expression of 209

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vesicular monoamine transporter (VMAT2), which facilitates incorporation of cytoplasmic dopamine into the vesicle, decrease neuromelanin synthesis (8,9). The dopamine neurons of the VTA and SNpc contain cells that are densely melanized and cells that are nonmelanized. In SNpc, 84% to 98% of cells are melanized, and the ratio between the melanized and nonmelanized neurons in the VTA is about 50:50 (10,11). Almost all of the melanized cells in the SNpc and VTA express tyrosine hydroxylase (TH) protein or mRNA (6,11). The melanized cells degenerate more than the nonmelanized cells (6), and accordingly loss of neurons in the VTA in PD is less severe than in the SNpc (11). In PD, 98% of the dopaminergic neurons in nigrosome 1, located in the ventrolateral tier of the SNpc, degenerate early. As the disease worsens, there is a medial and dorsal spatiotemporal pattern of progression of degeneration, ultimately, to include the dopamine cells of the VTA and the retrorubral nucleus (12,13). Even though highly melanized dopamine neurons of the 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 coeruleus (LC) neurons in PD; however, even amidst a densely degenerating group of nigral cells in the ventral and lateral nigrosome regions of the SNpc, pigmented neurons do survive. In the SNpc nigrosomes, 98% of the melanized cells degenerate, whereas, even though almost all LC neurons contain neuromelanin, only about 50% to 63% of melanized cells of the LC degenerate in PD. The most important function of neuromelanin may be to store and regulate iron, copper, zinc, and manganese ions, which play important roles in the normal function of TH and cytochrome a, b, and c within the catecholaminergic neurons (14). Neuromelanin has been proposed to play a neuroprotective role in the normal brain by preferentially sequestering pesticides, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat and other neurotoxins, iron, and other metallic ions for a significant duration, but, when this storage capacity is exceeded, the iron and pesticides may act as neurotoxic factors (8,14,15). VESICULAR MONOAMINE TRANSPORTER AND DOPAMINE TRANSPORTERS IN THE SUBSTANTIA NIGRA PARS COMPACTA 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 and 1-methyl-4-phenylpyridium (MPP+) into the vesicles (16). Dopamine that is not incorporated into the vesicles gets oxidized spontaneously or by monoamine oxidase type A (MAO-A), leading ultimately to the formation of reactive oxygen species that are neurotoxic. 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 (17,18). In concordance with these observations in animals, VMAT2 expression is low in the SNpc and high in the VTA, which corresponds not only to the ratio of melanized to nonmelanized cells in the VTA and SNpc, but also to the loss of an increased number of cells in the SNpc. VMAT2 expression is higher in the VTA than the SNpc and may be an indicator of relatively decreased vulnerability of cell death in the VTA than the SNpc (9,19).

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The dopaminergic synaptic transmission is terminated by the transportation of 95% of synaptic dopamine into the nigrostriatal terminals by the dopamine transporter (DAT) molecule (20). DAT also plays a major role in the neurotoxic effects of MPTP by transporting MPP+, the active mitochondrial toxic metabolite of MPTP, into the dopamine neuron terminals. DAT is an important and a specific marker for dopaminergic neurons (20,21). The intensity of expression of DAT mRNA in primate and human nigra is maximal at the caudal, ventral, and lateral group of dopamine neurons and gradually decreases medially in the VTA regions (19–23), corresponding with the pattern of dopaminergic cells that are highly melanized in the SNpc. 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 level of expression of DAT mRNA in the dopaminergic neurons of the arcuate and paraventricular nuclei of the hypothalamus, a group of dopamine neurons that do not degenerate in PD, is very low (20). In PD, the pattern of loss is directly proportional to the intensity of expression of DAT in these cells. The conclusions are supported by the observations that mice that over-express DAT are more vulnerable to neurotoxic effects of MPTP and DAT knockout mice are completely resistant to the neurotoxic effects of MPTP (24). Heptachlor and pyrethyroid pesticides increase the intensity of expression of DAT, which could lead to the transportation of endogenous and exogenous neurotoxins into the dopaminergic nerve terminals and cause toxic degeneration of SNpc neurons (24). These studies suggest that an increased intensity of expression of DAT in the highly melanized dopamine neurons of the SNpc could be an important factor that contributes to the increased vulnerability to neurotoxin-induced neurodegeneration (25). MIDBRAIN DOPAMINE NEURONS THAT EXPRESS CALCIUM BINDING PROTEINS Calcium binding proteins (CaBPs) are intracellular Ca2+ sensors that bind to Ca2+ and form a Ca2++CabP complex, which facilitate the activation of several enzymes and proteins and play a significant role in neurotransmission and the regulation of transcription factors (26). Among the numerous CaBPs, within the dopaminergic neurons of the midbrain, Calbindin D28K (CB), Calretinin (CR), and Parvalbumin (PV) are the most abundant (27). A significant number of CB-immunoreactive neurons have been noted in both VTA and SNpc neurons. CB-positive neurons immunostain for TH, suggesting that the CB-immunoreactive neurons in the VTA and SNpc are dopaminergic. The CBpositive neurons are located mostly in the dorsal tier of the SNpc. The TH-positive neurons of the ventral tier of the SNpc lack CB-immunoreactivity (27–31). CR is closely related to CB and has significant similarities in the homology of the amino acid sequence (32,33). CR-immunoreactive neurons are much less frequently observed in the entire brain. Approximately 50% of CR-immunoreactive cells in the SN/VTA complex also display TH-immunoreactivity (34,35). Within the midbrain, CR-immunoreactive cell bodies are more numerous in all the subdivisions of dopamine neurons of the VTA than in the SNpc. Within the SNpc, the CR-positive cells are more abundant in the dorsal tier of the SNpc than substantia nigra pars reticulate (SNpr) or substantia nigra pars lateralis (SNpl). The distribution pattern of PV-immunoreactive neurons in the ventral midbrain is distinctly different from the pattern of CB- and CR-immunoreactive neurons. PV-immunoreactive neurons are prominently absent in the dopaminergic neurons

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of the VTA and SNpc, but are expressed specifically in the gamma amino butyric acid (GABA)ergic nigrothalamic and nigrotectal neurons of the SNpr. The PV-positive neurons in the SNpr degenerate in progressive supranuclear palsy, but not in animal models of PD or idiopathic PD. Administration of 6-hydroxydopamine (6-OHDA) and MPTP results in degeneration of the CB-negative TH-positive neurons in the SNpc, but not the TH- and CBpositive neurons in the dorsal tier of the SNpc (36,37). Similar to these animal models, in human PD, the CB- and CR-positive neurons in the dorsal tier of the SNpc are preserved, whereas the CB- and CR-negative ventral tier neurons of the SNpc degenerate significantly (37–39). Although these studies in animals and humans suggest that the ventral tier of the SNpc dopamine neurons are more vulnerable to degeneration because of a lack of expression in CB, and that the VTA neurons are preserved because CB is coexpressed with TH in these neurons, the precise mechanisms of action of CaBPs in their presumed neuroprotective role have not been established. Studies in CB null mutant mice, CB null mutant weaver mice (40), as well as in anoxic models of neuronal loss in the hippocampus (41) suggest that CB may not be required for neuroprotection. MITOCHONDRIAL DNA MUTATIONS IN SUBSTANTIA NIGRA PARS COMPACTA Mitochondria’s own DNA (mtDNA), consisting of 16.6 kb of double strands of DNA organized in a circle, is located in the matrix compartment of the mitochondria. The mtDNA codes for 37 proteins—13 of the oxidative phosphorylation (OXPHOS) system, 22 tRNAs, and 2 rRNAs. Besides the regions coding the proteins of the OXPHOS system, the mtDNA also consists of a “noncoding region” (also called the hypervariable region, control region, or the D-loop), which is responsible for mitochondrial maintenance and mitochondrial replication. The nucleotide sequence in this control region also controls RNA and DNA synthesis. The nuclear DNA (nDNA) is also responsible for the synthesis of several other proteins that contribute to normal functions of the OXPHOS system. These polypeptides are synthesized in the cytoplasm and tagged to be transported specifically into the mitochondria, and the proteins are subsequently reassembled to form the OXPHOS system (42). Mutations of both mtDNA and nDNA, encoding for the proteins of the mitochondria, have been reported to cause neurological disorders (33,43,44). Since mtDNA is recycled more than the nDNA, mtDNA mutations are about 10 times higher than the nDNA. The mtDNA mutations appear to start at the age of 45 to 55 years and gradually increase in frequency (45). The high level of mtDNA mutations associated with aging has been proposed to be due to damage to mtDNA caused by life-long production of free radicals in the mitochondria (46). The role of mtDNA mutations in aging and neurodegenerative disorders was brought to attention by the study of the distribution of pattern I of mtDNA in different parts of the brain. These studies showed that the most common mutation of mtDNA, deletion of 4977 bp, was found in several nuclei of the brain and was higher with aging. A higher level of this mutation was found in the neurons of the cerebral cortex and putamen, but not in the cerebellum in aging brains (47). This mutation is noted in PD brains (48–50) and platelets (51) and does not appear to cause the disease but may be responsible for susceptibility to PD (52) and may be age-related (53).

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In PD, mtDNA mutations are higher than age-matched controls in the dopamine neurons of the SN (54). The mtDNA mutations are significantly higher in the substantia nigra than any other regions of the brain and are more common in PD than in the brains of persons with Alzheimer’s disease, multiple system atrophy, and diffuse Lewy body disease, as well as age-matched controls (55). The increased level of mtDNA mutations has been proposed to be due to an increased level of oxidative stress in the SNpc neurons. With aging, immunostaining for COX (cytochrome c or complex IV), an enzyme that has a significant role in cellular respiration, decreases significantly in the melanin positive neurons of the SN (56). The level of mtDNA mutations are higher in the COX-negative dopamine neurons of the SN than in the COX-positive neurons, raising the possibility that mtDNA mutations might contribute to the decrease in COX activity (45). The precise role played by these mtDNA mutations in the degenerative process of SN cells remains to be established. It is unclear whether they cause death directly or play a role in the aging process of the SN, increasing vulnerability to other factors that cause SN apoptosis. TRANSCRIPTION FACTOR PITX3 Yet another clue to the factor(s) that render the dopamine neurons of the SNpc vulnerable to neurodegeneration in PD is obtained from the studies on the role of the transcription factor Pitx3 in aphakic mice. Aphakic mice have small eyes with no lens and a loss of development of the anterior chamber of the eye (57,58). The clinical features of the aphakic mice result from a deletion of a large segment of the promotor region, exon 1, and intron regions of the Pitx3 gene (58). In addition to the ophthalmic dysgenesis, aphakic mice exhibit degeneration of dopamine neurons of the SNpc cells during development. Pitx3 expression is localized to TH-immunoreactivity. Pitx3 is necessary for the expression of TH as well as continued maintenance of TH expression, even during the rest of the life of midbrain dopamine neurons. Accordingly, Pitx3 is expressed during ontogenesis of dopamine neurons as well as throughout the rest of the life of the midbrain dopamine neurons in rodents and humans (59). The dopamine neurons that express Pitx3 also express the neuroprotective calcium binding protein calbindin. The number of Pitx + calbindin cells is much higher in the VTA (43%) than in the SNpc (16%). The level of Pitx3 mRNA is six times higher in the VTA neurons than in the SNpc and that of Calbindin is four times higher in the VTA than the SNpc. Within the SNpc, 84% of the cells that express Pitx3 are CB negative (60). Even though Pitx3 is expressed in all of the dopamine neurons of the midbrain during ontogenesis, the SNpc neurons degenerate significantly and selectively and the mesostriatal pathway terminating in the dorsolateral striatum also degenerates. The dopaminergic neurons of the VTA and their connectivity to the limbic striatum remain intact (61–64). With a profound loss of dopaminergic neurons of the SNpc, the levels of dopamine in the dorsal motor striatum are reduced to 10% of the level noted in the wild type (62). These aphakic mice demonstrate slow movements and shorter steps as in human PD (63,65,66), and these motor difficulties are easily reversed by the administration of levodopa (65,66). The intensity of expression of Pitx3 in 6-OHDA-induced PD in animals and in human mesencephalic dopamine neurons is significantly low (59). The neurochemical changes noted in the mesencephalic dopamine neurons of the aphakic mice have several similarities to the neuropathology that is noted in

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human PD. In both conditions, there is a significant and preferential loss of dopamine neurons of the SNpc; the level of expression of Pitx3 in the SNpc neurons is very low; the degenerating neurons are mostly CB negative neurons; and a greater than 80% loss of dopamine in the dorsolateral sensory-motor striatum leads to significant bradykinesia that is easily reversed by levodopa. The combined effects of a lower number of SNpc dopamine neurons expressing very low levels of Pitx3 and calbindin may be a factor in the increased vulnerability of SNpc neurons to neurodegeneration. UNCOUPLING PROTEINS Yet another clue toward the selective vulnerability of dopaminergic neurons in PD, especially the dopamine neurons of the SNpc more than the VTA neurons, is derived from the role played by uncoupling proteins (UCPs) in thermogenesis and obesity (67–71). UCPs are localized in the inner membrane of the mitochondria and promote a “leak” of protons from the intermembrane space back into the matrix region of the mitochondria and may have a neuroprotective role by decreasing excess of reactive oxygen species (ROS) in the mitochondria (68,69). Five different UCPs (UCP1 to UCP5) have been identified (67). Of these, UCP1 (thermogenin), the most wellstudied protein, is localized almost exclusively in the brown adipose tissue and UCP3 in skeletal and cardiac muscles play a major role in thermogenesis. UCP2, UCP4, and UCP5 are abundant in the brain. The distribution and role of UCP2 is better understood than for UCP4 or UCP5. The distribution pattern of mRNA for UCP4 and UCP5 in the brain remains to be studied. The mRNA for UCP2 is prominently localized to neurons of the hypothalamic system and within the basal ganglia (72). UCP2 is localized to both the VTA and SNpc dopaminergic neurons. The intensity of expression of UCP2, as studied by realtime PCR in weaver mutant mice, is three times higher in the VTA dopamine neurons than the more laterally placed dopamine neurons of the SNpc (73). In MPTP models of PD in mice, over expression of UCP2 protects the midbrain dopaminergic neurons from MPTP-induced neurotoxic death and mutations of UCP2 (73,74). UCP5 knockdown mice have an increased sensitivity to MPTP-induced dopaminergic neuronal loss (75). The lower level of expression of UCP2 in the SNpc when compared to the VTA neurons might account for an increased vulnerability of the SNpc to neurodegeneration. GIRK2 MUTATION Phenotypically, the weaver mouse exhibits profound ataxia resulting from a near total loss of granule cells in the cerebellum (76–78); tremor resulting from a 70% loss of dopamine in the dorsolateral striatum due to selective degeneration of dopamine neurons of the SNpc (79); male infertility due to degeneration of Sertoli and spermatogenic cells (80); and seizures possibly due to hippocampal abnormalities and hypothyroidism (81,82). An A153G point mutation, in the pore forming the H5 region of a G-proteincoupled inwardly rectifying potassium channel gene (GIRK2), has been proposed to be responsible for the weaver phenotype (83–85). The GIRK2 mutation alters the gating specificity of the GIRK2 channel, leading to a loss of ion selectivity of the GIRK2

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channel, allowing entry of calcium and sodium as well as outflow of potassium and G-protein sensitivity of the GIRK2 channel (84–86). GIRK2-immunoreactivity is densely in the external granule cell layer of the cerebellum in weaver mutant mice (87–89). Cerebellar degeneration is the most prominent pathology noted in the brain of the weaver mutant mice. The precursors of cerebellar granule cells proliferate normally in the external germinal layer, but fail to complete differentiation, and degenerate even before interacting with the Bergman glial cells and migrate into the internal granule cell layer (76–78,90). The Purkinje cells and neurons of the deep cerebellar nuclei, especially of the midline cerebellar nuclei, also demonstrate degenerative changes in homozygous weavers (91,92). In weaver mutant mice brains, the midbrain dopamine neurons, unlike the cerebellar granule cells, differentiate, migrate to the ventral mesencephalon, and extend their axons to the striatum. The weaver mutant mice have a normal number of dopamine neurons in the ventral mesencephalon at the time of birth, but significant degeneration of these neurons starts on postnatal day 1, and at least 50% of the neurons are lost by postnatal day 20 (93,94). The gene defect results in degeneration of neurons that are generated mostly after embryonic day 12 and the dopamine neurons in the SNpc that survive have CB colocalized (93). Among the different slicing variants of the Kir3.2, the dopamine neurons of the SNpc in rats are made of heteromeric assemblies of only Kir3.2a and Kir3.2c (95). Within the three dopamine-containing cell groups in the midbrain, the strongest GIRK2-immunoreactivity is seen in the SNpc. GIRK2-immunoreactive dopamine neurons are less prominent in the SNpl (96–98). Among the five different subdivisions of the VTA dopamine neurons, GIRK2 immunoreactivity is virtually absent in the TH-positive neurons of the rostral linear, caudal linear, and interfascicular nucleus (99,100). Only a few neurons of the nucleus parabrachialis pigmentosus and paranigralis coexpress TH and GIRK2. This pattern of GIRK2 distribution in the ventral midbrain coincides with the pattern of degeneration and sparing of dopamine neurons of the midbrain in weaver mutant mice. In the weaver mouse, among the mesencephalic dopamine neurons, the dopamine neurons of the SNpc are predominantly destroyed and the more laterally placed neurons in the SNpl and the VTA are mostly spared (96). Corresponding with the loss of dopamine neurons in SNpc regions within the striatum, the activity of TH, level of dopamine, dopamine uptake, as well as the activity of DAT is decreased significantly (101). The severity of the loss of TH-activity and dopamine content in the striatum is about 40% postnatal three to five days and about 70% in the adult weaver mutant mice (102–104). The decrease in the level of dopamine is observed selectively in the dorsal sensory-motor striatum, but not in the ventral limbic striatum (105). The pattern of degeneration of the mesencephalic dopamine neurons and loss of dopamine levels in the dorsal sensory-motor striatum in weaver mice bears significant similarities to the pattern of degeneration of midbrain dopamine neurons in human PD, as well as 6-OHDA-, MPTP-, and rotenone-induced animal models of PD. The weaver pathology points out the possibility that dysfunction of the GIRK2 channel may contribute to the selective vulnerability of the SNpc to degenerate early. Whether the gene defect of the GIRK2 mutation noted in weaver mice is the direct cause of neuronal degeneration has been a point of debate (106). The possibility that the degenerative effects of GIRK2 mutations may be mediated by dysfunction of

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adenosine triphosphate sensitive postassium (K-ATP) channels has been proposed (107). A study in a small number of familial as well as sporadic cases of PD did not find any mutation of the pore forming the H5 region of the GIRK2, inwardly rectifying K+ channel (108). ACTIVATION OF ADENOSINE TRIPHOSPHATE SENSITIVE POSTASSIUM (K-ATP) CHANNELS Among the different types of K+ channels (109,110) and varieties of the inward rectifier potassium channel family (111), activation of a specific subtype of inwardly rectifying K-ATP channel in the dopaminergic neurons of the SNpc has been suggested to contribute to the selective vulnerability to degeneration of SNpc dopamine neurons rather than the VTA neurons (112). K-ATP channels play a very important role as a sensor that link cellular metabolism to electrical activity of the cell. K-ATP channels are distributed in the muscle, brain, and pancreas (113). Pancreatic K-ATP channels play a role in insulin secretion and functional disruption of K-ATP channels due to mutations of the subunits or other causes have been shown to be responsible for either hypersecretion of insulin or inducing diabetes (114–118). K-ATP channels are made of two different proteins, namely the ion pore forming subunit Kir6.2 and the regulatory sulfonylurea receptor (SUR1) subunit. Kir6.2 has two transmembrane domains and consists of an ATP-binding region. The SUR1 subunit has two six-helix transmembrane domains, consisting of a site that has a high affinity to bind to sulfonylurea, the antidiabetic drug, and Mg++. Four of Kir6.2 and four of SUR1 form the K-ATP channel. The architecture of K-ATP channels has similarities to that of K-ATP channels in the pancreas (114). The mRNA for Kir6.2 is distributed widely in the brain, but very densely in the ventromedial and the paraventricular nuclei of the hypothalamus and also with moderate intensity in the mesencephalic dopamine neurons. K-ATP channels are expressed in all the mesencephalic dopamine neurons and play a significant role in the excitability and the distinctive electrophysiological properties of VTA and SNpc dopamine neurons (112). Among the SUR subunits, SUR1 mRNA is found in dopamine neurons of both VTA and SNpc, but SUR2B is found in less than 5% of dopamine neurons suggesting that SUR1 plays a major role in these mesencephalic dopamine neurons (73,112). The level of SUR1 mRNA expression in SNpc dopamine neurons is two-fold higher than that of the VTA dopamine neurons. Although the majority of the dopamine neurons of the midbrain express SUR1 mRNA, TH-positive SUR1 negative neurons are about 36% in the SNpc and 41% in the VTA (73). MPP+ and rotenone inhibit complex I of the electron transport chain throughout the brain and, possibly, in all tissues of the body; however, the various molecular factors that contribute to the selective vulnerability of dopamine neurons of the SNpc to neurodegeneration but not the VTA dopamine neurons are unknown. Among the mesencephalic dopamine neurons, the TH- and SUR1immunoreactive neurons of the SNpc appear to be specifically sensitive to the neurotoxins MPP+ and rotenone. MPP+ and rotenone models of PD in mice demonstrate that the K-ATP channels of the SNpc but not the VTA are selectively activated. MPP+ and rotenone induce complex I inhibition, increase production of ROS, decrease levels of ATP, and increase oxidative stress and dysfunction of the ubiquitin–proteasomal system (UPS). Complex I inhibition alone as well as decreased ATP levels and oxidative stress can activate K-ATP channel selectively. MPTP- and rotenone-

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induced neurotoxicity requires the presence of active K-ATP channels, since genetic inactivation of the Kir6.2 subunit of the K-ATP channels protects the SNpc neurons from degeneration in chronic MPTP models of PD in mice, as well as in weaver mutants (73,107,112). Preferential activation of the K-ATP channels in the SNpc dopamine neurons and not the K-ATP channels of the VTA dopamine neurons may be a factor that is responsible for the early degeneration of the SNpc dopamine but not the VTA dopamine neurons. The presence of functioning K-ATP channels along with preferential uncoupling of mitochondria due to decreased levels of expression of UCP2 in the SNpc but not in the VTA may contribute to the selective vulnerability of SNpc dopamine neurons to neurodegeneration (73). CONCLUSION The pathognomonic feature of idiopathic PD is the progressive degeneration of the dopaminergic neurons of the SNpc. The SNpc dopaminergic neurons degenerate early and more profoundly than any other melanin and nonmelanin containing neurons of the brain. The molecular characteristics of the SNpc dopamine neurons that make them more vulnerable to degeneration than the dopaminergic neurons of the VTA are that these cells: ■ ■

■ ■ ■ ■ ■ ■

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are highly melanized; do not express calcium binding proteins, especially calbindin DK28 or calretinin; express low levels of VMAT2 mRNA; express high levels of DAT mRNA and protein;, undergo increased mitochondrial stress; contain very high levels of mtDNA mutation; express low levels of the transcription factor Pitx3 or Pitx3 is absent; express low levels of UCP2, the protein that under normal conditions prevents excessive production of ROS in the mitochondria; express a specific subtype of GIRK2 type of inward rectifying K channel receptor; express a specific subtype of K-ATP channel that is activated.

The molecular and neurochemical factors that are unique to the dopamine neurons of the SNpc may either increase the susceptibility for PD or increase the vulnerability of these neurons to the neurotoxic effects of low-dose chronic exposure to either endogenous or exogenous neurotoxins. ACKNOWLEDGMENT Supported by The Grace and Tom Benson Parkinson’s disease research fund. REFERENCES 1. Bertoli-Avella AM, Oostra BA, Heutnik P. Chasing genes in Alzheimer’s and Parkinson’s disease. Hum Genet 2004; 114:413–438. 2. Ascherio A, Chen H, Weisskopf MG, et al. Pesticide exposure and risk for Parkinson’s disease. Ann Neurol 2006; 60:197–203. 3. Sano I, Gamo T, Kakimoto Y, Taniguchi K, Takesada M, Nishinuma K. Distribution of catechol compounds in human brain. Biochim Biophys Acta 1959; 32:586–587.

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Neurophysiology and Neurocircuitry Erwin B. Montgomery Department of Neurology, National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A.

John T. Gale Department of Neurosurgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, U.S.A.

INTRODUCTION In this era of incredible advances in molecular neurobiology, the understanding of the functional circuitry or physiology of the basal ganglia may seem quaint. Advances in the understanding of the molecular pathogenesis of Parkinson’s disease (PD) give hope that progressive neurodegeneration may be slowed, stopped, or even prevented. As long as there are patients disabled by symptoms, restoring the physiology is important, especially with the aging of the population and the increasing prevalence of those suffering from the disease. Although the resurgence of functional stereotactic surgery, both ablative and utilizing deep brain stimulaton (DBS), was fueled by improvement in surgical techniques such as image-based and microelectrode navigation, a justifying rationale based on better understanding of neuronal pathophysiology is important (1). Indeed, current theories of basal ganglia physiology and pathophysiology have been used to rationalize gene therapies in humans that target reversal of the excitatory output of the subthalamic nucleus (STN) (2). Current theories of basal ganglia function and dysfunction were largely inferred from the anatomical neurochemistry and behavioral/clinical pharmacology. However, such inferences at the least are incomplete and at the worst potentially misleading. There is no one-to-one correspondence between mechanisms of pathophysiology and pharmacology (3). The distinction is evident in the effectiveness of DBS when pharmacological manipulations (4) and even brain transplantation failed (5,6). The failures of fetal dopamine cell transplantation, particularly the occurrence of “runaway” dyskinesia (6), stress the importance of addressing the physiological controls on neuronal function. The effectiveness of DBS in the face of pharmacological failures, of which fetal cell transplantation is a variant, suggests that DBS addresses physiological mechanisms that are distinct from pharmacological issues. Theories of the role of the basal ganglia within the functional circuitry of the basal ganglia-thalamic-cortical system are entering a state of flux (3). Current theories, although of heuristic value in explaining many observations, are now inconsistent with an expanding body of knowledge. However, the basic observations upon which the current theories were built essentially are correct. If many of the basic observations underlying current theories are correct, then the failure of the supervening theories must lay elsewhere, perhaps in certain assumptions that link and extend the observations into the current theories. Failure of these assumptions will mean that fundamental conceptual changes will be necessary (3). Most likely, those observations supportive of current theories will be found to be special cases of a larger new theory or epiphenomenal consequences of methodological differences. 223

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This chapter reviews the anatomy of the basal ganglia and its connections with the thalamus and cortex. Then, the current theories of basal ganglia physiology and pathophysiology are reviewed, as well as their limitations. However, even more critical will be the review of why these theories developed as they did, as well as the fact that they do not and cannot address the time scale at which physiological functions occur, because they are extrapolations from anatomy and neurochemistry rather than physiology (3). Finally, the review will present an alternative model for physiological function based on neuronal oscillations. Examining the time course by which neurons are influenced by and influence other neurons results in a dramatically different conception of basal ganglia physiology (7). In fact, this reconceptualization demonstrates that the basal ganglia are not a sequential chain of nuclei that subserve different roles in processing physiological information, but rather a member of an extended system (e.g., basal ganglia-thalamiccortical system) where physiological function is represented as the activity of the whole network. Further, the inhibitory versus excitatory influence, for example, the globus pallidus internal segment (GPi) on the ventrolateral (VL) thalamus, should not be discussed without considering the time course and synchronization of activities on a scale where anatomy and pharmacology cannot provide insights. ANATOMY: THE BASICS FOR CIRCUITRY This section reviews the basic anatomical interconnections between neurons that make up the basal ganglia–thalamic–cortical circuits. The anatomy is discussed only to a level of detail necessary for conceptual understanding of current models of function and dysfunction and for possible futures theories. This section will neither cover a fine-grained analysis of interconnections nor the histology [for reviews see Refs. (8–12)]. Traditional approaches to the anatomy of the basal ganglia have been divided into input, output, and intermediary stages. This approach belies the key fundamental assumptions of current theories, because demarcation of input and output structures necessarily suggests a sequential and hierarchical organization (13), which are misleading from a physiological perspective (7). Rather, the anatomy can be reconsidered and viewed as a re-entrant circuit or closed loop. Just as it is hard to say where a circle starts and an arbitrary starting point must be selected, this description will begin with the striatum that is made up of the caudate nucleus and the putamen. The major sources of input to the striatum are glutaminergic projections from the cerebral cortex and thalamus. Virtually, the entire cortex projects to the striatum in a topographic fashion. The frontal cortex projects to the head of the caudate and anterior putamen, the motor and somatosensory cortices project to the postcommissural putamen, and the temporal cortex projects to the tail of the caudate. The cortex also projects directly to the STN. Inputs from the thalamus include projections from the centromedian, parafascicular, and VL thalamus. The substantia nigra pars compacta (SNpc) sends dopaminergic projections to the striatum. The striatum projects to the globus pallidus external segment (GPe), Gpi, and substantia nigra pars reticulata (SNr). There appears to be two separate groups of striatal neurons based on projection targets and neurotransmitters. All outputs from the striatum utilize gamma amino butyric acid (GABA) but differ in the polypeptide cotransmitter. Striatal neurons projecting to the GPe express enkephalin and have

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predominantly D2 receptors. Whereas striatal neurons projecting to GPi express substance P and dynorphin and have predominantly D1 receptors (14). The GPe has inhibitory GABAergic projections to the STN and GPi. The STN has excitatory glutamatergic projections to the GPi and SNr and back to GPe. The GPi has GABAergic outputs to the VL and ventroanterior (VA) nuclei of the thalamus, which then have extensive glutaminergic projections back to the cerebral cortex. In addition, the GPi projects to the pedunculopontine nucleus (PPN) in the brainstem. The PPN has received considerable attention, particularly as it relates to gait and balance. Injections of bicucullin, a GABA antagonist, into the PPN alleviates symptoms of experimental parkinsonism induced by administration of n-methyl-4phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) in nonhuman primates (15). There are case reports suggesting that DBS of the PPN may be helpful in PD, particularly for gait and postural abnormalities (16). The SNr has GABAergic projections to the superior colliculi and are thought to be involved in eye movements. The basic architecture is replicated for a number of different functional systems. For example, a network involving projections from the limbic cortex through the basal ganglia and back to the limbic cortex may serve emotional functions. Networks involving the orbital frontal cortex and the basal ganglia may involve cognitive functions. These different networks may be important for nonmotor symptoms of PD. As the motor symptoms increasingly are improved with current therapies, attention is shifting to the nonmotor symptoms. CURRENT CONCEPTS OF PARKINSON’S DISEASE PATHOPHYSIOLOGY The anatomical/neurochemical circuits have been conceptualized by current theories of physiology and pathophysiology, into direct, indirect and hyper-direct pathways (17–19). The direct pathway includes the striatum to the GPi to the VL thalamus, and finally to the motor cortex (MC) and supplementary motor area (SMA). The indirect pathway includes the striatum to the GPe to the STN, the striatum to the GPi to the VL thalamus, and then to the MC and SMA. The hyper-direct pathway involves projections from the cortex to the STN, to the GPi, to the VL, and then to the MC. Connections from the GPe to the GPi (9) and from the VL thalamus to the putamen (20) have now been recognized. SNpc dopamine neurons are excitatory on striatal neurons in the indirect pathway and inhibitory on striatal neurons in the direct pathway. Globus Pallidus Internal Segment Suppression Theory This theory posits that the loss of SNpc dopamine neurons causes decreased activity in the striatal neurons of the direct pathway. This results in a reduction of inhibition of GPi neurons, which in turn results in increased inhibition of the VL thalamus and a reduction of excitation of the MC and SMA, thus providing an explanation of loss and slowing of movements (Fig. 1). Loss of SNpc dopaminergic drive to striatal neurons of the indirect pathway results in decreased inhibition of these striatal neurons, which in turn increases inhibition of the GPe. Consequent decreased activity in the GPe reduces inhibition of and increases activity in the STN. The increased activity of the STN further increases activity in the GPi (Fig. 1). There is considerable empiric evidence in support of this model. Direct evidence comes from microelectrode recordings in nonhuman primates before and after

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FIGURE 1 Schematic representation of the basal ganglia-thalamic-cortical circuits. There are two general pathways termed the direct and indirect pathways. The direct pathway goes from the putamen directly to globus pallidus internal segment (GPi), whereas the indirect pathway goes through the globus pallidus external segment and subthalamic nucleus (STN) before reaching the GPi.These two pathways also differ by the effect of dopaminergic inputs from the substantia nigra pars compacta. The dopaminergic input is inhibitory on the putamen neurons in the indirect pathway and excitatory on those putamen neurons in the direct pathway. The figure on the left shows the normal circumstance and the figure on the right shows the consequence of dopamine depletion (represented by the broken arrows) such as occurs in Parkinson’s disease according to current theories. The net result is reduction of inhibition, represented by the thinner arrows, and an increase in excitatory input, represented by the thicker arrow, onto the GPi with increased inhibition of the ventrolateral thalamus. Not shown are the hyper-direct pathways of cortical projections onto the STN or the connections of the pedunculopontine nucleus.

the induction of experimental parkinsonism by the administration of MPTP, which selectively degenerates dopaminergic neurons (21). Some studies have demonstrated the predicted increases in GPi and STN neuronal activities, following experimental parkinsonism. Other studies in MPTP-treated animals have shown no significant changes in baseline neuronal activity of either the striatum, GPe, VL thalamus, or MC; although they were clearly parkinsonian, as evidenced by bradykinesia and changes in regional 2-deoxyglucose utilization typical of parkinsonian nonhuman primates (22). Filion and Tremblay (23) demonstrated that GPi neurons increased activity after MPTP, but the level of neuronal activity returned to baseline within a few weeks. It is interesting that Filion et al. (24,25) demonstrated no change in GPi-discharge rate with alternative methods of producing parkinsonism, such as electrolytic lesions and administration of dopamine antagonists. They discounted much of their previous data writing, “such changes in firing rates were not observed in our previous study of monkeys rendered parkinsonian by electrolytic midbrain lesions. Therefore our previous partial or unilateral electrolytic lesions of the nigrostriatal pathway may have been insufficient to alter the firing rates” (25). The lesions were, however, sufficient to produce parkinsonism. Microelectrode recordings in the STN of PD patients also do not have higher discharge rates than in epilepsy patients undergoing DBS (26). This is evidence that overactivity of the STN via the indirect pathway is not a necessary condition for

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parkinsonism. Other studies showed that GPi activity is not different in patients with Huntington’s disease (27) or dystonia (28). Studies of DBS demonstrate that both GPi and STN DBS drive the output of the GPi to high rates and, yet, DBS improves the symptoms of PD (29–31). One conclusion is that altered firing rates are neither necessary to produce parkinsonism nor are they sufficient. This model also has been criticized on a number of grounds, primarily anatomical and clinical (12,32). Basal Ganglia Selection Theory This theory posits that the basal ganglia are involved in the selection of motor programs. Bradykinesia and akinesia of PD results in the failure to select or engage appropriate motor programs, whereas levodopa-induced dyskinesia and other hyperkinetic disorders of the basal ganglia fail to suppress inappropriate motor programs (33). The genesis of this theory lies in the observations that most all interactions between nuclei of the basal ganglia are inhibitory with the exception of the output of the STN. Also, supporting the basal ganglia selection theory are the apparent observations that bradykinesia/akinesia appear to be reciprocally related to levodopa-induced hyperkinesia, suggesting reciprocally related dysfunctions and, by extension, reciprocally related functions. Finally, it is possible that widely recognized center-surround antagonistic receptive fields in sensory physiology could have inspired the basal ganglia selection theory. There are a number of problems with the basal ganglia selection theory. First, bradykinesia/akinesia and hyperkinesia are not reciprocal. Indeed, patients with PD can have hyperkinesia simultaneous with bradykinesia. Also, patient’s with Huntington’s disease manifest both hyperkinesia and bradykinesia (34). This argues against a common set of mechanisms and its reciprocals, such as abnormalities of motor program selection and engagement. Another significant problem with the basal ganglia selection theory is that it suggests that the brain has a library of possible motor programs and that the basal ganglia act as a librarian to pick and choose among the motor programs. However, there is no evidence that there are motor programs as separate engrams residing in the brain. No stimulation experiments have been able to elicit reproducible and separate motor responses. Striatal stimulation studies in freely moving laboratory animals resulted in either movement arrest or stereotypic flexion movements (35–38). Rather, representation of physiological function is dynamic and changing. For example, neurons in the motor cortex responding to a go signal in one task may be preferentially related to muscle activation in other task (39). Similar findings have been demonstrated with putamen neurons in the nonhuman primate (40). Other studies demonstrate that movement generation is not a unitary process from which one of a number of alternatives can be selected. Motor initiation is separate from motor execution (41). Finally, although the large majority of interconnections between nuclei of the basal ganglia are inhibitory, microelectrode recordings of neuronal activity consistently demonstrate that the large majority of MC, VL (42), and GPi (43,44) neurons increase their activities with behaviors. This would suggest that inhibition, which is a key feature of the basal ganglia suppression and basal ganglia selection theories, plays a relatively minor role. In addition, there is evidence that there is more than meets the eye with inhibitory inputs. For example, there is considerable evidence that inhibition is followed by rebound increased excitability (31,45,46). In a study of human VL thalamic neurons responding to GPi DBS, all of the neurons demonstrated an inhibition with a latency of approximately 3 ms and duration of approximately 3 ms,

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FIGURE 2 Poststimulation rasters and histograms of two ventrolateral thalamic neurons recorded in a human, undergoing globus pallidus internal segment (GPi) deep brain stimulation (DBS). In the raster displays, a DBS pulse occurs at time zero. Each row represents the interstimulus interval between successive DBS pulses.There is an initial highly consistent response at approximately 1 ms, which corresponds to antidromic activation. This is followed by normal baseline activity and then, at approximately 3.4 ms, there is an inhibition of activity consistent with activation of GPi inhibitory effects.The inhibition lasts approximately 2 ms.There is a return to baseline activity for approximately 2 ms followed by an increase in activity consistent with postinhibitory rebound increased excitability. The histograms represent the average neuronal activities following DBS pulses.The histograms have been normalized to represent the z-score changes from the prestimulation baseline. Thus, a z score of 1.96 represents an activity level that is 2 standard deviations above the mean discharge rate during the prestimulation baseline. Source: From Ref. 31.

consistent with activation of inhibitory inputs from GPi to VL thalamus (31). However, 24% of the VL neurons demonstrated a significant increase in neuronal activity, following the period of inhibition (Fig. 2). This percentage probably represents an underestimate of the number of neurons demonstrating postinhibitory rebound increased excitability by not detecting those neurons with rebound increased excitability below the threshold needed to generate extracellular action potentials detectable by microelectrode recordings. The Basal Ganglia-Thalamic-Cortical System as Nested Nonlinear Reentrant Oscillators in a Loosely Coupled Network (Oscillator Theory) One could view the basal ganglia-thalamic-cortical system as a set of nested oscillators, as shown in Figure 3. The dynamics of such a configuration and the alternations associated with PD comprise an alternative theory termed the oscillatory theory (7). This theory posits the basal ganglia-thalamic-cortical system to be organized as a large set of nested oscillators loosely coupled in a network. Within each set of nested oscillators, individual oscillators are made up of different combinations of neurons within the anatomical nuclei. Because different oscillators have different numbers of nodes, neuronal activities within these oscillators have different fundamental frequencies. Given combined conduction velocities and synaptic delays on the order of 3 to 4 ms, the oscillator frequencies can range from up to approximately 130 Hz. However, no neuron in the basal ganglia-thalamic-cortical system has a sustained frequency of 130 Hz. To explain this, the oscillator theory holds that each neuron within a node does not discharge with each cycle of the oscillation but rather at some fraction of cycles.

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Thus, individual neurons in a node act as rate dividers. The combined activities of all neurons in a node are sufficient to ensure that oscillations continue. According to the oscillator theory, physiological function is represented within specific basal ganglia-thalamic-cortical circuits and not within specific structures. For example, neurons that respond preferentially to the appearance of a go signal can be found in all the structures within the basal ganglia-thalamic-cortical circuit and, further, the timing of activity for these neurons is approximately the same (within the 10 ms time resolution of the studies) in the MC and putamen (47). The parallel and distributed nature of physiological function within the basal gangliathalamic-cortical system also explains why lesions in multiple structures within the basal ganglia-thalamic-cortical system, including the GPe, SMA, VL, and putamen, can produce parkinsonism (48–52) and why DBS of the GPi (4), MC (53), VL (54), GPe (55), and STN (4) can all improve the symptoms of PD. The oscillator theory’s corollary of parallel and distributed processing should not be misinterpreted to suggest that there is no correlation with specific constellations of symptoms and signs with lesions of specific structures. There is a correlation between anatomical locations of lesions and symptomotology, although some studies would suggest that there is not a strong correlation (48). Specific structures occupy unique nodes within different nested oscillators that make up the basal gangliathalamic-cortical system, as shown in Figure 3. For example, the putamen is common to at least two reentrant circuits (MC → putamen → GPe → STN → GPi → VL → MC and MC → putamen → GPi → VL → MC), whereas the STN is involved in different circuits (MC → STN → GPi → VL → MC). Consequently, lesions of different structures are likely to have very different consequences on function within the basal gangliathalamic-cortical system. One consequence of the oscillator theory is that physiological function is modular and localized but not within any particular structure and not in any particular

FIGURE 3 The architecture of the basal ganglia-thalamic-cortical system as nested oscillators of different lengths. There are a number of potential closed loops or circuits with different nodes, corresponding to anatomical structures. Different numbers of nodes cause different fundamental reentrant frequencies.

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set of neurons. Rather, there are sets of oscillators that differ in physiological function, and these different oscillators interact to orchestrate behavior. The modularity and localization is fixed to some degree. That is, oscillator circuits particularly related to responding to go signals tend to be more localized in those circuits containing the anterior putamen and anterior globus pallidus, whereas circuits related to execution involve more posterior putamen and globus pallidus (41). However, even within this scheme, representation of physiologic function is dynamic or fluid. Montgomery et al. (39) demonstrated that individual neurons are multipotential in that they can encode different physiological functions depending on the behavioral context. For example, a neuron that preferentially responds to the go signal in one task may change its preference to the onset of a muscle force change. Further, these changes do not require learning or repetition of the task within a consistent block of tasks. These changes do not appear to require any lead time and they seem to be inherent in the physiological architecture. At this juncture, a discussion of the mechanisms of action of DBS would be helpful. DBS played a central role in reconsideration of basal ganglia physiology and pathophysiology. DBS has proven to be effective, and patients failing in pharmacological manipulations and even brain cell transplants have benefited from DBS (5). Therefore, DBS must be addressing important neuronal pathophysiological mechanisms and, by extension, important physiological mechanisms. DBS has been a useful probe in studying the dynamics of the basal ganglia-thalamic-cortical system. NEURONAL MECHANISMS OF SUBTHALAMIC NUCLEUS DEEP BRAIN STIMULATION One of the first hypotheses regarding the neuronal mechanism of action of DBS is that DBS inhibits activities within the stimulated target. A number of studies demonstrated that activity in structures receiving input from the DBS target was consistent with increased, not decreased, output from the stimulated structure. An example of GPi activity before, during, and after STN DBS in a nonhuman primate is shown in Figure 4. Note in this example, there is a significant reduction of neuronal activity immediately following discontinuation of the DBS. The current state of knowledge regarding the pathophysiological mechanisms of DBS has recently been reviewed (56–60). A series of experiments studied the effects of STN DBS of different frequencies on neuronal responses in the GPi, GPe, MC, and putamen (61). The results demonstrated that the direct effects of DBS induced the same patterns of neuronal activities in these structures, regardless of the stimulation frequency (Fig. 5). The findings

FIGURE 4 Microelectrode recording of the extracellular action potentials of a globus pallidus internal segment neuron in response to deep brain stimulation in the vicinity of the subthalamic nucleus. This is a 30-second baseline recording followed by 30 seconds of stimulation and then recording for an additional 30 seconds.

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FIGURE 5 Representative poststimulus rasters and histograms of neuronal activity recorded from the cortex, putamen, globus pallidus external segment, and globus pallidus internal segment. The top portion of each figure is a raster of neuronal activity. Each dot represents the time of an extracellular action potential. Each row represents the segment of neuronal activity between successive stimulation pulses. Dividing the time into bins and summing across rows results in a histogram at the lower portion of each figure. For stimulation at 130 pulses per second (pps), the time of the rasters and histograms is 8 ms; for 100 pps, it is 10 ms; and for 50 pps, it is 20 ms. Abbreviations: GPe, globus pallidus external segment; GPi, globus pallidus internal segment.

counter theories that high frequency DBS inhibits the target structure whereas low frequencies activate the target. Further, these findings demonstrate that the DBS effect propagates throughout the basal ganglia-thalamic-cortical system, consistent with that system being comprised of multiple oscillators that span the entire system. Three types of responses have been found (61). The first are very early, with latencies less than 2 ms, in the MC and GPe. Figure 6 shows this early and narrow peak at approximately 1 to 2 ms, which is most consistent with, although not proof of, antidromic activation of the MC and GPe neurons whose axons project to the STN. The second response occurs at approximately 4 ms following the stimulus, and the third occurs at 6 to 8 ms (seen most clearly with the 100 and 50 pps DBS). STN DBS effects were examined in other structures, and similar patterns of response in the GPi, putamen, and VL thalamus were found except that these lacked the early response at latencies less than 2 ms, consistent with antidromic activation. We suspect that the intermediate peaks represent oligosynaptic orthodromic activity propagated within the basal ganglia-thalamic-cortical system, whereas the longer latency responses represent polysynaptic reentrant oscillatory activity through the basal ganglia-thalamic-cortical system. The third peak occurs between 6 to 8 ms following the DBS pulse. This also is the time that the subsequent DBS pulse would occur with DBS at 130 pps. It could be that the coincidence of the third peak in neuronal activity following a DBS pulse, and the next DBS pulse results in a re-enforcement of neuronal activity, causing an amplification or resonance effect. This would account for the increased magnitude of the neuronal responses associated with 130 pps DBS compared to 100 or 50 pps DBS, as shown in Figure 6. The oscillator theory posits reentrant oscillations within the basal gangliathalamic-cortical system. Further, the theory holds that the main oscillator is the

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FIGURE 6 Representative examples of normalized poststimulation histograms for individual neurons in various structures. Each graph represents the changes in probability of neuronal activity in time bins during the inter deep brain stimulation (DBS) stimulus interval. The graphs are represented as z-score changes from the no-DBS condition (31). Each graph represents data obtained during DBS at 130 Hz, 100 Hz, and 50 Hz. Visual inspection classified the poststimulation histograms into those where there is no difference in the responses with different DBS frequencies and those with differences. The numbers in each class are expressed as a ratio to the total number of neurons recorded in the structure presented in the top right-hand corner of the poststimulus histograms. In the cortex, most neurons (14/20) had the same pattern of response to different DBS frequencies; however, the 130 Hz produced the greatest early response. In 6/20, the patterns and magnitudes were not different. Similar results are shown for globus pallidus internal and external segments and the putamen. The z score was computed based on the mean and the standard deviation of the prestimulation baseline. Thus, if a neuron’s discharge rate went from a prestimulation average of 30 to 130 Hz with 130 Hz DBS, then the z score would be very large. Abbreviations: Ctx, cortex; GPe, globus pallidus external segment; GPi, globus pallidus internal segment; Pt, putamen.

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disynaptic positive feedback loop comprised of the MC and VL thalamus. Assuming an approximate 3.8-ms combined conduction velocity and synaptic delay for each limb of the disynaptic feedback loop (31), the reentrant frequency would be approximately 130 Hz. The other loops through the basal ganglia-thalamic-cortical system interact with the main loop MC ↔ VL to modulate activity within the MC and VL. An extension of the oscillator theory to DBS mechanisms of action is the resonance theory. The optimal DBS frequency of approximately 130 pps amplifies by resonance the inherent oscillator frequencies within the basal ganglia-thalamiccortical system. Studies in nonhuman primates provide direct evidence of multiple and high frequencies within the basal ganglia-thalamic-cortical system (62) and evidence of resonance amplification by DBS (63). There are some preliminary data for a behavioral resonance effect with STN DBS, as shown in Figure 7. A nonhuman primate was trained to perform an arm

FIGURE 7 Perievent rasters and histograms for a putamen neuron recorded in a nonhuman primate. There is no meaningful modulation of neuronal activity with behavior (appearance of the “go” signal at time zero is indicated by the up-arrow). However, with 130 pps and to a lesser extent with 100 pps deep brain stimulation (DBS), there is a consistent modulation, suggesting that the DBS has enlisted the neuron into being meaningfully related to the behavior. Abbreviation: DBS, deep brain stimulation.

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movement task in response to a go signal (61). Neuronal recordings were performed with no DBS of the STN, and then DBS at 130, 100, and 50 pps. There was no modulation of the putamen neuronal activity correlated with performance of the task under the no DBS condition. It appeared that this neuron was not involved with generating the behavior. However, with 130-pps STN DBS, the neuron modulated its activities consistent with the behavior. It is as though the neuron was recruited in the neuronal mechanisms associated with generating the behavior. Interestingly, DBS at 100 and 50 pps was less effective in recruiting the neuronal activity into the task. The oscillatory theory holds that the multiple frequency oscillations within the basal ganglia-thalamic-cortical system are organized in a precise manner to orchestrate the precise timing of agonist and antagonist muscle activities to carry out normal behavior. The main oscillator fundamental to this process is the approximately 130-Hz MC ↔ VL feedback loop. However, side loops at lower frequencies, such as MC → putamen → GPe → STN → GPi → VL → MC and MC → STN → GPi → VL, modulate the discharge activity of the MC in a manner necessary to appropriately drive agonist and antagonist muscles. Perhaps, these different oscillators interact as an inverse Fourier transformation. Such interactions can be based on resonance, synchronization, beat interactions, and others that go well beyond the one-dimensional push–pull systems, which exemplify the current theories (7). It also is possible for DBS at different frequencies to interact or resonate with other side loops and disrupt normal oscillator interactions within the basal gangliathalamic-cortical system. This may explain why STN DBS at low frequencies, such as 10 pps, worsens PD symptoms (64). Also, cycling STN DBS at the same overall frequency as regular DBS results in slower movement times in PD subjects (65). It has also been demonstrated that modulated and irregular STN DBS worsens PD motor performance. A patient with PD was implanted with bilateral STN DBS. The leads were externalized and stimulated before implantation of the implantable pulse generators. Stimulation was performed across the most proximal and distal contacts with bipolar current, ranging from 1 to 5 mA. Current was increased until any effect was noted. Each phase of the stimulation pulse was 0.2-ms long. The patterns of stimulation were regular, irregular, and modulated (Fig. 8). The different patterns were stimulated in a randomized sequence. An investigator blinded to the stimulation parameters assessed the patient. Measures were taken from the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS). These measures con-

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FIGURE 9 Changes in the Unified Parkinson’s Disease Rating Scale for finger-tapping in the lefthand contralateral to the deep brain stimulation (DBS) lead and to the ipsilateral hand (right) in a single subject with Parkinson’s disease and subthalamic nucleus DBS. The evaluator was blinded to the pattern of stimulation. The 130 pps DBS modulated at 2 Hz worsened motor performance (negative change in score), but regular DBS at 130 pps improved motor performance. Irregular DBS at 130 pps average did not have a marked effect.

sisted of (i) muscle tone, (ii) finger-tapping speed, (iii) hand opening–closing speed, (iv) arm pronation–supination speed, (v) rest tremor, and (vi) postural tremor. Other measures in the UPDRS motor section could not be performed, because the patient was restricted to the operating table. Computer programs controlled the stimulation patterns in which regular, irregular, and modulated 130-pps DBS was delivered (Fig. 8). The results of the stimulation are shown in Figure 9. For left-sided finger-tapping (contralateral to DBS), the greatest improvement was with regular stimulation and with stimulation modulated at 10 Hz, with the same overall stimulation frequency of 130 pps. All other stimulation patterns actually worsened finger-tapping. On the right side (ipsilateral to DBS), the only improvement was noted with regular stimulation. Thus, stimulation modulated at 5 and 2 Hz actually worsened finger-tapping, although the overall frequency was at the same high rate of 130 pps. Similar results were obtained for rapid left-hand opening and closing. The greatest improvement on the right-side DBS was with regular stimulation. Stimulation modulated at 10 Hz and 5 Hz produced some improvement, but stimulation modulated at 2 Hz produced no improvement in hand opening and closing. Stimulation at all patterns showed worsened performance on the right side that did not vary with stimulation pattern. Basal Ganglia-Thalamic-Cortical System as a Complex System The physiology and pathophysiology of the basal ganglia-thalamic-cortical system is complex. This is especially true when the physiology and pathophysiology are viewed at a time scale measured in milliseconds and at a resolution that approaches consideration of thousands of neurons interacting. The next generation of theories must consider basal ganglia function as a dynamical system. We will have to borrow heavily from the physics of information theory such as loosely coupled oscillators (66), “small world” dynamics (67), and scale-free networks (68). The complexity of the biological data will necessitate an understanding based on computational simulations. Consequently, the biology of the basal ganglia will move from in vivo and in vitro to in silico (69). We will still need careful animal studies, but these will have to be done in such a way as to capture the dynamics of the entire system.

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50. Wallays C, Feve A, Boudghene F, Fenelon G, Guillard A, Bigot JM. Hypoxic cerebral lesions. X-ray computed tomography and MRI aspects. Apropos of 20 cases. Selective vulnerability of the striatopallidum. J Neuroradiol 1995; 22:77–85. 51. Goto S, Matsumoto S, Ushio Y, Hirano A. Subregional loss of putaminal efferents to the basal ganglia output nuclei may cause parkinsonism in striatonigral degeneration. Neurology 1996; 47:1032–1036. 52. Friedman AK, Kang UJ, Tatemichi TK, Burke RE. A case of parkinsonism following striatal lacunar infarction. J Neurol Neurosurg Psychiatry 1986; 49:1087–1088. 53. Canavero S, Bonicalzi V, Paolotti R, et al. Therapeutic extradural cortical stimulation for movement disorders: a review. Neurol Res 2003; 25:118–122. 54. Koller W, Pahwa R, Busenbark K, et al. High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997; 42:292–299. 55. Vitek JL, Hashimoto T, Peoples J, DeLong MR, Bakay AE. Acute stimulation in the external segment of the globus pallidus improves Parkinsonian motor signs. Mov Disord 2004; 19:907–915. 56. Montgomery EB, Baker KB. Mechanisms of deep brain stimulation and future technical developments. Neurol Res 2000; 22:259–266. 57. Montgomery EB, Baker KB. Deep brain stimulation. In: Horch KW and Dhillon G, eds. Neuroprosthetics: Theory and Practice (Series on Bioengineering and Biomedical Engineering Vol.2), Singapore: World Scientific Publishing Co., 2002: Chapter 6.5, 915–935. 58. Montgomery EB, Gale J, Baker KB. High frequency subthalamic nucleus stimulation. In: Luders HD, ed. Deep Brain Stimulation and Epilepsy, London. M Dunitz publisher, 2002:131–143. 59. Lozano AM, Eltahawy H. How does DBS work? Clin Neurophysiol London, New York 2004; 57:733–736. 60. McIntyre CC, Savasta M, Walter BL, Vitek JL. How does deep brain stimulation work? Present understanding and future questions. J Clin Neurophysiol 2004; 21:40–50. 61. Gale JT. Basis of Periodic Activities in the Basal Ganglia-Thalamic-Cortical System of the Rhesus Macaque. Kent: Kent State University, 2004. 62. Gale JT, Montgomery EB Jr, Huang H. Evidence of multi-stable high frequency oscillatory activity in the basal ganglia-thalamic-cortical system of the macaque. 2004 Abstract Viewer/Itnerary Planner 2004:Program no. 70.77. 63. Gale JT, Montgomery EB. Stimulation-induced resonance frequencies in the basal ganglia-thalamic-cortical (BG-Th-Ctx) network. 2003 Abstract Viewer/Itinerary Planner 2003:Program No. 390.318. 64. Timmermann L, Wojtecki L, Gross J, et al. Ten-Hertz stimulation of subthalamic nucleus deteriorates motor symptoms in Parkinson’s disease. Mov Disord 2004; 19:1328–1333. 65. Montgomery EB, Effect of subthalamic nucleus stimulation patterns on motor performance in Parkinson’s disease. Parkinsonism Relat Disord 2005; 11:167–171. 66. Hoppensteadt FC, Izhikevic EM. Weakly Connected Neural Networks. In: Marsden JE and Sirovich L, eds. Weakly Connected Neural Networks in Applied Mathematical Sciences Vol. 126, New York: Springer-Verlag, 1997. 67. Hoppensteadt FC, Izhikevich EM. Weakly Connected Neural Networks. New York: Springer-Verlag, 1997. 68. Barabasi AL, Bonabeau E. Scale-free networks. Sci Am 2003; 288:60–69. 69. Palsson B. The challenges of in silico biology. Nat Biotech 2000; 18:1147–1150.

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Animal Models Giselle M. Petzinger and Michael W. Jakowec Department of Neurology, University of Southern California, Los Angeles, California, U.S.A.

INTRODUCTION The incidence of neurodegenerative disorders in nonhuman animals is rare, likely due to the selective pressures to remove affected animals from the population. However, the identification of spontaneous occurrences or the induction of specific phenotypes in a variety of animal species provides an important foundation to study neurological disorders and are critical for determining underlying disease mechanisms and developing new therapeutic modalities. In general, the utility of an animal model for a particular disease is often dependent on how closely the model replicates all or part of the human condition. In Parkinson’s disease (PD) and related parkinsonian disorders, there now exists a variety of animal models, each of which makes a unique contribution to our understanding of the human condition. These models have been derived in a variety of species (i.e., pig, nonhuman primate, rodent, and cat) using multiple techniques, including pharmacological manipulation, administration of neurotoxicants, genetic models, and surgical lesioning. Although these models are not identical to the human condition with respect to behavioral characteristics, brain anatomy, or disease progression, they have provided significant advancements in our understanding of the underlying mechanisms and treatment of movement disorders, such as PD. PD is characterized by bradykinesia, rigidity, postural instability, and resting tremor. The primary pathological and biochemical features of PD are the loss of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNpc), the appearance of intracellular inclusions called Lewy bodies, and the depletion of striatal dopamine. Clinical features are apparent when striatal dopamine depletion reaches 80% despite the fact that 45% to 60% of nigrostriatal dopaminergic neurons still remain (1). Other regions of the brain and other nondopaminergic neurotransmitter systems are also affected in PD, which must be taken into consideration in animal model development. Since the destruction of the nigrostriatal system and consequent depletion of striatal dopamine are key features in the human condition, attempts have been made in animal models to disrupt an analogous anatomical area through surgical, pharmacological, or neurotoxicant manipulation. The purpose of this chapter is to introduce the many different animal models utilized in PD research. Despite the fact that many of the animal models used are generated through acute intervention, although PD is a progressive neurodegenerative disorder, should not diminish their importance and potential impact. Recently, several toxin-induced, spontaneous, and transgenic models have been shown to display progressive motor deficits and/or degeneration. In this chapter, the most common models are discussed with respect to development, behavioral profile, biochemical and neuropathological alterations, and contribution to the field. 239

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PHARMACOLOGICAL-INDUCED MODELS OF PARKINSON’S DISEASE Pharmacological manipulation of the dopaminergic system can take on two basic forms either targeting dopamine biosynthesis or destruction of nigrostriatal dopaminergic neurons. Both reserpine and alpha-methyl-para-tyrosine (AMPT) interfere with dopamine production and result in a temporary dopamine depletion lasting hours to days, whereas neurotoxicants such as 6-hydroxydopamine (6OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) result in midbrain dopaminergic cell death. Methamphetamine (METH) is a class of compound that selectively destroys axonal terminals of nigrostriatal dopaminergic neurons usually without significant cell death. Recently, other compounds, particularly pesticides and proteasome inhibitors, have been utilized as selective toxins targeting the dopaminergic system since the mitochondria of these cells display enhanced vulnerability during chronic exposure. The utility of compounds to generate animal models of parkinsonism are discussed in the following sections. Reserpine The first demonstration of an animal model for PD was reported by Carlsson in the 1950s using rabbits treated with reserpine. Reserpine is a catecholamine-depleting agent that blocks vesicular storage of monoamines. The akinetic state, resulting from reserpine-induced dopamine depletion in the caudate nucleus and putamen, led Carlsson to speculate that PD was due to loss of dopamine neurotransmission. This speculation was supported by the discovery of reduced striatal dopamine in postmortem brain tissue of PD patients and led to the subsequent use of levodopa (in conjunction with a peripheral dopa-decarboxylase inhibitor) for symptomatic treatment of PD (2,3). Thus, the initial observations derived from an animal model led to an important clinical therapy that still remains the “gold standard.” Alpha-Methyl-Para-Tyrosine Although less commonly used, AMPT, like reserpine, serves as an effective catecholamine-depleting agent (4). By directly inhibiting tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis, the nascent synthesis of dopamine in neurons of the SNpc and ventral tegmental area (VTA) is prevented. Both reserpine and AMPT have been used to discover new dopaminomimetics for the treatment of PD, but since their effects are transient (hours to days), these models are primarily useful for acute studies. In addition, neither agent can duplicate the extensive biochemical nor pathological changes seen in PD. Consequently, other models with long-lasting neurochemical and behavioral alterations have been sought using site-specific neurotoxicant injury. NEUROTOXICANT-INDUCED MODELS OF PARKINSON’S DISEASE 6-Hydroxydopamine 6-OHDA or 2,4,5-trihydroxyphenylethylamine is a specific catecholaminergic neurotoxin structurally analogous to both dopamine and noradrenalin. Acting as a “false-substrate,” 6-OHDA is rapidly accumulated in catecholaminergic neurons. The mechanism of 6-OHDA toxicity is complex and involves alkylation; rapid autooxidization leading to the generation of hydrogen peroxide, superoxide, and

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hydroxyl radicals; and impairment of mitochondrial energy production (5,6). The 6OHDA-induced rat model of PD was initially carried out by Ungerstedt in 1968, using stereotaxic bilateral intracerebral injections into the substantia nigra or lateral hypothalamus targeting the medial forebrain bundle (7). The bilateral administration of 6-OHDA resulted in catalepsy, generalized inactivity, aphagia, adipsia, and a high degree of animal morbidity and mortality. Consequently, the administration of 6-OHDA was modified to a unilateral intracerebral lesion targeting the substantia nigra and/or medial forebrain bundle. With unilateral lesioning, there was minimal postoperative morbidity, behavioral asymmetry, and a nonlesioned side to serve as a control (8,9). An additional modification of 6-OHDA administration is using chronic low dose striatal injections. This can lead to progressive dopaminergic cell death thought to more closely resemble the human condition (10). An important caveat of 6-OHDA lesioning is that the time course of cell death may be on the order of one to three weeks and must be taken into consideration when studies using intervention strategies are employed (10,11). A distinctive behavioral feature of the unilateral lesioned model is rotation (12,13). This motor feature is due to asymmetry in dopaminergic neurotransmission between the lesioned and intact sides. Specifically, animals rotate away from the side of greater dopaminergic activity. Nomenclature describes the direction of rotation as either ipsilateral (toward) or contralateral (away) to the lesioned side. Initial reports of rotation examined both spontaneous and pharmacologically induced rotation. Spontaneous rotation consists of ipsilateral rotation, whereas pharmacologically induced rotation may be either contralateral or ipsilateral. For example, apomorphine and other dopamine agonists induce contralateral rotation. This is due to their direct action on super-sensitized dopaminergic receptors on the lesioned side. Conversely, d-amphetamine phenylisopropylamine (AMPH) induces ipsilateral rotation by blocking dopamine re-uptake and increasing dopamine receptor activity on the nonlesioned side. In general, a greater than 80% depletion of dopamine is necessary to manifest rotation in this model (4,14). Circling behavior can be measured either by observation or by special devices called rotameters. The rate of rotation correlates with the severity of the lesion, and animals with more extensive striatal dopamine depletions are less likely to show behavioral recovery. This simple model of rotation away from the side with the most dopamine receptor occupancy has recently proven much more complex and less predictable than previously thought, especially in the context of various pharmacological treatments and neuronal transplantation (15,16). In addition to rotation, other behavioral assessments in the 6OHDA model may include tests of forelimb use, bilateral tactile stimulation, single limb akinesia, and bracing [for review, see Ref. (17)]. A recent study on behavioral and electromyographic analysis in the 6-OHDA-lesioned rat showed gait impairment, differences in trajectory in lesioned versus nonlesioned rotation, and evidence of myoclonus (18). The 6-OHDA-lesioned rat model has proven to be a valuable tool in evaluating the pharmacological action of new drugs on the dopaminergic system, the mechanisms of motor complications, the neuroplasticity of the basal ganglia in response to nigrostriatal injury, and the safety and efficacy of neuronal transplantation in PD. Extensive pharmacological studies have utilized the 6-OHDA-lesioned rat to investigate the role of various dopamine receptor (D1 through D5) agonists and antagonists, and other neurotransmitter systems (including glutamate, adenosine, nicotine, and opiods) on modulating dopamine neurotransmission. These studies elucidate

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the role of these compounds on electrophysiological, behavioral, and molecular (signal transduction) properties of the basal ganglia (13). The 6-OHDA-lesioned rat model has also been an important tool in elucidating the mechanism(s) underlying motor complications (19,20). The chronic administration of levodopa (over a period of weeks) to the 6-OHDA rat has been demonstrated to lead to a shortening response similar to wearing off in idiopathic PD (21). This altered motor response occurs when greater than 95% of nigrostriatal dopaminergic neurons are lost. Studies using glutamate antagonists have demonstrated improvement in wearing off and have implicated the role of glutamate receptor subtypes in the development of motor complications (22–24). These findings have been supported by molecular studies that demonstrate alterations in the phosphorylation state of glutamate receptor subunits of the N-methyl-D-aspartate (NMDA) subtype (25). 6-OHDA-lesioned rats do not develop limb and truncal dyskinesia as seen in PD but a form more localized to the jaw (20,26). In the context of neuroplasticity, the 6-OHDA-lesioned rat model demonstrates behavioral recovery and has been instrumental in characterizing the neurochemical, molecular, and morphological alterations within the basal ganglia in response to nigrostriatal dopamine depletion (27). These mechanisms of neuroplasticity in surviving dopaminergic neurons and their striatal terminals include increased turnover of dopamine and its metabolites; alterations in the expression of tyrosine hydroxylase, the rate-limiting step in dopamine biosynthesis; decreased dopamine uptake through altered dopamine transporter (DAT) expression; alterations in the electrophysiological phenotype (both pattern and rate of neuronal firing) of striatal and substantia nigra neurons; and sprouting of new striatal dopaminergic terminals. These molecular mechanisms may provide new targets for novel therapeutic interventions such as growth factors to enhance the function of surviving dopaminergic neurons. The 6-OHDA-lesioned rat model has also been useful for determining important parameters for successful transplantation. These parameters include target site (striatum vs. substantia nigra); volume of innervation at the target site; number of cells transplanted; type and species of cells transplanted, including fetal mesencephalon, engineered cell lines, and stem cells; age of host and donor tissues; pretreatment of transplant tissue or host with neurotrophic factors, anti-oxidants, immunosuppressive therapy, or neuroprotective pharmacological agents; and surgical techniques, including needle design, cell suspension media, and transplant cell delivery methods (28,29). The near absence of dopaminergic neurons and terminals within the striatum due to 6-OHDA lesioning provides a template for the assessment of sprouting axons and terminals originating from the transplant. Measures of transplant success in this model include reduction in the rotational behavior and the survival, sprouting and innervation (synapse formation) of dopaminergic fibers within the denervated striatum. The reduction of rotational behavior suggests increased striatal dopamine production originating from the transplanted tissue. Interestingly, not all behavioral measures appear to respond to transplant. The advancements made in the 6-OHDA-lesioned rat provide a framework for the further testing of transplantation in nonhuman primates and human clinical trials. Although the 6-OHDA-lesioned rat model has many advantages, it serves primarily as a model of dopamine dysfunction. Lesioning with 6-OHDA is highly specific for catecholaminergic neurons and does not replicate all of the behavioral, neurochemical, and pathological features of human PD. For example, the 6-OHDA-lesioned

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rat does not manifest alterations in the cholinergic and serotonergic neurotransmitter systems, which are commonly affected in PD. Stereotaxic injections of 6-OHDA to precise targets does not replicate the extensive pathology of PD where other anatomical regions of the brain (including the locus coeruleus, nucleus basalis of Meynert, and raphe nuclei) are affected. In addition, Lewy body formation, a pathological hallmark of PD, has not been reported in this model. Interestingly, a recent report using a regimen of chronic administration of 6-OHDA into the third ventricle did show a more extensive lesioning pattern reminiscent of human PD (30). In addition to the rat, other species, including the nonhuman primate (specifically the marmoset), have served as models for 6-OHDA lesioning (31,32). Lesioning in nonhuman primates provides for the analysis of behaviors not observed in the rat, such as targeting and retrieval tasks of the arm and hand. In addition, lesioning in the nematode Caenorhabditis elegans provides a potential genetic tool to investigate mechanisms involved in cell death with this toxin and to provide large-scale screenings (33,34). Overall, lesioning with 6-OHDA has provided a rich source of information regarding the consequences of precise dopamine depletion and its effects on rotational behavior, dopamine biosynthesis, biochemical and morphological aspects of recovery, and serves as an excellent template to study both pharmacological and transplantation treatment modalities for PD. 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine The inadvertent self-administration of MPTP by heroin addicts in the 1980s induced an acute form of parkinsonism whose clinical and biochemical features were indistinguishable from idiopathic PD (35,36). Like PD, this MPTP cohort demonstrated an excellent response to levodopa and dopamine agonist treatment but developed motor complications within weeks. The rapidity with which these motor complications appeared presumably reflected the severity of substantia nigra neuronal degeneration induced by MPTP. Given the similarities between the human model of MPTP-induced parkinsonism and PD, it became evident that MPTP could be used to develop animal models of PD. The subsequent administration of MPTP to a number of different animals has demonstrated a wide variety of sensitivity to the toxic effects of MPTP. These differences were shown to be species, strain, and age dependent. For example, the nonhuman primate is the most sensitive to the toxic effects of MPTP. The mouse, cat, dog, and guinea pig are less sensitive and the rat is the least sensitive. Even within species there are strain differences. For example, the C57BL/6 mouse is the most sensitive of all mouse strains tested while strains such as CD-1 appear almost resistant (37,38). Some differences among strains may also depend on the supplier, as seen with variability in the Swiss Webster strain (39). In addition to strain, animal sensitivity to the neurotoxicant effects of MPTP may be influenced by the animal’s age with older mice, for example, being more sensitive (40,41). Studies suggest that agedependent differences may be due to differences in MPTP metabolism (42). To bypass potential confounders involved in MPTP delivery to the brain and its conversion to the 1-methyl-4-pyridinium (MPP+) toxin form, some investigators have utilized stereotaxic delivery via cannulae into the striatum (43). Similar to 6-OHDA lesioning, this approach still has technical issues regarding targeting and diffusion, and has yet to be tested in a wide range of species. The mechanism of MPTP toxicity has been thoroughly investigated. The meperidine analog MPTP is converted to MPP+ by monoamine oxidase B. MPP+ acts

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as a substrate of the DAT, leading to the inhibition of mitochondrial complex I, the depletion of adenosine triphosphate (ATP), and cell death of dopaminergic neurons. MPTP administration to mice and nonhuman primates selectively destroys dopaminergic neurons of the SNpc, the same neurons affected in PD (44). Similar to PD, other catecholaminergic neurons, such as those in the VTA and locus coeruleus, may be affected to a lesser degree. In addition, dopamine depletion occurs in both the putamen and caudate nucleus. The preferential lesioning of either the putamen or caudate nucleus may depend on animal species and regimen of MPTP administration (45–47). Unlike PD, Lewy bodies have not been reported; however, eosinophilic inclusions (reminiscent of Lewy bodies) have been described in aged nonhuman primates (48). The time course of MPTP-induced neurodegeneration is rapid, and therefore represents a major difference with idiopathic PD, which is a chronic progressive disease. Interestingly, data from humans exposed to MPTP indicate that the toxic effects of MPTP may be more protracted than initially believed (49). Details of MPTP toxicity, safety, and utility have been described in reviews (50,51). The MPTP-Lesioned Mouse Model The administration of MPTP to mice results in behavioral alterations that may resemble human parkinsonism. For example, hypokinesia, bradykinesia, and akinesia can be observed through various behavioral analyses, including open field activity monitoring, swim test, pole test, grip coordination, and rotarod. Whole body tremor and postural abnormalities have also been reported, but primarily in the acute phase (52). Cognitive changes have been reported with respect to spatial learning (53). In general, these behavioral alterations tend to be highly variable with some mice showing severe deficits while others show little or no behavioral change [for review, see Ref. (52)]. This behavioral variability may be due to a number of factors, including the degree of lesioning, mouse strain, time course after lesioning, and the reliability and validity of the behavioral analysis (54–58). The MPTP-lesioned mouse model has proven valuable to investigate potential mechanisms of neurotoxic-induced dopaminergic cell death. For example, mechanisms under investigation have included mitochondrial dysfunction, energy (ATP) depletion, free-radical production, apoptosis, and glutamate excitotoxicity (51). In addition to its utility in studying acute cell death, the MPTP-lesioned model also provides an opportunity to study injury-induced neuroplasticity. The MPTP-lesioned mouse displays the return of striatal dopamine several weeks to months after lesioning (45,47,59,60). The molecular mechanism of this neuroplasticity of the injured basal ganglia is an area of investigation in our laboratory and in others, and appears to encompass both neurochemical and morphological components. In addition, it has been shown that this plasticity may be facilitated through activity-dependent processes using treadmill training (61,62). MPTP-Lesioned Nonhuman Primate Administration of MPTP to nonhuman primates results in parkinsonian symptoms, including bradykinesia, postural instability, and rigidity. In some species, resting or action/postural tremor has been observed (63). Similar to PD, the MPTP-lesioned nonhuman primate responds to traditional anti-parkinsonian therapies, such as levodopa and dopamine agonists. Following the administration of MPTP, the nonhuman primate progresses through acute (hours), sub-acute (days), and chronic (weeks) behavioral phases of toxicity that are due to the peripheral and central effects of MPTP. The acute phase is characterized by sedation and a hyper-adrenergic

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state, the sub-acute phase by the development of varying degrees of parkinsonian features, and the chronic phase by initial recovery (by some, but not all animals) followed by the stabilization of motor deficits (64). In general, the behavioral response to MPTP-lesioning may vary at both the inter- and intra-species level. Variability may be due to age and species phylogeny. For example, older animals and Old World monkeys (such as rhesus, Macaca mulatta or African Green, Cercopithecus aethiops) tend to be more sensitive than young and New World monkeys (such as the squirrel monkey, Saimiri sciureus or marmoset, Callithrix jacchus) (65–67). Behavioral recovery after MPTP-induced parkinsonism has been reported in most species of nonhuman primate. The degree and time course of behavioral recovery is dependent on age, species, and mode of MPTP administration (64). In general, the more severely affected animal is less likely to recover (63). Study of the molecular mechanisms underlying behavioral recovery of the nonhuman primate has identified that the mechanisms underlying recovery may include alterations in dopamine biosynthesis (increased tyrosine hydroxylase protein and mRNA expression) and turnover; down-regulation of DAT; increased dopamine metabolism; sprouting and branching of tyrosine hydroxylase fibers; alterations of other neurotransmitter systems, including glutamate and serotonin; and alterations of signal transduction pathways in both the direct (D1) and indirect (D2) pathways (68,69). The administration of MPTP through a number of different dosing regimens has led to the development of several distinct models of parkinsonism in the nonhuman primate. Each model is characterized by unique behavioral and neurochemical parameters. As a result, numerous studies addressing a variety of hypotheses have been conducted. These studies consist of new pharmacological treatments, transplantation, mechanisms of motor complications, deep brain stimulation, behavioral recovery, cognitive impairment, and the development of novel neuroprotective and restorative therapies. For example, in some models, there is profound striatal dopamine depletion and denervation with little or no dopaminergic axons or terminals remaining. This model provides an optimal setting to test fetal tissue grafting since the presence of any tyrosine hydroxylase positive axons or sprouting cells would be due to transplanted tissue survival. Other models have less extensive dopamine depletion and only partial denervation, with a modest to moderate degree of dopaminergic axons and terminals remaining. This partially denervated model best resembles mild to moderately affected PD patients. Therefore, sufficient dopaminergic neurons and axons as well as compensatory mechanisms are likely to be present. The effects of growth factors (inducing sprouting) or neuroprotective factors (promoting cell survival) are best evaluated in this situation. The following section reviews the most commonly used MPTP-lesioned nonhuman primate models. In the systemic lesioned model, MPTP may be administered via intra-muscular, intra-venous, intra-peritoneal, or subcutaneous injection (70–73). This leads to bilateral depletion of striatal dopamine and nigrostriatal cell death. A feature of this model is that the degree of lesioning can be titrated, resulting in a range (mild to severe) of parkinsonian symptoms. The presence of clinical asymmetry is common, with one side more severely affected. Levodopa administration leads to the reversal of all behavioral signs of parkinsonism in a dose-dependent fashion. After several days to weeks of levodopa administration, animals develop reproducible motor complications, both wearing-off and dyskinesia. Animal behavior in this model and others may be assessed using cage-side or video-based observation, automated activity measurements in the cage through infrared-based motion detectors or accelerometers, and examination of hand-reaching movement tasks. The principal

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advantage of this model is that the behavioral syndrome closely resembles the clinical features of idiopathic PD. The systemic model has partial dopaminergic denervation bilaterally and probably best represents the degree of loss seen in all stages of PD, including end stage disease where some dopaminergic neurons are still present. This model is well suited for therapeutics that interact with remaining dopaminergic neurons, including growth factors, neuroprotective agents, and dopamine modulation. The easily reproducible dyskinesia in this model allows for extensive investigation of its underlying mechanism and treatment. Disadvantages of this model include spontaneous recovery in mildly affected animals. Alternatively, bilaterally severely affected animals may require extensive veterinary care and dopamine supplementation. Administration of MPTP via unilateral intracarotid infusion has been used to induce a hemiparkinsonian state in the primate, called the hemiparkinsonian model (74). The rapid metabolism of MPTP to MPP+ in the brain may account for the localized toxicity to the hemisphere ipsilateral to the infusion. Motor impairments appear primarily on the contralateral side. Hemi-neglect, manifested by a delayed motor reaction time, also develops on the contralateral side. In addition, spontaneous ipsilateral rotation may develop. Levodopa administration reverses the parkinsonian symptoms and induces contralateral rotation. Substantia nigra neurodegeneration and striatal dopamine depletion (greater than 99%) on the ipsilateral side to the injection is more extensive than seen in the systemic model. The degree of unilateral lesioning in this model is dose dependent. Major advantages of the hemi-lesioned model include the ability for animals to feed and maintain themselves without supportive care, the availability of the unaffected limb on the ipsilateral side to serve as a control, and the utility of the dopamine-induced rotation for pharmacological testing. In addition, due to the absence of dopaminergic innervation in the striatum, the hemi-lesioned model is well suited for examining neuronal sprouting of transplanted tissue. A disadvantage of this model is that only a subset of parkinsonian features are evident and are restricted to one side of the body, a situation not seen in idiopathic PD. The bilateral intracarotid model employs an intracarotid injection of MPTP followed several months later by another intracarotid injection on the opposite side (75). This model combines the less debilitating features of the carotid model as well as creating bilateral clinical features, a situation more closely resembling idiopathic PD. The advantage of this model is its prolonged stability and limited inter-animal variability. Similar to the hemi-lesioned model, where there is extensive striatal dopamine depletion and denervation, the bilateral intracarotid model is well suited for evaluation of transplanted tissue. However, levodopa administration may result in only partial improvement of parkinsonian motor features and food retrieval tasks. This can be a disadvantage since high doses of test drug may be needed to demonstrate efficacy, increasing the risk for medication-related adverse effects. A novel approach to MPTP lesioning is the administration of MPTP via intracarotid infusion, followed by a systemic injection. This over-lesioned model is characterized by severe dopamine depletion ipsilateral to the MPTP-carotid infusion and a partial depletion on the contralateral side due to the systemic MPTP injection. Consequently, animals are still able to maintain themselves due to a relatively intact side. The behavioral deficits consist of asymmetric parkinsonian features. The more severely affected side is contralateral to the intracarotid injection (76). Levodopa produces a dose-dependent improvement in behavioral features; however, the complications of levodopa therapy, such as dyskinesia, have not been as consistently

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observed. This model combines some of the advantages of both the systemic and intracarotid MPTP models, including stability. This model is suitable for both transplant studies, utilizing the more depleted side, and neuro-regeneration with growth factors, utilizing the partially depleted side where dopaminergic neurons still remain. Finally, the chronic low dose model consists of intravenous injections of a low dose of MPTP administration over a 5- to 13-month period (77). This model is characterized by cognitive deficits consistent with frontal lobe dysfunction reminiscent of PD or normal-aged monkeys. These animals have impaired attention and shortterm memory processes and perform poorly in tasks of delayed response or delayed alternation. Since gross parkinsonian motor symptoms are essentially absent at least in early stages, this model is well adapted for studying cognitive deficits analogous to those that accompany idiopathic PD. The MPTP-lesioned nonhuman primate has provided a valuable tool for investigating potential mechanisms underlying motor complications related to long-term levodopa use in human idiopathic PD. The MPTP-lesioned nonhuman primate has been shown to demonstrate both wearing-off and dyskinesia. Although the etiology of dyskinesia is unknown, electrophysiological, neurochemical, molecular, and neuroimaging studies in the nonhuman primate models suggest that the pulsatile delivery of levodopa may lead to changes in the neuronal firing rate and pattern of the globus pallidus and subthalamic nucleus; enhancement of D1- and/or D2-receptor mediated signal transduction pathways; super-sensitivity of the D2 receptor; alterations in the phosphorylation state and subcellular localization of glutamate (NMDA subtype) receptors; modifications in the functional links between dopamine receptor subtypes (D1 and D2, and D1 and D3); changes in glutamate receptors (AMPA and NMDA receptor subtypes); and enhancement of opiod-peptide mediated neurotransmission (78–82). While the presence of a nigral lesion has long been considered an important prerequisite for the development of dyskinesia in the MPTP model, recent studies demonstrate that even normal nonhuman primates when given sufficiently large doses of levodopa over two to eight weeks may develop peak-dose dyskinesia (83). The high levels of plasma levodopa in this dosing regimen may serve to exhaust the buffering capacity within the striatum of the normal animal, and therefore lead to pulsatile delivery of levodopa and priming of postsynaptic dopaminergic sites for dyskinesia. In addition to its central effects, the administration of MPTP may lead to systemic effects that may prove detrimental to any animal during the induction of a parkinsonian state. For example, the peripheral conversion of MPTP to MPP+ in the liver could lead to toxic injury of the liver and heart. To address these potential peripheral effects of MPTP, squirrel monkeys were administered MPTP (a series of six subcutaneous injections of 2 mg/kg, free-base, two weeks apart) and were given a comprehensive exam 1, 4, and 10 days after each injection. This exam included measurements of body weight, core body temperature, heart rate, blood pressure, liver and kidney function, and white blood cell count. Biochemical markers of hepatocellular toxicity were evident within days of MPTP lesioning and persisted for several weeks after the last injection. In addition, animals had significant hypothermia within 48 hours after lesioning that persisted for up to 10 days after the last MPTP injection (Petzinger et al. in preparation). The pathophysiology of these effects may be directly related to MPTP itself and/or its metabolites. The systemic effects of MPTP on animal models should be taken into consideration during the design of any pharmacological study.

