Handbook of Dementing Illnesses, Second Edition (Neurological Disease and Therapy)

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Handbook of Dementing Illnesses

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NEUROLOGICAL DISEASE AND THERAPY Advisory Board Gordon H. Baltuch, M.D., Ph.D. Department of Neurosurgery University of Pennsylvania Philadelphia, Pennsylvania, U.S.A.

Louis R. Caplan, M.D. Professor of Neurology Harvard University School of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts, U.S.A.

Mark A. Stacy, M.D. Movement Disorder Center Duke University Medical Center Durham, North Carolina, U.S.A.

Mark H. Tuszynski, M.D., Ph.D. Professor of Neurosciences Director, Center for Neural Repair University of California—San Diego La Jolla, California, U.S.A.

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1. Handbook of Parkinson’s Disease, edited by William C. Koller 2. Medical Therapy of Acute Stroke, edited by Mark Fisher 3. Familial Alzheimer’s Disease: Molecular Genetics and Clinical Perspectives, edited by Gary D. Miner, Ralph W. Richter, John P. Blass, Jimmie L. Valentine, and Linda A. Winters-Miner 4. Alzheimer’s Disease: Treatment and Long-Term Management, edited by Jeffrey L. Cummings and Bruce L. Miller 5. Therapy of Parkinson’s Disease, edited by William C. Koller and George Paulson 6. Handbook of Sleep Disorders, edited by Michael J. Thorpy 7. Epilepsy and Sudden Death, edited by Claire M. Lathers and Paul L. Schraeder 8. Handbook of Multiple Sclerosis, edited by Stuart D. Cook 9. Memory Disorders: Research and Clinical Practice, edited by Takehiko Yanagihara and Ronald C. Petersen 10. The Medical Treatment of Epilepsy, edited by Stanley R. Resor, Jr., and Henn Kutt 11. Cognitive Disorders: Pathophysiology and Treatment, edited by Leon J. Thal, Walter H. Moos, and Elkan R. Gamzu 12. Handbook of Amyotrophic Lateral Sclerosis, edited by Richard Alan Smith 13. Handbook of Parkinson’s Disease: Second Edition, Revised and Expanded, edited by William C. Koller 14. Handbook of Pediatric Epilepsy, edited by Jerome V. Murphy and Fereydoun Dehkharghani 15. Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders, edited by Roger Kurlan 16. Handbook of Cerebellar Diseases, edited by Richard Lechtenberg 17. Handbook of Cerebrovascular Diseases, edited by Harold P. Adams, Jr. 18. Parkinsonian Syndromes, edited by Matthew B. Stern and William C. Koller 19. Handbook of Head and Spine Trauma, edited by Jonathan Greenberg 20. Brain Tumors: A Comprehensive Text, edited by Robert A. Morantz and John W. Walsh 21. Monoamine Oxidase Inhibitors in Neurological Diseases, edited by Abraham Lieberman, C. Warren Olanow, Moussa B. H. Youdim, and Keith Tipton 22. Handbook of Dementing Illnesses, edited by John C. Morris 23. Handbook of Myasthenia Gravis and Myasthenic Syndromes, edited by Robert P. Lisak 24. Handbook of Neurorehabilitation, edited by David C. Good and James R. Couch, Jr. 25. Therapy with Botulinum Toxin, edited by Joseph Jankovic and Mark Hallett 26. Principles of Neurotoxicology, edited by Louis W. Chang 27. Handbook of Neurovirology, edited by Robert R. McKendall and William G. Stroop 28. Handbook of Neuro-Urology, edited by David N. Rushton 29. Handbook of Neuroepidemiology, edited by Philip B. Gorelick and Milton Alter 30. Handbook of Tremor Disorders, edited by Leslie J. Findley and William C. Koller

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31. Neuro-Ophthalmological Disorders: Diagnostic Work-Up and Management, edited by Ronald J. Tusa and Steven A. Newman 32. Handbook of Olfaction and Gustation, edited by Richard L. Doty 33. Handbook of Neurological Speech and Language Disorders, edited by Howard S. Kirshner 34. Therapy of Parkinson’s Disease: Second Edition, Revised and Expanded, edited by William C. Koller and George Paulson 35. Evaluation and Management of Gait Disorders, edited by Barney S. Spivack 36. Handbook of Neurotoxicology, edited by Louis W. Chang and Robert S. Dyer 37. Neurological Complications of Cancer, edited by Ronald G. Wiley 38. Handbook of Autonomic Nervous System Dysfunction, edited by Amos D. Korczyn 39. Handbook of Dystonia, edited by Joseph King Ching Tsui and Donald B. Calne 40. Etiology of Parkinson’s Disease, edited by Jonas H. Ellenberg, William C. Koller and J. William Langston 41. Practical Neurology of the Elderly, edited by Jacob I. Sage and Margery H. Mark 42. Handbook of Muscle Disease, edited by Russell J. M. Lane 43. Handbook of Multiple Sclerosis: Second Edition, Revised and Expanded, edited by Stuart D. Cook 44. Central Nervous System Infectious Diseases and Therapy, edited by Karen L. Roos 45. Subarachnoid Hemorrhage: Clinical Management, edited by Takehiko Yanagihara, David G. Piepgras, and John L. D. Atkinson 46. Neurology Practice Guidelines, edited by Richard Lechtenberg and Henry S. Schutta 47. Spinal Cord Diseases: Diagnosis and Treatment, edited by Gordon L. Engler, Jonathan Cole, and W. Louis Merton 48. Management of Acute Stroke, edited by Ashfaq Shuaib and Larry B. Goldstein 49. Sleep Disorders and Neurological Disease, edited by Antonio Culebras 50. Handbook of Ataxia Disorders, edited by Thomas Klockgether 51. The Autonomic Nervous System in Health and Disease, David S. Goldstein 52. Axonal Regeneration in the Central Nervous System, edited by Nicholas A. Ingoglia and Marion Murray 53. Handbook of Multiple Sclerosis: Third Edition, edited by Stuart D. Cook 54. Long-Term Effects of Stroke, edited by Julien Bogousslavsky 55. Handbook of the Autonomic Nervous System in Health and Disease, edited by C. Liana Bolis, Julio Licinio, and Stefano Govoni 56. Dopamine Receptors and Transporters: Function, Imaging, and Clinical Implication, Second Edition, edited by Anita Sidhu, Marc Laruelle, and Philippe Vernier 57. Handbook of Olfaction and Gustation: Second Edition, Revised and Expanded, edited by Richard L. Doty 58. Handbook of Stereotactic and Functional Neurosurgery, edited by Michael Schulder 59. Handbook of Parkinson’s Disease: Third Edition, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller

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60. Clinical Neurovirology, edited by Avindra Nath and Joseph R. Berger 61. Neuromuscular Junction Disorders: Diagnosis and Treatment, Matthew N. Meriggioli, James F. Howard, Jr., and C. Michel Harper 62. Drug-Induced Movement Disorders, edited by Kapil D. Sethi 63. Therapy of Parkinson’s Disease: Third Edition, Revised and Expanded, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller 64. Epilepsy: Scientific Foundations of Clinical Practice, edited by Jong M. Rho, Raman Sankar, and José E. Cavazos 65. Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders: Second Edition, edited by Roger Kurlan 66. Handbook of Cerebrovascular Diseases: Second Edition, Revised and Expanded, edited by Harold P. Adams, Jr. 67. Emerging Neurological Infections, edited by Christopher Power and Richard T. Johnson 68. Treatment of Pediatric Neurologic Disorders, edited by Harvey S. Singer, Eric H. Kossoff, Adam L. Hartman, and Thomas O. Crawford 69. Synaptic Plasticity : Basic Mechanisms to Clinical Applications, edited by Michel Baudry, Xiaoning Bi, and Steven S. Schreiber 70. Handbook of Essential Tremor and Other Tremor Disorders, edited by Kelly E. Lyons and Rajesh Pahwa 71. Handbook of Peripheral Neuropathy, edited by Mark B. Bromberg and A. Gordon Smith 72. Carotid Artery Stenosis: Current and Emerging Treatments, edited by Seemant Chaturvedi and Peter M. Rothwell 73. Gait Disorders: Evaluation and Management, edited by Jeffrey M. Hausdorff and Neil B. Alexander 74. Surgical Management of Movement Disorders (HBK), edited by Gordon H. Baltuch and Matthew B. Stern 75. Neurogenetics: Scientific and Clinical Advances, edited by David R. Lynch 76. Epilepsy Surgery: Principles and Controversies, edited by John W. Miller and Daniel L. Silbergeld 77. Clinician's Guide To Sleep Disorders, edited by Nathaniel F. Watson and Bradley Vaughn 78. Amyotrophic Lateral Sclerosis, edited by Hiroshi Mitsumoto, Serge Przedborski and Paul H. Gordon 79. Duchenne Muscular Dystrophy: Advances in Therapeutics, edited by Jeffrey S. Chamberlain and Thomas A. Rando 80. Handbook of Multiple Sclerosis, Fourth Edition, edited by Stuart D. Cook 81. Brain Embolism, edited by Louis R. Caplan and Warren J. Manning 82. Handbook of Secondary Dementias, edited by Roger Kurlan 83. Parkinson's Disease: Genetics and Pathogenesis, edited by Ted M. Dawson 84. Migraine, Russell Lane and Paul Davies 85. Migraine and Other Headache Disorders, edited by Richard B. Lipton and Marcelo Bigal 86. Restless Leg Syndrome, edited by William G. Ondo 87. Handbook of Dementing Illnesses, Second Edition, edited by John C. Morris, James E. Galvin, and David M. Holtzman

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Handbook of Dementing Illnesses Second Edition edited by

John C. Morris Washington University School of Medicine St. Louis, Missouri, U.S.A.

James E. Galvin Washington University School of Medicine St. Louis, Missouri, U.S.A.

David M. Holtzman Washington University School of Medicine St. Louis, Missouri, U.S.A.

New York London

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Published in 2006 by Taylor & Francis Group 270 Madison Avenue New York, NY 10016 © 2006 by Taylor & Francis Group, LLC 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: 0-8247-5838-2 (Hardcover) International Standard Book Number-13: 978-0-8247-5838-7 (Hardcover) Library of Congress Card Number 2006040383 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 dementing illnesses / edited by John C. Morris, James Galvin, David Holtzman.--2nd ed. p. ; cm. -- (Neurological disease and therapy ; v. 87) Includes bibliographical references and index. ISBN-13: 978-0-8247-5838-7 (alk. paper) ISBN-10: 0-8247-5838-2 (alk. paper) 1. Dementia. I. Morris, John C., 1948- II. Galvin, James E. III. Holtzman, David, 1961- IV. Series [DNLM: 1. Dementia. WM 220 H236 2006] RC521.H36 2006 616.8’3--dc22

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Preface

Much has been achieved about the diagnosis, management, and neurobiological understanding of the primary and secondary causes of dementia since the first edition of this Handbook was published in 1994. As but one example, the chapter on the treatment of dementing disorders in the first Handbook was entitled “Experimental Pharmacotherapy of the Primary Symptoms of Dementia” because no approved therapies existed when it was written. Subsequently, five drugs for the symptomatic treatment of Alzheimer’s disease have been approved by the United States Food and Drug Administration. An up-to-date compendium about dementing illnesses clearly is needed to present new knowledge and advances in a clinically meaningful text that is relevant for the diagnosis and care of individuals with dementia. We are grateful that Taylor & Francis has provided us with the opportunity to develop this second edition of the Handbook. We are particularly appreciative that the contributors to this monograph, all of whom are noted authorities in their field, delivered such masterful chapters and are indebted to them for their contributions. An unavoidable aspect of producing a multiauthored textbook is that chapters are submitted at differing time points, occasionally at some length prior to publication. Coupled with the remarkable pace of scientific and clinical advances in the dementing illnesses, this aspect necessarily demands that chapters represent the generally accepted body of knowledge concerning their respective topics rather than an up-to-the minute review of emerging concepts. In response, a unique feature of this Handbook is a timely update of selected issues in dementia that was published independently by one of the Editors (JCM) and permission was granted for it to be reprinted here. It is hoped that this feature will aid the interested reader in staying abreast of evolving concepts in the dementing illnesses as appreciated at the time it was written. We are deeply privileged to work with the investigators and staff of the Memory and Aging Project and the Alzheimer’s Disease Research Center at Washington University in St. Louis, Missouri. They have contributed in many ways, both large and small, to this Handbook and we thank them for their contributions to creating the stimulating environment in which we work each day. We also are grateful to our research participants and their study partners and to our patients and their families, who daily teach us about commitment to loved ones, grace under pressure, and the pressing need to conquer the dementing illnesses. iii

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This work would not have been accomplished without the gentle but effective guidance of Janice Palmer, RN, MSG, who displayed remarkable skills in bringing together innumerable and disparate pieces into a cohesive whole. Finally, we wish to dedicate this second edition of the Handbook of Dementing Illnesses to our spouses, Lucy Morris, Tracy Holtzman, and Doris Galvin, whose support make our work possible. John C. Morris James E. Galvin David M. Holtzman

Contents

Preface . . . . iii Contributors . . . . xiii 1. Ethical Issues in Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Jason H. T. Karlawish Introduction . . . . 1 The Foundations for Effective Decision Making . . . . 2 Addressing the Challenges of Specific Decisions . . . . 7 Conclusion . . . . 13 References . . . . 13 2. Epidemiology, Dementia, and Alzheimer’s Disease: Methods Influence Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Walter A. Kukull Introduction . . . . 17 Recognizing and Diagnosing Dementias . . . . 18 Prevalence . . . . 19 Incidence of Dementia . . . . 21 Analytic Epidemiology: Progression of Basic Study Designs . . . . 24 Genes and Alzheimer’s Disease: Epidemiologic Context . . . . 26 The Search for Causal Factors . . . . 28 References . . . . 31 3. Healthy Brain Aging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Joseph F. Quinn and Jeffrey Kaye Functional Changes Seen in Healthy Brain Aging—Noncognitive . . . . 41 Functional Changes Seen in Healthy Brain Aging—Cognitive . . . . 43 Structural Changes Seen in Healthy Brain Aging—Pathology . . . . 44 Structural Changes Seen in Healthy Brain Aging—Neuroimaging . . . . 48 Summary . . . . 51 References . . . . 52 v

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4. Neuropsychological Assessment of Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Kathleen A. Welsh-Bohmer and Stephanie Johnson Purpose of the Neuropsychological Assessment . . . . 60 Assessment of Cognitive Impairment . . . . 61 Neuropsychological Testing Procedures . . . . 63 References . . . . 80 5. Neuroimaging in Dementia: Structural Imaging . . . . . . . . . . . . . . . . . . . . . . . . . 89 Kejal Kantarci and Clifford Jack, Jr. Cross-Sectional Case-Control Studies in Which the Cases Are Patients with Probable AD . . . . 90 Cross-Sectional Case-Control Studies in Which the Cases Are Nondemented Individuals Who Are at Elevated Risk of Developing AD in the Future . . . . 92 Longitudinal Cohort Studies that Test the Ability of MR Techniques to Predict Future Progression to AD in Nondemented Individuals, Particularly Those Who Are at Elevated Risk of Developing AD in the Future . . . . 94 Radiological-Pathological Correlation Studies . . . . 95 Longitudinal Cohort Studies that Correlate Clinical Disease Progression Over Time with Change on Serial MRI . . . . 96 Therapeutic Trials in Which Serial MR Measurements Are Correlated with Clinical Disease Progression in Order to Assess Therapeutic Efficacy . . . . 98 Amyloid Imaging and Future Directions . . . . 98 References . . . . 100 6. Functional Imaging in Dementia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Reisa Sperling and Keith Johnson Functional Imaging Techniques . . . . 108 Image Interpretation, Qualitative, and Quantitative Analysis . . . . 109 Regional Patterns . . . . 111 Correlation with Clinical Parameters . . . . 112 Relationship of Functional Alterations to Atrophy . . . . 113 Diagnostic Accuracy . . . . 114 Functional Magnetic Resonance Imaging . . . . 116 Cognitive Activation Studies . . . . 117 Preclinical Diagnosis of Alzheimer’s Disease . . . . 118 Functional Imaging in Genetically “At-Risk” Subjects for AD . . . . 119 Longitudinal Studies . . . . 120 Use of Functional Neuroimaging in Clinical Practice . . . . 120 References . . . . 121 7. The Neuropathology of Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Suzanne S. Mirra and Lynette G. Sheffield Introduction . . . . 129 Alzheimer’s Disease . . . . 129

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Lewy Body Disorders . . . . 138 The Tauopathies . . . . 142 Huntington’s Disease . . . . 149 Vascular Dementias . . . . 150 Summary . . . . 153 References . . . . 153

8. Genetics of Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anne L. Brunkan and Alison M. Goate Introduction . . . . 163 Inherited Familial AD . . . . 163 Insights from Genetics . . . . 164 Challenges for the Future . . . . 170 References . . . . 171

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9. Biomarkers in Alzheimer’s Disease and Dementia . . . . . . . . . . . . . . . . . . . . . Douglas Galasko Introduction . . . . 175 Pathological Changes and Mechanisms Implicated in AD . . . . 178 CSF Biomarker Studies in AD and Dementia . . . . 179 Peripheral Biomarkers . . . . 184 Future Trends . . . . 185 References . . . . 186

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10. Alzheimer’s Disease and Mild Cognitive Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John C. Morris Nondemented Cognitive Aging . . . . 192 Definition of Dementia . . . . 192 Detection of Dementia . . . . 193 Alzheimer’s Disease . . . . 193 Differential Diagnosis of Alzheimer’s Disease . . . . 198 Mild Cognitive Impairment . . . . 201 References . . . . 203

11. Down’s Syndrome, Alzheimer’s Disease, and Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David J. Loren and David M. Holtzman History . . . . 209 Genetics . . . . 209 Clinical Issues in DS . . . . 210 Clinical Course of Dementia in Down’s Syndrome . . . . 211 Neuropathology in Down’s Syndrome . . . . 213

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Insights from Animal Models . . . . 215 Summary . . . . 216 References . . . . 217 12. Dementia in Parkinson’s Disease and Lewy Body Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James E. Galvin Introduction . . . . 221 Lewy Body Disease Subtypes . . . . 223 Neuropathology . . . . 228 Evaluation of LB Disorders . . . . 231 Treatment . . . . 232 References . . . . 233

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13. Frontotemporal Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Weichung Liu and Bruce L. Miller Demographics . . . . 241 Historical Issues in Nomenclature . . . . 241 Clinical Features . . . . 244 Genetics . . . . 246 Animal Models . . . . 247 Pathology . . . . 247 Prognosis and Diagnosis . . . . 247 Imaging and Treatment . . . . 248 References . . . . 248

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14. Vascular Dementia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Helena C. Chui Introduction . . . . 253 Diagnosis . . . . 255 Prognosis . . . . 264 Major CVD Risk Factors and Their Relationship to CVBI . . . . 266 Treatment . . . . 267 References . . . . 270

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15. Prion Diseases and Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James A. Mastrianni Introduction . . . . 277 Prion Protein . . . . 278 Doppel, the Prion-Like Protein . . . . 280 Clinical and Pathologic Subtypes of PrD . . . . 280 Creutzfeldt-Jakob Disease . . . . 281 Gerstmann-Stra¨ussler-Scheinker (GSS) Syndrome . . . . 289 Fatal Insomnia (FI) . . . . 291 The Polymorphic Codon 129 . . . . 292

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Acquired PrD . . . . 293 Differential Diagnosis . . . . 295 Therapy for PrD . . . . 295 References . . . . 296 16. Normal Pressure Hydrocephalus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thomas A. Krefft and Neill R. Graff-Radford Introduction . . . . 303 Differential Diagnosis, History, Clinical Examination and Neuropsychological Evaluation . . . . 304 Radiological Evaluation . . . . 306 Special Testing . . . . 309 Assessment for Patient Improvement . . . . 312 Shunt Complications . . . . 312 Which Shunt to Recommend . . . . 313 Associations of Idiopathic NPH with Implications Related to Etiology . . . . 313 Conclusion . . . . 316 References . . . . 316

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17. HIV-Associated Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 David B. Clifford and Mary Gould Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) . . . . 321 Epidemiology of HIV/AIDS . . . . 321 Natural History of HIV . . . . 322 Natural History and Classification of HIV-Associated Dementia . . . . 322 Epidemiology of HIV-Associated Dementia . . . . 323 Clinical Features of HAD . . . . 323 Pathology and Mechanisms . . . . 324 Diagnosis and Monitoring . . . . 325 Therapy . . . . 327 References . . . . 329 18. Influence of Comorbidities in Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dennis T. Villareal Introduction . . . . 333 Nutritional Disorders: Vitamin B Deficiency . . . . 333 Medication-Induced Dementia . . . . 335 Alcoholic Related-Dementia . . . . 336 Metabolic Disorders . . . . 336 Organ Failure . . . . 340 Frequency and Reversibility of Comorbidities in Dementia . . . . 343 Diagnostic Evaluation . . . . 344 References . . . . 344

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19. Depression and Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eugene H. Rubin Types of Depression . . . . 349 Important Issues About Depressive Disorders . . . . 351 Depression and Dementia . . . . 352 Conclusion . . . . 356 References . . . . 356

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20. Management of the Driver with Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David B. Carr, Bonnie M. Dobbs, and John C. Morris The Older Driver . . . . 361 Driving Patterns of Individuals with Dementia . . . . 362 Studies on the Impact of Dementia on Driving Competence . . . . 362 Office Assessment of Driving Competence in Individuals with a Dementia . . . . 363 Assessment of Driving Skills in Drivers with a Dementia . . . . 369 Assessing Comorbid Conditions . . . . 370 Driving Restriction and Cessation Issues . . . . 370 Ethical, Legal, and Public Policy Issues . . . . 372 Conclusion . . . . 373 References . . . . 373

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21. The Plan of Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mary A. Coats and Janice L. Palmer Introduction . . . . 377 Telling the Diagnosis . . . . 377 Safety Issues . . . . 378 Health Maintenance . . . . 383 Advance Directives . . . . 386 Family Caregiver Burden . . . . 386 Maintaining Activity . . . . 387 Preparing for Late Stage Issues . . . . 390 References . . . . 391

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22. Comprehensive Review of Caregiving for the Health Care Professional . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ann S. Morrison and Peter V. Rabins Overview of Caregiving . . . . 393 Problems Arising Directly and Indirectly from the Caregiving Situation . . . . 395 Outcomes of Caregiving . . . . 396 Modifying Caregiver Distress . . . . 397 Stage Specific Caregiving Responsibilities . . . . 398 Bereavement . . . . 401 Conclusions . . . . 401

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Appendix . . . . 402 References . . . . 402 23. Pharmacology for the Cognitive Symptoms of Dementia . . . . . . . . . . . . . . Martin R. Farlow Alzheimer’s Disease: Current Therapeutic Options . . . . 405 Treatment Options . . . . 406 Cholinesterase Inhibitors (General Features) . . . . 409 Alternative Treatment Options . . . . 409 Alzheimer’s Disease with Concomitant Vascular Dementia and Vascular Dementia (VaD) . . . . 412 Conclusions . . . . 412 References . . . . 412

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24. Treatment of the Neuropsychiatric Symptoms in Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417 Donna Masterman Importance of Treating Behavioral Disturbances in Alzheimer’s Disease . . . . 417 The Prevalence of Behavioral Symptoms in AD . . . . 417 The Cholinergic Deficit in AD and Neuropsychiatric Symptomatology . . . . 418 Evaluating Behavioral Disturbances in Patients with Dementia . . . . 421 Non-Pharmacological Behavioral Interventions . . . . 421 Pharmacological Interventions . . . . 422 Caregiver Support . . . . 426 Appendix 1 . . . . 427 Appendix 2 . . . . 427 References . . . . 428 25. Amyloid-Based Strategies to Treat and Prevent Alzheimer’s Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dennis J. Selkoe Introduction . . . . 433 Deciphering the Biochemistry of the Brain Lesions Yields Pathogenetic Insights . . . . 433 Ab Is Generated by Proteolytic Cleavages of a Large Precursor Protein . . . . 435 The Genetics of AD Validates Ab Inhibition as a Prevention and Treatment Strategy . . . . 438 Deciphering the Genotype to Phenotype Conversions of Familial AD . . . . 439 The Complex Pathogenetic Cascade of AD . . . . 442 Questions Abound . . . . 443 Therapeutic Opportunities Provided by the Ab Cascade . . . . 445 References . . . . 447

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26. Prevention Strategies for Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . Marı´a M. Corrada and Claudia H. Kawas Public Health Importance and Prevention . . . . 453 Types of Prevention . . . . 454 Potential Preventive Interventions . . . . 455 Causality . . . . 465 Primary and Secondary Prevention Trials . . . . 465 Public Health Impact of Delaying the Onset of AD . . . . 467 Summary . . . . 468 References . . . . 468

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27. Dementia Update 2006. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John C. Morris Alzheimer’s Disease . . . . 476 Mild Cognitive Impairment . . . . 488 Non-AD Dementias . . . . 490 Summary . . . . 493 References . . . . 495

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Index . . . . 505

Contributors

Anne L. Brunkan Washington University School of Medicine, St. Louis, Missouri, U.S.A. David B. Carr Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, Missouri, U.S.A. Helena C. Chui University of Southern California, Los Angeles, California, U.S.A. David B. Clifford Washington University School of Medicine, St. Louis, Missouri, U.S.A. Mary A. Coats

Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Marı´a M. Corrada Departments of Neurology, Neurobiology and Behavior, University of California Irvine, Irvine, California, U.S.A. Bonnie M. Dobbs Faculty of Rehabilitation Medicine and Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada Martin R. Farlow Indiana University School of Medicine, Indianapolis, Indiana, U.S.A. Douglas Galasko Department of Neurosciences, University of California and Neurology Service, Veterans Affairs Medical Center, San Diego, California, U.S.A. James E. Galvin Washington University School of Medicine, St. Louis, Missouri, U.S.A. Alison M. Goate Washington University School of Medicine, St. Louis, Missouri, U.S.A. Mary Gould Washington University School of Medicine, St. Louis, Missouri, U.S.A. Neill R. Graff-Radford

Mayo College of Medicine, Jacksonville, Florida, U.S.A.

David M. Holtzman Washington University School of Medicine, St. Louis, Missouri, U.S.A. Clifford Jack, Jr. Minnesota, U.S.A.

Department of Radiology, Mayo Clinic College of Medicine, Rochester,

Keith Johnson Memory Disorders Unit, Department of Neurology, and Division of Nuclear Medicine, Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A. Stephanie Johnson Department of Psychiatry and Joseph & Kathleen Bryan Alzheimer’s Disease Research Center–Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A. xiii

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Contributors

Kejal Kantarci Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A. Jason H. T. Karlawish University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. Claudia H. Kawas Departments of Neurology, Neurobiology and Behavior, University of California Irvine, Irvine, California, U.S.A. Jeffrey Kaye Department of Neurology, Oregon Health Science University, Portland, Oregon, U.S.A. Mayo Clinic Jacksonville, Jacksonville, Florida, U.S.A.

Thomas A. Krefft

Walter A. Kukull National Alzheimer’s Coordinating Center, Department of Epidemiology, University of Washington, Seattle, Washington, U.S.A. Weichung Liu University of California San Francisco, San Francisco, California, U.S.A. David J. Loren Washington University School of Medicine, St. Louis, Missouri, U.S.A. Donna Masterman California, U.S.A.

David Geffen School of Medicine at UCLA, Los Angeles,

James A. Mastrianni Center for Comprehensive Care and Research on Memory Disorders and Department of Neurology, University of Chicago, Chicago, Illinois, U.S.A. Bruce L. Miller

University of California San Francisco, San Francisco, California, U.S.A.

Suzanne S. Mirra Department of Pathology, SUNY Downstate Medical Center, Brooklyn, New York, U.S.A. John C. Morris Washington University School of Medicine, St. Louis, Missouri, U.S.A. Ann S. Morrison Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A. Janice L. Palmer

Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Joseph F. Quinn Oregon Health and Science University, Portland, Oregon, U.S.A. Peter V. Rabins

Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.

Eugene H. Rubin Washington University School of Medicine, St. Louis, Missouri, U.S.A. Dennis J. Selkoe Harvard Medical School, Boston, Massachusetts, U.S.A. Lynette G. Sheffield Department of Pathology, SUNY Downstate Medical Center, Brooklyn, New York, U.S.A. Reisa Sperling Memory Disorders Unit, Department of Neurology, Brigham and Women’s Hospital, and NMR Center, Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Dennis T. Villareal Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, Missouri, U.S.A. Kathleen A. Welsh-Bohmer Department of Psychiatry and Joseph & Kathleen Bryan Alzheimer’s Disease Research Center–Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A.

About the Editors

JOHN C. MORRIS is the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology, Professor of Pathology and Immunology and Physical Therapy, Washington University School of Medicine, St. Louis, Missouri. He received the M.D. degree from the University of Rochester School of Medicine and Dentistry, New York. JAMES E. GALVIN is Assistant Professor of Neurology, Anatomy and Neurobiology, and Director of the Memory Diagnostic Center and the Alan A. and Edith L. Wolff Neuroscience Laboratory, Washington University School of Medicine, St. Louis, Missouri. Dr. Galvin is involved in clinical and basic science research projects. Dr. Galvin received the B.A. degree from New York University, New York, the M.Sc. degree in nutrition from Rutgers University, New Brunswick, New Jersey, the M.D. degree from the University of Medicine and Dentistry of New Jersey, Newark, and the M.P.H. degree in public health from St. Louis University, Missouri. DAVID M. HOLTZMAN is the Andrew and Gretchen Jones Professor of Neurology and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri. He is also Head of the Department of Neurology at Washington University. Dr. Holtzman is involved in clinical and research activities at the Washington University Memory and Aging Project and the Alzheimer’s Disease Research Center. He received the B.S. and M.D. degrees from Northwestern University, Evanston and Chicago, Illinois.

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1 Ethical Issues in Dementia Jason H. T. Karlawish University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

INTRODUCTION Ethics is about choice, especially choice under uncertainty. It describes deciding what is the right thing to do. Ethics involves weighing rights and wrongs. The standard medical model of ethics is largely grounded in applying four principles to make choices: respect for autonomy (allowing a patient to direct his care), nonmaleficence (doing no harm to the patient), beneficence (maximizing the patient’s welfare), and justice (treating equal patients equally) (1). An ethical decision refers to a choice that has these principles in proper balance. The stereotype of this model is the competent patient who chooses his current care and plans for his future care (2). The paradigmatic ethical dilemma in this model is when a patient’s choice conflicts with the physician’s standard of care. In other words, this is a conflict between autonomy and beneficence. Classic examples of the failure to solve this dilemma are cases of futility and paternalism. The skills to address this dilemma are largely grounded in the practice of informed consent, trust, and good physician-patient communication. But physicians who care for persons with dementia need additional skills. Dementia raises unique moral challenges (3). The progressive loss of brain function transforms both the person with brain failure and the people who care for that person. The ability to make a competent decision is intermittent. Claims of what will benefit a patient or their caregiver are necessarily ambiguous, often cannot be reduced to simple professional medical dictums or policies, and require open communication about the meaning of the disease, and personhood. As a result, roles and relationships change. Physicians who focus entirely on balancing among the four principles may not be able to address these challenges. Absent of additional skills, the physician may provide care that is actually uncaring, harmful, or even immoral. This chapter has two broad goals. First, it reviews the foundations of effective decision making: competency, surrogate decision making, and the impact of healthcare systems on decision making. Next, these foundations are applied to common decisions faced in the lives of persons with dementia: diagnostic disclosure, treatment, advance care planning, driving, and research. In working through strategies to address these common decisions, physicians can master the essential skills of the ethics of dementia. 1

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THE FOUNDATIONS FOR EFFECTIVE DECISION MAKING Informed consent is a way for physicians and patients to make decisions that achieve a proper balance between a patient’s self-determination and the physician’s duty to benefit the patient. The elements of informed consent are a physician discloses the relevant information, and a patient voluntarily makes a competent choice (Table 1) (4). Informed consent does not only occur when a patient has to sign a form, such as prior to enrolling in research or receiving an invasive procedure such as a spinal tap. It occurs all throughout the practice of medicine. Doctors are constantly disclosing facts and asking patients to make decisions. However, in many routine clinical encounters they are often deficient in fulfilling these steps (5). This section reviews the three elements of informed consent (disclosure, voluntariness, and competency), and then provides practical methods to achieve them. The goal of mastering these elements is to foster ethical decisions with patients and their families. Disclosing Information The disclosure of information needs to fulfill a standard of adequate information. There are at least three standards for this: what a reasonable practitioner would disclose, what a reasonable patient would want to know, and what the particular patient would want to know. Discussions of these standards often describe the practitioner standard as “objective” or “professional” and the other two as “subjective.” The problem with these terms is that they carry tacit but not trivial message that

Table 1 The Elements of an Informed Consent Disclosing information Steps for disclosure: Before launching into a long narrative about the decision at hand, find out what the patient knows about the decisions: For example in the case of discussing a new treatment for Alzheimer’s disease, ask “Can you tell me what you know about Alzheimer’s disease?” The answer will reveal the patient’s understandings and appreciations as well as misunderstandings and misappreciations. This information is a useful guide for further discussion and disclosure. After disclosing information ask, “What else?” and then wait several seconds before speaking again. Pearl: Doctor means “teacher” and consent means “to feel together”. A good physician is an empathetic teacher.

Ensuring voluntariness Steps to ensure voluntariness: An environment such as a nursing home or assisted living facility can impact a person’s sense of freedom and choice. Most people do not recognize the subtle impact their day-to-day environment has on their voluntariness. Open-ended questions can elicit whether this is a problem: “Do you feel like you have a choice?” Give the person time to make a decision (unless it is an emergency). Pearl: Remind a person he is free to choose and give him time to choose.

Assessing competency Steps to assess competency: In situations where a patient is refusing what a physician considers “standard of care,” a competency assessment is essential, but it can be the source of discord. Reassure the patient that the final choice is his. “I am not here to argue. My duty as a doctor is to be a good teacher for you about your health and the options you have. I just want to make sure I’ve done an adequate job teaching you.” Then assess the patient’s understanding, appreciation, and reasoning using the format of the openended questions described in Table 2. Pearl: Competency derives from the ability to make a decision. Evidence of impaired decision-making capacity may be the first sign of clinically significant cognitive impairment.

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what physicians disclose is “value free.” Specifically, they imply that what the physician wants to disclose is “true,” that is, objective, while what the patient would want to know is merely personal and perhaps even capricious. In fact, physicians have values, and these are not uniform across physicians. For example, geographic variation in practice patterns of common procedures such as carotid endarterectomy, myocardial infarction, and breast cancer suggests that what physicians recommend is not uniform but affected by local customs and values (6–8). The significance of this is that physicians likely vary in how they present the facts to patients. Which of these standards is the appropriate guide for disclosure (9)? As a matter of law, each state defines whether a physician must disclose what a reasonable patient needs to know or a reasonable practitioner discloses. As a matter of ethics, there is every reason to want to disclose what the particular patient wants to know. In general, patients do desire information about their illness and the options for treatment. But physicians often underestimate this desire while at the same time overestimating the patient’s desire to make the decision (10). A useful guide to assure that the physician has given the patient (or the patient’s surrogate) enough information is to recall that “doctor” means teacher (from the Latin “doctore”) and that “consent” joins the Latin roots “con” (with) and “sentire” (to feel). Hence, a good doctor is an empathetic teacher. In the care of patients with dementia, impairments in insight are among the chief barriers to effective disclosure of information. A patient who cannot recognize he has a problem such as cognitive loss that impacts on the ability to perform activities of daily living cannot know what he wants or needs to know to make a decision to address that problem. But insight is not an all or nothing phenomenon. Patients with dementia often retain partial insight (11,12). Hence, it is inappropriate to assume that conversations about care with a dementia patient are uniformly empty speech. Some are, but some are not. Ensuring Voluntariness The second element of an informed consent is voluntariness. The term describes a condition that is free from the threat of harm or limits on choice. This element seems straightforward. Only a plainly immoral physician would threaten or coerce a patient to choose one way or the other. But more subtle circumstances can impact on voluntariness. In the care of persons with dementia, the typical setting that impacts on voluntariness is living in a total institution such as a nursing home or assisted living facility. The term “total institution” describes a place where the borders are obliterated between where people live, work, and play (13). Classic examples are prisons and boarding schools. In these settings, those who control the institution control the lives of the residents. Hence, the residents cannot freely leave a situation, both physically by going home, or in terms of the people they interact with, by switching doctors. Useful strategies to address this condition are proactively assuring the person that they are free to choose, and instead of bundling disclosure and decision into one session, giving the person time to make a choice. Assessing Competency The third element of informed consent is competency. The term describes a person who has adequate decision-making ability to make the choice at hand. The literature on competency has generated much confusion on the meaning of the term and the related terms capacity and decisionmaking ability. However, clear distinctions exist among these concepts. Competency has been described as a purely legal judgment. That is, only a judge can declare a person non-competent. In contrast, a physician judges whether someone has capacity to make a decision. The distinction made here is based solely on who is making the judgment and the role society assigns them. Judges do have the unique authority to declare a person not competent in a legal context, meaning in need of a guardian. But physicians make similar decisions all the time. On a day-to-day basis,

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clinicians judge that a patient is not competent to decide whether to take a medication and turn to a surrogate to choose for the patient. Hence, the terms competency and capacity can be used in order to distinguish between legal and medical judgments, but their outcomes are the same: a person can no longer choose for himself. The term decision-making abilities refers to the skills a person has to make a decision. There are four abilities: the ability to understand, to appreciate, to reason, and to choose (14). Table 2 defines each of these abilities and provides sample questions a clinician can use to assess these abilities. Unlike capacity or competency, which are categorical states (a person either is or is not competent), decision-making abilities are dimensional. This means that they are like weight, intelligence quotient, or verbal memory. They span a spectrum of performance. In the measurement of a decision-making ability, such as understanding, the general strategy is to ask a patient a series of questions that assess the person’s ability to say the meaning of the information disclosed. The examiner then scores each of the person’s answers using some kind of criteria (for example, adequateZ2, marginalZ1, or inadequateZ0). The sum of scores then represents a score on the measure of understanding. The clinician uses the same strategy to assess appreciation and reasoning too. Thus, at the close of a decision-making ability assessment, the examiner has a set of data that describe how well the person can make the decision. These data provide the substance for an assessment of their capacity (or competency) to make a decision. In many respects, an assessment of whether a patient is competent resembles an assessment of whether they have dementia. The examiner gathers facts using a semi-structured interview and then weighs those facts using criteria in order to decide whether a person is demented. But unlike a diagnosis of dementia, the criteria for a competency judgment vary. That is, the facts of the decision determine how the examiner should weigh the patient’s performance on the measures of capacity. Specifically, the compendious balance of the benefits and risks should inform the weights applied to the patient’s performance. In the case of a straightforward and clearly beneficial decision, the examiner may tolerate substantial errors in understanding as long as key facts are understood and appreciated. In contrast, in the case of a decision that involves competing risks and benefits or even

Table 2 Definitions of Each of the Decision-Making Abilities and Sample Questions a Clinician Can Use to Assess Them Understanding: The ability to state the meaning of the information disclosed. Example of assessing a person’s ability to understand the indication for a procedure: “Can you tell me in your own words the reason I am recommending a spinal tap?” Choice: The ability to state a decision. This is often linked to consistency, the ability to state the same decision over the course of an assessment of decision-making abilities. Example of assessing a person’s ability to make a choice: “I just want to make sure. Do you still not want to have the spinal tap?” Appreciation: The ability to recognize that the facts of a decision apply to the person; for example, the ability to recognize that a procedure might benefit the patient. A useful way to distinguish appreciation from understanding is the case of a person with psychosis who can respond that he has schizophrenia but does not accept that the delusion is actually false. Example of assessing a person’s ability to appreciate benefit: “I know you said that you do not want to have the spinal tap, but can you tell me how having it might benefit you?” Reasoning: There are two kinds of reasoning: consequential reasoning (inferring the potential results of a choice) and comparative reasoning (weighing the merits versus the demerits of options). Example of assessing a person’s ability to consequentially reason: “How might having the spinal tap affect your everyday activities?” Example of assessing a person’s ability to comparatively reason: “You say you are more likely to not want to have the spinal tap. How is not having it better than having it?”

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no benefit to the patient, the examiner may require the patient to show adequate understanding, appreciation and, reasoning of a variety of information. A classic example of this is enrolling a patient in research that does not present a reasonable prospect of benefit to the subject. Thus, capacity is in part bound to the decision at hand. Persons with dementia generally have impairments in their decision-making abilities (15–17). The severity of these impairments is well associated with the severity of their cognitive impairments. In particular, the more severe the patient performs on measures of executive function, the worse they perform on measures of ability (18). This makes sense because the task of making a decision requires organizing and weighing information. A person with impaired executive function has difficulty in doing these cognitive tasks. This relationship is borne out when performance on measures of capacity and competency is stratified by the stage of dementia. The common finding across studies is that there is even odds (that is, about 50–50) that a person with mild stage AD, as measured by a Mini-Mental State Exam (MMSE) score greater than 19, are competent (15–17). Hence, while a MMSE cannot be a substitute for an assessment of capacity, it is a useful screening test to identify subjects for whom it is worth making the effort to assess ability. Related studies of capacity among elderly persons show similar results to the capacity of persons with dementia. Consistent predictors of impairments in decision-making ability are older age and fewer years of education: the same risk factors for developing dementia (19). In sum, a clinician should recognize that older patients and caregivers, those with fewer years of education and patients with mild stage disease, are all persons who deserve a structured assessment of their ability to make a decision. In contrast, the lack of capacity of more severe stage patients is usually evident and can be confirmed with a few brief screening questions. A Final Note on Making Decisions with Patients The assumption of a model of informed consent is that patients want to make choices and control their care. But patients do not uniformly endorse a model of patient-directed care. Instead, many endorse a model of entrustment (20). In this model, the patient or caregiver will decide that the practitioner should decide (21). They want to delegate their control to their physician or family (22). This model is especially common among persons who are elderly: precisely the population of persons with dementia and their spousal caregivers (23). Hence, a clinician focused on dementia care is likely to encounter persons who prefer a model of entrustment. Still, this does not obviate the duty to identify what are the patient’s core values. In addition, while this kind of person may not desire decisional authority, they often desire information (10). Making Decisions with Surrogates The standard ethic of informed consent is that a non-competent patient cannot make the decision at hand. Instead, a surrogate does. Typically, this is a close family member such as a spouse. Sometimes, it is a guardian. Only in the case of an emergency, should it be the healthcare provider. In the care of a patient with dementia, this surrogate is likely to be their family caregiver. This section discusses the ethics of surrogate decision making with caregivers. The first key point is that caregivers who make decisions do this as part of a series of roles. They also serve as a knowledgeable informant to physicians about the patient’s illness and response to treatments, as a task doer to assist the patient in activities of daily living, and possibly too as a patient themselves as a result of depression and related mental health morbidity as a result of the stresses of caregiving. The ethical significance of these overlapping roles is that they define the moral conditions of caregivers as decision makers for a patient with AD. In many respects, these roles grant them the same status as parents. Caregivers, like parents, are in the best position to know what is right for a particular patient, and appreciate the interdependence of patient and caregiver.

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Converging lines of evidence support this. Studies of how patients and caregivers make decisions about the ethically challenging decision of enrolling in research show that caregivers recognize how these roles lead to an overlap of research risks and benefits: what harms the patient can harm the caregiver too (24). And this is true too in the more prosaic day-to-day life of patients. The writer John Bayley observed that the routines he developed with his wife Iris Murdoch in her severe stage of disease created a mutual dependency. “The sense of how we both needed each other was obscurely present: and it was a kind of blessing between us, for I knew quite well that if it were not for looking after Iris I would not enjoy my own drink, book, and supper in the same way at all. Without her, these vivid but solitary pleasures would vanish like a puff of smoke (25).” In sum, a caregiver who is in all these roles and the patient they live with are interdependent. A choice for the one is also a choice for the other. However, these overlapping roles also raise a concern. The psychiatric morbidity of caregiving can impact on their decision making. Research that investigates the association between depressive symptoms and capacity has consistently shown that depression does not exert a significant impact on the abilities to understand, appreciate, and reason (26,27). But severe depression may impact on the choice a person makes. Studies show that patients with major depression are more likely to refuse cardiopulmonary resuscitation and to change this preference as their symptoms decline (28–30). This is intuitively sensible as the hallmark symptoms of major depression include suicidality or a passive wish to die. Depression does impact on a caregiver’s willingness to treat their relative’s dementia (31). Specifically, the more depressed the caregiver is, the lower they rate the patients quality of life, and thus the less willing they are to want to treat their relative’s disease (32). Hence, a caregiver’s choice not to use a dementia treatment can be viewed as a signal that the caregiver may be suffering from potentially remediable depression. The second key point is that a caregiver’s role as a surrogate is not all or nothing. Up through the moderate stage of the disease, they are talking with their relative and involving them in decisions such as treatment and research (24,33,83). Caregivers report that as dementia severity worsens they are increasingly likely to make medical decisions for that patient instead of either allowing the patient to make the decision or making the decision together with the patient. As with the data on capacity, the caregiver dominated process generally appears in moderate stages of the dementia. What is not known is how well caregivers assess patients’ abilities to make a decision. While capacity assessment is a physician responsibility, in the day-to-day life of a patient with dementia, caregivers decide whether the patient can or cannot choose. But they may commit either of two errors, either overcalling or under-assessing the patient’s abilities. When it is clear that a patient cannot make a decision and their caregiver must decide for him or her, the standard ethical guidance is that the caregiver should make a substituted judgment (34). This means that the caregiver should choose what the patient would choose if the patient could decide. The justification for this approach is respect for the patient’s autonomy. The patient is still a person. Their incapacity should not remove the legitimacy of their will. The most stereotypical expression of this principle is the living will. This written advance directive details the care a person wants in the event he is not competent and faces certain medical circumstances (the typical circumstance is usually a terminal illness). For some people, such a directive is a valuable way to assure that even when they are no longer able to make decisions, their preferences are honored. However, many people’s preference is that their surrogate does not fulfill to the letter a written directive but instead act in their best interests. Two-thirds of a cohort of 150 dialysis patients wanted their surrogate to exercise at least “a little leeway” in interpreting their advance directive whether to withdraw dialysis if they had advanced Alzheimer’s disease (35). Typical features of these best interest directives are freedom from pain and suffering, quality of life, holding out for the possibility of a new treatment, avoiding indignity from continued treatment, financial impact on the family, and religious beliefs. For the clinician, these data suggest a useful way to guide a surrogate

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in making a decision. The clinician will invoke both the principles of substituted judgment and best interests using a phrase such as “Two useful guides as you think about what we should do are to think about what your wife would have wanted if she could tell us what to do, and what will maximize her dignity and quality of life (36).” Recognizing How Systems Impact on Decision Making The models of both patient-and surrogate-directed decision making have an implicit assumption. Physicians who provide information to patients and maximize their choices will improve patient care. This assumption dominates the approach to address ethically challenging decisions, especially decisions around the end of life. This seems intuitively sensible. Choices about how to care for someone who has severe to terminal stage dementia raise deeply personal issues and set core values in potential conflict. Hence, physicians should rely on the preferences of the caregiver and the advance preferences of the patient. But evidence shows that maximizing patient choice may not produce the outcomes that patients actually want. Individual choice may not be the sole guide for patient care because the health care system tacitly establishes choices and options. The assumption that maximizing patient choice will improve patient care has been put to the gold standard test: a large, multi-center, randomized, and controlled trial provided detailed prognostic information, facilitated communication between family, patient and, physician, and elicited very ill patient’s preferences for end of life care (37). But this study failed to show that this intervention improved the outcomes of the incidence and timing of do-not-resuscitate orders; patient-physician agreement on preferences for CPR; days in an ICU, in coma, or ventilated before death; presence of pain; and hospital resource use. This uniformly disappointing result suggests that eliciting patient preferences and maximizing patient choice is insufficient to improve the outcomes of care. Instead, the results suggest that the conditions that surround a patient’s choices influence outcomes. For example, the best determinant of where a patient dies is not their preference to die at home or in hospital, but the number of hospital beds and the availability of hospice programs and nursing homes (38). The finding that the system of care has substantial influence on the outcomes of care is especially important in the care of patients with dementia and their families. These patients are likely to require long-term care delivered either in home or in an institution such as an assisted living facility or nursing home. These settings create systems of care. In light of the lessons of the intervention study cited above (37), randomized trials may not be the best way to achieve change systems (39). Instead, clinicians should adopt strategies that can efficiently change systems and are sensitive to the local culture. One of the most effective techniques is quality improvement. This technique developed in industry involves cycles of planning an intervention, implementing it, assessing effect on key outcomes and readjusting the intervention to fit the outcomes (so called Plan, Do, Study, Act or PDSA) (40). For example, a long-term care community can set as a goal minimizing the use of feeding tubes at the end stages of dementia. The intervention to do this will involve many of the features of research, such as targeting eligible patients and assessing the outcomes, but it will adapt to the unique issues of the facility and readjust the intervention based on the outcomes data.

ADDRESSING THE CHALLENGES OF SPECIFIC DECISIONS The previous section reviewed the foundations of effective decision making. This section addresses ethical issues encountered in specific decisions common in the lives of persons with dementia: diagnostic disclosure, treatment, advance care planning, driving, and research.

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Diagnostic Disclosure Should a physician tell a person the diagnosis of dementia? Adherence to the principle of respect for autonomy supports disclosure. Failure to disclose denies a person information that is vital to making decisions about future care and plans. It leads to deception and even lying. Thus, failure to disclose undermines the very foundation of human relations: trust and honest communication. But disclosure may not be in the patient’s best interests. Families and clinicians can argue out of the principles of beneficence and nonmaleficence that this information can harm a patient. The disease is progressive and ultimately fatal. There is little that slows or halts the progression. Moreover, the patient is unlikely to understand the diagnosis. In sum, it is proper to withhold the information, especially from patients who are depressed or prone to depression. An approach to working through this dilemma addresses three issues. First, the clinician should identify the concerns of the person requesting no diagnostic disclosure. In general, a family worries that disclosure will either worsen or precipitate patient depression or that the patient is in denial, and they wish to respect this denial. In this case, the clinician should then learn what is the family’s understanding of their relative’s mood and insight. The point of this exercise is to determine how well what they believe the patient is experiencing corresponds with what the patient actually is experiencing. The issue here is the overlap in constructs. Specifically, symptoms of what seems to be depression may actually be apathy or insight, and symptoms of what appears to be denial may actually be apathy. Core features of apathy are blunted emotional response, indifference, low social engagement, diminished initiation, and poor persistence (41). These same symptoms can appear as depression. Core features of insight are awareness of problems with memory, doing tasks, and concentration. These same symptoms can also appear as depression. Core symptoms of depression focus on mood: dysphoria, suicidal ideation, self-criticism, guilt, pessimism, and hopelessness. Educating the family about which syndromes the patient is experiencing guides the value of disclosure. A patient whose depression is actually insight arguably knows what is going on and deserves the virtue of kind, hopeful but honest disclosure of the problem. In contrast, a patient with marked apathy may simply not understand or appreciate a diagnostic disclosure. They are not in denial. They simply lack the cognitive capacity to appreciate their problem. Finally, a patient with marked dysphoria requires a clear plan to address their mood disorder. In such patients, a plan for disclosure should be sensibly integrated into a treatment plan for depression that includes both drug therapy and counseling. A second step in addressing requests to withhold the diagnosis from the patient is to teach the family that a well-functioning caregiver-patient dyad requires recognizing the caregiving roles and intimacy between patient and caregiver. Failure to disclose the diagnosis can lead to an emotional distancing. Hence, diagnostic disclosure is actually in the patient’s and the caregiver’s best interest. Finally, there is the claim of what is the point of disclosure because nothing can be done. But even though there is no magic bullet treatment, a lot can be done. First, long before biomedicine took an interest in dementia as a disease, people still lived with it. Disclosure is a first step to making meaning out of the experience of an illness. Patients have kept diaries (42,43) and can participate in support groups (44). Insight can last far into the disease. The writer Jonathan Kozol records how his father, a neurologist who diagnosed himself with Alzheimer’s disease, even at a stage when he lived in a nursing home would struggle to explain how he had selective confusion because certain neurons had degenerated (45). Second, there is a clear need to recognize the value of nonpharmacologic interventions that begin with recognizing and naming a problem. Education and skill training can improve both patient and caregiver quality of life (46) and provide an opportunity for the patient to plan future care and complete unfinished tasks.

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Treatment The standard medical model of ethics largely situates decisions about treatment as a matter of informed consent. A physician discloses the treatment options and their risks and benefits. A competent patient makes a choice, or a surrogate makes a substituted judgment for a noncompetent patient. This same model generally applies to dementia treatment, but there are unique issues that largely center on quality of life and the care of patients in the profound to terminal stages of the disease. We should hold as a maxim that in the care of any progressive and incurable illness, quality of life needs to be a focus of care. Studies of the treatment preferences of caregivers confirm this (32,47). They generally regard living longer with dementia as morally ambiguous unless there is also assurance that quality of life is maintained. But if quality of life is the goal, whose assessment should guide decisions? The problem with relying on patients’ perspectives is that their apathy and impairments in insight make it difficult for them to assess whether a treatment has affected the usual measures of efficacy: cognition and function. Relying on patient assessments can lead to treatment plans that simply belie the facts. Relying on the caregiver may render a more accurate assessment, but these assessments are also affected by the caregiver’s experience of depression and burden (48,49). A useful strategy recognizes the value of each person’s perspective. The clinician should elicit both the caregiver and patient assessments. A useful question to inaugurate a discussion of quality of life is a global rating: “How would you rate your overall quality of life? Would you say poor, fair, good, very good or excellent?” Patients who answer that is it less than good generally are often suffering from depressive symptoms (50,51). Hence, an intervention should target these. In contrast, caregivers who answer that the patient’s quality of life is less than good may be experiencing significant distress, depression, or simply perceiving the severity of the patient’s functional losses (48). Hence, a treatment plan may need to focus on the caregiver’s mood and skills in caregiving. In summary, the focus of dementia care needs to be on the quality of lives—the patient and the caregiver. As dementia progresses, the physician should discuss the options for palliative care. The term describes “the management of patients with active, progressive, far-advanced disease for whom prognosis is limited and the focus of care is the quality of life” (52). In the setting of full palliative care, treatments that slow the dementia are typically withdrawn. The focus is on the relief of symptoms. Among the most difficult symptoms are dysphagia and aspiration pneumonia as a result of progressive loss of the ability to chew and swallow. A usual approach has been to recommend a percutaneuous enterogastrostomy tube, a so-called PEG-tube. The logic of this intervention is that bypassing the usual oropharyngeal route of eating will limit aspiration episodes. But the practice developed largely without clear evidence that it benefits clinical outcomes. Specifically, the available data do not support that PEG-tubes extend life, reduce episodes of aspiration or improve nutritional parameters (53). Moreover, survival after placement is poor, suggesting that aspiration marks a terminal event (54). Finally, maintaining a PEG tube includes risks and indignities such as restraining the patient, stool production that can lead to skin breakdown, and a loss of the intimacy from oral feeding. A reasonable approach to the management of neurogenic dysphagia is to offer a clear plan for careful oral feeding, and candidly discuss how this is a common event in the terminal phase of dementia. In cases where the family strongly wishes to use enteral feeding, a clinician should propose clear endpoints in order to reassess its efficacy. A final point on the ethics of treatment is the distinction between withdrawing versus withholding treatment and the claim that some kinds of treatment are not treatment. Both law and ethics have achieved consensus that no meaningful distinction exists between withdrawing versus withholding an unwanted treatment. This applies even if a consequence of the act is the patient’s death. The distinction rests on the claim that there is a moral difference between omission versus

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commission: withholding is an omission and withdrawing is a commission. But the distinction is ambiguous. Withdrawing can happen through an omission (i.e., withholding) such as not putting the infusion into a feeding tube. Withholding the next stage of treatment can be viewed as stopping treatment (i.e., withdrawing) (1). More importantly, acts of omission as well as commission can cause moral wrongs. The morality of choosing whether to withdraw or withhold treatment rests on the obligation the physician has to act in accordance with the patient’s interests and wishes in the particular situation (1). There is also consensus that so-called “artificial nutrition and hydration” are medical treatments just like drugs and surgery. Hence, the decision to withdraw a PEG tube from a patient with terminal dementia is as permissible as the decision to withhold an antibiotic to treat a pneumonia in that same patient. However, in some states, legal conditions describe the kind of the evidence that must support the decision to withdraw or withhold nutritional support. This is discussed below. Advance Care Planning In the last half of the 20th century, American society began to recognize how life-sustaining treatments such as enteral feeding and mechanical ventilation can keep seriously ill and noncompetent persons alive. Such cases raise a dilemma between the right to life versus the right to die. Advance care planning gained great popularity as a way to address this dilemma. Patients with dementia progressively lose cognition and in the severe to terminal stages experience a variety of life-threatening complications. Advance care planning has a clear appeal to guide their care. Advance care planning describes a competent patient who describes how to manage future medical problems when the patient is no longer able to make decisions. A patient can document these plans as witnessed legal documents (a living will) or they can remain as informal guides for care kept in a chart note or remembered conversation. In general, the process of advance care planning benefits patients: decreasing depression, enhancing a sense of being in control, and settling treatment preferences (55). Much of the history of advance directives is told in legal cases. The classic case that captured the attention of the public was Karen Ann Quinlan, a woman in a persistent vegetative state whose family sought to discontinue her enteral feeding tube. Advance directives were seen as a means to keep such cases out of the courts and to prevent dilemmas between the right to life versus the right to die in the care of non-competent patients in the advanced stages of serious and life-threatening illnesses. Subsequent cases have reaffirmed their legal and ethical value. Specifically, the case of Cruzan reaffirmed the right of patients or their surrogates to refuse all forms of medical treatment (including nutrition and hydration) but it also affirmed a state’s right to establish evidentiary standards for the removal of life-sustaining treatment. For example, in some states, artificial nutrition cannot be removed or refused unless a patient has explicitly declined it in a living will or authorized a surrogate to do so in a durable power of attorney for healthcare (56). Hence, a physician in one of these states has a clear duty to advise patients of this legal requirement. As appealing as advance directives are, they have three limitations. First, they have conceptual limitations. Living wills may seem to ensure the strictest adherence to a patient’s selfdetermination (e.g., “I do not want a feeding tube.”). However, these specific directives apply to specific conditions. The typical generic language of a living will focuses only on the condition of a “terminal illness.” This is ironic. The cases that motivated getting them are typically cases of a persistent vegetative state or severe dementia when the person is not clearly dying and may live for at least a year. This limited scope means they can fail to guide care if there is disagreement about the patient’s current state or prognosis. A solution to this problem is to make sure that advance care planning conversations focus on the patient’s goals, values, and concepts of best interests, and are amended to include conditions such as persistent vegetative state or profound dementia.

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A second limitation is that many patients do not value them. Specifically, patients may not want to make specific plans for their future care. Instead, they wish to entrust others to act in their best interests (35). This supports that some patients find decision-specific directives unappealing. The physician needs to determine how strictly a patient wants his advance directive followed. A third limitation is that a dementia patient’s impairments in abstract reasoning, planning, and insight may hinder their decision-making abilities to the degree that they lack the capacity to execute an advance directive (57). A useful strategy for the clinician is to present a patient a description of a person in the profound stage of dementia and ask the patient “Suppose that you were in this condition. How would you want to be cared for (58)?” The patient’s answer is then a starting point both to assess their ability to make decisions about their future care and for a discussion about their goals and values of care. These three limitations convey a clear message. Executing advance care documents is a means to a greater goal (except in states that set stringent evidentiary standards for the withdrawal or withholding of nutritional support). The goal of advance care planning is to create an understanding and appreciation of the patient’s future, and identify values that should help to shape that future. Driving Dementing illnesses cause cognitive and behavioral changes that can impair the ability to drive. Deficits in attention and perceptual-motor reaction time lead to mistakes at intersections, traffic signals, or changing lanes (59). The challenge to the clinician, family, and patient is deciding whether a patient should drive. The ability to drive is an expression of liberty and independence. It provides a sense of selfesteem and control of one’s everyday life. Most older Americans rely on the automobile as their primary means of transportation (60). Driving cessation often leads to decreased quality of life, loss of control, increased loneliness and isolation, and depression (61). But the law recognizes driving as a privilege and not a right. In many states, physicians have a duty to protect their patient’s lives and also maintain public safety. A physician must balance the autonomy and quality of life of their patient with the safety of their patient and society. Drivers with moderate to severe stages of Alzheimer’s disease pose a significant safety problem (62). They clearly should not drive. But drivers with very mild to mild dementia display driving impairment comparable to that tolerated in other segments of the driving population (63–65). Hence, a clinician cannot infer automatically from a diagnosis of dementia that a patient cannot drive (59,65–68). For these kinds of patients, a recommendation to limit or cease driving should be based on relevant criteria such as tests of functional competency. A useful strategy will focus on assessing the patient’s capacity to drive. A useful question to families is “Would you allow your relative to drive your children [or grandchildren]?” A negative answer to this strongly supports the need for a driving skills assessment or even simply disabling the car. Occupational therapists can perform formal driving screens that include tests of perception, cognition, reaction time, and on-the-road evaluation (66,69,70). Sometimes a patient or family will resist a driving evaluation because it is too expensive. A useful strategy to address this is to ask if they would pay the same amount of money to assure the safety of the car’s mechanical function. Clinicians should recognize that some states expect them to serve a public health role as well. Many states have laws requiring physicians to report patients with certain medical conditions that can impair driving ability to the Department of Transportation (69). For example, California requires physicians to report all cases of dementia to the motor vehicle licensing administration (71). Research Ethical dilemmas in clinical care typically center on competing claims of what will benefit a patient. Research raises a unique set of dilemmas. Unlike clinical care, research is an activity that is designed to generate generalizable knowledge, not to benefit the patient. Research exposes patients

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to risk in the pursuit of benefit to others. Hence, it creates a dilemma between the good of the patient and the good of society (72). This dilemma is especially vexing when the patients cannot themselves volunteer. On what grounds can another person enroll someone in an activity that benefits others, but not the person? At present, some states have laws that describe the proper conduct of research that involves adults who lack the capacity to provide an informed consent, but no nationally adopted policy exists to guide the proper conduct of research (73). However, proposed policies and guidelines do have common recommendations (74–76). The general model of these recommendations is that it is permissible to expose a non-competent subject to research risks provided (1) the research presents a reasonable prospect of benefit to the subjects, or (2) the research is not potentially beneficial but its risks are either minimal or the research promises to yield vitally important knowledge to the class of subjects under study and the subject has indicated in advance a willingness to participate in this kind of research. In all of these cases, there is general consensus that the subject should be able to assent to enroll. Unlike consent, assent describes a lesser standard of understanding. This model—with the exception of advance consent—is largely based on the federal regulations for research that involves children (77) (subpart D). While federal research regulations only carry authority at U.S. institutions that accept federal monies, they are widely respected as an ethical framework. The core of this model is the idea that research risks can be balanced against two kinds of benefits: the potential benefits to the subjects, if any, and the importance of the knowledge that can reasonably be expected to result (77) [§46.111(a)(2)]. This model is a useful starting point for investigators and institutional review boards, but three issues need further detail. First, some patients with dementia are competent to consent to enroll in research. Studies that measure the decision-making abilities of patients with dementia with Mini-mental State Exam scores of at least 19 show that a portion of patients do have adequate abilities to be competent to provide an informed consent (16,17). Researchers should use the same skills described in Table 2 to assess a patient’s abilities to understand, appreciate, reason, and choose. Second, as important as the term “minimal risk” is, it has two ambiguities. The term is defined as “the probability and magnitude of physical or psychological harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life, or during the performance of routine physical or psychological examinations or tests (77) [46.102(i)].” While this definition details the breadth of what risks should be assessed, it lacks a subject to compare these risks to (78). A second ambiguity is how to assess minimal risk (79). Specifically, does minimal risk cover all of the risks encountered in a research project, or only the research risks that are not balanced by potential benefits? The following case works through a solution to these ambiguities: An 18-month long trial will randomize subjects to one of two potential treatments for Alzheimer’s disease. Drug A is standard of care. Drug B is a new drug. Evidence suggests that it may be superior to A. A clinical trial is needed to prove this. Subjects receive periodic physical exams, cognitive testing. and blood tests. At first glance, this clinical trial seems greater than minimal risk. The subjects will receive a host of tests for one and one-half years. They receive drugs that have risks. But if legitimate uncertainty exists whether B is better than A, the potential risks of each intervention are balanced by the potential benefits. The issue in minimal risk is the risks that are not balanced by potential benefits. For example, if this clinical trial included more blood tests than are routinely part of treatment with standard of care drug A, the risks of the additional blood tests are research risks. So, too, if the trial includes additional cognitive testing. The general issue then is how the risks of these pure research procedures designed solely to generate generalizable knowledge compare to the risks routinely encountered in clinical care of the patients in the trial. Most reasonable people would agree that a blood draw and cognitive testing are among the routine tests in the care of persons with dementia. Hence, the study presents minimal risks. In summary, the assessment of research risks relies on a two step process: (1) demarcate risks that are solely part of research interventions from

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risks and benefits that are part of therapeutic interventions, and then, (2) compare the first set of research risks to the risks of the patients everyday lives. A third issue is the use of research advance directives (RADs). At first glance, the idea seems odd. Few people, if any, have RADs, and the small portion of persons who have clinical advance directives (10% to 20%) suggests that RADs might be just as uncommon (80). The net effect of a policy of prospective authorization is a hindrance in the progress of valuable research. But directives need not be policy. In clinical practice, advance directives are not required, patients generally endorse that they want to discuss advance planning and do not find the topic distressing (80–82). The same could be true for RADs. But policy needs to be informed by data. Specifically, policies have been advanced and criticized without adequately addressing two key issues: Do people who are likely to face research decisions value RADs? And, are elderly persons who are at risk of losing their capacity capable of executing a research advance directive? The answers to these questions will not decide whether we should have RADs, but they will go a long way in explaining the feasibility and acceptability of their use. CONCLUSION The ethical issues discussed above provide clinicians and researchers a theoretical foundation and skills to address common decisions and dilemmas in care and research that involves patients with dementia. But the parting message is a note of caution. Dementia is not just another serious and lifethreatening illness. It raises issues of the status of vulnerable persons in our society, family obligations, and even the nature of personhood. As a result, some ethical dilemmas are either not resolvable or their solution arrives too late. Such tragic cases are not so much clinicians’ and researchers’ failures. They are opportunities to behold the full drauma that is the human experience. REFERENCES 1. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. New York, Oxford: Oxford University Press, 1994. 2. U.S. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Making Health Care Decisions: A Report on the Ethical and Legal Implications of Informed Consent in Patient-Practitioner Relationship 1982. Washington, DC. 3. Post SG. The Moral Challenge of Alzheimer’s Disease. Baltimore: The Johns Hopkins University Press, 1995. 4. Faden RR, Beauchamp TL. A History and Theory of Informed Consent. New York: Oxford University Press, 1986 pp. 235–381. 5. Braddock CH, Edwards KA, Hasenberg NM, Laidley TL, Levinson W. Informed decision making in outpatient practice: time to get back to basics. JAMA 1999; 282:2313–2320. 6. Farrow DC, Hunt WC, Samet JM. Geographic variation in the treatment of localized breast cancer. N Engl J Med 1992; 326:1097–1101. 7. Nattinger AB, Gottlieb MS, Veum J, Yahnke D, Goodwin JS. Geographic variation in the use of breastconserving treatment for breast cancer. N Engl J Med 1992; 326:1102–1107. 8. Leape LL, Park RE, Solomon DH, Chassin MR, Kosecoff J, Brook RH. Relation between surgeons’ practice volumes and geographic variation in the rate of carotid endarterectomy. N Engl J Med 1989; 321:653–657. 9. Piper A, Jr. Truce on the battlefield: A proposal for a different approach to medical informed consent. J Law Med Ethics 1994; 22:301–313. 10. Strull WM, Lo B, Charles G. Do patients want to participate in medical decision making? JAMA 1984; 252:2990–2994. 11. Marzanski M. Would you like to know what is wrong with you? On telling the truth to patients with dementia J Med Ethics 2000; 26:108–113.

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12. Zanetti O, Vallotti B, Frisoni GB, et al. Insight in dementia: when does it occur? Evidence for a nonlinear relationship between insight and cognitive status. J Gerontol B Psychol Sci Soc Sci 1999; 54:100–106. 13. Goffman E. Asylumns: Essays on the Social Situation of Mental Patients and Other Inmates. Chicago: Aldine Publishing Company, 1961. 14. Grisso T, Appelbaum PS. Assessing Competence to Consent to Treatment. A Guide for Physicians and Other Health Professionals. New York: Oxford University Press, 1998 pp. 31–60. 15. Marson DC, McInturff B, Hawkins L, Bartolucci A, Harrell LE. Consistency of physician judgments of capacity to consent in mild Alzheimer’s disease. J Am Geriatr Soc 1997; 45:453–457. 16. Kim SYH, Caine ED, Currier GW, Leibovici A, Ryan JM. Assessing the competence of persons with Alzheimer’s disease in providing informed consent for participation in research. Am J Psychiatry 2001; 158:710–717. 17. Karlawish JHT, Casarett DJ, James BD. Alzheimer’s disease patients’ and caregivers’ capacity, competency and reasons to enroll in an early phase Alzheimer’s disease clinical trial. J Am Geriatr Soc 2002; 50:2019–2024. 18. Marson D, Harrell L. Executive dysfunction and loss of capacity to consent to medical treatment in patients with Alzheimer’s disease. Semin Clin Neuropsych 1999; 4:41–49. 19. Taub HA, Baker MT, Kline GE, Sturr JF. Comprehension of informed consent information by young-old through old-old volunteers. Exp Aging Res 1987; 13:173–178. 20. McKneally MF, Martin DK. An entrustment model of consent for surgical treatment of life-threatening illness: perspective of patients requiring esophagectomy. J Thorac Cardiovasc Surg 2000; 120:264–269. 21. Puchalski CM, Zhong Z, Jacobs MM, et al. Patients who want their family and physician to make resuscitation decisions for them: observations from SUPPORT and HELP. Study to understand prognoses and preferences for outcomes and risks of treatment. Hospitalized elderly longitudinal project. J Am Geriatr Soc 2000; 48:S84–S90. 22. Kelner M. Activists and delegators: elderly patients’ preferences about control at the end of life. Soc Sci Med 1995; 41:537–545. 23. Degner LF, Kristjanson LJ, Bowman D, et al. Information needs and decisional preferences in women with breast cancer. JAMA 1997; 277:1485–1492. 24. Karlawish JHT, Casarett D, Klocinksi J, Sankar P. How do AD patients and their caregivers decide whether to enroll in a clinical trial? Neurology 2001; 56:789–792. 25. Bayley J. I was Alone with Iris when She Died—Her Death was so Peaceful. London: The Daily Telegraph, 1999 p. 14. 26. Appelbaum PS, Grisso T, Frank E, O’Donnell S, Kupfer DJ. Competence of depressed patients for consent to research. Am J Psychiatry 1999; 156:1380–1384. 27. Appelbaum PS, Grisso T. The macarthur treatment competence study. I. Law Hum Behav 1995; 19:105–126. 28. Blank K, Robison J, Doherty E, Prigerson H, Duffy J, Schwartz HI. Life-sustaining treatment and assisted death choices in depressed older patients. J Am Geriatr Soc 2001; 49:153–161. 29. Lee MA, Ganzini L. Depression in the elderly: effect on patient attitudes toward life-sustaining therapy. J Am Geriatr Soc 1992; 40:983–988. 30. Hooper SC, Vaughan KJ, Tennant CC, Perz JM. Major depression and refusal of life-sustaining medical treatment in the elderly. Med J Aust 1996; 165:416–419. 31. Karlawish JH, Casarett DJ, James BD, Tenhave T, Clark CM, Asch DA. Why would caregivers not want to treat their relative’s Alzheimer’s disease? J Am Geriatr Soc 2003; 51:1391–1397. 32. Karlawish JHT, Klocinski J, Merz JF, Clark CM, Asch D. Caregivers’ preferences for the treatment of patients with Alzheimer’s disease. Neurology 2000; 55:1008–1014. 33. Karlawish JH, Casarett D, Propert KJ, James BD, Clark CM. Relationship between Alzheimer’s disease severity and patient participation in decisions about their medical care. J Geriatr Psych Neurol 2002; 15:68–72. 34. Buchanan AE, Brock DW. Deciding for Others: The Ethics of Surrogate Decision Making. Cambridge: Cambridge University Press, 1989. 35. Sehgal A, Galbraith A, Chesney M, Schoenfeld P, Charles G, Lo B. How strictly do dialysis patients want their advance directive followed? JAMA 1992; 267:59–63.

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36. Karlawish JHT, Quill T, Meier DE. A consensus-based approach to providing palliative care for patients who lack decision-making capacity. Ann Intern Med 1999; 130:835–840. 37. The SUPPORT Principal Investigators. A controlled trial to improve care for serously ill hospitalized patients: The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT). JAMA 1995; 274:1591–1598. 38. Pritchard RS, Fisher ES, Teno JM, et al. Influence of patient preferences and local health system characteristics on the place of death. J Am Geriatr Soc 1998; 46:1242–1250. 39. Lynn J, Arkes HR, Stevens M, et al. Rethinking fundamental assumptions: SUPPORT’s implications for future reform. J Am Geriatr Soc 2000; 48:S214–S221. 40. Berwick DM. Developing and testing changes in delivery of care. Ann Intern Med 1998; 128:651–656. 41. Landes AM, Sperry SD, Strauss ME. Apathy in Alzheimer’s disease. J Am Geriatr Soc 2001; 49:1700–1707. 42. McGowin DF. Living the Labyrinth: A Personal Journey Through the Maze of Alzheimer’s. New York: Dell Publishing, 1993. 43. Thomas H, Thomas N. How can my mind go AWOL? Lancet 2001; 358:S2. 44. Snyder L, Quayhagen MP, Shepard S, Bower D. Supportive seminar groups: an intervention for early stage dementia patients. Gerontologist 1995; 35:691–695. 45. Kozol J. Losing My Father One Day at a Time. New York: The New York Times, 2000 p. A21. 46. Mittelman M, Ferris S, Shulman E, Steinberg G, Levin B. A family intervention to delay nursing home placement of patients with Alzheimer’s disease: a randomized controlled trial. JAMA 1996; 276:1725–1731. 47. Post SG, Whitehouse PJ. Emerging antidementia drugs: a preliminary ethical view. J Am Geriatr Soc 1998; 46:784–787. 48. Karlawish JHT, Casarett D, Klocinski J, Clark CM. The relationship between caregivers’ global ratings of Alzheimer’s disease patients’ quality of life, disease severity and the caregiving experience. J Am Geriatr Soc 2001; 49:1066–1070. 49. Logsdon RG, Gibbons LE, McCurry SM, Teri L. Assessing quality of life in older adults with cognitive impairment. Psychosom Med 2002; 64:510–519. 50. Karlawish J, Casarett D, James B, Klocinski J, Marenberg M, Clark CM. The impact of depression and dementia severity on AD patients’ rating of their overall quality of life (abstract). Gerontologist 2001; 41S:S281. 51. Logsdon RG, Albert SM. Assessing quality of life in Alzheimer’s disease: conceptual and methodological issues. J Mental Health Aging 1999; 5:3–6. 52. Doyle D, Hanks GWC, MacDonald N. Oxford Textbook of Palliative Medicine. New York: Oxford University Press, 1998. 53. Finucane TE, Christmas C, Travis K. Tube feeding in patients with advanced dementia. A review of the evidence. JAMA 1999; 282:1365–1370. 54. Grant M, Rudberg M, Brody J. Gastrostomy placement and mortality among hospitalized medicare beneficiaries. JAMA 1998; 279:1973–1976. 55. Miles SH, Koepp R, Weber EP. Advance end-of-life treatment planning: a research review. Arch Intern Med 1996; 156:1062–1068. 56. Sieger CA, Arnold JF, Ahronheim JC. Refusing articifial nutrition and hydration: does statutory law send the wrong message? J Am Geriatr Soc 2002; 50:544–550. 57. Fazel S, Hope T, Jacoby R. Dementia, intelligence, and the competence to complete advance directives (research letter). Lancet 1999; 354:48. 58. Fazel S, Hope T, Jacoby R. Assessment of competence to complete advance directives: validation of a patient centered approach. BMJ 1999; 318:493–497. 59. Donnelly RE, Karlinsky H. The impact of Alzheimer’s disease on driving ability: a review. J Geriatr Psych Neurol 1990; 3:1990. 60. Jette AM, Branch LG. A ten-year follow-up of driving patterns among the community-dwelling elders. Hum Factors 1992; 34:25–31. 61. Marattoli RA, Mendes de Leon C, Glass TA, et al. Driving cessation and increased depressive symptoms: prospective evidence from the New Haven EPESE. J Am Geriatr Soc 1997; 45:202–206.

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62. Lucas-Blaustein MJ, Filipp L, Dungan C, Tune L. Driving in patients with dementia. J Am Geriatr Soc 1988; 36:1087–1091. 63. Dubinsky RM, Stein AC, Lyons K. Practice parameter: risk of driving and Alzheimer’s disease (an evidence-based review). Neurology 2000; 54:2205–2211. 64. Hunt L, Morris JC, Edwards D, Wilson BS. Driving performance in persons with mild senile dementia of the Alzheimer type. J Am Geriatr Soc 1993; 41:747–753. 65. Drachman DA, Swearer JM. Driving and Alzheimer’s disease: the risk of crashes. Neurology 1993; 43:2448–2456. 66. Odenheimer GL. Dementia and the older driver. Clin Geriatr Med 1993; 9:349–364. 67. Trobe JD, Waller PF, Cook-Flannagan CA, Teshima SM, Bieliauskas LA. Crashes and violations among drivers with Alzheimer disease. Arch Neurol 1996; 53:411–416. 68. Fitten LJ, Perryman KM, Wilkinson CJ, et al. Alzheimer and vascular dementias and driving. JAMA 1995; 273:1360–1365. 69. Pasupathy S, Lavizzo-Mourey R. Geriatric Secrets. In: Forciea MA, Lavizzo-Mourey R, eds. 2nd ed. Philadelphia: Hanley and Belfus, 2000:115–120. 70. Carr D, Schmader K, Bergman C, et al. A multidisciplinary approach in the evaluation of demented drivers referred to geriatric assessment centers. J Am Geriatr Soc 1991; 39:1132–1136. 71. West. California Health & Safety Code § 103900, 2000. 72. Jonas H. Experimentation with Human Subjects. In: Freund PA, ed. New York: George Braziller, 1969:1–31. 73. Hoffman DE, Schwartz J. Proxy consent to participation of the decisionally impaired in medical research—Maryland’s policy initiative. J Health Care Law Policy 1998; 1:123–153. 74. National Bioethics Advisory Commission. Research involving persons with mental disorders that may affect their decisionmaking capacity. Report and Recommendations. Vol. 1. Rockville, MD: U.S. Government Printing Office, 1998 p. 88. 75. New York State Advisory Work Group on Human Subjects Research Involving the Protected Classes. Recommendations on the Oversight of Human Subject Research Involving the Protected Classes. Albany, NY: State of New York Department of Health, 1998. 76. Anonymous. Attorney General’s Working Group. Office of the Maryland Attorney General. Third report of the attorney general’s research working group. Consent to research — Protection of decisionally incapacitated individuals. Baltimore: Office of the Maryland Attorney General, 1998. 77. Department of Health and Human Services. Common Rule, 45 CFR 46. Federal policy for the protection of human subjects; notices and rules. Fed Regist 1991; 56:28003–28032. 78. Karlawish JHT, Hall JB. The controversy over emergency research: a review of the issues and suggestions for a resolution. Am J Respir Crit Care Med 1996; 153:499–506. 79. Weijer C. The ethical analysis of risk. J Law Med Ethics 2000; 28:344–361. 80. Emanuel LL, Barry MJ, Stoeckle JD, Ettelson LM, Emanuel EJ. Advance directives for medical care—a case for greater use. N Engl J Med 1991; 324:889–895. 81. Virmani J, Schneiderman LJ, Kaplan RM. Relationship of advance directives to physician—patient communication. Arch Intern Med 1994; 154:909–913. 82. Reilly BM, Magnussen CR, Ross J, Ash J, Papa L, Wagner M. Can we talk? Inpatient discussions about advance directives in a community hospital. Attending physicians’ attitudes, their inpatients’ wishes, and reported experience Arch Intern Med 1994; 154:2299–2308. 83. Hirsohman KB, Joyce CM, Jamps BJ, Xie SX, Casarett D, Karlawish JHT. Would caregivers Alzheimers disease patients involve their relative in a decision to use an AD slowing medicine? AM J Geriatr Psych 2005; 13:1014–1021.

2 Epidemiology, Dementia, and Alzheimer’s Disease: Methods Influence Conclusions Walter A. Kukull National Alzheimer’s Coordinating Center, Department of Epidemiology, University of Washington, Seattle, Washington, U.S.A.

INTRODUCTION The brief descriptive epidemiology of dementia is included within, at most several paragraphs in many neurology and geriatric medicine texts. To paraphrase what texts often seem to say we offer the following; the first sub-paragraph is often all that is included under epidemiology: . . . Dementia has many causes, Alzheimer’s disease (AD) and vascular dementia (VaD) predominate. The occurrence of dementia is more common with increasing age; both the incidence (new cases per time) and the prevalence (proportion of persons living with dementia) increase almost exponentially with age after about age 60. There are more women living with dementia than there are men, yet for a given age group the occurrence of new cases per unit time may be similar in both genders. Estimates indicate 5% to 10% of persons over age 64 are living with dementia and 1% to 3% of those over age 64 acquire the syndrome annually in Europe, North America, and parts of Asia. For AD, few if any environmental causes or protective factors are widely accepted by the research community. Genes have been identified that may cause 25% to 50% of young onset Familial AD [amyloid precursor protein (APP) gene, and presenilin 1 (PS1) and presenilin 2 (PS2), mutations], though Familial AD accounts for perhaps 1%–5% of AD. Genes also increase the risk of the commonly occurring non-familial AD (apolipoprotein E epsilon 4 allele). Treatment is modestly effective to slow progression in early stages of AD, and to date has focused on increasing the availability of neurotransmitters, such as acetylcholine. VaD results principally from strokes and other cerebrovascular disease though it does not occur following all such insults. The predominant risk factors for VaD may be similar to those for stroke (e.g., hypertension, smoking) to date no specific causal genes have been identified, though genetic factors may play a role in increasing cerebrovascular disease risk. 17

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Lewy body disease is now also recognized as a frequent cause of dementia. Dementia also occurs in some persons with Parkinson’s disease, and other neurodegenerative conditions. Infections, including HIV/AIDS, also can lead to dementia. General medical disorders and trauma account for a smaller proportion of dementia occurrence.. The brief paraphrase above may be sufficient for many purposes, especially to obtain a thumbnail sketch of who, when, where, and why persons might develop dementia. It also fits well with the view that all one needs to know about epidemiology can be learned in about one hour. To arrive at the sketch above, however, many research questions must have been addressed, and their results critically evaluated. Some of those questions include: How is dementia, or a specific dementia, uniformly defined? How can cases be recognized and obtained for study so that one can be confident those cases are similar to all cases (or differ in known ways)? How can information about potential causal factors (environmental exposures, genetic factors) that may have influenced disease onset be obtained? How might we determine whether those factors might occur more frequently (or less frequently) among persons who develop dementia compared to those who do not develop it? Is there a critical period, in which a factor must be present to affect disease onset? How might we describe other factors that mix their effects with the ones of interest, causing us to over— or, under-estimate the true effect of a factor on disease onset? Are there co-existing factors that, in their presence cause a factor of interest to be more strongly or more weakly associated with disease? How can chance associations leading to spurious conclusions be avoided? How can we infer that an observed association between a factor (exposure) and disease is a causal association? Epidemiology is acutely concerned with simultaneously addressing all these questions, while attempting to describe who, when, where, and why, persons become diseased. In Olympic diving, this could be the rough equivalent of a reverse, triple twisting, three-and-a-half from a springboard.

RECOGNIZING AND DIAGNOSING DEMENTIAS Before attempting to count cases of dementia, one must have a relatively reliable and valid means of diagnosing it. The Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-III-R and DSM IV) (1) provides relatively reliable clinical criteria for dementia diagnosis. The DSM criteria have been recommended in the American Academy of Neurology (AAN) Practice Parameter for the diagnosis of dementia (2). Briefly, for dementia to be present there must be a decline from a previous level causing impairment in social or occupational functioning resulting from impaired memory in addition to one or more of the following: (1) difficulty naming objects, (2) inability to execute well known motor acts, (3) failure to recognize familiar objects despite intact senses, (4) disturbed ability to plan, initiate, sequence and to think abstractly: executive functioning. Typically, however, the DSM criteria are applied in a clinic setting and are based on neuropsychological testing, lab tests, history, and physical/neurological examination. The diagnosis of dementia is usually based on clinical judgment about the examination evidence. One schema for organizing evidence and assessing dementia severity is the Clinical Dementia Rating (CDR) (3,4). This process tool helps clinicians to describe and distinguish normal patients from those with early or mild dementia symptoms (“questionable dementia”) as well as from those patients with frank dementia at more severe levels. Identifying potential new dementia cases in a community survey or among patients who present at clinic with no cognitive complaints usually requires some type of brief and easily administered cognitive screening test. Such screening tests have attendant imperfect sensitivity and specificity, but are useful tools to apply in field studies before potential cases are sent for the full clinical exam. One such screening test is the Mini-Mental State Examination, (MMSE) (5). Because of its apparent sensitivity and specificity to identify early indications of dementia, the MMSE has

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also has been suggested for use by the AAN practice parameter (6,7). There are currently no widely used biological tests or markers to screen for or to diagnose dementia. The clinical diagnosis of dementia relies primarily on physician judgment to interpret the components of the examination (neuropsychological tests, laboratory tests, history, family reports, physical/neurological exams) as mentioned earlier. Further, the differential clinical dementia diagnosis itself is often presumptive; it is subject to substantiation by neuropathological examination. While AD is still acknowledged to account for O60% of dementia (discussed by Morris in Chapter 10) (8–12), there is now growing evidence that the second most common form of dementia may be dementia with Lewy bodies (DLB) (13,14), rather than VaD as previously thought (12). In fact, Lewy body disease and vascular pathology may coexist with the pathognomic Ab amyloid plaques and aggregated, tau protein-based, neurofibrillary tangles common in AD (15). Frontotemporal lobar degeneration (FTLD) (2,16–19) also known as its clinical phenotype frontotemporal dementia (FTD) (20,21) is an additional emerging condition, which is considerably less common than AD and Lewy body disease, but newer research shows it to be more common than previously expected. FTLD is discussed by Miller in Chapter 13. The accepted diagnostic criteria for FTD is put forth by Neary (16). Hippocampal sclerosis may cause a similar proportion of dementia cases as FTLD (12), but it may be distinguished primarily by neuropathology rather than clinical features. VaD, despite a number of clinical guidelines and relatively well-constructed diagnostic criteria (1,22–28) remains difficult to define reliably. Vascular pathology may also contribute to and coexist with AD leading some to suggest that AD itself may be a form of VaD (29–31) and thus, that VaD is perhaps the most common form of dementia (32,33). The topic of VaD is covered by Chui in Chapter 14. Parkinson’s disease [also a Lewy body disease (34)] can coexist with AD and also can cause dementia. Parkinson’s and Lewy body disorders are discussed by Galvin in Chapter 12. Prion diseases, such as Creutzfeldt-Jakob disease (CJD) and its variant forms (vCJD) lead to a spongiform encephalopathy and dementia (2,35–39). These disorders are reviewed by Mastrianni in Chapter 15. There are also a number of other causes of dementia but they are less common and potentially less easily confused with other forms of the disease. These include HIV associated dementia (40–42), normal pressure hydrocephalus, head trauma, substance abuse, and some general medical conditions (43). HIV dementia is discussed in Chapter 17, hydrocephalus in Chapter 16, and comorbid diseases in Chapter 18. The level of diagnostic uncertainty for any specific dementia can carry with it, what an epidemiologist would consider to be, a substantial degree of diagnostic misclassification. For the clinical diagnosis of AD, the sensitivity (and less often the specificity) has approached or exceeded 90% since 1990 (44–47), but even that level of misclassification may be sufficient to mask some risk factor associations. Other dementias have their individual levels of clinical diagnostic accuracy (19,24,48–51). Misclassification of the clinical diagnosis could cause error in the estimates of disease-specific incidence or prevalence; it can also attenuate risk factor associations in analytic epidemiology. For epidemiological studies to wait for autopsy confirmed cases, before beginning analytic risk factor studies, could carry the high price of selection bias. Relatively few dementia patients complete autopsy and neuropathological examination. Those that do reach autopsy may have genetic constitutions, exposure profiles or clinical and socio-demographic characteristics, which differ from non-autopsied dementia patients in a way specifically associated with their selection into the autopsy series. Thus, biased estimates of risk factor associations could result. Careful comparison of living, dead, and autopsied subjects’ characteristics would help the investigator estimate the magnitude and direction of a potential bias. Simply comparing age and gender of the autopsied and non-autopsied patients is usually insufficient for this purpose. PREVALENCE Prevalence is the proportion of living persons in a defined population or sample who have the disease in question at a particular point in time, e.g., “prevalence day.” Prevalence is a cross-sectional

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measure, though often called a rate, it is not a rate but a proportion. It is a measure of the disease burden on the community; it is not a measure of disease risk. (N.B.: Incidence, “new” cases per population time, reflects disease risk.) Prevalence is dependent on disease incidence and duration; it is also influenced by migration associated with disease status, in or out of the base population. Complete, accurate case finding and diagnosis are obviously important to determine prevalence. Also important is complete enumeration of the population sample from which the prevalence proportion will be determined. Strict statistical sampling methods where a sampling frame (target population) is chosen, then a statistically determined fraction of that frame is selected for dementia evaluation will lead to valid prevalence estimates for the sampling frame. Often more complicated sampling schemes and statistical methods are necessary. For example, the investigator may wish to determine the prevalence of dementia by selecting a sample of households, which include at least one person over age 65 within the geographic bounds of a city. Determination of the prevalence proportion also depends on the characteristics of the screening instruments used and the accuracy to the clinical diagnosis. Prevalence estimates can also be biased by differential refusal of potentially eligible subjects. To the extent that persons with early (or late stage) dementia may refuse (or accept) participation more frequently, compared to cognitively normal individuals, the prevalence estimate may be biased. Dementia prevalence is often reported as based on community living individuals. In that instance, persons residing in nursing homes or residential care facilities may not be considered part of the count, or the complete enumeration of a defined population. Such a prevalence survey could be completed accurately but it may or may not reflect the intended disease prevalence. For example, a community where 90% of demented individuals were enrolled in institutions soon after diagnosis would exhibit a smaller prevalence proportion, than a similar community where only 10% were enrolled in institutions, despite roughly equal numbers of demented and nondemented individuals in each. When investigators report dementia prevalence from within a particular defined population and infer that it represents the proportion of demented individuals in a much larger, non-enumerated population, outside their sampling frame, they are essentially taking an educated guess. They are relying that their sampling frame and the population to which they have extrapolated are similar in most respects. It is the reader’s responsibility, as well as the investigator’s, to carefully evaluate whether the extrapolation is plausible. Based on a Boston population sample evaluated for probable AD and dementia, Evans et al. (52) estimated 10.3% of persons over age 65 had prevalent probable AD. Evans then projected based on the U.S. census and the figures from Boston, that there were 2.88 million persons over age 65 or older with probable AD in the United States in 1980 and that there would be approximately 10.3 million by the year 2050 (53). Brookmeyer et al. (54) used prevalence estimates from a different study to estimate that approximately 2.3 million person in the United States were affected with AD in 1997 and that approximately 9 million would be affected by the year 2050. It follows that valid prevalence estimates from any specific study can be used to project onto a larger non-surveyed populations. The key to the accuracy of the projection lies in the similarity between the studied and the projected population. Factors that influence incidence (e.g., age) and duration of disease (e.g., social and medical factors) may be good primary indices of similarity. Lobo et al. (55) pooled information from 11 European population-based studies of persons 65 years and older to estimate dementia and subtype prevalence. Summary measures of age-standardized prevalence were: 6.4% for all cause dementia, 4.4% for AD, and 1.6% for VaD; AD accounted for approximately 54% of the prevalent cases in the analysis and VaD approximately 16%. Age-specific prevalence of all cause dementia increased substantially with age, ranging from approximately 0.8% in the 65 to 69 year age group, to approximately 28.5% among those 90 years and older. Similarly, AD prevalence ranged from 0.6% to 22.2%, and VaD increased from, 0.3% in the younger age group to 5.2% in persons aged 90 and older. Pooled estimates such as Lobo (55) presents can form a defensible basis for projection to a larger, similar population than projections made on the basis of a single study.

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Prevalence of AD in relation to VaD has been historically greater in North American and European populations than among Asian populations. Suh (56) reviewed studies between 1980 and 1999 from Japan, Korea, and China in comparison to those from Europe and the United States and reported that while earlier studies found lower prevalence of dementia and a greater VaD/AD ratio, studies in the 1990s reported similar overall prevalence cross-culturally and a comparable ratio of VaD to AD. Wimo et al. (57) used meta-analytic techniques to estimate that there were approximately 25 million demented persons worldwide in 2000. Of those, they estimated that 46% were living in Asia, 30% in Europe and the remaining 12% in North America. These figures are consistent with a prevalence of approximately 6.1% of all persons age 65 or older. Projecting prevalence to the year 2050 Wimo et al forecast that 114 million persons will have dementia and 74% of those will be in “less developed regions.” This is a near catastrophic burden on the public health worldwide. It will indeed be a challenge to meet those health care needs should the projection be realized. Decreasing the incidence of dementia could act to reduce prevalence, if preventive measures could be found in time. Even measures that delay dementia onset age, as Brookmeyer (54) suggests, may act through competing risks to lower the prevalence. Paradoxically, as healthcare improves in developing countries of Asia, persons will live well into the ages of greatest risk and those with dementia will likely survive longer, adding to the burgeoning prevalence.

INCIDENCE OF DEMENTIA Incidence refers to the occurrence of new events, such as disease onset. An incidence rate can be computed from the total events divided by the sum of person-years of observation each subject, included in the study, contributed prior to disease onset. An aggregate measure is often calculated from the new cases occurring in a population during a specific time period divided by the number of persons at-risk of becoming diseased, from that same population and time period. Incidence allows the determination of disease risk. Incidence is the basis for comparative risk indices such at the “relative risk” or rate ratio (incidence in exposed persons divided by incidence in the unexposed) and the attributable risk (i.e., disease incidence among those exposed to a specfic factor, which is due to that factor, defined as the incidence in exposed minus incidence in those persons unexposed to a potential risk factor). If, for example, AD were a reportable illness, such that essentially all newly diagnosed cases in a county were reported to the county health department, one could potentially compute an aggregate incidence rate from the count of new cases and the known county population (minus any already known to have dementia). Unfortunately, even if AD were “reportable,” it may be diagnosed incompletely or inconsistently in the community, leading to an inaccurate estimate. Counting all new cases admitted to hospitals in a region has similar problems of completeness and of specifying an appropriate denominator. At present the optimal way to observe dementia incidence is to conduct a longitudinal study. That study would enroll a suitable number of certified, cognitively-intact, persons and reexamine them at regular time intervals to determine whether dementia had begun. As with a prevalence survey (described above), incidence measures require adequate screening and diagnostic measures to detect any new cases as accurately as possible. Some investigators institute complex sampling schemes (58,59) on the group of study subjects being followed. This is often done to limit investigator time and expense when the followed cohort is quite large. Such sampling will result in valid incidence estimates when completed carefully and correctly. However, sample case-weighting factors can lead to difficulties in interpretation when the observed number of cases is small within a sample stratum. Often, investigators prefer to avoid complex sampling, relying on a more straightforward screening exam of all subjects, followed by diagnostic evaluation of screen positives. Occasionally, investigators may simply examine everyone being followed, at appropriate intervals, to detect the new dementia cases.