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MPTP-Lesioning in Other Species While mice and nonhuman primates continue to remain the primary species in the majority of studies with MPTP, researchers have reported the effects of MPTP in a wide range of other species. These include the leech (Hirudo medicinakis), planarian flatworm (Dugesia japonica), rainbow trout (Oncorhynchus mykiss), goldfish (Carassius auratus), zebra fish (Brachydanio rerio), frog (Rana pipiens and Rana clamitans), salamander (Taricha torosa), snake (Elaphe obsolete and Nerodia fasciata), lizard (Anolis carolinensis), chicken (Gallus gallus), rat (Rattus rattus and Rattus norvegicus), guinea pig (Cavia porcellus), rabbit (Oryctolagus cuniculus), dog (Canis familiaris), and pig (Susscrofa domestica). Some of these species may have some advantages, such as the zebra fish, where powerful genetic tools involved in large-scale screening can be applied (84). Despite the novel application of MPTP to these species, there are limitations that restrict their popularity, including animal availability, biosafety exposure and disposal, genetic background, and standardization of lesioning regimen and its efficacy. Methamphetamine Amphetamine and its derivatives lead to long-lasting depletion of both dopamine and serotonin when administered to rodents and nonhuman primates (85,86). METH, one of the most potent of these derivatives, leads to terminal degeneration of dopaminergic neurons in the caudate-putamen, nucleus accumbens, and neocortex. In contrast to MPTP, the axonal trunks and soma of SNpc and VTA neurons are spared (87). However, there have been occasional reports of METH-induced cell death in the substantia nigra (88). In general, the effects of severe METH lesioning are long lasting. There is evidence of recovery of dopaminergic innervation, depending on the METH regimen and species used (89). Despite the severe depletion of striatal dopamine, the motor behavioral alterations seen in rodents and nonhuman primates are subtle (90). The neurotoxic effects of METH are dependent on the efflux of dopamine since agents that deplete dopamine or block its uptake are neuroprotective (91,92). The metabolic mechanisms underlying METH-induced neurotoxicity involve the perturbation of antioxidant enzymes such as glutathione peroxidase or catalase, leading to the formation of reactive oxygen/nitrogen species, including H2O2, superoxide, and hydroxyl radicals (93–97). The administration of antioxidant therapies or overexpression of superoxide dismutase (SOD) in transgenic mice models is neuroprotective against METH toxicity (98,99). In addition, both glutamate receptors and nitric oxide synthase (NOS) are important to METH-induced neurotoxicity since the administration of either NMDA receptor antagonists or NOS inhibitors are also neuroprotective (100). Other factors important to METH-induced neurotoxicity include the inhibition of both tyrosine hydroxylase and DAT activity and METH-induced hyperthermia (96). The administration of METH to adult animals has played an important role in testing the molecular and biochemical mechanisms underlying dopaminergic and serotonergic neuronal axonal degeneration, especially the role of free radicals and glutamate neurotransmission. Understanding these mechanisms has led to testing different neuroprotective therapeutic modalities. An advantage of the METH model over MPTP is that the serotonergic and dopaminergic systems can be lesioned in utero during the early stages of the development of these neurotransmitter systems. Such studies have indicated that there is a tremendous degree of architectural rearrangement that occurs within the dopaminergic and serotonergic systems of

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injured animals as they develop. These changes may lead to altered behavior in the adult animal (101). In light of the toxic nature of these compounds in animals, studies in humans have suggested that abusers of METH and substituted amphetamines (including MDMA “ecstasy”) may suffer from the long-lasting effects of these drugs (102,103). Specifically, these individuals may be prone to develop parkinsonism (104). Rotenone Epidemiological studies have suggested that environmental factors such as pesticides may increase the risk for PD (105). The demonstration of specific neurochemical and pathological damage to dopaminergic neurons by the application of various pesticides such as rotenone have been consistent with these epidemiological findings. Rotenone is an inhibitor of mitochondrial complex I due to impaired oxidative phosphorylation through inhibition of NADH-ubiquitin reductase. For example, using a chronic rotenone infusion paradigm (2 or 3 mg/kg/day for three weeks) through either jugular vein cannulation or systemic delivery with an osmotic pump, Greenamyre et al. reported degeneration of a subset of nigrostriatal dopaminergic neurons; the formation of cytoplasmic inclusions; and the development of parkinsonian motor behavior, including hunched posture, rigidity, unsteady movement, and paw tremor in the rat (106,107). There are some limitations to the rotenone model that one must be aware of, including long administration period of weeks to months; variability due to dose; low animal survival; variable pathological outcomes and specificity; and species and strain differences (108–114). Despite these potential confounders, this model provides valuable insight into one potential mechanism relevant to the etiology of parkinsonism. Studies examining the different parameters of this and other pesticides in animal models may lead to insights into the mechanisms of neuronal death in PD (115). Paraquat Paraquat (N,N’-dimethyl-4-4’-bipyridium dichloride) is a pesticide analog of MPP+ and etiologically linked to parkinsonism through epidemiological studies (115–117). Paraquat acts to induce oxidative stress by interfering with mitochondria electron transport, especially in the more vulnerable nigrostriatal dopaminergic neurons with a mechanism different from rotenone and MPP+ (118–120). Acute exposure can result in extensive brain damage and death in humans without specific parkinsonianlike pathology (121,122). However, more chronic exposures in rodents (over 24 weeks) can manifest with many features due to dopaminergic dysfunction, including selective loss of nigrostriatal dopaminergic neurons and motor deficits (123,124). Therefore, paraquat, as well as a number of other related reagents, including other pesticides, may replicate features of human parkinsonism when administered in chronic but not acute delivery regimens most likely due to specific uptake and poisoning of nigrostriatal dopaminergic neurons. Paraquat-induced models have similar limitations as rotenone models, but due to issues of specificity and technical issues, this model has not achieved wide usage beyond studies in cell culture and limited animal studies. Proteasome Inhibitors An important regulatory system within cells is the ubiquitin proteasome system (UPS), a large enzymatic complex involved in detoxification and degradation of

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ubiquitin-tagged proteins (125,126). Inhibition of the UPS can lead to the inability to remove toxic protein moieties, accumulation of protein aggregates, neuronal dysfunction, and cell death (127,128). The identification of genes involved in familial forms of parkinsonism, especially parkin (an E3 ligase of UPS) and UCH-L1 (ubiquitin carboxy terminal hydrolase L1), have implicated a role of the UPS in PD (127–130). Therefore, targeting the UPS through elevated oxidative stress, introduction of various gene mutants, or pharmacological targeting have been tested for developing parkinsonian features in animal models. The infusion of inhibitors of the UPS such as lactacystin and epoxymycin to the basal ganglia has been reported to result in the loss of tyrosine hydroxylase and DAT immunoreactivity, dopamine depletion, and the occurrence of protein inclusions in midbrain dopaminergic neurons spared from cell death (131,132). The potential impact of using proteasome inhibitors to generate models of PD is in its early phase where the reproducibility of different regimens is being evaluated, including differences in species (rats vs. mice) and strain susceptibility, efficacy of different chemical agents, and mode of delivery. GENETIC MODELS OF PARKINSON’S DISEASE In addition to pharmacological and neurotoxicant models of PD, which can be induced in a variety of different species, there are also rodent models derived from either spontaneous or directed genetic manipulation. Spontaneous rodent models of movement disorders, such as the founder mutations seen in the weaver mouse and AS/AGU rat, tend to arise fortuitously and depend on their recognition by researchers, followed by successful breeding. Another approach for establishing genetic rodent models is through targeting specific genes of interest creating a transgenic mouse line. The recent identification of genes implicated in the etiology of familial forms of PD, including alpha-synuclein (PARK1), parkin (PARK2), UCH-L1 (PARK5), PINK1 (PARK6), DJ-1 (PARK7), and LRRK2 (PARK8), have provided a starting point in the development of specific transgenic mouse lines. The goal of these transgenic lines is to replicate in the rodent some of the neurochemical, pathological, or behavioral features of the human condition. This is not a simple matter, as illustrated by the wide range of outcomes in the characterization of alpha-synuclein transgenic lines. The findings from generating transgenic models targeting alpha-synuclein emphasize the complexity and variability in outcome measures with this approach. Although many different laboratories have generated alpha-synuclein transgenic mice, the importance of transgene sequence (wildtype or different mutant alleles), promoter strength and cell-type specificity, copy number, insertion site, and background strain all influence features of this model. The following sections will highlight both spontaneous and transgenic rodent models of PD, many of which are still in their early stages of development and characterization. Spontaneous Rodent Models for Parkinson’s Disease There are several naturally occurring spontaneous mutations in rodents that are of particular interest in PD. Spontaneous rodent models include the weaver, lurcher, reeler, Tshrhyt, tottering, and coloboma mice and the AS/AGU and circling (ci) rat. These models possess unique characteristics that may provide insight into neurodegenerative processes of PD and related disorders. Several of these spontaneous rodent models display altered dopaminergic function or neurodegeneration, and have

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deficits in motor behavior (133). For example, the weaver mouse displays cell death of dopaminergic neurons, whereas the tottering mouse displays tyrosine hydroxylase hyper-innervation. The AS/AGU rat is a spontaneous model characterized by progressive rigidity, staggering gait, tremor, and difficulty in initiating movements (134). This strain arises from a recessive mutation within the gene encoding protein kinase C-gamma, suggesting another interesting gene implicated in neurodegeneration (135,136) affecting both the dopaminergic and serotonergic systems (135). Microdialysis in the AS/AGU rat model has revealed that even prior to dopaminergic neuronal cell death, there is dysfunction in dopaminergic neurotransmission that correlates with behavioral deficits. Another potentially interesting rodent model is the circling (ci) rat (137). This animal model displays spontaneous rotational behavior, as a result of an imbalance in dopaminergic neurotransmission despite the absence of asymmetric nigral cell death. Another naturally occurring mutation is the aphakia mouse. This mutation affects a gene called Pitx3, which is a developmentally regulated homeobox containing transcription factor necessary for the establishment of midbrain dopaminergic neurons (138). Mice carrying mutations in Pitx3 display behavioral and neurochemical characteristics similar to the anatomical and functional deficits seen in PD, including cell loss in the substantia nigra dopaminergic neurons, a feature not seen in most transgenic mouse lines (139). The deficits in motor behavior can be rescued with levodopa replacement therapy. These mice demonstrate the importance of developmental factors for midbrain dopaminergic neurons and could reveal key therapeutic targets for treating PD (140). Transgenic Mouse Models The development of transgenic animal models is dependent on identifying the potential role of genes of interest to the etiology of PD. A transgenic mouse is an animal in which a specific gene of interest has been altered through one of several techniques, including (i) the excision of the host gene (knock-out), (ii) the introduction of a mutant gene (knock-in), and (iii) the alteration of gene expression (knock-down, null, or over-expression). In PD, one source of transgenic targeting is derived from genes identified through epidemiological and linkage analysis studies. Alphasynuclein and parkin are examples of genes that have been identified through linkage analysis in familial forms of parkinsonism. Once the transgene has been constructed, the degree of its expression and its impact on the phenotype of the animal depends on many factors, including the selection of sequence (mutant vs. wild-type), site of genomic integration, number of copies recombined, selection of transcription promoter, and upstream controlling elements (enhancers). Other important factors may include the background strain and age of the animal. These different features may account for some of the biochemical and pathological variations observed among transgenic mouse lines. Alpha-Synuclein Rare cases of autosomal dominant familial forms of PD (the Contursi, German, and Iowa kindreds) have been linked to A30P and A53T substitution mutations in the gene encoding alpha-synuclein or triplicate of the gene (141–143). The normal function of alpha-synuclein is unknown, but its localization and developmental expression suggests a role in neuroplasticity, neurotransmission, and vesicular function (144–146). The disruption of normal neuronal function may lead to the loss of synaptic maintenance

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and subsequent degeneration. It is interesting that mice with knockout of alphasynuclein are viable suggesting that a “gain-in-function” phenotype or other protein–protein interactions may contribute to neurodegeneration. Although no mutant forms of alpha-synuclein have been identified in idiopathic PD, its localization to Lewy bodies (including PD and related disorders) has suggested a pathophysiological link between alpha-synuclein aggregation and neurodegenerative disease (147,148). An interesting caveat is that the mutant allele of alpha-synuclein in the Contursi kindred is identical to the wild-type mouse suggesting that protein expression and/or protein–protein interactions, leading to a yet unidentified gain of function may be more important than loss of function due to missense mutation. Since the identification of alpha-synuclein in familial PD, many groups have developed transgenic mouse models (149–163). A review of the transgene construction parameters (species and/or mutant forms), promoter selection (neuron or glia specific), and gene and protein expression patterns or levels demonstrates a high degree of variability in the resulting transgenic strains. Some transgenic mouse lines show neurochemical or pathological changes in dopaminergic neurons (including inclusions, decreased striatal dopamine, and loss of striatal tyrosine hydroxylase immunoreactivity) and behavioral deficits (rotarod and attenuation of dopamine-dependent locomotor response to amphetamine), whereas other lines show no deficits. No group has reported the specific loss of substantia nigra dopaminergic neurons despite inclusion pathology or cell death in other areas of the brain. This range of results with different alphasynuclein constructs from different laboratories underscores the important link between protein expression (mutant vs. wild-type alleles) and pathological and behavioral outcome. Important applications of alpha-synuclein transgenic mice are occurring at the level of understanding the role of this protein in basal ganglia function. For example, the response of alpha-synuclein expression to neurotoxic injury as well as interactions with other proteins, including parkin, will provide valuable insights into mechanisms important to neurodegeneration (164). Some groups report evidence of neuronal dysfunction (either physiological or motor behavioral changes) without cell death. This suggests that cell death may in fact be a component of the late phase in the progression of basal ganglia degeneration while neuronal dysfunction may occur at the level of the synapse and connectivity. Parkin An autosomal recessive form of juvenile parkinsonism (AR-JP) led to the identification of a gene on chromosome 6q27 called parkin (165,166). Mutations in parkin may account for the majority of autosomal recessive familial cases of PD. Parkin protein has a large N-terminal ubiquitin-like domain and C-terminal cysteine ring structure and is expressed in the brain (167–169). Recent biochemical studies indicate that parkin protein may play a critical role in mediating interactions with a number of different proteins involved in the proteasome-mediated degradation pathway, including alpha-synuclein (164,170). Null mutations in mice appear normal with respect to motor behavior with no evidence of cell loss; however, striatal dopamine levels are elevated with enhanced synaptic excitability in striatal neurons (171). Mutations of the parkin gene have been introduced into transgenic mice. At present, there is very little known about pathological or behavioral alterations due to mutations in parkin protein. However, parkin transgenic models enable investigation of the ubiquitin-mediated protein degradation pathways and its relationship to neurodegenerative disease.

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DJ-1 Mutations in the DJ-1 gene are associated with rare forms of autosomal recessive early-onset PD (172). Mice with knock-out of DJ-1 appear hypoactive, show no apparent loss of midbrain dopaminergic neurons, but do display altered electrophysiological properties in striatal neurons that can be rescued by targeting dopamine receptor D1 (173). Analysis of the structure, function, and pattern of expression of DJ-1 in mice, Drosophila, and in cell culture indicate that DJ-1 protein interacts with mitochondria playing a role in oxidative stress and apoptosis (174,175). DJ-1 has been shown to interact with a number of other proteins implicated in familial parkinsonism, including alpha-synuclein, thus regulating its function and potential toxicity (176). UCH-L1 UCH-L1 is a member of the family of de-ubiquitinating enzymes responsible for mediating monomeric subunits from poly-ubiquitin chains (177). Mutations in UCHL1 result in impaired clearance of ubiquitin and ubiquitinated proteins, therefore leading to elevated cell toxicity, protein accumulation, and cell death. At present, transgenic mice with altered UCH-L1 expression have been examined in the context of spermatogenesis and not extensively on alterations in basal ganglia function (178,179). Some studies have reported increased synuclein accumulation and neuropathology in UCH-L1 transgenic mice supporting interactions between synuclein and the UPS (180). LRRK2 The leucine-rich repeat kinase 2 gene (LRRK2), also called Dardarin, encodes a large polymer of 2527 amino acids protein with multiple structural motifs (181). Mutations in this gene have been identified in familial forms of PD that result in autosomal dominant late-onset PD (182–184). The precise function of LRRK2 is currently unknown, but recent studies have suggested that this cytoplasmic protein can associate with other PD proteins, including parkin, and possesses kinase activity (185,186). Ongoing structural/functional analysis of this large complex protein will reveal more precisely its role in neurodegenerative disorders and will guide the development of transgenic animals for study. PINK1 A locus for a rare familial form of PD maps to chromosome 1p36 and is termed PINK1 (phosphatase and tensin homolog induced kinase-1) (187). The function of PINK1 is thought to be in the protection of mitochondria from oxidative stress (188,189). In addition, PINK1 may serve to control interactions with regulatory factors involved in apoptosis (189). Transgenic mice affecting PINK1 have not yet been reported. Nurr1 Nurr1 is a transcription factor that is highly expressed in early development, and disruption of this gene results in the failure to develop nigrostriatal dopaminergic neurons in postnatal life (190,191). Nurr1 expression decreases with age and in patients with PD, suggesting that this protein may play a role in maintaining dopamine cell function and integrity (192). Transgenic mice disrupting Nurr1 expression show lack of development of nigrostriatal dopaminergic neurons based on tyrosine hydroxylase immunoreactivity (193–197). Although the time course of midbrain dopaminergic cell death in PD is unclear, the Nurr1 transgenic strains may

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provide insight into understanding dopamine cell development, potential susceptibility to PD in the context of dopamine dysfunction, and elucidation of the role of Nurr1 may act to guide stem cells as a therapeutic replacement for lost neurons. Other Transgenic Mice and Vector Infusion The function of the basal ganglia is dependent on a wide range of proteins involved in dopamine biosynthesis, metabolism, uptake, and neurotransmission. To elucidate the role of numerous proteins in basal ganglia development, function, dysfunction, and their potential role in PD and its treatments, a wide spectrum of transgenic animals have been developed. These include transgenic mice targeting tyrosine hydroxylase, DAT, monoamine oxidase A and B, catechol-O-methyl-transferase (COMT), dopamine receptors, and vesicular monoamine transporter 2 (vmat-2). These mice are instrumental in elucidating the regulation of dopamine neurotransmission and its link to motor behavior. In addition, genes and proteins involved in other features of basal ganglia function or susceptibility to toxicity, but not directly involved in dopamine neurotransmission, have also been developed, including those for neurotrophic factors [such as brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and their receptors]; immune response components (IL-6, TNF-alpha); and other neurotransmitter systems, including those for glutamate, adenosine, and acetylcholine. It is important to recognize the importance of these various genetic models and their potential impact in understanding normal and diseased basal ganglia function and identifying new therapeutic treatments. It should be noted that with the advent of new vector technologies based on infectious viruses, including lentivirus and adenovirus, genes of interest are introduced directly into the brain using stereotaxic targeting. This allows genes to be introduced to adult animals avoiding the potential confounder in transgenic lines where some gene manipulations are embryonic lethal, fail to thrive postnatal, or other systems may compensate in development for a specific gene deficiency. For example, induction of neurodegeneration can be achieved by direct targeting of alpha-synuclein or tau into the midbrain dopaminergic neurons (198–201). Genes beneficial to neuron protection and repair can also be delivered directly to their site of action in the brain. These include those genes encoding neurotrophic factors like GDNF or dopamine biosynthesis (202–206). Targeting to specific regions to regulate basal ganglia function such as inhibition of the subthalamic nucleus has been reported with some success (207). Studies are still underway to evaluate different parameters of delivery, stability, toxicity, and long-term efficacy, as well as evaluation in nonhuman primate models prior to clinical applications. A number of clinical trials using viral vectors are currently in early phase studies. INVERTEBRATE MODELS Although the anatomical differences between Homo sapiens and Drosophila melanogaster are somewhat dramatic, invertebrates such as D. melanogaster are now providing an important avenue for understanding neurodegenerative disorders (208). Similar to studies in rodents, flies have served as a template for exposure to toxins implicated in PD, including rotenone and paraquat (209). A number of recently identified genes involved in familial forms of PD, including alphasynuclein, parkin, and DJ-1, in conjunction with the molecular tools available for gene transfer, have resulted in the establishment of transgenic fly lines expressing these genes (210). These new models are significant because they can be used to elucidate the

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biochemical function of these proteins, identify other interacting proteins and regulatory genes, and because of their less expensive costs and potential for high volume screening ultimately can be used to screen large chemical libraries for new therapeutic agents (211). One of the first examples of fly models of human neurodegenerative disorders was the introduction of both wild-type and mutant forms of human alphasynuclein that resulted in loss of tyrosine hydroxylase dopaminergic neurons, the formation of intra-cytoplasmic and neurite protein aggregates, and progressive motor behavior impairment (210). The availability of powerful transposon-based screens can be used to find compensatory mutants and proteins that interact with alphasynuclein, such as the chaperone protein Hsp-70, thus providing insights into structure and function relationships (212). The success of alpha-synuclein transgenic flies has provided a strong foundation for the development of other transgenic D. melanogaster models. For example, targeting the parkin gene, despite showing little evidence of specific dopaminergic neuron cell death (213), do manifest mitochondrial pathology and neuromuscular dysfunction (214). In addition, they show increased sensitivity to oxidative stress and wide-scale degeneration, which may provide insight into the relationship between vulnerability of high-energy demand cells to injury and death (215). Another example of the impact of D. melanogaster models in neurodegenerative disorders is the demonstration of the development of DJ-1 transgenic flies. D. melanogaster possess two alleles of DJ-1, but P-element-based gene disruption leads to impaired climbing ability that is progressive with age and localization to mitochondria, but no apparent loss of dopaminergic neurons (216). Recent studies in D. melanogaster suggest that DJ-1 may function as a redox-sensitive molecular chaperone that can protect against oxidative stress, underlying the susceptibility of mitochondria (217). Hence, flies with disruption of DJ-1 show increased sensitivity to induction of oxidative stress by hydrogen peroxide, rotenone, and paraquat (218). These studies highlight insights into the function of DJ-1 in D. melanogaster and provide a better understanding of its potential role in PD (219). MODELS OF PARKINSON’S DISEASE VARIANTS Although the models discussed earlier provide insights into PD as well as variants of PD such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), other models have been developed that share a greater similarity with these variants. Multiple System Atrophy and Striatonigral Degeneration MSA is a variant of PD characterized by a combination of clinical symptoms involving cerebellar, extra-pyramidal, and autonomic systems. The predominant subtype of MSA is striatonigral degeneration (SND), a form of levodopa unresponsive parkinsonism. Neuropathological changes of SND include degeneration of the nigrostriatal pathway, medium spiny striatal GABAergic projection pathways (putamen greater then caudate), as well as other regions of the brainstem, cerebellum, and spinal cord. Inclusion-like aggregates that immuno-stain for ubiquitin and alphasynuclein are seen in oligodendrocytes and neurons. The basis for developing an animal model for SND emerged from established animal models for both parkinsonism having SNpc pathology and Huntington’s disease (HD) with striatal pathology. For example, rodent models for SND have been

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generated through sequential stereotaxic injections of 6-OHDA and quinolinic acid (QA) into the medial forebrain bundle and striatum or striatal injections of MPP+ and 3-nitropropionic acid (3-NP) (220–222). These double-lesioning models are characterized morphologically by neuronal degeneration in the SNpc and ipsilateral striatum. The order of neurotoxic lesioning may influence the degree of nigral or striatal pathology. For example, animals receiving 6-OHDA prior to QA exhibit predominantly nigral pathology, whereas animals receiving QA prior to 6-OHDA show predominantly striatal pathology. This may be due to QA-induced terminal damage or other complex interactions after lesioning that reduce the terminal uptake of 6OHDA. Glial inclusions have not been reported in any of these models, indicating a significant difference compared with the human condition. Motor deficits in models for MSA and SND are assessed by ipsilateral and contralateral motor tasks (including stepping response, impaired paw reaching, and balance) and drug-induced circling behavior. As described earlier, characteristic drug-induced circling behavior occurs after 6-OHDA lesioning, resulting in ipsilateral rotation in response to amphetamine and contralateral rotation in response to apomorphine. The subsequent striatal lesioning with QA diminishes or has no affect on amphetamine-induced ipsilateral rotation and reduces or abolishes apomorphineinduced contralateral rotation. This observation may be mediated by dopamine release on the intact side in response to amphetamine and/or the loss of dopamine receptor activation on the lesioned side in response to apomorphine. The lack of response to apomorphine has been shown to correlate with the volume of the striatal lesion and is analogous to the diminished efficacy of levodopa therapy observed in the majority of SND patients. A nonhuman primate (Macaca fasicularis) model of SND has been generated through the sequential systemic administration of MPTP and 3-NP (220,223). The parkinsonian features after MPTP-lesioning are levodopa responsive; however, subsequent administration of 3-NP worsens motor symptoms and nearly eliminates the levodopa response. Levodopa occasionally induces facial dyskinesia as sometimes seen in human MSA. Similar to SND, morphological changes include cell loss in the SNpc (typical of MPTP-lesioning) and severe circumscribed degeneration of striatal GABAergic projection neurons (typical of 3-NP lesioning). Despite the similarities with the human condition, the MSA model is characterized by an equal degree of lesioning in the putamen and caudate nucleus, whereas in human SND, the putamen is more affected. In addition, inclusion bodies that may underlie the pathogenesis of SND have not been reported in the nonhuman primate model. Tauopathies Including Progressive Supranuclear Palsy and Other Tau-Related Disorders The low molecular weight microtubule-associated protein tau has been implicated in a number of neurodegenerative diseases, including Alzheimer’s disease, PSP, Pick’s disease, frontotemporal dementia with parkinsonism (FTDP), and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam. Together these neurodegenerative diseases are referred to as tauopathies since they share common neuropathological features, including abnormal hyper-phosphorylation and filamentous accumulation of aggregated tau proteins (224). Reports have implicated either alternative RNA splicing (generating different isoforms) or missense mutations as mechanisms underlying many of the tauopathies. Therefore, transgenic mice have been generated that over-express specific splice variants or missense mutation

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of tau (225). One such transgenic line has been developed to over-express the shortest human tau isoform (226). These mice showed progressive motor weakness, intraneuronal and intra-axonal inclusions (detectable by one-month postnatal), and reduced axonal transport. Fibrillary tau inclusions developed in the neocortical neurons after 18 months of age implicating age-specific processes in the pathogenesis of fibrous tau inclusions. An interesting tau transgenic has been developed in D. melanogaster where expression of a tau missense mutation showed no evidence of large filamentous aggregates (neurofibrillary tangles). However, aged flies showed evidence of vacuolization and degeneration of cortical neurons (227). These observations suggest that tau-mediated neurodegeneration is age-dependent and may take place independent of protein aggregation. CONCLUSIONS The understanding of PD and related disorders has been advanced through animal models using genetic, pharmacological, and neurotoxicant manipulation. Each animal model has its own unique strengths and limitations. There is no “best model” for PD. Investigators must select the most appropriate model for the specific research question under investigation. Therefore, justification of nonhuman primates, the 6OHDA rat, or the MPTP-mouse can be made in different cases and the most appropriate model should be selected. The nonhuman primate, rodent, cat, and Drosophila models have contributed to the development of symptomatic (dopamine modulation), neuroprotective (antioxidants, free-radical scavengers), and restorative (growth factors, transplantation) therapies. In addition, these animal models have furthered the understanding of important aspects in the human condition shedding light on critical aspects of PD, including motor complications (wearing-off and dyskinesia), neuronal cell death, nondopaminergic systems, and neuroplasticity of the basal ganglia. Future direction in PD research is through the continued development of animal models with altered genes and proteins of interest. In conjunction with existing models, these genetic-based models will help researchers better understand PD and will lead to improved treatments and the eventual cure of PD and related disorders. ACKNOWLEDGMENTS We would like to thank our colleagues at the University of Southern California for their support, and to Beth Fisher, Mickie Welsh, Tom McNeill, and Mark Lew for their suggestions. Studies in our laboratory were made possible through the generous support of the Parkinson’s Disease Foundation, The Baxter Foundation, The Zumberge Foundation, the NIH (1RO1NS44327), and US Army NETRP. Special thanks to the friends of the USC Parkinson’s Disease Research Group for their generous support, and to Nicolaus, Pascal, and Dominique for their patience and encouragement. REFERENCES 1. Jellinger K. Pathology of Parkinson’s syndrome. In: Calne, D.B., ed. Handbook of Experimental Pharmacology. Vol. 88. Berlin: Springer, 1988:47–112. 2. Birkmayer W, Hornykiewicz O. Der 1-3,4-dioxy-phenylanin (l-DOPA)-effek bei der Parkinson-akinesia. Klin Wochenschr 1961; 73:787.

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181. Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 2004; 44(4):595–600. 182. Mata IF, Kachergus JM, Taylor JP, et al. Lrrk2 pathogenic substitutions in Parkinson’s disease. Neurogenetics 2005; 6(4):171–177. 183. Skipper L, Shen H, Chua E, et al. Analysis of LRRK2 functional domains in nondominant Parkinson disease. Neurology 2005; 65(8):1319–1321. 184. Ozelius LJ, Senthil G, Saunders-Pullman R, et al. LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. N Engl J Med 2006; 354(4):424–425. 185. West AB, Moore DJ, Biskup S, et al. Parkinson’s disease-associated mutations in leucinerich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 2005; 102(46): 16,842–16,847. 186. Smith WW, Pei Z, Jiang H, et al. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci USA 2005; 102(51):18,676–18,681. 187. Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 2004; 304(5674):1158–1160. 188. Shen J, Cookson MR. Mitochondria and dopamine: new insights into recessive parkinsonism. Neuron 2004; 43(3):301–304. 189. Petit A, Kawarai T, Paitel E, et al. Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem 2005; 280(40):34,025–34,032. 190. Law SW, Conneely OM, DeMayo FJ, et al. Identification of a new brain-specific transcription factor, NURR1. Molec Endocrin 1992; 6(12):2129–2135. 191. Zetterstrom RH, Solomin L, Jansson L, et al. Dopamine neuron agenesis in Nurr1deficient mice. Science 1997; 276(5310):248–250. 192. Chu Y, Le W, Kompoliti K, et al. Nurr1 in Parkinson’s disease and related disorders. J Comp Neurol 2006; 494(3):495–514. 193. Tornqvist N, Hermanson E, Perlmann T, et al. Generation of tyrosine hydroxylaseimmunoreactive neurons in ventral mesencephalic tissue of Nurr1 deficient mice. Brain Res Dev Brain Res 2002; 133(1):37–47. 194. Jankovic J, Chen S, Le WD. The role of Nurr1 in the development of dopaminergic neurons and Parkinson’s disease. Prog Neurobiol 2005; 77(1–2):128–138. 195. Eells JB. The control of dopamine neuron development, function and survival: insights from transgenic mice and the relevance to human disease. Curr Med Chem 2003; 10(10):857–870. 196. Eells JB, Lipska BK, Yeung SK, et al. Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity. Behav Brain Res 2002; 136(1):267–275. 197. Witta J, Baffi JS, Palkovits M, et al. Nigrostriatal innervation is preserved in Nurr1-null mice, although dopaminergic neuron precursors are arrested from terminal differentiation. Brain Res Mol Brain Res 2000; 84(1–2):67–78. 198. Klein RL, Dayton RD, Lin WL, et al. Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat. Neurobiol Dis 2005; 20(1):64–73. 199. Kirik D, Georgievska B, Bjorklund A. Localized striatal delivery of GDNF as a treatment for Parkinson disease. Nat Neurosci 2004; 7(2):105–110. 200. Kirik D, Annett LE, Burger C, et al. Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci USA 2003; 100(5):2884–2889. 201. Klein RL, King MA, Hamby ME, et al. Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum Gene Ther 2002; 13(5): 605–612. 202. Bankiewicz KS, Eberling JL, Kohutnicka M, et al. Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol 2000; 164(1):2–14. 203. Azzouz M, Martin-Rendon E, Barber RD, et al. Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I induces sustained transgene expression, dopamine production,

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Genetics Akiko Imamura, Matthew J. Farrer, and Zbigniew K. Wszolek Mayo Clinic, Jacksonville, Florida, and Mayo School of Graduate Medical Education, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.

INTRODUCTION Despite considerable progress in understanding the clinical and pathological features of Parkinson’s disease (PD), the etiology of this condition is unknown (1,2). Current working hypotheses are based primarily on two plausible explanations: the environmental hypothesis and the genetic hypothesis. The environmental hypothesis, which was widely propagated in the 1980s, appears to have had only limited influence (3). The genetic hypothesis, which gained popularity in the 1990s, stemmed from considerable progress in the development of new molecular genetic techniques and from the description of several large families with a parkinsonian phenotype closely resembling that of sporadic PD (4–6). However, genetic factors still do not explain the etiology of all cases of PD (7). Thus, a combination of environmental and inherited risk factors may play a crucial role in the development of disease in most cases of parkinsonism. Understanding the causes of PD is further complicated by a lack of in vivo biological markers for diagnosis, which requires reliance on clinical or pathological criteria (8). In addition, rather than being a uniform clinical and pathological entity, PD most likely represents a cluster of heterogeneous syndromes (9,10). In this chapter, we discuss the contributions of epidemiologic, twin, kindred, and association studies in support of the genetic hypothesis of PD. EPIDEMIOLOGIC STUDIES Epidemiologic studies indicate a genetic contribution to the pathogenesis of PD. Lazzarini et al. (11) found that the likelihood of persons in New Jersey having PD at age 80 years was about 2% for the general population and about 5% to 6% if a parent or sibling was affected. However, if both a parent and a sibling were affected, the probability of having PD increased to 20% to 40%. Marder et al. (12) assessed the risk of PD among first-degree relatives living in the same geographic region (northern Manhattan, New York, U.S.A.). They found a 2% cumulative incidence of PD to age 75 years among first-degree relatives of patients with PD compared with a 1% incidence among first-degree relatives of control subjects. The risk of PD was greater in male than in female first-degree relatives [relative risk, 2.0; 95% confidence interval (CI): 1.1–3.4]. The risk of PD in any first-degree relative was also higher for whites than for African Americans or Hispanics (relative risk, 2.4; 95% CI: 1.4–4.1). Rocca et al. (13) reported that relatives of probands who were younger (<66 years) at onset of PD had a significantly increased risk (relative risk, 2.62; 95% CI: 1.66–4.15; P = 0.02), whereas relatives of probands with later onset had no increased risk. In an Italian case-control study (14), history of familial PD was the most relevant risk factor (odds ratio, 14.6; 95% CI: 7.2–29.6). In a Canadian study of PD patients (15), the prevalence rate in first- and second-degree relatives was more than 269

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five times higher than that of the general population. Even patients who reported a negative family history of PD actually had a prevalence rate in relatives more than three times higher than that of the general population. A study of the Icelandic population (16) revealed the presence of genetic as well as environmental components in the pathogenesis of late-onset PD (onset at >50 years of age). The risk ratio for PD in relatives of patients with late-onset PD was 6.7 (95% CI: 4.3–9.6) for siblings, 3.2 (95% CI: 1.2–7.8) for offspring, and 2.7 (95% CI: 1.6–3.9) for nephews and nieces. The findings of Maher et al. (17) for 203 sibling pairs with PD also supported a genetic contribution to the pathogenesis of PD. Sibling pairs with PD were found to be more similar in age at symptomatic disease onset than in year of symptomatic disease onset. The frequency of PD in parents (7%) and siblings (5.1%) was greater than that in spouses (2%). TWIN STUDIES Studies of twins may be used to estimate the genetic contribution to the pathogenesis of a neurodegenerative condition. If a genetic component is present, concordance will be greater in monozygotic twins than in dizygotic twins. If a disorder is exclusively genetic in origin and the diagnosis is not compounded by age-associated penetrance or stochastic or environmental factors, monozygotic concordance may be close to 100%. However, PD is a heterogeneous, age-associated disease with reduced penetrance. Even within families in whom parkinsonism is caused by a single-gene defect, the age at onset and the progression and severity of symptoms in affected carriers may vary widely. Thus, even large studies of hundreds of twin pairs are likely to be underpowered to exclude a genetic component (18). Although earlier twin studies in PD were inconclusive (19–21), Tanner et al. (22) demonstrated the presence of genetic factors in the pathogenesis of PD when disease begins at or before age 50 years. They studied twins enrolled in the twin registry of the National Academy of Science and the National Research Council World War II Veteran Twins Registry. No genetic component was evident when the onset of symptoms occurred after age 50 years. A more recent study using the Swedish Twin Registry, conducted by Wirdefeldt et al. (23), demonstrated low concordance rates in twins, whether monozygotic or dizygotic. However, both of these studies were largely based on limited, cross-sectional clinical observations, and diagnostic accuracy might be improved by longitudinal evaluations (24). Positron emission tomography (PET) studies with [18F]6-fluorodopa ([18F]6-FD) may help circumvent the need for extended follow-up. Indeed, reduced striatal uptake of [18F]6-FD has been demonstrated in some clinically asymptomatic co-twins (25). Using longitudinal evaluation with measurement of [18F]6-FD, Piccini et al. (26) demonstrated 75% concordance rate in monozygotic twins versus 22% in dizygotic twins. However, these results must be interpreted cautiously. At best, [18F]6-FD uptake is only a surrogate of PD and only 18 monozygotic and 16 dizygotic twins were studied. EVALUATION OF KINDREDS Kindreds with a parkinsonian phenotype have been reported in the world medical literature since the 19th century (27). In a 1926 literature review, Bell and Clark (28) described 10 families with “shaking palsy” believed to be hereditary. They also provided 20 references of earlier accounts of familial paralysis agitans. In 1937, Allen

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(29) detailed an additional 25 families with inherited parkinsonism and speculated that the inheritance was autosomal dominant and probably the result of a single autosomal gene in about two-thirds of these kindreds. In 1949, Mjönes (30) detailed eight pedigrees with inherited parkinsonism, some with atypical features such as myoclonic epilepsy. In the levodopa era (from the early 1960s to now), numerous reports described families with PD and parkinsonism-plus syndrome (31), including two large multigenerational kindreds known as the Contursi (32) and Family C (German-American) (33) kindreds. As molecular genetic techniques have improved, the importance of collecting data from parkinsonian families with PD has grown exponentially. Eleven monogenetic PARK loci have been identified (Table 1). The PARK4 locus was reclassified because it shares the same gene (SNCA; α-synuclein) as the PARK1 locus (34). The PARK9 locus has been described in the Kufor-Rakeb kindred, with affected family members having atypical parkinsonism associated with dementia, spasticity, and supranuclear palsy (35). Mutations in six genes have been implicated in parkinsonism: SNCA (PARK1) in 1997 (34), parkin (PARK2) in 1998 (36), UCHL1 (PARK5) in 1998 (37), DJ-1 (PARK7) in 2001 (38), PINK (PARK6) in 2004 (39), and LRRK2 (PARK8) in 2004 (40,41). LRRK2 G2019S has now become the most common cause of PD and may account for 1% to 1.6% of sporadic patients and 3% to 10% of familial patients in Europe, America, and Asia (41–52). However, the frequency is higher and the associated haplotype (60 kb[53]) is shorter in North African Arabs, for whom the mutation may be responsible for 40% of PD. Additional PARK loci and contributing genes are likely to be identified through family studies, ultimately facilitating a molecular rather than a clinicopathologic diagnosis. Mutations in genes implicated in parkinsonism have already been used to create in vivo models. These gene mutations can recapitulate the pathogenesis as well as the symptoms of disease, and they may provide powerful insight into neuronal degeneration. They facilitate validation of biomarkers of disease progression and neuroprotection strategies (54–56). Much as is the case with Alzheimer’s disease, these new tools bring the hope of novel therapies for PD that are designed to address the causes rather than merely the symptoms of the disease (57). The table summarizes the status of the current knowledge about the mendelian genetics of PD. It shows the types of inheritance and the location of known chromosomal loci and disease-linked mutations. The key references in the medical literature are also provided. ASSOCIATION STUDIES Despite substantial progress in identification, there are only a few known large pedigrees with PD. Furthermore, genetic linkage studies that use “identity-by-descent” mapping have been hampered because of the limited amount of DNA available from affected pedigree members, generally because of death, lack of consent, or geographic dispersion. Association or “identity-by-state” mapping is an alternate approach using groups of unrelated persons. Association studies measure differences in genetic variability between a group with the disease in question and a group of matched healthy persons. This method is most powerful in implicating genes for multigenic traits in homogeneous population isolates. Many past studies have been confounded by misconceived a priori notions about the causes of disease, by the candidate genes

SNCA Parkin Unknown UCHL1c PINK1 DJ-1 LRRK2 Unknown

4q21

6q25.2-27 2p13 4p14 1p35-36 1p36 12p11.2-q13.1 1p36

1p 2q36-37

PARK1, PARK4 PARK2 PARK3 PARK5 PARK6 PARK7 PARK8 PARK9

PARK10 PARK11

Unknown AD

AR AD AD AR AR AD AR

AD

Inheritance

Middle Middle to senior

Young Middle to senior Middle Middle Young to middle Middle to senior Young

Young to middle

Age at onseta

PD PD PD PD PD PD Atypical PD, D, PSP PD PD

PD and D

Phenotype

Unknown Unknown

LB or tau LBs Unknown Unknown Unknown LBs, tau(+) NFT Unknown

LBs

Pathologic findings

Good Good

Good Good Good Good Good Good Good

Good

Response to levodopa

(71) (72)

(36) (33) (70,71) (38) (37) (39,40) (35)

(34)

Reference

Note: Since the submission of this chapter two additional parkinsonian loci (PARK12 and PARK13) have been identified (Pankratz N, Nichols CW, Uniacke KS, et al. Genomewide linkage analysis and evidence of gene-by gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Mol Genet 2003; 15:2599–2608; Strauss KM, Martins LM, Plun-Favreau H, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 2005; 14:2099–2111). a Younger age at onset, ≤40 years; middle age at onset, between 41 and 60 years; senior age at onset, ≥60 years. b Three missense mutations or multiplications. c Two mutations. Abbreviations: AD, autosomal dominant; AR, autosomal recessive; D, dementia; LBs, Lewy bodies; NFT, neurofibrullary tangle; PD, Parkinson’s disease; PSP, progressive supranuclear palsy; UCH-L1, ubiquitin carboxy-terminal hydrolase L1.

Unknown Unknown

b

Gene

Chromosome

Locus

TABLE 1 Familial Parkinsonism with Reported Mutations or Loci

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or variants chosen for analysis, and by clinical, locus, and allelic heterogeneity. Results must be reproducible, preferably in different ethnic populations, and the genetic variability associated with disease should have some functional consequence (either directly or in disequilibrium) that alters gene expression or the resultant protein. The genes for SNCA, parkin, UCHL1, PINK1, DJ-1,and LRRK2 harbor mutations that segregate with parkinsonism in affected family members (35–48) (Fig. 1). Although the relevance of these findings for sporadic PD is still unclear, there is no doubt that these proteins mark a pathway that is perturbed in both familial and sporadic PD. Understanding the components of the pathway and its regulation is the first step toward elucidating the molecular causes of parkinsonism (49). In some studies, common genetic variability in genes for SNCA (58,59), UCHL1 (60–62), DJ-1 (63–65), PARK2 (66), PINK1 (67), and LRRK2 (47–52,68,69) has been implicated in sporadic PD by association. These genes clearly contribute to risk in at least a subset of patients with idiopathic PD. Genome-wide methods of association have taken a less biased view than candidate gene association studies in PD (69). Although promising, given their power and multiple testing, such methods nonetheless require genetic and functional validation of their results. CLINICAL MOLECULAR GENETIC TESTING At present, diagnostic molecular genetic testing is commercially available for parkin and PINK1 gene mutations and can be done for selected patients. However, appropriate counseling should be provided either by the treating physician or a clinical geneticist, along with psychological support. Commercial genetic testing for parkinsonian genes should be interpreted with caution. A positive finding contributes only to the probability that the person will become affected, because most mutations gain or lose function and are associated with age-dependent penetrance. Indeed, for most genes and mutations, the age-associated risk to carriers has yet to be formally described. Despite the explosive progress in genetic research, not all mutations in PD have been functionally validated and some rare variants could be benign polymorphisms. Technical problems in test-retest reliability may also occur. These issues should be carefully and comprehensively discussed with physicians and their patients who are seeking genetic advice, as well as with asymptomatic family members who are genealogically at risk. Patients and their families must continue contributing to genetic research to identify new genes, understand the molecular pathways affected, and develop new treatments. However, this genetic testing can be de-identified and blinded to test results to help make more general advances. There are many centers in the United States, Europe, Asia, and Australia that conduct molecular genetic research in PD. SUMMARY The genetics of PD and related conditions are complex, even in monogenic parkinsonism. The discovery of mutations in the genes for SNCA, parkin, UCHL1, PINK1, DJ-1, and LRRK2 has created a unique glimpse into the basic mechanisms responsible for this neurodegenerative process. Further genetic studies of already known PD loci will undoubtedly uncover more mutations in more genes. Subsequent clinical

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FIGURE 1 Genes and mutations associated with parkinsonism. Gene names are indicated in italics with their chromosomal assignment. (A) SNCA (4q21); (B) parkin (6q25.2-27); (C) UCHL1 (4p1415); (D) PINK1 (1p35-36); (E) DJ-1 (1p36); and (F) LRRK2 (12p11.2-q13.1). Boxes represent coding sequence. Amino acids (aa) are shown N’ to C’ terminal. Coding mutations are indicated above; splice-site mutations and exonic and nucleotide deletions are represented below (not to scale). *Coding polymorphism associated with disease. Source: From Ref. 57.

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and pathological correlations will aid not only our understanding of the mechanisms involved in cell dysfunction and death but also our ability to intervene. A large number of families have been described for which the genetic pathogenesis of PD has yet to be explored. The study of these families—and those yet to be discovered—will further enhance our knowledge of the biologic underpinnings of this neurodegenerative disease. With this background, an understanding of gene–gene and gene–environment interactions is also emerging. After almost 190 years, only short-term palliative remedies are presently available, but hope now exists that this work will lead to curative treatments for PD. REFERENCES 1. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999; 56:33–39. 2. Mizuno Y, Mori H, Kondo T. Parkinson’s disease: from etiology to treatment. Intern Med 1995; 34:1045–1054. 3. Kopin IJ. Tips from toxins: the MPTP model of Parkinson’s disease. In: Jolles G, Stutzman JM, eds. Neurodegenerative Diseases. San Diego: Academic Press Limited, 1994:143–154. 4. Golbe LI. Alpha-synuclein and Parkinson’s disease. Mov Disord 1999; 14:6–9. 5. Wszolek ZK, Uitti RJ, Markopoulou K. Familial Parkinson’s disease and related conditions: clinical genetics. Adv Neurol 2001; 86:33–43. 6. Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 2002; 51:296–301. 7. Payami H, Zareparsi S. Genetic epidemiology of Parkinson’s disease. J Geriatr Psychiatry Neurol 1998; 11:98–106. 8. Brooks DJ. Parkinson’s disease: a single clinical entity? QJM 1995; 88:81–91. 9. Calne DB. Parkinson’s disease is not one disease. Parkinsonism Relat Disord 2000; 7:3–7. 10. Uitti RJ, Calne DB, Dickson DW, Wszolek ZK. Is the neuropathological “gold standard” diagnosis dead? Implications of clinicopathologic findings in an autosomal dominant neurodegenerative disorder. Parkinsonism Relat Disord 2004; 10:461–463. 11. Lazzarini AM, Myers RH, Zimmerman TR Jr, et al. A clinical genetic study of Parkinson’s disease: evidence for dominant transmission. Neurology 1994; 44:499–506. 12. Marder K, Tang MX, Mejia H, et al. Risk of Parkinson’s disease among first-degree relatives: a community-based study. Neurology 1996; 47:155–160. 13. Rocca WA, McDonnell SK, Strain KJ, et al. Familial aggregation of Parkinson’s disease: the Mayo Clinic family study. Ann Neurol 2004; 56:495–502. 14. De Michele G, Filla A, Volpe G, et al. Environmental and genetic risk factors in Parkinson’s disease: a case-control study in southern Italy. Mov Disord 1996; 11:17–23. 15. Uitti RJ, Shinotoh H, Hayward M, Schulzer M, Mak E, Calne DB. “Familial Parkinson’s disease”: a case-control study of families. Can J Neurol Sci 1997; 24:127–132. 16. Sveinbjornsdottir S, Hicks AA, Jonsson T, et al. Familial aggregation of Parkinson’s disease in Iceland. N Engl J Med 2000; 343:1765–1770. 17. Maher NE, Golbe LI, Lazzarini AM, et al. Epidemiologic study of 203 sibling pairs with Parkinson’s disease: the GenePD study. Neurology 2002; 58:79–84. Erratum in: Neurology 2002; 58:1136. 18. Simon DK, Lin MT, Pascual-Leone A. “Nature versus nuture” and incompletely penetrant mutations. J Neurol Neurosurg Psychiatry 2002; 72:686–689. 19. Duvoisin RC, Eldridge R, Williams A, Nutt J, Calne D. Twin study of Parkinson disease. Neurology 1981; 31:77–80. 20. Ward CD, Duvoisin RC, Ince SE, Nutt JD, Eldridge R, Calne DB. Parkinson’s disease in 65 pairs of twins and in a set of quadruplets. Neurology 1983; 33:815–824. 21. Johnson WG, Hodge SE, Duvoisin R. Twin studies and the genetics of Parkinson’s disease: a reappraisal. Mov Disord 1990; 5:187–194. 22. Tanner CM, Ottman R, Goldman SM, et al. Parkinson disease in twins: an etiologic study. J Am Med Assoc 1999; 281:341–346.

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49. Goldwurm S, Di Fonzo A, Simons EJ, et al. The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor. J Med Genet 2005; 42:e65. 50. Bialecka M, Hui S, Klodowska-Duda G, Opala G, Tan EK, Drozdzik M. Analysis of LRRK2 G2019S and I2020T mutations in Parkinson’s disease. Neurosci Lett 2005; 390:1–3. 51. Lesage S, Ibanez P, Lohmann E, et al. French Parkinson’s Disease Genetics Study Group. G2019S LRRK2 mutation in French and North African families with Parkinson’s disease. Ann Neurol 2005; 58:784–787. 52. Bras JM, Guerreiro RJ, Ribeiro MH, et al. G2019S dardarin substitution is a common cause of Parkinson’s disease in a Portugese cohort. Mov Disord 2005; 20:1653–1655. 53. Lesage S, Dürr A, Tazir M, et al. LRRK2 G2019S as a Cause of Parkinson’s Diesease in North African Arabs. N Engl J Med 2006; 354:422–423. 54. Saigoh K, Wang YL, Suh JG, et al. Intragenic deletion of the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nat Genet 1999; 23:47–51. 55. Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 2000; 287:1265–1269. 56. Kahle PJ, Neumann M, Ozmen L, et al. Selective insolubility of α-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 2001; 159:2215–2225. 57. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-β attenuates Alzheimerdisease-like pathology in the PDAPP mouse. Nature 1999; 400:173–177. 58. Farrer M, Maraganore DM, Lockhart P, et al. α-Synuclein gene haplotypes are associated with Parkinson’s disease. Hum Mol Genet 2001; 10:1847–1851. 59. Kruger R, Vieira-Saecker AM, Kuhn W, et al. Increased susceptibility to sporadic Parkinson’s disease by a certain combined alpha-synuclein/apolipoprotein E genotype. Ann Neurol 1999; 45:611–617. 60. Maraganore DM, Farrer MJ, Hardy JA, Lincoln SJ, McDonnell SK, Rocca WA. Casecontrol study of the ubiquitin carboxy-terminal hydrolase L1 gene in Parkinson’s disease. Neurology 1999; 53:1858–1860. 61. Zhang J, Hattori N, Leroy E, et al. Association between a polymorphism of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene and sporadic Parkinson’s disease. Parkinsonism Relat Disord 2000; 6:195–197. 62. Satoh J, Kuroda Y. A polymorphic variation of serine to tyrosine at codon 18 in the ubiquitin C-terminal hydrolase-L1 gene is associated with a reduced risk of sporadic Parkinson’s disease in a Japanese population. J Neurol Sci 2001; 189:113–117. 63. Hague S, Rogaeva E, Hernandez D, et al. Early-onset Parkinson’s disease caused by a compound heterozygous DJ-1 mutation. Ann Neurol 2003; 54:271–274. 64. Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW. The role of pathogenic DJ-1 mutations in Parkinson’s disease. Ann Neurol 2003; 54:283–286. 65. Hedrich K, Djarmati A, Schafer N, et al. DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease. Neurology 2004; 62:389–394. 66. Sinha R, Racette B, Perlmutter JS, Parsian A. Prevalence of parkin gene mutations and variations in idiopathic Parkinson’s disease. Parkinsonism Relat Disord 2005; 11:341–347. 67. Valente EM, Salvi S, Ialongo T, et al. PINK1 mutations are associated with sporadic earlyonset parkinsonism. Ann Neurol 2004; 56:336–341. 68. Lesage S, Durr A, Tazir M, et al. French Parkinson’s Disease Genetics Study Group. LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. N Engl J Med 2006; 354:422–423. 69. Deng H, Le W, Guo Y, Hunter CB, Xie W, Jankovic J. Genetic and clinical identification of Parkinson’s disease patients with LRRK2 G2019S mutation. Ann Neurol 2005; 57:933–934. 70. Valente EM, Bentivoglio AR, Dixon PH, et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am J Hum Genet 2001 Apr; 68:895–900. 71. Valente EM, Brancati F, Ferraris A, et al. European Consortium on Genetic Susceptibility in Parkinson’s Disease. PARK6-linked parkinsonism occurs in several European families. Ann Neurol 2002; 51:14–18. 72. Hicks AA, Petursson H, Jonsson T, et al. A susceptibility gene for late-onset idiopathic Parkinson’s disease. Ann Neurol 2002; 52:549–555.

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Environmental Risk Factors Brad A. Racette Department of Neurology and American Parkinson Disease Association Advanced Center for Parkinson Research, Washington University School of Medicine, St. Louis, Missouri, U.S.A.

GENES VS. ENVIRONMENT In 1949, Mjones (1) conducted the first systematic study of the genetics of Parkinson’s disease (PD) and concluded that the disease was autosomal dominant with 60% penetrance. Subsequent studies have found a substantially lower prevalence of familial PD, beginning an ongoing debate regarding the relative importance of genetic versus environmental factors in the pathogenesis of PD. There are several techniques that have been used to determine the genetic and environmental contributions to the etiology of PD, including family studies, twin studies, and population kinship studies. Family studies are designed to answer three basic questions: (i) Does the disease cluster in families? (ii) Is the clustering due to genetic, shared environmental, or cultural factors? (iii) How is genetic susceptibility inherited? Clinic-based studies have found that approximately 20% of patients with PD have a positive family history, suggesting that environmental factors play a primary role in the majority of cases (2). Clusters of PD are rare but were described for decades before molecular biology techniques enabling gene isolation were developed (3,4). However, the majority of patients with PD who have a family history are not a member of a large, multi-incident pedigree. Reports of relative risk (RR) rates for first degree relatives of a PD patient vary from 2.3 to 14.6 depending upon methodology (5,6). Studies involving direct examination of all patients and controls typically found a lower genetic risk (Table 1). One family study (7) compared the relative risk of first-degree relatives of early- and late-onset cases to controls, and found a relative risk for siblings of early-onset patients of 7.9 with no increased risk in parents. However, in late-onset families, siblings (RR 3.6) and parents (RR 2.5) had an increased risk of PD compared to controls. Therefore, the heritability of PD, the proportion of variation directly attributable to genetic differences among individuals relative to the total variation in the population, is relatively low in older patients. These findings, in addition to the predominance of young-onset disease in the known genetic parkinsonisms (8–10), suggest that the younger-onset patients may have a different etiology. Twin studies can provide evidence for genetic or environmental contributions by comparing the concordance of monozygotic (MZ) twins with that of dizygotic (DZ) twins. Since twins typically share the same early environment and monozygotic twins are genetically identical, significantly higher concordance in MZ versus DZ twins implies a genetic basis of the disease. On the other hand, similar concordance in disease rate between MZ and DZ twins implicates early-life, environmental exposures in the etiology of a disease. Appropriately designed twin studies can provide powerful evidence for the genetic or environmental contributions to the disease; however, large sample sizes may be difficult to obtain, and the 279

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Racette TABLE 1 Relative Risk of Parkinson’s Disease Author Payami et al. (6) Seidler et al. (51) De Michele et al. (101) Marder et al. (5)

Examination of relatives

Relative risk

+ − + +

3.5

Odds ratio 12.6 14.6

2.3

twin environment is only controlled for approximately the first 20 years of life, confounding the interpretation of the environmental and gene-environmental contributions to the disease. Furthermore, most familial PD demonstrates age-dependent penetrance, making misclassification of phenotype possible without longitudinal follow-up of subjects. Early twin studies reporting concordance of MZ twins (11,12) were not supported in larger nonpopulation-based series (13,14). Subsequently, several population-based twin studies have found no difference in concordance between MZ and DZ twins in Finnish (15), Swedish (16), and American (17) populations. In one of these studies (17), the relative risk of PD in MZ twins was 6.0 for those with age at onset less than 50. However, these findings were based upon four concordant MZ, two concordant DZ, no discordant MZ, and 10 discordant DZ twins. Although these numbers are small, these findings are consistent with the family and linkage studies in which genetic contributions appear to be more common in younger-onset cases. Another technique to determine the relative importance of genetic and environmental influences in the etiology of PD utilizes detailed knowledge of genealogies to calculate a kinship coefficient. The kinship coefficient is defined as the probability that two alleles at the same locus, drawn at random (one from each person), are identical by descent, providing a measure of the degree of relatedness between two individuals. A large study of an Icelandic genetic database found that subjects with PD were significantly more related to each other than controls from the same population (18) leading to the discovery of the PARK10 locus (19). However, the findings of this study are population-specific and may not translate to other populations. For example, using the same methods, a recent study (20) in an Amish community found that subjects with PD were less related to each other than subjects without the evidence of PD. The authors concluded that adult environmental factors are the likely cause of PD in this community. GEOGRAPHIC DIFFERENCES IN RATES OF PARKINSON’S DISEASE Population-based prevalence and incidence studies can provide an indirect indication of potential environmental etiologies of PD, although it is impossible to compare between studies of different populations, given that genetic differences could account for the differing prevalence. Within a population, however, these studies can provide critical clues to environmental risk factors. A higher prevalence of PD in rural environments implicates regional farming practices, including pesticides, herbicides, and rural water sources. A higher prevalence of PD in urban environments potentially implicates byproducts of industrialization. Numerous studies demonstrate a higher risk of PD for individuals living in a rural environment in Alberta, Canada (21), Finland (21), the United States (22,23), and Italy (24). However, this relationship has not been found in all studies (25).

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Although the findings are inconsistent, a higher prevalence of PD in urban areas argues for byproducts of industrialization as risk factors for PD. Several studies suggest that increasing industrialization may increase PD risk. Schoenberg et al. compared the prevalence of PD in Copiah County, Mississippi, U.S.A. (341/100,000 over age 39) to Igbo-Ora, Nigeria (67/100,000 over age 39) using similar methodology, and studying genetically similar populations. They concluded that environmental factors may be responsible for the observed higher prevalence in the industrialized U.S. population (26). In contrast, a study (27) of PD in Estonia found a similar prevalence of PD in urban and rural regions, although the definitions of “urban” and “rural” were unclear. A small study (25) conducted in a health district in Canada found a lower risk of PD in industrialized areas of the district. In a population-based mortality study, Rybicki et al. (28) demonstrated that counties in Michigan, U.S.A. with a higher concentration of industries, with potential for heavy-metal exposures (iron, zinc, copper, mercury, magnesium, and manganese), had a higher PD death rate. Using levodopa prescription records as a surrogate for PD, two studies (29) have shown an increased risk of PD in areas with prominent employment in the wood pulp and steel alloy industries. Potential confounds to the surrogate diagnosis and study methodologies include inclusion of non-PD phenocopies and inability to separate working in an environment from living in an environment. Similarly, a study (30) of annual death rates by the state of U.S. World War II veterans found a higher PD death rate in a North–South gradient, with higher disease death rates in the more populated and industrialized Northern cities. Important methodologic limitations include inconsistent definitions of “rural living” and lack of information on timing of rural living, which may be a critical determinant of PD risk. If increasing world industrialization is a risk factor for PD, the incidence should be increasing throughout the last century. Only one study has addressed the incidence of PD over time. The yearly incidence of PD has not significantly changed between 1967 and 1979 in Rochester, Minnesota, U.S.A. (31). However, it is unlikely that there has been a substantial change in the industrialization of this relatively rural community over that period of time. The population prevalence of PD in the Midlands district of England increased between 1982 and 1992, potentially implicating greater regional industrialization or greater medical and public awareness of the disease (32). No preindustrial epidemiologic studies of PD exist, and many cases of PD likely went unrecognized in the beginning of industrialization in this country. It may be possible to reconcile these contradictory data with more attention to regional differences in industrial pollution and farming practices.

SPECIFIC ENVIRONMENTAL TOXINS Although studies suggest that PD may be largely an environmentally mediated disease, the clinical characteristics are unusual for a toxic process—most notably the prominent asymmetry. Several toxins have been implicated in outbreaks of parkinsonism, including carbon disulfide (33), manganese (34,35), 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (36), paraquat (37), and solvent abuse (38). In general, these cases appear to be much more symmetric than sporadic and genetic PD, as would be expected from a toxic etiology (39). It is possible that the type of exposures, including chronicity, mode of entry, and genetic factors, influence neurodegeneration but it remains unclear why environmentally mediated PD would be so strikingly asymmetric.

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Manganese Manganese (Mn) was first recognized as a neurotoxin in the 19th century with the report of four manganese ore crushers, developing a syndrome of a lower extremity predominant “muscular weakness,” festination, postural instability, facial masking, hypophonia, and sialorrhea (40). The syndrome was more clearly delineated by Rodier (35) in 1955 when he described a group of Moroccan manganese miners with a neurologic illness, characterized by parkinsonism, gait disorder, dystonia, psychosis, and emotional lability. All of these individuals worked underground, and the majority mined manganese ore. The latency to symptom onset from work exposure was one month to over 10 years. Rodier divided the syndrome into three phases: the prodromal period, the intermediate phase, and the established phase. The first phase was characterized by akinesia and apathy, followed by “manganese psychosis.” During this phase, the gait was described as “staggering,” and patients became aggressive. Early characteristics of the intermediate phase were hypophonia with vocal “freezing”, facial masking, and emotional lability. In the final phase, the patients developed rigidity, bradykinesia, tremor, flexed posture, shuffling gait, and postural instability. Some patients developed a dystonic, wide-based gait described as a “cock gait.” The disease progressed to total disability in most, despite discontinuing exposure (35). There are numerous other clinical reports of atypical parkinsonism in manganese-exposed workers (34,41). Exposure to manganese at much lower levels may also be associated with parkinsonism. The Occupational Safety and Health Administration has a permissible exposure limit ceiling for manganese of 5 mg/m3 (42). A cross-sectional epidemiologic study of workers in a manganese oxide and salt producing plant found that workers exposed to low levels of manganese (approximately 1 mg/m3) had slowed simple reaction times on a standardized reaction time test and increased hand tremor, as measured by a standardized hand steadiness assessment (43). Manganeseexposed foundry workers in Sweden (mean Mn exposure 0.18–0.41 mg/m3) demonstrated slower reaction time, reduced finger-tapping speed, reduced tapping endurance, and diadochokinesis (44–46). A larger, population-based study of workers in a manganese alloy facility found that exposed subjects had slower computerized finger-tapping scores and less hand steadiness (47). Lucchini et al. found an exposure-dependent increase in blood and urine manganese levels, and slowing of finger-tapping in workers in a ferroalloy plant exposed to low-level, chronic manganese. Even nonoccupational blood elevations in manganese are associated with an exposure-related slowing of motor tasks and difficulty with pointing tasks consistent with tremor (48). Although high-level, acute exposures are clearly associated with parkinsonism and lower-level exposures are associated with parkinsonian motor abnormalities, evidence implicating manganese in the etiology of PD is contradictory. In a population-based case-control study using blinded industrial hygiene exposure assessment, Gorell et al. (49) found that occupational exposure to copper [odds ratio (OR) = 2.49] and manganese (OR = 10.61) for more than 20 years was associated with the diagnosis of PD. However, their study only had three cases and one control with long-duration manganese exposure (50). Zayed et al. (25) found an increased risk of PD in subjects exposed to a combination of manganese, iron, and aluminum for greater than 30 years. This study did not analyze the effects of individual metals nor was there a dose-response relationship (the association was only significant with the longest duration of exposure). In addition, the study sample was small and occupational categories were broad. In a population-based German cohort, Seidler et al. (51)

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found no association between PD and occupational heavy-metal exposure, categorized in a job-exposure matrix. Another population-based study using self-reported occupational exposures found no association between PD and manganese (52). Differences in study design, populations studied, and exposures likely account for the discrepant findings in these studies. Pesticides/Herbicides Isolated reports of parkinsonism, developing after acute paraquat (37,53,54) and glyphosate (55) exposure, suggest a role of these pesticides as a risk factor for PD. However, PD is a common disease, and sporadic cases are substantial confounders to case reports. Ferraz et al. (56) performed a case-control study of parkinsonian features in a group of agricultural workers exposed to the manganese containing fungicide maneb. They found that the exposed workers (n = 50) were significantly more likely to have rigidity and a variety of constitutional symptoms than nonexposed workers (n = 19). There was no significant difference in other parkinsonian signs but the number of subjects was small. Of studies reporting a relationship between pesticide exposure and PD, the odds ratios ranged from 1.77 to 7.0 with relatively wide confidence intervals in many studies reflecting small sample sizes (51,57). Only one peer-reviewed study reported a significant odds ratio less than one for herbicides (58), and numerous studies found no relationship (22,25,59). If pesticide and herbicide exposures cause PD, those applying or working directly with the substances might be at higher risk. Few studies investigate the relative frequency of PD in pesticide/herbicide workers compared to those living (but not working) in rural environments. Gorell et al. (60) performed a population-based case-control study of 144 PD subjects with occupational exposure to pesticides and herbicides in Michigan, U.S.A. They found that occupational exposure to insecticides (OR = 3.55) and herbicides (OR = 4.10) were significant risk factors for PD; fungicide use was not associated with PD. Table 2 summarizes the positive case-control studies implicating pesticides as a risk factor for PD.

TABLE 2 Positive Parkinson’s Disease Case Control Studies for Pesticidesa Study Golbe et al. (57) Semchuk et al. (76) Hubble et al. (23) Liou et al. (102) Menegon et al. (103) Duzcan et al. (104)

Seidler et al. (51)

Gorell et al. (60) Weschler et al. (90) a

Exposure

Cases

Controls

Odds ratio (95%CI)

Pesticides Herbicides Insecticides Pesticidesa Pesticidesa Herbicides Pesticidesa Pesticidesa Insecticides/fungicides

106 130

106 260

31 120

43 240

95

95

7.0 (1.61,63.46) 3.06 (1.34,7.00) 2.05 (1.03,4.07) 3.42 (1.27,7.32) 2.89 (2.28,3.66) 3.22 2.41,4.31) 2.3 (1.2,4.4)

36

108

Herbicides Insecticides Organochlorines Insecticides Herbicides Organochlorines

380

755

144

464

34

22

a

Pesticides include all insecticides, herbicides, and fungicides.

2.96 (1.31,6.69) 4.52 (1.83,11.2) 1.97 (1.40,2.79) 1.77 (1.28,2.43) 2.31 (1.57,3.4) 3.55 (1.75,7.18) 4.10 (1.37,12.24) 5.0 (1.22,20.5)

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Carbon Disulfide An outbreak of an atypical parkinsonism in grain workers implicated the fumigant, carbon disulfide, as the cause of a syndrome characterized by cerebellar signs, bradykinesia, rest tremor, and sensory neuropathy (33,61). Atypical features such as magnetic resonance imaging (MRI) abnormalities, in some cases of paraquat exposure and atypical clinical features in carbon disulfide exposure (cerebellar signs and neuropathy), argue for a primary causative effect (37). Solvents There are several case reports of parkinsonism in humans following solvent exposures. A patient who abused lacquer thinner developed acute onset of asymmetric parkinsonism with levodopa responsiveness, but normal positron emission tomography (PET) with 6-[18F] fluorodopa ([18F]FDOPA PET) uptake (38). A patient exposed to occupational n-hexane also developed asymmetric parkinsonism with levodopa responsiveness, but reduced [18F]FDOPA PET uptake (62). A patient with mixed solvent exposures from petroleum waste developed transient parkinsonism associated with transient reduction in [18F]FDOPA PET uptake, suggesting that there may be a critical duration of exposure beyond which the symptoms are irreversible (63). Although normal [18F]FDOPA PET implies that the etiology of a patient’s parkinsonism is not likely idiopathic PD, we do not know the sensitivity and specificity of [18F]FDOPA PET for idiopathic PD. In case reports, it is difficult to elucidate causation from incidental, sporadic PD. A case-control study of 188 PD subjects drawn from a cohort study of occupational hydrocarbon exposures found that exposed subjects had a significantly earlier age of disease onset than PD controls, suggesting that hydrocarbons are an environmental accelerant (64). A follow-up study with more detailed dose reconstruction is needed to confirm these findings, as solvents are potentially an important risk factor for PD. SPECIFIC OCCUPATIONS AND PARKINSONISM Numerous epidemiologic studies have attempted to detect occupations at high risk for developing PD. Fall et al. (65) performed an occupation case-control study and found an increased risk of PD in carpenters (OR = 3.9), cabinet-makers (OR = 11), and cleaners (OR = 6.7), compared to a population-based control group. Tanner et al. (66) performed a case-control study (nonpopulation-based) of occupational exposures and PD in People’s Republic of China and found that occupations involving industrial chemical plants (OR = 2.39), printing plants (OR = 2.40), and quarries (OR = 4.50) were associated with a higher risk of PD. A population-based survey of PD in British Columbia found an association between PD and working in an orchard (adjusted OR = 2.30) or planer mill (adjusted OR = 4.97) (67). They hypothesized that industrial chemicals, including pesticides and herbicides, could be etiologic agents. Another nonpopulation-based case-control study in the same region found that occupational categories, including forestry, logging, mining, and oil/gas field work, had the highest odds ratios (3.79) (68). Although referral bias of affected subjects may have influenced the results, the number of subjects studied (n = 414) was substantial. Another nonpopulation-based case-control study in the Emilia-Romagna region of Italy found that occupational exposure to “industrial chemicals” was a risk factor for PD (OR = 2.13) (69). Among industrial chemicals, only organic solvents were identified

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as a risk factor (OR = 2.78). Limitations of this study include lack of specific information regarding occupations, small sample size, and subject selection bias. Occupational exposure to magnetic fields may be a risk factor for PD (70). A death certificate (population-based) case-control study in Colorado, U.S.A. utilizing a tiered exposure matrix found an adjusted odds ratio of 1.76 for PD subjects exposed to magnetic fields. Occupations included in this study were electronic technicians and engineers, repairers of electronic equipment, telephone and telephone line installers and repairers, electric power installers and repairers, supervisors of electricians and power transmission installers, power plant operators, motion picture projectionists, broadcast equipment operators, and electricians (70). Another study of electrical workers in a similar group of occupations found a nonsignificant, elevated odds ratio of 1.1 for PD compared to controls, but the study lacked power (71). Several studies have investigated the association between residential exposures to industrial toxins and PD. Using standard industrial code classifications, Rybicki et al. (28) found that residential exposure to industrial chemicals, iron, and paper were significantly associated with the development of PD. The counties in Michigan, U.S.A. with the highest concentration of these industries had the greatest death rate from PD, suggesting that these individuals resided in an environmentally high-risk region. In a case-control study in People’s Republic of China, subjects living near a rubber plant appeared to have a higher risk of PD; however, no specific data on those working in the plant were provided (72). Most epidemiologic studies have focused on categories of exposure and not on specific occupations. A few occupations warrant specific attention, given the type of chemical exposures or the amount of data supporting these occupations in the etiology of PD. Farming Studies demonstrate both an association (73–75) and lack of an association (51,76,77) between PD and farming. Duration of plantation work demonstrated a significant relationship with PD in the population-based Honolulu Heart study (78). In a nonpopulation-based case-control study (67), orchard workers had a higher risk of PD. The association between rural residences is difficult to dissociate from farming as an occupation for the more traditional family farms. Not all studies corrected for established PD confounders, such as tobacco use, and less-established environmental confounders, such as pesticide/herbicide use or well water. Most of these studies used standard clinical criteria or expert diagnosis and had relatively small sample sizes. Furthermore, none of the studies reported detailed clinical information that might suggest clinical differences between exposed and nonexposed subjects. Steel Industry There is some evidence that acute exposures to fumes in the steel industry are associated with an atypical parkinsonian syndrome (79–81). The primary exposure in the steel industry is manganese. Wang et al. (81) described an outbreak of parkinsonism in a Taiwanese (Republic of China) ferromanganese smelter due to a defective ventilation control system. Of those subjects with brief, high-level exposure to inhaled manganese (>28.8 mg/m3) six of eight subjects developed parkinsonism. Symptoms of affected individuals included bradykinesia, rigidity, gait abnormalities, and tremor. Only one subject developed a “cock gait,” a dystonic gait disorder

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reportedly characteristic of manganese exposure (82). No details on disease asymmetry or characteristics of tremor were reported, but subjects were noted to experience 50% improvement in parkinsonism with levodopa (81). Follow-up assessment demonstrated disease progression at five years in four subjects. Welding Some materials safety data sheets (MSDS) for welding consumables list parkinsonism as a potential hazard of welding, although the data upon which this claim is based is unclear. There are several clinical reports (80,83–85) of parkinsonism in welders, although many patients had atypical features, including cognitive abnormalities, disturbances of sleep, peripheral nerve complaints, and mild motor slowing. In a study of magnetic field exposed workers, Noonan et al. (70) found that welders were overrepresented in PD deaths (70). Blood manganese (85) and aluminum (84) levels may be elevated in welders, but no study convincingly demonstrates an association between motor signs and these metals. However, a small study (84) suggests that welders with exposure to manganese may be slower on peg-board and finger-tapping scores compared to welders without these exposures. In one study, 15 career welders were compared to consecutively ascertained and age-matched PD controls. Welders with PD were clinically identical to the control groups except for a significantly younger age of onset (46 years) (86). [18F]FDOPA PET imaging in two welders with PD demonstrated reduced [18F]FDOPA uptake more prominent in the posterior putamen contralateral to the most affected side (86). The authors concluded that parkinsonism in welders is distinguished clinically from idiopathic PD only by age of onset, suggesting that it may accelerate the onset of the disease. Levodopa responsiveness of parkinsonism in welders has been questioned by other investigators. Koller et al. (87) performed a double-blind, placebo-controlled study of levodopa in 13 welders with parkinsonism and found no difference in motor function. The reason for the differences between these studies is unclear. A recent study (88) of eight welders described syndromes of parkinsonism, myoclonus, and cognitive abnormalities associated with MRI abnormalities typical of manganese neurotoxicity, suggesting a broader potential phenotype among workers exposed to welding fumes. A recent survey (89) of three movement disorders clinics found only three welders among 2249 consecutive patients with PD; however, it is possible that welders were underrepresented in these relatively white collar communities. Studies of large welder cohorts and epidemiologic studies provide contradictory evidence regarding a relationship between welding and parkinsonism. A pilot epidemiologic study (90) suggested that occupational welding may be more common in PD patients compared to patients with other neurological disorders; however, this study was not population based and the number of subjects studied was small. Several studies (68,91–94) have been cited as evidence against a relationship between parkinsonism and welding. One population-based study (91) of veteran twins found an odds ratio of 1.0 for welders, but this study was likely underpowered to detect a relationship, given that the investigators only studied eight welders. In a death certificate study (92) of neurodegenerative disease and PD, welding related occupations were not listed among the highest ranked occupations in PDrelated deaths. However, death certificates may substantially underestimate the true prevalence of parkinsonism or PD, given the long clinical course and rarity of death due to PD-related morbidity. A case-control study (94) of PD and occupational

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exposures found no relationship with occupational exposure to heavy metals. However, only 19 PD subjects with metal exposure were studied, and welding as an occupation was not specifically identified. Other studies (51,93) have used broad occupational categories or reported exposure only to metals and did not specifically investigate welding. Several recent studies add to the controversy. A study (95) of 1423 Alabama welders referred for medical–legal evaluation found a substantially higher prevalence of parkinsonism in three standard occupational codes, using highly conservative assumptions. All patients were examined for parkinsonism with standardized videotaped assessments using the Unified Parkinson’s Disease Rating Scale motor scale. Patients provided information regarding exposure to welding fumes and job titles. Job titles were matched with Department of Labor Standard Occupational Codes (SOCs). Diagnoses for parkinsonism were assigned using quantitative criteria. The prevalence of parkinsonism in Alabama welders was calculated by using the number of active welders in this screening with parkinsonism as the numerator and the age-adjusted number of welders in each SOC as the denominator. This prevalence calculation then was compared with general population data from Copiah County, Mississippi, U.S.A.. The estimated prevalence of parkinsonism among active male welders aged 40 to 69 statewide was 977 to 1336 cases/100,000 population. The prevalence of parkinsonism was higher among welders when compared to age-standardized data for the general population (prevalence ratio = 10.19, 95%CI 4.43–23.43). Lack of a contemporary control group and lack of blinding for welding trades as occupations were the important limitations. A study (96) of occupations in a national death certificate database found an elevated mortality odds ratio of PD below age 65 in welders. However, there was no elevated mortality in the entire population of welders. A study (97) of Danish metalmanufacturing employees’ hospitalization rates found no elevation in hospitalizations for PD. PD is not typically a primary cause of hospitalization or death, although parkinsonian symptoms may contribute to morbidity from other diseases. Therefore, mortality rates and hospitalizations may not be sensitive indicators of parkinsonism. Furthermore, the health and safety commitment in the Danish shipyards may be substantially greater than in the United States. A recently published study (98) in Sweden found no relationship between welding and PD in Sweden using nationwide, population-based registers. These methods are likely more sensitive than hospitalization data, but the findings do not necessarily preclude a greater risk of parkinsonism using more sensitive methods or a greater risk in workplaces with less rigorous environmental controls. These studies highlight the need for an epidemiologic study using sensitive measures of parkinsonism and detailed dose reconstruction. The debate on the relationship between welding and parkinsonism will continue until this type of study is complete (99,100). CONCLUSIONS Population-based studies implicate environmental factors in the etiology of PD. It is possible that very specific toxins within complex exposures are the primary cause of PD in most patients. Occupational exposures to farming, pesticides/herbicides, metals, and welding fumes have all been implicated although, for each positive study, there are studies that refute these associations. Study design limitations including small sample size and lack of dose reconstruction are consistent limitations of PDenvironmental epidemiologic studies. Future studies need to include sample sizes that

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Amantadine and Anticholinergics Khashayar Dashtipour Division of Movement Disorders, Department of Neurology, Loma Linda University School of Medicine, Loma Linda, California, U.S.A.

Joseph S. Chung Department of Neurology, Movement Disorders Specialist, Southern California Kaiser Permanente, Los Angeles, California, U.S.A.

Allan D. Wu Division of Movement Disorders, Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, U.S.A.

Mark F. Lew Division of Movement Disorders, Keck/USC School of Medicine, Los Angeles, California, U.S.A.

INTRODUCTION Amantadine and anticholinergics have been used for several decades as therapy for Parkinson’s disease (PD). In spite of reduced interest in these compounds with the advent of more specific dopaminergic therapies, there remain clinical situations where amantadine and anticholinergics retain clinical usefulness and a role in the contemporary treatment of PD. In fact, in the last few years, amantadine is being prescribed more frequently to treat patients experiencing dyskinesia. AMANTADINE History Amantadine (Symmetrel®) was approved by the Food and Drug Administration in 1966 and was marketed as an antiviral agent. Its use as an antiparkinsonian agent was first described in 1969 when a woman with advanced PD serendipitously noted transient relief of tremor, rigidity, and bradykinesia, during a six-week course of flu prophylaxis with amantadine (1). Since that time, further studies confirmed a mild antiparkinsonian effect with amantadine (2). The use of amantadine has been limited, likely due to the development of dopamine agonists, better tolerance of levodopa with the advent of carbidopa, and the misconception of transient benefit, known as tachyphylaxis. Investigators have sought to examine the potential clinical uses for amantadine in the management of PD. Modulating effects of amantadine on motor complications in later stage PD have been documented in several studies (3–5). Many different mechanisms of action have been proposed for the antiparkinsonian effects of amantadine, but clear attribution has remained obscure. Traditional mechanisms for amantadine were usually ascribed to dopaminergic or anticholinergic mechanisms such as the proposed promotion of endogenous dopamine release 293

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(6). However, further studies have demonstrated a variety of biologic effects beyond these systems. For instance, studies have suggested that amantadine possesses glutamate-blocking activity (7). Pharmacokinetics and Dosing Amantadine is an aliphatic primary amine formulated as a hydrochloride salt for clinical use, as an oral preparation. It is a relatively inexpensive drug available as a 100-mg tablet or capsule and a 50-mg/mL liquid. Other than some anticholinergics and apomorphine, it is also one of the few PD medications available in a parenteral formulation (amantadine-sulfate). This intravenous preparation, however, is not available for use in the United States (8). The bioavailability of amantadine is 86% in the elderly and more than 90% in young adults in oral form (9). It is excreted virtually unmetabolized via the kidneys and has a large volume of distribution. In fasting, healthy patients, peak plasma concentration was found 1 to 4 hours after a single oral dose of 2.5 to 5 mg/kg. Plasma half-life in healthy elderly men has been reported between 18 and 45 hours, suggesting that steady state may take up to nine days (10). It crosses the blood–brain barrier and the placenta, and is excreted into the breast milk. Serum amantadine levels are not routinely drawn and are probably of limited clinical utility. Pharmacological studies have reported serum levels between 0.2 to 0.9 µg/mL at dosages of 200 mg/day (11). Fahn et al. (12) reported a patient with psychosis following acute intoxication with amantadine who had a level of 2.37 µg/mL. Few drug interactions have been reported with amantadine. Ethanol in combination with amantadine can increase central nervous system (CNS) side effects, such as dizziness, confusion, and orthostatic hypotension (13). Antimuscarinics and medication with significant anticholinergic activity may increase the anticholinergic side effects of amantadine (13). A potential interaction of amantadine with bupropion has been reported (13,14). Affected patients develop restlessness, agitation, gait disturbance, and dizziness, and may require hospitalization depending upon severity. There is also a case report, suggesting amantadine toxicity from an interaction with hydrochlorothiazide–triamterene (15). Routine dosing starts at 100 mg twice daily. Doses up to 500 mg have been reported for controlling motor complications in PD patients (16). The maximum tolerable doses are suggested at 400 to 500 mg each day, in patients with normal renal function (17); however, doses over 400 mg have no added benefit and have an increased incidence of side effects. Clinical Uses Early Parkinson’s Disease Amantadine is generally considered as a mild antiparkinsonian agent, with effects on tremor, rigidity, and bradykinesia, and a well-tolerated side-effect profile. It is used in early PD when considering levodopa sparing strategies or when symptoms are mild enough not to warrant more aggressive therapy. Amantadine has been studied in early PD as monotherapy, and in combination with anticholinergics in limited series and small controlled studies, with relatively short follow-up (18–20). However, review of randomized controlled trials of amantadine does not reveal sufficient evidence to support its efficacy in the treatment of early PD (21,22). The 2002 American Academy of Neurology guidelines for the initiation of PD treatment did not discuss the use of amantadine (23).

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Part of the rationale for considering amantadine monotherapy are suggestions that it may have neuroprotective properties to slow the progression of PD. Uitti et al. found that amantadine use was an independent predictor of improved survival in a retrospective analysis of all parkinsonism patients (92% PD) treated with amantadine compared to those not using this medication. The results are suggestive of either an ongoing symptomatic improvement or the presence of inherent neuroprotection (24). There has been no confirmatory evidence to suggest neuroprotection from studies in PD patients. Advanced Parkinson’s Disease Use of amantadine in managing PD motor complications was first described in 1987 by Shannon et al. (3) in a small open-label study. They reported improved motor fluctuations using a qualitative scale, examining on and off function in 20 PD patients. This notion has gained further support from Metman et al. who reported the results of double-blind, placebo-controlled, cross-over studies of amantadine in a small cohort of 14 PD patients. There was a 60% reduction in both peak dose dyskinesia and severity of off periods, along with a decreased duration of off time (25). One year later, these patients had maintained significant benefit (5). The Cochrane database systematically reviewed randomized controlled studies (26) that evaluated amantadine versus placebo in the treatment of levodopainduced dyskinesia, and reported a lack of evidence to support the efficacy of amantadine. Thomas et al. (27) conducted a double-blind, placebo-controlled study in 40 PD patients and concluded that 300 mg of amantadine was effective to control levodopa-induced dyskinesia by approximately 45%; however, the effect was maintained for less than eight months in all patients. Another randomized, double-blind, controlled study (28) of 18 PD patients found that the duration of levodopa-induced dyskinesia was reduced by using amantadine. The recognition of different dyskinesia phenomenology may be important in the response to amantadine. For instance, dystonic dyskinesia has shown varied inter-individual effects in a few studies (3,4). Also, specific efficacy for sudden on–offs or biphasic dyskinesia has not been formally investigated. Recent evidence suggests that amantadine produces its antidyskinetic effects via a glutamate N-methyl-D-aspartate (NMDA) antagonism (29). This independence from dopaminergic mechanisms was proposed as an explanation for the ability of amantadine to ameliorate levodopa-induced dyskinesia without worsening parkinsonism (25). Miscellaneous Considerations One frequent assumption about amantadine is that it offers only transient efficacy that typically lasts less than a year. However, this apparent loss of efficacy for ameliorating parkinsonian symptoms was reviewed and attributed largely to the progression of the disease itself. It has also been reported that early-stage PD patients may be treated effectively for years with amantadine, and still find that their symptoms noticeably worsen following drug withdrawal (16). Side Effects Amantadine is generally well tolerated. The most common idiosyncratic side effects include livedo reticularis and pedal edema. Livedo reticularis is a mottled bluishred reticular skin discoloration, which blanches to pressure. It is observed in more than 5% of patients receiving amantadine. It is more common in women (30) and is

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usually predominant in the lower extremities. The appearance is nonspecific, and skin biopsies of the area are normal (31). Livedo reticularis usually appears after weeks of treatment and it can occur up to one year from initiation of therapy. The etiology of livedo reticularis is unclear, but is believed to be caused by abnormal widespread dilatation of dermal blood vessels due to depletion of catecholamines at the peripheral nerve terminals (32). The cosmetic appearance is usually far more apparent than any physical adverse effects. Pedal edema can also appear idiosyncratically, and is independent of either renal or cardiac failure. Its presence has generally been attributed to a redistribution of fluid and does not appear to represent excess fluid. Quinn et al. (33) have reported a few cases of congestive heart failure occurring in association with the use of amantadine, but this appears to be an exception to routine clinical use. The presence of either livedo reticularis or pedal edema does not always necessitate discontinuation of amantadine. There is no specific treatment for the cosmetic discoloration associated with livedo reticularis. Symptoms are generally expected to resolve with discontinuation of the drug, but may take up to several weeks. Rarely, these conditions may be severe and associated with leg ulceration and peripheral neuropathy (34). A prudent combination of discontinuing the drug and providing appropriate referrals to exclude important secondary causes, such as a superimposed renal failure, cardiac failure, autoimmune or vasculitic livedo, and deep vein thrombosis, must be an important part of continued clinical follow-up for patients on amantadine. Rimantadine is an alpha-methyl derivative of amantadine. An open-label trial showed the effectiveness of rimantadine in controlling motor symptoms in PD (35). A retrospective study of seven patients with moderate-to-severe PD revealed that rimantadine was an effective alternative to amantadine, in patients experiencing amantadine-induced peripheral side effects such as livedo reticularis and lower limb edema (36). Side effects did not develop on rimantadine and patients showed good clinical efficacy. Amantadine-induced peripheral neuropathy has been rarely reported (37). It was hypothesized that amantadine transfers the blood supply to the peripheral nerves because of its effect on catecholamine storage (37). Nonspecific symptoms, such as lightheadedness, insomnia, jitteriness, depression, and concentration difficulties, are potential side effects of amantadine (10). Amantadine also possesses mild anticholinergic properties, which contribute to side effects such as dry mouth, orthostatic hypotension, constipation, dyspepsia, and urinary retention. Therefore, reasonable care should be taken when administering amantadine in conjunction with anticholinergics (38). One report (8) noted cardiac arrhythmias with amantadine. Amantadine is not recommended during pregnancy, as it has more teratogenic potential than the other PD medications (39). There are reports of ocular side effects, such as corneal lesions and edema, associated with the use of amantadine (40–42). Corneal side effects can occur within a few weeks to a few years after initiation of therapy and are generally reversible within a week of stopping the medication. Acute toxicity presenting as delirium (18), seizure (43), and psychosis (12) has been reported. Abrupt withdrawal has been described to produce delirium (44), as well as neuroleptic malignant syndrome (45). In many of these cases, patients either had baseline cognitive deficits, psychiatric background, or excess amantadine use beyond clinical recommendations. In general, the cognitive side effects such as confusion and concentration difficulties are more common in those with underlying, pre-existing cognitive dysfunction. In advanced PD, amantadine may even carry

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comparable propensity for cognitive side effects to levodopa (46). As such, conservative use in the elderly and avoidance of use even in the mildly cognitively impaired patient is necessary. Because of the renal predominant excretion of amantadine, patients with impaired kidney function carry a higher risk of toxicity. Dosing schedules have been developed for patients with poor renal function according to creatinine clearance (47). It is best to avoid the use of amantadine in patients with poor renal clearance. In the event of suspected toxicity, dialysis is not helpful in decreasing toxic levels, probably due to extensive tissue binding (48). Mechanisms of Action Many studies have suggested putative mechanisms of action for amantadine that may explain antiparkinsonian effects, but the clinical significance of any given individual mechanism remains uncertain. It seems likely that amantadine has a combination of multiple effects on both dopaminergic and nondopaminergic systems. Dopaminergic mechanisms described for amantadine include findings of increased dopamine release (49), increased dopamine synthesis (50), inhibition of dopamine reuptake (51), and modulation of dopamine D2 receptors, producing a high-affinity state (52). This latter effect may speculatively play a role in modulating levodopa-induced dyskinesia. The relevance of these dopaminergic mechanisms is uncertain, given that studies have demonstrated that the antiparkinsonian effects can occur without changes in brain concentrations of dopamine or its metabolites (53) and without evidence for dopamine synthesis or release (54). Other neurotransmitter effects reported with amantadine include serotonergic, noradrenergic (55), anticholinergic, and antiglutaminergic properties (56). The anticholinergic properties suggest a well-described antiparkinsonian interaction (57,58). In the past decade, renewed interest has arisen in the antiglutamate properties of amantadine. This can be attributed to two important clinical implications. First, it may provide a putative neuroprotective mechanism. Second, converging lines of evidence provide support to the idea that the antiglutamate properties of amantadine may be important for modulating motor complications in late-stage PD. Amantadine possesses mild anti-NMDA properties that have led to the suggestion that the drug may contribute to a possible neuroprotective effect in PD (59,60). Glutamate excitotoxicity, mediated via persistent or sustained activation of NMDA receptors, produces an excess calcium influx, activating a cascade of molecular events leading to the common final pathway of neuronal death. Blockade of NMDA glutamate receptors has been shown to experimentally diminish the excitotoxic effects of this cascade of reactions (61,62). In cell cultures, pre-exposure of substantia nigra dopaminergic neurons to glutamate antagonists provided protection when subsequently exposed to MPP+ (1-methyl-4-phenyl-pyridium ion, the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a common specific nigral toxin used to produce animal models of PD (63). Extension of these preclinical findings to clinical applicability in PD patients remains speculative, but probably best serves a role to stimulate future studies. The anti-NMDA properties of amantadine have also been implicated in its role modulating motor complications such as dyskinesia (64–66). Evidence has accumulated that glutamate NMDA receptors may play a significant role in the pathogenesis of motor complications. Loss of striatal dopamine and nonphysiologic stimulation by extrinsic levodopa, both cause sensitization of NMDA receptors on striatal medium

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spiny neurons in animal models (29). This sensitization may play a key role in altering normal basal ganglia responses to cortical glutaminergic input and produce the disordered motor output, which leads to motor complications. Recent studies have reported that striatal injection or systemic administration of glutamate antagonists in primate and rodent models of PD can decrease levodopa motor complications without decreasing benefits of dopaminergic treatment (7,67–70). Summary With improved management options for PD, patients are living longer and, as a result, more are suffering from long-term complications of disease and therapy. Although the influx of new medications has changed the landscape of pharmacologic options for PD patients, a reexamination of the older medications such as amantadine can offer evident benefit. Amantadine retains its primary utility as a mild antiparkinsonian agent to be used mostly as adjunctive therapy, and occasionally in early monotherapy as a means to avoid early use of levodopa. Most recently, it is frequently being utilized as the only available antiparkinsonian agent to diminish dyskinesia and offer improvement of the PD symptoms simultaneously (71). ANTICHOLINERGICS History Anticholinergics are the earliest class of pharmaceuticals used for the management of PD. Naturally occurring anticholinergics, such as the belladonna alkaloids, have been used for centuries to treat a variety of ailments. Since the mid-1900s and until the modern development of dopaminergic agents, anticholinergics were a major component of therapy for PD (72). In the 1940s, synthetic anticholinergics were introduced with trihexyphenidyl (Artane®) and similar agents, replacing impure herbal preparations of belladonna alkaloids in the treatment of PD. Eventually, a wide variety of anticholinergics, each with varying receptor specificities, blood–brain barrier penetration, and side effect profiles, became available. Historically and by physician’s preference, certain medications have gained popularity or notoriety for particular use in treating PD (73). This has varied throughout the decades. For instance, benzhexol was used as an antiparkinsonian medication in 1972 (73), but is not in common use today. With recent developments in PD therapy, anticholinergics have been relegated to a distinctly less prominent role. In particular, levodopa and dopamine agonists have largely replaced anticholinergics. Contemporary reviews and investigations continue to support anticholinergic use in certain clinical situations, such as PDassociated tremor or dystonia. Side effects have always been a prominent concern with anticholinergics, particularly in susceptible individuals such as the elderly. As such, careful risk–benefit assessment in anticholinergic use remains a prudent routine practice in PD patients. Pharmacokinetics and Dosing Anticholinergics are a diverse group of medications. The majority of the anticholinergic medications have good oral absorption, but precise figures on many are not known. In general, most have half-lives requiring at least twice and usually three times a day dosing. The antiparkinsonian effect of anticholinergics is largely attributed to centrally acting acetylcholine receptors (74). Most synthetic (tertiary) anticholinergics used in

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PD are predominantly in this class: biperiden (Akineton®), trihexyphenidyl (Artane®), benztropine (Cogentin®), procyclidine (Kemadrin®). Benztropine was formulated as a combination of the anticholinergic, atropine, and an antihistamine, diphenhydramine (Benadryl®). Benztropine, has useful central effects that can be used for PD management, is more potent than trihexyphenidyl, but has less sedating effects than antihistamines (75). Recommended doses and choice of particular anticholinergic vary by practitioner, but one rule is to start with a low dose and increase slowly and conservatively (Table 1). Clinical Uses Since the advent of levodopa therapy for PD in the 1960s, the usefulness and popularity of anticholinergics waned dramatically. However, an evidence-based review by the Cochrane Collaboration concluded that anticholinergics are effective in improving motor function in parkinsonian patients as monotherapy and adjunct therapy. Current data are not sufficient to allow comparison in efficacy or tolerability between individual anticholinergic medications (76). Tremor Predominant Parkinson’s Disease The most recognized use of anticholinergics is to treat tremor in early- or youngonset PD representing a levodopa-sparing strategy. In general, it appears that anticholinergics help tremor, but do not significantly affect bradykinesia or rigidity of PD. Anticholinergic agents may be used as initial therapy of tremor predominant PD (72). Schrag et al. (77) found equivalent reductions in tremor with a single dose of either a dopamine agonist (apomorphine) or an anticholinergic (biperiden), but only apomorphine reduced rigidity and akinesia. Although anticholinergics do not appear to have significant effects on akinesia and rigidity as therapy, deterioration of all parkinsonian symptoms has been described following abrupt withdrawal (78). Anticholinergics are useful in the early treatment of tremor predominant PD in young or mild patients if the primary indication for symptomatic therapy is tremor, and there are relatively minimal associated signs of rigidity or bradykinesia. Anticholinergics should be avoided in patients with baseline cognitive deficits, significant orthostatic hypotension, or urinary retention, as they are at higher risk for exacerbation of these symptoms. Parkinson’s Disease-Associated Dystonia Dystonia can occur in several clinical circumstances in association with PD. Anticholinergics can play an adjunctive role in managing such dystonia. Most PDassociated dystonia occurs in the context of motor complications, but can occur even in levodopa-naïve patients. Most commonly, an off-period dystonia characteristically causes painful foot- and toe-posturing when dopaminergic medication wears off in the morning. Levodopa-induced on-period dystonia can follow either biphasic or peak-dose patterns. Poewe et al. suggest that anticholinergics can play a role in helping relieve the severity of episodic dystonia in PD. However, limb dystonia as an early symptom in levodopa-naïve patients tended not to respond as well compared to dystonia associated with motor fluctuations (79). In practice, dopamine agonists seem more useful in treating most forms of PDassociated dystonia. Anticholinergics can be used as adjunctive therapy if dystonia persists despite dopaminergic therapy. Theoretically, on-period dystonia may be more amenable to anticholinergics, as dopaminergic agents risk prolonging peakdose effects.

Mechanisms

Central antimuscarinic

Central antimuscarinic

Central antimuscarinic

Benztropine (Cogentin®)

Biperiden (Akineton®)

Ethopropazine (Parsidol®, Parsitan®)

Atypical antipsychotic

12.5, 25 mg tablets; 12.5 mg liquid 10, 25, 50, 75, 100, 150 tablets; injection 10 mg/mL 25 mg tablets

50 mg tablets

2 mg tablets; 5 mg/mL ampules

0.5, 1, 2 mg tablets; injection 1 mg/mL

2, 5 mg tablets; 2 mg/5 mL elixir

Preparations

6.25–12.5 mg

12.5 mg qhs

25 mg qhs

12.5 mg tid/qid

1 mg bid

0.5 mg bid

1 mg qd–bid

Initial dose

Increase by 6.25– 12.5 mg every 2–3 nights

Increase by 25 mg every 3–4 days Increase by 12.5 mg every 2–3 nights

Increase to tid; every 3–4 days increase by 0.5–1 mg each dose Increase to tid; every 3–4 days increase by 0.5–1 mg each dose Increase to tid; every 3–4 days increase by 0.5–1 mg each dose Increase to tid; every 3–4 days increase by 12.5 mg each dose

Escalation schedule

100 mg

25 mg tid or 25–100 mg qhs 150 mg

50 mg tid–qid

3 mg tid

2 mg tid

2–3 mg tid

Maximum dose/day

May cause increased salivation

H1 blocker, also available parenterally

Not available in the United States

Also available parenterally

Also available parenterally

First synthetic anticholinergics

Comments

300

Clozapine (Clozaril®)

Diphenhydramine Antihistamine (Benadryl®) Amitryptiline Tricyclic (Elavil®) antidepressant

Secondary anticholinergic effects

Central antimuscarinic

Trihexyphenidyl (Artane®)

Primary anticholinergics

Name

TABLE 1 Common Anticholinergics Used in Parkinson’s Disease

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Miscellaneous Considerations Often anticholinergic agents can be used to treat miscellaneous indications. In this setting, agents are often chosen on the basis of secondary anticholinergic side effects. For example, if antidepressants are needed, a tricyclic antidepressant such as amitriptyline might be chosen for its anticholinergic properties to assist with insomnia or PD-related tremor. Diphenhydramine is an antihistamine commonly prescribed for allergies or insomnia, and possesses mild anticholinergic side effects that can be used for PD-associated sialorrhea and may help reduce tremor. Regarding sialorrhea, atropine drops in 1% solution administered sublingually twice daily has been reported as beneficial with no significant mental state changes (80). Another class of medications commonly used in PD is the atypical antipsychotics. Quetiapine (Seroquel®), olanzapine (Zyprexa®), and clozapine (Clozaril®) all have anticholinergic properties that may contribute to side effects and may be of only modest benefit. Clozapine, in particular, has significant anticholinergic-attributed sedation, but also can reduce tremor (81) and produce increased salivation and drooling. Amantadine also has modest anticholinergic properties, although its antiparkinsonian use is commonly chosen on its own merits (82). A partial list of commonly used medications with either primary or secondary anticholinergic properties and their use is shown in Table 1. Side Effects Side effects of anticholinergic agents are a significant clinical concern, which can limit their usefulness in the treatment of PD symptoms. Most antiparkinsonian effects are assumed to be mediated via central muscarinic acetylcholine receptors. Side effects may occur as either unintended central muscarinic effects or as incidental autonomic effects, attributed to peripheral binding to muscarinic and nicotinic acetylcholine receptors. In general, most effects are dose-dependent and respond to dose reductions. Central Side Effects Sedation, confusion, memory difficulties, and psychosis are well-described adverse events attributed to central nervous system anticholinergic toxicity. Scopolamine (Transderm-Scop®), an anticholinergic, was found to have effects on cognitive activities requiring rapid information processing in normal controls (83). Bedard et al. (84) found a transient induction of executive dysfunction in nondemented PD subjects with an acute subclinical dose of scopolamine. These findings underscore the necessity of being aware that, even in early PD patients with no clinical intellectual dysfunction, anticholinergics may have adverse effects on cognition. These drug-induced cognitive deficits are reversible, and persistent cognitive deficits off medications tend to be due to the progression of underlying disease rather than a direct adverse anticholinergic effect. In patients taking anticholinergics who develop psychosis, increased memory difficulties, and confusion, anticholinergic agents should be withdrawn promptly. Furthermore, in elderly parkinsonian patients, long-term use of anticholinergic medications has been associated with an increase in amyloid plaque densities and neurofibrillary tangles (85). Peripheral Side Effects Peripheral anticholinergic effects can produce a variety of autonomic dysfunction, including dry mouth, orthostatic hypotension, and urinary retention. Rare but potentially serious side effects such as narrow-angle glaucoma have also been described.

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Similar to central effects, peripheral effects are often exacerbated in PD patients due to an underlying baseline autonomic dysfunction or an increased susceptibility due to advanced age. Concomitant dopaminergic medications may further exacerbate anticholinergic symptoms such as orthostatic hypotension, constipation, or sedation. Orthostatic hypotension is a common problem in PD and can be exacerbated by addition of anticholinergic agents. Conservative therapies begin by considering a dose reduction of either the anticholinergic or other hypotensive medications (including dopaminergic agents). Dry mouth due to parasympathetic depression of salivary glands is a common and potentially uncomfortable side effect. In some patients with drooling, this effect may be advantageous. For excessive dry mouth, symptomatic oral moisturizing gel and other over-the-counter preparations such as specially formulated gum, mouthwash, and toothpaste may be used. Sipping ice water and sugarless sucking candies may also be helpful. The severity of dry mouth also improves with a decrease in anticholinergic dose and may improve with prolonged exposure. The addition of pyridostigmine (Mestinon®), which does not cross the blood–brain barrier has been reported as helpful (86). Anticholinergics are often used to treat urinary frequency, a symptom of PD-associated autonomic dysfunction. These include medications such as oxybutynin (Ditropan® 5 mg bid or tid), tolterodine (Detrol®1–2 mg bid), hyoscyamine (Anaspaz® 0.125–0.25 mg q4h), darifenacin (Enablex® 7.5–15 mg daily), trospium (Sanctura® 20 mg bid), flavoxate (Urispas® 100–200 mg tid/qid), and Solifenacine (VESIcare® 5–10 mg daily). Anticholinergics can also result in urinary retention due to excess parasympathetic inhibition, so caution must be exercised. Risks are particularly great in elderly men due to bladder outlet obstruction from benign prostate hypertrophy. If there is any history of urinary hesitancy or urgency, a urology evaluation is reasonable prior to initiation of anticholinergic therapy. Blurred vision is another common side effect with anticholinergics. This symptom is often attributed to relatively reduced accommodation due to parasympathetic blockade, and excessive dryness of the cornea may also contribute. For persistent symptoms, consultation with an ophthalmologist may be appropriate. Again, the use of pyridostigmine can be helpful. Rarely, anticholinergic therapy can precipitate narrow-angle glaucoma (closed-angle glaucoma), an ophthalmic emergency. The acute increase in intraocular pressure presents with pain and redness in the affected eye. In practice, this condition is extremely rare. Risk of narrow-angle glaucoma is minimal if there are normal pupillary responses and intact vision. Ophthalmology consultation should be sought during anticholinergic treatment if vision diminishes or pupillary responses become abnormal. In contrast, the more common open-angle glaucoma presents minimal risk for treatment with anticholinergics (73). Careful consideration of risk–benefit analysis is needed when prescribing anticholinergic medications. Patients should be counseled about the potential for side effects and instructed to call with any problems. In younger patients without comorbidity besides mild PD, anticholinergics are generally very well tolerated and represent a viable option for tremor-predominant symptoms. In more susceptible patients with clinically relevant autonomic dysfunction, cognitive dysfunction, or advanced age, anticholinergics should be used very sparingly. Mechanisms of Action Antiparkinsonian benefit is generally attributed to inhibition of central muscarinic acetylcholine receptors. For instance, Duvoisin and Katz reported an antiparkinsonian

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benefit to benztropine and scopolamine, both centrally acting anticholinergics, with an exacerbation of parkinsonism after a trial of physostigmine, a centrally acting anticholinesterase inhibitor. In contrast, peripheral anticholinergics (methyl scopolamine and propantheline) and a peripheral anticholinesterase (edrophonium) did not affect parkinsonian symptoms (74). Details of how centrally acting anticholinergics can modify PD symptoms, usually attributed to dopaminergic deficiency, remain unclear. Abnormalities in the central acetylcholine neurotransmitter system have been described in PD patients (87,88). An oversimplified, but clinically useful, conceptualization is that the anticholinergic use corrects an imbalance between dopamine and acetylcholine (89). The depleted nigrostriatal dopaminergic system in PD causes a relative increase in striatal acetylcholine–dopamine ratio, which can be normalized by the use of anticholinergics. The clinical consequences of disrupted neurotransmitter ratios are not precisely known. Other proposed mechanisms include inhibition of dopamine reuptake (90) and mild NMDA glutamate antagonism (91). The clinical significance of these findings remains to be determined. Summary Anticholinergics have relatively few clinical uses in PD other than the treatment of tremor in young-onset patients. Anticholinergics can be used in younger patients with PD-associated dystonia unresponsive to or intolerant of dopaminergic medications. Secondary anticholinergic effects may occasionally be helpful for sialorrhea or increased urinary frequency. Appropriate caution remains in judging risks of side effects versus benefits in anticholinergic use, particularly in patients who may be more susceptible to either the central or peripheral anticholinergic effects. CONCLUSION With the advent of specific dopaminergic agents, the roles of amantadine and anticholinergics have taken a back seat. Traditional uses still dominate with amantadine used as a mild antiparkinsonian agent, with a well-tolerated side-effect profile and anticholinergics, used to treat tremor predominant PD. In addition, there is evidence that amantadine has efficacy in the modulation of later stage PD motor complications. Careful judgment of use of both of these agents related to their respective side effect profiles remains a concern, particularly with anticholinergics in susceptible elderly patients. In summary, amantadine and anticholinergics are helpful agents in the practicing clinician’s arsenal when dealing with particular clinical PD scenarios. REFERENCES 1. Schwab RS, England AC Jr, Poskanzer DC, Young RR. Amantadine in the treatment of Parkinson’s disease. JAMA 1969; 208(7):1168–1170. 2. Danielczyk W. Twenty-five years of amantadine therapy in Parkinson’s disease. J Neural Transm 1995; 46:399–405. 3. Shannon KM, Goetz CG, Carroll VS, Tanner CM, Klawans HL. Amantadine and motor fluctuations in chronic Parkinson’s disease. Clin Neuropharmacol 1987; 10(6):522–526. 4. Adler CH, Stern MB, Vernon G, Hurtig HI. Amantadine in advanced Parkinson’s disease: good use of an old drug. J Neurol 1997; 244(5):336–337. 5. Metman LV, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 1999; 56(11): 1383–1386.

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Levodopa Stewart A. Factor Emory University School of Medicine, Department of Neurology, Wesley Woods Health Center, Atlanta, Georgia, U.S.A.

INTRODUCTION AND HISTORY Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the cardinal motor manifestations of bradykinesia/akinesia, rigidity, resting tremor, and postural instability, although nonmotor features play an important role as well, including cognitive, psychiatric, and autonomic features (1). Pathologically, there is a loss of nigrostriatal neurons in the substantia nigra pars compacta (SNpc), which is believed to represent a middle stage of the degenerative process that starts in the lower brainstem and olfactory nuclei and ascends throughout the cortex (2). Neurochemically, the key feature relating to current therapeutics and nigral cell death is a loss of dopamine (3). Levodopa (L-3,4-dihydroxyphenylalanine) is the cornerstone of symptomatic therapy for PD. It is a metabolic precursor of the neurotransmitter dopamine. Dopamine was synthesized in 1910 by Barger and Ewens, but not given its name until 1952, whereas D/L Dopa racemate was first synthesized in 1911 (3–5). Guggenhiem, in 1913, isolated levodopa from the broad bean plant Vicia faba (6), but concluded that it was devoid of biological activity (4). In 1938, Peter Holtz discovered the enzyme dopa decarboxylase that metabolized levodopa to dopamine in kidney tissue, and, a year later, Blaschko and Holtz postulated the biosynthetic pathways for catecholamines where dopamine is relegated to an intermediate in the synthesis of norepinephrine and epinephrine. The use of levodopa in PD only emerged after the important discoveries of various researchers in the late 1950s and early 1960s that ultimately led to the demonstration that dopamine depletion was characteristic of PD. Montagu (4) discovered dopamine and levodopa in the brain in 1957. Carlsson et al. (7,8) confirmed the presence of dopamine in animal brains and found that reserpine depleted brain dopamine along with other catecholamines. They also demonstrated that in animals rendered akinetic from reserpine, levodopa replenished dopamine and reversed parkinsonian symptoms. In addition, Bertler and Rosengren (7,8) reported that the striatum was the site of greatest dopamine concentration. Raab later made similar independent discoveries except that he did not recognize that the substance in the brain depleted by reserpine (he called it encephalin) was actually dopamine (4). Hornykiewicz (3,4,9) showed that the striatum of parkinsonian brains was depleted of dopamine, and Barbeau et al. (10) demonstrated reduced urinary excretion of dopamine in PD patients. Hornykiewicz (3,4) treated 20 parkinsonian patients with intravenous doses of levodopa (50 mg) and the results were “spectacular,” leading to complete abolition or substantial relief of motor and vocal symptoms for short periods of time. Barbeau et al. demonstrated the effectiveness of low-dose oral levodopa in improving rigidity. However, studies in the early and mid 1960s showed variable results with low doses, and some investigators denounced the practical effectiveness of levodopa 309

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nearly resulting in it being abandoned for the treatment of PD. It was the seminal work of Cotzias (11,12), who persevered with the use of high-dose oral levodopa for parkinsonism, that dramatically changed the landscape of PD treatment (11,12). Yahr (13) completed the first double-blind parallel group study in 1969. Levodopa was ultimately approved by the United States Food and Drug Administration for use in PD in 1970, 60 years after its discovery and more than 10 years after the realization that dopamine depletion was the key abnormality in PD (14). In 1973, the combined use of a peripheral aromatic amino acid decarboxylase (AAAD) inhibitor with levodopa was reported by Cotzias. Its use resulted in a decrease in peripheral metabolism of levodopa to dopamine and fewer peripheral side effects, such as hypotension, nausea, and vomiting (15,16). The resultant combination drug trade name “Sinemet®” carries the meaning “without vomiting.” Controlledrelease formulations were tested in the 1980s to treat fluctuations, and Sinemet CR® was approved in the United States in 1991(17–20). Although regarded as the most potent symptomatic therapy for PD, levodopa has its drawbacks. Adverse effects such as motor fluctuations and dyskinesia are often associated with chronic administration. Neuropsychiatric disturbances are frequent and can be serious adverse effects. Questions have arisen regarding its potential toxicity to nigrostriatal neurons, as well as a possible association with melanoma. The debate of when to initiate therapy with levodopa is still ongoing. This chapter will review several of these issues, including the pharmacology of levodopa, its role in the emergence and progression of motor complications, its potential toxic or protective effects, whether tolerance develops, its role in diagnosing PD, and its effect on mortality in PD. PHARMACOLOGY Dopamine depletion, particularly in the striatum, is the neurochemical hallmark responsible for the motor features of PD. Levodopa, an aromatic amino acid and precursor to dopamine, readily crosses the blood–brain barrier (BBB) and to some extent normalizes dopamine levels. Two major enzymatic pathways for levodopa exist, leading to the formation of 3-O-methyldopa (3-OMD) peripherally and dopamine both peripherally and centrally. Dopamine is subsequently converted to 3,4dioxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the CNS (Fig. 1). When it is administered orally, levodopa is converted to dopamine in the extracerebral tissues via decarboxylation. To lessen the peripheral effects of dopamine and increase the brain bioavailability of levodopa, it is co-administered with carbidopa or benserazide, aromatic amino acid decarboxylase inhibitors (AADIs). AADIs do not cross the BBB and, therefore, will not affect conversion to dopamine in the brain. Their use reduces the amount of levodopa required to attain an adequate response by approximately 75% and increases its plasma half-life from 50 to 90 min. The percent of levodopa entering the brain increases from ~3% to ~10%. The addition of a peripheral catechol-O-methyltransferase (COMT) inhibitor, entacapone or tolcapone, prevents peripheral metabolism to 3-OMD and increases the half-life of levodopa (21). Transport of levodopa across the gut mucosa and BBB involves an energydependent carrier-mediated system. Large neutral amino acids (LNAAs) compete for transport at the same sites. When oral levodopa is administered with a highprotein meal, there is an overall reduction in its plasma level. When IV levodopa is administered with a high-protein meal, the anticipated clinical response is

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Levodopa Peripheral Metabolism Levodopa ------------> 3-OMD COMT Levodopa ------------> Dopamine AAAD Central Metabolism Levodopa ------------> Dopamine AAAD Dopamine ------------> DOPAC MAO Dopamine ------------> 3-methoxytyramine ------------> HVA COMT

MAO

FIGURE 1 Peripheral and central metabolism of levodopa. Abbreviations: COMT, catecholO-methyltransferase; 3-OMD, 3-O-methyldopa; AAAD, aromatic amino acid decarboxylase; MAO, monoamine oxidase; DOPAC, 3,4-dioxyphenylacetic acid; HVA, homovanillic acid.

diminished, indicating a similar effect at the BBB as well (22). Upon entering the CNS, levodopa is taken up by dopaminergic neurons and converted to dopamine. Glial cells have the same potential as they contain dopa decarboxylase (23). The dopamine generated in the neuron is stored and released in a more physiological manner in early PD, but as the disease progresses and neurons die, glial cells take over the metabolic activity and release occurs in large bursts paralleling the peaks in plasma levels in a pattern that is nonphysiologic. MOTOR FLUCTUATIONS AND DYSKINESIA: DEFINITIONS There is a loss of 50% to 60% of nigrostriatal neurons or a reduction in striatal dopamine concentrations of approximately 70% associated with the onset of clinical symptoms of PD (24). The surviving neurons can initially compensate with increased dopamine synthesis, but subsequently, with continued disease progression and neuronal loss, these mechanisms fail. What follows is the loss of the ability of nigrostriatal neurons to store and release dopamine appropriately, followed by postsynaptic changes, both of which lead to a fluctuating response to levodopa (25). Glial cells can also convert levodopa to dopamine, but they lack the machinery for appropriate regulation (23). Hence, levodopa therapy leads to a substantial release of dopamine in the synapse in a pulsatile fashion. The levels of dopamine have been shown to be four-fold higher in the striatum of lesioned animals compared to normal, suggesting that a large pulse occurs in the synapse with oral medications in advanced disease (26). In PD, the loss of nigrostriatal innervation initially leads to putaminal D2 receptor upregulation, but a subsequent decline follows due to medical therapy (27). Presynaptic and postsynaptic changes are important not only for responsiveness to levodopa but also the occurrence of motor fluctuations (wearing-off, dyskinesia, and unpredictable responses). Historical literature suggests that the rate is approximately 50% for motor fluctuations and dyskinesia after five years of disease duration, and as high as 90% for patients with PD onset under age 40 (28). Ahlskog

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and Muenter (29) compared more recent literature to older studies and found that the rate is 35% to 40% after four to six years of disease with an increased frequency of 10% per year so that nearly 90% of patients experience these complications to some extent after a decade. Motor fluctuations have several facets. Muenter and Tyce defined the longduration response (LDR) as the gradual motor improvement seen after repeated dosing and subsequent decline over days upon levodopa withdrawal. This effect remains present even after long-term chronic therapy (30). The short-duration response (SDR) is defined as that which parallels the plasma concentrations of levodopa and seems to be present to some extent from the beginning of therapy. Nutt et al. showed that after a three-day withdrawal of levodopa, a patient receiving a single dose would have a full SDR, without a LDR. It has been suggested that the LDR may relate to storage capacity of dopaminergic neurons, although that is not the entire story since it occurs with levodopa and dopamine agonists (31) It may be that the LDR leads to the early and prolonged responsiveness to levodopa. Its loss results in the subsequent emergence and dependency on the SDR for symptomatic relief (32,33). A negative or inhibitory response has also been described; it is a worsening of motor function occurring prior to the SDR. It can last minutes to hours and has been termed a “super-off ” (34). These three responses are imposed on a diurnal pattern of motor function (better performance in the morning with subsequent decline throughout the day) and on top of the continued endogenous dopamine activity (35,36). Nutt et al. (32) proposed that the residual endogenous dopamine activity as well as the LDR essentially determine the off-time patients experience. Several patterns of motor fluctuations have been described (37–41). They progress from simple predictable patterns early to more complicated unpredictable ones. The earliest type is the wearing-off effect. With this pattern, the antiparkinsonian effect of levodopa wears off toward the end of a dose in a predictable fashion. This has also been referred to as end-of-dose failure. This is followed by complicated wearing-off, where the duration of response of levodopa becomes more variable and the timing of wearing-off becomes less predictable but is still attributable to timing of doses. Patients may also begin to experience delayed-on (a delay in onset of effect of levodopa) and dose failures (no-on). The on–off effect is when levodopa response varies in an unpredictable manner unrelated to timing of the dose. This often happens suddenly like a light switch being turned on and off (38–40). Dyskinesia can also occur in various patterns. The most common is peak-dose dyskinesia where choreic movements occur when plasma levodopa levels are at their peak. Diphasic dyskinesia is when mainly choreic or dystonic movements occur as plasma levels rise and at the end of the dose as plasma levels fall. Some patients have dyskinesia the entire time they are on, which is called square-wave dyskinesia. Dystonia may occur in the on or off states and includes early morning dystonia. Finally, patients may fluctuate abruptly from severe immobility to severe dyskinesia, which is referred to as yo-yoing (41). CLINICAL TRIALS OF LEVODOPA The initial therapeutic studies of levodopa in PD were carried out in the 1960s and early 1970s. The subjects were of varying disease durations, some quite advanced with dementia, and standard measures such as the Unified Parkinson’s Disease Rating Scale (UPDRS) were not yet devised; however, the results were dramatic (3). In 1967, Cotzias et al. (11) demonstrated the definitive effectiveness of high-dose

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L-Dopa (as opposed to D, L-Dopa). These investigators examined 28 patients in an open-label manner with intermittent blinded replacement with placebo and utilized levodopa without a dopa decarboxylase inhibitor. The duration of disease ranged from 1 to 30 years (mean 10 years). All patients responded, with 20 having a marked to dramatic improvement. All motor features improved. Some patients developed fluctuations and dyskinesia quickly and it was suggested that these problems related to duration of disease. Many studies followed which supported these findings (13,42–44). An example is that by Sweet and McDowell (45) who studied 100 patients treated for up to five years in an open-label fashion. Forty-seven of them completed the whole five years. All signs of PD improved remarkably by six months (60% of patients were more than 50% improved) and despite worsening over the next 4.5 years, the Cornell-weighted scores remained significantly better than baseline. The severity of parkinsonian features at initiation of therapy had little bearing on the ultimate response. Positive results were observed despite the fact that more than half the patients suffered from concomitant dementia. It became clear that levodopa was not a cure for PD as previously hoped, as it did not stop disease progression and was associated with several late complications, including motor fluctuations and dyskinesia. However, patients with advanced disease were included, dopa decarboxylase inhibitors were not used in a majority of patients, and patients were treated with the maximum tolerated dose, all of which may have increased the likelihood of dyskinesia and fluctuations. Other studies indicated that lower doses of levodopa result in a similar response with fewer complications (46), whereas others were not in agreement (47). Several studies reported in the last decade provide more information about the effectiveness of levodopa therapy. They include comparisons of the immediate release (IR) and controlled release (CR) formulations (48), comparisons of levodopa and dopamine agonists in early PD (49–58), and a dose-finding levodopa trial in very early disease (ELLDOPA) (59–60). The populations of patients in these studies were more homogeneous than the earlier trials, as the patients had PD < 5 years and were nonfluctuators at the time of initiation. Recent studies have shown varied frequencies of late complications even in these populations. The variances probably relate to the manner in which they are defined and detected. The CR First study (48) was a five-year, randomized, double-blind study comparing CR and IR carbidopa/levodopa in 618 levodopa naive patients (mean duration of disease of 2.3 years). The primary end point was the time until onset of motor fluctuations. Sixty percent of patients completed the five-year study. Mean doses of levodopa in both groups were low (400–500 mg/day). There were no differences between the two formulations with regard to efficacy or frequency of motor fluctuations. Despite low doses, there was a significant improvement in the UPDRS motor score that gradually diminished over time but remained better than the baseline score. Approximately 20% of patients in each group developed wearing-off and dyskinesia, which was far lower than previously reported frequencies. The CALM-PD study (49–50), a parallel-group, double-blind, randomized trial consisting of both clinical and imaging sub-studies, compared the rates of dopaminergic motor complications and dopamine transporter (DAT) ligand uptake after initial treatment of early PD with pramipexole versus levodopa. During the first 10 weeks of the study, patients were titrated with the study medication to one of three possible doses to treat disability, and from week 11 to month 48 were permitted to add open-label levodopa to treat continuing or emerging disability. After month 24,

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patients were permitted to alter the dosage of the study medication or change openlabel levodopa without losing the blind. The two-year data reported that 28% of patients assigned to pramipexole developed motor complications compared with 51% of patients assigned to levodopa (P < 0.001) (50). However, the mean improvement in UPDRS motor score was significantly greater in the levodopa group compared with pramipexole (9.2 vs. 4.5 units, P < 0.001). When extended to four years, slightly more than half (52%) of the patients initially assigned to the pramipexole group developed motor complications compared with 74% of the levodopa-treated patients (49). The mean improvement in UPDRS motor scores from baseline through 48 months was significantly greater in the levodopa group than the pramipexole group, which had a worsening compared to baseline. Fifty-five percent of patients in the pramipexole arm and 67% of the patients in the levodopa arm completed the study. The imaging portion of the study (51) included a subgroup of 82 patients that underwent four sequential [123]I B-CIT single photon emission tomography (SPECT) scans over a 46-month period to compare the rate of loss of DAT binding between the treatment groups. It was assumed that a reduction in striatal [123]I B-CIT uptake is a marker of dopamine neuron degeneration. A 40% relative reduction in the rate of loss of uptake when comparing pramipexole to levodopa was reported. A similar five-year comparison of ropinirole and levodopa (056 study) in 268 patients was reported (52). One subject was randomized to levodopa for every two that were randomized to ropinirole. Open-label levodopa supplementation was allowed. Approximately half of the patients completed the study. At a mean dose of 16.5 mg/day, ropinirole was well tolerated. The primary endpoint was the appearance of dyskinesia, as measured by item 32 on the UPDRS. They were shown to occur earlier and more frequently in patients treated with levodopa than ropinirole. Regardless of levodopa supplementation, 20% of ropinirole subjects experienced dyskinesia by the end of five years versus 45% of levodopa subjects. Prior to the addition of levodopa, 5% of the ropinirole group and 36% of the levodopa group developed dyskinesia. Twenty-three percent of the patients in the ropinirole arm and 34% in the levodopa arm developed wearing-off. The change from baseline in the UPDRS activities of daily living (ADL) score was similar between the two groups; however, there was a significantly greater improvement of 4.5 points in favor of the levodopa group in the UPDRS motor score. The REAL-PET study (53) was a prospective two-year, double-blind, randomized study comparing ropinirole and levodopa in early untreated PD. Open-label levodopa supplementation was allowed as necessary. The primary outcome measure was reduction in 18F-dopa uptake between baseline and two years, as measured by three-dimensional positron emission tomography (PET) scans. Patients were scanned after four weeks of therapy and at the end of two years. Clinical outcomes were secondary. There were 162 PD patients with less than two years of disease and Hoehn and Yahr stage < 2.5 randomized. There was a lower reduction in 18F-dopa uptake with ropinirole (-13.4%) compared to levodopa (-20.3%), a relative difference of 34% (similar to the CALM-PD results). Clinically, dyskinesia occurred in 4% of ropinirole-treated patients and 27% of levodopa-treated patients, but the UPDRS motor score improved by six points with levodopa and worsened by one point with ropinirole over the two-year period. The PELMOPET study (Pergolide versus L-Dopa Monotherapy and Positron Emission Tomography trial) (54) was a multicenter, double-blind, randomized, threeyear trial comparing pergolide (n = 148) to levodopa (n = 146) without levodopa res-

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cue in early untreated PD patients. The primary outcome measures were clinical efficacy (UPDRS), severity and time to onset of motor complications, and disease progression. During the three years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with levodopa (504 mg/day). However, time to onset of motor fluctuations was not longer in patients receiving pergolide after three years. UPDRS total, motor and ADL scores, and patient and physician global impressions of severity and improvement were significantly better in patients receiving levodopa. The PET results were similar to REAL-PET favoring pergolide. Whether these changes in SPECT and PET scans of the CALM-PD, REAL-PET, and PELMOPET studies suggest a protective effect of the dopamine agonist with respect to levodopa or that levodopa may accelerate the rate of loss of uptake or that this is a differential pharmacological effect between drugs is not clear, given the limits of the study designs (55–58). The potential for modification of the imaging outcomes pharmacologically by dopaminergic agents has led to a questioning of the value of such measures under these conditions. It should be noted that in these studies some patients had normal scans. These patients have been referred to as SWEDDs (scans without dopaminergic deficits) and were eliminated from the analyses. The diagnoses in these subjects remain unclear. The ELLDOPA (Early versus Later Levodopa Therapy in Parkinson’s Disease) study (59–60) was a multicenter, placebo-controlled, randomized, double-blind study. The objectives were to examine the impact of levodopa on disease progression. There were 361 PD patients with disease <2 years, Hoehn and Yahr stage <3, and not likely to require symptomatic therapy within the next nine months that were randomized to receive placebo, 50 mg levodopa three times a day (TID), 100 mg TID, or 200 mg TID; 311 completed the study. The study involved 40 weeks of therapy, including a three-day taper and a two-week withdrawal period. The primary outcome was the change in severity of parkinsonism between baseline and week 42, as measured by the total UPDRS score. There was a B-CIT SPECT sub-study of 142 subjects where a scan was completed at baseline and week 40. The clinical results were that levodopa, in a dose–response pattern, reduced the worsening of symptoms from baseline to week 42 (after washout) compared to placebo. This means that the higherdose subjects were less severely impaired after the two-week withdrawal than the other three groups. None of the active treatment groups deteriorated to the level of the placebo group after washout. There was also a strong symptomatic dose–response beginning at week nine. The maximum effect was reached at 24 weeks in the 600 mg/day group. The 150 mg/day group returned to baseline at week 27 and the 300 mg/day group at week 40; however, the 600 mg/day group remained better than baseline until withdrawal of the drug. However, the highest dose caused significantly more dyskinesia than placebo. The SPECT study had the opposite results. The reduction in percent uptake of B-CIT was greater in the levodopa-treated groups than controls, although the difference was not significant. However, when the 19 SWEDDs were removed, as in previous studies, the difference became significant (P = 0.036). The conclusions drawn from the study were that there was no clinical evidence that levodopa accelerated PD progression, in fact, the results suggested that levodopa might instead either slow progression of PD or have a persistent pharmacological effect that goes beyond the two-week washout (beyond the long-duration effect). Two findings that led to questioning the latter include that there was little deterioration of PD after the first week of withdrawal and a small subset of 38

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subjects were evaluated four weeks after washout and no further deterioration was detected. The explanation of this end result remains unresolved. The opposite finding on the imaging sub-study may be explained by the potential capability of levodopa to downregulate the DAT. From the standpoint of symptomatic effects of levodopa, the results demonstrated a striking symptomatic dose–response with the 600 mg group maintaining improvement beyond baseline for the entire nine months. Thirty years of experience and literature have led to several conclusions regarding levodopa therapy in PD. It is currently the most potent symptomatic therapy for PD and we have learned quite a bit about the nuances of treatment. We now treat with the lowest effective dose, not the highest tolerated one; we avoid frequent small doses, which only add to unpredictable responses; we often initiate treatment with a dopamine agonist and add levodopa when necessary; and we have developed adjunctive therapies that complement levodopa, all resulting in reduced longterm complications. Does Levodopa Cause Motor Fluctuations? It has been known since the early days of levodopa therapy for PD that motor fluctuations and dyskinesia were associated with drug therapy (12). Barbeau (61) referred to it as the “long-term levodopa syndrome.” At that time, with no alternative treatments available, he indicated that its existence did not counterbalance the great usefulness of the drug. The questions are what causes their onset and progression and what are the key risk factors? The main issues in the debate address whether they are a result of disease progression or primarily levodopa itself (or the manner in which it is delivered to the brain) or both. The answer is not totally clear, but this question has been examined extensively by (i) evaluating patient populations and examining which of the two factors correlates with the onset of fluctuations and dyskinesia and (ii) examining the actual response fluctuations in a controlled setting to determine possible etiologic explanations. In a retrospective study, Lesser et al. (62) collected data from 131 PD patients relating to severity of disease and late complications and assessed whether these problems were attributed to duration of disease or levodopa therapy. A relationship was seen between the presence of fluctuations and duration of therapy, since those with fluctuations tended to be treated for four years or more. This was not true for dyskinesia. They, therefore, associated fluctuations with levodopa therapy but did not rule out the possibility that those receiving levodopa longer had a more progressive disease. It was recommended that initiation of therapy be delayed until the patient “begins to function unsatisfactorily in occupational or social situations.” This is perhaps the most frequently quoted paper on the subject; however, the authors themselves pointed out the flaws in a retrospective study and indicated the need for a prospective evaluation of the problem. In another retrospective study, de Jong et al. (63) examined 129 PD patients to determine the role of age of onset, predominant symptom (tremor vs. akinetic/rigid vs. all three together), duration of therapy, and disease severity in the occurrence of motor fluctuations. There was no significant effect of age of onset, predominant symptom or duration of disease prior to levodopa therapy (but there was a trend). However, those patients with later therapy showed a lower frequency of fluctuations. Those patients treated in the earlier stages of disease (Hoehn and Yahr stages 1 and 2) did significantly worse with regard to the onset of fluctuations than patients

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initiating therapy in later stages (Hoehn and Yahr stages 3 and 4). They concluded that levodopa should not be started until stage 3 disease. Several studies have since been published which contradict these findings. Cedarbaum et al. (64) criticized the papers described earlier by indicating that the patients treated earlier had more severe disease prior to initiating therapy, continued to progress faster, and thus were more prone to the onset of motor fluctuations. They suggested that levodopa was not the cause of the late complications, nor did the drug itself lead to loss of efficacy. In their own retrospective study, 307 patients were surveyed or interviewed with regard to motor fluctuations and various demographic features and records were reviewed. Patients were evaluated as a whole and were divided into several subgroups based on duration of disease and duration of therapy. Analyses failed to show an association between initiation of levodopa therapy and fluctuations or dyskinesia. Both the duration of disease and duration of therapy were longer in the patients with response fluctuations and dyskinesia. Despite these findings, detailed statistical analyses of sub-groups failed to demonstrate that the age of onset and duration of therapy influenced the occurrence of fluctuations and dyskinesia. Mean delay in levodopa therapy was the same for fluctuators and nonfluctuators. However, patients with dyskinesia were more than three times as likely to have had initiation of levodopa delayed more than two years from diagnosis. The authors did not advocate delaying levodopa therapy because it, in fact, increased chances of dyskinesia. Blin et al. (65) agreed that the apparent acceleration of progression of disease after initiation of levodopa therapy related to the rapidity of disease progression prior to levodopa therapy and not the therapy itself. They also found that delayed initiation of levodopa led to quicker onset of dyskinesia. In a prospective study of 125 patients, Caraceni et al. (66) followed patients for a mean of six years from initiation of levodopa therapy to evaluate any risk factors for motor fluctuations and dyskinesia. To avoid bias, all patients, regardless of the course of progression, were started on levodopa at first diagnosis. Using a multivariable analysis, they found that the risk of late complications was greater in those with akinetic-rigid PD, younger age of onset, greater disability and duration of disease, and longer interval between disease onset and levodopa therapy. Duration and dose of levodopa therapy were not associated with onset of late complications. They concluded that levodopa did not accelerate the appearance of motor fluctuations, that these complications related to the severity and progression of PD, and that there is no need to delay treatment. Hoehn (67), based on her comparison of patients in pre and post levodopa eras, indicated that a delay in introduction of levodopa but not duration of treatment was associated with a poorer outcome. Horstink et al. (68) examined the relationship of duration of disease and duration of levodopa therapy and onset of peak-dose dyskinesia in 54 PD patients and found that both duration of disease and levodopa therapy were greater in the dyskinetic group. The two variables were closely linked, so they then studied patients with significantly asymmetric dyskinesia and found dyskinesia to be most prominent on the worst side, suggesting that disease severity is an important risk factor for dyskinesia, not duration of levodopa therapy. Roos et al. (69) retrospectively studied 89 PD patients and any clinical correlation’s that could be found with onset of response fluctuations (age of onset of PD, presenting symptom, duration of PD, stage of PD at initiation of levodopa, and mean and last dose of levodopa). They used survival and covariate analyses. No correlation was found between the dose of levodopa and the onset of fluctuations. However, a rapid increase in levodopa dose rather than the total dose seemed to determine the

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onset of fluctuations. They suggested that fluctuations occurred in patients with a more rapidly progressive disease requiring a more rapid escalation in levodopa dose. They also concluded that there are no good reasons to delay levodopa therapy if disability dictates its need. Finally, Kostic et al. (70) recently examined the effect of Hoehn and Yahr stage of disease at the onset of therapy on the length of time between initiation of levodopa therapy and the development of motor complications. Of 40 consecutive PD patients treated <5 years, 17 were treated in stage 1, 13 at stage 2, and 10 at stage 3. They found that severity of disease was an important factor in the onset of fluctuations and dyskinesia. Those patients initially treated at stage 3 developed dyskinesia and fluctuations significantly earlier than patients in stages 1 and 2. However, latencies from disease onset to development of fluctuations and dyskinesia were not different between groups. This result suggested the importance of disease duration and severity in the onset of late complications in PD. Although questions remain, the majority of studies suggest that disease duration, progression, and severity are important risk factors in the development of motor fluctuations and dyskinesia. In accepting this conclusion, one would agree that, based on the occurrence of motor complications, there is no reason to delay PD therapy. In fact, two of the studies indicate that a delay would increase the likelihood of dyskinesia. These findings are consistent with reports of patients with late-stage PD (12,70,71) or severe parkinsonism secondary to 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) developing fluctuations soon after the initiation of therapy. This has also been seen in MPTP-treated nonhuman primates (72) and postencephalitic parkinsonism (73). Several groups have studied the mechanism of motor fluctuations. The findings suggest that both duration of disease and levodopa therapy play a role. Fabbrini et al. (74) demonstrated that perhaps the initial feature that leads to the onset of fluctuations is the progression of degeneration of nigral dopaminergic neurons to a threshold level. Once this level is reached, motor fluctuations begin with wearingoff. In their studies, they examined four groups of patients: levodopa naive, levodopa-treated stable responders (nonfluctuators), patients with wearing-off, and patients with unpredictable on/off. They treated each patient with a continuous intravenous infusion of levodopa for 16 hours and then abruptly stopped it. They found that there was no change in pharmacokinetics of levodopa in the more advanced patients. However, it was noted that there was a decay of antiparkinsonian effect, which worsened significantly as the patients advanced from being levodopa naive to having on/off phenomenon. The authors concluded that the wearing-off effect is initiated as a consequence of the marked loss of presynaptic dopaminergic neurons. With loss to a threshold number of neurons, the dopamine system loses its ability to store and release dopamine, and thus buffer fluctuations in serum and cerebral levodopa and dopamine levels. These levels become dependent on peripheral availability of exogenous levodopa. It is believed that levodopa is converted to dopamine in nondopaminergic cells that lack the ability to store and release it in the normally tonic fashion (23). Stimulation at postsynaptic dopamine receptors then becomes intermittent (pulsatile), as a reflection of the peak and trough profile of oral levodopa therapy. It appears that as soon as this intermittent stimulation of dopamine receptors begins, postsynaptic changes are initiated. Studies have demonstrated a narrowing of the therapeutic window, alteration of threshold for onset of dyskinesia, and steepening of the anti-PD response slope,

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all which underlie progression toward a more unstable response to levodopa (75,76). On a cellular level, upregulation of preproenkephalin (PPE) mRNA and downregulation of dynorphin and substance P mRNA among others were found in parkinsonian rodents and primates (77). There is also a resulting change in firing rate and pattern for neurons in the postsynaptic regions, including basal ganglia, thalamus, and cortex. These changes and those resulting from pulsatile stimulation of postsynaptic receptors may lead to the development and progression of dyskinesia and fluctuations, particularly that related to PPE (77). In addition, studies have indicated that postsynaptic glutamate receptors become hypersensitive in relation to the development of motor fluctuations and dyskinesia as compared to patients without fluctuations (78). These findings support the involvement of postsynaptic mechanisms, reflecting an increased sensitivity of clinical response to small fluctuations in dopamine levels and differing pharmacological mechanisms for antiparkinsonian response and dyskinesia. It is, therefore, suggested that it is not the drug but the pulsatile nature of its delivery that is important. This conclusion is based on the reversal of fluctuations with continuous dopaminergic therapy, IV or duodenal levodopa, infusions of apomorphine and lisuride (79–82), but despite these findings, this conclusion remains controversial, especially in relation to the development of motor complications. In trials comparing levodopa to dopamine agonists (49,53), levodopa therapy leads to earlier onset and more frequent occurrence of dyskinesia and wearing-off. This would suggest that either the agonist prevents the onset of these problems or that levodopa, or its short duration of action, has a role in causing them. It does appear that once the progression threshold is reached, levodopa plays a role, via intermittent stimulation of postsynaptic receptors, in the progression of fluctuations to a more unpredictable pattern. One needs to consider that onset and progression are probably caused by different scenarios. It has been demonstrated that continuous infusion of levodopa and stimulation of the subthalamic nucleus (STN) can reduce motor fluctuations and dyskinesia (79,82,83). Some indicate that the reversibility of fluctuations implicates levodopa in the cause of fluctuations (84,85), but this is not the only interpretation. It can also mean that the role played by levodopa in motor fluctuations is potentially reversible. The dose of levodopa also appears to be important since higher doses probably lead to wider pulses. This was demonstrated in the ELLDOPA study where the group receiving 600 mg/day of levodopa developed earlier, more frequent dyskinesia compared to those on lower doses (59). Age of onset is one other risk factor independent of disease progression and levodopa that leads to motor complications. Several retrospective studies have demonstrated mixed results, perhaps due to the age range in the populations studied (63,66). Studies of young onset disease (age of onset <40) indicate a dyskinesia rate of 94% after five years (28). One population-based study examined the frequency of dyskinesia by decade starting with the age of onset 40 to see if the risk of dyskinesia changes over the age spectrum (86). The rate of dyskinesia at five years was examined in patients receiving levodopa as first line therapy and had been treated for at least five years. The incidence of dyskinesia declined, as the age of onset increased: for onset at 40 to 59 years, the frequency was 50%; for 60 to 69 years, frequency was 26%; and for >70 years, the frequency was 16%. The authors suggested that patients with onset of PD before 40 have a unique and unknown physiology, leading to substantial dyskinesia that is age-related, not necessarily levodopa-related.

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IS LEVODOPA TOXIC? The notion that levodopa may be toxic to dopaminergic neurons leading to more rapid nigral degeneration has been a controversy for 25 years. It is based on a body of evidence that suggests that oxyradicals play an important role in the pathogenesis of cell death in PD (87). Evidence includes decreased glutathione, increased Fe2+, increased malondialdehyde, and decreased mitochondrial complex I activity in the substantia nigra (SN) (77). These changes appear to lead to apoptotic mechanisms of cell death (88). Dopamine, when metabolized by monoamine oxidase (MAO) or auto-oxidized, forms H2O2, a precursor to the toxic hydroxyl radical. In PD, after loss of a substantial number of nigral cells, those surviving neurons increase their dopamine metabolism, thus possibly increasing the risk of further free radical formation and neurodegeneration, especially in an environment where protective mechanisms such as glutathione are diminished and iron has accumulated. The use of levodopa may lead to an increase in dopamine formation and, in turn, an increase in dopamine metabolism with greater free radical formation (89,90). Although this theory has gained appeal, and although laboratory evidence supports this possibility, the theory remains controversial (90,91). However, detailed reviews (77,92–94) have indicated that there is no convincing evidence to suggest that levodopa is toxic. The evaluations for levodopa toxicity have included both in vitro (cell culture) and in vivo studies in animals. In the cell culture studies, various cell types were used, including fetal mesencephalic cells, neuroblastoma, fetal fibroblasts, pheochromocytoma PC12 cells, chick sympathetic neurons, and others (95). Results of these studies were variable because of the levodopa concentrations used and culture conditions. High doses of levodopa are toxic to dopaminergic neurons in pure neuronal cultures. Mechanisms of toxicity include oxyradicals, mitochondrial toxicity, or apoptosis (96–98). However, as the conditions are set to more accurately reflect in vivo systems, the toxicity disappears and the neurons are able to resist injury. In fact, with exposure to previously toxic medium doses (20–100 µm) and with glial cells and ascorbic acid present, levodopa actually has a trophic influence increasing cell survival and enhancing neurite outgrowth (77,99–101). The glial cells contain the protective enzymes, catalase and glutathione peroxidase, and provide a nutritive and protective environment. Levodopa exposure to these cultures actually increases cellular concentrations of reduced glutathione peroxidase and other anti-apoptotic molecules and may have other neurotrophic properties. This effect of levodopa may be due to the development of a low-level injury that activates protective mechanisms. Hence, both toxicity and protection may occur due to free radical development, the difference relating to the magnitude of that injury. At levels that are likely present in the extracellular fluid in the striatum of patients, as measured in animals by microdialysis (picomolar levels), it is unlikely that levodopa has any effect (92). In vivo studies have included both unlesioned and lesioned animals. Several studies involved giving healthy animals levodopa for up to 18 months and they demonstrated no loss of dopaminergic neurons (102–106). Cotzias et al. (107) reported that mice that were given levodopa lived longer than the controls that were not given levodopa. Fahn (95) reviewed more than 15 studies of in vivo effects of levodopa and dopamine. Blunt et al. (108) lesioned rats with 6-OHDA, gave levodopa to some, and counted tyrosine hydroxylase (TH)-stained cells in the SN and ventral tegmental area (VTA). The unlesioned (healthy) side was unaffected by the levodopa, supporting the prior studies. The SN on the lesioned side lost 96% of its cells.

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The VTA was less affected with 23% to 65% of the cells remaining. Levodopa further reduced surviving cell numbers to 10% to 35%. They concluded that either levodopa suppressed TH activity or caused increased cell death; however, this work has been criticized (109) and they were later unable to duplicate these findings. Fukuda et al. (110) used MPTP-lesioned mice and examined the effect of levodopa and bromocriptine on total and TH+ cell counts. Levodopa further reduced cell counts in MPTP-treated mice, but it was of TH- cells; TH+ cells were unaffected. Bromocriptine had no effect and, interestingly enough, combined levodopa and bromocriptine actually resulted in a significant increase in surviving cells. Murer et al. (109) examined the effects of levodopa on nigrostriatal and VTA cells in rats with moderate and severe 6-OHDA lesions and sham-lesioned animals. Treatment was for six months, and the same experiment was performed at two separate times in two independent groups of rats. They measured three dopaminergic markers—TH, DAT, and vesicular monoamine transporter (VMAT2)—via radio-immunohistochemistry in the SN, VTA, and striatum. They also examined rotational behavior to assess pharmacologically relevant doses and postsynaptic receptor binding. The study failed to demonstrate any significant difference of effect on cell counts in SN and VTA in levodopa-treated animals compared to those treated with vehicle using all three markers. There was a trend toward increased TH staining in the SN of the moderately lesioned animals. At the level of the striatum, there was no effect of levodopa treatment in the sham-lesioned and severely lesioned animals; however, in the moderately lesioned animals, there was partial recovery of nerve terminals in the damaged area, suggesting a possible neurotrophic effect. The increased immunostaining in this region was significant compared to those rats treated with vehicle. It was suggested that this increased striatal activity with levodopa related to partial recovery via axonal sprouting by the remaining neurons. Levodopa also tended to reverse increased binding (upregulation) of dopamine receptors and diminished the development of behavioral supersensitivity, indicating that the doses of levodopa utilized were pharmacologically effective. These results indicate that levodopa was not toxic to neurons or their terminals in normal and moderately or severely lesioned animals. It may instead promote compensatory mechanisms at the terminals, and thus recovery of innervation of the striatum. Datla et al. (111) demonstrated similar findings in rats with 6-OHDA and FeCl3 lesions; levodopa had no short-term or long-term effects on the number of TH+ cells. In contrast, in the 6-OHDA model, there may have been a protective effect since there was an increase in TH+ cells after 24 weeks. Although results of these animal studies appear to be conflicting, the latter studies appear to provide evidence that levodopa is not toxic. Human studies have not supported the levodopa toxicity hypothesis. Quinn et al. (112) reported a non-PD patient who received high-dose levodopa for four years. Autopsy results demonstrated a normal SN. Rajput et al. (113,114) reported six patients with similar results. Three patients had essential tremor, two had doparesponsive dystonia, and one had nonprogressive parkinsonism. Autopsies in two patients were normal. None of the essential tremor patients developed parkinsonism and the others showed no progression of disease clinically. This would indicate that levodopa is not detrimental to patients with normal or dysfunctional SN. Yahr et al. (115) compared postmortem results in patients treated and never treated with levodopa and reported no difference in the pathology of the SNpc. Gwinn-Hardy et al. (116) examined the effect of levodopa on a family of autosomal-dominant levodoparesponsive parkinsonism (PARK 4—α-synuclein triplication). There were 12 affected

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individuals, and survival duration and disease progression were compared in those treated and not treated. Survival was significantly different between the two groups, as was progression of disease, both in favor of levodopa therapy. These findings would indicate a neuroprotective effect of levodopa, not neurotoxicity. Finally, the CALM-PD and REAL-PET studies utilized SPECT and PET imaging to compare progression of PD with an agonist versus levodopa therapy (49,51,53). The reduction in binding was less over several years for the agonists than for levodopa. This may be an indicator that levodopa is toxic or that the agonist is neuroprotective or it may simply reflect a differential pharmacological effect on the dopamine system measured by the imaging techniques. In the ELLDOPA study (59), the clinical data demonstrated less worsening of disease after levodopa washout in a dose–response fashion compared to placebo, suggesting neuroprotection. The SPECT data indicated that the reduction in B-CIT binding was greater with levodopa, suggesting neurotoxicity. Finally, if in fact the drug has a pharmacological effect on DATs, then the imaging results are invalid. If the clinical effect is due to a prolonged pharmacological effect of the drug, then the clinical data is invalid. At this point, the interpretation of these results remains elusive. When one looks at the data from cell culture, animals, and humans, there is no convincing evidence that levodopa is toxic. This should not be a concern when considering therapy in PD patients. Does Tolerance Develop to Levodopa? The lay literature is replete with information suggesting that levodopa loses its effect after about five years. This leads to some trepidation on the part of the patient and physician in initiating therapy. If that were the case, it would indicate that tolerance is a possible concern and would argue for delaying treatment. It is conceivable that, when all nigrostriatal cells are depleted, levodopa would lose all effectiveness since these are the cells that convert levodopa and release dopamine. Lesser et al. (70) found that longer duration of disease did not appear to adversely affect response to levodopa at the time of initiation of therapy, yet they demonstrated deterioration in response that did not correlate with duration of disease. Those receiving levodopa longer had more severe disease. The assumption made by the authors was that PD patients developed tolerance. Despite these findings, the authors did not rule out the possibility that those receiving levodopa longer had a more progressive disease. However, Blin et al. (65) noted that chronic treatment does not lead to decreased effectiveness. Evidence indicates that conversion of dopa to dopamine can occur at sites other than dopaminergic terminals in the striatum. Thus, levodopa continues to be effective throughout the disease course. Markham and Diamond (117,118) demonstrated that the potency of levodopa does not change with chronic use when they studied three groups of patients: those starting levodopa after one to three years of disease, four to six years, and seven to nine years. This study was started when levodopa was introduced so that they could assess whether the apparent loss of efficacy could relate to the disease duration or the duration of drug therapy. After six years of follow-up, they noted the following: (i) the disability scores were different for the three groups at initiation of levodopa and remained different thereafter; (ii) disability scores were the same for the three groups when they were matched for disease duration despite varied durations of therapy; and (iii) there was no significant difference with respect to the incidence of dyskinesia. In projecting the course of disease, it was found that all three groups ultimately

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followed the same predictable course of progression independent of the duration of levodopa therapy. This was confirmed after 12 years of follow-up of the first group (119,120). The authors concluded that levodopa works at all stages of PD, does not result in tolerance over time but does not stop progression of disease. In other words, changes in disability of PD are related to the duration of disease and not the duration of therapy or tolerance to levodopa. Aside from progression of disease, another cause of the apparent loss of efficacy relates to narrowing of the therapeutic window, resulting in increased sensitivity to adverse effects such as dyskinesia and hallucinations (64,65). The worsening of disease also comes from the onset and progression of symptoms not attributable to dopamine systems, such as postural instability, freezing, and dementia (65,121). Mortality of Parkinson’s Disease with Levodopa Several studies performed in the 1970s demonstrated that levodopa therapy improved mortality in PD. These studies compared the survival of levodopatreated patients to the mortality rate demonstrated in the pre-levodopa Hoehn and Yahr study (122), which demonstrated that mortality was three times greater than the normal population. Nearly all studies indicated that levodopa improved survival with rates of 1.4 to 2.4 (119,120,123,124). Some investigators suggested that survival approached normal, whereas others indicated that the effect was only seen in the early years of therapy and then disappeared, suggesting that improvement was based on symptomatic responses. However, many of the studies have been criticized due to methodological flaws, problems with patient selection, and possible biases. One study (125) utilized a population-based study design (retrospective) to avoid many of these flaws and examined the change in survival related to levodopa therapy. The study included patients treated from 1964 to 1978 to include patients treated early and late, as well as untreated cases. Results indicated that survival for all treated patients was significantly poorer than that of the general population, but was better in treated than in untreated PD. The improved survival over time was not linear. Throughout the 17 years of follow-up, there was reduced risk of death with levodopa therapy. Rajput (114) compared 10-year survival of 215 patients from the pre-levodopa era and 719 from the post-levodopa era. The survival was significantly greater for the post-levodopa group and particularly for those who initiated therapy at Hoehn and Yahr stage <2.5. This study suggests that the timing of levodopa therapy is important in relation to survival. Several other studies have supported this conclusion. Diamond et al. (123) examined 359 patients treated between 1968 and 1977. They divided patients into three groups: one to three years of PD, four to six years of PD, and seven to nine years of PD. They used observed-to-expected death rate ratios from a similar group in the general population as measures of survival. When the duration of therapy was held constant at 15 years, the ratio was higher for patients with longer duration of disease. When the duration of disease was held constant at 17 years, the patients with longer duration of therapy had a better mortality ratio than the other two groups, suggesting early initiation of levodopa was beneficial to life expectancy. Scigliano et al. (124) studied 145 patients seen from 1970 to 1983. Of those, 98 were treated for two or more years, whereas 47 were treated for less than two years. Mortality was found to be 2.5 times greater among the patients treated later, but a

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multivariate analysis taking into account age and disease severity made the difference nonsignificant. Nonetheless, the mortality among late starters was two times greater. There were biases that led to an underestimation of mortality in the delayed treatment group, including 47 patients who were lost to follow-up. The authors concluded that survival from early levodopa initiation is the same or better than late initiation. Is There an Association Between Levodopa Therapy and Melanoma? The connection between levodopa therapy, PD, and malignant melanoma has been a matter of debate for three decades. It originally derived from the biochemistry of the drug. Levodopa is a substrate for the development of dopamine, which, in turn, develops into neuromelanin in CNS nigral neurons. It is the dopaquinones derived from levodopa that are oxidized to form neuromelanin in these cells (126). Hence, it has been proposed that levodopa may also affect the activity of melanocytes in the skin, possibly promoting malignant transformation, although this connection has never been proven. In addition, it is now known that 70% of melanoma cases in the general population appear to be connected with a genetic mutation unrelated to PD. Thus, it would seem unlikely that there would be a connection between PD, levodopa, and melanoma. Nevertheless, reports of melanoma in patients treated in the 1970s led the FDA to require language in the package insert that cautions against the use of levodopa in PD patients with a history of melanoma. There are over 40 papers published on the subject (126) with conclusions varying from caution in using levodopa in patients with a history of melanoma, to no need for concern. In 1998, Pfutzner et al. (117) reported that although no causal relationship has been proven, patients with a history of malignant melanoma receiving levodopa therapy should be carefully followed for the development of new pigmented lesions. Other anecdotal reports exist in the literature of the potential carcinogenic effects of levodopa therapy and its potential to activate malignant melanoma (118). For these reasons, the warnings have not been lifted. Weiner et al. reviewed the literature and concluded that there is only anecdotal evidence at best to support a link between levodopa and melanoma. They reported nine patients with PD and a history of melanoma who were treated with levodopa with no recurrence. It was concluded that levodopa therapy could be used safely in PD patients with melanoma (127). Woofter reported a 74-year-old man with PD who was treated with levodopa and whose malignant melanoma was later discovered. Prior to the diagnosis of melanoma, it was estimated that the patient received 5.7 kg of levodopa over a six-year period. The patient continued with levodopa treatment for more than 10 years, with an additional 4.3 kg of levodopa prescribed, and no recurrence of his melanoma was observed. They also concluded that withholding levodopa therapy for fear of accelerating melanoma was unwarranted (118). Siple et al. (128) reviewed 34 case reports from 1966 to 1999 and indicated that the association between levodopa and induction or exacerbation of malignant melanoma was unlikely. Finally, in a review of 54 patients, 63% were taking levodopa, 31% were not, and, in the rest, the status was unknown (129). Seventeen percent were diagnosed with metastatic disease. After diagnosis of melanoma, 71% continued levodopa and there was no dose–response relationship. They found that the number of reported cases of melanoma in PD is well below that expected, based on prevalence of both disorders. In addition, recurrence rates are high with melanoma in the general population and not necessarily increased in PD.