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Jorm and Jolley (60) conducted a meta-analysis of dementia incidence based on 23 studies published between 1966 and 1997. The studies included must have had a population-based sample and usually a field survey for initial case finding. In addition, studies included were required to have reported age specific rates with sufficient information to estimate standard errors of the reported rates. Jorm and Jolley also noted the diagnostic criteria used to make diagnoses observing that studies which used DSM criteria (1) for dementia tended to have lower rates for “mild” dementia and higher incidence for “moderate” dementia. However, regarding AD incidence there was no significant difference between those using NINCDS/ADRDA criteria (9) and those using others. Age-specific incidence of dementia and AD, by five-year age group, was similar in European studies and those from the United States, but appeared somewhat lower in Asian studies. Aggregate age-specific rates for “moderate” dementia in Europe rose from 3.6 (95% confidence intervalZ1.3–9.6) per 1000 person-years in 65–69 year olds to 37.7 (17.1–83.0) in those aged 85–89 years. In the United States the same age groups showed rates per 1000 person-years of 2.4 (1.9–3.0) to 27.5 (23.7–32.0). East Asian studies of “mild” dementia only showed rates increasing from 3.5 (1.7–7.2) in the youngest group to 72.1 (48.0–108.2) among 85–89 year olds. For “mild” AD, European rates rose across the same age groups from 2.5 to 46.1 per 1000 person years compared with U.S. rates of 6.1 to 74.5 and East Asian rates of 0.7 to 39.7 cases per 1000 personyears. Generally speaking, the age- incidence curves showed similar exponential increase for both dementia and AD despite the apparent lower anchor points for East Asian studies. Jorm’s metaanalysis provided an important base of evidence against which to compare later studies. Recent studies have found relatively similar incidence of dementia and AD as those cited above. For example, Launer (61) conducted a combined analysis of data from the consortium of European dementia cohort studies. Launer calculated incidence rates for dementia of 2.5 per 1000 person-years in 65–69 age group and rising to 85.6 in the 90C age group. Similarly for AD, she showed the point estimate of incidence rate rising from 1.2 per 1000 person years to 63.5 per 1000 person-years across the same age groups. A number of U.S.-based cohort studies have also reported incidence estimates, several are cited below as examples. Kawas (10) observed AD incidence rates ranging from 1.3 to 64.8 per 1000-person years across approximately the same age groups. Ganguli (62) found incidence ranging from 2.1 to 31.1 across similar age groups but limiting to those subjects with a CDR(4) rating of O1.0. Kukull et al. (63) produced AD rates consistent with those above rising from 2.8 per 1000 person-years among 65–69 year olds to 41.9 in those aged 85–89. The Cache County study (64) presented their data in 3-year age groups it remains consistent with others, showing AD rising from 2.2. per 1000 personyears in 65–68 year olds to 73.3 among 87 to 89 year olds. Thus, incidence studies for dementia and AD appear to be showing relatively consistent occurrence patterns. However, it should be noted that these studies employed rather similar designs and methods, which may have helped in their calculation of rates. A number of other incidence studies (65–71) have presented results, which are relatively consistent with these. There is continuing interest of potential cross-cultural differences in the incidence of dementia and AD. Chandra (72) reported age standardized rates for incident AD for a cohort of subjects aged 65 or greater from India as compared to a similar one from the United States. Results showed much lower summary rates in India, 4.7 per 1000 person-years, compared to 17.5 in the U.S. comparison study. Hendrie et al. (73) conducted parallel population-based cohort studies, in the United States (African Americans), and in Nigeria (Yoruba); each included more than 2100 subjects followed for an average of five years. Age standardized AD incidence rates were lower for the Yoruba, 11.5 per 1000 person years (95% confidence interval: 9.6–13.5) as compared to 25.2 (14.0–36.4) among the African-American cohort. Although there was substantial loss to follow-up in both cohorts, that loss was not seen by the investigator as the basis of the rate difference. However, others have regarded the loss to follow-up difference as reason for substantial concern (74). Evans et al. (75) conducted an incidence study in a biracial urban community and found no increased risk due to race (similar numbers of whites and blacks were included in the study). The incidence rate rose from 14.5 per 1000 per year (8.9–20.1) for

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65 to 74 year olds up to 91.1 (73.6–109.0) in those over 85 years of age. Evans incidence figures appear to be somewhat higher than the studies reported above. They were presented as “cumulative incidence”; (cases per persons at risk per year; technically a risk), rather than as an “incidence density” rate (cases per person-years of observation). In addition, age groups had different bounds; this may have contributed to the apparently larger figures. Differences in incidence estimates can result from elements of the design and conduct of the study as well as the techniques of analysis used. Prospective cohort studies, which begin with substantial number of intact subjects (e.g., O2000) utilize sensitive and specific screening tests followed by complete diagnostic examination, minimize loss to follow-up, provide for both a relatively short follow-up interval and adequate accumulation of observation time generally can expect to achieve stable, reliable, and valid results. Potentially the biggest threat to validity for prospective cohort studies seeking to estimate incidence, is loss to follow-up. Loss to follow-up minimization procedures are integrated into the design of good cohort studies yet, loss to follow-up is essentially out of the direct control of the investigator. Because all such studies are likely to suffer some loss to follow-up and similar potential biases, it is incumbent upon the investigator to apply methods to determine what the potential magnitude and direction of this bias might be, and to report these effects along with the observed results. Sensitivity analysis is a term sometimes used for this process (76); various methods can be applied to achieve its needs. For example, incidence papers by Miech et al. (64), Hendrie et al. (73) and Kukull et al. (63) applied several sensitivity analysis techniques to help explain “what if” dropouts might have experienced dementia at a different rate from those who remained in the study, what then might be the effect on the observed incidence rates. The most stable incidence figures are reported for overall dementia and AD. Incidence studies for other conditions may be inherently unreliable because disease definitions are less uniformly applied or there may be competing clinical criteria for the condition. VaD may be an example (22,24,25,33) with its various definitions and their non-uniform clinical application. FTD (17,19) and Lewy body diseases (2,18,44,48,77,78) would likely have similar instabilities because the interpretation and understanding of these diagnoses, both clinically and pathologically appears to be changing rapidly. Recognition and diagnosis may improve with time and understanding although an antemortem, biological, diagnostic marker would provide the greatest contribution to this effort. Until such a marker becomes available, the next best results would likely be achieved through careful and comparable differential diagnosis in the context of a larger dementia study. Mild Cognitive Impairment Mild cognitive impairment embodies a variety of definitions and concepts (6,79–89). For epidemiology, the concept may be useful in that it may allow identification of very early signs and symptoms of eventual dementia. If diagnosed very accurately and very early, the specific dementias contained within the more generic bounds of mild cognitive impairment might be better studied for etiologic risk factor associations. Clinically, of course, early identification potentially increases the probability that interventions to delay disease progression or even to reverse the disease, may be more likely to succeed. Mild cognitive impairment among the elderly may include benign forgetfulness or may carry no memory deficit; it may include deficits in other cognitive domains that do not equate to dementia nor perhaps develop into it (6,83,87,89–91). Mild cognitive impairment may truly be the earliest stage of AD when defined specifically enough (80). Numerous studies have been conducted to date to describe the prevalence and incidence of this rather ill-defined entity or group of entities (82,86,88,92–101). Unfortunately, because of the diagnostic and theoretical heterogeneity involved, it is not yet possible to arrive at any reliable estimates of prevalence or incidence, nor describe the risk factors for progression to AD or other specific dementias. The AAN practice parameter (6) will likely aid researchers and clinicians alike to choose the definition most closely aligned with research questions and potential treatments until

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the consensus of definition prevails. Descriptive epidemiology can proceed but analytic epidemiology may depend on precise definitions in order to describe risk factor associations. ANALYTIC EPIDEMIOLOGY: PROGRESSION OF BASIC STUDY DESIGNS Three basic study designs are described below along with their advantages and disadvantages. These are, of course, not the only designs available for the conduct of analytic epidemiology, but they are the most frequently used. Hybrids of these designs, including “case-only” or “case-crossover” approaches and various sib-pair methods commonly used in genetic epidemiology will not be discussed here. Specific methods for the analysis of continuous, longitudinal data, such as random effects models and generalized estimating equations (102–104), which increasingly are becoming important for the evaluation of cognitive decline, are not discussed in the context of these basic designs. Cohort studies and clinical trials (105) with continuous outcomes will almost certainly need to apply these more sophisticated longitudinal methods to gain the most appropriate analysis. Case-Control Study Design From about 1980 until 1994 case-control designs dominated analytic epidemiology of dementia. Case-control studies are very powerful and economical as compared to other designs, but they have many possibilities for providing biased results. The basic design of a case-control study provides that well-defined “cases,” persons with the dementia of interest, should be selected along with “controls.” Controls are defined as persons similar to the cases, but without dementia (i.e., the disease being studied), who potentially would have been a part of the case series if they had contracted the disease. Cases should be selected as close to initial diagnosis as possible and control selection should be coincident in time. Early studies typically relied on available cases rather than newly diagnosed ones and may have preferentially selected longer lived, slower progressing ones in doing so. Further, the cases may have comprised a specific socio-demographic profile of persons who were likely to attend the clinic source. Control selection carries similar problems, but the basis of the problems is often more subtle. Controls who have agreed or volunteered to participate may have had better general health, higher education, or perhaps they were selected and agreed, because they were friends or relatives of persons with dementia. This could have caused the risk factor profile of the controls to be dependent upon their manner of selection and their status as controls. When the means or manner of case and control selection creates an association between disease status and the potential risk factors being studied, we have selection bias. Despite sophisticated statistical analysis and p-values less than 0.001, the observed risk factor associations would remain biased and spurious. Another pitfall for case control studies is in the differential (non-random) determination of risk factor exposure information. Was the quality or quantity of the information asked and obtained different between cases and controls? Was there “recall” bias because cases or controls, as a group could not remember enough detail, or were predisposed to recount too much detail about risk factor exposures? Differential determination of exposure because of disease status will cause an observed association to be biased and spurious despite statistical analysis and tiny p-values. In addition to these biases, case-control-based associations may be further biased or attenuated by diagnostic misclassification. Perhaps, in many early AD case control studies, a proportion of the cases could have been truly or predominantly Lewy body disease. If so, they would not have been clinically recognized as such at the time, because clinical criteria and pathological techniques were not available. If risk factors differed between AD and Lewy body disease the risk factor associations resulting from the older studies would be attenuated. A similar situation could arise for controls. Suppose clinical tests were insufficient to detect early dementia, or a study investigator relied only

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on the “problem list” from medical charts to define controls as not demented, again risk factor associations would likely be attenuated. Case control studies sound simple, but they can be difficult to do well, especially in the study of dementia. Despite their difficulties, case-control studies are a valid means of research. Cohort Study Designs In the early 1990s cohort studies began to approach center stage. Some studies were designed principally to examine aspects of dementia (e.g., 61–64,67,72,73,75,106–108) while in other instances, sub-studies focusing on dementia were added on to existing cohort studies initially designed to observe other diseases (e.g., 8,10,51,109–111). Because cohort studies in their simplest form begin with unaffected persons and follow them to observe disease incidence, they avoid many of the limitations common to case-control studies. Risk factor exposure information is obtained before disease onset, so recall bias is rarely a potential problem. Generally, one expects that errors or missing exposure information would be non-differential (random) between subjects who eventually become cases and those who remain intact at the time of comparison. Selection bias can be caused by differential disease associated drop out, after the study is begun, but it is not as often a problem in assembling and enrolling persons into the cohort. Cohort studies can also begin with a group, which was defined years in the past, and then traced up until present day, to find all cases as well as deaths, losses and non cases; this is a retrospective cohort approach. For either basic cohort design the critical limitations result from inadequate case ascertainment methods and excessive loss to follow-up. Dementia and AD are rather common diseases in the elderly so they are generally appropriate to be studied with a cohort design. The initial number of subjects must, however, be large enough to accrue sufficient cases during the study so that adequate power will be maintained for analysis. Loss, due to death and drop-out, also reduce the available pool substantially each year. Most active cohort studies of dementia begin with 2000 to 6000 subjects enrolled at baseline. If, for example, there were a stable, annual 1.5% risk of dementia and an additional 8.5% annual risk of death plus drop-out, we would expect that about 59% of the baseline enrollees would remain at risk by the end of 5 years. Cohort studies can also be used as a base to conduct internal case-control studies known as “nested case-control” or “case-cohort” studies. Cohort studies are expensive and time consuming, but they allow for direct observation of incidence and have fewer potential sources of bias than the usual case-control studies. Thus, the risk factor—dementia associations obtained from cohort study designs are viewed with less skepticism than those of case-control studies, other things being equal. Randomized Controlled Trials This study design is considered the Cadillac of study designs. Aspects of their design and analysis are well established in the dementia arena (105,112–114). The hallmark of this design is that subjects are randomly assigned to specific “treatments” by the investigator. These are experimental designs rather than the “observational” case-control and cohort study designs, discussed above. Typically, however, in the study of dementia, use of randomized controlled trials has been limited to either comparison of potential beneficial treatments, or evaluation of preventive (or delaying) factors. Obviously, randomizing subjects to a study treatment arm expected to increase the risk of dementia would be viewed as unethical by most institutional review boards. Randomized controlled trials, a.k.a. clinical trials, are recognized as having the least potential for bias and confounding, primarily because the randomization process is thought to equalize known and unknown confounding factors between the investigator-controlled treatment arms. Numerous trials have been conducted to observe the effects of particular substances on AD progression or outcome, e.g., (113,115–121). Fewer trails have focused or are focusing on primary prevention of dementia, e.g., (114,122–124). Thal (125) reviewed the status to trials to prevent or slow symptom onset as of

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2000. These trials involved hormones, growth factors, anti-amyloid, anti-inflammatory and antioxidant and other drugs and substances. Evidence from well-conducted primary prevention trials usually supercedes and replaces accumulated case-control and cohort study estimates of relative risk for any specific exposure. Critical Exposure Period Common to all the basic designs given above is the need to hypothesize, ascertain, or establish a critical period during which the potential exposure might exert its pathogenic or protective effect relative to the onset of disease. Exposures that occur after disease onset cannot prevent disease; they can, however, become the subject of treatment trials. The effect of a specific exposure factor may only persist in its ability to influence disease onset, for a limited time. Those exposures that occur too early or too late relative to their active time window or to disease pathogenesis, may show a statistical association with disease onset, but the association will be spurious and coincidental. The critical period also may be exposure specific rather than disease specific. For example, non-steroidal anti-inflammatory drugs taken regularly during a person’s third decade of life may have no ability to impact onset of AD in the eighth decade, while other exposures occurring in the third decade may be important (hypothetically). The investigator who studies etiologic exposure—disease associations must carefully evaluate the potential mechanisms by which a hypothesized exposure may promote or prevent disease, in order also, to hypothesize a plausible critical period for that exposure. Generally, too little is known about the pathogenesis of specific dementias, the action of particular drugs and other exposures (e.g., genetic, socio-demographic, occupational, environmental), to establish a particular critical period, a priori, with certainty. Thus, characterizing the potential critical exposure period should be included in the objectives as well as the design of etiologic epidemiologic studies. GENES AND ALZHEIMER’S DISEASE: EPIDEMIOLOGIC CONTEXT The study of genes that cause or influence AD has generated substantial research in recent years. Similar genetic research is progressing rapidly in other less common dementias and neurodegenerative conditions (e.g., FTD, DLB and Parkinson’s disease). The discussion below will describe briefly the basic genetic findings for AD we will then discuss the implications of genetic findings and methods for the epidemiologic study of AD. A large number of excellent reviews exist for AD genetics (126–131). The genetics of AD is covered in greater detail by Goate in chapter 7. Causal genes for AD were discovered with great expectations. Mutations in the APP gene were observed to cause very rare forms of the disease (132–136). Other APP mutations were found to cause hereditary cerebral hemorrhage with amyloidosis (137). The APP gene is located on chromosome 21. Initially, researchers speculated that the gene for AD might be APP because of the clinical and pathological observation that Down’s syndrome persons almost invariably develop pathological AD. However, it was found rather soon that the answer would not be that simple, no apparent duplications of APP were found in familial AD cases (138,139). Early genetic studies focused on large families who had many affected members. The affected members usually had disease onset at a very early age relative to the ordinary occurrence of AD; most were age 30 to 50 years when the disease struck. The early-onset familial form of the disease was thought an appropriate candidate for study because it might provide clues to the later onset, more common form. In 1995, specific genes were found on chromosomes 14q and 1q, in which many mutations were found to cause AD. These genes were named PS1 and PS2. Within the “familial” AD form, APP, PS1, and PS2 were found to account for approximately 50% of the cases; genes have not yet

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been found that might explain the remaining early onset familial cases. Despite this substantial breakthrough, the “familial” form of the disease (attributed to APP, PS1, PS2) is said to comprise only about 2% of the total AD incidence (140). The remaining 98% of AD received a boost when a relatively strong association was found between specific alleles of the apolipoprotein E gene,19q (APOE) (141,142). Of the common allelic forms: e2, e3, e4; the e4 allele carried an associated increased risk of AD while the e2 allele might be associated with decreased risk. APOE4 was not a causal gene, like APP, PS1 and PS2. Persons with 1 or 2 copies of APOE4 may not get AD and similarly, persons without APOE4 are still at-risk for AD. Meyers (126) estimates that 42% to 68% of late-onset AD patients do not have an APOE4 allele; while persons with one copy of APOE4 are at about a 3-fold increased risk and those with 2 copies are at about 8-fold increased risk of AD. About 2% of the U.S. population are APOE4 homozygotes (140) while the e3/e4 plus e4/e4 genotypes are present in about 50% of AD cases (140); this is relatively consistent with Myers and Goate (126) though ages of the cases may account for some of the difference. Therefore, APOE behaves very much like a moderately strong epidemiologic risk factor. Additional complexities were described by Farrer et al. (143) in a large meta analysis of existing data sets. The effect of APOE4 was also associated with age; the strength of the association began to decrease with age after about age 70. Further, the strength of the APOE4 association was lower in African-Americans and Hispanics, and somewhat greater among Japanese. APOE alleles are also associated with dyslipidemia and coronary heart disease. The e4 allele is associated with increased LDL cholesterol and significantly increased odds of coronary heart disease (after adjusting for hypertension, smoking, obesity, diabetes, HDL and LDL cholesterol) (140). The e2 allele is associated with elevated triglyceride levels. The association with heart disease raises the possibility of selection bias, if subjects are selected for an AD study, differentially with respect to heart disease. That is, if subjects are differentially eliminated (by exclusion, refusal or mortality) from the case group or from the comparison group because of factors related to heart disease, it may cause the estimated association between APOE and AD to be biased. The universality and consistency of the association between APOE and AD indicate that APOE genotype must be evaluated as a potential confounding factor or effect modifier whenever assessing associations between other potential risk factors and AD in epidemiologic studies. Failure to do so will likely lead to spurious conclusions. The association with heart disease noted with APOE should raise awareness that, in an epidemiologic or genetic association study, candidate genes cannot always be relied on to be unbiased by selection factors, as some have indicated (144). Associations between candidate genes and dementia could be the result of selection bias and should be evaluated for such an occurrence. Establishing a conservative Type 1 error level (which addresses chance alone) will have no effect on the potential bias. While the association between APOE and AD was found primarily through the application of case-control methods, Bertram et al. (145) suggest that family-based, sibship disequilibrium tests may provide a more consistent, perhaps more valid, method to determine candidate gene associations. Finckh (146) reports that of 113 candidate genes or loci initially reported for late onset AD as of 2003, few if any have been consistently replicated. Reason for this failure are unclear, but they may include problems of multiple comparisons and study designs in addition to biological considerations of how a particular gene product may be involved in disease pathogenesis. Stricter criteria for proposing candidate genes should include (according to Finckh) “disease linkage of the chromosomal region harboring the candidate gene,” “biochemical evidence of involvement of the candidate gene product in pathogenesis,” “presence of functional polymorphisms,” “several intragenic SNPs suitable for construction of frequent haplotypes” (146). One example of conflicting reports of association with candidate gene from skilled and careful investigators is the unfortunate controversy generated by alpha-2 macroglobulin. Despite fulfilling many of the proposed criteria (above), alpha-2 macroglobulin has shown controversial and conflicting reports of association. Following its initial report by Blacker et al. (147), other

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investigators failed to replicate the findings even with other overlapping samples from the same NIMH sample base (148–152). While type1 or type 2 errors may have been acting in either of the opposing results, or case-control designs versus sib-pair designs could have accounted for some of the difference in reports, it may also point toward a potential selection bias that was unrecognized by the investigators. Whether imposition of the stricter criteria proposed by Finkh (146) might have avoided the controversy, is unclear. It remains to be seen whether alpha-2 macroglobulin gene will ultimately be seen to play a role in AD, though the preponderance of the evidence at this time does not favor it. As for the outcome of the other 112 candidate genes proposed so far, a pessimist likely would not be disappointed. A different approach to examining genetic factors, which may influence dementia, AD, or other conditions, is through the study of biotransformation genes that metabolize xenobiotic substances (e.g., drugs, toxins) to which an individual might be exposed. This sort of geneenvironment interaction supposes that the xenobiotic substance may act to cause disease by virtue of the way it is processed in the body, through oxidative stress or failure to neutralize the toxin or possibly by other means. The family of cytochrome P-450 genes is involved in this sort of metabolism and could be important targets for research (153). The field of pharmacogenomics is expanding rapidly; it is based on identifying genetic factors or profiles associated with drug metabolism. Research into AD and other disease areas is growing rapidly (154–158). In the epidemiologic context, polymorphic or mutated biotransformation genes would be evaluated as effect modifiers of an environmental exposure. They would probably not be viewed as a direct cause of disease, as APP, PS1 or PS2 are. Adequate ascertainment of the exposure would face the usual problems of validity and accuracy as in most epidemiologic studies. THE SEARCH FOR CAUSAL FACTORS Factors associated with the onset or prevention of disease are central to epidemiologic research. Descriptive studies of the distribution of disease in persons, place, and time provide clues upon which to base causal hypotheses. Examination of the incidence data presented earlier shows a universal and strong association between increasing age and increasing incidence of dementia and AD. For AD, another risk factor that is widely accepted is APOE genotype. Family history of AD is often noted to be more common among AD cases than among control subjects, although whether this is due to selection factors or to genetic constitution is unclear. Little is known concerning environmental risk factors for Lewy body disease or FTD; few have studied these diseases in an epidemiologic context. In contrast, many risk factors for AD have been evaluated but few strong associations have been found that are temporally appropriate, biologically plausible, consistent/ reproducible, and where the strength of association is dependent on risk factor dose. Study designs, discussed earlier, vary with their ability to obtain accurate pre-disease exposure information. Casecontrol studies, specifically may be affected by the subject’s (or proxy respondent’s) ability to accurately recall past events or conditions; they may also be hampered by investigator time sequence errors (e.g., measuring the current serum cholesterol in an AD case and assuming it would have been the same prior to disease onset). Cohort designs generally tend to have unbiased reporting of exposure history, but exposure history quality varies with the factor in question and whether measurements, records, or self-report are the basis for the information. Cohort studies sometimes also ignore time-dependent exposures in their analyses. Such an oversight can lead to inappropriate conclusions, if there is a time-dependent relationship between exposure and disease. Except in situations where there is large loss to follow-up, evidence based on cohort studies generally is held in higher regard than that of case-control studies. History of head trauma has been a perennial favorite of AD risk factor studies, yet controversy and inconsistency still remain. Many case-control studies have reported increased risk of AD associated with head trauma (usually with loss of consciousness) for example, (159–165),

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while others have reported no increased risk (166,167). Cohort studies generally reported no significant association between head trauma and AD (168–171), although some do report an increased risk (172,173), as does a retrospective cohort study (174) with substantial loss to followup. Large cohort studies with modest loss to follow-up should provide the more valid, less biased, evidence for the association. Based primarily on design, one could conclude that a causal association between head injury and AD may be unlikely. Regardless, these findings are likely to have little impact on public health intervention to prevent head injury. Head injury is viewed as undesirable and a target for prevention because of its immediate dangers. Dietary factors are currently of great interest as factors that might influence the onset of AD or other dementias. Anti-oxidants in the diet or taken in supplements, if preventive, could reduce AD or dementia incidence. Englehart et al. (175), in the Rotterdam study, found that higher intake (i.e., greater than one standard deviation above the population mean) of vitamins C and E was associated with significantly decreased incidence of AD. Similarly, Morris et al. (176) found reported increased intake of vitamin E from foods but not from supplements appeared to decrease the risk of AD modestly, in analysis of data from a U.S.-based cohort study. However, in the Morris study, the association appeared to be present primarily in those subjects with an APOE4 genotype. In a similar cohort study (177), the investigators found no significant association between beta carotene or vitamin C or vitamin E, either from supplements or from foods, with the risk of AD. High flavonoid intake (178), and frequent fish consumption (179) were associated with lower risk of AD in French cohort studies; however the Rotterdam study found no significant association between high fat or cholesterol intake and the incidence of dementia or AD. However, high calorie and fat intake in the presence of APOE4 was associated with about a 2-fold increased risk for AD (180). The information presented above was derived from recent and relatively large cohort studies aimed at dementia and AD, but still there is some contradiction in their findings. This may be an area where more precise measurement of the exposure, perhaps through an anti-oxidant biomarker, would reduce the apparent confusion. Higher plasma homocysteine level was reported to be associated with increased risk of AD (181) in the Framingham study. In that study, levels of homocysteine at baseline that were greater than 1 standard deviation above the mean led to a 1.6- to 1.8-fold increase in risk. Homosysteine level has for some time been recognized as a cardiovascular disease risk factor, and thus vascular disease could be somehow involved in AD (31,182–184). Supplementation with folic acid, vitamin B6 and B12 have been shown to lower homocysteine levels, raising the potential for relatively easy intervention. Genetic defects in the methylenetetrahydofolate reductase gene do not appear to be differentially present among persons with high homocysteine (185,186) indicating that dietary change or supplementation may be a reasonable strategy for prevention should the association be established as a truly causal one. Medications and other pharmacologic agents may play a role in the prevention or promotion of AD. Several such agents have been under investigation in observational studies, usually with a wide range of relative risk estimates. Non-steroidal anti-inflammatory drugs (NSAID) (187–191) have been observed to exert a potential protective effect for the onset of AD. The magnitude of the association between NSAIDs and AD varies across studies according to the designs and methods used. Critical variations in methods are primarily those related to exposure determination. Current and past use were determined by self- or proxy-report, as well as by medical record review, or by pharmacy records. A detailed review of NSAIDs association studies is given by in’t Veld (192). Over-the-counter availability and episodic use, in addition to the possibility of “confounding by indication” make even the risk estimates based on the best data difficult to interpret. However, generally NSAIDs relative risk point estimates are !1.0 indicating a potential lower incidence among those who have taken the drug. The effect appears most protective among those who have taken NSAIDs more than 2 years (187). Therapeutic effects of NSAIDs on persons who already have been diagnosed with AD show no difference in cognitive decline between those treated or not

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treated with the drugs (116). A primary prevention trial to further elucidate the effects of NSAIDs on the development of AD is underway (123). History of hormone replacement therapy (HRT) among postmenopausal women, specifically related to estrogens, has been shown to exhibit relative risk estimates !1.0 for AD (i.e., protective) by a substantial number of epidemiological studies (192–194). Although selection factors (e.g., socioeconomic status, education) may have influenced those results, the preponderance of the evidence, mostly from case-control studies, appeared to support the conclusion of a protective effect for HRT. Treatment trials with HRT, however, did not appear to modify cognitive decline or the course of AD (118,192). Cardiovascular problems and stroke began to be seen as significantly more common among HRT users (195). Then, recently the Women’s Health Initiative Memory Study (WHIMS) published results from a randomized, double-blind, placebo-controlled trial showing an increased risk of dementia and AD among users of “estrogen plus progestin” (124). In that trial, 4235 women, free of dementia, age 65 or older were randomized to receive estrogen plus progestin or placebo. The hazard ratio for probable dementia was 2.05 (95% confidence interval: 1.21–3.48). This indicates that women taking estrogen plus progestin were at two-fold increased risk of dementia. Observational study evidence did not predict this outcome. Although the trial did not address risk of HRT among women younger than 65, it may be reasonable to generalize the WHIMS study findings to that group and to those women taking estrogen replacement without the addition of progestin. The Rotterdam study (196), a large cohort study, presented results at about the same time as the WHIMS trial was published, showing an elevated risk of dementia for women with higher endogenous estradiol levels. That finding appears to add further support to the WHIMS conclusion. More careful design and methods for earlier observational studies might have provided more conjecture about the value of HRT before the WHIMS study was undertaken, but that is difficult to tell. The reversal of findings, uncovering a rather substantial increased risk associated with HRT, draws attention not only for the need to conduct more careful observational studies but to mount randomized trials of potential protective factors whenever feasible. Lipid lowering agents and HMG CoA reductase inhibitors (statins) have been hypothesized to decrease incidence of dementia. Recent studies have shown results consistent with a potential decreased risk of dementia associated with those drugs (192,197,198). However, Scott and Laake (199,200) caution that conclusion of potential benefit regarding dementia and AD associated with statin use may be premature, because no randomized trials have been completed at this time. Statins are a relatively new drug with rapidly increasing use. This pattern of use may indicate that considering statin use as a time-dependent exposure may be a more appropriate means of analysis for cohort studies, rather than cumulative, ever-never classification of exposure. Statins may also have wider ranging effects than is typified by their reduction of cholesterol levels (201,202). Many other pharmacologic agents have been reviewed (192) including a potential protective effect associated with anti-hypertensive agents and a potential increased risk associated with benzodiazepines (203). The study of drug exposures potentially associated with onset of specific dementias is just beginning to be developed. As automated pharmacy databases become more commonplace, accurate and complete exposure determination will become easier for investigators and the associations developed will likely become more valid. The area of pharmacogenomics is also developing rapidly; it will likely identify further genetic risk factors for test. Light to moderate alcohol use has been shown to be associated with decreased risk of dementia and AD in a number of studies, (for example 204–208). However, determination of exposure to this factor probably suffers from political correctness of the response in an interview. This form of recall bias could be acting primarily in case-control studies where a case-proxy respondent may deny or underestimate the case’s alcohol more than a control subject might. In a cohort study, nondifferential (random) under-reporting could bias findings toward the null. Heavy use of alcohol is rather consistently associated with increased risk of dementia (167,206).

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Smoking was initially described in many case-control studies to exert a protective effect against AD. Rationale for that effect revolved around up-regulation of nicotinic receptors in the brain. Selection factors, as well as exposure misclassification, may have been pervasive causing the case control results to have been biased, however (209,210). Effects observed in cohort studies (e.g., 61,106,168,211,212) generally favoring an increased risk of dementia and AD associated with smoking may be more valid. The potential link between AD and vascular disease recognized by several cohort studies above may influence our search for other potentially common risk factors. Occupation and education are difficult to separate. One means to separate them is to identify particular or potentially toxic exposures related to particular occupations; for example, possible increased risk associated with pesticides, magnetic fields and solvents (213–218). Other investigators studying, group occupations by socioeconomic status and increased risk for AD associated with manual or less-skilled occupational levels (167,219–224). Educational level may lead to occupation and socioeconomic level, yet may still influence dementia incidence independently. Further, the effect of education may act differently in women than in men (10,61,62,225–227). Education may also contribute to a person’s ability to score well on a dementia-screening test, postponing early detection. One study observed that after adjusting for baseline screening test score the association between dementia and education was essentially null (63). In a recent twin study, educational attainment was found to be unrelated to dementia (228). Whether low education is truly a risk factor for AD or dementia within most developed countries, or whether it is the manifestation of socioeconomic and early life factors (229), is a subject for further research. Certainly, it appears that education should be treated as a potential confounding factor when assessing the strength of association between dementia and other exposures. Further occupational studies of specific exposure groups could provide sufficient power to evaluate exposures, which are relatively rare in a population sample. The array of potential exposures to be tested for their associations with dementia continues to grow. Drugs and medications, or associations with vascular disease and hypertension (122) along with a close eye to genetics will provide interesting areas for further risk factor research. Better recognition of dementia subtypes may influence risk factor studies based on mechanisms of tau, synuclein, or Ab aggregation (15). Epidemiologic identification of strong, consistent risk factors has a mixed record to date. Many of the risk factors discussed above are weak and inconsistent; none to date seems to compare with the current strength and consistency of APOE genotype (despite our limited knowledge of its contribution to the disease process). There has been much risk factor research activity as evidenced by the studies cited above and others not discussed here. The research needs to be completed; unfortunately, we have been unlucky in identifying targets for possible intervention. Discussion of potential biomarkers of disease is found in Galasko Chapter 8. Diagnostic and etiologic heterogeneity could be working to mask important associations by biasing observed associations toward the null. Differential or non-differential exposure misclassification coupled with other bias due to selection can influence risk factor estimates, as we have seen for HRT and possibly for smoking and other exposures. Continuing vigilance to promote the best study designs and analytic methods will help new risk factor investigations succeed. Close interaction with basic and clinical scientists will help us recognize innovative exposures to test. Careful, complete, and objective data collection will help us produce valid results. REFERENCES 1. American Psychiatric Association. Task Force on DSM-IV. In: Diagnostic and Statistical Manual of Mental Disorders: DSM-IV, 4th ed. Washington, D.C.: American Psychiatric Association, 1994:123–163. 2. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56:1143–1153.

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3 Healthy Brain Aging Joseph F. Quinn Oregon Health and Science University, Portland, Oregon, U.S.A.

Jeffrey Kaye Department of Neurology, Oregon Health Science University, Portland, Oregon, U.S.A.

Medical textbooks do not consider including chapters on “the mentally healthy” or on “mechanisms of health.” Yet virtually every textbook on neurodegenerative dementia includes an obligatory chapter on “healthy brain aging.” The goal may be to set healthy brain aging apart from dementia, but it remains to be determined whether these two states comprise a dichotomy or a continuum. The aging process itself is the most potent risk factor for most common dementing illness, and it has been suggested (but not proven) that dementia may be an inevitable consequence of aging. The definition of healthy brain aging is problematic. For example, a 90 year old has to perform only half as well as a 20 year old on some portions of the standard intelligence test to be considered “average” (1). Neuroradiologists are notoriously subjective about grading cerebral atrophy as “age-appropriate,” with the finding “normal for age” more closely linked to the age of the radiologist than the age of the patient. Even some pathologic diagnostic schemes call for ageadjustment, such that brain histology findings sufficient for a diagnosis of Alzheimer’s disease in a 50 year old may be considered “normal” in a 90 year old (2). Since an operational definition is unavoidable, “healthy brain aging” will be defined here as aging in the absence of dementia. The discussion will not exclude the phenomenon of an isolated memory deficit insufficient to warrant a diagnosis of dementia, now frequently called “mild cognitive impairment” (3). We still are left with the definition of aging. Many studies of aging have focused on subjects over the age of 65, a relatively arbitrary age that dates to a fiscally responsible criteria for retirement benefits in 1889, when the average life expectancy was 45 years (4). As large numbers of people live past age 75 and even 85, reliance on findings from aging studies in samples with a mean age of 70 years becomes tenuous. In keeping with the literature on aging, this chapter will describe the findings of a variety of aging studies describing subjects over the age of 65, recognizing that the “young old” aged 65–75 may differ in important ways from the “oldest old,” over the age of 85. FUNCTIONAL CHANGES SEEN IN HEALTHY BRAIN AGING—NONCOGNITIVE A variety of neurologic signs that would be considered “pathologic” in young patients emerge during healthy aging. The pupils become more miotic and less reactive to light, and up-gaze and 41

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convergence are predictably impaired (5). Remarkably, the decline of up-gaze with aging is a gradually progressive phenomenon, beginning as early as the third decade (6). Smooth ocular pursuit suffers “saccadic breakdown” (7) during healthy aging. A variety of causes converge to impair the senses of vision, hearing, and smell. Each of these cranial nerve findings has been described even in populations rigorously selected for good health (8,9). The motor system is also affected in healthy aging, with diminished power (especially in proximal lower extremities) and diminished bulk (especially in hands). These changes can clearly be modified by physical exercise, even into the tenth decade, as shown in an often-cited study of physical therapy in nonagenarians (10). Tremor increases in prevalence with age, although it is a matter of semantics whether this can be considered “healthy” brain aging (11,12). Parkinsonism and Parkinson’s disease are also age-dependent phenomenon (13), although again these features are not typically accepted as part of healthy aging (Table 1). Sensory nerve function, particularly distal vibratory sensation, is frequently impaired in the elderly (5), even those rigorously selected to exclude neurologic disease (8). Distal deep tendon reflexes (ankle jerks) are often depressed (14,15). Bladder function is frequently impaired, although only a portion of bladder dysfunction is “neurologic” in etiology (16). Gait and balance impairment are very common with aging (17,18), sometimes characterized as “Little’s disease”: a little peripheral neuropathy, a little cerebrovascular disease, a little Parkinsonism, etc. However, it is striking how frequently stance is impaired in healthy subjects over the age of 85 years with no clear-cut pathology at all. Even the healthiest 85 year olds have trouble standing on one foot (9). It is important to emphasize, however, that a number of treatable entities are in the differential diagnosis of geriatric patients with a functionally significant gait disorder (18). One case series found that the prevalence of treatable etiologies of ataxia in elderly patients was 25% (17), making the point that it is worthwhile to evaluate ataxic older adults to potentially uncover correctable factors. The re-emergence of “frontal release signs” during normal aging is a matter of some debate. While there is general agreement that an extensor plantar response (Babinski sign) is not expected in the absence of pathology in the elderly, the palmomental, snout, and glabellar disinhibition reflex have been reported to occur in 20–25% of elderly people (19–21). Other studies have argued that “rigorous exclusion” of subjects with neurodegenerative disease and stroke results in a much lower Table 1 Noncognitive Changes with Healthy Aging Function

Change with aging

Clinical implication

Olfaction Visual acuity Up-gaze Convergence Muscle strength

Impaired Impaired Impaired Impaired Reduced, especially hip flexors Often increased Diminished Increases with age Diminished or absent Diminished vibratory and proprioceptive Impaired

May interfere with appetite or nutrition May impair driving, reading. May compound gait deficits None known None known Associated with falls, a major cause of morbidity in geriatrics. Can be modified with strength training None known May interfere with time-dependent activities Essential tremor can be disabling None known, in the absence of other evidence of peripheral neuropathy Probably contributes to balance difficulties

Muscle tone Motor speed Tremor Deep tendon reflexes Sensation

Balance

Increased falls, diminished mobility

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prevalence of these signs (8). In the Oregon Brain Aging Study of optimally healthy subjects over the age of 85, a positive palmomental reflex was seen in 8.8% of subjects, abnormal glabellar reflex in 20.6%, and snout reflex in 44% (9). FUNCTIONAL CHANGES SEEN IN HEALTHY BRAIN AGING—COGNITIVE The aging changes that are often the most distressing are those that affect mentation. The tendency of the elderly to complain about their memory rather than other mental function calls to mind Benjamin Franklin’s observation on mental function and insight in the population at large: “Many complain of their memory; few of their judgment.” In fact, immediate memory, exemplified by digit span or keeping in mind a phone number while dialing, shows minimal change with healthy aging (22–25). Short-term memory, exemplified by free recall of a list of words or stories, begins to decline as early as the sixth decade (26–30). Long-term or remote memory is relatively resistant to the effects of aging. The cognitive mechanism underlying age-associated memory failure is actively debated and may have several components (31). One component may be the mental function that most clearly declines with even healthy aging: the speed of mental processing (32). Simple reaction times are slowed in the elderly, and comparable degrees of slowing of responses measured at the jaw, finger, and foot exclude the peripheral nervous system as the locus of the slowing (33). An additional degree of slowing is noted with choice reaction times, presumably because of the greater degree of mental processing compared to simple reaction times (Table 2) (34). Slowing is also seen in perception, as illustrated in experiments utilizing “backward masking.” This refers to the abolition of perception of a brief visual stimulus by a second visual stimulus. The ability of the second stimulus to interfere with perception of the first is dependent on the latency between the two. The inter-stimulus interval that produces “backward masking” increases 20–70% from the third to the seventh decade, suggesting that younger subjects “finish perceiving” the stimulus more quickly than their older counterparts (35–38). Table 2 Cognitive Changes with Healthy Brain Aging Function

Change with aging

Clinical significance

Memory

Working memory

Preserved immediate and long-term memory with age; short-term memory begins to decline in sixth decade Impaired

Executive function

Possibly impaired

Speed of information processing

Perception time and reaction time slow with age

Attention

Generally preserved into eighth decade

Visuospatial function

Decline in both perceptual and constructional abilities Syntax and word usage are preserved while naming and verbal fluency begin to decline in the eight decade

Deficits are not functionally significant in the absence of frank dementia Probably contributes to the decline in short-term memory with age Possibly contributes to decline in short-term memory with age Pervasive effects on neuropsychologic results, but does not interfere with daily functioning Marked attention impairments are pathologic Deficits on testing are not typically functionally significant Language problems beyond mild naming difficulty should be recognized as evidence of pathology

Language

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The pervasive effect of slowed information processing has been invoked to explain the age associated decline in multiple cognitive domains, because the slowing does not appear to be domain-specific (39). An analysis of the age-dependent variance in a variety of cognitive tests also supports a pervasive effect of mental speed, as much of the age-dependent variance can be explained by variation in the speed of information processing (40). Changes in other cognitive domains during healthy aging have also been described that may be independent of speed of processing. For example, the ability to simultaneously store and manipulate information, or “working memory,” declines with aging (41), and has been proposed as an alternative “pervasive influence” on cognition (42). However, it may be more appropriate to consider working memory and psychomotor speed as complementary rather than alternative mechanisms in cognitive aging, since a role for each is suggested by studies that examine both processes (42). Executive function, or the group of cognitive activities that control and integrate other cognitive actions (43), also changes during healthy aging. Examples of executive function include dealing with novelty, planning and implementing strategies, monitoring performance, adjusting responses to feedback, and inhibiting task-irrelevant information (43). Although it is controversial whether changes in executive function “explain” cognitive aging, older subjects typically perform less well than younger subjects on tests of executive function (44,45). Performance on visuospatial tasks declines with age in a manner that is not explained by changes in psychomotor slowing or working memory. Even with time constraints removed, older subjects performed less well on block design and object assembly tests from the Wechsler Adult Intelligence Scale (46). Figure drawing also declines in the elderly (47). The problem is not confined to visuospatial construction; visuospatial perception is impaired as well. Older subjects have more difficulty identifying incomplete figures (48), recognizing embedded figures (49), judging the adequacy of cube drawings (47), or matching pattern designs (48). Contrary to popular belief, age-associated visual perception and construction deficits are even greater than those observed for verbal memory tasks. The good news, however, is that some mental functions are preserved with age. Sustained and selective attention, for example, are preserved into the eighth or ninth decade (50). Most aspects of language function are also preserved, including phonological characteristics, lexical decisions (51,52), and syntactic knowledge (53,54). Some difficulty with naming may appear in the eighth decade (55,27), however, and verbal fluency also declines after the age of 70 years (27). STRUCTURAL CHANGES SEEN IN HEALTHY BRAIN AGING—PATHOLOGY Although the structural correlates of the noncognitive aspects of healthy brain aging are not well established, aging of subcortical brain structures is characterized by definite accumulation of abnormal material, and probable neuronal loss. “Corpora amylacea,” or “starchy bodies,” generally are considered to form within astrocytes. They become more numerous with age and are found in virtually all individuals over the age of 40, most abundantly in the dorsal columns of the spinal cord and in the basal ganglia (56). Lipofuscin, a “wear and tear” pigment derived from lysosomes, accumulates in a variety of neuronal populations, including the inferior olivary nuclei, dorsal root ganglia, and anterior horn cells of the spinal cord in childhood, and appears later in the dentate nuclei of the cerebellum. The Purkinje cells of the cerebellum are spared of lipofuscin even into late adult life, while large neurons in the cerebral cortex predictably accumulate lipofuscin at this stage of healthy aging (57). Neuromelanin is derived from the peroxidation of biogenic amines in lipofuscin granules, and although present in the locus coeruleus and substantia nigra from childhood, continues to accumulate in these brainstem nuclei until about 60 years of age (58). After that point, pigmentation of these nuclei declines progressively. Anterior horn motor neurons of the

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spinal cord also sometimes develop “colloid inclusions” (58). None of these age-dependent inclusions, however, are thought to be functionally significant, and none have been associated with any specific disease state. In contrast, Lewy bodies in the substantia nigra are associated with Parkinson’s disease, but are often found in brains from healthy aged subjects. The prevalence of incidental Lewy bodies in substantia nigra and locus ceruleus is as high as 7–10% of individuals over age 60 (58,59). Neuronal loss has also been described in a number of sub-cortical nuclei, including substantia nigra, locus ceruleus, putamen, and thalamus (58), although it is important to realize that neuronal counts are prone to methodologic problems. The pathologic basis for cognitive changes in healthy aging is not established, but candidate correlates include changes seen in cerebral white matter, cerebral gray matter, and the limbic system. Studies of post-mortem brain tissue suggests that between age 20 and 50, most brain tissue loss is in the cortical gray matter, whereas after age 50 white matter loss predominates (60). One study concluded that trends to lower white matter volume in aged brains is due to loss of small diameter myelinated fibers (61). At least one population-based study has found an association between dementia and white matter pallor (59). Alterations in cerebral white matter, however, also are commonly observed in healthy elderly individuals, but ironically are often more evident on neuroimaging studies than on direct gross examination of brain tissue. Microscopic examination of white matter that appears abnormal on MRI scanning has shed some light on this subject. This issue will be described at greater length in the next section. As in the subcortical structures, neuronal loss has been described in the limbic system and cerebral cortex of healthy aging subjects, but methodologic questions have been raised about many of these results and consensus has not been reached. Recent review articles (58) and textbooks (62,63) refer to loss of cortical neurons in layers II and IV in superior frontal, superior temporal, and precentral regions, with little change in the postcentral region, during healthy aging. However, application of stereologic methods have shown a loss of only 10% of total cortical neurons between age 20 and 90 (64). Stereological assessment also failed to reveal a loss of temporal cortex neurons between age 60 and 90 in healthy individuals (65). The latter study also examined the hippocampus, which has a clearly established role in memory and AD, and the entorhinal cortex, which provides the major neuronal input to the hippocampus. Although there was evidence of some entorhinal neurofibrillary tangle formation, there was no evidence of neuronal loss in any layer of the entorhinal cortex in the healthy elderly (66). Studies generally agree that healthy aging is associated with neuron loss in the subiculum of the hippocampus (67,68), and some have noted neuron loss in the dentate gyrus (67). There are some discrepancies with regard to the CA1 sector of the hippocampus, with neuronal loss reported in some (68) but not other (67,68) studies. One study including 1200 normal brains found that hippocampal neuronal change was associated with healthy aging while neocortical change is unique to Alzheimer’s disease (69). One study has even suggested that neuronal loss in the entorhinal cortex distinguishes mild cognitive impairment from healthy aging, but is comparable between mild cognitive impairment and AD (70). The studies agree, however, that AD-related neuronal loss in the entorhinal cortex and in CA1 is much more pronounced than that seen in healthy aging (67,68), supporting a dichotomous view of healthy brain aging and dementia (Fig. 1). Neurofibrillary tangles, which consist of intraneuronal accumulations of abnormal filamentous material, are a pathologic hallmark of Alzheimer’s disease but are also seen in healthy aging. In healthy aging, the neurofibrillary tangles are confined to the entorhinal cortex and possibly hippocampus, in contrast to the widespread cortical distribution seen in Alzheimer’s (71). It appears that most human beings over the age of 55 have neurofibrillary tangles in Layer II of entorhinal cortex (72), and that the topographic distribution of neurofibrillary tangles is quite predictable in both healthy aging and Alzheimer’s disease (71–73). The “Braak and Braak” staging system, in

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Figure 1 Hippocampal volumes in a healthy 65-year-old male (A), a healthy 97-year-old male (B), and a 77-year-old male with Alzheimer’s disease (C). The images are coronal T1 weighted MRI scans. The hippocampus and surrounding temporal horn of the lateral ventricle is traced in each figure.

which stages I and II are neurologically normal with neurofibrillary tangles confined to these limited areas, places healthy brain aging on a continuum with Alzheimer’s disease. Cerebral amyloidosis is also very common in healthy aging. Small argyrophilic particles with a mean diameter of 50–60 microns were first reported in the cerebral cortex of elderly patients (74) years before Alois Alzheimer associated these amyloid plaques with the disease that now bears his name. A variety of plaque types have been described, including “diffuse plaques,” (which do not contain any degenerating neuronal elements), “neuritic plaques” (which contain dystrophic neurites), and “cored” or “burnt out” plaques, (which consist of a compact mass of amyloid without prominent neuritic dystrophy). Most amyloid plaques in a healthy aging brain are the “diffuse” type, and the pathologic criteria for a diagnosis of Alzheimer’s disease are consequently focused on neuritic plaques. Even so, the neuritic plaque-based criteria for pathologic diagnosis are adjusted for age (2). A neuritic plaque burden sufficient for a diagnosis of Alzheimer’s disease in a young person is nondiagnostic in an older individual. Despite the age adjustment, neuropathologists encounter brains from non-demented individuals with pathology sufficient to meet diagnostic criteria for Alzheimer’s. The usual response is to blame either the pathologists or the clinicians: The patient was not examined carefully enough, the examination was not close enough to the time of death to expect any clinical-pathological correlation, or the pathologic criteria were not rigorous enough. However, recent reports have rebutted each of these arguments with cases of subjects who meet rigorous pathologic criteria for Alzheimer’s despite detailed neuropsychological examination close to the time of death. For example, Katzman et al. described 10 healthy aging subjects with abundant neuritic plaques and preserved mental status (75). The Washington University Memory and Aging Project reported finding abundant senile plaques in the brains of 9 of 21 healthy aging subjects with a mean age of 84.5G6.6 years (76). Seven of those nine individuals had minor memory problems, and these

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results were interpreted as evidence for a “preclinical” phase of AD. Another study graded 31 brains from cognitively healthy elderly subjects, according to established systems for assigning neuritic plaque (CERAD criteria) and neurofibrillary tangle (Braak and Braak) severity (77). Fourteen subjects were graded as “possible AD” by CERAD criteria, and 7 of 14 also were Braak stage III, usually associated with mild clinical manifestations. Neuropsychology scores were available on only 12 subjects overall, but did tend to predict “possible AD” pathology in that subgroup. The Mount Sinai AD Center also found both senile plaques (78) and neurofibrillary tangles (79) in healthy elderly, and also found that the amount of pathology distinguished subjects with mild cognitive impairment from those without. The Sanders-Brown Center on Aging examined 59 brains of non-demented elderly with a mean age 83.9G7.4 years and an average interval between cognitive exam and autopsy of 8G5 months. Each brain was assigned a diagnosis according to each of three neuropathologic criteria for Alzheimer’s disease, Katchaturian, CERAD, and Reagan criteria. The first two are based purely on neuritic plaque density; the Reagan criteria are based on both neuritic plaques and neurofibrillary tangles. Twenty-nine of these 59 non-demented subjects’ brains met the Katchaturian criteria for AD, 15 met CERAD criteria, and 7 met Reagan criteria, suggesting that the specificity of the criteria increase in that order (80). Even according to the most rigorous criteria, however, 11% of healthy aging individuals harbored pathology sufficient for a

Figure 2 Frontal lobe volumes in healthy aging. Images are coronal T1 weighted MRI scans: (A) frontal cortex of a 69-year-old female; (B) the same area in a cognitively healthy 92-year-old female.

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diagnosis of AD. Those subjects meeting the Reagan criteria for AD pathology differed from the rest of the subjects on some tests of memory, but the subjects meeting each of the other criteria were not neuropsychologically distinct (81). The Reagan criteria, however, are so stringent that sensitivity suffers even though specificity remains less than 100% (Fig. 2) (82). STRUCTURAL CHANGES SEEN IN HEALTHY BRAIN AGING—NEUROIMAGING The neuroanatomic correlates of these age-associated neurologic changes have also been examined with a variety of imaging modalities. We will focus on structural imaging studies, realizing that the rapidly expanding functional imaging literature (83) is beyond the scope of this chapter. The structural correlates of “noncognitive” brain aging may be sought in imaging studies of the aging subcortical brain. The brainstem, or at least the pons, does not appear to change in volume during normal aging (84). One study reported a gender-dependent atrophy of basal ganglia during healthy aging (85), another reported caudate atrophy with aging (86), and yet another study reported age-dependent atrophy of caudate and putamen in both genders (87). Basal ganglia hypointensity on T2-weighted MRI scans is well described in healthy aging (88), and is likely to represent iron deposition in these areas (89). Changes compatible with iron deposition are detectable in globus pallidus, red nucleus, and pars reticulata of the substantia nigra as early as the second decade, and changes in the putamen are seen beginning in the sixth decade (90,91). The pattern of age-related deposition of iron in the putamen is stereotyped, from postero-lateral to anteromedian (92). A relatively new MRI protocol, diffusion tensor imaging, has also been reported to show ageassociated changes in the basal ganglia, specifically the lentiform nucleus (93). The thalamus appears to be less affected by age than the basal ganglia. One study has reported a decline in thalamic volume with age (94), while another has argued that the thalamus is resistant to age-associated atrophy (86). No iron-related hypointensity of the thalamus has been seen with age (91). The thalamus has also been examined with diffusion tensor imaging with no significant age associated change noted (95–97). The cerebellum may lose some volume during aging (98–100), with reports differing on the issue of preferential white matter (100) vs. gray matter (99) loss. There may also be gender differences in the degree of cerebellar atrophy with age (85). While these structures are usually considered part of the “noncognitive” brain, a cognitive role for these subcortical structures cannot be excluded. For example, there are reports of thalamic atrophy in demented patients compared to healthy aging patients (101), and of correlations between thalamic volume and cognitive speed (94). Correlations between cerebellar volume and classical conditioning (102) have also been reported. Imaging studies of the cerebral cortex and limbic system are more easily related to cognitive brain aging, and it is tempting to speculate that age-associated changes in these structures relate to age-associated changes in short-term memory, frontal lobe functions (e.g., working memory and executive function) and speed of information processing. An extensive literature on hippocampal size may be relevant to the debate whether short-term memory decline is part of normal aging or a harbinger of dementia. Atrophy of the hippocampus, measurable on MRI, has been reproducibly demonstrated in Alzheimer’s patients compared to control subjects (103). Hippocampal atrophy has also been described in aged subjects at high risk of Alzheimer’s disease by virtue of a measurable memory impairment (“mild cognitive impairment”) (104,105). Atrophy of limbic structures including the hippocampus in healthy elderly over age 60 predicts impairment in explicit memory (106). Atrophy of the hippocampus has also been shown to predict subsequent dementia in subjects who have been followed over time (104,107). Changes in diffusion tensor imaging of the hippocampus have also been described in mild cognitive impairment but not healthy brain aging (97). Atrophy of the entorhinal cortex (which is the major projection to

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the hippocampus) has also been demonstrated in similar populations of aged subjects at risk of AD (105). It remains controversial, however, whether hippocampal or entorhinal atrophy is a feature of “healthy brain aging,” since populations of healthy aged subjects are usually contaminated by individuals who are destined to dement. In one study of optimally healthy elderly subjects, little hippocampal or other brain atrophy was appreciable with serial brain imaging (108). Rates of hippocampal volume loss are slower in healthy brain aging than in incipient dementia (109). Pathologic examination of hippocampi that have been MRI imaged during life also supports the view that healthy brain aging is not associated with hippocampal atrophy (110,111), as Alzheimer pathology was more common in hippocampi that were atrophic, regardless of whether the subject was clinically demented at the time of death or not. Loss of cortical volume during healthy brain aging is also of interest. Several studies have noted disproportionate atrophy of the frontal lobes compared to other cortical regions in elderly subjects (100,106,112–115), suggesting that this is a correlate of age-associated deficits in working memory and executive function. Some studies have demonstrated correlations between prefrontal brain volumes and performance on working memory (116) and executive function (106,117) tasks. Other studies, however, have noted healthy aging changes to be more pronounced in parietal (118) or temporal (119) lobes, and have pointed out the confounding effect of gender (120). The validity of the hypothesis that the frontal lobes are disproportionately affected by the aging process remains unproven (121). Changes in cerebral white matter have been extensively described, and are of particular interest in light of the fairly uniform finding of slowed information processing with age, a function that may be plausibly related to white matter integrity. Changes in both white matter volume and in the density of cerebral white matter hyper-intensities (WMH) have been described with aging. The discrete borders of the corpus callosum make this structure attractive as an index of cerebral white matter volume. Some have even argued that the corpus callosum reflects regional neuroanatomy (122) as a “mathematical model” (123). Atrophy of the corpus callosum has been described in a number of studies of healthy brain aging, with relatively greater loss of tissue in the anterior callosal regions (124–127). Gender effects may confound this measurement, however, as at least one author has noted that anterior callosal atrophy with age is seen in females but not males (128). The ability of MRI to resolve gray and white matter has permitted the measurement of white matter volumes beyond the corpus callosum. The total white matter “fraction” of the total intracranial volume was significantly reduced in one study of healthy old compared to young subjects (129). Another study found that in the pre-frontal cortex, preferential white matter volume loss is characteristic of healthy aging, in contrast to combined gray and white matter loss in Alzheimer’s disease (115). Yet another study noted atrophy of both gray and white matter with aging, although the white matter atrophy more strongly correlated with age (130). Other studies, however, have reported greater loss of gray than of white matter with healthy aging (113). Hyperintense white matter abnormalities have been perhaps the most intensively studied agerelated change on brain MRI scans. In clinical practice, these WMH or “UBO’s” (unidentified bright objects) are often described as “probably ischemic in nature.” However, it is increasingly clear that multiple processes probably contribute to generation of these lesions (131). Although the pathologic basis of WMH is probably quite variable, it is at least possible to distinguish enlarged perivascular Virchow-Robin spaces from “ischemic-appearing” lesions on MRI scans. As the Virchow Robin spaces follow CSF density on all sequences, they are isointense with brain (i.e., they “disappear”) on proton density sequences and hypo-intense on T1; whereas the gliosis and demyelination that surround an infarct are hyperintense on the proton density sequence. Many studies of WMH define them as hyperintense on both PD and T2 weighted images and not hypointense on T1 weighted images.

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Reports of a high prevalence of these “lesions” in elderly subjects began to appear shortly after MRI scans came into routine clinical use (132). Estimates of the prevalence of white matter high signal foci in the elderly range from 5–90% (133–136). Some of these studies have been large population based samples, with 1000 (133,135,137) to 3300 (134) healthy elderly. While many of the studies have found associations between WMH and vascular risk factors, an independent association with age has been consistently appreciated (133–136). Importantly, some studies have also demonstrated that treated hypertension was associated with less WMH than untreated hypertension (135,138). The consequences of WMH are also complex. For example, a number of studies have described relationships between the presence (139,140) and the location (141) of WMH and gait impairment in the elderly. Most large studies have also noted an association between WMH and cognitive impairment (133–136), although some very healthy elderly subjects display very prominent white matter changes (142). The specific cognitive correlates of WMH are not definitively established, but a meta-analysis of correlative studies found the strongest relationships between WMH and “global functioning” and “ speed” and a significant relationship between WMH and “executive function” and “delayed memory” (143). A marginal relationship was observed between WMH and “immediaterecent memory”; and no significant correlation between WMH and “fluid intelligence,” “crystallized intelligence,” or motor function (143). Pathologic examination of white matter that appears abnormal on MRI during life sometimes reveals frank infarction (144), but frequently reveals patchy demyelination around fibrohyalinotic arteries, suggesting some sort of ischemic damage that stops short of infarction (144,145). A review of more than 100 studies concluded that transient or incomplete ischemic events may be a common cause of these lesions (146). An earlier CT study of white matter lesions raised the additional possibility that these lesions might represent Wallerian degeneration, as areas of white matter lucency on CT demonstrated pallor on myelin stains and mild fibrillary astrocytosis, without infarction or hypertensive vasculopathy (147). The white matter changes were also most prominent in the areas of greatest gray matter atrophy, further arguing for Wallerian degeneration as the etiology (Table 3). There are relatively fewer longitudinal studies of white matter hyperintensities. One study found a correlation between increase in white matter hyperintensity volume and deterioration in gait stability in 70 elderly subjects (aged 74–88) with no gait impairment at baseline (148). Another study of 273 subjects (mean age 60G6) found evidence of progression of white matter abnormality in 18% of individuals over a 3-year period, with an association between diastolic BP and white matter lesion progression (149). A study of 13 healthy octogenarians found a modest increase in the volume of white matter hyperintensities over 5 years of follow-up despite preserved health (114). In summary, cortical white matter hyperintensities are common even during healthy brain aging, probably represent a diverse set of pathologies, and frequently increase in volume over time (Fig. 3). Table 3 Structure: Function Correlates in Cognitive Brain Aging Function Short-term memory impairment Impaired working memory and executive function Slowing of information processing

Structure

Aging vs. dementia

References

Hippocampal atrophy Prefrontal atrophy

Precursor to AD Healthy aging

(103–111) (112–121)

Cortical white matter hyperintensities; diminished cortical white matter volume

Healthy aging

(133–143)

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Figure 3 Variability in cortical white matter hyperintensity in healthy aging. Images are coronal proton density MRI scans: (A) cognitively healthy 92-year-old female with normal appearing white matter; (B) cognitively healthy 98-year-old female with white matter hyperintensities (arrow).

SUMMARY A variety of non-cognitive neurologic signs appear in the course of healthy brain aging, and a number of age-associated changes in subcortical gross anatomy and histology have been described. Neither the clinical signs nor the histology are considered to reflect disease states, and neither typically results in disability or other morbidity. No relationship between age-associated changes in non-cognitive brain function and subcortical brain anatomy have been firmly established, with the exception of an increased frequency of gait impairment in elderly subjects with WMH (139–141). Age-associated changes in cognition, in contrast, have been (to some degree) associated with changes in brain tissue, may represent early signs of dementia, and in the case of dementia do result in significant morbidity. Interpretation of this literature is complicated by the reality that any population of “healthy” aging subjects is going to contain individuals with preclinical dementia. The question of whether aging and dementia are dichotomous or continuous cannot be answered with certainty, but it is clear that the solution to the problem of late life dementia will require a more thorough understanding of the mechanisms involved in the aging process itself.

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4 Neuropsychological Assessment of Dementia Kathleen A. Welsh-Bohmer and Stephanie Johnson Department of Psychiatry and Joseph & Kathleen Bryan Alzheimer’s Disease Research Center–Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A.

Neuropsychological assessment plays an important part in the differential diagnosis of dementing disorders, particularly in clinically ambiguous situations (e.g., suspected early dementia) and in the context of confounding factors, such as the presence of a superimposed depression or advanced age (1,2). Within the medical evaluation of dementia, the neuropsychological evaluation provides unique information in the form of a “behavioral sample” that can be used to determine in an objective, quantifiable manner the presence of cognitive symptoms and their functional significance. To accomplish these basic aims, the neuropsychological examination employs rigorous, standardized psychometric tests of memory and cognitive function and relies heavily on the application of normative standards and on a fundamental understanding of brain function. The examination results in metric values for discrete cognitive and behavioral capacities, which can then be used by the examining clinician to arrive at diagnostic inferences, to make judgments of functional abilities, and to establish a benchmark for monitoring future change and responsiveness to medical treatments and therapies. With advances in both public awareness of dementia and greater availability of symptomatic treatments for Alzheimer’s disease (AD), there is an increasing tendency for patients to present to their primary care physicians with mild complaints of memory loss and cognitive disturbance (3,4). Disentangling what may be normal cognitive change from the pre-clinical stages of dementia is a daunting task and one that is not easily remedied with a quick bedside examination of mental status (5). In these situations, more detailed and sensitive assessment of function is needed, particularly if the complaint is persistent. The goal of this chapter is to provide a comprehensive discussion of the role of neuropsychological assessment in the context of the dementia evaluation. The chapter is divided into three sections with the broad aim of assisting medical professionals, neurologists, and other physicians in understanding the fundamentals of the neuropsychological examination of dementia. The first section focuses on the clinical utility of neuropsychological testing and addresses what the assessment entails. The second section turns to a discussion of how the test results are clinically interpreted, the use 59

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of normative standards, estimation of premorbid ability, and the common confounds to consider in testing, specifically the modifying effects of age, education, experience in testing, culture, and gender. The chapter concludes by contrasting examples of typical clinical presentations and testing profiles of common clinical disorders in the elderly, AD, MCI, and geriatric depression. PURPOSE OF THE NEUROPSYCHOLOGICAL ASSESSMENT Neuropsychological assessment in geriatric practice is frequently requested for the diagnosis and management of patients with memory complaints. Testing is typically ordered with four different goals in mind: (1) provision of diagnostic information, (2) functional competency assessment, (3) assessment of patient change over time and responsiveness to treatment, and (4) recommendations for interventional purposes. These various goals are not mutually exclusive and the information from an examination is commonly called upon to address each of these referral concerns. The following sections deal with the application of testing for each of these specified clinical goals. Diagnosis of Memory Disorders The primary goal when seeking a neuropsychological assessment is to assist in the differential diagnosis of memory disorders. Testing is frequently sought when the clinical situation is ambiguous and the observed changes in function may be reasonably ascribed to normal aging, emotional or psychiatric disorders (e.g., bereavement, depression, or anxiety), or an underlying neurodegenerative condition. In this situation, the neuropsychological examination offers a sensitive, reliable, and noninvasive approach to early symptom verification as well as a potentially cost-effective means for managing patients with memory disorders (6). Neuropsychological testing may be also ordered in instances where there is no doubt of cognitive disorder, such as in a fully manifest dementia. In these instances, the purpose is not for “detection” of dementia, as the condition is evident but rather, the goal is to assist in differential diagnosis. The specific pattern of cognitive functioning can help to identify neural systems involved in the disorder and point to potential etiologies with some profiles suggesting different types of dementia (e.g., AD vs. vascular dementia) or the combination of comorbid illnesses (e.g., depression and dementia). Determination of Functional Capacities A second common scenario for neuropsychological testing is to assist in the determination of functional capacities. The issues frequently raised are the individual’s ability to live independently, monitor their own medications, drive an automobile, and participate in personal financial decisionmaking. “Capacity” to carry out these activities cannot be considered a unitary trait. Although it is certainly true that in advanced dementia nearly all functional abilities are severely impacted, in mild to moderate stage dementia many of these capacities may be maintained (7). Evaluation of different cognitive processing domains helps to establish an individual’s ability to function autonomously in these unique functions (8). Isolated memory problems do not necessarily preclude the ability to participate in some decisions of everyday life. However, impairments in spatial ability and attention would certainly influence driving safety (9,10). Difficulties in conceptualization, reasoning, and language expression and comprehension would certainly influence financial capacity (11). Monitoring Change Over Time A third common reason for neuropsychological evaluation is to establish a baseline from which future changes can be determined and responses to treatment can be monitored objectively over time. Repeat testing is often needed to substantiate a diagnosis, providing information regarding

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the longitudinal trajectory of cognitive change. This information is often needed in the early stages of AD and other neurodegenerative conditions where there is some instability in the diagnosis (12). It is now well recognized that there is an early prodromal period in the clinical evolution of AD and possibly in other dementias, during which there are only subtle symptoms of cognitive impairment present. This transitional period, now commonly referred to as “MCI”; (13–15), carries a heightened risk of dementia with conversion rates to AD ranging from 7% to 20% per year (14,16). Similar to MCI, other nomenclature has been developed, mostly within the context of epidemiological studies, which refers to the transitional state in a broader sense. “Cognitive Impairment No Dementia” indicates a risk state for dementia more generally (17,18), and has a similar conversion rate to AD despite its more heterogeneous case definition (19–21). These subsyndromal states of dementia are highly unstable; nearly 30–40% of those classified as MCI or CIND in epidemiological samples revert back to normal on follow-up evaluation (20,22). Repeat testing over 12–18 months is quite useful in establishing reliable states of cognitive impairment, documenting further decline over time, and thereby validating the initial diagnostic assignment (23–25). Repeat testing is also useful for purposes of monitoring response to pharmacological treatments or other types of interventions, aimed at enhancing cognitive or functional impairments. The repeated observations can also be important in situations where affective or medical confounding factors coexist with memory symptoms. Comparing performance after the treatment of the medical condition allows potential disentanglement of the effects of the medical condition from those of an underlying dementing disorder. Development of Behavioral Management Strategies Finally, a neuropsychological evaluation can also be requested to determine possible avenues for cognitive or behavioral intervention. Traditionally, this type of referral has occurred within an inpatient setting, in the context of a patient displaying some type of behavioral disturbance and nonpharmacological management is sought to parallel other therapeutic attempts. A neuropsychological evaluation provides an assessment of cognitive strengths and weaknesses, behavioral features, and affective coping. This information can be used to target modifiable problems and to determine the most effective intervention approaches (26). This information can then guide clinicians in management decisions and can assist patients and their families in planning for the future. Patients diagnosed as early AD or MCI, frequently have retained insight and sufficient cognitive resources to participate in care decisions. In many instances, these patients are highly motivated to participate in their own care and actively seek methods for enhancing their functional capacities for as long as possible (27). ASSESSMENT OF COGNITIVE IMPAIRMENT The neuropsychological examination for dementia involves several components: (1) the clinical interview and history, (2) psychometric assessment of cognitive abilities and determination of functional loss, mood and, personality change, and (3) profile analysis and data interpretation. Each of these fundamental steps is discussed in the text that follows. Neuropsychological Interview and History An important part of the neuropsychological assessment is the clinical interview and review of medical history. The two pieces of information provide an interpretative context for the testing that will follow. The entry interview allows the neuropsychologist to observe in an informal manner communication patterns between the patient and family and to establish any obvious limitations in

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the patient’s awareness, insight, or neurobehavior function that may impact the patient’s ability to participate fully in the testing session and provide informed consent. The observations help establish the battery of tests that will be employed, so that they are appropriately targeted for the referral issues and for the level of patient impairment. An important aspect of the neuropsychological interview is the determination of premorbid function, since subsequent interpretation of test scores rests in part on judging deviations from an estimate of previous ability level (28). Critical pieces of information include a review of educational and occupational achievement, determination of any developmental disorders, and establishing the presence of any medical or social reasons for poor cognitive performance other than suspected newly acquired brain diseases (29). Often within the early stages of dementia, a patient can accurately convey this type of personal information (30). Later, as the dementia progresses, this information must be supplied by others who know the individual well (31); (see also informant interview below). It is important to remember that both sources of information, self or informant report are subject to biases and error (32). Reliability will vary according to each individual’s attitudes towards brain disease, their level of comfort in the interview, current level of stress, and other motivational factors (30,31). Another goal of the interview is to gather data with respect to patient mood, adaptive functions, and ability to cope or compensate for the perceived cognitive deficits. To assess this, the patient is interviewed for current mood state, functional abilities within the home and work environment, and the successful application of auxiliary aids (e.g., notes; reminder cues) in compensating for deficits. Each of these aspects of behavior (mood, functional ability, and compensatory success) can be quantified with patient or informant completed rating scales of these functions, discussed later in this text. However, these rating scales can only be considered suggestive of impairments in mood, adaptive function, or compensatory ability. A firm diagnosis of mood disorder or functional loss rests on a clinical inference, which must be based on all available sources of information, including, most importantly, the patient’s expressed affect and overall behavior. Finally, it should be noted that an entry interview is now a requisite of all neuropsychological testing to ensure truly informed consent before commencing psychometric testing (33). It is incumbent on the examiner to assure that the patient or their legal surrogate understands the purpose of testing, what is involved, and has had the opportunity to ask questions before consenting to the procedures. Typically, it is within the entry interview that a number of topics are discussed, such as the length of the examination, the risks and benefits of testing, the mechanisms for feedback, issues of confidentiality, and the limits to confidentiality when required by law (e.g., violation of confidentiality under conditions of court subpoena or when patient reveals intent to harm self or others). Informant Interview To secure reliable information in the dementia evaluation, the neuropsychologist must often rely on collateral sources, such as the patient’s family members, for provision of background contextual information and clinical history. A number of structured history questionnaires can be applied to allow uniformity in this aspect of clinical data collection. For determination of cognitive changes, methods such as the Informant Questionnaire on Cognitive Decline in the Elderly (31), the Dementia Questionnaire (34) and the standard queries used in calculating a Clinical Dementia Rating (CDR), a metric for staging dementia severity (described later in section on functional ability), are often applied in research studies. These methods or similar commercially supplied questionnaires for use with informants are also applied in clinical settings (35,36). Each of these methods essentially permits the characterization of the referring problem, the time course over which the symptoms have appeared, and the medical context. Additionally, there are brief rating scales that allow some quick quantification of global function based on the report of a close observer. These methods, discussed

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later in this text, include the Blessed Dementia Rating Scale (37), its revision [BDRS-CERAD, (38)], and the Brief Cognitive Rating Scale (39). It should be note that these shorter methods augment the clinical examination by structured rating of functions and behaviors, but are prone to potential biases when completed by emotionally close relatives or untrained observers (40,41). As a consequence, the typical neuropsychological examination may include rating scales but will not rely on them at the exclusion of a thorough interview. NEUROPSYCHOLOGICAL TESTING PROCEDURES The psychometric assessment itself is the essential crux of the neuropsychological evaluation of dementia. It should be noted that the neuropsychological assessment used in the evaluation of the elderly varies in its form across clinical practices. This variation is dependent on a number of factors including the nature of the referral issues, the complexity of the clinical case, and the availability of adequate normative information for various tests that can affect performance (e.g., age, education, culture, language) (42). Other sources of examination differences are related to the clinician’s theoretical orientation and training (35). Regardless of the approach utilized, there are some universal standards maintained in each examination. The standard neuropsychological examination of dementia contains an assessment of the following basic cognitive and behavioral domains: orientation, intelligence, memory, language, executive function, attention and, concentration, visuoperception, sensorimotor function, mood, personality, and functional capacity. The assessment is intended to provide a broad sampling of the patient’s behavior and functional abilities within a structured testing environment (as artificial and controlled as this situation may be). In the sections that follow, each cognitive domain assessed in the evaluation is discussed along with an overview of how the functions are affected by aging and brain disease, and the various neuropsychological tests that can be used to assess each domain. A comprehensive review of these topics is beyond the scope of this chapter. We refer the reader to several review sources for more detailed information on neuropsychological tests and normative information (35,36,43,44). Orientation Orientation is defined as the ability to relate to the current environment in an appropriate fashion, to understand current time (e.g., time of day, date, etc.), persona (who they are, who the examiner is), place (awareness of present physical location and location of their home), and the situation (what is going on and why). The ability to update oneself with respect to this basic information likely involves a number of fundamental cognitive capacities (e.g., memory, attention) and when intact, it permits the individual to understand the environment and his place within it. Disturbances in orientation suggest the presence of some type of abnormal condition requiring further investigation, including possibilities of brain disease, other neurological disorders, psychiatric illness, mental deficiency, or even malingering (45). Orientation can remain stable when attentional resources are fairly intact. Consequently, an absence of impairment in orientation does not imply normal cognitive function or absence of brain disease (35). There is little change in orientation within the context of normal aging. Occasional inaccuracy in stating date may occur (46). However, in AD, temporal orientation is often affected quite early in the process (47). Errors frequently occur in temporal orientation, although knowledge of place information, situation, and personal information are typically preserved early in the illness. Later in the disease, ability to orient to place and situation can be lost. Generally, personal knowledge is retained with the exception of age information (47). Given the importance of orientation in the assessment of basic mental competence, most tests of orientation have been developed within the context of mental status assessment and are not

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“stand-alone” tests per se (Table 1). The Mini Mental State Examination (MMSE) (49) is one of the most common tools used to assess mental status and orientation. Ten of the thirty possible points on the MMSE deal directly with orientation to time (date, month, year, day of week) and place (location, address information, state, county). There are some neuropsychological tests specifically designed to assess orientation, such as the Temporal Orientation Test (48) and the subscales of Orientation within the Wechsler Memory Scale (75). These latter tests have an advantage over some of the mental status tests in that there is empirically-derived normative information (76,77) for the orientation items and some information regarding discriminating capacity in brain disease and dementia (45,47). Intelligence Intelligence is defined as a general cognitive capacity that includes the integration of a number of verbal and nonverbal thinking functions, such as comprehension, problem solving, and ability to abstractly reason. Intelligence is considered an inherent trait of the individual, and is known to have a large genetic component and to be modifiable through environmental interactions early in development. Once established in late childhood, general intelligence is fairly resistant to additional change over the course of early to middle adulthood (78). However, with advanced aging and in the context of either brain injury or neurological illness, changes occur in selected aspects of intelligence (62). Intelligence is likely not a unitary capacity but rather a composite of different subdomains and components—some based on verbal abilities and others more reliant on nonverbal ability. Areas commonly affected most by aging are those functions that span verbal and nonverbal abilities and tend to tap into “fluid” intelligence, abilities such as abstraction, spatial judgment, and calculation that require flexibility in thinking, divergent thought, and multitasking (79). Areas less affected by aging and disease are subdomains of intelligence tests that assess knowledge or skills acquired over the lifetime. These so-called “crystallized” functions include abilities such as semantic knowledge, word usage, and simple perceptual judgments. Based on the relative resistance and vulnerability of these functions to aging and neurological illness, the verbal and nonverbal subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) are conceptualized as either “hold” or “don’t hold” tests. The most stable of the “hold” tests are the Vocabulary and Picture Completion subtests. The most vulnerable don’t hold tests are Block Design, Digit Symbol, and Similarities. Assessment of intelligence is an important aspect of the dementia evaluation, both for determining the presence of generalized cognitive loss, a critical feature of dementing illnesses (80) and for establishing premorbid level of ability as well. By utilizing the “hold” tests as markers of premorbid function, deviations from this expected level of function can be used to assess performance on other test measures (28). In the elderly, the vocabulary subtest is the most often used single measure to estimate premorbid function. Other hold tests, such as word reading, also are useful for this purpose (29). Recent studies suggest that compared to other methods for detecting early disease, such as longitudinal change scores, comparisons between measured performance on “hold” tests, such as verbal intelligence, and other measures sensitive to dementia (e.g., delayed memory) are particularly sensitive and reliable in identifying early cases of AD (28). However, it is important to keep in mind that performance on any of these “hold” tests is not absolutely invariant over time. Performance can be affected by a number of extraneous factors such as poor motivation, anxiety, and decreased initiative, common in depression and frontal lobe disease (81–84). Additionally, acquired language based disturbances, such as expressive or receptive aphasia as can occur after neurological illnesses or left hemisphere stroke, will obviously affect performance on verbal measures (85). These observations underscore the importance of not interpreting test scores in isolation. Rather it is incumbent on the clinician to consider performance on any test within the entire behavioral presentation and the medical context.

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Table 1 Common Neuropsychological Tests Used in Geriatric Assessment Domain Orientation Intellect Language

Memory: verbal

Memory: visual

Attention/ concentration

Executive function

Visuoperception

Sensorimotor Mood and personality

Tests commonly used Temporal orientation test Mini mental state examination (MMSE) Wechsler adult intelligence scale III Multilingual aphasia examination Boston diagnostic aphasia examination Boston naming test Arizona battery for communicative disorders of dementia CERAD category fluency Wechsler Memory Scale (WMS R, WMS III) California Verbal Learning Test (CVLT) ADAS Verbal Learning Test CERAD Word List Memory Test Rey Auditory Verbal Learning Test (Rey AVLT) Memory assessment scales Buschke selective reminding test Wechsler Memory Scale (WMS R, WMS III) Benton Visual Retention Test (VRT) Brief Visuospatial Memory Test (BVMT) Rey Osterrieth Complex Fig. Tests Fuld Object Memory Test (OME) Warrington recognition memory test for faces Subtests from the WMS III, WAIS III Digit span Digit symbol test Visual cancellation tests Short category test Wisconsin card sorting test Trail making test Stroop color word test Symbol digit modalities test Benton facial recognition test Judgment of line orientation test Tests of constructional praxis Grooved pegboard Finger oscillation MMPI./MMPI-2 NEO personality inventory CASE Beck depression inventory Geriatric depression scale

References Benton et al. (48) Folstein et al. (49) Wechsler (50) Benton and Hamsher (51) Kaplan et al. (52) Kaplan et al. (52) Bayles and Tomoeda (53) Morris et al. (38) Wechsler (50) Delis et al. (54) Welsh-Bohmer and Mohs (55) Rey (56) Williams (57) Buschke (58) Wechsler (50) Benton (45) Benedict (59) Rey (60); Osterreith (61) Fuld (62) Warrington (63) Wechsler (50) Wechsler (50) Wechsler (50) Diller et al. (64) Reitan and Wolfson (65) Grant and Berg (66) Heaton et al. (43) Stroop (67) Smith (68) Benton et al. (45) Benton et al. (45) Benton et al. (45) Matthews and Klove (69) Reitan and Wolfson (65) Butcher et al. (70) Costa and McCrae (71) Reynolds and Bigler (72) Beck et al. (73) Yesavage (74)

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There are different measures of intelligence available for clinical use. The Wechsler Adult Intelligence Scale (WAIS) and its revisions, the WAIS-Revised and more recently the WAIS-III (50), are by far the most commonly used tools applied in neuropsychological assessment. The psychometrics of these intelligence tests are among the best and great care has gone into assuring adequate normative samples to age 74, by the test developers, and beyond this age range upwards to 100 years by other groups (86,87). There is also representation of minority groups to mirror the U.S. Census. As such the tests are essentially unparalleled for their broad application, including their use in samples with low education and low premorbid ability. Although within each individual age strata the minority group representation will be small, the tests remain the best of those available, and there are precautions that can be exercised when interpreting findings to under-represented groups (88,89). Memory Assessment of recent memory function is a critical component of the dementia evaluation. Decrements in recent memory functions are noted over the course of normal aging (90,91) and typically these functions are profoundly disturbed in AD (92). Although memory may not be as deficient in vascular dementias, late life mood disorders, and other dementias when compared to AD (93–95), memory complaints are common in all of these conditions and therefore must be distinguished from the common disorders of normal aging and AD (30,96–98). To properly assess memory integrity, it is important to realize that “memory” is not a unitary function. The process of learning, retaining, and recalling information involves a number of different processing functions, including encoding of information, consolidation into permanent memory stores, and retrieval processes. Depending on the parameters of the to-be learned information, that is whether the stimulus characteristics are primarily confined to one sensory modality (e.g., auditory information) or are multimodal in nature (e.g., episodes with rich visual, auditory, olfactory information) will determine the neural systems involved in the processing of that information. The nature of a memory disturbance, and whether the functions impaired are highly specific (e.g., visual memory only affected) or more integrated in nature (e.g., recent recall for all information regardless of modality), point to the neural systems likely involved and allow the assessment of the involvement of localized versus distributed brain systems and underscore likely etiology (focal brain disorders, such as stroke or tumorversus diffuse brain diseases). A comprehensive review of the organization of memory processing can be found in other sources (99,100). The neuropsychological assessment of memory function involves the characterization of different processing functions including verbal learning, visual learning, multitasking (working memory), uncued recall of verbal and visual information over varied time intervals (immediate, 30 minute delays), and the recall of information with assistance or prompts. Given the complexity of memory, numerous measures are available to assess its various aspects. Among the most commonly used neuropsychological test developed for assessing the various functions affected by AD and aging is the Wechsler Memory Scales and its revisions (Table 2). Other tests that are commonly used for assessing verbal learning impairments of aging include the California Verbal Learning Test (CVLT) and a related test, the Hopkins Verbal Learning Test. The CVLT is also quite useful in discriminating between different forms of dementia (54). The task has rich information that allows characterization of disorders of consolidation, as occurs in AD, and disorders of retrieval, more common in depression and vascular conditions. For visual memory, the Benton Visual Retention test and the Brief Visuospatial Memory Test have appeal. Tests such as the Selective Reminding Test are also popular and are proving more culturally sensitive by virtue of their multisensory nature and the lack of reliance on reading skills. Short tests, like the Word List Memory Test from the CERAD battery also have appeal given that they are quickly administered and carry little subject burden.

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Table 2 Clinical Syndromes and Associated Neuropsychological Profiles Clinical syndrome Normal aging Subjective memory complaints Problems are annoying but not disabling Often problem with name retrieval Minor difficulties in recalling detailed events Clinical dementia rating of 0 (normal) GDS of 1 (normal) or 2 (very mild cognitive decline) Mild cognitive impairment Subjective memory complaints Problem disturbs some independent ADLs but is not disabling Noticeable change in memory from informants Clinical dementia rating of 0.5 (questionable/very mild decline) GDS of 3 (mild cognitive decline) Alzheimer’s disease Insidious onset Progressive impairment Prominent memory impairment Disorders in aphasia, apraxia, agnosia Problem is disabling Clinical dementia rating 0.5 (questionable/ very mild) to 5 (severe impairment) GDS range between 4 (moderate cognitive decline) and 7 (severe cognitive decline) Dementia of geriatric depression Affective disorder Psychomotor slowing Memory complaints Cognitive complaints linked temporally to the depressive disorder

Neuropsychological profile Impaired fluid abilities (novel problem solving) Deficiencies in memory retrieval Decreased general speed of processing Lowered performance on executive tasks Visuospatial skills/visuomotor speed Able to apply retrieval strategies and benefit from cueing

Memory performance 1.5 SD below age matched peers Otherwise intact neurocognitive function Functional disorder limited to mild interference from the memory difficulty Insight is generally preserved

Impaired memory consolidation with rapid forgetting Diminished executive skills Impaired semantic fluency and naming Impaired visuospatial analysis and praxis As progresses impairment in intellectual capacities and nearly all areas of cognition Insight becomes diminished

Impaired performance on tasks involving effortful processing Impaired attention, concentration, sequencing, cognitive flexibility, and executive control Retrieval memory difficulty Memory often improves with cueing/recognition Behavioral tendencies to abandon tasks, poor motivation

Language Similar to memory, language processing involves a number of integrated cognitive functions that permit expression of thought and the comprehension of both spoken and written communication. The processes involved in these integrative functions are intrinsically complex, but have been localized to discrete neural networks, primarily confined to the left hemisphere in most individuals. The frontal areas, particularly the left frontal operculum, have been linked to expressive language

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functions, the integrity of which can be assessed through tests of word generation (verbal fluency), ratings of conversational discourse, word and, sentence repetition, and confrontation naming tasks. The left temporal lobe cortex has been implicated in aural comprehension whereas the parietal and occipital areas appear to be related to writing and reading, respectively. In AD dementia, expressive language function is often involved early in the disease process (85). Commonly, patients observe difficulties in name and more general word retrieval. On casual observation, language expression and communicational discourse may seem rather normal. However, upon more careful scrutiny there is an empty quality to the speech content and, in an effort to compensate, the individual must resort either to less precise word substitutions or circumlocution (description of the item, rather than the use of a succinct term) to allow expression. The deficits in AD tend to be localized to expressive output and are characterized by word search and anomia. Language comprehension tends to be intact until later in the illness. A number of test batteries have been developed to assess language function in neurological illness. These batteries include the Boston Diagnostic Aphasia Examination (BDAE) (52), the Multilingual Aphasia Examination (MAE) (51), and the Arizona Battery for Communicative Disorders (53) among others (35). These test batteries allow examination of multiple dimensions of language production and expression that can be affected by neurological injury. Functions assessed include visual, tactile, and auditory naming, word or phoneme production, repetition of complex phrases, reading comprehension, aural comprehension, writing and, spelling. In the neuropsychological evaluation of an elderly patient suspected to have a degenerative dementia, a comprehensive examination of language function is rarely necessary. Targeted aspects of the aphasia batteries are often selected for inclusion in the neuropsychological evaluation rather than a detailed assessment of all functions. Because expressive difficulties are common in AD dementia and other dementing disorders of aging, such as frontal dementias and subcortical conditions, tests of fluency and naming will often suffice. The most common tests used for this purpose are the Controlled Oral Word Association test from the MAE. This test examines lexical fluency by having the patient generate words to specified letters (e.g., C,F,L). Visual naming is assessed using the Visual Naming Test from the MAE or the 60 item Boston Naming Test (52). Shorter versions of the latter test are now available. The 15-item version from the CERAD battery enjoys popular use but is limited by serious ceiling effects, making it too easy for many early dementia patients and normal controls (101). Alternate short versions do not suffer this same tendency are preferred, but in the cases of early dementia where some expressive language problems are suspected utilizing either the full naming test or a split half version are more judicious choices (102). Executive Function and Attention Executive function and attention are both central control processes that play a critical role in the allocation of processing resources and mental energy. Their influence is exerted on other functions such as language, memory, spatial integration, and motor coordination. As central coordinating functions, they play a critical role in maintaining necessary attentional focus (concentration) for effective completion of tasks, creative problem solving, and inhibition of competing behaviors that may serve to divert energy from tasks at hand. Like memory and intellect, the mental capacities that are encompassed in these broad constructs are many. Executive control processes include abstract attitude, flexible thought, foresight and, planning, creativity, decision making, behavioral regulation, and self-awareness. These interactive processes are important in sizing up situations, establishing probable outcomes of different actions, hypothesis generation, and ability to make decisions and shift behavior when necessary for successful outcomes. Attentional control refers to the behavioral focus or spotlight maintained during the execution of behaviors. This construct is often subdivided into different component processes important for maintaining a general state of alertness. Attentional capacities are further parsed discrete functions important for directing the

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individual’s attention to a stimulus in the environment, sustaining attentional focus (vigilance), and dividing attentional processes effectively across simultaneous tasks, activities, or functional demands. These various functions of executive control and attention are believed to be mediated primarily by discrete neural systems within the prefrontal cortex. Deficits in executive function and attentional processes are a defining hallmark feature of the frontal lobe dementias including frontotemporal dementia and Picks disease (82). Executive disorders and severe attentional disturbances are also prototypical of some forms of geriatric depression. These control processes are also exceptionally vulnerable to the effects of psychoactive medications and the general health state of the individual. Over the course of AD, these control processes are invariably affected. Early in the disorder, the problems are generally manifest as decreased ability to multitask and think creatively. These problems progress to difficulties in maintaining attentional focus and simple decision making. To some extent these same executive functions are affected by the normal aging of the nervous system, but to a less extreme effect. Within normal aging, specific weaknesses are noted on tests involving effortful processing, rapid shifts in attention, and in aspects of divided attention (103–105). Given the ubiquitous nature of deficits in attention and executive function across a host of medical conditions of aging, it is important that these functions are thoroughly assessed both for differential diagnostic purposes as well as for addressing the possible modifying effects these deficits may be exerting on other aspects of mentation. There are a number of tests employed in the neuropsychological evaluation to assess executive function. Two tests have been generally equated as tests of executive processing: the Category Test and the Wisconsin Card Sorting Test. Both these tests require adopting an abstract attitude and an ability to form hypotheses and shift behavior. The Category Test involves observing four stimuli and determining an underlying principle they share (e.g., number of objects in each). The Wisconsin Card Sort involves the sorting of cards into discrete categories of color, shape or number of objects. In this test, the patient must establish the rule for sorting based only on feedback from the examiner. Then the rules unexpectedly shift as the test continues. Both tests perform well in determining functional problems in decision making, flexible behavior, and abstraction. They are however somewhat lengthy and tedious by nature, causing some subject frustration. In the elderly, where fatigue and length of exams are issues, briefer measures may be preferred, such as the Trail Making Test (65) or the Stroop Color Word Test (67). Visuoperception, Visuospatial, and Construction Ability Visuoperception, spatial analysis, and constructional ability are a group of related functions that permit the individual to apprehend, process, and interact with the environment around them. These functions while distinct, are interactive and are typically ascribed to separable neural systems in the right temporal lobe, the occipitoparietal junction bilaterally, and the high parietal cortices (angular gyrus, parietal operculum) bilaterally (106,107). Form perception is often assessed by tests of face discrimination or figure ground differentiation. Integrity of this function can be assessed by tests such as the Benton Facial Recognition Test or the Benton Visual Recognition Test (45). Both of these tests are a matching to sample procedure, requiring the patient to match a stimulus figure with its exact equal from an array of choices. The difficulty of the items is varied in their visual complexity and spatial arrangements to allow for both gross and fine detail discriminations. Difficulties in form perception can lead to an apperceptive agnosia, where the individual has impairments in correctly recognizing objects in the environment (108). The disorder is associated with specific impairments of neural systems confined to the inferior temporal and occipital regions of the right hemisphere (109). Spatial judgment, tested by procedures involving judgments of angular relationships, locations in space, or movement, is associated with lesions confined to neural systems in the occipitoparietal junction (107). Impairments in spatial ability can lead to disturbances in

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comprehending relationships within intrapersonal and extrapersonal space. The consequences of spatial impairments include difficulties in directing attention and in spatial orientation, depending on which particular brain systems are impaired. In everyday life, these impairments may be exhibited by difficulties in driving and to a phenomenon of “looking without seeing” objects in the immediate environment. To determine the presence of spatial disturbances, any of a number of neuropsychological tests can be used. Procedures, such as the Judgment of Line Orientation Test, involve a matching of visual stimuli according to their spatial orientation and do not require a manual response (45). It is considered a relatively pure test of spatial judgment by virtue of the processing demands and the restriction of responses to eliminate the need for motor praxis. Commonly, tests are selected for the examination, which involve integrated visuospatial functions. The Block Design subtest from the WAIS is one such measure that taps visuoperception, spatial judgment, and motor integration (50). Another measure, the Hooper Visual Organization Test, involves mental rotation and form integration but does not require a motor response (110). Constructional ability is assessed with tests of motor praxis, such as block design tests or drawing of complex geometric figures. Apraxia is associated with bilateral defects in the temporal and parietal lobes and results in difficulties executing motor movements in the absence of hemiparesis. As a consequence, the patient may have difficulties in drawing simple figures, using common tools or other small manipulable objects (silverware, comb), or completing tasks like dressing. Constructional apraxia is a common problem in AD dementia, although gross problems in this area tend to appear relatively late in the course of illness (111). This problem is often easily documented in the demented patient by having the individual copy simple figures, such as those from the CERAD battery, or by attempting to produce a clock face to command (112). The dementia syndrome of AD has been classically defined as comprised of the “four A’s” denoting: amnesia (referring to the prominent early memory loss), aphasia (typically described as expressive language problems), apraxia (problems in spatial and motor integration) and agnosia (difficulties recognizing common familiar objects including faces) (113,114). In aging visuospatial functions show some generalized decline, which are only partially attributable to motor slowing and sensory changes common in these aged groups. A number of studies document declines in nonverbal function over the past 25 years (115), often ascribed to selective vulnerability of the right hemispheric functions to aging, although this interpretation has been refuted (116,117). The fundamental observations remain firm however, that decrements in function occur with advancing age on tests of three dimensional spatial judgment, mental rotations, and nonverbal abstraction (118). Consistently, large performance decrements are seen in older age groups compared to the young on the nonverbal subtests of the WAIS-R including the Block Design subtest and Picture Arrangement subtest. This results in considerable “age-associated” adjustments in the normative sample. Beyond this, the same nonverbal performance deficits are seen in longitudinal studies. By studying changes over time within the same individuals, comparisons can be made across groups and within subjects allowing a relatively unbiased appreciation of effects due to aging versus other possible explanations related to differences in the age cohorts or sampling. Motor Function The neuropsychological evaluation is not simply confined to assessing cognitive functions. The assessment also includes tests of simple motor speed, manual dexterity, and coordinated motor skills. Because a goal of testing is to identify patterns of behavior suggestive of differing neuronal disorders, some assessment of sensorimotor function is a requisite of the neuropsychological examination. Performance impairments on tests of fine motor skills, in the absence of competing explanation (e.g., physical injury, arthritis), raise the possibility of neurological disorders involving either the pyramidal or extrapyramidal motor systems. In cerebrovascular disease, subtle motor findings are common and are useful both for the differential diagnosis of stoke versus other causes of impairment (119,120). Testing of motor function is useful in these instances may be helpful in identifying the

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areas of regional brain dysfunction (109). Disorders of the basal ganglia and its connections, as occurs in Parkinson’s disease (121), Huntington’s disease (120), Lewy body dementia (122), and small vessel stroke (123), can also result in generalized slowing on tests of motor control. Tests of fine motor control include the Grooved Pegboard Test or Purdue Pegboard Test, both measures involve the manipulation of small pegs to place them correctly in a board with grooved slots (69,124). The test is timed, and successful performance is judged against normative standards for age (43). Simple motor speed is often testing with the Finger Oscillation task from the Reitan neuropsychological battery (65,125). This test involves placing the hand on a flat board so that the index finger is extended and resting on a metal tapping lever attached to a counting device. The goal of the task is to tap as many times as feasible within a short period of time (10 seconds). This is repeated for at least five trials, with a rest break occurring after the second trial, in order to achieve a reliable estimate of performance with each hand. Deficits in unimanual skills, on either of the tests described, can suggest lateralized brain dysfunction, such as stroke, tumor, or focal frontal impairments (119). However, caution must be exercised with impairment on any a single test of motor function, as there are limits to the ability to predict lateralized brain dysfunction to the right or left hemisphere based on a single test alone (119,126). Generalized motor slowing, impairments in sensorimotor integration, and slowing in reaction time occurs in normal aging (127), and these normal age associated changes in motor function are accounted for in the normative values available for test interpretation (43). Decrements in sensorimotor function beyond that of normal aging, or inconsistency in test performance across motor tasks, may suggest subcortical brain disease or neurodegenerative conditions such as AD (123). Mood and Personality Assessing mood and personality features is an important part of the neuropsychological evaluation. Disorders of mood are prevalent in the elderly with estimates ranging from 15% in community dwelling samples (128) to 30% or higher in medically ill older patients (129). In demented subjects, the prevalence of neuropsychiatric symptoms is also quite high. Findings from large cohort studies, such as the Cardiovascular Health Study (130) and the Cache County Study of Memory in Utah (131), suggest that the majority of patients with AD and related dementias will develop some form of neuropsychiatric disorder over the course of their illness, and that depression accounts for the greatest proportion of these psychiatric disorders (approximately 30% of the symptoms) across studies. The impact of late life depression on cognition, behavior, and function cannot be minimized. It has significant effects on the patient’s overall health, level of functional ability, and quality of life. It also negatively influences relationships with family members and care providers and may lead to an enhanced risk for other medical illnesses, social isolation, and functional disability (132). From a cognitive perspective, depression can lead to serious disturbances in mentation that may be confused with dementia (113). When cognitive impairments occur due to depression they are typically impairments in sustained attention, general cognitive efficiency, executive function, and highly selective aspects of memory processing (133–135). This pattern is often described as “subcortical” in nature, affecting functions requiring effortful processing and generally ascribed to the basal ganglia and its projections into the prefrontal lobe (136). Directed retrieval of information from memory stores is deficient, leading to the difficulties on tests of fluency, naming, and memory recall, but is often facilitated to normal or near normal with examiner provided structural support, such as retrieval cues or recognition memory procedures (137). It should be noted that the pattern and extent of the cognitive impairment accompanying late-life depression is not monotonic (138). Differing profiles of impairment can emerge dependent on the symptom severity (139) and the presence of other disease comorbidities, such as vascular disease (140). In relatively mild depression, the profile of dysexecutive problems and forgetfulness can overlap considerably with the typical symptom complex of normal aging; whereas, in more severely depressed patients, the cognitive disorder of a

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more profound memory deficit can appear very similar to neuroprogressive dementias (140). The diagnosis relies on careful attention to the profile features while considering the overall affective presentation and clinical history. Commonly, depression and its cognitive consequences are entirely overlooked in older patients (129), in part due to variation within the presentation of mood disorders in the elderly. Although depression in both young and old individuals presents with the same symptom profiles (141), affective disorders within the elderly may have more prominent psychological and behavioral changes such as anhedonia and reduced positive affect whereas in their younger counterparts there may be more obvious affective change, frank dysphoria, and vegetative symptoms (142,143). When present in the context of neurodegenerative conditions, obvious depressive disorders can complicate the diagnosis by making it difficult for the clinician to discern the effects of depression from those of dementia (113). Additionally, depression can exacerbate dementia symptoms, leading to more profound levels of impairment or “excess disability” than would be present in the absence of depression (144). In either instance, the goal is to effectively treat the depression with the intent of improving cognition, reducing functional disability and medical burden, and improving the patient and caregiver’s overall quality of life (132). Neuropsychological evaluation can be helpful in the differential diagnosis of dementia and depression. Assessment of mood state is best accomplished by the administration of a number of different standardized measures that allow clinician, informant, and subject report of subjective mood state. Tools for this purpose include patient completed inventories. Brief self-report measures, such as the Beck Depression Inventory (73) and the geriatric depression scale (GDS) (74), can be useful screens for depression (145). Other more comprehensive instruments include the Minnesota multiphasic personality inventory (MMPI) and the clinical assessment scale of the elderly (CASE) (72). Both are quite lengthy but permit an assessment of acute psychopathology in the elderly. The MMPI and its revision, the MMPI-2, have an extensive literature to document their psychometric properties and their application in diverse groups. The test consists of 566 items and is typically not done in routine dementia evaluations due to its tedious nature and the risk of patient fatigue. The CASE is a newer tool, similar to the MMPI in its construction, but has been specifically developed for use in the elderly. It shows promise and has a number of advantages including both patient and informant report forms, and some very useful scales that assess patient awareness of cognitive change with age and fears of aging and mortality. Like the MMPI, the CASE is somewhat lengthy, requiring 40 minutes to complete, making it less ideal for situations where testing burden and patient fatigue are issues. Typically, the examination of geriatric patients will involve the use of brief, screening measures specifically developed for older adults and patients with dementia. By far the most popular patient completed rating scale is the GDS (74). This is a 16 item self-report measure that queries a number of psychological and behavioral features of depression using a yes/no format. It can be completed reliably by normal older adults and patients with mild dementia (146). Screening with self-report measures is typically augmented in the neuropsychological evaluation by clinician ratings, such as the montgomery asberg depression rating scale (MADRS) (147,148) or the Hamilton Depression Rating Scale (149), in order to clarify the extent, severity, and frequency of affective and behavioral symptoms. Functional Ability/Activities of Daily Living Function in daily life cannot be directly assessed with neuropsychological tools of memory and cognition. Although it is certainly true that performance on neuropsychological tests is directly related to functional ability (150), there is not a one-to-one correspondence between neuropsychological ability and function (151–153). To achieve a better indication of function in every day life, a number of rating scales have been developed that can be completed by an informant,

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a patient, or both independently to rate abilities in a number of common daily activities (154). Some of the most commonly used instruments for this purpose include the Index of Activities of Daily Living (155), the Lawton-Brody Instrumental Activities of Daily Living (156), the Functional Activities Questionnaire (157) the Structured Assessment of Independent Living Scales (158) and the Blessed Dementia Rating Scale (37). Typically these scales have two major subdivisions to them, for purposes of capturing basic activities of daily living (e.g., eating, bathing, and toileting) and higher order functions required for independence in daily life (e.g., managing money, meal preparation). To facilitate the assessment of true change in function, unencumbered by educational and other experiential confounds, there are a number of new measures available that are performance based, and require the patient to demonstrate some common activities important for independent function, such as balancing a checkbook, dialing a telephone, addressing a letter and the like (159,160). Again, this proxy information, as well as other supportive information, such as the results of auxiliary tests conducted and brain imaging studies, are considered when interpreting abnormal test findings. It should be noted that many of the functional ability measures developed are brief in nature and are limited in their sensitivity to detect subtle changes as would be expected in mild stage dementia or in cognitive disorders falling short of dementia (e.g., MCI or CIND). Similarly, their use in isolation without considering other sources of validating information may render what is learned on these forms as suspect. To this end, there can often be large discrepancies between patient and informant report of symptoms. Older adults with memory problems tend to inflate their functional competence, whereas informants tend to underestimate the patient’s abilities (41). Assessing function on just one source of information may lead to erroneous conclusions. Other approaches that may be considered include the application of structured informant interviews, which also include patient observations. One such method coming under increasing use, particularly in research applications and clinical trials, is the standardization of the CDR Scale (161). The CDR (162) is a series of structured queries done typically in the interview of informants. Based on a number of detailed questions and discussion of how the patient fares in common scenarios, the clinician is able to form ratings of multiple intersecting domains of function: including orientation, memory, language, self care, social function, mobility, and continence. The scores for each of these domains can be summed to arrive at a continuum of scores, useful for staging the severity of AD from no impairment (CDRZ0), to questionable or very mild cognitive/functional impairment (CDRZ0.5), and gradations of dementia that range from mild (CDRZ1.0), moderate (CDRZ2), severe (CDRZ3), profound (CDR 4.0), or terminal/ end-staged in severity (CDR 5.0). In this respect the CDR is very similar to the Global Deterioration Scale (39), which provides ratings of dementia from stages 1–7 (no cognitive decline to very severe cognitive decline). However, the CDR permits clear ratings along the different functional areas affected in AD. Criticized in the past for poor interrater reliability and construct validity (163), the standardized version of the CDR now used in clinical trials is much improved (161). Additionally, there is an informant-completed version of the CDR available, the Dementia Severity Rating Scale (164) that can be completed readily by knowledgeable caregivers or family members and is a useful alternative. Interpretation Process The critically important part of the neuropsychological evaluation is the interpretation of the test findings. This is an iterative process, which begins by first taking the obtained test scores and determining whether impairment on any of the measures exists. Once this is established, the neuropsychologist will consider the pattern of overall findings and whether these results conform to an identifiable disorder or are suggestive of some dysfunctional underlying neural systems. It is this inferential process that separates the neuropsychologist from technicians trained to administer tests or from computerized algorithms. As in other aspects of medicine, establishing the differential

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diagnosis of a memory complaint requires the integration of the test findings with other ancillary sources of information, including the medical context and the patient’s own unique background. The neuropsychologist will begin by considering a variety of different hypotheses (e.g., normal aging versus early degenerative disease) and then based on the weight of the clinical evidence determine the most parsimonious explanation of the findings and the eventual diagnosis. Determining impairment requires the use of appropriate normative information. Over the course of normal aging, considerable changes in cognitive function occur (165,166). To interpret impairment, it is incumbent upon the clinician to consider what normal expected change is for the patient’s age. Until recently testing of the elderly was hampered somewhat by the relative lack of normative reference groups in older age ranges. Even the most carefully developed psychometric tools, such as the WAIS-R and Wechsler Memory Scale, have normative information extending only to age 74. In dementia evaluations, the common age at presentation is in the mid to late 70s and 80s. In more recent years a number of studies have contributing important information for clinician use. Now the most commonly used tests including the Wechsler tests, the Rey Auditory Verbal Learning test and others have published normative information extending into the tenth decade (86,87,167,168). Epidemiological studies of the elderly are also providing information on some of the shorter screening batteries, such as the neuropsychological battery from the CERAD study, the Trail Making Test, and Benton Visual Retention test (102,169–171). The interpretation of impairment is further bolstered by considering deviations from premorbid ability. As noted previously, in the absence of baseline measures of function, premorbid function can be estimated using tests fairly resistant to the effects of aging and neurological impairment. Tests used for this purpose are often tests of vocabulary, verbal intelligence, or word reading [e.g., North American Adult Reading Test, (172)]. Another approach estimates premorbid ability based on demographically derived factors known to relate to premorbid ability, such as the patients occupational and educational achievements (173). Use of these demographically-based methods has some merit, particularly when there is reason to doubt the representativeness of vocabulary or other hold tests as predictors of function. It must be acknowledged, however, that education and occupation as surrogates of premorbid function are not without their own limitations. In aged individuals, incomplete schooling may be more historically common than in younger groups, and may have occurred for reasons other than ability. Additionally, use of educational level may not accurately predict ability in some minority groups, where educational inequities have been common (88,89). Combining approaches, such as the use of deviation scores and premorbid estimates may offer some advantages in terms of enhancing reliable judgments of changes in functions and cognitive decline (28). Longitudinal follow-up within a 12–18 month period may also be considered in an effort to bolster diagnostic confidence. This is particularly useful in conditions, which are suspected to be unstable or progressive in nature (174). The next step in interpreting the test results is observing patterns of consistency in performance (e.g., impairments repeatedly observed in memory or another domain) to support a reliable finding and not a spuriously low test score. Additionally, the effects of modifying variables on cognitive performance and test variability are considered. Factors that are known to be associated with lower testing performance include advanced age, low education, and neurodevelopment disorders, such as mental retardation, dyslexia and, other learning disabilities. Individual factors present at the time of the testing may also interfere with maximal performance. The presence of mood depression, poor motivation, test anxiety, distractions in the testing situation, and sensorimotor limitations (poor vision, auditory acuity, or motor performance) can all result in variability within the testing results and lead to mistaken impressions of impairment where none may exist (175). Recent investigations based on epidemiological data indicate that the careful application of neuropsychological testing in elderly groups is both sensitive to early stage dementia and is nearly as useful as more exhaustive medical evaluations (102). However, the accuracy of the assignment of cases is greatly enhanced by the inclusion of functional information such as ratings

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of daily function when arriving at final diagnostic groupings (102,176) and that many cases of late life neurological disorders may be missed if case detection relies solely on psychometric test results (25). Profile Interpretation With adequate accounting for the potential sources of confounding, the profile can then be assessed according to known neurobehavioral syndromes or to specific neural system impairment. On the basis of functional neuroanatomy, the neuropsychologist is positioned to determine if patterns of impairment suggest dysfunction in localizable neural systems (109). Also necessary at this step is a basic knowledge of the base rates and age distribution of various neurological, medical, and psychiatric disorders of aging, along with their typical clinical presentations. Recognizing that there is some inherent variability in the clinical presentations of many dementing disorders as well as significant variation in normal cognitive performance, the neuropsychologist must be cautious when arriving at statements of causation. Typically there is some consideration of ancillary data to support or refute the working diagnostic hypotheses. In the diagnosis of dementia, the results from laboratory tests (e.g., thyroid function, apolipoprotein E genotyping), structural tests [e.g., magnetic resonance imaging (MRI), computed tomography (CT)] and functional neuroimaging studies [e.g., positron emission tomography (PET)] of the central nervous system, clinical history, and informant reports are all weighed when determining the likelihood of different explanatory mechanisms (175). One important purpose of testing beyond its role in clarifying a patient’s diagnosis is the capability of objectively monitoring change in the patient’s condition over time and response to interventions. The interpretation of repeat testing has its own challenges with respect to discerning reliable change. Typically on repeat testing, there is a normal tendency to show test-retest improved performance on the second session. This effect and the statistical phenomenon of regression to the mean (the tendency for the lowest performers on tests to show performance on subsequent testing that is higher and the reverse situation of high performers showing decrements on subsequent testing) can complicate the interpretation of what seems to be statistical improvement or decline. To mitigate these problems, the neuropsychologist will look for consistency in the effects observed, such as evidence of similar tests behaving in like fashion and supportive information from the clinical history of functional change paralleling the test findings. Beyond that, there are now more powerful statistical approaches emerging based on regression methods that when applied reduce the confounding effects of regression to the mean and spurious findings. Profiles of Normal Aging, Geriatric Depression, and Dementia As discussed, neuropsychological assessment is most commonly requested in geriatric patients to facilitate the differential diagnosis of AD, to separate out confounding effects of late-life depression on cognition, and to make fine-grain distinctions between the effects of normal aging and early neurodegenerative conditions. A summary of the cognitive syndrome and examples of typical neuropsychological profiles for normal aging, AD, MCI, and geriatric depression are presented in Tables 2 through 4 as well as summarized briefly in the text that follows. Characteristically, normal aging presents clinically with subjective complaints of mild forgetfulness in the context of no significant impairments in instrumental or basic activities of daily function. Name retrieval difficulties, characterized as word blocking or slowness in retrieval are also quite common. On formal neuropsychological testing, normal adults typically show very specific deficiencies when compared to their younger counterparts on tests involving memory retrieval, speed of processing, visuospatial processing, and flexible thought (78,117,177). Commonly, delayed recall is deficient but performance is normal and close to that of younger groups when recognition formats are employed (178). The nonverbal subscales on tests of intelligence (such as the WAIS-R) may be somewhat lower when contrasted to the verbal subscales. Rapid motor tests,

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such as symbol substitution, and tests that tax central processing speed or working memory are also lower in normal aged groups (e.g., Backward Digit Span). The results from both longitudinal and cross-sectional studies underscore that these shifts in cognitive function are fundamentally related to aging effects as opposed to confounding due to cohort differences (i.e., uniqueness of life experiences and educational exposure occurring over the past 50 decades). As a consequence of these well-recognized “normal aging changes” age specific norms have been adjusted where appropriate to accommodate for these differences. Without doing so, nearly all individuals over age 75 would likely show “impairment” on normative values derived from young adults. To be considered clinically normal for one’s age, an individual’s test scores must fall within one standard deviation of their age appropriate normative values. Scores within 1.5 to 2.0 standard deviations are generally considered “borderline” and worthy of some note. At 2.0 standard deviation or beyond impairment, the psychologist begins the iterative process of exploring for patterns of consistent deficits. Contrasting normal aging, the clinical presentation of AD is one that is dominated by a progressive, unremitting problem in memory function that leads to impairments in ability to function in everyday life. The clinical contrast is to some extent subjective and dependent on the level of severity of the memory complaint and its consequences on function (80,179,180). Because of the subjectivity in making clinical determinations based on self or informant descriptions alone, the early stages of the disorder can be confused with the normal effects of aging. The cognitive profile, however, is quite distinctive and helpful in making more objective judgments of presence or absence of clinically significant impairment. Profound decrements in the ability to learn and retain new information are characteristic of the condition throughout its course (92,111,181). Unlike normal aging, retrieval cues provide little benefit in bolstering the memory retrieval process. Beyond the memory problem, there are almost always impairments in expressive language, visuospatial judgment, and motor praxis (111,182). On testing, these difficulties are documented on tests of memory, naming, verbal fluency, and constructional copy. The difficulties seen parallel the neuropathological trajectory of the illness in the brain, as it evolves from largely confined to the mesial temporal lobe structures (hippocampus and parahippocampal areas) to the multimodal projection areas in the temporoparietal and prefrontal cortices (183). Geriatric depression, as discussed previously, can be somewhat difficult to disentangle from normal aging and dementia based on clinical examination alone. The condition includes memory complaints and difficulty in flexible thought (83). Obvious disturbances may or may not be present, but almost always the psychiatric examination will reveal signs of the affective disorder, such as sleep disturbance accompanied by anhedonia, lassitude, and psychomotor slowing. The neuropsychological profile of late life depression has unique features, which distinguish it from normal aging cognitive change and AD. Dominating the profile are difficulties in executive functions, such as impairments in attentional shifting and inhibitory control regulation (83,184). Processing speed is often slower and working memory is selectively disturbed (137,185), resulting in problems on tests of both semantic and episodic memory, particularly when there is no structural support mechanisms (e.g., cueing formats). The problems in cognition often persist in some form, despite improved mood and function with treatment, suggesting that these particularly problems on neuropsychological testing are trait characteristics of the disorder (186). To further illustrate how these various conditions present within the neuropsychological evaluation, the following fictional case studies exemplify typical profiles corresponding to AD, geriatric depression, and the transitional state, MCI. These examples utilize tests that are commonly ordered in the neuropsychological evaluation of the elderly and highlight the profile of test scores common to each. As can be seen in each example, the assessed cognitive functions or domains are not equally affected by these disorders, rather there is a pattern of fairly typical strengths and weaknesses that emerges with each condition. Surveying the profile for common (and less common)

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patterns allows the neuropsychologist to draw inferences of likely etiology for the patient’s cognitive complaints. The data in Table 3 contrast the cognitive performance of a normal older individual to a demographically similar individual with late-life depression. The normal aging profile seen here is characterized by a pattern of relative strengths (e.g., verbal conceptualization, spatial judgment) and weaknesses (e.g., working memory), with scores falling within a normal band of variation. By contrast, the performance of the depressed individual is characterized by deficiencies on more effortful tests, such as the WAIS-III perceptual tests and tests of processing speed. There are also impairments on tests of memory and fluency, procedures again that require effortful retrieval (e.g., delay recall, fluency). Note that there is normal or near normal performance on other similar tests of language retrieval (e.g., naming) and recent memory (e.g., recognition) when retrieval support, such as cues, are provided to facilitate recall. The profile of AD, exemplified in Table 4, is readily distinguished from that of aging and depression by the profound disturbance in recent memory which benefits very little from retrieval cues or recognition formats. Language retrieval is impaired, albeit to a lesser extent typically, and can be demonstrated by tests of fluency and naming. Spatial problems may be detected and commonly there is a characteristic split between verbal and nonverbal intelligence. MCI using Petersen criteria (14), is also illustrated in Table 4 and bears some resemblance to AD with respect to the profound memory disturbance. Unlike AD all other assessed aspects of cognition are intact. In this respect, MCI is indistinguishable from normal aging. The close alignment of some aspects of the cognitive profiles with normal aging and other aspects with AD dementia, has earned MCI the distinction of being considered a “transitional state” or “borderzone condition” lying between normal brain aging and dementia, as already discussed. Summary and Conclusions In summary, the neuropsychological assessment forms a valuable part of the dementia evaluation, providing information important to differential diagnosis and patient care decisions. Although testing of this nature is not required in all instances for diagnostic purposes, it does enjoy particular utility in clinical situations where the memory symptoms are either subtle, ambiguous, or confounded by other medical factors such as depression. By utilizing neuropsychological testing in these challenging scenarios, it may be possible to identify brain diseases early in their course, offering opportunities to implement pharmacological therapies and other interventions at a point in illness when such interventions are likely to be optimal (187). Additionally, the tests may be used to exclude brain conditions, and provide reassurance to the “worried well” patients who may be at some risk for cognitive decline by virtue of age and other factors but do not yet show evidence of such impairment on formal testing. Within this latter context, the neuropsychological evaluation is very useful for tracking patient progress over time from an established baseline. Over the course of neurodegenerative disease, cognitive functions are expected to decline; in normal aging these abilities are expected to remain stable or show test-retest improvement. Neuropsychological examination can be used to assess the patient’s functional status, his or her improvement, stability, or decline over short and long intervals from an established baseline. Armed with this type of objective information regarding retained abilities, deficits, and change over time, the managing physician can guide patients and their families as together they negotiate important care decisions related to retained independence, competency, and safety. It is in this application that the neuropsychological evaluation provides a unique contributing piece to patient care. Other biological and surrogate markers of dementia, such as functional imaging or presence of certain AD-risk genotypes, do not enjoy this type of obvious and direct relationship with behavioral function. Whereas these measures may be able to determine presence of disease and make predictions of symptom severity and

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Table 3 Testing Profile for Normal Aging and Mild Geriatric Depression Test administered Age Education Gender Orientation (MMSE) Total Orientation Intelligence (WAIS-III) FSIQ VIQ PIQ Verbal comprehension Perceptual organization Working memory Processing speed Memory (WMS-III) Auditory immediate Visual immediate General immediate memory Auditory delayed Visual delayed Auditory recognition Overall general memory Working memory Language (multilingual aphasia exam) Fluency (COWA) Visual naming Visuoperception (Benton tests) Form vision (Benton FRT) Spatial judgment (JLO) Sensorimotor (tapping; pegboard) Tapping (dominant hand) Tapping (nondominant) Pegboard (dominant hand) Pegboard (nondominant) Executive function (trails) Trails A (sec, errors) Trails B (sec, errors) Mood (BDI) Total score (Beck) Functional change (CDR) tsave Total CDR score

Normal

Percentile and interpretation

66 12 Male

Depressed

Percentile and interpretation

67 12 Male

29/30 9/10

Normal Normal

24/30 8/10

Impaired WNL

105 108 101 112 103

63% Average 70% Average 53% Average 77% High average 58% Average

92 99 85 101 89

30% Average 47% Average 16% Low average 53% Average 23% Low average

102 100

55% Average 50% Average

83 77

12% Low average 7% Borderline

105 103 104

63% Average 58% Average 61% Average

82 94 87

11% Low average 35% Average 20% Low average

104 105 110 104

61% Average 63% Average 75% High average 61% Average

64 79 90 83

1% Impaired 8% Borderline 25% Average 12% Low average

99

47% Average

70

2% Borderline

35C6 54C4

25–75% Average 75% Average

29C6 52C4

6–11% Borderline 64% Average

43C0 29C1

32% Normal 74% High normal

40C2 19C2

22% Low normal 22% Low normal

13 12 11 12

Normal Normal Normal Normal

8 6 3 5

Low average Impaired Impaired Impaired

34,0 53,0

Average High average

2

Euthymic

22

Depressed

0

Normal

1.0

Mild dementia

50,1 220,2

Mild impaired Impaired

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Table 4 Testing Profile of AD and MCI Test administered

AD

Age Education Gender Orientation (MMSE) Total Orientation Intelligence (WAIS-III) FSIQ VIQ PIQ Verbal comprehension Perceptual organization Working memory Processing speed Memory (WMS-III) Auditory immediate Visual immediate General immediate memory Auditory delayed Visual delayed Auditory recognition Overall general memory Working memory Language (multilingual aphasia exam) Fluency (COWA) Naming Visuoperception (Benton tests) Facial recognition test Judgment of line orientation Sensorimotor (tapping; pegboard) Tapping (dominant hand) Tapping (nondominant) Pegboard (dominant hand) Pegboard (nondominant) Executive function (trails) Trails A (sec, errors) Trails B (sec, errors) Mood (BDI) Beck total score Functional change (CDR) Total score

69 14 Female

Percentile and interpretation

MCI

Percentile and interpretation

71 12 Female

24 7/10

Impaired Impaired

28 9/10

Normal Normal

108 117 95 112 89 106 108

70% 87% 37% 79% 23% 65% 70%

Average High average Average High average Low average Average Average

95 93 98 93 95 95 98

37% 32% 45% 32% 37% 37% 45%

95 95 95 77 78 90 80 83

37% Average 37% Average 37% Average 6% Low average 7% Low average 25% Average 9% Low average 13% Low average

95 94 95 74 76 80 79 87

37% Average 34% Average 37% Low average 1% Impaired 6% Impaired 9% Low average 8% Impaired 20% Low average

27C3 46C2

12–22% Low average 18% Low average

45C6 56C4

77–89% High average 87% Superior

43C2 14C4

49% Normal 5% Defective

41C2 22C4

32% Normal 57% Normal

SSZ12 SSZ11 SSZ7

Normal Normal Low normal

SsZ9 SsZ10 SsZ8

Normal Normal Normal

SSZ8

Normal

SsZ7

Low normal

50 (0) 140 (2)

Mild impairment Mild impairment

48 (0) 123 (0)

Normal Normal

11

Mild mood swings

7

Euthymic

1.0

Mild dementia

0.5

Questionable dementia

Average Average Average Average Average Average Average

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trajectory of change, these measures cannot determine whether a patient is still capable of driving, managing finances, or living independently. Nor can these surrogate markers easily guide the choice of behavioral intervention strategy or cognitive intervention approach. Only the neuropsychological assessment with its emphasis on characterizing strengths and weaknesses in the reciprocal domains of observed behavior: cognition, functional ability, and mood, provides the type of information needed for determining sensitive care needs and behavioral treatment strategies. Because of its different roles in diagnosis, surveillance of dementia progress, patient management, and care decisions the neuropsychological evaluation can contribute useful information for patient care at all stages of the dementia and across all symptom severities. Continued attention in the future towards the development of short, streamlined assessments may allow even more cost-effective and practical alternatives for the neuropsychological evaluation and management of dementia patients.

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5 Neuroimaging in Dementia: Structural Imaging Kejal Kantarci and Clifford Jack, Jr. Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. It is well established that the number of affected individuals will grow dramatically with increasing life expectancy. In the absence of a definitive biomarker, early diagnosis and disease progression are assessed with clinical and neuropsychometric measures. While these are certainly essential, the link between cognitive performance and pathological disease stage is often less direct than desirable. Improved noninvasive surrogate measures for early diagnosis and assessment of disease progression are therefore desirable for clinical management in individual cases. In addition, because diseasemodifying therapies are being developed and evaluated, surrogate markers of disease progression are also required for measuring treatment effects in therapeutic trials. The ideal surrogate marker should be able to detect a fundamental feature of Alzheimer’s neuropathology, be diagnostically sensitive and specific as verified through neuropathologically confirmed cases, and have high test re-test reproducibility. Few biomarkers are likely to perform ideally in all three categories. The most promising candidates in neuroimaging are amyloid labeling agents used in positron emission tomography (PET) imaging (1–3). It is our belief that indirect measures of AD with quantitative magnetic resonance (MR) techniques can also be valid biomarkers as well, particularly of disease progression. This is the subject matter addressed in this review. Various quantitative MR techniques that measure the anatomic, biochemical, microstructural, functional, and blood-flow changes in AD have been and continue to be evaluated. Validating the utility of MR measurements as surrogate markers for AD ideally follows hierarchical testing in the following sequential manner: 1. Cross-sectional case-control studies in which the cases are patients with probable AD 2. Cross-sectional case-control studies in which the cases are nondemented individuals who are at elevated risk of developing AD in the future 3. Longitudinal cohort studies that test the ability of MR techniques to predict future progression to AD in nondemented individuals, particularly those who are at elevated risk of developing AD in the future 4. Radiological-pathological correlation studies 5. Longitudinal cohort studies that correlate clinical disease progression over time with change on serial magnetic resonance imaging (MRI) 89

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6. Therapeutic trials in which serial MR measurements are correlated with clinical disease progression in order to assess therapeutic efficacy. The most extensively studied MR technique, and the only one for which all the validation steps listed previously have been evaluated, is structural MRI measures of brain atrophy. This chapter will review the literature on quantitative MR techniques as potential surrogate markers in AD, classified according to the validation steps listed above.

CROSS-SECTIONAL CASE-CONTROL STUDIES IN WHICH THE CASES ARE PATIENTS WITH PROBABLE AD Progression of the neurofibrillary pathology of AD follows a hierarchical topographical course in the brain. It involves the medial temporal limbic cortical structures; the entorhinal cortex, and hippocampus during the earliest stages, later progressing to paralimbic cortical areas, and involving the neocortex at the later stages of the disease (4). This orderly anatomical progression of the neuronal pathology is important in evaluating potential surrogate MR markers for early diagnosis, and disease progression, specifically for methods utilizing measurements from predetermined anatomic regions of interest. Because each MR marker measures a certain feature of AD pathology, the strategic choice of regions to study must be based on the progression of the target pathology and the stage of the disease being studied. It is expected that this approach would identify different MR measurements from different brain regions of interest that would be sensitive to pathological progression at different stages of disease severity. Memory impairment is the earliest symptom of AD. In keeping with that observation, medial temporal lobe limbic cortical regions, which are essential for episodic memory function, are involved with the pathology of AD early in the disease course (4). Neuron and tissue loss correlate closely with the neurofibrillary pathology of AD, and atrophy is the resultant macroscopic change (5). For this reason, the medial temporal lobe is an attractive target for MR-based volume measurements. Volume measurements from different medial temporal lobe structures have been extensively studied to differentiate patients with AD from cognitively normal elderly (6–15). Of these, the entorhinal cortex, and hippocampus volumes are generally considered to be the most accurate in differentiating patients clinically diagnosed as AD from normal. The abilities of these measures to discriminate patients with AD from normal do not differ significantly (16,17). However, greater difficulty with MRI boundary definition of the entorhinal cortex compared to hippocampus is noted, which results in better the test-retest reproducibility of hippocampal measurements. In addition to the region of interest-based approaches outlined above, an entirely different brain mapping approach to case-control comparisons with structural MRI has received increasing attention. Among the brain mapping methods, perhaps the most widely applied to AD is voxel based morphometry (VBM) (18,19). With VBM, gray matter density is calculated at each voxel position in an appropriately masked three-dimensional structural MRI volume for each subject’s scan in the study. Gray matter density is compared on a voxel-wise basis between groups of subjects. A casecontrol comparison study with VBM can be thought of as a statistical test of inter-group gray matter density differences between the cases and controls at each voxel position. Corrections for multiple comparisons for demographic covariates and inter-individual differences in brain size are commonly incorporated into VBM comparisons of patients with AD versus cognitively healthy elderly controls The largest differences typically found between AD and normal elderly are in areas of the brain predicted by the known progression of neurofibrillary pathology—e.g., limbic cortex, lateral temporal-parietal neocortical association areas, and in younger AD patients the posterior cingulate gyrus (Fig. 1) (20–25). Cross-sectional maps of three-dimensional morphometric differences between cases and controls may also be constructed using more elaborate registration algorithms.

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Figure 1 Voxel-based morphometry. Maps comparing 43 cognitively normal elderly with 51 patients with AD. Maps were threshold at p!0.05 with family-wise error correction. The most striking intergroup differences in gray matter density are indicated in red (gray); basal limbic and lateral posterior temporal neocortical association cortex.

Such maps, which are sometimes referred to by the term tensor-based morphometry (TBM), enable more precise matching of intricate gyral patterns across individuals (26–29). Proton MR spectroscopy (1H MRS) is a diagnostic imaging technique that is sensitive to the changes in the brain at the cellular level. With 1H MRS, several of the major proton-containing metabolites in the brain are measured during a common data acquisition period. The metabolite N-acetyl aspartate (AA) is a marker for neuronal integrity. NAA decreases in a variety of neurological disorders, including AD (30–34). The decrease of NAA or the NAA /creatine (Cr) ratio shows a regional variation in AD (35–37). In patients with mild to moderate AD, NAA /Cr levels are lower than normal in the posterior cingulate gyrus, while they are normal in the medial occipital lobe, including the visual cortex (36). This regional pattern is in agreement with the distribution of the neurofibrillary pathology and the associated neuron loss in people with mild to moderate AD, indicating that regional NAA /Cr levels are potential surrogates for disease progression. Another metabolite that is consistently found to be abnormal in people with AD is myo-inositol (mI) or mI /Cr ratios (36,38,39). The mI peak consists of glial metabolites that are responsible for osmoregulation (40,41). Elevated mI levels correlate with glial proliferation in inflammatory central nervous system (CNS) demyelination (42). It is thought that the elevation of the mI peak is related to glial proliferation and astrocytic activation in AD (36,38,39,43). One other metabolite peak of interest in the 1H MRS of the brain in AD is the choline (Cho) peak. While some studies identified elevated Cho

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and Cho /Cr ratios, some reported normal levels in people with AD compared to normal (44). The largest amount of choline in the brain is in the choline bound membrane phospholipids that are precursors of choline and acetylcholine synthesis. It has been postulated that the elevation of Cho peak is the consequence of membrane phosphotidylcholine catabolism in order to provide free choline for the chronically deficient acetylcholine production in AD (45,46). Diffusion-weighted MR imaging (DWI) is sensitive to the microscopic structural changes in the brain through measuring diffusivity of water molecules. The apparent diffusion coefficient measurements of DWI indicate that the diffusivity of water is higher in the hippocampus and white matter regions in patients with AD than cognitively normal elderly (47–50). Elevation of the apparent diffusion coefficients in the brains of people with AD is attributed to the expansion of the extracellular space owing to the loss of neuron cell bodies and dendrites in the gray matter and Wallerian degeneration in the white matter. Another MR technique that is sensitive to the mobility of water molecules is magnetization transfer (MT) MRI. The MT ratio of immobile protons to free protons in the hippocampus and in the whole brain is lower in patients with AD than normal (51–53). DWI and MT MRI are both sensitive to the ultrastructural changes in the brains of people with AD, and their usefulness in early diagnosis and disease progression remain to be explored with longitudinal studies. Cerebral blood volume MR measurements using contrast agents indicate a reduction in temporoparietal blood volume in patients with AD (54–56). Another technique sensitive to cerebral blood flow is arterial spin labeling (ASL). Significant blood flow reductions were identified in the temporal, parietal, frontal, and posterior cingulate cortices of patients with AD relative to controls (57). ASL is an appealing technique for blood flow measurements because it does not require contrast injection or ionizing radiation. Studies comparing the accuracy of ASL to nuclear medicine imaging modalities as surrogate markers for blood flow changes in AD are needed. Changes in cognitive function accompany and may even precede the MR-detectable microscopic and macroscopic structural changes related to AD pathology in the brain. For this reason, functional imaging methods are of interest for early diagnosis. Measurements of brain activation with functional MRI (fMRI) show that activation patterns are different in people with AD compared to cognitively normal elderly using activation paradigms such as visual saccades, visual and motor responses, semantic processing, angle discrimination, and memory (58–73). A related technique sometimes referred to as resting state fMRI tests whether fluctuations in signal intensity over a defined observation period are spatially correlated (74). This test is administered in a manner similar to traditional activation fMRI, except that the subject is asked to rest quietly without administration of an activation task. The physiological basis underlying this approach is the expectation that temporally correlated intensity fluctuations in an fMRI time series will occur in those cortical regions that are functionally connected. Findings with this approach indicate that the same brain areas known to be vulnerable to neurofibrillary deposition display derangement in normal functional connectivity (75). All MR measurements discussed in this section are sensitive to a certain feature of AD pathology in people who are clinically diagnosed as AD. Autopsy studies, however, indicate that the pathology of AD precedes the clinical diagnosis of dementia, perhaps by decades. One way of evaluating MR markers for early AD pathology is through studying risk groups, which will be discussed in the next section. CROSS-SECTIONAL CASE-CONTROL STUDIES IN WHICH THE CASES ARE NONDEMENTED INDIVIDUALS WHO ARE AT ELEVATED RISK OF DEVELOPING AD IN THE FUTURE Although tangles and plaques are the pathological signatures of AD, they are also commonly encountered in individuals who are not clinically demented (76,77). Typically this pathology manifests as clinical AD only after a certain quantitative threshold is reached. By the time the

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individual is diagnosed with AD, a significant synapse and neuron loss had already occurred (78). The most favorable stage for disease-modifying therapies in AD is before the irreversible damage takes place. People who possess early AD pathology but are not yet demented are of particular interest for preventive therapies and for determining surrogate markers of early pathology. One way of identifying people who possess early AD pathology is by studying risk groups. Old age is the strongest risk factor for AD. Higher risk groups in the aging population are composed of individuals who have a greater probability of developing AD than their peers. The higher risk groups are identified either through clinical examination or family history and genetic testing. Memory impairment is the earliest symptom of AD. Many elderly individuals with memory impairment, however, do not meet current clinical criteria for dementia. The syndrome of mild cognitive impairment (MCI) was defined on clinical grounds in order to identify these people with memory impairment who are not clinically demented (79). Recently, these individuals have been sub-classified as amnestic MCI, single non-memory domain, and multiple-domain MCI (80). Only the outcome of people with amnestic MCI has been validated with longitudinal studies, revealing that people with amnestic MCI have a higher risk of developing AD than their cognitively normal peers (81) and that most of the people with amnestic MCI will progress to AD during their lifetime (82). In accordance with this, autopsy studies show that most people with amnestic MCI have early AD pathology in the limbic cortical structures responsible for memory function (78,82). People with MCI, therefore, are an important clinical group for preventive trials, and for evaluating surrogate MR markers for early diagnosis and monitoring disease progression at the early stages of the disease. In line with the autopsy findings, MR-based volume measurements indicate that the hippocampus and entorhinal cortex volumes of people with mild impairment syndromes are smaller than normal (Fig. 2) (83–88). VBM analyses reveal selective gray matter loss in medial temporal lobe limbic areas, consistent with the Braak and Braak limbic phase of AD (89–91). VBM analysis also indicates that the specific pattern of cortical atrophy may differ between MCI subjects with single domain amnestic MCI vs. MCI patients with multi-domain type MCI (92). Furthermore, similar to AD, people with MCI when compared with normal people have higher 1H MRS measurements of the posterior cingulate gyri mI /Cr ratios (36,93), lower medial temporal lobe NAA /Cr ratios (Fig. 3) (94,95), higher DWI measurements of the hippocampal apparent diffusion coefficients (49,96), and lower MT MRI measurements of temporal lobe MT ratios (53,97). These MR measurements are in agreement with the clinically transitional nature of MCI, residing between normality and dementia. An important consideration in evaluating imaging markers for early AD is that some members of any

Figure 2 Hippocampal differences between normal and MCI. Normal control (81-year-old female) on left and MCI patient (82-year-old female) on right. The left hippocampus is outlined in both subjects. Note the hippocampal atrophy in the patient compared to the control subject.

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Amnestic MCI

NAA

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Figure 3 1H MRS in amnestic MCI and AD. The gray horizontal line indicates the level of Cr, which is a reference compound. The spectral amplitude has been normalized to the level of the Cr peak in each of the three spectra. As disease severity progresses from normal to MCI to AD, the NAA peak declines and the mI and choline peaks increase in amplitude.

cognitively normal control group will likely have preclinical AD pathology. Moreover all things being equal, older control cohorts will tend to have an increasingly greater proportional contamination by subjects with preclinical AD. The expectation from imaging markers, therefore, should not be complete separation of cognitively-impaired individuals from individuals who on clinical grounds appear normal at the time. Some degree of overlap between the clinically identified groups is expected given that preclinical AD pathology is common in the elderly. A recent fMRI study showed that people with MCI and AD have similarly low medial temporal lobe activation on a memory task when compared to cognitively normal elderly (98). However on the whole the fMRI literature is not clear cut. Some publications find decreased activation in MCI (or other risk groups) compared to normal controls, while others find increased activation (99–104). The explanation for increased activation in MCI is overactivation in cortical areas that are engaged as part of a compensatory strategy for functional deficits elsewhere. Memory dysfunction is common to both MCI and AD. Longitudinal studies are needed to test if fMRI is sensitive to the functional changes before memory impairment becomes clinically apparent, such as in cognitively normal people who are destined to develop MCI or AD in the future. Yet another fMRI-based approach involves assessing the fMRI response to a pharmacological challenge (105,106). The APOE 34 allele increases the risk of developing AD in a dose-dependent fashion and also lowers the average age of disease onset (107). Studies that investigated the association between APOE genotype and quantitative MR measurements report conflicting findings. Some found smaller whole brain and medial temporal lobe volumes in patients with AD possessing the APOE 34 allele (108,109) while others did not find statistically significant differences in the hippocampal volumes of APOE 34 positive and negative individuals (110–112). One 1H MRS study showed that metabolic alterations in postmortem AD brain are exaggerated by APOE 34 (113), but another did not identify such an effect (114). The differences in age, disease duration, and the number of subjects in these studies may be responsible for the discrepancies.

LONGITUDINAL COHORT STUDIES THAT TEST THE ABILITY OF MR TECHNIQUES TO PREDICT FUTURE PROGRESSION TO AD IN NONDEMENTED INDIVIDUALS, PARTICULARLY THOSE WHO ARE AT ELEVATED RISK OF DEVELOPING AD IN THE FUTURE The value of quantitative MR techniques for predicting future progression to AD, both in cognitively normal elderly and in risk groups, is assessed through longitudinal studies that test if

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Figure 4 Hippocampal volume and prediction of conversion from MCI to AD. Hippocampal volumes are cast as W scores that can be thought of as age and gender adjusted Z scores. W scoreZ0 indicates a hippocampal volume at the expected mean for a normal subject of a certain age and gender; W scoreZK2.5 is equivalent to a volume 2.5 SD below the expected mean for a normal subject of a certain age and gender. Kaplan-Meier curves of patients whose hippocampal W score at baseline is R0 (nZ13), 0OWOK2.5 (nZ54), and %K2.5 (nZ13). Patients with lower (i.e., atrophic) hippocampal W scores at baseline progress to AD faster than those with higher (i.e., nonatrophic) W scores. Source: From Ref. 116.

baseline MR measurements can predict clinical outcome in these individuals after several years of follow-up. People with mild impairment syndromes are an attractive group to study for identifying quantitative MR techniques for predicting clinical outcome, because most of them eventually progress to AD and do so at different rates. MR-based medial temporal lobe, hippocampal, and entorhinal cortex volumetry is predictive of subsequent progression to AD in people with mild impairment syndromes (115–120). One such study tested the ability of hippocampal volume to predict the rate of progression to AD in people with MCI. A Kaplan-Meier analysis performed on 80 patients with MCI who were followed at an average of 32.6 months indicates that patients with a smaller hippocampal volume at baseline progress to AD faster than the ones with larger volumes (Fig. 4) (116). Hippocampal diffusivity on DWI is another useful MRI measurement for predicting future development of AD; increased hippocampal diffusivity predicted progression to AD in patients with MCI as well as hippocampal volumetry (121). A variation on this theme is the use of rates of change from serial imaging studies to predict future progression. This type of analysis has been performed with structural MRI; rates of change of whole brain and ventricle are related in the predicted manner to the risk of subsequent decline. This has been shown to be true in younger individuals with familial AD (122–124), and also in older individuals who progress from amnestic MCI to late onset AD (125). Moreover, rates of whole brain and ventricular expansion measured from serial MRI provide additive, nonoverlapping information to measures of hippocampal atrophy at a single baseline time point about risk rate of conversion from MCI to AD (125).

RADIOLOGICAL-PATHOLOGICAL CORRELATION STUDIES Histopathological findings are considered to be the “gold standard” in evaluating surrogate markers for diagnosis and disease progression in AD. Few studies, however, have correlated quantitative MR measurements with the histopathologic diagnosis and staging so far. The correlation between

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antemortem MR measurements of the hippocampal volumes and postmortem Braak and Braak staging (4) indicate that hippocampal atrophy, while not specific for AD, is a fairly sensitive marker of pathologic stage (126) and hippocampal neurofibrillary tangle burden (127). MR-based hippocampal volume measurements on postmortem samples further show a strong correlation between hippocampal volumes and neuron numbers, validating the technique’s sensitivity to hippocampal neurodegeneration (128). Neurofibrillary pathology and associated neuron loss are present in some elderly individuals with normal cognition. This pathology in normal elderly is usually confined to the medial temporal lobe corresponding to the Braak stages I and II. MR-based hippocampal volumetry on postmortem scans of the Nun Study participants suggest that hippocampal volumes may be useful in identifying early pathology of AD in nondemented individuals (129). Both antemortem and postmortem MR studies indicate that MR-based hippocampal volumetry is a valid marker for the pathologic stages of AD, regardless of the clinical diagnosis. LONGITUDINAL COHORT STUDIES THAT CORRELATE CLINICAL DISEASE PROGRESSION OVER TIME WITH CHANGE ON SERIAL MRI The neurodegenerative pathology of AD causes progressive atrophy and deformation of the brain overtime. Serial MR measurements that are sensitive to this change can potentially be useful for tracking the pathological progression. Rates of atrophy on serial MRI studies can be measured in a variety of ways. Region of interest methods (ROI) in which the volume of specific anatomic structures are measured over time have consistently shown greater rates of atrophy in patients with AD compared to those in cognitively normal elderly controls subjects. This is true for a variety of structural measures, hippocampus, entorhinal cortex, corpus callosum, and serial measures of lobar atrophy (115,130–134). In addition to simply comparing rates of atrophy between control and AD subjects, atrophy rates using ROI methods have been shown to track with clinical progression over time in a logical way. Rates of hippocampal, entorhinal cortex, whole brain and ventricular atrophy are greater in MCI subjects who convert to AD vs MCI subjects who remain cognitively stable (135,136). These same rates are greater in controls who remain stable vs. those who convert to MCI, and greater in AD subjects who clinically progress rapidly vs. AD patients who progress clinically at a slower rate (Fig. 5) (135,136). Automated or semi-automated MR volumetry techniques that are less labor-intensive than tracing specific regions of interest are being used to track the structural changes that take place within the brain during the progression of AD. One of the most studied techniques used for this purpose is the brain boundary shift integral (BSI) developed by Fox and Freeborough (137). The BSI measures the change in brain boundaries first by spatially co-registering three dimensional scans acquired at different points in time, then measuring the intensity difference over the three dimensional surface of the brain in the combined data. Thus the longitudinal shrinkage of the whole brain volume, and the expansion of the ventricular volume can be measured. Using BSI, brain atrophy rates on serial scans of 18 patients with AD were 2.37%G1.11% per year compared to 0.41%G0.47% per year in an age and gender matched control group (138). Furthermore, the rate of atrophy correlated with the cognitive decline in AD based on the MMSE scores implying the relevance of this marker to clinical progression (139). One drawback of global cerebral atrophy measurements is that this phenomenon is not specific to AD. A variety of neurological disorders can cause global or regional atrophy in the brain. For example, cerebrovascular disease is a common disorder in the elderly and may confound the rates of cerebral atrophy in a patient with AD. Measurements of regional atrophy may be more specific to the pathological process of AD. The topology of AD pathology in the brain varies with disease progression. The rate of atrophy at specific strategic regions such as the hippocampus may be most

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Figure 5 Serial MRI in a patient converting from MCI to AD. Serial MRI studies that have been coned down to a view of the right anterior temporal lobe. This 83-year-old man carried a diagnosis of MCI when first scanned in 1993. Over time, significant progressive atrophy of the anterio-medial temporal lobe is evident— particularly of the hippocampus. This is accompanied by dilation of the temporal horn. The patient converted from MCI to AD in 2001. The patient’s MMSE score is presented in brackets at each time point. Significant atrophy on MRI occurred from 1993–1999 while the MMSE score remained constant over this period.

significant during the early stages. However, as the pathology spreads to the neocortex, rate of atrophy in other regions of the brain may be more significant than the rate of hippocampal atrophy. Because of this regional variability in the rate of atrophy, deformation of the brain is nonlinear. Algorithms that register serial scans to a baseline scan with high degrees of freedom provide a unique noninvasive window into local morphometric change over time. Such algorithms, known as deformation based, fluid based, or TBM, are particularly well suited to the study of AD, which is characterized by shifting patterns of maximal atrophy over time as the disease progresses. These methods permit true four-dimensional analyses of morphometric change over time from serial MRI. For example, a fluid registration model developed by Freeborough and Fox (140) uses a viscous fluid model to compute a deformation field throughout the baseline image at the voxel level, giving an estimate of volume change occurring at each voxel with serial scans over time. Statistical parametric mapping (SPM) was used to compare the deformation computed by fluid registration in 10 people with mild AD, 12 people with moderate AD, and four presymptomatic cases with a family history of autosomal dominant early onset AD who progressed to AD during the follow-up (141). There was a regional variation in the rate of atrophy with increasing disease severity, which correlated with the pathologic progression of the disease. Increased rates of hippocampal and medial parietal lobe atrophy were identified in presymptomatic and mildly affected patients. Increased atrophy rates spread to the temporal and parietal lobes in people with mild to moderate AD. Atrophy rates of the frontal lobe were increased only in people with moderate AD. Thompson et al. (142–144) have demonstrated a similar progression of cortical atrophy over time in patients with AD vs. cognitively normal elderly. As would be predicted on the basis of neurofibrillary pathologic progression, cortical atrophy was shown to progress from limbic to temporal neocortex to frontal neocortex. Regional structural markers for disease progression may vary with the pathologic stages of AD. Measuring global atrophy rates and statistical mapping of the difference from normal at different stages of disease severity may reveal the best regional measurement for each stage of disease progression. Longitudinally-followed cognitively normal elderly and people with MCI would be of interest in such studies for understanding the earliest structural changes that may be useful as surrogate markers for therapies.

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The only other MR technique that has been employed for serial measurements in AD is 1H MRS. Three such longitudinal studies have been published so far. While one study identified a longitudinal decrease in NAA levels in 12 people with AD (145), another did not reveal a change in medial temporal lobe NAA /Cr levels in 13 people with AD (146). Both studies identified a correlation between cognitive decline and NAA levels. One recent study identified a significant decrease in left but not right hippocampal NAA levels in 8 people with AD (147). Longitudinal 1H MRS studies in larger subject groups are necessary to clarify these discrepancies.

THERAPEUTIC TRIALS IN WHICH SERIAL MR MEASUREMENTS ARE CORRELATED WITH CLINICAL DISEASE PROGRESSION IN ORDER TO ASSESS THERAPEUTIC EFFICACY Power estimates from natural history studies indicate that sample sizes required to detect a fixed effect size (i.e., reduction of the rate of change on serial assessments) should be significantly less with serial structural MRI measures than with standard clinical/neuropsychometric measures (136,138,148). The feasibility of MR based volumetry as a treatment outcome measure in AD was tested in a multisite therapeutic trial of milameline, a centrally active muscarinic agonist (149). Using a centrally coordinated quality control program for MRI, the hippocampal volume measurements were found to be consistent across sites, validating the feasibility of multisite acquisition MRbased volumetry in AD. A widely publicized b-amyloid immunization trial employed MRI-based measures of atrophy rates using the BSI as an outcome metric (150). Although the study was halted due to side effects in a small proportion of participants, a therapeutic effect was detected in the BSI data. Those patients who mounted a positive response had significantly different brain atrophy rates than those who did not. The effect was in the direction opposite that predicted a priori causing much debate about mechanism. Nonetheless, a significant signal due to disease modifying therapeutic intervention was detected with this structural MRI technique. In another centrally acting muscarinic agonist (xanomeline) trial, brain Cho/Cr ratios were measured with 1H MRS two times within the trial period of 6 months (151). Cho/Cr levels declined in 10 AD patients who were taking xanomeline, and were stable in two AD patients who were taking placebo. The decline in Cho /Cr ratio was attributed to decreased free choline levels based on the hypothesis that muscarinic agonists reduce neuronal membrane breakdown by reducing the cellular requirement for free choline for acetylcholine synthesis. A recent randomized, double-blind placebo controlled pilot study that assessed the effects of cholinesterase inhibitor donepezil on 1H MRS metabolites showed that NAA levels recovered in the treatment group early during the first 12–18 weeks where as NAA declined afterwards returning to baseline levels at endpoint (152). While these studies suggests that 1H MRS may be useful in detecting therapeutic response to cholinergic agonists and cholinesterase inhibitors, long-term trials in larger groups are required to validate 1H MRS as a therapeutic outcome measure in AD.

AMYLOID IMAGING AND FUTURE DIRECTIONS A major breakthrough in the field of imaging in AD has been the development of amyloid imaging tracers for PET (1–3,153). Several groups have also pursued imaging of amyloid plaques with MR microimaging (154–163). A motivation for this effort is that, unlike other modalities, MRI can resolve individual plaques noninvasively. The work in MRI has taken several directions. One is imaging of plaques in ex vivo human or transgenic mouse specimens, typically with long imaging times that may exceed 10 hours (154–159,161). Another is imaging of plaques in AD mice

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Figure 6 In vivo visualization of amyloid plaques by MR microimaging in transgenic mice. Three-way correlation in a 26-month AD mouse. Panels A, C, and E are full FOV and panels B, D, and F illustrate a magnified sub-sampled area centered on the hippocampus, of the parent image to its left. The numbered arrows point to identical spatial coordinate positions in the common space of the three spatially registered volumes (in vivo, ex vivo, histological) using a linked cursor system. Spatially matched in vivo (A,B), ex vivo (C,D), and histological sections (E,F) conclusively demonstrate that the dark areas seen in vivo do indeed represent plaques. (E) Scale bar Z500 mm. (F) Scale bar Z200 mm. Plaque sharpness in vivo approaches but is clearly inferior to that obtained on ex vivo MRMI. Source: From Ref. 162.

following administration of exogenous plaque labeling contrast media (156,160,161). The final direction is MRI of plaques without exogenous contrast media in the living AD mouse (Fig. 6) (162–164). The basis for intrinsic MRI contrast (i.e., without administration of an exogenous labeling agent) between individual plaques and normal background tissue is presumed to be related to iron content of plaques that accelerates T2 and T2* relaxation rates of tissue water protons in and adjacent to plaques (154). As we enter the age of imaging the amyloid pathology of AD, new research questions arise. While amyloid plaques are one of the key mechanisms in AD, the social and economic impact of the disease on both the individual and the society depends on the clinical dementia severity. One important question is: How well does amyloid plaque density correlate with the clinical disease severity? Autopsy data show that synaptic loss is a better correlate of disease severity than the amyloid plaque burden. Amyloid imaging will require studies correlating clinical severity with amyloid plaque density. Another area that needs to be explored is amyloid imaging for therapy decisions. Amyloid plaques are common in cognitively normal elderly people (165). For example, will a cognitively normal person with amyloid plaques need preventive therapy, and will the change in amyloid plaque burden be a surrogate marker for clinical dementia progression? It is unclear at this point whether amyloid imaging with MRI, which is now being evaluated in transgenic mice, will ever become feasible in humans. And even if MRI amyloid imaging in humans is feasible, will it be competitive with scintigraphic methods in terms of clinical utility? If both of these conditions are met, direct MR measures of the AD pathology will need to undergo a validation process similar to that described above for indirect MRI methods.

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145. Adalsteinsson E, Sullivan EV, Kleinhans N, Spielman DM, Pfefferbaum A. Longitudinal decline of the neuronal marker N-acetyl aspartate in Alzheimer’s disease. Lancet 2000; 355:1696–1697. 146. Jessen F, Block W, Traber F, et al. Decrease of N-acetylaspartate in the MTL correlates with cognitive decline of AD patients. Neurology 2001; 57:930–932. 147. Dixon RM, Bradley KM, Budge MM, Styles P, Smith AD. Longitudinal quantitative proton magnetic resonance spectroscopy of the hippocampus in Alzheimer’s disease. Brain 2002; 125:2332–2341. 148. Bradley KM, Bydder GM, Budge MM, et al. Serial brain MRI at 3–6 month intervals as a surrogate marker for Alzheimer’s disease. Br J Radiol 2002; 75:506–513. 149. Jack CR, Jr., Slomkowski M, Gracon S, et al. MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD. Neurology 2003; 60:253–260. 150. Fox N, Black RS, Gilman S, et al. Effects of AB immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 2005; 64:1563–1572. 151. Satlin A, Bodick N, Offen WW, Renshaw PF. Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer’s disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist. Am J Psychiatry 1997; 154:1459–1461. 152. Krishnan KR, Charles HC, Doraiswamy PM, et al. Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer’s disease. Am J Psychiatry 2003; 160:2003–2011. 153. Mathis CA, Bacskai BJ, Kajdasz ST, et al. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem 2002; 12:295–298. 154. Beneviste H, Einstein G, Kim KR, Hulette C, Johnson GA. Detection of neuritic plaques in Alzheimer’s disease by magnetic resonance microscopy. Proc Natl Acad Sci USA 1999; 96:14079–14084. 155. Dhenain M, Privat N, Duyckaerts C, Jacobs RE. Senile plaques do not induce susceptibility effects in T2*- weighted MR microscopic images. NMR Biomed 2002; 15:197–203. 156. Poduslo JF, Wengenack TM, Curran GL, et al. Molecular targeting of Alzheimer’s amyloid plaques for contrast-enhanced magnetic resonance imaging. Neurobiol Dis 2002; 11:315–329. 157. Helpern JA, Lee S-P, Falangola MF, et al. MRI assessment of neuropathology in a transgenic mouse model of Alzheimer’s disease. Magn Reson Med 2004; 51:794–798. 158. Lee S-P, Falangola MF, Nixon RA, Duff K, Helpern JA. Visualization of amyloid plaques in a transgenic mouse model of Alzheimer’s disease using MR microscopy without contrast reagents. Magn Reson Med 2004; 52:538–544. 159. Zhang J, Yarowsky P, Gordon MN, et al. Detection of amyloid plaques in mouse models of Alzheimer’s disease by magnetic resonance imaging. Magn Reson Med 2004; 51:452–457. 160. Higuchi M, Iwata N, Matsuba Y, Sato K, Sasamoto K, Saido T. 19F and 1H MRI detection of amyloid Beta plaques in vivo. Nat Neurosci 2005; 8:527–533. 161. Wadghiri YZ, Sigurdsson EM, Sadowski M, et al. Detection of Alzheimer’s amyloid in transgenic mice using magnetic resonance microimaging. Mag Res Med 2003; 50:293–302. 162. Jack CR, Jr., Garwood M, Wengenack TM, et al. In vivo visualization of Alzheimer’s amyloid plaques by MRI in transgenic mice without a contrast agent. Magn Reson Med 2004; 52:1263–1271. 163. Jack CR, Jr., Wengenack TM, Reyes DA, et al. In vivo magnetic resonance microimaging of individual amyloid plaques in Alzheimer’s transgenic mice. J Neuroscience in press, 2005. 164. Vanhoutte G, Dewachter I, Borghgraef P, Van Leuven F, Van der Linden A. Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer’s disease. Magn Reson Med 2005; 53:607–613. 165. Guillozet AL, Weintraub S, Mash DC, Mesulam MM. Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 2003; 60:729–736.

6 Functional Imaging in Dementia Reisa Sperling Memory Disorders Unit, Department of Neurology, Brigham and Women’s Hospital, and NMR Center, Massachusetts General Hospital, Boston, Massachusetts, U.S.A.

Keith Johnson Memory Disorders Unit, Department of Neurology, and Division of Nuclear Medicine, Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A.

Although the diagnosis of dementia remains primarily clinically based, the past decade has yielded important advances in adjunctive tests, particularly in the use of neuroimaging. Until recently, neuroimaging was primarily used to exclude causes of dementia other than Alzheimer’s disease (AD), such as cerebrovascular disease, and more rarely, tumor, subdural hematoma or normal pressure hydrocephalus. Several neuroimaging techniques, however, have now shown promise in making a more accurate, positive diagnosis of AD. This chapter will focus on functional neuroimaging. Functional imaging techniques, particularly positron emission tomography (PET) and single-photon emission computed tomography (SPECT), have now been shown to improve diagnostic accuracy in patients with AD. Recently, functional neuroimaging techniques have also been used to predict subsequent diagnosis of AD prior to the onset of clinical dementia. Early, accurate diagnosis of dementia will become increasingly important over the next decade, as potential disease modifying therapies for AD become available. This chapter will review the techniques used in functional neuroimaging, the clinical utility of PET and SPECT in patients with dementia, and the data on early diagnosis of AD. In addition, functional neuroimaging continues to play an important role in elucidating the neural systems that subserve complex cognitive processes, and the alterations in these systems that occur in dementia patients. This chapter will also review recent “activation” PET and functional magnetic resonance imaging (fMRI) studies using cognitive tasks in patients with dementia. 107

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FUNCTIONAL IMAGING TECHNIQUES PET and SPECT are nuclear medicine techniques in which a small quantity of a radioactive substance or “tracer“ is administered to the subject and absorbed by the brain in proportion to neural activity. The location of tracer molecules is detected externally by a gamma-ray camera and converted by computer into brain images. The images reflect brain activity because the tracer is taken up by the brain either as an indication of glucose metabolism or of perfusion, both of which are tightly coupled with neural activity. A newer technique, fMRI, which does not require any radioactive substances, will be described later in the chapter. Nuclear medicine techniques have several potential advantages for use in dementia patients. The scanners are less enclosed than magnetic resonance imaging (MRI) scanners, thus many patients are less likely to experience claustrophobia. In addition, small amounts of head motion are less problematic with PET or SPECT than with MRI, and thus subjects with more severe dementia may be more easily imaged. Much of the pioneering work in functional imaging has been accomplished at PET centers where relationships between radio-tracers and brain metabolites have been precisely measured and modeled. PET imaging uses radio-tracers that emit positrons, particles which are emitted from the atomic nucleus, migrate for a few millimeters, and then fly apart to form two high-energy (511 KeV) photons. The most commonly used PET tracer is 18Fdeoxyglucose (FDG), a glucose analog labeled with 18flourine, to measure cerebral metabolism (Table 1). Spatial resolution, the threshold below which two points in an image cannot be distinguished is, for PET, typically 4–9 mm, depending on Table 1 Representative PET and SPECT Brain Radiopharmaceuticals Radionuclide

Physical half-life

PET Carbon 11

20.4 min

Radiopharmaceutical 11

C-deoxyglucose C-carfentanil 11 C-raclopride 11 C-flunitrazepam 15 O-water 15 O-oxygen 15 O-carbon monoxide 13 N-ammonia 13 N-amino acids 18 F-fluorodeoxyglucose 18 F-spiroperidol 18 F-fluoro-L-dopa

Glucose metabolism Opiate receptor distribution Dopamine receptor distribution Benzodiazepine receptor distribution Perfusion Oxygen metabolism Blood volume Perfusion Amino acid transport Glucose metabolism Dopamine receptor distribution Presynaptic dopaminergic function

99

Perfusion

11

Oxygen 15

2.04 min

Nitrogen 13

9.96 min

Fluorine 18

110 min

SPECT Technetium 99m

6.03 hr

Iodine 123

Xenon 133

13 hr

3.08 days

Parameter measured

mTc-HMPAO (hexamethylpropyleneamineoxime) 99 mTC-ECD (ethyl cyteinate dimer) 123 I-IMP (isopropylamphetamine) 123 I-QNB (3-quinuclidinyl-4-iodobenzilate) I123 -Altropane-DT I123 -beta-CIT-DT 133 Xe-inert gas

Perfusion Perfusion Muscarinic acetylcholine receptors Dopamine transport Dopamine transport Perfusion

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the age of the equipment. Temporal resolution, the epoch of time represented in the image, ranges from 30 seconds for 15O blood flow measurement to 45 minutes for FDG. Thus, the functional “state” of the brain is represented in a particular volume of tissue during a particular epoch of time. Until recently, PET was offered only at major academic centers and was quite expensive, as PET tracers have very short physical half-lives, and must be made at a pharmaceutical level of purity and rapidly delivered to the site of imaging. However, the number of PET facilities is rapidly increasing because of expanded use in oncology, and the cost of the FDG tracer has decreased significantly. SPECT imaging differs from PET primarily in that lower energy photons (usually 140 KeV) are emitted from readily available tracers, which are detected by instruments available in most medical centers. Commonly used radiotracers in SPECT are technetium-labeled exametazime (99mHMPAO or CeretecTM) or ethylcysteinate dimer (ECD or NeuroliteTM). These agents are taken up by the brain in proportion to blood flow, which is tightly coupled to cerebral metabolism and neural function. The resulting image is essentially a “snapshot” of the cerebral state present during the several minutes during which the tracer was absorbed by the brain. Thus, the spatial and temporal resolutions of SPECT are 7–9 mm and 3–5 minutes, respectively. SPECT produces images that are similar to PET, but with lower spatial resolution. SPECT brain imaging is less expensive than PET, and more widely available, as gamma cameras are used in most hospitals. Thus, until recently, many of the studies with large numbers of dementia patients have been performed using SPECT (1–3). Both PET and SPECT can be used to assess regional concentration of specific chemical receptor types (4–6), such as the dopamine transporter (7) and markers of acetylcholine activity (8). Imaging of receptor populations is currently an area of active research, particularly in psychiatric and movement disorders. Such methods may, in the future, prove useful in the characterization of other neurodegenerative diseases in addition to AD and may provide useful information in assessing pharmacologic effects in the treatment of dementia. IMAGE INTERPRETATION, QUALITATIVE, AND QUANTITATIVE ANALYSIS Once acquired, using either a PET or SPECT system, functional images may be interpreted using a variety of methods, ranging from visual inspection to activity measurements within brain “regions of interest,” to highly sophisticated, automated, quantitative techniques. As indicated above, functional images reflect the “state” of the brain observed over a specific period of time and with a specific degree of spatial detail. The intensity of each of the picture elements, or “pixels,” that comprise the image depends on the number of radioactive counts detected at a given location over a given time. For example, Figure 1 shows a typical SPECT image in which areas of greatest tracer uptake, i.e., greatest perfusion due to greatest neural activity, are seen as bright yellow or white because they have the highest pixel intensity. In normal subjects, cortical regions typically have rather homogeneous high pixel values, corresponding to high perfusion. Visual inspection of the image can be carried out to determine whether a pattern of tracer uptake is present that corresponds to a pattern that is characteristic of a particular disorder, e.g., association neocortical dysfunction in AD. This method is easily applied and has been the most widely used method both in research and in clinical nuclear medicine. An example of this approach is the scoring scheme developed by Holman for the diagnosis of AD (1). Despite the appeal of this approach, there are several potential disadvantages, including the element of subjectivity and the frequent need for a consensus opinion of several expert readers. Most importantly, the amount and quality of the information employed by visual inspection is lower than can be extracted from the images using image processing and statistical methods linked to advanced computer processing power. Such quantitative methods are now being applied to the domain of dementia imaging research and are finding a place in clinical neuroimaging practice, as well as clinical imaging of cardiac function. For this reason, some fundamentals of these procedures are worthy of a brief review, as follows.

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Figure 1 Perfusion SPECT with technetium 99mHMPAO. Regions shown in bright yellow and white reflect the greatest uptake and highest perfusion, and regions in blue reflect lower uptake and perfusion. (A) Axial plane of SPECT image of a normal older control subject showing relatively uniform tracer distribution in neocortex. (B) Axial plane of SPECT image of a patient with probable Alzheimer’s disease showing reduced perfusion which is most prominent in association cortex in the parietal lobes bilaterally. (See color insert.)

The numerical value obtained directly from each pixel is in units of density of radioactive decays, (i.e., counts per pixel). These count density data may be transformed into more complex dimensions, (e.g., “absolute” glucose metabolism), by the use of mathematical models of physiological processes, which require the input of additional information. For example, arterial catheterization can be employed to sample blood and measure the appearance and disappearance of radioactivity in the subject’s blood at the time of imaging, permitting precise calculation of regional cerebral glucose use. Methods involving this so-called “absolute” quantitation have been used in AD, but they are less well tolerated by patients and more cumbersome to apply. The overall information yield of this complex procedure has been questioned by some investigators (9), and most PET centers do not use this procedure for routine AD studies, despite its critical importance in some research settings. More commonly used quantitative approaches are those that use count density data without further physiologic modeling to detect functional differences in specific brain regions across groups of dementia patients and normal control subjects. Such methods are of two general types, region-ofinterest (ROI) methods and “voxel-based” methods, each with numerous specific implementations. ROI methods involve the identification of a specific structure (e.g., the posterior cingulate gyrus) in each subject’s image data-set, an often arduous process, but one which permits a focused investigation of a specific hypothesis (e.g., that the posterior cingulate gyrus had reduced function in AD). The ROI method is tailored to individual anatomy and has important statistical advantages, particularly when small samples of subjects are involved. However, there are important disadvantages to this approach as well. Defining the ROIs may require careful input from an investigator skilled in neuroanatomy, contain an element of subjectivity, and are difficult to apply over the entire brain. Recent work in automated brain parcellation (10) has indicated that many of these limitations may soon be resolved. In addition, the count density averaged over an ROI can obscure important findings that are within the ROI. Finally, the ROI approach requires a priori hypotheses, and may miss interesting findings that occur in regions that were not sampled. Limitations of the ROI approach, along with improvements in computer processing power, motivated the development of “voxel-based” methods. A voxel is the three-dimensional or volumetric representation of a pixel, (i.e., it includes the thickness of the tomographic slice). Each

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Figure 2 Statistical map of group differences in SPECT perfusion. Regions in red are voxels which showed a significant reduction (p!0001) in SPECT perfusion in a group of mild to moderate AD patients (n = 29) compared to age-matched normal controls (n = 64). Accuracy of SPECT to discriminate these subjects (using split-half replication) is 92%. (See color insert.)

voxel represents a count density measurement. The entire brain volume can be subjected to statistical analysis as a voxel-by-voxel comparison (e.g., one subject or group to a control group). Figure 2 demonstrates the voxels, which showed significant reductions in SPECT perfusion in a group of mild AD patients compared to a group of age-matched normal controls. Since brains vary in size and shape, each individual data-set must be “warped” to a standard shape in order to permit comparisons between brains. This entails computerized regional compression or expansion of each data-set to conform to a standard target, or “canonical,” brain. Once this spatial normalization step is taken, various uni- or multi-variate statistical methods can be used to test group differences, and this has been an area of active investigation in the recent past. It is important that suitable protective measures are taken to prevent capitalization on chance findings from multiple comparisons. Regardless of the type of quantitative analysis, global (whole brain) variations in cerebral metabolism or perfusion are commonly encountered and optimal identification of regional patterns of abnormality requires that the global effects be removed. A number of methods for doing this have been developed and successfully applied to PET and SPECT. One such method divides regional activity by mean activity in another brain region relatively unaffected in AD, such as the cerebellum, primary visual cortex, or pons (11–13) or by whole brain activity. Methods to control for global functional effects have been refined by the use of analysis of covariance in both activation (14) and resting paradigms (2). More recently, “neural net” methodology and data-driven statistical techniques, including singular value decomposition to principal components, have been successfully applied to image diagnostic classification of AD (15–18). Use of these advanced analysis methods should improve the ability to detect the earliest functional alterations in AD.

REGIONAL PATTERNS Since the earliest studies of functional imaging in AD (19–23), it has been observed that the regions of greatest reduction in functional activity are found in heteromodal association cortices, primarily in the posterior parietal and temporal lobes. This finding remains somewhat puzzling, as although the temporo-parietal neocortical pathology may be seen early in AD (24,25) plaques and tangles are certainly not specific to these areas, and often temporo-parietal functional abnormalities are observed in the absence of significant pathology in these regions (26). Possible explanations for these findings are selective loss of cholinergic terminals in temporal cortex (27) or “deafferentation” of these areas secondary to pathology in deep regions, such as the hippocampal

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complex and basal forebrain (28). One recent clinical study found a significant positive relationship between degree of hippocampal atrophy and hypometabolism in temporal association cortex, supporting the theory of hippocampal-neocortical disconnection in AD patients (29). This regional pattern, or “functional signature,” of temporo-parietal decreases in resting metabolism or perfusion (Figs. 1 and 2) has been replicated by numerous PET, SPECT, and recent fMRI studies (2,26,30–33). Premotor and prefrontal cortex abnormalities have also been reported in a number of studies (34,35), but others have observed relative sparing of frontal cortex (20). These apparent discrepancies may reflect variations in clinical presentation or disease severity, as most studies have reported temporoparietal abnormalities earlier in the course of dementia, with frontal abnormalities appearing later in the disease. Primary sensory and somatomotor cortices are usually relatively spared, as are deep gray matter structures and the cerebellum. It remains somewhat uncertain why the temporoparietal association cortices show the most significant reduction on functional imaging. Most studies have also found that the degree of right-left asymmetry of metabolic activity, or cerebral perfusion, is increased in patients with AD compared to age-matched controls (36). The majority of patients show greater reductions in left-hemisphere metabolism than right, but a subgroup shows the reverse asymmetry. These asymmetries in blood flow remain stable over time and have been shown to correlate with variations in clinical presentation. CORRELATION WITH CLINICAL PARAMETERS Numerous PET and SPECT studies have reported good correlations between the degree of dementia severity and resting metabolic, or perfusion, abnormality (20,21,37,38). Most of these studies utilize standard cognitive assessment scales, such as the Mini-Mental State Examination (MMSE) (39), the Blessed Dementia Scale (40), or the Mattis Dementia Rating Scale (41). In addition, a number of studies have demonstrated relationships between specific cognitive symptoms and patterns of functional imaging abnormalities. Foster et al. (42) examined a group of patients with moderate-to-severe AD with focal neuropsychological syndromes and demonstrated hypometabolism in left perisylvian regions in patients with predominate language abnormalities and hypometabolism in right posterior parietal regions in patients with predominant visuospatial deficits. Perani et al. (43) demonstrated that asymmetry in relative perfusion between cerebral hemispheres were related to relative language versus visuospatial functional impairment. Buck et al. (44) have also reported that deficits in spatial attention were related to SPECT hypoperfusion in right parietal regions, while deficits in object-based attention were related to SPECT hypoperfusion in left parietal regions. Haxby et al. (34) also found that lateral asymmetry of cerebral glucose metabolism was associated with relative degree of language and visuospatial impairments in early AD. In another study, Haxby et al. (45) reported that the parietal/frontal metabolic ratios correlated significantly with neuropsychological deficits in patients with moderate AD. Patients with greater parietal hypometabolism showed impairment of verbal comprehension, calculations, visuospatial construction, and immediate visuospatial memory span, whereas patients with greater frontal hypometabolism show more impairment in verbal fluency and complex attention. Longitudinal follow-up showed that parietal/frontal metabolic ratios and the associated neuropsychological patterns were stable over time. Behavioral and psychiatric symptoms of AD have also shown correlations with specific patterns of regional functional alterations. Starkstein et al. (46) used SPECT to study 16 AD patients with delusions and 29 AD patients without delusions. The patients with delusions had significantly lower cerebral blood flow than patients without delusions in left and right temporal regions, but no significant differences were found in frontal, parietal, basal ganglionic, or thalamic blood flow. Craig et al. (47) reported that the presence of apathy in patients with AD was correlated with prefrontal and anterior temporal hypoperfusion, and not with posterior temporal or parietal hypoperfusion. Ott et al. (48) reported that apathy and

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loss of insight in AD patients was associated with decreased right temporo-occipital perfusion on SPECT imaging. Investigators have also examined the relationship between cerebral perfusion and metabolism in AD and premorbid intellectual abilities. Stern et al. (49) reported that after controlling for dementia severity, higher level of education in patients with AD was associated with greater reductions in parietotemporal perfusion. Alexander et al. (50) found that higher premorbid intellectual ability in individuals with the same degree of dementia was associated with lower metabolic rates in several frontal regions and left superior parietal association areas. These studies suggest that a greater burden of pathology may be required to manifest the same level of impairment in individuals with higher education or intellectual capabilities, and support the hypothesis that “cognitive reserve” may affect the clinical expression of dementia. These findings may have significant implications for the “preclinical” diagnosis of AD with functional imaging. Finally, several PET and SPECT studies have suggested that the degree of hypometabolism, or hypoperfusion, in posterior association cortices may predict the clinical course of dementia. Patients with more severe hypometabolism or hypoperfusion in posterior association cortices show a more rapid rate of cognitive decline and decreased overall survival (51,52). RELATIONSHIP OF FUNCTIONAL ALTERATIONS TO ATROPHY One of the potential difficulties in the interpretation of SPECT or PET images in older subjects and patients with dementia is the artifactual underestimate of “function” due to cerebral atrophy (53). Typical functional maps of the normal brain at rest demonstrate fairly uniform activity in gray matter. When the images indicate an area of abnormal function, several underlying causes should be considered. Diminished metabolism or blood flow is often interpreted as a pure reduction in functional activity, but may actually be due to alterations in underlying structure, such as atrophy or infarction. These defects likely reflect tissue loss rather than tissue dysfunction. Most functional image analyses yield activity in counts per unit volume of space, not in counts per unit volume of brain, a potentially important dimension that more fairly represents functional activity. In diseases associated with aging and neurodegeneration, reduced brain volume is the rule, and any attempt to quantitate a purely functional abnormality would ideally correct for the associated atrophy. Several groups have applied an “atrophy correction” to their functional imaging studies of AD (54–56). Most of these studies reported a significant increase in “corrected” perfusion, or metabolic rates, in patients with AD compared to control subjects, although temporoparietal functional abnormalities remained significant after atrophy correction. Recently, several investigators have begun examining perfusion or metabolism within volumes of interest defined by MR anatomy (Fig. 3). These techniques also provide partial correction for atrophy and still demonstrate relative reductions in metabolism and perfusion in subjects destined to develop AD (57,58).

Figure 3 MRI defined regions of interest for sampling perfusion. (A) Regions are drawn on each subjects’ individual MRI: anterior cingulate will show as turquoise, amygdala as dark blue, temporal horn of the lateral ventricle as red, and the hippocampus as yellow. MR and SPECT volumes are co-registered, and (B) SPECT perfusion is measured in each of the MR volumes. (See color insert.)

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Reiman and colleagues (59) reported that PET images showed significant metabolic reductions in homozygote apolipoprotein 24 carriers without evidence of significant hippocampal atrophy prior to any evidence of cognitive impairment. These findings suggest that functional and structural alterations may not always occur in parallel, and that functional image abnormalities may precede significant tissue loss that is detectable by structural imaging. DIAGNOSTIC ACCURACY Multiple studies have attempted to calculate the diagnostic accuracy of PET or SPECT in differentiating AD from normal controls (Table 2 for representative studies). The studies vary widely in the numbers of subjects, the severity of dementia, and the image analysis methodology. Many of these studies are plagued by the lack of a “gold standard” for definitive diagnosis, but a few recent studies have calculated the sensitivity and specificity of SPECT or PET in patients with pathologic confirmation of diagnosis in large numbers of subjects (Table 2) (3,66,72). Some of the early studies reported low sensitivity of functional image abnormalities in mild AD. Powers et al. (73) evaluated the non-quantitative assessments of PET images by blinded reviewers and reported a low sensitivity (38%) but fairly high specificity (88%) using bilateral temporoparietal reductions as the only criteria. The sensitivity improved to 92%, however, when the criteria were broadened to include other image abnormalities, and the sensitivity decreased to 85%. Reed et al. (74) reported 5/21 AD patients with mild memory impairment did not show temporal or parietal perfusion abnormalities. Most studies, however, have reported sensitivity and specificity in the range of 80–90% in diagnosing AD patients. Holman and colleagues (1) performed a prospective study of SPECT scans in 132 patients referred for imaging as part of their workup for memory loss or other cognitive abnormalities. Images were evaluated qualitatively without knowledge of the clinical history. The probability of AD, defined by clinical diagnosis at 1 year follow-up, for patients with bilateral temporoparietal perfusion defects was 82%, but lower for patients with unilateral temporoparietal or frontal perfusion defects. Johnson et al. (12) reported 88% sensitivity and 87% specificity with a qualitative analysis of IMP-SPECT in probable AD patients compared with age-matched controls. In a subsequent study using quantitative image analysis and HMPAO-SPECT, they reported a sensitivity of 91% and specificity of 86% (2). Bonte et al. (66) performed SPECT on 54 patients with dementia who had histopathological confirmation of their diagnosis. They found SPECT to have 86% sensitivity, 73% specificity, and to have 92% positive predictive value. Combining structural and functional imaging techniques may improve the accuracy of diagnosis. Pearlson and colleagues (75) found combining measures of mesial temporal atrophy on MRI with SPECT measures of temporoparietal perfusion yield 100% discrimination between a group of 15 patients with AD and 16 normal control subjects. In a larger study of 71 histopathologically confirmed cases of dementia and 84 control subjects, Jobst, and associates (64) found the combination of medial temporal lobe atrophy, as assessed by CT, and parietotemporal hypoperfusion on SPECT yielded a sensitivity of 90%, with a specificity of 97% for the diagnosis of AD (Fig. 2). Fewer studies have examined the ability of functional imaging to differentiate AD from patients with other causes of dementia. Similar patterns of temporoparietal hypometabolism/hypoperfusion have been reported in Parkinson’s disease with dementia (PDD) (76–78). The overlap between AD and PDD may reflect the high incidence of Alzheimer’s pathology found in patients with PDD (79). Two recent studies (80,81) demonstrated a distinct pattern of reduced occipital glucose metabolism in patients suspected to have dementia with Lewy bodies (DLB) as compared with AD. Parkinson’s disease without dementia shows a cortical metabolic pattern similar to normals (82). The ability to reliably discriminate AD from multi-infarct or vascular dementia remains controversial. Several studies, using qualitative blinded assessments, have reported significant differences in the perfusion patterns of AD patients vs. patients with clinically diagnosed vascular

Duara et al. (1989) (30) Salmon et al. (1994) (70) Szeilies et al. (1994) (65) Mielke et al. (1994) (63) Ishii et al. (1998) (67) Hoffman et al. (2000) (26) Higuchi et al. (2000) (68) Silverman et al. (2001) (71)

AD vs. other dementias

PET PET PET PET PET PET PET PET

PET PET PET SPECT PET PET PET SPECT PET PET SPECT PET PET SPECT PET PET PET

Technique

AD AD AD AD AD AD AD AD

AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD

(nZ41) (nZ25) (nZ41) (nZ15) (nZ50) (nZ34) (nZ22) (nZ78) (nZ10) (13) (nZ84) (nZ15) (nZ22) (nZ29) (12) (nZ10) (nZ10)

(nZ50) VD (nZ17) (nZ65) OD (nZ64) (nZ24) VD (nZ19) (nZ10) VD (nZ12) (nZ12) DLB (nZ12) (nZ16) OD (nZ6) (nZ11) DLB (nZ7) (nZ206) OD (nZ78)

(nZ50) Controls (nZ30) Controls (nZ33) Controls (nZ58) Controls (nZ41) Controls (nZ37) Controls (nZ19) Controls (nZ29) Controls (nZ21) Controls (nZ10) Controls (nZ47) Controls (nZ24) Controls (nZ37) Controls (nZ54) Controls (nZ12) Controls (nZ11) Controls (nZ21) Controls

Populations compared

88% 86% 75% 90% 92% 88% 91% 93%

88% 96% 61% 88% 90% 89% 95% 91% 100% 90% 90% 75% 97% 86% 92% 91% 86%

Sensitivity

Abbreviations: AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; VD, vascular dementia; OD, other dementias.

Duara et al. (1989) (30) Fazekas et al. (1989) (53) Grady et al. (1990) (60) Johnson et al. (1990) (12) Kippenhan et al. (1992) (17) Herholz et al. (1993) (61) Azari et al. (1993) (15) Johnson et al. (1993) (2) Messa et al. (1994) (62) Mielke et al. (1994) (63) Jobst et al. (1994) (64) Szeilies et al. (1994) (65) Minoshima et al. (1995) Bonte et al. (1997) (60) Ishii et al. (1998) (67) Higuchi et al. (2000) (68) Ohyama et al. (2000) (69)

AD vs. normal controls

Study

Table 2 Representative PET and SPECT Studies Examining Accuracy of Dementia Diagnosis

18% 61% 53% 58% 67% 67% 86% 76%

54% 84% 100% 87% 70% 85% 95% 86% 90% 62% 97% 67% 100% 73% 17% 30% 90%

Specificity

Clinical Clinical/path in 5 Clinical Clinical Clinical Pathologic Clinical Clinical/path in 138

Clinical Clinical Clinical/path in 7 Clinical Clinical Clinical Clinical Clinical Clinical Clinical Pathologic Clinical Clinical Pathologic Clinical Clinical Clinical

Diagnostic standard

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dementia (19,83,84), although Duara and coworkers (30) did not find a characteristic pattern of metabolic deficits that differentiated AD from vascular dementia in a larger PET study. Clearly, combining structural imaging and functional imaging techniques may be helpful in differentiating vascular dementia from AD. A substantial subset of patients, however, likely suffer from a mixed dementia with both AD pathology and cerebrovascular disease contributing to the clinical symptomatology, thus making the diagnostic distinction with any method extremely difficult. Functional imaging studies of the frontotemporal dementias caused by Pick’s disease and related pathologies show a distinct pattern with frontal and anterior temporal hypometabolism/hypoperfusion and relative sparing of posterior temporal and parietal cortices (85,86). This distinctive pattern led to the recent approval by the Centers for Medicare and Medicaid Services (CMS) of reimbursement for PET as an adjunctive diagnostic study when an experienced physician’s examination is unable to differentiate between frontotemporal dementia and AD. Studies of patients with specific cognitive degenerative syndromes, such as primary progressive aphasia, have demonstrated lateralizing functional abnormalities (87,88). Distinct functional image patterns have also been reported with Jakob-Creutzfeldt disease (89) and corticobasal ganglionic degeneration (90). Several studies have found differences in regional metabolic or perfusion patterns between AD and the “subcortical dementias.” Patients with progressive supranuclear palsy demonstrate primarily frontal functional abnormalities (91–93). Normal pressure hydrocephalus has been reported to cause more global metabolic reductions without regional abnormalities (94), and the dementia associated with HIV has been associated with widespread multifocal defects (95,96). The “pseudodementia” associated with depression has been reported to show prefrontal and limbic system hypoperfusion (97–99). A recent PET study by Silverman et al. (72) combining two large cohorts of dementia patients with histopathologic confirmation of the diagnoses in 138 subjects and 2-year clinical follow-up in an additional 146 patients, demonstrated 93% sensitivity and 76% sensitivity in diagnosis of AD versus dementia from a variety of other etiologies.

FUNCTIONAL MAGNETIC RESONANCE IMAGING A number of MRI techniques have been developed that map cerebral function, either as regional blood volume or blood flow. Several studies have been performed with dynamic susceptibility contrast MRI (DSCMRI) in patients with AD. The principle behind this technique is that passage of a concentrated bolus of a paramagnetic contrast agent distorts the local magnetic field sufficiently to cause a transient loss of MR signal on pulse sequences designed to be maximally susceptible to magnetic field inhomogeneities, for example, a T2*-weighted sequence (100). The passage of contrast is imaged over time by sequential rapid scanning of the same slice. The rate of change of signal intensity over time can be calculated and gives a measure that has been shown in animal studies to be directly proportional to cerebral blood volume (CBV). Gonzalez and collaborators (101) studied 10 patients with various types of dementia, including five with probable AD, with both PET and DSCMRI. They found a significant correlation between the modalities both quantitatively, and qualitatively. Similarly, Johnson, and colleagues (102) found CBV, as measured by DSCMRI, to correlate well with perfusion by SPECT in 16 patients with AD and 10 age-matched controls. Another MR technique, which does not require any extrinisic contrast, involves labeling the protons by applying a 180-degree inversion radiofrequency pulse to protons in the arterial water. Sandson and colleagues (33) performed noninvasive perfusion MRI (103) in 11 patients with AD and eight age- and education-matched controls. Focal areas of hypoperfusion were seen in the posterior temporoparietal-occipital region in seven of the patients with AD (Fig. 3). Parietooccipital and temporooccipital to whole-slice signal intensity ratios were significantly lower in the AD

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patients, and parietooccipital ratios did correlate with dementia severity, as measured by the Blessed Dementia Scale-Information-Memory-Concentration subtest (41). The sensitivity and specificity of the perfusion MRI techniques reported in these preliminary studies are comparable to those reported for PET and SPECT (12,66,104). One advantage of the fMRI techniques over other functional neuroimaging modalities is that the MR structural imaging study can be performed during the same scanning session with the same scan plane, image size (field-of-view), and slice thickness as the functional MR scan. Specific regions of interest (ROI) can, therefore, be selected with a high degree of certainty on the structural image and directly transferred to the perfusion image at the same anatomical site. Furthermore, there is no exposure to ionizing radiation. Quantification of cerebral blood flow is possible with both DSCMRI and spin labeled perfusion MR (105,106), but these techniques are not widely used in research or clinical practice at this time. Several other functional MRI techniques have recently been developed and applied to subjects with cognitive impairment and AD patients. Small et al. (107) have reported a novel MR technique that examines the resting T2* weighted (magnetic susceptibility) signal, which has shown alterations in the entorhinal cortex of older subjects with “pathologic” memory decline (108). Blood Oxygen Level Dependent (BOLD) fMRI imaging (109) utilizes changes in MR signal related to the ratio of oxygenated to deoxyhemoglobin in capillary beds to infer information about neural activity. This technique is completely non-invasive and is particularly amenable for cognitive activation studies. COGNITIVE ACTIVATION STUDIES While the majority of functional imaging studies in AD have been acquired during a resting condition, several recent studies have attempted to study “activation patterns” that are associated with the performance of specific cognitive tasks. Cerebral blood flow studies as early as the 1970s, by Ingvar et al. (23), found that patients with AD had a decrease in the expected flow augmentation when performing mental tasks such as digit span backward and Raven matrices. Some of these patients actually showed a decrease from baseline blood flow in association cortices during task activation. More recently, Mentis et al. (110) performed PET scans on 10 patients with AD and 12 control subjects. They measured cerebral blood flow in response to a visual patterned flash stimulus at varying frequencies. Controls showed a significantly greater increase than AD patients in middle temporal regions and striate cortex in response to higher frequency stimulation. Becker and associates (111) used PET to study verbal memory in patients with AD and age-matched controls. Patients were asked to repeat or recall word lists of varying lengths during PET acquisition. Paradoxically, the AD patients showed a larger area of activation than controls in regions involved in verbal memory, and also showed activation in some cortical areas that did not activate in controls. The authors speculate that this may represent a functional reallocation of brain resources to compensate for dysfunction. Stern et al. (112) have also found evidence of activation in “alternate,” or compensatory, networks in AD patients during the performance of verbal recognition tasks. Petrini et al. (113) compared regional cerebral glucose metabolism at rest and during passive audiovisual stimulation in AD patients. They reported that parietal glucose metabolism correlated with dementia severity during rest and stimulation, but that additional neocortical regions, including primary auditory and visual cortices, showed correlations with dementia severity only during stimulation. Several PET activation studies have provided evidence that lack of activation in the hippocampus is associated with the poor memory performance seen in early AD. Backman et al. (114) reported that AD subjects failed to show increased PET activation in the hippocampal formation during a cued-recall task. Grady et al. recently (115) reported evidence of a functional “disconnection” between activity in the prefrontal cortex and the hippocampus in AD patients during a face memory task with PET.

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More recently, studies using BOLD fMRI (109) during cognitive activation tasks have been performed in patients with mild AD (116–119). These fMRI studies have examined changes in MR signals to visualize areas of regional brain “activation” during a memory task compared to a control condition. All of these studies have reported decreased fMRI activation in hippocampal or parahippocampal regions in patients with AD compared with older control subjects (Fig. 4). BOLD fMRI has the advantage of being completely non-invasive and can be performed at the same time as conventional structural MR imaging. There are several potential limitations of using fMRI in AD patients, however, including the sensitivity of these techniques to head motion and the inability of dementia patients to adequately perform the cognitive tasks in the magnet. PRECLINICAL DIAGNOSIS OF ALZHEIMER’S DISEASE Increasing evidence from neuropsychological, neuropathological, structural, and functional imaging studies suggest that the pathophysiological disease process in AD may begin years or even decades prior to the onset of clinical dementia (120,121). It is increasingly imperative to identify individuals in this “preclinical” phase, as emerging pharmacological therapies, such as amyloid modifying agents, would likely be most effective in very early stages of the degenerative process. Recent studies suggest that cerebral perfusion and metabolic patterns may predict cognitive decline and subsequent diagnosis of AD in subjects with mild memory deficits. Johnson et al. (16) found a distinct pattern of regional hypoperfusion in subjects with an initial Clinical Dementia Rating [CDR (122)] scale of 0.5 (questionable dementia), who progressed over 2 years to reach a CDR of 1.0, meeting criteria for probable AD. Significant SPECT perfusion abnormalities were observed in the posterior cingulate, hippocampal-amygdaloid complex, and other limbic structures of 18 subjects who “converted” to AD within 2 years, compared to 27 subjects who did not show cognitive decline. Minoshima and coworkers (123) also reported posterior cingulate and cinguloparietal hypometabolism in a PET study of eight patients with mild memory impairment who later progressed to a diagnosis of probable AD. Functional imaging may also prove useful in identifying subjects who will progress from normal to Mild Cognitive Impairment (MCI). de Leon et al. (124) reported that baseline decreases

Figure 4 Functional MRI using BOLD imaging during a face-name associative memory task. Activation maps show regions in red and yellow which are significantly (p!0.00001) activated during the encoding of novel face-name pairs (N) compared to the viewing of repeated face-name pairs (R). MR signal from the right hippocampus is shown below each activation map for (A) young controls (nZ8), (B) older controls (nZ8) and (C) patients with mild AD (nZ7), who do not show evidence of paradigm related activity in the hippocampus. (See color insert.)

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in FDG/PET metabolism in the entorhinal cortex of normal subjects predicted subsequent cognitive decline to meet criteria for MCI. This group (58) has also reported that alterations in hippocampal and neocortical glucose metabolism were superior to MRI volume measures in discriminating groups of normal, MCI, and AD subjects.

FUNCTIONAL IMAGING IN GENETICALLY “AT-RISK” SUBJECTS FOR AD Several recent reports have suggested that the presence of genetic risk factors for AD, such as the apolipoprotein E 24 allele, may alter the pattern of cerebral metabolism even prior to the onset of any evidence of cognitive impairment. Small and coworkers (125) found evidence of parietal hypometabolism and increased parietal asymmetry in nondemented relatives of patients with AD who carried one or two ApoE 24 alleles. Reiman and coworkers (13) reported reduced glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal regions in cognitively normal individuals with a family history of AD who were homozygous for the ApoE 24 allele. Reiman et al. (59) also reported that the neocortical reductions in metabolism were present prior to the time of significant hippocampal atrophy in the 24 subjects. These findings support the hypothesis that the apolipoprotein E 24 allele may be associated with early pathology in individuals who are still cognitively normal. Two fMRI studies have examined the effects of ApoE genotype on activation (126,127). Smith et al. (126) reported that female subjects at risk for developing AD on the basis of their ApoE status and family history of AD showed areas of significantly reduced activation in the mid- and posterior infero-temporal regions bilaterally during visual naming and letter tasks. In contrast, Bookheimer et al. (127) reported that subjects with ApoE 24 alleles showed increased activation in the left hippocampus, prefrontal, and parietal regions during word-paired associate memory tasks. Moreover, they reported that degree of fMRI activation at baseline was correlated with degree of decline in memory assessed 2 years later. The authors speculated that the increased activation might represent compensatory recruitment in performance capability in the difficult memory task, but mentioned the alternative hypothesis that these regions might have lower baseline perfusion, and thus show a relatively greater change during activation. Functional imaging studies in individuals with autosomal dominant mutations for familial AD, such as Presenilin-1, have also found evidence of altered cerebral perfusion in asymptomatic carriers (128). Johnson et al. (128) reported that subjects with the PS-1 mutation, who were asymptomatic at the time of SPECT imaging, demonstrated reduced perfusion in the hippocampal complex, anterior, and posterior cingulate, posterior parietal lobe, and anterior frontal lobe, in comparison with non-carrier normal subjects from the same kindred. These individuals were studied many years and in some cases decades prior to the expected onset of clinical dementia. Since this mutation is completely penetrant, individual carriers will invariably develop AD. Kennedy et al. (129) examined individuals from families with autosomal dominant familial AD who were asymptomatic. They demonstrated decreased glucose metabolism in temporoparietal and frontal regions among such subjects. These studies provide compelling evidence that functional neuroimaging can detect functional abnormalities related to early AD pathology prior to onset of any cognitive impairment. The influence of the APOE 24 allele in patients who already have a clinical diagnosis of AD is less clear. Corder and colleagues (130) reported no significant difference in cerebral perfusion patterns in patients with AD, with or without ApoE 24 alleles, while other studies have suggested that there may be at least some image features that differ in patients with AD with 24 alleles (131–133).

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LONGITUDINAL STUDIES Relatively few longitudinal studies examining the change in functional imaging over time in AD patients have been published to date. Jagust et al. (31) studied six AD patients with two PET scans over a mean interval of 15.5 months, and reported a significant decline in parietal metabolic rates as patients worsened clinically. The change over time in the frontal/parietal metabolic ratio correlated with the decline in neuropsychological performance. Left-right metabolic asymmetry was preserved in frontal and occipital regions, but not in parietal regions in this sample. Haxby and coworkers (36) reported a longitudinal study of neuropsychological patterns and cerebral metabolic asymmetries. The direction of asymmetry (e.g., left Oright) tended to remain constant at follow-up. In addition, the correlation for either predominately verbal deficits and left hemispheric abnormalities or visuospatial deficits and right hemispheric abnormalities, increased over time. There are also two recent longitudinal PET studies of ApoE 24 carriers (134,135). Small et al. (134) reported decreases in metabolism in the left posterior cingulate, inferior parietal, and lateral temporal regions associated with cognitive decline in ApoE 24 carriers over a 2-year period. Reiman et al. (135) found that 24 heterozygotes had showed decline in metabolism in parahippocampal gyrus, thalamus, basal forebrain, posterior cingulate, temporal, and prefrontal cortices over a 2-year follow-up period.

USE OF FUNCTIONAL NEUROIMAGING IN CLINICAL PRACTICE In this age of shrinking resources for diagnostic workup, the obvious question arises as to the clinical utility of functional imaging in routine clinical practice. There is mounting evidence that PET and SPECT may improve diagnostic accuracy over clinical evaluation alone, not only in the primary care setting where the overwhelming portion of patients are evaluated, but likely also in specialty dementia clinics (76). The most recent American Academy of Neurology guidelines (136) do not recommend routine use of PET in the diagnosis of dementia, but these guidelines were developed prior to the publication of the most recent PET studies with autopsy confirmation. The issue of optimal use of neuroimaging resources in the diagnosis of dementia will likely continue to evolve, as reflected in the decision by CMS to reimburse PET studies for the differentiation of frontotemporal dementia and AD. Clearly, functional imaging may not be necessary when there is a classic history of gradual memory and functional impairment over several years in an otherwise healthy older individual. We have found functional imaging particularly useful, however, in evaluating patients whose clinical presentation is unusual or complex. Specifically, functional imaging may be useful in patients with prominent behavioral symptoms early in the course of their dementia, when the differential is frontotemporal dementia versus AD. It may also have utility in evaluating the cognitive symptoms associated with mood disorders, such as distinguishing the “pseudodementia” of depression from abulia and depressive symptomatology associated with early AD. We have also found functional imaging to be helpful diagnostically in patients who present with a dementing illness at a younger age than typical AD, and who demonstrate typical temporoparietal abnormalities. Functional imaging may also be used to provide additional evidence of a correct diagnosis in a patient with a clinical course typical of early AD, if family members or loved ones are anxious for further confirmation. Conversely, functional imaging can be reassuring in older patients with subjective complaints of memory impairment, but who show a normal perfusion pattern and may help to avoid multiple other diagnostic procedures. As quantitative methodology becomes more widely used, functional imaging may be very helpful in identifying patients in the earliest stages of AD for pharmaceutical trials (137). In addition, these techniques may prove useful in identifying image features that may predict response to pharmacological therapy (138) and as a physiological marker of response to therapy (139–141).

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116. Small SA, Perera GM, DeLaPaz R, Mayeux R, Stern Y. Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer’s disease. Ann Neurol 1999; 45:466–472. 117. Rombouts SA, Barkhof F, Veltman DJ, et al. Functional MR imaging in Alzheimer’s disease during memory encoding. AJNR Am J Neuroradiol 2000; 21:1869–1875. 118. Kato T, Knopman D, Liu H. Dissociation of regional activation in mild AD during visual encoding: A functional MRI study. Neurology 2001; 57:812–816. 119. Sperling R, Cocchiarella A, Bates J, et al. Functional MRI studies of face-name associations in healthy elderly and mild AD. [Abstract]. Neurology 2000; 54:A475. 120. Morris JC, Storandt M, McKeel DW, Jr., et al. Cerebral amyloid deposition and diffuse plaques in “normal” aging: evidence for presymptomatic and very mild Alzheimer’s disease. Neurology 1996; 46:707–719. 121. Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR. Linguistic ability in early life and cognitive function and Alzheimer’s disease in late life. Findings from the Nun Study. JAMA 1996; 275:528–532. 122. Morris JC, Ernesto C, Schafer K, et al. Clinical dementia rating training and reliability in multicenter studies: the Alzheimer’s Disease Cooperative Study experience. Neurology 1997; 48:1508–1510. 123. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 1997; 42:85–94. 124. de Leon MJ, Convit A, Wolf OT, et al. Prediction of cognitive decline in normal elderly subjects with 2[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc Natl Acad Sci USA 2001; 98:10966–10971. 125. Small GW, Mazziotta JC, Collins MT, et al. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 1995; 273:942–947. 126. Smith CD, Andersen AH, Kryscio RJ, et al. Altered brain activation in cognitively intact individuals at high risk for Alzheimer’s disease. Neurology 1999; 53:1391–1396. 127. Bookheimer SY, Strojwas MH, Cohen MS, et al. Patterns of brain activation in people at risk for Alzheimer’s disease [see comments]. N Engl J Med 2000; 343:450–456. 128. Johnson KA, Lopera F, Jones K, et al. Presenilin-1-associated abnormalities in regional cerebral perfusion. Neurology 2001; 56:1545–1551. 129. Kennedy AM, Frackowiak RS, Newman SK, et al. Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer’s disease. Neurosci Lett 1995; 186:17–20. 130. Corder EH, Jelic V, Basun H, et al. No difference in cerebral glucose metabolism in patients with Alzheimer disease and differing apolipoprotein E genotypes. Arch Neurol 1997; 54:273–277. 131. Sperling RA, Jones KJ, Rentz DM, et.al. SPECT cerebral perfusion and apolipoprotein E genotype. American Academy of Neurology 50th Annual Meeting Program 1998: A438. 132. Higuchi M, Arai H, Nakagawa T, et al. Regional cerebral glucose utilization is modulated by the dosage of apolipoprotein E type 4 allele and alpha1-antichymotrypsin type A allele in Alzheimer’s disease. Neuroreport 1997; 8:2639–2643. 133. Lehtovirta M, Soininen H, Laakso MP, et al. SPECT and MRI analysis in Alzheimer’s disease: relation to apolipoprotein E epsilon 4 allele. J Neurol Neurosurg Psychiatry 1996; 60:644–649. 134. Small GW, Ercoli LM, Silverman DH, et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA 2000; 97:6037–6042. 135. Reiman EM, Caselli RJ, Chen K, Alexander GE, Bandy D, Frost J. Declining brain activity in cognitively normal apolipoprotein E varepsilon 4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer’s disease. Proc Natl Acad Sci USA 2001; 98:3334–3339. 136. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2001; 56:1143–1153. 137. Foster NL. In: Terry RD, Katzman R, Bick KL, eds. PET Imaging, in Alzheimer’s Disease. New York: Raven press, 1994:87–103.

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7 The Neuropathology of Dementia Suzanne S. Mirra and Lynette G. Sheffield Department of Pathology, SUNY Downstate Medical Center, Brooklyn, New York, U.S.A.

INTRODUCTION This chapter will focus on the neuropathology of Alzheimer’s disease (AD), by far the most common cause of dementia in adults in our increasingly aging society. Although the neuropathology of important dementing illnesses is described in chapters in this volume, key gross and microscopic features considered by the neuropathologist in the differential diagnosis of dementia, especially neuropathological features of neurodegenerative disorders, will be highlighted here. It is important to recognize that considerable neuropathological overlap occurs among dementing illnesses. In community-based series, for example, many AD cases exhibit concomitant vascular pathology, most often gross or microscopic infarction, and/or neuropathological features of Parkinson’s disease (PD) such as pallor of the substantia nigra and Lewy bodies in brain stem and cerebral cortex, referred to as “dementia with Lewy bodies” (DLB) in the context of a patient with primary dementia. These overlapping pathologies will be discussed in greater detail in this chapter. In addition, in cases clinically and neuropathologically diagnosed as AD, it is possible to overlook more subtle concomitant pathologies, e.g., changes of progressive supranuclear palsy.

ALZHEIMER’S DISEASE In general, the clinical diagnosis of AD in the hands of an experienced physician can be made with considerable confidence. The clinical features and diagnosis of AD is covered in chapter 10 by Morris. In the experience of CERAD (Consortium to Establish a Registry for AD), a prospective National Institute on Aging (NIA)-sponsored multi-center study using standard clinical and neuropathological measures, about 87% of patients clinically diagnosed with probable AD had the diagnosis confirmed at autopsy (1,2). Although the clinical diagnosis of AD is often accurate, a definite diagnosis of AD still rests on tissue confirmation—usually obtained through autopsy. In addition to desiring confirmation of the clinical diagnosis, family members granting permission for autopsies often wish to contribute tissue for research. Indeed, substantive advances in our understanding of the molecular biology, genetics, and biochemistry of AD have resulted from information gleaned through AD autopsy studies. Although many autopsy cases of confirmed AD have been collected over the past few 129

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decades, especially by the NIA-supported Alzheimer Disease Centers, the autopsy remains an important source of new information. Postmortem cases derived from individuals with early AD or mild cognitive impairment (MCI) may be particularly valuable for studying early changes and disease progression. Autopsies also may be used to assess new biomarkers and to monitor outcomes of new therapeutic modalities. For example, autopsy studies on three patients receiving betaamyloid (Ab) immunization (3–5) have documented a potential reduction in AD neuropathology as well as a complicating meningoencephalitis in two of these cases. Gross Features of AD Although the definitive diagnosis of AD rests on microscopic evaluation of brain sections, characteristic changes are often seen on gross examination. Cortical atrophy, i.e., narrowing of the gyri with widening of the sulci, occurs to varying degrees (Fig. 1) and is generally observed in the frontal, temporal, and parietal cortex. Brain sectioning reveals variable enlargement of the lateral and third ventricles. Disproportionate enlargement of the temporal horn of the lateral ventricle is commonly encountered, with concomitant atrophy of the entorhinal cortex, amygdala, and hippocampus, structures invariably affected in AD (Fig. 2) (6–8). Pallor of the locus ceruleus is almost always observed in AD patients with longstanding dementia. The substantia nigra shows pallor in about onethird of AD cases (Fig. 8), commonly in association with concomitant PD changes, i.e., nigral degeneration and Lewy bodies at one or more sites (9,10). The presence of Lewy bodies in individuals with primary dementia and concomitant AD changes has been called “Lewy body variant of AD” (11); others have used the term “diffuse Lewy body disease” (12) in cases that may lack concomitant AD pathology. In 1996, a consensus group proposed clinical and neuropathological guidelines for the diagnosis of DLB (13), encompassing cases with and without concomitant AD; these diagnostic guidelines have been updated (14). The locus ceruleus is frequently pale in autopsy cases of AD (15) regardless of the presence or absence of Lewy bodies within these noradrenergic neurons. (Lewy Body disorder is covered in greater detail in chapter 12 by Galvin).

Figure 1 Atrophy of the cerebral cortex is seen in a patient with AD.

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Figure 2 Coronal sections from the brain of an AD patient showing prominent ventricular dilatation and atrophy of the entorhinal cortex, amygdala (A) and hippocampus (B).

Microscopic Features of AD The microscopic hallmarks of AD were described in 1907 when the Bavarian neuropathologist Alois Alzheimer reported the now famous case of a 55-year-old woman who died after a 4-year history of dementia (16). Using the Bielschowsky silver stain similar to the one used in many pathology laboratories today, Alzheimer observed neurofibrillary tangles and senile plaques, the latter change described even earlier as miliary plaques by Blocq and Marinesco (17). Decades later, sections of the brain of Alzheimer’s patient, Auguste D., were located in the Institute of Neuropathology at the University of Munich (18). The sections demonstrated typical AD neuropathology, i.e., numerous senile plaques and neurofibrillary tangles. Today, however, we know considerably more about these structures than when they were first described. Senile Plaques Most neuropathologists now recognize two major types of senile plaques—neuritic and diffuse. Neuritic plaques, seen best on silver stains (Fig. 3A), are largely extracellular spherical structures of varying size, averaging about 80mm in diameter. They are characterized by abnormal thickened neurites (neuronal processes, i.e., axons or dendrites) often arranged radially around a clearly visible central core of amyloid (Fig. 4A). Most neuritic plaques, however, display the abnormal neurites without well-formed amyloid cores. By electron microscopy, the abnormal neurites contain

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Figure 3 (A) Numerous neuritic plaques are evident in this section of neocortex from an AD patient. Original magnification !100. (B) Neurofibrillary tangles in CA1 of the hippocampus of a patient with AD. Original magnification !400. Silver stains.

dense bodies thought to be lysosomes, mitochondria, and paired helical filaments (Fig. 4C). Fibrillar amyloid, morphologically identical but biochemically distinct from other amyloids, comprises the cores seen by light microscopy and is interspersed between neurites in the extracellular space. The plaques have complex porous structures with normal myelinated axons and other processes coursing through them (19). Immunohistochemical studies have highlighted the molecular diversity of plaque components (20). The diffuse plaque, on the other hand, is a more amorphous structure that lacks the thickened neurites and prominent amyloid core seen in the neuritic plaque (Fig. 4B). Diffuse plaques vary considerably in size, ranging from those as small as 10mm or less in diameter often arranged in spraylike clusters to larger discrete spherical or irregular structures averaging about 80 mm in diameter. Although little or no fibrillar amyloid is seen in diffuse plaques by electron microscopy (21), both diffuse and neuritic plaques share antigenic determinants with the Ab amyloid protein isolated from AD plaques and blood vessels (Fig. 5B) (22–24). Plaques of both types are found in varying proportions in AD in neocortex, hippocampus, entorhinal cortex, amygdala, and other regions. Although diffuse plaques may evolve into neuritic forms in some regions such as neocortex, in many parts of the brain such as the striatum, hypothalamus, and cerebellum, diffuse plaques predominate, regardless of disease duration (25). Neurofibrillary Tangles and Neuropil Threads Neurofibrillary tangles (NFT) are intraneuronal silver-positive fibrillar structures occupying the cell body and apical dendrite of neurons (Fig. 3B). NFT often assume the shape of the neurons they

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Figure 4 (A) A neuritic plaque exhibits a prominent amyloid core surrounded by abnormal neurites. (B) Diffuse plaques lack the abnormal neurites but stain with silver preparations and Aß antibodies. Bielschowsky; original magnification !400. (C) Electron micrograph of a neuritic plaque in a patient with AD. The amyloid core is visible in the upper left surrounded by abnormal neurites containing dense bodies (arrow) and paired helical filaments (arrowheads). Original magnification !5750.

occupy. Thus, NFT within pyramidal cells of the hippocampus are flame-shaped whereas those within neurons of the nucleus basalis of Meynert or locus ceruleus have a more rounded contour. Studies of the distribution of NFT in AD have revealed common localization in CA1 and the subiculum of the hippocampus, layers II and IV of the entorhinal cortex, as well as certain neocortical regions and laminae (8,26). Arnold and coworkers found that primary sensory cortex has relatively few NFT, with increasing numbers in the adjacent unimodal association cortex, and the largest number found in high-order (multimodal) association cortex such as the superior temporal sulcus or inferior temporal gyrus (26). Moreover, a relatively predictable pattern of progression of neurofibrillary degeneration with differentiation into six stages from the transentorhinal/entorhinal cortex to isocortex has been described by Braak and Braak (27). Subcortical structures commonly exhibiting NFT in AD include the amygdala, nucleus basalis of

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Figure 5 Sections of neocortex from AD cases. (A) Numerous senile plaques are observed, along with cerebral amyloid angiopathy in meningeal and parenchymal blood vessels. Thioflavine S; original magnification !40. (B) Senile plaques and cortical blood vessels are labeled with antibody to Aß. Original magnification !40. (C) Neurofibrillary tangles and neuropil threads (arrows) are labeled by tau antibody. Original magnification !200.

Meynert, locus ceruleus, and the dorsal raphe nucleus. Longstanding NFT within CA1 of hippocampus and entorhinal cortex may persist after the cells in which they reside have apparently died and lost their cell membrane; these are termed “ghost” or “extracellular” tangles. Not specific to AD, NFT may also be observed in cognitively normal or mildly impaired individuals in the entorhinal cortex and occur in other conditions (28), including progressive supranuclear palsy (PSP), dementia pugilistica, subacute sclerosing panencephalitis, NeimannPick’s disease type C (29,30), Down syndrome, post-encephalitic parkinsonism, myotonic dystrophy, congenital muscular dystrophy (Fukuyama type), Kufs’ disease, Cockayne’s syndrome, Hallervorden-Spatz disease, Gerstmann-Stra¨ussler-Scheinker syndrome (31) and ALS-parkinsonism dementia complex of Guam. Most of these disorders, however, are quite rare and NFT remain a key

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histological feature of AD, one that has been incorporated into the neuropathological criteria for this disorder (32). Furthermore, the density of NFT in AD correlates with the duration and severity of cognitive impairment (33–35). At a fine structural level, NFT are comprised primarily of paired helical filaments, i.e., two filaments measuring approximately 10 nm each, that appear to rotate at regular 80-nm intervals (Fig. 6). The major constituent of paired helical filaments is an abnormally phosphorylated form of tau, the typically axonal microtubule-associated protein (36–38). However, NFT also share

Figure 6 (A) Electron micrograph of a neuron with paired helical filaments (asterisk) comprising a neurofibrillary tangle. !5700. (B) High power electron micrograph of paired helical filaments reveals typical periodicity. !57,000.

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antigenic determinants with a battery of proteins (39), including ubiquitin, casein kinase II, protease nexin I, heparin sulfate proteoglycan, fibroblast growth factor, and microtubule-associated protein-5. Within the neuropil of the AD cortex and other gray matter regions, individual thickened processes distinct from neuritic plaques are often seen. These “neuropil threads” stain with silver methods and are labeled by antibodies to tau (Fig. 5C), ubiquitin, PHF, neurofilament protein, and acetylcholine esterase (39). They have been interpreted as a cytoskeletal change, often involving dendrites (40,41). The frequency of neuropil threads reportedly correlates more closely with cognitive status than either plaques or tangles (42). Strong correlation has been found between loss of synapses, as measured by reduction in synaptic proteins (especially the presynaptic protein synaptophysin), and the level of cognitive impairment in AD (43–46). Terry and colleagues found a powerful correlation between the density of neocortical synapses and cognitive alterations, and concluded that synapse loss is the major correlate of cognitive impairment (45). Cerebral Amyloid Angiopathy (CAA) Amyloid is deposited in the walls of arteries and arterioles in the subarachnoid space and cerebral and cerebellar cortex in AD (Fig. 5A). Capillaries and venules may also be involved with general sparing of blood vessels in the white matter. Although CAA is encountered in virtually every case of AD, considerable variation exists in the extent of this change. In general, the occipital cortex is most severely involved. CAA also occurs in the brains of elderly individuals without AD (47–49), and lobar hemorrhages may occur either with or without AD (50). The severity of CAA has been linked to both the 34 and 32 alleles of apolipoprotein E (ApoE) (50–54) with the 32 allele more closely related to cases exhibiting cerebral hemorrhages (55–57). Other Changes Another change commonly found in AD is the Hirano body, an eosinophilic rod that labels with antibodies to actin and actin-binding proteins (58,59). Hirano bodies are most commonly encountered in CA1 pyramidal cell processes in the hippocampus. Not specific for AD, Hirano bodies also are seen in ALS-parkinsonism dementia complex of Guam, normal elderly, Pick’s disease, and other disorders. Often coexisting in the cytoplasm of the same neurons harboring Hirano bodies and/or NFT is a change known as granulovacuolar degeneration. Small granules sharing antigenic determinants with tubulin (60), phosphorylated neurofilaments (61), tau (62,63), and ubiquitin (64) occur within clusters of cytoplasmic vacuoles. These structures, too, are not unique to AD as they also occur in normal elderly individuals and in other conditions including Pick’s disease, ALS-parkinsonism dementia complex of Guam, Down syndrome, tuberous sclerosis, hypothalamic gangliocytoma, and PSP (39). Subcortical Pathology in AD Despite frequent classification as a “cortical” dementia, AD consistently involves certain subcortical structures as well. The nucleus basalis of Meynert, located in the substantia innominata with extensive cortical and other projections, shows loss of cholinergic neurons and gliosis with NFT common in residual neurons (65). Cholinergic dysfunction is believed to play an important role in the memory disturbance in AD and other disorders (66). Loss of cholinergic markers including choline acetyltransferase (CAT), the enzyme involved in acetylcholine synthesis, and acetylcholinesterase, has been correlated with cognitive decline and plaque and tangle frequency, at least in late-stage AD. Interestingly, patients with early or mild AD may not exhibit decline in these cholinergic markers (67).

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In about one-fifth to one-third of AD cases, the substantia nigra exhibits PD-like changes, with loss of dopaminergic neurons, gliosis, pigmentary incontinence, and cytoplasmic Lewy bodies in residual nigral neurons (15). More widespread Lewy bodies are often encountered as well. The classification of cases of AD with Lewy bodies is discussed above under gross features and in the section on dementia with Lewy bodies. The locus ceruleus in the rostral pons manifests loss of noradrenergic neurons with depigmentation, particularly in longstanding cases as mentioned previously in the section on Gross Features; some but not all investigators have linked this noradrenergic cell loss to depression. NFT are common within the locus ceruleus as well. The dorsal raphe nucleus, a serotonergic nucleus, almost invariably displays frequent NFT in AD, along with variable cell loss. Loss of dopaminergic neurons of the substantia nigra and ventral tegmental area may also occur, albeit not in all cases. Other subcortical structures also are involved in AD: Plaques and tangles occur frequently in thalamic nuclei, for example, and diffuse plaques are common in the corpus striatum, hypothalamus, and cerebellar cortex. Neuropathological Criteria for the Diagnosis of AD The criteria used for the neuropathological diagnosis of AD have evolved over the last two decades. The widely used “Khachaturian criteria,” developed by a panel of neuropathologists in 1984 (68), required an age-related minimum number of senile plaques per square millimeter of neocortex; the older the patient, the more plaques were required. For example, in an individual with dementia over 75 years of age, over 15 plaques per low-power field were needed to make the diagnosis of AD; in a younger individual 50–65 years of age, only eight plaques were required. These criteria, although adequate for the majority of AD cases, did not allow for characterization of less clear-cut cases, e.g., those with less than minimal criteria or meeting the neuropathological criteria but lacking a history of dementia. Differences in stain sensitivity that might appreciably alter plaque counts also were not taken into account. A survey of United States and Canadian neuropathologists several years later revealed persistent significant disparities in diagnostic approach (69). In an effort to standardize the neuropathological assessment of AD, the Neuropathology Task Force of CERAD developed a neuropathology data base with an illustrated guidebook and diagnostic algorithm (1,2). The CERAD approach used semi-quantitative determinations of neuritic plaque frequency in neocortex (Fig. 7), that were then integrated with age and available information on the presence or absence of dementia (Table 1). This protocol provided levels of diagnostic certainty and promoted common language among centers. A multicenter study conducted by CERAD confirmed that semi-quantitative determinations of plaque and tangle frequency were more reliable than quantitative determinations, especially when pooling data among centers (70). Since its development, the CERAD protocol has been widely used in numerous clinical-pathological, genetic, and other studies worldwide. This protocol also has been incorporated into the recommendations of the Consortium on DLB (13) and the NIA-Reagan Institute Working Group on the diagnosis of AD (32). The NIA-Reagan Group recommended using the CERAD approach, additionally emphasizing examination of the hippocampus and neocortex for NFT to strengthen the diagnosis of AD. The group also proposed use of the Braak and Braak staging of neurofibrillary degeneration in research settings. Cases with frequent neuritic plaques by CERAD evaluation and widely distributed neurofibrillary degeneration (Stage V/VI of Braak and Braak) would be assessed as having a high likelihood of AD (Table 1). Emphasis on neurofibrillary pathology was fueled by demonstrations that NFT frequency correlates well with duration and severity of AD (33,35,71). The use of NFT as major determinants of likelihood of AD, however, operationally downgrades as less likely to be AD cases of concomitant Lewy body disease with relatively few NFT (72) while

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Figure 7 Neuritic plaques per !100 microscopic field. This drawing from CERAD provides a guide to semiquantitative assessment of neuritic plaque frequency. Reprinted with permission from Ref. 2.

leaving a significant subset of Lewy body cases with greater tangle frequency classified as AD with DLB (73). Whether these operational criteria can be justified on a biological or clinical basis remains uncertain.