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In contrast, Olsen et al. (130) discovered that among 14,088 PD patients, there was a small increased relative risk for malignant melanoma and other nonmelanotic skin cancers, although no information was gathered on levodopa therapy. The cause of this increased risk is not known. On the basis of the information available, it can be concluded that there may be a small increase in the risk of developing malignant melanoma in PD, but the causal relationship specifically between levodopa and the occurrence or recurrence of this cancer is uncertain but unlikely. A history of melanoma in a PD patient should not prohibit the use of levodopa, but it is not unreasonable to have a high-level of vigilance for malignant melanoma in patients with a history of skin cancer. LEVODOPA AND HOMOCYSTEINE An evolving concern with levodopa therapy relates to its association with elevated homocysteine (HC) levels. Since the late 1990s, several studies have indicated that levodopa dose correlates with elevation of HC. Postuma and Lang (131) reviewed this literature, and the relevance of the increase of HC to PD and patient health remains unclear. The concern relates to data suggesting that elevated HC levels increase the risk of stroke, coronary artery disease, and dementia (132–134). HC is metabolized from dietary methionine through two intermediates: SAM (s-adenosylmethionine) and SAH (s-adenosylhomocysteine). HC is metabolized back to methionine via methylene tetrahydrofolate reductase (MTHFR) or to cysteine via other mechanisms. These enzymatic reactions occur in the presence of folate and vitamins B12 and B6. Hence, deficiency of any of these could lead to elevated HC. This is true for the presence of the C677T MTHFR polymorphism, which decreases metabolism of HC. In PD, it is the conversion of levodopa to 3-OMD via COMT that drives the formation of HC. SAM is the methyl donor for this reaction yielding SAH that is rapidly converted to HC (131). The resulting elevation of HC is generally modest. One study (135) demonstrated after 110 days an increase of 8.2 µmol/L. Another study indicated that the increase was modest and did not elevate HC to levels beyond the normal range and therefore may not be of concern (136). It has been demonstrated that an increase of 5 µmol increases the risk of stroke by 65% and ischemic heart disease by 42% (137). However, studies of the risk of stroke in PD have not consistently demonstrated an increased risk. In fact, two studies were positive, four negative, and three others showed a reverse association (131). Rogers et al. (138) suggested that PD patients only in the higher quartile of HC levels had a higher prevalence of coronary heart disease. In contrast, one study showed that the measure of biomarkers for endothelial function in PD patients with modestly elevated HC was normal (139). Hence, the impact of HC changes in PD patients regarding atherosclerotic disease remains to be discerned. The finding that elevated HC is associated with Alzheimer’s disease and vascular dementia might suggest an association with dementia in PD. Zoccolella et al. (140) compared HC levels in 14 PD patients with cognitive dysfunction to 21 patients without cognitive dysfunction, all receiving chronic levodopa therapy. HC levels were significantly higher in the group with cognitive dysfunction versus the nondemented group (21.2 µmol/L vs. 15.8). There was a correlation between cognitive dysfunction and HC levels. Another study (136) demonstrated that patients with higher HC levels performed more poorly on cognitive and depression measures. These findings are preliminary and require confirmation. Potential mechanisms of action of HC in its deleterious effects include free radical formation, excitotoxicity, and inflammation, all relevant to PD progression (131).

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The relation between disease progression and HC level also warrants further study. Whether PD patients treated with levodopa require supplementation with vitamins B6, B12, and folate or with COMT inhibitors to prevent elevation of HC levels still needs to be studied. Three small trials with the COMT inhibitor entacapone have demonstrated that its use prevents the elevation of HC to some extent (141–143). The impact of this effect on the health of PD patients will require the completion of a longterm prospective trial. A final finding is that elevated HC levels may be associated with the development of osteoporosis and secondary fractures. One study examined 199 women with PD and found that patients with the highest quartile level of HC were at greater risk for hip fractures (144). These results warrant further examination. LEVODOPA CHALLENGE TEST It can be difficult to accurately differentiate PD from other forms of parkinsonism, especially during the early stages of disease. Levodopa administration can be used for diagnostic purposes, as PD patients respond more frequently and robustly to levodopa compared with other forms of parkinsonism. Clarke and Davies (145) reviewed 13 studies that examined whether an acute levodopa or apomorphine challenge test could aid in the diagnosis of PD. Four studies examined de novo patients and nine examined patients with clinically established PD. Although there was significant variability in the methodologies employed, abstracted sensitivity and specificity data were summarized from the studies and the two challenge tests compared as to their ability to accurately predict patients’ diagnosis. The sensitivity for the diagnosis of established PD for apomorphine was 0.86 [95% confidence interval (CI)], acute levodopa 0.75 (95% CI), and chronic levodopa therapy 0.91 (95% CI). The specificity for the diagnosis of established PD was apomorphine 0.85 (95% CI), acute levodopa 0.87 (95% CI), and chronic levodopa therapy 0.77 (95% CI). The number of patients positive for each test divided by the number with clinically diagnosed de novo disease was apomorphine 0.63 (95% CI), acute levodopa therapy 0.69 (95% CI), and chronic levodopa therapy 0.76 (95% CI). Three of the studies allowed for the possibility to cross correlate agonist or acute levodopa with chronic levodopa therapy. Twenty-one chronic levodopa patients described as having a positive response initially had a negative result with acute levodopa. The authors concluded that the accuracy of the acute levodopa and apomorphine tests was similar but not superior to that of chronic levodopa therapy, and that these were not more accurate than the established accuracy of clinical diagnosis of PD (75–80% accuracy). In addition, given the additional costs and adverse effects associated with their use, they could not recommend using the challenge tests. Rossi (146) reported the use of acute challenges with apomorphine and levodopa in patients with clinically defined forms of parkinsonism to assess the potential accuracy of the tests in making a diagnosis. Motor responses to the acute administration of levodopa and apomorphine were analyzed in a series of 134 parkinsonian patients (83 with a clinical diagnosis of PD, 28 patients with multiple system atrophy (MSA), 6 with progressive supranuclear palsy, and 17 unclassified patients). The duration of disease or the clinical stage of the patients was not described. UPDRS motor scores were evaluated one hour following levodopa administration and 20 minutes after apomorphine injection. The motor evaluation was matched with the clinical diagnosis and the response to chronic levodopa therapy. Those patients who had improvement of at least 16% on the UPDRS were more likely to have PD when compared to non-PD patients. When comparing PD with

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MSA patients, those who improved at least 18% on the UPDRS were more likely to have PD rather than MSA. If a patient responded to the challenge test with at least a 14.5% improvement in UPDRS, they were more likely to respond favorably to chronic levodopa therapy. The authors conclude that use of the challenge test was helpful in making treatment decisions regarding long-term levodopa therapy. It appears that, overall, an acute levodopa test is not very useful in improving our ability to diagnose PD. Questions remain about its use in making treatment decisions. LEVODOPA PREPARATIONS Levodopa is available with carbidopa as immediate release carbidopa/levodopa 10/100, 25/100, and 25/250. It is also available in a sustained-release form as carbidopa/levodopa 25/100 and 50/200. An orally dissolvable form of immediate release carbidopa/levodopa (Parcopa®) is available as 10/100, 25/100, and 25/250. Finally, levodopa is available with the COMT inhibitor, entacapone, in the following combinations: Stalevo® 50 (carbidopa 12.5 mg/levodopa 50 mg/entacapone 200 mg), Stalevo® 100 (carbidopa 25/levodopa 100/entacapone 200), and Stalevo® 150 (carbidopa 37.5/levodopa 150/entacapone 200). CONCLUSIONS Levodopa remains the most potent symptomatic treatment for PD and the gold standard with which other drugs are compared, even after 35 plus years of availability. Over time, the strategies employed for its use have changed. We now use the lowest possible effective dose rather than the highest tolerated dose. We avoid frequent small doses, as this can contribute to unpredictable responses, and it is usually prescribed with adjunctive therapies, such as dopamine agonists and COMT inhibitors. As such, fewer early and late complications occur today than those reported in the past; however, late complications still occur and continue to be a concern in advanced PD. The exact role of levodopa in the development of motor complications is controversial but it is likely to play some role, particularly in relation to the progression of already existing fluctuations to a more unpredictable pattern. In particular, it may be the pulsatile delivery of orally ingested levodopa that leads to this problem, not the drug itself. It is possible that fluctuations are a reversible pharmacological effect, as demonstrated with infusion therapies and deep brain stimulation. It is established that disease duration, progression, severity, and age of onset do play important roles in the development of fluctuations and dyskinesia, perhaps more important than the pulsatile delivery. Although dopamine agonists provide greater protection against the development of motor complications, this benefit in the long run is unclear. This is especially true since they are inferior to levodopa from a symptomatic standpoint and nearly all patients ultimately require levodopa. What is clear is that levodopa is consistently more potent at any stage of disease, and that its delay contributes to a higher degree of disability and possibly mortality and dyskinesia. Recent studies have contradicted the findings of older ones regarding whether levodopa is toxic. A critical review of the literature demonstrates that if in vivo conditions are established, not only is levodopa not toxic but may in fact be protective. This is further supported by the improved mortality rates of PD since the availability of levodopa. Such a neuroprotective effect needs to be confirmed, especially since imaging studies have demonstrated the opposite result from clinical outcomes. Further confirmatory studies of the neuroprotective potential of levodopa are needed.

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There is no study to date that can conclusively establish a causative link between the use of levodopa and the potential development and recurrence of malignant melanoma. However, a recent study suggested a small but significant increase in the risk of melanoma in PD but did not address the role of levodopa. Although the literature indicates that a history of melanoma should not keep a patient from taking the drug, it is reasonable to provide appropriate vigilance. The connection between levodopa therapy and elevated HC is a newer concern. Although it is established that levodopa elevates HC, it is unclear if this change is clinically significant. HC is a risk factor for atherosclerotic disease and dementia, but the literature does not demonstrate an increase in cerebrovascular or coronary artery disease in PD. Any connection to dementia is not established and further research is needed. Differentiating early PD from other forms of parkinsonism can be a challenge; most studies quote a clinical accuracy of 75% to 80% when compared with pathologic diagnosis. It is widely held that PD patients frequently show a significant and robust response to levodopa therapy when compared to other forms of parkinsonism. Despite this, studies to date cannot recommend the use of a single acute levodopa challenge, as the results have not demonstrated accuracy superior to clinical diagnosis. ACKNOWLEDGMENTS This work supported by the Emory Parkinson’s Research Fund and the Movement Disorders Professorship Fund. REFERENCES 1. Nutt JG, Wooten GF. Clinical practice. Diagnosis and initial management of Parkinson’s disease. N Engl J Med 2005; 353(10):1021–1027. 2. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24(2): 197–211. 3. Hornykiewicz O. Dopamine miracle: from brain homogenate to dopamine replacement. Mov Disord 2002; 17(3):501–508. 4. Hornykiewicz O. L-DOPA: from a biologically inactive amino acid to a successful therapeutic agent. Amino Acids 2002; 23(1–3):65–70. 5. Funk C. Synthase des d, 1-3-4, dioxyphenalanins. Chem Zenttralbl I 1911. 6. Guggenhiem M. Dioxyphenlalanin, eine neue Aminosarue aus Vicia faba. Z Phy Chem 1913. 7. Carlsson A, Lindqvist M, Magmusson T. 3,4 - dihydroxyphenylalanine and 5-hydroxytriptophan as reserpine antagonists. Nature (London) 1957; 180:1200. 8. Carlsson A, Linqvist M, Magmusson T, Waldbeck B. On the presence of 3hydroxytyramine in the brain. Science 1958; 127(471). 9. Ehringer H, Hornykiewicz O. Verteilung von noradrenalin und dopamin im gehirn des menschwen und ihr verhalten bei erkrankingen des extrapyramidalen systems. Klin Wochensher 1960; 38:1236–1239. 10. Barbeau A, Murphy GF, Sourkes TL. Excretion of dopamine in diseases of basal ganglia. Science 1961; 133:1706–1707. 11. Cotzias GC, Van Woert M, Shiffer L. Aromatic amino acides and modification of parkinsonism. N Engl J Med 1967; 276:374–379. 12. Cotzias GC, Papavasiliou PS, Gellene R. Modification of parkinsonism-chronic treatment with L-DOPA. N Engl J Med 1969; 280:337–345. 13. Yahr MD, Duvoisin RC, Schear MJ, Barrett RE, Hoehn MM. Treatment of parkinsonism with levodopa. Arch Neurol 1969; 21(4):343–354.

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Dopamine Agonists Valerie Street and Mark Stacy Division of Neurology, Duke University Medical School, Durham, North Carolina, U.S.A.

INTRODUCTION Dopamine agonists have been used to treat Parkinson’s disease (PD) since the late 1970s (1). These agents were initially introduced as adjunctive therapy to levodopa. In the last 30 years, dopamine agonists have demonstrated therapeutic benefit in all stages of PD, both in combination with levodopa and as monotherapy. Clinical, neuroimaging, animal, and cellular data suggest not only a levodopasparing effect and a delay in the incidence of motor fluctuations, but also a potential neuroprotective effect (2–5). A number of hypotheses have been proposed including a reduction of free radical formation by limiting levodopa exposure or an increase in the activity of radical-scavenging systems, perhaps by changing mitochondrial membrane potential. In addition, some investigators suggest that dopamine agonists may provide neurotrophic activity. However, there is currently no definitive evidence of disease modification beyond the delay of levodopainduced motor complications. This chapter reviews the history of dopamine agonists in the treatment of PD and provides a summary of data concerning efficacy, treatment approaches, and comparisons between commonly prescribed dopamine agonists. Similarly designed clinical trials will be discussed, including direct comparative trials, in an effort to better define the relative efficacies of these agents. DOPAMINE AGONISTS AND DOPAMINE RECEPTORS The dopamine agonists used in the treatment of PD include: apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, and rotigotine. All of these agents activate D2 receptors, whereas pergolide has been shown to be a mild D1 agonist, and pramipexole may have higher affinity for D3 receptors (Table 1). Five subtypes of dopamine agonist receptors have been identified and may be classified into striatal (D1 and D2) receptors or cortical (D3, D4, and D5) receptors. The D3–5 receptors are present in the mesolimbic and mesocortical dopaminergic pathways. The D1-receptor (D1,5) family is associated with activation of adenylate cyclase and dopamine, and dopamine agonists activate the D2-receptor family (D2–4) (6). Postmortem examination of brains of patients with PD revealed upregulation of striatal D2 and downregulation of the D1 receptors. It is postulated that these changes lead to alteration of the indirect D2-mediated pathway and disinhibition of the subthalamic nucleus (STN). Studies comparing apomorphine, a rapid acting dopamine agonist, to deep brain stimulation found comparable changes in Unified Parkinson’s Disease Rating Scale (UPDRS) and intracortical inhibition with STN stimulation, globus pallidus stimulation, and apomorphine infusion, suggesting a connection between the nigral dopaminergic pathway and the thalamocortical motor pathway (7). 335

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Street and Stacy TABLE 1 Dopamine Agonists in Parkinson’s Disease Dopamine agonist Dopamine Bromocriptine Pergolide Pramipexole Ropinirole Apomorphine

D1

D2

D3

D4

D5

5-HT

NE

ACh

+ − + 0 0 −

++ ++ +++ +++ +++ ++

+++ + +++ +++ +++ ++

++ + +++ ++ 0 +++

+++ + + 0 0 ++

0 − 0 + 0 −

0 + + + 0 +

0 0 0 + 0 0

Abbreviations: 5-HT, 5-hydroxytryptamine; Ach, acetylcholine; D, dopamine; NE, norepinephrine. Source: From Ref. 6.

Apomorphine The Food and Drug Administration (FDA) approved apomorphine, a nonergoline dopamine agonist, as a subcutaneously injected treatment for severe off episodes in 2004. It was first used in the 1930s as an emetic and was found to have benefit for PD over 50 years ago. Although the mechanism of action is unclear, it is thought that apomorphine ameliorates symptoms of PD by stimulating D2 receptors within the caudate nucleus and putamen. It has a high affinity for D4 receptors; moderate affinity for D2, D3, and D5; moderate affinity for adrenergic receptors; and low affinity for D1 and 5-hydroxytryptamine (5-HT) receptors (Table 1). In addition to the FDAapproved formulation administered subcutaneously, it has also been administered as an intravenous infusion, intranasal spray, sublingual tablet, and as a rectal suppository (8). Although intravenous administration of apomorphine results in consistent motor control, allowing for a reduction in oral medications, unanticipated intravascular thrombotic complications, secondary to apomorphine crystal accumulation, have led to termination of this route of administration (9). Subcutaneously administered apomorphine has a rapid onset of 7.3 to 14 minutes after administration and a short half-life of 45 to 90 minutes. The rate of uptake after apomorphine injection is influenced by factors such as location, temperature, depth of injection, and body fat. Plasma protein binding of apomorphine is approximately 30%, and its metabolism is unclear (Table 2) (10). Apomorphine may be given subcutaneously every two hours. A test dose of 2 mg is administered to determine the initial dosing, and may be titrated to an effective dosage by 1 mg increments up to a maximum single exposure of 6 mg (11). There are limited data for dosing over five times per day, and at this dosing frequency, continuous subcutaneous infusion should be considered. Side effects of apomorphine include nausea, vomiting, QT-interval prolongation on EKG, and hypotension. Because of the powerful emetic action of apomorphine, treatment is initiated three TABLE 2 Dopamine Agonists in Parkinson’s Disease Dopamine agonist Bromocriptine Pergolide Pramipexole Ropinirole Apomorphine

t1/2

Metabolism

N

S

H

OH

RPF

3–8 hr 27 hr 8–12 hr 4–6 hr 40 min

Hepatic Hepatic Renal Hepatic Unclear

37 24 18 20 30

8 6 13 12 35

12 14 19 15 10

44 2 16 17 20

2–5% 2–5% 0 0 0

Abbreviations: H, hallucinations; N, nausea; OH, orthostatic hypotension; RPF, retroperitoneal or pulmonary fibrosis; S, somnolence. Source: From Ref. 1. Additional data are collected from published package inserts.

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days after beginning antiemetic agents—domperidone or trimethobenzamide (12). Apomorphine should not be administered with antiemetic serotonin type 3 receptor (5HT3) antagonists, such as ondansetron, granisetron, dolasetron, and palonosetron, because of the risks of severe hypotension and syncope. QT-interval prolongation has been found to be insignificant with doses less than 6 mg. Dewey et al. (13) demonstrated a 62% improvement in off-state UPDRS scores in subjects with advanced PD, 20 minutes after administering apomorphine in a 2:1 randomized, placebo-controlled trial. Subcutaneously administered apomorphine was also shown to be effective in 30 patients for up to five years of therapy (14). Bromocriptine Bromocriptine was approved in the United States in 1978. This ergot alkaloid is a partial D2 agonist and a mild adrenergic agonist. It also has mild D1 and 5-HT- antagonist properties (Table 1). When taken orally, bromocriptine is rapidly absorbed and 90% degraded through first-pass hepatic metabolism. Peak drug levels are achieved in 70 to 100 minutes, and it has a half-life of three to eight hours. Less than 5% of the drug is excreted into the urine, and it is highly protein bound (Table 2). Bromocriptine is formulated into 2.5 mg-scored tablets and 5 mg capsules (1). Bromocriptine is initiated at 1.25 mg/d and is generally increased to 20 mg/d in three divided doses over the course of seven weeks; however, some patients may require dosages higher than 60 mg/d (Table 3) (15). Although the side effects of all dopamine agonists are similar, only the ergotderived compounds have been associated with retroperitoneal fibrosis—a rare but serious condition associated with severe pulmonary and renal complications (16). Erythromelalgia, a painful reddish discoloration of the anterior shin, may also be more prevalent in patients taking ergoline dopamine agonists. The side effects of nausea, vomiting, sleepiness, orthostatic hypotension, and hallucinations are common to all dopamine agonists and in pivotal trials these side effects were 8% to 12% more common with bromocriptine than with placebo (17) (Table 2). Bromocriptine has been investigated in de novo and levodopa-treated PD patients (18–22). A systematic review of all randomized, controlled trials of bromocriptine monotherapy compared with levodopa monotherapy in PD found that methodological factors or lack of control populations have led to a lack of evidence to guide clinical decisions (19–21). From 1974 to 1999, six studies randomizing more than 850 PD patients to bromocriptine or levodopa were reported, but only TABLE 3 Agonist Titration Schedule Time Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Maximum dosage Source: From Ref. 15.

Bromocriptine

Pergolide

Pramipexole

Ropinirole

1.25 mg qd 1.25 mg bid 1.25 mg tid 2.50 mg tid 3.75 mg tid 5.00 mg tid 5.00 mg qid

0.05 mg qd 0.05 mg tid 0.10 mg tid 0.15 mg tid 0.25 mg tid 0.50 mg tid 0.75 mg tid 1.00 mg tid 2.00 mg qid

0.125 mg tid 0.25 mg tid 0.50 mg tid 0.75 mg tid 1.00 mg tid

0.25 mg tid 0.50 mg tid 0.75 mg tid 1.00 mg tid 1.50 mg tid 2.00 mg tid 2.50 mg tid 3.00 mg tid 8.00 mg tid

15.0 mg qid

1.5 mg tid

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two trials used a double-blind design (19–21). These studies indicated a reduced frequency of dyskinesia and a trend toward less wearing off with bromocriptine. However, the larger number of dropouts in the bromocriptine group leaves these data subject to varied interpretations. In the treatment of early PD, bromocriptine may be beneficial in delaying motor complications and dyskinesia with comparable effects on impairment and disability in patients who tolerate the drug. Numerous studies have demonstrated the benefits of bromocriptine in advanced PD. A double-blind, placebo-controlled, multicenter trial of bromocriptine in patients with motor fluctuations reported a 14% improvement in UPDRS activities of daily living (ADL), a 23.8% improvement in UPDRS motor scores and a 29.7% reduction in off time after nine months, with a mean daily dosage of 22.8 mg of bromocriptine (22). Pergolide Pergolide, an ergoline-derived dopamine agonist, was approved in the United States in 1989. Like bromocriptine, pergolide has high affinity for the D2 receptor and mild α2-adrenergic activity, but it does not have 5-HT activity. In addition, pergolide has significant D3 activity and mild D1-agonist activity (Table 1) (1). Pergolide is available in three tablet sizes, 0.05 mg, 0.25 mg, and 1.0 mg, and is usually titrated to an effective dosage or an initial maximum dosage of 3 mg/d in three divided doses over the course of six to eight weeks (Table 3) (15). If clinical benefit is seen at 3 mg/d, this dosage may be increased if needed to a maximum of 6 to 8 mg/d. This agent is rapidly absorbed from the gut and reaches a peak plasma concentration in one to three hours. Although the duration of action is typically four to eight hours, the half-life ranges from 15 to 42 hours with a mean of 27 hours. Pergolide is highly protein bound, and greater than 50% of the drug is excreted through the kidney (1). Side effects of pergolide are similar to bromocriptine, and include retroperitoneal fibrosis, erythromelalgia, somnolence, orthostatic hypotension, and hallucinations. These side effects are 2% to 12% higher with pergolide than with placebo (Table 2) (15,23). Pergolide has been demonstrated to be effective in both early and advanced PD (24, 25). A de novo PD study, Pergolide versus L-Dopa Monotherapy and Positron Emission Tomography trial (PELMOPET) with randomization to levodopa or pergolide and concurrent positron emission tomography (PET) scanning was completed. In this double-blind study, 294 subjects were randomized to pergolide (n = 148) or levodopa (n = 146) and treated without levodopa rescue for 36 months (4). Seventy-seven subjects (52%) receiving pergolide compared to 90 subjects (61.6%) treated with levodopa completed the study. The mean dosage of pergolide was 3.23 mg/d, whereas subjects receiving levodopa averaged 504 mg/d. Although differences were noted in change from baseline UPDRS motor score (13.4 ± 8.8 pergolide vs. 18.1 ± 10.1 levodopa), dyskinesia was three times more frequent in the levodopa group. In addition, 88 subjects were followed by 18F-Dopa PET scans. There was a decrease in uptake in the putamen of 7.9% in the pergolide group and 14.5% in the levodopa group, but these were nonsignificant differences (P = 0.288). Olanow et al. reported a 24-week, double-blind trial of 377 PD subjects with motor fluctuations randomized to pergolide (n = 189) or placebo (n = 187). Significant improvements were seen in UPDRS motor scores and off time, and levodopa dosages were reduced by approximately 25% in the pergolide group (26). A database review, comparing efficacy in adjunct therapy trials of pergolide and bromocriptine, found that pergolide was superior to bromocriptine in regards

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to motor function and ADLs (19). In addition, more subjects recorded a marked or moderate improvement with pergolide than with bromocriptine. However, no significant differences in motor fluctuations, dyskinesia, levodopa dose reduction, dropouts, or adverse events were found. Cardiopulmonary fibrosis has been reported in patients on long-term pergolide therapy. One patient with no previous underlying pulmonary disease was reported to develop pulmonary symptoms 16 years after the start of bromocriptine and 11 years after starting pergolide. Chest radiograph and CT defined a mass in the right upper lobe, and a biopsy revealed pleural and parenchymal fibrosis. The patient improved after a change from pergolide to pramipexole (27). A subsequent chart review compared 55 patients taking pergolide to 63 control patients (28). Echocardiograms revealed aortic regurgitation in 45% of the pergolide group compared to 21% in the control group (P = 0.006). In the pergolide group, other diseases affected the tricuspid (11%) and mitral (13%) valves, and the aortic valve involvement was judged to be moderate to severe in 13% of subjects. There was also some suggestion of a dosage effect with higher daily doses of pergolide, possibly associated with moderate to severe aortic regurgitation (P = 0.05). Pramipexole Pramipexole was approved in the United States in 1997 and is a synthetic, nonergot dopamine agonist. Like the ergot-derived dopamine agonists, this agent is active at the D2, D3, and D4 receptors. Pramipexole also has affinity for α- and β-adrenoreceptors, acetylcholine receptors, and 5-HT receptors (Table 1). The drug is available in 0.125, 0.25, 0.5, 1.0, and 1.5 mg tablets, and the usual dosage is 3.0 mg/d in three divided doses titrated over five weeks (Table 3) (15). This drug reaches peak plasma levels within one to three hours and has an elimination half-life of 8 to 12 hours. The agent is excreted mostly unchanged in the urine and less than 20% is protein bound. Pivotal trials with pramipexole report that nausea, vomiting, somnolence, and orthostatic hypotension were 0% to 13% higher than in subjects randomized to placebo (Table 2) (2,29–32). Pramipexole has been studied in de novo and advanced PD populations. Three large trials evaluated the effectiveness of pramipexole as monotherapy in early PD (2,29–32). A large dose-ranging trial (n = 264) conducted by the Parkinson Study Group found most patients tolerated dosages of 6 mg/d or less of pramipexole. In this 10-week study, 98% (placebo), 81% (1.5 mg/d), 92% (3.0 mg/d), 78% (4.5 mg/d), and 67% (6.0 mg/d) of subjects tolerated the drug (29). A 20% benefit in UPDRS motor scores was seen in all active treatment groups, and it was determined that the optimum dosage range was 1.5 to 4.5 mg/d. In a 6-month study, 335 subjects were randomized to pramipexole (n = 164) or placebo (n = 171). Investigators reported a greater than 20% improvement in the UPDRS ADL and motor scores in the active treatment group (30). Side effects in these investigations included nausea, somnolence, dizziness, and hallucinations. The Parkinson Study Group reported data comparing pramipexole to levodopa in early PD in the Comparison of the Agonist Pramipexole versus Levodopa on Motor Complications in Parkinson’s Disease (CALM-PD) trial (2,31,32). In this trial, 301 subjects were randomized to pramipexole or levodopa and were followed for four years. At the conclusion of the trial, 52% of pramipexole and 74% of levodopa subjects reached the primary endpoint of motor complications. Furthermore, dyskinesia occurred in 25% on pramipexole and 54% on levodopa, and wearing off occurred in 47% of the pramipexole group and 67% of the levodopa group. However, UPDRS assessments

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found significant improvements (~4 points) in subjects receiving levodopa (31). Eighty-two subjects in the CALM-PD cohort also underwent single photon emission computed tomography (SPECT) imaging with β-CIT to assess striatal uptake of this dopamine transporter (2). Comparisons between the pramipexole group (n = 42) and the levodopa group (n = 40) found significant differences ranging from 6.4% to 9.5% in transporter uptake at 22, 34, and 46 months, suggesting less functional decline with pramipexole. Supplemental levodopa was allowed in the CALM-PD study, whereas it was not allowed in the PELMOPET study, comparing pergolide to levodopa. The dosages of pramipexole averaged 2.78 mg/d with 48% of subjects receiving a mean levodopa supplement of 264 mg/d, whereas 36% of the levodopa-treated subjects required levodopa supplementation with a mean dosage of 509 mg/d. Two randomized clinical trials of pramipexole in levodopa-treated patients demonstrated significant benefit in off time (31% and 15%), ADLs (22% and 27%), motor function (25% and 35%), and levodopa dosage reduction (27%) (30,33). The mean dosage of pramipexole was 3.36 mg/d, and side effects included dyskinesia, orthostatic hypotension, dizziness, insomnia, hallucinations, nausea, confusion, and headache (30, 33) (Table 2). Since pramipexole has come to market, unexpected sleep episodes and increased impulsivity such as pathological gambling have been reported, and although seen with other dopamine agents, are most often associated with this agent (34–39). Ropinirole Ropinirole was approved in the United States in 1998. This dopamine agonist is a nonergot compound with affinity for the D2 family of receptors, but not the D1 or D5 receptors. In addition, unlike pergolide or pramipexole, ropinirole lacks affinity for adrenergic, cholinergic, or serotonergic receptors (Table 1). This drug is also rapidly absorbed from the gut with peak plasma concentrations occurring in one to two hours and 40% remaining protein bound (1). The elimination half-life is six hours. The P450 CYP1A2 hepatic enzyme pathway metabolizes the drug. Ropinirole is available in 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, and 5.0 mg tablets, and is initially titrated to 9 mg/d in three divided doses over an eight-week period. Clinical improvement is usually not seen until patients are taking at least 6 mg/d. Due to the longer dosing range, up to 24 mg/d, this agent is often prescribed at subtherapeutic doses (Table 2) (15). The common side effects are similar to those seen with the other dopamine agonists, including nausea, somnolence, hallucinations, and orthostatic hypotension (Table 2) (40). Ropinirole has been evaluated in early and advanced PD. Adler et al. (41) randomized 241 de novo subjects to ropinirole (n = 116) or placebo (n = 125) in a 24-week trial. Responders were defined as subjects achieving at least a 30% improvement in UPDRS total and motor scores. In addition, subjects were assessed for time to levodopa initiation by a clinical global improvement scale. With an average dosage of 15.7 mg/d, 47% of ropinirole subjects were identified as responders, whereas only 20% of subjects responded in the placebo arm. The mean changes in UPDRS scores were significant with a 24% improvement in the ropinirole group and 3% with placebo. Time to levodopa initiation significantly differed with 11% of ropinirole subjects and 29% of placebo subjects, requiring additional therapy. Requirement for levodopa therapy for the ropinirole subjects was 16%, 27%, and 40% at one, two, and three years, respectively (41). A five-year clinical trial randomized 268 subjects to ropinirole (n = 179) or levodopa (n = 89) in a 2:1 fashion, allowing add-on levodopa at the discretion of the

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investigator (ropinirole 056 study) (42). In this study, 85 subjects in the ropinirole group (47%) and 45 subjects in the levodopa group (51%) completed the study. In the ropinirole group, 29 of the 85 subjects (34%) had not received levodopa supplementation at five years. The analysis of the time to dyskinesia showed a significant difference in favor of ropinirole and, at five years, the cumulative incidence of dyskinesia, regardless of levodopa supplementation, was 20% in the ropinirole group and 45% in the levodopa group. The mean daily dose of ropinirole at the end of the study was 16.5 mg/d. The average dosage for levodopa supplementation was 427 mg/d. The subjects randomized to levodopa received an average of 753 mg/d. The results of a PET analysis comparing ropinirole to levodopa have been reported (REAL-PET) (3). This two-year randomized trial found a significant difference in striatal uptake, comparing ropinirole to levodopa in 186 subjects. Of these subjects, 162 had abnormal baseline 18F-dopa PET scans (ropinirole n = 87; levodopa n = 75). There was a 75% completion rate for each group. The mean dosage in the ropinirole group was 12.2 mg/d and in the levodopa group 559 mg/d. Fifteen out of the 87 subjects taking ropinirole needed levodopa supplementation some time during the two-year trial. Subjects in the ropinirole group had a slower decline in putamenal F-dopa uptake Ki compared to the levodopa group [− 14.1% (n = 68) vs. − 22.9% (n = 59); P < 0.001]. Subjects in the ropinirole group worsened by 0.70 points on the UPDRS motor scale from baseline, compared to an improvement of 5.64 points in the levodopa group. The ropinirole group also had dyskinesia at a significantly decreased rate when compared to the levodopa group after two years (3.4% vs. 26.7%; P < 0.001). Lang et al. reviewed ropinirole data to assess the risk of the development of dyskinesia in subjects exposed to early dopamine agonist monotherapy. They found that once levodopa was initiated, the time to the development of dyskinesia was similar, regardless of whether levodopa was preceded by a dopamine agonist (43). A six-month, placebo-controlled trial of 149 PD subjects with motor fluctuations randomized to ropinirole (n = 95) or placebo (n = 54) examined the reduction in levodopa and off time. In this study, levodopa dosage was reduced on an average of 31% in ropinirole subjects compared to 6% in placebo subjects. Off time was reduced by 12% in the ropinirole group and 5% in the placebo group, which was a decrease in off time of slightly more than 1 hr/day (40). A 24-hour prolonged release formulation of ropinirole has been developed to allow for once per day dosing—an easier and more rapid titration schedule than immediate release ropinirole. A six-month, double-blind, placebo-controlled study of 393 PD subjects not optimally controlled with levodopa reported a significant decrease in daily off time of 2.1 hours with ropinirole 24-hour prolonged release, compared to a decrease of 0.3 hours in the placebo group. There were also significant improvements with ropinirole prolonged release in daily on time, on time without troublesome dyskinesia, and UPDRS ADL and motor scores, compared to placebo. Adverse events were as expected for a dopamine agonist, including dyskinesia, nausea, dizziness, somnolence, hallucinations, and orthostatic hypotension (44). Cabergoline Cabergoline is a once daily ergot-derived dopamine agonist, commonly used in Europe, but available in the United States for the treatment of hyperprolactinemia. Cabergoline has been evaluated in de novo and advanced PD populations. In a double-blind, 2:1 placebo-controlled trial of 188 PD subjects taking levodopa, the

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addition of cabergoline allowed for an 18% reduction in levodopa and a 16% improvement in motor scores (45). In a larger placebo-controlled comparison of 419 treatmentnaive subjects randomized to receive either cabergoline (n = 211) or levodopa (n = 209), similar benefit was found (46). Motor complications were significantly delayed (P = 0.0175) and occurred less frequently with cabergoline than with levodopa (22.3% vs. 33.7%). Similar to other studies, the levodopa-treated subjects demonstrated significantly (P < 0.001) greater improvement in motor disability. Cabergoline-treated patients experienced a significantly higher frequency of peripheral edema (16.1% vs. 3.4%, respectively; P < 0.0001). Clarke and Deane (47) compared cabergoline to bromocriptine in a metaanalysis of five randomized, double-blind, parallel-group studies in 1071 subjects. Cabergoline produced benefits similar to bromocriptine in off-time reduction, motor impairment and disability ratings, and levodopa dose reduction over the first three months of therapy. Dyskinesia and confusion were increased with cabergoline, but otherwise the frequency of adverse events and withdrawals from treatment were similar with the two agonists. Side effects of cabergoline are similar to other dopamine agonists, but also include severe restrictive mitral regurgitation and male sexual dysfunction (48). Rotigotine Rotigotine is a novel, nonergoline dopamine agonist, which is unique in that it is delivered through a silicone-based, skin patch system. It affects all of the dopamine receptors, with a 20-fold prevalence for D3 over D2 and 100-fold prevalence of D2 over D1 receptors. Rotigotine also exhibits antagonistic activity on alpha-2 receptors and agonistic activity on 5-HT1A receptors comparable to that of D2 and D1 receptors (49). Administration of this drug through a transdermal application can deliver a stable drug release and a steady-state plasma concentration over a 24-hour period, reduce peak dose or wearing-off adverse effects, and circumvent gastrointestinal metabolism (50). Side effects for rotigotine are similar to other dopamine agonists, but also include skin reactions from the patch. Currently, this drug is approved in Europe and has received an approvable letter in the United States. In a multicenter, dose-ranging trial of rotigotine versus placebo, 242 subjects with early, untreated, idiopathic PD (average duration of PD 1.3 years) were assessed. For 11 weeks, subjects were randomly assigned to treatment with patches containing 4.5, 9.0, 13.5, or 18.0 mg of active or placebo monotherapy. The primary outcome was the change in the sum of the UPDRS ADL and motor scales between baseline and the 11-week visit. ADL scores were significantly improved relative to placebo in the 18.0 mg group only, whereas the motor score was improved in both the 13.5 and 18.0 mg groups. There was a dose-response relationship from 4.5 to 13.5 mg, with a plateau between 13.5 and 18.0 mg. The sum scores of UPDRS ADL and motor subscales showed significant improvement by week 4 in the 9.0, 13.5, and 18.0 mg groups and persisted throughout the maintenance phase (51). In a second trial, 277 patients with early PD were enrolled in a double-blind, placebo-controlled, 27-week trial. Subjects were randomized to either rotigotine or placebo in a 2:1 ratio, and titrated weekly in 4.5 mg increments to an optimal response or maximum dose of 13.5 mg/d . The rotigotine group had a significant mean improvement of 4 points in UPDRS ADL and motor scores compared to a worsening of 1.3 points in the placebo group (P < 0.0001) (52).

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Studies evaluating the efficacy of rotigotine in patients with advanced PD as an adjunctive therapy to levodopa have also demonstrated efficacy. One multicenter study of 351 subjects with advanced PD inadequately controlled with levodopa randomized subjects to rotigotine (18 or 27 mg/d) or placebo in a 29-week study. Those who received rotigotine at 27 mg had a decrease in off time of 2.1 hours, the 18 mg group had a decrease of 2.7 hours, and the placebo group had a decrease of 0.9 hours. There was no increase in troublesome dyskinesia (53). Piribedil Piribedil is a nonergoline selective D2/D3 agonist with alpha-1 antagonist activity. Oral doses of this medication range between 80 and 250 mg/d. Once blood levels are stabilized with a piribedil dose of at least 150 mg/d, it has a mean half-life of approximately 21 hours. Simon et al. (54) assessed the efficacy of a single intravenous infusion of piribedil in 10 subjects with PD who received escalating doses of piribedil (2, 4, 8, and 16 mg) or placebo. These subjects continued their PD medications, including dopamine agonists, levodopa, catechol-O-methyl-transferase (COMT) inhibitors, anticholinergic drugs, and amantadine, but they were withheld 12 hours before and up to three hours after the infusion. In addition, patients were pretreated with the antiemetic, domperidone prior to the infusion. This study showed improvement in wearing off in 7 out of 10 subjects. Motor status, including akinesia, improved at 15 minutes with a maximum benefit at one hour and effects continuing up to three hours, even with the lowest dose of 2 mg. Mild-to-moderate side effects were seen at the 8-mg dose and above and included flushing, nausea, vomiting, abdominal pain, and somnolence (54). Several studies demonstrated the efficacy of piribedil as monotherapy and as an adjunct to levodopa. Castro-Caldas et al. (55) performed a 12-month, randomized, double-blind study evaluating the benefit of piribedil (150 mg/d) on motor function compared to bromocriptine (25 mg/d) as adjunct therapy with levodopa in 425 PD subjects. There were no significant differences between piribedil (58.4% response) and bromocriptine (55.3%) in UPDRS motor scores, response rate, or cognitive performance. Although subjects randomized to piribedil required less levodopa increase than those on bromocriptine (7.6 ± 121.9 mg vs. 16.7 ± 91.3 mg), this was not significant. COMPARISONS BETWEEN DOPAMINE AGONISTS Tan and Jankovic (6) summarized 15 comparative trials between dopamine agonists, and reported conversion factors of 10:1 for bromocriptine to pergolide, 1:1 for pergolide to pramipexole, 1:6 for pergolide to ropinirole, and 10:6 for bromocriptine to ropinirole. Hanna et al. (56) followed 21 stable subjects on pergolide and switched them to pramipexole in a 1:1 ratio. Although not significant, levodopa dosages were reduced by 16.5%, and 13 of the 21 (62%) subjects reported improvement with the change in regimen. Hauser et al. reported the conversion of stable subjects on levodopa and pramipexole to levodopa and ropinirole in a 1:3 mg ratio. A gradual transition was better tolerated than a rapid change (57). However, in retrospect, the difficulties reported by subjects may have been improved with a higher conversion factor for ropinirole. Although there are obvious difficulties when making direct comparisons in studies to determine dosage equivalence, a reasonable equation of relative dopamine

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agonist potency would suggest bromocriptine × 10 = pergolide = pramipexole = ropinirole × 6 on a mg:mg basis. Perhaps a better measure of treatment response is to review similar trials of dopamine agonist therapy. In the early PD population, UPDRS data are similar. Placebo-controlled studies of pramipexole and ropinirole found remarkably similar benefit. Another potential comparison is to evaluate trials comparing two active interventions, such as a dopamine agonist and levodopa. In the imaging trials of pergolide, pramipexole, and ropinirole, subjects treated with an agonist demonstrated similar benefit, which was less than that with levodopa. The PELMOPET, CALM-PD, ropinirole 056, and REAL-PET trials may represent the most rigorous and careful information gathered about these compounds, and it is therefore useful to compare them (2–4). Subjects treated with pergolide at an average dosage of 3.23 mg/d demonstrated a UPDRS motor scale worsening of 3 points over 36 months, whereas subjects randomized to levodopa demonstrated an improvement of 2.5 points in the same time interval. Although the dopamine agonist/levodopa trials using pramipexole and ropinirole allowed for levodopa supplementation and had different durations, like the 5.5 point difference seen between pergolide and levodopa in the PELMOPET trial, the differences between pramipexole (− 3.4) and levodopa (−7.3) at 23.5 months (difference = 3.9 points) and ropinirole (−0.8) and levodopa (−4.8) at 60 months (difference = 4 points) are similar. The neuroimaging data from these investigations are also similar for dosages of pergolide 3.23 mg/d, pramipexole 2.78 mg/d, and ropinirole 16.5 mg/d. Modifications of these data to reflect a ratio of dopamine agonist to levodopa striatal decline produce percentages ranging from 52.6% to 65%. F-dopa PET demonstrates ropinirole striatal decline 65% of levodopa at 24 months and pergolide striatal decline 54.5% of levodopa at 36 months. SPECT imaging with β-CIT demonstrates 52.6%, 55.6%, and 62.7% pramipexole to levodopa decline at 22, 34, and 46 months of treatment, respectively. The imaging impact of added levodopa in the pramipexole and ropinirole groups is unknown. In summary, similar designs between pergolide, pramipexole, and ropinirole demonstrate similar benefits in terms of levodopa dosage reduction, levodopa percent reduction, treatment responders, and decrease in off time in adjunctive therapy trials. In these studies, subject selection, methodological design, and data collected differed to the point that trends are less reliable than in the early patient studies, but, in general, similar improvements in all variables are seen. INITIATION OF DOPAMINE AGONIST THERAPY Dopamine agonists provide substantial improvement in PD symptoms while delaying the development of motor fluctuations and dyskinesia (32,42,58). Similar trials comparing dopamine agonists (pergolide, pramipexole, ropinirole) to levodopa in a randomized fashion suggest possible long-term benefit according to the functional imaging measures (2,3). The reduction in striatal and nigral decline in F-dopa and β-CIT uptake suggest these agents have some benefit over levodopa for up to 46 months of treatment. In a clinical setting of a 30-year-old patient, it is quite compelling to delay levodopa therapy in favor of a dopamine agonist because of the potentially long clinical horizon (59). Conversely, in an 80-year-old patient with other health concerns, treatment with levodopa may be better tolerated. The decisions regarding initial therapy in the 50 years between these two examples is dependent on the health of the patient, the side-effect profiles, and cost of the drugs (Table 2).

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Dopaminergic medications have similar side effect profiles: nausea, sleepiness, confusion, orthostatic hypotension, and hallucinations among others (Table 2). Besides these problems, lower extremity edema, hair loss, and weight gain have also been seen with dopamine agonist use. The ergoline-derivatives, bromocriptine, cabergoline, and pergolide, also have a slight risk of erythromelalgia and pulmonary and retroperitoneal fibrosis, which have been reported in 2% to 5% of patients exposed to these agents (1). With all dopaminergic agents, it is possible that excessive daytime sleepiness, unexpected sleep episodes, and reduced impulse control leading to behaviors such as pathological gambling could occur in a small percentage of patients (34–39). Therefore, patients should be educated to be vigilant of these potential side effects and notify their physician if they occur. The side effects of these agents are quite similar, but vary from patient to patient, so it is important for a patient to understand that if he or she does not tolerate the first dopamine agonist; there is no reason to expect that none of the medications in this class will provide benefit. Initiation of dopamine agonist therapy is somewhat dependent on the needs and emotional state of the patient. Each of the dopamine agonists requires a titration period from four to eight weeks (Table 3). In the healthy patient seeking to improve quickly, initiation of a rapidly titrated agent may be preferred, whereas the more slowly titrated schedules may suit the needs of a patient reluctant to take any drugs. Each patient should be reminded that the differences in titration time usually are less than three weeks, a brief period of time in the context of a 20-year treatment horizon. CONCLUSIONS The development of dopamine agonists, particularly, pramipexole and ropinirole, has gradually shifted treatment paradigms in PD. In the last 20 years, many PD specialists have moved from using dopamine agonists only as adjunctive therapy to levodopa to initiating antiparkinson therapy with one of these agents (58). Imaging data with SPECT and PET scanning has produced debate regarding the possible “neuroprotective” advantages of dopamine agonists when compared to levodopa (2–4). In this regard, some have questioned whether these agents should be initiated sooner in the disease course, perhaps before obvious disability develops. Regardless of when dopamine agonist therapy is initiated, patients benefit from the choice of several agents for treating PD symptoms. REFERENCES 1. Factor SA. Dopamine Agonists. Med Clin North Am 1999; 83:415–443. 2. Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs. levodopa on Parkinson disease progression. JAMA 2002; 287:1653–1661. 3. Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 2003; 54:93–101. 4. Oertel WH, Wolters E, Sampaio C, et al. Pergolide versus levodopa monotherapy in early Parkinson’s disease patients: The PELMOPET study. Mov Disord 2006; 21:343–353. 5. Le WD, Jankovic J. Are dopamine receptor agonists neuroprotective in Parkinson’s disease? Drugs Aging 2001; 18:389–396. 6. Tan EK, Jankovic J. Choosing dopamine agonists in Parkinson’s disease. Clin Neuropharmacol 2001; 24:247–253. 7. Pierantozzi M, Palmieri MG, Mazzone P, et al. Deep brain stimulation of both subthalamic nucleus and internal globus pallidus restores intracortical inhibition in Parkinson’s

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33. Pinter MM, Pogarell O, Oertel WH. Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson’s disease: a double blind, placebo controlled, randomised, multicentre study. J Neurol Neurosurg Psychiatry. 1999; 66:436–441. 34. Frucht S, Rogers JD, Greene PE, et al. Falling asleep at the wheel; motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 1999; 52:1908–1910. 35. Stacy M. Sleep disorders in Parkinson’s disease: Epidemiology and management. Drugs Aging 2002; 19:733–739. 36. Rissling I, Geller F, Bandmann O, et al. Dopamine receptor gene polymorphisms in Parkinson’s disease patients reporting “sleep attacks”. Mov Disord 2004; 19:1279–1284. 37. Samanta JES, Stacy M. Pathologic Gambling in Parkinson’s disease. Mov Disord 1998; 15(suppl 3):111. 38. Gschwandtner U, Astar J, Renard S, Fuhr P. Pathologic gambling in patients with Parkinson’s disease. Clin Neuropharmacol 2001; 24:170–172. 39. Dodd ML, Kloss KJ, Bower KH, et al. Pathological gambling caused by drugs used to treat Parkinson’s disease. Arch Neurol 2005; 62:1–5. 40. Lieberman A, Olanow CW, Sethi K, et al. A multicenter trial of ropinirole as adjunct treatment for Parkinson’s disease. Neurology 1998; 51:1057–1061. 41. Adler CH, Sethi KD, Hauser RA, et al. Ropinirole for the treatment of early Parkinson’s disease. Neurology 1997; 49:393–399. 42. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342:1484–1491. 43. Lang AE, Rascol O, Brooks DJ, et al. The development of dyskinesias in Parkinson’s disease patients receiving ropinirole and given supplemental l-dopa. Neurology 2002; 58(suppl 3):A82. 44. Pahwa R, Factor SA, Elmer LW. Ropinirole 24-hour prolonged release reduces awake time spent “off ” in patients with Parkinson’s disease not optimally controlled with L-dopa. Neurology 2006; 66(suppl 2):A292–A293. 45. Hutton JT, Koller WC, Ahlskog JE, et al. Multicenter, placebo-controlled trial of cabergoline taken once daily in Parkinson’s disease. Neurology 1996; 46:1062–1065. 46. Bracco F, Battaglia A, Chouza C, et al. The long-acting dopamine receptor agonist cabergoline in early Parkinson’s disease: final results of a 5-year, double-blind, levodopacontrolled study. CNS Drugs 2004; 18:733–746. 47. Clarke CE, Deane KD. Cabergoline versus bromocriptine for levodopa-induced complications in Parkinson’s disease. Cochrane Database Syst Rev 2001; (1):CD001519. 48. Pinero A, Marcos-Alberca P, Fortes J. Cabergoline-related severe restrictive mitral regurgitation. N Engl J Med 2005; 353:1976–1977. 49. Jenner P. A novel dopamine agonist for the transdermal treatment of Parkinson’s disease. Neurology 2005; 65(suppl 1):S3–S5. 50. Pfeiffer RF. A promising new technology for Parkinson’s disease. Neurology 2005; 65(suppl 1):S6–S10. 51. Parkinson Study Group. A controlled trial of rotigotine monotherapy in early Parkinson’s disease. Arch. Neurol. 2003; 60:1721–1728. 52. Watts RL, Wendt RL, Nausieda P. Efficacy, safety, and tolerability of the rotigotine transdermal patch in patients with early stage, idiopathic Parkinson’s disease: a multicenter, multinational, randomized, double-blind, placebo-controlled trial. Mov Disord 2004; 10(suppl 9):S258. 53. LeWitt P, Nausieda P, Chang F-L, et al. Rotigotine transdermal system in a multicenter trial of patients with advanced-stage Parkinson’s disease as adjunctive therapy to levodopa. Neurology 2006; 66(suppl 2):A184–A185. 54. Simon N, Micallef J, Reynier JC, et al. End-of-dose akinesia after a single intravenous infusion of the dopaminergic agonist piribedil in Parkinson’s disease patients: a pharmacokinetic/pharmacodynamic, randomized, double-blind study. Mov Disord 2005; 20(7):803–809. 55. Castro-Caldas A, Delwaide P, Jost W, et al. The Parkinson-Control study: A 1-year randomized, double-blind trial comparing piribedil (150 mg/d) with bromocriptine (25mg/d) in early combination with levodopa in Parkinson’s disease. Mov Disord 2006; 21:500–509.

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Monoamine Oxidase Inhibitors Alex Rajput Division of Neurology, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Theresa A. Zesiewicz and Robert A. Hauser Parkinson’s Disease and Movement Disorders Center, University of South Florida, NPF Center of Excellence, Tampa, Florida, U.S.A.

INTRODUCTION The monoamines include the catecholamine neurotransmitters dopamine, norepinephrine, and 5-hydroxytryptamine. Monoamine oxidases (MAOs) are intracellular enzymes found in the outer mitochondrial membrane that catabolize these amines (1). The first MAO identified was tyramine oxidase in 1928 (2). Monoamine oxidase inhibitors (MAOIs) inhibit the action of MAOs. In the 1950s and 1960s, patients were reported to “dance in the hall” following treatment with antituberculosis drugs (3). One of these medications, iproniazid, was noted to have potent MAO inhibitory properties (4). An open-label trial of iproniazid found significant mood improvement in institutionalized depressed patients (5), and it was later introduced as the first antidepressant medication (6). In 1965, Knoll and Ecseri (7,8) synthesized phenylisopropyl-N-methylpropinylamine or E-250. E-250 was a strong, irreversible MAO inhibitor that metabolized tyramine (9), phenylethylamine (9), and benzylamine (8). The compound was separated into two isomers, and the L-form was named deprenyl. In 1968, Johnston synthesized a compound structurally similar to deprenyl, 2,3-dichlorophenoxypropyl-N-methylpropinylamine, or clorgyline (10). He arbitrarily called the MAO with greater affinity for clorgyline MAO-A and for deprenyl MAO-B. MECHANISMS OF ACTION MAOs are intracellular enzymes found throughout the body, with most bound tightly to the outer mitochondrial membrane (11,12). The MAOs oxidatively deaminate monoamines in the presence of oxygen (13). MAO-A is the primary form in the intestine, pancreas, and spleen, and the sole form in human placenta (14–16). MAO-B predominates in skin and skeletal muscle, and is the sole form in platelets. Although the human liver contains both forms, MAO is absent in plasma and red blood cells (17). Human brain MAO is 70% to 80% type B (18), whereas MAO-A predominates in rodent brain (19). MAO-A in the brain is found in the locus ceruleus, nucleus subceruleus, periventricular regions of the hypothalamus, and striatal dopaminergic neurons (20,21). MAO-A content of primate substantia nigra is low, relative to the number of tyrosine hydroxylase positive cells (21). Astrocytes are the main repository of brain MAO-B (21). With increasing age, human brain MAO-B but not MAO-A activity increases (22). The rate of increased activity varies between brain regions; higher in 349

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the basal ganglia and substantia nigra than the cerebral cortex or medulla (22). Glial MAO-B activity is reported to increase in neurodegenerative disorders (22). Both MAO-A and MAO-B catabolize dopamine, epinephrine, norepinephrine, tyramine, tryptamine, 3-methoxytyramine, and kynuramine (23). MAO-A primarily catabolizes serotonin and octopamine and MAO-B metabolizes benzylamine, phenylethylamine, milacemide, and N-methylhistamine. MAO-B also converts the protoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to 1-methyl-4-phenyl-pyridium ion (MPP+) (23). MAO-A and MAO-B are structurally similar, and the flavin sites on each are identical (24). True selectivity of most MAO inhibitors is present only at low concentrations (25). HYPERTENSIVE CRISIS Tyramine is a sympathomimetic amine normally metabolized by gut MAO-A. When tyramine rich foods such as red wines, pickled herring, or aged cheeses are ingested by someone taking an irreversible MAO-A inhibitor (clorgyline) or nonselective MAO inhibitor (e.g., phenelzine, tranylcypromine), the tyramine is absorbed rather than metabolized, causing norepinephrine release and potentially hypertensive crisis (26). This is known as the “cheese effect.” Levodopa is contraindicated with MAO-Aor nonselective MAO inhibitors, as it may cause a similar hypertensive crisis. The MAO-B selective inhibitor selegiline (deprenyl, Eldepryl®) at oral doses up to 10 mg/day is safe to be taken with levodopa and requires no dietary restrictions. Transient blood pressure changes have been reported with selegiline doses of 20 mg/day; therefore, doses above 10 mg/day are usually not recommended, as the selectivity may be lost. The second generation MAO-B selective inhibitor rasagiline (Azilect®) was approved in the European Union in 2005 and by the Food and Drug Administration (FDA) in the United States in May 2006. The risk of a tyramine reaction with rasagiline also appears to be very low at recommended dosages. In clinical trials, there were no tyramine reactions observed at the recommended doses, even when there were no dietary restrictions. However, because the dose at which rasagiline loses MAO-B selectivity is not known, it is currently recommended that patients on rasagiline avoid tyramine-rich foods and beverages. NEUROPROTECTIVE EFFECTS OF MONOAMINE OXIDASE INHIBITORS Neuroprotective effects of the MAO-B inhibitors, selegiline and rasagiline, are dependent on their propargyl moiety and independent of their MAO inhibitory properties. The selegiline metabolite, desmethylselegiline, is responsible for the potential neuroprotective effects of selegiline. The S-isomer of rasagiline, TVP 1022, is one thousand times less potent at inhibiting MAO-B, yet demonstrates similar potential neuroprotective effects (27). Both selegiline and rasagiline have demonstrated neuroprotection in multiple in vitro and animal models (27–41). Selegiline and rasagiline inhibit apoptosis, or programmed cell death, in cell lines (28,30,34,35,42). Although the selegiline metabolite L-methamphetamine inhibits the anti-apoptotic activities of selegiline, the rasagiline metabolite aminoindan does not (43). The mitochondrial permeability transition pore (MPTp) appears only in the setting of apoptosis (27). Anti-apoptotic proteins stabilize the MPTp whereas proapoptotic proteins allow pore opening, with loss of mitochondrial membrane potential (27,41). This causes an apoptotic cascade including release of cytochrome c and

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activation of caspases, particularly caspase-3. MAOIs increase the anti-apoptotic proteins Bcl-2, Bcl-XL, and Bcl-w, and downregulate the pro-apoptotic proteins Bad, Bax, and Fas (27,42). The “death receptor” Fas and its ligand FasL (which interact with pro-apoptotic proteins on the outer mitochondrial membrane) are downregulated by MAOIs (27,44). Oxygen free radical (OFR) scavenging proteins, superoxide dismutase 1 (SOD 1), superoxide dismutase 2 (SOD 2), catalase, and glutathione are all increased with MAOIs (32,45). The MAOIs themselves may possess OFR scavenging ability (46). Trophic factors including glial derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), and basic fibroblast growth factor (FGF2) are also increased by MAOIs (37,47). Other mechanisms of neuroprotection mediated by MAOIs include: protein kinase C (PKC) α- and ε-activation that inhibit formation of the activated cleaved form of caspase-3; the cleavage of PARP-1, a caspase substrate; and Fas, the conversion of amyloid precursor protein (APP) into soluble (nonamyloidogenic) APPα, which itself has neurotrophic and neuroprotective properties; and the inhibition of nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (27,44). Models that have demonstrated neuroprotection by either rasagiline or selegiline include glutamate toxicity in hippocampal neurons (48), focal brain ischemia in rats (39,40), memory and learning tasks following anoxic brain injury (49) and motor and spatial memory in a rodent closed head injury model (50), optic nerve crush injury (51), rescue of dorsal root ganglia sensory neurons (52) and of axotomized motoneurons (53), and protection against cell death in rat pheochromocytoma PC-12 cells deprived of oxygen and glucose (54). Selegiline given after intrathecal injection of rat pups with cerebrospinal fluid from human amyotrophic lateral sclerosis (ALS) subjects protects against anterior horn cell loss (55). Pretreatment with rasagiline is neuroprotective in primate MPTP (56) and rodent 6-OHDA models of PD (38). Primates treated with selegiline and MPTP simultaneously do not develop parkinsonism (57). SELEGILINE Selegiline is a lipophilic, relatively selective MAO-B inhibitor, which is readily absorbed from the gastrointestinal tract. Maximal concentrations occur 30 to 120 minutes after ingestion (58), and over 90% is bound to plasma proteins (59). Platelet MAO-B activity is inhibited by more than 85% within four hours after selegiline 5 mg, and by almost 98% within 24 hours after selegiline 10 mg (60). Selegiline passes through the blood–brain barrier and accumulates in MAO-B rich brain areas, including the striatum, thalamus, cortex, and brain stem (61). Selegiline is considered a “suicide inhibitor,” as it forms an irreversible covalent bond with MAO-B. Enzyme activity returns only when new MAO-B is produced. Selegiline is primarily metabolized by the liver P-450 system with some extrahepatic metabolism (62). Three metabolites are identified in serum and urine: l-(−)-methamphetamine, l-(−)-amphetamine, and (−)-desmethylselegiline (63). Desmethylselegiline has neuroprotective activity (34) and also irreversibly inhibits MAO-B (although less so than selegiline) (64–66). Symptomatic benefit from selegiline in PD is mediated through MAO-B inhibition, thereby inhibiting catabolism of dopamine, both endogenous and exogenous (from levodopa). Selegiline may also inhibit dopamine reuptake (66) and block presynaptic dopamine receptors (67). Amphetamine metabolites of selegiline may also promote dopamine release.

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Oral selegiline is generally well tolerated. The usual dose is 5 mg with breakfast and lunch. Potential adverse effects include nausea, dizziness, confusion, anxiety, dry mouth, and hallucinations. Selegiline is not recommended after early afternoon because of the risk of insomnia from its amphetamine metabolites. With concomitant levodopa use, orthostatic hypotension may be significant. Selegiline added to levodopa may worsen dyskinesia. Dopaminergic side effects including dyskinesia can usually be managed by lowering the dose of levodopa. Serotonin syndrome may be seen when selegiline is combined with selective serotonin reuptake inhibitors (SSRIs); however, this interaction is rare (68). Selegiline may produce altered mental state, rigidity, and fever in some patients receiving meperidine (69). Concomitant use of selegiline with meperidine is contraindicated, and this contraindication is often extended to other opioids. CLINICAL TRIALS OF SELEGILINE DATATOP The DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) study (70) evaluated 800 PD subjects randomized to receive selegiline 10 mg/day or placebo. The total Unified Parkinson’s Disease Rating Scale (UPDRS) scores were improved in the selegiline-treated group compared with placebo at one month (2.1 vs. 0.1; P < 0.001) and at three months (1.6 vs. −1.3; P < 0.001). The motor UPDRS scores also improved significantly in the selegiline compared with the placebo group at one month (1.4 vs. 0.01, P < 0.001) and at three months (0.9 vs. −0.8; P < 0.001). In the DATATOP trial, selegiline delayed the need for levodopa by approximately nine months compared with placebo. Following selegiline withdrawal, there was no loss of benefit at one month but at two months, total UPDRS had worsened 3.2 points in selegiline-treated patients compared to 0.5 in placebo-treated patients (P < 0.001). Selegiline monotherapy slowed decline in parkinsonian disability in the DATATOP trial and other clinical trials (71,72), as measured by motor or total UPDRS scores or other standardized rating scales (73). A DATATOP open-label extension study (74) evaluated subjects who had reached endpoint (need for levodopa) in the original DATATOP trial (70). In this study (74), 352 of 371 subjects completed the 18-month follow-up; all were treated with selegiline 10 mg/day and levodopa as needed. Patients originally treated with selegiline had taken levodopa for a significantly shorter period of time (P < 0.0001) and received significantly lower total cumulative levodopa dosages (P < 0.02) over that 18-month period than those initially randomized to placebo in the DATATOP trial. However, the total daily levodopa dosage at final evaluation was similar between groups, and wearing off, dyskinesia, and freezing occurred in the same proportion of patients originally treated with selegiline compared with placebo. Subjects who completed the original DATATOP trial but did not reach the endpoint (i.e., did not require levodopa) were initially withdrawn from selegiline or placebo for two months, and then were placed on open-label selegiline 10 mg/day in another extension study (75). The original treatment blind was maintained. Whereas subjects treated with selegiline had better total UPDRS scores than placebo subjects prior to selegiline withdrawal, after the two-month selegiline withdrawal, total UPDRS scores were not different between the groups. These two open-label DATATOP extension studies (74,75) suggest a symptomatic rather than neuroprotective benefit of selegiline.

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Original DATATOP subjects (n=368)who had required levodopa therapy and were on open-label selegiline underwent an independent second randomization (76). One half were assigned to continue selegiline 10 mg/day and the other half received placebo. Subjects were followed over two years. There was no significant overall difference between the two groups in the primary outcome measure of occurrence of motor fluctuations. There was a nonsignificant difference in wearing off (52% placebo vs. 41% selegiline); however, dyskinesia occurred significantly more often in subjects assigned to selegiline compared with placebo (34% vs. 19%; P = 0.006). Secondary outcome measures included time until motor fluctuations, freezing of gait, confusion, and dementia. Gait freezing was reported in 29% of the placebo group and 16% of selegiline-treated subjects (P = 0.0003). In addition, there was significantly less decline in UPDRS total (P = 0.0002), motor (P = 0.0006), and activities of daily living (ADL) (P = 0.0045) subscales in the selegiline-treated group. These results again suggest a mild symptomatic benefit of selegiline with better UPDRS scores, less likelihood of freezing, and a higher rate of dyskinesia when compared with placebo (76). Other Trials in Early Parkinson’s Disease Palhagen et al. (72) reported a study of selegiline in 157 de novo PD subjects. Selegiline 10 mg/day delayed the need for levodopa by four months compared with placebo (P = 0.028). There was a “wash-in” effect at six weeks and three months, with total and motor UPDRS scores significantly better in the selegiline group. At six months, the rate of disease progression was significantly slower for both total UPDRS (−1.9 vs. 3.5; P < 0.001) and motor UPDRS (−1.5 vs. 2.5; P < 0.001) (negative numbers refer to improvement and positive numbers refer to worsening). Between baseline and the end of an eight week washout period, there was significantly slower progression of total UPDRS scores in the selegiline group (11.3) compared with the placebo group (14.2), when length of time to reach the endpoint was used as a covariate (P = 0.033) (72). The French Selegiline Multicenter Trial (77) randomized 93 de novo PD subjects to selegiline 10 mg/day or placebo. Significant improvements in total and motor UPDRS scores were noted at one and three months. In a small double-blind randomized trial (71) of 54 early PD patients, selegiline 10 mg/day delayed the need for levodopa by eight months (log rank test, P < 0.002), and delayed disease progression as assessed by five different scales (including UPDRS motor score) by 40% to 83% per year compared to placebo. The Finnish Study of selegiline monotherapy found that selegiline delayed the need for levodopa by nearly six months (P = 0.03), and disability measured by three different scales was reduced at 12 months with selegiline compared with placebo. At the end of two years on levodopa, the increase in daily levodopa dosage was significantly lower in the selegiline group compared with placebo (86 mg vs. 250 mg; P < 0.001) (73) . The selegiline group could also be managed with fewer mean daily doses of levodopa compared with placebo (3.5 vs. 4.5) (73). In the SINDEPAR (Sinemet-Deprenyl-Parlodel) study (78), 101 untreated PD patients were randomized to selegiline or placebo, in addition to being randomized to symptomatic treatment with bromocriptine or levodopa [i.e., four treatment arms − (selegiline or placebo) + (levodopa or bromocriptine)]. After a two-month washout of selegiline and a one-week washout of bromocriptine and levodopa, endpoint evaluation at 14 months revealed significantly less worsening of total UPDRS scores with selegiline compared to placebo regardless of the symptomatic treatment used (0.4 vs. 5.8, P < 0.001) (78).

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Advanced Parkinson’s Disease Selegiline has mild to moderate benefit as adjunct therapy to levodopa in advanced PD patients and is approved by the FDA in the United States for this indication. In a small double-blind placebo-controlled trial (79) of selegiline 10 mg/day in PD subjects (n = 38) on stable levodopa doses, selegiline reduced daily levodopa dosage requirements (P < 0.05) and significantly improved tremor (P = 0.02) over eight weeks. Thirty subjects (selegiline n = 18, placebo n = 12) completed a 16-month follow-up (79). Both mean levodopa dosage (−133 mg/day) and dosing frequency were significantly reduced in the selegiline-treated group. Significantly less end–of-dose akinesia was reported in double-blind crossover trials with selegiline (80,81). Golbe et al. (82) randomized 96 PD patients with motor fluctuations that could not be improved with levodopa adjustments to selegiline 10 mg/day or placebo. Mean hourly symptom control in subjects randomized to selegiline was significantly improved compared to placebo (58% vs. 26%; P < 0.01). On average, patients had one hour more on time with selegiline 10 mg/day (82). Adjunct use of selegiline reduced daily levodopa requirements by 10% to 25% (79–82). Selegiline may worsen levodopa-induced dyskinesia but once levodopa dosage adjustments are made, they are typically no worse than at baseline. Nearly 60% of subjects receiving selegiline and 30% treated with placebo reported worsened dyskinesia within three days after starting treatment (82), with most subjects reporting improvement after reduction of the levodopa dose. A seven-year extension of the original Palhagen study (72,83) reported 140 of the original 157 PD subjects who participated in the initial study; all were treated with levodopa and randomized to receive selegiline 10 mg/day or placebo. Selegiline slowed disease progression as measured by UPDRS total scores (P = 0.003), motor scores (P = 0.002), and ADL scores (P = 0.0002) compared with placebo. After five years, subjects on placebo had mean UPDRS total scores that were 10 points worse (P = 0.07) and were receiving 19% more levodopa (P = 0.0002) than those treated with selegiline. Wearing off fluctuations were experienced by 27% of subjects, with a trend for fluctuations to be less common (20% vs. 34%; P = 0.053) and appear later (p = 0.076) in the selegiline group over the entire seven years. Dyskinesia developed in 37% of subjects, with no significant difference in frequency (selegiline 35%, placebo 40%) or time to appearance between groups. Nausea, but not hallucinations or diarrhea, was more common in the selegiline group (24% vs. 10%, P = 0.033). This study provided evidence of long-term benefit and suggests that selegiline may reduce progression of disability in PD (83). SELEGILINE AND MORTALITY The Parkinson’s Disease Research Group of the United Kingdom (84) reported an increased mortality rate in PD patients randomized to levodopa and selegiline, compared to levodopa alone. Forty-four (17.7%) deaths were observed in the levodopa group compared with 76 (28%) deaths in the levodopa plus selegiline group, after a mean duration of 5.6 years (P = 0.05). Methodologic questions were raised (85), and both groups had higher than expected mortality rates. Other studies have not reported higher mortality with selegiline. Analysis of the DATATOP trial and subsequent open-label extensions revealed an overall death rate of 17.1% (137 of 800), or 2.1% per year through a mean of 8.2 years of observation (86), and mortality rate was not affected by any of the treatments. Cumulative exposure to selegiline was not associated with increased mortality in the 13-year follow-up of the

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DATATOP cohort (87). Overall, there is no definitive evidence linking selegiline use to increased mortality. ZYDIS SELEGILINE Orally disintegrating Zydis selegiline (Zelapar®) was approved by the U.S. FDA in June of 2006 as an adjunct in the management of patients with PD being treated with carbidopa/levodopa, who exhibited deterioration in the quality of their response to this therapy. The recommended dose is 1.25 mg once a day, which can be increased to 2.5 mg once a day after six weeks if necessary. It is a sublingually absorbed preparation that dissolves rapidly on the tongue (88). This preparation is a drug impregnated, water-soluble polymer matrix that is rapidly absorbed through the oral mucosa. Nearly one-third of a Zydis selegiline 10 mg dose is absorbed pregastrically within one minute in healthy volunteers (89). Zydis selegiline produces nearly five times higher plasma selegiline concentrations and significantly lower (>90%) plasma concentrations of selegiline metabolites compared with oral selegiline (89). Mucosal absorption of the drug bypasses most of selegiline’s metabolism to amphetamine compounds such that smaller doses equally inhibit central nervous system MAO-B without compromising systemic MAO-B specificity or accumulating amphetamine metabolites. Clarke et al. (90) reported three studies of Zydis selegiline. In the first study, both 1.25 mg/day and 10 mg/day Zydis formulations were compared to oral selegiline 10 mg/day. In those who switched from oral selegiline 10 mg/day to Zydis selegiline 1.25 mg/day, the mean adjusted total UPDRS score was improved slightly at 12 weeks (−2.50, P = 0.01); however, there was no difference in subjects who switched from oral selegiline 10 mg/day to Zydis selegiline 10 mg/day. In the second study, more PD patients preferred the Zydis formulation to standard oral selegiline irrespective of swallowing and salivation problems (90). Tyramine pressor effect was measured in healthy volunteers in the third study (90). After 14 days of Zydis selegiline 1.25 mg/day, there was no change in pressor response to 400 mg of tyramine. In contrast, after 14 days of oral selegiline 10 mg/day, the threshold for pressor response was reduced to 200 mg of tyramine (90). In a three-month study (91), Zydis selegiline significantly reduced off time. PD patients (n = 144) with a minimum of three hours daily off time were randomized 2:1 to Zydis selegiline or placebo. Initial dosage of Zydis selegiline was 1.25 mg/day, and this was increased to 2.5 mg/day at week 6. Overall, the drug was well tolerated and over 90% of each group completed the trial. Drug-related adverse events occurred in 32% of Zydis selegiline and 21% of placebo subjects. The most frequent adverse events in the Zydis selegiline group were dizziness, dyskinesia, hallucinations, headache, and dyspepsia. At weeks 4 to 6, off time was reduced 1.4 hours with Zydis selegiline 1.25 mg/day compared with 0.5 hours for placebo (P = 0.003); at weeks 10 to 12, off time was reduced by 2.2 hours with Zydis selegiline 2.5 mg/day compared with 0.6 hours for placebo (P < 0.001). Dyskinesia-free on time was also significantly increased at weeks 6 and 12. There was no significant difference in daily on time with dyskinesia in the Zydis and placebo groups at weeks 6 and 12. A second, identically designed trial did not show a significant decrease in off time with Zydis selegiline compared to placebo possibly due to a large placebo response. However, when the data of these two studies were pooled, there was a reduction in daily off time of 12.4% with Zydis selegiline versus a 6.9% reduction in the placebo group (P = 0.003) (92).