LEWY BODY DISORDERS Any discussion of the neuropathology of Lewy body disorders must take into consideration still controversial nosological issues. This issue is covered in greater detail in chapter 12 by Galvin. Classification of Lewy body disorders may be influenced by clinical factors including presentation, e.g., primary dementia versus primary movement disorder, and the nature of the clinical setting, e.g., community versus specialized movement disorder or memory disorders clinic, as well as the neuropathological evaluation of mixed or overlapping features of AD, PD, and other changes noted at autopsy (39). Moreover, it is covered in greater detail in chapter 12 by Galvin. Moreover, it is problematic for the pathologist to make a diagnosis of PD in the absence of a history of parkinsonism or a diagnosis of AD in the absence of dementia. In fact, when evaluating a case exhibiting nigral degeneration with Lewy bodies in the substantia nigra and other subcortical and

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Table 1 Diagnostic Criteria for Alzheimer’s Disease Diagnosis Definite AD Probably AD Possible AD (subtype 1) Possible AD (subtype 2) Not AD Not AD

Likelihood of AD High Intermediate Low

CERAD criteriaa NP score

Clinical history

Cb Bc Ad Bc or Cb 0e or Ad 0e

Dementia Dementia Dementia No dementia No dementia Dementia

NIA-Reagan criteriaf Braak and Braak stage of neurofibrillary CERAD NP score degeneration Frequent NP Moderate NP Sparse NP

Stage V/VI Stage III/IV Stage I/II

Isocortical Limbic Transentorhinal

Age-related NP frequency. a Summarized from Ref. 2. b CZfrequent NP at any age, moderate NP !75 yr, sparse NP !50 yr. c BZmoderate NP O75 yr, sparse NP 50–75 yr. d AZsparse NP O75 yr. e 0Zno NP. f Summarized from Ref. 32.

cortical locations, the neuropathologist cannot ascertain on pathological grounds alone whether the patient had idiopathic PD or dementia or both. Some neuropathologists have suggested using a purely descriptive approach, at least for research purposes (74). Others suggest pooling available clinical and neuropathological information to reach the most reasonable final diagnosis. Dementia with Lewy Bodies Proposed as the second most common cause of dementia after AD, DLB has been accepted by many as a distinct clinical and pathological entity. Yet, relatively few cases of DLB are “pure” as most display varying degrees of AD neuropathology, supporting the view of some that DLB is actually a variant of AD. In fact, the name “Lewy body variant of AD” is one of several terms applied to such overlapping pathologies (11). Certain clinical-pathological features may lead the clinician to favor the diagnosis of DLB (11,13,75), including impairment of visuospatial skills, problem solving, and attention; fluctuation of cognitive function, visual hallucinations, and evidence of parkinsonism such as rigidity or bradykinesia. Consensus guidelines for the diagnosis of DLB proposed by McKeith and colleagues included neuropathological features of Lewy bodies within brainstem and cortex and other non-requisite findings, e.g., Lewy neurites, nigral cell loss and gliosis, and spongiform change within the neuropil (13). Subsequent studies neuropathology protocol for tissue sampling and assessment was also recommended. Subsequent studies assessing the validity of the consortium criteria have yielded mixed results (76–79). In addition, regional Lewy body densities did not necessarily correlate with clinical features of DLB (80). Updated guidelines by the DLB consortium now include identification of Lewy bodies and Lewy neurites by a-synuclein immunohistochemistry, documenting regional involvement and grading lesion density in a semiquantitative manner (14). The NIA-Reagan criteria (32) as well as the CERAD neuropathology protocol for tissue sampling and assessment also are incorporated.

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Gross Features of DLB The major gross finding in most cases of DLB is a variable degree of pallor of the substantia nigra (Fig. 8A). Pallor of the locus ceruleus may occur in DLB, but is not a distinguishing feature as it is seen in most longstanding cases of AD, regardless of the presence or absence of Lewy bodies. Finally, if the case of DLB shows concomitant AD pathology, as is very common, all of the gross features pertinent to AD may be found (see the previous section on AD neuropathology).

Figure 8 (A) Marked pallor of the substantia nigra is noted in the brain of a patient with DLB with concomitant AD. (B) The substantia nigra of a patient with “pure AD” shows normal pigmentation. Lewy bodies (arrows) in the substantia nigra (C) and cerebral cortex (D,E) of a patient with DLB and AD. Hematoxylin and eosin (C,D) and ubiquitin immunohistochemistry (E). Original magnification !200.

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Microscopic Changes of DLB Corresponding to the nigral pallor seen grossly, loss of pigmented neurons, gliosis and pigmentary incontinence are observed at a microscopic level. As expected, the degeneration of dopaminergic neurons in the nigra in DLB is reflected in loss of tyrosine hydroxylase immunoreactivity in the striatum (81). However, the most distinctive histopathological feature of both DLB and idiopathic PD is the Lewy body. Single or multiple Lewy bodies are found within the cytoplasm of dopaminergic neurons in the pars compacta of the substantia nigra. These eosinophilic to weakly basophilic inclusions range in diameter from about 3 to 20 mm. They often have concentric configurations with peripheral halos (Fig. 8C). By electron microscopy, Lewy bodies display amorphous material and 10–20 nm filaments with irregular contours. Lewy bodies also are found within neuromelanin-bearing neurons of the locus ceruleus and dorsal nucleus of the vagus, as well as in non-pigmented neurons of the nucleus basalis of Meynert, entorhinal cortex, neocortex, amygdala, and other sites. They may occur in the same cells as NFT, particularly in neurons of the substantia nigra or locus ceruleus. Cortical Lewy bodies are less well defined than their counterparts in the brainstem, often displaying a relatively amorphous eosinophilia, expanding the cytoplasm and displacing the nucleus to the periphery of the cell (Fig. 8D). The concentric pattern and peripheral halos that characterize Lewy bodies in brainstem and other sites are uncommon. Cortical Lewy bodies are usually found in small- to medium-sized pyramidal neurons, often involving the deeper cortical layers. Common cortical sites include the parahippocampal and inferior and middle temporal gyri, the cingulate gyrus, and the insular cortex. Antibodies to ubiquitin and a-synuclein label virtually all Lewy bodies but are especially helpful in the detection of cortical Lewy bodies (Figs. 8E and 9A). Since the finding of missense mutations in the a-synuclein gene in familial PD in Italian and Greek families (82,83), a-synuclein, a 140-amino-acid presynaptic protein, has been recognized as a major component and marker of Lewy bodies and neurites (84–90). Alpha-synuclein antibodies also label the characteristic glial cytoplasmic inclusions in multisystem atrophy (89,91). Another interesting neuropathological feature of DLB is the presence of so-called “Lewy neurites”. Perhaps most prominent in CA2-3 of Ammon’s horn of the hippocampus (92,93) (Fig. 9B), these ubiquitin and a-synuclein-immunoreactive structures are found in multiple sites including the substantia nigra, nucleus basalis of Meynert, and amygdala. The CA2-3 neurites occur in most cases exhibiting Lewy bodies, whether they fall under the rubric of DLB, idiopathic PD, or other disorders such as PSP with concomitant Lewy bodies (94). Still another neuropathological feature of some but not all cases of DLB is an intriguing spongiform change, not unlike that encountered in Creutzfeldt-Jakob disease (95). The distribution of this spongiform change is relatively stereotypical, involving the superior and inferior temporal cortex, insular and entorhinal cortex, and amygdala. Neuropathology of Idiopathic Parkinson’s Disease with Dementia Confirmation of the diagnosis of idiopathic PD rests with autopsy. In a study of 100 cases clinically diagnosed with idiopathic PD, almost one-quarter proved to have other conditions, e.g., PSP, AD, vascular disease, and multisystem atrophy (96). Several of these conditions also may be associated with dementia. Classic and well-accepted neuropathological changes associated with idiopathic PD with or without dementia are virtually identical to those described above in DLB. These include loss of dopaminergic neurons and gliosis of the pars compacta of the substantia nigra and the presence of Lewy bodies in pigmented nuclei (substantia nigra, locus ceruleus, and dorsal vagus nucleus), nucleus basalis, cerebral cortex, and other sites. Neurons may contain one or more Lewy bodies in their cytoplasm. Immunohistochemistry using antibodies to ubiquitin, a-synuclein, or

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Figure 9 Alpha-synuclein immunoreactivity in DLB. (A) Cortical Lewy bodies (arrows) and (B) Lewy neurites (arrows) within CA2-3 of hippocampus are immunopositive with antibody to a-synuclein. Original magnification !400 (A) and !200 (B).

neurofilament protein has enhanced detection of cortical Lewy bodies. In fact, in a study of 76 pathologically confirmed PD cases in which ubiquitin immunohistochemistry was performed, cortical Lewy bodies were identified in 100% of idiopathic PD cases (96). Approximately 10–15% of individuals with idiopathic PD develop dementia (97,98) and PD patients with severe extrapyramidal signs are particularly vulnerable (99). Although the ApoE 34 allele conveys increased risk for the development of AD, no association has been found between PD with dementia and apolipoprotein E genotype (100). The underlying cause of dementia in association with idiopathic PD is not always clearcut. In a clinical-pathological study of idiopathic PD patients with a clinical history of dementia, Hughes and coworkers found AD to be the underlying cause in 29 of 44 cases (66%); ten cases showed numerous cortical Lewy bodies and six had a possible vascular cause (96,101). Another change implicated in dementia with PD is degeneration of the nucleus basalis of Meynert; however, this is seen in idiopathic PD patients both with and without dementia (39). Degeneration of the locus ceruleus also has been proposed as an underlying cause of the dementia (102,103). More recent investigations have suggested that the best neuropathological correlates of dementia in PD are a-synuclein positive neurites in CA2-3 (104) or Lewy bodies (105). THE TAUOPATHIES It has become increasingly apparent that a group of neurodegenerative disorders displays abnormal accumulations of tau filaments within neurons and glial cells. Although AD is the

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most important example of this, tau pathology is a key feature of other disorders with diverse neuropathological and clinical phenotypes, including Pick’s disease, PSP, corticobasal degeneration, and frontotemporal dementia with parkinsonism linked to chromosome 17 (and tau mutations) (FTDP-17). Dementia may be a presenting clinical feature of these conditions or may develop later. These disorders are discussed in detail in chapter 13 by Miller. Pick’s Disease Over the years, Pick’s disease has been characterized in different ways based on clinical and neuropathological features (106–109). Although most cases of Pick’s disease have been sporadic, familial cases with an autosomal dominant pattern of inheritance have been reported. Recently familial frontotemporal dementias with a Pick-like phenotype have been associated with tau mutations (110–113), although differences from sporadic cases in biochemical and molecular features have been reported. Thus, the definition of Pick’s disease continues to evolve. Although Pick’s disease is infrequently encountered by neuropathologists (one case of Pick’s disease for every 50-100 cases of AD), the changes are often so distinctive that the diagnosis can be readily made. External examination often provides clues that the neuropathologist is dealing with a frontotemporal dementia likely to be Pick’s disease. Disproportionate temporal-frontal atrophy (Fig. 10) may be so severe that the cortex has a “knife edge-like” appearance. Typically, relative sparing of the posterior two-thirds of the superior temporal gyrus is observed (Fig. 10A); this is distinct from Down’s syndrome, where approximately half the cases show disproportionate narrowing of the superior temporal gyrus. Striking cortical asymmetry is common in Pick’s disease (Fig. 10B). The lateral ventricles are dilated secondary to loss of gray and white matter (hydrocephalus ex vacuo). Atrophy of the hippocampus and amygdala is often observed and variable degeneration of the corpus striatum, globus pallidus and substantia nigra occurs as well. Corresponding to the areas of degeneration, neuronal loss, gliosis and spongiosis is prominent. Scattered Pick cells, ballooned neurons with expanded eosinophilic cytoplasm immunopositive for neurofilament protein, may be present in these regions. Pick cells are virtually identical to the ballooned neurons seen in corticobasal degeneration (Fig. 14) and other conditions (114). The most salient microscopic feature in Pick’s disease is the presence of Pick bodies, cytoplasmic inclusions that are weakly basophilic on routine H&E preparations but stain prominently using silver methods (Fig. 11). Usually found in the limbic and paralimbic cortices and ventral temporal lobe (115), Pick bodies are most common in the granular cells of the dentate gyrus (Fig. 11) and in the pyramidal cell layer of the hippocampus. They are also found in the basal ganglia, hypothalamus, and periaqueductal gray matter. The major component of Pick bodies is tau (116); other proteins are less consistently identified. Biochemical analyses of sarkosyl-insoluble tau on immunoblots have demonstrated different patterns among AD, Pick’s disease, PSP, and corticobasal degeneration (117,118). Progressive Supranuclear Palsy Although the dementia in PSP is usually mild, it may be the presenting feature (119). Thus, the pathologist may encounter PSP cases in patients clinically diagnosed as AD. To further complicate matters, PSP may coexist with AD and, in this scenario, the often more subtle changes of PSP may be overlooked. The neuropathological features of PSP are stereotypical, generally conforming to those described in the seminal work of Steele, Richardson, and Olszewski in 1964 (120). Although the gross changes in PSP are less obvious than those of Pick’s disease, they are sufficiently characteristic to suggest the diagnosis. Pallor of the substantia nigra is common (Fig. 12B), corresponding to neuronal loss with accompanying globose NFT in residual neurons. Even more typical, however, is enlargement of the aqueduct of Sylvius (Fig. 12B), reflecting involvement of the periaqueductal gray matter and superior colliculi. Variable enlargement of the third (Fig. 12A)

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Figure 10 Lateral view (A) and coronal section (B) from case of Pick’s disease. Atrophy of the right inferior and middle temporal gyri is seen with relative sparing of the superior temporal gyrus.

and fourth ventricles may also be seen; this may be severe in longstanding cases. Occasionally, atrophy of other commonly involved regions, e.g., the globus pallidus (Fig. 13A) or the subthalamic nucleus, can be detected grossly. Microscopic examination reveals variable neuronal loss and gliosis in the globus pallidus, subthalamic nucleus, periaqueductal gray matter, substantia nigra, inferior olivary nucleus, dentate nucleus, and other sites. In these regions, one may find the globose NFT that characterize PSP (Fig. 13B). Neocortical degeneration also occurs, usually later in the course of the disease, along with tau-positive neuronal and glial tangles (121–126). Synaptic loss also has been suggested as a

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Figure 11 Pick bodies in the dentate neurons in the hippocampus of a patient with Pick’s disease. Bielschowsky stain; original magnification !400.

determinant of dementia in PSP (127). Grumose degeneration of the dentate nucleus with granular eosinophilic deposits overlying neuronal dendrites and cell bodies also occurs in PSP. The eosinophilic granules apparently correspond to retrograde degenerative changes in axonal terminals synapsing onto dentate neurons (128,129). Similar changes have been observed in other neurodegenerative diseases affecting the dentate nucleus. The distribution of the neuropathology is particularly fascinating as most of the regions involved in PSP, e.g., globus pallidus, subthalamic nucleus, inferior olivary nucleus, and dentate nucleus, are relatively spared in AD. Yet, the tangles in PSP share antigenic determinants with tau (116), as do the NFT of AD. Unlike the tangles in AD, however, the PSP tangles are generally composed of 15-nm straight filaments rather than paired helical filaments (130,131). Moreover, the biochemical and molecular profile of tau in PSP differs from that of AD (117,118,132). Corticobasal Degeneration Although corticobasal degeneration (CBD) is primarily a movement disorder, dementia is a common feature (133). As with PSP, dementia may be the presenting symptom. The characteristic gross abnormality in CBD is asymmetrical atrophy of the perirolandic gyri (Fig. 14A); cases with prominent dementia may display a more anterior-frontal pattern of cortical involvement. Loss of myelin and axons is observed in the underlying white matter. Microscopically, involved cortical regions exhibit variable neuronal loss and gliosis. These changes also occur within other regions, such as the basal ganglia, thalamus, substantia nigra, and cerebellum, but are highly variable. A characteristic, although not pathognomonic, feature is the presence of eosinophilic ballooned or achromatic neurons (Fig. 14B) filled with intermediate

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Figure 12 Coronal section (A) from the brain of a PSP patient shows enlargement of the third ventricle. Enlargement of the aqueduct and pallor of the substantia nigra are evident on a section of midbrain (B) from the same patient.

filaments sharing antigenic determinants with phosphorylated neurofilament protein (Fig. 14C), and abcrystallin; these neurons occur in other conditions including Pick’s disease (“Pick cells”) and Creutzfeldt-Jakob disease (114). Dickson and colleagues have highlighted the importance of tau cytopathology in CBD, mainly involving glia of the white matter, as well as cortical neurons and astrocytes (134,135). They also called attention to the characteristic tau-positive astrocytic plaques, found within cortex in cases of CBD. These findings led to increasing recognition that CBD is also a tauopathy. The biochemical and molecular profile of tau in CBD is similar to that seen in PSP, but differs from that

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Figure 13 (A) The globus pallidus is discolored and atrophic in this PSP patient. (B) Globose neurofibrillary tangles in the globus pallidus of the same case. Sevier-Munger silver stain; original magnification !200.

of AD (117). Reports of families with tau mutations displaying CBD-like clinical or neuropathological phenotypes (136–138) have further stimulated interest in this disorder. Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17 (FTDP-17) A heterogeneous group of familial disorders exhibiting varying degrees of dementia, neurobehavioral abnormalities, e.g., hyperorality or obsessive-compulsive features, parkinsonism,

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Figure 14 (A) Asymmetrical atrophy of the cerebral cortex with striking involvement of the left perirolandic cortex is observed in a patient with corticobasal degeneration. (B) A characteristic ballooned neuron is seen in neocortex (hematoxylin and eosin). (C) A ballooned neuron is labeled by antibody to neurofilament protein. Original magnification !400.

language deficit, and loss of frontal executive functions has been identified (139). A common neuropathological feature of these disorders is extensive tau deposition in multiple gray and white matter regions, leading Spillantini and colleagues to characterize these disorders as tauopathies (140,141). Tau mutations have emerged as an underlying cause of many of these familial disorders. Most cases of FTDP-17 exhibit frontal and temporal cortical atrophy with corresponding neuronal loss and gliosis (Fig. 15). Loss of myelin and axons in the underlying white matter also occurs. Subcortical nuclei may be involved to varying degrees, and the substantia nigra may show loss of pigment corresponding to neuronal degeneration and gliosis. Deposition of tau filaments producing tangle-like structures within neurons and glia is found. Members of some of these families have exhibited a neuropathological phenotype resembling Pick’s disease (110–113), CBD

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Figure 15 Frontotemporal degeneration in a family with dementia and a P301L tau mutation. A coronal section from the brain of a 55-year-old woman clinically diagnosed as having AD exhibits atrophy of frontal and temporal cortex with loss of underlying white matter and dilatation of the lateral ventricles. Extensive tau deposition (tauopathy) in neurons and glia was observed microscopically (136).

(136–138), or PSP (142). A tau mutation also has been identified in familial progressive subcortical gliosis (143). Other Frontotemporal Dementias Other conditions with frontotemporal degeneration and dementia listed below generally lack prominent tau pathology and have less well-defined clinical or neuropathological features: † † † † † †

Hereditary dysphasic dementia Primary progressive aphasia Frontal lobe dementia Motor neuron disease with dementia Dementia lacking distinctive histology Progressive subcortical gliosis.

HUNTINGTON’S DISEASE Huntington’s disease (HD) is caused by an expansion of CAG repeats (polyglutamine) within the coding region of the gene for huntingtin on chromosome 4 (144). The function of huntingtin and the mechanism by which this mutation and its polyglutamine expansion cause the disease is not understood. The dementia of HD may precede the onset of chorea; morphometric studies have revealed loss of cortical neurons that may account for some of the cognitive and neuropsychiatric impairment (145–147). At autopsy, 80% of HD brains exhibit atrophy of the frontal lobes (147). The most striking neuropathological finding in HD, as reviewed by Vonsattel and DiFiglia (147), however, is bilateral symmetrical atrophy of the striatum, particularly involving the caudate nuclei. Gradation in the degree of neuropathological changes occurs and may parallel the degree of clinical disability (148). Typically, the tail of the caudate is more severely involved than the body, which is more involved than the head of the caudate. When the pathological changes are severe (Fig. 16),

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Figure 16 Coronal section from a patient with Huntington’s disease shows bilateral atrophy of the caudate nuclei.

sections reveal the bilateral symmetrical atrophy of the head of the caudate nucleus with flattening of its normally convex contour. Although this appearance is highly suggestive of HD, similar gross changes may occasionally be encountered in other conditions, e.g., AIDS encephalopathy and Pick’s disease, the latter in association with lobar atrophy. Rarely, autopsy studies have failed to reveal the typical neuropathology, even when patients have clinical features of HD and have been genetically confirmed (149). Corresponding to the striatal atrophy seen grossly, loss of neurons and fibrillary gliosis are the major histopathological changes observed. In the striatum, medium-sized spiny neurons containing gamma-aminobutyric acid (GABA), are preferentially affected (147); residual large aspiny neurons containing somatostatin and neuropeptide Y are relatively spared. Recent investigations have revealed intriguing inclusions within nuclei and, to a lesser extent, within dendrites, dendritic spines, and axons. These aggregates of polyglutamine label with antibodies to huntingtin and, less consistently, with ubiquitin (150,151). Interestingly, the inclusions are more common in cortex than striatum and apparently do not signal impending cell loss. Instead, mutant huntingtin aggregation may actually protect against polyglutamine-induced neurotoxicity (152).

VASCULAR DEMENTIAS Confounding Factors The relationship between cerebrovascular disease and dementia is a complex one, and our understanding of the extent to which vascular disease contributes to dementia in general as well as to AD continues to evolve. Any comprehensive analysis of this subject must take into consideration the numerous confounding factors that potentially affect data (153,154): The lack of standard

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instruments for collecting and comparing clinical, neuropsychological, neuroimaging, and neuropathology information; disparate operational definitions of dementia; use of imaging technology with varying sensitivities; as well as the relative infrequency of neuropathological confirmation mitigates the value of many clinical studies. Sampling bias, inadequate sample size, and lack of consensus on significance of neuropathological and clinical findings further compound the problem. Criteria for the diagnosis of vascular dementia and ischemic vascular dementia have been proposed (155–157) and their validity is being tested (155,158,159). Yet, neuropathological criteria for the diagnosis of vascular dementia remain problematic. The clinical features of vascular dementia are covered in detail in chapter 14 by Chui. Vascular Dementia and AD Although a significant subset of neuropathologically-confirmed AD cases exhibit some degree of vascular pathology at autopsy, the significance of this overlapping pathology remains controversial. Community autopsy series often reveal mixed or overlapping pathologies of AD, vascular lesions, and PD changes (160–162). Prospective studies conducted by CERAD revealed that about one-third of AD cases exhibit concomitant infarcts and/or hemorrhages (1); such individuals had poorer cognitive function and were older than cases of “pure” AD (163), but no significant differences were identified between the two groups in semi-quantitative plaque or NFT frequencies. Others using different methods of quantification have reported fewer neuritic plaques and NFT in AD cases with cerebral infarcts or with coexistent vascular and PD pathology (164–166). In contrast to the relatively large proportion of dementia cases diagnosed clinically as vascular dementia (167), “pure” vascular pathology is rarely encountered by neuropathologists (168), although exceptions have been reported (169,170). In clinical-pathological studies of patients clinically diagnosed as having AD, only a minority of cases (about 1–2%) are interpreted by the pathologist as having a vascular basis for the dementia (2,171,172). To some extent, the relative rarity with which vascular disease-based dementia is observed by neuropathologists may reflect the largely white patient population seen in many large centers caring for dementia patients. Both autopsy and clinical studies suggest that the frequency of dementia with cerebrovascular disease is higher among blacks (173–175), and black and Hispanic patients exhibit increased risk of developing dementia three months after stroke (176). Potential Links Between Cerebrovascular Disease and AD Several reports have challenged the notion that the overlap between cerebrovascular disease and AD is merely coincidental. Neuropathological studies have revealed an association between cerebral amyloid angiopathy, a common feature of AD, and cerebral infarctions and hemorrhages (177–181). This association apparently is not related to ApoE 34 genotype frequency (179). New information has emerged on the relationship among cholesterol, amyloid, and dementia. Epidemiological studies have suggested a decline in dementia prevalence in individuals taking statins (182). In parallel, laboratory studies have shown that lowering cholesterol reduces Ab production from amyloid precursor protein (APP) (183,184). Conversely, increasing dietary cholesterol in transgenic mice increases Ab deposition (185), recalling earlier observations of Sparks regarding an association between senile plaques and coronary artery disease (186,187). Cholesterol accumulation in senile plaques has also been noted (188). Dementia Associated with Major Strokes and Multi-Infarct Dementia Both volume and location may be critical factors in determining whether dementia occurs following large single or multiple infarcts (176,189). Infarcts involving the left hemisphere, limbic system,

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and subcortical white matter may have greater propensity to cause dementia as do bilateral infarcts with more involvement of the dominant hemisphere (39). Hachinski characterized the vascular disease responsible for dementia as multi-infarct dementia, caused by small or large vessel infarcts, usually involving deep gray and/or white matter (190). Multiple foci of softening and/or cystic change are usually seen, most frequently involving the deep gray matter of the thalamus and basal ganglia and often affecting the cerebral white matter as well (Fig. 17). Ventricles may be enlarged, often asymmetrically, reflecting the loss of brain tissue. The large vessels of the circle of Willis and extracranial blood vessels may show significant atherosclerosis, potentially leading to local thromboses or emboli. Emboli also may result from cardiac arrhythmias or infarction, sickle cell anemia, and other disorders predisposing to thrombosis, systemic lupus erythematosus, familial cerebrovascular disease associated with cerebral amyloid angiopathy, and other disorders such as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). CADASIL, a familial vascular dementia (191) associated with mutations in the Notch 3 gene (192), is a rare disorder characterized by strokes in midlife and often accompanied by dementia (193–196). Multiple foci of infarction may occur, especially involving frontal white matter and basal ganglia. The characteristic pathological feature is the presence of basophilic PAS-positive granular deposits surrounding smooth muscle cells in small- and medium-sized arteries accompanied by degeneration of the smooth muscle layer in the vascular wall (197–201). Understanding the changes in CADASIL may help clarify the pathogenesis of other more common forms of cerebrovascular disease associated with dementia (202). Lacunar infarcts are cavitary lesions involving gray and white matter that generally measure about one centimeter in diameter. Smaller lesions, sometimes called “lacunes”, are small foci of ischemic necrosis most commonly occurring in the basal ganglia, thalamus, deep white matter or pons, and are often found in association with hypertension. Multiple small lacunes in gray matter may be referred to as “lacunar state” or “e´tat lacunaire”; a similar picture in the white matter is called “cribriform state” or “e´tat crible´.” Esiri found that severe cribriform change with associated subcortical white matter damage and microinfarction was more common in a group of 24 elderly demented subjects with “pure” cerebrovascular disease when compared with nondemented individuals with and without cerebrovascular disease (203). Emphasis on microvascular disease was echoed in the work of Vinters and coworkers who found microinfarcts and lacunar infarcts to be common features at autopsy in a longitudinal study of vascular dementia subjects (204).

Figure 17 Coronal section showing lacunes, contraction of tissue, and softenings in the basal ganglia, thalamus, and white matter of a patient with multi-infarct dementia.

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Binswanger’s Disease Although the definition of Binswanger’s disease is still controversial, generally accepted neuropathological features include diffuse loss of myelin with multiple small infarcts in the white matter. Penetrating arteries and arterioles are thickened and hyalinized, and deep gray matter and other structures, e.g., the brain stem, may demonstrate concomitant vascular changes with lacunar infarction. Ventricles are often dilated as a consequence of white-matter loss. There is usually sparing of the cerebral cortex. Strongly associated with hypertension, many view this entity as a particularly severe form of hypertensive vascular disease. Others attribute the extensive white matter damage to hydrocephalus. Familial Disorders with Cerebral Amyloid Angiopathy The following familial disorders are characterized by deposition of amyloid within cerebral blood vessels and an association with dementia. Many of these conditions are associated with vascular lesions such as hemorrhages and infarctions (39), and each has been attributed to point mutations in respective genes: † Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) (APP gene) † Hereditary cerebral hemorrhage with amyloidosis, Icelandic type (HCHWA-I) (cystatin C gene) † Gelsolin-related amyloidosis (familial amyloidosis, Finnish type) (gelsolin gene) † British dementia with amyloid angiopathy (BRI gene) † Familial Danish dementia (BRI gene).

SUMMARY This chapter has highlighted some of the disorders encountered by the neuropathologist in evaluating autopsy brains from patients with dementing illnesses. While the majority of these cases prove to be AD, the neuropathologist must be alert to clues suggesting other diagnoses. Identifying non-AD dementias provides valuable information for clinicians, scientists, and family members. Although some of these conditions are relatively rare, even a single case may point toward future areas of investigation and treatment of more common disorders. In addition, the heterogeneity and overlap seen in AD, as well as the presence of concomitant disorders, make the neuropathological assessment of dementia a challenging one.

ACKNOWLEDGMENTS This work is supported by the National Institute on Aging, National Institutes of Health (Bethesda, MD) grant K07 AG00959.

REFERENCES 1. Gearing M, Mirra SS, Hedreen JC, Sumi SM, Hansen LA, Heyman A. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer’s disease. Neurology 1995; 45:461–466. 2. Mirra SS, Heyman A, McKeel D, et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991; 41:479–486.

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168. Hulette C, Nochlin D, McKeel D, et al. Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases. Neurology 1997; 48:668–672. 169. Erkinjuntti T, Haltia M, Palo J, Sulkava R, Paetau A. Accuracy of the clinical diagnosis of vascular dementia: a prospective clinical and post-mortem neuropathological study. J Neurol Neurosurg Psychiatry 1988; 51:1037–1044. 170. Knopman DS, Parisi JE, Boeve BF, et al. Vascular dementia in a population-based autopsy study. Arch Neurol 2003; 60:569–575. 171. Mendez MF, Mastri AR, Sung JH, Frey WHD. Clinically diagnosed Alzheimer disease: neuropathologic findings in 650 cases. Alzheimer Dis Assoc Disord 1992; 6:35–43. 172. Joachim CL, Morris JH, Selkoe DJ. Clinically diagnosed Alzheimer’s disease: autopsy results in 150 cases. Ann Neurol 1988; 24:50–56. 173. de la Monte SM, Hutchins GM, Moore GW. Racial differences in the etiology of dementia and frequency of Alzheimer lesions in the brain. J Nat Med Assoc 1989; 81:644–652. 174. Heyman A, Fillenbaum G, Prosnitz B, Raiford K, Burchett B, Clark C. Estimated prevalence of dementia among elderly black and white community residents. Arch Neurol 1991; 48:594–598. 175. Auchus AP. Dementia in urban black outpatients: initial experience at the Emory satellite clinics. Gerontologist 1997; 37:25–29. 176. Desmond DW, Moroney JT, Paik MC, et al. Frequency and clinical determinants of dementia after ischemic stroke. Neurology 2000; 54:1124–1131. 177. Cadavid D, Mena H, Koeller K, Frommelt RA. Cerebral beta amyloid angiopathy is a risk factor for cerebral ischemic infarction. A case control study in human brain biopsies. J Neuropathol Exp Neurol 2000; 59:768–773. 178. Ellis RJ, Olichney JM, Thal LJ, et al. Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience. Part XV. Neurology 1996; 46:1592–1596. 179. Olichney JM, Hansen LA, Hofstetter CR, Lee JH, Katzman R, Thal LJ. Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer disease is not a spurious one attributable to apolipoprotein E4. Arch Neurol 2000; 57:869–874. 180. Olichney JM, Hansen LA, Hofstetter CR, Grundman M, Katzman R, Thal LJ. Cerebral infarction in Alzheimer’s disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol 1995; 52:702–708. 181. Olichney JM, Ellis RJ, Katzman R, Sabbagh MN, Hansen L. Types of cerebrovascular lesions associated with severe cerebral amyloid angiopathy in Alzheimer’s disease. Ann NY Acad Sci 1997; 826:493–497. 182. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet 2000; 356:1627–1631. 183. Fassbender K, Simons M, Bergmann C, et al. Simvastatin strongly reduces levels of Alzheimer’s disease beta - amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci USA 2001; 98:5856–5861. 184. Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM 10. Proc Natl Acad Sci USA 2001; 98:5815–5820. 185. Refolo LM, Pappolla MA, Malester B, et al. Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis 2000; 7:321–331. 186. Sparks DL, Hunsaker JC, III, Scheff SW, Kryscio RJ, Henson JL, Markesberg WR. Cortical senile plaques in coronary artery disease, aging and Alzheimer’s disease. Neurobiol Aging 1990; 11:601–607. 187. Sparks DL. Coronary artery disease, hypertension, ApoE, and cholesterol: a link to Alzheimer’s disease? Ann NY Acad Sci 1997; 826:128–146. 188. Mori T, Paris D, Town T, et al. Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APPsw mice. J Neuropathol Exp Neurol 2001; 60:778–785. 189. Zekry D, Duyckaerts C, Belmin J, et al. The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy. Neurobiol Aging 2003; 24:213–219. 190. Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia. A cause of mental deterioration in the elderly. Lancet 1974; 2:207–210.

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191. Thomas NJ, Morris CM, Scaravilli F, et al. Hereditary vascular dementia linked to notch 3 mutations. CADASIL in British families. Ann NY Acad Sci 2000; 903:293–298. 192. Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996; 383:707–710. 193. Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 1998; 44:731–739. 194. Kalimo H, Viitanen M, Amberla K, et al. CADASIL: hereditary disease of arteries causing brain infarcts and dementia. Neuropathol Appl Neurobiol 1999; 25:257–265. 195. Filley CM, Thompson LL, Sze CI, Simon JA, Paskavitz JF, Kleinschmidt-DeMasters BK. White matter dementia in CADASIL. J Neurol Sci 1999; 163:163–167. 196. Desmond DW, Moroney JT, Lynch T, et al. CADASIL in a North American family: clinical, pathologic, and radiologic findings. Neurology 1998; 51:844–849. 197. Ebke M, Dichgans M, Bergmann M, et al. CADASIL: skin biopsy allows diagnosis in early stages. Acta Neurol Scand 1997; 95:351–357. 198. Ruchoux MM, Maurage CA. Endothelial changes in muscle and skin biopsies in patients with CADASIL. Neuropathol Appl Neurobiol 1998; 24:60–65. 199. Schroder JM, Sellhaus B, Jorg J. Identification of the characteristic vascular changes in a sural nerve biopsy of a case with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Acta Neuropathol 1995; 89:116–121. 200. Lammie GA, Rakshi J, Rossor MN, Harding AE, Scaravilli F. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)—confirmation by cerebral biopsy in 2 cases. Clin Neuropathol 1995; 14:201–206. 201. Lechner-Scott J, Engelter S, Steck A, Dellas S, Tolnay M, Probst A. A patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) confirmed by sural nerve biopsy. J Neurol Neurosurg Psychiatry 1996; 60:235–236. 202. Ruchoux MM, Brulin P, Brillault J, Dehouck MP, Cecchelli R, Bataillard M. Lessons from CADASIL. Ann NY Acad Sci 2002; 977:224–231. 203. Esiri MM, Wilcock GK, Morris JH. Neuropathological assessment of the lesions of significance in vascular dementia. J Neurol Neurosurg Psychiatry 1997; 63:749–753. 204. Vinters HV, Ellis WG, Zarow C, et al. Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 2000; 59:931–945.

8 Genetics of Dementia Anne L. Brunkan and Alison M. Goate Washington University School of Medicine, St. Louis, Missouri, U.S.A.

INTRODUCTION Recognition that genes play an important role in determining risk for Alzheimer’s disease (AD) in the majority of cases is a recent phenomenon and is the direct result of molecular genetic studies during the last two decades. We now know that AD is a complex disease with multiple causes, although the underlying mechanism may be similar in all cases. Early-onset familial AD (FAD) is linked to specific rare, highly penetrant mutations (1). In contrast, risk for late-onset AD is likely the result of a combination of genetic and environmental risk factors. Interactions between AD genes and the environment are still poorly defined. However, studies from the past 10–15 years have given many insights into genes that play a role in AD and have produced models of the underlying molecular interactions that lead to disease.

INHERITED FAMILIAL AD Three lines of evidence suggest a role for genes in AD pathogenesis. The first clues come from large families that have a history of AD. A second observation suggests a genetic component to AD, in that individuals with Down’s syndrome (DS) all develop AD if they live long enough. Finally, twin studies also support a role for genes in AD. Patients with FAD account for !1% of all AD cases, but large pedigrees have been an invaluable source for genetic analysis of AD. In the majority of these kindreds, AD presents as an early onset (!65 years old), fully penetrant, autosomal dominant trait. Members of these families may show signs of disease at ages as early as 30–40 years. DS patients over the age of 40 years often develop AD symptoms, and the brains from these people invariably show AD neuropathology. People with DS have an extra copy of chromosome 21, suggesting that this chromosome contains a gene or genes that may be involved in AD. In fact, the b-Amyloid Precursor Protein (APP) gene is located on chromosome 21, and a 38–43 amino acid fragment of this protein (Ab) is the main component of the aggregates in the AD brain. The extra copy of this locus in DS leads to an increase in Ab, and thus an earlier accumulation of amyloid 163

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plaques that is probably linked with an early onset of symptoms. Other genes on chromosome 21 may also contribute to the AD phenotype seen in older DS individuals. Twin studies are a traditional technique to gather information about genetically-transmitted disease. A fully penetrant disease should show 100% concordance in monozygotic (MZ) twins and 50% concordance in dizygotic (DZ) twins. Equal levels of concordance in MZ and DZ twins would suggest that risk for the disease is environmental rather than inherited. Multiple studies have found higher concordance rates for AD in MZ twins than in DZ twins (2). However, these studies probably underestimate the contribution of genetics to late onset AD due to death from other causes before onset of AD and variation in the age of onset between the twins (3). Twin studies of late onset AD suggest that genetics plays a role but environmental factors also make a major contribution to disease. Genetic mapping and positional cloning using the large FAD families has led to the identification of four genes that are associated with AD: APP, presenilin 1 (PS1), presenilin 2 (PS2), and apolipoprotein E (APOE). Further studies of these genes and their protein products have given us insights into the mechanisms of AD pathogenesis.

INSIGHTS FROM GENETICS The Amyloid Precursor Protein Gene Purification of the major proteinaceous component of amyloid plaques in the AD brain identified a 38–43 amino acid peptide, subsequently named Ab (4). This peptide is excised from a larger precursor protein, APP, that is encoded by a gene located on chromosome 21. Mammals express 3 isoforms of APP, 751- and 770- amino acid forms in most tissues and a 695-amino-acid form in neurons. The non-neuronal forms of APP contain a domain that allows APP to function as a serine protease inhibitor in the coagulation cascade (5). Mutations in APP have been identified in FAD (Table 1). These mutations are located at the cleavage sites that flank the Ab peptide and affect the length and form of the Ab peptide, pinpointing Table 1 Mutations in the APP Gene Name Swedish Flemish Dutch Arctic Iowa Iranian Austrian French German Florida London

Australian a

Site

Mutation

Disease

670/671 692 693 693 694 714 714 715 715 716 717 717 717 717 723

KM/NL A/G E/Q E/G D/N T/A T/I V/M V/A I/V V/I V/G V/F V/L L/P

AD AD or stroke HCHWA-D AD AD, CAA AD AD AD AD AD AD AD AD AD AD

Age of onset 45–61 (6) 40–60 (7) 45–65 (8) 54–61 (9) 50–69 (10) 55a (11) 33–39 (12) 40–60 (13) 47a (7) 53a (14) 50–60 (7) 45–62 (7) 42–52 (7) 35–40 (15) 56a (16)

Mean age of onset. Abbreviations: AD, Alzheimer’s disease; HCHWA-D, hereditary cerebral hemorrhage with amyloidosis-Dutch type; CAA, cerebral amyloid angiopathy.

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Ab as a primary cause of disease. Most of these mutations alter the ratio of Ab42:Ab40 (42-residue versus 40-residue forms), leading to an AD phenotype (17). A mutation that causes a glu-to-gln substitution at residue 693 results in an increase in Ab fibril formation and stability, leading to a second amyloid disease, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) (18). The phenotypes of both diseases involve early deposition of amyloid fibrils, resulting in the formation of plaques in the brain. However, the plaques in HCHWA-D are not neuritic, and amyloid deposition in the cerebral vessels is much more severe (19,20). The majority of AD mutations in APP are single missense mutations (Table 1), with the exception of the Swedish mutation that has missense mutations in two consecutive codons, 670 and 671. Mutations in APP are very rare: mutations at codons 670/671, 692, 714, 715, 716, and 723 have been found in single families, the E693G and V715A mutations have each been identified in two families, while multiple mutations at codon 717 have been identified in approximately 20 pedigrees (17). The Swedish mutation causes an increase in both Aß40 and Aß42 because more APP is cleaved by ß-secretase (21,22). Most of the other mutations cause an increase in the ratio of Ab42:Ab40, however, they act through slightly varying mechanisms. The Austrian (T714I) and French (V715M) mutations decrease the amount of the Ab40 species (12,13), while codon 717 (V717I/G/F/L) mutations increase the amount of Ab42 (12,14,15). These mutations implicate the altered Ab42:Ab40 ratio in causing AD. Ab42 is the predominant form of Aß in the plaques deposited in AD brains (5). In vitro studies have demonstrated that Ab42 forms fibrils more rapidly than Ab40 (23). However, the Arctic (E693G) mutation at codon 693 causes a decrease in both Ab species while the rate of fibril formation is greatly accelerated, suggesting a different mechanism of disease relying on Ab fibrillogenesis rather than the amount or ratio of various Ab species being secreted (9). APP is a type I transmembrane protein with a large N-terminal extracellular domain, a single transmembrane domain, and a short cytoplasmic C-terminus. It undergoes multiple processing steps to release the Ab peptide (Fig. 1). APP is first cleaved by either a- or b-secretase, truncating the extracellular domain to form an 83- or 99-residue protein. These truncated APP molecules are then cleaved within the transmembrane domain by g-secretase [see reviews (5,24)]. The g-secretase cleavage at the C-terminus of Ab varies to produceSˇSˇ a peptide that ranges from 38–43 amino acids in length and an approximately 50-residue C-terminal peptide that may interact with nuclear factors to

Extracellular

Intracellular

APP +H N 3

COOβ α

γ

Aβ β

γ

plaque

Figure 1 APP processing. APP is cleaved by either a- or b-secretase, followed by g-secretase cleavage. The combination of b- and g-secretase cleavage releases the Ab peptide that aggregates to form plaques in the AD brain.

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regulate gene expression (25–29). The remaining 25- or 40-residue peptides, p3 and Ab, are released from the membrane extracellularly. The presence of Ab in AD plaques, the identification of AD-linked mutations in APP, and the role these mutations play in APP processing to Ab all suggest that Ab is a central factor in the AD phenotype. Mouse models of APP mutations confirm this relationship between APP and AD (30). Mice that overexpress an FAD mutant APP transgene show age-dependent amyloid deposition and some cognitive deficits, establishing a direct relationship between the APP gene and these features of the AD phenotype. The results of AD mutation analysis, molecular studies, and transgenic mice all support the hypothesis that Ab deposition plays a major role in AD. The accelerated formation of fibrils that results from an increase in Ab42 is the key step that results in early deposition of amyloid in the brain, driving other manifestations of disease. The Presenilin (PS1 and PS2) Genes Genetic analysis linked a region on chromosome 14 with early onset FAD, and positional cloning then identified the PS1 gene in this region (31). PS2, a homologue of PS1, was subsequently mapped to chromosome 1 (17,32). These genes are highly conserved throughout evolution and are found in species that range from rice to worms to mammals. The presenilins are expressed in many tissues with no known function at the time that they were first identified. Over 100 FAD mutations have now been identified in PS1, and 6 have been identified in PS2. PS mutations are responsible for 30–50% of FAD cases and cause onset of disease at ages ranging from 28–75 years. The majority of these are missense mutations that cause an increase in the ratio of Ab42:Ab40, leading to the AD phenotype. Multiple mutations have been identified at 26 sites in PS1 (e.g., M139 changed to I, T, or V and M146 changed to I, L, or V) and one residue (M239 changed to I or V) in PS2. Thirty one mutations in PS1 have been identified in multiple families, the majority in two families but some in as many as twelve (M146L, E280A), ten (H163R), or six (A79V, M139V, P246L) families. The N141I mutation in PS2, with average disease onset at 57 years, has been identified in seven families (33). A founder effect has been reported for the E280A (34) and G206A (35) mutations in PS1 and for the so-called Volga-German mutation in PS2 (N141I) (36), such that the multiple families with each of these mutations result from a single common founder in each case. In contrast, most FAD mutations, such as the V717I mutation in APP, arise in numerous families through multiple spontaneous mutation events. One individual was identified that has two PS1 mutations: M146V/S365Y; it is unknown whether these are in the same PS1 molecule. Two siblings were also identified as carrying two PS1 mutations; they inherited their father’s I143T allele and their mother’s I439V allele. Both groups of double mutations caused an age of onset % 35 years (37). The majority of AD mutations in PS1 are missense mutations that change a single amino acid, but there are also a handful of insertion and deletion mutations. Seven families with mean disease onset at 36 years have a point mutation in a splice site at intron four that produces an insertion of a threonine residue between 113 and 114 (37). In eight families, genomic deletions or splice site mutations result in the deletion of exon 9 accompanied by a change in codon 290 from a serine to a cysteine residue (38), with onset of disease ranging from 45–53 years (33). Deletion of exon 9 removes the endoproteolytic site in PS, as a result this mutant PS cannot be cleaved (see PS processing below). In vitro experiments have linked the AD phenotype to the S290C point mutation rather than the exon 9 deletion (39). A six nucleotide deletion results in the removal of two amino acids, I83 and M84, from one family (40). One individual had an insertion of an arginine residue between codons 352 and 353, and one family with an age of onset of 28 years had an insertion of two amino acids, FI, between codons 155 and 156 (37). Although most PS mutations cause an AD phenotype, a handful of mutations result in multiple disease phenotypes. Patients with the DIM83/84 and DE9 deletions and point mutations V261F and

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R278T all display a spastic paraparesis phenotype accompanying the AD phenotype. Rather than the diffuse or neuritic plaques found in the brains of AD patients, PS1 mutations causing spastic paraparesis result in “cotton wool” plaques that lack dense amyloid cores (41). Ab42 is a major component of these plaques, suggesting that PS mutations cause both AD and spastic paraparesis by affecting the formation of Ab (42). Families with AD PS1 mutations have also been described with other accompanying phenotypes, such as frontotemporal dementia (FTD) (L113P), myoclonic seizures (S169P), and epilepsy (L392P) (33). PS are multi-pass transmembrane proteins, crossing the membrane 6–8 times. Most AD mutations fall within these transmembrane regions. PS are synthesized as a full-length molecule that is processed to create two fragments, which remain associated with each other to produce the main form of PS that is present in vivo. The 6th and 7th transmembrane domains contain aspartic acid residues that are hypothesized to form the active site for a PS aspartyl protease activity. PS enzymatic activity occurs within the g-secretase protein complex that has three additional known members: nicastrin, APH-1, and PEN-2 [see review (43)]. Cleavage of APP by g-secretase determines the C-terminal residue of Ab. PS mutations thus cause an increase in the Ab42:Ab40 ratio by affecting the cleavage that distinguishes between these two forms of Ab. PS is required for this cleavage event to take place (44). Studies with transgenic mice confirm the importance of PS. Mice that have the PS1 gene knocked out die before birth. Transgenic mice that overexpress a mutant form of human PS1 have an increase in Ab42 levels in the brain (45). When crossed with mice expressing a mutant form of APP, the doubly transgenic animals show accelerated age-dependent amyloid deposition that occurs at an earlier age and is more severe than either of the singly transgenic animals (46–48). These animals also have some cognitive deficits, similar to those seen in the mutant APP transgenic animals (48). This argues that PS1 modifies APP cleavage to Sˇ influence an early formation of amyloid deposits, confirming the relationship between the PS1 gene and the AD phenotype. The role that PS plays in AD appears to be through its effect on the processing of APP to Ab. Research on three genes identified through genetic analysis, APP, PS1, and PS2, have identified three Mendelian forms of FAD that all promote fibrillar Ab, placing amyloid deposition as a central step in the development of AD.

The Apolipoprotein E4 Polymorphism APOE was tied to AD through a combination of genetic approaches. Analysis in late-onset AD (LOAD) families observed linkage to a region of chromosome 19 (49). APOE was located in this region and emerged as a candidate gene from biological evidence that it is present in plaques and tangles in the AD brain and can be isolated bound to Ab in cerebrospinal fluid. Subsequently an association was found between the E4 allele of APOE and LOAD in case control samples, identifying it as a risk factor for AD. Humans express 3 isoforms of APOE, the E2, E3, and E4 alleles. The Apolipoprotein E4 (APOE4) allele is linked to AD and cerebral amyloid angiopathy (CAA), while the APOE2 allele may have a protective effect. Approximately 45–60% of AD patients carry an APOE4 allele (50,51). It is the most common risk factor so far identified for both early-onset AD and LOAD. However, not every person carrying an APOE4 allele will develop AD. The reasons for this are not completely understood. The frequency of the APOE4 allele varies by ethnicity (Table 2) and this may influence the differences in contribution to AD risk by APOE4 in various populations (52). The risk associated with APOE4 is dose-dependent such that two copies of the E4 allele cause increased amyloid deposition and an earlier age of onset of disease compared to one copy of the E4 allele. People carrying one APOE4 allele have an odds ratio (OR) of developing AD that ranges from 2.2 to 4.4 compared to individuals with two APOE3 alleles, while individuals carrying two

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Table 2 APOE Allele Frequency in AD in Different Populations

African American (52) Caribbean Hispanics (53) Caucasian (52) Han Chinese (54) Hispanic (52) Japanese (52)

Controls Cases Controls Cases Controls Cases Controls Cases Controls Cases Controls Cases

E2

E3

E4

8.3 7.7 3.0 3.0 8.4 3.9 6.3 7.7 6.7 6.3 4.2 2.7

72.7 59.1 74.0 64.5 77.9 59.4 86.0 72.1 82.3 74.5 86.9 69.5

19.0 32.2 23.2 32.4 13.7 36.7 7.8 20.3 11.0 19.2 8.9 27.8

APOE4 alleles have an OR between 5.1 and 34.3. The OR varies by ethnicity, for example, the E3/E4 OR for Caucasians is 3.2 while for Japanese it is 5.6, for Hispanics it is 2.2, and for African Americans it is 1.1. The E4/E4 ORs for these groups are 14.9, 33.1, 2.2, and 5.7, respectively (52). AD risk associated with the APOE4 allele also varies by gender: Caucasian and possibly Hispanic women have an increased susceptibility for AD compared with men when carrying the E3/E4 genotype (52,55). Thus the APOE4 allele is not an accurate marker for predicting development of AD in an individual, because it is not always associated with the disease and risk is influenced by multiple factors. APOE plays a role in normal lipid and cholesterol metabolism. It functions in the transport and delivery of lipids between tissues and cell types as a component of lipoprotein particles, acting as a ligand for receptors that take up and metabolize lipids. In the periphery APOE also can inhibit triglyceride hydrolysis by accumulating on lipoproteins, and can directly influence triglyceride and VLDL levels through variation in the amount of APOE available to interact with triglycerides and VLDL particles. APOE plays a role in cholesterol movement in and out of cells, and acts as a ligand for delivery of cholesterol-containing HDL particles to the liver (56). In the brain, APOE is present in HDL-like lipoproteins, and its role in lipid metabolism there is less defined. Studies on the interaction of APOE and Ab have suggested a role for APOE in Ab deposition (Fig. 2). In vitro analysis demonstrated that APOE4 bound Ab more rapidly and caused an increase in formation of Ab fibrils compared to APOE3. Other data show a possible role for APOE in clearance of Ab by neurons and astrocytes, acting as a ligand for receptor-mediated uptake of Ab by neurons and astrocytes. APOE4 was less able to clear Ab than APOE3. The contribution of APOE4 to AD centers on an increase in Ab fibrils and the levels of Ab available for aggregation and deposition (55). Animal models confirm the connection between APOE and AD. When a mouse expressing an APP mutant transgene was crossed with an APOE knockout mouse, the resulting progeny developed fewer Ab deposits and no true amyloid plaques compared to littermates with endogenous APOE. An intermediate level of amyloid deposition was seen in the APOE heterozygote, demonstrating a dose-dependent phenotype similar to that seen in human AD cases (57). The contribution of APOE to AD centers on the formation and deposition of Ab fibrils, confirming the evidence from PS and APP mutations that points to Ab deposition as the key step in AD pathogenesis. Furthermore, mice expressing human APOE4 and a mutant APP gene develop neuritic plaques at an earlier age than mice expressing APOE3 (58,59).

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plaque

Aβ APOE APOE receptor(s)

neuron/glial cell

Figure 2 The APOE4 allele causes an increase in formation of Ab fibrils and may also be less able to clear Ab through receptor-mediated uptake by neurons and astrocytes.

Primacy of Ab versus Tau in AD AD is one of a large number of neurodegenerative diseases that have tau-based pathology (60). A hyper-phosphorylated form of tau produces neurofibrillary tangles in AD brains. One hypothesis for the molecular mechanism of AD centers on the role that tau pathology may play in AD. However, mutations in tau do not lead to AD, but rather lead to frontotemporal dementia (FTD). Mutations in tau lead to fibril formation of a hyper-phosphorylated form of tau, but these mutations do not cause amyloid deposition (60). In FTD with Parkinsonism linked to chromosome 17 (FTDP-17), mutations in tau cause early onset disease with autosomal dominant inheritance. Such mutations have been identified in over 50 families. The majority of these mutations are missense mutations that occur near or within microtubule-binding domains in the C-terminus of tau and disrupt the ability of tau to bind to microtubules. Other types of tau mutations in FTDP-17 include a deletion of residue K280 and splice site mutations around the exons encoding the microtubule-binding domains (particularly exon 10). These affect production of relative amounts of the tau isoforms by disrupting regulatory elements around the splice sites (61). Several transgenic animals have been made that express mutant forms of tau. Most lead to expression of phosphorylated tau, and some animals develop neurofibrillary tangles. These animals do not develop amyloid deposition (60). Tau-mutant transgenic mice were crossed with APP-mutant transgenic mice to study the interaction of Ab and tau pathologies. In the progeny of these crosses, Ab plaques formed at an age similar to that of the APP-mutant mouse. Older mice, however, had a marked increase in neurofibrillary tangles in the hippocampus compared to either parent, confirming that Ab deposition exacerbated tau pathology in the doubly-mutant animal (62). Ab-rich plaques and tau-containing neurofibrillary tangles are the hallmark pathologies observed in AD brains. Although both may be important for the AD phenotype, amyloid deposition appears to impact tau pathology, centering on Ab as the key contributor in the development of AD.

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CHALLENGES FOR THE FUTURE FAD accounts for less than 1% of all AD cases, and mutations in APP, PS1, and PS2, along with risk provided by the APOE4 allele, are responsible for about 50% of cases (1). It is therefore likely that there are other genetic factors involved in AD that have yet to be identified. Finding these genes could have important implications, for example, they might enable presymptomatic diagnosis of AD. Currently, select people can have PS1 sequenced to determine whether they have a mutation, but this procedure is only efficacious for members of FAD families and requires that the entire gene undergo sequence analysis. A factor that would highlight risk for AD in the general population would be more widely useful. Genetic linkage studies in sibling pairs and families have been performed to identify susceptibility genes for late onset AD. Several chromosomal regions have been identified in multiple studies including those on chromosomes 9, 10 and 12 (63–65). The linked regions on each of these chromosomes contain a large number of genes that must yet be sifted through to identify the particular gene or genes responsible for the association of each region with AD. Candidate genes in these areas are being searched for genetic mutations while further linkage and association studies are being used to narrow in on the AD gene [see review (66)]. A quantitative trait locus for plasma Aß42 levels has also been linked to the same region of chromosome 10, suggesting that the chromosome 10 AD locus may also influence risk for AD through an Aß-dependent mechanism (67). On chromosome 10, one attractive candidate is the gene encoding the insulin-degrading enzyme (IDE), which may function in Ab degradation (68). However, analysis of this gene has failed to identify any coding variants or any association with disease (69). Multiple studies have also identified regions of linkage to LOAD at different locations on chromosome 12. These areas contain two appealing candidate genes that encode the low-density lipoprotein receptor-related protein (LRP) and a2-macroglobulin (A2M). LRP may play a role in cellular uptake and degradation of APP, APOE, and A2M. Sequencing has identified rare LRP alleles but none of these explain the chromosome 12 linkage data with AD. A2M may also mediate degradation of Ab but consistent association with disease has not been observed with the polymorphisms studied to date. Regulatory elements of LRP have yet to be screened for AD-associated mutations, and genetic studies on both these and other candidate genes may soon identify the gene(s) on chromosome 12 that affect the development of AD (66). Although LOAD is assumed to be a complex disease, as yet we have relatively little understanding of the gene-environment and gene-gene interactions that modify risk for disease. Future understanding of gene-environment interactions should enable lifestyle changes that will reduce risk for disease in a similar manner to cholesterol management in heart disease. Treatment of AD is still in its infancy with the first drugs approved for treatment less than a decade ago. As new drugs with different modes of action are introduced, pharmacogenomics will also become more important. It is already well established that genetic variability can influence response to particular drugs and the ability to predict an individual’s response to specific drugs will improve treatment. Identification of new AD genes also offers the possibility of providing a biomarker for disease. A good biomarker could be easily screened as people approach ages of susceptibility. Such a factor would allow early detection of susceptibility for AD, allowing for early treatment and ideally, prevention of the development of symptoms. Genetics can potentially contribute to the development of treatments for AD. Identification of other AD genes or biomarkers may provide more options for genetic screening. Recently, preimplantation diagnosis was used for the first time to ensure implantation of a healthy embryo in a woman carrying a mutation in the APP gene (70). This raises considerable ethical questions that have yet to be debated thoroughly in the field.

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PS1 gene APP gene mutations PS2 gene mutations mutations

Aβ fibrillarization

Altered APP metabolism

TAU gene mutations

Vascular amyloid

Amyloid deposition

Neuritic plaques

Unknown mutations Trisomy 21

APOE Environmental factors

Neurofibrillary tangles and neuropil threads

Neuronal damage, depletion of transmitters, etc.

Dementia

Figure 3 Many genetic and environmental factors can contribute to the development of Alzheimer’s disease.

Most cases of AD are likely to result from multiple genetic as well as environmental contributions (Fig. 3). As all the genetic components are identified, treatments may be tailored to work most effectively with a person’s specific combination of genes. Understanding the molecular mechanism of AD has already led to the development and current testing of drugs that will inhibit the production of the Ab peptide from APP precursor (see Chapter 26). Genetics offers the hope of identifying further factors involved in AD and providing insights into both the mechanism of the disease and the possibilities for developing treatments for AD.

ACKNOWLEDGMENTS The authors acknowledge support by the following grants from NIA: AG16208, AG17050, and AG05681.

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9 Biomarkers in Alzheimer’s Disease and Dementia Douglas Galasko Department of Neurosciences, University of California and Neurology Service, Veterans Affairs Medical Center, San Diego, California, U.S.A.

INTRODUCTION Biomarkers are biochemical or other measurements that relate to a disease process, and they have an intuitive appeal as objective measurements that can aid in diagnosis or treatment. Some biomarkers are currently widely used as diagnostic aids in clinical practice, for example serum prostate specific antigen (PSA) for prostate cancer or bone densitometry for osteoporosis. In principle, a biomarker could also serve as an index of disease progression or activity, which could lead to its use as a surrogate measure of how the disease responds to treatment. This is a difficult standard to attain, because changes in the biomarker must extrapolate directly to meaningful changes in robust clinical outcomes. Treatment effects on surrogate biomarkers do not always map directly onto beneficial clinical outcomes, because drugs may have broad mechanisms of action and diseases may have complex pathways of pathogenesis (1). Consequently, few biomarkers are accepted as valid surrogates. An intermediate but important use of biomarkers is to provide indices that the treatment is affecting pathways related to the disease, which can aid in clinical drug development and dose finding. Interest in biomarkers for dementia, particularly Alzheimer’s Disease (AD), has burgeoned in the past decade, but a clear role has not yet emerged for biomarkers in clinical practice. This chapter discusses the methods and principles involved in validating biomarkers for AD, and reviews research into biochemical markers for AD, while touching on biomarkers in other dementing disorders. Neuroimaging techniques provide important indices of structure, metabolism, and function of specific brain regions, and have been widely investigated as potential biomarkers for dementia. These will not be reviewed in this chapter, but are covered in part in chapter 5. Clinical Approaches to Diagnose and Follow Patients with Dementia Clinical measures form the backbone of dementia assessment and are applied to screen patients for the possible presence of dementia, to make specific diagnoses, and to follow changes over time and 175

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in response to treatment. In particular, brief overall cognitive tests such as the Mini-Mental State Examination (MMSE), and informant reports about subjects’ functional abilities are currently applied to all of these situations. Although cognitive and other clinical measures represent the most practical and convenient way to assess dementia, they have limitations. Cognitive performance is influenced by a patient’s age, education, motivation, mood, vision, hearing, and movement speed, and on interactions with the examiner. As attention shifts to the very early diagnosis of AD, clinicians increasingly need to assess patients with mild memory complaints who have very mild functional impairment, impaired performance on objective tests of memory, or both, but do not meet formal criteria for AD (2,3). Such patients are at risk of progressing to develop overt dementia and have been labeled as having Mild Cognitive Impairment (MCI) (3). Most patients who are carefully categorized as MCI or equivalent are likely to progress to develop dementia on follow-up (3–5), and already have structural AD pathology (4). Initiating treatment at this stage is an important strategy, before irreversible pathological changes have spread throughout the brain. Brief clinical testing is insensitive for detecting the earliest deficits of MCI, screening for MCI, or predicting which patients are likely to progress to overt dementia. Detailed cognitive test batteries, or in-depth evaluations of subjects and informants by expert clinicians are more effective, but require expertise and are time-consuming and relatively expensive. Biomarkers could complement the clinical evaluation if they provide additional information that helps to identify which patients are likely to harbor AD pathology or progress to develop overt dementia. Biomarkers as Diagnostic Tools Biomarkers could supplement clinical measures by providing extra information related to the brain pathology of dementia, risk factors, or mechanisms of disease. A rigorous series of studies must be carried out to evaluate biomarkers. In 1997, an expert working group proposed an agenda to develop biomarkers for AD, applicable to dementia in general (6). The group identified many possible uses of biomarkers in AD: screening for disease; assisting in the diagnosis of AD, including early or preclinical detection and differential diagnosis, following disease progression, and monitoring responses to treatment. They noted that the characteristics of a biomarker depend on its intended use. For example, if a biomarker is used as a screening test to trigger a more detailed clinical evaluation, then high sensitivity, ease of acquisition, and low cost are priorities. By contrast, if a biomarker is used to increase or decrease the diagnostic certainty of AD, both sensitivity and specificity must be high. If a biomarker is used as an outcome measure of the response to treatment of AD, then it should show a strong relationship to the clinical progression of dementia. The working group proposed criteria for ideal biomarkers for AD and made recommendations for carrying out studies to validate biomarkers (Table 1). An ideal biomarker for AD should detect a fundamental feature of AD pathology and be validated against autopsy-proven AD cases. It should diagnose AD precisely, and it should be useful in early detection and differential diagnosis from other causes of dementia. Finally, the ideal biomarker should be reliable, non-invasive, simple to perform, and inexpensive. Some of these characteristics depend on the use of the biomarker and the context of treatment. For example, blood or urine are the most likely sources of inexpensive and minimally invasive tests, but are difficult to relate to the pathology of AD, because this is restricted to the brain. Biomarkers that require slightly more invasive procedures (such as lumbar puncture for cerebrospinal fluid (CSF), or a skin biopsy), or expensive tests such as volumetric MRI are more likely to relate to neuropathology, but are less practical to serve as screening tests. If a diseasemodifying treatment becomes available for AD, and a biomarker greatly facilitates early diagnosis, then less weight might be assigned to factors such as expense, complexity or invasiveness of the biomarker.

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The statement from the working group outlined benchmarks to validate biomarkers for the diagnosis of AD. The biomarker should discriminate between AD and nondemented elderly individuals with sensitivity and specificity that both exceed 80%, because the clinical diagnosis of AD is at least that accurate in expert hands, and positive predictive value should approach 90%. Because the accuracy of clinical diagnosis of AD is not 100%, the sensitivity of a biomarker in a clinical study is unlikely to exceed 80–90%. To support differential diagnosis, the biomarker should have high specificity for AD compared to other causes of dementia, again in excess of 80%. There are several constraints to the specificity of a biomarker for AD. First, elderly controls who serve as a source of normative data are likely to include individuals with AD pathology. Second, the clinical diagnosis of non-AD dementias is not perfect (7), and some individuals may have AD or concomitant AD pathology; this is particularly troublesome for vascular dementia and Lewy Body Dementia. At least two independent studies should document the sensitivity and specificity of the biomarker. These studies should be well powered, carried out by expert investigators, and should be submitted for peer-reviewed publication. Studies should include normal control subjects as well as those with dementia due to conditions other than AD. After a marker is accepted, follow-up data should be obtained to calibrate the accuracy of the biomarker against neuropathologicallyconfirmed diagnoses. An evidence-based review of all published studies on the diagnosis of dementia from 1985–1999 found that very few studies of biomarkers met the highest standard of research quality, designated as Type I evidence (7). This indicates a gap between the initial exploration of biomarkers and the design of studies to investigate their utility. The authors suggested further steps to evaluate diagnostic biomarkers. Once a biomarker has shown reasonable sensitivity and specificity, it is important to assess the degree of benefit of using the biomarker over and above a good clinical diagnosis. Also, the utility of the biomarker should be studied in patients representative of those seen in routine clinical practice, not only in those referred to tertiary medical centers. Table 1 summarizes the goals that need to be met in diagnostic biomarker studies. Applying Biomarkers to the Treatment of AD At present, clinical methods are the mainstay of diagnosing AD (7). To track the progression of dementia, clinicians make use of repeated psychometric testing, ratings of patients’ functional abilities or global severity of dementia. For most standard clinical measures the test-retest Table 1 Features of Ideal Diagnostic Biomarkers for AD 1

2

3

4

The biomarker detects a fundamental feature of AD pathology † Lesions or processes leading to their formation; e.g., plaques, tangles † Mechanisms involved in neurodegeneration; e.g., inflammation, oxidative damage The biomarker is accurate and convenient † Reliable: quantitative and sensitive measurement, with high test-retest reliability † Non-invasive: blood, urine or an MRI are minimally invasive. Slightly more invasive tests such as lumbar puncture or skin biopsy may also be acceptable † Simple to measure: e.g., a biochemical assay should be feasible for clinical chemistry laboratories † Inexpensive The biomarker is precise and provides diagnostic utility † High sensitivity and specificity of AD versus normal older controls † High sensitivity and specificity for early diagnosis; e.g., mild cognitive impairment (MCI) † Differential diagnosis: distinguishes AD from other neurological disorders and dementias † Validated against diagnoses confirmed by neuropathological examination at autopsy Provides incremental value compared to a good clinical diagnosis

Source: Adapted from Refs. 6, 7.

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variability is high relative to the amount that test scores change as part of the natural history of dementia. Thus, the assessment of change improves as the length of follow-up increases. This leads to questions about how best to measure the effects of disease-modifying therapeutic approaches in research studies and clinical practice. Successful disease-modifying treatment is likely to slow the progression of dementia. Because the pathologic changes in AD are widespread and involve progressive loss and degeneration of neurons and synaptic terminals, it follows that the earlier that disease-modifying treatment starts, the greater the potential for benefit. Clinical trials to test whether treatment slows the progression of AD typically require large groups of patients in each arm of the study, and follow-up periods of 12 months or longer (8). This is especially problematic in MCI, where only 5-15% of patients show clinical progression to AD per year (3). Measurement problems are equally important in routine clinical practice, where the time available to assess patients is limited. It is difficult to decide based on clinical measures or scores whether an individual patient is responding to treatment or not, and brief clinical measures are inadequate tools to detect dementia early and to track change. Biomarkers could fill several niches in evaluating disease-modifying treatment. They could help to clarify the diagnosis of MCI, by providing evidence for or against the presence of underlying AD pathology. In early phase clinical studies of medications thought to have disease-modifying potential, biomarkers may provide quantitative measures of the pharmacological actions and biological effects of the drug. In this way, evidence for these effects could be explored before committing drugs to definitive clinical trials. If biological markers are easy to obtain and measure in large numbers of patients, they could serve as surrogate outcome measures. To attain the status of surrogate markers, biological markers must be evaluated in the setting of treatment that benefits clinical outcome measures. Formal criteria to validate a surrogate marker require the demonstration that the treatment beneficially influences both the surrogate and the clinical outcome measures; changes in each of these measures correlate well; and the effect of treatment on the clinical outcome is mediated through an effect on the surrogate (9). Before using biomarkers in treatment studies, the extent of variability of the biomarker, and how it changes with disease progression must be known. Biomarkers may show different patterns of change as dementia progresses. For example, neuroimaging measures show that total brain volume decreases over time as AD progresses, indicating worsening atrophy. The loss of volume of brain tissue may not be linear or constant over the course of AD, and it may accelerate in the transition from mild to moderate dementia. CSF markers may also show varying patterns of change over time. If a CSF biomarker is released into CSF chiefly by those neurons that are actively undergoing degeneration or death, then its levels will depend on the rate of neuronal damage and the size of the pool of neurons at risk. For example. after an acute stroke, CSF levels of tau rise, peak at 1–2 weeks, then fall as tau is cleared (10). The peak level is proportional to the size of the stroke on neuroimaging. In AD, CSF tau is stably elevated over months to years, consistent with a fairly stable tempo of active, ongoing neurodegeneration. If a biomarker reflects a widespread feature of AD pathology that progressively increases over time, then levels of the marker could increase in CSF in direct correlation to increasing dementia severity. PATHOLOGICAL CHANGES AND MECHANISMS IMPLICATED IN AD As mentioned, the easiest biomarkers to justify are those that bear a direct relationship to pathologic changes in the brain in AD. A brief survey of AD pathology is presented here, and dealt with in greater detail in chapter 7. The defining lesions of AD, senile plaques (SP), and neurofibrillary tangles (NFT) can also be found in elderly subjects not known to be clinically demented during life (11), but typically occur in higher density or wider distribution in AD, accompanied by extensive loss of synapses and neurons. SP are not part of the pathology of any other dementing illness, but tangles can

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be found in conditions such as frontotemporal dementia, Progressive Supranuclear palsy (PSP), Parkinson-dementia complex of Guam, post-encephalitic, and pugilistic dementia. Evidence of inflammation and oxidative damage is conspicuous in the brain in AD (12). Inflammatory markers include proteins such as complement and cytokines, and cells such as activated microglia and reactive astrocytes. Oxidative damage affects DNA, proteins, and lipids. SPs begin as diffuse, fine deposits of amyloid, and pass through a series of stages. Mature SPs consist of amyloid cores, surrounded by amorphous amyloid material, degenerating neurites, activated microglial cells, and reactive astrocytes (12). The molecule central to plaques is beta amyloid protein (Ab), which is produced by cleavage of a larger precursor, amyloid protein precursor (APP), by a set of secretase enzymes (13). Ab varies in length, and longer forms of this peptide that end at amino acid 42 of the Ab sequence are the major components of deposits in the brain. In almost all early onset inherited forms of AD, Ab42 is overproduced (14). Ab42 is a minor species of Ab, accounting for about 10–15% of Ab, but is the predominant species found in plaques (15). Relative to shorter forms of Ab, Ab42 aggregates more readily and is toxic to cells at lower concentration. The major constituent of tangles is the microtubule-associated protein tau. Tau is a neuronspecific protein whose normal roles include stabilizing microtubule alignment. In AD tau forms insoluble aggregates of paired helical filaments (PHF), comprising highly phosphorylated forms of tau (P-tau) (16). The brain in AD is littered with molecular clues, and it is challenging to decipher which of the many possible markers are primary and part of the initiating pathology and which are secondary, representing downstream parts of a cascade or tissue responses to initiating events. Aggregates or oligomers of Ab, abnormal phosphorylation of cytoskeletal proteins (perhaps triggered by aberrant mitotic signaling), release of cytokines, oxidative damage, and defective axonal transport have all been implicated in AD. Secondary or downstream markers are less likely to be specific to AD, but can provide indices related to processes such as neuronal damage or astrogliosis. These may be common to all neurodegenerative disorders. Even though biomarkers of downstream events may not be disease-specific, they may be important in evaluating treatment. Interventions that lead to neuroprotection, whether they affect the initiators of pathology or not, may influence these downstream markers. Unfortunately, not all pathological events in neurons generate measurable biomarkers. For example, intraneuronal aggregates of proteins are a common feature of many degenerative disorders. These would not be detectable in CSF or blood unless the neurons die and release their contents. In addition to being released from cells, a biomarker must reach high enough concentrations to be detectable. Those biomarkers that have been examined in clinical studies thus represent a subset of molecules of interest.

CSF BIOMARKER STUDIES IN AD AND DEMENTIA CSF Tau and Neuronal Damage CSF tau is the most widely studied biomarker for AD. The low levels of tau in CSF are measured by sandwich ELISAs, which have sensitive lower limits of detection and excellent reproducibility. CSF tau does not show a cranial-caudal concentration gradient, and levels are unaffected by time of day. There is evidence for release of truncated forms of tau, as well as phosphorylated tau, and possibly full length tau, into CSF (17–19). Using ELISAs that detect all forms of tau (total tau), over 25 studies have reported increased levels of CSF tau in AD compared to controls (20–26). It is not easy to pool the data across studies, because of varying patient populations and controls, and technical factors related to ELISA. In studies with large numbers of subjects, about 65–85% of AD patients show increased CSF total tau compared to nondemented controls. Tau levels are elevated in early stages of AD (24,25,27), and do not correlate with age, sex, age at onset of dementia, dementia

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severity or apolipoprotein E (APO-E) genotype. In a few recent studies, increased levels of tau were found in about 70–85% of patients with MCI (28). The criteria for MCI were not clearly defined, and these studies most likely include patients with mild AD, but provide preliminary evidence supporting diagnostic utility in MCI (Table 2). CSF total tau has diagnostic limitations, because it is increased in many disorders. In patients with neurological diseases such as encephalitis, Guillain-Barre syndrome, multiple sclerosis or amyotrophic lateral sclerosis (20,25,26), about 10–25% of patients have increased CSF tau levels. In a few conditions besides AD, CSF tau is almost always increased: Creutzfeld-Jakob disease (CJD), brain trauma, and acute stroke (10,29). After an acute stroke, CSF tau increases and peaks at about 1–2 weeks, then declines to baseline over another 2–3 weeks (10). In CJD, CSF tau levels are markedly elevated; a recent study found that CSF tau levels in excess of 1300 pg/ml had over 90% sensitivity and about 90% specificity for distinguishing CJD from AD and a variety of other conditions (29), and performed at least as well as another CSF biomarker for CJD, 14-3-3 protein. As discussed above, these data suggest that increased CSF total tau denotes damage to neurons or axons, and absolute levels depend on the rate of damage or the number of neurons undergoing damage. About 20–40% of patients with vascular dementia have increased CSF tau (25,26). Some patients with vascular dementia have prominent white matter hypodensity on CT scan, possibly due Table 2 Examples of Biomarkers for AD Biochemical marker AD lesions: plaques and tangles

Ab Ab42

GM-CSF AD7C/NTP

Deposited in senile plaques Earliest and major form of Ab deposited in plaques Selectively increased in autosomal dominant familial AD Major component of tangles and PHF A structural axonal protein, released after neuronal damage Phosphorylation at specific sites on tau is associated with lesions of AD and certain other dementias Markers of lipid peroxidation, increased in the brain in AD Results from oxidative damage to DNA Proinflammatory cytokines Produced by astrocytes and activated microglia in AD brain Cytokines with roles in inflammation, cell death Pro-inflammatory cytokine, can influence Ab production and deposition, and may modulate damage to brain microvasculature Neurotrophic signaling molecule, made by astrocytes, ? role in plaque maturation Nonspecific inflammatory marker Found in plaques in AD Cytokine that influences microglial activation and migration Increased staining of neurons, NFT in AD

Platelet APP isoforms

Possible marker of APP processing

Plasma homocysteine

Risk factor for vascular damage

Tau

Phospho-tau Oxidative damage F-2-Isoprostanes 8-hydrodeoxyguanine Inflammation Interleukins TNFa TGFb

S100b a1ACT

Less clear relationship to brain pathology

Relation to AD pathology

Abbreviations: Ab, amyloid beta protein; PHF, paired helical filaments; TNFa, tumor necrosis factor alpha; TGFb, transforming growth factor beta; a1ACT, alpha-1-antichymotrypsin; GM-CSF, granulocyte-macrophage colony stimulating factor; NTP, neuronal thread protein; APP, amyloid precursor protein.

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to ischemia to white matter tracts, and it has been suggested that they form a subgroup with high levels of CSF tau (30). In frontotemporal dementia there are varying reports of normal range tau values (31) or greater than normal levels in a substantial percentage of patients (24,32). In summary, increased total tau is not specific for AD, but may occur in degenerative conditions withor without tau pathology, or in rapidly progressive disorders. This problem of lack of disease specificity may limit the utility of CSF tau in the differential diagnosis of dementia. This does not negate the value of CSF tau in MCI, where the chief clinical question often is whether the memory problems are due to structural damage or degeneration in the brain (most commonly due to AD pathology), or whether they are due to conditions less likely to be harbingers of AD, such as age-associated cognitive changes, depression or CNS-active medications. As mentioned, preliminary reports have found that CSF tau is increased in MCI patients, with sensitivity that is very similar to that reported for AD. Patients with MCI who have increased CSF tau appear to have higher risk of progressive cognitive decline. More systematic studies of CSF tau—and other biomarkers—in MCI are required to confirm these findings and assess the gain in diagnostic accuracy from measuring the biomarker. Longitudinal data on CSF tau illustrate the possibility of using this biomarker to monitor the effects of treatment of AD. CSF tau levels remain elevated for up to 24 months in AD, and initial and follow-up levels of total tau correlate quite strongly (23,33). This suggests that the tempo of neurodegeneration remains fairly stable over 6–24 months. If a treatment for AD achieves neuroprotection, it is likely that levels of CSF tau will decrease over time. Following an acute stroke, tau is cleared from CSF within 2–4 weeks (10). Therefore it is possible that a beneficial response to a disease-modifying agent could result in a decline in CSF tau after a relatively short period of treatment—weeks to months. This conjecture will be explored as anti-amyloid and neuroprotective medications are developed. CSF Phospho-Tau: Moving Closer to AD? Because CSF tau lacks specificity for AD, assays have been developed to detect P-tau in CSF. Many epitopes of tau are phosphorylated under normal conditions as well as in AD, and it has been difficult to implicate a specific phosphorylation event or site as unique to AD (16). Some investigators have attributed neurodegeneration in AD to abortive attempts by neurons to respond to aberrant mitotic signaling, and several kinases implicated in mitosis can phosphorylate tau epitopes found in tangles. The first attempts to quantify phospho-tau in CSF have focused on epitopes such as serine199 (18), threonine 231 (18,34), or threonine 181 (35), some of which are phosphorylation sites for mitotic kinases. Monoclonal antibodies that recognize phosphorylated epitopes at specific sites of tau are valuable tools to develop ELISAs. It is difficult to develop pure P-tau standards to calibrate these assays, and highly phosphorylated tau purified from PHFs has been used instead. These standards are probably not homogeneous, and likely contain a mixture of various forms of tau, not all of which are highly phosphorylated. This makes it difficult to measure the precise concentration of P-tau in CSF, and values that are expressed relative to those of a brain extract are less satisfactory. To date only the P-tau181 assay uses a synthetic phosphopeptide for standardization. Regardless of the antibody combinations (or epitopes) that were used, levels of P-tau measured by all reported assays have shown increased levels in AD relative to controls. It is not clear at present whether these assays measure distinct species of tau or whether CSF tau is phosphorylated at more than one site. The sensitivity for AD compared to controls varies; in an initial study, P-tau231/235 was less sensitive than total tau (18). However, the evidence suggests that CSF P-tau may be a more specific marker of AD than total tau. For example, P-tau181 was not increased in CSF after an acute stroke (10), and was not increased in patients with frontotemporal dementia (19). Initial studies using ELISAs for Ptau199, Ptau231/235, and P-tau231 also have

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found that P-tau is less frequently increased than total tau in disorders such as vascular dementia. A recent large study of P-tau199 found that both sensitivity and specificity for AD versus normal controls and patients with other neurological disorders were about 85% (26). This is encouraging, and it will be important to confirm and extend these findings to compare different P-tau assays and to evaluate P-tau in MCI. CSF Beta-Amyloid Ab40 is the major species of Ab produced by cells, accounting for over 70% of total Ab, while about 15% is Ab42 and the remainder comprises a variety of other minor species (14). Similar ratios of these forms of Ab are found in CSF. As mentioned above, the amyloid hypothesis of AD implicates Ab as an initiator of pathology, and as this hypothesis has been refined over the years, evidence has accumulated against Ab42. The CSF levels of secreted forms of APP (the parent molecule of Ab) are unchanged or slightly decreased in AD compared to controls (36). To selectively quantify different forms of Ab, ELISAs have been developed using end-specific antibodies and have excellent specificity and reproducibility. Ab42 and Ab40 levels do not show a cranio-caudal concentration gradient within CSF and do not correlate with age or sex. CSF Ab40 (or total Ab) does not differ significantly in AD and controls (22,37). Curiously, the levels of CSF Ab42 are significantly decreased in AD compared to normal and neurological controls (22,24,25,37,38). About 70–90% of patients with AD have decreased levels of CSF Ab42. It should be noted that one study of patients with MCI showed similar or elevated levels of Ab42 as compared to age-matched controls (39). It is not certain why the CSF levels of Ab42 are low in AD. One possibility is that Ab42 in AD is less soluble, and deposits or aggregates of this molecule may form a sink that binds otherwise diffusible Ab42 and retards its access into CSF. It is also possible that as AD progresses, Ab42 which is generated by neurons is decreased as more cells are sick and degenerating. Another possibility is that, the clearance of Ab42 into CSF may be decreased in AD. Apo-E may enhance the deposition or clearance of Ab, and CSF Ab42 levels decrease in dose-dependent fashion in relation to the APO-E e4 allele (24,25). While CSF Ab42 appears to show quite high sensitivity for AD, as in the case of tau, disease specificity is not optimal. In non-AD disorders without dementia, such as Parkinson’s disease, CSF Ab42 levels rarely fall below control levels. About 30% of patients with non-AD dementias show decreased CSF Ab42, particularly patients who have one or two APO-E e4 alleles (24,25). In CJD, CSF Ab42 levels are fairly consistently decreased (40). One possible explanation is that AD pathology, or Ab deposition, could coexist in some of these patients. Another possibility is that compromised neurons in dementing conditions produce less Ab42. Consistent with this idea, the concentration of CSF Ab42 in AD correlates with the extent of brain hypometabolism shown by SPECT studies (41). Also, CSF Ab42 decreases to a small degree in correlation with dementia severity in AD (24,42), suggesting that the levels depend to some extent on the numbers of adequately functioning neurons. Longitudinal studies show that CSF levels of Ab42 remain stably decreased in AD for at least 6–12 months, with a high correlation between initial and follow-up levels (38). This implies that serial levels of CSF Ab42 could be used to monitor treatment in AD. However, the effects of treatment on CSF Ab42 levels may prove difficult to interpret. For example, inhibitors of the b- or g-secretase enzymes that cleave Ab from APP could decrease the overall production of Ab in the brain. In patients with AD, blocking the production of Ab might not result in a decline in the CSF levels of Ab42, because these are already low. Fortunately, there are a number of ways to circumvent this problem. Early-phase studies of the drug could be carried out in non-demented individuals first, to detect Ab-lowering effects in people in whom the efflux of Ab into CSF is normal. For studies of secretase inhibitors in AD, levels of Ab40 could be monitored, because CSF

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levels of Ab40 appear to be uninfluenced by the pool of aggregated or deposited b-amyloid in the brain, and Ab40 is produced by the same set of secretases as Ab42. In a recent study, patients with AD treated with a selective M1 (muscarinic) agonist for 4 weeks showed a decrease in serial CSF levels of total Ab by about 20%, whereas CSF Ab was unchanged in other groups of patients treated with chloroquine or physostigmine for similar periods (43). Muscarinic agonists increase the alphasecretase cleavage of APP in vitro, which may lead to decreased production of full length Ab. The clinical significance of this small decrease in total Ab levels has not been determined. Markers of Oxidative Damage Although oxidative damage affects lipids, proteins, and DNA in the brains of patients with AD (44), it has been difficult to develop biomarkers that can be stably measured. While markers of oxidation such as 8-hydrodeoxyguanine or 4-hydroxynonenal are increased in ventricular (autopsy) CSF (45), these molecules have not been reported in samples from living patients. Isoprostanes are chemically-stable, oxidized products of prostaglandins, and are increased in concentration in the brain in AD (46) and in transgenic models of amyloid deposition (47). In CSF, total F2-isoprostanes (48) and 8,12-iso-iPF2a-VI (49) have been measured by methods utilizing mass spectroscopy and found to be increased in patients with AD compared to controls. Combining the information from F-2 isoprostanes, Ab42 and tau levels improved diagnostic accuracy in one recent study (50). In the study of 8,12-iso-iPF2a-VI, this marker also was elevated in plasma and urine in AD, suggesting that it may serve as a conveniently accessible biomarker. However, this isoprostane was not studied in other dementing disorders or conditions such as Parkinson’s disease. Also, isoprostane levels can be influenced by factors such as hyperlipidemia, diabetes, and smoking, which need to be considered in interpreting results. It is technically difficult to quantify sensitive assays for specific classes of isoprostanes, an obstacle to more widespread use. Although the initial data appear promising, further studies are warranted, as are analyses of other markers of oxidative damage. Markers of Inflammation Inflammatory markers are prominently associated with the lesions of AD, including increased numbers of activated microglia and reactive astrocytes in the vicinity of plaques, and increased expression of mediators of inflammation such as activated complement, cytokines, and chemokines (51). It has proven difficult to identify soluble molecules that could correlate with this inflammatory state in CSF or plasma in AD. Most cytokines are undetectable or occur at marginally measurable levels in CSF and plasma, e.g., interleukins 1, 6, 8, and 12 and interferons (52). After a-1 antichymotrypsin (a1ACT) was identified as a constituent of plaques and shown to bind to Ab, it received much attention as a possible biomarker. Serum or plasma levels of a1ACT are increased in only a small percentage of patients with AD compared to controls, with much overlap (53–55). In CSF, levels of a1ACT increase with dementia severity in AD, but overlap with levels in controls (56). S100beta is a neurotrophic signaling molecule made by astrocytes, and may play a role in the evolution of plaques into complex structures. CSF levels of S100beta were increased in AD patients relative to controls only at the stage of mild to moderate dementia, and did not differ in severe dementia (57). One research group has carried out a series of studies on inflammatory mediators in AD, controls, and vascular dementia. They have reported increases in tumor necrosis factor alpha (TNF-a) (58), granulocyte-macrophage colony-stimulating factor (GM-CSF) (59), and transforming growth factor (TGF) b (60) in patients with AD relative to controls. The levels of GM-CSF and TGF-b were also increased in patients clinically diagnosed with vascular dementia. Plasma levels of GM-CSF and of IL-10 were also found to be increased in AD and vascular dementia relative to controls. These findings need further study, because the ability to measure indices of inflammation could be helpful in delineating subsets of patients with AD or to assess the impact of anti-inflammatory medications.

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Other CSF Biomarkers Neurofilaments (NFs) are highly abundant structural proteins of neurons, especially in axons of the motor neurons of the spinal cord. There are three main forms: light, middle, and heavy molecular weight, and they undergo phosphorylation. Light chain NFs can be quantified by ELISA and have been widely studied. Their CSF levels are increased in a variety of conditions in which damage involves the axons of neurons in the brain or spinal cord, including ALS (61), AD, Frontotemporal dementia and some patients with vascular dementia associated with white matter hypodensity on neuro-imaging (30,31). However, other conditions that injure axonal processes, including lumbosacral disc herniation, can elevate CSF NF levels (62), which greatly limits diagnostic specificity. An interesting recent report measured levels of phosphorylated NFs in CSF. Levels of total NFs and phosphorylated NFs increased with aging. Increased levels of phosphorylated NFs were found in AD, but not in vascular dementia, relative to controls (63). This promising finding will require further study. Neuronal thread proteins (NTPs) are expressed in the brain, predominantly in neurons, and can be measured by an ELISA named AD7C-NTP. Their relationship to AD pathology is unclear, but levels appear to be increased in CSF in AD compared to controls (64). Relatively few patients have been systematically studied with this marker, but in one small study, it had sensitivity similar to that of CSF tau for diagnosing AD (65). PERIPHERAL BIOMARKERS Because the pathology of AD is restricted to the brain, it may be difficult to envision how a biomarker related to the pathology of AD would be detectable after passage from CSF to blood or urine. Some substances do cross the blood-brain barrier in reverse, and can be measured in plasma. Interestingly evidence from animal models of AD strongly argues that a substantial amount of CNS-derived Ab is rapidly transported from the CNS to the blood (66,67) and that this appears to occur via an active process (68). As another example, over 95% of the plasma content of 24S-OHcholesterol, a byproduct of sterol metabolism, originates from the brain (69). Levels of this marker are minimally increased in AD, but substantially overlap control levels (70). When levels of peripheral biomarkers are altered in AD, they may result from general factors that may predispose to AD rather than reflecting brain chemistry. For example, patients with AD have slightly higher plasma homocysteine levels than non-demented controls (71). Homocysteine is a risk factor for cardiovascular disease, and elevated levels may lead to vascular changes in the cerebral circulation that promote AD pathology or interact with it to make dementia manifest earlier. It was recently found, in a community-based study, that those people whose plasma homocysteine levels fell in the highest quartile have a greater than two-fold increased risk of developing dementia when followed for up to eight years (72). Plasma Ab The CSF levels of Ab40 and A42 are higher than those in plasma, consistent with the brain being the major site of production of Ab. Nevertheless, plasma Ab levels may provide insights that have a bearing on AD. Levels of specific forms of Ab in plasma can be measured reliably by ELISA (73) and are very stable over short intervals. Ab40 accounts for about 70% or more of total Ab, and Ab42 about 10–20%. Plasma Ab42 is increased in patients with early onset familial AD due to APP or Presenilin mutations that lead to relative overproduction of Ab42 (14), and in patients with Down’s syndrome, in which there are two copies of the gene for APP (74). However, plasma levels of Ab 40 or 42 are increased in only 10–15% of sporadic AD relative to controls (75). Because plasma is far easier to obtain than CSF, it will be important to examine whether medications that alter Ab production have measurable effects in plasma, even though plasma and CSF levels of

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Ab42 do not correlate with one another (73,75). Studies of family members of patients with AD have shown that plasma levels of Ab depend to an extent on hereditary factors (76). As an extension to these studies, plasma Ab levels were used as a quantitative trait in genetic linkage studies that have provided evidence for a locus for late-onset AD on chromosome 10 (77). Both plasma Ab40 and Ab42 levels increase with aging, and it is conceivable that this rise may herald the onset of AD. There is limited evidence for this from an incidence study of AD in which elderly people with plasma Ab42 levels in the highest quartile had a two-fold increased risk of developing clinical AD over the next 24 months (78). As with many other biomarkers, these interesting findings require replication. Platelet APP Platelets have a high content of APP, and can release Ab on stimulation or activation. Several different forms of APP have been visualized on Western blots prepared from platelets, with a higher molecular weight band at about 130 kDa and a set of lower bands from 106–110 kDa. The precise nature of these APP bands is unknown, but the ratio between the upper and lower bands has been found to be reduced in AD (79,80). A recent multicenter study evaluated the ratios of platelet APP in patients with mild, moderate or severe AD, patients with non-AD dementia and controls (81). The APP ratio was significantly decreased in AD compared to either normal controls or non-AD dementias. Within AD, levels correlated directly with MMSE scores, with the most severely demented patients showing the lowest ratio. There was excellent discrimination between AD and controls. The best cutoff had sensitivity and specificity that both exceeded 85% in discriminating AD from controls and other dementias. Further studies of these platelet markers will be important, but an even greater priority will be to understand more about the biology of the APP bands that were measured. Without knowing how the APP bands originate, and whether the ratios depend on enzymatic cleavage, differential splicing or post-translational changes in APP, this marker remains enigmatic. Other Markers in Plasma and Urine As discussed above, markers of oxidation, such as isoprostanes, can be detected in plasma and urine and have been reported to be elevated in AD in a preliminary study. Similarly, there is evidence for increases in several inflammatory markers, e.g., cytokines and a1ACT in some studies in AD compared to controls. None of these markers has been validated to date in a large scale study. Because oxidation and inflammation are mechanisms of tissue injury in many diseases, it is likely that a host of conditions will be associated with slight alterations in the peripheral levels of these markers, which may limit there utility. FUTURE TRENDS So far, ideas for candidate biomarkers have come from findings in AD genetics or pathology. There have been few attempts, using proteomic or related approaches, to conduct broad searches to discover novel biomarkers. The discovery of the 14-3-3 protein in CSF in CJD came from a detailed analysis of protein patterns in CSF that initially used two-dimensional gels and highly sensitive silver staining to identify relative amounts of large numbers of proteins (82). Technological advances in proteomic methods may fuel a resurgence of these types of approaches. Combinations of biomarkers may offer the best approach to disease specificity in dementia and AD. For example, in several studies, the combination of CSF Ab and tau leads to higher specificity for AD than either marker alone. Measurement of tau and P-tau may also lead to gains in sensitivity and specificity for AD. At present, CSF tau, P-tau, and Ab42 appear to be the promising biomarkers for AD. These and several other markers deserve wider study, especially as diagnostic

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adjuncts to MCI. Biomarkers and neuroimaging measures may provide an excellent combination of measures for early diagnosis or to assist in clinical drug trials. Attention to study design is likely to gain greater prominence as promising biomarkers emerge. Diagnostic studies will evaluate patients with MCI, examine the additive value of biomarkers to screening tests or other components of the clinical evaluation, and analyze biomarkers in relation to genetic risk factors for AD.

ACKNOWLEDGMENTS Supported by a Merit Grant from the VA and by NIH grant AGO 5131.

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39. Jensen M, Schroder J, Blomber M, et al. Cerebrospinal fluid Abeta42 is increased early in sporadic Alzheimer’s disease and declines with disease progression. Ann Neurol 1999; 45:504–511. 40. Otto M, Esselmann H, Schulz-Shaeffer W, et al. Decreased beta-amyloid1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurology 2000; 54:1099–1102. 41. Okamura N, Arai H, Higuchi M, et al. Cerebrospinal fluid levels of amyloid beta-peptide1-42, but not tau have positive correlation with brain glucose metabolism in humans. Neurosci Lett 1999; 273:203–207. 42. Riemenschneider M, Schmolke M, Lautenschlager N, et al. Cerebrospinal beta-amyloid [(1-42)] in early Alzheimer’s disease: association with apolipoprotein E genotype and cognitive decline. Neurosci Lett 2000; 284:85–88. 43. Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH. The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 2000; 48:913–918. 44. Markesbery WR. The role of oxidative stress in Alzheimer disease. Arch Neurol 1999; 56:1449–1452. 45. Lovell MA, Markesbery WR. Ratio of 8-hydroxyguanine in intact DNA to free 8-hydroxyguanine is increased in Alzheimer disease ventricular cerebrospinal fluid. Arch Neurol 2001; 58:392–396. 46. Reich EE, Marksbery WR, Roberts LJ, Swift LL, Morrow JD, Montine TJ. Quantification of F-ring and D/E-ring isoprostanes and neuroprostanes in Alzherimer’s disease. Adv Exp Med Biol 2001; 500:253–256. 47. Pratico D, Uryu K, Leight S, Trojanoswki JQ, Lee VM. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 2001; 21:4183–4187. 48. Montine TJ, Markesbery WR, Morrow JD, Roberts LJ, II. Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer’s disease. Ann Neurol 1998; 44:410–413. 49. Pratico D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, FitzGerald GA. Increased 8,12-iso-iPF2alphaVI in Alzheimer’s disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 2000; 48:809–812. 50. Montine TJ, Kaye JA, Montine KS, McFarland L, Morrow JD, Quinn JF. Cerebrospinal fluid abeta42, tau, and f2-isoprostane concentrations in patients with Alzheimer disease, other dementias, and in agematched controls. Arch Pathol Lab Med 2001; 125:510–512. 51. Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000; 21:383–421. 52. Engelborghs S, De Brabander M, De Cree J, et al. Unchanged levels of interleukins, neopterin, interferon-gamma and tumor necrosis factor-alpha in cerebrospinal fluid of patients with dementia of the Alzheimer type. Neurochem Int 1999; 34:523–530. 53. Hinds TR, Kukull WA, Van Belle G, Schellenberg GD, Villacres EC, Larson EB. Relationship between serum alpha 1-antichymotrypsin and Alzheimer’s disease. Neurobiol Aging 1994; 15:21–27. 54. Licastro F, Pedrini S, Caputo L, et al. Increased plasma levels of interleukin-1, interleukin-6 and alpha-1antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain? J Neuroimmunol 2000; 103:97–102. 55. Scacchi R, Ruggeri M, Gambina G, Martini MC, Ferrari G, Corbo RM. Plasma alpha1-antichymotrypsin in Alzheimer’s disease; relationships with APOE genotypes. Neurobiol Aging 2001; 22:413–416. 56. Pirttila T, Mehta PD, Frey H, Wisniewski HM. Alpha 1-antichymotrypsin and IL-1 beta are not increased in CSF or serum in Alzheimer’s disease. Neurobiol Aging 1994; 15:313–317. 57. Peskind ER, Griffin WS, Akama KT, Raskind MA, Van Eldik LJ. Cerebrospinal fluid S100B is elevated in the earlier stages of Alzheimer’s disease. Neurochem Int 2001; 39:409–413. 58. Tarkowski E, Liljeroth AM, Nilsson A, et al. TNF gene polymorphism and its relation to intracerebral production of TNFalpha and TNFbeta in AD. Neurology 2000; 54:2077–2081. 59. Tarkowski E, Wallin A, Regland B, Blennow K, Tarkowski A. Local and systemic GM-CSF increase in Alzheimer’s disease and vascular dementia. Acta Neurol Scand 2001; 103:166–174. 60. Tarkowski E, Issa R, Sjogren M, et al. Increased intrathecal levels of the angiogenic factors VEGF and TGF- beta in Alzheimer’s disease and vascular dementia. Neurobiol Aging 2002; 23:237–243. 61. Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelso C. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 1996; 67:2013–2018. 62. Brisby H, Olmarker K, Rosengren L, Cederlund CG, Rydevik B. Markers of nerve tissue injury in the cerebrospinal fluid in patients with lumbar disc herniation and sciatica. Spine 1999; 24:742–746.

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63. Hu YY, He SS, Wang XC, et al. Elevated levels of phosphorylated neurofilament proteins in cerebrospinal fluid of Alzheimer disease patients. Neurosci Lett 2002; 320:156–160. 64. Monte SM, Ghanbari K, Frey WH, et al. Characterization of the AD7C-NTP cDNA expression in Alzheimer’s disease and measurement of a 41-kD protein in cerebrospinal fluid. J Clin Invest 1997; 100:3093–3104. 65. Kahle PJ, Jakowec M, Teipel SJ, et al. Combined assessment of tau and neuronal thread protein in Alzheimer’s disease CSF. Neurology 2000; 54:1498–1504. 66. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. Brain to plasma amyloid-b efflux: a measure of brain amyloid burden in a mouse model of Alzhiemer’s disease. Science 2002; 295:2264–2267. 67. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-Ab antibody alters CNS and plasma Ab clearance and decreases brain Ab burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2001; 98:8850–8855. 10.1073/pnas.151261398. 68. Ji Y, Permanne B, Sigurdsson EM, Holtzman DM, Wisniewski T. Amyloid b40/42 clearance across the blood-brain barrier following intraventricular injections in wild-type, apoE knock-out and human apoE3 or E4 expressing transgenic mice. J Alzheimer’s Dis 2001; 3:23–30. 69. Bjorkhem I, Lutjohann D, Diczfalusy U, Stahle L, Ahlborg G, Wahren J. Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for an age-dependent flux of 24Shydroxycholesterol from the brain into the circulation. J Lipid Res 1998; 39:1594–1600. 70. Lutjohann D, Papassotiropolous A, Bjrokhem I, et al. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res 2000; 41:195–198. 71. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998; 55:1449–1455. 72. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002; 346:476–483. 73. Vanderstichele H, Van Kerschaver E, Hesse C, et al. Standardization of measurement of beta-amyloid(142) in cerebrospinal fluid and plasma. Amyloid 2000; 7:245–258. 74. Tokuda T, Fukushima T, Ikeda S, et al. Plasma levels of amyloid beta proteins Abeta1-40 and Abeta142(43) are elevated in Down’s syndrome. Ann Neurol 1997; 41:271–273. 75. Mehta PD, Pirttila T, Patrick BA, Barshatzky M, Mehta SP. Amyloid beta protein 1-40 and 1-42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci Lett 2001; 304:102–106. 76. Ertekin-Taner N, Graff-Radford N, Younkin LH, et al. Heritability of plasma amyloid beta in typical lateonset Alzheimer’s disease pedigrees. Genet Epidemiol 2001; 21:19–30. 77. Ertekin-Taner N, Graff-Radford N, Younkin LH, et al. Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Science 2000; 290:2303–2304. 78. Mayeux R, Tang MX, Jacobs DM, et al. Plasma amyloid beta-peptide 1-42 and incipient Alzheimer’s disease. Ann Neurol 1999; 46:412–416. 79. Di Luca M, Pastorino L, Cattabeni F, et al. Abnormal pattern of platelet APP isoforms in Alzheimer disease and Down syndrome. Arch Neurol 1996; 53:1162–1166. 80. Rosenberg RN, Baskin F, Fosmire JA, et al. Altered amyloid protein processing in platelets of patients with Alzheimer disease. Arch Neurol 1997; 54:139–144. 81. Padovani A, Pastorino L, Borroni B, et al. Amyloid precursor protein in platelets: a peripheral marker for the diagnosis of sporadic AD. Neurology 2001; 57:2243–2248. 82. Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med 1996; 335:924–930.

10 Alzheimer’s Disease and Mild Cognitive Impairment John C. Morris Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Alois Alzheimer reported a “peculiar” dementia in a 51-year-old woman at the meeting of SouthWest Germany Psychiatrists in Tu¨binge´n on November 3 and 4, 1906. Alzheimer’s seminal contribution was to correlate the cognitive and behavioral features of the disorder with the histopathological findings of “miliary foci” and neurofibrillary change in the cerebral cortex following the woman’s death at age 55 years (1). On the 100th anniversary of Alzheimer’s report of the disease that now bears his name, it is appropriate to review the approach to the diagnosis of Alzheimer’s disease (AD), the most common cause of dementia in older adults. The incidence of AD (rate of occurrence of new cases) grows exponentially as a function of age and doubles every 5 years after age 65 years (2). The 2000 U.S. census data suggest that 4.5 million Americans have AD. Of these, 7% are 65–74 years of age, 53% are 75–84 years of age, and 40% are 85 years and older (3). Contrary to public perception, the typical individual with AD is not profoundly demented. Forty-eight percent of cases are in the mild stage of AD, 31% are moderate stage, and only 21% are severe stage (3). Population trends ensure that the prevalence of AD (determined by its incidence and by the duration of its clinical course) will increase with longevity as older age groups continue to expand in numbers. Recent epidemiological studies suggest that the prevalence of AD in developing countries, where the elderly populations also are growing, closely approximates that of Western countries (4). Without truly effective therapies or preventive measures, the already substantial public health costs of AD [estimated in 1994 to approach $100 billion annually in the United States alone (5)] will become enormous. This chapter reviews the assessment, clinical presentation, and course of AD with a focus on its earliest symptomatic stages. In doing so, the viewpoint of a clinician is adopted in addressing two questions in the evaluation of an individual with suspected AD: (1) is the person demented; and (2) if so, what is the cause? This chapter thus complements many of the other chapters in this Handbook, particularly those that address the epidemiology of AD (Chapter 2), its genetic basis (Chapter 8), the neuropsychological, neuroimaging, and other aids used in its detection (Chapters 4–6), and its pharmacological and nonpharmacological management (Chapters 20–24). 191

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NONDEMENTED COGNITIVE AGING Aging and AD are not synonymous. An important clinical distinction between these two conditions is that the cognitive changes of aging are benign and relatively static whereas in AD they are progressive and disabling. Although it is commonly held that cognitive performance declines substantially with increasing age, longitudinal cognitive performances of individuals who are carefully assessed to avoid contamination by those with incipient dementia often demonstrate a largely “flat” trajectory (6–10). That is, cognitive function appears generally to be maintained in truly healthy older adults well into the 9th decade of life. The factors that often are cited as contributing to these stable performances (e.g., practice effects from prior exposure to the neuropsychological measures, effective test-taking strategies, and acclimation to the testing environment) all imply learning and adaptation—the very abilities that are lost in dementia. There have been many studies of the cognitive changes associated with healthy aging (see Chapter 3, Healthy Brain Aging). Some reports of substantial declines as a function of age may have included individuals with unrecognized mild dementia and thus may have inadvertently attributed the decline to age rather than to the age-associated dementing illness (6). In the absence of disease, the cognitive changes experienced by older adults usually are minimal and nondisabling. The use of compensatory strategies, including keeping lists and calendars, allows cognitively normal older adults to overcome minor age-related declines in the learning of new information (11) and in reduced cerebral-processing resources needed to retrieve information (12). Nondemented older adults typically are independent from a cognitive standpoint and carry out their accustomed activities without assistance, although they may take longer in doing so. Attempts to characterize a greater degree of cognitive change with aging have resulted in terms such as “age-associated memory impairment” (13) and “age-associated cognitive decline” (14). Although these concepts were intended to refer to part of the spectrum of normal aging, enhanced understanding of truly healthy cognitive aging and improved detection of early-stage dementia suggest that instead these terms often characterize the incipient symptoms of an underlying pathologic substrate (15).

DEFINITION OF DEMENTIA Dementia is an acquired syndrome of impaired cognition produced by brain dysfunction. There are many potential causes of dementia, including neurodegenerative disorders, cerebrovascular disease, prion-associated disease, neurogenetic disorders, infections, toxic/metabolic encephalopathies, and other disease entities (16). In practical terms, dementia represents a decline from a previously established level of intellectual function that is sufficient to interfere with the everyday performance of the individual. The definition for dementia developed by the Work Group of the National Institute on Neurological and Communicative Disorders and Stroke-AD and Related Disorders Association (NINCDS/ADRDA) describes a decline, relative to prior abilities in memory and other cognitive functions, as determined by impaired performance and by abnormalities on clinical examination and neuropsychological tests (17). This definition is comparable to that published in the Diagnostic and Statistical Manual (DSM), 3rd Edition, Revised: The essential feature of dementia is impairment in short- and long-term memory, associated with impairment in abstract thinking, impaired judgment, other disturbances of higher cortical function, or personality change. The disturbance is severe enough to interfere significantly with work or usual social activities or relationships with others (18). [Note: the DSM-IIIR (18) and the DSM-IV (19) definitions are closely related].

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DETECTION OF DEMENTIA The confirmation of dementia traditionally has rested on the demonstration of measurable abnormalities in two or more cognitive domains. The determination of “abnormality” in turn often involves comparison of an individual’s neuropsychological performance with that of normal controls matched for age, sex, and education. Neuropsychological tests, however, may have limited ability to identify dementia in its early stages because of uncertain relation of test performance to function in the “real world,” inherent educational, ethnic, and cultural biases in the test measures, (20,21) and insensitivity or “ceiling effect” of many measures for very mild impairment, especially in highly intelligent individuals. The contamination of normative data by inclusion of individuals with unrecognized, very mild dementia (22) may inappropriately lower the age norms, further blurring the neuropsychological distinction between very mild dementia and truly healthy cognitive aging. The relevant information for the detection of dementia is not the comparing of how an individual performs relative to others, but rather how an individual has declined relative to his/her past abilities (intra-individual change).

ALZHEIMER’S DISEASE Much has become known about the clinical, behavioral, and functional impairments associated with AD since the introduction in 1984 of standard criteria for its clinical diagnosis by the NINCDS/ADRDA Work Group (17). These criteria were widely adopted and popularized by AD research programs, including the multicenter international Consortium to Establish a Registry for AD (CERAD) (23). The NINCDS/ADRDA criteria for “probable AD” correspond to DSM criteria for “dementia of the Alzheimer type” (Table 1); both sets of criteria have acceptable sensitivity (81%) and specificity (70%) for AD (25) Use of these criteria is associated with autopsy confirmation rates for AD of 85% or greater (26). The American Academy of Neurology’s (AAN) Practice Parameter for the diagnosis of dementia (25) and similar guidelines published by the American Geriatrics Society (27) describe the fundamental approach to the assessment of suspected AD: first establish the presence of dementia, and then determine the differential diagnosis of its probable cause or causes. Because the large majority of individuals with typical AD can be accurately identified during life, AD now is considered an inclusionary (rather than exclusionary) diagnosis (28). The diagnosis of AD is a clinical diagnosis. No test replaces an assessment by an experienced clinician. Diagnostic methods include a history of the onset, presenting features, and course of the cognitive and functional impairments; an evaluation of the cognitive and behavioral status of the patient; and general physical and neurological examinations of the patient, coupled with a minimal laboratory evaluation to exclude other potentially dementing disorders. The history “should be taken from the patient and an informant who is well acquainted with the affected individual. This approach is essential to establish a history of progressive deterioration and for identifying tasks that the patient no longer can perform adequately ” (17). The history alone can be diagnostic in many instances; informant scales perform as well as cognitive screening tests for dementia detection (29). Informantbased measures offer several advantages in dementia assessment. They provide observations of the patient’s functioning over time, whereas cognitive tests administered at a single point in time lack this longitudinal perspective. Moreover, they address the patient’s cognitive performance in everyday life (“face validity”) rather than in an artificial test environment that often is unpleasant (testing makes patients aware of their deficits). Informant-based measures also are much less affected than tests by potential educational and cultural biases because individuals are judged in relation to their own previous abilities rather than to group data (30). A disadvantage is that informants may not always be available. When they are, however, their observations about the individual’s cognitive functioning generally are highly accurate (31). The combination of informant

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Table 1 Clinical Diagnostic Criteria for Alzheimer’s Disease (AD) A

B

a b

NINCDS-ADRDA Criteria for ADa † Criteria for PROBABLE AD Dementia, established by clinical examination and documented by cognitive screening tests such as the Mini-Mental State Exam (MMSE) (24) Deficits in two or more cognitive domains Progressive deterioration of memory and other cognitive deficits No disturbance of consciousness Onset between 40 and 90 years Absence of other causative brain disorders Supported by impaired activities of daily living, altered behavior, family history of a similar disorder, and neuroimaging evidence of cerebral atrophy † Criteria for POSSIBLE AD Variations in the onset, presentation (including a single progressive cognitive deficit) or course of suspected AD OR Suspected AD in the presence of other potentially causative brain disorders † Criteria for DEFINITE AD Histopathological confirmation of probable AD DSM-IV Criteria for Dementia of the Alzheimer Typeb † Multiple cognitive deficits, including: Memory impairment At least one of the following: aphasia, apraxia, agnosia, or disturbed executive functioning (planning, organizing, and sequencing; abstract thinking) † Course characterized by gradual cognitive and functional decline † Deficits interfere with social and occupational function † Deficits represent a decline from past abilities † Other dementia causes (medical, psychiatric, neurologic) are excluded

Source: Adapted from Ref. 17. Source: Adapted from Ref. 19.

observations with mental status testing of the patient improves the accurate predication of probable AD in nondemented older adults (32) and in the detection of very mild AD (33). Many cognitive screening measures (24,34,35) and behavioral scales (36–38) have been developed to document impairment. These measures provide information to aid in the diagnosis but are not themselves diagnostic (insufficient sensitivity and specificity), and thus the results must be placed in context of the clinical presentation. Nonetheless, such instruments are useful to quantitatively measure impairment and monitor cognitive decline or response to therapeutic interventions (see Chapter 4, Neuropsychological Assessment in Dementia). A full neuropsychological battery usually is not required in clinical practice but is valuable for research investigations of dementia profiles and to carefully monitor cognitive change (e.g., in clinical drug trials). Most AD batteries incorporate measures of episodic memory (e.g., delayed recall tasks) and of executive function (e.g., fluency tasks; tasks requiring attention switching), among other cognitive domains (e.g., language, attention, visuospatial function, psychomotor performance). One standard battery used in many clinical trials of antidementia agents is the Alzheimer’s Disease Assessment Scale (39). Rarely the history and examination may fail to predict the presence of an intracranial process, such as a neoplasm, subdural hematoma, or hydrocephalus, that can produce cognitive impairment. Structural neuroimaging [noncontrast computed tomography (CT) or magnetic resonance imaging (MRI)] thus is recommended during the initial assessment of dementia (27). Other imaging modalities are not routinely recommended; in exceptional circumstances when the differentiation between AD and frontotemporal lobar degeneration is unclear to an experienced physician, an

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assessment of hypometabolism in specific brain regions with positron emission tomography (PET) may be an adjunctive diagnostic tool. There is no current evidence to support the use of cerebrospinal fluid (CSF) analytes, other putative biomarkers, or genetic analyses (including apolipoprotein E genotype) in routine diagnosis (see Chapter 9, Biomarkers in Dementia) (40,41). Screening for depression, vitamin B12 deficiency, and hypothyroidism is recommended, however, as these comorbidities may exacerbate dementia caused by AD. Syphilis screening is not justified in dementia assessment unless specific risk factors are present (25). The availability of standard clinical diagnostic criteria for AD notwithstanding, practicing physicians still fail to recognize cognitive impairment in the majority of affected patients (42–44). Multiple factors may contribute to this under-recognition, including a lack of knowledge about AD by health care professionals, therapeutic nihilism regarding currently approved anti-dementia drugs, and insufficient time and resources for appropriate diagnosis and management (45). To address this later concern, brief but reliable measures would be desirable to evaluate patients with memory loss (46). A brief informant questionnaire (47) and a separate brief objective screen (48) have been proposed recently to discriminate demented individuals from nondemented older adults and appear to have good-to-excellent sensitivity and specificity. The informant questionnaire contains 8 items that query changes in memory, orientation, judgment, and function (Table 2) and takes less than 3 minutes to complete. The recall of a 5-item name and address (“John, Brown, 42 Market Street, Chicago”), derived from a widely used dementia screening battery, (35) and a verbal fluency test (animal naming), wherein all animals named in 1-minute are scored, (49) comprise the objective screen; both the recall and fluency tests are simple to administer (e.g., do not require test materials) and together are completed in 3 minutes or less. The informant questionnaire and the brief test battery have yet to be evaluated in clinical practice settings alone or in combination, but their brevity, simplicity, and positive predictive value suggest that they may aid in screening for dementia in the office. A sampling of more established assessment instruments for dementia can be found in Table 3. The majority of individuals with AD lack insight into their impairment (57), perhaps explaining why many do not seek medical attention for their cognitive difficulties (58). The diagnostic value of the presence or absence of memory complaints by the individual is poor: there was little or no correlation of self-reported memory complaints with the onset of dementia in nondemented persons or with progression of dementia in individuals with AD (33). Impaired insight in individuals with AD contributes to the problems frequently encountered by families in trying to obtain patient acquiescence for lifestyle changes to improve safety and security, such as driving cessation or a change in residence (see Chapter 20: Management of the Driver with Dementia, and Chapter 21: The Plan of Care).

Table 2 AD8: Brief Informant Interview to Differentiate Aging and Dementia: Report Only a Change Caused by Memory and Thinking Difficulties Is there repetition of questions, stories, or statements? Are appointments forgotten? Is there poor judgment (e.g., buys inappropriate items, poor driving decisions)? Is there difficulty with financial affairs (e.g., paying bills, balancing checkbook)? Is there difficulty in learning or operating appliances (e.g., television remote control, microwave oven)? Is the correct month or year forgotten? Is there decreased interest in hobbies and usual activities? Is there overall a problem with thinking and/or memory? Source: Adapted from Galvin JE et al. The AD8: a brief informant-interview to detect dementia. Neurology, 2005; 65:1–6. Copyright Lippincott, Williams and Wilkins.

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Table 3 Selected Clinical Measures in Evaluating Patients Suspected of Dementia Measure

Comments

Brief Cognitive Screening Tests (Bedside Mental Status Examinations) Short Blessed Test Six-item weighted version of the Information-Memory-Concentration (SBT) Test; usually completed within 5 minutes; also correlated with Alzheimer’s histopathology (35) Mini-Mental State Nineteen items measuring orientation, memory, concentration, language, Examination and praxis; requires some test materials; most widely used screening (MMSE) test (24) 7-Minute Screen Four tests (orientation, memory, clock drawing, and verbal fluency); usually completed in 7 to 8 minutes (50) General Practitioner Includes a six-item screening test similar to the SBT, a clock drawing Assessment of task, and a five-item informant questionnaire; w10 minutes to Cognition (GPCOG) administer (51) Clinical Staging Instruments (Global Measures of Dementia Severity) Clinical Dementia Five-point ordinal scale; assesses cognitive ability by a structured Rating (CDR) informant interview and patient testing in six domains with descriptors for each level of severity (52,53) Global Deterioration Seven-point ordinal scale; has global descriptors for each severity Scale (GDS) level (54) Five-point ordinal scale; uses a structured informant interview and Cambridge Mental Disorders of the patient testing; includes the Dementia Scale and the Mini-Mental Elderly Examination Stage; has global descriptors for each severity level (55) (CAMDEX) Behavioral Scales (Noncognitive Disturbances: e.g., Affective Disorders, Psychoses, Increased Activity and Personality Changes) Geriatric Depression Assesses 30 items (either self- or observer-rated) of depressive Scale (GDS) symptomatology in older adults (36) Agitation Inventory Assesses the frequency of 29 agitated behaviors by a caregiver questionnaire in three categories: physically aggressive, physically nonaggressive (e.g., disrobing and restlessness), and verbally disruptive (e.g., asking repetitious questions and screaming) (37) Neuropsychiatric Assesses 10 behavioral disturbances for frequency and severity based Inventory (NPI) on informant interview; positive responses on screening items elicit more detailed sub-questions, therefore assessment duration depends on the number of neuropsychiatric behaviors (38) Consortium to Combination of items from other instruments; informant-based Establish a Registry evaluation of many behavioral problems and psychiatric symptoms of patients with dementia (56) for Alzheimer’s Disease (CERAD) Behavior Rating Scale or Dementia These instruments represent only a portion of available measures.

Clinical Phenomenology of AD Aspects of the clinical presentation of AD vary widely among individuals, including for age at onset, family history, appearance of noncognitive features such as behavioral and psychological changes, motor abnormalities, and survival. Furthermore, some features predominate at certain stages of dementia but not others. Virtually all individuals with AD, however, share in common the

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core features of gradual onset and progression of deficits in memory and executive abilities and in everyday function. The age of onset of AD exceptionally can occur as early as the third decade of life in autosomal dominantly inherited forms of the disorder (59,60) caused by mutations in one of three genes encoding for amyloid precursor protein, presenilin 1, or presenilin 2. Fewer than 1% of all AD is caused by these early-onset dominantly inherited forms (see Chapter 8, Genetics of Dementia). Instead, AD almost always is a highly age-dependent, “sporadic” late-onset disorder, and 93% of affected individuals are 75 years or older when dementia is diagnosed (3). Both genetic and environmental risk and protective factors have been implicated in the development of AD and may explain variations in age at onset. The genetic risk associated with the vast majority of “sporadic” late-onset AD is conferred by a family history of dementia (61) or the apolipoprotein E (APOE) genotype (62). The risk of the 34 allele at APOE for AD is most influential at relatively early ages (before age 75 years) (62). The magnitude of an increased risk for AD as a function of family history status varies both with the age of onset of AD for the proband and the age of the relative. There is progressively lower attributable risk of family history with increasing age. In one study, the relative risk was 5.3 when the age of onset for the proband was %70 years but 2.6 when the age of onset for the proband was R80 years (63). The presence of AD adversely affects survival; risk of mortality is increased 40% with AD (64). Death certificates often list cardiovascular, infectious, or respiratory causes of death rather than AD. Although the duration of AD can be for 15 years or longer in some individuals, the median survival after AD diagnosis is about 4 years for men and 6 years for women (65). Mortality increases substantially with dementia severity. In older adults, the presence of dementia is the strongest predictor of mortality, exceeding the risk of diabetes, heart disease, and other life-threatening illnesses by two to three fold (66). Initial Presentation (Very Mild and Mild AD) The symptoms of AD almost always begin insidiously such that the precise date of onset cannot be determined. Several years of slow cognitive decline may occur before the individual is brought to medical attention. The usual presenting complaint (generally noted by the family or other observers, as the patient typically does not appreciate that there is a problem) is forgetfulness or “short-term memory loss” reflecting the inability to retain new information. The clinical differentiation from the memory complaints sometimes voiced by nondemented older adults is that the early-stage forgetfulness of AD represents a consistent change from prior abilities, is progressive, and subtly interferes with daily life (e.g., missed appointments; failure to recall conversations and events). Characteristic symptoms include repetition of questions or statements, misplacement of items without independent retrieval, and failure to recall names of people well-known to the individual. In contrast to the common complaint of nondemented elderly of being unable to retrieve names when needed, in AD the forgotten name does not eventually “come to mind”. Recent events are recalled imperfectly, whereas highly learned material from the past may be remembered accurately. Minor temporal and geographical disorientation may be present, requiring frequent reminders as to the date or day of the week or increased aid in arriving at destinations. Impaired executive function often is manifested by poor judgment (e.g., inappropriate financial decisions) and uncharacteristic difficulty in handling daily tasks that require organization, planning, and reasoning. Tasks commonly affected include driving a motor vehicle, preparing meals, managing household finances, and operation of appliances (e.g., the television remote control device). Occasionally language difficulties may be apparent, including dysnomia or hesitancy of speech and circumlocution. Personality changes include passivity, diminished interest and initiative, and a tendency to remain quiet in social

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situations. Depressive features occur in approximately 20% of individuals with early-stage AD. Troublesome behaviors (e.g., agitation; delusions) are rare in the initial stages of AD. Persons in the initial stages of AD usually appear normal to those who do not know them well. They may remain engaged in activities outside the home, including socializing with family and friends, albeit at a slightly lower level of function. Two-thirds of very mildly demented individuals with AD and 41% of mildly demented individuals in one study continued to drive a car (67). Moreover, many demented individuals continue to vote, including in national elections, although may require assistance to do so (68). Persons with early-stage AD generally are independent in aspects of self-care (dressing, bathing, toileting, eating), although there may be a tendency to wear soiled clothes or pay less attention to grooming. The neurological examination typically is unremarkable beyond changes associated with aging (69). Moderate and Severe AD These stages are marked by continued deterioration of all cognitive abilities, the emergence of disruptive behaviors in some individuals, and increasing dependence on others to perform even basic activities of daily living. Recall of highly learned events now may be inaccurate; new information is quickly forgotten. Disorientation may occur even in familiar environments, and the individual may fail to recognize their residence or well-known individuals (even close relatives). The performance of simple tasks (e.g., washing dishes) often requires supervision by others to be accomplished properly; driving, managing the checkbook, and other complicated tasks simply are abandoned in this stage. The behavioral and psychological symptoms of dementia do not occur in all individuals with AD, but in those affected they typically emerge in the moderate to severe stages. Symptoms include apathy, disruption of sleep-wake cycles, agitation, anxiety, restlessness and wandering, delusions (including the “theft” of misplaced items), and hallucinations. These behavioral symptoms add to the functional disability of the patient and represent major management problems for the family and the physician. Extrapyramidal dysfunction and gait disturbances (including falls) may accompany these stages; these complications increase with dementia severity. In advanced AD there is nearly complete dependence on caregivers for basic functions, failure to recognize close family members, and markedly reduced language abilities. Dysphagia and weight loss often herald death (70), which results from aspiration, infection, inanition, and other complications of debilitation. Neurological Examination Mild-to-moderate AD usually is unaccompanied by specific abnormal findings. With disease progression, motor abnormalities increasingly become apparent. Extrapyramidal features, including a parkinsonian gait and disturbed balance, rigidity, bradykinesia, and diminished speech and facial expression, occur in perhaps one-third of AD individuals; rest tremor is infrequent (71). Other common findings with advancing disease include the emergence of “release” signs such as heightened jaw and facial jerks and the snout reflex. Myoclonus may be present in severe stages of AD; generalized tonic-clonic seizures also can complicate advanced AD (72). End-stage AD results in a nonambulatory, uncomprehending, mute, vegetative condition.

DIFFERENTIAL DIAGNOSIS OF ALZHEIMER’S DISEASE The gradual onset and progression in late life of memory loss that is sufficient to interfere with the ability to perform accustomed activities of daily living is highly suggestive of a neurodegenerative dementia, and AD is by far the most prevalent neurodegenerative disorder in older adults. Although a specific diagnostic test for AD is lacking, the focused informant-based clinical

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assessment that elicits a history of progressive cognitive impairment in an older person with a clear state of consciousness almost always indicates AD, with or without the presence of comorbid disorders (28). In a series of 382 consecutive brains from demented individuals from the community and memory clinics and referred to the State of Florida Brain Bank, AD was by far the most frequent pathological diagnosis (77%) (73). Fifty-four percent of the individuals with AD had no other pathologic entity that could contribute to dementia (“pure” AD), but concomitant pathologies (including Lewy bodies in 22% and cerebral infarcts in 18%) affected the remaining cases. Moreover, AD was present in 66% of cases of dementia with Lewy bodies and 77% of cases of vascular dementia. Although in many individuals dementia may be a multifactorial process, this study confirms the high rate of AD in demented persons (73). Key diagnostic points that may suggest a non-AD disorder are summarized here; a fuller description of these disorders can be found in the relevant chapters of this text. A simplistic guide to the differential diagnosis of dementia is shown in Figure 1. AD is characterized by gradual onset and progression and prominent deficits in memory and executive function. The rapid onset and course of cognitive impairment suggests a non-neurodegenerative disorder, such as delirium or (rarely) a prion-associated illness such as Creutzfeldt-Jakob disease. Disproportionate and disabling behavioral or language disturbances early in the course indicate Frontotemporal Lobar Degeneration, particularly if onset is before 70 years of age. The presence of visual hallucinations and parkinsonism when dementia is only mild in severity may indicate Dementia with Lewy Bodies. Abrupt onset of dementia in association with occurrence of known cerebrovascular disease suggests vascular dementia. Dementia with Lewy Bodies and vascular dementia occur most often in combination with AD rather than as the “pure” disorder. Dementia with Lewy Bodies (See Chap. 12) The second most common form of dementia after AD, dementia with Lewy bodies (DLB) is clinically characterized by progressive dementia, visual hallucinations, fluctuating cognition, and parkinsonism (74). The core features develop with or after the onset of dementia and are apparent when dementia severity is relatively mild. The diagnostic accuracy for DLB is below 50%, however, even in specialty clinics, (25,75) in part because not all DLB individuals show these cardinal features. In addition, the age at onset and the clinical features of dementia closely resemble those of AD, perhaps because concomitant AD neuropathology usually is present in DLB cases (73,75).

Alzheimer's disease

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Figure 1 Clues to differential diagnosis.

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Recurrent visual hallucinations are reported in 42% of DLB individuals and the prevalence of spontaneous motor features of parkinsonism is 55% (rest tremor is rare in DLB). Only 27% of individuals in one study demonstrated both these core features (75). The presence of fluctuating cognition (waxing and waning of cognitive and functional abilities and of arousal) has been difficult to report reliably, resulting in discrepancies in its prevalence in DLB that range from 15% to 85%. Daytime drowsiness or lethargy, daytime sleep of O2 hours, “staring into space,” and episodes of disorganized speech have been proposed as characteristics of fluctuations that distinguish DLB from AD and from nondemented aging (76). Another feature that may help to distinguish DLB is a REM sleep behavior disorder with increased muscle tone and activity and dreaming, with or without dream enactment behavior (77). The Lewy body (LB) is the pathological inclusion shared by DLB and Parkinson’s disease (PD). Dementia is common in PD and is arbitrarily distinguished from DLB by the occurrence of dementia after the diagnosis of PD is established. Predictors of dementia in PD include increasing age, hallucinations, and more severe motor features (78). Although it has been proposed that DLB and PD represent a clinicopathological spectrum where the clinical phenotype reflects the relative distribution of cortical (DLB) and subcortical (PD) LBs, the role of PD pathology in the pathogenesis of dementia in PD and DLB individuals remains to be characterized (79). Frontotemporal Lobar Degeneration (See Chap. 13) The frontotemporal lobar degeneration (FTLDs) are a heterogeneous group of disorders that are characterized by progressive and disproportionate involvement of the frontal and temporal lobes. Up to 50% of the FTLDs are familial cases (80) and some families have mutations in the gene for the tau protein (81). The pathological correlates of the FTLDs also are heterogeneous (82). Dementia in the FTLDs typically develops before the age of 70 years. Although the overall prevalence of the FTLDs is much less than for AD, below the age of 55 years the two conditions have comparable age-specific incidence rates (83). Many different terminologies have been used for the FTLDs but there are two major clinical presentations (84). The behavioral (frontal) variant often is termed Frontotemporal Dementia (FTD) and is characterized by progressive personality changes that disrupt social conduct. Features include disinhibited and inappropriate behavior, executive dysfunction (poor planning, sequencing, and reasoning), loss of empathy, disordered eating patterns, stereotypical behavior, and apathy. The aphasic (temporal) variant includes two subtypes: the nonfluent Primary Progressive Aphasia with disrupted speech output and phonological errors and the fluent Semantic Dementia in which the loss of the knowledge base underlying language leads to marked anomia and impaired word comprehension. Other clinical syndromes associated with FTLD include corticobasal degeneration and FTD with motor neuron disease. The fully expressed FTLDs generally do not present a challenge in diagnosis. In the initial stages, however, it may be difficult to distinguish early symptoms from those of mild AD. Frontal lobe hypometabolism, as demonstrated by PET, has been proposed as a useful adjunct to the diagnosis of FTLD in these circumstances (85). Vascular Dementia (See Chap. 14) Prior to the advent of successful treatments for the causes of cerebrovascular disease, arteriosclerotic disease and general paresis were dominant forms of dementia (86). Alois Alzheimer, (87) among others, helped to establish the concept that vascular dementia (VaD) represents cognitive impairment resulting from vascular brain injury. Now VaD almost certainly is overdiagnosed as a primary cause of dementia. Vascular contributions to AD remain important, however, as is underscored by the recognition that risk factors for cerebrovascular disease also are risk factors for AD (88). Cerebral vascular lesions commonly accompany AD pathology (73) but

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also frequently are found in the brains of nondemented older individuals, such that it often is difficult to determine the relative contribution of vascular lesions to the dementia. The pathologic features proposed to be associated with VaD vary widely, from large volume infarcts to strategically located lacunar infarcts to microinfarcts (89). The pathologic diagnosis of VaD is problematic because it is difficult to determine whether the infarct was causal, contributory, or incidental to dementia. Clinical diagnostic criteria for VaD generally emphasize objective evidence of stroke by neurological examination and neuroimaging studies and require a temporal relationship between the onset of dementia and stroke occurrence, (90) but even so have less than optimal diagnostic utility (91,92). The percent of dementia cases caused by stroke alone, at least in the United States, is less than 5% (73,93). The emerging concept of “mixed dementia” (94) suggests that vascular lesions can precipitate the appearance of dementia in AD or contribute to the cognitive impairment in early stages but that the vascular contributions are overshadowed once the clinical syndrome of AD is fully established (89). Medical and Psychiatric Disorders (See Chaps. 18 and 19) Depression and dysthymia may be mistaken for dementia and vice versa. Depression often results in subjective memory complaints (33) and minor cognitive deficits (95) in nondemented individuals. There is no evidence, however, that depression is a cause of dementia (“pseudodementia”), although depression may be a predictor of dementia (96). Some symptoms (e.g., apathy, loss of interest, diminished energy, poor concentration) used to diagnose depression in adults frequently occur in AD, suggesting that depression may be overdiagnosed in some older individuals (97). Provisional diagnostic criteria for depression in AD have been proposed to recognize the overlap of depressive signs and symptoms with the non-mood-related symptoms of dementia and to acknowledge that the severity of depressive features in AD is less than seen with major depressive disorder (98). Depression was present in about 20% of early-stage AD individuals in one study and did not appear to worsen cognitive performance beyond the effect of AD (95). Specific recommendations for the treatment of depression in AD are lacking, as is conclusive evidence for efficacy of antidepressant therapy. Delirium is an acquired syndrome of cognitive impairment that is accompanied by disturbances in attention, alertness, and perception. Visual misperceptions, illusions, and hallucinations are common. It is distinguished from AD by an acute onset and the clouding of consciousness. Delirium is caused by toxic, infectious, or metabolic perturbations and their correction (e.g., removal of an offending pharmacological agent; treatment of an underlying infection) results in clearing of the encephalopathy. Dementia is a risk factor for delirium and the prevalence of delirium is higher in older adults. Potentially reversible medical conditions (e.g., vitamin B12 deficiency) rarely are the sole cause of dementia (99). Although comorbid conditions may contribute to the cognitive impairment of AD, there is little evidence of cognitive benefit from treatment of the medical problem once AD is clinically established (100). Potentially dementing neurological (e.g., stroke), psychiatric (e.g., depression), and medical (hypothyroidism; B12 deficiency) comorbidities appear not to meaningfully affect the outcomes of AD, (101) suggesting that whatever deleterious effects these disorders may have for cognition is superceded by the global dementia of AD. MILD COGNITIVE IMPAIRMENT There is intense interest in mild cognitive impairment (MCI) as a possible prodromal stage of dementia. The MCI construct was developed to characterize older adults who were neither cognitively normal nor overtly demented. The AAN’s Practice Parameter on early detection of dementia and MCI (102) recommended clinical monitoring for MCI individuals because of their increased risk of

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progressing to dementia (annual “conversion rate” of approximately 10–15%, compared with 1–2% for nondemented elderly aged 80 years or less). However, estimates of the prevalence of MCI and related constructs, including “age-associated cognitive decline” (AACD) (14) and “cognitive impairment no dementia” (CIND), (103) have varied greatly as have rates of “conversion” to dementia (104,105). Sources of variability include different criteria used to define MCI, differing methods to implement the criteria, and differences in the ascertainment and characteristics of individuals in the study samples. Resulting controversies about the boundaries of the condition in relation to normal cognitive aging and early-stage dementia have prompted refinement of the definition of MCI (Fig. 2) to broaden the concept and include prodromal forms of non-AD dementias (106). Basic criteria for MCI include cognitive complaints that are documented by objective cognitive testing in the presence of generally preserved activities of daily living (thus falling short of criteria for dementia) (106). MCI can result from multiple etiologies, including some that may be stable (e.g., posttraumatic encephalopathy) or reversible (e.g., depression; medication-induced cognitive dysfunction; substance abuse). Several subtypes of MCI have been proposed (107). The most frequently studied subtype is amnestic MCI, in which memory deficits predominate. When the memory deficit is relatively isolated, the subtype is “amnestic MCI, single domain”; when other cognitive domains (e.g., attention, executive function, visuospatial skills, language) also are impaired, the subtype is “amnestic MCI, multiple domain.” When the presentation is in a non-memory cognitive domain, the subtypes are “nonamnestic MCI, single domain” and “non-amnestic MCI, multiple domain,” depending on the number of impaired domains. The reliability and validity of this classification scheme, the prevalence and incidence of MCI subtypes, and their underlying etiologies all remain to be determined. There are conceptual and practical difficulties in applying criteria for mild cognitive impairment (MCI) in the clinic. The diagnosis of amnestic MCI, for example, can be based on the subjective memory complaint of the individual, even if lacking corroboration by an informant. Selfreported memory problems, however, correlate better with depressive features than with future development of dementia whereas informant-reported cognitive difficulties are predictive of dementia (33). Informants are needed also to determine whether activities of daily living are impaired. Recent studies indicate that individuals with MCI experience changes in everyday function. For example, individuals with amnestic MCI demonstrated impaired ability to manage cash transactions, bank statements, and bill payments and had reduced overall financial capacity (108). The criterion of “generally preserved activities of daily living” thus becomes dependent on how carefully changes are sought by the clinician and whether informant observations are solicited. Furthermore, the cognitive deficits in MCI may be more widespread than was initially appreciated. A multicenter trial evaluating potential treatment effects of donepezil or vitamin E enrolled 769 participants with amnestic MCI from 69 centers in the United States and Canada; as expected, the greatest objective impairments were demonstrated in measures of episodic memory but impairments, albeit very mild, also were observed in multiple other cognitive domains (109). Clinical Presentation MCI Amnestic MCI Multiple Domain MCI Single Nonmemory Domain

Possible etiologies Degenerative Vascular Metabolic Traumatic Psychiatric Others?

Figure 2 Heterogeneity of clinical presentation of MCI and potential multiple aetiologies. Source: Adapted from Ref. 106.

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It can be argued that MCI individuals, who experience memory deficits, have compromised function in activities of daily living and are impaired in other cognitive domains already fulfill criteria for dementia, although at a very mild stage that may be below the current diagnostic threshold of most clinicians. Informant-based methods have been shown to reliably detect early-stage AD in individuals who meet criteria for amnestic MCI; autopsy confirmation of AD in this series was 84% (110). Longitudinal studies of individuals with amnestic MCI demonstrate progressive cognitive decline at rates that are influenced by the severity of impairment at baseline (9). Moreover, the neurobiological phenotype of amnestic MCI closely resembles that of clinically diagnosed AD, although at a milder stage. Features in common include neuropsychiatric symptoms, (111,112) overrepresentation of the APOE 34 allele, (113) selective volumetric loss in the entorhinal cortex and hippocampus as measured by MRI, (114,115) neuronal loss in vulnerable brain regions, (116) increased brain markers of oxidative stress, (117) cell cycle changes, (118) and abnormalities of the cholinergic system (119). The views of this author regarding MCI in relation to AD can be summarized as follows: 1. MCI is heterogeneous; not all individuals with MCI will have AD. 2. Clinical methods incorporating informant interviews can accurately identify the subset of MCI with prodromal AD. 3. Clinically expressed AD begins with the MCI phase and, in these individuals, the etiology of MCI is the underlying AD. 4. The MCI phenotype for this subset is that of AD, only milder. 5. In this clinically-defined subset, MCI is not a risk factor for AD, it already is AD at its earliest symptomatic stage. If some cases of MCI can be identified by their physicians as highly likely to represent earlystage AD, then counseling and treatment become important issues. Attention to possible safety and security issues (e.g., driving), financial and insurance planning, advance directives, and related topics may be appropriate at this stage when the individual still is able to engage in decision making. No drug treatments have been approved by the FDA for the indication of MCI. An industry-sponsored randomized placebo-controlled trial of donepezil 10 mg a day for 24 weeks found no treatment effect for MCI individuals on the primary efficacy measures, although some secondary cognitive measures showed effects favoring donepezil (120). Treatment results from a multicenter trial suggest that, although there was no difference in the three treatment groups (donepezil, vitamin E, placebo) for the primary endpoint of “conversion to AD” at 3 years, donepezil (but not vitamin E) was associated with reduced risk of “conversion” to AD 12 months (and up to 36 months in the subset of participants with at least one APOE 34 allele) (121). No uniform recommendations regarding MCI as a treatment target can be provided at this time. In the absence of published data clearly demonstrating a benefit of pharmacotherapy for MCI but with increasing recognition that at least some MCI individuals have underlying AD, treatment issues are evolving. On an individual basis, when the clinician believes on clinical grounds that MCI is caused by AD, there may be a rationale not only for counseling but also for cholinesterase inhibitor therapy based on the likelihood of early-stage AD (122). As a diagnostic threshold for AD moves back to earlier stages of impairment, there is growing impetus to develop effective therapies to guide intervention at these early stages (123).

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11 Down’s Syndrome, Alzheimer’s Disease, and Dementia David J. Loren and David M. Holtzman Washington University School of Medicine, St. Louis, Missouri, U.S.A.

HISTORY Down’s syndrome (DS) is one of the oldest known human malformation syndromes; paintings dating back to the sixteenth century have been found that suggest depictions of individuals with phenotypic features of DS. The pattern of malformation was formally recognized during a lecture given in 1846 by Edouard Seguin. The syndrome’s namesake, Dr. John Langdon Down, described this congenital syndrome characterized by stereotypic facial and cognitive features for the first time in the medical literature in 1866 (1,2). Although advanced maternal age was understood to be a risk factor for DS, trisomy 21 as the cause of DS was not appreciated until 1959 when Lejeune confirmed the presence of three copies of human chromosome 21 in nine infants with DS (3). In 1948, Jervis reported finding neuropathologic features of Alzheimer’s disease [AD, originally described by Alzheimer in 1907 (4)] in three adults with DS at 35, 42, and 47 years of age (5). DS is one of the most common human genetic disorders with a prevalence of approximately 1 in 700 births (including live and still births) (6).

GENETICS The nondysjunction of chromosome 21 (HSA21) is not a gender-neutral event, with the male: female ratio 1.3:1. Longitudinal study over 20 years has shown that the prevalence of DS is 1.66 per 1000; approximately 2% of DS cases are stillbirths and approximately 30% are electively aborted (7). In one large analysis of aneuploid 21 pregnancies, 95% were trisomies, and the remainders were 14/21 translocations or mosaics. Nondysjunction originates in the egg 95% of time and sperm 5%, and about half of these conception products spontaneously abort (8–10). HSA21 is the smallest chromosome (Fig. 1) among human autosomes, containing approximately 225 genes (11). Shortly after trisomy 21 was recognized as the cause of DS, efforts were made to dissect which parts of the chromosome were responsible for specific DS features. By 1975, chromosome banding techniques suggested that the long arm (21q) of HSA21 was likely the region responsible for the DS phenotype. Subsequently, over the next decade, identification of 209

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Figure 1 Gene map of human chromosome 21 (HSA21) with several approximate known gene and marker locations. Source: Courtesy of National Center for Biotechnology Information.

unique HSA21 translocations or partial trisomies led to the postulation that 21q22 is the DS critical region, termed the DCR (12,13). It is now known that 21q22 possesses most of the transcriptionally active DNA on HSA21. This region accounts for the major phenotypic features of congenital heart disease, craniofacial anomalies, and mental retardation (14,15). In spite of copious evidence that the DCR is alone necessary and sufficient for the DS phenotype, challenges to the DCR paradigm have been recognized. In 1944 Daumer-Haas et al. (16) reported a 33-month-old girl with craniofacial features of DS and delayed speech development but only mild motor retardation. This child had tetrasomy 21pter-Oq22.1 (4 copies of the region between the centromere of HSA21 and SOD1, inclusive of the APP region, Fig. 1) and thus possessed excess of only part of the putative DCR (16). In spite of these challenges, defining loci of HSA21 responsible for specific phenotypic features remains a key focus of DS research. Effects of triplication of HSA21 are immediate and global in the developing embryo, although the mechanism by which the gene over-dosage disrupts development is not well understood (17). On a cellular level, DS malformations appear to be disorders of incomplete tissue development rather than abnormal embryogenesis. General intrauterine growth appears to be diminished with decreased body weight and decreased organ weight but normal placental weight (18). Dysregulation of normal apoptosis is suggested by examples of organogenesis that sometimes lack normal patterns of cellular involution such as atrioventricular canal, tracheo-esophageal fistula, syndactyly, imperforate anus, and duodenal stenosis (19). CLINICAL ISSUES IN DS Despite the challenge of providing adequate care to people with DS, this population is living much longer. For individuals with DS, survival in the first year of life has changed from below 50% to

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above 90%. From 1983 to 1997, the mean age of death for individuals with DS increased from 29 years to 49 years, although there is a significant racial disparity with non-Caucasian subjects having a shorter lifespan (20,21). In a 2002 study by Yang et al. death certificates of 17,897 people with DS in the United States were analyzed and from them, standardized mortality odds ratios were calculated for 17 disorders. The authors found that there was a significantly increased mortality odds ratio for the diagnosis of dementia (21.2-fold increase). Only congenital heart disease (29.1-fold increase) was over-represented to a greater extent; diagnoses of hypothyroidism (20.3-fold increase) and leukemia (1.6-fold increase) were also significantly linked to mortality (21). Mental function as measured by IQ in DS individuals ranges from mild (IQ 50-70) to moderate (IQ 35–50) disability, and only rarely to severe (IQ 20–35) disability (22). In children with DS, evolution of language skills tends to follow behind nonverbal skills, and expressive language may be poor until age 4–5 years (19). Seizure disorders, including infantile spasms, occur in about 15% of the DS population, rising to 50% in individuals with dementia (23,24). Approximately 25% of DS individuals are diagnosed with AXIS II psychiatric disorders, notably depression and anxiety (19). While no single person with DS has ever been described possessing all of the known clinical features of the syndrome (Table 1), characteristic phenotypic features are readily identifiable in anyone with DS (17). Estimates report approximately half of all the genes in the human genome contribute to central nervous system development and function (40). At this time, at least ten genes on HSA21 are listed in OMIM (Online Mendelian Inheritance in Man, an online database of human genes and genetic disorders developed by the National Center for Biotechnology Information) as CNS related genes. Among these genes are Amyloid Precursor Protein (APP), Superoxide Dismutase (SOD1), S100b, Minibrain (MNB), and GARS-AIRS-GART, all of which have been implicated in specific components of DS neuropathology (41). Trisomy 21 affects all stages of brain development—neuronal differentiation, migration, synaptogenesis and maturation (42). In neonates, neuronal density is reduced in specific regions and the dendrite population and arborization is greater than normal. However, this is rapidly followed by neuronal atrophy in some brain areas beginning at 4 months age (37). CLINICAL COURSE OF DEMENTIA IN DOWN’S SYNDROME Dementia in DS was reported nearly immediately after Down provided his classical description. Indeed, adult mortality was often attributed to “. .. nothing more than general decay—a sort of precipitated senility” (43). In 1995, Zigman et al. reported that adults with DS had a marked risk for developing dementia (odds ratio 1.68–8.56) (44). Clinical dementia (e.g., NINCDS-ADRDA criteria) occurs in over 30% of DS subjects by 40 years of age and increases to near 90% of DS individuals by 60 years of age (42,45,46). While only 8–10% of DS subjects show cognitive decline between 35 to 50 years age, over 75% of DS individuals have been reported to experience decline beyond 60 years of age (47). Neuropsychiatric testing in DS subjects reveals diminished long term memory, impaired visuospatial performance and age-related changes in the P300 component of event related testing after age 37 (48). Neuroimaging via position emission tomography (PET) scan has also shown that DS brains have unique metabolic activity with decreased glucose metabolism in both the temporal and parietal cortical regions (49,50). Numerous authors have attempted to define diagnostic batteries that determine the degree of dementia in DS. Both clinical criteria (e.g., presence of epilepsy), and cognitive testing (e.g., Daily Living Skills Questionnaire, modified DSM-IV criteria, Down’s Syndrome Mental Status Examination) have been employed with the best predictive results obtained from using a combination of both clinical and cognitive criteria (51). Despite these studies, the specific factors that influence the age of onset of dementia in DS are unclear. There is no consensus on which cognitive assessment tasks and batteries distinguish DS adults who have

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Table 1 Phenotypic Features of DS: Prevalence Percentages Are Shown in Parentheses Craniofacial: Classic facial features include brachycephaly with flattened occiput, up-slanting palpebral fissures, epicanthal folds, and small nose with low nasal bridge (25) Ophthalmic: Both general examination and direct ophthalmoscopy reveal Brushfield spots, myopia (70%), strabismus (45%), and acquired cataracts (30–60%) (26) ENT: Chronic serous otitis media leading to conductive hearing loss (60–90%) is common as is sleep apnea due to relative nasopharyngeal underdevelopment with adenoid enlargement. These features combined with a relative immune dysfunction predispose to risk of sinusitis and rhinitis (27) Cardiovascular: Approximately 40% of DS individuals have congenital heart disease, with atrioventricular septal defects (AV canal) comprising roughly 60% of the cases, followed by isolated ventricular septal defects and atrial septal defects. Tricuspid valve or atrial valve regurgitation may also occur by age 20 (28,29) Gastrointestinal: Duodenal stenosis and imperforate anus occur in about 10% of the DS population. Failure to thrive secondary to recurrent illnesses is also a risk for these children (30,31) Endocrine: Approximately 15% of DS individuals have clinical hypothyroidism. Male infertility is almost guaranteed and females typically have poor fertility. Of note however, is that pubarche, menarche, and adrenarche all occur at about the same age as in the non-DS population (32) Hematologic: There is a 1% risk of acute lymphocytic leukemia during the entire lifetime in DS. Although there is a lower risk of development of malignancies in DS (1/10 rate of general population), neoplasms that do occur may be more refractory to treatment (21,33) Hands: Classic extremity manifestations of DS include shortened metacarpals and phalanges, clinodactyly & a single palmar crease (50%) or Simian crease (45%). These findings frequently prompt the initial discovery of undiagnosed DS in the neonatal period (25) Skin: Loose neck folds (80%) occur in infancy and may even be appreciable on antenatal ultrasound. Hyperkeratotic skin (75%) and fine, sparse hair presents a challenge for adequate dermatologic care and adds to the already increased risk for perigenital infections during adolescence (22) Stature: Significant short stature is common, with males attaining average of 5ft and females an average of 4.5ft (34) Musculoskeletal: As a rule, newborns with DS have obvious hyotonia and joint laxity that places these babies at great risk of significant delay in achieving motor milestones. Typically, these children are sitting at 1 year and walking by 2 years of age. Muscle tone improves with age, while development slows. Ligamentous laxity also creates a risk for hip and knee dislocations. Abnormalities of bone development are also evident in DS; plain radiographs reveal delayed ossification and there is also an increased prevalence of early onset arthritis. Atlantoaxial dislocation occurs in 10–20% of individuals although cord related symptoms are rare (25,35,36) Neurologic: DS is the most frequently identified cause of mental retardation. At the gross level, DS brains are small for age and weigh less than age matched controls. This relative hypoplasia is notable primarily in the cerebellum and brainstem. Furthermore, the depth and number of sulci are reduced. Decreased neuronal density has been described in several brain regions (37–39)

dementia in its early stages (52). Nevertheless, efforts to characterize intellectual deterioration in an intellectually disabled population have led to the suggestion of standardized criteria by Aylward et al. in 1997 (53). Identification of mood disturbances can be a real clinical dilemma in the psychiatric care of people with DS. Indeed, major depression can sometimes masquerade as dementia (24). In 1998, Chicoine described a study of 148 DS adults at a residential center noting that 55% of the population had an Axis II disorder. Mood disorders predominated (31%) with anxiety and obsessive-compulsive disorders representing most of the balance (13% and 12%, respectively) (24). Furthermore, there exists the challenge of distinguishing neurocognitive decline in a mentallyretarded population. With healthy aging, there should not be significant deterioration of baseline abilities. The clinical challenge then is to define baseline function through a good informant or

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proxy. In practice, the informant-based method is the best way to determine whether an individual with DS is developing cognitive decline as a good informant will best know whether there is a true change from baseline. Numerous case-control and longitudinal studies performed in the 1980s attempted to characterize and quantify the course of mental deterioration in the DS population. While uniformly descriptive of dementia evolution, many of these studies had small sample sizes (N!175, usually N! 25) (54). A prospective study of DS subjects with dementia by Lai and Williams in 1989 suggested three phases of clinical deterioration. The first phase is characterized by impaired short-term memory and reduced expressive language. In individuals with greater premorbid impairment, the first signs of dementia are apathy, inattention, and decreased social interaction. The second phase is characterized by motor impairments with slowing and shuffling of gait. Activity-of-daily-living (ADL) skills such as dressing, use of utensils, and toileting are also lost. Seizures may be present during this phase and are more frequent than occurs in late-onset AD. Indeed, the prevalence of epilepsy approaches 50% over age 50 (55). In the third phase, individuals become non-ambulatory. Spasticity and appearance of pathologic release reflexes also occur at this time (47,54). Once dementia that is not due to stroke or a reversible cause is recognized in a DS individual, decline is usually rapid. The mean time to death after the diagnosis of dementia is established is approximately 5 years (56). Brugge et al. reported in 1994 on a group of adults with DS, 22 to 51 years old, with a matched control group on various behavioral and cognitive tests. They found that a subgroup of the DS patients showed memory and cognitive impairment characteristic of dementia occurring in a temporal fashion “in which neuropathologic manifestations of AD are predicted to be developing” (57). It is now recognized that dementia in adults with DS appears to be secondary to AD type neuropathology and associated changes. Neurodegeneration appears to occur earlier in females. In one small study of individuals with DS (17 males and 11 females between 10 and 74 years) female DS cases (48.8C/K 1.9 years, mean C/K SEM) had an earlier onset of dementia than male DS cases (53.6C/K 1.3 years) and also appeared to exhibit a more severe form of AD with a greater number of neurofibrillary tangles (58). NEUROPATHOLOGY IN DOWN’S SYNDROME In the thirty years after Jervis’ 1948 description of a link between DS and AD, numerous studies demonstrated the homology between the neuropathology of AD and DS (59). The neuropathology of AD is covered in detail in Chapter 7 by Mirra. In 1972, Malamud published his groundbreaking pathologic study, reporting that “microscopic characteristics of AD were ubiquitous in brain samples from individuals with DS over age 40 years” (60). Since then, a number of post-mortem studies have shown that nearly 100% of DS individuals develop neuropathologic and histologic features of AD by the fourth decade of life (61). Specifically, all of the classic neurohistologic features of AD are present including diffuse and neuritic plaques, neurofibrillary tangles, neuronal loss, synaptic loss, and gliosis (62–64). Though AD neuropathology is present in all DS individuals by age 35–40, dementia usually does not ensue until a mean age of approximately 50 years (52). It may be that a critical threshold of brain damage due to amyloid-beta (Ab) deposition, neurofibrillary pathology, and other factors are required before cognitive decline appears. Ab, and its precursor APP, appears to be centrally involved in the neuropathology of AD in DS. Just as in AD, evidence that Ab is a key initiator in the neuropathology of dementia in DS is now well recognized (65). The APP gene, composed of 19 exons, encodes for a large, transmembrane protein expressed by many cells but at highest levels by neurons. Cleavage of APP by a-secretase yields two fragments that precludes formation of Ab (Fig. 2). Sequential cleavage by b- and g-secretase yields predominantly a 40- or 42-amino acid residue peptide (amyloid-b, also called Ab). Ab is normally present in a soluble form in many tissues and body fluids; its highest concentration being found in the CNS (e.g., in CSF) (67). Ab can change structural shape from a

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predominantly random coil or a-helix to soluble and insoluble forms in the extracellular space of the brain (e.g., plaques) with a high b-sheet content. What controls this change in conformation is not entirely clear although Ab-binding molecules such as apolipoprotein E (ApoE) appear to play an important role (68). It is recognized that overproduction of Ab, particularly Ab42, due to mutations in APP or presenilins appears to drive the early Ab accumulation of early-onset, autosomal dominant, familial AD (69). The neuropathology of AD in DS has all the classic features of AD with some minor variations. Because the neuropathology of DS appears to match that in AD, post-mortem study of DS brains has been used to estimate the likely progression of Ab deposition in late-onset AD in the non-DS population. LeMere et al. in 1996 examined the brains of 29 DS patients from 3 to 73 years old. Deposition of Ab42 was the earliest form found in almost half of the patients between 3 and 30 years, the youngest at age 12 (70). Ab42 deposition in plaques precedes Ab40, and often occurs by late childhood (70–72). Complete AD pathology with neuritic plaques and tangles is present in almost 100% of cases by age 35 (61). Interestingly, as previously mentioned, dementia does not begin until a mean age of 50. A very similar “pre-clinical” phase of AD (characterized by robust plaque and tangle pathology in the absence of dementia) also occurs years prior to the development of dementia in late-onset AD (73). Histopathological changes characteristic of AD are seen in DS brains; neurofibrillary tangles are present typically in the neocortex, hippocampus, amygdala, nucleus basalis of Meynert, and raphe complex (74). Diffuse and neuritic plaques are seen primarily in the first three regions. Changes in the nucleus basalis and raphe complex suggest architectural and biochemical disturbance of serotonergic and cholinergic neurotransmitter systems just as in AD (75,76). Given that the gene for APP is triplicated in DS, many investigators have been compelled to attribute overproduction of Ab (due to 3 as opposed to two copies of APP) as the causative agent in development of Ab accumulation and subsequent AD pathology in DS. Early reports suggested that APP mRNA was present at up to five times normal levels; however, as noted below, this hypothesis has been refined (77). Teller et al. noted that soluble Ab was found in half of their studied DS fetal brains while none was detected in age matched controls (78). Rumble et al. in 1989, demonstrated that deposition of Ab in plaques in the brains of 26 DS subjects began 50 years earlier than in 127 non-DS controls, while the rate of Ab deposition (once Ab deposition began) was similar in the two groups. The same researchers also compared the level of serum APP in 17 patients with DS with 33 healthy, normal elderly controls. They found that serum APP was present at 1.5 times higher concentration in the DS patients versus the controls (72). In an attempt to characterize the temperospatial deposition of Ab, numerous researchers in the 1990s showed that Ab deposition in

Figure 2 APP and the complete sequence of Ab. Beta (b), alpha (a) and gamma (g) secretase enzyme cleavage sites are shown. Each letter in the sequence signifies an amino acid. Source: Adapted from Ref. 66.

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DS progressed from superficial to deep cortical layers and appeared early in the frontal cortex (59,79). These findings may partially explain the appearance of frontal lobe symptoms seen early in the course of DS-related dementia. The apolipoprotein E gene (ApoE), located on HSA19, has three alleles (32, 33, 34). The 34 allele is the only proven genetic risk factor for late-onset AD as well as for cerebral amyloid angiopathy while the 32 allele appears to protect against AD (68,80). Interestingly, as in late-onset AD, the 34 allele appears to also confer risk for earlier onset of dementia in DS (81–83). This, along with substantial data from animal models with AD pathology and in humans with late-onset AD strongly suggests that apoE exerts its effects on dementia by influencing Ab metabolism and structure (68). Efforts to evaluate the contribution of APP gene triplication as causative of DS neuropathology have led to the search for an individual with only two copies of the APP gene but three copies of genes on the remainder of HSA21 (including the putative critical DS region leading to craniofacial and cardiac anomalies). Identification of an individual who had three copies of the DS critical region exclusive of APP on HSA21 and who did not develop AD pathology would help implicate over-expression of APP and subsequent overproduction of Ab as the pathologic cause of AD in DS. Identification of an individual with triplication of only APP and surrounding regions in the absence of the DS critical region who developed AD pathology would similarly implicate APP and Ab. In 1998, Prasher et al. reported discovery of an informative individual. This case had partial trisomy 21 {46,XX,rec(21)dup q,inv[21(p12q22.1)]}—i.e., two copies of APP and three copies of much of the remainder of the long arm of HSA21. This subject had no evidence of dementia on neuropsychological evaluations into her seventh decade of life. She functioned at only a mild level of intellectual disability. Her death at age 78 was from pneumonia. Her autopsy revealed no ADrelated pathology (84). In total, evidence implicating APP and coincident Ab overproduction in the development of AD neuropathology in DS is quite compelling (85).

INSIGHTS FROM ANIMAL MODELS Genetically modified animals can provide invaluable information regarding the role of specific genes and gene regions in the DS phenotype. HSA21 has large regions of homology with regions on mouse chromosome 16 (MMU16), 17 (MMU17), and 10 (MMU10), with MMU16 having the greatest similarity. The first trisomic mouse model of DS, Ts16, was of somewhat limited utility since these mice die just prior to or at the time of birth (75). Furthermore, MMU16 contains numerous human counterpart genes located on chromosomes other than HSA21, and several HSA21 genes implicated in DS are not located on MMU16. Nevertheless, Ts16 mice do possess several typical DS cardiac, craniofacial and ocular anomalies (86,87). Ts16 mice display several characteristic embryonic defects also seen in DS including abnormalities of neurogenesis, a delay in generation of neocortical and basal forebrain cholinergic neurons, and a proportional reduction of the total CNS neuron population (38). In an effort to develop better genetic mouse models of DS, other partially trisomic mouse models have been generated. Two partially trisomic mouse models have been described, each bearing supplemental MMU16 genetic material (88,89). Ts65Dn contains three copies of the region between App and Mx1 on MMU16 and demonstrates some abnormalities typical of DS (90). Ts65Dn mice possess reduced adenylyl cyclase signaling pathways in the cerebral cortex and hippocampus, but not in the cerebellum (38). Behaviorally, these mice demonstrate impaired development and learning when they are young, perhaps analogous to mental retardation (90,91). Ts65Dn mice also have age-related degeneration of septohippocampal cholinergic neurons and show astrocyte hypertrophy, histological changes also seen in the DS brain (87,91,92). Though Ts65Dn mice have three copies of App, they do not

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develop Ab deposition. This is likely because of the fact that mouse Ab differs from human Ab by three amino acid residues, possibly precluding the conversion of Ab into amyloid in vivo. Ts1Cje mice are trisomic for the region in MMU16 between Sod1 and Mx1—a smaller region than Ts65Dn. These animals carry a disrupted Sod1 allele and so are not functionally trisomic for Sod1 (93). These mice do not manifest all the cognitive and neuropathologic changes seen in Ts65Dn mice, suggesting that the App to Sod1 region of MMU16 is critical for some of the DS neurological phenotype including atrophy of basal forebrain cholinergic neurons. The App to Sod1 region is, however, triplicated in a new trisomic model, Ms1Ts65 and further analysis of these mice may prove useful (38). The first DS candidate gene transgenic (tg) animal was an animal over-expressing human SOD-1. SOD-1 tg mice possess abnormal neuromuscular junctions, decreased serum serotonin levels, and increased biogenic amine function; findings shared with human DS (94,95). A second tg mouse, tg PFKL, overexpressed liver-type phosphofructokinase. In these animals, brain glucose metabolism was disordered in a fashion somewhat similar to DS in young adults (96). Overexpression of S100b, a protein released by astroglia, can cause abnormal dendritic development and premature dendrite loss. It has been postulated that S100b over expression could contribute to disrupted learning given its potential role in hippocampal long-termpotentiation (97). Games et al. in 1995 reported production of a tg mouse overexpressing a mutant form of human APP in the brain that results in a familial autosomal dominant form of AD. These APPV717F—also called PDAPP tg—mice develop many of the pathological hallmarks of AD including Ab deposition, neuritic plaque formation and gliosis. They do not develop neurofibrillary tangles (98). Subsequent to this work, numerous APP tg mice have been generated that develop neuropathology seen in AD (95,99). However, overexpression of wild-type, non-mutant human APP in mice has not yet been shown to lead to the development of Ab deposition and amyloid plaques (86,100). This shortcoming may be a function of the short (relative to human) lifespan of the mouse or to the requirement for higher than a 1.5-fold increase in human Ab in mice to generate Ab deposition. Further study of this area is warranted to understand how alterations in Ab synthesis and metabolism can lead to Ab aggregation in an age-dependent fashion. SUMMARY Appreciation of the genetics and molecular biology of DS has progressed dramatically since DS was first recognized as an identifiable syndrome over 150 years ago. Correlations between genotype and phenotype have permitted identification of a specific region of genes on HSA21 that is implicated in development of the classic craniofacial, cardiac, and neuropathologic features of DS (15). Triplication of the HSA21 genome has effects in all tissues, with the brain alterations being perhaps the most disabling. The dementia described in DS, occurring at some point by the fourth to sixth decades in almost everyone with DS, appears to follow both the temporal and histopathologic course of AD typically seen in non-DS individuals at much later ages. Located on HSA21, APP and its protein products, APP and Ab, appear to play pivotal roles in the neuropathology of both AD and DS. As in late-onset AD, apoE4 also appears to be a dementia risk factor in DS. The exact mechanism by which the AD neuropathology seen in DS ultimately leads to dementia is not entirely known. Animal models have been helpful in furthering our understanding of the effects of specific increases in gene dosage and particularly, the role of APP and Ab metabolism in DS. Recent completion of the catalog of genes on HSA21 will certainly further our understanding of the contribution of specific genes to the DS phenotype. However, the function of most of these genes is, as yet, unknown (11). Given the almost universal development of AD in the DS population, there is an increasing effort to involve DS individuals in clinical trials testing molecules that may ameliorate or prevent AD (101). This may be a good group to try anti-Ab therapies including active and passive immunization, secretase inhibitors, as well as drugs that have antioxidant and other properties

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(65,102). Such novel therapies could offer a population that has already seen dramatic improvements in longevity a chance to prevent further cognitive decline.

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12 Dementia in Parkinson’s Disease and Lewy Body Disorders James E. Galvin Washington University School of Medicine, St. Louis, Missouri, U.S.A.

INTRODUCTION Dementia is a major public health problem, crossing gender, socioeconomic, and ethnic lines. The incidence of dementia increases with age and prevalence increases every decade after age 65 (1,2). Alzheimer’s disease (AD), the most common cause of dementia, is covered in detail by Morris in Chapter 10. The differential diagnosis of dementia includes a wide range of disorders, many of which are covered by other authors in this volume. The focus of this chapter will be on disorders where Lewy bodies (LBs) are the predominant distinctive pathology whether or not AD pathologic lesions [senile plaques (SPs) and neurofibrillary tangles (NFTs)] are also found. In this chapter we will review three disorders that share common clinical and cognitive features as well as pathologic lesions. Lewy body diseases comprise syndromes of late-life dementia and variable parkinsonism, visual misperceptions, and hallucinations. Memory deficits may not be a prominent feature early in the course of the disease. The following subtypes will be considered throughout this chapter: Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and Lewy body variant of Alzheimer’s disease (LBV). Parkinson’s Disease The clinical features are dominated by a movement disorder in which the cardinal features include bradykinesia, cogwheel rigidity, resting tremor, and postural instability. There is variable dementia (PD-associated dementia) occurring typically late in the course of the illness. The pathologic features of PD are characterized by neuronal loss and gliosis in the substantia nigra with the presence of LBs (3,4). Dementia with Lewy Bodies The clinical features are dominated by dementia with visuospatial and behavioral abnormalities and clinical fluctuation. A movement disorder (including postural instability and gait abnormalities) 221

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may also be present. The key pathologic feature is the presence of limbic and neocortical LBs. AD-related pathology (SPs and to a lesser extent NFTs) may or may not also be present (5). Lewy Body Variant of Alzheimer’s Disease This term is still used by a few investigators to describe a clinical state consistent with typical AD followed later by the development of parkinsonian signs and hallucinations. The key pathologic features are SPs and NFTs sufficient to meet published criteria for AD. Additionally there are neocortical and limbic LBs (6). There are estimated to be at least four million Americans affected with AD (1,2). As a result, much of dementia research effort has focused on AD. However, AD accounts for only 65% of the cases of dementia. The second leading cause of neurodegenerative dementias can be attributed to LB disease (5,7–9), a heterogeneous syndrome of combined cognitive dysfunction, parkinsonism, and visual hallucinations, thought to contribute to 10–15% of cases (5,7,8). In addition, approximately 25% of AD patients develop extrapyramidal signs (EPS) (10–13) and many of these patients will have cortical LBs upon autopsy (7). These patients are sometimes referred to as LBV (14–17). PD is the most common neurodegenerative movement disorder affecting one out of every 100 persons over the age of 60 (approximately 1 million Americans) (9,18). Estimates of the yearly incidence of dementia in PD increase with age from 2.7%/year (ages 55–64) to 13.7%/year (ages 70–79) (19–23). It remains uncertain whether PD alone can cause dementia or whether dementia occurs only in the presence of cortical LBs (i.e., DLB) or in association with co-existent AD pathology. The combined number of patients with PD, DLB, and related dementing disorders may approach two million individuals over the age of 60. PD is classically diagnosed by the presence of nigral LBs; the extent to which cortical LBs are present is uncertain. DLB is diagnosed by the presence of cortical LBs but often nigral LBs are also present. It has been suggested that the two disorders represent parts of a parkinsonian spectrum wherein the key clinical features reflect the topography of the major neuropathologic involvement (i.e., nigral Z PD, cortical Z DLB). The interrelationship of pathologies (e.g., AD, PD, DLB) on the onset and progression of dementia is not well understood and the question of the precise burden of AD and LB pathology required to cause dementia is unresolved. Because many individuals clinically diagnosed with AD also have cortical LBs at autopsy in the absence of parkinsonism during life, it is possible that both the distribution (cortex vs. brainstem) as well as the density of these lesions interact to produce specific clinical phenotypes. Alternatively, cortical LBs simply may be the “downstream” lesions that relate only weakly, if at all, to the clinical dysfunction produced by a more salient pathologic process. The understanding of the clinical and pathologic features of dementias associated with parkinsonian states thus is important for diagnostic, prognostic, and therapeutic considerations as well as for elucidation of etiology. The recent advances in the biology of aggregated amyloid, tau, and synuclein proteins have provided some insights into the pathogenesis of PD and DLB, but many questions remain. While many investigators have described cortical LBs in the brains of all individuals with PD (24,25), it is unknown how many of these individuals developed dementia. Additionally, it is unclear what burden of LB pathology is necessary to cause dementia. Further difficulty arises from the fact that the conceptual framework for these disorders is based on pathologic grounds that differ greatly in extension and scope, rather than clear-cut clinicopathologic boundaries (7,14). The following algorithm illustrates the perplexity in distinguishing these disorders (Fig. 1). In this example, a patient may present at the initial visit (T1) with features of dementia or parkinsonism. At some later visit (T2), several possible scenarios can lead to the presentation of one of three possible clinical phenotypes: dementia alone, parkinsonism alone, or a combination of parkinsonism and dementia. At autopsy, the clinical phenotypes initially described at the T1 visit can have three possible patterns of pathology [AD-related pathology (SPs) alone, PD-related pathology (LBs) alone, or both]. Thus

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Figure 1 Algorithm of clinical and pathologic outcomes in dementia and parkinsonism.

the patient initially presenting with dementia in this scenario can have one of three possible final neuropathological diagnoses: AD, AD C DLB or DLB. The patient who initially presented with parkinsonism has four possible neuropathologic diagnoses: PD, PD C AD, DLB or DLB C AD. Critical questions that need to be addressed in LB disorders include: (1) What burden of LB-related pathology is required to cause dementia in PD, AD, and DLB, and (2) do demented patients who develop parkinsonism later in their course differ from PD patients who later develop dementia in clinical presentation and cognitive performance? These questions exemplify the issues that remain unanswered in the understanding and characterization the parkinsonian dementias and suggest a common spectrum and shared pathogenesis but the overlap obscures possible distinctions and relationships. There is a lack of uniform terminology, both clinical and pathologic, but evidence suggests that these disorders can have three general presentations: (1) LB disease has a distinctive profile, (2) LB disease can mimic the clinical profile of AD, or (3) LB disease can co-exist with AD. LEWY BODY DISEASE SUBTYPES Parkinson’s Disease PD is a progressive neurodegenerative disorder that gradually results in accumulating motor disability manifesting as bradykinesia, rigidity, loss of postural reflexes and tremor. PD affects one out of every 100 persons over the age of 60 (approximately 1.5 million Americans) (3,4,7,9,18). While PD is predominantly a motor disorder, research over the past two decades has provided evidence of the cognitive deficits associated with PD. Although there exists debate about absolute numbers of cases of PD dementia, yearly prevalence estimates of dementia in PD increase with age (19–21,23,26). In addition, the incidence of depression in PD ranges between 30–50% (27) and this also may affect cognitive performance. Estimates of dementia in PD vary widely. Prevalence estimates of dementia in PD have been reported from less than 10% to greater than 80% (28–31). More precise population-based studies of PD estimate prevalence of dementia in 20–40% of patients (32–36). Incidence estimates of PD dementia also range widely, from 43 to 113/1000 person-years of observation (19,33,35,37–39) with a two-fold greater risk of dementia compared to control populations (36,39–41). Cognitive impairment in PD has wide-ranging effects on quality of life (42), caregiver distress (43), co-morbid disease, and nursing home placement (43). Dementia in PD patients also appears to significantly reduce survival (44–50). Mortality is increased up to three-fold for PD patients with dementia compared to those nondemented PD patients independent of severity of motor impairment. Risk factors identified for dementia in PD include age and severity of EPS (19,23,31,38,39,48,51–53). The duration of disease tends to be longer in demented as compared to nondemented PD patients (19). It is unclear if there is a significant gender effect. It has been

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reported that the frequency of dementia is higher in men (38,54–58) although this is not a consistent finding (33,39,45,59). As is the case of many of the dementias, lower educational level may also be associated with the risk of dementia in PD (57). The biological substrate underlying cognitive impairment in PD remains controversial (60). With few exceptions (61), most studies have been limited to small sample sizes and the use of retrospective chart reviews to make the determination of cognitive impairment. Only two studies reviewed included prospective cognitive assessments proximate to death using screening mental status tests (62,63). Although a few studies have attempted to systematically evaluate the contribution of both subcortical and cortical pathology to cognitive impairment in PD (64–67), these were conducted before the availability of AS immunostaining. Recent studies of PD dementia used anti-AS antibodies to detect cortical LBs but retrospectively diagnosed dementia based on medical records (68–70). While cognitive problems are recognized in many PD patients, the report of dementia in PD varies. This is due in part to the difficulty of separating the contribution of motor symptoms from cognitive function. The motor dysfunction that predominates early in the course of PD may impair the patients’ abilities to respond appropriately to timed-attention tasks and other tasks that require set-switching leading to the difficult decision of whether a patient is demented or not. It is also possible that the psychomotor slowing and impaired attention is characteristic of the cognitive impairment of PD rather than being related to motor impairment. PD patients move slower than nondemented controls (bradykinesia) and may think slower than nondemented controls (bradyphrenia). It is hypothesized that while bradykinesia is a feature of PD, bradyphrenia is not. Bradyphrenia instead is a sign of cognitive impairment in PD. A loss of attentional control may underlie many of the cognitive deficits in PD (71). Arousal and affect may be impaired (72) and PD patients are more prone to interference in the presence of distracter items than control subjects in tests of visual attention (73). In addition there are deficits in working memory and visuoconstructive functions (74). Current clinicometric measurements of motor disturbance in PD include the Columbia University rating scale, the New York University PD Evaluation, the Short PD Evaluation Scale and the most commonly used, the Unified Parkinson’s Disease Rating Scale (UPDRS). Forty percent of items in the UPDRS are dedicated to bradykinesia (75,76); none, however, are specifically designed to assess bradyphrenia. Bradykinesia Of all the cardinal features of PD, bradykinesia is considered the most important and is the obligatory sign of the United Kingdom Brain Bank Diagnostic criteria (4,77). The major pathoanatomical sites for bradykinesia appear to be alterations in globus pallidus and putamen dopaminergic projections (78). Tasks such as finger tapping may be useful clinical measures of bradykinesia (75,77). Measurements of movement can be divided into two separate components. First there is slowness in initiating a new movement out of the resting position, termed reaction time (RT). Second there is the slowness in initiating a second, even opposing, movement once movement has already been initiated, termed switching time (ST). Both RT and ST are significantly slower in PD compared to controls (77). The mechanisms of bradykinesia are not well understood but RT may be a more accurate marker of bradykinesia than ST (79). The more advanced the disease, the slower the RT (80). It has been proposed that bradykinesia is attributable to a deficit in cognitive motor slowing rather than simply impairment in motor initiation and execution (81). Bradyphrenia The issue of whether in PD there exists a cognitive slowing analogous to bradykinesia remains controversial (27). Most assessments of the speed of information processing such as the Digit Symbol subtest involve measurements of RT. However, since motor responses are slowed in PD,

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timed motor tasks may be unsuited to PD studies of bradyphrenia (80). Bradyphrenia is likely a multifaceted problem (82). Depression, dementia, premorbid intelligence, attentional deficits, PD treatments, and normal aging likely all influence mental speed. Bradykinesia can also have an intervening effect. Attentional deficits may rely on disturbance of dopaminergic projections from the ventral tegmental area to dorsolateral prefrontal lobe (71). Mayeux and colleagues however suggested that bradyphrenia might be more closely correlated with noradrenergic or cholinergic systems (83). Evidence for this assumption is on the basis that dopamine replacement (as L-DOPA) does not correct attentional or RT deficits (82). The effect of task complexity in response time (speed of information processing) is slowed in PD (82). Wilson demonstrated that older PD patients showed slowing of memory scanning (84). Responses of PD patients older than 65 were slower than the control group at all points and worsened as the disease progressed. Slowness of thinking appears to correlate with severity of PD motor symptoms and depression but not with age, duration of disease or treatment. Duncombe on the other hand was unable to demonstrate bradyphrenia in PD using RT measures (27). Mayeux studied PD patients in comparison to normal controls and AD patients with a computerized test of mental speed. PD individuals were differentiated into two groups; those without evidence of cognitive impairment and those who had fewer correct responses that either the control or AD groups (83). The general intellectual functioning of this subgroup was similar to the AD group. It was concluded that bradyphrenia is an impairment of attention and vigilance that may be associated with dementia (83) and is not of feature of PD itself (80,82). Visual Tracking Deficits During natural behavior, we move our gaze around a complex visual environment actively searching for information relevant to current goals (85). Such scanning gives rise to a series of saccadic movements. The efficiency by which a particular target can be found in a visual scene is a component of both RT and ST (86). Visual search requires focused attention that has to be serially applied to the items in the display until the target is found. Treisman and Gelade examined visual attention in PD using two paradigms: simple feature search and conjoined feature search (87). In these tasks, attentional deficits were thought to be due to frontal lobe dysfunction. While PD patients display overall increased visuomotor RT with respect to control subjects, they also show clear improvement in RT when provided external visual cues (88). In PD there is a normal accuracy of predictive saccadic movements but an impaired saccade frequency and latency (abnormal ST) (88). These experiments suggest that PD patients display intact capabilities to store and reproduce regular movement frequencies but with significantly increased latencies. The difficulties PD patients have in performing visuospatial and visuoconstructive tasks may be related to impairment in saccadic working memory (85). Simply put, PD patients may forget the arrangement of the tasks every time they look away. These abnormalities may be related to degeneration of frontostriatal and oculomotor connections. Correlations Between Motor and Cognitive Slowing in PD Although it is not easy to separate motor and cognitive components of behavior, clinical observation of PD patients would suggest that slowing in PD is not restricted to motor functioning, but also involves cognition (81). If poor performance is due to bradykinesia, then a positive correlation should be seen between motor ratings and cognitive RTs. This raises the possibility that defective motor control must be considered for each individual task to account for the specific nature of the movement required to complete the task effectively (71). Jordan demonstrated that simple RT to a motor task correlated with perseverative responses on the Wisconsin Card Sorting test (89). Frontal lobe function and connection to subcortical regions may be a critical influence in the genesis of slowed response speed in PD. This response may be exaggerated in dual task conditions. Many paradigms to test cognitive speed have used RT measurements that use identical motor responses after a cognitive task. The problem is that these measurements carry an assumption

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that a difference in RT between two tasks would correspond to the time required for cognitive processing, because the motor response is identical (81). In a study of PD and controls for mental and visual tasks requiring increasing processing speeds, there was a significant difference between the performance of PD and control groups (81). These effects may not be seen in RT tasks because it is difficult to separate the interaction between cognitive and motor domains. The advantage of mental-operation tasks is the ability to assess cognitive speed without involving immediate motor behavior. It is postulated that the most appropriate way to consider bradyphrenia is as an internalized analogue of bradykinesia. RT may, therefore, be a greater measure of bradykinesia (external movement) whereas ST may be a better measure of bradyphrenia (internal movement). In a study by Mahieux and colleagues (37), 81 initially nondemented PD patients were reassessed after a mean of 3.5 years. Nineteen patients developed dementia. Predictors of incident dementia included the Picture Completion subtest of the WAIS-R, the interference section of the Stroop test, and letter fluency. The pattern of cognitive impairment in the preclinical stages of dementia in PD suggested early deficits in executive dysfunction (22,37), unlike the neuropsychological pattern characteristic of the early stages of AD, mainly characterized by deficits in delayed recall and naming (90–93). These patterns of executive dysfunction have been demonstrated in nondemented PD patients and relate to the severity of motor impairment (93). Goldman reported a cross-sectional analysis of 58 PD subjects who were clinically classified as nondemented. PD subjects performed significantly poorer on all measures of cognitive performance than the nondemented non-PD controls (94). As the cognitive deficits did not interfere sufficiently with daily functioning, the clinician did not judge these subjects to meet criteria for very mild dementia (94). An alternative interpretation of these results could be that PD is associated with subtle but global cognitive deficits despite normal performance in usual activities (i.e., normal ADL) and this distinction may have been due in part to the difficulty in separating impairment based on motor dysfunction from that due to cognitive decline. These patients largely were rated as Clinical Dementia Rating (CDR) zero (non-demented), but the CDR alone may be insensitive to detecting dementia in PD, especially in its initial stages given the CDR scoring algorithm’s heavy reliance on memory deficits. Dementia with Lewy Bodies DLB is the second most common form of neurodegenerative dementia after AD, comprising 10–15% cases of dementia (5,7). Rather than a single entity, DLB consists of a heterogeneous group of disorders that are characterized clinically by a progressive decline in cognitive function and pathologically by the presence of LBs in the cerebral cortex. In general, DLB affects a similar age group to AD patients with a mean age of 74.7 years. The male to female ratio approaches 1. It has been reported that DLB patients progress at a more rapid rate to severe stages of dementia compared to AD, although this is difficult to fully substantiate due to small sample sizes (5). Compared to nondemented PD, DLB is also thought to be more rapidly progressive (7,8). In recognition of the fact that DLB is the second most common form of dementia after AD and because of the confusion about the nomenclature and diagnostic criteria, a consortium formalized the clinical and pathologic diagnosis of these diverse disorders (5,7). Clinical features that were most characteristic of DLB were a progressive dementia and at least two of the following three characteristics: (1) extrapyramidal (parkinsonian) signs (typically bradykinesia, rigidity, and postural instability, but rarely tremor), (2) fluctuating course, and (3) prominent visual hallucinations. Other features that are supportive but not required for diagnosis include: (1) increased sensitivity to classic neuroleptics (i.e., haloperidol), (2) repeated falls, (3) syncope (fainting spells) or transient loss of consciousness; (4) systematized delusions, and (5) hallucinations

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in other modalities (auditory, olfactory, etc.) (5). REM behavioral disorder is also reported at a higher frequency in patients with underlying LB disease (PD or DLB) (95). The fluctuation in cognition has been the most confusing aspect of the diagnosis and the most difficult feature to identify and agree on. Cognitive fluctuation has been defined as the spontaneous impairment of alertness and concentration (appear drowsy but awake, look dazed, not be aware of what is going on) that varies from day to day or week to week (i.e., become worse for a while then improved, up and down course) (5,96). It has been reported that fluctuation of five points or more in the Mini-Mental State Exam (MMSE) total score over three administrations in a 6-month period can be considered significant fluctuation (97,98). The problem with this recommendation is that it would be rare to evaluate a patient so often in a clinician’s office unless the patient was part of a specific research protocol. More recently, several rating scales have been proposed to quantify the presence and severity of fluctuation, one of which can be administered by the caregiver (99). Extrapyramidal (parkinsonian) signs have been correlated with the severity of dementia in DLB. There are several features that may help distinguish DLB from PD: (1) myoclonus, (2) absence of rest tremor, (3) no response to levodopa, or (4) no perceived need to treat with levodopa (100). These signs were 10 times more likely to be associated with DLB than PD and are not characteristic of AD. Although clinicians tend to think of DLB only in the presence of parkinsonian signs, these features are not absolutely required for the diagnosis. It remains uncertain why some DLB cases have little or no extrapyramidal dysfunction. Several studies have reliably demonstrated that in the presence of a progressive dementia, fluctuation, and visual hallucinations, the clinical diagnosis of DLB can be made (14,100). Studies retrospectively examining the psychometric profile of patients with DLB using MMSE scores, the information-memory-concentration scores of the Blessed scale or the Mattis Dementia rating scale have demonstrated that patients with DLB perform worse than AD patients in tests of visual tracking and visual attention shifting (16,97,101–103). DLB patients showed impaired verbal and motor initiation capacities and inability to abstract similarities (97,103). When these same tasks were applied prospectively to patients who met clinical criteria for DLB, these patients were found to be more impaired than AD patients in areas of visuospatial working memory, timed attention tasks, and copying two- and three-dimensional drawings and the clock draw (16,97,98). Patients with DLB performed similarly to AD patients in regards to verbal and semantic memory, naming, abstraction, and episodic memory tasks (97,104). DLB patients tended to experience a more rapid cognitive decline than seen in AD, especially when motor symptoms were present (73,103). Demented patients (both DLB and AD) with extrapyramidal motor symptoms deteriorated 67% faster on the MMSE) (4.5 points per year) than patients without motor symptoms (2.7 points per year) (73). Another study comparing DLB and AD patients reported that the average rate of MMSE decline in DLB was 5.8 points per year compared to 4.1 points per year in AD (105). Visual hallucinations are the most frequently reported psychotic symptom in DLB; delusions also occur frequently. Compared with AD, DLB patients are more likely to experience hallucinations and delusions early in the course of the illness. Hallucinations are commonly well-formed visual hallucinations (typically animals or small children) and are rarely frightening to the patient. Visual hallucinations appear to be more common in patients with poor eyesight (97,106). Auditory hallucinations also occur more commonly in DLB compared to AD. Tactile and olfactory hallucinations are rare. Those patients who experienced hallucinations early in the course of their dementia were more likely to show cortical LBs on autopsy than those with hallucinations of late onset (97,106). Hallucinations in DLB generally appear prior to the fourth year of symptoms and persist till death in 71% of cases (97,98). The most common form of delusions in DLB are misidentification delusions (i.e., delusions that someone is in the home, delusions that the patient’s home is not his/her own or that TV or movie personalities are actually present in the room) followed by persecutory/paranoid delusions

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(delusions that people are stealing things or conspiring against the patient), phantom boarder delusions (the belief that an unwanted person is living in the house) and abandonment delusions (97,98,107). Depression also is significantly more common in DLB compared to AD at any stage of illness (5,26,97) and is a common feature in PD (26). Other behavioral manifestations reported to occur more commonly in DLB and PD compared to AD include anxiety, irritability, apathy, violent or aggressive behavior, insomnia, nocturnal confusion, agitation, and restlessness and pacing (16,97,98,101,102,108–110). Lewy Body Variant of Alzheimer’s Disease AD is the most common form of dementing illness among middle and older adults, affecting over four million Americans and many millions worldwide (1,2). The earliest symptoms often include loss of recent memory, faulty judgment, and changes in personality. Approximately 25% of AD patients develop PD-like symptoms during the course of their illness and many of these individuals have LBs found at autopsy involving cortical and subcortical regions (5,7,8). The presence of numerous cortical and subcortical LBs, SPs, and NFTs defines a subtype of AD with parkinsonian features sometimes referred to as LBV (6). LBs are frequently found in brain regions of patients with familial forms of AD with PS-1 and APP mutations (111) and in older individuals with Down’s syndrome (112). NEUROPATHOLOGY The LB was first described by Dr. Freidrich Lewy in 1912 (7,8,25). Since that time, LBs have been described in virtually all PD cases in the dopaminergic neurons of the substantia nigra (7,8,24,25). In addition to the substantia nigra neurons, LBs may be found in other populations of neurons that degenerate in PD in the cerebral cortex and brainstem such as the locus ceruleus, dorsal motor nucleus, and hypothalamus. The filaments of nigral and cortical LBs in of PD and DLB are formed by aggregation of asynuclein (AS) (7,9,25,113–117). In transgenic mouse models overexpressing AS, motor, and cognitive deficits have been demonstrated suggesting that AS aggregation may play a key role in neuronal function (118). AS has been implicated as a major protein component of inclusions found in other neurodegenerative disorders that share the combination of extrapyramidal parkinsonian signs and dementia (7). Multiple systems atrophy is characterized by the presence of AS-immunoreactive glial and LB-like neuronal inclusions (119). Neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome) is characterized pathologically by axonal dilatations known as spheroids, glial, and neuronal LB-like inclusions also composed of AS (120). LBs in the substantia nigra typically have a characteristic spherical appearance with a loose radiating array of filaments in the periphery or “corona” surrounding a matted meshwork of filaments in the center or “core”. It was not until almost 50 years later that LBs were described in cortical neurons in severely demented patients (121). This is due to the more inconspicuous appearance of cortical LBs by light microscopy. In contrast to the characteristically round nigral LBs, cortical LBs generally assume a more irregular geometry and extend into the proximal segments of the neuronal processes (7,8). Today LBs in the brain are best demonstrated with the use of specific antibodies against the AS protein (7,25). These antibodies have helped to greatly understand the vast spectrum of neurodegenerative disorders that contain LBs (7). Pathologic Diagnosis of LB Disorders LB disorders can be divided into three groups on the basis of LB pathology: (1) Type A, diffuse type, (2) Type B, transitional type, and (3) Type C, brainstem type related to PD (5). The

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diffuse type has been further classified into two subgroups: (1) the “common” form in which SPs and NFTs in sufficient quantity to meet criteria for AD are present in addition to cortical LBs (i.e., LBV), and (2) the “pure” form in abundant cortical LBs are present but plaques and tangles are not of sufficient quantity to meet criteria for the diagnosis of AD. It should be noted that the “common” form is indeed more common comprising upto 90% of cases. This nomenclature can be confusing and led the consortium to develop pathologic criteria to standardize the diagnosis and classified all the subgroups under the generic term DLB (5). The defined pathologic criteria for DLB require LBs as essential for the diagnosis. Associated but not essential features includes Lewy-related dystrophic neurites, SPs, NFTs, regional neuronal loss especially in the brainstem areas associated with PD (substantia nigra) and basal forebrain (nucleus basalis of Meynert), microvacuolation, synaptic loss, and neurochemical deficits. In order to substantiate the pathologic diagnosis, the consensus criteria recommends examination of at least three cortical brain regions (frontal, parietal, and temporal), two limbic regions (anterior cingulate and transentorhinal cortices) and brainstem regions (substantia nigra, locus ceruleus, and dorsal vagal nucleus) to establish a definite neuropathological diagnosis. In addition, several other areas may show substantial LB pathology including the amygdala, insula, anterior (ventral) striatum and basal forebrain (5,7). Cortical LBs are found in small and mid-sized neuron, in predominantly deeper layers of the cortex of every lobe with a predilection for limbic structures (cingulate, insula, anterior frontal, medial temporal areas). Neuritic degeneration of the CA2/3 region of the hippocampus is associated with LB disorders but is not seen in AD or normal aging (114). These dystrophic neurites can also been in other areas of the cortex and in subcortical structures. Synaptic loss can be seen in the medial temporal lobe structures important in memory and behavior (perforant pathway). These degenerate synaptic terminals contain aggregations of nonfibrillar AS (122). In addition, two closely related proteins (b-synuclein and g-synuclein) aggregate in the perforant pathway in LB disorders but not in AD or normal aging (122). There are significant neurochemical deficits in DLB. There is a reduction in choline acetyltransferase that has been found to be more severe in persons with hallucinations (80–85% reduction) than in those without (50–55%) (123). These reductions were greatest in neocortical areas (parietal, temporal) and were more marked in hippocampus and entorhinal cortex than seen in AD. There appears to be at least some attempt at compensation for this deficit as the post-synaptic acetylcholine receptors are increased in DLB. In addition to reductions in acetylcholine, deficits in dopamine have been described. Losses of 40–60% of dopamine in DLB brains have been reported compared with an 80% loss of dopamine seen in PD (5,7). There is also a significant loss of the ventral tegmental neurons in DLB. These neurons are the source of dopamine projections to the limbic areas that are vulnerable to LB formation. Of all these potential markers, it is the presence of cortical LBs that correlates most closely with the severity of dementia (7,8,25,68). In an analysis of patients with DLB, the presence of three or more cortical LBs per high power microscopic field is a more sensitive and specific marker of dementia than the presence of plaques, tangles, dystrophic neurites or even the combination of all markers of dementia pathology. The most sensitive tool to examine for LBs is staining of brain sections with an AS antibody. Pathologic Basis for PD Dementia The signature histopathological hallmark of PD is the LB (7–9,25,120,124). In addition to being found in the dopaminergic neurons of the SNpc (3,7,8,25), LBs are also seen in all other populations of neurons that selectively degenerate in the PD brain and may be found in the cerebral cortex as well as in brainstem nuclei. Examination of the pathology of PD subjects with dementia

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demonstrated that 26% had LBs in the substantia nigra and cortex, 74% had nigral LBs and AD changes in the cortex (some of these also had cortical LBs) (4). Cortical LBs have been described in nearly all cases of PD (4,7,8), however most reports have not commented on whether these individuals were demented. It is also unknown whether cases previously diagnosed with PDassociated dementia would now be diagnosed as DLB using modern immunohistochemical techniques. Three theories predominate regarding the pathological basis of dementia in PD. First, concomitant AD may be the cause of dementia in PD because AD pathologies are more severe in demented than in nondemented PD patients (125,126). Second, pathological studies demonstrating greater numbers of LBs in the medial substantia nigra (127,128), ventral tegmental area (129), locus ceruleus (129,130), and nucleus basalis of Meynert (64,129,131) in PD with dementia compared to PD without dementia support the idea that subcortical LB pathology might be sufficient to cause dementia in PD. Third, since the wider recognition of DLB as a cause of dementia (5,7,132), it has been proposed that cognitive impairment in PD may correlate with the “spread” of the LB pathology from brainstem neurons to higher cortical areas (7,68). Whether there is a spread of LBs, implying that PD and DLB are part of a continuum, or whether cortical and subcortical LB pathology occur concurrently remains unknown. Alternatively, LB formation and degeneration of subcortical structures may reduce the threshold at which AD changes may cause dementia in PD (133,134). Alzheimer Changes PD patients may have more AD cortical pathology than age-matched controls (135) although this has not been a consistent finding (136–140). Clinicopathologic correlation studies have examined the relationship between cognitive impairment (MMSE scores) (141) with AD pathology (62) have been described. The contribution of subcortical LBs to cognitive impairment in PD patients has not been fully evaluated. There are substantial differences in the distribution and extent of AD pathology in PD patients compared to AD patients (67,134,138,139,142). These studies suggest in the case of PD that AD pathology is different in some fundamental way than in the setting of AD alone. Subcortical Pathology There is now sufficient evidence that subcortical pathology (neuronal loss and LBs) may be the pathologic substrate for PD dementia in the absence of significant AD pathology (64,105,137,143–146). In particular, loss of cholinergic neurons in the nucleus basalis of Meynert has been observed in PD independently of AD cortical pathology (146,147). However, many of these studies preceded the use of AS immunostaining making it difficult to assess the actual contribution of cortical LBs to cognitive impairment. Hughes reported 31 patients with dementia from his larger series of 100 PD brains (4). The pathologic basis of dementia in these 31 cases was thought to be AD in nine (29%), vascular causes in two (6%), and DLB (using anti-ubiquitin antibodies) in three (10%). In 17 demented patients (55%) “no definite cause” for the dementia was found. Cognitive assessment was limited to the MMSE and the time between the last screening examination for dementia and death is not stated. Two conclusions can be made from these observations. First is that subcortical pathology of PD might represent the substrate of dementia in these cases. Alternatively, the absence of more sensitive screening methods for LBs using AS antibodies missed many cases of DLB. Furthermore, Hughes noted that five of the 17 cases without a definite cause for dementia had “plentiful LBs.” These cases did not fulfill Kosaka’s criteria (148) of O5 cortical LBs per 100! microscopic field used at a time prior to the DLB consortium. The use of unbiased quantitative methods to assess SN neuronal loss supports the notion that subcortical pathology is correlated with dementia in PD. Neuronal loss in the substantia nigra from medial to lateral regions correlates with the presence of cognitive and motor symptoms (149).

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Motor symptoms such as rigidity and bradykinesia correlated with neuronal loss in the lateral nigra while the loss of medial SN neurons were inversely correlated with dementia (149). When the nigra was assessed as a whole, a loss of pigmented neurons correlated with disease duration and severity in PD (150) but not in AD (151). Cortical Lewy Bodies We performed a detailed neuropathologic examination of 42 patients meeting the clinical criteria for PD, with at least 3 of 4 cardinal signs to determine whether there is distinctive cortical histopathology associated the dementia and PD. Dementia was evaluated by clinician’s global impression, caregiver interviews and MMSE scores. Twenty-two of the patients became clinically demented at least two years after the onset of motor symptoms. Postmortem examination of 20 nondemented and 22 demented cases was performed and evaluated for AD related pathology (NFTs and SPs), and PD/DLB related pathology (LBs and LNs). The densities of cortical LBs, plaques, tangles, and neurites were graded in the medial temporal lobe and four neocortices (68). The neuropathological diagnosis of PD was made if there was abundant neuronal loss and LBs in the substantia nigra with no more than rare cortical LBs and insufficient SPs and NFTs to make the diagnosis of AD by CERAD criteria. A diagnosis of DLB was made if there were abundant cortical LBs irrespective of nigral pathology and criteria for AD was not met. A diagnosis of LBV was made if the patient met criteria for AD and had abundant cortical LBs. Ninety percent (18/20) of those classified as PD without dementia had a pathologic diagnosis of PD (no AD pathology and a cortical LB score of zero or one). In contrast, 91% (20/22) of patients diagnosed as demented had cortical pathology of dementia (cortical LB score two–three). The four principle markers of brain pathology examined in this study were LBs, NFTs, SPs, and dystrophic neuritis (24). Ninety-one percent of subjects with PD who had a LB score of two–three were demented (sensitivity), where as 90% of those who were not demented had a cortical LB score !2 (specificity). A score of two or greater for any of the four markers is highly sensitive (less than 5% of the patients with dementia had a score of zero or one for any marker), but the specificity of any marker is only 55% (i.e., 45% of those without dementia had a score of two or greater). The comprehensive assessment of the validity of these four commonly used histopathologic markers of cortical pathology in the setting of PD demonstrated that cortical LBs are the single best correlate of dementia (odds ratio 31.5, 95% confidence interval 4.2–150.4) and AS is the single best marker of pathology (7,68). Mattila and colleagues (69) evaluated cognitive impairment retrospectively from hospital records using the Global Deterioration Scale and found that both the total number of cortical LBs and NFTs in the temporal cortex were both significant predictors of dementia in PD. The contribution of the degree and extension of subcortical LBs to dementia in PD was not considered. Two other studies exclusively assessing limbic and neocortical regions found a correlation of cognitive impairment in PD with Lewy neurites in the CA2 hippocampal field (63) and in the periamygdaloid cortex (152) using anti-ubiquitin immunostaining. A recent study comparing nondemented and demented PD patients found that LB counts in demented PD were increased ten-fold in cortex and limbic areas compared to nondemented PD cases, with only modest AD pathology (60). NFTs were significantly higher in the hippocampal CA1 fields of demented patients compared to nondemented individuals. The summary of these studies suggests the threshold of AD pathology required to induce dementia may be lowered in the presence of cortical LBs. EVALUATION OF LB DISORDERS The evaluation of LB dementias is dependent on an informed source of history in order to establish and determine the time-course of dementia, motor symptoms, hallucinations, and fluctuations. The

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physical examination often will give clues to the presence of Parkinsonian signs as well as rule out other potential medical and neurological causes of dementia. There is no laboratory test specific for LB disorders. Laboratory evaluation is used to exclude other potential causes of dementia and can include an evaluation of thyroid function, vitamin B12 levels, liver function tests, and a test for syphilis. Neuroimaging with magnetic resonance imaging may reveal cerebral atrophy. Functional imaging studies with positron emission tomography (PET) showed a more severe glucose hypometabolism in DLB compared with AD in the cerebellar hemispheres and the temporal-parietal-occipital association cortices, especially in the medial and lateral occipital lobes. This is in contrast to AD where the greatest deficits have been found in the medial temporal, parietal, and cingulate regions. For a more in-depth review of functional imaging in dementia, see Chapter 6 by Sperling. Psychometric testing, although varying from center to center should include tests for verbal and non-verbal memory, attention, concentration, abstraction, visuospatial abilities, and construction. Another useful tool in evaluating the patient would include an assessment of activities of daily living including personal hygiene/grooming, ambulation, dressing, and feeding. The neuropsychological assessment of dementia is described in detail in Chapter 4 of this volume.

TREATMENT Because of the known deficits in the cholinergic system and the knowledge of compensatory mechanisms, there has been interest in the use of the centrally active cholinesterase inhibitors for the treatment of the cognitive symptoms of DLB. Studies with donepezil have demonstrated improvements in hallucinations with some suggestion of improvement in cognition and overall function (153). More recently, trials with rivastigmine have suggested that there may be greater improvement in cognition and neuropsychiatric symptoms than similarly treated patients with AD. Behavioral domains that improved on rivastigmine included apathy, indifference, anxiety, delusions, hallucinations, and aberrant motor behavior (154). These effects were lost once the medication was withdrawn. Data are now becoming available for use of galantamine in DLB (155). For a more detailed review of cholinesterase inhibitors and other pharmacotherapeutics for the treatment of dementia, readers are referred to Chapter 23. Perhaps even more disturbing than the cognitive symptoms (particularly to the caregiver) are the psychotic and behavior manifestations of DLB (5,7,8,25). As mentioned above, these symptoms can include agitation, delusions, and hallucinations. Management of these issues has been problematic because of problems with DLB patients taking antipsychotic medications. The early clinical diagnosis of DLB is critical given that DLB patients are more likely to experience an adverse reaction to classic neuroleptics such as haloperidol compared to AD patients (81% compared to 29%). In order to lessen the risk of potential side effects, treatment strategies have focused on the use of atypical neuroleptics such as quetiapine, risperidone, and olanzapine. These newer agents have significantly less binding to dopamine receptors that the classic neuroleptics however, an exacerbation of extrapyramidal symptoms can be seen with risperidone and olazapine that still have anti-dopaminergic modes of action. Quetiapine, with serotonergic blockade as its primary mechanism of action, does not appear to significantly worsen motor symptoms (156,157). Further discussion of the treatment of psychotic symptoms of dementia patients is found in Chapter 24. Depressive features also need to be addressed. Many of the antidepressant medications available today are safe and effective for the treatment of depression in the geriatric population. Among the most commonly prescribed antidepressants are the serotonin reuptake inhibitors such as citalopram, sertraline, fluoxetine, and paroxetine. The evaluation and treatment of depression in dementia is discussed in greater detail in Chapter 19 (53).

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ACKNOWLEDGMENTS This work was supported by National Institute on Aging, grants AG20764, AG03991, and AG05681; the Paul Beeson Physician Faculty Scholar in Aging Research Award from the American Federation on Aging Research; and a generous gift from the Alan A. and Edith L. Wolff Charitable Trust.

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13 Frontotemporal Dementia Weichung Liu and Bruce L. Miller University of California San Francisco, San Francisco, California, U.S.A.

In this chapter we describe the demographic, historical, clinical, genetic, and pathological features of frontotemporal dementia (FTD). This group of disorders have received increasing attention over the past few years, in part triggered by the discovery of genetic cases caused by mutations in the tau gene. The FTD field is still young and only in the past few years have there been systematic efforts to characterize patients with this disorder. Many issues still remain related to etiology and nomenclature that should be clarified as more clinically characterized cases come to pathology and as the genetic basis for FTD is better defined. FTD remains a clinically fascinating disorder, often diagnosed as a psychiatric disturbance before it is recognized as a dementia. These disorders offer many insights into how slow and selective loss of function in the frontal and anterior temporal lobes modifies the psychological and psychiatric well-being of a previously normal individual. As careful clinical and imaging studies emerge, FTD should help to understand many aspects of self-reflection, emotion, social pragmatics, language, and executive functions. DEMOGRAPHICS FTD is predominantly a pre-senile degenerative dementia that affects people under the age of 70 years. Typically, the disease presents in the sixth or seventh decade, but very early (Markowitsch) and lateonset cases have been reported. In a fascinating epidemiological study by Ratnavalli and colleagues of patients of patients with early onset dementia the mean age for FTD patients was 52 years and there was a very strong male predominance. In our own studies at UCLA and UCSF the mean age at onset has ranged around 56 years, with a male to female ratio very close to 1:1. The Ratnavalli study suggested that the prevalence of FTD was similar to that of Alzheimer’s disease (AD). HISTORICAL ISSUES IN NOMENCLATURE Today, the term FTD encompasses a variety of clinically and pathologically heterogeneous dementing disorders and syndromes that affect the frontal and anterior temporal lobes, basal ganglia, and motor neurons. Since the first descriptions by Arnold Pick of the disorder in 1892, there has been a steady evolution of the terminology related to what constitutes the center and the edge of 241

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the FTD syndrome. Historically, different investigators have used pathology, clinical features, neuropsychology, genetics, and imaging to group and divide the syndrome now known as FTD. In this section of the chapter, we describe the changing nomenclature related to patients who are now classified as FTD and emphasize some of the current thinking in the field. In 1892, the neuropsychiatrist Arnold Pick described a patient who developed progressive language impairment in the setting of dementia. At autopsy this patient had left anterior temporal atrophy associated with an aphasia syndrome, which Pick called amnestic aphasia. This was the first description of a patient with what is now classified as FTD (1). Later, Alois Alzheimer reported ballooned neuronal cells that contained argyophilic inclusions in a patient with focal anterior atrophy. These silver-staining, hematoxylin, and eosin-positive neuronal cellular inclusions became known as Pick bodies, while the cells that are swollen with these inclusions were called Pick cells. Beyond the presence of these Pick bodies, these patients were distinctive from those with Alzheimer’s disease (AD) due to the absence of senile plaques and neurofibrillary tangles. Pick himself never emphasized the importance of the cellular inclusions that now carry his name, and the term Pick’s disease was later introduced by Onari and Spatz in 1926 (72). For many decades, Pick’s disease was defined as a neuropathological syndrome that encompassed progressive dementia cases with frontal and temporal atrophy. In 1967 Neumann and Cohn described an FTD subtype—progressive subcortical gliosis (PSG) where the pathology was localized primarily to subcortical regions (10). In 1974 Constantinidis developed a neuropathology system for classifying Pick’s disease dividing the disorder into three groups: (1) classic Pick’s disease cases with ballooned cells and Pick bodies, (2) S cortical gliosis and atrophy in the parietal regions [many cases today would now be classified as showing corticobasal ganglionic degeneration (CBD)] (3) heterogeneous group without the features of either group one or two who would now be classified as showing PSG (2). Whether or not to include CBD as a subtype of FTD still remains a controversy that was recently debated by Kertesz and Neary. In the 1980s dementia research focused on AD rather than Pick’s disease, and contemporary neurology textbooks suggested that Pick’s disease was both rare and indistinguishable from AD. Running against this trend, two European groups led by Brun and Gustafson in Sweden, and Neary, Bowen and, Snowden in England, refocused the field on both the clinical and pathological classification of Pick’s disease, eventually coining the term FTD. The careful clinical assessment of their dementia cohorts, by Gustafson, Neary and, Snowden helped to capture the clinical distinction between FTD and AD (4). They emphasized the behavioral disinhibition, eating disorder, apathy and, frontal executive deficits of FTD and became able to recognize FTD in distinction from AD prior to post-mortem assessment. Simultaneously, Brun helped to redefine the histopathology of patients suffering from the clinical syndrome of FTD, and he emphasized the presence of neuronal loss, gliosis, and vacuolization localized to the first three layers of the frontal cortex. Brun also reported that Pick bodies were found only in a minority of the FTD cases (3). Mesulam (1982) and Morris et al. (1984) reported patients presenting with a primary progressive aphasia (PPA) who had unilateral left frontal or left anterior temporal involvement (15,16). Morris and colleagues emphasized both the familial and sometimes highly asymmetric degeneration associated with FTD pathology. In a family with “hereditary dysphasic dementia” selective left frontoparietal degeneration seemed to be inherited in as an autosomal dominant disease. Later linked to chromosome 17, the specific genetic mutation that causes this remarkable disorder has yet to be determined. In 1993 Miller et al. described primarily behavioral abnormalities in patients with predominantly right-sided atrophy (17). Over the years, a variety of other disorders have also fallen under the rubric of FTD such as amyotrophic lateral sclerosis (ALS). In 1993 Mitsuyama described a series of 26 patients in whom selective frontal lobe degeneration was associated with motor neuron disease. Caselli, described a sporadic case of progressive aphasia associated with motor neuron disease (12). In their pathological study of FTD, Jackson and, Lowe noted a subtype with the histopathology of pale,

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achromatic inclusions in parietal neurons (14). Links between FTD and subcortical disease has also been reported by Knopman and colleagues. In their evaluation of patients with “dementia lacking distinctive histology” multi-system involvement was noted, particularly in the basal ganglia, thalamus and, hypoglossal nuclei (5). Similarly, Wszolek reported upon a patient with an autosomal dominant familial disorder that led to a syndrome with remarkable parallels to progressive supranuclear palsy (PSP). In 1994, the Lund and Manchester groups joined together to coin the term that is most commonly used today—FTD. As the name suggests, this term includes patients with primarily frontal and/or anterior temporal lobe involvement. Under the assumption that FTD was under diagnosed, the Lund and Manchester groups aimed to improve its recognition by describing the clinical features of FTD and by organizing new research criteria for FTD (8). The utility of the new research criteria was widely accepted and Miller and colleagues found that a subset of items from the Lund-Manchester Criteria including disinhibition, apathy, hyperorality, progressive loss of speech, and sparing of visuospatial skills effectively differentiated most FTD patients from those with AD (9). Similarly, using these criteria Lopez and colleagues were able to accurately recognize nearly all FTD patients. Kertesz and colleagues (1994) broadened the group of disorders associated with the FTD syndrome and proposed the concept of “Pick complex.” Pick-complex disorder included other neurodegenerative diseases characterized by focal cortical degeneration, such as (PPA), ALS and CBD (7). In 1998, members of an international workshop on FTD concluded with a set of consensus criteria now known as the Neary criteria. Many members of the workshop had participated in the previous attempts to define diagnostic guidelines, and their aim was to expand and build upon previous criteria and determine both core and supportive criteria, and inclusion and exclusion criteria for the FTD syndrome. The expectation was that these criteria would improve recognition of FTD and would provide a strong basis for ongoing and future research into FTD (19). At this meeting a consensus criteria was established. This group used the umbrella term Frontotemporal Lobar Degeneration (FTLD) clinically and described the three subtypes of the disorder: (1) (FTD)—characterized primarily by behavioral, social, and personality changes (2) Progressive nonfluent aphasia—which presented with non-fluent speech (3) Semantic Dementia (SD)— presenting with a loss of semantic knowledge (19). Following the publication of the Neary criteria, numerous studies have attempted to define the genetics, neuropathology, epidemiology, imaging, behavioral, and neuropsychological aspects of these three syndromes. Studies by Bozeat and colleagues (2000) and Edwards-Lee and colleagues (1997) have attempted to describe the disease in terms of frontal (fvFTD) and temporal (tvFTD) variants (18,28). In a recent multi-center neuropathology-based study of the Neary criteria, sensitivity and, specificity approaching 90% was reached for a cohort that consisted primarily of patients with the Neary FTD subtype. Whether the criteria for the SD and progressive non-fluent aphasia groups will prove as sensitive or specific will require formal study. Finally, a consensus group led by McKhann (73) established criteria for FTD that were designed to help clinicians in non-research environments to identify this disorder. With these new research criteria Trojanowski and other pathologists delineated the FTD neuropathology subtypes based upon the types of neuronal inclusions and the genetics. In recent years there has been greater interest in neuronal inclusions, tau-positive or tau-negative, to separate FTD into etiologic subtypes. The Trojanowski Neuropathology criteria have emphasized this key feature of FTD. The historical nomenclature transformations related to FTD have been complicated and confusing. Much of this complexity has been based upon the evolving concepts about what constitutes FTD. Another factor has been the frequent shifts in whether the disease should be grouped based on histopathology, location of involvement, clinical picture, behavioral picture, or genetics. Recent research has focused on the genetic basis of the disease, and this has pushed the nomenclature in new directions. In particular, the heterogeneity of syndromes within and between families with

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identical mutations has supported broadening the parameters for the clinical FTD-syndrome. In reported FTD cases that have been linked to chromosome 17 a variety of clinical syndromes have been reported with features of FTD, PPA, CBD, PSP, and ALS supporting the idea that these distinctive neurological disorders should be included under the FTD umbrella (20,21).