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RASAGILINE Rasagiline [R(+)-N-propargyl-1-aminoindan] mesylate (Azilect®) was approved by the FDA in May of 2006 as monotherapy in early disease and as an adjunct to levodopa in more advanced disease. The recommended doses are 1 mg once a day in early disease and an initial dose of 0.5 mg once a day in advanced disease that can be increased to 1 mg once a day if needed. It produces selective irreversible MAO-B inhibition (93). Platelet MAO-B inhibition is dose-dependent; one hour after ingestion, platelet MAOB inhibition is 35% with 1 mg rasagiline and 99% with 10 mg rasagiline. By day 6, rasagiline 2 mg/day inhibits over 99% of platelet MAO-B (93). After discontinuing rasagiline, it takes approximately two weeks for MAO-B activity to return to baseline values (93). The area under the curve (AUC) and maximum concentration (Cmax) increase linearly with rasagiline dosage. The plasma half-lives of rasagiline and its active metabolite 1(R)-aminoindan are 3.5 hours and 11 hours, respectively. As rasagiline irreversibly inhibits MAO-B, the serum (pharmacokinetic) half-life does not correlate with its functional (pharmacodynamic) half-life. Rasagiline up to 20 mg/day was well tolerated in healthy male volunteers (93). Dry mouth, headache, nausea, thirst, and abdominal discomfort were the most common adverse effects but tended to be mild. There were no significant effects on vital signs, lab values, physical exam, or EKG. CLINICAL TRIALS OF RASAGILINE TEMPO Subjects with early PD (n = 404) were evaluated in a phase III study called TEMPO (Rasagiline Mesylate [TVP-1012] in Early Monotherapy for Parkinson’s Disease Outpatients) (94). Subjects were randomized to receive rasagiline 1 mg/day (n = 134), rasagiline 2 mg/day (n = 132), or placebo (n = 138), with the change in total UPDRS scores between baseline and 26 weeks as the primary outcome measure. Significant improvements in total UPDRS scores were observed for both rasagiline 1 mg/day and rasagiline 2 mg/day (−4.2 and −3.6, respectively) compared with placebo (P < 0.001 for each comparison) (94). Two-thirds of both rasagiline groups compared to approximately one-half of the placebo group were responders (defined as less than 3 points worsening in total UPDRS scores from baseline to week 26; P < 0.01 for each rasagiline group compared with placebo). Secondary endpoints including UPDRS motor and ADL subscales, and the Parkinson’s disease quality of life scale (PDQUALIF), an assessment of quality of life, significantly favored both dosages of rasagiline compared with placebo. The need for levodopa did not differ among the groups (16.7% for placebo, 11.2% for rasagiline 1 mg, and 16.7% for rasagiline 2 mg). Rasagiline was very well tolerated. The TEMPO study included an open treatment phase, in which all subjects who completed 26 weeks of the double-blind, placebo-controlled phase were placed on rasagiline. Those treated with rasagiline 1 mg/day or 2 mg/day from the start remained on that dosage for the full 12 months, whereas subjects initially treated with placebo for the first six months were then treated with rasagiline 2 mg/day (delayed start) (95). There were 380 subjects enrolled, and the intention-to-treat cohort consisted of 371 subjects. The primary outcome measure was the change in total UPDRS from baseline to 12 months. Subjects treated with rasagiline 2 mg/day for one year were 2.29 points better on the total UPDRS than subjects initially treated with placebo for six months followed by rasagiline 2 mg/day for six months

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(P = 0.01). Subjects who received rasagiline 1 mg/day for one year also experienced less worsening of total UPDRS scores than those treated with placebo for six months followed by rasagiline 2 mg/day for 6 months (1.82 points better total UPDRS in the 1 mg/d group; P = 0.05). The better outcome of patients who took rasagiline for the full year suggests that rasagiline may slow progression of disability in PD. Further studies are currently underway to confirm this effect. PRESTO The PRESTO (Parkinson’s Rasagiline: Efficacy and Safety in the Treatment of Off) study evaluated rasagiline as an adjunct in PD patients with motor fluctuations on levodopa (96). In this study, 472 PD patients with at least 2.5 hours of daily off time were randomized to rasagiline 0.5 mg/day, 1 mg/day, or placebo. Primary outcome was the change in off time as measured by patients’ home diaries from baseline to 26 weeks. Mean adjusted off time improved with each treatment—rasagiline 1 mg/day (1.85 hours), rasagiline 0.5 mg/day (1.41 hours), and placebo (0.91 hours). Compared with placebo, the differences were significant for both rasagiline 1 mg/day (P < 0.001) and rasagiline 0.5 mg/day (P = 0.02). There was a small but significant increase in on time with troublesome dyskinesia in the rasagiline 1 mg group (P = 0.03). The secondary endpoints of UPDRS ADL “off,” motor UPDRS “on,” and clinical global impression were all significantly improved with both dosages of rasagiline, and 1 mg/day rasagiline was also associated with significant improvement on the Schwab and England scale during off time. LARGO The LARGO (Lasting Effect in Adjunct Therapy with Rasagiline Given Once Daily) study evaluated once daily rasagiline and entacapone administered with each levodopa dose, compared with placebo as adjuncts to levodopa in patients with motor fluctuations. In this 18-week, double-blind, parallel-group trial (97), 687 subjects were randomized to receive rasagiline 1 mg daily, entacapone 200 mg with each levodopa dose, or placebo. Off hours were significantly reduced in both the rasagiline (−1.2 hours; P = 0.0001) and entacapone (−1.2 hours; P < 0.0001) groups compared with placebo (−0.4 hours). In addition, both active treatment groups did better on the secondary outcomes of clinical global impression, UPDRS ADL scores in the off state and UPDRS motor scores in the on state, compared with placebo. Neither rasagiline nor entacapone caused any worsening of dyskinesia. Rasagiline, but not entacapone, improved three exploratory UPDRS subscores, postural instability/gait disorder, freezing, and motor score in the practically defined off state. Although the placebo group had a slight increase (+5 mg) in mean daily levodopa dosage at the end of 18 weeks, both rasagiline (−24 mg, P = 0.0003 vs. placebo) and entacapone (−19 mg, P = 0.0024 vs. placebo) were associated with small but significant reductions in daily levodopa requirement. Benefits of rasagiline were independent of age and concomitant dopamine agonist therapy, and posthoc analysis revealed no increase in dopaminergic adverse effects in those over age 70 years. Gait freezing was examined in an auxiliary study of LARGO (98). Advanced PD subjects (n = 454) who had been randomized to rasagiline (1 mg/day; n = 150), entacapone (200 mg with each dose of levodopa; n = 150), or placebo (n = 154) were evaluated with a Freezing of Gait Questionnaire (FOG-Q) (98). Compared with baseline, the rasagiline and entacapone groups demonstrated a mean FOG-Q improvement of

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1.2 points (P = 0.045) and 1.1 points (P = 0.066), respectively, at 10 weeks compared with a 0.5 point worsening in the placebo group. RASAGILINE ADVERSE EVENTS Adverse events were no more common with rasagiline than placebo in the TEMPO study (94) of early patients; the two most common adverse events were infection and headache. In the active treatment phase, there were no significant differences in the most common adverse events occurring in the second six months of the study (infection, headache, unintentional injury, and dizziness). There were eight newly diagnosed malignancies detected over the 12 months of the TEMPO study including six skin cancers (3 squamous cell, 2 melanoma, 1 basal cell carcinoma). Although this may be higher than what would be expected in the general population, it appears that the risk of skin cancers is higher in PD patients in general and does not appear to be specifically related to rasagiline. Given the potential interaction between tyramine and MAO inhibition, a subset of patients on rasagiline also underwent uneventful tyramine challenge tests and blood pressures were generally unchanged after 75 mg of tyramine (99). However, it is recommended that patients should avoid foods and beverages high in tyramine when on rasagiline. In the PRESTO study of advanced patients (96), balance difficulty was more common with rasagiline 0.5 mg/day than placebo, and weight loss, anorexia, and vomiting were each more common with rasagiline 1 mg/day than placebo (P < 0.05 for each). The safety of rasagiline in elderly (70 years and older) PD patients was reported (100). The authors analyzed the data (including both 1 mg/day and 2 mg/day dosages of rasagiline) from PRESTO (96) and TEMPO (95) studies. They found that older subjects were more prone to develop serious adverse effects than younger subjects, but this was irrespective of treatment with rasagiline or placebo (100). In the PRESTO study, the total number of adverse effects was higher with rasagiline compared to placebo (P = 0.03) and more subjects experienced dyskinesia with rasagiline (P = 0.02), but this was seen in both older and younger subjects. Elderly subjects in both TEMPO (P = 0.06) and PRESTO (P = 0.01) were more prone to develop hallucinations regardless of treatment. Although the authors acknowledge that this was a secondary analysis and not specifically powered to detect age–rasagiline interactions directly, no significant interaction between age and rasagiline use was identified as a risk factor for adverse effects (100). CONCLUSION MAOIs provide symptomatic benefit in PD. Selegiline monotherapy delays the need for levodopa by approximately nine months, and permits lower levodopa dosages once levodopa is required. As an adjunct to levodopa, selegiline reduces off time and improves symptom control in more advanced disease. Dopaminergic side effects and dyskinesia may worsen with selegiline and require reduction of levodopa dosage. Zydis selegiline is rapidly absorbed in the buccal mucosa and was approved by the FDA in June 2006 as an adjunct to levodopa. Rasagiline is about 10 times more potent than selegiline and may provide greater symptomatic benefit. In May 2006, it was approved by the FDA for monotherapy in early PD and as an adjunct to levodopa in more advanced disease. Rasagiline is well tolerated in early disease and, generally well tolerated in advanced disease and in the elderly (70 years and older). Early initiation of rasagiline may provide greater benefit than delayed initiation, as demonstrated in the TEMPO study.

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73. Myllylä VV, Sotaniemi KA, Vuorinen JA, et al. Selegiline in de novo parkinsonian patients: The Finnish study. Mov Disord 1993; 8(suppl 1):41–44. 74. Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann Neurol 1996; 39:37–45. 75. Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP subjects not requiring levodopa. Ann Neurol 1996; 39:29–36. 76. Shoulson I, Oakes D, Fahn S, et al. Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol 2002; 51:604–612. 77. Allain H, Cougnard J, Neukirch HC. Selgiline in de novo parkinsonian patients: The French Selegiline Multicenter Trial. Acta Neurol Scand Suppl 1991; 136:73–78. 78. Olanow CW, Hauser RA, Gauger L, et al. The effect of deprenyl and levodopa on the progression of signs and symptoms in Parkinson’s disease. Ann Neurol 1995; 38:771–777. 79. Sivertsen B, Dupont E, Mikkelsen B, et al. Selegiline and levodopa in early or moderately advanced Parkinson’s disease: A double-blind controlled short and long-term study. Acta Neurol Scand 1989; 126:147–152. 80. Heinonen EH, Rinne UK. Selegiline in the treatment of Parkinson’s disease. Acta Neurol Scand 1989; 126:103–111. 81. Lees AJ. Current controversies in the use of selegiline hydrochloride. J Neural Transm 1987; 25:157–162. 82. Golbe LI, Lieberman AN, Muenter MD, et al. Deprenyl in the treatment of symptom fluctuations in advanced Parkinson’s disease. Clin Neuropharmacol 1988; 11:45–55. 83. Palhagen S, Heinonen E, Hagglund J, et al. Selegiline slows the progression of the symptoms of Parkinson disease. Neurology 2006; 66:1200–1206. 84. Lees AJ, Parkinson’s Disease Research Group of the United Kingdom. Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early mild Parkinson’s disease. BMJ 1995; 311:1602–1607. 85. Olanow CW, Fahn S, Langston JW, et al. Selegiline and mortality: A point of view. Ann Neurol 1996; 40:841–845. 86. Parkinson Study Group. Mortality in DATATOP: a multicenter trial in early Parkinson’s disease. Ann Neurol 1998; 43:318–325. 87. Marras C, McDermott MP, Rochon PA, Tanner CM, Naglie G, Rudolph A et al. Survival in Parkinson disease: Thirteen-year follow-up of the DATATOP cohort. Neurology 2005; 64:87–93. 88. Seager H. Drug-delivery products and the Zydis fast-dissolving dosage Form. J Pharm Pharmacol 1998; 50:375–382. 89. Clarke A, Brewer F, Johnson ES, et al. A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition. J Neural Transm 2003; 110:1241–1255. 90. Clarke A, Johnson ES, Mallard N, et al. A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition. J Neural Transm 2003; 110:1257–1271. 91. Waters CH, Sethi KD, Hauser RA, Molho E, Bertoni JM, Zydis Selegiline Study Group. Zydis selegiline reduces off time in Parkinson’s disease patients with motor fluctuations: a 3-month, randomized, placebo-controlled study. Mov Disord 2004; 19(4):426–432. 92. Ondo WG. Pooled analysis of two identical phase 3 studies of a novel selegiline preparation as adjunctive therapy for Parkinson’s disease. Mov Disord 2006; 21(suppl 13):S126. 93. Thebault JJ, Guillaume M, Levy R. Tolerability, safety, pharmacodynamics, and pharmacokinetics of rasagiline: a potent, selective and irreversible monoamine oxidase type B inhibitor. Pharmacotherapy 2004; 24(10):1295–1305. 94. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease. Arch Neurol 2002; 59:1937–1943. 95. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61:561–566. 96. Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations. Arch Neurol 2005; 62:241–248.

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97. Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallelgroup trial. Lancet 2005; 365:947–954. 98. Giladi N, Rascol O, Brooks DJ, et al. Rasagiline treatment can improve freezing of gait in advanced Parkinson’s disease: A prospective randomized, double blind, placebo and entacapone controlled study. Neurology 2004; 62(suppl 5):A329–A330. 99. Parkinson Study Group. Tyramine challenge to assess the safety of rasagiline monotherapy in a placebo-controlled multicenter trial for early Parkinson’s disease (the TEMPO study). Neurology 2001; 56(suppl 3):A345. 100. Goetz C, Schwid SR, Eberly SW, Oakes D, Shoulson I, Parkinson Study Group TEMPO and PRESTO Investigators. Safety of rasagiline in elderly patients with Parkinson disease. Neurology 2006; 66(9):1427–1429.

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Catechol-O-Methyltransferase Inhibitors Ronald F. Pfeiffer Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, U.S.A.

The introduction of levodopa therapy for Parkinson’s disease (PD), initially by Birkmayer et al. (1) in 1961, by Barbeau et al. (2) in 1962, and in its ultimately successful form by Cotzias et al. (3) in 1967, still represents the defining landmark in the treatment of PD. This dramatic advance was preceded by methodical basic laboratory research in the late 1950s and early 1960s, which formed a groundwork documenting the presence of striatal dopamine deficiency in PD (4–8) and paved the road for the application of this knowledge in the clinical arena. These developments took place against a broader backdrop in which both the role of catecholamines and their metabolic pathways in the body and brain were being unraveled (9). As part of this panorama, Axelrod in 1957 first suggested that one of the metabolic pathways for catecholamines might be via O-methylation (9–11), and in the same year, Shaw et al. (12) proposed that catechol-O-methyltransferase (COMT) might be important in the inactivation of dihydroxyphenylalanine (DOPA) and dopamine. By 1964, the metabolic pathways for DOPA and dopamine had been delineated and the enzymes involved were identified. Aromatic amino acid decarboxylase (AAAD) and COMT were identified as being responsible for converting DOPA to dopamine and 3-O-methyldopa (3-OMD), respectively, whereas monoamine oxidase (MAO) and COMT were documented to convert dopamine to 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT), respectively. As early as 1964, it was suggested that agents inhibiting COMT might potentiate the effects of DOPA (13). COMT is present throughout the body, with highest concentrations in the liver, kidneys, gastrointestinal tract, spleen, and lungs (14–17). It is also present in the brain, where it resides primarily in non-neuronal cells such as glia. There is little COMT in neurons and none has been identified in nigrostriatal dopaminergic neurons (18). COMT exists in a soluble form within the cytoplasm in most tissues, but membrane-bound COMT accounts for 70% of the total enzyme present in the brain (19). A number of substrates are acted upon by COMT, including catecholamines, such as epinephrine, norepinephrine, and dopamine, and their hydroxylated metabolites, but all known substrates have a catechol configuration (11). COMT mediates the transfer of a methyl group from S-adenosylmethionine to a hydroxyl group on the catechol molecule. Its actions, especially in the peripheral structures such as intestinal mucosa, seem to be primarily directed toward protecting the body by inactivating biologically active or toxic catechol compounds (11,18–20). Both levodopa and dopamine are examples of such biologically active compounds. The COMT gene has been identified on chromosome 22 (21). Two alleles, one thermostable with high activity and one thermolabile with low activity, have been identified, with a three- to four-fold difference in activity (19,22). The clinical relevance of this polymorphism is uncertain. Recognition of the bioavailability of orally administered levodopa in the treatment of PD, with perhaps only 1% of it actually reaching the brain because of extensive peripheral metabolism by both AAAD and COMT (18,23), fueled the search for 365

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drugs that might inhibit the two enzymes and improve levodopa’s therapeutic efficacy. This led to the introduction of two inhibitors of AAAD, carbidopa and benserazide, as adjunctive agents administered concomitantly with levodopa to PD patients (24,25). Administering levodopa in conjunction with an AAAD inhibitor remains the standard today. However, the use of these agents only expands the amount of levodopa reaching the brain to an estimated 10% of an administered dose, primarily because blocking AAAD simply shunts levodopa into the COMT metabolic pathway, with an increased peripheral formation of 3-OMD (23). FIRST GENERATION CATECHOL-O-METHYLTRANSFERASE INHIBITORS During the 1960s and 1970s, a number of COMT inhibitors were identified and studied. Pyrogallol (1,2,3-trihydroxybenzene) was the first COMT inhibitor to be identified (26,27), but its short duration of action, toxicity (methemoglobinemia and renal impairment), and probable lack of COMT specificity precluded its clinical use (11). The list of additional COMT inhibitors that were studied and subsequently abandoned as potential therapeutic agents is quite long. Catechol itself, adnamine and noradnamine, various flavonoids, tropolone and its derivatives, 8hydroxyquinolines, S-adenosylhomocysteine, sulfhydryl-binding agents, pyrones and pyridones, papaveroline, methylspinazarin, 2-hydroxylated estrogens, and 3mercaptotyramine represent only a partial listing of such compounds (11). Even the two agents that are primarily recognized as inhibitors of AAAD, carbidopa and benserazide, have some modest COMT-inhibiting properties, although not enough to be clinically relevant (11). Several of these early COMT inhibitors did undergo pilot testing in humans. N-butyl gallate (GPA 1714), a derivative of gallic acid, was found to be effective in alleviating signs and symptoms of PD when administered to 10 patients (28). The dose of levodopa was reduced by an average of 29% and the drug was also noted to alleviate nausea and vomiting. No significant adverse effects were noted in this initial study, but testing was eventually abandoned because of its toxicity (29). Another compound, 3,4-dihydroxy-2-methylpropiophenone (U-0521), demonstrated significant COMT inhibition in animal studies, but when it was administered orally to a single human in progressively increasing doses, it demonstrated no effect on erythrocyte COMT activity (29). SECOND GENERATION CATECHOL-O-METHYLTRANSFERASE INHIBITORS Little attention was devoted to COMT inhibitors for the treatment of PD during the mid-1980s, but the 1990s ushered in renewed interest in the potential clinical usefulness of these compounds. This renewed attention was prompted by the development of a “second generation” of COMT inhibitors, substances that were more potent, more selective, and less toxic than their predecessors. Several nitrocatechol compounds, eventually bearing the names nitecapone, entacapone, and tolcapone, became the focus of laboratory and clinical study. Nitecapone Nitecapone (OR 462) was demonstrated to be well tolerated and modestly effective when administered to mice, rats, and monkeys (30–32). Its actions were confined to the periphery since it did not cross the blood–brain barrier (33), and its primary

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action appeared to be in the intestinal mucosa (34,35). In subsequent human studies, it was noted to “slightly but significantly” increase the relative bioavailability of levodopa and to reduce plasma 3-OMD (36), but it eventually ceded its place in clinical PD development to entacapone (OR 611), which was judged the more effective compound. Entacapone Entacapone is readily absorbed across the intestinal mucosa and does not seem to be significantly affected by first-pass metabolism in the liver. The bioavailability of an oral dose of entacapone ranges from 30% to 46% (18,37–40). It is highly (98%) protein bound and metabolized via glucuronidation. Most reports place the elimination half-life of entacapone between 0.4 and 0.7 hours (18,37–39). Entacapone does not cross the blood–brain barrier to any significant extent and appears to exert its action exclusively in the periphery (41), although some inhibition of striatal COMT activity following entacapone administration in rats has been described (41,42). When administered to humans, the inhibition of COMT activity by entacapone is dose dependent. Soluble COMT is reduced by 82% with an entacapone dose of 800 mg, the maximum amount that has been administered (43). In multiple dose studies, 100 mg of entacapone, given four to six times daily with levodopa, reduced COMT activity by 25% compared to placebo, while 200 mg produced a 33% reduction and 400 mg generated a 32% diminution in COMT activity (38). Entacapone also has a dose-related effect on both levodopa and 3-OMD pharmacokinetics. In the same group of patients noted earlier, the elimination half-life (T1/2) of levodopa was prolonged by 23%, 26%, and 48% at entacapone doses of 100, 200, and 400 mg, respectively, while the area under the levodopa plasma curve (AUC) was increased by 17%, 27%, and 37%, respectively (38). Investigators in two earlier studies, however, had noted a leveling off of the levodopa AUC increase between entacapone doses of 200 and 400 mg and suggested that this might be due to the interference in carbidopa absorption by entacapone at a higher dose (44,45). In other studies, utilizing an entacapone dose of 200 mg, increases in the levodopa AUC have ranged between 23% and 48% and prolongation of the levodopa T1/2 has been around 40% (18). Despite these rather dramatic alterations, no significant increase in the time to reach the maximum plasma levodopa concentration (Tmax) or the maximum plasma levodopa concentration itself (Cmax) is seen following the concomitant administration of levodopa and entacapone. The Tmax remains between 30 and 60 minutes (18,34,46–49). Nutt (50) notes that the absence of an effect on the levodopa Tmax and Cmax is true only for the initial dose of the day and that some modest progressive elevation of the levodopa Cmax develops with repeated doses during the day. This does not carry over to the next day, however, and a progressive escalation of COMT inhibition does not occur (18,46). Concomitant with these changes in levodopa pharmacokinetics, entacapone also induces a significant reduction in the plasma AUC of 3-OMD, reflecting a reduced COMT-mediated peripheral metabolism of levodopa to 3-OMD (18,38,40). It was predicted that the clinical correlate of these pharmacokinetic alterations would be an extended efficacy of a levodopa dose, due to the combination of the prolonged T1/2 and an increased AUC of levodopa and the reduced AUC of 3-OMD, possibly without an increase in levodopa-related toxicity in light of the absence of change in levodopa Cmax. Subsequent full-scale clinical trials have largely validated these predictions and confirmed the safety and efficacy of entacapone.

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The Safety and Efficacy of Entacapone Study Assessing Wearing-Off (SEESAW) double-blind placebo-controlled trial, evaluated the safety and efficacy of entacapone over a six-month period in 205 PD patients on levodopa with motor fluctuations (51,52). A significant 5% increase in daily “on” time (approximately one hour) was documented in patients receiving entacapone, compared to the placebo group. Motor function, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) (53), improved slightly in the entacapone-treated group, whereas it deteriorated in the placebo group during the six month trial. The average daily levodopa dosage diminished by 12% (from 791 to 700 mg/day) in the entacapone-treated group, but did not change in the placebo group. Adverse effects were generally mild and manageable, consisting primarily of symptoms consistent with enhanced dopaminergic activity, such as dyskinesia, nausea, and dizziness. Dyskinesia was reported as an adverse effect by 53% (55/103) of patients on entacapone, compared to 32% (33/102) of individuals on placebo. Yellow/orange discoloration of the urine also occurred in 37% of those receiving entacapone, but diarrhea was infrequent (7%). A second large multicenter study, the NOMECOMT study, had both a trial design very similar to the SEESAW study and very similar results (50,52,54). This trial (also six months in duration) included 171 PD patients on levodopa who were experiencing motor fluctuations. In the entacapone-treated group, the mean “on” time increased by 1.4 hours, compared to an increase of 0.2 hours in the placebo group. This relative increase of 13% in the treatment group was significant. Average daily levodopa dosage diminished by 12% in the entacapone group, compared to a 2% increase in the placebo group. Adverse effects in this study were similar to those in the SEESAW study, except that the worsening of dyskinesia was reported by only 8.2% of entacapone-treated participants (vs. 1.2% of those on placebo), whereas diarrhea was reported by 20%. An open-label three-year extension of this study demonstrated a sustained benefit of entacapone (55). More recent studies have augmented the findings of the SEESAW and NOMECOMT studies. Two additional large multicenter trials have investigated the safety and efficacy of entacapone in PD patients (56,57). In an open-label study of eight weeks duration, 489 patients were administered entacapone in conjunction with each dose of levodopa up to a maximum of 10 doses/day (56). Some reduction in “off ” time was experienced by approximately 41% of patients, and the quality of life, as measured by the PDQ-39, was also improved. In a double-blind study of 301 PD patients, most of whom were experiencing motor fluctuations, significant improvement in both motor function and activities of daily living was documented with entacapone compared to placebo (57). However, in another double-blind study, a trend toward improvement was noted but significance was not achieved (58). Concerns that the efficacy of entacapone might be reduced when used in conjunction with controlled-release levodopa preparations, because of a potential “mismatch” in absorption and metabolism of the two drugs, led several groups of investigators to address the issue (45,57,59–62). The effect of entacapone was, for the most part, found to be comparable between the standard and controlled-release levodopa preparations. Delaying entacapone administration until 30 or 90 minutes after levodopa administration did not produce any alteration in levodopa pharmacokinetics, compared with the concomitant administration (61). In a study that compared rasagiline, entacapone, and placebo, both rasagiline and entacapone reduced “off ” time by similar amounts (1.18 and 1.20 hours, respectively) compared with a 0.4-hour reduction for placebo (63). A postmarketing surveillance study of 464 patients taking entacapone reported an approximate 57%

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reduction in the mean “off ” time. In this trial, diarrhea was the most frequently reported adverse event, occurring in approximately 8% of individuals (64). Two large open-label studies of 899 and 479 patients demonstrated improvement in both patient perception of quality of life and physician perception of global improvement (65,66). In another postmarketing report, Parashos et al. (67) found that in their clinical practice the most common reason for discontinuation of entacapone was not the adverse effects, but rather the lack of efficacy. Actual aggravation of parkinsonism (worsening of symptoms) was the next most frequent reason for discontinuing the drug. Although hepatic toxicity has primarily been associated with tolcapone, at least one report has described entacapone-induced hepatotoxicity (68). Excessive daytime sleepiness, including “sleep attacks,” has also been described with entacapone (69). Drug interactions are not a prominent problem with entacapone, although the capability of entacapone to chelate iron in the gastrointestinal tract has been noted (70), and it has been suggested that an interval of two to three hours be allowed between entacapone and iron ingestion (18). Although animal studies have suggested that COMT inhibition may increase apomorphine bioavailability (71), such an effect has not been demonstrated in humans, even when administering a double dose of 400 mg entacapone (72). Levodopa may increase plasma homocysteine levels in individuals with PD (73–77). The clinical significance, if any, of this elevation is uncertain. Elevated homocysteine has been reported as a risk factor for vascular disease (78,79), dementia (80), and depression (81); but whether this holds true for the modest elevations of homocysteine seen in levodopa-treated PD patients is less clear. Entacapone is able to prevent the levodopa-induced rise in homocysteine (82,83) Stalevo The efficacy of entacapone in prolonging the effect of levodopa, along with the recognition that it must be administered with each dose of levodopa, prompted the creation of a preparation combining levodopa, carbidopa, and entacapone into a single tablet. Several clinical trials have demonstrated the bioequivalence of this combination drug (Stalevo) to the administration of carbidopa/levodopa (or benserazide/ levodopa) and entacapone as separate medications (84,85). Patients perceive both the reduction in the number of pills enabled by Stalevo and the smaller size of the Stalevo tablets to be desirable conveniences (86,87). Using a sophisticated mathematical modeling process that accounts for both individual and societal benefits, Findley et al. (88) have concluded that Stalevo is cost-effective when compared with treatment with carbidopa/levodopa alone. Tolcapone Tolcapone (Ro 40-7592), like entacapone, is rapidly absorbed after oral administration; in contrast to entacapone, it reaches Tmax in approximately 1.5 to 2 hours (18,89,90). The bioavailability of an oral dose is about 60% (91). Tolcapone is very highly (99.9%) protein bound (92). Metabolism of tolcapone is primarily, but not exclusively, via glucuronidation (93) since both methylation and oxidation also occur (94). The elimination T1/2 of tolcapone is between two and three hours, which is distinctly longer than that of entacapone (89). At doses above 200 mg three times a day (TID), some accumulation of tolcapone can occur, but this appears to be of no

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real practical significance since levels, even at doses of 800 mg TID, remain well below those associated with toxicity in animals (89). Unlike entacapone, tolcapone is sufficiently lipophilic to cross the blood–brain barrier, to some degree (95). Tolcapone-induced inhibition of COMT within the brain has been demonstrated in animal experiments (94,96). In primates, where administered tolcapone doses were within the therapeutic range, COMT activity within the cerebellum was reduced by 60% (97). It has been less convincingly demonstrated that similar central COMT inhibition takes place in humans receiving tolcapone in clinically relevant doses. However, fluorodopa positron emission tomography (PET) studies have provided some evidence that such central COMT inhibition does take place with tolcapone doses of 200 mg (98). Tolcapone has also been identified in the cerebrospinal fluid (CSF) of patients with PD one to four hours after oral intake of 200 mg of tolcapone in concentrations sufficient to reduce CSF COMT activity by 75% (99). Inhibition of COMT within both peripheral and CNS structures provides some theoretical advantages over peripheral inhibition alone since, in addition to the peripheral levodopa-sparing capability, concomitant central COMT inhibition would not only reduce metabolism of levodopa to 3-OMD within the striatum, but would also block one route of the metabolism of dopamine itself. Single dose studies demonstrated tolcapone to be a noticeably more potent COMT inhibitor than entacapone. At a dose of 200 mg, tolcapone increases the levodopa AUC from 50% to 100%, prolongs the levodopa T1/2 by 60% to 80%, and reduces the AUC of 3-OMD by 64% (18,50,100,101). No appreciable increase in the levodopa Cmax or Tmax is seen at this dose of tolcapone, although some delay in the Tmax becomes evident at higher doses (100). A number of double-blind, placebo-controlled clinical trials have confirmed the efficacy of tolcapone in reducing motor fluctuations in individuals with PD (102–105). In each of these multicenter trials, which varied in length from six weeks to six months, significant increases in “on” time and reductions in “off ” time were documented in the tolcapone-treated groups, compared with the placebo groups. Reduction in both total daily levodopa dosage and number of levodopa doses taken was often evident in the tolcapone-treated groups. In these four multicenter studies, in which 517 patients (out of 745 enrolled) received tolcapone in various doses ranging from 50 to 400 mg TID, adverse effects were generally mild and most often dopaminergic in character (102–105). In the three studies, where the treatment groups consisted of placebo versus 100 mg TID versus 200 mg TID, dyskinesia was reported as an adverse event in 19% to 21%, 37% to 62%, and 53% to 66%, respectively (103–105). Tolcapone has been compared favorably with two dopamine agonists, bromocriptine and pergolide, in clinical trials (106,107), although these trials were open-label and possibly underpowered (108). Diarrhea, at times unresponsive to medication and of sufficient severity to warrant drug discontinuation, was reported in a small percentage of individuals receiving tolcapone, possibly in a dose-related pattern (50,104,105). The mechanism of the diarrhea is uncertain, although tolcapone has been noted to trigger intestinal fluid and electrolyte secretion, albeit not the actual diarrhea, in dogs (18,109). As with entacapone, yellow/orange urine discoloration also occurred in some individuals. In the initial multicenter trials, elevation of liver transaminase levels occurred in a small number of individuals, but all were clinically asymptomatic and the laboratory abnormalities sometimes returned to normal, despite continued treatment.

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In all clinical trials of tolcapone the reported incidence of transaminase elevations greater than three times the upper limit of normal was approximately 1% at a dose of 100 mg TID and 3% at a dose of 200 mg TID (110). However, following introduction of tolcapone into routine clinical use, three cases of fulminant hepatic failure with a fatal outcome occurred, which led regulatory agencies in Europe and Canada to withdraw tolcapone from the market, and the Food and Drug Administration in the United States to severely limit its use to situations where other drugs had not provided sufficient benefit (111). No further deaths have been reported and recently these restrictions have been relaxed. Tolcapone can once again be used in Europe, with appropriate monitoring of liver function, in persons with symptom fluctuations receiving levodopa who cannot tolerate or have not responded to other COMT inhibitors (112). A report from the Quality Standards Subcommittee of the American Academy of Neurology also provides similar guidelines for tolcapone use (113). Baseline liver function tests must be normal and the monitoring of liver function must be performed on a regular basis (every two to four weeks for the first six months and thereafter as clinically necessary) in patients receiving tolcapone (113). The mechanism of tolcapone-induced hepatotoxicity is not entirely clear. Uncoupling of oxidative phosphorylation in mitochondria (112,114,115), perhaps mediated by oxidation of tolcapone metabolites to reactive intermediates (116), has been suggested. Tolcapone may also provoke cellular damage by a mechanism independent of its effects on oxidative phosphorylation, perhaps by opening the mitochondrial permeability transition pore, with consequent apoptotic cell death (115). CURRENT STATUS OF CATECHOL-O-METHYLTRANSFERASE INHIBITORS Two COMT inhibitors are currently available for use as adjunctive therapy in PD, to be used in conjunction with levodopa and an AAAD inhibitor in patients, who have developed motor fluctuations with end-of-dose wearing off. Tolcapone is the more potent of the two and, with its longer T1/2, can be given on a TID basis. Its potential to produce hepatic failure has limited its use to individuals in whom entacapone has been ineffective or not tolerated (117). Because of the tolcapone-related safety issues, clinical use of COMT inhibition has largely centered on entacapone, despite its lesser relative potency. Because of its short T1/2 entacapone must be administered with each dose of levodopa. At first glance this seems inconvenient, but since it really does not entail any more frequent dosing than that already being employed for the levodopa, the inconvenience is more perceived than real. The additional one to two hours of “on” time per day that a COMT inhibitor typically affords to a fluctuating patient can be very welcome. A cost-effectiveness analysis of entacapone concluded that the additional drug costs when entacapone is employed are offset by reductions in other costs and improvement (6%) in “quality-adjusted life years” (118). Another study in Finland also concluded that entacapone (and the MAO-B inhibitor rasagiline) is costeffective when used in conjunction with levodopa compared to levodopa alone and provides slightly over five months of quality-adjusted life years (119). Findley et al. (88) reached similar conclusions with regard to Stalevo. While it is quite clear that COMT inhibitors provide quantifiable improvement in function for PD patients with motor fluctuations, their potential benefit in stable PD patients who have not yet developed motor fluctuations has received much less attention. Two clinical trials have addressed this question with tolcapone (120,121). In the larger of the two trials (120), significant improvement in both the activities of

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daily living and the motor sections of the UPDRS were documented. Improvement was most evident in more severely affected patients. Fewer patients in the tolcaponetreated group developed motor fluctuations during the duration of the trial, which extended to a maximum of 12 months for some participants (average 8.5 months). Adverse events were similar to those encountered in earlier trials described in the previous sections. The second, smaller, trial did not examine nonfluctuating PD patients, but rather evaluated individuals who had previously experienced wearing off with levodopa, which had been successfully controlled by levodopa dosage adjustment (121). A greater reduction of levodopa dosage was achieved in the tolcapone-treated group, but this was not significant. A single tolcapone trial in levodopa-untreated patients demonstrated no clinical benefit (122). In a double-blind study involving 300 patients, 128 of whom were not experiencing motor fluctuations, entacapone produced improvement in both the fluctuating and the nonfluctuating groups (123). In the group without motor fluctuations, a significant improvement in UPDRS activities of daily living was evident in patients receiving entacapone compared with those receiving placebo, although no difference in motor scores was found. A larger increase in levodopa dosage in the placebo group also occurred. In another double-blind, placebo-controlled study involving a total of 750 levodopa-treated subjects who were not experiencing motor fluctuations, entacapone did not produce improvement in UPDRS motor scores, but a significant improvement was documented in some quality of life measures (124). THE FUTURE FOR CATECHOL-O-METHYLTRANSFERASE INHIBITORS The pathogenesis of motor fluctuations in individuals with PD receiving levodopa has been the subject of much speculation, but little certainty, over the years. Both peripheral and central mechanisms have been hypothesized. Both may actually be active, but it appears that most often the predominant mechanisms driving the pathogenic process are within the CNS. Evidence has begun to accumulate that with PD progression the dwindling number of surviving nigrostriatal dopaminergic neurons are unable to maintain the normal synaptic atmosphere of constant dopaminergic stimulation; instead the environment becomes one in which dopamine receptor stimulation is intermittent, characterized by pulses of dopaminergic stimulation coincident with levodopa administration. It appears that this pulsatile stimulation may, in turn, incite a cascade of changes within the postsynaptic striatal spiny neurons that produces sensitization of glutamate receptors and altered motor responses (125,126). If this is correct, providing and maintaining a synaptic environment of more constant dopaminergic stimulation from the beginning of treatment might forestall the development of the postsynaptic alterations and delay or prevent the appearance of motor fluctuations. This has led to the proposal that a COMT inhibitor, such as entacapone, may be administered along with levodopa and carbidopa right from the initiation of therapy (127,128). Jenner and coworkers reported that in marmosets with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, initiation of treatment with frequent doses of levodopa combined with entacapone resulted in less frequent and less severe dyskinesia than that which developed in animals treated with comparable doses of levodopa alone (129). Studies are currently underway in humans, and if a reduction or delay in the development of motor fluctuations with such treatment is demonstrated, the role for COMT inhibitors in the treatment of PD may expand dramatically.

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112. Borges N. Tolcapone in Parkinson’s disease: liver toxicity and clinical efficacy. Expert Opin Drug Saf 2005; 4(1):69–73. 113. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 66(7):983–995. 114. Nissinen E, Kaheinen P, Penttila KE, et al. Entacapone, a novel catecholO-methyltransferase inhibitor for Parkinson’s disease, does not impair mitochondrial energy production. Eur J Pharmacol 1997; 340(2–3):287–294. 115. Korlipara LVP, Cooper JM, Schapira AHV. Differences in toxicity of the catecholO-methyl transferase inhibitor, tolcapone and entacapone to cultured human neuroblastoma cells. Neuropharmacology 2004; 46(4):562–569. 116. Smith KS, Smith PL, Heady TN, et al. In vitro metabolism of tolcapone to reactive intermediates: relevance to tolcapone liver toxicity. Chen Res Toxicol 2003; 16(2):123–128. 117. Keating GM, Lyseng-Williamson KA. Tolcapone: a review of its use in the management of Parkinson’s disease. CNS Drugs 2005; 19(2):165–184. 118. Nuijten MJ, van Iperen P, Palmer C, et al. Cost-effectiveness analysis of entacapone in Parkinson’s disease: a Markov process analysis. Value Health 2001; 4:316–328. 119. Hudry J, Rinne JO, Keranen T, et al. Cost utility model of rasagiline in the treatment of advanced Parkinson’s disease in Finland. Ann Pharmacother 2006; 40(4):651–657. 120. Waters CH, Kurth M, Bailey P, et al. Tolcapone in stable Parkinson’s disease: efficacy and safety of long-term treatment. The Tolcapone Stable Study Group. Neurology 1997; 49(3):665–671. 121. Dupont E, Burgunder J-M, Findley LJ, et al. Tolcapone added to levodopa in stable parkinsonian patients: a double-blind placebo- controlled study. Tolcapone in Parkinson’s Disease Study Group II (TIPS II). Mov Disord 1997; 12(6):928–934. 122. Hauser RA, Molho E, Shale H, et al. A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson’s disease patients. Tolcapone De Novo Study Group. Mov Disord 1998; 13(4):643–647. 123. Brooks DJ, Sagar H, the UK-Irish Entacapone Study Group. Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson’s disease: a randomised, placebo-controlled, double blind, six-month study. J Neurol Neurosurg Psychiatry 2003; 74(8):1071–1079. 124. Olanow CW, Kieburtz K, Stern M, et al. Double-blind, placebo-controlled study of entacapone in levodopa-treated patients with stable Parkinson disease. Arch Neurol 2004; 61(10):1563–1568. 125. Chase TN. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology 1998; 50(suppl 5):S17–S25. 126. Chase TN, Oh JD. Striatal dopamine- and glutamate-mediated dysregulation in experimental parkinsonism. Trends Neurosci 2000; 23(suppl):S86–S91. 127. Olanow CW, Obeso JA. Pulsatile stimulation of dopamine receptors and levodopainduced motor complications in Parkinson’s disease. Implications for the early use of COMT inhibitors. Neurology 2000; 55(suppl 4):S72–S77. 128. Olanow CW, Stocchi F. COMT inhibitors in Parkinson’s disease: can they prevent and/or reverse levodopa-induced motor complications? Neurology 2004; 62(1 suppl 1):S72–S81. 129. Smith LA, Jackson MJ, Al-Barghouthy G, et al. Multiple small doses of levodopa plus entacapone produce continuous dopaminergic stimulation and reduce dyskinesia induction in MPTP-treated drug-naïve primates. Mov Disord 2005; 20(3):306–314.

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Investigational Pharmacological Treatments William G. Ondo Department of Neurology, Baylor College of Medicine, Houston, Texas, U.S.A.

INTRODUCTION Effective therapy for Parkinson’s disease (PD) has existed for over 45 years. Currently, levodopa, the precursor to dopamine, remains the most consistently effective symptomatic treatment. Pharmacological treatments, such as dopamine agonists and monoamine oxidase (MAO) inhibitors, augment and replace endogenous dopamine loss. Other treatments such as anticholinergic medications and amantadine often help symptoms through nondopaminergic mechanisms. Numerous other medications such as antidepressants and antipsychotics are used to treat specific symptoms in PD. Conceptually, there are two major shortcomings to our current dopaminergic armamentarium: loss of effect and lack of effect. Dopaminergic medications often initially improve motor symptoms; however, as the disease progresses, patients develop motor complications. Initially, the duration of medication action shortens with the subsequent development of dyskinesia and on/off fluctuations that complicate dosing and can worsen quality of life. This is particularly problematic in younger patients. Certain aspects of PD do not respond well to dopaminergic drugs, such as sleep disturbances, cognition, mood, balance, freezing of gait, gastroenterological and urological symptoms, and bulbar symptoms, as these symptoms often result from nondopaminergic pathology. Finally, no available medication can definitely claim to offer anything other than symptomatic benefit. New medications can be broadly classified into three categories: (i) improved versions of drugs that employ similar mechanisms of action as currently available medications, (ii) drugs with novel mechanisms of action, and (iii) drugs designed to treat only a particular aspect of the disease (psychosis, dementia, etc.). In this chapter, we will only discuss new drugs designed to treat the motor features of PD. NEW DOPAMINERGIC AGENTS The general goals of dopaminergic therapies are to maximize the therapeutic effect while minimizing adverse events including sedation, nausea, hallucinations, pedal edema, hypotension, and motor complications. Clinically, a rapid onset of action is also desirable. Furthermore, there is increasing evidence that continuous dopaminergic stimulation may delay the appearance of motor complications. The new dopaminergics were developed to achieve these goals. Levodopa Preparations Vadova® Vadova tablets (Impax Pharmaceuticals[31]) have shown favorable pharmacokinetic properties. (1) It is a combination tablet comprising immediate-release levodopa along with sustained-release levodopa. The onset of action is faster than individual 379

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controlled release pills and the area under the curve extends beyond immediate release pills. The initial peak plasma level occurs 30 minutes post-ingestion and adverse events were similar to traditional preparations. Duodopa® Duodenal infusions of levodopa have been used in a small number of PD subjects for years. One group reported 28 advanced PD patients with on/off fluctuations who received a median of 1050 mg/day of Duodopa (levodopa gel; Solvay, NeoPharma) for a median of 44 months (range 2–83 months). They reported significant benefits of Duodopa that were maintained for up to 7 years (2). A recent report demonstrated improved quality of life and amelioration of fluctuations in six advanced PD patients using Duodopa, with a mean infusion rate of 88 mg/hr starting at 8 AM and ending at 11 PM (3). Large, multicenter studies are planned. Levodopa Methyl Ester Levodopa methyl-ester/carbidopa effervescent tablets (CNP-1512) are currently approved for rescue therapy in PD in Italy (Chiesi Farmaceutici). Outside of Italy, the drug (V1512) is owned by Vernalis Pharmaceuticals. This preparation is approximately 250 times more soluble in water and can thus be easily dissolved and orally administered. Studies comparing the drug with standard levodopa preparations demonstrate a faster onset of action (by a mean of 8.5 minutes) and a longer total duration of action (mean 15 minutes longer) with fewer dose failures. A large 39-center European trial compared levodopa methyl-ester with standard levodopa in patients already on levodopa who were experiencing at least two hours of “off ” time. At 12 weeks, subjects on levodopa methyl-ester tended to have less off time than levodopa (−39.4 vs. +3.4 minutes, P = 0.07). No unexpected adverse events have been noted. Phase III North American and European studies are planned (4). Etilevodopa® Etilevodopa (TV-1203/carbidopa; Teva Pharmaceuticals) is an ethyl ester derivative of levodopa. This prodrug was designed to be absorbed more rapidly and reliably in the gut than levodopa, primarily because it is more soluble in aqueous solutions. A large Phase III trial failed to demonstrate any benefit over existing carbidopa/levodopa preparations (5). Dopamine Agonists Ropinirole 24-Hour Prolonged Release Ropinirole 24-hour prolonged release (GlaxoSmithKline) has completed Phase II/III trials for PD. The dopamine agonist component is identical to the currently available drug, ropinirole. The prolonged release tablet employs a Geomatrix® technology involving altering layers of active drug and erodible hydroxypropyl methylcellulose polymers, which slow absorption of the drug potentially leading to a smoother pharmacokinetic profile, improved tolerability and efficacy, and reduced motor fluctuations. This formulation is already used in medications marketed within the United States including Paxil CR®. The ropinirole Geomatrix system differs slightly from previous systems in that it employs a carboxymethylcellulose sodium. Pharmacokinetic studies show that this safely slows absorption without any dose dumping. A 393-patient multicenter, Phase III trial recently compared the 24-hour prolonged

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release ropinirole preparation and placebo (6). The initial dose was 2 mg/day which was titrated over four weeks to 8 mg/day and if needed to a maximum dose of 24 mg/day over a period of 8 weeks. Overall, off time was reduced by 2.1 hr/day compared to 0.3 hr/day with placebo (P < 0.0001). No unexpected adverse events were reported, and compared with studies evaluating immediate release ropinirole, adverse events appeared to be reduced. Rotigotine Patch Rotigotine CDS® (constant delivery system), (−)-5,6,7,8-tetrahydro-6 [propyl-2-(2thienyl-ethyl) amino]-1-naphthalenolis (Neupro®, Schwarz Pharma) is a siliconebased lipophilic nonergotamine D2 agonist patch designed to deliver constant drug levels over a 24-hour period (7). Detectable serum levels are achieved two to three hours after initial application and a serum steady state is achieved after approximately 24 hours. In the current formulation, the 9 mg (20 cm2) patch delivered approximately 4 mg of drug over a 24-hour period. Similarly, the 40 cm2 patch has 18 mg of the drug and delivers 8 mg over a period of 24 hours and the 60 cm2 patch has 27 mg of rotigotine and delivers 12 mg over 24 hours. Increased dermal sizes appear to proportionally increase serum drug levels. Pharmacokinetic studies demonstrate that the drug has a T1/2 of about five to seven hours, but maintains steady-state levels while the patch is worn. The current design is formulated to be worn for 24 hours. There were no measurable metabolites. Rotigotine has been compared with placebo and other dopamine agonists in both early and advanced PD (8–13). In general, the studies have shown efficacy and an AE profile similar to that of other dopamine agonists. Phase IIa dose finding studies showed a linear dose–response curve, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS), between 4.5 and 54 mg/day (120 cm2). A multicenter, double-blind study of rotigotine in early PD demonstrated significant benefit in UPDRS scores compared with placebo. The majority of patients (90%) reached a dose level of 13.5 mg/day (12). A multicenter, double-blind study of advanced PD compared rotigotine 40 cm2 (n = 111), rotigotine 60 cm2 (n = 120), and placebo (n = 120) and reported a decrease in off time of 2.7, 2.1, and 0.9 hours, respectively (13). The most common adverse events have been application site reactions, somnolence, nausea, vomiting, dizziness, dyskinesia, and edema. Lisuride Patch Daily-administered lisuride patches (an ergot dopamine agonist) are also under development for both PD and restless legs syndrome, but have not been extensively studied (Prestwick Pharmaceuticals). Small published trials have shown efficacy for both conditions (14,15). A randomized placebo-controlled study of 22 PD patients reported a 50% to 75% decrease in oral medication, reduction of motor fluctuations, improved quality of life, decreased daytime somnolence, and increased duration of nighttime sleep (16). Skin irritation has been reported. To date, no cardiac valvular pathology or other presumed ergotamine adverse events have been reported. Piribedil Piribedil is a nonergot selective D2/D3 agonist with significant antagonist action on alpha2A and alpha2C adrenergic receptor subtypes, which has shown efficacy in PD. It is available in some countries. The medication is orally administered once daily, typically at 150 mg (17–20). A 12-month, multicenter controlled study demonstrated similar efficacy between 150 mg of piribedil and 25 mg of bromocriptine as adjunctive

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therapy (17). Piribedil patients required less levodopa dose increase than those on bromocriptine. Intravenous administration of piribedil has also been reported (21). SLV308 SLV308 (Solvay Pharmaceuticals) is a mixed partial dopamine agonist/antagonist. With low dopaminergic tone, the drug stimulates dopamine receptors; however, with high dopaminergic tone, such as after apomorphine administration, the drug antagonizes dopamine receptors. SLV308 is also a potent 5-HT1A agonist. Theoretically, this could help PD symptoms, depression and anxiety, and prevent druginduced dyskinesia in PD. One controlled trial in PD tested doses of SLV308 ranging from 9 to 45 mg/day in 138 subjects with early PD. There was a significant improvement in motor scores, activities of daily living scores, and global impressions. Additional studies are planned (22). Sumanirole Sumanirole maleate (PNU-95666E, Pfizer) is a novel oral D2 agonist, which differs from existing dopamine agonists secondary to its low affinity for the D3 receptor. Phase II and Phase III trials in early and advanced PD patients have generally reported efficacy similar to that of other dopamine agonists at doses ranging from 2 to 48 mg/day, but no clear advantages over existing dopamine agonists. Further research trials are not planned. MONOAMINE OXIDASE INHIBITOR Safinamide Safinamide (formerly PNU-151774E) (Newron Pharmaceuticals) is a sodium and calcium channel modulator, which also inhibits MAO-B. Pharmacokinetics of enteric safinamide is linear and proportionally related to the administered doses. The absorption of safinamide is rapid and the T1/2 is about 22 hours. Safinamide reversibly and specifically inhibits the MAO-B enzyme. No evidence of MAO-A inhibition was observed even at the highest single dose of 10 mg/kg (23). A three-month controlled trial of safinamide in de novo and dopamine agonist treated patients was conducted (24). A median safinamide dose of 70 mg/day (range 40–90 mg/day) increased the percentage of parkinsonian patients that improved their motor scores by 30% compared to placebo (37.5% vs. 21.4%, P < 0.05). In a subgroup of 101 patients under stable treatment with a single dopamine agonist, addition of safinamide magnified the response (47.1% responders, mean 4.7-point motor score decrease; P = 0.05). Brasofensine Brasofensine (BMS-204756) is a dopamine re-uptake inhibitor and MAO inhibitor. It has demonstrated improved kinesis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) marmosets (25). A safety trial in humans demonstrated good tolerability, but did not show motor improvement as add-on therapy in an eight-patient cross-over trial (26). Future development is unclear. AGENTS WITH NOVEL MECHANISMS OF ACTION Adenosine receptors are found throughout the central nervous system; however, type A2A receptors are seen almost exclusively on gamma-aminobutyric acid

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(GABA), enkephalin, and cholinergic (ACh) spiny neurons in the striatum. These neurons receive inhibitory dopaminergic input from the substantia nigra and then project to inhibit pallidal neurons as part of the indirect pathway of the basal ganglia. Therefore, in PD, dopaminergic cell loss results in disinhibition of striatal spiny neurons that subsequently overly inhibit the globus pallidus externus, which in turn overly stimulate the subthalamic and globus pallidus internus nuclei. This increased activity in the final basal ganglia outflow pathway finalizes PD symptoms. Antagonism of the adenosine A2A receptor appears to modulate GABA and ACh release in a manner that could counteract the deleterious effects of reduced dopaminergic stimulation (27). Istradefylline Istradefylline [KW-6002; (E)-1,3-diethyl-8-(3,4-dimethoxystryl)-7-methyl-3,7-dihydro1H-purine-2,6-dione; Kyowa Pharmaceuticals] is a novel adenosine A2A antagonist. It has been shown that istradefylline can directly stimulate dopamine release in the rat nucleus accumbens (28) and beneficial motor effects have been consistently shown in 6-hydroxydopamine (6-OHDA) rodents and MPTP primates (29,30). A single dose typically improved locomotion for about 10 hours and motor hyperactivity (dyskinesia) did not develop with long-term administration. When used in combination with dopaminergic drugs in these models, istradefylline potentiated the duration of benefit and also allowed for dose reduction and improved dyskinesia, while maintaining improved locomotion. Hauser et al. (31) reported a 12-week, double-blind, randomized, placebocontrolled, exploratory study in which PD subjects with both motor fluctuations and peak-dose dyskinesia were randomized to treatment with placebo (n = 29), istradefylline up to 20 mg/day (n = 26), or istradefylline up to 40 mg/day (n = 28). As assessed by home diaries, subjects assigned to istradefylline experienced a mean reduction in the proportion of awake time spent in the off state of 7.1% compared with an increase of 2.2% in the placebo group (P = 0.008). Dyskinesia severity was unchanged, but on time with dyskinesia increased in the istradefylline group compared with the placebo group. No differences were observed in change in UPDRS scores or Clinical Global Impression. Adverse events were minimal and additional studies are ongoing. BIIB014/V2006 BIIB014/V2006 (Vernalis Pharmaceuticals) is another adenosine A2A receptor antagonist undergoing human trials. Absorption is rapid and the T1/2 averages 10 to 25 hours. No clear pattern of AE or laboratory abnormalities has emerged during Phase I trials. Other adenosine A2A receptor antagonists are in various stages of preclinical development (4). CEP-1347 CEP-1347 (Cephalon Inc.) is a 5,16-bis[(ethylthio)methyl] derivative of indolocarbazole, k252a, that is being tested for neurodegenerative diseases, including PD. The drug inhibits proteins in the mixed lineage kinase family (32,33). These proteins activate c-Jun N-terminal kinase, which is a key kinase in the stress-activated protein kinase pathway. Therefore, the drug is thought to inhibit programmed cell death. Two 28-day trials in PD did not show any symptomatic clinical effect or change on

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[123I] B–CIT SPECT and an interim analysis of a large multicenter trial indicated that the trial was unlikely to demonstrate evidence of a significant effect leading to Cephalon’s discontinuation of the study (34). E2007 E2007 (Eisai Pharmaceuticals) is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist that has completed Phase II trials in fluctuating PD. Results are yet to be published but one Phase IIb study revealed that both the 1 and 2 mg daily doses reduced off time without any worsening of dyskinesia. Adverse events were minimal and there are no known interactions (35). SIB-1508Y SIB-1508Y (SIBIA Neurosciences) is a selective alpha-4-beta-2 nicotinic acetylcholine receptor agonist. This drug is of interest in PD as nicotinic receptor stimulation augments dopamine release. A dose finding study in 77 early PD patients demonstrated no clear antiparkinsonian effect or cognitive benefit (36). Light headedness was a common dosage-related adverse event, leading to frequent dosage reductions. A maximally tolerated dosage of 10 mg daily was identified. Further plans for development of this agent are not known. Glial-Derived Neurotrophic Factor Glial-derived neurotrophic factor (GDNF; Amgen Inc.) is a recombinant neuropeptide, which may promote survival or regenerate dopaminergic neurons. Open-label reports of continuous infusion directly into the putamen reported improvement in UPDRS motor scores and on time (37). Lang et al. (38) reported a 34-patient randomized trial of bilateral continuous GDNF infusion, 15 µg/putamen/day or placebo. At six months, the mean percentage improvements in off UPDRS motor score were 10.0% with GDNF and 4.5% with placebo (P = 0.53). Secondary endpoint results were similar between the groups. A positron emission tomography (PET) scan analysis revealed a 32.5% treatment difference favoring GDNF in the mean 18F-dopa influx constant (P = 0.019). These results led to the discontinuation of further development of this drug by Amgen. However, GDNF continues to create enthusiasm in some researchers who posit that differences in the delivery systems may account for the discordant results. Alternative methods of delivery, including viral vector delivery and encapsulated cell delivery systems, are also under development for this and other nerve growth factors such as CERE-120 (Neurturin) (39,40). GPI-1485 GPI-1485 (Guilford Pharmaceuticals) binds to intracellular neuro-immunophilin receptor proteins. Neuro-immunophilin drugs, through unknown mechanisms, possess neurotrophic properties, which may restore cell viability (41). A large, controlled trial of GPI-1485 failed to show benefit superior to placebo. Ongoing open-label trials in PD were consequently discontinued. Creatine Creatine is converted to phosphocreatine by creatine kinase. Phosphocreatine can transfer a phosphoryl group to adenosine diphosphate to make adenosine triphos-

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phate (ATP). ATP is used as an energy source for multiple biochemical reactions. Creatine helps prevent MPTP-induced neuronal injury in rats (42). High oral doses, capable of increasing central nervous system creatine levels, are generally well tolerated. A recent futility trial demonstrated good tolerability in early PD (43) and it was concluded that further trials were justified. Minocycline Minocycline is a tetracycline antibiotic with good diffusion across the blood–brain barrier. Minocycline is also a caspase inhibitor. In vivo research has demonstrated beneficial effects on inflammation, microglial activation, matrix metalloproteinases, nitric oxide production, and apoptotic cell death. It has been shown to possess neuroprotective effects in 6-OHDA and MPTP animal models of PD, as well as other neurodegeneration models (44–46). A futility trial demonstrated that 77% of early PD patients tolerated minocycline for one year. It was concluded that further trials were justified; however, benefit and risk ratios must be taken into consideration (43). Coenzyme Q10 Coenzyme Q10 (CoQ) is an electron acceptor for complexes I and II in the mitochondrial electron transport chain. It is necessary for energy production and particularly abundant in metabolically active cells such as in the brain. Complex I involvement in PD was first demonstrated in MPTP toxicity. Subsequent research showed that complex I activity is reduced in all PD subjects, even very early in the disease (47,48). Shults et al. (49) found reduced CoQ levels in mitochondria of PD subjects, which correlated with complex I activity. Prophylactic oral supplementation of CoQ partially inhibited MPTP-induced loss of striatal dopamine and dopaminergic axons of mice (50). Shults et al. (51) conducted an 80-subject, multicenter, parallel design study comparing placebo, 300, 600, and 1200 mg of oral CoQ over 16 months. The total UPDRS scores improved with the 1200 mg dose compared with placebo. There was a trend (P = 0.09) between dosage and the mean UPDRS scores. These improvements were largely powered by part II (ADL section) of the UPDRS. There were no significant differences in the motor examination. The effect size was greatest at 16 months but changes in activities of daily living could be seen at one month. Adverse events were minimal. The assay of NADH to cytochrome-C reductase suggests increased endogenous complex I activity in subjects taking CoQ. A second small controlled trial also demonstrated a modest symptomatic benefit at four weeks (52). DRUGS FOR DYSKINESIA Sarizotan Sarizotan (Merck KgaA) is a novel compound belonging to the aminomethyl chromane chemical group, which was initially developed as an atypical antipsychotic, but is now being evaluated to treat dopaminergic-induced dyskinesia in PD. The drug has affinity for 5-HT1A, D2, D3, and D4 receptors. After oral ingestion, it is rapidly absorbed and highly protein bound, but readily crosses the blood–brain barrier. The terminal serum T1/2 is approximately seven hours, and the drug is extensively metabolized by N-dealkylation and hydroxylation (53). In animal models of PD, including MPTP primates, sarizotan improved druginduced dyskinesia without worsening motor function (54). In an open-label trial of

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64 dyskinetic PD subjects, sarizotan, at doses ranging from 2 mg BID to 10 mg BID, prolonged the amount of on time without dyskinesia (55). PD symptoms were not worsened, as assessed by amount of off time or UPDRS scores, although some patients did report worsening of parkinsonism as an adverse event. Additional adverse events reported included sedation and nausea. Higher doses have been associated with suppression of the cortisol response to ACTH challenge, but this was not seen in PD. A large multicenter Phase III trial did not demonstrate a difference between sarizotan and placebo and consequently the development of this compound for PD has been abandoned (56). Levetiracetam Levetiracetam (Keppra®, UCB Pharma) is an anti-epileptic medication that is used for several hyperkinetic movement disorders. The drug has no affinity for most major neurotransmitter receptors, but does seem to oppose the action of GABAA antagonists. Evidence has been provided that suggests that the receptor-binding site for this drug is the SV2A receptor (57). Levetiracetam has improved drug-induced dyskinesia in MPTP animal models of PD; however, human trials have generally shown that levetiracetam is not well tolerated in PD patients and has a minimal effect on dyskinesia (58,59). ACP-103 ACP-103 (Acadia Pharmaceuticals) is a once daily, potent 5-HT2A/C antagonist that is being developed as an antipsychotic for both schizophrenia and PD and as an antidyskinesia drug for PD. The initial controlled trial for PD psychosis showed efficacy and good tolerability. Dyskinesia trials are ongoing (60). Fipamezole Fipamezole (JP-1730, Juvantia Pharma) is an alpha-2 adrenergic antagonist, similar to yohimbine and idazoxan. Animal models of MPTP marmosets showed both increased on time and reduced dyskinesia when used with levodopa (61). Single dose intravenous controlled trials in PD patients have also demonstrated increased duration of a levodopa dose with concomitant reduction of dyskinesia (62). CONCLUSIONS The past 10 years have seen a marked acceleration in therapeutic research for PD. In addition to novel pharmacological agents, novel surgical approaches and drug delivery systems are under development to address the unmet needs of PD management. Continued research into disease pathogenesis and continued integration of governmental, academic, and pharmaceutical industrial resources will no doubt foster innovative treatment strategies and hopefully cure PD. REFERENCES 1. Liang E, Wang X, Khor S, Hsu A. Comparison of pharmacokinetics of levodopa and carbidopa between IPX054 and Sinemet and Sinemet CR tablets in healthy subjects under fasting conditions. Mov Disord 2006; 21(suppl 13):S125. 2. Nilsson D, Nyholm D, Aquilonius SM. Duodenal levodopa infusion in Parkinson’s disease—long-term experience. Acta Neurol Scand 2001; 104(6):343–348.

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26. Frackiewicz EJ, Jhee SS, Shiovitz TM, et al. Brasofensine treatment for Parkinson’s disease in combination with levodopa/carbidopa. Ann Pharmacother 2002; 36:225–230. 27. Jenner P. A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD. Neurology 2003; 61(suppl 6):S32–S38. 28. Harper LK, Beckett SR, Marsden CA, McCreary AC, Alexander SP. Effects of the A(2A) adenosine receptor antagonist KW6002 in the nucleus accumbens in vitro and in vivo. Pharmacol Biochem Behav 2006; 83:114–121. 29. Chase TN, Bibbiani F, Bara-Jimenez W, Dimitrova T, Oh-Lee JD. Translating A2A antagonist KW6002 from animal models to parkinsonian patients. Neurology 2003; 61:S107–S111. 30. Kase H, Aoyama S, Ichimura M, et al. Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson’s disease. Neurology 2003; 61:S97–S100. 31. Hauser RA, Hubble JP, Truong DD. Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology 2003; 61:297–303. 32. Harris CA, Deshmukh M, Tsui-Pierchala B, Maroney AC, Johnson EM Jr., Ylikoski J. Inhibition of the c-Jun N-terminal kinase signaling pathway by the mixed lineage kinase inhibitor CEP-1347 (KT7515) preserves metabolism and growth of trophic factordeprived neurons. J Neurosci 2002; 22:103–113. 33. Maroney AC, Glicksman MA, Basma AN, et al. Motoneuron apoptosis is blocked by CEP1347 (KT 7515), a novel inhibitor of the JNK signaling pathway. J Neurosci 1998; 18:104–111. 34. www.cephalon.com. 35. www.eisai.com. 36. Parkinson Study Group. Randomized placebo-controlled study of the nicotinic agonist SIB-1508Y in Parkinson disease. Neurology 2006; 66:408–410. 37. Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol 2005; 57:298–302. 38. Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006; 59: 459–466. 39. Ericson C, Georgievska B, Lundberg C. Ex vivo gene delivery of GDNF using primary astrocytes transduced with a lentiviral vector provides neuroprotection in a rat model of Parkinson’s disease. Eur J Neurosci 2005; 22:2755–2764. 40. Sajadi A, Bensadoun JC, Schneider BL, Lo Bianco C, Aebischer P. Transient striatal delivery of GDNF via encapsulated cells leads to sustained behavioral improvement in a bilateral model of Parkinson disease. Neurobiol Dis 2006; 22:119–129. 41. Poulter MO, Payne KB, Steiner JP. Neuroimmunophilins: a novel drug therapy for the reversal of neurodegenerative disease? Neuroscience 2004; 128:1–6. 42. Matthews RT, Ferrante RJ, Klivenyi P, et al. Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol 1999;157:142–149. 43. NINDS NET-PD Investigators. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 2006; 66:664–671. 44. Zemke D, Majid A. The potential of minocycline for neuroprotection in human neurologic disease. Clin Neuropharmacol 2004; 27:293–298. 45. Thomas M, Le WD. Minocycline: neuroprotective mechanisms in Parkinson’s disease. Curr Pharm Des 2004; 10:679–686. 46. Wu DC, Jackson-Lewis V, Vila M, et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 2002; 22:1763–1771. 47. Schapira AH, Mann VM, Cooper JM, et al. Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. Journal of Neurochemistry 1990; 55:2142–2145. 48. Krige D, Carroll MT, Cooper JM, Marsden CD, Schapira AH. Platelet mitochondrial function in Parkinson’s disease. The Royal Kings and Queens Parkinson Disease Research Group. Ann Neurol 1992; 32:782–788.

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49. Shults CW, Haas RH, Passov D, Beal MF. Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects. Ann Neurol 1997; 42:261–264. 50. Beal MF, Matthews RT, Tieleman A, Shults CW. Coenzyme Q10 attenuates the 1-methyl4-phenyl-1,2,3,tetrahydropyridine (MPTP) induced loss of striatal dopamine and dopaminergic axons in aged mice. Brain Res 1998; 783:109–114. 51. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002; 59:1541–1550. 52. Muller T, Buttner T, Gholipour AF, Kuhn W. Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson’s disease. Neurosci Lett 2003; 341:201–204. 53. Bartoszyk GD, Van Amsterdam C, Greiner HE, Rautenberg W, Russ H, Seyfried CA. Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile. J Neural Transm 2004; 111:113–126. 54. Bibbiani F, Oh JD, Chase TN. Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models. Neurology 2001; 57:1829–1834. 55. Olanow CW, Damier P, Goetz CG, et al. Multicenter, open-label, trial of sarizotan in Parkinson disease patients with levodopa-induced dyskinesias (the SPLENDID Study). Clin Neuropharmacol 2004;27:58–62. 56. www.merck.de. 57. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA 2004; 101:9861–9866. 58. Tousi B, Subramanian T. The effect of levetiracetam on levodopa induced dyskinesia in patients with Parkinson’s disease. Parkinsonism Relat Disord 2005; 11:333–334. 59. Lyons KE, Pahwa R. Efficacy and tolerability of levetiracetam in Parkinson disease patients with levodopa-induced dyskinesia. Clin Neuropharmacol 2006; 29:148–153. 60. www.acadia-pharm.com. 61. Savola JM, Hill M, Engstrom M, et al. Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson’s disease. Mov Disord 2003; 18:872–883. 62. www.juvantia.com.

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23

Lesion Surgeries Michael Samuel Department of Neurology, King’s College Hospital, Denmark Hill, London, U.K.

Keyoumars Ashkan Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, Queen Square, London, U.K.

Anthony E. Lang Department of Medicine, Division of Neurology, The Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

EARLY SURGICAL EXPERIMENTS Early attempts to treat tremor by open resection of motor and premotor cortex resulted in the substitution of disabling extrapyramidal symptoms with disabling hemiparesis (1,2). A major advance came about with the publications of Russell Meyers in 1942 and 1951, showing that surgical resection of the head of the caudate nucleus and pallidofugal fibers (3,4) could resolve tremor and rigidity without inducing paresis. This paved the way for the next 20 years of experimental basal ganglia lesion surgery as a treatment for extrapyramidal syndromes. Surgical precision was improved and comorbidity was reduced with the development of the stereotaxic technique (5). Subsequently, stereotaxic chemopallidectomy using procaine oil (6), alcohol (7), and pallidal electrocoagulation (8,9) were reported to effectively improve tremor and rigidity. At that time, results were not reported in an objective manner and lesion locations within the pallidum were not precisely documented. The target was the anterodorsal pallidum, a target now proposed to be part of the associative circuits involved in motor control (10). The benefit of a more ventral lesion had already been documented with lesions that included the ansa lenticularis (11). Benefit was also reported from more posterior lesions in five patients who had gained only temporary relief from tremor from anterodorsal pallidotomy, but gained sustained antitremor benefits when their lesions were extended by 4 to 6 mm posteriorly (12). Svennilson et al. (13) varied the position of their lesions in the first 32 cases from their cohort of 81 patients between 1953 and 1957 and showed sustained improvements in rigidity (79%) and tremor (82%) when the lesion was in the posteromedial aspect of the pallidum. They also reported additional benefit to general motor function, as assessed by their patients’ ability to return to work (25%) or become independent in activities of daily living (37%). Lesion locations were varied, not just within the pallidum but within the basal ganglia. Some early evidence suggested the superiority of thalamotomy in resolving tremor and rigidity (7,14). These reports were later extended to specify ventrolateral (VL) and ventral intermediate thalamotomy (15,16). In 1967, the introduction of levodopa (17) led to a worldwide reduction in the use of pallidotomy and thalamotomy to treat parkinsonism. Lesion surgery later re-emerged with a new role as a result of identification of new indications and new targets 391

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within the basal ganglia (18), although it has largely been replaced by deep brain stimulation (DBS) (19,20). PATIENT SELECTION Indications for Surgery The modern incentive to re-evaluate surgical therapy for Parkinson’s disease (PD) has been driven by the realization of the inadequacy of chronic dopaminergic replacement as a main strategy of treatment, namely that dopaminergic replacement treatment is associated with the development of disabling motor fluctuations and dyskinesia (21,22). With disease progression, in some patients, neither parkinsonism nor drug-related side effects can be managed optimally with medications and surgery may be warranted. The primary objective of the surgery is to alleviate dyskinesia and motor fluctuations (pallidotomy or subthalamotomy) and tremor (thalamotomy). Considering a Patient for a Surgical Procedure Prior to enrolling a patient into a surgical program, it is generally recommended that patients are assessed by a neurologist with experience in movement disorders since it is essential to document that the patient does indeed have PD which cannot be medically managed. There have been a few case reports of the use of lesion surgery in the management of Parkinson-plus syndromes and the success rates are generally disappointing (23,24). Additionally, it is necessary to show that a patient has a good response to dopaminergic drugs since the antiparkinsonian benefit from levodopa correlates with the antiparkinsonian response to surgery (with the exception of tremor which may be more improved with surgery). Patients should receive appropriate trials of available medication before considering surgery. A levodopa challenge test, as described in the core assessment program for intracerebral transplantations (CAPIT) (25) or core assessment program for surgical interventional therapies in PD (CAPSIT-PD) (26), is an indicator of a patient’s response to surgery (27). Speech, swallowing, and gait disturbances are common in advanced PD. Although these symptoms are less likely to improve following surgery and indeed may deteriorate postoperatively, especially following bilateral procedures (28–31), they should be recognized as relative, and not absolute, contra-indications. By the time of referral to a surgical program, most patients will have late stage disease, possibly with cognitive or active psychiatric symptoms. Patients with moderate or significant cognitive decline may have less benefit from surgery and may further decompensate postoperatively (24,32). It should be recognized by the patient, family, and carers that their benefit/risk ratio is lower than in a cognitively intact patient. Centers should obtain formal neuropsychometric testing prior to surgery and utilize these results in considering surgical candidacy. Psychiatric symptoms (hypomania, depression, suicide, or impulse control disorders) can be aggravated or induced by functional neurosurgery (33). Patients referred for surgical consideration are usually referred in the knowledge that they have an absence of dementia or active psychiatric symptoms, and yet a recent review revealed that the presence of depression (60%), anxiety (40%), and psychosis (35%) with 23% of the 40 patients assessed requiring preoperative psychiatric management (34). A magnetic resonance imaging (MRI) scan of the brain is essential to assess the normality of the target structures, degree of cortical atrophy, ventriculomegaly, and

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white matter changes. Patients are required to have a realistic expectation of the expected outcomes and limitations from functional neurosurgery. The assistance of a carer or a relative is desirable to aid with personal and emotional support and communication and the understanding of the risk benefit ratio. In 2006, in the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) recommended that functional neurosurgery is performed in the setting of an experienced multidisciplinary team; overall, it was felt that stimulation surgery is preferable to lesion surgeries, but specifically that subthalamotomy should only be performed in the setting of special arrangements for consent, audit, and research (35). Recent comparative evidence supports this notion in indicating that generally bilateral ablative procedures carry more risk than unilateral ablative lesions and that stimulation surgery carries less side-effect risk than ablation (36). Considering Lesion Surgery over Deep Brain Stimulation It is generally accepted that subthalamic nucleus (STN) DBS is effective, allows lower overall drug requirements, and may involve less permanent risk compared to lesion surgery since the target is not electrocoagulated. The consequences of inaccurate targeting are more reversible with DBS, but irreversible with lesion surgery. This has most importance when considering bilateral procedures since the risks of dysphasia, dysarthria, dysphagia, and cognitive deficits are increased in bilateral procedures (28–31). There are no clear blinded, evidence-based trial data to indicate which type of surgery to offer. However, if a patient requires a bilateral procedure, then bilateral DBS is usually preferred over bilateral lesion surgery. This is the case for most patients with advanced PD. If a patient has already had a unilateral surgical procedure and requires a second procedure in the other hemisphere, or a bilateral procedure in a different location, then DBS should be considered in preference to a lesion since any new side effects from the second procedure are more likely to be reversible. If a patient is considered for a unilateral procedure, then lesion surgery and DBS should be considered according to the local preference of the patient and surgical center. The likelihood of needing a second contralateral procedure in the future should also be weighed in this decision. Long-term results include 10 years of follow-up for pallidotomy (37) and 13 years for thalamotomy (16). There are some general advantages of lesions compared with DBS. First, when health resources of either an individual or a healthcare provider are limited, it is usual to adopt the more economical option. Lesion surgery avoids the cost of the hardware, the potential cost of replacing the implantable pulse generators due to battery failure or depletion over the remaining lifetime of the patient, as well as the manpower expenses for programming the stimulators. Secondly, for patients who live in areas that have no local expertise in maintenance of deep brain stimulators, the placement of a lesion may avoid frequent journeys to a neurosurgical center for stimulator programming. Thirdly, it is possible that with time we shall discover more unique but deleterious complications of stimulators interacting with other electrical systems, such as diathermy for dental treatment (38). Finally, DBS electrodes can fracture, become infected, cause skin erosion, or the battery lifetime may become impractically short. In these instances, a lesion may be the only alternative for patients for whom DBS is no longer suitable for technical reasons. Oh et al. (39) described two patients in whom therapy was changed from DBS to a lesion because one patient needed four battery replacements in five years, whereas the others developed skin erosions over the electrode leads.

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ASSESSMENTS AND PROCEDURES The three main basal ganglia targets are the pallidum, thalamus, and STN and each has been lesioned unilaterally and bilaterally. In considering the results from different reports, it should be emphasized that the methods of clinical assessment, site of lesion, method of target localization, and method of target confirmation have varied widely among centers. These factors may account for the differences in clinical outcomes across centers. The most comprehensive assessment would include: 1. Pre- and postoperative rating scales, such as the Unified Parkinson’s Disease Rating Scale (UPDRS), Hoehn and Yahr, timed motor tests (25,26), dyskinesia rating scale (40), and cognitive and psychiatric assessments. 2. Identification of the anatomical target by CT, MRI, or CT-MRI fusion. 3. Identification of the physiological target. Some centers use microelectrode recordings, whereas others rely on macro-stimulation to check for adverse effects, which most commonly manifest as contraction of the face, arm or foot, sensory changes, ocular deviations, phosphenes, or speech arrest. 4. Verification of lesion size and location postoperatively by volumetric stereotaxic MRI. 5. Long-term follow-up. Unilateral Pallidotomy To date, the results of only two short, randomized, single-blinded trials of pallidotomy have been published. The most recent study showed improvements of 75% in contralateral dyskinesia, 45% with respect to complications of therapy (UPDRS IV), 36% in ipsilateral dyskinesia, and 34% in parkinsonism at six months follow-up compared with medical therapy in which these aspects generally worsened (41). In the other study (42), 37 patients, who were matched for age and severity of PD, were randomized to receive either unilateral pallidotomy within one month (n = 19) or maximal medical therapy for six months (n = 18). Although the nonoperated group showed an 8% deterioration of median UPDRS motor scores and no change in dyskinesia, the operated group showed 31% and 50% improvements in parkinsonism and dyskinesia scores, respectively. This group more recently showed that, as expected, unilateral pallidotomy is less efficacious in improving parkinsonism than bilateral subthalamic stimulation, reducing the UPDRS by 9.5 points compared with 25 points for STN DBS (43). There have been only two nonblinded studies of patients treated by pallidotomy compared with a medically treated group (44), with each study supporting the findings of the randomized single-blinded studies. Numerous other open-labeled nonrandomized trials (27, 45–61) have generally drawn the same conclusion (Table 1) indicating that the most dramatic response is the reduction in contralateral dyskinesia by 80% to 95% which is sustained for up to 5.5 years (61). Overall, the off UPDRS score improves by 24% to 37% and declines thereafter to about 18%, although this continues to remain significantly improved at 5.5 years from baseline (49,61). Individual items of contralateral tremor, rigidity, and akinesia generally mirror this response, although the magnitude of the antitremor effect (up to 65%) appears greater and more sustained than that of rigidity (43%) or akinesia (falling from 46% at six months to 17% at 5.5 years). Despite these sustained differences in UPDRS subset scores, an initial improvement in activities of daily living of 37% is not sustained (61), but results from patient self-assessments imply that patients continue to benefit

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(49). In contrast to contralateral off scores, ipsilateral off scores, and both contralateral and ipsilateral on scores are not significantly sustained, although an initial improvement of up to 27% may occur. Ipsilateral on dyskinesia scores appear to be improved initially by 30%. This effect is also decreased with time and is not significant after 12 months postsurgery (49). The responses of axial symptoms and gait are variable. Complex analysis of posturography has shown that an improvement in gait and posture may be maintained for up to 12 months (62). It is possible that the gait improvement results from a decrease in dyskinesia when on. Three-dimensional motion capture analysis of walking suggests that the effect is mainly due to an improvement in speed of walking (63). More traditional UPDRS gait/postural instability subset scores, however, show only an initial modest improvement (26–37%), which is lost within subsequent years (49,61). It is possible that the effect of pallidotomy on gait may be mediated in part via descending influences on the brainstem, as well as ascending influences on thalamo-cortical circuits (62). Longer follow-up of complex gait analyses is required before reliable conclusions can be drawn. The frequency of severe complications is approximately 5%, with transient facial and limb paresis being the most common. Hemianopsia or quadrantanopsia are potential complications of lesioning the nearby optic tract. There is a welldocumented consistent feature of a mild but asymptomatic decrease in verbal fluency (30), mostly following left-sided unilateral pallidotomy (64), but permanent cognitive adverse effects did not seem to persist in one small study of 11 patients at four years of follow-up (65). Postoperative weight gain has been described (66). This “side effect” was found in 23% of patients in one study (67). It was highly correlated with the improvement in off motor UPDRS scores, but not with changes in energy intake or dyskinesia scores. Some series have reported a higher overall incidence of major complications. In the controlled trial of de Bie et al., nine of the 19 (47%) operated patients had surgical morbidity (two major, four minor persistent, and three minor transient). Lesion locations were not presented; however, this level of high morbidity has also been documented by other independent groups (27,60). It is likely that the variability of lesion locations and surgical techniques account for these differences. A systematic attempt to correlate outcome with lesion location has been made. Gross et al. (68,69) studied the variability in lesion location within the ventral pallidum in 33 patients with PD. Lesions were not distributed randomly within the internal pallidum but were distributed along a line running anteromedially-posterolaterally, parallel to the lateral border of the posterior limb of the internal capsule. In this cohort, anteromedial lesions were associated with a greater improvement in dyskinesia, whereas central lesions lead to a greater improvement in akinesia scores and gait disturbance (69). This result may partly explain the variable results in resolution of dyskinesia and akinesia among different neurosurgical centers and demonstrates the precision that is required to perform pallidotomy. Bilateral Pallidotomy Laitinen (57) and Iacono et al. (70) reported early good outcomes in 12 and 10 bilaterally operated patients, respectively. There are, however, concerns regarding permanent cognitive and bulbar side effects of bilateral pallidotomy, which have been confirmed in a study of four patients in whom bilateral pallidotomy was performed (71). Despite a 40% improvement in motor UPDRS scores and resolution of dyskinesia, one patient developed dysarthria, dysphagia, and eyelid opening apraxia,

Laitinen (57) Kondziolka et al. (47) Iacono et al. (46) Jankovic et al. (55) Lang et al. (58) Alterman et al. (50) Masterman et al. (59) Hirai et al. (54) de Bie et al. (52) Shannon et al. (60) Samuel et al. (27)

Author “Fair, good, poor” UPDRS “Minor, good or excellent” MT UPDRS +Goetz UPDRS + timed motor tests UPDRS “Fair, good or excellent” UPDRS + Goetz UPDRS UPDRS

CT/MRI + MES MRI + MES MRI + Ventriculography + MES MRI + MER + MES MRI + MER + MES MRI + MER + MES MRI + MER + MES MRI + MER + MES Ventriculography MRI + MER + MES CT + MER + MES

259b 58

55

40

34

32

28

26

26

26

41

Main clinical assessment

Surgical method

n

3 mo

6 mo

43 (B)

Not given

54

Not given

“Good”

24c

33

33c

26 A + T + R

83

Improved (B)

23 (B)

50%

43

24

Tremor ∆%

82% “good” 50

“Excellent”

24

Akinesia ∆%

7

0

Dramatic in 8 38

30

Not given

42 transient

Not given

“Excellent”

Not given 0

Gait ∆%

67

73

50

Improved (B)

“Effectively relieved” 61 (B)

83

Not given

“Excellent”

Not given 40

Dyskinesia ∆%

8

4

0

0

0

0

0

Not given

0

0 0

Overall mortality%

58

30

50

0

16

10

38

Not given

7

7 7

Overall morbidity%

396

5 mo

6 mo

3–6 mo

6 mo

3–24 mo

3 mo

1–24 mo

<48 hr 6–24 mo

Follow–up interval

TABLE 1 Summary of Selected Large Pallidotomy Series in Order of Study Sizea

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CT-MRI fusion + MER+ MES MRI + MER + MES CT/MRI + MER + MES CT/MRI + MER + MES CT + MES

20

20 15

38

Writing, drawing, walking in a circle

UPDRS

UPDRS +Goetz UPDRS

CT + MES

20

11

UPDRS v/VAS PLM UPDRS + GOETZ + PPT UPDRS

CT/MRI + MES

22

2–71 mo

12–48 mo

66 mo 12 mo

3–12 mo

24 mo

12 mo

Excellent in 26/32

≥40 in 35/36g

43

65% 100 in 7/8 cases Not given

62

22 + R

18% ≥50g

90

0

0

0

≥23g

Not given

43% Not given

0

0

0

71% 100 in 9/10 cases “Did not return” “Greatly improved”

71

83

33

0

Not given

Not given 0

0

5e

0

22

Not given

Not given 20

45

5f

19d

Note: For comparison, the original series of Laitinen is at the bottom. a Some studies with different patient numbers from the same institutions have overlapping samples. b Some patients had Parkinson-plus syndromes and others had combined pallidotomy and thalamotomy. c Marginally significant result. d One patient developed anarthria and two patients required re-operation as they had no benefit from the first pallidotomy. e One death two weeks postoperatively secondary to ipsilateral intracerebral hemorrhage. f One patient required re-operation as had no benefit from the first. g Figure calculated from a graph in manuscript Abbreviations: n, number of patients; MES, macroelectrode stimulation at target site; MER, microelectrode recording at target site; MT, finger movement time between two adjacent targets; Goetz, the Goetz dyskinesia rating scale; ∆%, % change; A+T+R, combined score for akinesia, tremor, and rigidity reported; +R, combined score with rigidity reported; v/VAS, video and visual assessment scale; PLM, electronic recording of posturolocomotion manual test; PPT, Purdue pegboard test; (B), assumed bilateral as no distinction made between contralateral and ipsilateral scores.