CLINICAL FEATURES Many patients with FTD have frontal and anterior temporal lobe involvement, both clinically and pathologically. However, the tendency to selectively occupy either the frontal or temporal lobes has led to the nomenclature division into the frontal and temporal variants both of which have significant overlap and key differences. Common findings in both FTD (fvFTD) and SD (tvFTD) include progressive increases apathy, disinhibition, euphoria, compulsive behaviors and dietary changes. Similarly, with these FTLD subtypes a predisposition towards Parkinsonism and motor neuron disease is evident. The frontal variant, also known as FTD or the fvFTD, is characterized predominantly by early behavioral and personality type changes emphasizing the importance of the frontal lobes in the genesis of appropriate behavior and normal personality profiles. The behavioral manifestations of FTD include disinhibition, social withdrawal, apathy, emotional blunting, and lack of empathy, and lack of insight (22,23). Dramatic change in personality has been reported including an actual change in well-established patterns of dress, religious, and philosophical ideology. Patients often present to clinic denying deficits, while the caregivers complain of severe behavioral symptoms. Profound apathy is more prominent in the fvFTD than the tvFTD. Others patients exhibit a dysexecutive syndrome, and have difficulty planning and organizing their daily schedules. Their thought processes are concrete, and they are unable to adapt to new ideas or situations. Social interactions may become disrupted, some patients become socially withdrawn, while others lose the ability to control themselves in social situations. Disinhibition often manifests as disregard for personal boundaries, talking to strangers as if they have been friends for years, and making inappropriate comments. Antisocial behaviors including stealing, indecent exposure, and financial indiscretions are common. Patients express verbal disinhibition, irritability, and impulsiveness. Issues of safety may arise because of aggressive behavior such as violent outbursts. Lack of insight and apathy may also appear in the form of lack of personal hygiene and grooming. Patients become more self-centered and caregivers often complain of a lack of concern and empathy for family and friends. Perseveration can be seen as excessive or impulse buying and collecting or hoarding certain objects. Also, repetitive movements such as hand-rubbing or foot tapping may develop. There is often increased intake or change of food preference. It has been reported that many enjoy eating sweets or junk food. Hyperorality may also come in the form of new habits such as smoking, excessive alcohol consumption or eating of inedible objects (23). Gorging is common with this FTLD subtype. Neuropsychologically the most striking finding is the relative lack of deficits in orientation and recall compared to AD patients. However, executive symptoms are prominent with tests that examine frontal lobe functions (Verbal Fluency, Stroop Category Test, Trail Making Test, Wisconsin Card Sorting Test). Thought process become concrete so that patients have difficulty with abstract reasoning such as interpreting proverbs. Language assessments using neuropsychological protocols like the Boston Diagnostic Aphasia Examination and the Western Aphasia Battery can help to characterize the pattern of language decline. Imaging data support the assumption that FTD or the fvFTD is mainly a frontal disorder. The frontal lobes are usually affected bilaterally, and the pattern may be symmetric or asymmetric with more involvement of the right frontal lobe common. A recent study has shown that patients clinically defined as frontal variant have distinct areas of frontal atrophy affecting the ventromedial

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frontal cortex, the posterior orbital frontal regions bilaterally, the insula bilaterally, and the anterior cingulate cortex (24). Patients with progressive nonfluent aphasia have early expressive language deficits. They have effortful speech, phonologic, and grammatical errors, word-finding difficulties but relatively preserved comprehension. These deficits present as phonemic paraphasias (saying “tephelone” instead of “telephone”), anomia (difficulty on Boston Naming Test), and agrammatism (e.g., deletion of prepositions— “She went store”) (23,25). Verbal apraxia a disorder characterized by articulatory groping, and the inability to reliably order the components of speech is also common. In these patients the phrase “Methodist Episcopal” might be said in a variety of different ways due to the inability to organize and produce a series of syllable, i.e., “Medothist Espicoal, Esopist Methistobal, Siscopist, Melhisbothal.” The early and prominent involvement of the left insula may account for these insular abnormalities. In contrast, right-hemisphere functions such as visuoconstruction ability can be remarkably spared. We have seen individuals with this FTLD variant continue to work and function in an effective social fashion despite the loss of language. Of the three FTLD groups, in the early stages of the illness, the PPA group have the fewest behavioral changes. In contrast to FTD, insight into the illness is often preserved and the patients are usually the first to notice that they are unable to express themselves. Of all the FTLD syndromes, this one is most easily confused with AD because of the lack of behavioral symptoms in the early phase of the illness and due to the high prevalence of nonfluent aphasia in some AD patients. Characteristically the neuroimaging features of these patients show asymmetric left frontal and left perisylvian atrophy (26). There are patients who will meet the research criteria for progressive nonfluent aphasia who demonstrate predominantly posterior atrophy with a focus in the left angular gyrus and insula. These patients may ultimately prove to have AD pathology. SD or the tvFTD is characterized by loss of knowledge about objects and words. Interestingly, the patients first described by Arnold Pick would now be classified as suffering from SD. These patients’ inability to communicate stems from both a loss of words and a simultaneous loss of the meaning of words—semantic knowledge. The speech is often fluent, but they have difficulty with object recognition, word comprehension, and word-retrieval. In conversation it is common to hear these patients query what the meaning of a word is that they have recently heard. “What is a key?” As the disease progresses speech becomes emptier and patients begin to rely upon stereotyped phrases. For example, all household items may become “things” or all animals become “duck.” Semantic paraphasias are common with one word replacing another. Non-language symptoms are common in SD. In some patients the disease affects facial and object recognition or emotion. Loss of empathy is common and diminished perception and interest in the feelings of others is manifest. We have seen many instances of patients who do not respond to the medical crises of others. An abnormal preoccupation with computer games, finding coins, playing puzzles, knitting or painting is common. True visual or musical creativity has emerged in a significant minority of SD patients. Many patients with SD suffer from left anterior temporal lobe disease, while in others the right anterior temporal lobe is asymmetrically involved. Rosen and colleagues have demonstrated that nearly all of these patients show atrophy of one or both amygdala. Even though the syndrome is defined by the presence of language deficits in nearly one-half of the patients the illness is associated with asymmetric involvement of the right more than the left anterior temporal region. Neuropsychological testing shows a characteristic pattern of naming semantic and visual recognition impairment. Naming, general information and verbal memory deficits are evident, even early in the course of the illness. In contrast, drawing and fluency appear normal. Neuroimaging shows bilateral anterior temporal and orbitofrontal atrophy with sparing of the remaining areas of the brain (22,24). Imaging and clinical data has lead to studies examining a possible alternative approach to differentiating the clinical subtypes of FTD. A four-quadrant approach divides groups into left

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frontal, right frontal, left temporal, and right temporal. As discussed above, imaging data on PPA show predominant left frontal atrophy making them the left frontal variant. SD patients usually have greater left anterior temporal atrophy and would, therefore, be considered the left temporal variant (27). A study that looked at cases of asymmetric right frontal atrophy found that these patients presented more frequently and severely with loss of insight, psychosis, compulsions, flattened affect, and behavioral disinhibition when compared with left sided cases (17). Another study comparing both left and right temporal variants with each other and with frontal variants, found that aphasia separated left temporal groups from the other two. Right temporal variants, on the other hand, presented with more behavioral disturbances of irritability, impulsiveness, bizarre alterations in dress and grooming, limited and fixed ideas, decreased facial expression, and increased visual alertness (28). A more formal set of criteria distinguishing the right subtypes has yet to be established.

GENETICS Studies looking at the genetics of FTD were inspired by the discovery in 1994 of a chromosome 17q21–22 linkage to a form of familial FTD that included symptoms of Parkinsonism and motor neuron diseae (29). It is estimated that about 30 to 40% of FTD cases are familial, and in many of these familial cases the mode of inheritance is autosomal dominant in pattern (30,31). FTD families present with a wide variety of behavioral disorders. In one family, members may exhibit alcoholism, depression, schizophrenia, criminal behavior, and psychotic disorders. Neurologic symptoms are also varied including dementia, Parkinsonism, and amyotrophy. All affected members, however, will eventually develop dementia consistent with FTD (32). Tau mutations have been detected in familial cases of FTD but are rare in sporadic FTD (33). Some familial cases lead to abnormalities in tau—overexpression, underexpression or expression of an altered conformation of tau (34). Tau normally functions in axonal transport and by maintaining cytoskeletal structure through microtubule assembly in both neurons and glial cells (35,36). In addition to FTD, inclusions that contain tau are also found in AD, PSP, and corticobasal degeneration (CBD) (37). Tau is a soluble protein with six major isoforms and is encoded by exons 9 through 12. Alternative splicing of exon 10 yields two forms 4R tau and 3R tau. In the adult brain they are found in 1:1 proportions, but in the fetal brain, 3R tau predominates. The first mutation found in 12 FTD families was a 5’ splice site mutation that causes an increase in 4Rtau expression (34). This discovery is consistent with the histopathological findings of inclusions containing mostly 4R tau in these families. In addition, families with mutations outside exon 10 have inclusions that contain all six isoforms (38). The mechanism of tau aggregation has been inferred through studies of specific mutations. Mutant tau proteins expressed from FTD families with missense mutations have been found by in vitro experiments to decrease the affinity of tau to microtubules (38,39). In addition, certain missense mutations on exon 10 have been found to increase tau filament formation (40). Other mutations that affect splicing of exon 10 cause increased 4R tau (41,42). Taken together a proposed mechanism is that increased amounts of tau filaments may be responsible for neurodegeneration. An overabundance of soluble 4R tau either through the inability to bind microtubules or increased production may make more 4R tau available to form filaments (43–45). The mechanism by which these filaments cause neuronal degeneration has yet to be elicited. Although studies into a tau-based mechanism seem promising, in many cases with linkage to chromosome 17, a specific tau mutation has yet to be found. In fact, the majority of familial and sporadic cases do not involve tau (46). In addition, variants with close links with ALS often do not have tau pathology on autopsy. In one group of familial cases tau was even found to be absent in the brain (47). Recently, a mutation on chromosome 3 has been identified in one family and chromosome

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9 in another (48,49). A study of sporadic cases suggests a possible link to alternative transcription sizes of the Presenilin 1 gene. These results suggest possible alternative mechanisms (50). ANIMAL MODELS Advances in genetics has lead to development of animal models of FTD. One mouse model expressed mutant human tau derived from a familial FTD-parkinsonism mutation. In addition to finding tau aggregation in the hippocampus and accumulation of RNA and phosphorylated tau, there was evidence of neuronal degeneration, reduction of neural activity and behavioral abnormalities in the mice (51). In another mouse model, the shortest isoform of tau is overexpressed. These mice also exhibited neurodegeneration, gliosis, and tau positive inclusions (52). PATHOLOGY As the name FTD implies, primary and most severe areas of atrophy involve the frontal and/or anterior temporal lobes. Atrophy may be symmetric, asymmetric or unilateral and the parietal and occipital lobes are usually spared (3,6,53,54). The insula, amygdala, and hippocampus are also often involved (8,55). In addition, subcortical areas are sometimes affected including the thalamus, substantia nigra, globus pallidus, and putamen. These cases are usually associated with motor abnormalities such as parkinsonism and ALS. Also, in cases with motor neuron involvement, anterior horn cells have also shown pathologic changes (6,54). A significant number of cases fall under the category of lacking distinct histopathology. Cortical gliosis, neuronal and synaptic loss, and spongiosis are seen usually in the first three layers of the cortex. In patients with motor neuron disease, there is additional damage to the brain stem nuclei- hypoglossal and nucleus ambiguous. As previously described by Alois Alzheimer, many cases exhibit swollen neurons “balloon cells” that contain inclusions. The inclusions often stain positive for tau. Some familial cases have tau positive glial inclusion but tau negative neuronal inclusion (56). Cases of Pick’s disease that have classic “Pick bodies” the swollen cells have cellular inclusions that are silver-staining, hematoxylin, and eosin-positive. These inclusions also stain positive for both ubiquitin and 3R tau (57). Gliosis is prominent and widespread, but there is little spongiosis. Macroscopically, atrophy tends to be more focal sparing the pre- and postcentral gyri and the posterior portion of the superior temporal gyrus (3,6). Three other related disorders PSP, CBD, and PSG are sometimes considered to be included under the term FTD, because of their similar histopathologic patterns. One link stems from research showing that in some cases of PPA, cortical basal degeneration is sometimes also present (58,59) Similar to FTD, CBD pathology shows neuronal loss, gliosis, and tau positive inclusions in both neurons and glial cells (60). However, unlike most FTD cases, the pattern of involvement includes the parietal lobe. PSP neurodegeneration occurs in the areas of the subthalamic nucleus, substantia nigra, pontine nuclei, and cerebellar dentate nucleus. The motor cortex displays tau positive inclusions in the glial cells (59,60). Similar to FTD, PSG cases have clinical presentation of behavioral symptoms including disinhibition, social dysfunction, and stereotype behavior. The pattern of cortical atrophy is similar; however, subcortical white matter is affected more so than the cortex (61). PROGNOSIS AND DIAGNOSIS It is difficult to assess the prevalence of FTD in the population since in most epidemiological studies of dementias, surveys have looked only at populations over age 65. In most cases of FTD, the onset is before age 65. The early behavioral symptoms that predominate in FTD has led many cases to

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being misdiagnosed as psychiatric in origin. In 1993, a report found that out of 21 patients that were later found to have Pick’s disease according to autopsy, 18 were diagnosed as having AD during life (64). Recent epidemiological studies have found that FTD is widely underrecognized, accounts for at least 20% of presenile demenitias, and is more prevalent among men (62,63). It is estimated that after initial onset or diagnosis, patients may live anywhere from 3 to 15 years. In addition, prognosis is difficult to assess since patients with initial language present tend to presentations to clinic earlier than those with initial behavioral changes. Often, behavioral symptoms are overlooked as psychiatric disorders. Added to that, most behavioral cases tend to also lack insight into their illness. Those with motor neuron diseases associated with FTD such as the ALS subtype tend to have a shorter prognosis. Using the Lund-Manchester criteria, in a retrospective approach, a recent study found 97% sensitivity and 97% specificity when comparing groups of pathologically confirmed cases of FTD, AD, PSP, and DLB. In a study of the recent Neary criteria in which the three subtypes are delineated, sensitivity was 97% and specificity was 97%. Two studies have also confirmed that specific subsets of the criteria may be effective in distinguishing FTD from AD (18,65). Rosen et al. found that out of 30 patients with autopsy-confirmed FTD and 30 patients with confirmed AD, a specific subset of criteria—social conduct disorders, hyperorality, akinesia, absence of amnesia, and the visuo-spatial perceptual disorder correctly classified 93% of patients with FTD and 97% of patients with AD (65). These studies reiterate the point that behavioral manifestations in FTD are the key features that differentiates it from other dementing disorders. Recently, investigators have examined tau and AB42 as possible molecular markers in the hopes of diagnostic utility. However, levels seen in FTD were not specific to FTD, and positive predictive values of 50% and negative predictive value of 97% may only serve to exclude FTD from the differential (66).

IMAGING AND TREATMENT Several imaging studies have shown quantitative differences in FTD patients versus normals and FTD patients versus AD patients. Magnetic resonance imaging (MRI) show greater amounts of frontal and anterior temporal lobe atrophy compared with normals (67). Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) of FTD patients also show more severe decreases in glucose metabolism and blood flow in these regions when compared with AD patients (68). SPECT studies have shown a high diagnostic value with an accuracy of 90% when distinguishing FTD patients from AD patients (22). The current lack of knowledge regarding the mechanism behind FTD, leaves little in terms of treatment options. It is hypothesized that FTD patients have some type of dysfunction in the serotonergic system and, therefore, treatment with selective seratonin reuptake inhibitors may be effective. One study showed improvement in symptoms of compulsive behavior, carbohydrate craving, and disinhibition in the majority of subjects that had the dysfunction (69,70). To treat aggressive behavior and Kluver-Bucy syndrome, SSRI are still the preferred first line treatment because of their safety. However, drugs such as sodium valproate, leuprolide, small doses of rsperidone, olanzapine, or trazodone have been found to be effective for aggression in FTD. Carbamazepine, propanolol, and leuprolide are effective for Kluver-Bucy syndrome. Benzodiazepines and high doses of neuroleptics are generally contraindicated (13,69,71).

REFERENCES 1. Pick A. Uber die beziehungen der senilen hirnatrophie zur aphasie. Prager Med Wochenschr 1892; 17:165–167.

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55. Mann DM, South PW. The topographic distribution of brain atrophy in frontal lobe dementia. Acta Neuropathol 1993; 85:334–340. 56. Kertesz A, et al. Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions. Neurology 2000; 54:818–827. 57. Delacourte A. Biochemical and molecular characterization of neurofibrillary degeneration in frontotemporal dementias. Dement Geriatr Cogn Disord 1999; 10:75–79. 58. Mathuranath PS, et al. Corticobasal ganglionic degeneration and/or frontotemporal dementia? A report of two overlap cases and review of literature J Neurol Neurosurg Psychiatry 2000; 68:304–312. 59. Kertesz A, et al. The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia. Neurology 2000; 55:1368–1375. 60. Dickson DW. Neuropathology of Alzheimer’s disease and other dementias. Clin Geriatr Med 2001; 17:209–228. 61. Lanska DJ, et al. Familial progressive subcortical gliosis. Neurology 1994; 44:1633–1643. 62. Ratnavalli E, et al. The prevalence of frontotemporal dementia. Neurology 2002; 58:1615–1621. 63. Snowden JS, Neary D, Mann DM. Frontotemporal dementia. Br J Psychiatry 2002; 180:140–143. 64. Mendez MF, et al. Pick’s disease versus Alzheimer’s disease: a comparison of clinical characteristics. Neurology 1993; 43:289–292. 65. Rosen HJ, et al. Utility of clinical criteria in differentiating frontotemporal lobar degeneration (FTLD) from AD. Neurology 2002; 58:1608–1615. 66. Riemenschneider M, et al. Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration. Neurology 2002; 58:1622–1628. 67. Kitagaki H, et al. Frontotemporal dementia and Alzheimer’s disease: evaluation of cortical atrophy with automated hemispheric surface display generated with MR images. Radiology 1998; 208:431–439. 68. Ishii K, et al. Cerebral glucose metabolism in patients with frontotemporal dementia. J Nucl Med 1998; 39:1875–1878. 69. Perry RJ, Miller BL. Behavior and treatment in frontotemporal dementia. Neurology 2001; 56:S46–S51. 70. Swartz JR, et al. Frontotemporal dementia: treatment response to serotonin selective reuptake inhibitors. J Clin Psychiatry 1997; 58:212–216 published erratum appears in J Clin Psychiatry Jun;58(6):275. 71. Litvan I. Therapy and management of frontal lobe dementia patients. Neurology 2001; 56:S41–S45. 72. Berrios GE. The History of Mental Symptoms: Descriptive Psychopathology Since the Nineteenth Century. Cambridge: Cambridge University Press, 1996. 73. McKhann GM, et al. Clinical and pathological diagnosis of frontotemporal dementia: report of work group on frontotemporal dementia and pick’s disease. Arch Neurol 2001; 58:1803–1809.

14 Vascular Dementia Helena C. Chui University of Southern California, Los Angeles, California, U.S.A.

INTRODUCTION After neurodegenerative disorders such as Alzheimer’s disease (AD), cerebrovascular disease (CVD) accounts for the second largest group of dementias (1). There is some confusion about this in the literature where it is sometimes stated that dementia with Lewy bodies is the second most common cause of dementia (2). In autopsy series and among neurodegenerative disorders, this may be true. However, in epidemiological surveys and certainly when stroke dementia is included, vascular dementias rate second (3). In some Asian countries, such as Japan, vascular dementia even outranks AD (4). This chapter is written for clinicians who are evaluating patients with cognitive impairment, making a differential diagnosis of dementia, counseling the patient and family regarding prognosis, and developing a treatment plan. The reader is reminded that Vascular dementia (VaD) is a syndrome (like hemiparesis) that is caused by CVD; VaD is not itself a disease. VaD results when cerebro- or cardiovascular disease (CVD) leads to cerebrovascular brain injury (CVBI) that disrupts functional networks for memory and thinking leading to cognitive impairment (CI) or dementia (D) as shown in the diagram: Vascular Risk factors →

CVD → CVBI

→ CI or D

A major challenge in vascular disease is how to organize the tremendous heterogeneity that is encountered at every step of the pathway (risk factors, CVD, CVBI, and CI/D) (Table 1) (5). Another challenge is to understand the relationships between CVD, CVBI, and CI/D. Since this chapter is written for practicing clinicians, it starts with issues of clinical and pathological diagnosis—specifically, the elusive relationship (in the diagram between CI/D observed by mental status and CVBI detected by neuroimaging examination). Subsequently, the chapter covers earlier steps in the pathogenetic process to discuss the relationship between risk factors and subtypes of CVD and CVBI. These earlier events provide the foundation for a closing discussion of prevention and treatment. Less attention is paid in this chapter to the molecular pathways leading to ischemic brain injury (e.g., energy failure, calcium entry, excitotoxic or oxidative injury) or to the wide variety of pathological changes associated with CVBI. 253

Modifiable Hypertension

Blood content Hypoglycemia Hypoxemia Hemoglobinopathy Coagulopathy

Cardiac Atrial fibrillation Endocarditis Myopathy Mural thrombus

Anomaly

Vein

Capillaries

Large arteries Small arterioles

Borderzone

Small arteriole Capillary

Single artery Large artery

Vascular distribution

Anoxia

Leaky BBB

Hemorrhage

Hypoperfusion

Chronic

Embolism

Acute Thrombosis

Ischemia

Mechanism of brain injury

Neuronal loss with gliosis

Hematoma

farction

Incomplete

Symptomatic and silent complete infarction

Neuropathological phenotype: “Infarct”

Deep white matter connections

Cortico-basal ganglia-thalamocortical loops

Multi-modal association areas

Limbic-diencephalic memory system

Location/neural network

Binswanger syndrome

Lacunar state Strategic infarct dementia

Multi-infarct dementia

Clinical phenotype or syndrome: “Stroke” vascular dementia

Abbreviations: CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; HCHWA-D, hereditary cerebral hemorrhage with amyloidosis, Dutch type; HCHWA-I, hereditary cerebral hemorrhage with amyloidosis, Icelandic type; BBB, blood brain barrier. Source: From Ref. 5.

Non-modifiable Age Gender (Estrogen) Race Heredity (CADASIL HCHWA-D HCHWA-I)

(Apolipoproteins) Smoking Obesity

Arteriolosclerosis Amyloid angiopathy Vasculitis Tortuosity

Cerebrovascular Atherosclerosis

Risk factors

Hyperglycemia Hyperlipidemia

Vascular phenotype: “Cerebrovascular disease (CVD)”

Table 1 The Spectrum of Vascular Dementia

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The chapter is organized around practical clinical issues. As much as possible, the literature is reviewed with an eye for quantitative measures used in evidence-based medicine: 1. for diagnosis, this includes sensitivity, specificity, and positive likelihood ratio (LRCZsensitivity divided by 1-specificity) 2. for prognosis, survival rates 3. for treatment, numbers needed to treat (NNT) and 4. for risk factors, relative risk (RR) and odds ratios (OR). Each section concludes with a practical recommendation for the clinician. In discussing subtypes of VaD (e.g., stroke D, subcortical vascular D) or vascular risk factors, an effort is made to estimate relative prevalence or impact. This is a daunting challenge because the literature lacks consistency in how VaD and its subtypes are defined and because there is overlap among different subtypes. For example, it is common practice to classify VaD by type of CD (e.g., large-vessel, small-vessel), by mechanism of brain injury (e.g., ischemic, hypoperfusive, hemorrhagic, anoxic), or by clinical phenotype (e.g., multi-infarct D, strategic infarct D, lacunar state, Binswanger syndrome) (Table 1) (5). In organizing this chapter, we have opted to emphasize risk factors (e.g., hypertension, diabetes, heart disease) and their influence on CVBI (symptomatic infarcts, SI, and WMH), because risk factors can be targeted immediately for prevention and treatment. DIAGNOSIS Clinical Diagnosis of VaD According to many published criteria, three basic elements are required for a diagnosis of VaD (Table 2): 1. Evidence of D or CI 2. Evidence of cerebrovascular brain injury (CVBI) 3. Evidence of a relationship between D/CI and CVBI The newer criteria require neuroimaging and offer guidelines for interpretation of infarcts and white matter changes. The Hachinski Ischemic Score (HIS) predated neuroimaging, and therefore relied on the presence of focal neurological signs, risk factors, and associated physical signs of atherosclerosis (10). The recent emphasis on causal relationship departs from the HIS where the clinical features suggestive of CVD are simply summed: HIS R7 are more likely to be associated with VaD than AD; HIS %4 vice versa. Application of the DSM-IV (6), ICD-10 (7), ADDTC (8), and NINDS-AIREN (9) criteria results in up to four-fold differences in patient classification (11–13). The DSM-IV criteria are more liberal. The NINDS-AIREN criteria, which require temporal relationship and focal neurological signs, are the most conservative. The NINDS-AIREN criteria have been adopted in recent pharmacological drug trials, but it would be just as reasonable to choose other consensus criteria for clinical or research purposes. In the absence of an accepted gold standard, comparison of their relative merits is inconclusive (14). Spectrum:

Liberal

→

→

→

Conservative

Criteria:

Hachinski

DSM-IV

ADDTC

ICD-10

NINDS-AIREN

Large gaps persist in our knowledge about the pathogenesis of VaD. Onset of D within 3 months of stroke is generally accepted as evidence of causality. Unfortunately, the requirement for temporal relationship constrains the diagnosis of VaD to patients with acute stroke syndromes.

Possible

Possible NINDS-AIREN(9) Probable

Probable

ADDTC (8)

ICD-10 (7)

Hachinski Ischemic Score (0–17 points) (10) HISR7 suggests MID HIS 5–6 suggests MIX HIS %4 suggests AD DSM-IV (6)

Diagnostic criteria

Memory loss plus impairment in two other cognitive domains

Evidence of causal relationship

Either imaging findings, abrupt onset, stepwise or temporal relationship

Focal neuro signs Imaging findings

Abrupt onset Stepwise progression Temporal relationship to onset of cognitive impairment

2 infarcts or 1 infarct with temporal relationship to onset of cognitive impairment Not required

From the history, examination, or test, there is evidence of significant cerebrovascular disease, which may reasonably be judged to be etiologically related to the dementia (history of stroke, evidence of cerebral infarction)

CVD risk factors (HTN, ASCVD) Not specifically required Sudden onset Stepwise progression Focal neurological signs and symptoms Evidence from the history, physical examination, or Stepwise deteriorationg course, and laboratory tests of significant cerebrovascular disease that “patchy” distribution of deficits, is judged to be etiologically related to the disturbance focal neurologic signs and symptoms

CVBI

Memory loss Sufficient to interfere No clouding of consciousness There is evidence of focal brain Unequal distribution of damage, manifest as at least one deficits in higher of the following: unilateral spastic cognitive functions with weakness of the limbs, unilaterally some affected and others increased tendon reflexes, an relatively spared extensor plantar response, pseudobulbar palsy Infarct outside cerebellum by imaging Multi-faceted cognitive impairment sufficient 1 infarct outside cerebellum by to interfere with imaging or confluent white matter customary affairs of change life

No specific criteria

Dementia

Table 2 Clinical Criteria for Vascular Dementia (VaD)

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The relative importance of other variables (e.g., volume, size, location of infarcts and deep white matter changes) that relate CVBI to CI are not firmly established. Significantly more is known when D is associated with symptomatic stroke, less is understood when infarcts or white matter changes are discovered “incidentally” on MRI. The possibility of concomitant AD often clouds the relationship between CVBI and CI. The AD-confound is particularly relevant when there is a history of slowly progressive D in older individuals (since the pathological and clinical manifestations of AD are strongly age-related). Unfortunately, there are still no quantitative and specific clinical markers for AD. The contribution of AD cannot be resolved until autopsy. For these reasons, the recent emphasis on causal relationship in the diagnosis of VaD while laudable, is still out-of-reach. CVBI

+ AD? →

CI/D

Pathologic Diagnosis of VaD Despite the importance of autopsy, diagnostic accuracy in VaD cannot be addressed using the same pathological approaches used in AD. Pathological examination is invaluable to: 1. Confirm or detect CVBI, especially for lesions that are below the threshold of detection by neuroimaging (e.g., small cystic infarcts, selective neuronal loss, microinfarcts) 2. Confirm or identify the type of underlying CVD (e.g., arteriolosclerosis, amyloid angiopathy) 3. Ascertain the presence and extent of coincidental AD pathology. The neuropathologist is no better positioned than the clinician to judge the causal relationship between CVBI and CI/D. Neuropathology can inform us about CVD and AD, but in the foreseeable future cannot be expected to provide the reference standard for VaD that incorporates the notion of causality. Clinical-pathological correlations to date have used several different pathological definitions of VaD. In a meta-analysis of the HIS (Hachinski et al., 1975), multi-infarct dementia (MID) was defined pathologically as multiple ischemic lesions in the cortex or subcortical regions without marked concomitant AD changes (15). In this multi-center study, clinical, and pathological data were retrospectively analyzed for 312 cases (165 AD, 109 MID, 38 Mixed AD/MID). MID was defined clinically by HIS R7, Mixed AD/MID by a score of 5–6, and AD by HIS %4. LRCwas 4.6 for a clinical diagnosis of MID (84% sensitive, 82% specific). LRCwas 3.5 for a diagnosis of MIX (sensitivity 83%, specificity 76%). Accuracy of the clinical diagnosis using four different sets of clinical criteria has been reported in a study of 89 autopsy cases (16). Vascular D was defined pathologically by the presence of cortical infarcts in at least three areas, exclusive or primary and secondary visual cortices. In this study, vascular lesions confined to subcortical structures were not considered for the diagnosis of VaD. In general, the clinical criteria were specific, but insensitive (Table 3), suggesting that the clinical criteria underestimate the extent of ischemic brain injury. This is not surprising, since a clinical requirement for focal neurological signs will artificially restrict the sites of CVBI qualifying for a clinical diagnosis of VaD. In summary, the diagnosis of VaD remains problematic. There is lack of consensus regarding both the clinical and pathological definitions. Among patients with slowly progressive D, the possibility of concomitant AD usually arises but cannot be confidently assessed until autopsy. *For the time being, the practicing neurologist can use any one of several published criteria, but should

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Table 3 Sensitivity and Specificity of Clinical Criteria for VaD Against a Pathologic Reference Standard Clinical criteria

Sensitivity

Specificity

CLR

DSM IV ICD-10 ADDTC Probable Possible NINDS-AIREN Probable Possible

0.50 0.20

0.84 0.94

3.1 3.3

0.25 0.70

0.91 0.78

3.1 5.8

0.20 0.55

0.93 0.84

2.8 3.4

Source: From Ref. 16.

recognize their sensitivity and specificity in comparison to others (Table 3). The clinician should also assess the likelihood of concomitant AD using the best available method(s) (e.g., neuropsychological profile, bi-parietal hypometabolism on positron emission tomography (PET) or single photon emission computed tomography (SPECT), or AD-type neuropathology). The future development of a method to more accurately characterize the independent severity of CVD- and AD-related brain injury remains an important priority. Evidence of Cognitive Impairment and Associated Behavioral Change There is no singular or specific CI profile that is characteristic of CVD, although characteristic patterns may be associated with individual CVD-subtypes (17,18). Attention, learning and memory, language, and visual-spatial and executive function may be impacted in various degrees and combinations, related to the size and location of CVBI. Several neurobehavioral syndromes are well-recognized as the focal consequences of stroke. The major left and right hemisphere MCA stroke syndromes are associated with aphasia and neglect. Major anterior cerebral artery syndromes are associated with amnesia and akinetic mutism. Major left and right posterior cerebral artery syndromes are associated with verbal or visual memory loss, anomia, and agnosia. Lacunar infarcts and deep white matter changes are preferentially located in frontal-subcortical networks (19,20). Impairment of judgement, abstraction, problem solving, and slowing of processing speed, as well as apathy and depression are characteristically seen in the small-vessel subtype of CVD (also known as subcortical vascular D) (21). Typical D screening instruments [e.g., Mini-Mental State Exam (MMSE) (22); Alzheimers Disease Assessment Scale (ADAS)-cog (23)] are more sensitive for detecting AD than VaD. These instruments sample verbal memory, language, and visual-spatial functions that are subserved by temporal-parietal networks and are affected early in AD. Measures of executive function and speed should be added in order to improve detection of vascular CI (24,25). Bedside tests of executive function include: similarities, verbal fluency, initiation, perseveration, and clock-drawing. Formal neuropsychological tests for frontal executive performance include: Raven progressive matrices, the Wisconsin card sort, and the Stroop interference test. Neuropsychological measures that assess processing speed include the digit-symbol substitution test and reaction time. RECOMMENDATION: The MMSE should be supplemented with tests sensitive to executive dysfunction and slowing of processing speed. Screening instruments with broader coverage may also be considered, including the Modified Mini-Mental State (3MS) (26) or Cambridge Cognitive Assessment (CAMCOG) (27). RECOMMENDATION: Mood and behavior should also be assessed. Commonly-used instruments include the Geriatric Depression Scale (28) or the Neuropsychiatric Inventory (29).

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Evidence of Cerebrovascular Brain Injury (CVBI): Symptomatic Infarcts, Silent Infarcts, Deep White Matter Changes Structural Imaging Modalities Structural neuroimaging has greatly increased our ability to detect CVBI. Either magnetic resonance imaging (MRI) or computed tomography (CT) will detect CVBI more often than the clinician will elicit a history of focal symptoms or discern focal neurologic signs on examination. MRI is more sensitive than CT in detecting CVBI. Despite major advances in detecting CVBI, the clinician should bear in mind that neither CT nor MRI identify microinfarcts or the full extent of anoxic brain injury, apart from disclosing secondary loss of brain volume (i.e., atrophy). Also, signal or density changes on MRI and CT are non-specific and may result from other types of changes (e.g., inflammation, edema, or dilation of perivascular spaces). Symptomatic Infarcts Among subjects with symptomatic stroke, a corresponding cortical or subcortical lesion usually can be found on CT or MRI. Cortical infarcts are wedge-shaped lesions that conform either to the distribution of a single occluded artery or to the borderzone between two or more arteries. Acute infarcts are associated with edema, luxury perfusion, or hemorrhagic conversion. Over time, macrophages clear necrotic brain tissue and the infarct becomes cystic. Subcortical or lacunar infarcts are spherical or slit-like lesions, ranging in size from 3–15 mm in diameter, and located in the deep gray nuclei or white matter. Lacunes appear bright on T-2 weighted and proton density MRI and dark on T-1 weighted MRI or CT. Asymptomatic, but Discrete, Areas of Hyperintensity on T-2 Weighted MRI or Decreased Attenuation on CT Among 10–40% of neurologically-asymptomatic elderly persons (30–34), small discrete lesions can be visualized as hyperintensities on T-2, proton density, and fluid-attenuated inversion recovery (FLAIR) MRI, and as variable areas of hypointensity on the corresponding T-1 weighted image (Fig. 1). These so-called silent infarcts (SI) were observed five times more frequently than symptomatic infarcts (20% versus 4%) in the Rotterdam scan community study (34). Prevalence of SI increases with age and history of hypertension (31,34,35). SIs are most frequently found in the white matter or the deep gray nuclei (33). SI are not benign, as they are associated with increased risk of subsequent stroke (ORZ10.48, 95% CIZ3.63–30.21) (31). Care must be taken to distinguish SI from CSF-filled perivascular spaces (PVS), which may be especially prominent in the putamen and infra-putaminal regions, as well as near the anterior commissure (Fig. 1) (36,37). On T-2 weighted MRI, SI, PVS, and CSF are all equally hyperintense. On proton density or FLAIR sequences, however, SI and PVS can usually be distinguished. SI are hyperintense while PVS are isointense to CSF. An exception to this rule are cystic infarcts, which are filled with CSF and therefore are isointense with, CSF. Diffuse White Matter Hyperintensities/Decreased Attenuation Diffuse hyperintensities on T-2 weighted MR (so-called white matter hyperintensities or WMH) are observed frequently in the periventricular and deep white matter of asymptomatic as well as symptomatic elderly persons. When extensive, WMH may be visualized as corresponding hypointensities (so-called black holes) on T-1 weighted MRI or as areas of decreased attenuation or rarefaction on CT (so-called leukoaraiosis or LA). Severity of WMH increases with age and hypertension (Fig. 2) (38,39). The deep white matter is perfused by long-penetrating end-arterioles and is susceptible to hypoperfusion. This typically occurs in patients with widespread stenosis of small penetrating arterioles (e.g., arteriolosclerosis or amyloid angiopathy), particularly when coupled with systemic hypotension (40–42). In patients with severe arteriolosclerosis, WMH is

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Figure 1 Distinguishing lacunes, perivascular spaces and cystic lacunes on MRI. All three lesions are bright on T-2 weighted MRI (top row). Perivascular spaces (PVS) are isointense to CSF on proton weighted images. They may be quite large when located beneath the putamen or near the anterior commissure. By contrast, lacunes are generally hyperintense relative to CSF on proton density MRI. An exception are cystic lacunes which, like PVS, are also isointense relative to CSF and dark on T-1 weighted MRI. Cystic lacunes can be distinguished from perivascular spaces when found distant to the infraputaminal and anterior commissure regions. Sometimes cystic lacunes have a rim of hyperintensity on proton density MRI as seen in this figure.

associated pathologically with loss of myelin and later axons (43–45). WMH are not benign, but are associated with increased risk of stroke (ORZ4.81, 95% CIZ1.13–20.58) (31). Hippocampal and Cortical Atrophy Diffuse cerebral and hippocampal atrophy traditionally are considered hallmarks of AD. Recent studies show that hippocampal and cerebral atrophy correlate with severity of CI, regardless of the presence or absence of lacunes (46,47). In poststroke D, severity of CI has also been correlated with severity of medial temporal atrophy (48). Hippocampal atrophy may be associated with neurofibrillary degeneration or hippocampal sclerosis. Hippocampal sclerosis refers to segmental loss of neurons, usually starting in the CA1 sector and sometimes extending to the subiculum (49,50). The pathogenesis of hippocampal sclerosis remains controversial, but may be related to ischemic vascular disease. The pathogenesis of the diffuse cortical atrophy in CVD, if and when there is no significant AD pathology, remains unknown. RECOMMENDATION: A neuroimaging study is recommended by the AAN practice parameter at least once during the course of a dementing illness (51). Discrete or confluent hyperintensities in gray and white matter provides a marker for CVBI, assuming other etiologies have been ruled out (e.g., demyelination, inflammation, etc). Absence of T-2 weighted hyperintensities makes CVBI far less likely, but does not rule out microinfarcts or anoxia. Hippocampal atrophy is characteristic of AD, but may also occur with hippocampal sclerosis. Cerebral atrophy correlates with D, regardless of the etiological subtype.

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Figure 2 Cardiovascular Health Study (CHS) white matter rating scale: (1) no white matter findings, (2) discontinous periventricular rim with minimal dots of subcortical disease, (3) thin, continuous periventricular rim with few patches of subcortical disease, (4) thicker, shaggier periventricular rim with mild subcortical disease, (5) mild periventricular confluence surrounding the frontal and occipital horns, (6) moderate periventricular confluence surrounding the frontal and occipital horns, (7) periventricular confluence with moderate involvement of the centrum semiovale, (8) periventricular confluence involving most of the centrum semiovale, (9) findings more remarkable than grade 8. Source: From Ref. 39.

Evidence of Relationship Between CVBI and CI: Three Common Temporal Scenarios Ideally, the clinician could ascertain the likelihood (high, medium, low) that CVBI assessed by a neuroimaging study contributed to CI. Input data would include the size and location of the CVBI and the pattern and severity of CI. The likelihood of a causal relation would be weighed against an intimate knowledge of the topology and functional integration of complex neurobehavioral networks. This approach works fairly well for large symptomatic strokes (scenario A), but not for many other types of CVBI (Fig. 3). † Scenario A: Onset of CI follows stroke (post-stroke D) † Scenario B: Slowly progressive cognitive decline precedes stroke † Scenario C: CI is associated with silent lesions on MRI (SI or WMH) Traditionally, investigators have assumed that slowly progressive D indicates a neurodegenerative D, while abrupt, stepwise decline in cognition indicates multi-infarct or vascular D. While this distinction is undoubtedly true in many cases, limited autopsy data has left these assumptions untested. Autopsy series in Alzheimer’s disease centers typically have excluded cases with stroke or vascular D; epidemiologic surveys and stroke registries rarely conduct autopsies. A few longitudinal studies do include serial neuropsychological testing and autopsy of subjects with vascular disease [e.g., the Nun Study, Religious Orders Study, Honolulu Asia Aging study, and the Ischemic Vascular Dementia (IVD) Program Project] and will be positioned to test traditional assumptions about temporal course and etiology.

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CVD:

Mixed Alzheimer's Disease AD/CVD

Silent Infarcts, WMH Microinfarcts Stroke

Figure 3 Combinations of AD and CVD: (A) Onset of cognitive impairment follows stroke (post-stroke dementia), (B) Slowly progressive cognitive decline precedes stroke (AD with incidental stroke, Mixed AD/CVD or Binswanger?), (C) Cognitive impairment is associated with silent vascular lesions on MRI (SI or WMH).

Scenario A: Acute Onset Cognitive Impairments (Post-Stroke Dementia) Between 26 and 32% of patients hospitalized with incident stroke meet criteria for D when tested three months later (52,53). Since 500,000 cases of stroke are estimated to occur in the United States each year (54), there may be 125,000 to 150,000 new cases of stroke D each year. This compares to an estimated 360,000 new cases of AD in the United States each year (55). Among patients with D and stroke in the Columbia Stroke Registry, the topographic and temporal relationship between CVBI and D were examined: 1. Dementia related to the focal effects of stroke, where infarction(s) in strategic locations singular or additive effects appeared to account for the behavioral syndrome (26%) 2. New onset D after a stroke whose location or size did not explain the global mental changes using traditional concepts of functional neuroanatomy (30%) 3. “ADCCVA” where a history of functional and memory impairment antedated the index stroke (36%) (see Scenario B). For patients with a clinical history of stroke, there is an extensive case-based literature describing associated focal cognitive syndromes. The lesions likely to produce Broca’s, Wernicke’s, conduction aphasia or neglect syndromes have been mapped out (56). Cognitive and behavioral disturbances associated with lacunar strokes in the thalamus (57,58), capsular genu (59), and head of caudate (60). A stroke neurologist can look at a major or minor artery infarct on CT/MRI and predict the patient’s neurological deficits, including likely CI, with a high degree of certainty. In these instances, there is almost always a well-documented temporal relationship between the stroke and the abrupt onset of CI. These cases conform to the classical syndrome of MID and meet NINDSAIREN criteria for probable VaD. Risk factors have been compared in stroke patients with versus without D. In the ColumbiaPresbyterian stroke study, risk factors for D following stroke included age, low education, and nonwhite race, as well as history of prior stroke (OR 2.7), diabetes mellitus (OR 2.6), lacunar subtype of stroke (OR 2.7), or left hemispheric lesions (OR 4.7) (61). D was especially common with infarctions in the left posterior cerebral and anterior cerebral artery territories. In the Helskinki Stroke Aging Memory Study, D following stroke was associated with dysphasia (OR 5.6), major dominant stroke syndrome (OR 5.0), history of prior CD (OR 2.0), and low educational level (OR 1.1) (53). MRI features predictive of D included severity of WMH (OR 1.3) and medial temporal atrophy (OR 2.1) (48). The factors associated with D are multifactorial and complex. Tatemichi (61) proposed that D results when infarcts of sufficient size strike strategic locations

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involved in higher cortical function, especially the limbic system and association cortex, including the white matter pathways that interconnect them. Scenario B: Cognitive Decline Preceding Stroke (AD?CCVA) When a patient with stroke presents with an antecedent history of slowly progressive D, the presence of AD is considered likely (52,53,62). In the Columbia-Presbyterian Stroke Cohort, a history of cognitive decline preceded the index stroke in 36% of cases with stroke D. In the Lille University Stroke Cohort, symptoms of antecedent D were ascertained using the Informant Questionnaire on Cognitive Decline in the Elderly in 16% of persons at the time of their first stroke (62). Such cases were more likely to show atrophy and leukoaraiosis on CT scan, endorse a family history of D and be female. Most investigators postulate that a history of antecedent cognitive decline signifies the presence of concomitant AD. This, however, remains to be confirmed by neuropathological study. Scenario B cases represent a significant proportion of stroke cases. In our experience, they are heterogeneous in composition, most often representing mixed cases of AD/CVD, but also cases of relatively pure CVD including Binswanger syndrome. These cases would likely meet Hachinski, DSM-IV, ICD-10, ADDTC criteria, but would unlikely meet NINDS-AIREN criteria for VaD. Scenario C: Cognitive Impairment with SI or WMH, without Symptomatic Stroke Less is known about the relations between SI and CI. SI have been correlated with CI (63), slowing on digit symbol and finger tapping, number of abnormalities on neurological examination (64), and depression (65). On the other hand, only weak correlations between silent lacunes (especially if located in the thalamus) and CI were observed in a study of small-vessel VaD (47). There appears to be a threshold between WMH volume and CI (66). Symptomatic changes are observed only once WMH exceeds O0.5% intracranial volume (67) or O5 on the 8-point Cardiovascular Health Study rating scale (39) (Fig. 2). Severity of WMH has been correlated with slowing of gait (39), slowing of mental speed (39,68), and depression (69). In summary, SI and WMH are highly prevalent findings in the elderly, particularly those with vascular risk factors. These lesions may contribute to depression and mild CI (also known as vascular CI) more than fully-developed D. Subjects with SI or confluent WMH (without a clinical history of stroke) would meet ADDTC criteria for possible IVD, but not NINDS-AIREN criteria for probable or possible VaD. RECOMMENDATION: The clinician should recognize that there remains variable certainty/uncertainty by which CVBI can be related to CI. In cases with symptomatic stroke with a temporal relationship to the onset of D, the certainty is high. On the other hand, when there is a history of slowly progressive CI and the finding of “silent” infarcts and WMH on neuroimaging study, the level of certainty is substantially lower. Additional research is needed. How Useful is Apolipoprotein E 34 for the Diagnosis of AD or VaD? Controversy exists over whether the apoplipoprotein E (APOE) 34 allele confers increased risk of stroke and VaD, as it does for AD (70) and coronary artery disease (71). A pooled analysis of the Rotterdam and North Manhattan D studies reported that compared to APOE 33 homozygotes, APOE 34 heterozygotes had nearly a two-fold increased risk for a D with stroke (72). The odds ratio was higher for cases of mixed AD-CVD [2.2 (95% confidence interval 1.2–3.8)] than for VaD [1.3 (95% CI, 0.8–2.2)]. Other investigators have not found an increased frequency of APOE 34 in VaD or VCI (73). In an autopsy study with pathologically-confirmed diagnoses (NZ166), the frequency of APOE 34 was increased in mixed AD-CVD as might be expected, but was not increased in cases of pure vascular D (74). A unifying explanation is that APOE 34 increases the risk for the AD component of

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mixed AD-CVD. RECOMMENDATION: The positive and negative predictive values of APOE 34 are too low to be used alone as a diagnostic marker for AD (70).

PROGNOSIS The two types of outcomes considered in this chapter are mortality and cognitive decline rates. The discussion below includes population studies, pharmacological trials, and a longitudinal cohort study with sample sizes greater than 100 subjects. Mortality Mortality differs between the two most common causes of D, AD, and VaD. In a 14-year follow-up study, mortality was higher for VaD than AD (75). Among subjects aged 75 years and older, the RR of death in VaD was 3.5 (95% CI, 2.4–5.1) and in AD, 2.8 (95% CI, 2.1–3.6). Similar difference in RR values were reported for 75C year-old incident cases of VaD (RRZ3.3 (95% CI, 2.0–5.3) and AD [RRZ2.0 (95% CI, 1.5–2.7)], although due to small sample size these differences did not reach statistical significance (76). In the latter study, the mean survival times for VaD and AD were 2.8 years (95% CI, 2.2–3.4) and 3.1 years (95% CI, 2.8–3.5), respectively. These differences in mortality most likely reflect the effects of more severe cardiovascular co-morbidity and physical disability in VaD (77). Within VaD, excess mortality varies by gender, time from diagnosis, severity of D, and functional disability. Among subjects with VaD, survival rates are lower for men than women (75,78,79). In a 14-year follow-up study, overall survival was only 1.7% among subjects with VaD compared to 13.3% expected. The expected and observed rates diverged up to 5 years after study entry, when the survival was only 30% of expected and then became parallel (75). Using Cox proportional hazard analyses, survival in VaD is negatively correlated with severity of D (78,80) and functional disability (75,79). In the Kungsholmen project, the two factors carrying significantly increased hazard ratios for death were baseline age (years) [HR 1.06 (95% CI, 1.0 to 1.1)] and the Katz ADL index [HR1.78 (95% CI, 1.3 to 2.4)]. Of interest, functional disability predicted death for subjects with VaD, but not AD; whereas, baseline co-morbidity predicted death in AD, but not VaD. Cognitive Decline Community Studies The follow-up status 7 years later has been described for a representative sample of elderly patients with D living in Kungsholmen, Sweden (79). In the initial prevalence survey, 225 cases of D were identified and classified based on clinical criteria (without neuroimaging data) as 121 AD, 52 VaD, and 80 other D or questionable D. The AD and VaD groups had similar MMSE scores at study entry (17.3G5.0 and 15.3G5.7). At first follow-up examination (2.75G0.54 years later), 109 had died (48%) and 110 subjects (49%) were re-examined. At the second follow-up examination (4.04G.42 years later; 6.8 years from study onset), 194 subjects had died (86%) and 27 subjects (12%) were re-evaluated. The MMSE served as the main cognitive outcome measure, although neuropsychological testing was added at the first follow-up visit. During the first follow-up period, the average annual rate of change on the MMSE was greater for AD (K2.75, 95% CI, K3.32 to K2.18, nZ51) than VaD (K1.75, 95% CI, K2.67 to K0.85, nZ19). During the second follow-up period (when death had exacted significant attrition), rate of decline was also greater in the AD group. Multiple regression analyses identified D subtype (AD versus other; betaZK1.54, pZ0.6), Katz Activities of Daily Living (betaZK0.37, pZ0.02),

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and initial MMSE score (betaZK0.12, pZ0.04) as three significant predictors of cognitive decline. Neuropsychological testing was administered to 108 subjects at the first follow-up visit and repeated for 41 survivors, 2.5 years later (5.5 years after study onset) (81,82). No significant differences in rate of decline were noted between the AD and VaD groups, but the sample size by this time was small (nZ26, nZ10) and no longer representative. In the Kungsholmen project, functional disability proved to be the most important predictor of death as well as cognitive decline. Hospital Studies In follow-up studies of 151 subjects in the Columbia-Presbyterian Stroke Cohort, improvement was observed in neuropsychological performance for some individuals, 1-year post stroke (83). Probability of improvement was 54% for a patient with left hemisphere stroke or major hemispheral syndrome, but only 12% for patients with concomitant diabetes mellitus. The reason for poorer prognosis in the latter group is not clear, but may be related to more widespread and progressive small-vessel CVD associated with diabetes. Slower rate of cognitive and functional decline has been reported in a cohort of African Americans with VaD (nZ79; diagnosed by NINDS-AIREN criteria) compared to AD (nZ113) or stroke without D (SWD; nZ56) (84). On the MMSE, the mean annual decline was –0.87 points for the VaD compared to -1.86 for AD, and -0.20 for SWD. The differences in outcome, however, were confounded by significant group differences in baseline MMSE score. Normal Controls in Pharmacological Drug Trials The placebo-arms of clinical trials provide another source of data regarding natural progression. In clinical trials, untreated AD subjects typically show an 8-point/year decline in the ADAS-cog (85). During a 48 week placebo-phase of the MN 304 propentofylline study, 304 patients with VaD showed relatively little deterioration (mean decline of one point on the ADAS-cog) (86). In a doubleblind, placebo-controlled trial of galantamine, the placebo group with probable VaD (nZ67) showed no significant change in the ADAS-cog, while the placebo group with mixed AD-CVD (nZ87) showed a 1-point decline in the ADAS-cog (87). Since the NINDS-AIREN criteria are typically used in clinical trials, subjects with probable VaD typically represent cases with stroke D. The data from placebo control groups indicate that this subgroup of VaD experiences relatively little decline on the ADAS-cog over a 6- to 12-month trial period. MRI as Predictors of Cognitive Decline The value of quantitative MRI measures as predictors of cognitive decline are under study in the IVD program project. Follow-up studies have been completed for 120 participants followed for a mean of 2.95 years (SDZ1.20), who included cognitively normal, cognitively impaired, and demented individuals with and without subcortical lacunes (88). A global cognitive measure with linear measurement properties was derived from a battery of neuropsychological tests. MRI measures of atrophy [volume of cortical gray matter (cGM) and hippocampus] and ischemic vascular pathology (volume of WMH, and lacunes) were obtained using computerized segmentation software followed by hand editing. Random-effects modeling was used to identify baseline MRI variables that predicted decline in the Global Cognitive measure. Of interest, the vascular MRI measures (i.e., SI and WMH) were not significant predictor of cognitive decline. On the other hand, cGM atrophy was a significant predictor of cognitive decline, regardless of whether or not there were lacunes. Hippocampal atrophy predicted decline in the non-lacune (predominantly AD), but not in the lacune group. These findings are consistent with previous reports that atrophy predicts decline in AD (89), but that vascular lesions do not predict decline in CVD (90). This is the first report suggesting that the severity of cortical atrophy also predicts decline in SIVD.

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RECOMMENDATION: In counseling the patient and family regarding prognosis, the clinician may note that mortality is increased, particularly among those with significant functional impairment and more severe CVD. Prognosis for cognitive function is variable, depending upon prevention of additional CVBI and the presence of concomitant AD. On neuroimaging, greater cerebral atrophy predicts greater cognitive decline.

MAJOR CVD RISK FACTORS AND THEIR RELATIONSHIP TO CVBI The major risk factors for VaD are essentially the same as those for stroke (Table 4) (4,91,92). These include hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation, valvular heart disease, and cerebral amyloid angiopathy. Although there is substantial overlap, large-, medium-, and small-sized arteries may be differentially affected by specific risk factors. The brunt of chronic hypertension falls on medium- and small-sized arteries (93). Occlusion of penetrating arterioles leads to lacunar infarcts; chronic or repeated hypoperfusion leads to periventricular and deep WMH. In contrast, valvular heart disease is a risk factor for major stroke, which results when a cardiac embolus occludes a large feeding artery. Similarly, hyperlipidemia accelerates atherosclerosis of the carotid artery, which leads to artery-to-artery embolism and large-artery stroke syndromes. Thus, there is an association between the type of vascular risk factors and the type of resulting CVD and CVBI. Table 4 Major Risk Factors and Subtypes of CVD CVBI Risk factor

PAR

CVD

CxI

ScI

SI

WMH

Examination

xx

xx

xx

x

x

x

Retinal A/V ratio, hard exudates, left ventricular hypertrophy, impaired creatinine clearance Carotid intimal thickness Microaneurysms, dot hemorrhages, hard exudates

x

x

x

Hypertension

High

Small vessel disease (arteriolosclerosis/ lipohyalinosis)

x

Hyperlipidemia

Medium

xx

Diabetes mellitus

Low

Atrial fibrillation

Low

Valvular heart disease/ cardiomyopathy Cerebral amyloid angiopathy

Medium

Large vessel disease (atherosclerosis) Microvascular disease (thickening of capillary basement) Small or large artery embolism Large vesselcardio-embolism

CADASIL

Low

Very low

Electrocardiogram

x

Large, small, and ICH microvascular disease Small vessel disease

Echocardiogram

x

x

x

x

x

Genetic testing

Abbreviations: CADASIL, cerebral autosomal dominant arteriosclerotic subcortical infarcts and leukoencephalopathy; CxI, cortical infarct; ICH, intracerebral hemorrhage; ScI, subcortical infarct; SI, silent infarct; WMH, white matter hyperintensity; PAR, population attributable risk for stroke; A/V, arterial/venous.

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Some data suggest that the type and location of lacunes and WMH may differ by risk factor. For white matter lacunes, age, hypertension, and female gender were significant predictors (35). For basal ganglia lacunes, age, ischemic heart disease, and carotid stenosis were predictors. Periventricular WMH, but not subcortical WMH, have been correlated with atherosclerosis, carotid intima thickening (94), and lower levels of serum carotenoids (95). Atrial fibrillation is a risk factor for both symptomatic and SI [OR 2.4 (95% CI 1.07–5.68)] (34). A genetic disorder affecting the Notch3 gene, known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), affects the smallarteries of the brain (96,97). It is estimated that there are 500 CADASIL families in the world, suggesting that this entity may be more common than familial AD. CADASIL is associated with progressive degeneration of vascular smooth muscle cell and the accumulation of granular osmiophilic deposits in the vascular basal lamina. The MRI is characterized by subcortical infarcts and severe confluent WMH, involving temporal lobe, claustrum, and corpus callosum, as well as frontal-parietal white matter (98). Recurrent attacks of migraine, ischemic events, and progressive subcortical D leads to premature death (mean age 65 years). Although the diagnosis can be confirmed via genetic testing, at the present time only symptomatic treatment is available. RECOMMENDATION: As best as possible, vascular risk factors should be identified and targeted for both primary and secondary prevention of CVD and CVBI (Table 4). Many important risk factors and evidence of target end-organ damage can be ascertained by physical examination and laboratory studies. High blood pressure is measured by sphingomanometry. The effects of chronic hypertension on the heart, kidneys, and eyes are manifest as left ventricular hypertrophy, reduced creatinine clearance, and narrowing of retinal arteries. Hyperlipidemia is ascertained by fasting serum levels of total, low-density, and high-density cholesterol. The severity of atherosclerosis can be assessed by thickening of the carotid intima on ultrasound. Cerebral amyloid angiopathy may be suspected in the differential diagnosis of severe WMH, but often is not suspected prior to the onset of a lobar hemorrhage (99). Thus, not all risk factors and CVD can be adequately assessed by current methods of physical and laboratory examination.

TREATMENT Primary Prevention: Depends on Identification of Underlying CVD and CVD Risk Factors Hypertensive Treatment A 6 mm Hg-reduction of systolic or diastolic blood pressure in persons with hypertension reduces the risk of initial stroke by 40% (100). Several observational and a few randomized trials support the notion that effective antihypertensive treatment also reduces the risk of CVBI and VaD, as well as stroke. In the Rotterdam Study of 7046 elderly persons, subjects taking antihypertensive medication at baseline (nZ2015) had a reduced incidence of vascular D 2.2 years later [adjusted RR, 0.30 (95% CI, 0.11–0.99)] (101). Antihypertensive treatment was also associated with reduced incidence of stroke 4.6 years later [RRZ0.61 (95% CI, 3–61)] (102). The number of patients needed to be treated to prevent one stroke over 5 years was 46 [i.e., NNTZ46 (95% CI, 29–599)]. In the Rotterdam Scan Study (nZ1077), successful versus inadequate antihypertensive treatment history was associated with decreased risk of WMH (OR 3.3 versus 8.4) (103). These findings support the view that effective treatment of hypertension prevents the development of WMH, stroke, and associated CI. In the Epidemiology of Vascular Ageing MRI cohort study (nZ845), the risk of having severe WMH was significantly reduced in subjects with normal blood pressure taking antihypertensive medication compared to subjects with high blood pressure (O160/95) taking

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anti-hypertensive agents (104). This prospective observational study also supports the notion that WMH can be prevented by effective treatment of hypertension. Similarly, in the Honolulu Asia Aging Study of 3605 surviving subjects, those with elevated but untreated SBP in mid-life were at increased risk for poor cognitive function in latelife [OR 2.6 (95% CI, 0.7 to 10.0)]. The risk was higher among those persons with an apolipoprotein 34 allele [OR 13.0 (95% CI, 1.9 to 83.8)] (105). History of BP treatment in midlife, on the other hand, was not associated with increased risk of subsequent CI, even in the presence of apoE 34 [ORZ1.9 (0.7 to 4.5)]. These findings suggest an interaction between SBP and apoE 34 on cognition, which can be moderated by the treatment of SBP. In a large multi-center study, 4,736 elderly persons with isolated systolic hypertension were randomized to anti-hypertensive treatment or placebo for 5 years (106). The RR reduction for stroke was 35% (95% CI, 17–49); with 43 treated patients needed to prevent one additional stroke (95% CI, 27–95). A more recent randomized double-blind, placebo-controlled trial of hypertension included cognition as a major endpoint. A 50% reduction in the risk of D was observed over 5 years [NNTZ52 (i.e., treat BP for 5 years, save one case of D)] (107), although the mechanism of risk reduction remains unclear. Treatment of Other Vascular Risk Factors Treatment of hyperlipidemia and atrial fibrillation decreases the risk of stroke, but few studies have examined cognitive function as an endpoint. A 25% reduction in LDL cholesterol using hydroxymethylglutaryl coenzyme-A reductase inhibitors (statins) reduces the risk of stroke by 19 to 31% (108). Anticoagulation with warfarin (coumadin) reduces the risk of stroke associated with atrial fibrillation by 68% (109). Little data is available regarding the efficacy of treating diabetes mellitus on the prevention of CVBI. RECOMMENDATIONS: The best treatment for stroke, CVBI, and VaD is prevention. A primary care physician should be identified to manage known vascular risk factors. Secondary Prevention (Prevention of Recurrent CVBI) Treatment of Hypertension There is a continuous relationship between the level of blood pressure and the risk of recurrent stroke. Overall, 15% of stroke survivors experience a second stroke within 5 years (110). In the United Kingdom TIA Trial, risk for recurrent stroke increased by 28% for every incremental increase of 10 mm Hg in systolic blood pressure between 130 to 160 mm Hg (111). A meta-analysis of nine randomized controlled clinical trials showed that active treatment with blood pressure lowering drugs reduces the risk of recurrent stroke by 28% [RRZ0.72; (CI, 0.61–0.85, p !.0001)] (112). The recent PROGRESS study (113) found that antihypertensive treatment with perindopril of 14 patients for 5 years saved one case of recurrent stroke. Despite the demonstrated importance of managing hypertension, more than 50% of survivors of stroke or myocardial infarction with hypertension do not have their blood pressures controlled below 140/90 recommended by the Sixth Report of the Joint National Committee on High Blood Pressure (114). Neurologists should pay close attention to the management of hypertension. Avoidance of Hypotension in Certain Subgroups of Patients There are subgroups of patients who appear to be at increased risk for CI with relatively lower blood pressures. In a 2-year observational study of 35 chronic hypertensive patients with MID, 34% showed declines on a mental status examination, while 66% stabilized or improved (115). The subgroup of hypertensive patient who stabilized or improved had higher mean SBP (137 mm Hg) than those who worsened (mean SBPZ127) [tZ2.72 (33 df); p !0.03], suggesting that lowering systolic blood pressure below 135 mm Hg may be detrimental in this group of patients. In another observational

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study of 13,635 patients admitted to academic medical centers in Italy between 1995–1997, 1,583 had congestive heart failure (CHF) (116). CI was found in 26% of patients with CHF and in 19% of remaining subjects. Systolic blood pressure !130 mm was associated with CI only among participants with heart failure. Among some chronic hypertensive patients with MID or cardiac patients with low-output states, it may be especially important to maintain perfusion pressure and to avoid hypotension. Further prospective studies are needed. Anti-Platelet and Anti-Coagulant Medication Anti-platelet and anti-coagulant medications reduce the risk of stroke. However, randomized control trials have not included cognitive function as an endpoint. The RR of subsequent stroke in persons with TIA or minor stroke is reduced by antiplatelet medications: 17% by aspirin and 25% by ticlopidine (117). In patients with symptomatic high grade carotid artery stenosis (70–99%), the RR of subsequent stroke in patients surgically treated with carotid endarterectomy is reduced by 51% compared to those treated with best medical therapy (118). The recent WARSS study (119), which excluded patients with primary cardioembolic stroke, observed no differences in primary end-points (death or recurrrent ischemic stroke within 2 years) between aspirin (16%) and warfarin (18%). The rates of major hemorrhage were also comparably low in both aspirin and warfarintreatment groups (1.5 and 2.2 per 100 patient-years) (Note: the target INR in the warfarin group was relatively low, 1.4 to 2.8, which may explain the acceptably low bleeding rate). Therefore, while warfarin is generally the preferred treatment for patients with atrial fibrillation or valvular heart disease, either aspirin or warfarin may be considered reasonable alternatives for the prevention of other stroke subtypes. RECOMMENDATIONS: It is not too late to prevent recurrent stroke or to prevent progression of vascular CI. The cognitive status of certain patients (e.g., those with severe brain end- organ damage or low-output cardiac states) may be adversely susceptible to relative hypotension. A physician must be identified to optimize the management of vascular risk factors and cardiovascular function. Tertiary Amelioration (Symptomatic and Supportive Care) Tertiary amelioration refers to symptomatic improvement of cognition, behavior, or mood. Several agents have shown modest efficacy on cognitive function in randomized controlled clinical trials. These agents include piracetam, oxiracetam, nicergoline, citicoline, pentoxyfylline, propentofylline, nimodipine, triflusal, and Gingko biloba (120). In a recent trial of mild to moderate VaD (nZ321), 20 mg/day of memantine, a non-competitive NMDA (N-methyl-D-aspartate) receptor antagonist, was associated with improved cognition, stabilization of global function and behavior, as well as good tolerance and safety (121). Four cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine) have been approved by the Food and Drug Administration for the treatment of AD. Recently, these agents have also shown beneficial effects in VaD (87,122,123). In a 24-week, double-blind, placebo-controlled study (nZ592), galantamine (12 mg/day) was associated with a 1.7 point mean increase in the ADAS-cog score (87). The VaD group was heterogeneous: 40% met NINDS-AIREN criteria for probable VaD, while the remaining had mild to moderate AD with stroke/vascular risk factors. The sample size was too small to separate ADCCVD from VaD treatment group effects. In two separate 24-week trials of donepezil [Study 307 (nZ603) and Study 308 (nZ616)], the treatment groups (5 mg or 10 mg/day) showed an approximately 2.0 point higher mean ADAS-cog score compared to the placebo groups (123). In the donepezil trials, 74% of subjects met NINDS-AIREN criteria for probable VaD. Efficacy in three independent studies, two with mostly probable VaD and relatively few mixed AD/CVD diagnoses, supports the conclusion that there is a specific VaD treatment response to cholinesterase inhibitors.

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Depression and apathy are common affective symptoms associated with VaD. Selective serotonin reuptake inhibitors are generally well tolerated and effective (124). The older tricyclic antidepressants (TCAs) can also be effective, but are less well tolerated. TCA with significant anticholinergic side-effects (e.g., amitriptyline) should be avoided. Agitation, psychotic symptoms, and disruptive behavior occur less commonly in VaD than AD, but if present, may be managed with antipyschotic medications if nonpharmacologic approaches are ineffective and the deleterious effects of the behaviors outweigh potential adverse events of the medications. The newer atypical antipsychotic medications (e.g., quetiapine, respiridone, olanzepine) are preferred (125), particularly if there are pre-existing extrapyramidal signs or gait disturbance. Physical, occupational, and speech therapy may be valuable on an individual case basis. As with all chronic D, education, and support for the caregiver are paramount in the optimal management of persons with VaD. The clinician should also deal proactively with regard to care planning issues such as safety, advanced directives, palliative care, and quality of life. Encouragingly, there are a growing number of potentially helpful options for the symptomatic and supportive treatment of patients with VaD.

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15 Prion Diseases and Dementia James A. Mastrianni Center for Comprehensive Care and Research on Memory Disorder and Department of Neurology, University of Chicago, Chicago, Illinois, U.S.A.

INTRODUCTION The prion diseases (PrD) are a group of unusual neurodegenerative disorders that affect both humans and animals, are associated with a variety of phenotypes, and are transmissible. The earliest description of PrD was that of Creutzfeldt and then Jakob in the early 1900s (1,2) as a progressive dementia associated with gait abnormalities and extensive vacuolation and astrocytic gliosis of the brain. In the mid-1950s, while studying primitive cultures in the Highlands of New Guinea, Carleton Gajdusek recognized and described a disease the Fore people, living in this region, called “kuru.” Sufferers of kuru developed a progressive gait ataxia, unusual behavior, and a relatively rapid progression to death. Gajdusek’s studies suggested that this disease was the result of a transmissible agent carried within the brain of the affected individual that was horizontally transmitted during rituals that involved cannibalism. Women and children were most affected by the disease, likely due to their greater contact with infectious tissue during both the preparation of the feast and the ritualistic ceremony. Pathologic examination of the kuru brain revealed the same pattern of vacuolation (also called spongiform change) that was observed in the disease described by Creutzfeldt and Jakob. Most importantly, however, this same pathology was astutely recognized by the veterinarian William Hadlow as the same pathology present in scrapie, a known transmissible disease of sheep associated with similar features of gait dysfunction, behavioral changes, and a rapid progression to death. It was natural to speculate that Creutzfeldt-Jakob disease (CJD) and kuru were similarly transmissible, which was confirmed in the mid-1960s (3,4). These results led to the recognition of several other transmissible spongiform encephalopathies (TSEs). Until relatively recently, the infectious agent of the TSEs was considered to be a slow virus (5), yet despite considerable effort, evidence for a virus has not materialized. Instead, a wealth of data has accumulated to implicate an abnormal isoform of the prion protein (PrP) as the etiologic agent in these diseases (6). Several years after Gajdusek received the first Nobel Prize for linking the transmissible nature of these diseases, Stanley Prusiner captured the second TSE-related Nobel Prize for his discovery of the prion, the infectious protein of PrD. 277

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PRION PROTEIN The PrP is a cell surface glycoprotein encoded by the PRNP gene, located on the short arm of chromosome 20. It is abundantly expressed in neurons, but is also present in several peripheral tissues including heart, lung, and white blood cells, among others (7). In its normal state, PrP is expressed in a non-pathogenic conformation (PrPC) and translocated to the cell surface where it is anchored to the outer membrane by a glycosylphosphatidylinositol (GPI) tail (Fig. 1). It contains two asparagine-linked glycosylation sites and a single disulfide bond. The primary function of PrP is unknown, although evidence supports several possible roles, including synapse formation (8,9), signal transduction (10), and copper delivery to cells (11–14). The underlying feature of PrD is the conversion of the primarily a-helical, nonpathogenic PrPC isoform to the predominantly b-sheet, pathogenic scrapie isoform (PrPSc). Compared with PrPC, PrPSc is insoluble in detergent solutions and is relatively resistant to protease digestion, a feature that allows detection of the abnormal protein in the brain of affected patients (Fig. 2). How is PrPSc initially generated? While “infection” with PrPSc is often considered to be the primary method for initiation of disease, it is, in fact, the least common. Only iatrogenic CJD and variant CJD are known to occur by exogenous introduction of PrPSc, whereas the majority of human PrD cases appear to be sporadic, without genetic linkage, and cannot be traced to an infectious source (Fig. 3). A spontaneous conversion of PrPC to PrPSc within the brain of a healthy individual is the most likely scenario, although the reasons for this spontaneous event have not been elucidated. It is likely that predisposing genes or environment (or even aging itself) may predispose to the conversion process. The genetic forms of PrD are well known and are most easily explained as the result of a destabilizing mutation in PrP that predisposes PrPC to convert to PrPSc. Along the same lines, a somatic mutation has been postulated as a potential cause of sporadic PrD. Regardless of the mode, once PrPSc is generated, it acts as a conformational template that complexes with PrPC

CHOs 23

octarepeat region

β-strands 181N

PrPC

1 S1

N197

2 S2

3

231

GPI

S

S

plasma membrane

N PrPSc

1

N

2

3 S

GPI

S

Extension of β-strand segment (?)

Figure 1 General organization of PrPC and PrPSc. PrPC is a 253 amino acid protein encoded by the PRNP gene on chromosome 20. The mature form of PrPC is 20% amino acids, the first and last 22 amino acids are removed in the ER during processing. Additional processing in the ER includes the attachment of a GPI moiety for anchoring to the membrane, glycosylation at two asparagine (N)-linked glycosylation sites, and a disulfide bridge. Three alpha-helical regions are designated 1, 2, and 3 whereas two short beta-strand segments are labeled S1 and S2. An octarepeat region is composed of five repeating motifs of the sequence [Pro-(His/Gln)Gly-Gly-Gly-(-/Gly)-Trp-Gly-Gln]. Conversion of PrPC to PrPSc results from the extension of b-strand into the region of the protein that is without obvious structure in PrPC. This results in b-sheet formation, protein aggregation, and presumably, the infectious property of PrPSc.

Prion Diseases and Dementia

279 PrPSc

PrPC -Non-pathogenic -Soluble -Protease sensitive

+ proteinase

-Pathogenic -Insoluble -Protease resistant

+ proteinase

K

Complete digestion

K

Protease-resistant PrPSc core

Figure 2 Comparison of the physicochemical properties of PrPC and PrPSc. The altered conformation of PrPSc induces the protein to aggregate and develop a relative resistance to protease digestion. A proteaseresistant core that carries the glycosylation sites can be demonstrated by Western blot of brain extracts from patients with PrD.

Generation of PrPSc PrPC

Spontaneous conformational shift

sCJD, ?sFI

Germline mutation of PRNP

fCJD, GSS, FFI

Somatic mutation of PRNP

?sCJD, ?sFI

Exposure to PrPSc

Kuru, iCJD, vCJD, ?sCJD

PrPSc

Figure 3 Several possible mechanisms may lead to the generation of PrPSc. A spontaneous conformational shift from PrPC to PrPSc is the most likely mechanism in sCJD and possibly sFI. One theory suggests that misfolded PrP is constantly being generated, but quality control mechanisms in the cell refold the protein to its natural conformation. Problems with the refolding mechanisms may allow misfolded PrPSc to be generated and initiate prion disease. A germline mutation of the PRNP gene results in mutated PrPC that may be predisposed to adopting the abnormal PrPSc conformation. This explains the familial forms of prion disease, while a somatic mutation in a single neuron may explain some sporadic prion diseases. Finally, exposure to prions has been documented in certain forms of prion disease, and questioned as a cause of sCJD, although the epidemiologic evidence for the latter is lacking.

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PrPSc Propagation

PrPSc

PrPC

Spontaneously generated* or exogenously derived

Normal neuronal constituent

PrPSc PrPC Sc

PrP -PrP complex forms

PrPSc PrP PrPC

C

PrP

PrPC converted to new PrPSc

PrPC PrPC Additional PrPC recruited

PrPSc

C

PrPC C PrP C PrPC PrPC C PrP C PrP PrPC PrP PrPC

PrPSc

PrPSc

C

PrPSc

Recruitment of PrPC by PrPSc becomes more efficient as PrPSc levels increase

PrPSc

PrPScSc PrPSc PrP Sc PrPSc Sc PrP Sc PrP ScPrPSc PrP Sc PrP ScPrPSc PrP ScPrPScPrP PrP Sc PrP PrPSc PrPSc accumulation results in cellular dysfunction and neuron death

Figure 4 Once generated, PrPSc complexes with PrPC by protein-protein association and converts it to additional PrPSc. Propagation of PrPSc may proceed geometrically because of the doubling with each conversion cycle. The actual ratio of molecular conversion is not known, although this concept helps to explain the rapid rate of neuronal death and disease progression. *ZAs described in Fig. 3.

and converts it to additional PrPSc (Fig. 4). Accumulation of PrPSc in the brain generally correlates with disease progression, although the actual mechanism of cell death in PrD is not yet understood. As with other neurodegenerative diseases, the usual suspects of apoptosis, cellular inflammation (cytokines in particular), and oxidation, have been implicated. DOPPEL, THE PRION-LIKE PROTEIN Recent studies have identified a second gene that may be linked to PrD. Downstream from the PRNP gene is the prion-like protein (PRND) gene, so named because its gene product has over 30% homology with the C-terminal region of PrP (15). As in PrP, doppel has three (a-helices, two short b-strands), and two glycosylation sites, but rather than one, there are two disulfide bonds. Overall, the three dimensional structure of doppel (Dpl) is similar to that of PrPC, suggesting a potential overlap of function (16). No mutations have yet been found in PRND that are consistently associated with human PrD, although several polymorphisms have been identified (17,18). While no studies in humans have yet shown an upregulation of doppel in PrD, there is evidence that overexpression of doppel in transgenic mice promotes cerebellar cell death and the development of ataxia (19,20). The role of doppel as a modifier of PrD is currently under study. CLINICAL AND PATHOLOGIC SUBTYPES OF PrD In contrast to most other neurodegenerative diseases, with the exception, perhaps, of the frontotemporal dementias (FTDs), PrD is associated with several clinicopathologic profiles. This became obviously apparent once the PRNP gene was discovered and a specific antibody to PrP was generated. With the advent of these tools, several individuals originally diagnosed with Alzheimer’s or other nonspecific diseases were subsequently recognized to be PrD. Additionally, the

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demonstration of GSS type amyloid plaques in diseases not previously considered to be GSS, broadened the scope of that disease, in particular. These findings further emphasized that common pathologic features could be observed in diseases with quite disparate clinical presentations. While it is clear that PrPSc is associated with a major conformational shift from a-helical to b-sheet structure, recent studies suggest that there may be several conformational variants of PrPSc , each of which may produce a particular “strain” or phenotype of PrD (21,22). Five distinct clinicopathologic phenotypes of PrD, based in part on the clinical presentation of disease, but primarily on the brain pathology, have thus far emerged; these include (1) kuru, (2) CJD, (3) Gerstmann-Stra¨ussler-Scheinker syndrome (GSS), (4) fatal insomnia (FI), and (5) new variant CJD (vCJD). Although kuru is no longer observed because cannibalism has ostensibly ceased, it is mentioned for its historical significance. The pathologic picture of kuru is characterized by the presence of dense-core amyloid plaques, also known as “kuru plaques,” deposited primarily within the cerebellum, although they may be diffusely spread throughout the brain. GSS is also a plaqueforming disease, although the plaques in this case are typically of the multicentric type, in which an amyloid core is surrounded by smaller satellites of amyloid. Depending on the specific GSS subtype, these plaques may also be isolated to the cerebellum, cerebrum, or diffusely spread throughout both. Spongiform change is significantly less prominent in GSS than it is in CJD and kuru. CJD is typically devoid of plaques, yet replete with diffuse spongiform change. Occasionally, in perhaps less than 10% of cases, small round kuru-type plaques may be evident on detailed inspection. FI was initially defined on the basis of its unique clinical phenotype and subsequently determined to be a PrD, based on genetic studies of the familial form of FI (FFI). This occurred because the pathology is uncharacteristic of PrD, consisting primarily of gliosis and neuron loss within the thalamus and brainstem, while spongiform change is minimal to absent. In recent years, a new subtype of PrD that carries a fifth pathologic variant, defined by the presence of dense-core amyloid plaque deposits surrounded by a halo of spongiform change, labeled “florid plaques” has emerged. This subtype, labeled vCJD, is unique among the PrDs, as it represents a human PrP thought to result from the ingestion of beef contaminated with bovine spongiform encephalopathy (BSE). The clinical features of the current human subtypes are detailed in the following sections.

CREUTZFELDT-JAKOB DISEASE Sporadic CJD (sCJD) The first case of CJD was described by Hans Creutzfeldt in 1921 as “spastic pseudosclerosis” (1). A year later, Alfons Jakob (2) described the “sponge-like” pathologic features in the brain of a patient that had similar clinical features as the one described by Creutzfeldt, which was fortuitous since the overall clinical features of Creutzfeldt’s patient was inconsistent with CJD. Today, CJD is defined by the presence of extensive spongiform change throughout the gray matter of the cerebrum, cerebellum, and deep nuclei. CJD is by far the most common subtype of PrD. Still, the worldwide incidence of disease is only w1 per million per year. While this reported incidence has been steady for over 25 years, its accuracy is lowered by the less than rigorous efforts to track disease occurrence prior to the emergence of vCJD in 1995. Surveillance efforts have since increased and new numbers will likely be generated. CJD most often presents in the 6th or 7th decade, although a handful of teenagers and nonagenarians have been reported. There is no obvious gender bias, as observed in Alzheimer’s disease. The “classic tetrad” of CJD includes a rapidly progressive dementia, ataxia, myoclonus, and an abnormal electroencephalogram (EEG). It should be noted, however, that a host of neurologic signs and symptoms may be present. These include, but are not limited to, diffuse and focal weakness, aphasia, painful neuropathy, choreiform movements, hallucinations, supranuclear ophthalmoplegia, cortical blindness, amyotrophy, and alien hand syndrome (23–27). Thus, while

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the classic tetrad represents the core features that help to establish the diagnosis of CJD, they are not the sole features observed in sCJD and, more importantly, they may not be the presenting features, making it often difficult to diagnose CJD early in the disease course. Criteria for the diagnosis of “definite,” “probable,” and “possible” CJD have been recently proposed by the World Health Organization (Table 1). Estimates of the sensitivity and specificity of these criteria for defining “probable CJD” have been recently reported to be approximately 65% and 95%, respectively, while inclusion of the “possible CJD” category changes these figures to 91% and 28%, respectively, suggesting that the criteria for possible CJD increases the sensitivity but reduces specificity (28). Overall, it was estimated that 12% of CJD was missed by these criteria, supporting the need for better diagnostic methods. The most common presenting feature is cognitive decline, which occurs in about 70% of patients, either alone or in combination with ataxia, while w25% will present only with ataxia, and a smaller percentage will develop cortical blindness, referred to as the Heidenhain variant (29). Pyramidal and extrapyramidal features may be present at onset in about 1–2% of cases, yet eventually develop in approximately 50% of patients during the course of disease. In general, most cases of CJD develop subacutely over the course of several weeks, although about 10% of cases will have a more abrupt onset that suggests encephalitis, stroke, or acute inflammatory disease of the brain. A prodromal period, characterized by vague complaints of fatigue, vertigo, headache, sleep disturbance, and anxiety, may be apparent in 25% of patients prior to the onset of clinically obvious disease. The most common feature at time of onset is memory loss or confusion. This may be evident only when the patient has to perform unfamiliar tasks or is placed in unfamiliar situations. The patient may complain of problems concentrating, difficulty performing calculations in the head, or maintaining train of thought. Such vague complaints may quickly escalate to specific impairments of immediate and/or delayed recall, aphasia, constructional apraxias, and any other cortical based function, thereby mimicking the early stages of AD. These features alone may bring Table 1 WHO Criteria for the Diagnosis of sCJD Definite CJD Diagnosed by standard neuropathological techniques and/or Immunocytochemically and/or Western blot confirmed protease-resistant PrP and/or Presence of scrapie-associated fibrils Probable CJD Progressive dementia, and At least 2 of the following 4 clinical features: † Myoclonus † Visual or cerebellar disturbance † Pyramidal/extrapyramidal signs † Akinetic mutism and Periodic discharges on the EEG, and/or a positive 14-3-3 CSF assay, and a clinical duration to death !2 years Routine investigations should not suggest an alternative diagnosis Possible CJD Progressive dementia and At least 2 of the following 4 clinical features: † Myoclonus † Visual or cerebellar disturbance † Pyramidal/extrapyramidal signs † Akinetic mutism and No EEG available or atypical EEG, and Duration !2 years

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the patient to medical attention, although the onset of physical or behavioral symptoms often provide the greatest motive for seeking medical assistance. Ataxia commonly presents within weeks of the onset of dementia, although a delay until midway into the course of disease is not uncommon. As mentioned, about one-quarter of CJD patients present exclusively with ataxia. Gait or truncal ataxia is the most prominent feature, although appendicular ataxia may appear simultaneously or shortly follow. Other signs and symptoms of ataxia include vertigo, nystagmus, ocular dysmetria, intention tremor, and dysarthria. Once symptoms become prominent enough to bring the patient to medical attention, the disease generally takes an accelerated course. Dementia becomes more obvious, as cortical involvement of disease expands. Examination at this time may show impairment of short- and longterm memory, difficulty with expressive and/or receptive language (dysphasia), problems with calculations (dyscalculia), difficulty in carrying out a complex motor movement (dyspraxia), or loss of the ability to write (dysgraphia). Often, the presenting feature is most obviously and severely affected by the time other features of disease appear. Because of the relatively rapid rate of progression, it is not uncommon to hear reports from family members that the patient had mild confusion and memory problems one week and by the next week was unable to recognize family members. If ataxia is present, its progression will be evident primarily by an increased frequency of falls, which eventually confines the patient to a wheel chair. Incoordination of swallowing, manifested initially as coughing during eating or drinking, may also become evident at this point, as does the risk for aspiration pneumonia, a common cause of death in these patients. Other features of disease, including pyramidal and extrapyramidal signs and symptoms, sensory changes, pseudobulbar signs, oculomotor disturbances, and a multitude of other possible neurologic features, may appear at this time, as may the loss of bowel and bladder control. More than 75% of CJD patients will develop myoclonus, which typically appears at the mid or late stage of disease. This appears as a spontaneous or stimulus-induced irregular multifocal jerking of large muscle groups. Startle myoclonus may be induced by a loud noise, such as from clapping the hands or dropping a book on the table, or following a tactile stimulus. In some cases, this response may be so prominent that simply walking into the room, initiating speech during a quiet period, or turning on the light in a dark room may provoke the response. As with the Moro response in an infant, the CJD patient may exhibit repetitive jerking of all four limbs for several seconds after the stimulus. In the final stage of disease, the typical picture is one of a bedridden, akinetic, and mute patient. Sleep-wake cycles may be evident and myoclonus may be prominent. Death typically results from aspiration pneumonia or urosepsis secondary to the debilitated state. Total disease duration is generally under 6 months, although less typical cases may extend beyond a year. Laboratory Investigations for CJD Currently, there is no single diagnostic test for CJD, although considerable effort is underway to develop a simple assay for detecting PrPSc from blood or CSF. Certain studies, however, are useful in providing support for the diagnosis of CJD. Early in the course of disease, the EEG may show nonspecific slow wave activity, but with disease progression, a characteristic pattern of periodic paroxysms of triphasic or sharp waves with a frequency of 0.5–2 Hz, against a slow background will appear (Fig. 5) (30–32). Roughly, only 70% of pathologically proven sCJD patients will demonstrate periodic sharp wave complexes (PSWCs) on the EEG, due in part to the lack of typical EEG changes in the ataxic forms of sCJD, but also because PSWCs may not be present in the early stage of disease and often disappear once the disease reaches the end stages, leaving a somewhat narrow window of opportunity (30,33,34). It is important, therefore, to repeat the EEG at regular intervals, perhaps weekly, to increase the capture rate, if suspicion of CJD is high.

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Figure 5 The typical pattern of periodic sharp or slow wave complexes (PSWCs) of CJD consist of triphasic type waves occurring at a regular period of every 0.5-2 sec. Initially, these may appear unilaterally or focally, then spread bilaterally. In this case, the periodic activity is primarily left sided (top half of EEG in typical “double banana” orientation), but smaller amplitude complexes are beginning to appear in the right hemisphere. This patient presented with language dysfunction early in the disease.

Brain imaging with MRI is done primarily to rule out structural or vascular abnormalities as a cause for the observed clinical features. In the early stage of disease mild to moderate generalized atrophy may be present on T1-weighted images. Early estimates suggested that in 10-15% of cases, T2-weighted images may demonstrate hyperintensity of the basal ganglia (35–37). Recent estimates suggest that up to 80% of cases may carry this sign, although a rigorous study to determine the true sensitivity and specificity of this sign has not yet been provided. In our experience, this sign is somewhat MR-operator dependent and therefore used with caution. In contrast, diffusion-weighted MRI (DWI) promises greater sensitivity and specificity in this regard (38–42). In some reports, increased signal in DWI appeared within the cortical ribbon even prior to deep structures (43). Anatomical studies suggest that the hyperintense signal on DWI correlates with the spongiform and/or gliotic pathology of the brain (42,44). This finding has also been noted in a few cases of familial CJD (45,46) and in a single report of possible iatrogenic CJD (47). Hyperintensity of the basal ganglia and head of the caudate is most commonly observed in sCJD, while pulvinar hyperintensity may be seen in variant CJD (discussed later). PET or SPECT scanning appears to be of limited usefulness in CJD patients, as the findings show nonspecific and diffuse cortical hypoactivity that may, in some cases, show a frontal predominance (48,49). In some reports, a reduction in perfusion to specific brain regions correlated with the clinical symptoms observed in the patient (i.e., left frontal and occipital cortex hypoactivity in a patient with language and visual deficits) (50,51). Thus, in contrast to the noted utility of PET and SPECT to discriminate FTD from AD, there is no typical diagnostic pattern for CJD. One exception, however, is in the diagnosis of FI, which is associated with a specific reduction in activity within the thalamus (discussed later). Because of the progressive nature of the disease and the need to rule out an active and potentially treatable CNS infection or inflammatory process, CSF examination is routinely

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performed as part of the evaluation. An immunologic response is not present in the CSF, although a minor elevation in protein is common. In recent years, several proteins from the CSF have been studied as markers for PrD, including S-100 (52,53), neuron specific enolase (NSE) (54,55) and the 14-3-3 protein (52,56,57), none of which are specific for CJD. The 14-3-3 protein, however, appears to have the greatest overall sensitivity and specificity as a marker for PrD, but it carries with it limitations. The 14-3-3 proteins are abundant in the nervous system and function in signal transduction, cell cycle regulation, apoptosis, and the cellular stress response (58,59). As neurons die, 14-3-3 is released from the dying neurons into the CSF where it can be detected. It is important to note that 14-3-3 is not a specific marker for PrD, but rather a marker for cell death. Because the rate of cell death associated with PrD is rapid, the 14-3-3 protein accumulates in CSF to a significant level. Sporadic CJD, which has the most rapid rate of progression, is more likely to be associated with elevated 14-3-3 protein than the slowly progressive familial forms. It should also be noted that false positive and negative results occur with the 14-3-3 test. Also, as with EEG testing, an initially negative 14-3-3 may convert to a positive result upon repeated testing. Some reports suggest the test to be 95% specific and sensitive in a well-selected population of patients with a high suspicion of PrD (52,56,57), whereas others report much lower sensitivity and specificity (Table 2) (60–62). Conditions that result in a high false positive rate include herpes encephalitis and hypoxic brain damage due to stroke (56,63), although elevated levels of 14-3-3 have also been reported with Hashimoto’s encephalopathy (64), Alzheimer’s disease (62), and multiple sclerosis (65). It has been suggested that certain isoforms of 14-3-3, in particular the g-isoform, may be more specific for PrD (66). A more appropriate test would be the detection of PrPSc from CSF, however, attempts to isolate measurable quantities of protease-resistant PrPSc from the CSF of patients have been unsuccessful, although PrPC can be detected by Western blot (67). Intracerebral inoculation of CSF from patients with PrD to nonhuman primates has, however, successfully transmitted disease (68), indicating that prions are present but perhaps at levels too low to be detected by Western analysis. Methods to detect PrPSc by an ELISA-based system predicted to have higher sensitivity than Western, analysis, are currently under development. Familial CJD About one in every 8-10 CJD patients show an autosomal dominant pattern of inheritance due to a mutation of the PRNP gene. There are now over 25 mutations of the PRNP gene associated with PrD (Table 3 and Fig. 6). Most mutations are single base pair mismatches that induce a change in coding of a single amino acid in PrP but do not change the overall length of the protein, while a series of variable length insertions of the gene act to substantially increase the size of PrP, and two point mutations result in a foreshortened PrP, by the generation of a premature stop translation signal. Most familial forms of PrD are associated with a relatively younger age at onset compared with sCJD, with approximately 90% occurring under the age of 60 and the majority occurring under 50 years; a feature that helps to distinguish familial from sCJD, the latter presenting typically in the 60s and 70s. A further distinction is the protracted course of fCJD, which extends from about 1 to 3 years, compared with the typical 4-6-month duration of sCJD. This prolonged course contributes to the reduced recognition and frequent misdiagnosis of fCJD, as it may closely resemble AD or other slowly evolving dementia. It is, therefore, of critical importance to obtain a detailed family history as part of the evaluation of patients with suspected PrD. Since the onset of familial PrD occurs relatively early in life, there is likely to be evidence of other family members with a similar disease; however, because of inaccuracies in making the diagnosis, the family history may include a variety of neurological conditions, including Huntington’s disease (HD), amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease, among others. It is also important to determine if a parent died at a young age from an unrelated condition or accident,

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Table 2 Diagnostic Studies for Evaluation of PrD Subtypes Disease

EEG

Neuroimaging

CSF Studies

Biopsya

sCJD

~70% of cases have PSWCs

Non-specific atrophy T2 14-3-3 positive in most cases of highly hyperintensity of basal probable CJD, ganglia in some although not diagincreased signal in nostic on its own basal ganglia or cortex with DWI May need to repeat to increase sensitivity Mild, non-specific protein elevation common in all PrD

Frontal cortex shows spongiform change negative in tonsils and lymphoid organs

fCJD

Mutation-dependent: V2101, and E200K carriers, generally positive; most others, negative

Similar to sCJD, but may be mutation dependent

Less consistent results with fCJD, some positive, most not

Mutation-dependent, but most will have positive spongiform change by frontal cortex biopsy studies of lymphoid tissues lacking

iCJD

Slow waves

Insufficient data

Insufficient data

GSS

Typically, no PSWC’s

Non-specific?

14-3-3 typically negative

May show regional pathology, cerebellar or frontal plaque density

Insufficient data on DWI

–

FI

Slow waves

PET useful–thalamic hypometabolism

Insufficient data

Minimal bipathology at cortex, may therefore be unhelpful

vCJD

Slow waves

T2 hyperintensity of pulvinar and proton-weighted increased signal on DWI

!50% 14-3-3 positive

Tonsils, lymph nodes may contain proteaseresistant PrP cerebral cortex shows florid plaque pathology

a

Biopsy often reserved for younger patients and those with other findings consistent with PrD.

thereby masking the presence of a genetic disease in the family. There are several mutations of PRNP that are associated with the CJD phenotype (Table 2). Details of the specific clinical phenotypes of several of these mutations can be found elsewhere (69), although the E200K mutation will be discussed as an example of a point mutation, and the insertion/deletion mutations will be discussed as a group. fCJD (E200K) One of the first mutations of PRNP to be described, which is also the most commonly represented mutation of PRNP worldwide, is a coding change of glutamate (E) to lysine (K) at codon 200 (E200K) (70). Carriers of this mutation most commonly develop a CJD-like presentation of dementia, ataxia, myoclonus, and a periodic EEG. The pathology of the brain is also characteristic

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Table 3 Mutations and Polymorphisms of PRNP Codon affected Disease associated point mutations 102 105 117 131 145 160 178 180 183 187 198 200 208 210 211 217 232 Non-disease associated polymorphisms 23 129 171 188 219 Insertional mutations Octarepeatc

Amino acid change

Phenotype

Pro(P)/Leu(L) Pro(P)/Leu(L) Ala(A)/Val(V) Gly(G)/Val(V) Tys(Y)/Stop Gln(Q)/Stop Asp(D)/Asn(N) Val(V)/Ile(I) Thr(T)/Ala(A) His(H)/Arg(R) Phe(F)/Ser(S) Glu(E)/Lys(K) Arg(R)/His(H) Val(V)/Ile(I) Glu(E)/Gln(Q) Gln(Q)/Arg(R) Met(M)/Arg(R)

GSS GSS GSS GSS GSS GSS CJD or FIa CJD CJD/atypical CJD GSS CJD CJD CJD CJD GSS CJD/GSS

Pro(P)/Ser(S) Met(M)/Val(V) Asn(N)/Ser(S) Thr(T)/Arg(R) Glu(E)/Lys(K)

– Modifier Schizophrenia?b – Protective?

K1 C1 C2 C4 C5 C6 C7 C8 C9

Normal CJD CJD CJD CJD CJD CJD GSS/HD-liked GSS

a

FI is seen when codon 129 is Met, and fCJD occurs when 129 is Val. Polymorphism reported in normal controls and some patients with schizophrenia. c [Pro-(His/Gln)-Gly-Gly-Gly-(-/Gly)-Trp-Gly-Gln]!5. d Huntington’s disease-like phenotype. b

of typical CJD, with diffuse vacuolation (spongiosis) of the cerebral and cerebellar cortex and deep nuclei. This mutation is most prevalent in a population of Libyan Jews now living in Israel (71). Other clusters of the E200K mutation have also been recognized in Slovakia, Morocco, and Chile (72,73). While most mutations of PRNP result in disease onset before age 55, carriers of the E200K mutation show an age-dependent risk to disease, with 65% of carriers affected by age 55, and nearly 100% by age 90 (74,75). Because of the late onset of disease in some carriers, death may occur from diseases of older age prior to developing CJD, accounting for the “skipped generation” observed in some families.

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P23S

E219K

T188R

N171S

-1

1 1 2 4

2

3

-2

5 6

M232R Q217R

D178N

P102L P105L A117V G131V Y145(-)

V180I T183A H187R E211Q T188K Q160(-) F198S R208H

7

E200K

8 9

extra octarepeats

point mutations

[P(H/Q)GGG(-/G)TGQ]

Figure 6 Mutations and polymorphisms of PRNP. Three major types of mutations are known: insertions that increase the length of the protein, deletions or stop mutations that shorten or truncate the protein, and point mutations that change the sequence of amino acids but do not alter the length of the mature protein. A single deletion of one octarepeat (24 base pairs, 8 amino acids) is considered a nonpathogenic polymorphism, whereas the remaining polymorphisms (denoted at the top of the gene schematic) may influence the risk to disease or the ultimate phenotype; the Ml29V polymorphism is best characterized. Debate exists about the N171S polymorphism, which has been reported in normals and some members of a family with schizophrenia. The T188R is recently reported without clear distinction as to its role in disease, and the E219K has been proposed to be protective. Numbers indicate the amino acid mutated and letters indicate the change in coding (left side of number is original coding). Boxed mutations indicate those with true linkage to disease, defined by LOD scores greater than 3.0. In most others, the number of families is too low to attain linkage, but association with disease within families is 100%. Octarepeat insertions include 1-9, except three, inserts. Letter codes are the following: Abbreviations: A, alanine; D, aspartate; E, glutamate; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; Y, tyrosine; (-), stop signal.

Insertions and Deletions of PRNP Within the amino terminal end of PrP, from amino acid 51 to 91, there are five repeating stretches of eight amino acids each, known also as the octarepeat region. These repeats are rich in glycine, in contrast to the glutamate repeats of the trinucleotide diseases (Fig. 6). Insertions from 1 to 9 repeats are known, most of which are associated with a fCJD phenotype, with the exception of the longest inserts of 7, 8, and 9 repeats, which are associated primarily with GSS-like pathology (76–79), although exceptions have been noted (80). Unlike the trinucleotide repeat diseases, anticipation is not observed with these repeats and the insert length is unaffected during meosis (81). Longer insertions appear to be associated with an earlier onset (30s rather than 50s) and have a more protracted course of disease than short insertions (120 vs. 5 months) (82,83). The clinical phenotype of patients carrying an insertion of PRNP is quite variable, but commonly presents with atypical features such as dysphasia, apraxia, and a personality disorder, and eventual development of dementia. Cerebellar ataxia, pyramidal, and extrapyramidal features are also prevalent, while myoclonus is observed in roughly half of cases, and PSWCs on the EEG are present in less than 30%. In general, focal or diffuse spongiform change is present at autopsy, but the neuropathologic features

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are quite variable in that some families or members within a family have little or no spongiform pathology (76,77,84). One could speculate that the long insertions allow greater flexibility of PrP that may allow for the generation of multiple conformers of PrPSc, which ultimately lead to the development of different disease phenotypes. Laboratory Investigations for fCJD Diagnostic testing in fCJD is less helpful than in sCJD. The EEG is less likely to show periodic discharges, although this depends partly on the associated mutation. For instance, Lanska et al. (31) reported that nearly 100% of 29 carriers of the E200K mutation studied had an EEG with PSWCs, whereas those carrying the mutation at codon 178 have a much lower frequency. Imaging studies may also be similar to those observed with sCJD, yet positive findings may be less common. Scattered reports of CSF levels of 14-3-3 protein vary depending on the series and associated mutation (45,85–88) although, in general, it is less likely to be positive than in sCJD. It appears that mutations associated with a phenotype that more closely resembles the rapidly progressive sCJD, such as what is seen with the E200K and V210I mutations, are more likely to feature positive results from EEG, MRI, and the 14-3-3 tests. Genetic testing for these mutations could be used as supportive evidence for fCJD, although this service is not commercially available. Only a few centers in the country perform gene sequencing on a research basis. It is important, however, not to substitute genetic testing for a complete diagnostic evaluation, to avoid missing a potentially treatable disease. ¨ USSLER-SCHEINKER (GSS) SYNDROME GERSTMANN-STRA This subtype of PrD was initially described by Josef Gerstmann in 1928 (89) and later detailed in collaboration with Ernst Stra¨ussler and Isaak Scheinker in 1936 (90). GSS is an exclusively genetic form of PrD. Although one report suggested a sporadic form of GSS, this was later shown to be associated with a mutation of the PRNP gene (91,92). In fact, the analysis of families with GSS assisted in the initial linkage of PRNP to PrD (93,94). GSS typically begins in the 4-6th decade, heralded by the insidious onset of cerebellar ataxia, manifest typically as unsteady gait and mild dysarthria. Psychiatric or behavioral symptoms are atypical. Neurological examination may reveal signs of pyramidal and/or extrapyramidal involvement. Cognitive dysfunction is generally not apparent early on, which attests to the cerebellar focus of this disease, although with progression, bradyphrenia, or slowness of thought processing, may be evident. Over the next 3–5 years, the disease progresses at a relatively leisurely, but relentless pace. Cerebellar dysfunction produces severe dysarthria, gait and appendicular ataxia, ocular dysmetria, and eventual dyscoordination of swallowing. Extrapyramidal involvement is common also and include bradykinesia, increased muscle tone with or without cogwheeling, and masked facies, although a rest tremor is uncommon. With continued progression of disease, cognitive decline, particularly with respect to concentration and focus, may become evident. Compared with CJD, patients with GSS will be wheel chair bound sooner and show cognitive impairment later in the course of their disease. In the terminal stage of disease, the patient becomes bedridden from the disabling ataxia, is unable to swallow because of dyscoordination, and is unable to communicate because of the profound dysarthria, yet insight into his/her condition may persist. Ancillary studies are generally uninformative in GSS. The EEG may exhibit slow waves, but it does not demonstrate PSWCs. The number of studies regarding 14-3-3 protein in GSS are too few to report, but because of the slower rate of disease progression, it is likely that this test would not be helpful. In addition, brain imaging by MRI and especially DWI, has not been studied in detail. A definite diagnosis of GSS is made following pathologic review of the brain. The presence of plaque deposits to which anti-PrP antibodies are immunoreactive is the defining pathologic

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hallmark of GSS. In general, gliosis is associated with plaques, and spongiform change is minimal compared with CJD. The plaques are PAS positive and show birefringence under polarized light following Congo red staining. Multiple plaque types have been observed, although the most common is the multicentric plaque, which consists of a dense central amyloid core surrounded by smaller amyloid satellites (Fig. 7). In some varieties of GSS, plaques are confined primarily to the cerebellum, while in others both cerebrum and cerebellum are involved. The plaques are composed of amino and carboxy terminal truncated polypeptides spanning the region anywhere from amino acid 50 to w150 of the PrP holoprotein (95). The above description of GSS is most characteristic of the P102L mutation, which also happens to be the first PRNP mutation described (93), the most common GSS-related mutation worldwide, and the mutation carried by the family initially described by Gerstmann (96). With the development of a specific antibody to human PrP, identification of GSS plaques became easier, and in some cases, revealed that patients previously diagnosed at autopsy with AD, actually had GSS (97). The combination of antibody availability and identification of the PRNP gene led to the recognition of GSS-associated mutations with presentations less typical of the classic GSS description. Mutations that cosegregate with GSS (Table 1) include point mutations at codons 102, 105, 117, 145,160, 198, and 217, and insertions of 7-9 repeats within the octarepeat segment of PrP. The largest known GSS kindred carries a phenylalanine (F) to serine (S) mutation at amino acid 198 (98). The presentation in these patients is similar to that of the P102L mutation, and includes progressive ataxia, dysarthria, and mild short-term memory problems, often associated with extrapyramidal signs of bradykinesia and rigidity, and less often pyramidal tract signs. Ocular

Pathology

Spongiform change

Gliosis

PrP-amyloid plaques, multicentric type

Florid PrP plaque

Associated Diseases -extensive in all CJD-types -minimal in FI and FFI -minimal in GSS

-extensive in all CJD-types -focally, in thalamus and brainstem of FI and FFI -mostly adjacent to plaques in GSS

-GSS only

-vCJD only

Figure 7 Pathologic features observed in PrD. Spongiform change and gliosis are common to several forms of PrD, whereas amyloid plaques composed of PrP are deposited in specific patterns depending on the subtype of disease. The spongiform pathology and vCJD section are hematoxylin and eosin stains. Gliosis was detected by anti-GFAP stain, and GSS plaque was demonstrated with anti-PrP antibody. Source: Photomicrograph of vCJD kindly provided by Dr. J.W. Ironside, University of Edinburgh, U.K.