Johansson et al. (56) Samii et al. (48) Dalvi et al. (51) Fine et al. (61) Baron et al. (49) Fazzini et al. (53) Laitinen et al. (45)

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another developed abulia, and a third developed mental automatisms. Scott et al. (30) described hypophonia, increased salivation, and reduced verbal fluency, following bilateral simultaneous pallidotomy. An open-labeled trial of bilateral simultaneous pallidotomy compared with unilateral pallidotomy plus DBS had to be halted early, as all three patients with bilateral lesions developed deterioration in speech, swallowing, salivation, depression, apathy, freezing, and falling (72). In another series, staged bilateral pallidotomy was associated with a deficit in speech in four patients: one patient had a decline in memory and there were three cases of cerebral infarction (73). These results are similar to the study of De Bie et al. (74) who showed that seven out of 13 patients developed dysarthria and one suffered a severe delayed infarction. Further, a reduced response to levodopa has been documented in a small number of patients undergoing bilateral staged pallidotomy (73). These results are in contrast to the milder side effects reported in one series of 14 patients who underwent staged bilateral pallidotomy, in whom no overall effect on speech or cognitive function was detected six months postoperatively, but five had mild hypophonia, two had transient confusion, two had deterioration of gait, and one had deterioration of a pre-existing dysarthria postoperatively (75). A larger series of 53 bilaterally operated patients, combined from U.K. and Australian centers, has also been presented with full follow-up of a subgroup of 17 patients for 12 months (76). Major deterioration in speech (defined as a two-point decline on the UPDRS subset score) occurred in 8% of bilaterally operated patients compared with 4% of unilaterally operated patients, although the study was not specifically designed to compare the two procedures. Similarly, postoperative major deterioration in salivation occurred in 13% and 10% of bilaterally and unilaterally operated patients, respectively. Gait freezing while on and handwriting each deteriorated with a frequency of 11% in the bilaterally operated group, and medically unresponsive eyelid opening apraxia occurred in 6%. Dysphagia was not reported. The authors suggest that these relatively low rates of complications may be attributable to the placement of a smaller lesion (100 mm3) in the medial pallidum contributing to the lesser affected hemibody compared with the medial pallidum corresponding to the worse-affected hemibody (150 mm3). Complications were only defined according to their occurrence on the UPDRS rather than by using specific questions designed to assess their presence and severity. Additionally, precise lesion locations and cognitive results were omitted. The question of safety and timing of bilateral pallidotomy, therefore, currently remains controversial and this procedure has not been undertaken by many groups. It is likely to continue to fall out of favor, especially where bilateral DBS is available as an alternative. Unilateral Thalamotomy Thalamotomy has been performed since the 1950s when some surgeons noted excellent relief of tremor compared with pallidotomy (anterodorsal). Hassler et al. (77) reported the successful treatment of a patient by making a lesion in the ventral tier of lateral thalamus, and Cooper also advocated that this was the optimal target (14). The VL region of the thalamus contains at least three important motor nuclei. According to Hassler’s classification and running from anterior to posterior, these are the ventral oralis anterior (Voa), ventral oralis posterior (Vop), and ventral intermediate (Vim). In a more recent nomenclature, the Voa and Vop nuclei are grouped together as the nucleus VL anterior (VLa), and the Vim is referred to as the nucleus VL posterior (VLp). Hassler subsequently refined the target to the Vop for tremor

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and Voa for rigidity (78). It is now generally agreed that the optimal target for tremor control is the Vim nucleus, which receives its input primarily from the cerebellum. Although most surgeons now target Vim, other subthalamic sites, such as the zona incerta and fields of Forel targeted in the past, are again being examined (79). The method of targeting is similar in principle to that of pallidotomy, relying on initial anatomical targeting possibly followed by electrophysiological refinement. Because of current limitations of the imaging techniques in directly visualizing the subnuclei of the thalamus, indirect targeting is generally applied. This is dependent on standard brain atlases to derive the coordinates of the target, which are then translated into the patient’s anatomy in relation to the patient’s ventricular landmarks obtained by ventriculography, CT, or MRI. Intraoperative electrophysiological evaluation, microelectrode or field potential recording, may be used to take account of interindividual variability in the position of the target. These can correctly identify “tremor cells” and help to avoid the neighboring structures, such as the internal capsule (80–82). Lesion sizes tend to be smaller (about 60 mm3) (83) compared with pallidotomy (about 220 mm3) (24). There have been few long-term follow-up reports of thalamotomy in PD. Kelly (84) reported the 10-year follow-up of 60 parkinsonian patients who had thalamotomy between 1965 and 1967 and showed the sustained improvement in tremor and rigidity, but the continued progression of bradykinesia. Later, 12 patients were reported who also had a marked improvement or cessation in contralateral tremor without complications (15). A larger series of 103 patients operated between 1964 and 1969, also followed-up for 10 years, showed that overall 87 patients had a “good” effect and in only seven patients were tremor or rigidity not alleviated completely (29). In a more recent series from 1984 to 1989, all 36 patients underwent CT and microelectrodeguided VL thalamotomy and 86% showed complete cessation of tremor, with a further 5% showing a significant improvement up to 68 months of follow-up (85). The antitremor effect was shown to be maintained in one blinded retrospective study, following thalamotomy alone, subthalamotomy alone, or combined thalamotomy and subthalamotomy (86). In another study, the records of 42 patients with PD who underwent thalamotomy were reviewed and 86% were found to have cessation of or moderate to marked improvement in their contralateral tremor, with a concomitant improvement in function which persisted for as long as 13 years. The mean daily dose of levodopa was reduced by 156 mg and lesion location was in the Vim (87). Postoperatively, rigidity improved by 30%, ipsilateral tremor worsened, and there was no significant change in other features of parkinsonism. The complication rates of unilateral thalamotomy range from 10% transient confusion and 8% facial weakness or numbness (29) to 58% transient and 23% persistent complications of contralateral weakness, balance deficits, and blepharospasm (16). In the series of Fox et al., 22 of the 36 patients (61%) experienced complications. Half of these cleared by seven days and only 6% were permanent or bothersome, including dysarthria, dyspraxia, or cognitive dysfunction (85). Deficits of speech, language, and verbal memory such as dysarthria, hypophonia, dysfluency, and aphasia have been described following unilateral thalamotomy and are more common after left- than right-sided procedures (88,89). Schuurman et al. (90) compared the short-term safety and efficacy of Vim thalamotomy with Vim stimulation (90). Marked improvement or tremor resolution was detected in 79% of the lesioned group compared with 90% in the stimulated group. These results were not statistically different, but only 23% of the lesioned group had an improved functional status compared with 53% of the stimulated

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group. Additionally, the complication rate for the stimulated group was 17% compared with 47% in the lesioned group, but there was one death in the stimulated group. These positive and negative effects of thalamotomy and thalamic DBS are very similar to a retrospective report comparing the two treatments (91), in which it was additionally shown that tremor recurrence occurred in 15% of patients with thalamotomy, but only in 5% of patients with DBS. Furthermore, 15% of patients with thalamotomy required reoperation to achieve good clinical outcome. These studies show the expected improved morbidity of DBS compared with irreversible lesioning. However, long-term follow-up (up to 66 months) has highlighted the potential hardware complications of DBS, which include lead fracture, erosion or migration, infection, CSF leak, and short or open circuits or other system malfunctions (92). In one study, hardware-related complications typically appeared late, 12 months or more after the surgery (93). It is estimated that a significant number of patients with DBS may require subsequent surgery to maintain the hardware (92–94). Further longterm clinical and economic comparative studies are necessary to define whether the benefits of DBS outweigh its higher maintenance and costs. One factor that continues to confound our understanding of thalamotomy is the variability of lesion locations across series. This is more problematic than with pallidotomy since the boundaries of the thalamic nuclei are not anatomically as well demarcated as in the pallidal complex and also the nomenclature of the thalamic nuclei varies across series and also from human to primate. Atkinson et al. reported on accurate localization of 31 lesions performed in patients with tremor-dominant PD. The optimal improvement of tremor occurred with Vim lesions, which also included its posterior boundary with the sensory nucleus ventralis posterior, suggesting the involvement of the proprioceptive thalamus in parkinsonian tremor (95). These studies support a role for Vim thalamotomy in patients whose predominant symptom is medically intractable asymmetrical tremor and who are not suitable for DBS, for example, because of inability to cope with the stimulator or the potentially demanding follow-up schedule (96). The majority of patients with PD are, however, likely to have progressive bradykinesia, even if this is not present at the time of surgery. This symptom is not modified by Vim thalamotomy, and so thalamotomy (and Vim DBS) in the treatment of PD has largely been replaced by alternative therapies. Bilateral Thalamotomy The clinical efficacy of bilateral thalamotomy in terms of resolution of bilateral tremor is as effective as unilateral thalamotomy for unilateral tremor (87). However, a high incidence of speech disturbance has been noted in several series [e.g., 18% (29), 44% (28), and 60% (97)]. The high rate of speech and cognitive deficits following bilateral thalamic lesions has led to an alternative to bilateral thalamotomy, if bilateral surgical treatment is required. Unilateral Subthalamic Nucleotomy The occurrence of cognitive deficits that have been reported with thalamotomy and pallidotomy, and the failure of thalamotomy to improve features other than tremor, has driven an interest in trying to find alternative targets to lesion, especially for patients who require bilateral procedures and are not suitable for DBS. The realization that the neurons of the STN in parkinsonian monkeys are overactive led to an interest in this nucleus as a possible target for PD (98). Surgeons had

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previously avoided the STN given the long-standing awareness that lesions of the normal STN in normal primates can cause hemiballism (99), and this is a well known consequence of infarcts and hemorrhages in this region in humans. In contrast, it has been shown that excitotoxic (100) or thermocoagulation (101) lesions of the pathological STN in MPTP-treated primates can alleviate parkinsonism. However, these thermocoagulation lesions also involved the internal capsule, ansa lenticularis, and globus pallidus (101,102), and so the clinical benefit in these cases may not have been solely due to deactivation of the STN. Early studies of deactivation of the subthalamic area by lesioning cannot be used to provide good quality evidence by today’s standards because the lesions in this region of the brain were not anatomically well defined (103). When the STN became a logical target in the surgical treatment of PD, concern over the possibility of introducing chorea/ballism led neurosurgeons to apply stimulation rather than electrocoagulation to this site since the former can be successful and yet is more reversible (104). However, the relatively high technological demands and costs of DBS have encouraged some groups to attempt subthalamic nucleotomy. There have been a few open-labeled, nonrandomized reports of the use of unilateral subthalamic nucleotomy in PD. The target in one study was the sensorimotor region of the dorsal STN, defined by semi-microrecordings and stimulation (18). These authors showed a sustained reduction in off motor UPDRS scores by 50% in 10/11 patients and this effect was maintained in 4/11 patients for two years. UPDRS on scores and ADL scores also improved. Ipsilateral bradykinesia improved by 20%, but this effect was not sustained at 12 months. Axial scores for gait and postural instability showed marked and sustained improvements. Dyskinesia was seen in the contralateral limbs of five patients during lesioning and lasted up to 12 hours before abating spontaneously. One patient developed transient delayed chorea. Another patient developed a postoperative infarction affecting the area of the lesioned STN, zona incerta, and ventral thalamus. This resulted in severe contralateral dyskinesia that persisted despite cessation of all levodopa and eventually required treatment with a pallidotomy on the same side as the subthalamotomy. Apart from this patient, the dose of medication was maintained for 12 months, unlike cases of bilateral STN DBS in which medication doses can be reduced significantly. In the second series, the target was the central area of the subthalamus in nine patients and lesioning was guided by macrostimulation (17). Efficacy results were not reported but only one patient developed chorea postoperatively, which initially required medical treatment but then subsided spontaneously to only mild movements. Four subjects had their medication doses reduced. In the series of Gill and Heywood (105), five patients had unilateral and five had bilateral small subthalamotomies with improved parkinsonism and only one case had mild dyskinesia. This group’s larger report on 17 tremor-predominant, unilaterally operated patients followed for two years suggested improvement in all the features of parkinsonism, but greatest for tremor, with a 50% reduction in dopaminergic medication (106). Similar results were reported by Su et al. (107). The target lesion in one series included the dorsolateral STN and pallidufugal fibers (Forel’s field H2). Postoperative chorea was mild and transient, except in one patient in whom the lesion was confined to the STN only. The chorea in this instance was controlled by the subsequent insertion of a deep brain stimulator in the field H2 fibers and zona incerta. A similar phenomenon was described by comparison of two cases by Chen et al. (108); that is, a subthalamotomy that included the dorsal extranuclear fibers of the zona incerta led to less dyskinesia than a lesion confined to the STN only. Tseng et al. (109) described another patient with a lesion large

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enough to have included all of the STN, zona incerta, and lenticular fasciculus that caused delayed onset but permanent hemiballism that eventually led to death. The optimal target for lesions in the subthalamic area therefore needs further careful confirmation. It could be hypothesized, for example, that discrete small lesions confined to the nucleus (i.e., subthalamic nucleotomy) may be more likely to lead to chorea, whereas modest lesions which include the dorsolateral STN but also extend dorsally (i.e., subthalamic nucleotomy with additional interruption of the ansa lenticularis, zona incerta, and lenticular fasciculus) may be less likely to induce chorea since any potential to induce chorea may be counteracted by the concurrent interruption of these efferent fibers from the internal pallidum. A somewhat unique side effect of unilateral subthalamotomy is leaning away from the side of the lesion. This can be responsive to dopaminergic medication, but in one report (110), the postural asymmetry resolved following a further subthalamotomy on the other side. This observation is reminiscent of the asymmetric benefit that becomes apparent in bilaterally affected patients with akinetic-rigid symptoms following unilateral pallidotomy, and indicates that for these patients a bilateral procedure—typically bilateral STN DBS—should usually be offered. Currently, therefore, the exact location and role of unilateral lesions of the subthalamic region in clinical practice remains unclear. Bilateral Subthalamotomy The effects of bilateral subthalamic nucleotomy were reported earlier than unilateral subthalamotomy. One early report of two patients claimed that small lesions in the dorsolateral STN could reduce the off motor UPDRS scores by over 68%, without inducing dyskinesia (111). Both patients were reported to have no complications and to have medication withdrawn. This group later reported that bilateral subthalamotomy had been accomplished safely in five subjects (105). Detailed imaging was not presented. A larger series of seven staged bilateral and 11 simultaneous procedures was reported to show a 50% reduction in off parkinsonism, 36% reduction in onperiod parkinsonian features, 50% reduction in dyskinesia, and 47% reduction in levodopa-equivalent medication at three years of follow-up. Three patients had severe long-term dysarthria, whereas 11/18 had intraoperative or transient postoperative mild chorea. In three cases, the chorea lasted for three to six months before resolving fully (112). Merello et al. (113) described two patients who, preoperatively, had amantadine-responsive levodopa-induced dyskinesia and who received bilateral subthalamotomy. Immediate postoperative unilateral chorea ensued, which persisted despite cessation of levodopa. The addition of amantadine in the first month had no effect on the dyskinesia. The dyskinesia resolved spontaneously within six months. This observation suggests that the pathophysiology of levodopainduced dyskinesia and subthalamotomy-induced dyskinesia differs. CONCLUSION In conclusion, the single most consistent result of unilateral pallidotomy is the resolution of contralateral dyskinesia and so this therapy is best reserved for those few patients who exhibit asymmetrical disabling dyskinesia and whose level of parkinsonism is unacceptable when the medication is reduced. In general, the thalamic target has been largely abandoned in the surgical management of PD. Unilateral thalamotomy could be considered for those few patients

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who exhibit asymmetrical long-standing tremor that is unresponsive to maximum tolerated doses of medication and who have few or nonprogressive signs of parkinsonism, or for patients who have required repeated battery changes following unilateral stimulation of the Vim nucleus. It should be noted that these groups comprise only a small minority of patients with advanced PD in whom the signs are typically bilateral and progressive. In this situation, currently the optimal therapy is bilateral DBS of the STN or internal pallidum, although the STN is generally favored. Bilateral pallidotomy and thalamotomy are rarely performed due to concerns about postoperative speech and cognitive decline. The role of unilateral and bilateral lesions of the subthalamic region remains to be established. Few data are available on long-term follow-up and lesion site, size, the inclusion of external pallidum, ansa lenticularis, Voa/Vop, STN, peri-STN structures, the need for microelectrode recordings, and the safety and efficacy of bilateral lesions all remain important and controversial issues in the field of lesion surgeries. REFERENCES 1. Bucy JC, Case TJ. Tremor: physiological mechanisms and abolition by surgical means. Arch Neurol Psychiatry 1939; 41:721. 2. Bucy JC, Case TJ. Cortical extirpation in the treatment of involuntary movements. Arch Neurol Psychiatry 1942; 21:551. 3. Meyers R. The modification of alternating tremors, rigidity and festination by surgery of the basal ganglia. Res Publ Nerv Ment Dis Proc 1942; 20:602–665. 4. Meyers R. Surgical experiments in the therapy of certain “extrapyramidal” diseases: a current evaluation. Acta Psychiatr Neurol Suppl 1951; 67:3–42. 5. Spiegel EA, Wycis HT, Marks M, Lee AST. Stereotaxic apparatus for operations on the human brain. Science 1947; 106:349–350. 6. Narabayashi H, Okuma T. Procaine-oil blocking of the globus pallidus for the treatment of rigidity and tremor of parkinsonism. Proc Japan Acad 1953; 29:134–137. 7. Cooper IS, Bravo G. Chemopallidectomy and chemothalamectomy. J Neurosurg 1958; 15:244–250. 8. Guiot G, Brion S. Traitement des mouvements anormaux par la coagulation pallidale. Technique et résultats. Rev Neurol 1953; 89:578–580. 9. Guiot G. Le traitement des syndromes parkinsoniens par la destruction du pallidum interne. Neurochirurgia 1958; 1:94–98. 10. Alexander GE, Crutcher MD, DeLong MR. Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res 1990; 85:119–146. 11. Spiegel EA, Wycis HT. Ansotomy in paralysis agitans. Arch Neurol 1954; 71:598–614. 12. Spiegel E, Wycis H, Baird H. Long-range effects of electropallidoansotomy in extrapyramidal and convulsive disorders. Neurology 1958; 8:734–740. 13. Svennilson E, Torvik A, Lowe R, Leksell L. Treatment of parkinsonism by stereotactic thermolesions in the pallidal region. Acta Psychiatr Neurol Scand 1960; 35:358–377. 14. Cooper IS, Bravo G. Implications of a 5-year study of 700 basal ganglia operations. Neurology 1958; 8:701–707. 15. Kelly PJ, Ahlskog JE, Goerss SJ, Daube JR, Duffy JR, Kall BA. Computer-assisted stereotactic ventralis lateralis thalamotomy with microelectrode recording control in patients with Parkinson’s disease. Mayo Clin Proc 1987; 62:655–664. 16. Jankovic J, Cardoso F, Grossman RG, Hamilton WJ. Outcome after stereotactic thalamotomy for parkinsonian, essential, and other types of tremor. Neurosurgery 1995; 37:680–686. 17. Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinsonism. N Engl J Med 1967; 276:374–379. 18. Alvarez L, Macias R, Guridi J, et al. Dorsal subthalamotomy for Parkinson’s disease. Mov Disord 2001; 16:72–78.

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87. Jankovic J, Hamilton WJ, Grossman RG. Thalamic surgery for movement disorders. Adv Neurol 1997; 74:221–233. 88. Ojemann GA, Hoyenga KB, Ward AA. Prediction of short-term verbal memory disturbance after ventrolateral thalamotomy. J Neurosurg 1971; 35:203–210. 89. Bruce BB, Foote KD, Rosenbek J, et al. Aphasia and thalamotomy: important issues. Stereotact Funct Neurosurg 2004; 82:186–190. 90. Schuurman PR, Bosch DA, Bossuyt PM, et al. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 2000; 342:461–468. 91. Tasker RR. Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg Neurol 1998; 49:145–153. 92. Lyons KE, Koller WC, Wilkinson SB, Pahwa R. Long term safety and efficacy of unilateral deep brain stimulation of the thalamus for parkinsonian tremor. J Neurol Neurosurg Psychiatry 2001; 71:682–684. 93. Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM. Long-term hardware-related complications of deep brain stimulation. Neurosurgery 2002; 50:1268–1274. 94. Pahwa R, Lyons KE, Wilkinson SB, et al. Comparison of thalamotomy to deep brain stimulation of the thalamus in essential tremor. Mov Disord 2001; 16:140–143. 95. Atkinson JD, Collins DL, Bertrand G, Peters TM, Pike GB, Sadikot AF. Optimal location of thalamotomy lesions for tremor associated with Parkinson disease: a probabilistic analysis based on postoperative magnetic resonance imaging and an integrated digital atlas. J Neurosurg 2002; 96:854–866. 96. Speelman JD, Schuurman R, de Bie RM, Esselink RA, Bosch A. Stereotactic neurosurgery for tremor. Mov Disord 2002; 17(suppl 3):S84–S88. 97. Rossitch E, Zeidman SM, Nashold BS, et al. Evaluation of memory and language function pre- and postthalamotomy with an attempt to define those patients at risk for postoperative dysfunction. Surg Neurol 1988; 29:11–16. 98. Wichmann T, Bergman H, DeLong MR. The primate subthalamic nucleus. I. Functional properties in intact animals. J Neurophysiol 1994; 72:494–506. 99. Carpenter M, Whittier J, Mettler F. Analysis of choreic hyperkinesia in the rhesus monkey. Surgical and pharmacological analysis of hyperkinesia resulting form lesions in the subthalamic nucleus of Luys. J Comp Neurol 1950; 92:293–331. 100. Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990; 249:1436–1438. 101. Aziz TZ, Peggs D, Sambrook MA, Crossman AR. Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord 1991; 6:288–292. 102. Aziz TZ, Peggs D, Agarwal E, Sambrook MA, Crossman AR. Subthalamic nucleotomy alleviates parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)exposed primate. Br J Neurosurg 1992; 6:575–582. 103. Fager CA. Evaluation of thalamic and subthalamic surgical lesions in the alleviation of Parkinson’s disease. J Neurosurg 1968; 28:145–149. 104. Limousin P, Pollak P, Benazzouz A, et al. Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Mov Disord 1995; 10:672–674. 105. Gill S, Heywood P. Bilateral subthalamic nucleotomy can be accomplished safely. Mov Disord 1998; 13(suppl 2):201. 106. Patel NK, Heywood P, O’Sullivan K, McCarter R, Love S, Gill SS. Unilateral subthalamotomy in the treatment of Parkinson’s disease. Brain 2003; 126:1136–1145. 107. Su PC, Tseng HM, Liu HM, Yen RF, Liou HH. Treatment of advanced Parkinson’s disease by subthalamotomy: one-year results. Mov Disord 2003; 18:531–538. 108. Chen CC, Lee ST, Wu T, Chen CJ, Huang CC, Lu CS. Hemiballism after subthalamotomy in patients with Parkinson’s disease: report of 2 cases. Mov Disord 2002; 17:1367–1371. 109. Tseng HM, Su PC, Liu HM. Persistent hemiballism after subthalamotomy: the size of the lesion matters more than the location. Mov Disord 2003; 18:1209–1211. 110. Su PC, Tseng HM, Liou HH. Postural asymmetries following unilateral subthalomotomy for advanced Parkinson’s disease. Mov Disord 2002; 17:191–194. 111. Gill SS, Heywood P. Bilateral dorsolateral subthalamotomy for advanced Parkinson’s disease. Lancet 1997; 350:1224.

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112. Alvarez L, Macias R, Lopez G, et al. Bilateral subthalamotomy in Parkinson’s disease: initial and long-term response. Brain 2005; 128:570–583. 113. Merello M, Perez-Lloret S, Antico J, Obeso JA. Dyskinesias induced by subthalamotomy in Parkinson’s disease are unresponsive to amantadine. J Neurol Neurosurg Psychiatry 2006; 77:172–174.

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Deep Brain Stimulation Kelly E. Lyons and Rajesh Pahwa Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.

Stereotactic surgeries for movement disorders were introduced in the late 1940s (1–3) but were not widely accepted due to significant morbidity, mortality, and limited knowledge of the appropriate target for symptomatic benefit. With advances in pharmacological therapy, particularly the availability of levodopa, these surgeries were rarely performed for Parkinson’s disease (PD) until the late 1980s (4). Based on the limitations of drug treatments for PD, and a better understanding of the physiology and circuitry of the basal ganglia there has been a marked increase in the use of surgical treatments for PD. In addition, advances in surgical techniques, neuroimaging, and improved electrophysiological recordings allow stereotactic procedures to be done more accurately leading to reduced morbidity. Deep brain stimulation (DBS) has largely replaced lesion surgery as the preferred procedure for PD. There are currently three targets for DBS in PD: the ventral intermediate (VIM) nucleus of the thalamus, the globus pallidus interna (GPi), and the subthalamic nucleus (STN). HISTORY Benabid et al. (4) were the pioneers of DBS surgery. In the late 1980s, during thalamic lesioning, they observed that low-frequency stimulation increased tremor, whereas frequencies above 100 Hz reduced tremor. They confirmed these observations by implanting an electrode in the contralateral motor thalamus of a patient who had undergone thalamotomy and needed surgery on the second side. This was done to avoid the higher rate of complications known to occur with bilateral lesion surgeries. The results were satisfactory and thalamic stimulation increasingly replaced thalamotomy even in patients undergoing unilateral procedures (5). Similarly, DBS of the GPi (6) and STN (7) largely replaced pallidotomy and DBS of the STN has become the most commonly performed surgical treatment for PD. DEEP BRAIN STIMULATION HARDWARE The Activa® Tremor Control and the Activa® Parkinson Control therapies (Medtronic, Minneapolis, Minnesota, U.S.A.) are approved for the treatment of PD. The Activa therapies consist of a DBS lead, an implantable pulse generator (IPG) that is the power source for the system, and an extension wire that connects the DBS lead to the IPG. There are two DBS leads available. The intracranial end of both leads has four platinum-iridium contacts. One lead has contacts that are separated by 1.5 mm (Model 3387, Medtronic, Minneapolis, Minnesota, U.S.A.) and the second lead has contacts that are separated by 0.5 mm (Model 3389, Medtronic, Minneapolis, Minnesota, U.S.A.). The DBS leads are connected to the IPG by an extension wire that is tunneled under the skin down the neck to the IPG, which is generally placed in the 409

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infraclavicular area. The DBS leads are implanted stereotactically while the patient is awake and the extension wire and IPG are implanted under general anesthesia. There are two IPGs currently available; the Soletra® (Medtronic, Inc., Minneapolis, Minnesota, U.S.A.) and the Kinetra® (Medtronic, Inc., Minneapolis, Minnesota, U.S.A.). The Kinetra® has the advantage of using one stimulator to control the leads for both sides of the body, instead of two separate Soletra® neurostimulators, one for each side. The neurostimulators can be programmed for monopolar stimulation or bipolar stimulation. Adjustable parameters include pulse width, amplitude, stimulation frequency, and the choice of active contacts. The patient can turn the stimulator on or off using a hand held magnet or using an Access Review Therapy Controller®, which also has a feature to tell the patient if the neurostimulator is on or off. The typical stimulation parameters are frequency of 135 to 185 Hz, pulse width of 60 to 120 µs, and amplitude of 1 to 3 V. ADVANTAGES AND DISADVANTAGES OF DEEP BRAIN STIMULATION The advantages of DBS compared to lesion surgeries include no destructive lesion in the brain, the ability to adjust stimulation parameters to increase efficacy or reduce adverse effects, the performance of bilateral procedures with increased safety and reduced adverse effects, and the reversibility of the system to accommodate the potential use of future therapies. The disadvantages include cost of the system, time and effort involved in programming the system, repeat surgeries related to device complications, the use of general anesthesia for IPG and extension wire implantation, and battery replacement every three to five years. DEEP BRAIN STIMULATION OF THE THALAMUS DBS of the thalamus has largely replaced thalamotomy as the preferred surgery for the treatment of medication resistant tremor. There are multiple reports demonstrating a significant reduction in tremor in 63% to 95% of patients receiving thalamic DBS for parkinsonian tremor (8–11); however, currently, it is rarely used for PD as the majority of the studies have reported that even though tremor is markedly improved, other symptoms continue to progress and cause significant disability (12,13). Therefore, this procedure is restricted to PD patients whose primary disability is tremor. Several studies have demonstrated long-term benefit in PD tremor with thalamic DBS. Pollak et al. (14) reported 80 PD patients who had DBS of the thalamus for drug-resistant tremor. After up to seven years of follow-up (mean three years), global evaluations showed the best control for parkinsonian rest tremor and the least satisfactory control for action tremor. There was no dramatic effect on other symptoms like bradykinesia, rigidity, or dyskinesia. Lyons et al. (12) reported the results of 12 PD patients with a mean follow-up of 40 months and a maximum follow-up of 66 months. Although tremor scores continued to be improved by 87% there was a worsening of Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores suggesting the worsening of other parkinsonian symptoms. Finally, Pahwa et al. (13) reported a multicenter trial of 19 PD patients who received thalamic DBS (11 unilateral and 8 bilateral) and were followed up to five years after surgery. There was a mean improvement in tremor of 85% in the targeted limb for the unilaterally operated patients and for bilaterally operated patients there was a 100% improvement in tremor on the left side and 90% on the right side. There were no improvements in symptoms other than tremor and it was concluded that thalamic DBS has limited use in the surgical treatment of PD.

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DEEP BRAIN STIMULATION OF THE GLOBUS PALLIDUS INTERNA Surgery targeting the internal segment of the globus pallidus has been shown to improve all of the cardinal features of PD including bradykinesia, rigidity, and tremor as well as levodopa-induced dyskinesia. Due to concerns of complications related to speech, balance, and cognition with bilateral pallidal lesions, bilateral DBS of the GPi is preferred to pallidotomy. Multiple studies have reported the efficacy of GPi stimulation for PD (15–20) (Table 1). Many of these studies have a small number of patients and/or a relatively short follow-up period. Kumar et al. (19) reported 22 PD patients who were treated with either unilateral (n = 5) or bilateral (n = 17) GPi stimulation. Evaluations performed in the medication off/stimulation on state at six months reported a 32% improvement in UPDRS motor scores and a 40% improvement in UPDRS activities of daily living (ADL) scores compared to baseline medication off scores. There was also a 68% reduction in dyskinesia. The Deep Brain Stimulation for Parkinson’s Disease Study Group (16) reported a multinational, prospective study of bilateral GPi stimulation in PD. Forty-one patients were enrolled and electrodes were implanted in 38 patients. Two patients had cerebral hemorrhages and one patient had intraoperative confusion. In comparison to baseline, there was a significant improvement of 33% in UPDRS motor scores in the medication off/stimulation on state. More specifically, tremor was reduced by 59%, rigidity was reduced 31%, bradykinesia was reduced 26%, gait improved by 35%, and postural instability improved by 36%. Patient diaries revealed that the percentage of on time without dyskinesia increased from 28% to 64% and daily off time was reduced from 37% to 24%. The mean daily dose of levodopa equivalents was unchanged between baseline and six months. Several studies have examined the long-term benefits of DBS of the GPi (Table 1). Anderson et al. (21) reported 10 PD patients one year after bilateral GPi DBS. TABLE 1 Selected Studies of Deep Brain Stimulation of the Globus Pallidus Interna

Author Kumar et al. (19) DBSPDSG (16) Volkmann et al. (44) Loher et al. (17) Loher et al. (17) Anderson et al. (21) Ghika et al. (18) Lyons et al. (22) Rodriguez-Oroz et al. (23) Rodriguez-Oroz et al. (23) Volkmann et al. (20) Volkmann et al. (20) Volkmann et al. (20) a

UPDRS improvementa

Follow-up (mo)

ADL (%)

Motor (%)

Dyskinesiab (%)

6 6 12 12 12 12 24–30 25–81

40 36 42 33 34 18 68 21

32 33 68 38 41 39 50 37

68 67 80 55 71 89 65 64

12

32

43

72

20 bilateral

36–48

28

39

76

10 bilateral 9 bilateral 6 bilateral

12 36 60

49 26 −1.5

56 49 23

58 63 64

Number of patients 17 bilateral/ 5 unilateral 38 bilateral 11 bilateral 9 unilateral 10 bilateral 10 bilateral 6 bilateral 6 bilateral/ 3 unilateral 20 bilateral

Percentage improvement from baseline medication off state to medication off/stimulation on at follow-up. Percentage reduction in dyskinesia. Abbreviations: ADL, activities of daily living; DBSPDSG, Deep Brain Stimulation for Parkinson’s Disease Study Group; UPDRS, Unified Parkinson’s Disease Rating Scale.

b

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In the medication off state they showed an 18% improvement in UPDRS ADL scores and a 39% improvement in UPDRS motor scores with stimulation compared to baseline medication off scores. There was also an 89% reduction in dyskinesia and a 3% reduction in antiparkinsonian medications. Lyons et al. (22) reported nine patients (three unilateral and six bilateral) with a mean follow-up of 48.5 months (range 25–81 months) after GPi DBS. There was a significant improvement in UPDRS ADL scores of 21% and a 37% improvement in UPDRS motor scores. Dyskinesia was reduced by 64% and there were no reductions in antiparkinsonian medications. Rodriguez-Oroz et al. (23) reported results of a multicenter study of 20 PD patients who received bilateral GPi DBS. After three to four years of follow-up, significant improvements in UPDRS ADL and motor scores in the medication off/stimulation on condition compared with the baseline medication off state were maintained. More specifically, at the three-to-four-year visit, there were significant improvements in tremor, rigidity, bradykinesia, gait, and dyskinesia compared to baseline and there was no significant worsening compared to the one-year visit. In contrast, some studies have shown a loss of effect of GPi DBS over time (18,20). Ghika et al. (18) reported six PD patients with a minimum follow-up of 24 months after GPi DBS. The mean improvement in UPDRS motor scores in the medication off/stimulation on state compared to the baseline medication off condition was 50% and for UPDRS ADL scores it was 68%. Mean daily off time decreased from 40% to 10% and dyskinesia was reduced by 65%. Although the improvements persisted beyond two years after surgery, signs of decreased efficacy were seen after 12 months. Volkmann et al. (20) reported long-term outcomes of bilateral GPi DBS 12, 36, and 60 months after surgery (Table 1). UPDRS motor scores were significantly improved in the medication off/stimulation on condition compared to baseline by 56% at 12 months and 43% at 36 months. However, at 60 months there was a nonsignificant improvement of 24% compared to baseline. Similarly, for UPDRS ADL scores, at 12 months, there was a significant improvement of 49% compared to baseline; however, a 26% improvement at 36 months was not significantly different from baseline and at 60 months there was a worsening of 1.5%. More specifically, at 12 months, there was a significant improvement in bradykinesia, rigidity, tremor, and postural instability/gait, at 36 months there were significant improvements only in bradykinesia and postural instability/gait, and by 60 months, there was a significant improvement only in rigidity. In contrast, dyskinesia continued to be significantly improved throughout the five-year follow-up. In summary, multiple studies have demonstrated the short-term benefits of GPi DBS in controlling the cardinal symptoms of PD and reducing dyskinesia. Results have been inconsistent regarding the long-term benefits in the cardinal symptoms of PD with GPi DBS; however, there is consensus regarding a significant and sustained reduction in levodopa-induced dyskinesia despite minimal if any reductions in antiparkinsonian medications. Further research is necessary to confirm the long-term benefits of GPi DBS. DEEP BRAIN STIMULATION OF THE SUBTHALAMIC NUCLEUS Multiple reports have demonstrated the short-term benefits of STN DBS in controlling the cardinal features of PD and reducing dyskinesia and antiparkinsonian medications (16,24–31). One of the largest studies was conducted by the Deep Brain Stimulation for Parkinson’s Disease Study Group (16). This was a multicenter study in which 96 PD patients received bilateral STN DBS and 91 completed the

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six-month follow-up visit. In the medication off/stimulation on condition at six months compared to the baseline medication off condition there was a mean improvement of 44% in the UPDRS ADL scores and a 51% improvement in UPDRS motor scores. More specifically, tremor was improved by 79%, rigidity by 58%, bradykinesia by 42%, gait by 56%, and postural instability by 50%, all of which were significant improvements compared to baseline. According to patient diaries, there was a significant decrease in daily off time from 49% to 19%, a significant increase in on time without dyskinesia from 27% to 74% and a decrease in on time with dyskinesia from 23% to 7%. The Rush Dyskinesia Scale demonstrated a significant improvement in dyskinesia of 58% and antiparkinsonian medications were reduced an average of 37%. Several studies have demonstrated the long-term benefits of STN DBS (23,32–37) (Table 2). Rodriguez-Oroz et al. (23) examined 49 PD patients who received bilateral STN DBS as part of the original Deep Brain Stimulation for Parkinson’s Disease Study Group trial (16), three to four years after initial implant. They demonstrated a 43% improvement in UPDRS ADL scores and a 50% improvement in UPDRS motor scores in the medication off/stimulation on condition compared to the baseline medication off state. More specifically, there was an 87% improvement in tremor, a 59% improvement in rigidity, a 42% improvement in bradykinesia, a 41% improvement in gait, a 31% improvement in postural instability, a 59% reduction in dyskinesia, and a 34% reduction in levodopa compared to baseline. Compared with TABLE 2 Selected Studies of Bilateral Deep Brain Stimulation of the Subthalamic Nucleus

Author DBSPDSG (16) Ostergaard et al. (31) Vesper et al. (27) Anderson et al. (21) Pahwa et al. (36) Kleiner-Fisman, et al. (35) Krause et al. (33) Romito et al. (34) Romito et al. (34) Rodriguez-Oroz et al. (23) Rodriguez-Oroz et al. (23) Schupbach et al. (32) Schupbach et al. (32) Krack et al. (37) Krack et al. (37) Krack et al. (37) a

UPDRSa

Number of patients

Follow-up (mo)

ADL (%)

Motor (%)

Dyskinesiab (%)

Medicationb (%)

96

6

44

51

58

37

26 38

12 12

66 —

64 52

86 72

19 53

10 19

12 28

28 27

48 28

62 Significant

38 57

25 27 15 13

30 30 24 36

24 17 68 65

41 44 50 49

80 70 Significant Significant

36 30 64 52

49

12

50

57

51

41

49

36–48

43

50

59

34

32

24

68

69

86

63

30 43 42 42

60 12 36 60

40 66 51 49

54 66 59 54

79 71 71 71

58 59 63 63

Percentage improvement from baseline medication off state to medication off/stimulation on at follow-up. Percentage reduction. Abbreviations: ADL, activities of daily living; DBSPDSG, Deep Brain Stimulation for Parkinson’s Disease Study Group; UPDRS, Unified Parkinson’s Disease Rating Scale.

b

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the one-year visit, at three to four years after implant, there was a worsening in UPDRS ADL and motor scores, gait, postural instability, and speech in the medication off/stimulation on condition although other than speech which was never improved, they were all still significantly improved compared to the baseline medication off state. Two studies have reported five-year post-STN DBS outcomes (32,37). Schupbach et al. (32) examined 30 PD patients five years after STN DBS. They found that UPDRS ADL (40%) and motor scores (54%) as well as axial symptoms (43%) were significantly improved at five years in the medication off/stimulation on condition compared to the baseline medication off state. However, there was a significant worsening in each of these scores compared to the two-year assessment. Dyskinesia (79%) and levodopa equivalent dose (58%) were significantly reduced at five years and there were no significant changes in these variables throughout the five-year period. On the other hand, there was a significant worsening at five years in UPDRS mentation scores, Mattis Dementia Rating Scale scores, and frontal scores compared to baseline. Similarly, Krack et al. (37) examined 42 PD patients 60 months after bilateral STN DBS. In the medication off/stimulation on condition compared to baseline, there was a 54% improvement in UPDRS motor scores and a 49% improvement in UPDRS ADL scores. Significant improvements were seen for tremor (75%), rigidity (71%), akinesia (49%), postural instability (44%), gait (52%), writing (37%), and freezing (46%). Although significantly better than baseline, compared to the one-year visit, there was significant worsening in UPDRS motor and ADL scores, akinesia, gait, and freezing. However, there were sustained reductions in dyskinesia of 71% and daily levodopa equivalence dose of 63%. In summary, STN DBS has been shown to control tremor, rigidity, bradykinesia, and dyskinesia up to five years after surgery while allowing a significant reduction in antiparkinsonian medications. Although there is some deterioration over time, this appears to be related to the natural progression of the disease and the majority of symptoms remain improved compared to before surgery. PREDICTORS OF OUTCOME AFTER SUBTHALAMIC NUCLEUS DEEP BRAIN STIMULATION Several studies have examined the factors predictive of a positive outcome after STN DBS (25,35,38–40). Charles et al. (38) examined 54 PD patients after bilateral STN DBS and found that age and preoperative levodopa response were the strongest predictors of outcome. In a study of 41 PD patients who had STN DBS, Welter et al. used regression analyses to identify age and disease duration as predictors of outcome. They found that patients 56 years of age or younger had a 71% improvement in UPDRS ADL and motor scores compared to improvements of 57% and 62% for those older than 56 years. Similarly, those with disease duration less than 16 years had significantly better responses to surgery than those with disease duration greater than 16 years. The authors concluded that in addition to age and disease duration, levodopa responsiveness was the strongest predictor of outcome after STN DBS. Kleiner-Fisman et al. (35) examined age, sex, disease duration, medication usage, dyskinesia, age of onset, and levodopa responsiveness in 25 PD patients who received bilateral STN DBS. Levodopa responsiveness was the only factor related to outcome. Jaggi et al. (39) examined 39 patients after STN DBS. They found that age, preoperative change in UPDRS motor scores with medication, and disease duration were the strongest predictors of outcome. Finally, Pahwa et al. (40) examined

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45 patients after bilateral STN DBS and found that the preoperative change in UPDRS motor scores with medication was the strongest predictor of outcome. They found no relationship with age or disease duration. The American Academy of Neurology Practice Parameter: Treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review) (41) concluded that preoperative response to levodopa is probably predictive of postsurgical improvement and younger age and disease duration less than 16 years are possibly predictive of greater improvement after STN DBS. It was recommended that preoperative response to levodopa should be considered as a factor predictive of outcome after STN DBS, whereas, age and disease duration may be considered as predictive factors. DEEP BRAIN STIMULATION OF THE GLOBUS PALLIDUS INTERNA OR THE SUBTHALAMIC NUCLEUS? There are only a few studies that have directly compared patients who have undergone GPi or STN DBS and most of these studies are not randomized and the number of patients is small. Krack et al. (42) retrospectively compared eight patients who had STN DBS with five who had GPi DBS six months after surgery. In the medication off state, UPDRS motor scores improved by 71% with STN stimulation and by 39% with GPi stimulation and UPDRS ADL scores were also more improved in the STN group. Rigidity and tremor showed comparable improvement in both groups but bradykinesia was more improved in the STN group. There was a reduction in levodopa equivalence dose only in the STN group. Scotto di Luzio et al. (43) retrospectively compared nine patients who had undergone STN stimulation to five who had undergone GPi stimulation 12 months after surgery. UPDRS motor scores in the medication off/stimulation on condition improved by 56.6% with STN stimulation and 41.7% with GPi stimulation. Both groups had a significant reduction in dyskinesia but there was a reduction in levodopa dose only in the STN group. Volkmann et al. (44) retrospectively compared 16 patients who had undergone STN stimulation with 11 patients who had undergone GPi stimulation. There was a 67% improvement in UPDRS motor scores with STN stimulation compared with a 54% improvement with GPi stimulation. However, there were no significant differences between the two groups in terms of off medication motor function, dyskinesia, or motor fluctuations. Medication was reduced only in the STN group and the GPi group required significantly more electrical power compared to the STN group. In another study, Krause et al. (45) compared six GPi patients with 12 STN patients 12 months after surgery. GPi stimulation directly reduced dyskinesia, whereas STN stimulation reduced antiparkinsonian medications resulting in a reduction of dyskinesia. STN stimulation also improved UPDRS motor scores but GPi stimulation did not have a similar effect. There has been only one blinded, randomized trial of GPi DBS versus STN DBS published to date. Anderson et al. (21) compared 10 patients who received bilateral STN DBS with 10 patients who received bilateral GPi DBS 12 months after surgery. UPDRS scores were significantly improved for both groups and there were no significant differences between the STN and GPi DBS groups. More specifically, UPDRS motor scores were improved 48% with STN DBS and 39% with GPi DBS; UPDRS ADL scores were improved by 28% with STN DBS and 18% with GPi DBS; bradykinesia was improved by 44% with STN DBS and 33% with GPi DBS; tremor was improved 89% with STN DBS and 79% with GPi DBS; rigidity was improved 48% with STN DBS and 47% with GPi DBS; and axial symptoms were improved 44% with

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STN DBS and 40% with GPi DBS. In addition, dyskinesia was reduced by 62% with STN DBS and 89% with GPi DBS; however, there was a levodopa reduction of 38% with STN DBS and only 3% with GPi DBS. Although the sample size was small, this study suggests that cognitive and behavioral problems may be more common after STN DBS compared to GPi DBS. It was also suggested that follow-up care may be more difficult after STN DBS due to the medication adjustments during stimulation parameter optimization, which are generally not required after GPi DBS. In summary, the majority of the small retrospective reports have suggested that STN DBS is more effective than GPi DBS. In fact, the American Academy of Neurology Practice Parameter: Treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review) (41) concluded that STN DBS is possibly effective in improving motor function and reducing motor fluctuations, dyskinesia, and antiparkinsonian medication usage and may be considered as a treatment option in PD patients. In contrast, it was concluded that there were insufficient data to determine whether GPi DBS is an effective treatment option for PD. However, given the results of Anderson et al.’s blinded, randomized study, which found the outcomes from the two targets to be very similar, the results of larger, randomized, blinded studies are necessary before the two targets can be adequately compared. PATIENT SELECTION FOR PALLIDAL AND SUBTHALAMIC DEEP BRAIN STIMULATION The criteria for patient selection for DBS of the GPi and STN for PD are similar. The ideal candidate is a patient with idiopathic levodopa responsive PD who has medication resistant motor fluctuations and/or dyskinesia. It is recommended that patients undergo a levodopa challenge. Generally, patients arrive at the clinic 12 hours after not taking any antiparkinsonian medications at which time they are evaluated with a complete UPDRS and other site-specific measures. After these evaluations either the regular dose of antiparkinsonian medication or at some sites a dose of levodopa 150% of the usual dose (without any other antiparkinsonian medication) is usually given and evaluations are repeated after the patient has reached the best medication on state. Usually, a 30% or greater improvement in UPDRS motor scores between the medication off and on conditions is required to recommend surgery. Patients older than 75 years are generally not considered candidates as they may have difficulty in tolerating the procedure and the programming. Patients should have been tried on combinations of different antiparkinsonian medications and evaluated by a movement disorder specialist, if possible, before being recommended for surgery. Patients with disabling medication resistant tremor or an inability to tolerate antiparkinsonian medications may also be candidates for STN or GPi DBS. There should be no evidence of dementia or significant cognitive, psychiatric or behavioral abnormalities as these can worsen after surgery. To rule these out, patients should undergo detailed neuropsychological testing. There should be no significant abnormalities on neuroimaging and no other medical conditions that might increase surgical risk. Finally, the patient should have an adequate support network and be able to attend multiple visits to the surgical site for programming. ADVERSE EFFECTS OF DEEP BRAIN STIMULATION Complications of DBS are similar for the three targets, VIM, GPi, and STN. Complications can be divided into those related to the surgical procedure, those associated with the DBS hardware and those associated with stimulation. The occurrence of

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these complications is related to the technique and experience of the neurosurgeon, accurate placement of the DBS leads, and appropriate patient selection and postsurgical management. Surgical Complications Surgical complications are those that occur within 30 days of surgery. These complications are typical of those seen with other intracranial stereotactic procedures and generally occur in less than 5% of the patients. These complications include hemorrhage, ischemic lesions, seizures, infections, and misplaced leads. Several studies have focused on the examination of surgical complications related to DBS. Beric et al. (46) reported 86 patients who received 149 DBS implants in the VIM nucleus of the thalamus, GPi or STN for PD, essential tremor, multiple sclerosis, or dystonia. In this cohort, 2.3% (n = 2) of the patients had a hemorrhage, 2.3% (n = 2) had seizures, 1.2% (n = 1) had a delayed hematoma two months after surgery, and 4.7% (n = 4) had postsurgical confusion. Umemura et al. (47) reported surgical complications in 109 patients receiving DBS of the VIM nucleus of the thalamus, GPi, STN, or anterior nucleus of the thalamus for PD, essential tremor, epilepsy, or dystonia. They reported two deaths, one from a pulmonary embolus and the other from pneumonia. Other surgical complications included pulmonary embolism (1.8%; n = 2), subcortical hemorrhage (1.8%; n = 2), chronic subdural hematoma (1.8%; n = 2), venous infarction (0.9%; n = 1), seizure (0.9%; n = 1), infection (3.7%; n = 4), cerebral spinal fluid leak (0.9%; n = 1), and skin erosion on the scalp (0.9%; n = 1). In addition to these complications, several patients had postoperative sterile seromas at the IPG and three had transient confusion. Finally, Lyons et al. (48) reported complications in 81 PD patients after 160 STN DBS procedures. In this series, 4.9% (n = 4) of the procedures were aborted due to adverse events in the operating room in three and inability to get a response in one. There were no deaths or permanent neurological deficits related to surgery. Surgical complications included hemorrhage in 1.2% (n = 1) of patients, seizure in 1.2% (n = 1), system infection in 2.5% (n = 2), IPG infection in 3.7% (n = 3), and misplaced leads in 12.5% (n = 10). Hardware-Related Complications Several reports have also focused on hardware complications related to DBS. Beric et al. (46) examined complications for 86 DBS patients and found electrode failure in 3.5% (n = 3), extension wire failure in 4.7% (n = 4), IPG malfunction in 1.2% (n = 1), and pain at the IPG in 1.2% (n = 1). Kondziolka et al. (49) examined hardware complications in 66 patients undergoing unilateral thalamic DBS for either essential tremor, parkinsonian tremor, multiple sclerosis, or other forms of tremor. There were a total of 23 hardware-related complications affecting 27% of the patients. Lead breakage occurred in 10 patients (15.2%), system infection in seven patients (10.6%), connector erosion in two patients (3.0%), and cranial lead migration, chronic subdural hematoma, defective IPG, and a defective connector each in one patient (1.5%, each). Oh et al. (50) reported hardware complications for 79 patients who received 124 DBS implants. DBS was done for PD, essential tremor, pain, epilepsy, dystonia, multiple sclerosis, and Huntington’s disease and placed either in the STN, GPi, thalamus, or periventricular gray matter. In total, 20 patients (25.3%) had 26 hardware complications that involved 23 (18.5%) of the devices. More specifically, 5.1% (n = 4) had lead fractures, 5.1% (n = 4) had lead migrations, 3.8% (n = 3) had short circuits or open circuits, 15.2% (n = 12) had an infection or device erosion, 2.5% (n = 2) had an allergic reaction, and 1.3% (n = 1) had a cerebral spinal fluid leak. Similarly, Lyons et al. (48)

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reported hardware complications from 80 PD patients with 155 DBS implants in the STN. Hardware complications occurred in 26.2% (n = 21) of patients with 10% (n = 8) of patients having complications of the lead or extension wire that required additional neurosurgery and 18.8% (n = 15) of patients having IPG complications that required additional surgery in the subcutaneous tissue of the chest. More specifically, lead fractures occurred in 2.5% (n = 2), lead migrations in 6.3% (n = 5), extension wire fractures in 2.5% (n = 2), extension wire erosions in 1.3% (n = 1), and IPG malfunctions in 13.8% (n = 11). In this report, complications were reduced as the experience of the neurosurgeon was increased. Stimulation Complications Stimulation-related adverse effects depend on the exact location of the lead and the intensity of stimulation. The majority of these adverse effects can be reduced by changing the active electrode contact or by reducing the stimulation intensity. These adverse effects include eyelid apraxia, double vision, dystonic posturing, dysarthria, dyskinesia, paresthesia, limb and facial muscle spasms, depression, mood changes, paresthesias, visual disturbances, and pain. Occasionally, nonspecific sensations like anxiety, panic, palpitations, and nausea can also occur. If these adverse effects persist, this usually indicates that the electrode is not in the ideal position. There has been some concern about an increase in suicide after DBS. Burkhard et al. (51) reported a suicide rate of 4.6% in patients with movement disorders and DBS. Risk factors in this report were history of severe depression and multiple successive DBS surgeries. There was no relationship found with the underlying condition, DBS target, stimulation parameters, or treatment adjustments. Benabid et al. (52) have also suggested that depression and suicide in patients after DBS are related to pre-existing conditions rather than the surgical procedure or subsequent stimulation. CONCLUSIONS DBS is an effective and relatively safe treatment for levodopa-responsive PD patients with medication resistant motor fluctuations and dyskinesia. DBS of the thalamus clearly reduces parkinsonian tremor; however, bradykinesia, rigidity, and dyskinesia are not significantly affected. Therefore, VIM DBS is reserved for disabling tremor predominant PD. DBS of the GPi and STN both significantly improve all of the cardinal symptoms of PD as well as dyskinesia. DBS of the STN often results in a significant reduction in antiparkinsonian medication, whereas PD medications are generally not significantly reduced after GPi DBS. Currently, DBS of the STN is the most commonly performed surgical procedure for PD; however, additional outcome data are necessary to determine the role for GPi DBS in PD. Finally, DBS is a relatively safe procedure; however, patients should be counseled about the surgical and hardware complications that can occur and can require additional surgeries. REFERENCES 1. Svennilson E, Torvik A, Lowe R, Leksell L. Treatment of parkinsonism by stereotatic thermolesions in the pallidal region. A clinical evaluation of 81 cases. Acta Psychiatr Scand 1960; 35:358–377. 2. Hassler R, Riechert T. Indications and localization of stereotactic brain operations. Nervenarzt 1954; 25(11):441–447.

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25. Welter ML, Houeto JL, Tezenas du Montcel S, et al. Clinical predictive factors of subthalamic stimulation in Parkinson’s disease. Brain 2002; 125(Pt 3):575–583. 26. Kumar R, Lozano AM, Kim YJ, et al. Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology 1998; 51(3):850–855. 27. Vesper J, Klostermann F, Stockhammer F, Funk T, Brock M. Results of chronic subthalamic nucleus stimulation for Parkinson’s disease: a 1-year follow-up study. Surg Neurol 2002; 57(5):306–311; discussion 311–303. 28. Doshi PK, Chhaya NA, Bhatt MA. Bilateral subthalamic nucleus stimulation for Parkinson’s disease. Neurol India 2003; 51(1):43–48. 29. Limousin P, Krack P, Pollak P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998; 339(16):1105–1111. 30. Rodriguez-Oroz MC, Gorospe A, Guridi J, et al. Bilateral deep brain stimulation of the subthalamic nucleus in Parkinson’s disease. Neurology 2000; 55(12 suppl 6):S45–S51. 31. Ostergaard K, Sunde N, Dupont E. Effects of bilateral stimulation of the subthalamic nucleus in patients with severe Parkinson’s disease and motor fluctuations. Mov Disord 2002; 17(4):693–700. 32. Schupbach WM, Chastan N, Welter ML, et al. Stimulation of the subthalamic nucleus in Parkinson’s disease: a 5 year follow up. J Neurol Neurosurg Psychiatry 2005; 76(12): 1640–1644. 33. Krause M, Fogel W, Mayer P, Kloss M, Tronnier V. Chronic inhibition of the subthalamic nucleus in Parkinson’s disease. J Neurol Sci 2004; 219(1–2):119–124. 34. Romito LM, Scerrati M, Contarino MF, Iacoangeli M, Bentivoglio AR, Albanese A. Bilateral high frequency subthalamic stimulation in Parkinson’s disease: long-term neurological follow-up. J Neurosurg Sci 2003; 47(3):119–128. 35. Kleiner-Fisman G, Fisman DN, Sime E, Saint-Cyr JA, Lozano AM, Lang AE. Long-term follow up of bilateral deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinson disease. J Neurosurg 2003; 99(3):489–495. 36. Pahwa R, Wilkinson SB, Overman J, Lyons KE. Bilateral subthalamic stimulation in patients with Parkinson disease: long-term follow up. J Neurosurg 2003; 99(1):71–77. 37. Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease [see comment]. N Engl J Med 2003; 349(20):1925–1934. 38. Charles PD, Van Blercom N, Krack P, et al. Predictors of effective bilateral subthalamic nucleus stimulation for PD. Neurology 2002; 59(6):932–934. 39. Jaggi JL, Umemura A, Hurtig HI, et al. Bilateral stimulation of the subthalamic nucleus in Parkinson’s disease: surgical efficacy and prediction of outcome. Stereotact Funct Neurosurg 2004; 82(2–3):104–114. 40. Pahwa R, Wilkinson SB, Overman J, Lyons KE. Preoperative clinical predictors of response to bilateral subthalamic stimulation in patients with Parkinson’s disease. Stereotact Funct Neurosurg 2005; 83(2–3):80–83. 41. Pahwa R, Factor SA, Lyons KE, et al. Practice Parameter: Treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 66:983–995. 42. Krack P, Pollak P, Limousin P, et al. Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain 1998; 121(Pt 3):451–457. 43. Scotto di Luzio A, Ammannati F, Marini P, Sorbi S, Mennonna P. Which target for DBS in Parkinson’s disease? Subthalamic nucleus versus globus pallidus internus. Neurol Sci 2001; 22(1):87–88. 44. Volkmann J, Allert N, Voges J, Weiss PH, Freund HJ, Sturm V. Safety and efficacy of pallidal or subthalamic nucleus stimulation in advanced PD [erratum appears in Neurology 2001; 57(7):1354]. Neurology 2001; 56(4):548–551. 45. Krause M, Fogel W, Heck A, et al. Deep brain stimulation for the treatment of Parkinson’s disease: subthalamic nucleus versus globus pallidus internus. J Neurol Neurosurg Psychiatry 2001; 70(4):464–470. 46. Beric A, Kelly PJ, Rezai A, et al. Complications of deep brain stimulation surgery. Stereotact Funct Neurosurg 2001; 77(1–4):73–78.

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47. Umemura A, Jaggi JL, Hurtig HI, et al. Deep brain stimulation for movement disorders: morbidity and mortality in 109 patients. J Neurosurg 2003; 98(4):779–784. 48. Lyons KE, Wilkinson SB, Overman J, Pahwa R. Surgical and hardware complications of subthalamic stimulation: a series of 160 procedures. Neurology 2004; 63(4):612–616. 49. Kondziolka D, Whiting D, Germanwala A, Oh M. Hardware-related complications after placement of thalamic deep brain stimulator systems. Stereotact Funct Neurosurg 2002; 79(3–4):228–233. 50. Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM. Long-term hardware-related complications of deep brain stimulation. Neurosurgery 2002; 50(6):1268–1274; discussion 1274–1266. 51. Burkhard PR, Vingerhoets FJ, Berney A, Bogousslavsky J, Villemure JG, Ghika J. Suicide after successful deep brain stimulation for movement disorders. Neurology 2004; 63(11): 2170–2172. 52. Benabid AL, Chabardes S, Seigneuret E. Deep-brain stimulation in Parkinson’s disease: long-term efficacy and safety—What happened this year? Curr Opin Neurol 2005; 18(6):623–630.

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Investigational Surgical Therapies Joseph S. Neimat Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A.

Parag G. Patil Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, U.S.A.

Andres M. Lozano Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada

INTRODUCTION Parkinson’s disease (PD) treatment has undergone a dramatic change in the last decade, as the technology of deep brain stimulation (DBS) therapy has become an accepted part of the armamentarium. Surgical procedures, both ablative and neural stimulation, have been demonstrated to recapitulate the effects of best medical therapy while simultaneously reducing dyskinesia and the dosage of required medication. The number of PD patients treated with DBS in the last decade approaches 30,000. The ultimate goal of new therapies is to reverse the underlying pathophysiology of PD and restore function to the extrapyramidal motor system. This chapter will discuss novel surgical therapies that have been investigated in recent years and for which research continues to be conducted. The outcomes of many of these studies are uncertain, but the possibilities presented are among the most interesting and novel concepts in the field of PD today.

SHORTCOMINGS OF CURRENT SURGICAL THERAPIES Despite the recent success of DBS and the benefit it provides in treating advanced PD, DBS has a number of adverse effects. These range from psychiatric effects of mania or depression to effects of vocal hypophonia, weight gain, eyelid apraxia, increased libido, sialorrhea, decreased memory, dyskinesia, and dystonia. A review of reported series noted the occurrence of adverse effects in 19% of patients receiving DBS of the subthalamic nucleus (STN) (1–5). Another issue is the apparently high suicide rate among patients having undergone DBS surgery; one study noted a rate of 4.3% in a cohort of 140 patients (6). Secondly, there are many elements that reflect the progression of the disease that are not effectively addressed by DBS. These include the prominent gait and balance issues that are inherent to PD and the gradual cognitive and emotional decline that is known to occur from extranigral neuronal attrition (7). There remains a need to investigate and refine the effect of DBS for PD. Several areas of research deal with refining the technique of neural stimulation. The exploration of novel targets may also lead to stimulatory therapies that address some of the current shortcomings. It is hoped that some of these targets will yield similar or greater benefits while producing more limited side effects. Beyond improvements in stimulatory therapies lie restorative treatments that offer the hope of reversing the pathology of PD. 423

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NOVEL STIMULATION APPROACHES Current surgical therapies are based upon a model of basal ganglia function, which suggests that motor activity is regulated by the balanced activity of two separate circuits within the basal ganglia (8). This model was able to explain the effect of known ablative targets, such as the globus pallidus interna (GPi), STN, and thalamus. Although the model has been instructive, further study has demonstrated a far greater complexity within the basal ganglia than previously appreciated. Numerous anatomic studies have unveiled a far more complex connectivity in the basal ganglia than accounted for in the model. It is clear now that there are dopaminergic projections to the pallidum and STN, as well as to the striatum. The thalamic centromedian and parafascicular nuclei form important “stabilizing” circuits with the pallidum and STN (9,10). The pedunculopontine nucleus (PPN) is also considered to be a potentially important output nucleus, which receives projections from the STN (11). These findings point to a more complex, internally regulating system, of which the traditionally described direct and indirect pathways tell only part of the story (12–17). With this increased understanding of basal ganglia structure and complexity, new surgical targets have been suggested. Pedunculopontine Nucleus The PPN is an important output target of the STN. It has also been implicated in the mediation of gait and posture; aspects of PD which are not well treated by DBS of the STN or GPi (14). Aziz et al. (18,19) published a report of low-frequency PPN stimulation in primates that improved symptoms of akinesia. Mazzone et al. reported two patients, with PD causing significant gait disturbance, who underwent implantation of PPN DBS electrodes. They demonstrated the safety of the procedure and the ability of low-frequency intraoperative stimulation to improve selective elements of the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scale (20). A study by Plaha and Gill (21) also reported two patients who underwent PPN DBS implantation and demonstrated that both patients had improvements both in UPDRS motor scores and in scales measuring balance and gait. These reports will need validation by larger series and prospective trials, but there seems to be promise to this novel target. As our knowledge of the subcortical circuitry underlying motor regulation improves, DBS may be tailored to the pathologies of individual patients; perhaps selecting or adding the PPN target in gait-predominant PD. Motor Cortex Stimulation There has been anecdotal evidence of improvement in patients treated with stimulation of the motor cortex for chronic pain (22,23). This has led to the suggestion that stimulation of the motor cortex might be an effective means of treating patients with tremor-dominant PD. A group in Italy has performed motor cortex stimulation for PD in three patients (24–26). They reported that a benefit comparable to STN DBS could be achieved with low-frequency not high-frequency stimulation. Advantages of this procedure might include safer placement, without the risk of deep hemorrhage, and perhaps greater efficacy. Early Deep Brain Stimulation Several groups have suggested the possibility of using early DBS to slow the pathologic progress of PD. Theoretically, glutamatergic projections from the STN to the substantia

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nigra pars compacta (SNc) represent an excitotoxic circuit. Thus, early dopaminergic loss causes increased STN activity, which, in turn, increases excitation and injury in the SNc. This process could have a similar toxic effect on the STN’s other targets, including the GPi, substantia nigra pars reticulate (SNr), and PPN (14). This has been supported in rodent models demonstrating that previous STN ablation has a protective effect on the SNc from mitochondrial toxins known to cause dopaminergic attrition (27). This concept remains controversial, as there is no clear evidence supporting neuroprotection in human DBS subjects. It is not clear that STN DBS reduces glutamate output. Indeed, there is some evidence to the contrary. One study has demonstrated continued dopaminergic loss in the striatum of patients treated with STN DBS. In these patients, fluorodopa uptake decreased by 9% to 12% a year in 30 patients. This reduction is similar to known progression rates in unoperated patients (28). A multicenter trial is currently underway to assess the utility of early DBS treatment. INTRACEREBRAL DRUG INFUSION Glial Cell Line-Derived Neurotrophic Factor Glial cell line-derived neurotrophic factor (GDNF) was first identified in the early 1990s as a member of the transforming growth factor (TGF)-beta superfamily with potent effects on embryonic neuronal cultures and specifically on dopaminergic cell lines (29). It was subsequently found to be potently expressed in the developing rodent striatum (30). Its potential as a possible agent for the protection of dopaminergic projections was quickly recognized and there was investigation into the delivery of the agent in animal PD models. Early studies showed that local GDNF administration was able to protect and restore dopaminergic cells in rodent models of PD (31,32). Shortly thereafter, trials in primates confirmed the ability of GDNF both to protect dopaminergic cells from degeneration and to improve functional assessments of motor behavior in 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys (33,34). The success of these studies generated hope for the clinical utility of GDNF in patients with PD (35,36). Anecdotal reports, however, were mixed, with some indicating improvement (37) and others indicating treatment futility (38). Overall, there were few publications from which conclusions could be drawn. However, the preclinical evidence was sufficiently compelling to spur broader investigation. The first, large, randomized trial of intraventricular GDNF was published in 2003. In this trial, 50 patients underwent placement of pumps and intraventricular catheters. The patients were randomized to receive either carrier alone or one of several concentrations of recombinant GDNF. At six to eight months, none of the GDNF groups had demonstrated improvements over placebo and several of the groups had worsened (39). Additionally, adverse effects were noted in 100% of patients receiving GDNF. These included nausea, anorexia, and shock-like sensory symptoms resembling Lhermitte’s phenomena. It was suggested that the relative size of the human brain makes the transependymal diffusion of GDNF insufficient to create the necessary concentrations to produce an effect (40). A series of trials were also underway to evaluate the effects of intrastriatal microinfusion of GDNF. A phase I safety study published by Gill et al. reported that microinfusion in five parkinsonian patients produced no significant adverse effects and improved UPDRS scores by 48%. Furthermore, positron emission tomography (PET) scanning demonstrated increased striatal dopamine uptake (40). Notable side effects also included anorexia, with significant weight loss, and Lhermitte’s phenomenon. The results of this study were sufficient to begin a phase II study with a

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randomized blinded design for the striatal administration of GDNF or carrier. This study included 34 patients who underwent implantation of intraputaminal catheters and pumps and then received either GDNF or saline carrier alone. At six months, the GDNF-treated patients failed to show significant changes in their off-medication UPDRS motor scores compared with placebo. Although there was a trend for more severely affected patients to derive improvement, this did not meet significance. Additionally, four of the patients developed anti-GDNF antibodies during or subsequent to the six-month period of study, raising concerns that autoimmune consequences might ensue (41). Despite the failure of clinical response in this study, PET imaging performed in treated patients demonstrated an average 23.1% increase in F-dopa uptake compared to a decrease of 8.8% in placebo-treated patients (41). This objective sign of treatment effect and the benefits demonstrated in previous openlabel studies raise the possibility that GDNF treatment may still hold promise. Current hopes rest on cell- and viral-based gene therapy treatments. Neurturin Neurturin is a GDNF homolog (42), which is also expressed in the developing midbrain (43). It has been demonstrated to exert potent trophic effects on dopaminergic neurons in vitro and in vivo (43). When injected into the substantia nigra of 6-hydroxydopamine (6-OHDA)-lesioned rats, neurturin significantly protected dopaminergic nigral cells, resulting in greater cell survival. These results were nearly identical to the effects of GDNF (43,44). Protective results have also been noted in rats treated with striatal neurturin injections preceding lesioning (44). Both studies correlated these results with behavioral improvements. Other members of this gene family have also been identified and tested for dopaminergic neuroprotection (45–47). It is possible that these agents may also be considered for future clinical therapies. Like GDNF, gene therapy may represent the most effective means of delivery for these agents. Specific studies are examined in the section “Gene Therapy.” FETAL TRANSPLANTATION Among PD treatments, no therapy has raised greater hopes or stirred more controversy than that of fetal transplantation. Although clinical trial failures have curtailed interest in this therapy, it remains an area of considerable research and discussion. Understanding the work that has been done in this area may be instrumental in guiding future cellular restorative therapies such as stem cell transplantation. Rodent and primate models of PD have shown dramatic response to the transplantation of fetal cells (48–51). The demonstration of behavioral improvements (52–54) and histological reinnervation of striatal regions by dopaminergic transplants (51) suggested that a successful treatment strategy had been identified. The first human cases of fetal transplantation for PD were reported in 1990 (55,56). Early anecdotal cases reported dramatic benefit. Several of these studies were also able to corroborate observed clinical improvements with PET evidence of increased dopamine uptake or with histological evidence of reinnervation by transplanted fetal cells (57). An open-label study demonstrated significant improvements in each of seven treated patients for 12 to 46 months following surgery. All seven patients demonstrated improvement in activities of daily living (ADLs). Five of the seven patients had significant improvements in UPDRS motor scores. The group also demonstrated medication reductions by an average of 39% (58).

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In 2001, a double-blind sham-surgery controlled study was published. Patients treated with fetal transplantation showed no significant difference in the primary outcome measure of subjective self-reported improvement. Neither the treated patients nor the sham-surgery controls reported any subjective benefit. Secondary objective measures, including UPDRS motor scores, were slightly more promising. Treated patients demonstrated an 18% improvement in UPDRS motor scores off medication, compared with no improvement in sham controls. The effect was more pronounced in the group of patients less than 60 years of age, whose scores improved 34%. No additional benefit was accrued in the medication on state in any group. Notably, the study was performed without immunosuppression (59). The negative results produced by this study after such promising early trials spurred a second double-blind controlled trial. In this study by Olanow et al., 34 patients were randomized to sham surgery, or intraputaminal implantation with one or four grafts per side. Notably, solid mesencephalic grafts were used (as opposed to dissociated cell suspensions) and patients were kept on immunosuppression for a period of six months. Patients were followed for a total of 24 months and the primary endpoint was objective change in the UPDRS motor score. In this study, results demonstrated no significant improvement in either treatment group when compared to placebo. At six months, the treatment groups showed significant benefit compared to controls; however, this effect was gradually lost over the subsequent six to nine months. This suggests that immunosuppression may have an important protective role in cellular therapies. Further subgroup analysis demonstrated that patients with less severe disease (UPDRS motor score < 49) did show significant improvement and that there was further significant benefit to treatment with multiple donors (60). The blinded studies also demonstrated a significant incidence of graft-induced dyskinesia. This troubling side effect was reported in 15% of patients in the study by Freed et al. (59) and in 58% of patients in the Olanow et al. study (60). It is not clear if this effect is the result of partial reinnervation of immunologic graft rejection producing atypical dopamine release or some other mechanism. The failure of double-blind studies to demonstrate consistent benefit has curtailed that application of fetal transplantation. However, the apparent success of individual patients and the evidence for substantive reinnervation as demonstrated by histology or by PET imaging have led investigators to identify factors that may contribute to treatment success (61). Several factors seem to have had influence on the results. First, the amount and age of transplanted tissue may be of importance. One group has reported an optimal fetal age of 5.5 to 8 weeks for transplantation (62). Secondly, the handling of fetal tissue prior to implantation may also have a critical effect. This has been evidenced in part by the few patients who came to autopsy. These reports demonstrate significant variability in the extent of striatal reinnervation by transplanted neurons. One study demonstrated a single patient who had derived significant benefit from his transplantation and was found at autopsy to have widespread and confluent striatal innervation with minimal inflammatory reaction (57). Contrasting histological reports demonstrated far more limited survival from fetal transplants that were older or had undergone cryopreservation (63,64). Finally, several studies have examined the necessity of immunosuppression to allow cellular integration of the foreign transplants. The Olanow et al. study suggested that steroid suppression was beneficial up to six months and its withdrawal might account for the subsequent worsening of UPDRS motor scores in transplanted patients. Piccini et al. identified six patients who underwent steroid suppression for

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more than two years. In these patients, the withdrawal of steroids at an average of 29 months produced no rebound in UPDRS motor scores and no changes in striatal dopamine uptake on PET scanning (61). These studies demonstrate the extremely tenuous nature of this technique. It may be that the failed transplantation trials resulted from technical sensitivities and not from a failure of principle. This observation provides hope that new cellularbased therapies may be effective if larger numbers of cells can be transplanted or greater cell survival can be achieved. STEM CELL THERAPY Although the transplantation of human embryonic mesencephalic cells into patients with PD has not yet shown clear clinical efficacy, these studies demonstrate that neural integration of foreign cells into the basal ganglia is both possible and potentially therapeutic. In comparison, stem cell therapies attempt to treat advanced PD through the transplantation of neurons that are not harvested from fetal tissue but produced through molecular manipulation of cultured cells. The field is both sophisticated and complex. The principal lines of investigation are examined subsequently. For a more complete discussion, the reader is referred to several reviews (65–67). Features of Stem Cells Stem cells are developmentally immature cells from which more differentiated daughter cells arise. The quintessential stem cell is the fertilized egg. It is totipotent, meaning that all cells in the body may be derived from it. Pluripotent stem cells, such as from the inner cell layer of the blastula of an embryo, give rise to many types of cells, but not all of them. Multipotent stem cells give rise to specialized types of cells, typically in a single organ or system. For example, some bone marrow-derived hematopoetic stem cells are multipotent and give rise to all cell types in blood, but not those of other tissues, such as the liver or lung. In addition to serving as progenitors for mature differentiated cells, stem cells have the important added capacity for maintenance in culture through clonal expansion. This arises from the fact that stem cells can divide and grow to produce a potentially large supply of identical stem cells in culture. The ability to produce large numbers of cells from a far smaller number of donor cells is a critical advantage for stem cell therapies. In contrast, multiple fetal donor sources must be combined for each non-stem cell transplant, a feature fraught with procurement difficulties and moral disagreement. Goals for Stem Cell Transplantation The strategy of stem cell approaches to PD is to hormonally induce stem cell differentiation into nigrostriatal dopaminergic neurons or their precursors and then to transplant them into patients. The hope is that these transplanted cells will survive, re-innervate the striatum, and functionally replace dopaminergic cells that have been lost as a result of disease progression. These goals result in considerable challenge and complexity. The ideal stem cell source would have the capacity for indefinite clonal expansion to allow a small number of donor sources to be utilized to treat a much larger number of patients. This expansion would have to be free of genetic mutation and would have to cease once transplantation took place. The cells would also require

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the capacity for controlled differentiation into phenotypically appropriate dopaminergic neurons. For example, the generated neurons should not only produce dopamine but also must have the similar capacity for regulation and other aspects of functionality as native neurons. During production, not all stem cells would be expected to differentiate into the same progeny cells. Although some cells may form neurons, others may form glial cells. A mechanism through which to select neurons from this heterogeneous background of surrounding cells in culture would be required. Of course, proper functioning of transplanted neurons may require the presence of supporting cells, which would also need to be produced and sustained in the transplanted tissue. The transplanted stem cells would have to cease to divide or to differentiate in an uncoordinated or uncontrolled fashion once transplantation had taken place. Otherwise, the transplant might either become a tumor, if growth continued, or lose functionality over time, if differentiation progressed. Methods to ensure that the transplanted cells are not rejected by the recipient would also have to be developed. As described earlier, immunological rejection may have been a critical factor in the failure of fetal transplantation studies. Finally, and most importantly, transplantation of these cells would have to result in the substantial improvement or reversal of the symptoms of PD. Loss of dopaminergic neurons is associated with bradykinesia, rigidity, postural instability, and tremor. These symptoms might be expected to improve with stem cell transplantation. However, additional nondopaminergic symptoms such as dementia, autonomic dysfunction, depression, and sleep disturbance would likely remain. Furthermore, stem cell therapies should not produce disabling dopamine-associated side effects, such as troubling dyskinesia. As with any invasive or complex therapy, serious consideration will have to be given to cost relative to changes in patient quality of life. Despite these substantial challenges, several different stem cell types have been considered and studied. Embryonic Stem Cells Embryonic stem cells arise from the inner cell mass of the blastocyst, the five-dayold preimplantation embryo. Embryonic stem cells are pluripotent. Embryonic stem cells from mouse, nonhuman primate, and humans (68) have been differentiated into dopaminergic neurons. In current research, human embryonic stem cells typically have been donated as excess material, following in vitro fertilization. When implanted into animal models, these stem cell-derived neurons reinnervate the striatum and ameliorate some parkinsonian symptoms (69,70). One concern has been the development of teratomas in the brains of some (71) but not all (72) animals. Recent studies have encouraged differentiation of stem cells into dopaminergic neurons through genetic manipulation and hormonal treatment, such as over-expression of the Nurr-1 transcription factor and exposure to fibroblast growth factor (FGF) and Sonic Hedgehog (73). Neuronal Stem Cells A second source of stem cells is the brain itself. Neuronal stem cells have been identified in the adult mammalian subventricular zone and the subgranular region of the hippocampal dentate gyrus. Adult neuronal stem cells possess the theoretical advantage that they may be obtained from individual adult patients, potentially circumventing issues of graft rejection. As an additional potential advantage to embryonic stem cells, neuronal stem cells are committed to a neuronal phenotype and, there-

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fore, production of dopaminergic neurons from neuronal stem cells may be more straightforward than from other stem cell lines (74). Although dopaminergic neurons have been obtained from neuronal stem cell lines, particularly after treatment with FGF, GDNF, and other modulators of cell signaling (75), the dominant cell type produced is often not neuronal but astroglial. Nonetheless, some encouraging results have been obtained in animal models transplanted with neuronal stem cells (76). Other Non-Neuronal Stem Cells Several other stem cell types have also been considered. Genetic and hormonal manipulations of stem cells from bone marrow (77), skin (78), and umbilical cord blood (79) have produced cells with neuronal characteristics. Some bone marrowderived cells express tyrosine hydroxylase (80), though evidence to prove that these cells produce dopamine is lacking. In addition, some of the apparent conversion of stem cells to neurons may be due to cell fusion not differentiation (81). In light of their increased complexity, the use of non-neuronal stem cells to generate neurons for the treatment of PD remains controversial. Stem cells provide a potential solution to the problems associated with the acquisition and transplantation of fetal dopaminergic neurons for the treatment of PD. However, the use of stem cells also introduces additional complexity, as greater control of cellular growth and differentiation is required. The results, though preliminary, are encouraging, as stem cell transplantation has been demonstrated to produce functional improvements in animal models of PD. Human studies, however, must await the solution to the many technical and safety challenges. GENE THERAPY Perhaps the most promising prospects for the future therapy of PD lie in gene therapy. Theoretically, the alteration or insertion of genetic material to correct or compensate diseased neurons should provide the most comprehensive therapy for a degenerative disease such as PD. A host of complex technologies are currently in various stages of clinical and preclinical study (82). Strategies of Gene Therapy Ongoing research in gene therapy has segregated itself into several specific strategies of disease treatment. These include the viral transmission of enzymes in the dopamine synthesis pathway to restore local dopamine concentrations; the transmission of genes for neurotrophic factors such as GDNF and neurturin to support and protect remaining dopaminergic neurons; the delivery of genes like parkin designed to restore underlying genetic deficits; and the delivery of genes that alter the phenotypic function of local cells to perpetually balance the aberrant function of the basal ganglia. Each of these methods has benefits and it is possible that a combination will be most effective. All share the advantage that, if they are effective, they could provide a single intervention for PD without the need for pump refilling or battery changes and without the potential ethical complications of cellular transplantation therapies. Dopamine Synthesis Gene Therapy The most direct rationale for treating PD is to confer a dopaminergic phenotype to cells within the striatum. This method should result in local production of levodopa

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or dopamine, thereby avoiding side effects of systemic drug delivery. To this end, several groups have designed therapies that deliver, via a viral carrier, genes in the dopamine biosynthetic pathway. The first reports in the early 1990s relied on the implantation of exogenously modified fibroblasts. These cells were harvested, amplified, and then genetically modified to produce enzymes such as tyrosine hydroxylase. Reimplantation resulted in an increase in striatal dopamine levels in rodent models (83–85). Later studies accomplished the delivery of such genes directly to striatal cells with viral agents. A study by During et al. demonstrated that direct striatal transmission of tyrosine hydroxylase to rats by defective herpes simplex virus (HSV) produced substantial increases in levodopa and dopamine (as measured by striatal microdialysis), and produced a 60% reduction in amphetamine-induced spinning behavior which was maintained for a full year after treatment (86). Another study demonstrated the adeno-associated virus (AAV) delivery of aromatic amino acid decarboxylase (AADC) in a rat model of PD. Transfer of the AADC gene restored dopamine production from 5% to 50% of normal in 6-OHDA-lesioned rats. In these rats, behavioral effects were also noted, but this required the administration of systemic levodopa, although in smaller doses (87). The generation and release of dopamine is a complex process. Dopamine synthesis requires tyrosine hydroxylase, guanosine triphosphate cyclohydrolase I (GTP-CHI), and AADC (87–89). Further, production alone does not confer the machinery for transmitter packaging and organized release. For this reason, several researchers have adopted strategies designed to deliver the multiple genes involved in dopamine production. Results suggest that the combined delivery of these genes is more effective than transduction with individual genes (90). One study additionally provided a vesicular monoamine transporter (VAT-2), enabling coordinated dopamine release and preventing elevated dopamine in the cytosol from inhibiting the action of tyrosine hydroxylase. This construct had a greater effect on rotational behavior than constructs without the VAT-2 gene and produced local levels of dopamine that were similar to those measured in normal rats (91). The conference of multiple enzymes has been shown to decrease drug-induced dyskinesia by 85%. It is thought that the continuous release of dopamine conferred by gene transfer corrects the otherwise pulsatile delivery, even when medical therapies are ongoing (92). Studies have been extended to primate models as well. An early study demonstrated the feasibility of transfecting tyrosine hydroxylase and AADC to produce dopamine in the primate striatum but showed no significant behavioral changes (93). Later, Matsumura et al. demonstrated that AAV transmission of tyrosine hydroxylase, AADC, and GTP-CHI in primates produced substantial improvements in manual dexterity tasks and resulted in increased striatal dopamine levels relative to the untreated side (94). These techniques certainly hold great promise for the clinical treatment of PD by methods that are more physiologic with potentially fewer side effects. Clinical trials employing viral delivery of dopamine synthetic enzymes are ongoing. Genetic Delivery of Neurotrophins The second strategy relies on the neuroprotective effects of the neurotrophin GDNF or its close relative neurturin. These factors have previously been demonstrated to provide substantial preservation of dopaminergic inputs to striatum. Evidence for this effect in animal models and in clinical case reports represent a considerable body

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of evidence that the strategy is sound. Despite the recent negative trials of GDNF micro-infusion by intraventricular administration (39,95) and by direct administration into the striatum (41), it is possible that local expression of GDNF provided by gene therapy would generate sufficient product to create benefit (96). Local production might also limit the side effects noted with exogenous delivery. Numerous studies have demonstrated success of viral GDNF therapy in rats. Several viral vectors have been used to deliver GDNF to the striatum and SNc, including adenovirus, AAV, herpes virus, and lentiviruses. Of these, herpes viruses were noted to be problematic, providing only limited benefit and demonstrating significant toxicity related to purification methods (97). The other models have demonstrated the ability to generate stable and sufficient quantities of GDNF, to maintain or restore tyrosine hydroxylase activity, and, in several cases, to improve parkinsonian behavioral correlates (98,99). Recent studies have adopted more complex models to more nearly approximate PD. In one study, Brizard et al. selected a rat model for progressive degeneration by injecting on SNc with a partial dose of 6-OHDA. This model is thought to more closely approximate the gradual degeneration of PD. They found that, four weeks after lesioning, addition of a lentiviral vector conferring GDNF production (lenti-GDNF) restored dopaminergic innervation of the striatum to near normal levels. This was accompanied by behavioral improvements in a task requiring pawreaching to obtain food pellets (100). Similar studies have examined performance of complex motor selection tasks in rats pretreated with lenti-GDNF prior to 6-OHDA lesioning (101). These studies suggest treatment success in behavioral models more relevant to human disease. Several other neurotrophins have been tested for their protective effect on nigrostriatal neurons. A study by Fjord-Larsen et al. demonstrated that in vivo lentiviral delivery of a modified neurturin construct produced neuroprotection of rat nigrostriatal projections. Tyrosine hydroxylase immunoreactive neurons were 91% of the unlesioned side. This was equivalent to the effect of lentiviral GDNF transduction (102). A similar study using HSV delivery to compare the effect of GDNF and brain-derived neurotrophic factor (BDNF) in vivo demonstrated that BDNF is less efficient in preserving nigrostriatal neurons or restoring normal behavior than GDNF (103). GDNF delivery by lentivirus has been demonstrated in primates to produce stable transmission of the GDNF gene in both aged unlesioned monkeys and in young MPTP-lesioned monkeys. PET studies in the aged monkeys, who had received lentiviral GDNF administration to both the striatum and the substantia nigra, demonstrated that putaminal GDNF administration increased fluorodopa uptake by 37% on the treated side. Histological analysis demonstrated stable delivery of GDNF and migration from the injection site into the pallidum. Tyrosine hydroxylase immunoreactivity was also increased to 39% and 44% in the caudate and putamen, respectively. The number of tyrosine hydroxylase-reactive cells in the substantia nigra increased 85% on the side of GDNF viral delivery. Young monkeys were treated with GDNF one week after unilateral administration of MPTP. Treatment with the lenti-GDNF showed significant increases in striatal fluorodopa uptake, averaging a three-fold increase, compared to controls. These animals were monitored for several months for performance on a hand-reaching task and for assessment with a modified clinical rating scale. The treated monkeys showed significant improvements both in the clinical assessment and in their speed on the hand-reaching task (104).

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The expression of GDNF after viral delivery has been noted specifically to increase the number of tyrosine hydroxylase expressing striatal cells by an average of seven-fold. This suggests that the addition of GDNF may act to confer a dopaminergic phenotype to adult striatal cells, in addition to preserving dopaminergic nigral inputs onto the striatum (105). Now established in rodent and primate models, GDNF gene therapy holds considerable promise for the treatment of PD. Gene Therapy to Alter Basal Ganglia Physiology The manipulation of basal ganglia circuit function may be possible by the strategic placement of genes designed specifically to alter normal function. Recent studies by Kaplitt et al. have used gene therapy to change the normal excitatory input of the STN-GPi projection to an inhibitory gamma amino butyric acid (GABA)ergic projection. Rats with chemical lesions in the substantia nigra were treated with viral delivery of glutamic acid decarboxylase (GAD) via an AAV vector into the STN. They subsequently showed a reversal of SNr responses to STN stimulation with excitatory and inhibitory ratios changing from 83% and 6% to 17% and 78%, respectively. This was associated with a 65% decrease in amphetamine-induced rotational behavior (106). A clinical study is now underway, exploring the role of this potent new therapy in the treatment of PD (107). Parkin Gene Therapy The apparent success of gene therapy in conferring novel capabilities to nigral and striatal cells has led some researchers to question if the pathology underlying PD can be reversed in a more physiologic manner. Genetic analyses of PD families have demonstrated a number of genes linked to the disease. These mutations seem to share a role in intracellular housekeeping and the processing of intracellular protein residue. It is estimated that approximately 0.4% to 0.7% of patients diagnosed with idiopathic PD have Parkin mutations. This proportion dramatically increases to nearly 20% in cases of early-onset sporadic PD, and to almost 50% if there is evidence of familial transmission (108). In these patients, loss of Parkin’s E3 ligase activity leads to degeneration of dopaminergic neurons. LoBianco et al. have used lentiviral delivery to increase expression of the normal Parkin gene in the substantia nigra of rats that were also transfected with the human alpha-synuclein gene. Viral expression of alpha-synuclein is known to cause degeneration of dopaminergic nigral neurons in rats. The addition of a vector delivering a wild-type parkin gene was found to have a substantial protective effect, reducing dopaminergic cell loss from 31% to 9%. Interestingly, this was accompanied by a 45% increase in alpha-synuclein inclusions, suggesting that Parkin exerts its neuroprotective effect by precipitating an otherwise soluble toxic synuclein compound (109). This has significant implications for the pathogenesis of the disease. It also suggests a potential therapy that could be used to halt the progression of PD. A similar study has examined the effect of chaperone heat-shock protein-70 (Hsp-70) in nigral protection. Hsp-70 has been shown to be a suppressor of alphasynuclein toxicity in Drosophila models of PD (110). A study by Dong et al. used an AAV carrier to deliver Hsp-70 to the substantia nigra of MPTP-treated mice. They demonstrated that expression of the gene reduced nigral cell loss from 37% in control animals to 16%. It also was found to produce an increase in amphetamineinduced rotational behavior, indicating that behaviorally significant neuroprotection had occurred (111). The common strategy of providing or restoring protective factors

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in cells failing to process cellular waste is particularly appealing, as it targets and reverses what may be the central pathology of PD. Intravenous Gene Delivery Although the majority of gene therapy studies have relied on a surgical delivery of genetically altered cells or of viral vectors to transmit the desired genes, a recent line of research has experimented with engineered liposomes that are immunologically targeted to be taken up by neurons. Plasmid DNA containing the gene intended for transfer (such as tyrosine hydroxylase) is packaged in a 100-nm liposome. The structure is stabilized by the incorporation of several thousand polyethylene glycol residues. A percentage of these are conjugated to monoclonal antibodies that target either the insulin or transferrin receptors. The antibody targeting causes the liposomes to be selectively taken up in the brain. Association of the desired gene with a glial fibrillary acidic protein (GFAP) promoter further specifies the location of gene activity (112). Genes packaged by this technique can be delivered by a simple intravenous administration. Pardridge et al. (112) have demonstrated the ability of this technique to deliver a desired gene specifically to the brain in both rodents and in rhesus monkeys. They have further shown that the same intravenous delivery of the tyrosine hydroxylase gene can reverse rotational behavior in 6-OHDA-lesioned rats (112–114). Although these studies are still quite preliminary, they offer the additional hope that the genetic modifications described earlier might eventually be delivered with decreased risk and discomfort to the patient. This might also allow a more measured and gradual titration of delivery to maximize benefit and limit side effects. SUMMARY The future of PD treatment will be influenced by several innovative therapeutic modalities. Transient or perhaps permanent roles will be played by the techniques of neural stimulation, cellular transplantation, and gene therapy. Considerable research in each of these areas is already underway. In time, the stimulatory interventions that have been so successful in the last decade may give way to more innovative cellular and genetic strategies that can restore and, perhaps, eventually will reverse the degenerative pathology of PD. REFERENCES 1. Hamani C, Richter E, Schwalb JM, Lozano AM. Bilateral subthalamic nucleus stimulation for Parkinson’s disease: a systematic review of the clinical literature. Neurosurgery 2005; 56(6):1313–1321; discussion 1321–1324. 2. Gentil M, Garcia-Ruiz P, Pollak P, Benabid AL. Effect of bilateral deep-brain stimulation on oral control of patients with parkinsonism. Eur Neurol 2000; 44(3):147–152. 3. Dromey C, Kumar R, Lang AE, Lozano AM. An investigation of the effects of subthalamic nucleus stimulation on acoustic measures of voice. Mov Disord 2000; 15(6):1132–1138. 4. Saint-Cyr JA, Trépanier LL, Kumar R, Lozano AM, Lang AE. Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson’s disease. Brain 2000; 123(Pt 10):2091–2108. 5. Santens P, De Letter M, Van Borsel J, De Reuck J, Caemaert J. Lateralized effects of subthalamic nucleus stimulation on different aspects of speech in Parkinson’s disease. Brain Lang 2003; 87(2):253–258.

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Physical and Occupational Therapy Atul T. Patel Department of Rehabilitation, Research Medical Center, Kansas City Bone and Joint Clinic, Overland Park, Kansas, U.S.A.

Sean Shire Department of Rehabilitation, Research Medical Center, RMC-Brookeside, Kansas City, Missouri, U.S.A.

INTRODUCTION The deficiency of dopamine in Parkinson’s disease (PD) leads to several problems. One key problem is the interruption of smooth, coordinated muscle function. This in turn can affect complex tasks such as speech, mobility, and coordinated use of the limbs. PD is a progressive neurodegenerative disorder, which can be treated with various medications and surgical procedures. However, since this condition is progressive, it invariably affects functional activities such as mobility and activities of daily living at some point. There are two main factors that often impact functional activities in patients with PD. One is the direct result of the neurodegenerative process and its effect on coordination and other neurological functions. The other is the myriad of indirect effects related to neurological deficits and debilitation. Some of these secondary problems include problems such as decreased activity, deconditioning, depression, weight gain, joint pain and contractures, cognitive problems, drooling, constipation, and poor hygiene. These in turn lead to further disability and impairment. PD is more prevalent in older persons and, often, these patients have other comorbid conditions such as osteoarthritis, hypertension, diabetes, and cardiovascular disease. All of these comorbidities can worsen with deconditioning and further impact functional status. The focus of rehabilitation interventions in patients with PD is to maintain and possibly improve function. Although physical therapy (PT) and occupational therapy (OT) may have little or no impact on the progression of PD, they can have a very significant effect on quality of life, functioning, and prevention of secondary problems. ASSESSMENT Assessment needs to be comprehensive, focusing on function. A thorough history should be obtained to determine all the factors that may have an impact on the patient’s functioning. These include general medical history, functional history, vocational and avocational history, living situation, and support system. The neurodegenerative disease process of PD produces a host of physical impairments that affect the PD patient’s functional mobility and ability to participate in activities of daily living. Rigidity, tremor, bradykinesia, loss of postural control, and postural instability can all be present to some degree in PD patients, and these impairments in turn affect the ability to perform gross and fine motor tasks (1,2). Rigidity, especially trunk rigidity, negatively affects the ability to transfer when a sequence of segmental movements of several regions of the body is required. Tremor 441

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is often present and can be one of the first outward signs of PD; however, it seldom causes functional deficits since it usually stops when performing transfers or fine motor activities. Bradykinesia creates difficulty in the ability to perform repetitive movements. The progressively smaller movement arcs seen with bradykinesia are particularly evident in gait. It is also demonstrated by micrographia. Akinesia or freezing is another motor manifestation of PD and is characterized by difficulty in initiating a movement or a tendency to stop movement part way through a motor sequence. Attention to environmental distractions, such as a change in floor surface or doorways, is thought to be one cause of freezing during the gait cycle. Many individuals with PD also demonstrate difficulty in terminating action sequences. When walking, this can increase the risk of falling. Tremor, dyskinesia, and other unwanted and nonfunctional movements may be present to some degree and affect the individual’s functional mobility. Dystonia may occur when the patient has had prolonged overactivity of a certain muscle or muscle group or can be a side effect of levodopa. Dystonia can negatively affect posture and movement patterns (1). Numerous studies indicate that rehabilitative interventions can increase the ability to maintain independence with transfers, to ambulate safely in the home and community, to perform fine motor tasks, and to maintain a basic level of fitness for as long as possible (1–6). Definitions Physical Therapy The American Physical Therapy Association describes physical therapists as “health care professionals who diagnose and treat people of all ages who have medical problems or other health-related conditions that limit their abilities to move and perform functional activities in their daily lives. They also help prevent conditions associated with loss of mobility through fitness and wellness programs that achieve healthy and active lifestyles. Physical therapists examine individuals and develop plans using treatment techniques that promote the ability to move, reduce pain, restore function, and prevent disability.” The focus of the physical therapist in the management of PD is to address gross motor, strength, flexibility, and balance deficits that limit functional mobility such as transfers and ambulation (7). Occupational Therapy The American Occupational Therapy Association describes the occupational therapist’s role in the management of patients with a physical disability as “first focusing on performing critical daily routines such as dressing, grooming, bathing, and eating. Once these skills are mastered, a program is then built around the skills needed to perform tasks such as participating in education, caring for a home and family or seeking and maintaining employment.” The focus of the occupational therapist is to evaluate the fine motor deficits that affect the PD patient’s ability to manipulate objects with their hands and to perform activities of daily living (8). Terms Associated with Function The World Health Organization (WHO), in its 1980 international classification of functioning, disability, and health, defined impairment as an abnormality of a structure or function (e.g., abnormal muscle tone) (9). Disability was defined as the functional consequence of the impairment (e.g., the inability to walk safely). Handicap was defined as the social consequence of impairment (e.g., having to make a career

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change as a result of mobility difficulties). Using these definitions, distinctions can be made as to how one can function as a result of certain impairments. Not all impairments result in disabilities. One may also be disabled but not handicapped. The most recent revision of the WHO classification of functioning views an individual’s circumstances along the dimensions of body function, structure and activity, and participation. Hence, an impairment or problem in body functions or structure (abnormal muscle tone) may or may not affect an individual’s difficulty in the performance of activities (walking). Participation refers to the individual’s involvement in life situations and society’s response to the individual’s level of functioning. The purpose of the classification is to provide a unified and standard language that characterizes the consequences of health conditions (10). Therapy Evaluation History Evaluation of the PD patient is focused on determining the patient’s functional limitations. Range of motion, strength and balance deficits, postural deviations, general mobility, and level of conditioning are all assessed to determine their contribution to the patient’s overall activity level. The evaluation consists of three parts: the history, physical examination, and the functional assessment. This information is then utilized to determine a plan of care (11). The first component of both the PT and the OT evaluation is to take the history of a PD patient. It is important to determine at what state in the disease process the patient is presenting to the therapist. Information is obtained regarding the patient’s ability to perform a variety of functional tasks, including bed mobility, transfers, community ambulation, activities of daily living, work tasks, and recreational tasks. It is important to determine the patient’s medication schedule and any on/off fluctuations that may affect exercise performance. An account of freezing episodes, falls or near falls, or any specific situations in which mobility seems to be compromised needs to be noted. Comorbidities such as high blood pressure, heart disease, diabetes, pulmonary problems, cancer history, recent surgical history, depression, and dementia are all factors that affect the patient’s ability to participate in a rehabilitation program and must be assessed. It is also important to obtain a complete list of all medications that the patient is taking, not just PD medications, as medication can affect activity performance. During the course of taking the patient’s history, the therapist is generally able to determine any barriers the patient may have such as vision deficits, hearing impairment, or cognitive deficits that can affect ability to both learn and perform in a rehabilitation program. It is then crucial to discuss and set the goals of therapy with the patient and family. PD is a progressive condition and, generally, a return to prediagnosis level of function is not possible. The patient should be allowed to identify from their point of view, which deficits they want to improve the most and what level of function they think they can safely and realistically obtain. Whenever possible, the primary caregiver and other family members who are involved in the care of the patient should be engaged in this information gathering stage. Their point of view is often helpful in developing an appropriate rehabilitation program and modification of the patient’s activities. The OT evaluation includes many of the earlier noted elements in the history. The focus of the OT evaluation is to obtain information about specific tasks, requiring upper extremity dexterity for self-care skills and activities of daily living. Specifically, questions regarding level of independence with bathing, dressing, grooming, eating (including swallowing problems and oral control), toileting, functional communication

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(telephone use, writing, and keyboarding), housekeeping activities, cooking, driving, shopping, and work activities requiring upper extremity coordination (1,2,11). Physical Therapy Examination Posture Assessment Sitting and standing posture are observed with attention to trunk flexion, forward head, or uneven lower extremity weight-bearing. Postural deficits alter the body’s center of gravity during movement. Postural deficits also create muscle imbalances due to overly tight and overly stretched muscles that can contribute additional impairment to the rigidity and weakness, usually accompanying PD. Range of Motion The range of movements of all extremity joints, as well as the cervical and lumbar spine, are observed with the deficits or asymmetries recorded. A therapist will often use a goniometer and/or inclinometer to record exact range of motion (ROM). Precise measurements allow the clinician to establish a baseline to record improvement or disease progression. Flexibility is assessed with particular attention to large muscle groups such as the hamstrings, hip flexors, gastrocnemius–soleus complex, and the pelvic and shoulder girdle muscles (1). Strength Manual muscle testing is performed for all major muscle groups of the extremities, cervical spine, and core stabilization musculature. Weakness in PD patients tends to be due to deconditioning and other comorbidities. General Mobility The patient’s overall ability to move in a functional manner is recorded. In patients with PD, turning in bed, supine-to-sit and sit-to-stand transfers tend to be particularly difficult. Observation of rigidity patterns and loss of segmental movement are often noted with bed mobility. Difficulties with supine-to-sit transfer can result from core muscle group weakness, whereas sit-to-stand transfers can be compromised by inefficiency in shifting the center of gravity forward during the movement sequence. Gait Analysis Gait is evaluated on a level surface and, if possible, without the support device the patient may be using. Careful attention is paid to any postural changes, contributing to deviations in gait mechanics, deficits in dynamic balance, or safety with walking. The kinematics of the patient’s gait cycle is compared to normal standards and deviations are objectively recorded. It is possible to quantify elements of a patient’s gait by measuring velocity (i.e., time to cover a fixed distance) and stride length (i.e., number of steps taken over a fixed distance). If safe and appropriate, it is also important to observe the patient negotiate stairs, curbs, inclines, and uneven surfaces. Balance and Coordination Visser et al. (12) found the retropulsion test recommended by Nutt et al. (13) to be the best evaluation procedure for postural instability. The examiner stands behind the patient and, after an explanation and practice test, the patient is jerked backward by the shoulders. A normal test is taking a step or two backwards to correct. Several steps backwards or a fall into the examiner is defined as a balance deficit. Static balance can

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also be quantified by timing the patient’s ability to stand on one leg. A less objective but sometimes utilized method is to simply challenge the patient’s static balance in a random series of pushes or pulls on the patient’s shoulders, as they sit and stand. Dynamic balance can be assessed in a number of ways, including challenges to the patient’s center of gravity such as high knee walking, heel walking, toe walking, tandem walking, and a carioca or “braiding” side step. There are a number of simple tests utilized to assess coordination of movement. Finger to nose, pronation/supination of the wrists, tapping the hand on the knee, alternate heel to knee, and drawing a circle in the air are a few of the maneuvers observed and rated on their difficulty of performance. Other Elements A thorough palpatory examination of the musculature should be performed noting muscle tone and areas of pain. Other elements of the evaluation that should be assessed include inspection of the skin paying close attention to friction abrasions or bruising from falls, sensory testing, and deep tendon reflex testing. Occupational Therapy Evaluation The OT evaluation of the PD patient includes some of the same elements as noted for physical therapy. The focus in OT is generally on upper extremity coordination and control and in the context of activities of daily living and self-care activities (14). Range of Motion and Strength Testing ROM of the upper extremity and shoulder girdle are assessed. Cervical ROM is evaluated, as it may directly affect the patient’s ability to focus visually on the tasks they are performing. In addition to routine upper limb strength testing, grip and pinch dynamometer measurements are also made. Coordination In addition to the upper extremity coordination maneuvers described in the PT evaluation, an occupational therapist may utilize standardized tests of fine motor hand coordination, such as the Jebsen–Taylor Hand Function test, the Minnesota Rate of Manipulation test, and the Purdue Pegboard test (11). Functional Activities In this portion of the examination, a sample of activities of daily living and functional use of the upper extremities are actually simulated and performed by the patient. As the patient performs writing tasks, manipulates eating utensils, or puts on an article of clothing for example, careful attention to tremor, quality of movement, speed of performing tasks, and proficiency are recorded. Treatment Planning Once the evaluations are completed, a detailed problem list is derived and specific deficits that can be addressed with a rehabilitative treatment plan are outlined. Many underlying causes such as trunk rigidity, inflexibility, postural deviations, balance deficits, diminished fine motor control, core weakness, and general deconditioning can be used to develop a patient specific exercise and educational program. The treatment plan must contain both short- and long-term treatment goals. The problem list and goals help structure the exercise routine, the functional adaptations, patient and family education, and treatment strategies to be utilized, as the patient progresses

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through the short-term goals to the desired treatment outcome and long-term goal attainment at the time of discharge from therapy. REHABILITATION INTERVENTIONS Many of the problems the patient may have with functional mobility and ambulation may be significantly improved by directing an exercise and educational intervention to the secondary effects of the disease. Exercise Postural instability is created by a pattern of weakness, muscular tightness, and standing alignment changes that diminish the patient’s ability to control their center of gravity during transfers and gait. A common presentation is that of a stooped forward posture of the upper body with tight anterior chest wall musculature and a crouched lower body posture. A series of stretching exercises designed to diminish kyphosis of the thoracic spine and increase flexibility in the pectoralis major and minor muscles can lead to improved upper body posture and upper limb function. In the lower aspect of the body, strengthening of the lumbar paraspinal musculature and stretching of the hamstring and hip flexor muscles can be used to improve posture. It is important not only to stretch the key muscles in patients with poor posture, but to also strengthen the appropriate muscles to achieve good biomechanical alignment. To improve muscle length, therapists use several techniques, including heat and cold modalities, stretching postures, bracing, strengthening of antagonist muscles, and proper positioning of the affected limb. Frequently, thoracic extension and scapular stabilization exercises are utilized to assist with correcting a kyphotic posture, and abdominal, paraspinal, and pelvic girdle strengthening exercises are used to help improve trunk control. Difficulty with bed mobility and transfers is usually the result of trunk rigidity and core weakness. These problems are tackled by exercises to increase trunk flexibility and segmental mobility, and core muscle strengthening of the abdominals, paraspinal, and pelvic girdle muscles. Many patients with PD present with generalized weakness (1,2). The weakness is often both in strength and endurance. Strength can be targeted with the use of specific exercises for the affected area. Closed kinetic chain functional strengthening is used for lower limb strengthening. Gentle aerobic exercises may also be introduced, once the patient is able to safely tolerate more exercises. This can be helpful not only for strengthening but also for general conditioning. A walking program, utilization of aerobic exercise equipment such as a stationary bike or elliptical glider, or an aquatic conditioning program may all be implemented to address large muscle group weakness and general deconditioning. Simple balance training exercises such as practicing one-legged stance, tandem walking, heel and toe walking, and carioca or “braiding” are often employed to enhance dynamic balance with walking and transfers. Exercise for the PD patient should be individualized to their functional deficits, ROM, and strength and balance deficits. Safety with ambulation is often an issue for the PD patient (1,2). Dynamic balance, bradykinesia, and postural instability all contribute to impairments with walking and negotiating obstacles in the home and community. PD patients seem to ambulate more easily with external cues that are visual, auditory, or proprioceptive (1).

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For example, placing lines on the floor of an appropriate stride length or placing small objects on the floor for the patient to step over help to facilitate a more normal stride length and swing through leg clearance (2). If appropriate, dynamic balance exercises may improve foot placement, center of gravity control, and postural control during the gait cycle. These are typically introduced to the patient in the parallel bars initially, with instruction on how to safely duplicate the exercise activity in the home. Depending on the disease severity, instruction on the use of canes or walkers and evaluation for a manual wheelchair, a motorized scooter, or a motorized wheelchair may be needed. Activity Modification The negative effects of PD on the basal ganglia and supplementary motor area seem to cause the individual to utilize the premotor cortex to a greater degree to control movement (1). Both physical and occupational therapists utilize this concept to help break down activities into their component parts and instruct the patient to utilize cognitive strategies to control movement. Thus, working with a patient to get out of bed becomes a sequence of individual tasks such as roll to side, bend at knees and hip, move lower legs off edge of bed, pushup with elbow, bring body to upright position at edge of bed, lean upper body forward, and stand up to accomplish the end result of “getting out of bed.” Occupational therapists would similarly break down fine motor self-care activities such as writing and feeding. With a combination of the adaptive equipment and aids, simple tasks such as opening jars, operation of small appliances, and shuffling cards can all be broken down into component parts that the patient can then work to control. Education One of the most critical elements in the rehabilitation efforts directed at a PD patient is education. A physical therapist is often best equipped to explain movement and modified movement strategies to the patient and their caregivers (2). Similarly, the occupational therapist is best able to recommend adaptive equipment and alternate movement strategies during activities of daily living and self-care tasks. All rehabilitation clinicians involved in the case should be aware of community resources and educational material and be able to direct their patients to these resources. The PD patient in later stages of the disease often needs assistance with transfers and bed mobility, making appropriate lifting technique and body mechanics instruction critical. Adaptive Equipment and Environmental Changes Occupational therapists can often recommend adaptive equipment to make activities of daily living easier, such as modified eating utensils, reaching aids, and dressing aids to facilitate ease of performance. Both PT and OT therapists can assist and educate the patient and caregiver on changing the environment of their home to make it easier to maneuver in the home and to enhance safety and reduce falls. As the patient’s function warrants, grab bars may need to be installed to assist with sitto-stand transfers from the toilet and other low surfaces. Other equipment to consider includes high-rise toilets and shower chairs. A home visit can be helpful to identify risks for falls and recommendations to eliminate throw rugs and clutter on the floor, and placement of nightlights.

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EVIDENCE There are several studies in the literature that show the usefulness of PT and rehabilitation in the management of PD patients (15–17); however, there is sparse evidence in the literature supportive of the effectiveness of PT and OT in the treatment of patients with PD. One Cochrane review included 11 trials (18). They identified several limitations in the studies, including small number of patients examined, methodological flaws, and the possibility of publication bias, resulting in insufficient evidence to support or refute the efficacy of PT in PD. Ten of the 11 trials claimed a positive effect from PT; however, few outcomes measured were statistically significant. Significant improvement was noted in walking speed and stride length in two studies. A randomized controlled trial assessed the efficacy of group PT in patients with PD and found benefits in the short term on function and quality of life (3). Another Cochrane review assessed different PT techniques and found seven randomized controlled trials. Small numbers and other methodological problems made it difficult to support or refute the efficacy of any given form of PT over another for PD (19). FUTURE STUDIES The Cochrane review recommended that future studies specify the stage of PD at which the PT is provided; functional outcomes with particular relevance to the patients, caregivers, and physicians be monitored for at least six months to determine the duration of any beneficial effects; and future studies adhere to the Consolidated Standards of Reporting Trials (CONSORT) guidelines (20). In addition, there is a need for assessment of different therapy interventions to better identify the most effective treatments. Currently, there is a marked variation in the setting and type of therapies provided. Better identification of therapies in different settings (home, outpatient, group, individual, etc.) would be useful. SUMMARY Therapy and rehabilitation interventions can potentially slow the deterioration of function due to PD and possibly even enhance function, especially when comorbid conditions are addressed. The impact of therapy intervention needs to be further assessed with respect to the quality of life, depression, reduction in falls, reduction in hospitalizations or institutionalization, reduction in pain, and the general functional status. REFERENCES 1. Morris ME. Movement disorders in people with Parkinson disease: a model for physical therapy. Phys Ther 2000; 80:578–597. 2. Turnbull G. Clinics in Physical Therapy: Physical Therapy Management of Parkinson’s Disease. New York: Churchill Livingstone, 1992. 3. Ellis T, de Goede CJ, Feldman RG, Wolters EC, Kwakkel G, Wagenaar RC. Efficacy of a physical therapy program in patients with Parkinson’s disease: a randomized controlled trial. Arch Phys Med Rehabil 2005; 86:626–632. 4. Stankovic I. The effect of physical therapy on balance of patients with Parkinson’s disease. Int J Rehabil Res 2004; 27:53–57. 5. Schenkman M, Cutson TM, Kuchibhatla M, et al. Exercise to improve spinal flexibility and function for people with Parkinson’s isease: a randomized, controlled trial. J Am Geriatr Soc 1998; 46:1207—1216.

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6. Gage H, Storey L. Rehabilitation for Parkinson’s disease: a systematic review of available evidence. Clin Rehabil 2004; 18:463–482. 7. http://www.apta.org 8. http://www.aota.org 9. WHO: International Classification of Impairments, Disabilities, and Handicaps: A Manual of Classification Relating to the Consequences of Disease. Geneva, Switzerland, World Health Organization, 1980. 10. http://www.who.int/en/ 11. O’Sullivan S, Schmitz T. Physical Rehabilitation Assessment and Treatment. 3rd ed. Philadelphia FA: Davis Company, 1994. 12. Visser M, Marinus J, Bloem B, Kisjes H, van cen Berg B, van Hilten J. Clinical tests for the evaluation of postural instability in patients with Parkinson’s disease. Arch Phys Med Rehabil 2003; 84:1669–1674. 13. Nutt JG, Hammerstad JP, Gancher ST. Parkinson’s Disease: 100 Maxims. London: Edward Arnold, 1992. 14. Crepeau EB, Cohn ES, Boyt Schell BA (eds.). Willard and Spackman’s Occupational Therapy. 10th ed.. Lippincott, Williams, & Wilkins: Philadelphia, 2003. 15. Hirsch MA, Toole T, Maitland CG, Rider RA. The effect of balance training and highintensity resistance training on persons with idiopathic Parkinson’s disease. Arch Phys Med Rehabil 2003; 84:1109–1117. 16. Pohl M, Rockstroh G, Ruckriem S, Mrass G, Mehrholz J. Immediate effects of speeddependent treadmill training on gait parameters in early Parkinson’s disease. Arch Phys Med Rehabil 2003; 84:1760–1766. 17. Wade DT, Gage H, Owen C, Trend P, Grossmith C, Kaye J. Multidisciplinary rehabilitation for people with Parkinson’s disease: a randomized controlled study. J Neurol Neurosurg Psychiatry 2003; 74:158–162. 18. Deane KH, Jones D, Playford ED, Ben-Shiomo Y, Clarke CE. Physiotherapy versus placebo or no intervention in Parkinson’s disease. Cochrane Database Systematic Rev 2001; 1. 19. Deane KH, Jones D, Ellis-Hill C, Playford ED, Ben-Shiomo Y. Physiotherapy for Parkinson’s disease. Cochrane Database Systematic Rev 2001; 1. 20. Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA1996; 276:637–639.

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Voice, Speech, and Swallowing Disorders Shimon Sapir Department of Communication Sciences and Disorders, University of Haifa, Haifa, Israel

Lorraine Olson Ramig Department of Speech, Language, Hearing Sciences, University of Colorado, Boulder, and National Center for Voice and Speech, Denver, Colorado, U.S.A.

Cynthia Fox Tucson, Arizona, National Center for Voice and Speech, Denver, Colorado, U.S.A.

INTRODUCTION Nearly 90% of individuals with Parkinson’s disease (PD) develop voice and speech disorders during the course of their disease (1,2). These disorders are characterized by reduced voice volume (hypophonia); a breathy, hoarse, or harsh voice quality (dysphonia); imprecise consonant and vowel articulation due to reduced range of articulatory movements (hypokinetic articulation) and a tendency of these movements to decay and/or accelerate toward the end of a sentence; reduced voice pitch inflections (hypoprosodia, monotone); and rushed, dysfluent, hesitant, or stutteredlike speech (palilalia). Collectively, these disorders have been termed hypokinetic dysarthria (3). They may be among the first signs of PD, with hypophonia and dysphonia typically preceding articulation, prosodic and fluency disorders (1,2,4). Hypokinetic dysarthria in individuals with PD typically results in reduced speech intelligibility. Reduced facial expression (hypomimia) is also common in individuals with PD. Together, these can be interpreted as a person being cold, withdrawn, unintelligent, and moody (5,6). These factors may also impair the ability to socialize, convey important medical information, interact with family members, and maintain employment (5). Nearly 90% of individuals with PD will also develop swallowing disorders (dysphagia) at some point (7). Dysphagia symptoms in PD include difficulty with lingual motility, reduced initiation of swallow, difficulty with bolus formation, delayed pharyngeal response, and decreased pharyngeal contraction (7–9). These symptoms are often accompanied by weight loss and lack of enjoyment of eating. Aspiration pneumonia is common, especially in the later stages, and can be a cause of death in PD (10). Although neuropharmacologic and neurosurgical approaches have been shown to be effective in improving motor function of PD, their impact on voice, speech, and swallowing remains unclear (11). Traditional speech treatment of hypokinetic dysarthria has focused on rate, articulation, prosodic pitch inflection, and speaking in a louder voice, with only modest, short-lived therapeutic results (12,13). Swallowing treatment has focused on behavioral changes and diet modifications (9). A speech and voice treatment approach, known as the Lee Silverman Voice Treatment (LSVT®), has generated the first short- and long-term efficacy data (8,14,15) for suc451

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cessfully treating voice and speech disorders in PD. The LSVT ® has also been shown to improve tongue strength and motility (16), swallowing (8), facial expression (17), and brain function (18) in individuals with PD, but these research findings are preliminary. SPEECH AND VOICE CHARACTERISTICS Perceptual, acoustic, aerodynamic, kinematic, videostroboscopic, electroglottographic (EGG), and electromyographic (EMG) studies have documented disorders of laryngeal, respiratory, articulatory, and velopharyngeal function in individuals with PD (19–21). The neural mechanisms underlying these voice and speech disorders are unclear (22–25). Traditionally, these abnormalities have been attributed to rigidity, bradykinesia, hypokinesia, and tremor secondary to dopamine deficiency, yet there is little evidence in support of these etiologic factors. Alternative explanations for the speech and voice disorders have been proposed, such as deficits in internal cueing, sensory gating, scaling of movement amplitude, and self-regulation of vocal effort (4,26–28). These deficits have been hypothesized to be related to nondopaminergic or special dopaminergic mechanisms (29,30). Perceptual and Phonetic Characteristics of Voice and Speech Disorders in Parkinson’s Disease Darley et al. (3) reported one of the first systematic descriptions of perceptual characteristics of speech and voice in individuals with PD (3,31,32). They identified reduced loudness, monopitch, monoloudness, reduced stress, breathy, hoarse voice quality, imprecise articulation, and short rushes of speech as the most characteristic of the speech and voice disorders in PD. They termed these symptoms hypokinetic dysarthria. Logemann et al. (2) used phonetic and perceptual analyses to characterize voice and speech abnormalities in 200 nonmedicated individuals with PD. Of these individuals, 89% were found to have voice quality problems such as breathiness, hoarseness, roughness, and tremor and 45% also had speech prosody or articulation problems. Ho et al. (1) used perceptual and phonetic methods to characterize voice and speech problems in 200 individuals with PD. They found that voice problems were first to occur, with other speech problems (prosody, articulation, and fluency) gradually appearing later with more advanced disease. Sapir et al. (4) studied voice, prosody, fluency, and articulation abnormalities in 42 PD patients with speech problems. Of these individuals, 86% were found to have voice abnormalities, which tended to occur early in the course of the disease, and 45% had prosodic, fluency, and articulation abnormalities, which tended to occur at later stages. Acoustic Measures of Abnormal Voice and Speech in Parkinson’s Disease Acoustic analyses of voice and speech in individuals with PD have confirmed the perceptual descriptions of hypokinetic dysarthria. Fox and Ramig (33) documented reduced vocal sound pressure level (vocSPL) by 2 to 4 dB (at 30 cm) on a number of speech tasks in 29 individuals with PD, compared with age- and gender-matched controls, which is equal to a 40% change in vocal loudness. Ho et al. (34) found vocSPL in PD to decay much faster than in neurologically normal speakers. They interpreted this fading as symptomatic of frontostriatal dysfunction. Rosen et al. (35) examined intensity decay in the phonation of persons with and without PD on various speech

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tasks. They found that vocSPL declined more rapidly in PD than in normal, agematched speakers during syllable repetition [speech diadochokinesis (DDK)]. They also found that in some of the individuals with PD, there were abnormally abrupt changes in vocSPL during conversation. However, during sustained vowel phonation, vocSPL did not show decay more than that of normal controls. Some early studies (36,37) did not confirm a reduction in vocSPL even though the speech of individuals with PD was perceptually characterized by reduced loudness. The reasons for these discrepant findings are not clear. The presence or absence of vocal decay in parkinsonian speech is related, at least partially, to the specific speech task being performed (35), as well as to the severity of hypokinetic dysarthria (34). Prosodic pitch inflection in speech, measured acoustically as fundamental frequency (F0) variability, or standard deviation from the mean F0 (SDF0) has been reported to be consistently lower in individuals with PD when compared with controls. These findings are consistent with the perceptual characterization of parkinsonian speech as monotone or monopitch (31,32). A reduction in maximum fundamental frequency range has also been observed in the dysarthric speech of individuals with PD, when compared with the normal speech of healthy speakers (38). Voice quality is measured in terms of jitter (random cycle-to-cycle variation in the periodicity of the voice waveform), shimmer (random cycle-to-cycle variation in the amplitude of the voice waveform), and harmonics-to-noise ratio. These are acoustic indices of short-term phonatory stability. Such instability has been documented in the speech of individuals with PD, consistent with various perceptual characteristics of disordered voice quality (e.g., hoarse, breathy, harsh) (39,40). Longterm phonatory instability, reflected mainly in rhythmic changes in F0, has also been documented in individuals with PD (40). Physiologic Measures of Laryngeal Dysfunction in Parkinson’s Disease Disordered laryngeal function has been documented in a number of videoendoscopic and videostroboscopic studies. Hansen et al. (22) reported vocal fold bowing resulting in poor glottic closure in 94% of 32 PD patients, together with greater amplitude of vibration and laryngeal asymmetry. Smith et al. (41), using videostroboscopic observations, found that 57% of 21 PD patients had a form of glottal incompetence (bowing, anterior or posterior chink) on fiberoptic examination. Perez et al. (42) observed laryngeal tremor in 55% of 29 PD patients. The primary site of tremor was vertical laryngeal motion; however, the most striking stroboscopic findings in this study were abnormal phase closure and phase asymmetry. Additional data to support the laryngeal closure problems in PD come from analyses of EGG signals. Gerratt et al. (43) reported abnormally large speed quotient and poorly defined closing period in PD patients. Blumin et al. (44) used videostroboscopy and fiberoptic endoscopic techniques, as well as a voice handicap index (VHI) questionnaire, to assess laryngeal function in 15 individuals with severe PD. Of these individuals, 13 (87%) had significant vocal fold bowing and 14 (93%) selfreported significant voice handicap. These observations were consistent with the slow vocal fold opening relative to the rate of closure and incomplete closure of the vocal folds. EMG studies of the laryngeal muscles provided further information regarding laryngeal pathology in PD. Hirose and Joshita (45) studied the EMG data from the thyroarytenoid (TA) muscles in an individual with PD who had limited vocal fold movement. They observed no reduction in the number of motor unit discharges and

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no pathologic discharge patterns. They did find loss of reciprocal suppression of the TA during inspiration and interpreted this finding as evidence of deterioration in the reciprocal adjustment of the antagonist muscles. Their finding is consistent with deficits in sensory gating characteristics of PD (45). Luschei et al. (46) studied single motor unit activity in the TA muscle in individuals with PD and found a decreased firing rate in TA in male PD subjects. They interpreted these findings to suggest that PD affects rate and variability in motor unit activation (firing) in the laryngeal musculature. Baker et al. (21) found that absolute TA amplitudes during a loudness level task in individuals with PD were lower than that of young normal adults and normal aging adults. Gallena et al. (47) used TA EMG and nasoendoscopy to compare laryngeal physiology during speech of individuals with PD with and without levodopa and controls. Some patients were observed to have higher levels of laryngeal muscle activation, more vocal fold bowing, and greater impairment in voice onset and offset control with levodopa than without levodopa as well as in comparison to the controls. The seemingly conflicting reports of excessive and reduced TA activity may represent a common problem underlying laryngeal motor control, namely a deficit in sensorimotor gating. Respiratory Dysfunction in Parkinson’s Disease A number of studies have provided evidence, through various aerodynamic measurements, for disordered respiratory function in individuals with PD. These disorders include reduced vital capacity, reduced total amount of air expended during maximum phonation tasks, reduced intraoral air pressure during consonant/vowel productions, and abnormal airflow patterns (48–50). The origins of these airflow abnormalities are not clear but they may be related to variations in airflow resistance due to abnormal movements of the vocal folds and supralaryngeal area (50) or abnormal chest wall movements and respiratory muscle activation patterns (23,48,51). Articulatory and Velopharyngeal Disorders: Acoustic and Kinematic Correlates of Articulatory Abnormalities in Parkinson’s Disease Imprecise consonants and vowels may be present in 45% of PD patients with dysarthria (2,28). Logemann et al. (2) reported articulation problems in 45% of 200 unmedicated patients. They suggested that inadequate narrowing of the vocal tract due to hypokinetic articulatory movements may underlie problems with stops /p/, /b/, affricates/ sh/, /ch/, and fricatives /s/, /f/. Acoustic correlates of disordered articulation include problems with timing of vocal onsets and offsets (voicing during normally voiceless closure intervals of voiceless stops) (24) and spirantization (presence of fricative-like, aperiodic noise during stop closures), as well as problems with articulatory undershoot, reflected in vowel formant frequencies (28). Dysarthric speakers with PD showed longer voice onset times (VOTs) than normal (52). Such abnormal VOTs may reflect a problem with movement initiation (52), which may be related to deficits in internal cueing, timing, and/or sensory gating (4,53). Sapir et al. (4) reported abnormal articulation in 50% of 42 medicated patients with PD. In another study, Sapir et al. (28) analyzed acoustic parameters of vowel articulation in individuals with and without PD reading sentences aloud. They found abnormally high second formant (F2) during the production of the vowel /u/, and abnormally low ratio of F2 of the vowel /i/ and

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the vowel /u/ (F2i/F2u) in the speech of individuals with PD compared with the speech of the neurologically normal age-matched controls. These acoustic abnormalities most likely reflect reduced range of articulatory movements during vowel production. Kinematic analyses of jaw movements demonstrated disordered articulatory movements in individuals with PD (52,54–57). These individuals show a significant reduction in the size and peak velocity of jaw movements during speech when compared with neurologically healthy individuals without speech problems (52,57–59). Also, jaw movement of individuals with PD is approximately half the size of the jaw movements observed in nondisordered speakers. Although the reduction in range of movement has been attributed to rigidity of the articulatory muscles (60), it is more likely that these movement abnormalities are related to problems with sensorimotor gating, perception, and/or amplitude scaling of speech and nonspeech movements (1,26,27,53). In contrast to range of movements, durations of movements in individuals with PD have been reported to be similar to those of healthy individuals (52). EMG studies of the lip and jaw muscles in individuals with and without PD have provided some evidence for increased levels of tonic resting and background activity (19,20,61), as well as loss of reciprocity between agonist and antagonistic muscle groups in these individuals (19,20). These findings are consistent with evidence for abnormal sensorimotor gating in the orofacial and limb systems, which are presumably related to basal ganglia dysfunction (62,63). Whether these abnormal sensorimotor findings are indicative of excess rigidity in the speech musculature is not clear (56,57,64). Hunker et al. (58) found evidence to suggest a positive correlation between muscle stiffness and decrements in the range of lip movement. However, Conner et al. (56,57) found no evidence for excess rigidity in jaw muscles during speech movements, but they did find some abnormalities during nonspeech, visually guided movements. They concluded that motor impairment in PD may be taskdependent. Caliguiri (64) obtained measures of labial muscle rigidity and movement for 12 parkinsonian and 9 age-matched control subjects. Displacement amplitude, peak instantaneous velocity, and movement time were evaluated during repetitive syllable productions. He reported that although mean displacement amplitudes and velocities were lower for the subjects with PD compared with the normal controls, there was no statistical relationship between labial rigidity and the degree of movement abnormality. He concluded that although rigidity may play a part in the overall disability, it does not sufficiently explain the labial articulatory difficulties associated with PD. He further argued that rigidity and bradykinesia probably represent independent pathophysiologic phenomena. Disordered vs. Compensated Rate of Speech in Parkinson’s Disease Disordered rate of speech has been reported in some individuals with PD, and rapid rate or short rushes of speech have been reported in 6% to 13% of individuals with PD. Palilalia or stuttering-like speech disfluencies have been observed in a small percent of individuals with parkinsonism (30,31). The discrepant findings of speech rate in parkinsonian speech (slow vs. rapid) may be related to the presence or absence of compensatory mechanisms. Caliguiri (55) found, using kinematic analyses, that lip movements were normal when individuals with PD spoke at a rate of 3 to 5 syllable/sec, but hypokinetic when the rate increased to 5 to 7 syllable/sec, which is the typical rate of conversational speech. Similarly, Ackermann et al. (53) described a

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patient with akinetic-rigid PD who was instructed to synchronize labial DDK to sequences of periodic acoustic stimuli (2.5 – 6 Hz). This individual was able to synchronize his DDK to the stimulus rate up to 4 Hz, but when the stimulus rate exceeded 4 Hz, his DDK was uncontrollably produced at 8 to 9 Hz, indicating speech hastening. These findings suggest that some patients may slow down their speech to prevent the tendency for the articulator to uncontrollably accelerate and deteriorate beyond a certain rate (65). Resonance Problems in Parkinson’s Disease Resonance problems are not common in PD, but when they are present, the voice often sounds like a foghorn. The acoustic and physiologic nature of this phenomenon is not clear, and perceptually, it is difficult to determine whether the voice is hypernasal or hyponasal. Aerodynamic and kinematic studies suggest that velopharyngeal movements may be reduced in some of these individuals (22,52,56). Abnormal tongue posture may also contribute to the resonance in parkinsonian speech. The abnormal resonance may also reflect motor symptoms not directly caused by PD such as pharmacologically induced dystonic or dyskinetic movements of the velopharyngeal and/or tongue muscles. Sensorimotor and Perceptual Deficits Underlying Motor Dysfunction in Parkinson’s Disease Sensory problems in PD have been recognized for years (66), and these problems may underlie some of the disorders of the speech system. Sensorimotor deficits in the orofacial system (62,63,67) and abnormal auditory, temporal, and perceptual processing of voice and speech (26,27,53,68) have been documented in PD (28,63) and have been implicated as important etiologic factors in hypokinetic dysarthria secondary to PD (69). Schneider et al. (63) found marked sensorimotor deficits in the orofacial and limb systems of individuals with PD. They observed that individuals with PD, compared with age-matched controls, showed greater deficits in tests of sensory function and sensorimotor integration. They suggested that PD patients might have complex deficits in the utilization of specific sensory inputs to organize and guide movements due to abnormal sensory gating or filtering associated with basal ganglia motor dysfunction. Caliguiri and Abbs (62) described abnormal orofacial reflexes in some but not all individuals with PD. Problems in sensory perception of effort have been identified as an important focus of successful speech and voice treatment for individuals with PD (70). It has been observed (33) that when individuals with PD are asked to produce loud speech, they increased their otherwise underscaled soft speech to a level within normal limits but felt they were talking too loud. Thus, it appears that sensory kinesthesia problems may be a factor in the speech and voice disorder observed in individuals with PD. Ho et al. (27) compared voice loudness perception in individuals with PD and hypophonic dysarthria with that of neurologically normal speakers. They found that unlike the normal speakers, the patients overestimated the loudness of their speech during both reading and conversation. They interpreted these findings to suggest that either impaired speech production is driven by a basic perceptual fault or that abnormal speech perception is a consequence of impaired mechanisms involved in the generation of soft speech. The latter explanation may be related to the phenomenon of central inhibitory influences of the vocal motor system, via feed-forward mechanisms, on auditory cortical activity during self-produced vocalization.

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This phenomenon has been demonstrated in humans and animals (71–73) and has been argued to be defective in PD, thus interfering with self-monitoring and selfregulation of vocal loudness and effort (28). Ho et al. (26) also examined the ability of individuals with PD and neurologically normal individuals to adjust their voice volume in response to two types of implicit cues, background noise and instantaneous auditory feedback. Control subjects demonstrated the Lombard effect by automatically speaking louder in the presence of background noise. They also decreased speech loudness in the presence of increasing levels of facilitative instantaneous auditory feedback. Subjects with PD demonstrated a decreased overall speech loudness; they were less able than controls to appropriately increase loudness as background noise increased and to decrease volume as auditory feedback increased. However, under explicit loudness instructions, the ability of subjects with PD to regulate loudness was similar to that of the normal controls, suggesting that individuals with PD have the capacity to speak with normal loudness, provided that they consciously attend to speaking loudly. The subjects with PD had overall speech loudness that was always lower than for control subjects, suggesting either a reduction of cortical motor input to the speech subsystems, or abnormal perception of their own voice via motor-to-sensory inhibitory mechanisms. It has been suggested that the main function of the basal ganglia is to serve as an amplifier, by controlling the gain, through gating and scaling, of cortically generated movement patterns (74). Penny et al. (75,76) suggested that basal ganglia excitatory circuits inadequately activate cortical motor centers, and as a result, motor-neuron pools are not provided with adequate facilitation, thus movements are small and slow. Berardelli et al. (77) suggested that the defect in motor cortex activation is due to a perceptual failure to select the muscle commands to match the external force and speed requirements. Maschke et al. (78) referred to this as a problem with kinesthesia and stated that when individuals with PD match their effort to their kinesthetic feedback, they will constantly underscale their movement. In sum, the neurophysiologic mechanisms underlying hypokinetic dysarthria in PD are poorly understood; however, speech motor abnormalities are at least partially secondary to sensorimotor gating abnormalities and poor perception of one’s own voice. SWALLOWING DISORDERS Swallowing disorders occur in up to 90% of individuals with PD (69) and may be among the first, though subtle or covert, signs of the disease (9). Identification of swallowing disorders is extremely important in this population, given the ramifications on nutrition and the ability to take oral medication appropriately. Silent aspiration may be observed and pneumonia can be a cause of death in advanced PD. Swallowing abnormalities have been reported in all stages of PD (79) and many individuals with PD have more than one type of swallowing dysfunction (7). Disorders in both oral and pharyngeal stages of swallowing have been observed (7,79). Sharkawi et al. (8) found abnormalities in the oral phase of swallowing in PD, the most predominant being reduced tongue control and strength and reduced oral transit times. Others have reported a rocking-like motion of the tongue during the oral phase (9). This motion seemed to occur when the patients were unable to lower the posterior portion of the tongue to propel the bolus into the pharynx. Inability or delayed ability to trigger the swallowing reflex has also been observed in this population (9). These

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disorders may limit the ability of the individual with PD to control the food or liquid bolus while in the oral cavity. These problems may lead to choking, penetration, or aspiration of the food or liquid. Reduced nutritional intake, lack of enjoyment in eating, and difficulty taking medications appropriately can result from oral-phase swallowing dysfunction. The specific neurophysiologic mechanisms underlying such dysphagic abnormalities in PD are not clear. Sensory gating and cueing deficits, which have been implicated in the hypokinetic dysarthria of individuals with PD, may also be etiologic factors in dysphagia during the oral phase. Pharyngeal stage dysfunction includes residue in the valleculae due to reduced tongue base retraction. Sharkawi et al. (8) reported this problem to be the most common disorder in the pharyngeal stage of swallowing. Blumin et al. (44) reported that 15 (100%) patients with severe PD had some degree of pharyngeal residue of solids on videostroboscopy and fiberoptic endoscopic evaluation of swallowing. Aspiration may occur in these patients as a result of the residue left in the pharynx after the swallow is complete (9). Leopold and Kagel (7) found several disorders of laryngeal movement during swallowing in PD. These included slow closure, incomplete closure, absent closure, and slowed or delayed laryngeal excursion (7). Increased pharyngeal transit time was also reported. Silent aspiration has been observed in the later stages of PD and can be a contributory cause of death (10). Dysfunction in the pharyngeal stage of swallowing may also lead to choking, penetration, aspiration, reduced nutritional intake, or reduced ability to take medication orally. Again, sensory and internal cueing deficits may underlie these swallowing problems. It is unlikely that muscle rigidity is responsible for the dysphagia, since swallowing dysfunction occurs even when individuals with PD are considered optimally medicated. Referral for swallowing evaluation is extremely important at the first sign of problems even if this is early in the disease. Dysphagia is not merely a sensorimotor disorder. As suggested by Leopold and Kagel (7), swallowing involves a five-stage process of ingestion: preoral (anticipatory), preparatory, lingual, pharyngeal, and esophageal. The first stage involves an interaction of preoral motor, cognitive, psychosocial, and somataesthetic elements engendered by the meal. If deficits in internal cueing, sensorimotor gating, scaling of movement amplitude, and self-regulation of effort affect swallowing, especially during the preoral, preparatory, and lingual stages, and if mealtime is a social event, swallowing and conversation may be performed simultaneously or alternatively and might be especially problematic for individuals with PD creating a greater risk for dysphagia and aspiration. EFFECT OF MEDICAL TREATMENTS FOR PARKINSON’S DISEASE ON SPEECH AND SWALLOWING Although neuropharmacologic and neurosurgical approaches have had positive effects on the primary symptoms of PD, their effects on voice, speech, and swallowing have been inconsistent. Several studies have assessed the effects of levodopa and dopamine agonists on voice and speech functions in PD. Gallena et al. (47) studied the effects of levodopa on laryngeal function in six persons with early PD who were not receiving medication. They found that levodopa reduced excessive laryngeal muscle activity and vocal fold bowing and improved voice onset and offset control during speech in some patients. De Letter et al. (80) reported significant improvement in speech intelligibility with levodopa. Goberman et al. (81) examined the acoustic-phonatory characteristics of speech in nine individuals with PD and motor

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fluctuations before and after taking levodopa. They found that the voice F0 variability in vowels and mean F0 were higher, and intensity range was lower when onmedication, compared with off-medication. They also found that differences in speech between on- and off-medication were small, although in some individuals phonation clearly improved. Jiang et al (82) assessed the effects of levodopa on vocal function in 15 PD patients with tremor using airflow and EGG measures. The subjects were recorded as they sustained vowel phonation before and after taking medication. Speed quotient, acoustic shimmer, and extent of tremor derived from acoustic intensity contours were found to significantly decrease, and vocSPL tended to increase after medication, indicating improvement in vocal function with levodopa. Sanabria et al. (83) used acoustic measures to study the effects of levodopa treatment on vocal function in 20 PD patients before and after levodopa. When compared with pre-medication, post-medication voice F0 was significantly increased, and jitter, soft phonation index (noise parameter), and frequency tremor intensity index significantly decreased. Cahill et al. (84) studied the effects of levodopa on lip function in 16 patients with PD, using a computerized semiconductor lip pressure transducer. Lip pressures recorded during both speech and nonspeech tasks tended to improve after levodopa administration. Although these studies indicate improvement in phonatory and articulatory functions with levodopa, numerous studies (85,86) have failed to find significant improvement in voice and speech functions with levodopa or dopamine agonists. These negative findings have raised questions regarding the role of dopamine as the sole, or major, etiologic factor in hypokinetic dysarthria and have raised the possibility that either nondopaminergic or special dopaminergic mechanisms may play an important etiologic role. Future studies should assess the therapeutic role of such nondopaminergic mechanisms on parkinsonian speech. Interestingly, clonazepam (dosage 0.25–0.5 mg/day), a nondopaminergic agent, has been reported to significantly improve speech in 10 of 11 individuals with PD and hypokinetic dysarthria (87). EFFECT OF SURGICAL TREATMENTS FOR PARKINSON’S DISEASE ON SPEECH AND SWALLOWING Deep Brain Stimulation Many studies of deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus internus (GPi), and ventral intermediate (Vim) nucleus of the thalamus have reported dysarthria and dysphagia as side effects (88–90). Several studies examined specific aspects of voice, speech, swallowing and related orofacial, and respiratory–laryngeal functions associated with DBS treatment of PD. Santens et al. (91) found that left-brain stimulation had a profound negative effect on prosody, articulation, and intelligibility not seen with right-brain stimulation. With bilateral stimulation, no differences in speech characteristics were observed on- and off-stimulation. Wang et al. (92) also studied the effects of unilateral STN DBS on respiratory/phonatory subsystems of speech production in PD. Speech recordings were made in the medication-off state at baseline and three months post-DBS with stimulation-on and -off, in six righthanded patients. Three patients who received left-brain STN DBS showed a significant decline in vocal intensity and vowel duration compared with baseline, which the authors attributed to microlesions of the dominant hemisphere for speech. Some studies indicate improvement in voice and speech functions with DBS. Gentil et al. (93) assessed the effects of bilateral STN DBS on hypokinetic dysarthria using force measurements of the articulatory organs and acoustic analysis in 16 PD

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patients. They noted that STN DBS-reduced reaction and movement time of the articulatory organs, increased maximal strength and precision of these organs, and improved respiratory and phonatory functions. Gentil et al. (94) also compared the effects of bilateral STN DBS versus Vim DBS on oral control in 14 individuals with PD. They used force transducers to sample ramp-and-hold force contractions generated by the upper lip, lower lip, and tongue at 1- and 2-N target force levels, as well as maximal force. With STN stimulation, dynamic and static control of the articulatory organs improved greatly, whereas with Vim stimulation it worsened. In another study of 26 individuals with PD treated with bilateral STN DBS, Gentil et al. (95), using acoustic analysis of voice, found that stimulation resulted in longer duration of sustained vowels, shorter duration of sentences, words, and pauses, increased variability in voice F0 in sentences, and increased stability of voice F0 during sustained vowels. There was no difference in vocal intensity between the on- and off-stimulation conditions. Pinto et al. (96) assessed the impact of bilateral STN DBS on forces and control of the upper lip, lower lip, and tongue in 26 dysarthric individuals with PD before and after DBS surgery. They reported that with stimulation, there was an improvement in the maximal voluntary force, reaction time, movement time, precision of the peak force, and the hold phase during an articulatory force task. They also reported that these beneficial effects of DBS on articulatory forces persisted up to five years. Dromey et al. (97) studied the effects of bilateral STN DBS on acoustic measures of voice in seven individuals with PD. Acoustic recordings of voice were made before surgery in the medication-off and medication-on conditions and after surgery with and without stimulation in the medication-on and -off conditions. Six months after surgery, there were significant though small increases in vocSPL and F0 variability when on-medication with DBS. Rousseaux et al. (98) studied the effects of bilateral STN DBS on speech parameters and intelligibility in seven dysarthric PD patients. Speech was evaluated before and three months after surgery with stimulation-off and -on and with and without a suprathreshold levodopa dose. Modest beneficial effects were reported on several motor speech parameters, especially lip movements. Modulation of voice pitch and loudness improved mildly. Articulation was not affected and speech intelligibility was slightly reduced in the onstimulation condition, especially when patients received levodopa. Marked negative effects on intelligibility were observed in two patients, due to increased facial and trunk dyskinesia. In sum, DBS can result in a moderate benefit on the speech motor system during nonspeech tasks and minimal therapeutic or adverse effects on voice and speech functions. Although the follow-up studies suggest deterioration in speech following DBS, it is not clear to what extent this deterioration is due to the DBS surgery, to voltage spread from the stimulating electrodes (99), and to the natural progression of PD. Transcranial and Extradural Brain Stimulation Dias et al. (100) studied the effects of repetitive transcranial magnetic stimulation (rTMS) on vocal function in 30 individuals with PD. Stimulation of the primary motor cortex (M1)-mouth area induced a significant improvement in voice F0 and intensity. Stimulation of the left dorsolateral prefrontal cortex resulted in subjective improvement of voice-related quality of life, but not in objective measures of voice F0 and intensity. Pagni et al. (101) studied the effects of extradural motor cortex stimulation in three individuals with PD. They reported that unilateral stimulation

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resulted in improvement in speech and swallowing. Additional research is necessary to confirm these effects. Ablative Surgery Pallidotomy The effects of pallidotomy on speech have been assessed in several studies. Schulz et al. (102) assessed six PD patients after pallidotomy and found all six to have positive changes in at least one acoustic measure. In another study, Schulz et al. (103) assessed changes in vocSPL following unilateral pallidotomy in 25 hypokinetic dysarthric individuals with PD. They found that mildly dysarthric individuals had significantly greater increases in vocSPL following pallidotomy, whereas moderately or severely dysarthric individuals had decreases in vocSPL. Uitti et al. (104) assessed 57 PD patients after pallidotomy and found that speech intelligibility was preserved, with a tendency to decline mildly in one-third of patients. Scott et al. (105) compared the effects of unilateral and bilateral pallidotomy three months after surgery and reported a fall in speech diadochokinetic rates and self-perceived worsening of pre-existing dysarthria, hypophonia, and hypersalivation/drooling following bilateral pallidotomy. Thalamotomy and Subthalamotomy Nagulic et al. (106) used acoustic analyses to assess the effects of stereotactic thalamotomy in seven male patients with PD and found that the mean vocSPL during the initial segment of the speech signal and the voice F0 increased after thalamotomy. The voice formants F1 and F2 shifted to the higher energy and frequency regions. Parkin et al. (107) studied the effects of bilateral subthalamotomy for PD and reported speech disturbance as one of three major complications. Farrell et al. (108) studied the effects of various neurosurgical procedures (pallidotomy, thalamotomy, DBS) on perceptual speech characteristics, speech intelligibility, and oromotor function in 22 individuals with PD. The surgical group was compared with a group of 16 participants with PD who did not undergo neurosurgery and 25 neurologically healthy individuals matched for age and sex. Results indicated that none of the neurosurgical interventions significantly changed perceptual speech dimensions or oromotor function, in spite of significant postoperative improvements in general motor function. Peripheral Surgery for Voice and Swallowing Problems Collagen Augmentation of Vocal Folds for Hypophonia The effects of collagen augmentation of the vocal folds via percutaneous injection and with fiberoptic guidance on phonation in hypophonic individuals with PD were reported in two studies. Berke et al. (109) assessed 35 hypophonic PD patients treated with collagen augmentation with a telephone survey and found that 75% expressed satisfaction with the improvement in their voice, compared with 16% who expressed dissatisfaction with the results of collagen augmentation. Kim et al. (110), using a telephone interview of 18 PD patients treated with this procedure, found that 11 patients (61%) considered their voice improved for at least two months. Of the seven patients who were not improved with this procedure, five (28%) were aphonic before and after the collagen injection. They concluded that although the majority of patients are likely to benefit from the procedure, patients with advanced neurologic disease with aphonia, difficulty with speech initiation, dysphagia, or ambulatory difficulty

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are less likely to respond to this procedure. Although these preliminary results are promising, more objective methods of voice evaluation are needed, as are long-term, controlled outcome studies. Cricopharyngeal Myotomy for Swallowing Born et al. (111) assessed the effects of cricopharyngeal myotomy in four patients with PD and dysphagia associated with cricopharyngeal dysfunction, diagnosed with radiological and manometric methods. They reported positive results with sustained improvement in swallowing. BEHAVIORAL SPEECH, VOICE, AND SWALLOWING TREATMENT FOR PARKINSON’S DISEASE Although the incidence of speech and voice disorders in individuals with PD is extremely high, only 3% to 4% receive speech treatment (112). One explanation for this is that carryover and long-term treatment outcomes have been disappointing and consequently the primary challenges in the treatment of hypokinetic dysarthria associated with PD. Clinicians have long been aware that when dysarthric PD patients are receiving direct stimulation, prodding, or feedback from the speech clinician or an external cue (113,114), they are likely to show a dramatic improvement in speech and voice production and overall intelligibility. However, maintaining these improvements without these external cues is extremely difficult for most of these individuals. One explanation for the inability of individuals with PD to maximize and maintain treatment gains may be their deficits in internal cueing, vigilance, scaling amplitude of vocal output, and self-perception and self-regulation of vocal loudness and efforts (63,77). To maximize and maintain treatment effects, speech therapy of dysarthric PD patients should address these deficits. Ramig et al. (14,15) documented that improving amplitude of vocal output and sensory perception of vocal loudness and effort, as obtained via the LSVT ® program, are key elements in successful speech treatment for individuals with PD. In addition, deficits in implicit or procedural learning (115) may underlie the challenges that individuals with PD have in maintaining long-term treatment effects and in learning to habituate newly acquired methods of speech production. Efforts to overcome these cognitive problems as part of treatment may also facilitate long-term outcome. Intensive Voice Treatment for Parkinson’s Disease It is hypothesized that there are three features underlying the voice disorder in individuals with PD: (i) an overall amplitude scale down (75,76) to the speech mechanism (reduced amplitude of neural drive to the muscles of the speech mechanism), which results in hypophonia, hypoprosodia, and hypokinetic articulation; (ii) problems in the perception of vocal loudness and effort (77), which prevent the individuals with PD from accurately monitoring and scaling their vocal output; and (iii) difficulty in independently generating (internal cueing/scaling) the right amount of effort (78) to produce adequate vocal output (loudness, prosodic inflection, and amplitude of articulatory movement). The LSVT ® has been designed to address these problems. The LSVT® has five essential concepts: (i) focus on voice (increases the amplitude of phonatory output); (ii) improve sensory perception of vocal loudness and effort; (iii) administer treatment in a high effort style; (iv) administer treatment intensively; and (v) quantify treatment-related changes. Treatment techniques are

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LSVT ® Model for Treatment of Individuals with Parkinson Disease PRE-TREATMENT Problem self-perception/ self-monitoring Problem scaling amplitude of movement patterns

Soft Voice

Reduced amplitude of output

TREATMENT FOCUS IMPROVE self-perception/ self-monitoring

“calibration” TRAIN ABILITY TO ACCURATELY program target and scale output

“high effort” “intensive”

Increase Loudness

INCREASE amplitude of output

“high effort” “intensive” FIGURE 1 This figure graphically summarizes the hypothesized neural basis for the Lee Silverman Voice Treatment (LSVT®) approach to treating individuals with Parkinson’s disease. Pre-treatment (top circle): the “soft voice” of the patient may be a result of reduced amplitude of output to the speech mechanism. The soft voice is maintained because patients have reduced self-perception/monitoring and fail to realize that the voice is “too” soft. Therefore, when they program output for another utterance, they down scale the output and continue to produce a soft voice. The LSVT® focus (bottom circle) addresses the soft voice at three levels. High effort, intensive treatment is designed to train increased amplitude of output to the respiratory phonatory system to generate increased loudness. Patients are then trained to improve self-perception/monitoring of effort, so they understand the relationship between increased effort and successful communication. In this way, when they generate an utterance on their own, they are able to “carry over” adequate effort and loudness for communication success outside the treatment room.

designed to scale up amplitude to the respiratory and phonatory systems and train sensory perception of effort, internal cueing, and scaling of adequate output. This approach is graphically represented in Figure 1. Administration of treatment four times a week for one month is consistent with principles of motor learning, skill acquisition, and muscle training. In addition, the LSVT ® is administered in a manner to maximize patient compliance and motivation in treatment by assigning treatment activities that make an immediate impact on daily functional communication. The rationale for the five concepts of the LSVT ® is graphically represented in Figure 2.

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Goal: Improved functional oral communication that “lasts”

LSVT ® 5 CONCEPTS AND TECHNIQUES (voice focus, high effort, intensive, sensory calibration, quantification)

Neural

Motor Learning

SCALING AMPLITUDE SENSORY PROCESSING

Sensory Processing Intense Practice Specific context Simple focus (root)

Neuropsychology

slow thinking slow learning problems sustaining attention problems shifting cognitive set problems internally cueing problems in procedural memory

Muscle Training

Overload Progressive resistance Specificity Physiologic Compliance and Respiratory drive Motivation Laryngeal valving (ROM, stability) System-wide effects “LOUD” (effort, coordination)

FIGURE 2 This figure graphically summarizes the rationale underlying the five essential concepts and techniques of the Lee Silverman Voice Treatment (LSVT®) from a neural, speech mechanism physiology, motor learning, muscle training, neuropsychological, and compliance perspective. The neural bases are the reduction in muscle activation and self-monitoring and consequent problem in programming an output target with adequate amplitude. The physiologic basis is the focus on respiratory drive and laryngeal valving to generate a maximally efficient vocal source. “Loud” is used as the system trigger for improving effort and coordination across the speech mechanism. The LSVT® is administered in a manner consistent with principles of motor learning in order to maximize the treatment effectiveness. Emphasis on sensory processing, increased practice, practice within specific context, and a simple “root” focus (e.g., loud) are key elements of treatment. The neuropsychologic aspects of Parkinson’s disease: slow thinking, slow learning, problems sustaining attention, problems shifting cognitive set, problems internally cueing, and problems in procedural memory are also taken into account with the LSVT®. The LSVT® is also administered in a way consistent with muscle training. Treatment technique overloads the muscles using progressive resistance in specific activities. The LSVT is designed to maximize patient compliance. From day 1 of treatment, activities are designed to maximize the impact on daily functional communication. Abbreviations: LSVT, Lee Silverman Voice Treatment.