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findings include supranuclear gaze palsy, jerky pursuits, and gaze-evoked nystagmus in all directions. Myoclonus is variably present. Pathologically, GSS plaques are diffusely spread throughout the cerebellum and cerebrum. In addition, positive neurofibrillary tangles are found primarily in frontal, parahippocampal, and insular cortex, in addition to the cingulate gyrus (99). Interestingly, an asymptomatic carrier of this kindred died at 42 years of age from other causes, but was found on autopsy to have numerous PrP plaque deposits in cerebellar but not cerebral cortex, illustrating that this disease begins in the cerebellum, and pathology begins in advance of symptom onset. An interesting point mutation associated with GSS occurs at amino acid 145 of PrP. This mutation converts a tryrosine to a stop codon, thereby resulting in the expression of PrP truncated at amino acid 145 (100). The patient reported with this mutation had a 20-year course of memory problems, leading eventually to severe dementia and death at age 59. This patient was clinically diagnosed with Alzheimer’s disease prior to analysis of the PRNP gene. The pathology was consistent with GSS, although PrP deposits had an unusual distribution, in that they were concentrated in and around small and medium sized blood vessels, giving this disease the label of “vascular variant” (101). In addition, NFTs were evident throughout the cerebral cortex. Recently, a similar truncation mutation, with an early stop signal at 160 has been identified, the clinical features of which appeared consistent with Alzheimer’s disease (personal communication, Thomas Bird, University of Washington, Seattle). Other GSS mutations have been associated with the onset of spastic paraparesis (P105L) (102), dementia rather than ataxia as the primary feature (Al 17V) (103), and neurofibrillary tangles in addition to plaques, as in the F198S as in sally F198S and Q217R mutations (104). FATAL INSOMNIA (FI) Fatal insomnia (FI) was not initially considered to be a PrD. In fact, in the early descriptions of this disease, it was argued that the lack of spongiform pathology made it unlikely to be a PrD (105). Genetic analysis of families with FI, and those previously diagnosed with a disorder known as thalamic dementia were later found to carry a mutation of the PRNP gene that results in a change in coding from aspartate (D) to asparagine (N) at codon 178 (106–111). Interestingly, this mutation was not specifically associated with FFI, but rather fCJD with a somewhat variable phenotype. A specific genotype-phenotype correlation emerged when it was astutely observed that the polymorphic codon 129 on the same allele as the D178N mutation predicted whether the CJD or FI phenotype was present; VI29 was associated with the fCJD phenotype, while M129 was always present in FFI (112). Further, analysis of the pathogenic PrP (PrPSc ) by limited proteolysis and Western analysis of each disease indicated that the protein conformations also differ between these two diseases. There are now well over 20 kindreds identified throughout the world with FFI. FI is not, however, an exclusively familial disease; evidence for a sporadic form of FI was provided in 1999 with the recognition of a patient with the classic presentation of FI, characteristic pathology on autopsy, and transmission characteristics to susceptible transgenic mice, but no mutation of the PRNP gene (113). Additional examples of sporadic FI (sFI) followed (114), providing strong evidence for a nongenetic form of FI. Interestingly, although these patients were homozygous for Met at codon 129, the electrophoretic pattern of the protease-resistant PrP from each was comparable to that seen in FFI, suggesting that the conformation, rather than the sequence of PrP is the ultimate determinant of strain or phenotype of prion disease. The classic phenotype of FI is fairly stereotypical. Occurring in mid life is the insidious or subacute onset of insomnia, initially manifest as a mild, then more severe, reduction in overall sleep time. When sleep is achieved, vivid dreams are common. A disturbance in autonomic function then emerges, which may manifest as elevated blood pressure, episodic hyperventilation, excessive lacrimation, sexual and urinary tract dysfunction, and/or a change in basal body temperature. Signs of

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brainstem involvement, such as decreased upgaze, skew deviations, abnormal saccadic movements, or dysarthric speech, may also appear in some patients. With continued progression over the next few to several months, patients will develop truncal and/or appendicular ataxia. Mental status may show reduced speed of processing, as is commonly observed in subcortical dementing states, and variable degrees of memory impairment, but compared with other more prominent features of disease, cognitive capacity is relatively spared until late in the course. Advancing disease results in progressively greater loss of total sleep time, worsening ataxia, and more profound confusion, leading ultimately to an awake but stuporous state as death approaches. As with most forms of PrD, debilitation leading to feeding difficulties and loss of airway protection is the most common immediate cause of death. The typical duration of disease is 12–16 months. The presentation described above is striking and should be easily recognizable; however, since insomnia is common and FI is rare, it is not generally considered until obvious signs of brainstem involvement and/or ataxia develop. Further, the insomnia is not always obvious early in the disease, and may require overnight polysomnographic sleep studies to document a reduction in total sleep time. The insomnia that does develop is poorly responsive to hypnotics, although a temporary benefit may be realized before it soon becomes refractory to therapy. As with GSS, the EEG does not show PSWCs but may show diffuse slowing, and detection of the 14-3-3 protein in the CSF has not been thoroughly studied in this form of PrD. Anatomical imaging studies are generally unhelpful in the diagnosis of this PrD subtype, although PET typically shows a focal reduction in metabolic activity in the thalamus (Fig. 8). This finding may be detected early in the course and it correlates well with the underlying pathology, which is characterized by the presence of mild or absent spongiform change, but prominent neuronal dropout and astrocytic gliosis centered primarily within the thalamus and inferior olivary nucleus of the brainstem (105,115). The specificity of the pathology is remarkable in that gliosis and neuronal dropout is confined to the anteromedial and dorsolateral nuclei of the thalamus, in addition to the inferior olivary nucleus.

THE POLYMORPHIC CODON 129 In addition to autosomal dominant forms of familial PrD, polymorphisms of the PRNP gene also appear to play a role in directing the phenotype of several forms of PrD, and modifying the risk to

Figure 8 PET scan of FI compared with age-matched control. An early and consistent finding in FI is the reduced rate of fluorodeoxyglucose uptake within the thalami (arrows). The thalamus is the primary site of pathology in both familial and sporadic forms of FI.

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development of disease. The polymorphic codon at position 129 may be either ATG, which encodes methionine (Met) or GTG, which encodes valine (Val). In the general Caucasian population, the allelic frequency of Val is 0.34, while that of Met is 0.66, and the resulting genotype distribution is 37% Met/Met, 12% Val/Val, and 51% Met/Val. In contrast to the relatively equal proportion of heterozygous and homozygous genotypes in the normal population, several genetic surveys from the United Kingdom, France, Italy, and the United States, agree that from 80% to 90% of patients with sCJD carry the homozygous Met/Met or Val/Val state, suggesting that homozygosity is a risk factor for development of PrD (116,117). Homozygosity at codon 129 is also over-represented in patients who develop iCJD and vCJD. In fact, all vCJD cases thus far reported are homozygous for Met. In addition to disease risk, the genotype at 129 appears also to direct the phenotype of both sporadic and familial PrD. The best demonstration of the phenotypic influence of the polymorphic 129 amino acid is in the case of the dominant D178N mutation described in the section on FFI. In other cases of familial PrD, homozygosity may reduce the age at onset of disease and shorten the course of disease (98). In sCJD, the Met/Met genotype is more typically associated with a rapidly progressive dementia and cerebral spongiform pathology, while the Val/Val genotype is associated with hindbrain pathology and an ataxic onset. Interestingly, it was noted that gel electrophoresis of the protease-resistant PrPSc from Met/Met patients differed from Val/Val patients in that the former migrates slower through the gel than the latter. The slower migrating form is designated type 1 PrPSc and the faster, type 2. The majority of Met/Met cases carry type 1 PrPSc and the Val homozygotes carry type 2 PrPSc, while heterozygotes have a roughly equal split of type 1 and type 2. The classification of PrPSc types and their association to phenotype continue to evolve, and in the case of vCJD, issues and debates over differences in the glycosylation pattern of the protease-resistant fraction of PrPSc from these brains, adds new levels of complexity, and hopefully, improved understanding to this field. ACQUIRED PrD Acquired PrD results from the horizontal transmission of prions to humans. Kuru, which was propagated during cannibalistic rituals, is the quintessential example of acquired PrD. With the banning of cannibalistic practices, this disease has been largely eliminated, leaving two major forms of acquired PrD in humans; iatrogenic (i) CJD and new variant (v) CJD. Iatrogenic CJD, caused by the transmission of prions via contaminated biologicals, has been known for many years, and constituted the principle form of acquired PrD until recently, when vCJD, thought to originate from cattle affected by BSE, took the spotlight as a major threat for spreading CJD among humans. More recently, deer and elk have been detected with a naturally occurring PrD known as chronic wasting disease (CWD) that has raised concerns about a new threat to humans. Iatrogenic CJD The potential for transmission of CJD via contaminated biologicals or medical instruments was initially recognized in 1974 when a recipient of a corneal transplant developed CJD, the same disease diagnosed years earlier in the donor (118). Three years later, two patients who underwent stereotaxic localization of a seizure focus with a depth electrode that was used in a CJD patient 2 months earlier, developed CJD (119). Although the electrode was subjected to standard sterilization procedures, the conditions required for inactivation of prions are much more rigorous than those required for common bacterial and viral agents. Proof that the electrode was the source of infection came from the subsequent transmission of CJD to a chimpanzee following implantation of the electrode into its cerebral cortex (120). Since these initial cases of iCJD, several others have

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been reported, the most onerous of which was the contamination of human growth hormone (hGH) derived from cadaveric pituitaries used to treat children with hypopituitarism and related short stature. To date, more than 130 individuals from the United States, United Kingdom, France, South America, Australia, and New Zealand have developed CJD as a result of such injections (121–125). The children that received the greatest number of injections were at greatest risk for developing CJD (126). In contrast to sCJD, patients with iCJD due to contaminated hGH typically develop cerebellar ataxia, rather than memory problems as an early feature, and the EEG shows a diffuse slow wave pattern rather than PSWCs (127). With the introduction of recombinant hGH in 1985, the rate of hGH-related iCJD has declined precipitously. However, since an incubation period of up to 30 years is possible, an occasional patient may still be present. The second most common form of iCJD is that resulting from the use of contaminated dura mater grafts. More than 110 patients throughout the world developed iCJD after receiving dural tissue grafts originating from a single supplier in Germany whose preparative process was inadequate to eliminate prions from infected tissues (128–130). Iatrogenic CJD has also been attributed to contamination of neurosurgical instruments in five cases (131,132) and gonadotrophic hormone injections in four patients (133–135). vCJD In 1996, Will et al. (136) reported 10 cases of PrD with unique clinical and pathologic features that they labeled vCJD. The appearance of this new strain of PrD followed closely on the heels of an epidemic of BSE, commonly referred to as mad cow disease (137). Early speculation that vCJD was the result of BSE transmission to humans was met with resistance but eventually substantiated (138–140). Several lines of evidence now suggest that humans with vCJD were infected with BSE. The cause of the BSE epidemic appeared to result from a change in the rendering practice as a costcutting measure, which likely reduced the clearance of prions from offal produced from cows afflicted with the disease. When this was used in meat and bone meal (MBM) preparations that were fed to cattle, in effect as a form of cow cannibalism, the disease was spread at an alarming rate. In a move to eliminate BSE from the United Kingdom, the Ministry of Agriculture Fisheries and Food (MAFF) ordered the slaughter of 2 million cattle and banned the feeding to cattle of cattlederived MBM. Several features distinguish vCJD from other forms of PrD. First and foremost is the population at risk. For unclear reasons, but probably related in part to the time of exposure and host susceptibility to disease, vCJD predominantly affects teens and young adults, with an average age at onset of 29 years (range of 18-53 years) (141). It should be noted, however, that a 74-year-old man was diagnosed with vCJD, raising questions about the true extent of this disease. Second, the onset of symptoms in vCJD is commonly psychiatric or behavioral (especially depression and apathy) and, in many cases, a persistent painful sensory syndrome, rather than confusion and memory impairment. These early features may persist for several weeks or months until ataxia and then dementia emerge as prominent features. Third, the pathology of vCJD is distinct and characterized by the presence of diffusely distributed florid plaques; defined as large PrP-amyloid deposits, circumscribed by extensive vacuolation. With respect to the diagnostic work-up, the EEG is generally not periodic and the 14-3-3 test is positive in less than 50% of cases (143,144), making these studies even less useful than in sCJD. The MRI, on the other hand, appears to have some utility in the diagnosis of this form of PrD; T2 and proton-weighted images typically show hyperintensity of the pulvinar division of the thalamus (145). This contrasts with the caudate and basal ganglia signal hypersensitivity observed in sCJD. At the time of writing, well over 140 individuals from the United Kingdom, two from France, and one from Ireland have been diagnosed with vCJD. No cases have yet been

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diagnosed in the United States, with the exception of a woman in Florida who was born and raised in the United Kingdom. While the connection of vCJD to BSE is clear, the mechanism of exposure is less clear. The time of exposure is not known, although the period of greatest risk to exposure was between 1989 and 1994, at the height of the BSE epidemic. Although the period of exposure may be estimated, history tells us that CJD can be delayed by up to 30 years following exposure, as was demonstrated with hGH-related iCJD. Because of this, it appears that we are not yet able to determine if the incidence of vCJD has peaked or it is still the beginning of a potential epidemic. Are those who have been affected by vCJD the most susceptible of the population, or the ones who received the greatest exposure? These questions are currently unanswered. In response to the BSE threat, surveillance centers in the United Kingdom have been established to better monitor the disease, and in the United States, the CDC has begun to establish voluntary reporting of PrD. BSE had not been detected in the United States, until December 2003, when a single cow in the state of Washington was detected with the disease. The cow was traced back to Canada, where BSE had been previously reported. This sentinel cow triggered a change in the standards by which cows are screened for BSE and allowed to enter the food supply. DIFFERENTIAL DIAGNOSIS It should be clear that PrD may take on several forms and presentations, some of which may still be undiscovered. Because of this, and the fact that dementia, psychiatric symptoms, and a movement disorder may occur alone or in combination, several neurodegenerative and infectious diseases should be considered at the time of presentation. These include, but are not limited to Alzheimer’s disease, dementia with Lewy bodies (DLB), FTD, and spinocerebellar ataxia (SCA). Herpes and other viral encephalitides, in addition to bacterial causes, should also be considered, although rarely does PrD present with the abrupt onset seen in these conditions. In some patients, a stroke-like onset has been reported, but appropriate imaging studies should help to rule out a vascular etiology. A variety of other potentially treatable diseases need to be considered, including autoimmune diseases such as Hashimoto’s thyroiditis and related encephalopathy, limbic encephalitis, and CNS or systemic vasculitides. A cerebellar paraneoplastic syndrome due to antibody secretion of antiPurkinje cell antibodies (anti-Yo antibodies) from an occult lung tumor should be ruled out. The ataxia of GSS may be mistaken for multiple sclerosis or SCA, especially since this disease may affect younger patients. Toxin-related causes should be considered in the differential diagnosis, especially bismuth and lithium toxicity, both of which can induce mental status changes and cerebellar ataxia, in addition to producing an EEG that mimics the PSWCs observed in CJD. Overall, the diagnostic work-up for PrD is one of exclusion of other potentially treatable diseases. A systematic approach will generally include MRI, lumbar puncture, EEG, metabolic studies, a careful search for more common bacterial or viral pathogens, inflammatory and autoimmune panels, possibly an angiogram, and heavy metal studies.

THERAPY FOR PrD Currently, there exists no treatment for prion-related diseases; management is largely symptomatic. Seizures can be treated with general anticonvulsants (diphenylhydantoin, carbamazepine), whereas myoclonus may be treated with more selective agents (clonazepam). Psychiatric symptoms are best controlled with atypical antipsychotics (risperidal, olanzepine, quietipine, etc.), although these and other behavior-modifying agents may be minimally effective. At the time of this writing, there is an active and aggressive search underway for effective therapeutic agents. A variety of substances, including amphotericin B (146–148), dapsone (149,150),

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pentosan polysulfate (142,151–153), cyclic tetrapyrroles (154), Congo red (155–157), anti-PrP antibodies (158), quinacrine, and chlorpromazine (159,160) have shown some effect. The mechanisms by which these agents inhibit prions are quite varied and not well defined, although theories include blocking the misfolding of PrPC to PrPSc, inhibiting or disassembling PrP amyloid, sequestering PrPC away from PrPSc, or perhaps by affecting the degradation of one or both isoforms. While many of these substances have shown promise in the inhibition of prion generation in cell culture assay systems or cell free systems, their efficacy in treating or inhibiting the onset of PrD in experimental animal models has been modest and is best demonstrated when the agent is administered just prior to inoculating the animal with prions. This feature speaks to the predicted difficulty of treatment of these diseases once symptoms have started. As such, those at risk, especially carriers of a PRNP mutation, would benefit most from a therapy that could be administered prophylactically far in advance of symptom onset (142). This finding also emphasizes the need to develop a sensitive assay with which to test patients who are potentially “incubating” prions prior to manifestation of symptoms.

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42. Na DL, Suh CK, Choi SH, et al. Diffusion-weighted magnetic resonance imaging in probable Creutzfeldt-Jakob disease: a clinical-anatomic correlation. Arch Neurol 1999; 56:951–957. 43. Tribl GG, Strasser G, Zeitlhofer J, et al. Sequential MRI in a case of Creutzfeldt-Jakob disease. Neuroradiology 2002; 44:223–226. 44. Mittal S, Farmer P, Kalina P, Kingsley PB, Halperin J. Correlation of diffusion-weighted magnetic resonance imaging with neuropathology in Creutzfeldt-Jakob disease. Arch Neurol 2002; 59:128–134. 45. Huang N, Marie SK, Kok F, Nitrini R. Familial Creutzfeldt-Jakob disease associated with a point mutation at codon 210 of the prion protein gene. Arq Neuropsiquiatr 2001; 59:932–935. 46. Nitrini R, Mendonca RA, Huang N, LeBlanc A, Livramento JA, Marie SK. Diffusion-weighted MRI in two cases of familial Creutzfeldt-Jakob disease. J Neurol Sci 2001; 184:163–167. 47. Rabinstein AA, Whiteman ML, Shebert RT. Abnormal diffusion-weighted magnetic resonance imaging in Creutzfeldt-Jakob disease following corneal transplantations. Arch Neurol 2002; 59:637–639. 48. Matsuda M, Tabata K, Hattori T, Miki J, Ikeda S. Brain SPECT with 123I-IMP for the early diagnosis of Creutzfeldt-Jakob disease. J Neurol Sci 2001; 183:5–12. 49. Watanabe N, Seto H, Shimizu M, et al. Brain SPECT of Creutzfeldt-Jakob disease. Clin Nucl Med 1996; 21:236–241. 50. Kirk A, Ang LC. Unilateral Creutzfeldt-Jakob disease presenting as rapidly progressive aphasia. Can J Neurol Sci 1994; 21:350–352. 51. Mathews D, Unwin DH. Quantitative cerebral blood flow imaging in a patient with the Heidenhain variant of Creutzfeldt-Jakob disease. Clin Nucl Med 2001; 26:770–773. 52. Beaudry P, Cohen P, Brandel JP, et al. 14-3-3 Protein, neuron-specific enolase, and S-100 protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Dement Geriatr Cogn Disord 1999; 10:40–46. 53. Otto M, Wiltfang J, Schutz E, et al. Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: prospective case-control study. BMJ 1998; 316:577–582. 54. Jimi T, Wakayama Y, Shibuya S, et al. High levels of nervous system-specific proteins in cerebrospinal fluid in patients with early stage Creutzfeldt-Jakob disease. Clin Chim Acta 1992; 211:37–46. 55. Kropp S, Zerr I, Schulz-Schaeffer WJ, et al. Increase of neuron-specific enolase in patients with Creutzfeldt-Jakob disease. Neurosc Lett 1999; 261:124–126. 56. Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med 1996; 335:924–930. 57. Zerr I, Bodemer M, Gefeller O, et al. Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Ann Neurol 1998; 43:32–40. 58. Aitken A, Collinge DB, van Heusden BP, et al. 14-3-3 Proteins: a highly conserved, widespread family of eukaryotic proteins. Trends Biochem Sci 1992; 17:498–501. 59. Aitken A, Jones D, Soneji Y, Howell S. 14-3-3 Proteins: biological function and domain structure. Biochem Soc Trans 1995; 23:605–611. 60. Chapman T, McKeel DW, Morris JC. Misleading results with the 14-3-3 assay for the diagnosis of Creutzfeldt-Jakob disease. Neurology 2000; 55:1396–1397. 61. Satoh J, Kurohara K, Yukitake M, Kuroda Y. The 14-3-3 protein detectable in the cerebrospinal fluid of patients with prion-unrelated neurological diseases is expressed constitutively in neurons and glial cells in culture. Eur Neurol 1999; 41:216–225. 62. Tschampa HJ, Neumann M, Zerr I, et al. Patients with Alzheimer’s disease and dementia with Lewy bodies mistaken for Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 2001; 71:33–39. 63. Lee KH, Harrington MG. Premortem diagnosis of Creutzfeldt-Jakob disease by cerebrospinal fluid analysis. Lancet 1996; 348:887. 64. Hernandez-Echebarria H, Saiz A, Grauss F, et al. Detection of 14-3-3 protein in the CSF of a patient with Hashimoto’s encephalopathy. Neurology 2000; 54:1539–1540. 65. Martinez-Yelamos A, Saiz A, Sanchez-Valle R, et al. 14-3-3 Protein in the CSF as prognostic marker in early multiple sclero-sis. Neurology 2001; 57:722–724. 66. Takahashi H, Iwata T, Kitagawa Y, et al. Increased levels of epsilon and gamma isoforms of 14-3-3 proteins in cerebrospinal fluid in patients with Creutzfeldt-Jakob diseasev. Clin Diagn Lab Immunol 1999; 6:983–985.

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16 Normal Pressure Hydrocephalus Thomas A. Krefft Mayo Clinic Jacksonville, Jacksonville, Florida, U.S.A.

Neill R. Graff-Radford Mayo College of Medicine, Jacksonville, Florida, U.S.A.

INTRODUCTION Normal pressure hydrocephalus (NPH), also termed symptomatic hydrocephalus, may cause dementia in up to 6% of patients (2) and thus not infrequently enters the differential diagnosis of dementia. The diagnosis and treatment of NPH are problematic. The cardinal symptoms (gait difficulty, cognitive decline, and incontinence of urine) are not pathognomonic for the diagnosis, commonly occur in the elderly (3–5), and may be caused by multiple disease processes. Cerebral ventricle size increases with age (6) and in common dementing illnesses such as Alzheimer’s disease (AD) (7), so that ventriculomegaly is frequent in an older population. Current diagnostic tests for NPH give both false positive and false negative results. Its surgical treatment carries important short and long term risks. Finally, the cause or pathogenesis of many NPH cases is unknown. This chapter will address the reasons why the diagnosis is difficult as well as the differential diagnosis, features of the history, examination, and neuropsychological assessment in NPH that may help clinicians with management. It also will discuss the radiological evaluation, including computed tomography (CT), magnetic resonance imaging (MRI), cisternography and single photon emission tomography (SPET), and special testing including lumbar puncture (LP), continuous cerebrospinal fluid (CSF) drainage, CSF absorption tests, and CSF pressure monitoring. The chapter also will address how to measure surgical outcome, surgical complications, and choice of shunt. Lastly, it will discuss associations with idiopathic NPH that might have bearing on the etiology. This chapter thus presents a practical approach to the management of these patients.

This chapter is based in part on: Graff-Radford, N.R., Symptomatic or normal pressure hydrocephalus in the elderly. In, Behavioral Neurology and Neuropsychology, Eds., TE Feinberg and MJ Farah, McGraw Hill, New York, New York 1997; 627–637, and on Normal Pressure Hydrocephalus, The Neurologist 12(1): 57–58.

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DIFFERENTIAL DIAGNOSIS, HISTORY, CLINICAL EXAMINATION AND NEUROPSYCHOLOGICAL EVALUATION Differential Diagnosis The differential diagnosis of NPH is noted in Table 1. Note the first three diagnoses may overlap. Clinical Evaluation General Factors The clinician should evaluate the patient’s general medical health. Factors that theoretically could aggravate hydrocephalus include systemic hypertension (association with hydrocephalus) and recent head injury (particularly pertinent in individuals with gait difficulty). Also the clinician should evaluate for sleep apnea, congestive heart failure, and lung disease, all of which could increase jugular venous pressure and decrease CSF flow into the cerebral venous sinuses. If the patient is on long-term anticoagulants, such as coumadin for atrial fibrillation, take into account the increased risk of brain hemorrhage during and after surgery. History Several specific questions should be asked when taking a history from patients and their families. Ask how long the patient has been demented. If dementia has been evident for more than two years, it is unlikely that the patient will respond to shunting (8,9). In our series, the response to this question predicted 5/7 unimproved and 21/23 improved patients (Table 2) (9). Ask which started first, gait abnormality or dementia. If the gait abnormality began before or at the same time as dementia, then there is a better chance for successful surgery. If dementia started before gait abnormality, shunting is less likely to help. In our series this question predicted 3/7 unimproved and 23/23 improved patients (Table 2) (9). This observation also has been reported by Fisher (10). Alcohol abuse is a poor prognostic indicator (11). Table 1 Differential Diagnosis of NPH Alzheimer’s disease with extrapyramidal features Cognitive impairment in the setting of Parkinson’s disease or parkinsonian syndromes; e.g., progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration Dementia with Lewy bodies Frontotemporal dementia, which may have extrapyramidal symptoms; the scan may show caudate atrophy Cervical spondylosis with cord compromise in the setting of degenerative dementia Phenothiazine use Multiple sensory deprivation syndrome (such as a diabetic with peripheral neuropathy and visual impairment) Vascular dementia, including the controversial entity subcortical ischemic encephalo pathy (Binswanger’s disease) Combination diseases such as: Alzheimer’s disease, cervical spondylosis, and prostatism or stress incontinence Alzheimer’s disease, spinal stenosis, arthritis of the hips or knees, and prostatism or stress incontinence Source: From Ref. 1.

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Table 2 Variables Predicting Surgical Outcome in Symptomatic Hydrocephalus Correct classification Variable Demographic (nZ30) Age Education Gender Clinical (nZ30) Gait abnormality (years) Incontinence (years) Dementia (years) Order of onset (gait vs. dementia) Neuropsychological (nZ25) Visual naming test Visual naming, pass/fail Radiologic (nZ30) Cerebral blood flow (anterior/posterior ratio, slice 4) CSF pressure (nZ28) % time B waves present % time pressure O15 mmHg % time pressure O20 mmHg CSF conductance (nZ23) CSF conductance CSF conductance, 0.08 as cutoff value

Unimproved

Improved

Regression analysis Odds ratio

P valuea

95% CIb

1.031 0.906 4.615

0.59 0.41 0.215c

0.919–1.157 0.716–1.146 0.423–233.0

0.51 0.402 !0.001 0.009c

0.789–1.626 0.614–3.408 1.542–52.56 0–0.425

0.093 0.058c

0.875–1.013 0.887–113.3

5/7 3/7

21/23 23/23

1.133 1.441 9.002 0

2/7 5/7

17/18 14/18

0.941 8.750

5/7

22/23

1.120

!0.001

1.026–1.224

2/6 0/6

22/22 22/22

0.969 0.968

0.04 0.055

0.937–1.001 0.930–1.006

0.979

0.23

0.940–1.020

0.254 1.071

0.956 1.00c

0–infinity 0.065–67.354

a

P value based on likelihood ratio test. 95% confidence interval for odds ratio, based on Wald test (which is slightly different from likelihood ratio test) or on Fisher’s exact test (when this test was used). c P value based on Fisher’s exact test. Source: From Ref. 9. b

Ask if there are secondary causes for hydrocephalus such as subarachnoid hemorrhage, meningitis, previous brain surgery, and head injury. If any of these are present, the chances of improvement with surgery are better (8,11,12). Determine whether the patient has a large head size (e.g., needing a large hat) as a potential indicator of congenital hydrocephalus that has become symptomatic in later life (Fig. 1) (13). Examination On examination, the following issues should be addressed. Measure the head circumference. If greater than 59 cm in males or 57.5 cm in females (i.e., greater than the 98th percentile for head circumference) the patient could have congenital hydrocephalus (13).

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Figure 1 MRI of a patient with congenital hydrocephalus showing ventriculomegaly without periventricular high signal on axial T2-weighted images. An Arnold-Chiari type I abnormality is present on the midsagittal cut (T1-weighted) with protrusion of the cerebellar tonsils through the foramen magnum. Source: From Ref. 13.

Look for signs of diseases that may mimic NPH. Especially consider those affecting gait and cognition, such as AD with extrapyramidal features, Parkinson’s disease or Parkinsonian syndromes, Dementia with Lewy Bodies, Frontotemporal Dementia, phenothiazine use, and multiple subcortical infarctions. Also look for cervical spondylosis with spinal cord compression; arthritis of the hips, knees or lumbar spine; and multiple sensory deprivation (as might occur in diabetics with peripheral neuropathy and visual impairment). Neuropsychology Look for evidence of aphasia. If there is evidence of aphasia (e.g., anomia) this is a poor prognostic indicator for surgical success (Table 2) (9,11).

RADIOLOGICAL EVALUATION Computed Tomography (CT) The documentation of ventriculomegaly has become easier since the advent of CT. A patient has ventriculomegaly (above the 95th percentile) when the modified Evan’s ratio (maximum width of the frontal horns / measure of the inner table at the same place) is greater than 0.31 (14). The ventricles normally enlarge with age (6); there is slow ventricular enlargement before age 60 years and then the rate of enlargement increases. In Barron’s study (6), the mean ventricular size was 5.2% (percent of intracranial area) in the decade 50 to 59 years, 6.4% 60 to 69 years, 11.5% 70 to 79 years and 14.1% 80 to 89 years. If a patient has hydrocephalus without sulcal enlargement, this is a favorable surgical prognostic factor. Patients might still improve with surgery, however, even if there is sulcal

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enlargement and hydrocephalus. Borgesen and Gjerris (15) measured the largest sulcus in the high frontal or parietal region and found that if the cortical sulci were less than 1.9 mm, 17 of 17 patients shunted improved, if the sulci were 1.9 to 5 mm, 17 of 20 shunted improved and if the sulci were 5 mm or more, 15 of 27 shunted improved. Magnetic Resonance Imaging (MRI) Detecting Congenital Hydrocephalus MRI is an excellent method for evaluating patients with possible symptomatic hydrocephalus and is the neuroimaging study of choice in NPH patients. It has the advantage of being able to visualize relevant structures in the posterior fossa including cerebral aqueduct stenosis, cerebellar tonsil herniation and infarctions in the brain stem. Further, MRI can be used to obtain volumetric measures of medial temporal lobe structures, a technique that has been shown to be useful in separating Alzheimer disease patients from normal elderly controls (16). Up to 10% of elderly patients with symptomatic hydrocephalus may have congenital hydrocephalus that only becomes symptomatic in later years (13). A clinical clue to this possibility is a head circumference above the 98th percentile. On MRI, the ventricular enlargement shows no or little associated periventricular increased signal on T2-weighted imaging, indicating a chronic process. In addition, a cause for the congenital hydrocephalus may be found, such as an Arnold Chiari malformation. White Matter Lesions and NPH Some report that the presence of transependymal flow may be related to a good surgical prognosis. In Borgesen and Gjerris’s study (15), 16 of 16 with periventricular hypodensity on CT improved with surgery. In Bradley and colleagues study (17), the MR images were rated for deep white matter changes and the presence or extent of these did not correlate with outcome. In 1996, Krauss and colleagues reported that the degree of improvement after shunt surgery depended on the extent and severity of white matter lesions (18), such that the more extensive the white matter lesions, the less the improvement. In a subsequent report (19) they compared MRI findings in NPH to an age matched control group and found that the periventricular white matter lesions (PVLs) correlated with deep white matter lesions (DWMLs) in both groups. In the control group, the white matter lesions correlated significantly with age and the anterior horn index (frontal horn width divided by the horizontal intracranial width). In contrast, in the NPH group, there was no correlation of white matter lesions with age. There was a significant negative correlation between the white matter lesions and the frontal horn index, i.e., the wider the frontal horns the less white matter lesions present. They argued that the white matter lesions did not cause the hydrocephalus but that the common link between the frequent coexistence of idiopathic NPH and vascular encephalopathy (as evidenced by white matter lesions) was arterial hypertension. See below for further discussion on the association of systemic hypertension and NPH. In a post-mortem MRI study of autopsied brains and the histological analysis of the same brains, Munoz et al. (20) found the white matter changes seen on MRI correlated with decreased density of axons and myelinated fibers, diffuse vacuolation of white matter (spongiosis), and decreased density of glia. Infarctions were not common in these areas. While this study does not necessarily apply to the white matter changes seen in hydrocephalic patients, it indicates that white matter MRI findings do not necessarily indicate irreversible periventricular infarctions. MRI Differentiation of NPH and AD Traditionally the presence of ventriculomegaly without sulcal enlargement has been a radiological finding believed to indicate NPH when accompanied by the classic clinical triad of symptoms. However Holodny (21) and Kitagaki (22) have pointed out the occasional occurrence of focally

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dilated sulci over the convexity or medial surface of a hemisphere in NPH patients, unlike the diffuse sulcal enlargement seen in AD. Kitagaki also demonstrated greater sylvian CSF volume in idiopathic NPH compared with AD patients, supporting the notion that NPH indicates a “suprasylvian block.” Another area where MRI has the potential to be helpful prognostically is in volumetric measurements of certain structures in the temporal lobe. There is enlargement of the temporal horns of the lateral ventricles in both NPH and AD patients. Jack and colleagues (16) developed a technique for measuring the volumes of structures in the anterior temporal lobe and hippocampal formation. Holodny (23) measured the CSF volumes of the perihippocampal fissures (PHF), the lateral aspect of the transverse fissure of Bichat, and the choroidal and hippocampal fissures. He showed that the PHFs were significantly enlarged in AD patients compared to NPH patients. This was detectable both by visible inspection and computer volumetrics. MR-based volumetric measurements of the hippocampal formation have been shown to be useful in discriminating between AD and normal elderly controls (16). Though Golomb (24) found smaller hippocampal volumes in NPH patients compared to controls, Savolainen (25) only found a minor left side decrease. However, Savolainen importantly detected significantly larger hippocampi in NPH patients compared to AD patients. Flow Void on MRI as a Predictive Test of Surgical Outcome In 1991, Bradley and coworkers (17) retrospectively reviewed the MRI scans of 20 patients who had undergone ventriculoperitoneal shunt surgery for NPH. They rated initial surgical outcome as excellent, good or poor, and correlated this with the extent of flow void in the cerebral aqueduct. They found a significant correlation (P!0.003) between extent of increased aqueduct flow void and initial surgical outcome. More specifically, 8 out of 10 with an increased CSF flow void score had an excellent or good response to surgery, whereas only 1 out of 9 who had a normal flow void score improved with surgery. In a subsequent study of 18 NPH patients, Bradley and colleagues (26) studied the CSF stroke volume (see his article for methods) and the CSF flow void score. The 12 patients with a CSF stroke volume of 42mL all improved, but of those patients with a CSF stroke volume of less than 42mL, 3 improved and 3 did not. Using the flow void score, 4 of 15 improved patients had false negative tests and 1 of 3 unimproved patients had a false positive test. Krauss and colleagues report that the flow void in the cerebral aqueduct of 37 idiopathic NPH patients was not different from that in 37 age-matched controls (27). Further, the extent of the flow void extension into the 3rd, 4th and lateral ventricles did not correlate with the amount of improvement in these patients, but rather correlated with the width of the ventricles. Unfortunately, this study does not confirm earlier reports that measures of CSF flow through the cerebral aqueduct can be used to predict surgical outcome. Hakim and Black (28), in a small study of 12 patients of whom 10 improved, found that the MRI-CSF flow studies were correct in 6 patients but 5 had false negatives and 1 patient had a false positive, casting doubt on this diagnostic test. Summary of Factors to be Addressed when Looking at the CT or MRI Hydrocephalus must be present. The modified Evan’s ratio should be greater than 0.31 (14). Is cortical atrophy prominent? If there is extensive cortical atrophy, this reduces but does not eliminate the chance of improvement with surgery (8,15). The pattern of atrophy may be useful diagnostically (e.g., does it involve the medial temporal lobes as seen in AD?). Although data on this point are lacking, it may be that prominent medial temporal cortical atrophy decreases the chances for surgical improvement because these patients may have AD (16,29).

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Is there evidence of congenital hydrocephalus? For example, is there aqueductal stenosis or an Arnold Chiari Malformation (13,30)? Newer MRI techniques, such as Cine-MRI involving the analysis of a CSF flow void in the aqueduct of Sylvius were first thought to be helpful (17,26), but unfortunately have not been confirmed in subsequent studies (27,28). Regional Cerebral Blood Flow (rCBF) It has been reported that rCBF is decreased in the frontal areas in hydrocephalus (31), and in the parietotemporal areas in AD (32). On the presumption that many of the non-improved group have Alzheimer’s disease, which we confirmed in two such patients who came to autopsy and Bech and colleagues have shown more recently (29), we tried to differentiate those who will respond to shunt surgery from those who will not based on the pattern of preoperative CBF (33). To do this, we calculated the ratio of frontal over posterior regional blood flow expecting a lower frontal-posterior ratio in true symptomatic hydrocephalus and a higher ratio in pseudo-symptomatic hydrocephalus patients who have AD. This has been a good method in predicting surgical outcome: the ratio predicted 5/7 unimproved and 22/23 improved patients in our series (Table 2) (9). Cisternography Our experience with cisternography is limited but the literature reports numerous cases with a positive test (radioisotope seen within the ventricles 48–72 hours after being injected in the lumber area) who do not improve with surgery and patients with equivocal or negative tests who do improve. Further, the test itself may be difficult to interpret. Black et al. (34), in a review of their experience with this test, found the following: of 11 patients who had a positive test, 9 improved and 2 did not; of 6 patients who had mixed results, 3 improved and 3 did not; of 6 who had negative results, 4 improved and 2 did not. They suggest a positive test is helpful but an equivocal or negative test is not. A more recent study by Vanneste et al. (35) reported that “cisternography did not improve the accuracy of combined clinical and computerized tomography in patients with presumed normal-pressure hydrocephalus.” SPECIAL TESTING CSF Drainage Procedures If the patient’s gait improves after removing a large quantity of CSF by LP (removal of 30 to 35 cc; can be repeated daily), this person is a good candidate for shunt surgery (36,37). A modification of this technique, continuous CSF drainage via a catheter placed in the lumbar CSF space has been reported (38,39). Krauss and colleagues (40) reported their experience removing CSF directly from the ventricles. They removed 15–18 ml at once from 20 patients and 24 ml over 6 hours from 4 more patients. There were no complications. The 6 who showed a significant improvement with removal of the CSF and subsequently underwent shunt surgery had an excellent response to surgery. However, the 6 who had a moderate response to ventricular CSF removal had a more variable outcome. There are shortcomings to these diagnostic tests. Patients who eventually responded to shunt surgery may have no obvious improvement for the first post- surgical week. The drainage test could give a falsely negative result in these patients. When doing the CSF drainage test, the patient may improve for the duration of the test (the placebo effect) but not maintain their response, leading to a false positive result. In addition, meningitis and subdural hematoma are remote but possible complications of the continuous CSF drainage procedures.

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If either one of the LP CSF drainage tests is strongly positive, this is a useful prognostic indicator. If there is a mild response or the test is negative, one cannot accurately predict surgical outcome. CSF Infusion Tests Borgesen and Gjerris (15,41) described the CSF conductance test, in which CSF absorption is measured at different CSF pressures. They reported a greater than 90% accuracy in predicting shortterm prognosis following shunt surgery and about an 85% accuracy in predicting long-term prognosis. The concept is that the greater the pressure needed to obtain an amount of absorption, the better the chances of that patient improving with shunt surgery. Absorption is calculated by infusing fluid through an LP needle for a given time (5 minutes) while catching the overflow from a ventricular catheter. There is some evidence to show that the amount of CSF produced does not vary much at different CSF pressures and is about 0.4cc/min. Because how much is infused through the LP needle and how much overflows through the ventricular catheter are known, the amount absorbed in this time period can be calculated. The following equation gives absorption: Absorption Z Infused ðmeasuredÞ C Produced ðassumedÞKOverflow ðmeasuredÞ The overflow pressure for the ventricular catheter is then raised and absorption calculated at this new pressure (Fig. 2). Between 6 and 8 absorptions at different pressures are obtained in this way to plot absorption against pressure and calculate the slope of the line, i.e., absorption / pressure. The slope of this line is called the conductance (Fig. 3). Borgesen and Gjerris reported that a conductance of !0.08 predicted a favorable outcome. The inverse of the conductance gives the Resistance to Outflow (Rcsf). A conductance of 0.08ZRcsf of 12.5 mmHg/ml/min. Boon and colleagues (42) reported the first multiple center randomized study evaluating the predictive value of measuring Rcsf of the cerebrospinal fluid for shunt surgery. They enrolled 101 patients and measured the Rcsf of CSF by infusing saline through a 19 gauge LP needle at 1.4 to 1.6 ml/min until a stable pressure plateau was reached or the pressure exceeded 50 mmHg. The Rcsf was calculated as the difference between the plateau and the baseline pressure divided by the infusion rate. They randomized the patients to receive either low or medium pressure valves. Outcome measures were an NPH scale (sum of gait and dementia measures) and the modified Rankin scale (43). Follow-up was at 1, 3, 6, 9, and 12 months. Intention to treat analysis was performed on all 101 patients and 57% showed improvement in the NPH scale and 59% in the modified Rankin scale at 1 year. When all known serious events unrelated to NPH that clearly interfered with neurological function were excluded, 95 patients were left. In these patients, 76% had a meaningful improvement on the NPH scale and 69% improved one grade on the modified Rankin scale. Using a cutoff of the resistance to CSF outflow of !18 mmHg/ml/min, 20/59 had no improvement on the NPH scale. Above this cutoff, 3/36 had no improvement on the NPH scale. The authors concluded that the Rcsf obtained by lumbar CSF infusion is a reliable method for selecting patients for shunt surgery if the Rcsf cutoff is 18 mmHg/ml/min or greater. Patients with an Rcsf less than 18 mmHg/ml/min should only undergo shunt placement when characteristic clinical features of NPH are present. Unfortunately, the majority of patients (O60%) under consideration for shunt surgery have a Rcsf of less than 18 mmHg/ml/min and this diagnostic test is not helpful in this group. CSF Pressure Monitoring There have been reports of a relationship between measures of intracranial CSF pressure monitoring and surgical outcome for symptomatic hydrocephalus, e.g., in Borgesen and Gjerris

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Figure 2 Position in which CSF conductance test is performed. A ventricular catheter is in place at the same time a lumbar puncture needle is inserted. When the CSF pressure is steady at the ventricular overflow pressure, fluid is infused through the LP needle at a given rate for 5 minutes and the overflow from the ventricular catheter is collected and measured. Absorption at that overflow pressure is calculated by the equation: AbsorptionZ InfusionCProduction (which is known)—Overflow. The test is repeated at the same overflow pressure and then the overflow spout is raised to a new pressure and the test repeated. At least six measurements are made.

Figure 3 For each measurement taken, the absorption in ml/min is plotted against the pressure in mmHg.

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study (15) and in our study (9). The greater the percentage of time B waves were present, the greater the chance of a good outcome (Table 2). Krauss and colleagues (44) have pointed out that there is a relationship of the quantity and type of B waves to the stage of sleep. Investigators should take into account the sleep stages when calculating the amount of time B waves are present on the recording. Also, in our series, the longer the pressure was more than 15 mmHg, the better the chance of successful surgery (Table 2). This implies that increased pressure may be pathogenic in symptomatic hydrocephalus. These data raise the issue about what is meant by NPH. Does it mean normal pressure at one spinal tap or does it imply the pressure remains normal all the time? We do not know what is normal for 24-hour CSF pressure recordings. It follows that we do not know if the pressure is normal or abnormal in those who respond to surgery but have CSF pressures greater than 15mmHg for a percentage of time. For this reason, at present, we prefer the term symptomatic hydrocephalus to NPH. ASSESSMENT FOR PATIENT IMPROVEMENT Traditionally, patient improvement has been assessed on a five point rating scale (15,45). This may be problematic because levels on the scale overlap, and it is a subjective judgment into which level the patient falls. We have tried to develop more objective measures and use the following: 1. Serial videotaping of the patient’s gait (9,46) 2. Katz Index of Activities of Daily Living (47) This scale rates the patient on six items: bathing, dressing, toileting, transferring, continence, and feeding. The worst score for each item is 3 and the best is 1. Thus the worst obtainable score is 18 and the best is 6. There is a written description for each score of each item. We regard a change of 2 or more in this index as significant. This allows measurements of small but functionally important changes. An example of a two point improvement on this index might be as follows: a change from “occasional urinary accidents” to “controls urination and bowel movements completely by self” (one point improvement) plus “moves in and out of bed or chair with assistance” to “moves in and out of bed as well as chair without assistance” (one point improvement). 3. Neuropsychological testing Our patients receive a battery of neuropsychological tests pre- and 2 and 6 months postoperatively (9). These tests sample orientation, intelligence, verbal and visual memory, language, visuospatial functioning and executive control. We judge the patient neuropsychologically improved when there has been a significant increase in the test scores in two or more neuropsychological areas evaluated, provided there is no decline in another area. Only about 50% of those responding to shunt surgery improve cognitively by the above criteria. Other investigators have developed equally acceptable methods of evaluating surgical outcome objectively (18,42,48).

SHUNT COMPLICATIONS Shunt complications, both major and minor, occur in 30% to 40% of patients (8,45). These include intraoperative complications related to general anesthesia, intracranial hemorrhage from ventricular catheter placement, intra-abdominal injury (rare), and arrhythmias from incorrect ventriculoatrial distal catheter placement. Perioperative complications include infection (3–8% of cases), CSF

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hypotensive headaches, and the development of subdural effusions or hematoma. The latter problem is more likely to occur in those with marked reduction in ventricular size post shunting and is more common when low-pressure valves are utilized for treatment. Depending on symptoms, conservative or surgical therapy may be indicated. Long-term complications are primarily related to shunt occlusion or catheter breakage. Infection after the first 2 months is unusual. WHICH SHUNT TO RECOMMEND The first randomized prospective study of NPH was completed in the Netherlands (48). One of the questions addressed by this study was to compare the outcome after placement of low- or mediumpressure shunt valves in NPH patients. Improvement was noted in 74% (marked to excellent in 45%) with low-pressure valves, whereas 53% (marked to excellent in 28%) improved with medium-pressure valves. The difference in improvement between the two groups approached significance (pZ0.06). Reduction in ventricular size was greater in the low-pressure valve group (pZ0.009). However, subdural effusions occurred in 71% of the low-pressure group and in 34% of the medium-pressure group; most were transient but 32% were not. These authors advised the use of the low-pressure valve. The dual-switch valve (49) has two parallel valve chambers in one device. One is blocked by a heavy tantalum ball in the upright position, avoiding over-drainage and the complication of slit ventricle syndrome (more common in children) and subdural hematomata (more common in adults). Yamashita et al. (50) reported their experience with the Codman-Hakim programmable valve. This valve can have its opening pressure changed non-invasively with an externally applied programmer. The programmer transmits codified magnetic impulses. The opening pressure can be set from 30 mm H2O to 180 mm H2O in 18 steps. Settings can be verified with x-ray. There were no postoperative complications in their 85 NPH patients (20 were idiopathic). About 40% of the secondary NPH patients and 60% of the idiopathic NPH patients required reprogramming. In their total group of 168 patients reprogramming was performed in 87 (50.6%) and symptoms or radiological findings (ventricular size) improved in 81 (93.1%). Because the valve is poorly resistant to magnetic fields, it is necessary to confirm opening pressure after every MR imaging procedure. Mitchell (51) obtained improvement in 3 of 4 NPH patients after performing third ventriculostomy. Interestingly this occurred despite pre- and post-operative ventricular pressure recordings that suggested the absence of improvement in ventricular pressures. He suggested third ventriculostomy relieves pulsatile tissue stress (from the waterhammer effect) by reducing the systolic transaqueductal pressure gradient.

ASSOCIATIONS OF IDIOPATHIC NPH WITH IMPLICATIONS RELATED TO ETIOLOGY Histopathology of Idiopathic NPH In a unique study, Bech and colleagues (29) reported their experience with 38 consecutive patients with idiopathic NPH. They monitored and performed absorption tests and performed brain biopsies on all. Twenty-nine of 38 patients fulfilled hydrodynamic criteria for shunt surgery (Rcsf of 10 Hg/ml/min with or without B activity for more than 50% of the monitoring period). Of 29 individuals shunted, 27 had follow up and of these 9 (33.3%) improved, 10 (37%) remained stable and 8 (29.6%) deteriorated. These results are not necessarily representative of all series in which idiopathic NPH patients undergo shunt surgery. In our series, for example, more than 70% improved (9) and in the series of Boon and colleagues (48) 53% of the medium pressure valve group

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Table 3 Biopsy Findings in 37 Consecutive Patients with Idiopathic NPH Arachnoid fibrosis Normal parenchyma Alzheimer’s disease Arteriosclerosis Subrecent ischemic encephalomalacia Alzheimer’s disease and arteriosclerosis Alzheimer’s disease and encephalitis Encephalitis Nonspecific cortical degeneration Cerebral hemorrhage, sequelae

12 of 25 (not all biopsies had arachnoid tissue) 17 8 4 4 1 1 1 1 1

Source: From Ref. 29.

and 74% of the low-pressure valve group improved. Nonetheless, the biopsy findings are of great interest and are shown in Table 3. There was no association of the presence or absence of arachnoid fibrosis with the hydrodynamic measures. The Bech study has important implications. Ten of 38 patients who were thought clinically possible to have NPH had biopsy verified AD. The criteria used to diagnose AD were conservative, that is, 10 neuritic plaques per high power field in the frontal lobe. It is possible that at autopsy several additional patients may have had AD. In a follow-up paper (52) Bech found no correlation between clinical outcome after shunting NPH patients and the presence or absence of AD pathology. He also found that vascular disease and arachnoid fibrosis did not correlate with outcome. Golomb (53) found AD pathology in 23 of 56 (41%) biopsied NPH patients. The NPH patients with concomitant AD had more impairment of gait and cognition than the “pure” NPH patients. Only 18% of the patients with Global Deterioration Scores (GDS) of 3 and below had AD positive biopsies, whereas 75% of those with GDS 6 or above were AD positive. There was comparable improvement in gait velocity in NPH patients regardless of the presence of AD pathology. No consistent cognitive improvement occurred in either group after shunting. Savolainen (54) found concomitant AD pathology by biopsy in 31% of 51 consecutive NPH patients. Three studies (52–54) show that AD pathology is frequent in patients diagnosed with idiopathic NPH. Further, some of the patients have gait improvement after shunting. The implication is that NPH and AD may occur simultaneously in the same patient. Future studies should investigate if CSF markers, such as the amyloid b protein 1–42 (55,56) and tau protein (55,56), may be helpful in these cases.

The Relationship of Idiopathic NPH and Systemic Hypertension Several lines of evidence in the literature now point to a relationship between hydrocephalus and systemic hypertension. Clinical and Autopsy Studies of NPH Patients A number of postmortem examinations of NPH patients and case control studies have reported the association of systemic hypertension and NPH (57–61). In our own series (46) a higher prevalence of systemic hypertension was found in idiopathic NPH patients compared with matched, demented controls and to the published prevalence of hypertension in the US

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population, matched for age. A more recent, larger case control study (62) of 65 idiopathic NPH patients versus 70 matched control patients found a prevalence of 83% of systemic hypertension in the NPH patients compared to 36% in the control group (p!0.001). Boon (63) showed that cerebrovascular risk factors (hypertension, diabetes mellitus, cardiac disease, peripheral vascular disease, male gender, and advancing age) did not influence outcome after shunt placement. However the presence of cerebrovascular disease (history of stroke, cerebral infarction noted on, C.T., or moderate-to-severe white matter hypodense lesions on CT) was an important predictor of poor outcome. Nonetheless, although 74% of those without concomitant cerebrovascular disease improved with shunting, 49% with it also improved. In fact, four of the seven patients with the most severe white matter hypodense lesions responded favorably to shunting. There are more questions than answers regarding the relationship between hypertension, Subcortical Arteriosclerotic Encephalopathy (SAE), and NPH. Are hypertension, white matter changes, and cerebrovascular disease merely frequent concomitants of NPH? Do NPH and SAE represent a spectrum [as suggested by Gallassi (64)]? Is one causative of the other? Hydrocephalus Following Subarachnoid Hemorrhage Another line of evidence showing that systemic hypertension and hydrocephalus may be related comes from the Cooperative Aneurysm Study (65). In over 3000 patients with subarachnoid hemorrhage, it was found that a preoperative history of hypertension, the admission blood pressure measurement, and sustained hypertension during hospitalization after surgery, all were highly related to patients developing hydrocephalus. Hypertension in Patients with Aqueductal Stenosis Greitz et al. (66) found a high prevalence of systemic hypertension in patients with hydrocephalus from aqueductal stenosis. Hydrocephalus in the Spontaneously Hypertensive Rat The association of hypertension and hydrocephalus are corroborated by reports in the animal literature. Ritter and Dinh (67) showed that the spontaneously hypertensive rat develops hydrocephalus. Experimental Models of Hydrocephalus, Ventricular Pulse Pressure and Systemic Hypertension Portnoy et al. (68) showed, in dogs, that infusing dopamine and norepinephrine led to increased systemic blood pressure, which, in turn, resulted in an increased CSF pressure and pulse pressure. Experimentally creating an increased CSF pulse pressure with an inflatable balloon in the lateral ventricle of sheep leads to hydrocephalus within hours (68). Bering and Salibi (69) performed seminal work on hydrocephalus in dogs. They tied off the jugular veins in the dogs and also measured the intraventricular pulse pressure. They concluded that the mechanism involved in the ventricular enlargement seemed to be a combination of at least two factors: “One was the possible failure of CSF absorption in the face of increased superior sagittal sinus venous pressure and the other the increased intraventricular pulse pressure from the choroid plexus.” Thus, a body of information is accumulating that systemic hypertension and hydrocephalus are associated. It remains to be shown whether hypertension causes hydrocephalus or hydrocephalus causes hypertension, or both.

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Table 4 Prognostic Factors in Deciding on Shunt Surgery Factors favoring clinical improvement in NPH after shunting Secondary NPH Gait disturbance preceding cognitive impairment Mild impairment in cognition Short duration of cognitive impairment Clinical improvement (usually in gait) following lumbar puncture or continuous lumbar CSF drainage Resistance to CSF outflow of 18 mm Hg/ml/min or greater during continuous lumbar CSF infusion test Presence of B-waves for 50% of the time or greater during continuous lumbar CSF monitoring Factors weighing against clinical improvement after shunting Moderate or severe cognitive impairment Cognitive impairment preceding gait disturbance Presence of aphasia History of ethanol abuse MRI with significant white matter involvement or diffuse cerebral atrophy Factors of unproven significance Long duration of gait disturbance Absence of aqueductal flow void despite patent aqueduct (on MRI) No clinical improvement after lumbar puncture Cisternography CBF measurements

CONCLUSION When confronted with a patient with possible NPH, the following systematic approach is useful. Keeping in mind the differential diagnosis, look for pertinent factors in the history and examination and neuropsychological evaluation that have a bearing on diagnosis and surgical prognosis. On the MRI, look at the amount and pattern of atrophy and white matter changes. Perform between one and three large volume removal spinal taps, and evaluate the effect on gait. If findings are consistent with NPH, you may wish to advise about shunt surgery. The patient and family must be aware of both the possible benefits and the risks of the surgery (Table 4). If they choose surgery, follow the patient carefully to see if there is improvement and to detect possible surgical complications. If you are uncertain whether the patient should undergo surgery or the family and patient decide against surgery, establish a baseline from which you can follow the patient. Ideally, this includes a video of their gait, a brain MRI and neuropsychological testing. Follow the patient at three-month intervals with serial videotaping of gait. Stability or deterioration of the gait often helps both the family and doctor determine further action.

REFERENCES 1. Graff-Radford NR. Normal pressure hydrocephalus. Neurologist 1999; 5:194–204. 2. Wells CE. Diagnosis of dementia. Psychosomatics 1979; 29:517–522. 3. Sudarsky L, Ronthal M. Gait disorders among elderly patients: a survey of 50 patients. Arch Neurol 1983; 40:740–743. 4. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA 1989; 262:2551–2556.

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5. Yarnell J, Leger A. The prevalence, severity and factors associated with urinary incontinence in a random sample of the elderly. Age Ageing 1979; 8:81–85. 6. Barron S, Jacobs L, Kinkel W. Changes in size of the normal lateral ventricles during aging determined by computerized tomography. Neurology 1976; 26:183–192. 7. Damasio H, Eslinger P, Damasio A. Quantitative computed tomographic analysis in the diagnosis of dementia. Arch Neurol 1983; 40:715–719. 8. Petersen RC, Mokri B, Laws ER, Jr. Surgical treatment of idiopathic hydrocephalus in elderly patients. Neurology 1985; 35:307–311. 9. Graff-Radford NR, Godersky JC, Jones MP. Variables predicting surgical outcome in symptomatic hydrocephalus in the elderly. Neurology 1989; 39:1601–1604. 10. Fisher CM. The clinical picture in occult hydrocephalus. Clin Neurosurg 1977; 24:270–284. 11. De Mol J. Prognostic factors for therapeutic outcome in normal pressure hydrocephalus. Review of the literature and personal study. Acta Neurol Belg 1985; 85:13–29. 12. Black PM, Ojemann RG, Tzouras A. CSF shunts for dementia, incontinence, and gait disturbance. Clin Neurosurg 1985; 32:632–651. 13. Graff-Radford NR, Godersky JC. Symptomatic congenital hydrocephalus in the elderly simulating normal pressure hydrocephalus. Neurology 1989; 39:1596–1600. 14. Gyldenstad C. Measurements of the normal ventricular system and hemispheric sulci of 100 adults with computerized tomography. Neuroradiology 1977; 14:183–192. 15. Borgesen S, Gjerris S. The predictive value of conductance to outflow of CSF in normal pressure hydrocephalus. Brain 1982; 105:65–86. 16. Jack CR, Petersen RC, O’Brien PC, Tangalos EG. MR-based hippocampal volume in the diagnosis of Alzheimer’s disease. Neurology 1992; 42:183–188. 17. Bradley WG, Jr., Whittemore A, Kortman K, et al. Marked cerebrospinal fluid void: indicator of successful shunt in patients with suspected normal pressure hydrocephalus. Radiology 1991; 178:459–466. 18. Krauss JK, Droste DW, Vach W, et al. Cerebrospinal fluid shunting in idiopathic normal pressure hydrocephalus of the elderly: effect of periventricular and deep white matter lesions. Neurosurgery 1996; 39:292–299 discussion 299–300. 19. Krauss JK, Regel JP, Vach W, et al. White matter lesions in patients with idiopathic normal pressure hydrocephalus and in an age-matched control group: a comparative study. Neurosurgery 1997; 40:491–495 discussion 495–496. 20. Munoz DG, Hasak SM, Harper B, Lee D, Hachinski VC. Pathological correlates of increased signals of the centrum ovale on magnetic resonance imaging. Arch Neurol 1993; 50:492–497. 21. Holodny AI, George AE, de Leon MJ, Golomb J, Kalnin AJ, Cooper PR. Focal dilation and paradoxical collapse of cortical fissures and sulci in patients with normal pressure hydrocephalus. J Neurosurg 1998; 89:742–747. 22. Kitagaki H, Mori E, Ishii K, Yamaji S, Hirono N, Imamura T. CSF spaces in idiopathic normal pressure hydrocephalus: morphology and volumetry. Am J Neuroradiol 1998; 19:1277–1284. 23. Holodny AI, Waxman R, George AE, Rusinek H, Kalnin AJ, de Leon M. MR differential diagnosis of normal pressure hydrocephalus and Alzheimer’s disease: significance of perihippocampal fissures. Am J Neuroradiol 1998; 19:813–819. 24. Golomb J, de Leon MJ, George AE, et al. Hippocampal atrophy correlates with severe cognitive impairment in elderly patients with suspected normal pressure hydrocephalus. J Neurol, Neurosurg Psychiatry 1994; 57:590–593. 25. Savolainen S, Laakso MP, Paljarvi L, et al. MR imaging of the hippocampus in normal pressure hydrocephalus: correlations with cortical Alzheimer’s disease confirmed by pathologic analysis. Am J Neuroradiol 2000; 21:409–414. 26. Bradley WG, Jr., Scalzo D, Queralt J, Nitz WN, Atkinson DJ, Wong P. Normal pressure hydrocephalus: evaluation with cerebrospinal fluid flow measurements at MR imaging. Radiology 1996; 198:523–529. 27. Krauss JK, Regel JP, Vach W, Jungling FD, Droste DW, Wakhloo AK. Flow void of cerebrospinal fluid in idiopathic normal pressure hydrocephalus of the elderly: can it predict outcome after shunting? Neurosurgery 1997; 40:67–73 discussion 73–74.

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28. Hakim R, Black PM. Correlation between lumbo-ventricular perfusion and MRI-CSF flow studies in idiopathic normal pressure hydrocephalus. Surg Neurol 1998; 49:14–19 discussion 19–20. 29. Bech RA, Juhler M, Waldemar G, Klinken L, Gjerris F. Frontal brain and leptomeningeal biopsy specimens correlated with cerebrospinal fluid outflow resistance and B-wave activity in patients suspected of normal pressure hydrocephalus. Neurosurgery 1997; 40:497–502. 30. McHugh P. Occult hydrocephalus. QJM 1964; 130:297–308. 31. Jagust W, Friedland R, Budinger T. Positron emission tomography with (18F)-fluodeoxyglucose differentiates normal pressure hydrocephalus from Alzheimer’s dementia. J Neurol Neurosurg Psychiatry 1985; 48:1091–1096. 32. Foster NL, Chase TN, Fedio P, Patronas NJ, Brooks RA, Di Chiro G. Alzheimer’s disease: focal cortical changes shown by positron emission tomography. Neurology 1983; 33:961–965. 33. Graff-Radford NR, Rezai K, Godersky JC, Eslinger P, Damasio H, Kirchner PT. Regional cerebral blood flow in normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 1987; 50:1589–1596. 34. Black PM. Normal pressure hydrocephalus: current understanding of diagnostic tests and shunting. Postgrad Med 1982; 71:57–61 also see pp. 65–67. 35. Vanneste J, Augustijn P, Dirven C, Tan WF, Goedhart ZD. Shunting normal pressure hydrocephalus (1982) do the benefits outweigh the risks? A multicenter study and literature review Neurology 1992; 42:54–59. 36. Wikkelso C, Andersson H, Blomstrand C, Lindqvist G. The clinical effect of lumbar puncture in normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 1982; 45:64–69. 37. Wikkelso C, Andersson H, Blomstrand C, Lindqvist G, Svendsen P. Normal pressure hydrocephalus. Predictive value of the cerebrospinal fluid tap-test. Acta Neurol Scand 1986; 73:566–573. 38. Hanley D, Borel C, Hedeman S. Normal pressure hydrocephalus. In: Johnson R, ed. Current Therapy in Neurological Diseases. Philadelphia: Dekker, 1990:305–309. 39. Haan J, Thomeer RT. Predictive value of temporary external lumbar drainage in normal pressure hydrocephalus. Neurosurgery 1988; 22:388–391. 40. Krauss JK, Regel JP. The predictive value of ventricular CSF removal in normal pressure hydrocephalus. Neurol Res 1997; 19:357–360. 41. Borgesen SE. Conductance to outflow of CSF in normal pressure hydrocephalus. Acta Neurochir 1984; 71:1–45. 42. Boon AJW, Tans JTJ, Delwel EJ, et al. Dutch Normal Pressure Hydrocephalus Study: Prediction of outcome after shunting by resistance to outflow of cerebrospinal fluid. J Neurosurg 1997; 87:687–693. 43. Van Swietan JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. “Interobserver agreement for the assessment of handicap in stroke patients”. Stroke 1988; 19:604–607. 44. Krauss JK, Droste DW, Bohus M, et al. The relation of intracranial pressure B-waves to different sleep stages in patients with suspected normal pressure hydrocephalus. Acta Neurochir 1995; 136:195–203. 45. Black PM. Idiopathic normal pressure hydrocephalus. Results of shunting in 62 patients. J Neurosurg 1980; 52:371–377. 46. Graff-Radford NR, Godersky JC. Idiopathic normal pressure hydrocephalus and systemic hypertension. Neurology 1987; 37:868–871. 47. Kane RA, Kane RL. Assessing the Elderly. Lexington MA: Lexington Books, 1981. 48. Boon AJ, Tans JT, Delwel EJ, et al. Dutch Normal Pressure Hydrocephalus Study: randomized comparison of low- and medium-pressure shunts. J Neurosurg 1998; 88:490–495. 49. Sprung C, Miethke C, Shaken K, Lanksch WR. The importance of the dual-switch valve for the treatment of adult normotensive or hypertensive hydrocephalus. Eur J Pediatr Surg 1997; 7:38–40. 50. Yamashita N, Kamiya K, Yamada K. Experience with a programmable valve shunt system. J Neurosurg 1999; 91:26–31. 51. Mitchell P, Mathew B. Third ventriculostomy in normal pressure hydrocephalus. Br J Neurosurg 1999; 13:382–385. 52. Bech RA, Waldemar G, Gjerris F, Klinken L, Juhler M. Shunting effects in patients with idiopathic normal pressure hydrocephalus; correlation with cerebral and leptomeningeal biopsy findings. Acta Neurochir 1999; 141:633–639. 53. Golomb J, Wisoff J, Miller DC, et al. Alzheimer’s disease comorbidity in normal pressure hydrocephalus: prevalence and shunt response. J Neurol Neurosurg Psychiatry 2000; 68:778–781.

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54. Savolainen S, Paljarvi L, Vapalahti M. Prevalence of Alzheimer’s disease in patients investigated for presumed normal pressure hydrocephalus: a clinical and neuropathological study. Acta Neurochir 1999; 141:849–853. 55. Arai H, Clark CM, Ewbank DC, et al. Cerebrospinal fluid Tau protein as a potential diagnostic marker in Alzheimer’s disease. Neurobiol Aging 1998; 19:125–126. 56. Galasko D, Chang L, Motter R, et al. High cerebrospinal tau and low amyloid beta 42 levels in the clinical diagnosis of Alzheimer’s disease and relation to Apolipoprotein E genotype. Arch Neurol 1998; 55:937–945. 57. Koto A, Rosenberg G, Zingesser LH, Horoupian D, Katzman R. Syndrome of normal pressure hydrocephalus: possible relation to hypertensive and arteriosclerotic vasculopathy. J Neurol Neurosurg Psychiatry 1977; 40:73–79. 58. Earnest MP, Fahn S, Karp JH, Rowland RP. Normal pressure hydrocephalus and hypertensive cerebrovascular disease. Arch Neurol 1974; 31:262–266. 59. Haidri N, Modri S. Normal pressure hydrocephalus and hypertensive cerebrovascular disease. Dis Nerv Syst 1977; 38:918–921. 60. Shukla D, Singh B, Strobos R. Hypertensive cerebrovascular disease and normal pressure hydrocephalus. Neurology 1980; 30:998–1000. 61. Casmiro M, D’Alessandro R, Cacciatore FM, Daidone R, Calbucci F, Lugaresi E. Risk factors for the syndrome of ventricular enlargement with gait apraxia (idiopathic normal pressure hydrocephalus): a case-control study. J Neurol Neurosurg Psychiatry 1989; 52:847–852. 62. Krauss JK, Regel JP, Vach W, Droste DW, Borremans JJ, Mergner T. Vascular risk factors and arteriosclerotic disease in idiopathic normal pressure hydrocephalus of the elderly. Stroke 1996; 27:24–29. 63. Boon AJ, Tans JT, Delwel EJ, et al. Dutch Normal Pressure Hydrocephalus Study: the role of cerebrovascular disease. J Neurosurg 1999; 90:221–226. 64. Gallassi R, Morreale A, Montagna P, Sacquegna T, Di Sarro R, Lugaresi E. Binswanger’s disease and normal pressure hydrocephalus. Clinical and neuropsychological comparison. Arch Neurol 1991; 48:1156–1159. 65. Graff-Radford NR, Torner J, Adams HP, Kassell NF. Factors associated with hydrocephalus after subarachnoid hemorrhage: a report of the Cooperative Aneurysm Study. Arch Neurol 1989; 46:744–752. 66. Greitz T, Levander B, Lopez J. High blood pressure and epilepsy in hydrocephalus due to stenosis of the aqueduct of Sylvius. Acta Neurochir (Wien) 1971; 24:201–206. 67. Ritter S, Dinh T. Progressive postnatal dilation of brain ventricules in spontaneously hypertensive rats. Brain Res 1986; 370:327–332. 68. Portnoy H, Chopp M, Branch C. Hydraulic model of myogenic autoregulation and the cerebrovascular bed: the effects of altering systemic blood pressure. Neurosurgery 1986; 13:482–498. 69. Bering RJ, Salibi B. Production of hydrocephalus by increased cephalic-venous pressure. Arch Neurol Psychiatry 1959; 81:693–698.

17 HIV-Associated Dementia David B. Clifford and Mary Gould Washington University School of Medicine, St. Louis, Missouri, U.S.A.

HUMAN IMMUNODEFICIENCY VIRUS (HIV)/ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) Recognition of the global epidemic now known as HIV/AIDS began in 1981 with the report of five cases of Pneumocystis carinii pneumonia (PCP) in young, previously healthy men living in California (1). At that time a rare infection, PCP occurred only in the setting of underlying immune deficiency. This event, and subsequent reports of sudden increases in the incidence of other opportunistic conditions, such as Kaposi’s sarcoma, fungal infections, and mycobacterial infections, touched off a scientific inquiry that led to the identification in 1983 of the HIV-1 virus. The virus was found to be a retrovirus, characterized by transcription of the RNA genome into DNA in host cells. It is a member of the subgroup of lentiviruses, so named because of their generally indolent course of infection (2). Pathogenic features of lentiviruses include specificity for cells of the immune system (for HIV, CD4 lymphocytes and monocytes), a prolonged asymptomatic period, and neurological damage. In these respects, HIV-1 bears similarities to other lentiviruses, including visna (which causes a demyelinating encephalomyelitis in sheep), simian immunodeficiency virus (which causes a condition similar to AIDS in monkeys), caprine arthritis encephalitis virus, and feline immunodeficiency virus (3). An aspect of the HIV virus that has proven to have major implications in defining approaches to treatment is its rapid and persistent rate of replication (4). It has a half-life of only a few days in the plasma compartment; thus, a high viral load correlates with a synthesis rate estimated at 109 to 1010 virions/day. In addition, a high mutation rate allows rapid changes in the genetics of the virus even in the same individual over time. Given a high turnover rate and high mutation rate, the HIV virus can generate resistant strains quickly and efficiently.

EPIDEMIOLOGY OF HIV/AIDS The World Health Organization estimates that, as of the end of 2001, 40 million people were living with HIV worldwide (5). Now in its twentieth year, the epidemic has reached all parts of the world and disproportionately affects developing countries. HIV/AIDS is the leading cause 321

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of death in sub-Saharan Africa, where approximately 28 million people are infected. Moreover, young adults, and particularly women, are especially vulnerable to acquiring the infection. The economic impact of the disease has created a cycle of poverty, with decreases in life expectancy, loss of human infrastructure in health and education, and the devastation of family institutions. Although tragic, the epidemic presents challenges and opportunities for medical researchers to gain insights into human pathobiology that may help to develop treatments for other diseases as well. It has expanded scientific knowledge not only of infectious diseases, but also of oncology, immunology, nephrology, gastroenterology, ophthalmology, metabolism, and neurology. HIV-1 is transmitted by person-to-person blood and body fluid transfer, most commonly during sexual intercourse, blood transfusion, from mother to child by way of fetal transmission or breast milk, and through contaminated needles. While the epidemic began in the United States with a cohort of males who had histories of homosexual contact, globally the infection is spread predominantly through heterosexual contact and use of contaminated needles. As a result, the demographics of the disease are shifting toward a younger population, with a heavy impact on women and children. Thus, the medical challenges of treatment are entwined with the social and economic challenges of health care delivery and lifestyle changes. NATURAL HISTORY OF HIV Following infection with the virus, most hosts experience an acute retroviral syndrome, characterized by fever, myalgia, headache, and sometimes a rash. At this time, the CD4 lymphocyte count falls precipitously and plasma viremia levels are high. As host immune response develops, serologic tests for HIV become positive, and plasma viral load declines to a “set point,” where it remains for a variable length of time. At this time, the strength of the host’s immune response determines the course of untreated infection. In a host with a strong immune response, viral load falls to a low level, and clinical progression is very slow, leading to more than a decade of asymptomatic infection in some “non-progressors.” Less complete control of infection results in higher viral loads and more rapid onset of clinical symptoms associated with increasing immunodeficiency. Determining clinical state and prognosis has been refined by the monitoring of plasma CD4 cell counts and HIV RNA viral loads. The CD4 lymphocyte count declines over time in the setting of infection and is a useful marker of immunosuppression. Late-stage disease is characterized by a CD4 cell count below 200/mm3, at which point opportunistic infections develop and clinical symptoms, such as weight loss, diarrhea, and fever, occur. At this point, those conditions defined by the Centers for Disease Control and Prevention as AIDS indicators typically begin to occur (6). PCP, toxoplasma encephalitis (TE), progressive multifocal leukoencephalopathy (PML), and HIV-associated dementia (HAD) are among these complications of advanced HIV infection or “AIDS.” NATURAL HISTORY AND CLASSIFICATION OF HIV-ASSOCIATED DEMENTIA HIV-1 is known to enter the central nervous system early in the course of infection (7). In some individuals, CNS infection is manifested by an early meningitis (“aseptic” meningitis) that clears with development of the immune response. However, most complications of the nervous system do not appear until advanced stages of infection, when immunodeficiency has developed. The spectrum of HIV-related neurological disease includes both opportunistic complications, or secondary conditions, as well as primary HIV-associated neurological conditions. Of the former, the most prominent are cryptococcal meningitis, TE, cytomegalovirus (CMV) encephalitis and radiculomyelitis, PML, neurosyphilis, and primary central nervous system lymphoma (PCNSL). Neurological complications associated with primary HIV infection include peripheral neuropathy,

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myelopathy, and encephalopathy. The encephalopathy characterized early in the epidemic (8) has historically been termed AIDS dementia complex (ADC). It was first described as progressive cognitive impairment that evolved over a period of months and was accompanied by motor and behavioral disturbances. ADC includes a range of motor-cognitive disorders, from early insidious symptoms, which in some patients has an indolent course, to severe dementia, accompanied by mutism, incontinence, or paraplegia. Over time, as treatments have evolved and survival has been extended, this broad definition has been refined to recognize and stage the various manifestations of neurocognitive deficits (9). HAD is the most recent term for the severe, disabling condition that occurs late in HIV disease in the setting of immunodeficiency. It is synonymous with ADC, HIV dementia, and HIV encephalopathy. These clinical terms should be distinguished from HIV encephalitis, which is used to characterize pathologic changes in the brain. Milder clinical presentations of cognitive and motor impairment are termed HIV-associated Minor Cognitive Motor Disorder (MCMD). The most widely used classification scheme uses the criteria developed by the American Academy of Neurology (AAN) (10). This diagnostic tool integrates cognitive symptoms, performance on neuropsychological tests, and impact on day-to-day functioning. Under this scheme, an operational definition of HAD would include abnormalities in at least two cognitive domains (attention/speed of information processing, motor skills, learning, memory, and abstraction) present for at least one month and interfering markedly with work or day-to-day activities. It also requires the presence of motor and/or behavioral dysfunction and absence of other medical or psychiatric etiologies. A diagnosis of MCMD would include abnormal performance 1.0 standard deviation below age and education matched controls on two of a series of standardized neuropsychological tests and only mild interference with daily activities. The use of these definitions has assisted in establishing reliability across studies and among clinicians. EPIDEMIOLOGY OF HIV-ASSOCIATED DEMENTIA Early estimates of HAD ranged widely, from 7 to 66 percent (9). In a 1986 study of 70 autopsied AIDS patients (11), 46 were found to have progressive dementia. Other findings have been considerably lower (12). Over the past decade since the development of potent anti-retroviral therapy, there appears to have been a drastic decline in the frequency of dementia to approximately 7 percent in the advanced stages of HIV infection, and this has been stable for a few years. McArthur and Grant hypothesize that this stability reflects the “competing forces” of widespread anti-retroviral use, decreasing the occurrence of HAD, and increased survival during advanced HIV infection, when dementia is more likely to occur. Others predict that because of the difficulties of drug penetration into the CSF compartment, neurologic complications will actually constitute a larger portion of advanced HIV complications in the future. The prevalence of MCMD is still not well characterized, in part because it is a relatively recent diagnostic category. In general, increases in neurologic complications parallel the progression of systemic illness, but studies of this association have not been conclusive (13). In studies of possible risk factors for development of dementia (14), some of those identified have been anemia, lower body mass before the onset of AIDS, greater number of constitutional symptoms prior to the onset of AIDS, and increasing age. Age and education significantly impact the results of neuropsychological tests. Therefore, it is important for studies to have closely matched controls for these independent risk factors. CLINICAL FEATURES OF HAD The symptoms and manifestations of HAD are characteristic of a subcortical dementia with the predominant features of cognitive decline and motor slowing (15). In addition, there may be

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behavioral changes to a variable degree. Cognitive decline is usually gradual and insidious in the early stages. Abrupt cognitive changes are usually attributable to other etiologies and suggest the need to search for possible underlying opportunistic conditions (16). Early in the process patients are aware of changes in cognition and may complain of increased difficulty with concentration on such activities as reading, watching television, or working on hobbies. Memory impairment is common, necessitating keeping lists and written reminders. Sometimes disorientation to place occurs, with reports of becoming lost while driving or forgetting a destination. Motor slowing is almost always present, manifested in affected gait and in performance on fine motor tasks. Changes characteristic of HAD are almost always symmetrical, and any major degree of lateralized asymmetry should arouse suspicion that other opportunistic processes are involved. Behavioral changes vary. Depressed affect is common in this population but is not a reliable indicator of cognitive deficit, which can usually be clearly distinguished on the basis of performance deficits. Less frequently, frank psychotic behavior occurs but is generally brief in duration. Advanced HAD may include urinary and fecal incontinence, preceded in most cases by urgency and frequency typical of neurogenic bladder dysfunction. Other possible neurologic problems include seizures and increased complaints of headaches. Again, other underlying causes for these symptoms should be carefully assessed, since CNS opportunistic infections often have these presentations. Cryptococcal meningitis, for example, may present in this population with headaches in the absence of meningeal signs. In untreated patients, this syndrome is subacutely progressive and typically leads to death in six months. However, because anti-retroviral therapy blunts or arrests progression, it has a variable course in patients on treatment. PATHOLOGY AND MECHANISMS As described above, HAD has the clinical appearance of a subcortical dementia. It is not surprising, then, that evidence of involvement in subcortical structures has been a focus of considerable attention. White matter changes include leukoencephalopathy resulting from macrophage infiltration and multinucleated giant cells. A more common finding is diffuse myelin pallor, which has been found to correlate with the presence of dementia (15). It has also been suggested by several groups that diffuse myelin pallor may indicate a leak in the blood-brain barrier, allowing toxic proteins access to cortical and subcortical areas (17). The subcortical gray matter also seems to be involved. Early PET scans demonstrated association with hypermetabolism in deep gray structures (18), followed by loss of volume that is notable in MR scans where basal ganglia atrophy develops in association with HAD (19). Atrophy is also reflected in enlargement of the cerebral ventricles. Astrocytosis is also a common finding in HAD and may play a crucial role in HIVassociated neuron damage. Although neuron loss has been demonstrated to occur, there is not as direct a relationship with the degree of loss and the severity of symptoms as might be seen in other types of dementing diseases (17). Neuronal apoptosis is currently thought to be a more generalized finding in advanced HIV and is not confined to patients with HAD. These neuropathologic structural changes are not tightly correlated with clinical symptoms, leading to the widespread belief that the mechanisms of neuronal dysfunction are indirect (17,20). In fact, there have been many documented cases of patients without dementia who exhibit HIV-related neuropathology, as well as patients with dementia in the absence of pathologic evidence (21). Similarly, in some cases a high cerebrospinal fluid viral load may be present without dementia, and some patients with dementia have a low viral load. HIV enters the brain by way of infected blood monocytes and targets macrophages and microglial cells. Susceptibility of these target cells is established by their expression of certain surface proteins, notably CD4 and chemokine receptors, which allow entry and infection to take place. A number of neurotoxic products secreted by infected macrophages/microglia are thought to be instrumental in both direct and indirect injury to nervous system tissue. Among the suspects are

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cytokines, notably tumor necrosis factor alpha (TNF-a), a proinflammatory cytokine that can upregulate the production of HIV-1 in infected cells (17). Reports of increased mRNA for TNFalpha in the brains of demented patients versus those of non-demented patients support the possible role of this cytokine in the pathogenesis of HAD (22). Another contributor to the neurotoxic cascade may be arachidonic acid. Macrophages are heavy producers of arachidonic acid, which plays a vital role in the formation of prostaglandins and thromboxanes, both of which have been found to be elevated in the CSF of demented patients (23). Platelet Activating Factor (PAF), another neurotoxin found in increased amounts in the CSF of HIV-infected individuals, has been produced in HIV-infected monocyte cultures (17). Quinolinic acid is a naturally occurring product of L-tryptophan metabolism. Increased production results from increase of indoleamine 2,3 dioxygenase (IDO) activity caused by either interferon gamma or cytokines, resulting in increased shunting of L-tryptophan metabolism via a kynurenine pathway to quinolinate. Increasing levels of quinolinic acid have been measured in the CSF with advancing HAD, but similarly high levels are seen with other CNS infections (24). Quinolinic acid is known to be an agonist of N-methyl D-aspartate (NMDA) excitatory amino acid receptors in the brain, which in turn are believed to be important in excitatory transmitter-mediated neurotoxic mechanisms. It has been postulated that quinolinic acid may be a marker of CNS neurologic disease. Other mechanisms are suggested by studies of the effects of the viral envelope glycoprotein gp120 on cells from the nervous system. Brenneman and his colleagues (25) reported that picomolar concentrations of gp120 are neurotoxic to hippocampal cells in culture, a finding that Dreyer and his co-workers also found in retinal cells in tissue culture (26). Thus, there are numerous possibilities, both direct and indirect, for gp120 associated pathogenesis of HAD. Other viral proteins have also been implicated in pathogenesis of neuroAIDS. In particular the role of TAT and nef are notable as mediators of the neurotoxic cascade (27). Astrocytes have been demonstrated to play a role in the detoxification of excitatory amino acids, in macrophage activation, and in maintaining the blood-brain barrier. They may be crucial in a feedback loop that increases the susceptibility of neurons to neurotoxins. Astrocyte apoptosis in the brains of patients with advanced dementia has been documented (28,29). Although therapeutic drug activity within the CNS seems of critical importance to understanding treatment of HIV-associated dementia, regimens with poor CSF penetration still appear to maintain protective benefit. This observation would be consistent with the hypothesis that the development of dementia may be initiated outside the brain. Gartner (30) has hypothesized that peripheral events may be primary in triggering AIDS dementia. She suggests that bone marrow populations are activated in late stage disease, leading to development of monocyte subsets associated with HAD. The activated cells transmigrate into the brain, setting up the physiologic changes leading to dementia. If this hypothesis were true, peripheral control of the disease should protect subjects from dementia. The alternative scenario is that the CNS represents a distinct compartment in which HIV infection can develop unimpeded by drug treatments and become the nidus of treatment failure, resulting in neurologic complications in advanced disease (31). Longitudinal studies to assess the dynamic interaction between peripheral and central HIV viral infection are critical to a more certain understanding of this relationship.

DIAGNOSIS AND MONITORING Diagnosis of HAD requires, in addition to clinical symptoms in the setting of HIV infection, exclusion of other underlying medical, psychiatric, or psychosocial etiologies, as outlined in the AAN diagnostic scheme. Effective ancillary measures include brain imaging, CSF evaluation, and neuropsychological testing. No single measure can be conclusive but must be considered as adjunctive to the neurological evaluation.

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Brain Imaging Although not diagnostic of HAD, brain imaging is a critical tool for excluding alternative diagnoses that may mimic dementia. Computerized tomography (CT) with iodinated contrast injection can reliably exclude most mass lesions, including TE and PCNSL. However, magnetic resonance (MR) brain imaging is more sensitive than CT in screening for opportunistic lesions and for detecting subtle white matter changes. T2-weighted images provide the best visualization of the variable focal, multifocal, and diffuse periventricular changes in the white matter. These changes may be confused with PML, and definitive diagnosis may require documentation by brain biopsy. Other conditions that have especially characteristic abnormalities on MR are TE, PML, and PCNSL. These findings can alert the clinician to consider alternative causes of neurologic changes. Finally, brain imaging that documents the absence of space occupying mass lesions supports the safety of performing lumbar puncture, which is also indicated in the diagnostic evaluation of such a subject. Recent advances in MR imaging include functional neuroimaging by means of magnetic resonance spectroscopy (MRS) (32,33). This non-invasive technique, by measuring several brain metabolites that reflect neurons and glia, allows high-resolution visualization of brain function in addition to brain structure. Thus, it may be able to detect changes in the brain before structural damage has occurred. Decreasing N-acetylaspartate (NAA) and increasing choline, markers of neuronal loss and gliosis, have been associated with progressive HAD (34). In addition, perfusion MR scanning may allow monitoring of cerebral blood flow, which appears to diminish as HAD progresses (35). Continued evaluation of MRS is warranted since it appears to provide a reproducible, quantitative measurement that may change with very mild brain involvement, and could be used to trace the response to therapeutic efforts in clinical trials. CSF Findings Although CSF findings are non-specific and cannot confirm the diagnosis of HAD, they are important in ruling out other treatable conditions. Cryptococcal meningitis may be clinically similar to HAD and is essentially excluded when cryptococcal antigen is absent from CSF. CMV encephalitis, another serious consideration in the differential diagnosis, can be excluded by the absence of CMV DNA on PCR testing. PML is supported by the presence of JC virus DNA in CSF. Neurosyphilis should also be ruled out by CSF testing. Typical CSF findings may include a few mononuclear cells, slightly elevated protein, and normal glucose. Oligoclonal bands may be present in HIV infection but are not exclusive to HAD. CSF HIV viral loads do not necessarily correlate with the presence of HIV-associated dementia. Although overall, individuals with HAD have higher viral loads than non-demented subjects, there is not a close correlation. Elevated viral loads have been seen in the absence of dementia, and sometimes dementia is seen in the absence of increased viral loads. CSF findings that correlate with HAD include increased b-2 microglobulin (36,37), neopterin (38,39), and quinolinic acid (24). Elevated levels of soluble Fas and Fas ligand in the CSF were recently described by Sabri (40). Fas is postulated to be a link to astrocytic apoptosis associated with neurologic impairment. Successful treatment resulting in decreased HIV viral loads has been associated with an accompanying decrease in these markers. Neuropsychological Testing Most clinical studies of HAD utilize neuropsychological testing to quantify the severity of cognitive impairment. The series of tests augments but cannot replace the neurological evaluation. Longitudinal assessment is most reliable in determining neuropsychological changes because of the variability in performance that can be attributed to motivation, stress, physical symptoms, age, and education (9).

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The battery of tests used to assess HAD is based on the subcortical nature of neurocognitive disorder in HIV infection. These include the domains of attention and speed of information processing, motor skills, learning, memory, and abstraction. Because of the differences in sensitivity and specificity among the various tests, ideally two tests within each domain should be included (9). Most studies use timed tests since motor slowing is an almost universal feature of HAD. Examples of tests that have been widely applied in monitoring the progress of HAD include timed gait, grooved pegboard manipulation, and finger tapping speed. Other commonly used assessments include a verbal learning test (learning, memory), trail making (abstraction, executive function), digit symbol (perceptual-motor), and serial addition tests (speed of information processing) (41). In addition, a measure of mood state is usually included, although the nature of the interaction between depression and HAD has not been firmly established. Documentation of decline in at least two cognitive domains is considered reliable evidence for a change in cognitive ability. In interpreting results of testing it is important to consider premorbid and underlying conditions, such as head trauma, substance abuse, and learning disability, as well as age and education (14,42). THERAPY In comparison to other areas of medicine, therapy for HIV infection has had a history of rapid changes, accompanied by a remarkable evolution of major issues to be confronted. Early in the epidemic, most of the successful therapeutic interventions were directed toward improving management of the opportunistic problems. Substantial improvements in the quality of survival and some improvements in duration of survival were achieved through these interventions. Prophylaxis for PCP proved to reduce the incidence of TE as well as lethal pneumonia. More effective oral treatments for thrush probably resulted in changes in the incidence of cryptococcal disease. Further, successful application of HIV therapy, starting with the introduction of zidovudine in the late 1980s, resulted in changes in both the incidence of HAD and the pathologic manifestations of HIV encephalitis (43). Anti-retroviral therapy has evolved through three eras. During the initial era (1987 to w1991), monotherapy restricted to nucleoside reverse transcriptase inhibitor anti-retrovirals showed some early promise in disease symptom modification, but sadly, transient responses to this therapy resulted in little change in long term prognosis. A second era (w1992 to 1996) was heralded by efforts to use at least two anti-retrovirals at the same time. However, the only drugs available were nucleoside reverse transcriptase inhibitors, which permitted only modestly improved therapeutic results. The third era was ushered in by introduction of protease inhibitor (PI) antiretroviral drugs and the availability of non-nucleoside reverse transcriptase inhibitors (NNRTI). Used in combination with nucleoside reverse transcriptase inhibitors with at least three drugs used simultaneously, the clinical responses clearly improved. This combination of therapy has been termed highly active anti-retroviral therapy or HAART. Use of multiple drugs, generally with at least two sites of action, substantially reduces the rate at which viral mutation is able to defeat therapeutic efficacy and has resulted in prolonged control of viral replication below the limits of currently available assays. This, in turn, has resulted in variable but generally very important degrees of immune re-constitution that vastly reduce the frequency of opportunistic complications. Current issues with therapy focus on the optimal combinations of therapy, on improving the convenience and tolerability of the medications, and on minimizing the long-term consequences of exposure to these drugs. Rational combinations are now being formulated to reduce the number of pills required. The most recent preparation of this sort combines zidovudine, lamivudine, and abacavir in a potent therapy that can be administered twice a day with a single preparation. When treating neurologically impaired individuals, simplicity, and convenience of the regimen are particularly important since complicated schedules are almost certain to fail in such patients. Longer acting preparations and development of longer half life drugs, are in some cases making

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once-a-day dosing a reality for HIV patients. Developments in therapy include additions to current classes of drugs with greater potency, and fewer or different side effects. In addition, new mechanisms including HIV entry inhibitors and integrase inhibitors promise to expand the armamentarium against this infection. The spectrum of side effects that results from exposure to HAART has become a major focus of attention. Success in limiting these troublesome side effects is of great importance in ultimately successful therapy. Metabolic side effects in particular have recently become a serious concern. PIs have been associated with glucose intolerance, and sometimes frank diabetes. Blood cholesterol and lipids are often substantially elevated, raising concerns in conjunction with glucose intolerance, that accelerated vascular disease will complicate the care of these patients over time. Further, the drugs result in lipid redistribution such that subcutaneous fat is lost in the face, but deposited over the back with the appearance of chronic steroid use lipodystrophy. These cosmetically disturbing side effects affect the willingness of patients to comply with their drug regimens. Finally, while replication of virus is markedly impaired, clearly a low level of replication continues. Unavoidable interruptions of therapy in the setting of a continuing background of viral activity will likely result in eventual failure of treatments due to development of resistance. Determining the optimal use of currently available drugs is an active and ongoing evaluation process. The neurologic complications of anti-retroviral therapy are also of importance. The most serious complication of therapy is the distal sensory peripheral neuropathy (DSPN) that is associated with the nucleoside reverse transcriptase inhibitor drugs. The situation is complicated, since advanced HIV itself is associated with a virtually identical DSPN. However, didanosine, stavudine, and zalcitabine are all clearly associated with development of DSPN. The mechanism is believed to be through mitochondrial toxicity of these drugs. It is interesting that other RTI drugs, zidovudine, and lamivudine, appear not to share the tissue-specific toxicity in peripheral nerve, although zidovudine has a separate mitochondrial toxicity in muscle. DSPN has become a very common problem that complicates therapy as subjects struggle to construct effective treatment regimens that are tolerable while keeping the HIV viral load under control. Neuroprotective therapy to block this toxicity would be a highly beneficial development, but to date no treatments have been demonstrated to achieve this goal. Another unique neurologic toxicity is associated with the NNRTI, efavirenz. More than half of patients taking this drug describe a variety of sensations, including changes in sleep, dreaming, attention, and alertness. Fortunately, the severity of these symptoms is most often mild, and appears to decline with ongoing therapy, so that most patients can benefit from this drug despite the side effects. At present, the mechanism of this unique issue is not known, and in a few patients where it remains troublesome, it is best to substitute an alternate NNRTI drug such as nevirapine. Management of HIV therapy is best directed by infectious disease experts who have substantial numbers of patients under treatment. Progress in constructing optimal treatment combinations, and knowledge about very important drug interactions and necessary monitoring, are sufficiently complicated that optimal results will only be obtained when there is a major commitment to maintaining current knowledge about therapy. In general, texts are seriously outdated, but ongoing revisions in treatment recommendations may be reviewed on the Internet, where consensus expert opinions on therapy are found at such sites as http://www.hivatis.org/. The impact of therapy on HIV neurologic disease has been profound. Whereas a majority of surviving AIDS patients probably suffered from some degree of HAD in the pre-treatment era, current estimates are that substantially less than 10% will have HAD in the current treatment era (44). Most subjects developing HAD either have it as a presenting HIV complication or develop it due to inability to maintain effective antiviral therapy. When HAART is started after the development of HAD, often marked improvements in neurologic performance occur, underscoring a significant reversible component to this disorder. While some cases of HAD seem to have developed on systemically effective HIV therapy, this remains extraordinarily rare. A greater concern is that

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subtler neurologic dysfunction resulting from ongoing low level infection may be missed and could continue to develop in long term survivors. Careful monitoring of the activity of the infection in the nervous system, and of potentially serious behavioral manifestations that fall short of HAD, remains a priority for ongoing investigation. Although optimal treatment with HAART currently offers the most effective support for patients with HAD, adjunctive therapies may prove to have an important role in the future. With increasing evidence for indirect mechanisms in the etiology of neuronal damage, a number of possible interventions are being considered for evaluation. Mediators of toxicity supported by in vitro evidence include calcium-mediated toxicity, oxidative stress, and damage attributed to cytokines, PAF, nitric oxide, gp120, and tat. Characterizing the interactions of both direct and indirect damage leading to cognitive impairment in HIV infection will remain an important focus for clinical neurologic studies in the next decade. Ongoing therapeutic trials are directed at extending the mechanisms of protection for the brain in the face of chronic infection (16). The most recent trial tests selegiline administered via a transdermal patch. Based on promising small trials, selegiline may have an anti-apoptotic mechanism at very small doses (45). Current clinical trial information may be found on the website of the Neurologic AIDS Research Consortium (NARC) at www.neuro.wustl.edu/narc. Patients with any degree of cognitive decline are encouraged to consider participation in clinical trials seeking to further delineate neuroprotective strategies.

REFERENCES 1. Sepkowitz KA. AIDS—The first 20 years. NEJM 2001; 344:1764–1772. 2. Harrison M, McArthur J. AIDS and Neurology. Edinburgh: Churchill Livingstone, 1996. 3. Greene W. The molecular biology of human immunodeficiency virus type 1 infection. N Engl J Med 1991; 324:308–317. 4. Young B, Kuritzkes DR. Viral kinetics: implications for treatment. AIDS 1999; 13:S11–S17. 5. UNAIDS, World Health Organization (WHO). AIDS epidemic update, 2002. Geneva, UNAIDS/WHO. 6. Centers for disease control and prevention. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and mortality weekly report, 1992; 41:(RR-17). 7. Davis LE, Hjelle B, Miller VE, et al. Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology 1992; 42:1736–1739. 8. Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I Clinical features. Ann Neurol 1986; 19:517–524. 9. McArthur JC, Grant I. In: Gendelman HE, Lipton SA, Epstein L, Swindells S, eds. HIV Neurocognitive Disorders. In: The Neurology of AIDS. New York: Chapman and Hall, 1998:499–523. 10. Working Group of the American Academy of Neurology AIDS Task Force. Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Neurology 1991; 41:778–785. 11. Navia BA, Cho ES, Petito CK, Price RW. The AIDS dementia complex: II Neuropathology. Ann Neurol 1986; 19:525–535. 12. Portegies P, Enting RH, de Gans J, et al. Presentation and course of AIDS dementia complex: 10 years of follow-up in Amsterdam, the Netherlands. AIDS 1993; 7:669–675. 13. Heaton RK, Grant I, Neal B. The HNRC 500 - Neuropsychology of HIV infection at different disease stages. J Int Neuropsychol Soc 1995; 1:231–251. 14. McArthur JC, Hoover DR, Bacellar H, et al. Dementia in AIDS patients: incidence and risk factors. Neurology 1993; 43:2245–2252. 15. Glass JD, Wesselingh SL, Selnes OA, McArthur JC. Clinical-neuropathologic correlation in HIVassociated dementia. Neurology 1993; 43:2230–2237. 16. Clifford DB. Human immunodeficiency virus-associated dementia. Arch Neurol 2000; 57:321–324.

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17. Glass JD, Wesselingh SL. Microglia in HIV-associated neurological diseases. Microsc Res Tech 2001; 54:95–105. 18. Rottenberg DA, Moeller JR, Strother SC, et al. The metabolic pathology of the AIDS dementia complex. Ann Neurol 1987; 22:700–706. 19. Aylward EH, Henderer JD, McArthur JC, et al. Reduced basal ganglia volume in HIV-1-associated dementia: results from quantitative neuroimaging. Neurology 1993; 43:2099–2104. 20. Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 2001; 410:988–994. 21. Johnson RT, Glass JD, McArthur JC, Chesebro BW. Quantitation of human immunodeficiency virus in brains of demented and nondemented patients with acquired immunodeficiency syndrome. Ann Neurol 1996; 39:392–395. 22. Wesselingh SL, Power C, Glass JD, et al. Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. Ann Neurol 1993; 33:576–582. 23. Griffin DE, Wesselingh SL, McArthur JC. Elevated central nervous system prostaglandins in HIVassociated dementia. Ann Neurol 1994; 35:592–597. 24. Heyes MP, Ellis RJ, Ryan L, et al. Elevated cerebrospinal fluid quinolinic acid levels are associated with region-specific cerebral volume loss in HIV infection. Brain 2001; 124:1033–1042. 25. Brenneman DE, Westbrook GL, Fitzgerald SP, et al. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature 1988; 335:639–642. 26. Dreyer EB, Kaiser PK, Offermann JT, Lipton SA. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science 1990; 248:364–367. 27. Kruman II, Nath A, Mattson MP. HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol 1998; 154:276–288. 28. Seilhean D, Kobayashi K, He Y, et al. Tumor necrosis factor-a, microglia and astrocytes in AIDS dementia complex. Acta Neuropathol 1997; 93:508–517. 29. Thompson KA, McArthur JC, Wesselingh SL. Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia. Ann Neurol 2001; 49:745–752. 30. Gartner S. AIDS: HIV infection and dementia. Science 2000; 287:602–604. 31. Major EO, Rausch D, Marra C, Clifford D. HIV-associated dementia. Science 2000; 288:439. 32. Chang L, Ernst T, Leonido-Yee M, Walot I, Singer E. Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex. Neurology 1999; 52:100–108. 33. Chang L, Ernst T, Leonido-Yee M, et al. Highly active anti-retroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurology 1999; 53:782–789. 34. Tracey I, Carr CA, Guimaraes AR, Worth JL, Navia BA, Gonzalez RG. Brain choline-containing compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex: a proton magnetic resonance spectroscopic study. Neurology 1996; 46:783–788. 35. Chang L, Ernst T, Leonido-Yee M, Speck O. Perfusion MRI detects rCBF abnormalities in early stages of HIV-cognitive motor complex. Neurology 2000; 54:389–396. 36. Brew BJ, Bhalla RB, Paul M, et al. Cerebrospinal fluid b2-microglobulin in patients with AIDS dementia complex: an expanded series including response to zidovudine treatment. AIDS 1992; 6:461–465. 37. McArthur JC, Nance-Sproson TE, Griffin DE, et al. The diagnostic utility of elevation in cerebrospinal fluid b2-microglobulin in HIV-1 dementia. Neurology 1992; 42:1707–1712. 38. Brew BJ, Bhalla RB, Paul M, et al. Cerebrospinal fluid neopterin in human immunodeficiency virus type 1 infection. Ann Neurol 1990; 28:556–560. 39. Griffin DE. Perspectives series: cytokines and the brain. J Clin Invest 1997; 100:2948–2951. 40. Sabri F, DeMilito A, Pirskanen R, et al. Elevated levels of soluble fas and fas ligand in cerebrospinal fluid of patients with AIDS dementia complex. J Neuroimmunol 2001; 114:197–206. 41. Grant I, Atkinson JH, Hesselink JR, et al. Evidence for Early Central Nervous System Involvement in the Acquired Immunodeficiency Syndrome (AIDS) and Other Human Immunodeficiency Virus (HIV) Infections. Ann Intern Med 1987; 107:828–836. 42. Wilkins JW, Robertson KR, van der Horst C, et al. The importance of confounding factors in the evaluation of neuropsychological changes in patients infected with human immunodeficiency virus. J Acquir Immune Defic Syndr 1990; 3:938–942.

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43. Gray F, Be´lec L, Keohane C, et al. Zidovudine therapy and HIV encephalitis: a 10-year neuropathological survey. AIDS 1994; 8:489–493. 44. Sacktor N, Lyles RH, Skolasky R, et al. HIV-associated neurologic disease incidence changes: multicenter AIDS cohort study, 1990–1998. Neurology 2001; 56:257–260. 45. Sacktor N, Schifitto G, McDermott MP, Marder K, McArthur JC, kieburtz K. Transdermal selegiline in HIV-associated cognitive impairment: pilot, placebo-controlled study. Neurology 2000; 54:233–235.