Furthermore, LSVT® is designed to comply with the principles of motor plasticity training, namely intensive training of motor tasks, increased practice of motor tasks, active engagement in tasks, and the sensory experience of the motor task (116,117). The training should also address the most prominent etiologic factors underlying the behavior to be changed, with the target behavior having a significant ameliorating impact of these etiologic factors. In the case of voice and speech disorders in PD, training should address deficits in internal cueing, sensorimotor gating, scaling amplitude of speech movement patterns, and self-perception and regulation of vocal effort and output (86). Specifically, the LSVT ® uses high effort, but not strenuous, loud phonation to encourage optimal glottic closure and maximum phonatory efficiency. Patients are

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taken through exercises on a daily basis, repeatedly practicing and emphasizing maximum duration loud phonations, maximum high- and low-pitch phonations, and speech exercises with improved loudness. This improved phonation is then carried over into speech and conversation following a standardized hierarchy, with focus on monitoring the amount of effort required to sustain sufficient vocal loudness (“calibration”). No direct attention is given to speech rate, prosodic pitch inflection, or articulation. Therapy is administered four times per week over four weeks, each session lasting 50 to 60 minutes. The goal of the LSVT ® is to improve functional communication for at least six to 12 months without additional treatment. After 16 sessions of individual treatment, most patients will be able to maintain speech and voice changes for at least six months and sometimes for up to one (4) or two years (15,118) without additional speech treatment. Within the 16 initial sessions of treatment, patients are encouraged to establish a daily homework routine that they maintain on their own once treatment is over. All patients are encouraged to return for a reassessment at six months, at which time some patients may benefit from a few additional sessions. Further details of the LSVT ® have been described elsewhere (73). Treatment data suggest that individuals with mild to moderate PD have the most positive treatment outcomes following the LSVT ®. Early administration of the LSVT® or other intensive voice and speech treatment programs is also important, since research shows that the most effective ways to induce neural plasticity and neural protection with behavioral treatment is to apply therapy before neurotoxicity and before the degenerative process is severe (116,117,119). Patients with severe PD, severe depression, or severe dementia have a poor prognosis with LSVT®; however, patients with co-occurring mild to moderate depression and dementia can benefit (14). Because treatment focuses on voice, all patients must have a laryngeal examination before treatment to rule out any contraindications (e.g., vocal nodules, gastric reflux, laryngeal cancer). It is important to clarify that the goal of the LSVT® is to maximize phonatory efficiency. It is never the goal to teach “tight or pressed” voice but rather to improve vocal fold adduction for optimum loudness and quality without undue strain. Effectiveness of Lee Silverman Voice Treatment on Voice The LSVT® was developed during the late 1980s. Initially, case studies, single-subject designs, and nonrandomized studies were published (120). These studies provided the first evidence of successful treatment outcomes for individuals with PD and suggested that intensive treatment focusing on increasing phonatory effort and selfmonitoring of such effort could improve vocal communication in individuals with PD. On the basis of those findings, a number of randomized and blinded studies were conducted. In one study, 45 individuals with PD were randomly assigned to one of two forms of treatment: respiratory effort treatment (RET) or LSVT®. Short(14) and long-term (15,118,121) data have been reported from these studies. Only subjects who received the LSVT® rated a significant decrease after treatment on the impact of PD on their communication. Corresponding perceptual ratings by blinded raters (122) revealed only the male subjects who had the LSVT® improved in ratings of breathiness and intonation. The acoustic findings were supported in studies at one-year (15) and two-year follow-up (118). Only those subjects in the LSVT® group improved or maintained vocal SPL above pre-treatment levels. In addition, perceptual reports by patients and family members supported the positive impact of LSVT®

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on functional daily communication. In another study (123), 29 individuals with PD were studied over six months. Half the group received LSVT® and half of the group served as an untreated control group. In addition, neurologically healthy, agematched controls were studied over this time period. Only subjects who received the LSVT® demonstrated significant increases in variables such as vocSPL (related to loudness) and semitone standard deviation (related to intonation) at post and sixmonth follow-up. Improvement in laryngeal function with LSVT® has been documented physiologically. Smith et al. (41) found increases in vocal fold closure following treatment in individuals who received the LSVT® but not in individuals who received RET. These data were collected by clinicians not directly involved in the study and therefore support carryover of treatment effects. Importantly, laryngeal examination has shown no evidence of hyperfunctional laryngeal behaviors or vocal fold pathology induced by loud phonation training with LSVT®. In fact, it has been shown that LSVT® tends to decrease pre-treatment hyperfunctional behavior (false fold overclosure, anterior–posterior hyperfunction, laryngeal elevation) (124), increase subglottal air pressure and maximum flow declination rate (125), and reduce breathiness and hoarseness in individuals with PD (122). These findings reflect increased respiratory drive, improved vocal fold adduction, less abusive or strenuous voice use, and more efficient voice production after LSVT®. Effects of Lee Silverman Voice Treatment on the Orofacial System Not only does LSVT® improve phonatory effort and vocal characteristics (loudness, pitch variability, vocal quality), it also improves speech articulation. Dromey (59) compared the effects of two treatment approaches, LSVT®, and exaggerated articulation during speech and found that the LSVT® was significantly more effective in improving speech articulation. Sapir et al. (28) used acoustic and perceptual analyses to assess the impact of LSVT® on vowel articulation in dysarthric individuals with PD (n = 14). There was a significant improvement in both vowel acoustics (formants) and perceptual ratings (vowel goodness post-relative to pre-LSVT®), as well as in VocSPL, in the group receiving LSVT®, but not in individuals with PD (n = 15) and healthy agematched controls (n = 14) who did not receive treatment. The improvement in vowel acoustics and rating were interpreted as evidence for improvement in vowel articulation associated with LSVT®. These findings are consistent with a previous perceptual study (4) documenting increased ratings of speech loudness and speech quality in individuals with PD receiving LSVT®, but not in individuals with PD receiving RET. The improvement in vowel articulation with LSVT® in individuals with PD is consistent with Schulman (126), showing that as a speaker talks louder, there are accompanying vocal tract and articulatory changes. These effects have been longlasting and treatment-specific as documented in a 12-month follow-up study (121). LSVT® has also been shown to improve facial expression (17), tongue strength and motility (16), and swallowing (8) in individuals with PD. Effects of Lee Silverman Voice Treatment on Brain Activity Recent positron-emission tomography (PET) scan data (18) have demonstrated functional reorganization of speech-motor areas within the brain following the LSVT®. Treatment-related changes were found in the right globus pallidus (GP) and in the supplementary motor area (SMA). In the GP resting state, rCBF was significantly reduced post-treatment when compared with pre-treatment and significantly

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increased during sustained phonation when compared with rest. The authors concluded that the LSVT® reduced baseline GP overactivity, resembling the effect of pallidotomy. However, the LSVT® increased GP activity during vocalization. These findings document the neural basis for behavioral changes following the LSVT®. Swallowing Treatment for Parkinson’s Disease Treatment of swallowing disorders in PD has not been well studied. Conventional techniques have included oral motor exercises to improve muscle strength, range of motion and coordination, and behavioral modifications such as effortful breath-hold, chin positioning, double swallow, the Mendelsohn maneuver, swallow/cough, effortful swallow, and diet and liquid modifications (13,127). Effectiveness of these techniques varies and can be dependent on patient motivation and cooperation, family support, and the timeliness of the referral for a swallowing evaluation. Efficacy studies of the impact of behavioral treatment on dysphagia in PD are lacking (128). The effects of LSVT® on swallowing dysfunction in individuals with PD have been studied by Sharkawi et al. (8). These researchers found that the LSVT® reduced swallowing motility disorders by 51%. Some temporal measures of swallowing were also reduced, as was the amount of residue. This is the first study to find positive changes in both voice and swallowing function following intensive voice therapy alone without a therapy focusing on swallowing. A study by De Angelis et al. (129) has documented improved voice, speech, and swallowing functions in individuals with PD participating in an intensive treatment with a schedule similar to that of the LSVT® and with a clinical goal of improved glottic closure. These studies collectively point to the utility of intensive voice treatment for the reduction of swallowing dysfunction. Effects of Lee Silverman Voice Treatment on Facial Expression in Parkinson’s Disease Spielman et al. (17) examined the impact of LSVT® on facial expression in individuals with PD. Videos of 44 individuals with PD before and after one month of either LSVT® or RET were randomized and rated by trained raters, who judged each video clip for facial mobility and engagement. Overall, members of the LSVT® group received more ratings of increased facial mobility and engagement following treatment relative to members of the RET group. Administration of Lee Silverman Voice Treatment by Electronic Devices and Virtual Clinicians Several electronic devices have been recently adapted to make LSVT® available to individuals who are far away from the clinic, to improve practice at home, and to reduce cost of treatment and clinician time. These devices, for example, a personal digital assistant (PDA), have been adapted with special software to deliver LSVT® or other types of speech therapy programs (130). One such PDA, named the LSVT® companion (LSVTC), has been programmed to collect acoustic data and provide feedback as it guides the patient through the LSVT® exercises. Instead of the usual 16 treatment sessions of clinician-delivered LSVT®, only 9 sessions are with a clinician and the other seven are completed independently at home by the patient utilizing the LSVTC and a virtual clinician. Pilot studies have demonstrated a marked and long-term (six-month follow-up) improvement in voice and speech with the LSVTC, with treatment outcome comparable to that obtained with the original clinician-administered LSVT® (130).

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These findings support the feasibility of using state-of-the-art technology to administer speech treatment and keep records of patients’ progress. ACKNOWLEDGMENT This work was supported in part by grants from the National Institutes of Health— National Institute on Deafness and Other Communication Disorders R01 DC01150, P60 DC00976, and the Office of Education—National Institute for Disability and Rehabilitative Research 8133G40108. REFERENCES 1. Ho AK, Iansek R, Marigliani C, Bradshaw JL, Gates S. Speech impairment in a large sample of patients with Parkinson’s disease. Behav Neurol 1998; 11:131–137. 2. Logemann JA, Fisher HB, Boshes B, Blonsky ER. Frequency and coocurrence of vocal tract dysfunctions in the speech of a large sample of Parkinson patients. J Speech Hear Disord 1978; 43:47–57. 3. Darley FL, Aronson AE, Brown JR. Motor Speech Disorders. Philadelphia: WB Saunders, 1975. 4. Sapir S, Ramig L, Hoyt P, et al. Phonatory-Respiratory effort (LSVT®) vs. respiratory effort treatment for hypokinetic dysarthria: comparing speech loudness and quality before and 12 months after treatment. Folia Phoniatrica 2002; 54:296–303. 5. Miller N, Noble E, Jones D, Burn D. Life with communication changes in Parkinson’s disease. Age Ageing 2006; 35:235–239. 6. Pitcairn TK, Clemie S, Gray JM, Pentland B. Impressions of parkinsonian patients from their recorded voices. Br J Disord Commun 1990; 25:85–92. 7. Leopold NA, Kagel MA. Laryngeal deglutition movement in Parkinson’s disease. Neurology 1997; 48:373–375. 8. Sharkawi AE, Ramig L, Logemann JA, et al. Swallowing and voice effects of Lee Silverman Voice Treatment (LSVT®): a pilot study. J Neurol Neurosurg Psychiatry 2002; 72:31–36. 9. Logemann JA. Evaluation and Treatment of Swallowing Disorders. Texas: Pro-Ed, 1998. 10. Robbins J, Logemann JA, Kirshner H. Swallowing and speech production in Parkinson’s disease. Ann Neurol 1986; 11:283–287. 11. Larson K, Ramig LO, Scherer RC. Acoustic and glottographic voice analysis during drug-related fluctuations in Parkinson’s disease. J Med Speech Lang Pathol 1994; 2:211–226. 12. Yorkston KM. Treatment efficacy: dysarthria. J Speech Hear Res 1996; 39:S46–S57. 13. Helm N. Management of palilalia with a pacing board. J Speech Hear Disord 1979; 44:350–353. 14. Ramig LO, Countryman S, Thompson LL, Horii Y. Comparison of two forms of intensive speech treatment for Parkinson disease. J Speech Hear Res 1995; 38:1232–1251. 15. Ramig LO, Countryman S, O’Brien C, Hoehn M, Thompson L. Intensive speech treatment for patients with Parkinson’s disease: short and long term comparison of two techniques. Neurology 1996; 47:1496–1504. 16. Ward E, Theodoros D, Murdoch B, et al. Changes in maximum capacity tongue function following the Lee Silverman Voice Treatment program. J Med Speech Lang Pathol 2000; 8:331–335. 17. Spielman JL, Borod JC, Ramig LO. The effects of intensive voice treatment on facial expressiveness in Parkinson disease: preliminary data. Cogn Behav Neurol 2003; 16:177–188. 18. Liotti M, Ramig LO, Vogel D, et al. Hypophonia in Parkinson’s disease: neural correlates of voice treatment revealed by PET. Neurology 2003; 60:432–440. 19. Leanderson R, Meyerson BA, Persson A. Lip muscle function in Parkinsonian dysarthria. Acta Otolaryngol 1972; 74:350–357. 20. Leanderson R, Meyerson BA, Persson, A. Effect of L-dopa on speech in Parkinsonism an EMG study of labial articulatory function. J Neurol Neurosurg Psychiatry 1971; 43:679–681.

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Alternative Therapies Jill Marjama-Lyons Albuquerque, New Mexico, U.S.A.

INTRODUCTION Alternative therapies have long been accepted and practiced among Eastern and Middle Eastern cultures. The interest in Eastern medical approaches among Western cultures is growing and more Westerners are practicing and seeking out alternative therapies for the treatment of many physical conditions including Parkinson’s disease (PD). According to one survey, the use of complementary alternative medicine (CAM) in the United States increased by 45% from 1990 to 1996 with over 600 million visits per year and over 27 billion dollars spent by public consumers most of which was not reimbursed by insurance companies (1). This trend has also been observed among persons diagnosed with PD. One study surveyed 75 persons with PD and found that 48% regularly practiced some form of alternative therapy (2). More specifically, 48% practiced tai chi, 45% spiritual healing or prayer, 36% yoga, 36% massage therapy, 27% acupuncture, 24% meditation, and 15% herbal therapies. Similarly, another survey found 40% of PD patients practiced at least one alternative therapy specifically for the treatment of PD (3). One of the reasons people are exploring alternative therapies is because of the limitations of current medical and surgical therapies for PD. Over years or decades, conventional therapies are less effective in the majority of PD patients and the motor symptoms of PD typically worsen. This often results in a reduction of independence and quality of daily life of both the person and the family affected by PD. Because no cure currently exists for PD and even with the best available conventional therapies the motor symptoms continue to worsen, some patients turn to alternative therapies. Many persons seeking alternative therapies are hoping that these therapies may slow or even cure PD. Some of these false hopes are a direct result of misinformation about particular therapies often found on the internet or in layperson health magazines and nonconventional medical journals as well as marketing of the product or service. It is imperative that a greater understanding of the potential risks and benefits of nonconventional therapies for the treatment of PD is gained in order to provide sound and safe medical advice. Given the increasing interest and use of CAM, it behooves both Eastern and Western healthcare providers to work together to bridge the gap between these two medical approaches and to better define whether any of these therapies are beneficial and could be used in the treatment of PD and which are potentially harmful or ineffective for PD. This chapter reviews the more common Eastern and nonconventional medical models and describes many of the more commonly practiced alternative therapies for PD. DEFINING ALTERNATIVE THERAPIES Western medical therapies are those generally used by a medical doctor trained in the United States or by a standard Western medical curriculum. This involves a disease model approach, performing a detailed history and physical examination to 475

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identify a specific condition and attempting to treat the condition with specific medications, rehabilitative therapies, and sometimes surgery. The terms conventional and allopathic are often used when referring to Western-based therapies. A larger variety of terms are used when referring to alternative therapies. These include alternative, Eastern medicine, complementary medicine, CAM, integrative, functional, natural, and holistic medicine. In essence, what all of these terms imply is a form of therapy not considered to be a standard Western medical approach. Hence, the list of alternative therapies is infinite and might include a variety of treatments such as aroma therapy, magnet therapy, chelation, acupuncture, and meditation. Because there is such a vast array of different alternative approaches, it is important to define the specific therapy such as a particular herbal remedy or exercise when discussing and assessing the response to a therapy rather than using the term “alternative.” There is also considerable confusion about whether to classify the numerous therapies available as alternative or conventional. For instance, chiropractics, often labeled as alternative, has gained wider acceptance among Western society such that it is frequently considered to be conventional by many Western laypersons and has always been viewed as such by most European societies. In fact, what is typically viewed as alternative by Western society is often accepted as mainstream therapy by non-Western societies. The frame of reference or culture may determine whether a particular therapy is defined as conventional or alternative. In 1995, the Office of Alternative Medicine in an effort to alleviate some of this confusion came up with the following definition: CAM is a broad domain of healing resources that encompasses all health systems, modalities, and practices and their accompanying theories and beliefs, other than those intrinsic to the politically dominant health system of a particular society or culture in a given historical period. CAM includes all such practices and ideas self-defined by their uses as preventing or treating illness or promoting well-being. Boundaries within CAM and between the CAM domain and the domain of the dominant system are not always sharp or fixed (4)[12].

Another way of defining CAM is any therapy that is not within the dominant healthcare system, i.e., outside of the accepted medical practices, scientific knowledge, or university teachings. This chapter will focus mostly on Eastern medical therapies, but recognizes that potentially beneficial treatments and medical approaches that may exist beyond those discussed herein. Another important point is that the term “alternative” does not imply that one should use CAM in place of conventional therapy or that one approach is exclusive of or better than the other when in fact both have value. Western therapies have been more rigorously studied for their proven efficacy in the treatment of the motor symptoms of PD than Eastern therapies, yet Eastern medical models have been in existence for thousands of years as effective systems of health promotion and disease treatment and prevention. It is recommended that alternative therapies may be considered supplemental rather than replacements for conventional treatments of PD. The terms complementary, integrative, or holistic may be more appropriate as they imply and encourage the use of a combination of a variety of Eastern and Western modalities as well as other nonconventional therapies for a more comprehensive health program.

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NON-WESTERN MEDICAL SYSTEMS Traditional Chinese Medicine Traditional Chinese Medicine (TCM) has existed for thousands of years, long before Western medicine. Rather than following the disease model of Western medicine, TCM focuses on a symptom approach such that a person with PD who has mostly tremor would be evaluated and treated differently than another person whose symptoms were mostly gait and balance difficulty with no tremor. The specific symptoms of the individual signal a deficiency in the body fluids/blood that is unable to properly nourish the energy flow or “chi” or “Qi” of the entire organism. There are three main symptom approaches under TCM (5). The first is Qi and blood deficiency, which is believed to arise from anger, emotional stress, frustration, and resentment. The second is phlegm-fire-agitating wind (yang), which is the result of poor diet, in particular eating greasy, fried, sweet, sugary foods and alcohol. The third is kidney and liver (yin) deficiency, which results from a lack of rest and overwork as well as part of the aging process and a subsequent overall imbalance of the natural body rhythm. PD is thought primarily to occur from a yin or liver and kidney deficiency. The liver, as all organs in TCM, is thought to function through energy channels or meridians that connect to all other body parts. The liver is believed to regulate normal body movement such that when it is deficient, the body develops tremor, stiffness, and slowed, uncoordinated motor function. A physician of TCM often referred to as a Doctor of Oriental Medicine would prescribe specific treatments to strengthen yin deficiency, reduce overactive wind, restore blood circulation, and unclog phlegm obstruction which would likely involve a particular diet, specific herbs, acupuncture, proper rest, and exercise (Tai Chi and Qi Gong breathing) all with the ultimate goal of restoring proper “chi,” the life energy source. Ayurvedic Medicine Ayurvedic medicine is the traditional medical system in India, which has existed for over 5000 years. The term Ayurveda literally means science of life or life knowledge. PD is documented to have existed in ancient India and was called “Kampavata.” Similar to the TCM system, physical illness is thought to result from emotional imbalance, unhealthy lifestyle, and toxins that ultimately upset the balance of the three doshas or regulatory systems of a person (5). These three doshas are vata, which symbolizes physical movement, pitta, which represents heat, metabolism, and energy, and kapha, which stands for physical structure and balance. Although all three systems may be affected in PD, therapy focuses heavily upon treatment of the vata disturbance through oleation with massage along with enemas and ingestion of oils. Proper harmony of the three doshas is achieved by specific diet and nutrition, a number of herbs, meditation, breathing exercises, massage, and yoga poses. Stress reduction with a peaceful environment that is not overstimulating along with daily meditation, yoga, and techniques to reduce internal stress is the foundation of a complete Ayurvedic program. All of these modalities, not just one, are necessary to practice on a daily basis, thus requiring an entire lifestyle change for a holistic health program. NATUROPATHY Naturopathic doctors exist in large numbers in Europe, but are growing in the United States with established four-year accredited naturopathic schools and now

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over 1000 naturopaths practicing in America. Naturopathy incorporates many of the modalities of TCM and Ayurveda, such as acupuncture, herbs, nutrition, massage, and homeopathy with the goal of achieving a balance between one’s physical, emotional, mental, and spiritual health by allowing the body and mind to heal itself through its own natural mechanisms. Additional information can be found in Ref. (6). HOMEOPATHY The practice of homeopathy was founded in the late 1800s. It is based upon the theory that “like cures like” or the law of similars. This law states that the body’s ability to heal itself and fight an illness is stimulated by orally ingesting very minute amounts of a homeopathic remedy containing a substance that at higher concentrations would cause the very symptoms the person wants to get rid of. For instance, if a particular substance is known to cause tremor, diluting it several hundred or thousand-fold is believed to trigger the body to reject or lessen the tremor. The belief is that the remedy stimulates the body to use its own natural healing mechanisms. This is similar in theory to how allergy shots or vaccines are believed to work. Homeopaths use herbs, minerals, or animal products which they crush and dissolve in grain alcohol or lactose and then store and refer to as the “mother of tincture.” They then dilute the tincture typically into 1:10 or 1:100. These remedies are prescribed to be taken several times daily for short periods for a few days. Homeopathy was very popular in the 1800s in the United States before the development of pharmaceutical companies. It remains heavily practiced in Europe and is regaining popularity in the United States with an estimated 3000 practitioners and over 25 homeopathic schools in the United States. Additional information can be found in Ref. (7). CHIROPRACTIC Chiropractic theory is similar to TCM and Ayurveda in that it views the body as having an innate ability to heal itself and naturally adapt to changes in its internal and external environments to maintain a natural state of health. Chiropractic practitioners focus on the nervous system knowing that the brain sends messages through the spinal cord to all the organs, muscles, blood vessels, and cells of the body. The nervous system helps to coordinate and regulate a vast array of chemical reactions that affect how a person thinks, feels, sleeps, digests food, physically moves, etc. Chiropractic theory is based upon the belief that when bones of the spine become misaligned they block normal flow and communication of the nervous system to the entire body and thereby result in impairment of normal body function that leads to a variety of physical symptoms and possibly the development of disease states. Chiropractic literally means “to be done by hand” and it was founded in 1895 with the theory that all diseases are caused by spinal subluxations and restoration of nerve flow is essential to healing. Spinal manipulation is the primary therapy performed by chiropractors with the goal of manually realigning the vertebral bodies in order to restore communication of the nervous system with the entire body and thereby restore normal body function and rid the body of disease. General information about chiropractics can be found in Refs. (8) and (9).

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COMPLEMENTARY THERAPIES FOR PARKINSON’S DISEASE What Do We Really Know? There are very few well-designed studies and consequently very little evidence to support or refute the use of most complementary therapies for the treatment of PD. This does not mean that alternative therapies cannot help someone with PD, but for Western-trained healthcare providers treating someone with PD who is considering alternative therapies, it is difficult to know what and how to advise them. The first rule in medicine is do no harm, so if a particular therapy such as massage therapy is not thought to be harmful then it might be recommended. On the other hand, ingesting an herb, injecting glutathione, or ingesting a homeopathic remedy without any proof that it is beneficial and without knowing the potential harmful effects or drug interactions may not be in the best interest of a person with PD. Specific complementary therapies that are commonly prescribed by alternative practitioners are reviewed in the following section. As the majority of these therapies, especially those involving oral and intravenous modalities, have not been formally studied for efficacy or potential harm for the treatment of PD, the author of this chapter and editors of this book do not specifically recommend any of these treatments and strongly encourage their use only under the direct guidance of licensed health professionals with expertise in the specific therapy the individual is considering. Antioxidants/Cell-Supporting Agents A number of theories as to what causes PD at the cellular level include oxidative stress and free radical formation, mitochondrial impairment, intracellular protein clumping, inflammation, apoptosis (programmed cell death), and excitotoxicity (5). Many of the prescribed supplements, minerals, and vitamins by alternative practitioners are based upon these theories and the belief or hope that cellular function will be restored and/or future brain cell injury prevented with their use. Currently, there is little if any scientific study to support the use of most of these supplements in the treatment of PD and it is critical to acknowledge that their use specifically for the treatment of PD is based upon theory only and not upon evidence-based clinical research. Despite the lack of research supporting their use for PD, some of these, in particular, the antioxidants that control potentially damaging free radicals or support mitochondrial function may hold the greatest promise for finding a neuroprotective agent. Some naturally occurring free radical scavengers that exist in the human body at lower levels of activity in PD are superoxide dismutase, glutathione, and coenzyme Q10 (CoQ10). It seems reasonable, therefore, to consider future scientific study of agents that would either promote the production or prevent the degradation of these endogenous antioxidants. In the meantime, the spread of these theories into the public and alternative health field has led to an enormous rise in the use of many supplements, vitamins, and nutrients thought to support basic cellular brain function. Again, their prescribed use is based upon theory and most of the reports supporting their use in PD are anecdotal or at best based upon small, open-label studies (5). The more commonly used agents include those that may increase glutathione levels and promote antioxidant activity such as alpha-lipoic acid, glutathione (orally or intravenous), nicotinamide adenine dinucleotide hydrogen (NADH), and CoQ10 (ubiquinone). Other promoters of cellular function often prescribed by alternative practitioners include acetyl-L-carnitine, selenium, vitamin C, vitamin E, phosphatidyl serine, lecithin, choline, omega-3 fatty acids (fish oil), and flavonoids found in grape seed and pine bark extract called proanthocyanidins. There are few studies to support

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the use of any of these for the treatment of PD with the possible exception of CoQ10. One small multcenter, randomized, double-blind, placebo-controlled study treated 80 de novo PD patients with either oral CoQ10 (300, 600, or 1200 mg/day) or a placebo for 16 months (10). At 16 months, the 1200 mg/day CoQ10 group scored 44% better in motor function according to the Unified Parkinson’s Disease Rating Scale (UPDRS) than the placebo group. Further studies of CoQ10 are warranted. Diet What a person ingests can have a dramatic impact upon the person’s health for better or for worse. Ayurvedics, TCM, and naturopaths believe that diet is critical to disease prevention and health promotion. Most holistic practitioners would prescribe a specific diet based upon the individual’s particular body type and imbalance and their specific training. A review of the many Eastern diet approaches is well beyond the scope of this chapter. It is therefore recommended that persons with PD seek out a licensed nutritionist either Western or Eastern trained to help develop a proper diet. Though there is no specific diet proven to prevent or slow the progression of PD, some general guidelines (5,11) to consider are as follows: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

minimize alcohol intake, avoid high sugar containing foods (desserts, candy, soft drinks), avoid artificial sweeteners (i.e., aspartame), reduce processed foods with added chemicals/preservatives, avoid well water and consider purified or filtered water, avoid foods sprayed with pesticides (nonorganic fruits, vegetables, coffee), lower dairy products, especially nonorganic milk, eat a high fiber diet, eat foods rich in antioxidants, eat good fats.

Reduction of high sugar or a low glycemic diet is something to consider. Many holistic practitioners believe a diet that avoids high levels of blood sugar is critical to reduce inflammation and balance the endocrine system for optimal health and disease prevention. Foods rich in carbohydrates can be evaluated by their glycemic index. A low glycemic index is preferred as it is less likely to cause a high blood sugar level. White rice, pasta and breads, desserts, and candy are some foods known to have high glycemic indexes. Eating carbohydrates in combination with equal amounts of fiber and good fat is also recommended. Maximizing digestion of food is important as the gastrointestinal system may be slowed in PD. Constipation, abdominal bloating, and nausea may result from PD or as side effects from the conventional medications used to treat PD. One can improve digestion by eating smaller, more frequent meals, adequately chewing to break food down into smaller more digestible pieces, drinking 64 ounces of water or liquid, and eating high amounts of fiber (25—30 g) on a daily basis. Foods rich in fiber are nonprocessed fresh fruits and vegetables and whole grains. In addition, supplements to aid in digestion by breaking down protein include pepsin, betaine hydrochloride, and bromelain. Ingestion of probiotics (acidophilus), found in capsule form and in yogurt and miso, helps promote healthy gut bacteria and minimize intestinal inflammation and malabsorption. Eating good fats and avoiding bad fats should be part of any healthy diet. The best fats are the omega-3 fatty acids found in certain fish and often referred to as fish

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oil. The best food sources of these fats are salmon, tuna, herring, mackerel, sardines, and anchovies. Wild ocean fish have a higher content of the omega-3 fatty acids than farm-raised fish; some fish such as swordfish, mackerel, and shark, despite having high good fat content, should be avoided due to high toxin ratings. Fish oil can also be taken in supplement forms often called omega-3 fatty acids. Additional sources of healthy fats are found in olive oil, avocados, fish, and nuts. Foods to avoid are those labeled as trans-monosaturated and hydrogenated or partially hydrogenated, such as many margarines, crackers, cookies, processed snacks (pretzels, potato chips), shortening, cooking oils, and fast foods. Foods rich in antioxidants should be part of a daily diet. These include most fresh fruits and vegetables. Blueberries receive the highest antioxidant score with basic science studies showing reduced age-related changes in brain cells and cognitive function in rats treated with a blueberry-supplemented diet (12). Another study reported middle-aged rats treated with blueberry extract to have improved brain transplant cell survival and growth in the hippocampus (13). Cyanohydroxybutene may increase glutathione and can be found in broccoli, cauliflower, brussel sprouts, and cabbage. Other detoxifying and DNA-supporting extracts include luteolin found in basil, parsley, celery, and artichokes, ellagic acid found in raspberries and strawberries, sulphorophane and glucosinolates found in broccoli, and polyphenol in green tea. Foods rich in the antioxidant vitamin E include nuts, wheat germ, spinach, and green leafy vegetables and those rich in vitamin C include citrus fruits. Though there are no clinical studies to support a particular diet for the treatment of PD, the potential impact of diet on PD has led the National Institute of Neurological Disorders and Stroke and the National Center for Complementary Medicine to fund future research to examine whether antioxidants, folate, coffee, fats, alcohol, and dairy products can have a positive impact on the symptoms and/or progression of PD. Herbs A variety of herbs may be useful to treat the motor symptoms of PD as well as some of the associated symptoms or possible side effects from PD medications (14). Ayurvedic Herbs Mucuna pruriens is a natural plant, indigenous to India, which contains levodopa. It is also called kawach, cowage, cowhage, or velvet bean. It has been studied extensively and shown to reduce the motor symptoms of PD similar to carbidopa/levodopa (15). In fact, mucuna seeds have been prescribed by Ayurvedic physicians in India for over 4500 years to successfully treat PD. In 1936, levodopa was first isolated from the plant mucuna, but it was not until the discovery in the 1960s that dopamine deficiency in the brain was linked to PD that this herb was given international attention for its potential treatment of PD. However, the development of synthetic levodopa resulted in little use of mucuna outside of India (16). The herb has been developed and manufactured into a drug called HP200, which is a powder that is mixed with water just before ingestion. It has been studied in animals for safety, and when compared with the same amounts of synthetic levodopa, it has been found to be two to three times more potent or effective, meaning that lower doses of mucuna achieve the same results as with synthetic levodopa. No major adverse effects have occurred at high doses in animal studies (17,18). A subsequent study of 60 PD patients who took HP200 for three months showed significant improvement in the

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motor symptoms of PD with minimal side effects (19). HP200 under the name of Zandopar is approved for the treatment of PD in India. Additional ayurvedic herbs that may be added to mucuna pruriens to support vata at its origin in the colon include moist laxatives such as psyllium (plantago psyllium), flaxeed (linum usitatissimum), and triphala. Rigidity may benefit from herbs that relax muscles such as jatamansi (nardostachys jatamansi) and shank pushpi (canscora dicussata). Depression may be treated with gotu kola (hydrocotyle asiatica) and St. Johns Wort (hypericum perforatum). If the pitta dosha is affected in addition to the vata, the herbs gotu kola and gaducci (tinospora cordifolia) may help cool and tonify the mind and reduce anger and stress. Chinese Herbs A number of herbs based upon the Chinese concept of PD would likely be prescribed and be tailored for the specific symptoms of the individual (14). Herbs that support liver and kidney function to replenish the deficient yin state thought to occur in PD are lycium fruit and ho-shou-wu. Supplemental herbs that might be added to these to boost yin are rehmannia, dioscorea, cornus, peony, tortoise shell, ligustrum, and achyranthes. Yang deficiency may also occur and would be treated with cistanche and cuscuta that would gently support yang while also benefiting yin. More advanced PD is thought to result from stagnation of the body fluids or phlegm obstruction of the channels (meridians and blood vessels) and would benefit from the herbs acorus, arisaema, and pinellia. Herbs to support blood circulation include ginseng, hoelen, atactylodes, licorice, rehmannia, tagkuei, peony, and cnidium all found in the Bazhen Tang formula. Specific symptoms such as tremor might be treated with the addition of gastrodia, uncaria, oyster shell, mother of pearl, or scorpion, whereas chaenomeles, peony, and magnolia bark would be prescribed to lessen rigidity. Though there are no controlled, double blind studies on herbal therapies for the treatment of PD, several open label studies have reported a reduction in the motor symptoms of PD. One study reported 40 persons with PD treated with a standard herbal prescription (20 g of Ho-shou-we, 12 g of lycium, 12 g of cistanche, 15 g of gastrodia, 18 g of uncaria, 18 g cnidium, 10 g of acorus) (20). The standard herbal remedy was then altered with the addition of specific herbs according to the particular symptoms of the individual patient (i.e., magnolia bark, peony, and chaenomeles for rigidity). A tea with the herbs was made and ingested three times daily for three months and all prior Western dopaminergic medications were discontinued during the study. Only five patients (8%) were reported to be markedly improved and 15 (27%) reported some improvement in the motor symptoms of PD, whereas the remainder (65%) had little improvement, no improvement, or a worsening of PD symptoms. Guoshong (21) reported 32 persons with PD randomly assigned to receive the herbal remedy, Wengan Zhichan Jianonang at 2000 mg three times daily or carbidopa/levodopa for up to 12 weeks. There were no differences in motor symptoms between the two groups suggesting that the herbal therapy was as effective as the most potent conventional PD medication. Specific herbs for some of the associated symptoms of PD include some of the following (5). Datura stramonium seeds provide anticholinergic effects and can reduce tremor and rigidity. Evening primrose oil (oenothera biennis) may lessen tremor by increasing bioavailability of levodopa. Ginger (zingiber officinalis) minimizes nausea and vomiting which may occur as a side effect from dopaminergic medications. Banisterine and Nicotiana tabacum both have monoamine oxidase

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inhibitor activity similar to that of selegiline and rasagiline, and thereby may enhance the activity by reducing the metabolism of naturally occurring endogenous dopamine as well as synthetic dopamine. Passion flower (passiflora incarnata) may lessen anxiety and insomnia as well as enhance sexual libido. St. John’s Wart (hypericum perforatum) has been studied and shown to reduce symptoms of mild depression. Memory may improve with use of ginko biloba and constipation can be treated with triphala. Acupuncture Acupuncture is based upon TCM and is one of the main therapies used by TCM physicians, but also practiced by naturopaths, osteopaths, and a variety of healthcare professionals. Acupuncture involves the placement of needles at specific points along meridians with the goal of restoring the balance of yin and yang and proper chi or qi flow to promote health. Persons with PD receiving acupuncture report a reduction in pain and sometimes improved sleep and mood and increased energy. Reduction of pain has consistently been reported by persons receiving acupuncture for a variety of conditions. Stimulation of the nerve fibers with the acupuncture needles is thought to activate the nervous, lymphatic, and electromagnetic pathways and result in a release of hormones that reduce pain as well as stimulate the immune system and improve circulation. Treatments often last 40 to 90 minutes while laying on one’s back with needles in place and to be effective may need to be done a minimum of one to three times weekly for a series of 10 to 12 weeks and then continue on a maintenance program of one to two times monthly. There are a few limited studies suggesting potential benefit of acupuncture for PD. One study involved 53 patients, 29 who received acupuncture every other day for a total of three months and 24 who received no acupuncture and did not change their Western medications for PD (22). A significant improvement in PD motor symptoms was reported in the patients receiving acupuncture as well as an ability to reduce their dopaminergic medications, whereas the control group reported an overall worsening of symptoms. In similar studies, persons with PD have reported no change in symptoms or have withdrawn from the study due to lack of perceived benefit (23); however, in some studies improvements in sleep, depression, and quality of life were observed (24,25). Massage Therapy Massage therapy involves the use of a therapist’s hands and sometimes elbows and knees or in some cases hand-held wooden thumbs or rocks along with special ointments and aromas that are directly applied to the body’s muscles and soft tissues (5). Its origins date back to over 4000 years as a form of TCM therapy to promote health and prevent disease. It is also a primary treatment in the Ayurvedic system. Similar to acupuncture theory, the direct manipulation of the body tissues is thought to activate the immune system, clear waste products from the lymphatic system, increase endorphin production, and restore chi flow. Though massage therapy is not a proven therapy specifically for PD, the potential benefits often reported include stress reduction, emotional calmness, reduced muscle stiffness and associated pain, along with increased range of motion of the limbs, neck, and trunk and increased energy levels. These benefits are often immediate and relatively short lasting; thus, similar to acupuncture, it may require a regular schedule for maximal, continued benefit. The practice of massage therapy is growing rapidly in the United States with over 125,000

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licensed massage therapists. There are over 100 massages or body energy therapies such as deep tissue Swedish, craniosacral, acupressure or Shiatsu, rolfing, myofacial release, reflexology, hot rock, and soft light tissue techniques such as Rekki. Although there are no double-blind, controlled studies supporting massage as a specific treatment of PD, it may have a role as an adjunctive treatment of muscle rigidity and associated pain as well as stress reduction and promotion of a sense of well being. Exercise An endless list of available exercises to consider for overall health promotion exists (i.e., weight lifting, conditioning, isometric/pilates, aerobic, stretching, martial arts, specific sports, etc.). Exercise can positively impact any person’s health and in particular a person with PD by increasing muscle strength (thereby increasing one’s ability to get up, walk, swallow, speak, and breath), flexibility (reducing muscle rigidity/joint stiffness and increasing range of motion), and bone density (reducing the risk of a limb fracture related to falling). Additional benefits include enhanced cardiovascular and respiratory function and subsequent blood flow and delivery of oxygen and nutrients to the brain. Exercise may also increase daily energy levels, reduce emotional and mental stress, improve mood by raising endorphin levels, and result in better sleep patterns. Many controlled, randomized clinical studies of the benefits of exercise in the elderly can be found in the medical literature (26–28). Exercises that improve balance and promote more efficient body movement such as yoga and tai chi may be of particular interest to persons with PD. A randomized, single-blind, controlled study of 30 persons with PD found that those who practiced tai chi regularly over three months had an 18 times greater reduced risk of falling compared with the control group (29). Similar benefits have been reported with smaller open-label studies along with numerous anecdotal reports of the benefits of yoga for PD. There is also animal data from the 6-hydroxydopamine mouse model of PD suggesting the possible neuroprotective role of aerobic exercise by increasing the production of endogenous neurotrophic factors in the brain (30). Human clinical studies with newly diagnosed PD patients are examining whether aerobic exercise can increase neurotrophic factors and improve motor function and possibly slow the progression of PD. Chelation Chelation is typically used as an intravenous therapy (sometimes oral) to remove a particular substance that is found to occur at a toxic level in the body such as lead, copper, mercury, or arsenic. The amino acid complex, ethylene-diamine-tetraacetic acid, is the most commonly used chelating agent, though herbs and supplements may sometimes be used. Though there is a higher incidence of PD occurring in persons with chronic exposure to heavy metals such as manganese and copper and also with exposure to pesticides and herbicides, no specific toxic agent directly linked to the cause of PD has ever been identified and it is unclear what one would attempt to chelate out of the body of someone with PD. There is no scientific evidence to support the use of chelation therapy for the treatment of PD. In fact, chelation therapy has come under investigation and criticism for making false statements about its curative powers for a number of diseases such as multiple sclerosis, Alzheimer’s disease, and PD with no data to support such claims. Potential harm from chelation includes kidney damage, depletion of essential minerals, such as iron, calcium, and zinc, and peeling, blistering skin. Additional information can be found in Ref. (31).

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Homeopathy Some of the agents a homeopath might recommend would include diluted amounts of mercurius vivus, causticum, argentum nitricum, and zincum metallicum. Tremor might be treated with anthimonium tartaricum, mercurius corrosivus, and agaricus. Rigidity and tremor would likely be treated with rhus toxicodendron, and fatigue, weakness, and staggering gait might be treated with gelsemium. These are typically prescribed in a liquid form or in pellets that are dissolved in water and taken several times daily until the motor symptoms improve. There are no published controlled or open label studies indicating the benefit of homeopathic remedies for the treatment of PD and similar to chelation therapy, homeopathy is not accepted or recommended as a treatment for PD. Chiropractic There is no scientific evidence to support the fundamentalist chiropractic theory that spinal manipulation is curative of any serious health condition including PD, and the National Council Against Health Fraud noted that the chiropractic profession has failed to make any significant contribution to the medical scientific community over the past 110 years of its existence. Despite that chiropractics is not a curative therapy for PD, it may have practical value in musculoskeletal symptom relief such as reduction of muscle spasms, pain, and increasing range of motion similar to physical therapies performed by osteopaths, physical therapists, sports trainers, massage therapists, and physiatrists. However, like all therapies, it is not without potential risks including possible stroke from tearing of the vertebral arteries worsening of malalignment of the vertebrae and subsequent pain, nerve root impingement or spinal cord compression, and a possible increase in pain and muscle spasms. Regarding the treatment of PD, there are no published studies to support chiropractic therapy and only one case report in the chiropractic literature (32). THE NEED FOR EVIDENCE-BASED RESEARCH Many users of CAM fail to question the potential harm or benefit of such therapies. There is a tendency of laypersons and many alternative medicine practitioners to view anything labeled as alternative, natural, or holistic as safe. This is a false assumption and should not be made regarding any therapy. There is nothing natural about chelating minerals out of or injecting glutathione or acupuncture needles into a person’s body. Conventional medicine demands that its prescribed treatments be carefully scrutinized by evidence-based research, mostly in the form of randomized, double-blind, placebo-controlled clinical trials. These trials scientifically examine both the short and long-term adverse events and potential efficacy of the treatment and also determine detailed guidelines and standards for prescribing a particular therapy. A large discrepancy exists between the popularity of CAM and the concern or interest among its many users and prescribers for good evidencebased research. This is reflected in the scientific medical literature that is marked by a paucity of evidence-based research for the use of CAM in general and specifically for PD. Popularity does not equal safety or efficacy and the author of this chapter and the editors of this book along with most of the conventional scientific community expect and demand well-designed randomized, double-blind, placebo-controlled studies for CAM treatments before readily recommending or prescribing them. This is to support the use of CAM by establishing clear guidelines and expectations

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regarding which therapies are potentially beneficial and which are not or may have associated harmful effects. Gains of future studies of CAM include a wider acceptance of their use by conventional healthcare providers and a bridging of conventional and alternative therapies into a more integrative healthcare system. CAM that are scientifically proven as effective and safe stand a much better chance of becoming incorporated into the mainstream medical system. This may in turn pave the way toward financial reimbursement by health insurance companies. Some therapies may in fact prove to be more cost effective than current conventional therapies. A challenge for researchers of CAM is that some therapies are difficult to study in the conventional double-blind, placebo-controlled design. For instance, how does one conduct a double-blind, placebo-controlled study of massage therapy, acupuncture, or reflexology? Finally, many alternative healthcare providers would make the argument that there is no one specific therapy to treat a person with PD, but rather numerous therapies and the need for a specific life style long-term to positively impact or prevent any disease state. Eastern medicine operates on the assumption that if one supports the body, mind, and spirit by an array of healthy lifestyle behaviors and prescribed Eastern therapies, the individual will recover from or improve in his or her condition by allowing the body to heal itself. Then one could argue that in order to attempt to truly study the benefits of Eastern medical therapy and the impact upon PD, one would have to perform long-term studies using a combination of a number of Eastern medical treatments. Though there are many challenges to future scientific study of CAM for the treatment of PD, many of these obstacles can be overcome by creative and dedicated alternative and conventional researchers. The future use and role of CAM is evolving. How it evolves in Western society and how it is incorporated into conventional medicine will largely depend upon society, government, and conventional and alternative healthcare professionals as a whole. CONCLUSION Much of this book describes accepted conventional therapies for the treatment of PD. The conventional therapies have been carefully studied and scrutinized by the scientific community. Complementary alternative medical approaches are not proven treatments for PD, as they have not been adequately studied. Therefore, which alternative therapies to recommend, especially by Western medical healthcare professionals, largely remains a mystery. The lack of scientific support for many alternative therapies does not, however, discredit their potential benefits. On the contrary, some CAM therapies may have a more important role of health promotion and though not proven to treat a particular symptom or aspect of PD, may in fact lessen the impact of PD by supporting the mind, body, and spiritual healing capabilities. The hope is that future scientific study using conventional medical standards will help define which CAM therapies should be considered for the treatment of PD in conjunction with accepted conventional therapies and that ultimately persons with PD will benefit by integration of the two into a more holistic health program. REFERENCES 1. Eisenberg DM, Davis RB, Ettner SA, et al. Trends in alternative medicine use in the United States 1990–1997: results of a follow-up national survey. JAMA 1998; 280:1569–1575. 2. Marjama-Lyons J, Smith L, Mylar B, Urso J, Carriero L, Boggs D. Alternative medicine in Parkinson’s disease: a survey of 75 patients. Mov Disord 2002; 17(suppl 5):S70.

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3. Rajendran PR, Thompson RE, Reich SG. The use of alternative therapies by patients with Parkinson’s disease. Neurology 2001; 57:790–794. 4. Kelner M, Wellman B (eds). Complementary and Alternative Medicine Challenge and Change. Toronto, Canada: Hardwood Academic Publishers, 2000. 5. Marjama-Lyons J, Shomon M. What Your Doctor May Not Tell You About Parkinson’s Disease: A Holistic Program for Optimal Wellness. 1st ed. New York: Warner Books, 2003. 6. http://www.naturopathic.org 7. http://www.homeopathic.org. 8. http://www.chiroweb.com 9. http://www.naturalhealers.com 10. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson’s disease: evidence of slowing of functional decline. Arch Neurol 2002; 59:1541–1550. 11. Somer E. Health Media of America. The Essential Guide to Vitamins and Minerals. New York, NY: Harper Collins Publishers, 1992. 12. Joseph JA, Shukitt-Hale B, Denisova NA, et al. Reversal of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach or strawberry diet supplementation. J Neurosci 1999; 19(18):8114–8121. 13. Willis L, Bickford P, Zaman V, Moore A, Granholm AC. Blueberry extract enhances survival of intraocular hippocampal transplants. Cell Transplant 2005; 14(4):213–223. 14. Tillotson AK, Tillotson NH, Abel R. The One Earth Herbal Sourcebook: Everything You Need to Know About Chinese, Western and Ayurvedic Herbal Treatments. New York, NY: Kensington Publishing, 2001. 15. Katzenschlager R, Evans A, Manson A, et al. Mucuna pruriens in Parkinson’s disease: a double blind clinical and pharmacological study. J Neurol Neursurg Psychiatry 2004; 75(12):1672–1677. 16. Manyam BV. Paralysis agitans and levodopa in ayurveda: ancient Indian medical treatise. Mov Disord 1990; 5(1):47–48. 17. Vaidya AB, Rajagopalan TG, Mankodi NA, et al. Treatment of Parkinson’s disease with the cowhage plant-Mucuna pruriens. Neurol India 1978; 26(4):171–176. 18. Manyam BV, Dhanasekaran M, Hare TA. Effect of antiparkinson drug HP-200 (Mucuna pruriens) on the central monoaminergic neurotransmitters. Phytother Res 2004; 18(2):97–101. 19. HP-200 in Parkinson’s Disease Study Group. An alternative medicine treatment for Parkinson’s disease: results of a multicenter clinical trial. J Altern Complement Med 1995; 1(3):249–255. 20. Chen J, Guo J, Sun J, Jiang W, Wu B. TCM treatment of Parkinson’s syndrome: a report of 40 cases. J Tradit Chin Med 2003; 23(3):168–169. 21. Guoshong G. Clinical study on treatment of Parkinson’s disease with Wengan Zhichan [abstr]. International Congress on Traditional Medicine, Beijing, April 2000. 22. Zhuang X, Wang L. Acupuncture treatment of Parkinson’s disease: a report of 29 cases. J Tradit Chin Med 2000; 20(4):264–267. 23. Cristian A, Katz M, Cutrone E, Walker RH. Evaluation of acupuncture in the treatment of Parkinson’s disease: a double blind pilot study. Mov Disord 2005; 20(9):1185–1188. 24. Shulman LM, Wen X, Weiner WJ, et al. Acupuncture therapy for the symptoms of Parkinson’s disease. Mov Disord 2002; 17(4):799–802. 25. Eng ML, Lyons KE, Greene MS, Pahwa R. Open-label trial regarding the use of acupuncture and yin tui na in Parkinson’s disease outpatients: a pilot study on efficacy, tolerability and quality of life. J Altern Complement Med 2006; 12(4):395–399. 26. Lord SR, Castell S, Corcoran J, et al. The effect of group exercise on physical functioning and falls in frail older people living in retirement villages: a randomized controlled trial. J Am Geriatr Soc 2003; 51:1685–1692. 27. Kuroda K, Tatara K, Takatorige T, Shinsho F. Effect of physical exercise on mortality in patients with Parkinson’s disease. Acta Neurol Scand 1992; 86:55–59. 28. Kessenich C. Tai Chi as a method of fall prevention in the elderly. Orthop Nurs 1998; 17(4):27–29. 29. Marjama-Lyons J, Smith L, Mylar B, Nelson J, Holliday G, Seracino D. Tai Chi and reduced rate of falling in Parkinson’s disease: a single blinded pilot study. Mov Disord 2002; 17 (suppl 5):S70–S71.

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Index

Abalative surgery, 120–121 speech and swallowing disorders, 461–468 collagen augmentation, 461–462 cricopharyngeal myotomy, 462 pallidotomy, 461 thalamotomy and subthalamotomy, 461 voice treatment, 462–465 Acoustic analyses, speech and voice disorders and, 452–453 Activity modification, therapy rehabilitation interventions and, 447 Acupuncture, 483 Adaptive equipment, 447 Advanced Parkinson’s disease amantadine therapy and, 294–295 seligiline clinical trials and, 354 Alpha methyl para tyrosine, 240 Alpha synuclein, 251–252 Alternative therapies, 475–486 acupuncture, 483 antioxidants, 479 cell-supporting agents, 479–480 chelation, 484 chiropractic, 478, 485 defining, 475–476 diet, 480–481 evidence-based research, 485–486 exercise, 484 herbs, 481–483 homeopathy, 478, 485 massage therapy, 483–484 naturopathy, 477–478 non-Western, 476–477 Ayurvedic medicine, 477 Chinese, 476–477 Amantadine therapy, 293–303 clinical uses, 294–295 advanced Parkinson’s Disease, 294–295 early Parkinson’s Disease, 294 miscellaneous considerations, 295 dosing, 293–294 history, 293

[Amantadine therapy] mechanisms of action, 296–297 pharmacokinetics, 293–294 side effects, 295–296 Animal models neurotoxicant induced, 240–250 Parkinson’s disease and, 239–257 Anticholinergic therapy, 293–303 clinical uses, 299–300 miscellaneous considerations, 300–301 Parkinson’s disease associated dystonia, 300 tremor predominant Parkinson’s disease, 300 common types, 298 history, 299 mechanisms of action, 302–303 pharmacokinetics and dosing, 299 side effects, 301–302 Anticholinergics, 119 Antidepressants side effects of, 136 trycyclic, 141–142 Antioxidants, 479 Antipsychotic drugs, 157–162 test results of, 158 Anxiety, 118–119 detection and recognition, 134–135 epidemiology of, 133 management of, 133–136 mechanisms of, 134 treatment, 135 antidepressant side effects, 136 benzodiazepines, 135 buspirone, 136 selective serotonin reuptake inhibitors, 135–136 Apomorphine, 336–337 Aripiprazole, 161–162 Articulatory disorders, 454–455 Assessment depression and, 139–141 lesion surgeries and, 394–402

489

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490 Attention functions dementia and, 116–117 neuropsychology dysfunction without dementia, 114–115 Automobile driving excessive daytime sleepiness and, 97 sudden onset of sleep and, 97 Autonomic dysfunction diagnostic testing for, 77–79 common tests, 79 metaidobenzylguanidine scintigraphy, 78–79 features of, 78 frequency of, 77 management of, 77–87 symptoms and management of, 79–87 constipation, 83–84 dysphagia, 81–82 orthostatic hypotension, 79–81 sexual dysfunction, 85–86 sialorrhea, 82–83 sweating dysfunction, 86–87 urinary bladder dysfunction, 84–85 testing, 79 Ayurvedic herbs, 481–482 medicine, 477 Balance and coordination, 444–445 Basal ganglia physiology, gene therapy and, 433 selection theory, 227–228 nested nonlinear reentrant oscillators, 228–230 thalamic cortical system, 235 Behavioral neurology, 109–110 treatment, speech and swallowing disorders and, 462 Benzodiazepines, 135 Bilateral subthalamotomy, 402 thalamotomy, 400 Bradykinesia, parkinsonian symptoms and signs, 52–54 Brain activity, LSVT and, 466–467 Brain lesions, 37 Brain stimulation, 121 Brasofensine, 382 Briomocriptine, 337–338 Brissaud, Eduard, 15 Buspirone, 136

Index Cabergoline, 341–342 Calcium binding proteins, 211–212 Carbon disulfide, 284 Catechol-O-Methyltransferase inhibitors, 365–372 current usage of, 371–372 first generation, 366 future of, 372 second generation, 366 entacapone, 367–369 nitecapone, 366–367 stalevo, 369 tolcapone, 369–371 Cell supporting agents, 479–480 Central side effects to anticholinergic therapy, 300 Charcot, Jean-Martin, 7–13 Salpetriere School, 7–13 Chelation, 484 Chinese herbs, 482–483 medicine, 476–477 Chiropractic therapy, 478, 485 Cholinesterase inhibitors, 119, 162–163, 166–169 properties of, 166 studies of, 168 Clinical assessment, parkinsonian symptoms and signs, 49–62 Clinical molecular genetic testing, 273 Clinical trials levodopa and, 312–319 rasagiline and, 356 Clozapine, 157, 159 Coenzyme Q10, 385 Collagen augmentation, hypophonia, 461–462 Compensated rate of speech, 455–456 Complex system basal ganglia thalamic cortical system, 235 neurocircuitry and, 235 Constipation, 83–84 Coordination, 445 Corticabasal degeneration, 34–35, 123, 200–202 Creatine, 384–385 Cricopharyngeal myotomy, 462 Datatop, seligiline clinical trials and, 352–353 Deep brain stimulation, 121, 409–418 advantages and disadvantages, 410 adverse effects, 416–418

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Index [Deep brain stimulation] early, 424–425 globus pallidus interna, 411–412 vs. subthalamic nucleus, 415–416 hardware, 409–410 related complications, 417–418 history of, 409 lesion surgeries vs., 393 stimulation complications, 418 subthalmic nucleus, 412–414 surgical complications, 417 swallowing disorder treatment and, 459–461 extradural, 460–461 transcranial, 460–461 thalamus, 410 Dementia, 116–118 affect and emotion, 117 attention and executive functions, 116–117 incidence of, 164–165 language, 117 Lewy bodies, 34 management of, 163–169 memory, 117 neuropathology of Parkinson’s disease, 197–198 pathophysiology of, 165 prevalence of, 164–165 pugilistica, 203 risk factors, 117–118, 165–166 treatment general, 165–166 specifics, 166–169 cholinesterase inhibitors, 166–169 other types, 169 visuoperceptual functions, 117 Depression, 118, 136–146 detection and assessment, 139–141 epidemiology of, 136–137 management of, 136–146 mechanisms, 137–139 pharmacologic treatment of, 141–144 dopamine agonists, 144 miscellaneous agents, 142–144 selective serotonin reuptake inhibitors, 142 tricyclic antidepressants, 141–142 treatment, 141–145 efficacy assessment, 144 nonpharmacologic, 144–145

491 [Depression; treatment] pharmacologic, 141–144 Detection and recognition anxiety and, 134–135 depression and, 139–141 Diagnostic criteria, Parkinson’s disease and, 40–42 Diet, alternative therapies and, 480–481 Differential diagnosis idiopathic, 29–31 neuroimaging and, 181–182 Parkinson and essential tremor, 55 parkinsonism and, 29–42 rapid eye movement sleep behavior disorder and, 95–96 Disability, 442 Disability assessment, parkinsonian symptoms and signs and, 61–62 Disordered rate of speech, 455–456 DNA mutations, 212–213 Dopa responsive dystonia, 38 Dopamine agonists, 119–120, 144, 335–345 apomorphine, 336–337 bromocriptine, 337–338 cabergoline, 341–342 new types, 380–382 lisuride patch, 381 piribedil, 381–382 ropinirole 24 hour prolonged release, 380–381 rotigotine patch, 381 SLV308, 382 sumanirole, 382 pergolide, 338–339 piribedil, 343 pramipexole, 339–340 receptors, 335–343 ropinirole, 340–341 rotigotine, 342–343 therapy, 344–345 titration schedule, 337 type comparison, 343–344 Dopamine receptors, 335–343 Dopamine synthesis gene therapy, 430–431 Dopamine transporters, 210–211 Dosing amantadine, 293–294 anticholinergic therapy and, 299 Drug induced parkinsonism, 31–32 sleep disruption, 98

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492

Index

Duodopa, 380 Dyskinesia levodopa and, 311–312 Dyskinesia treatment, 385–386 fipamezole, 386 levetiracetam, 386 sarizotan, 385–386 Dysphagia, 81–82

Farming, 285 Fetal transplantation, 426–428 Fipamezole, 386 Freezing, parkinsonian symptoms and signs, 59–60 Frontotemporal dementia, 35 Functional activities, 445

Early deep brain stimulation, 424–425 Early Parkinson’s disease amantadine therapy and, 294 seligiline clinical trials and, 353 Electroconvulsive therapy, 163 Embryonic stem cells, 429 Emotion, dementia and, 117 Entacapone, 367–369 Environmental changes, 447 Environmental risk factors, 279–288 genes vs., 279–280 geographic impact, 280–281 occupational hazards, 284–287 risk factors, toxins, 281–284 Epidemiology anxiety and, 133 depression and, 136–137 genetics studies, 269–270 parkinsonism, 19–24 sleep dysfunction and, 91–103 Essential tremor (ET), 19 differentiation, 31 misdiagnosis, 19 neuropsychology and, 121–123 parkinsonian differential diagnosis of, 55 ET. See Essential tremor. Ethnicity, Parkinson’s disease and, 23–24 Etilevodopa, 380 Evidence based research, alternative therapies and, 485–486 Excessive daytime sleepiness, 96–97 automobile driving, 97 treatment for, 102 Executive functions dementia and, 116–117 neuropsychology dysfunction without dementia, 114–115 Exercise, 484 therapy, 446–447 Extradural brain stimulation, 460–461

Gait abnormalities, parkinsonian symptoms and signs, 59–60 Gait analysis, 444 Gender risk of Parkinson’s disease, 23 Gene therapy, 430–431 basal ganglia physiology, 433 dopamine synthesis, 430–431 intravenous, 434 neurotrophin genetic delivery, 431–433 parkin, 433–434 strategies, 430 General mobility, physical therapy examination and, 444 Genes vs. environmental risk factors, 279–280 Genetics, 269–275 association studies, 271, 273 clinical molecular testing, 273 epidemiologic studies, 269–270 kindred evaluations, 270–271 models Parkinsons’s disease and, 250–254 rodents, 250–251 transgenic mouse, 251 studies of twins, 270 Geographic impact, environmental risk factors and, 280–281 Geography, Parkinson’s disease and, 23–24 Gilial cell line derived neurotrophic factor, 425–426 Gilial-derived neurotrophic factor, 384 GIRK2 mutation, 214–216 Globus pallidus interna deep brain stimulation and, 411–412 selected studies, 411 patient selection, 416 Globus pallidus internal segment suppression theory, 225–227 Gowers, William, 14 Guam Parkinsonism Dementia Complex, 202–203

Facial expressions, LSVT and, 467 Familial parkinsonism, 203–204 kindred evaluations and, 272

Hallervorden-Spatz disease. See Pantothenate kinase-associated neurodegeneration. Handicap, 442

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Index Hardware, deep brain stimulation and, 409–410 hardware-related complications, 417–418 Head trauma, 36 Hemiparkinsonism Hemiatrophy Syndrome, 40 Herbicides, 283 Herbs, 481–483 ayurvedic, 481–482 Chinese, 482–483 Homeopathy, 478, 485 Homocysteine, levodopa and, 325–326 Huntington’s disease, juvenile, 40 Hydropcephalus parkinsonism, 37 Hypertensive crisis, monamine oxidase inhibitors and, 350 Hypophonia, 461–462 Idiopathic Parkinson’s disease, 29–31 Imaging technology, 177–179 Impairment, 442 Incidence rates of Parkinson’s disease, 21 Infectious parkinsonism, 37–38 Intracerebral drug infusion, 425–426 gilial cell line-derived neurotrophic factor, 425–426 neurturin, 426 Intravenous gene therapy, 434 Invertebrate models, 254–255 Investigational pharmacological treatments, 379–386 Investigational surgical therapies, 423–434 current therapies, status, 423 fetal transplantation, 426–428 gene therapy, 430–431 intracerebral drug infusion, 425–426 novel stimulation approaches, 423–424 early deep brain stimulation, 424–425 motor cortex stimulation, 424 pedunculopontine nucleus, 424 stem cell therapy, 428 Istradefylline, 383 Juvenile Huntington’s disease, 40 Kindred evaluations Familial parkinsonism, 272 genetics and, 270–272 Language dementia and, 117 neuropsychology dysfunction without dementia, 115

493 LARGO study, 357–358 Laryngeal dysfunction, physiologic measures, 453–454 Learning, neuropsychology dysfunction without dementia, 115 Lee Silverman Voice Treatment. See LSVT. Lesion surgeries, 291–403 assessments and procedures, 394–402 bilateral palidotomy, 395, 398 bilateral subthalamotomy, 402 bilateral thalamotomy, 400 palidotomy study size, 396–397 unilateral palidotomy, 394–395 unilateral subthalamic nucleotomy, 400–402 unilateral thalamotomy, 398–400 deep brain stimulation vs., 393 early attempts, 390–392 indications for, 392 patient considerations, 392–393 selection, 392–393 Lesions, 244–248 brain, 37 Levetiracetam, 386 Levodopa, 119–120, 309–328 available forms of, 327 challenge test, 326–327 clinical trials, 312–319 melanoma, 324–325 mortality, 323–324 motor fluctuation levels, 316–319 tolerance, 322–323 toxicity, 320–325 dyskinesia, 311–312 history of, 309–310 homocysteine, 325–326 importance of, 327–328 motor fluctuations, 311–312 new types, 379–380 duodopa, 380 etilevodopa, 380 methyl ester, 380 vadova, 379–380 pharmacology of, 310–311 Life expectancy, 21–22 Lisuride patch, 381 LSVT (Lee Silverman Voice Treatment), 462–468 administration of, 467–468 effectiveness of, 465–466 brain activity, 466–467

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494 [LSVT (Lee Silverman Voice Treatment)] orofacial system, 466 facial expressions, 467 swallowing disorders and, 467 Management of autonomic dysfunction, 79–87 Manganese, 282–283 Massage therapy, 483–484 Mechanisms anxiety and, 134 depression and, 137–139 Mechanisms of action amantadine and, 296–297 anticholinergic therapy and, 302–303 monamine oxidase inhibitors and, 349–350 Melanized midbrain dopamine neurons, 209–210 Melanoma, levodopa and, 324–325 Memory dementia and, 117 neuropsychology dysfunction without dementia, 115 Methamphetamine, 248–249 Methyl ester levodopa, 380 Midbrain dopamine neurons, 211–212 calcium binding proteins, 211–212 Mimicking conditions, Parkinson’s disease, 30–31 Minocycline, 385 Mitochrondrial DNA mutations, 212–213 Monamine oxidase inhibitors, 349–358, 382 brasofensine, 382 hypertensive crisis, 350 mechanisms of action, 349–350 neuroprotective effects, 350–351 safinamide, 382 seligiline, 351–352 Mortality levodopa and, 323–324 seligiline and, 354–355 Motor cortex stimulation, 424 Motor features, parkinsonian symptoms and signs, 52 Motor fluctuations, levodopa and, 311–312, 316–319 Mouse models, 251 MPTP lesioned mouse model, 244 nonhuman primate model, 244–247 other species, 248 Multi-infarct parkinsonism, 36–37

Index Multiple system atrophy, 33–34 122–123, 198, 255–256 Mutations, 212–213 Naturopathy, 477–478 Nested nonlinear reentrant oscillators, 228–230 Neurocanthocytosis, 40 Neurochemistry of nigral degeneration, 209–217 Neurocircuitry, 223–235 anatomy, 224–225 basal ganglia selection theory, 227–228 basal ganglia thalamic cortical system, 235 complex system, 235 globus pallidus internal segment suppression theory, 225–227 oscillatory theory, 228–230 Parkinson’s Disease pathophysiology, 225 subthalmic nucleus deep brain stimulation, 230–235 Neuroimaging, 177–188 accuracy of, 179–181 differential diagnosis, 181–182 disease progression, 182–186 imaging technology, 177–179 preclinical Parkinson’s disease, 186–187 Neurology, behaviorial, 109–110 Neuronal mechanisms, 230–235 Neuronal stem cells, 429–430 Neuropathology clinical features, 195–197 corticobasal degeneration, 200–202 dementia pugilistica, 203 dementia, 197–198 familial parkinsonism, 203–204 multiple system atrophy, 198 parkinsonism and, 195–204 postencephalitic, 202 progressive supranuclear palsy, 199–200 Neurophysiology, 223–235 Neuroprotective effects, monamine oxidase inhibitors and, 350–351 Neuropsychiatric comorbidities, 98 Neuropsychiatric issues, treatment for, 102 Neuropsychiatry, 109–110 Neuropsychological aspects, 109–123 surgical interventions, 120–121 Neuropsychology, 109–110 anxiety, 118–119 cognitive domain assessed tests, 111 depression, 118

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495

Index [Neuropsychology] dysfunction with dementia, 116–118 without dementia, 114–115 attention and executive functions, 114–115 language, 115 learning and memory, 115 visuospatial perception, 115 essential tremor, 121–123 evaluation types, 110–111 findings in Parkinson’s disease, 113–114 managing Parkinson’s disease, 112–113 Parkinson-plus syndromes, 121–123 corticobasal degeneration, 123 multiple system atrophies, 122–123 progressive supranuclear palsy, 122 pharmacologic treatments, 119–121 Neurotoxicant induced animal models, 240–250 methamphetamine, 248–249 paraquat, 249 proteasome inhibitors, 249–250 rotenone, 249 Neurotrophin genetic delivery, 431–433 Neurturin, 426 Nigral degeneration, 209–217 adenosine triphosphate sensitive postassium (K-ATP) channels, 216–217 dopamine transporters, 210–211 GIRK2 mutation, 214–216 melanized midbrain dopamine neurons, 209–210 midbrain dopamine neurons, 211–212 substantia nigra pars compacta, 210–211 transcription factor PitX3, 213–214 uncoupling proteins, 214 vesicular monamine transporter, 210–211 Nitecapone, 366–367 Nocturia, 97–98 Nocturnal akinesia, 94 treatment for, 102 Non-neuronal stem cells, 430 Nonpharmacologic treatment of depression, 144–145 Non-western alternative therapies, 476–477 Nucleotomy, unilateral subthalamic, 400–402 Occupational hazards farming, 285 steel industry, 285–286 welding, 286–287

Occupational therapy 441–448 definition of, 442 evaluation, 445–446 coordination, 445 functional activities, 445 range of motion, 445 strength testing, 445 Odansetron, 162 Olanzapine, 160 Orofacial system, 466 Orthostatic hypotension, 79–81 Oscillatory theory, 228–230 Osler, William, 14–15 Pallidotomy, 461 bilateral, 395, 398 study size, 396–397 unilateral, 394–395 Palsy, progressive supranuclear, 199–200, 256–257 Pantothenate kinase-associated neurodegeneration (HallervordenSpatz disease), 39–40 Paraquat, 249 Parasomnias, 94–98 rapid eye movement sleep behavior disorder, 94–95 Parkin, 252 gene therapy, 433–434 Parkinson plus syndrome, 121–123 corticobasal degeneration, 123 multiple system atrophies, 122–123 progressive supranuclear palsy, 122 Parkinson, essential tremor, differential diagnosis of, 55 Parkinson, James, early life of, 3–6 Parkinson’s disease advanced, 294–295 seligiline clinical trials and, 354 alternate diagnosis, 30 animal models, 239–257 associated dystonia, 300 corticobasal degeneration, 200–202 diagnostic criteria, 40–42 differential diagnosis, 29–31 classification, 30 idiopathic, 29–31 mimicking conditions, 30–31 early, 294 seligiline clinical trials and, 353 early writings on, 1–15 Brissaud, 15

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496 [Parkinson’s disease] Charcot, 7–13 Gowers, 14 Osler, 14–15 Sauvages, 1 Shakespeare, 1 von Humoldt, 1, 3 essential tremor differentiation, 31 genetic models, 250–254 history of, 1–15 invertebrate models, 254–255 James Parkinson, 3–6 model variants, 255–257 multiple system atrophy, 255–256 striatonigral degeneration, 255–256 taupathies, 256–257 multiple system atrophy, 198 neuropathology, clinical features, 195–197 neuropsychological aspects, 109–123 anxiety, 118–119 depression, 118 pharmacologic treatments, 119–121 surgical interventions, 120–121 neuropsychology, dysfunction with dementia, 116–118 dysfunction without dementia, 114–115 pathophysiology, neurocircuitry and, 225 postencephalitic, 202 preclinical, 186–187 progression neuroimaging and, 182–186 progressive supranuclear palsy, 199–200 relative risk of, 280 tremor predominant, 300 Parkinsonian symptoms and signs assessment of disability, 61–62 Bradykinesia, 52–54 freezing, 59–60 gait abnormalities, 59–60 motor features, 52 other motor manifestations, 60–61 pathophysiology and clinical assessment, 49–62 postural instability, 59 rigidity and postural abnormalities, 56–59 tremor, 55–56 Unified Parkinson’s Disease Rating Scalea, 68–75 Parkinsonism differential diagnosis, 29–42 epidemiology, 19–24 incidence rates, 21 inclusion criteria, 19–20

Index [Parkinsonism] life expectancy, 21–22 misdiagnosis, 19 prevalence of, 22–23 gender risk, 23 geography, ethnicity, race, 23–24 magnetic resonance imaging, 35 neuropathology and, 195–204 other causes, 31–41 brain lesions, 37 corticobasal degeneration, 34–35 dementia Lewy bodies, 34 drug induced, 31–32 frontotemporal dementia, 35 head trauma, 36 hydrocephalus, 37 infectious, 37–38 multi-infarct, 36–37 multiple system atrophy, 33–34 postinfectious, 37–38 progressive supranuclear palsy, 32–33 psychogenic, 38 toxin-induced, 36 young adults, 38–40 dopa responsive dystonia, 38 Hemiparkinsonism Hemiatrophy Syndrome, 40 juvenile Huntington’s disease, 40 neuroacanthocytosis, 40 pantothenate kinase-associated neurodegeneration, 39–40 Wilson’s disease, 38–39 X-linked dystonia parkinsonism, 40 Pathophysiology dementia and, 165 Parkinsonian symptoms and signs, 49–62 psychosis, 156–157 sleep dysfunction, 93 Patient assessment, physical and occupational therapy, 441–442 Patient considerations, lesion surgeries and, 392–393 Patient selection, lesion surgeries and, 392–393 Pedunculopontine nucleus, 424 Perceptual deficits, 456–457 Pergolide, 338–339 Periodic limb movement, 97 Peripheral side effects to anticholinergic therapy, 301–302 Pesticides, 283

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497

Index Pharmacokinetics amantadine, 293–294 anticholinergic therapy and, 299 Pharmacologic treatment anticholinergics, 119 cholinesterase inhibitors, 119 depression dopamine agonists, 144 miscellaneous agents, 142–144 selective serotonin reuptake inhibitors, 142 tricyclic antidepressants, 141–142 dopamine agonists, 119–120 levodopa, 119–120 neuropsychological aspects of, 119–121 rasagiline, 120 selegiline, 120 Pharmacological induced animal models, 240 reserpine, 240 Pharmacological treatments, new, 379–386 coenzyme Q10, 385 creatine, 384–385 dopamine agonists, 380–382 dyskinesia, 385–386 gilial-derived neurotrophic factor, 384 istradefylline, 383 levodopa preparations, 379–380 minocycline, 385 monamine oxidase inhibitor, 382 Pharmacology, levodopa and, 310–311 Physical and occupational therapy, 441–448 definitions, 441–442 disability, 442 handicap, 442 impairment, 442 occupational, 442 definitions, physical, 442 specific terms, 442–443 evaluation, 443–446 evidence of, 448 future of, 448 patient assessment, 441–442 rehabilitation interventions, 446–447 Physical therapy, 444–445 definition of, 442 examination, 444–445 balance and coordination, 444–445 gait analysis, 444 general mobility, 444 other points, 445 posture assessment, 444

[Physical therapy] range of motion, 444 strength, 444 Piribedil, 343 Postencephalitic parkinsonism, 202 Postinfectious parkinsonism, 37–38 Postural abnormalities, parkinsonian symptoms and signs, 56–59 instability, Parkinsonian symptoms and signs, 59 Posture assessment, 444 Pramipexole, 339–340 Preclinical Parkinson’s disease, neuroimaging and, 186–187 Prevalence of Parkinson’s disease, 22–23 Pribedil, 381–382 Progressive supranuclear palsy, 32–33, 122, 199–200, 256–257 Proteasome inhibitors, 249–250 Psychogenic parkinsonism, 38 Psychosis background of, 155–156 management of, 155–163 pathophysiology of, 156–157 risk factors, 156–157 treatment of general, 157 long-term outcome, 163 specifics, 157–163 aripiprazole, 161–162 cholinesterase inhibitors, 162–163 clozapine, 157, 159 electroconvulsive therapy, 163 odansetron, 162 olanzapine, 160 quetiapine, 160–161 risperidone, 159–160 ziprasidone, 161 test results of antipsychotic drugs, 158 Quetiapine, 160–161 Race, Parkinson’s disease and, 23–24 Range of motion, 444–445 Rapid eye movement sleep behavior disorder, 94–95 clinical features, 95 differential diagnosis, 95–96 drug-induced, 98 excessive daytime sleepiness, 96–97 neuropsychiatric comorbidities, 98

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498 [Rapid eye movement sleep behavior disorder] nocturia, 97–98 periodic limb movement, 97 restless leg syndrome, 97 sleep-disordered breathing, 97 sudden onset of sleep, 96–97 treatment of, 102–103 Rasagiline, 120, 356 adverse effects, 358 clinical trials, 356 LARGO study, 357–358 PRESTO study, 357 TEMPO study, 356 Rate of speech compensated, 455–456 disordered, 455–456 Rehabilitation interventions, physical and occupational therapy and, 446–447 Reserpine, 240 Resonance problems, 456 Respiratory dysfunction, 454–455 articulatory, 454–455 velopharyngeal, 454–455 Restless leg syndrome, 97 treatment of, 102–103 Rigidity, parkinsonian symptoms and signs, 56–59 Risk factors dementia and, 164–165 environmental, 279–288 psychosis and, 156–157 Risperidone, 159–160 Ropinirole, 340–341 Rotenone, 249 Rotigotine, 342–343 patch, 381 Safinamide, 382 Salpetriere School, Jean-Martin Charcot and, 7–13 Sarizotan, 385–386 Sauvages, François Boissier de, 2 Selective serotonin reuptake inhibitors, 135–136, 142 Selegiline, 120, 351–352 clinical trials, 352–354 Advanced Parkinson’s disease, 354 datatop, 352–353 early Parkinson’s disease, 353 mortality, 354–355 rasagiline, 356 zydis, 355

Index Sensorimotor deficits, 456–457 Severity, neuroimaging and, 181–182 Sexual dysfunction, 85–86 Shakespeare, William, 2 Sialorrhea, 82–83 Side effects amantadine and, 295–296 anticholinergic therapy and, 301–302 antidepressants and, 136 Sleep disordered breathing, 97 Sleep dysfunction, 91–103 causes of, 92 epidemiology and symptoms, 91–103 management strategies for, 100–101 measuring of, 98–99 pathophysiology, 93 subthalamic nucleus deep brain stimulation, 103 symptoms, 94–98 nocturnal akinesia, 94 parasomnias, 94–98 treatment of, 99–103 excessive daytime sleepiness, 102 neuropsychiatric problems, 102 nocturnal akinesia, 102 rapid eye movement behavior disorder, 102–103 restless leg syndrome, 102–103 Sleep hygiene, 101 Speech and voice characteristics, 452–458 Speech and voice disorders, 451–457 acoustic measures, 452–453 disordered vs. compensated rate of speech, 455–456 laryngeal dysfunction, 453–454 perceptual characteristics, 452 perceptual deficits, 456–457 phonetic characteristics, 452 resonance problems, 456 respiratory dysfunction, 454–455 sensorimotor deficits, 456–457 Speech disorders, treatment, 458–459 abalative surgery, 461–468 collagen augmentation, 461–462 pallidotomy, 461 thalamotomy and subthalamotomy, 461 voice treatment, 462–465 treatment, behavorial treatment, 462 Stalevo, 369 Stem cell therapy, 428–430 embryonic, 429 features, 428

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Index [Stem cell therapy] goals, 428–429 neuronal stem cells, 429–430 non-neuronal stem cells, 430 Strength physical therapy examination and, 444 testing, 445 Striatonigral degeneration, 255–256 Subthalamic nucleus deep brain stimulation, 103, 230–235, 412–414 neuronal mechanisms, 230–235 predictive outcome factors, 414–415 selected studies, 413 Subthalamic nucleus globus pallidus interna vs., deep brain stimulation, 415–416 Subthalamic nucleus patient selection, 416 Subthalamotomy, 461 Sudden onset of sleep, 96–97 automobile driving, 97 Sumanirole dopamine agonist, 382 Surgeries, lesion, 291–403 Surgical complications, deep brain stimulation and, 417 Surgical interventions, neuropsychological aspects and, 120–121 ablative surgeries, 120–121 deep brain stimulation, 121 transplantation, 121 surgical therapies, investigational, 423–434 Swallowing disorders, 457–458 LSVT and, 467 treatment, 458–459 abalative surgery, 461–468 collagen augmentation, 461–462 cricopharyngeal myotomy, 462 pallidotomy, 461 thalamotomy and subthalamotomy, 461 behavorial treatment, 462 deep brain stimulation, 459–461 extradural, 460–461 transcranial, 460–461 Sweating dysfunction, 86–87 Symptoms autonomic dysfunction and, 79–87 sleep dysfunction and, 91–103 Taupathies progressive supranuclear palsy, 256–257 related disorders, 256–257

499 Thalamotomy, 461 bilateral, 400 unilateral, 398–400 Thalamus, deep brain stimulation and, 410 Therapies, alternative, 475 Therapy evaluation, 443–446 occupational, 445–446 physical examination, 444–445 treatment planning, 445–446 Therapy, physical and occupational, 441–448 Therapy, rehabilitation interventions activity modification, 447 adaptive equipment, 447 education, 447 environmental changes, 447 exercise, 446–447 Titration schedule, dopamine agonists and, 337 Tolcapone, 369–371 Tolerance, levodopa and, 322–323 Toxicity, levodopa and, 320–325 Toxin-induced parkinsonism, 36 Toxins, 281–284 carbon disulfide, 284 manganese, 282–283 pesticides/herbicides, 283 solvents, 284 Transcranial brain stimulation, 460–461 Transgenic mouse models, 251 alpha synuclein, 251–252 DJ-1, 253 LRRK2, 253 miscellaneous types, 254 Nurr1, 253–254 parkin, 252 PINK1, 253 UCH-L1, 253 vector infusion, 254 Transplantation, 121 Trauma, head, 36 Treatment anxiety and, 135 depression and, 141–145 Tremor, Parkinsonian, symptoms and signs, 55–56 Tremor, predominant Parkinson’s disease, anticholinergic therapy and, 300 Trycyclic antidepressants, 141–142 Twin studies, genetics and, 270 Uncoupling proteins, nigral degeneration and, 214

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Index

Unified Parkinson’s Disease Rating Scale, 68–75 Unilateral palidotomy, lesion surgeries and, 394–395 Unilateral subthalamic nucleotomy, 400–402 Unilateral thalamotomy, 398–400 Urinary bladder dysfunction, 84–85

[Voice treatment] speech and swallowing disorders and, 462–465 Von Humoldt, Wilhelm, 1, 3

Vadova, 379–380 Vector infusion, transgenic mouse models and, 254 Velopharyngeal disorders, 454–455 Vesicular monamine transporter, 210–211 substantia nigra pars compacta, 210–211 Visuoperceptual functions, dementia and, 117 Visuospatial perception, 115 Voice disorders, 451–457 Voice treatment LSVT (Lee Silverman Voice Treatment), 462–468

Young adults, parkinsonism, 38–40 dopa responsive dystonia, 38 Hemiparkinsonism Hemiatrophy Syndrome, 40 juvenile Huntington’s disease, 40 neuroacanthocytosis, 40 pantothenate kinase-associated neurodegeneration, 39–40 Wilson’s disease, 38–39 X-linked dystonia parkinsonism, 40

Wilson’s disease, 38–39 X-Linked dystonia parkinsonism, 40

Ziprasidone, 161 Zydis seligiline, 355