18 Influence of Comorbidities in Dementia Dennis T. Villareal Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, Missouri, U.S.A.

INTRODUCTION Dementia in the elderly is a major and increasing public health problem that is often treatable. Because of advancing age, most dementia patients experience several concurrent medical problems. Only 13% of nursing home residents are free of chronic illness, and 50% have two or more chronic illnesses. Many of these comorbid conditions are capable of altering brain function and can on their own produce a dementia-type syndrome or contribute to dementia. It is important to identify these comorbidities because treatment not only can slow the cognitive decline or dementing process, but also in some cases, reverse the dementia. In addition, treatment of comorbid disorders may improve quality of life, morbidity, and survival of older patients with dementia. This chapter will review the comorbid conditions that can adversely affect cognition and complicate the presentation of older persons with dementia.

NUTRITIONAL DISORDERS: VITAMIN B DEFICIENCY Vitamin B12 and folate are cofactors for the methylation of homocysteine to methionine, which is required for the synthesis of S-adenosylmethionine. This end product is a universal methyl donor that is needed for various methylation reactions in the brain, including neurotransmitter metabolism (1). When either vitamin B12 or folate is deficient, the impairment of transmethylation reactions can produce neurocognitive dysfunction. Although such deficiencies have long been associated with dementia, it is only from recent findings that hyperhomocysteinemia resulting from either vitamin B12 or folate deficiency has been recognized as the causative factor. Not only is hyperhomocysteinemia a risk factor for vascular disease (2) it also has a neurotoxic effect that can lead to cell death or neurologic disturbances such as Alzheimer’s disease (3). In a case-control study, low blood levels of folate and vitamin B12 as well as elevated homocysteine levels were found to be associated with Alzheimer’s disease (4). Although isolated vitamin B12 deficiency is a rare cause of dementia, it may be a contributory factor in up to 27% of dementia in the elderly (5). Dementia in this setting tends to have a 333

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subcortical picture with concurrent depressive symptoms that mimic the dementia of depression (6). Other symptoms include the nonspecific changes of apathy, irritability, and confusion. Agitation and paranoid psychosis may also be present. Pathologically, there is degeneration of white matter, swelling of myelin sheaths, and, sometimes gliosis. Other neurologic disorders associated with vitamin B12 deficiency include peripheral neuropathy, myelopathy, and optic neuropathy (7). These neurological symptoms can occur in the absence of anemia or macrocytosis in 14–25% of cases (8,9). The prevalence of vitamin B12 deficiency ranges from 10–20% in different elderly populations (10). This relatively high frequency of B12 deficiency is mainly due to: (1) antibodies to intrinsic factor, which results in pernicious anemia or (2) atrophic gastritis, which results in hypochloridia and decreased ability to absorb food-bound vitamin B12. Acid-suppressing drugs commonly taken by elderly people may worsen the hypochloridia. Most laboratories report a normal range for vitamin B12 of more than 300 ng/ml. Only about 50% of patients with levels between 150–250 ng/ml are actually B12 deficient, although B12 levels below 150 ng/ml are sensitive for diagnosing tissue vitamin B12 deficiency. Therefore, in those with borderline B12 values, it is recommended to measure the metabolites, homocysteine, and methylmalonyl acid (11). If both are elevated and the patient does not have chronic renal insufficiency, it is likely that the patient has vitamin B12 deficiency. If only homocysteine is elevated, the consideration is folate deficiency, which is consistent with low folate levels. Levels of homocysteine and methylmalonyl acid can be followed to document correction of deficient tissue levels. It is important to recognize individuals with vitamin B12 deficiency early on because prompt treatment may improve or completely resolve the neurological symptoms. Moreover, treatment with B12 replacement is easy, inexpensive, and devoid of side effects. Mild cases of peripheral neuropathy may improve within several weeks of B12 replacement, while ataxia may take as long as a year to improve. Dementia also may improve, although the response to B12 replacement has not been universal. In a study from two New York hospitals, 8 of 13 patients with memory loss had complete recovery, while three recovered partially with cobalamin therapy (8). On the other hand, in a study of “reversible” causes of dementia, none of the 13 patients with B12 deficiency improved with treatment (12). It is possible that long-standing vitamin B12 deficiency has produced irreversible abnormalities (e.g., cerebrovascular disease from hyperhomocysteinemia), which are not resolved with B12 replacement. Treatment of B12 deficiency consists of a daily dose of 1000 mg IM ! 7, followed by weekly doses until there is clear-cut improvement in the abnormalities, followed by monthly doses. Alternatively, oral supplementation with at least 1000 mg (1 mg) per day can be given. Because the underlying defect causing vitamin B12 deficiency is usually irreversible, lifelong replacement is required. Low folate levels are associated with an increased risk of stroke that may contribute to dementia. Low folate and vitamin B12 levels are associated with hypercysteinemia, which is itself a risk factor for stroke (2) and may contribute to the development of Alzheimer’s disease (4,13). It is unclear whether low folate levels contribute to dementia or whether demented patients have an increased prevalence of low folate levels, as cognitive impairment leads to a reduced dietary intake in these patients. Most neurological symptoms are reversible with folate replacement. The recommended oral supplement dose is 1–5 mg of folic acid daily. Niacin (vitamin B3) serves as a precursor of two coenzymes, NAD, and NADP, which are important in numerous oxidation and reduction reactions in the body. Niacin deficiency results in pellagra, which is a triad of dementia, dermatitis, and diarrhea. Because of niacin supplementation in the diet, pellagra is rare in the United States except in young alcoholics or in those with gastrointestinal problems that impair absorption. In niacin deficiency, the neuropsychiatric component may include memory loss, confusion, disorientation, delusions, ataxia, and peripheral neuropathy with no typical order of progression. These symptoms usually improve within days to weeks of replacement with 500 mg of niacinamide daily (14).

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MEDICATION-INDUCED DEMENTIA Because of the high frequency of systemic disorders in older persons, many are treated with a variety of pharmaceutical agents, both prescribed and self-administered. People over age 65 represent 13% of the U.S. population but consume about 25% of all prescriptions annually and are the leading users of over-the-counter medications. Not only do older people tend to have polypharmacy, but also they are more sensitive to medications, having unexpected responses to commonly used drugs. This sensitivity is due to age-related changes in the dose-response relationship, which in turn is affected by the pharmacokinetics and pharmacodynamics of the drug (15). Generally, the results of these changes in elderly patients are a longer duration of activity, a greater or lesser drug effect, and an increase in the incidence of drug toxicity and adverse drug reactions (15,16). Almost any drug taken in excess can produce central nervous system toxicity, with impaired concentration, disorientation, memory loss, psychomotor disturbance, stupor, and coma at higher doses. Table 1 summarizes some therapeutic agents associated with dementia at usual dosages. Dementia caused by most therapeutic agents is reversible with discontinuation of the medication. However, some drugs (e.g., oral contraceptives, ergot alkaloids) may cause irreversible vascular dementia through hypercoagulability or cerebrovascular disease (17). Hypoglycemic agents can cause permanent central nervous system damage by depleting the brain of glucose. Table 1 Drugs Associated with Cognitive Impairment and Dementia Anticholinergic drugs Scopolamine Atropine Trihexphenidyl Benztropine Oxybutinin Hypnotics/sedatives Benzodiazepines Barbiturates Opioid analgesics Morphine Meperidine Antipsychotics Phenothiazines Butyrophenones Antiparkinsonian drugs Levodopa Bromocriptine Amantadine Ethosuximide Histamine H2 receptor antagonists Cimetidine Ranitidine Famotidine Antidepressants Tricyclic antidepressants SSRIs Lithium

Cardiac drugs Digoxin Antiarrhythmic agents Beta blockers Methyldopa ACE inhibitors Clonidine Nonsteroidal anti-inflammatory drugs Salicylate Indomethacin Ibuprofen Naproxen Antibiotics Penicillins Cephalosporins Quinolones Rifampin Anticonvulsants Phenytoin Primidone Carbamazepine Antineoplastic agents Methotrexate Cisplatin Interferon Asparaginase Miscellaneous drugs Hypoglycemic agents Oral contraceptives Steroids Ergot alkaloids

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The possibility of a drug-related complication in the elderly may be heralded by the new onset of geriatric syndromes such as gait instability, falls, orthostatic hypotension, depression, behavioral disturbance and psychosis, or incontinence. In these patients, the presence of cognitive dysfunction warrants a careful review of both prescribed and nonprescribed medications. To the extent that the patient’s health is not at risk, a period of close observation is recommended during which all medications are withdrawn. If discontinuing a drug is not possible, assessment of its contribution to the cognitive problem may be attempted by other means, such as measuring drug levels or substituting another agent with equal efficacy but different mode of action.

ALCOHOLIC RELATED-DEMENTIA Chronic, excessive use of alcohol may result in deterioration of cognitive function sufficient to interfere with occupational and social activities, mimicking early Alzheimer’s disease. However, in contrast to Alzheimer’s disease, the progression of cognitive and functional impairment may slow with cessation of drinking alcohol, although full return to premorbid functioning is uncommon (18). The clinical presentation is usually mild and nonprogressive or only slowly progressive and may include memory loss, psychomotor retardation, disorientation, and perseveration. This cognitive decline may be accompanied by neuroanatomic and neuropsychological changes, which may be at least partially reversible, if identified early and followed by a protracted period of abstinence (18,19). In addition to the direct neurotoxic effects of alcohol, chronic alcoholic patients are susceptible to Wernicke’s encephalopathy and Korsakoff’s syndrome, both of which are due to thiamine deficiency. Wernicke’s encephalopathy consists of the triad of confusion, ataxia, and opthalmoplegia (typically sixth nerve), although this classic presentation may not be present. Because the mortality rate is 17% if left untreated, Wernicke’s encephalopathy should be considered a possible diagnosis in comatose patients with hypothermia (20). Korsakoff’s syndrome is a common sequel that is characterized by severe short-and-long term memory impairments with confabulation. Immediate memory, however, may be fairly well preserved. Neuroimaging shows symmetrical lesions in the mammillary bodies, in the periventricular regions of the thalamus and hypothalamus and in the periaqueductal midbrain. Early recognition and treatment of Wernicke’s encephalopathy and Korsakoff’s syndrome with parenteral thiamine (100 mg/day) can minimize brain damage and alleviate symptoms.

METABOLIC DISORDERS Although metabolic disorders usually produce transient effects on cognition (delirium), when these effects persist for an extended period, dementia is diagnosed. This dementia-like syndrome can be confused with early Alzheimer’s disease. However, in metabolic illnesses, the altered cognition is a secondary symptom rather than the major clinical feature. Thus, the key to the correct diagnosis is attention to the associated systemic signs and symptoms. Elderly patients are more likely than young patients to present with dementia as the major sign of a metabolic disorder. In most cases, the dementia is reversible with treatment of the underlying cause, provided it has not permanently damaged the brain. Unlike in the progressive degenerative cases, the dementia associated with metabolic disorders usually has a rapid onset with a clear beginning. The history is often short, decline reported in weeks to months rather than years and there may be periods of apparent stabilization. The dementia is almost always mild or moderate and language is rarely affected. Furthermore, the memory deficit is likely to fluctuate more widely than Alzheimer’s disease. The major metabolic conditions that cause dementia are listed in Table 2.

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Table 2 Metabolic Conditions that May Present as Dementia Endocrine disorders Thyroid disease Parathyroid disease Diabetes mellitus Adrenal disease Organ failure Congestive heart failure Pulmonary insufficiency Liver failure Renal failure Chronic alcoholism Chronic dehydration Electrolyte abnormalities

Thyroid Disorders Normal thyroid function is important for the functional development and maturation of the central nervous system. Untreated congenital hypothyroidism produces cretinism and profound mental retardation. Primary clinical hypothyroidism in adults also has a variety of adverse effects on adaptive neurcognitive function, including deficits in memory, psychomotor slowing, and visuoperceptual and construction skills (21). Based on generalized cognitive screening tests, many studies have reported clinically significant and relentless impairment in patients with untreated hypothyroidism (22,23). In elderly hypothyroid patients, dementia has been found to occur in up to 5% and may be the only apparent disorder. Hypothyroidism may be difficult to diagnose on the bases of classic physical signs (e.g., weight loss, hair loss, and fatigue), which can mimic the changes of normal aging. The cognitive impairment may be insidiously progressive and accompanied by nonspecific symptoms such as irritability, insomnia, and lability of mood or depression. Because of the relatively high prevalence of hypothyroidism in elderly women, it has been suggested that they undergo screening with measurement of serum thyrotropin levels (24). Even with only modest elevations of serum thyrotropin and no other signs of hypothyroidism, dementia, and milder neurocognitive impairment may be seen, suggesting the need for thyroid hormone replacement (25). Although hypothyroidism is traditionally cited as a cause of reversible dementia, cognitive function may only partially be recovered following hormone replacement therapy, (26) especially in the presence of congenital hypothyroidism. However, thyroid hormone replacement often may improve physical symptoms and general well being. Dementia is reportedly less common and severe in hyperthyroidism than in hypothyroidism. On the other hand, affective psychoses and schizophrenia-like symptoms are more prevalent in hyperthyroidism (27,28). Dementia may appear in elderly hyperthyroid patients in conjunction with confusion, apathy or depression. In some cases, dementia may begin as subtle impairment of attention, memory, and calculation, and may be the presenting clinical feature of hyperthyroidism (29). Other neuropsychiatric symptoms include myopathy, peripheral neuropathy, chorea, seizures, hyperactivity, and irritability. Treatment with antithyroid drugs usually reverses the neuropsychiatric symptoms, including the dementia, although complete recovery may take up to a year (30). The key to the diagnosis is the detection of a highly suppressed thyrotropin based on a sensitive thyrotropin assay. In the Rotterdam prospective study, a reduced thyrotropin level at baseline was found to be associated with a more than threefold increased risk of dementia and of Alzheimer’s disease (31).

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Alterations in Serum Calcium Hypercalcemia can result from a variety of medical conditions, including hyperparathyroidism, malignancy, sarcoidosis, vitamin D intoxication, thiazide diuretics, and immobilization. Although hypercalcemia can be a manifestation of a serious illness, it often is detected coincidentally by laboratory testing in the absence of symptoms. In most cases, a complete medical history will indicate the underlying cause of hypercalcemia. Hypercalcemia is confirmed with demonstration of an elevated free (ionized) calcium level. Hypercalcemia from any cause can result in mental confusion. Although there is a variable relation from one patient to the next, the cognitive symptoms usually correlate with the severity of the hypercalcemia. Serum levels between 15 to 18 mg/dl are associated with delirium and may produce coma. Lower levels may be associated with depression, memory loss, and personality change. Although hypercalcemia usually causes an acute confusional state, chronic dementia has been reported to occur in 12% of hyperparathryoid patients in the absence of other signs (32). In patients 75 years and older, the dementia of hyperparathyroidism has been found to occur in up to 40% (33). Treatment is directed at the underlying cause of the hypercalcemia or hyperparathyroidism. In patients with parathyroid adenoma, parathyroidectomy can significantly improve dementia when the duration of symptoms is less than 2 years (34). Hypocalcemia usually is due to hypoparathyroidism, vitamin D deficiency, renal failure, and hypomagnesemia. Depending on the rate of development of hypocalcemia, mental status changes can result, which include irritability and varying combinations of agitation and confusion. The patient may have tremors and myoclonus, suggesting the metabolic nature of the problem, but often these signs may be subtle. When the onset of hypocalcemia is slow and insidious, dementia may be the initial manifestation. The dementia usually reverses with medical therapy, in parallel with normalization of serum calcium (35). Even in the absence of hypocalcemia, dementia can occur in hypoparathyroid patients and readily responds to therapy with 1,25-dihyroxy-vitamin (36). Corticosteroids Although chronic glucocorticoid excess can be caused by a corticotropin-producing tumor (Cushing’s disease), other causes of hypercortisolism are more common. In fact many elderly patients are treated with steroids for various medical conditions resulting in iatrogenic Cushing’s syndrome. Chronic exposure to elevated levels of cortisol is associated with deficits in several areas of cognition, particularly those involving processing of selective attention and visual components (37). The hippocampus has the highest concentration of glucocorticoid receptors and chronic steroid treatment induces neuropathological alterations, such as dendritic atrophy in hippocampal neurons, which are paralleled by cognitive deficits (38,39). In patients with Cushing’s syndrome, the severity of neuropsychiatric symptoms correlates with the degree of cortisol elevation (40). The dementia improves with reduction in cortisol levels, although complete recovery may take several months to years. Even milder chronic elevations of cortisol due to activation of the hypothalamic-pituitaryadrenal axis by stress or depression may be detrimental to cognitive function (39,41). Low cortisol levels can be caused by destruction of the adrenal cortex or deficient pituitary ACTH secretion. Memory impairment can occur in affected patients and in those with severe or long-standing adrenal insufficiency, this can progress to confusion, delirium, and stupor (42). Other symptoms include depression, manifested by apathy and lack of initiative. Most of these symptoms disappear within a few days after adequate glucocorticoid therapy is initiated. Hypoglycemia The most common cause of hypoglycemia is insulin treatment in the management of diabetes. Other etiologies include insulinoma, liver failure, uremia, postgastrecomy, alcohol-related, antibodies to

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insulin receptors, and medications (e.g., b-blockers). When plasma glucose is less than 45 mg/dl, there is brain glucose deprivation and neuroglycopenic symptoms occur. These include weakness and fatigue, difficulty in thinking or confusion, as well as more severe cognitive failure, behavioral changes, seizures, coma, and ultimately death (43). Usually these also are accompanied by neurogenic (autonomic) symptoms, such as tremulousness, palpitations, and anxiety, which prompt the patient to act (e.g., eat) to abort the episode (43). However, patients with tightly controlled diabetes or insulinomas may have hypoglycemic unawareness (44,45). Prolonged or repeated hypoglycemia can present with severe memory impairment accompanied by personality change, aggressive behavior, emotional lability, or depression. Pathologic changes in the brain produced by hypoglycemia include patchy necrosis and loss of neurons in the cerebral cortex, basal ganglia, and cerebellum (46). A serum glucose that is persistently below 45 mg/dl should warrant investigation for a hypoglycemic disorder. Treatment of the underlying cause of hypoglycemia may arrest progression of the dementia although may not reverse existing deficits. Hyperglycemia Very high blood glucose (O600 mg/dl) associated with dehydration and hemoconcentration results in impaired consciousness. This syndrome, referred to as hyperglycemic hyperosmolar nonketotic state, is associated with a calculated osmolality that often exceeds 350 mOsm/L. The typical patient is an elderly with non-insulin dependent diabetes mellitus who develops a complication such a severe infection. The patient usually presents with confusion and lethargy, but can progress to the point of coma in 20% or more. Focal neurological signs may also be present. Correction of hyperosmolality with vigorous hydration, along with treatment of the precipitating condition, will result in return to normal level of consciousness (47). Although diabetes mellitus has long been recognized as a risk factor for vascular dementia, recent studies suggest that it may also contribute to the risk of Alzheimer’s disease. In the prospective study from Rotterdam, the diabetes attributable risk for dementia was 8.8% (48). Because advanced glycation end products (AGE) have been found in both plaques and tangles in the brains of Alzheimer’s disease’ patients (49), it has been suggested that excessive AGE formation by chronic hyperglycemia may mediate neurodegeneration (50). Additionally, chronic hyperglycemia is thought to be associated with neuronal insulin receptor resistance, which can result in abnormalities in cerebral glucose metabolism (51). Individuals with type 1 or type 2 diabetes mellitus have been reported to show performance deficits in a wide range of neuropsychological tests, including learning and memory, problem solving, mental, motor speed, and complex information processing. These cognitive deficits have been shown to parallel neurophysiological (e.g., increased latencies of evoke potentials) (52) and neurological (increased white-matter hyperintensities) changes (53), consistent with “diabetic encepalopathy.” Although the pathogenesis of “diabetic encepalopathy” is multifactorial and not yet completely understood, it is thought to share features of brain aging and pathogenesis of diabetic neuropathy (54). Electrolyte Abnormalities and Chronic Dehydration Hypernatremia is common in older people and is usually accompanied by hypertonic dehydration (55,56). Several factors contribute to the increased risk of dehydration in this age group. Body water is decreased as a proportion of total body weight because of the relative increase in fat content of normal elderly persons. In addition, elderly people have a blunted thirst response to hypertonicity, and there usually is a marked impairment in the renal response to antiduiretic hormone. Symptoms of hypernatremia are predominantly neurologic and are thought to be secondary to brain shrinkage with resultant dysfunction. Obtundation, lethargy, and coma can result. Management entails

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correction of intravascular volume depletion using physiologic saline, followed by correction of the hypertonicity using hypotonic fluids. Generally the correction should occur over a 24–72 hr period so as to avoid cerebral edema and seizures. Hyponatremia is the most common electrolyte disorder in the elderly, occurring in as many as one quarter of all hospitalized or institutionalized elderly patients (57,58). It usually is due to a combination of factors including: (1) decreased ability to excrete water, (2) water intoxication in the setting of diuretic therapy, and (3) oversecretion of antiduiretic hormone (59,60). Although symptoms are uncommon with mild hyponatremia (plasma sodium above 125 mmol/L), when hyponatremia develops rapidly or is severe, the neurologic symptoms may mimic dementia (61). These symptoms include confusion, disorientation, restlessness, lethargy, and generalized weakness. If left untreated, the situation can progress to stupor, coma, and seizures. The pathologic findings in the central nervous system include generalized edema, which is most prominent in the white matter. Appropriate treatment depends on the etiology of the hyponatremia and whether the patient is dehydrated, euvolemic, or hypervolemic. If symptoms require specific electrolytic therapy, particular caution should be paid to the rate of administration of hypertonic or physiologic saline to older patients because of the higher likelihood of developing central pontine myelinolysis. In general, it is advisable to limit the rate of correction to less than 12 mmol/L per day.

ORGAN FAILURE Congestive Heart Failure Heart failure affects some 4.5 million Americans and is increasing in prevalence. Heart failure is frequently associated with cognitive impairment, as demonstrated in patients with end-stage heart failure awaiting cardiac transplantation (62,63) or in those admitted to a cardiac rehabilitation service (64). Heart failure may lead to dementia through cardioembolic stroke or cerebral hypoperfusion (65). The cause of the cardiac emboli is likely left ventricular dysfunction with increased end diastolic volume and stasis, which predisposes to thrombus formation. The cause of cerebral hypoperfusion is likely decreased cardiac output, which may be worsened by hypotension from cardiac ischemia, arrhythmia, or overmedication in the presence of impaired autoregulation. It may be difficult to determine in these patients whether multiple emboli or hypoperfusion is the cause of dementia, as they may occur together. Evidence for the cardiac effects on the brain include: (1) a higher frequency of cerebral infarcts and of cortical and ventricular atrophy (66) and (2) that cardiac failure is a risk factor for white matter low attenuation of brain (67). Heart failure may be a major unrecognized contributor to cognitive impairment in the elderly; it is potentially reversible with measures that improve cardiac output. Indeed improvement in cognition has been noted in these patients following cardiac transplantation (63). Coronary Artery Bypass Surgery Although post-operative delirium and short-term cognitive changes have been well-recognized complications of coronary artery bypass grafting (CABG), long-term cognitive changes have received increased attention recently. These long-term cognitive changes are often subtle, involving problems with following directions, mental arithmetic, and planning complex actions. In a prospective study by Newman et al. (68), a biphasic course to cognitive change after surgery was observed—an immediate postoperative decline followed by improvement and then a subsequent decline. Late cognitive decline was noted in 42% of patients undergoing CABG: these patients tended to be older and less educated, and had a higher cognitive performance at baseline. Although the mechanisms for the cognitive changes are likely to be multifactorial, it seems possible that a combination of hypoperfusion and microemboli results in initial brain injury during CABG (69).

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Patients at possible risk for late cognitive decline after CABG may benefit with attempts to slow the progress of atherosclerosis by means of diet, medications, and changes in life style and habits. Chronic Obstructive Pulmonary Disease Hypoxia and hypercapnea in chronic obstructive pulmonary disease COPD may contribute to cognitive decline. In one study, 48.5% of patients with COPD were found to have a specific pattern of cognitive deterioration characterized by a dramatic impairment in verbal and verbal memory tasks, well-preserved visual attention, and diffuse worsening of other functions (70). Furthermore, cognitive impairment was significantly and positively correlated with hypoxic-hypercapnic chronic respiratory failure. Another study showed that patients with COPD performed significantly worse than controls on verbal fluency tasks, although they were not in the clinically impaired range (71). It was thought that oxygen therapy might have partially accounted for preservation of cognitive function in these patients. Long-term oxygen therapy is largely used in the management of severe hypoxemia in patients with chronic obstructive lung disease. In these patients, long-term oxygen therapy improves not only cognitive function (72) but also emotional status and quality of life (73). Sleep Apnea The incidence of sleep apnea increases with age. Sleep apnea often accompanies degenerative conditions such as Alzheimer’s disease and multi-infarct dementia (74,75). In patients with sleep apnea, impairment of cognitive function, e.g., deficits in memory, attention, and visuoconstructive abilities are common. Sleep apnea may contribute to cognitive dysfunction through hypoxemia during sleep and damage sleep structure with few episodes of rapid eye movement (REM) sleep (76); both factors are associated with a decrease in acetylcholinergic neurotransmitter activity (77). Numerous case reports have described sleep apnea causing either delirium or dementia, managed successfully with nasal continuous positive airway pressure (78–80). Although sleep apnea has been found to be more common in patients with probable Alzheimer’s disease (than in either healthy or depressed controls), and the apnea index has been correlated with dementia severity (as graded by the Blessed Dementia Rating Scale) (74), the extent to which it exacerbates and/or is caused by the condition is still to be established. The possibility of sleep apnea should be considered in the elderly in the differential diagnosis of “reversible dementias,” increased daytime sleepiness, or unexplained right-sided heart failure. Liver Failure Hepatic encephalopathy is a well-recognized clinical complication of chronic liver disease, the most common of which is alcoholic-induced cirrhosis. It is a characterized by a wide spectrum of neuropsychiatric abnormalities. Clinical manifestations range from slightly altered mental status to stupor and coma. Neuromuscular symptoms range from tremor and asterixis (“flapping tremor”) to hypereflexia and decerebrate posture. The encephalopathy may be acute and reversible or chronic and progressive. In severe cases, irreversible coma and death may occur. The electroencephalogram characteristically shows bilateral synchronous slow waves. The specific cause of hepatic encephalopathy is unknown. However, it is likely that metabolic toxins from the intestine bypass the liver, cross the blood-brain barrier, and exert direct or indirect effects on the central nervous system (81). Although not all patients with hepatic encephalopathy have elevated blood levels, ammonia is the substance most often incriminated (82). False neurochemical transmitters, resulting from alterations in plasma levels of aromatic and branchedchain amino acids, may also play a role. Accumulation of gama-aminobutyric acid, the major inhibitory neurotransmitter in the central nervous system, may be important in the reduced levels of

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consciousness. There is also evidence for excessive manganese deposition in the basal ganglia that may contribute to the hepatic encephalopathy (83). Neuropathologically, hyperplasia of astrocytes with nuclear glycogen inclusions, laminar necrosis and gliosis of the cerebral cortex, zones of myelin degeneration and fine vacuolization characterize hepatic encephalopathy (84). Positron emission tomography (PET) has shown significant decreased glucose utilization in the cerebral cortex, suggesting that cerebral hypometabolism could explain the neuropsychiatric abnormalities characteristic of hepatic encephalopathy (85). Therapy includes timely recognition and correction of precipitating factors (e.g., gastrointestinal bleeding). Standard therapy consists of administration of nonabsorbable disaccharides such as lactulose. The mode of action is uncertain but may involve bacteriostatic effects, cathartic effects, or enhancement of conversion of ammonia to ammonium. Nonabsorbable antibiotics (e.g., neomycin) are also effective, although absorption of a small fraction may cause ototoxic and nephrotoxic side effects. Limitation of protein in the diet may be useful for a short period but is not recommended for long-term use because of potential worsening of already compromised nutrition. Experimental therapies include use of branch chain amino acids and flumazenil. Often it is a reversible metabolic syndrome. Renal Failure The symptoms of uremic encephalopathy are dependent on the magnitude of renal failure as well as the rate of development of uremia (86,87). As with most metabolic encephalopathies, alterations of alertness and awareness of the environment are early symptoms. Patients may complain of mild headache, inability to concentrate, and they may appear apathetic. The patient and their families may not appreciate these subtle disturbances of central nervous function. Behavioral changes and errors in judgment soon follow, which may be associated with neuromuscular irritability, including cramps, hiccoughs, and fasciculations. With the progression of uremia, confusion and disorientation may ensue. The attention span may be further shortened, and memory failure occurs. The patterns of sensorial changes are characteristic of delirium and are distinguishable from that of early dementia. In terminal uremia, stupor and subsequently coma occur. The coma may be severe with total unresponsiveness. With treatment of uremia, mental status usually is recovered. However, despite dialysis, some patients may continue to have mild cognitive impairment and nonspecific symptoms of fatigue and irritability. Neurologic Complications of Dialysis Dialysis disequilibrium may occur during the first few dialyses in association with rapid reduction of blood urea levels (86,88). It is manifested clinically by nausea, emesis, drowsiness, headache, muscle cramps, and, rarely, seizures. The syndrome has been attributed to cerebral edema and increased intracranial pressure due to the rapid (dialysis-induced) shifts of osmolality and pH between extracellular and intracellular fluids (89). The use of slower blood flow rates and the addition of an osmotically active solute to the dialysate during dialysis has led to a decreased incidence of dialysis disequilibrium. Dialysis dementia is a fatal condition that complicates chronic dialysis. The condition is characterized by subacute progression of speech dyspraxia, dysarthria, and dysphasia. Subsequently, facial grimacing, asterixis, and generalized myoclonus may develop. In the terminal stage of the syndrome, generalized seizures and dementia are noted. The leading theory is that aluminum intoxication is the major contributor to the syndrome (86,90) Accordingly, purification of the dialysate, as well as decreasing the amount of aluminum ingested by end stage renal disease

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patients has resulted in a near disappearance of this syndrome. The recommended treatment is infusion of deferoxamine, a chelating agent.

FREQUENCY AND REVERSIBILITY OF COMORBIDITIES IN DEMENTIA The frequency and nature of comorbidities in dementia will vary depending on the population surveyed. For example, persons with dementia who present to hospitals or primary care clinics are likely to have worse comorbidities than those who present to specialized memory centers (e.g., Alzheimer’s disease research centers). Most information on dementia comes from detailed characterization of participants in research centers. In a longitudinal study of healthy aging and dementia of the Alzheimer’s type (DAT) at Washington University, 489 research participants evaluated from 1990–1998 met criteria for DAT. Of these 489 participants with DAT, 145 (30%) had comorbidities with the potential to cause dementia. However, based on the criteria of: (1) a clear association of the comorbidity with the onset of the dementia and/or (2) a clear alteration in the course of the dementia with the occurrence of the comorbidity, only 29 (6%) had comorbidities believed to contribute to the DAT. Table 3 shows the distribution of the comorbidities complicating DAT in this sample. Compared with those with “pure” DAT, the presence of comorbidities was found to predict worse psychometric (e.g., psychomotor speed) and functional (e.g., personal care) impairment (91). An important goal in the initial evaluation of dementia is the identification and treatment of potentially reversible causes. However, although many comorbidities are potentially reversible, the

Table 3 Distribution of Comorbidities Among 489 Subjects with Dementia of the Alzheimer’s Type (DAT) Participating in the Longitudinal Study of Healthy Aging and DAT at Washington University from 1990–1998 DAT-NCa

Depression Cerebrovascular disease Hypothyroidism Parkinson’s disease Head trauma B12 deficiency Alcoholism Medication-induced Other neurologic/ medical diseases Cardiovascular disease Neurologic disease Neoplastic disease Rheumatologic disease Diabetes mellitus Hematologic disease Pulmonary disease Miscellaneous a

DAT-Cb n

(%)

73 25 11 10 8 7 5 3

(38) (13) (6) (5) (4) (4) (3) (1)

12 11 7 6 3 2 1 8 192

(6) (6) (4) (3) (1) (1) (.5) (4)

Depression Cerebrovascular disease Medication-induced Parkinson’s disease Head trauma B12 deficiency Alcoholism Hypothyroidism Other neurologic/ medical diseases Cardiovascular disease Neurologic disease Rheumatologic disease Pulmonary disease

n

(%)

18 8 2 2 1 1 1 1

(41) (18) (5) (5) (2) (2) (2) (2)

4 2 2 1/43

(9) (5) (5) (2)

DAT-NC Z DAT with comorbidity believed not to contribute to the dementia. DAT-C Z DAT with comorbidity believed to contribute to the dementia; some participants had more than one comorbidity. b

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proportion of comorbidities that actually reverse with treatment may be less than previously believed. In Clarfield’s meta-analyses of 32 studies (2,889 subjects) from 1966 to 1987 (92), 13.2% of subjects were determined to have potentially “reversible” causes of dementia. In the 11 studies that provided follow-up, 11% resolved, either partially (8%) or fully (3%). The most common reversible causes were medications (28%), depression (26%), and metabolic conditions (15%). However, most studies were from tertiary centers and because of various biases (e.g., selection), it was concluded that the true incidence of reversible dementias in the community was overestimated. On the other hand, in a more recent meta-analyses of 16 studies from 1972 to 1994, Weytingh et al. (93) reported that the percentages of reversible dementia varied widely: from 0 to 23% for partial and from 0 to 10% for full reversal. In the four most recent studies, less than 1% had reversible dementia. The decrease in number of reversible causes was attributed to the shift from an inpatient to an outpatient setting and the use of stricter diagnostic methods for dementia.

DIAGNOSTIC EVALUATION Although dementia rarely is reversible, it is important to evaluate the patient for comorbidities, because treatment may slow or stop neurological deterioration. This is of particular importance in the elderly, who commonly have coexisting disorders that can adversely affect cognitive function. The evaluation should include a careful history (including mode of onset and history of progression of the illness) and physical examination to determine any signs and symptoms suggesting existing medical, neurologic, or psychiatric illnesses. All patients should be screened for depression. Prescription and nonprescription drugs should be reviewed carefully as a potential cause of cognitive impairment. In the laboratory evaluation for treatable factors, it is important to follow a cost-effective approach. In general, diagnostic tests include a complete blood count, electrolytes, liver functions, blood urea nitrogen/creatinine, folate, and B12 levels, and thyroid function. These simple laboratory tests usually are sufficient to diagnose the majority of treatable dementias (94). Other tests such as toxicology screen, electroencephalogram, or cerebrospinal fluid analyses are obtained only as indicated by the history and based on clinical judgment. To complete the work-up, a neuroimaging study may be obtained, but is not usually required for diagnosis unless warranted by unusual findings.

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64. Barclay LL, Weiss EM, Mattis S, Bond O, Blass JP. Unrecognized cognitive impairment in cardiac rehabilitation patients. J Am Geriatr Soc 1988; 36:22–28. 65. Pullicino PM, Hart J. Cognitive impairment in congestive heart failure?: embolism versus hypoperfusion Neurology 2001; 57:1945–1946. 66. Schmidt R, Fazekas F, Offenbacher H, Dusleag J, Lechner H. Brain magnetic resonance imaging and neuropsychologic evaluation of patients with idiopathic dilated cardiomyopathy. Stroke 1991; 22:195–199. 67. Raiha I, Tarvonen S, Kurki T, Rajala T, Sourander L. Relationship between vascular factors and white matter low attenuation of the brain. Acta Neurol Scand 1993; 87:286–289. 68. Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal assessment of neurocognitive function after coronary- artery bypass surgery. N Engl J Med 2001; 344:395–402. 69. Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998; 55:1475–1482. 70. Incalzi RA, Gemma A, Marra C, Muzzolon R, Capparella O, Carbonin P. Chronic obstructive pulmonary disease. An original model of cognitive decline. Am Rev Respir Dis 1993; 148:418–424. 71. Kozora E, Filley CM, Julian LJ, Cullum CM. Cognitive functioning in patients with chronic obstructive pulmonary disease and mild hypoxemia compared with patients with mild Alzheimer disease and normal controls. Neuropsychiatry Neuropsychol Behav Neurol 1999; 12:178–183. 72. Hjalmarsen A, Waterloo K, Dahl A, Jorde R, Viitanen M. Effect of long-term oxygen therapy on cognitive and neurological dysfunction in chronic obstructive pulmonary disease. Eur Neurol 1999; 42:27–35. 73. Zielinski J. Effects of long-term oxygen therapy in patients with chronic obstructive pulmonary disease. Curr Opin Pulm Med 1999; 5:81–87. 74. Erkinjuntti T, Partinen M, Sulkava R, Telakivi T, Salmi T, Tilvis R. Sleep apnea in multiinfarct dementia and Alzheimer’s disease. Sleep 1987; 10:419–425. 75. Reynolds CF, III, Kupfer DJ, Taska LS, et al. Sleep apnea in Alzheimer’s dementia: correlation with mental deterioration. J Clin Psychiatry 1985; 46:257–261. 76. Ferguson KA, Fleetham JA. Sleep-related breathing disorders, 4. Consequences of sleep disordered breathing. Thorax 1995; 50:998–1004. 77. Gibson GE, Jope R, Blass JP. Decreased synthesis of acetylcholine accompanying impaired oxidation of pyruvic acid in rat brain minces. Biochem J 1975; 148:17–23. 78. Steiner MC, Ward MJ, Ali NJ. Dementia and snoring. Lancet 1999; 353:204. 79. Whitney JF, Gannon DE. Obstructive sleep apnea presenting as acute delirium. Am J Emerg Med 1996; 14:270–271. 80. Munoz X, Marti S, Sumalla J, Bosch J, Sampol G. Acute delirium as a manifestation of obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1998; 158:1306–1307. 81. Abou-Assi S, Vlahcevic ZR. Hepatic encephalopathy. Metabolic consequence of cirrhosis often is reversible. Postgrad Med 2001; 109:52–60. See also page 63. 82. Jones EA. Pathogenesis of hepatic encephalopathy. Clin Liver Dis 2000; 4:467–485. 83. Rose C, Butterworth RF, Zayed J, et al. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology 1999; 117:640–644. 84. Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome: a clinical and pathological study of 245 patients, 82 with post-mortem examinations. Contemp Neurol Serv 1971; 7:1–206. 85. Kato A, Suzuki K, Kaneta H, Obara H, Fujishima Y, Sato S. Regional differences in cerebral glucose metabolism in cirrhotic patients with subclinical hepatic encephalopathy using positron emission tomography. Hepatol Res 2000; 3:237–248. See also pages 6–17. 86. Palmer CA. Neurologic manifestations of renal disease. Neurol Clin 2002; 20:23–34. 87. Mahoney CA, Arieff AI. Uremic encephalopathies: clinical, biochemical, and experimental features. Am J Kidney Dis 1982; 2:324–336. 88. Harris CP, Townsend JJ. Dialysis disequilibrium syndrome. West J Med 1989; 151:52–55. 89. Arieff AI, Massry SG, Barrientos A, Kleeman CR. Brain water and electrolyte metabolism in uremia: effects of slow and rapid hemodialysis. Kidney Int 1973; 4:177–187. 90. Mach JR, Jr., Korchik WP, Mahowald MW. Dialysis dementia. Clin Geriatr Med 1988; 4:853–867.

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91. Villareal DT, Grant E, Dominguez J, Morris J. The role of comorbidity in alzheimer’s disease (abstr). J Am Geriatr Soc 2000; 48:S109. 92. Clarfield AM. The reversible dementias: do they reverse? Ann Intern Med 1988; 109:476–486. 93. Weytingh MD, Bossuyt PM, van Crevel H. Reversible dementia: more than 10% or less than 1%? A quantitative review J Neurol 1995; 242:466–471. 94. Larson EB, Reifler BV, Sumi SM, Canfield CG, Chinn NM. Diagnostic tests in the evaluation of dementia. A prospective study of 200 elderly outpatients. Arch Intern Med 1986; 146:1917–1922.

19 Depression and Dementia Eugene H. Rubin Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Depressive disorders are common and are among the most disabling medical illnesses (1–3). The morbidity and mortality associated with major medical disorders are substantially increased when a depressive disorder co-occurs (3–6). Dementias are another group of central nervous system disorders that are devastating and disabling. Depression occurring in the presence of dementia leads to increased disability, suffering, and mortality (7,8). In this chapter, general issues concerning depressive disorders will be reviewed, followed by a discussion of the interactions and influences of depression on dementia of the Alzheimer’s type (DAT). The final section will deal with treatment approaches. TYPES OF DEPRESSION Depressive disorders are a group of brain disorders that involve the dysregulation of several of the following CNS functions: mood, self-esteem, self-preservation, concentration, ability to maintain interest, energy, motor activity, sleep, and appetite (9). There are different types of depression (Table 1). Some of these subtypes may be differentiated on a quantitative basis, i.e., involving severity and consistency of symptoms, whereas other subtypes may have qualitative differences. Although subtypes of depressions that are qualitatively different have yet to be defined pathophysiologically, differentiating them is useful because the pharmacologic treatments are different. Early onset bipolar affective disorder, depressed phase and early onset psychotic depression are two such disorders. Depression can occur as part of bipolar affective disorder. This type of depression usually begins at a young age and requires different treatment strategies than other depressive disorders. Mood stabilizers, such as lithium or valproate, are important elements of the treatment plan. A psychiatrist is usually involved in the management of patients with bipolar disorder and dementia, and this type of depression will not be further discussed. Another type of depressive disorder, psychotic depression, is characterized by psychotic symptoms in addition to the depressive symptoms considered as core symptoms of depression (Table 2). When a clear-cut psychotic depression occurs in a young or middle-aged individual, treatment with antipsychotic medication in addition to antidepressants or the use of electroconvulsive 349

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Table 1 Types of Depression Major unipolar depression Minor depression Dysthymia Subsyndromal depression Bipolar affective disorder, depressed phase Major depression with psychosis

therapy is usually a necessary part of treatment. Patients with young-onset, recurrent psychotic depression are usually followed by a psychiatrist. As patients age, some will develop DAT, and the psychiatrist most likely will remain involved with treatment. When an elderly patient with dementia develops a new-onset depression, psychotic symptoms, if present, usually resemble the psychotic symptoms that are common in DAT. It may be difficult to determine whether the psychotic symptoms are a result of depression, DAT, or both. The management of these patients will be discussed in the treatment section of this chapter. The above are two examples of depressive syndromes that are qualitatively different from the depressive syndromes that occur with dementias. These types of depressive disorders include major non-psychotic unipolar depression, minor depression, dysthymia, and subsyndromal depressions. Each of these disorders may be viewed as part of a continuum of depressive disorders. All of these disorders are associated with substantial disability, and treatment approaches are qualitatively similar. The exact definitional distinctions of these disorders may become blurred when dealing with the depressed patient with concurrent medical disorders (9–12). Major depressive disorder involves the consistent presence of at least five depressive symptoms (Table 2) over several weeks or longer. “Consistent” is defined as being present nearly every day for at least two weeks; furthermore, symptoms of depressed mood and diminished interest need to be present “most of the day, nearly every day” (9). Minor depression is less well characterized, but the proposed criteria for this disorder involve the presence of depressed mood and several other depressive criteria, but not enough to qualify as major depression, occurring over at least several weeks. Dysthymia involves depressive symptoms that are present for two years or longer but the number and consistency of the symptoms do not qualify as a chronic major depressive disorder. Subsyndromal depressions represent clinically significant depressive symptoms (sometimes defined by a mildly elevated score on a depression rating scale) that do not fulfill criteria for major, minor, or dysthymic depressive syndromes (11). Depression not otherwise specified (NOS) is a term for clinically significant depressive symptoms that do not easily fit into major depression, dysthymia, or bipolar affective disorder, depressed phase categories. Minor depression and subsyndromal depression, for example, could be classified as depression NOS unless a particular study specified these subtypes with defined criteria. Although it is unknown Table 2 Depressive Symptoms Depressed mood Diminished interest Low self-esteem or feelings of guilt Diminished desire to live/suicidal thoughts or plans Decreased concentration Diminished energy Psychomotor changes Changes in sleep patterns Changes in weight/appetite

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whether these disorders represent a continuum in terms of mechanism, even the mildest depressive disorder—subsyndromal depression—is associated with substantial disability and therefore deserves medical attention.

IMPORTANT ISSUES ABOUT DEPRESSIVE DISORDERS Morbidity Depressive disorders are associated with increased mortality and marked morbidity (1–3,13). Major depressive disorder is the illness most frequently associated with completed suicides, and the majority of people who take their own lives are ill with major depression, alcoholism, or both illnesses at the time of their deaths (14,15). The rates of completed suicides are higher in males than females. The rate of completed suicides in women peaks during midlife and then decreases (14). The rate of completed suicides in white males dramatically and continuously increases with age and reaches an annual rate exceeding 65 per 100,000 in men 85 years and older (16). Depressive disorders kill in ways other than suicide. People with depression in addition to other disorders like heart disease, diabetes, or cerebrovascular disease have increased morbidity and mortality from these other disorders (3,5,17). Increased morbidity and disability are associated with all types of depression including subsyndromal depression (11). Worldwide, depressive disorders are currently considered the fourth most disabling disorder and are predicted to be the second most disabling illness by 2020, second only to ischemic heart disease (2). Disabilities associated with depression have major impact on many aspects of life. Depressions are painful states and interfere with many bodily functions such as sleep, appetite, energy, and concentration. Untreated, these disorders lead to disruption involving school, jobs, and relationships. Simply stated, depressions can ruin lives. Prevalence Depressive disorders are common. About 10% to 15% of people suffer from a major depressive disorder during their lifetimes and 3% to 6% develop dysthymic disorder. Over a one-year period about 5% to 9% of adults develop a major depression and 2% dysthymia (1,18). Although the rates of minor depression and subsyndromal depression are less clearly documented, in people 60 and older minor depressive disorder occurs almost as frequently as major depressive disorder, and subsyndromal depressive disorder is more common than the other subtypes (11). Natural History The natural history of depressive disorder is extremely variable (19,20). Over two-thirds of people with this disorder have recurrent episodes throughout their lives, averaging an episode every five years. Only about 10–15% have a single episode, while up to 20% have chronic symptoms. Some patients with chronic illness, however, eventually improve (21). Mechanisms The mechanisms underlying depressive disorders are not fully understood. There is a substantial genetic component; these disorders tend to run in families (3). The susceptibility genes that increase risk have yet to be identified, but several will likely be characterized in the near future. In addition to genetic risk factors, stressors can be associated with depression (22). Although many people with a genetic diathesis have depressive episodes unassociated with concurrent stressors, the risk of depression, especially in those with genetic susceptibility, is increased by the presence of significant life stressors.

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The brain pathways responsible for depressive symptoms are being elucidated with the help of neuroimaging. Brain circuits involved with depression include portions of the frontal cortex, amygdala, thalamus, and striatum (23). Recent work has demonstrated that in familial depressions, there is substantial loss of glia in a specific portion of the frontal lobe (24,25). Central nervous system disorders that directly influence these circuits can be highly associated with depressions. Examples of such disorders include Parkinson’s disease, Huntington’s disease, and strokes, especially those involving frontal cortex. DEPRESSION AND DEMENTIA DAT is a disabling brain disorder. The “depression related” pathways described above are likely to be influenced by the neuropathologic changes associated with DAT. Neurotransmitters such as norepinephrine, serotonin, and dopamine have been implicated in depression, and the cells involved with these transmitters also can be influenced by DAT (12). In addition, DAT is a functionimpairing medical disorder with substantial associated stress. Therefore, both the direct CNS damage and the stress associated with a function-impairing illness would make it likely that clinically significant depressive symptoms co-occur commonly with DAT. Diagnosing Depression in Persons with DAT Diagnosing depression in a persons with DAT may be difficult for several reasons (12,26–28). Symptoms associated with DAT may overlap with depressive symptoms. For instance, diminished interest, concentration, and energy, as well as decreased psychomotor activity, are common in DAT. Although these symptoms may be more common and clinically more profound in people with both depression and DAT, without one or more of the psychological depressive features (low mood, diminished enjoyment, low self-esteem, guilt, suicidal thoughts) they are unlikely to represent depression (12). In addition, there may be a syndrome of apathy that coexists with DAT and may be distinct from depressive disorder (29,30). Obtaining an accurate history from a person with DAT may be problematic. The diagnosis of depressive disorder is usually derived from the history provided by the depressed individual with supporting information from collateral sources and medical records. At times a person with DAT may not recall his or her symptoms accurately. Therefore, information from a knowledgeable collateral source is essential. A person with DAT may become quieter and less interactive, which a collateral source may interpret incorrectly as depression. The clinician needs to seek objective evidence of depressive symptoms by asking whether the person specifically talks about being down, worthless or guilt-ridden; cries often; or wishes s/he were dead. The underlying brain deterioration resulting from DAT may interfere with the phenotypic appearance of depression. For instance, to fulfill the research definition of major depressive disorder, a person needs to have consistent symptoms, almost every day, for at least two weeks in a row. A person with DAT may not demonstrate persistent depressive symptoms. It is possible that the brain circuitry associated with depressive symptoms is variably disrupted resulting in fluctuating symptoms. In a recent study involving people with DAT who were also clinically depressed, it was rare for symptoms to be present continuously (28). It would be difficult to differentiate whether major depressive disorder presents differently in people with DAT or if true major depression is rare in these individuals and that they develop other depressive disorders like dysthymia, minor depression, or subsyndromal depressive disorder instead (31). It is, therefore, difficult to accurately subtype depressive disorder in people with DAT, and the clinician should be attentive to clinically significant depressive symptoms even if they fluctuate. The distinguishing symptoms of clinically significant depressive disorder include the psychologic features such as low mood, crying spells, diminished self-esteem, and thoughts related to suicide or wishing death would

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occur. If symptoms occur only occasionally, then the clinician should document how long they last, how frequently they occur, and the degree of associated suffering and disability. Brief screening questions may be helpful but in assessing depression in persons with DAT, questions should be asked of both the patient and collateral source (32). A simple question addressing the amount of time in the last month that the person has felt down or sad may be a good screening question (32,33). Another brief alternative is the 4-item version of the Geriatric Depression Scale (32,34,35). Morbidity of Depression Together with DAT When depressive disorder coexists with DAT, patients suffer more and are more disabled. Depression can exacerbate both the cognitive and non-cognitive symptoms of DAT (8,36,37). Depression in DAT is associated with increased aggressivity and possibly with psychotic symptoms (38). When depression co-occurs with DAT, hospitalization rates increase (39). Depression shortens the life expectancy of persons with DAT (7). Depressive symptoms frequently respond to treatment, therefore, not to recognize this disorder is doing the patient a disservice. Issues Related to the Onset of Depression and Dementia Cognitive deficits can occur in people with depressive disorders (27,40,41). Sometimes these deficits are subtle, sometimes substantial. The deficits may involve attention, motivation, and concentration and may interfere with memory and new learning. In a younger person suffering from depression with cognitive deficits, DAT is usually not considered. If the cognitive deficits are closely time-linked to the depression and especially if the patient had prior cognition-impairing depressions that remitted, the cognitive changes are considered part of the depression and not an independent dementia. If the deficits in this younger, depressed person are substantial, the symptoms might be best described as a dementia of depression. In most of these young patients, the cognitive deficits reverse with successful treatment of the other depressive symptoms. When these people reach old age, it is unclear whether there is an increased risk for developing a degenerative dementia such as DAT. Depressive disorders can occur for the first time during the earliest stages of DAT. The preponderance of data suggests that depression does not predispose people to DAT, but rather that clinically significant depressive symptoms can occur at the very beginning of the DAT (42–47). It is becoming increasingly clear that very early stages of DAT (incipient DAT) can be accurately diagnosed and that progression of the disease may be very slow (48,49). Little is known about the mechanisms underlying depressive symptoms that occur during this early stage of DAT. The presence of depressive symptoms may be related to neuroanatomic influences on the depressionogenic pathways. Disturbances of depression-related neurotransmitter pathways may be occurring. It is also possible that some people are aware of subtle cognitive changes and that this becomes a stressor that contributes to the depressive symptoms. Some patients present to the clinician with a new-onset, late-life depression with accompanying cognitive deficits. In some cases, it may be difficult to differentiate a dementia of depression from depression with DAT. A careful history gathered from both the patient and a knowledgeable collateral source will often clarify the diagnosis. It may become evident that months or years of subtle but definite and progressive cognitive decline preceded the development of a depressive syndrome and that the depressive disorder has exacerbated these cognitive symptoms so that they have become more evident. In such cases, it is likely that both incipient DAT and the depressive disorder contributed to the symptoms. People with established DAT can become depressed during the course of their dementia. As described earlier, the symptoms of the depression may fluctuate. When the dementia progresses to a moderate or severe stage, it becomes increasingly difficult to determine if a depressive disorder is also present. Patients may have varying degrees of aphasia. Also, their ability to comprehend

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questions pertaining to depression is significantly compromised. They may not be able to describe or even recognize their emotions. When patients with moderate to severe dementia have a change in behavior especially involving crying spells, sleep changes, loss of appetite, and agitation, depression must be considered. Since similar behaviors may occur if the patient develops psychotic symptoms or even a delirium, careful observation is important, coupled with a high index of suspicion for common medical causes of delirium. Information from a knowledgeable collateral source is very useful. After careful evaluation, empirical treatment for depression may be warranted. Treatment Issues The mechanisms underlying depressive disorders accompanying DAT may include one or more of the following: genetic predisposition (especially in patients with early onset depressive disorder), stress associated with having a function-impairing medical disorder, direct neuroanatomic influence on depressionogenic pathways or neurotransmitters by the processes underlying DAT, underlying medical disorders, or pharmacologic treatments that may exacerbate depressive symptoms. The preponderance of evidence regarding depressive disorders, including depressive disorders associated with DAT, is that depressive symptoms can improve with treatment (12,50–53). Treatment strategies must be individualized to the patient. It is important to evaluate patients medically to check whether depressive symptoms are related to other medical disorders or drugs. For instance, a patient who has been recently placed on high doses of steroids may develop a depression that remits when the dose of steroid is decreased. Depressive disorders are associated with suicide, and it is absolutely imperative for the clinician to evaluate the patient for suicidal thoughts or plans. The patient’s family should be asked if the patient has demonstrated suicidal symptoms. It is important to have family involvement in minimizing the risks of a person shooting or hanging him or herself, overdosing on medication, or asphyxiating from car or stovetop/oven fumes. If suicide risk is high, then the patient should be treated as a person with a medical emergency and referred for urgent treatment. The clinician should evaluate the frequency and severity of depressive symptoms. This can be done by assessing each symptom and developing a personalized scale regarding the symptoms that the clinician wants to target. A standardized battery such as the Geriatric Depression Scale (34) or the Hamilton Rating Scale for Depression (54) may also be useful. With more demented individuals, assessing the degree of agitation, crying, sleep, and appetite disruption from information provided by the collateral source or nursing home can be useful. Specific treatment strategies may involve a combination of psychologic and pharmacologic approaches (12,50–52,55,56). Importantly, both the patient and the collateral source should be educated about the nature of depression and the effect that this illness can have on how a person feels and functions. The patient and family need to know that the depressive symptoms are treatable and that the physician and treatment team care about the patient’s mental health and will be available. The therapeutic value of instilling hope and comfort is extremely important in dealing with an illness like depression. Frequent follow-up, independent of specific psychotherapy, is important. The purpose of frequent follow-up is to provide continued education about the illness, assess progress, encourage compliance with treatment, and convey continued hope and interest. In a primary care setting, such follow-up is associated with decreased symptoms and increased compliance (57). If the patient has only recently been diagnosed with DAT and is not yet receiving treatment for DAT, then the initial pharmacologic approach in treating the depression may be to initiate pharmacologic treatment for the dementia. This assumes that the depressive symptoms are not severe. Cholinesterase inhibitors may lead to improvement of non-cognitive symptoms of DAT including mild depressive symptoms (58). Therefore, if appropriate in terms of the dementia, initiating a cholinesterase inhibitor together with the non-specific psychologic treatments

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mentioned above may be sufficient to help a person with mild depression and DAT. Again, frequent visits to assess benefit and provide support are important. If depressive symptoms are severe or if milder depressions haven’t responded to the above treatments, then specific therapies targeting depression are necessary (12,53,59). In people who are cognitively capable of participating in depression-specific psychotherapies, cognitive therapy or interpersonal therapy may be beneficial (12,55,56). There are data demonstrating that these approaches can be helpful in depressed patients with or without accompanying medical illnesses. Although the effectiveness of these approaches in patients with dementia is less documented, some patients with incipient or very mild DAT and depression may prefer psychotherapy to pharmacotherapy. This preference might improve the effectiveness of the psychotherapy and such patients can be referred for a course of treatment. It is strongly recommended that the physician also follow the patient to monitor symptoms. If deterioration should occur, then pharmacotherapy should be added. Some patients prefer pharmacotherapy over specific psychotherapy. There are many effective antidepressants. The tricyclic antidepressants are no longer first-line treatments. They can be effective but have significant side effects related to their anticholinergic properties, sedative effects, and orthostatic hypotensive effects. The new generation antidepressants including serotonin selective reuptake inhibitors (fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine) and other agents (such as venlafaxine, nefazodone, mirtazepine) can be effective (59). It is best for the treating physician to become familiar with several agents. One needs to be aware of potential drug interactions especially involving inhibition of the cytochrome p450 systems (60). Antidepressants need to be taken for several weeks before a response is to be expected. Dosing should take into account a specific agent’s pharmacokinetic profile, other agents that the person is taking, and the age and illness-adjusted functional integrity of the organs that clear the specific drug (liver and/or kidney). Good pharmacotherapy involves more than prescribing a pill. Non-specific therapeutic interventions including concern, education, and frequent follow-up remain important. If a good response isn’t achieved after a 6–8 week trial of an antidepressant agent at a reasonable dose, then changing to a different antidepressant is indicated (61). If the patient’s affective condition deteriorates or the patient isn’t following treatment recommendations, referral to a psychiatrist is indicated. Psychiatrists may utilize combinations of medications or consider augmenting the antidepressant with a mood stabilizer such as lithium or valproate. Also, for severe depression, electroconvulsive therapy offers the psychiatrist another viable and sometimes lifesaving treatment (62,63). Treatment should be continued for 6–9 months after resolution of symptoms. If a person has a history of recurrent depressions, long-term treatment may be indicated. As is always true, the clinician must evaluate risk of treatment versus potential and actual benefit. If a decision to stop treatment is reached, slow tapering is recommended. Should symptoms re-emerge, a return to the effective dose is indicated. Patients with DAT and depression may also have psychotic symptoms. Psychosis is common in DAT without depression and can also occur with depression alone. Psychotic symptoms (delusions and/or hallucinations) may improve with the treatment strategies discussed previously, i.e., non-specific support, antidementia medications, and/or antidepressants. If psychotic symptoms persist after such interventions, the next pharmacologic step would likely be a trial of a new generation antipsychotic. Such treatment is more effective than placebo for agitation and psychotic symptoms but can have significant side effects, including a small increased risk of death (64). A careful risk/benefit decision would need to be made and should incorporate an evaluation of the severity and morbidity resulting from the psychotic symptoms as well as patient and family wishes. Sometimes the psychotic symptoms are mild and not uncomfortable to the patient. If the family learns to not overreact to such symptoms, patients may do better with support and tolerance than with yet another medication. For painful or disruptive behaviors resulting from psychotic

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symptoms, an antipsychotic medication is indicated. Each of the current new generation agents including clozapine, risperidone, olanzapine, and ziprazodone has different advantages and disadvantages. Any physician who works with patients with DAT should become familiar with the pharmacologic properties of several of these agents. If symptoms do not respond, referral to a psychiatrist who is familiar with these agents and other pharmacologic approaches should be considered. Extreme caution is necessary when using an antipsychotic medication in patients with Lewy body dementia because these patients exhibit extreme sensitivity to the Parkinsonian side effects (65). Old generation antipsychotics like haloperidol are contraindicated in Lewy body dementia. If an antipsychotic is necessary, the physician should consider very low doses of a new generation antipsychotic. CONCLUSION Depressive disorders are common and among the most disabling illnesses to plague humankind. Depressive symptoms likely involve depressionogenic brain pathways. Depressive disorders have genetic, environmental, and, at times, neuroanatomic causes or correlates. Depressive disorders can co-occur with DAT. Symptoms of depression may be influenced by DAT and fluctuate more than in depressed patients without DAT. DAT alone is associated with symptoms that can be confused with depression, especially diminished interest, concentration, and energy. Diagnosis is also hampered by the variable ability of the patient to give an accurate history, and therefore an informed collateral source is helpful. Once depression is diagnosed, treatment is usually effective. Treatment should involve non-specific, supportive, and educational therapy together with either pharmacotherapy, specific psychotherapy, or both. If symptoms involve suicidality or if the depressive symptoms continue to deteriorate despite initial treatment attempts, then referral to a psychiatrist with expertise in geriatrics is indicated.

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20 Management of the Driver with Dementia David B. Carr Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Bonnie M. Dobbs Faculty of Rehabilitation Medicine and Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada

John C. Morris Washington University School of Medicine, St. Louis, Missouri, U.S.A.

THE OLDER DRIVER In North America, the dramatic aging of the population has led to older drivers being the fastest growing segment of the driving population (1). Currently, there are 23 million licensed drivers over the age of 65 years in the United States and this number is expected to increase in the next few decades (2). In addition, trends indicate that not only are older adults increasing the number of miles driven per year (3), they also are driving longer into old age. For instance it is estimated that at age 70, older adults can expect about 11 years of driving life expectancy (4). Thus, over the next few decades, there will be a greater number of older adult drivers on our roadways. Efforts to evaluate driving safety and revoke privileges of unsafe older drivers, particularly drivers with a dementia, have increased in recent years. Those efforts may appear unwarranted based on the absolute crash rate of older drivers. That is, adult drivers over age 65 account for a small percentage of all motor vehicle crashes and injuries because there are fewer licensed drivers in this age group relative to other age groups and because of the reduced driving exposures (e.g., miles driven) of older drivers (5). Nonetheless, safety concerns about driving performance of at-risk older drivers are justified when crash rates based on exposure are taken into consideration. Studies indicate that the crash rates per mile driven for elderly drivers aged 65 to 74 are two-fold higher when compared with middle age drivers, and that rate increases to six-times higher for drivers 85 years and older (6). This increased crash rate per miles driven has been attributed in part to age related changes in sensory, motor, and cognitive changes (7). However, it also is likely that increases in crash rates of older drivers, in comparison to middle-age drivers, are caused by the deleterious effects of diseases and the medications used to treat them (8). 361

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DRIVING PATTERNS OF INDIVIDUALS WITH DEMENTIA Dementia of the Alzheimer’s type (DAT), the most common dementing illness, currently afflicts over 4.5 million individuals, or approximately 15% of adults over age 75, in the United States (9). In Canada, approximately 5% of individuals 65 years of age and older have Alzheimer’s disease, increasing to 25% for those 85 years of age and older. Cognitive symptoms of DAT and related dementias include difficulties in recent memory, orientation, concentration, information processing, attentional deficits, and disturbances in executive functions. These cognitive impairments increasingly interfere with social and occupational functioning and performance of accustomed activities, including driving. Dementia is a major factor in driving cessation, as all individuals with progressive dementia eventually become unable to drive. Research on driving and dementia indicates that many drivers with a dementing illness continue to drive (11,12), many well into the disease process. It has been estimated that 4% of current drivers aged 75C have cognitive deficits consistent with dementia (13). Results from one study that examined the mental status of older adults during driver license renewal using a brief cognitive screen found that as many as 6% of persons 65 to 69 year old and almost 20% of those 80 years and older were impaired (14). Taken together, these studies may underestimate the actual number of demented drivers on the road since some older drivers with memory loss may choose not to renew their license or may forget to do so as they continue to drive. Some studies suggest that drivers with dementia limit their driving exposure. For example, Trobe and colleagues found that individuals with DAT drove an average of 4800 kilometers annually in the two years before they stopped driving, compared to an annual average of 8000 kilometers driven for all drivers aged 70 to 74 (15). Other studies also indicate that, as a group, older demented drivers limit their driving exposure (16,17). Despite the reduced exposure, drivers with a dementia have crash rates that exceed those of healthy older drivers, a point that will be elaborated in the section that follows.

STUDIES ON THE IMPACT OF DEMENTIA ON DRIVING COMPETENCE Studies assessing the effects of dementia on driving performance have addressed different patient populations, levels of dementia severity, and outcomes. Most have focused on the general syndrome of “dementia” or DAT although a few have included subjects with vascular dementia (18,19). We are unaware of any studies that focus on driving and atypical dementias, such as dementia with Lewy bodies or frontotemporal dementias. Thus, this chapter focuses primarily on driving studies related to DAT. Crash data, in general, indicate that drivers with a dementia have higher rates of crashes than cognitively intact drivers of the same age. The evidence suggests that drivers with a dementia have a two- to eight-fold greater risk of crashes compared to those that are not demented (20), but this increased risk is not found in all studies (15). The variability in findings can be explained by the varied definitions of crashes (self-report vs. state recorded) and settings (referral centers vs. community settings). Importantly, reports of crashes obtained by questionnaire from drivers with DAT or their caregivers commonly underestimate the number of crashes because of inaccurate recall or unwillingness to provide information (21). In addition, the risk of a crash for DAT appears to increase with the duration of driving after disease onset (22). It has been stated that reductions in exposure may compensate for the driving impairments of drivers with a dementia. However, despite the limitation in exposure by those with a dementia, the higher crash rates of drivers with a dementia argue against the assumption of reduced risk due to compensatory driving behaviors. Rather, the increased crash rates of drivers with a dementia indicate that there is cause for concern. Moreover, driving exposure patterns for older drivers are changing. Currently, drivers age 65 and older are increasing their exposure at a faster rate than

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drivers under age 65, and that trend is expected to continue. In addition, future generations of elderly drivers will likely have an increased reliance on their automobile and drive considerably more miles, suggesting that per capita crash rates may well increase in this age group. Combined with the growing number of older drivers with a dementia over the next few decades, increased driving exposure will exacerbate public safety concerns regarding drivers with a dementia or other forms of cognitive impairment. In addition to crash rates, performance-based evaluations such as road tests and simulators have been used to assess the driving competency of those with a dementia. Those studies are summarized in Table 1 (23). Results of those studies indicate that many, but not all, demented individuals have difficulty in actual driving situations. That is, some drivers in the early stages of the disease are still competent to drive, indicating that decisions about driving competency cannot be based on diagnosis alone.

OFFICE ASSESSMENT OF DRIVING COMPETENCE IN INDIVIDUALS WITH A DEMENTIA Consensus Statements A number of guidelines and consensus statements related to drivers with dementia have been published over the last several decades to assist clinicians in evaluating drivers with dementia. Guidelines and consensus statements, in general, have the potential to improve consistency in decision making by practitioners in the clinical setting. However, both have limitations (24), including the lack of supporting evidence, a focus on a single medical condition versus the reality of multiple medical problems, multiple medications, the combined effects of co-morbidities and medications in this patient population, and the broadness of the guidelines/statements. A summary of recent consensus statements is presented in Table 2 (23). Common themes are identified within the various consensus statements. These themes include the recommendation for physicians to play an active role with respect to issues of driving in their demented patients. In addition, on-road assessments of driving competence serve as the “gold standard” evaluation for patients in the early stages of the dementia. There is less agreement, however, on the use of psychometric tests and global mental status screens such as the Mini-Mental State Examination (MMSE) (25) as the basis for decisions about driving competency. The American Academy of Neurology guidelines (26) recommend that persons in the mild stage of DAT discontinue driving. This recommendation discounts evidence that at least some drivers with mild dementia still perform well on road tests (27). Indeed, crash rates using state-recorded data were no different for mildly demented drivers compared to controls in one study (28). Although the development and publication of consensus guidelines represent important steps in providing assistance to clinicians in caring for individuals with dementia who drive, the determination of who is able to drive safely, who is not, and consequently when to revoke driving privileges remains a highly individualized process. Dementia Diagnosis It has been argued that the diagnosis of dementia alone is sufficient for the recommendation to cease driving. However, some demented drivers may be competent to drive in the early stages of their illness (27). Licensing decisions based only on the diagnosis of dementia may unfairly penalize patients and prematurely limit independence and mobility. Thus, a diagnosis of dementia should not be the sole justification for the revocation of a driver’s license. Unfortunately, primary care clinicians may not always utilize available screening measures for dementia, and the diagnosis often is undetected in some settings (29). Recent educational interventions with physicians suggest

Prosp

Prosp

Prosp

Prosp

Prosp

Hunt et al. (27) 1997

Fitten et al. (18) 1995

Harvey et al. (80) 1995

Rizzo et al. (81) 1997

Rebok et al. (82) 1994

DAT

DAT (10) focal dementia (3)

DATVMild (12) DATMild (13) DAT/MID

Dementia mostly DAT

Diagnosis

SZ21 CZ18 SZ10 CZ12

SZ65 CZ58 PDATZ15 PMIDZ12 CDIABZ15 COZ26 CYZ16 SZ13

SZ115 CoZ35 CYZ23

Sample size

DPI, DAS, neuropsych tests

Driving simulator

Driving simulator

54% patients “normal” performance 46% patients “poor” performance 29% of S “crashed” vs. 0% for controls; S twice as likely to experience close calls compared to controls S scored significantly worse on 3 of the 5 performance subscales of the DPI; S significantly slower on simple, two choice and conditional RT and significant increase in number of false alarms and pedal errors

Isolated 3 categories of driving errors (1) Non-discriminating—made by all drivers (2) Discriminating—rarely by young, most often by old, frequently by cognitively impaired (3) Hazardous or catastrophic—made only by cognitively impaired 40% of mild S failed road test; all controls and S (very mild) passed the road test Dementia patients significantly worse on road test

Road test, neuropsych battery, neurocog battery

Road test, neuropsych tests Road test, neurocog tests, C/G crash reports

Results

Criterion

Abbreviations: S, subjects with dementia or DAT; Co, older control; DPI, driver performance test; DAT, dementia of the Alzheimer type; Cy, young control; DAS, driver advisement system; C, controls; Prosp, prospecive study; CDR, clinical dementia rating.

Prosp

Study design

Dobbs et al. (47) 1997

Study

Table 1 Summary of Road Tests and Driving Simulators on DAT/Dementia

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Evidence-based review Consensus statement

Evidence-based review Clinical consensus

Clinical consensus

Evidence-based review Clinical consensus

The American Academy of Neurology (17)

American Association of Automotive Medicine (AAAM) Medical Conditions Policy Guidelines (83)

The Canadian Medical Association (84)

The Canadian Consensus Conference on Dementia (85)

(Continued)

(1) Persons with AD with a severity of CDRa of 1or greater should not drive an automobile. (2) Persons with AD with a severity of CDR 0.5 should be referred for a driving performance. evaluation by a qualified examiner. Because of the high likelihood of progression, dementia severity and appropriateness of continued driving should be reassessed every 6 months. Physicians should: (1) Conduct focused medical assessments that include a history of driving difficulties and a physical exam focused on cognitive abilities such as memory, attention, reaction time, judgment, and visuospatial abilities. (2) Be aware that driving difficulties may indicate other cognitive/functional problems. (3) Encourage early planning for eventual cessation of driving privileges. (4) Advocate for the establishment and access to affordable, validated performance-based driving assessments. (1) Those with a MMSE of ! 24 are prohibited from driving any class of motor vehicle pending a complete neurological assessment. The ineligibility to drive applies until irreversible mental impairment is confirmed or denied. (2) Persons with an MMSE of 24 or higher who show signs of poor judgment, poor reasoning ability, poor abstract thinking, and poor insight should be evaluated for driving ability. When caring for patients with cognitive impairment, physicians should: (1) Consider risks associated with driving. Focused medical assessments are recommended in addition to the medical evaluation. (2) Be aware that driving difficulties may indicate other cognitive/functional problems that need to be addressed. (3) Encourage patients and their caregivers to plan early for eventual driving cessation and provide support to those who lose their capacity to drive. (4) Notify licensing bodies of concern regarding competence to drive, even in those provinces that do not have legislated mandatory reporting, unless patient gives up driving voluntarily. (5) Advocate strongly for the establishment and access to affordable, validated performance-based driving assessments.

Table 2 Summary of Consensus Statements on Driving and Dementia

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Clinical consensus

Geriatric Assessment Center Multidisciplinary Approach (87)

(1) Those with moderate to severe dementia should not drive (CDRZ2, 3). (2) Those with mild dementia (CDR 0.5 – 1) should be assessed, preferably by an on-road test. (3) When dementia is mild, but the patient shows signs of functional deterioration (e.g., impairments in IADLH), a thorough assessment of driving and driving-related abilities should be conducted. Recommend restriction or cessation of driving if the following are present in a patient with cognitive impairment: (1) Presence of impaired driving. (2) Functional dependencies in ADLsb and IADLsc. (3) Use of drugs or alcohol that may increase crash risk. (4) Severe cognitive deficits relevant to driving as indicated by neuropsychological testing. (5) Inability to be restricted or drive in a low risk environment. (6) Further evidence of impairment by a driver rehabilitation program. (7) Re-evaluation of drivers with cognitive impairment at regular intervals (history, physical exam, functional and cognitive testing, may also include a road test.

b

Clinical dementia rating. ADL, activities of daily living. c IADL, instrumental activities of daily living. Source: Adapted from Dobbs B, Carr DB, Morris JC. Evaluation and management of the driver with dementia. The Neurologist 2002; 8:61–70.

a

Evidence-based review Clinical consensus

The 1994 International Consensus Conference on Dementia and Driving (86)

Table 2 Summary of Consensus Statements on Driving and Dementia (Continued)

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that a continuing education approach may influence clinicians to address issues of driving and dementia in a clinical practice (30).

Mental Status Screens and Psychometric Tests Mental status screens (e.g., MMSE) or psychometric tests have been advocated as a means for determining the driving fitness of those with dementia (31,32). However, studies indicate that performance on mental status tests have limited utility for predicting crashes or on-road performance in dementia (33). Some studies report good overall correlations between MMSE scores and driving performance for drivers with a dementia, but little correlation between driving scores at the upper end of the MMSE scale where the prediction is most needed (18). Persons with intermediate MMSE scores (23–25) have been reported to have more adverse driving events than those with either higher or lower scores (34). Because of the low predictive power, performance on the MMSE is insufficient to use as the sole determinant regarding a patient’s driving abilities. Rather, the MMSE and other psychometric status screens can help to identify those individuals who may be in need of an on-road evaluation or some other validated evaluation process. Tests designed explicitly for prediction of driving abilities are stronger predictors of driving competence. For example, a battery of these tests was found to be 95 percent accurate in predicting on-road performance in cognitively impaired drivers (35). The American Medical Association has recently published a guide for the assessment and counseling of older drivers (36). One chapter of the guide is devoted to formal office assessment of driving, including assessment of vision, cognition, and motor function. However, as noted by Hogan (37) the “approach outlined has not been studied to determine whether it actually decreases risks for seniors and others on the road.” As such, performance on these tests should not be used at the sole determinant of driving ability but, rather, as a means of identifying drivers that should be referred on for further testing. Information on how to obtain a copy of the guide is provided in Table 3.

The Use of Global Assessments of Dementia Severity The Clinical Dementia Rating Scale (CDR) (38) is a global assessment of dementia severity that utilizes specific cognitive and functional assessments with detailed information from a collateral source. The CDR scale is used to rate ability in six cognitive-functional categories: Memory, Orientation, Judgment, Community Affairs, Home and Hobbies, and Personal Care. Category scores are used to determine an overall CDR score, with a score of 0 indicative of no impairment, 0.5 indicates very mild impairment, 1 indicates mild impairment, 2 indicates moderate impairment, and 3 indicates severe impairment. There is agreement between two of the consensus groups that staging instruments such as the CDR can be utilized in assessments of driving competence. However, the CDR requires considerable training and skill in its administration and scoring, limiting it usefulness on a broad scale. Given the limited amount of research correlating CDR severity and driving outcomes, more studies assessing the reliability and the validity of CDR scores in determining driving competence are needed before recommending the use of the CDR scale for driving competence decisions. For those that are proficient in administering the CDR, however, key elements from the CDR that may assist in identifying those at-risk drivers include (a) an individual’s previous level of performance and (b) global dementia staging based on evaluating several areas of cognitive and functional abilities (CDR 0.5 and 1). A recent study indicated that many of the study participants who had recently stopped driving were still at the very mild (CDRZ0.5) level of dementia severity (39).

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Table 3 Clinician and Caregiver Resources for Demented Drivers Clinicians American Occupational Therapy Association (AOTA): www.aota.org/olderdriver The Association for Driver Rehabilitation Specialists (ADRS): www.aded.net National Highway Traffic Safety Administration (NHTSA): http://www.nhtsa.dot.gov/ American Medical Association (AMA): Physician’s Guide to Assessing and Counseling Older Drivers: www.ama-assn.org/go/olderdrivers Dementia and Driving Toolkit: The Dementia Network of Ottawa: http://rgapottawa. com/dementia/rationale_en.asp Administration on Aging (AOA): www.aoa.gov/ American Association of Motor Vehicle Administrators’ older driver program: www.granddriver.info Insurance Institute for Highway Safety (IIHS): http://www.iihs.org/safetyfacts/ state_laws/older_drivers_html www.driveable.com Educational material for demented drivers Family and Friends Concerned About an Older Driver; Other older driver information and materials: http://www.nhtsa.dot.gov/people/injury/olddrive/ We Need to Talk and At the Crossroads: A Guide to Alzheimer’s Disease, Dementia, and Driving: http://www.thehartford.com/talkwitholderdrivers/brochure/brochure.htm, http://www.thehartford.com/alzheimers/brochure.html Nancy L. Mace, Peter V. Rabins The 36-Hour Day: A Family Guide to Caring for Persons With Alzheimer’s Disease, Related Dementing Illnesses, and Memory Loss in Later Life, 2001 Alternative transportation options AOA Eldercare locator: www.eldercare.gov AAA Foundation for Traffic Safety: www.seniordrivers.org Community Transportation Association of America’s senior information: www.ctaa. org/ntrc/senior_publications.asp Locate a Local Transportation Provider: http://www.publictransportation.org/systems/, or the Local Agency on Aging Source: Adapted from Carr D, Rebok GW. The older driver. In: Gallo JJ, Bogner HR, Fulmar T, Paverzga GJ, eds. Handbook of Geriatric Assessment. 4th ed. Boston, Masschusetts: Jones and Bartlett Publications, pp. 45–54.

Thus, unsafe driving behaviors or general concern regarding operating a motor vehicle with cognitive impairment may play a role in driving cessation even in the very early stages of the disease. Referral to Specialists Patients with dementia may be referred to specialists such as geriatricians, neurologists, geriatric psychiatrists, and neuropsychologists. However, the lack of reliable and valid tools for in-office assessments of driving skills remain a major challenge (40). For example, a recent study indicates that a physician specializing in dementia was able to more appropriately gauge driving abilities (safe, marginal, unsafe) in patients with a dementia (74% correct classification) compared to participants (53%) and informants (64%) (41). However, in that same study, driver instructor ratings on the relationship between driving ability and on-road driving scores were five times more sensitive than those of the physician. Research is clearly needed on tools to assist physicians in identifying potentially at-risk drivers. Informant Reports During the course of taking a driving history, caregivers and other family members should be queried about the driving performance of those with a dementia. The discussion should cover

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crashes, citations, close calls, following the rules of the road, and whether the patient becomes lost while driving in familiar areas. In undiagnosed individuals, a history of becoming lost while driving may help to identify dementia (42). It is important to note if informant concerns about driving abilities represent a change from prior performance. However, failure of informants to report problem-driving behaviors does not necessarily mean there is not a problem, as caregiver reports of driving ability do not always correlate with results from on-road assessments (43). The informant also may rely on the driver for transportation needs, which could result in a bias against reporting problems. Nonetheless, family members or caregivers may appreciate and communicate a decline in skills regarding driving performance. ASSESSMENT OF DRIVING SKILLS IN DRIVERS WITH A DEMENTIA Drivers with mild cognitive impairment or isolated short-term memory impairment may have a low risk for crashes, although there are few data relevant to driving safety in these early stages of what later may be recognized as DAT. An objective evaluation of driving skills in these very early stages may be indicated, particularly if there is objective evidence of driving impairment (crashes, traffic violations) or subjective concerns from the family about driving abilities. Some patients with DAT in more advanced stages of the illness have obvious problems with driving, such as crashes, failure to follow the rules of the road, and/or impairments in on-road driving performance. It probably is unnecessary to objectively test these patients. Rather, efforts should be focused on terminating driving privileges and finding alternative means of transportation. Testing is most useful for patients with very mild or mild DAT who continue to drive without apparent or known difficulties. Because almost half of all DAT patients are mild stage, there are sizeable numbers of individuals for whom formal driving assessment should be considered. For the majority of patients with mild and very mild dementia, performance-based measures of driving skill are recommended. Road tests and driving simulators have been used to assess driving competency in healthy older and cognitively impaired older drivers. Driving simulators typically observe and record an individual’s driving-related abilities using an array of simple-to-complex driving situations in a simulated driving environment. The major advantage is that the observations occur in a safe environment, but the artificial setting raises the issue of validity for even the most sophisticated simulators. To date, there has been insufficient correlation of simulator performance with on-road driving performance or crash data to recommend their use. Road tests are the preferred method to assess driving competency (44,45) because they are the only measure that directly evaluates on-road driving performance. A number of on-road assessments are available. Private driving schools, rehabilitation centers, or the Department of Motor Vehicles (DMV) may be able to road test patients with dementia. However, the standard driving examination was developed to assess the novice driver and may not be useful in the patient with dementia. Basic driving skills are highly ingrained in older drivers and often preserved even when mental abilities decline. Occupational therapists, often based at rehabilitation centers, have specific training and experience in evaluating drivers with medical impairments, particularly those with physical impairments. However, the majority of these evaluations are scored subjectively and lack standardization across jurisdictions (46). Driving evaluations that are designed specifically for the older driver with cognitive impairment may be preferable to determine driving competence. A scientifically-based driving assessment that meets these criteria is available in some parts of Canada and the United States (47). Costs of driving evaluations can be a barrier to assessing drivers with a dementia. Although on-road evaluations for medically at-risk drivers may be covered by third party providers, often they are not. Out-of-pocket expenses to an individual for an on-road assessment may range from $200 to $450 in Canada and $250–$400 in the United States. If older adults with dementia pass the

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initial road evaluation, future testing is warranted. With a progressive illness such as DAT, deterioration of driving skills is a certainty (48) and repeat testing should occur at six-to twelve-month intervals.

ASSESSING COMORBID CONDITIONS It is important to assess the presence of comorbid conditions that may increase risk for a crash or driving cessation in older adult drivers with cognitive impairment. Many conditions can impair driving (34,49–51). Polypharmacy also is common in older adults. There are many medication classes that have been noted to either increase crash risk or impair driving skills as assessed by simulators or road tests. These classes include: narcotics, benzodiazepines, antihistamines, antidepressants, antipsychotics, hypnotics, alcohol, and muscle relaxants. Very few investigations of the deleterious effects of medications have focused on older drivers, but a recent study noted that use of long acting benzodiazepines by elderly drivers was associated with increased crash rates (52). The presence of nonsteroidal anti-inflammatory drugs also may be a risk factor for crashes (53). Older adults may drive while intoxicated or under the influence of other medications (54,55). Careful attention to these issues, not only in cognitively intact older drivers, but also in drivers with a dementia is warranted.

DRIVING RESTRICTION AND CESSATION ISSUES Driving Restriction/Use of a Co-Pilot Restricted licenses for patients with dementia have been suggested. The presumption is that the restrictions define geographic areas or driving conditions that are less cognitively demanding and thus would be within the limited competence of the person with dementia. Some restrictions may be reasonable for older drivers who are nondemented due to sensory deprivation (e.g., not driving at night, not driving during peak traffic periods). However, compromised cognitive processing abilities in demented patients may result in unsafe driving even in a familiar environment, and it is questionable whether a cognitively impaired patient could consistently follow verbal recommendations. The use of a co-pilot has been advanced as a means of keeping the driver with a dementia mobile (56). However, no data are available to indicate that a co-pilot enhances driving safety. Rather, a person with dementia may perform less well by trying to direct attention both to the road and the co-pilot, as divided attention tasks are impaired in dementia (57). Thus, use of a co-pilot is strongly discouraged. Voluntary Driving Cessation Dementia is a major factor in driving cessation, as all individuals with progressive dementia eventually become unable to drive. Research suggests that many patients with dementia stop driving without input from their physician or an authority such as the DMV. For example, one study from a tertiary referral center indicated that 50% of drivers with dementia stop driving within 3 years of their diagnosis (58). Other studies have found that a significant number of individuals with even very mild or mild dementia had stopped driving (13). In general, individuals appear to respond better to advice from their physician to stop driving than to entreaties from their family (59). However, they may lack insight into the implications of their cognitive deficits and make compliance with driving restrictions or cessation an emotionally charged matter (47).

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Involuntary Driving Cessation Driving is central to independence and mobility. It is not surprising, therefore, that the stop driving directive is met with resistance. In individuals with a dementia, that resistance may be heightened due to impairments in insight. In addition to families, many older drivers prefer to hear about driving concerns from their physicians (60–62). Caregivers of drivers with dementia have also indicated that they desire physicians to take an active role regarding advice on driving retirement (63). Thus strategies that utilize physician input to stop driving may be more successful than reliance on family members alone. However, not all families will comply with the “stop driving” directive from a physician: results from a Canadian study indicated that 27% of individuals who had unsafe evaluations were continuing to drive even after physician directives to stop (64). Communication with the Patient and Family National organizations such as the American Medical Association (AMA), call on physicians and health professionals to assist patients and families with driving-related decisions (65). Because of the saliency of a driver’s license, discussions about driving can be emotionally charged. It is important, therefore, for health professionals to discuss recommendations for driving cessation in a sensitive manner. These discussions should be documented in the patients’ chart and in the presence of a responsible caregiver whenever possible. Providing information verbally and in writing to the patient and family member may be helpful in reinforcing these recommendations (66). Different strategies, which may include enforced driving retirement, have been suggested in the literature (67). In addition, conversations that acknowledge the negative consequences with revocation of driving privileges, and discussions about alternative ways to stay mobile may help to minimize the loss. Alternate Methods of Transportation Public transportation systems are available in all urban communities and in some rural communities (68), often with reduced fares for senior citizens. However, this form of transportation is likely to be suitable only for cognitively impaired individuals who are accompanied by others. State or locally sponsored “door-to-door” transport for older adults often is more appropriate for cognitively-impaired individuals. However, these services are not available in all areas. Local communities, societies, retirement centers, or local church groups may use funds or volunteers to provide transportation to physician offices, grocery stores, and meetings. Again, these services may be more appropriate for those with dementia as they are more likely to offer “door-to-door” or “arm-to-arm” service. The majority of those with dementia who have retired from driving, however, rely on rides from their informal support system (e.g., families, and friends). Unfortunately, many also cited difficulty in reaching social and recreational destinations despite having a licensed driver at home (69). Individualized transportation options are sorely needed for older adults with dementia in the community who lack the informal network of family or friends that can fulfill this role (70). Methods to Reinforce Recommendations for Driving Cessation Patients with DAT who refuse to stop driving despite the physician’s recommendation often lack insight. In these cases, the clinician may consider writing a letter to the state DMV outlining the need for revocation of driving privileges. In situations where the patient continues to drive against physician advice, other efforts to enforce driving cessation include involving the police or DMV to confiscate the drivers’ license, having the family remove access to car keys, moving the automobile off premises, changing the car door locks, filing down the ignition keys, or disabling the battery cable. These reported interventions are, however, largely anecdotal in nature, with research on their efficacy needed. Unfortunately, it often is the caregiver who must enforce the directive to stop driving. Currently, there are few, if any, programs available to assist the caregiver with this

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difficult task. Recently, specialized driving cessation support groups have shown improved outcomes compared to regular support groups in helping both the patients and caregivers to deal with the loss of driving privileges (71). Counseling regarding driving retirement and identifying alternate sources of transportation early in the disease process may help patients prepare for when they can longer drive (72). The Hartford guides “We Need to Talk” and “At the Crossroads” are excellent educational tools for the caregiver and should be considered as important steps in this process (73). In addition, recent focus group studies indicate that caregivers utilize community support groups such as the Alzheimer’s Association for assistance with driving retirement issues (74). Issues of driving cessation are difficult for patients, families, and health professionals. Nurse specialists can assist in reinforcing these recommendations and determining compliance. Social workers can recommend additional modes of transportation or living situations with a change in level of care. The Alzheimer’s Association may be able to assist with counseling, literature, support groups, and educational materials. Websites and organizations that may be of assistance regarding evaluation and/or counseling of demented drivers are listed in Table 3. ETHICAL, LEGAL, AND PUBLIC POLICY ISSUES Patients do not always comply or agree with a recommendation to stop driving. Physicians may simply decide to document this refusal in the chart, as long as the opinion is given to someone who has decisionmaking capacity. This situation may justify a letter to the state DMV. This breach of confidentiality may be ethically appropriate when performed in the best interest of the community (75). Most DMVs take into consideration the advice of the physician in revoking licensure, although there are appeal processes that are available to drivers. However, some physicians believe that the physician-patient relationship is negatively affected by reporting (76). Thus, this may be a substantial barrier to involving the state authorities. Physicians may find themselves in a double bind when it comes to the driving issue. They may fear litigation from the patient should they report the patient to the DMV, yet also fear they could be held liable for failing to report a medically unfit driver. A relevant cited U.S. case is Freese v. Lemmon in which a claim was brought against the physician of a patient who was known to have epilepsy and who had a seizure while driving, resulting in a crash (77). The Supreme Court of Iowa held that the attending physician negligently failed to advise the motorist not to drive and failed to warn him of the dangers of driving following a seizure. Forseability means that the patient’s medical condition is such that the physician could reasonably predict that it could lead to a crash, and was the basis for the judgment in this case. Because the common law and statues vary among states/provinces, legal counsel should be obtained to help guide this process for each locality. Some states such as California require physicians to report specific medical conditions such as dementia to the public health department. Clinicians should contact their state DMV and request a copy of the medical standards for a driver’s license, along with any legal or voluntary requirements for reporting unsafe drivers. A recent survey suggested that many clinicians are unaware of their state laws (78). Currently, the public safety problem posed by drivers with a dementia may not warrant routine screening for cognitive impairment during driver’s license renewal. In fact, a decision analysis utilizing a fairly high rate of crash risk concluded that this approach would currently not be cost-effective (79). However, the resulting increase in older adult drivers and the increasing prevalence of dementia and the resulting increase in older adult drivers with dementia, the public safety issue may eventually become prominent enough to warrant screening. Detection of a cognitive impairment in a DMV setting could result in a referral for a physician for an evaluation of cognitive abilities. If an individual fails the vision screen in most states, they are referred to an ophthalmologist for evaluation and treatment. Referral would not only assist in the identification of impaired drivers, but also detect those dementing illnesses that could respond to treatment.

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However, implementation of DMV cognitive screening has several obstacles, including selection of diagnostic instruments with appropriate sensitivity and specificity, and cost considerations. A brief test that identifies a driver with a dementing illness during driver’s license renewal, however, may be useful for referring for performance road testing and ultimately be helpful in reducing the number of unsafe drivers on our roadways. CONCLUSION There are significant numbers of drivers with dementia now, and that number is projected to increase significantly over the next several decades. Identifying and appropriately assessing those who may be at-risk are both critical issues if we are to reduce vehicle crash injuries and fatalities. Physicians are uniquely positioned to play a key role in the identification of drivers with a dementia whose driving abilities have declined to an unsafe level. However, physicians are hampered by the lack of valid and reliable in-office tools to assist them in identifying those who may be at-risk. In addition, physicians need access to performance-based driving assessments that are valid and reliable. Barriers to referral for those assessments, such as availability and affordability, need to be addressed. Reimbursement for physicians for in-office screening of at-risk drivers is needed. The lack of legal protection for physicians who do report an at-risk driver may deter physicians from participating in fitness-to-driver decisions; immunity protection should be implemented in all jurisdictions, with a move to consistency across states/provinces. Finally, medical education related to identification and evaluation of the medically at-risk driver needs to be introduced into the medical curriculum, along with the implementation of continuing medical education courses for practicing physicians.

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43. Hunt L, Morris JC, Edwards D, Wilson BS. Driving performance in persons with mild senile dementia of the Alzheimer type. J Am Geriatr Soc 1993; 41:747–753. 44. Donnelly R, Karlinsky H. The impact of Alzheimer’s disease on driving ability: a review. J Geriatr Psychiatry Neurol 1990; 3:67–72. 45. Kapust L, Weintraub S. To drive or not to drive: preliminary results from road testing of patients with dementia. J Geriatr Psychiatry Neurol 1992; 5:210–216. 46. Korner-Bitensky N, Sofer S, Kaizer F, et al. Assessing ability to drive following an acute neurological event: are we on the right track? Can J Occup Ther 1994; 61:141–148. 47. Dobbs AR. Evaluating the driving competence of dementia patients. Alzheimer Dis Assoc Disord 1997; 11:8–12. 48. Duchek J, Carr DB, Hunt L, et al. Longitudinal driving performance in early stage dementia of the Alzheimer’s type. J Am Geriatr Soc 2003; 51:1342–1347. 49. Reuben D. Assessment of older drivers. Clin Geriatr Med 1993; 9:449–459. 50. Underwood M. The older driver. Clinical assessment and injury prevention. Arch Inter Med 1992; 152:735–740. 51. Foley KT, Mitchell SJ. The elderly driver: what physicians need to know. Cleve Clin J Med 1997; 64:423–428. 52. Hemmelgarn B, Suissa S, Huang A, Boivin JF, Pinard G. Benzodiazepine use and the risk of motor vehicle crash in the elderly. J Am Med Assoc 1997; 278:27–31. 53. Rizzo M, Reinach S, McGehee D, Dawson J. Simulated car crashes and crash predictors in drivers with Alzheimer’s disease. Arch Neurol 1997; 54:545–551. 54. Higgins JP, Wright SW, Wrenn KD. Alcohol, the elderly, and motor vehicle crashes. Am J Emerg Med 1996; 14:265–267. 55. Johansson K, Bryding G, Dahl ML, Holmgren P, Viitanen M. Traffic dangerous drugs are often found in fatally injured older male drivers. J Am Geriatr Soc 1997; 45:1029–1031. 56. Shua-Haim JR, Gross JS. The co-pilot driver syndrome. J Am Geriatr Soc 1996; 44:815–817. 57. Parasuraman R, Haxby JV. Attention and brain function in Alzheimer’s disease: a review. Neuropsychology 1993; 7:242–272. 58. Gilley DW, Wilson RS, Bennett DA, et al. Cessation of driving and unsafe motor vehicles operation by dementia patients. Arch Inter Med 1991; 151:941–946. 59. Persson D. The elderly driver: deciding when to stop. Gerontologist 1993; 1:88–91. 60. Trobe JD, Waller PF, Cook-Flanagan CA, Teshima SM, Bieliauskas LA. Crashes and violations among drivers with Alzheimer’s disease. Arch Neurol 1996; 53:411–416. 61. O’Neill D, Dobbs BM. Age-related disease, mobility, and driving. Transportation in an aging society. Transportation Res Board 2004:56–66. 62. Adler G, Kuskowski M. Driving cessation in older men with dementia. Alzheimer’s Dis Assoc Disord 2003; 17:68–71. 63. Perkinson MA, Berg-Weger ML, Carr DB, et al. Driving and dementia of the Alzheimer’s type: beliefs and cessation strategies among stakeholders. The Gerontologist 2005; 45:676–685. 64. Dobbs AR. Evaluating the driving competence of dementia patients. Alzheimer Dis Assoc Disord 1997; 11:8–12. 65. Wang C, Carr D. Older driver safety: a report from the older drivers project. J Am Geriatr Soc 2004; 52:143–149. 66. Odenheimer GL. Dementia and the older driver. Clin Geriatr Med 1993; 9:349–364. 67. Jett K, Tappen RM, Rosselli M. Imposed versus involved: different strategies to effect driving cessation in cognitively impaired older adults. Geriatr Nurs 2005; 26:11–16. 68. Roper TA, Mulley GP. Caring for older people. Public transport. BMJ 1996; 313:415–418. 69. Taylor BD, Tripodes S. The effects of driving cessation on the elderly with dementia and their caregivers. Accid Anal Prev 2001; 33:519–528. 70. Freund K. Independent transportation network: alternative transportation for the elderly. TR News 2000; 206:3–12. 71. Dobbs BM. The impact of driving cessation on older drivers and caregivers. Paper presented at the 33rd Annual Scientific and Educational Meeting of the Canadian Association on Gerontology. Victoria, BC. October, 2004.

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72. Staplin L, Hunt L. Driver programs. Transportation in an aging society. Transportation Res Board 2004:69–94. 73. We Need to talk: Family Conversations with Older Drivers. 2004. At the Crossroads: A Guide to Alzheimer’s Disease, Dementia, and Driving, 2000. Hartfort, CT: The Hartford and Hartford Insurance Group. 74. Sterns HL, Sterns R. Social Structures and Processes in Public and Private Transportation Mobility and Transportation in the Elderly. New York: Springer Publishing Co., 2000 pp. 125–143. 75. Graca JL. Driving and aging. Clin Geriatr Med 1986; 2:577. 76. Marshall SC, Gilbert N. Saskatchewan physicians’ attitudes and knowledge regarding assessment of medical fitness to drive. CMAJ 1999; 160:1701–1704. 77. Iowa (1973). Freese v Lemmon, 210, NW2d 576. 78. Cable G, Reisner M, Gerges S, Thirumavalavan V. Knowledge, attitudes, and practices of geriatricians regarding patients with dementia who are potentially dangerous automobile drivers: a national survey. J Am Geriatr Soc 2000; 48:14–17. 79. Retchin SM, Hillner BE. The costs and benefits of a screening program to detect dementia in older drivers. Med Decis Making 1994; 14:315–324. 80. Harvey R, Fraser D, Bonner D, Warnes A, Warrington E, Rossor M. Dementia and driving: results of a semi-realistic simulator study. Int J Geriatr Psychiatry 2004; 10:859–864. 81. Rizzo M, Reinach S, McGehee D, Dawson J. Simulated car crashes and crash predictors in drivers with Alzheimer’s disease. Arch Neurol 1997; 54:545–551. 82. Rebok GW, Keyl PM, Bylsma FW, Blaustein MJ, Tune L. The effects of Alzheimer disease on drivingrelated abilities. Alzheimer Dis Assoc Disord 1994; 8:228–240. 83. Dobbs BM, Carr D, Ebhard J, et al. Determining medical fitness to drive: guidelines for physicians. American Association of Automotive Medicine/National Highway Traffic Safety Association. Consensus Meeting 2000. 84. Canadian Medical Association. 6th ed. Determining Medical Fitness to Drive: A Guide for Physicians. Ottawa: CMA Publications, 2000. 85. Patterson CJS, Gauthier S, Bergman H, et al. The recognition, assessment and management of dementing disorders: conclusions from the Canadian consensus conference on dementia. CMAJ 1999; 160:S1–S15. 86. Johannson K, Lundberg C. The 1994 International Consensus Conference on dementia and driving: a brief report. Alzhiemer’s Assoc Relat Disord 1997; 11:62–69. 87. Carr D, Schmader K, Bergman C, et al. A multidisciplinary approach in the evaluation of demented drivers referred to geriatric assessment centers. J Am Geriatr Soc 1991; 151:941–946.

21 The Plan of Care Mary A. Coats and Janice L. Palmer Washington University School of Medicine, St. Louis, Missouri, U.S.A.

INTRODUCTION The patient with dementia and his or her caregiver present a challenging client model to the health care provider because they represent a dyad rather than two separate entities. The patient’s wellbeing depends on how well the dyad adjusts and copes with the effects of the dementia and the attendant decisions that come with its progression. We focus in this chapter on seven issues to consider while caring for the patient-caregiver dyad: (1) telling the diagnosis, (2) safety, (3) health maintenance, (4) legal issues, (5) caregiver burden, (6) maintaining activity, and (7) preparing for late stage dementia. We base our recommendations on our experience in caring for patients diagnosed with dementia of the Alzheimer type (DAT) but they also are applicable to patients with other dementing illnesses. Regardless of the dementia type, it is important to individualize patient care.

TELLING THE DIAGNOSIS Informing patients of the diagnosis at an early stage of dementia makes it more likely that they will understand the information. They also are better able in early stages to participate in decisions related to treatment options and research participation, settle personal affairs, and maximize autonomy by leaving advance directives (1). Patients want to be included and consulted about their potential options and fear their wishes will be discounted or that they will be treated as incompetent and, therefore, not consulted for decisions (2). Patients with mild dementia demonstrate the ability to comprehend important information pertinent to their condition (3). Support group participants who are mildly demented are able to discuss in-depth issues related to diagnosis, disease related deficits, and changes in interpersonal relationships (4,5). Patients who are told the diagnosis along with an empathetic message of treatment possibilities and support often are accepting of the diagnosis and focus on what needs to be done to assure their quality of life and security (6). When giving the diagnosis, the Alzheimer’s Association recommends calling the dementing illness by name and not generating “unnecessary despair” (1). Hearing the diagnosis allows the 377

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patient and caregiver to move past the task of finding out what is wrong. Hope can be fostered by giving information about treatment options and resources for more information and services. The provider also can recommend interventions that promote self-esteem, such as keeping socially active, participating in support groups, and maintaining pleasurable activities. Although telling patients the diagnosis is recommended in most cases, clinician judgment determines when and how the diagnosis should be given and if there are exceptional circumstances that make disclosure of the diagnosis inappropriate. Patients with advanced dementia lack insight into their illness and may not be able to appreciate the situation. Also, providers must balance the patient’s “right-to-know” about the diagnosis in instances where harm may result. For example, a recent report underscored that, although very infrequent, certain high-risk individuals may contemplate suicide when faced with the diagnosis of DAT. Risk factors include: mild dementia severity, preserved insight, declared suicidal ideation, depressive symptoms, and male gender (7). Diagnostic disclosure also should involve consideration of the cultural values of the dyad. Some cultures believe that the decision to disclose the diagnosis to the patient should be left to the family and that disclosure may be unnecessarily burdensome to the patient (1). Diagnostic Feedback Conference A diagnostic feedback conference of the clinician, patient, and caregiver, allows an informed and empathetic disclosure process. In our practice, a health care professional (e.g., nurse or social worker) participates in this conference with the physician to provide multidisciplinary input and to record important information (Fig. 1) for later referral by the dyad. A recent study by the Alzheimer’s Association reported a gap between what caregivers believe providers have told them and what the providers believe they told caregivers (8). Documenting the feedback facilitates communication. Referral to local chapters of the Alzheimer’s Association or other support services can be helpful in providing supplemental information about research opportunities, support, respite services, and other educational materials (Table 1).

SAFETY ISSUES Patients with dementia often have a diminished attention span, poor judgment, problems with recognition and orientation, altered communication, impaired decision-making abilities, and limited self-care abilities, all of which make them vulnerable to environmental dangers. To promote patient safety, it is important for caregivers and others to observe for warning signs of potentially dangerous situations. Examples include: burned pots and pans, spoiled or no food in the kitchen, taking much longer than expected to arrive to familiar places when driving, unexplained dents in the car, weight loss, and inappropriately displaying money to others. Environmental Safety Gitlin and Corcoran list six key safety concerns for the home dwelling patient: “injury from falls, injury from ingestion of dangerous substances, exiting home and getting lost, injury to self or others from sharp objects, fire or burns from inappropriate use of appliances, and inability to respond rapidly to crisis” (9). Caregivers may need instruction to anticipate safety hazards. Suggestions for safe-proofing the home, restricting risky activities (driving, cooking, self-medication, etc.), and anticipating potentially dangerous situations like wandering and tripping are helpful. Removing extension cords, throw rugs, clutter, and other obstacles may prevent falls. Identification bracelets and/ or necklaces can help restore lost patients to their caregivers.

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Date:______________________________ Nurse:_____________________________

Telephone:(

)_______________

Patient Specific Feedback Information

Drug Treatment Information: FDA approved or Clinical Trials

Referral to the Alzheimer’s Association

St. Louis Chapter: 314-432-3422 or 1-800-980-9080 www.alzstl.org National: 1-800-272-3900 www.alz.org

Diagnostic or Laboratory Test Scheduling Proxy Document Information Distributed Referral to ________, Social Worker or Geriatric Care Manager, (Telephone number) Other:

Figure 1 Sample diagnostic feedback sheet.

Driving A common safety concern for caregivers and providers is the demented driver. It is difficult for the provider to determine a patient’s driving ability based solely on an office assessment unless the patient is medically disabled, severely impaired cognitively, or has focal deficits (e.g., severe apraxia or visuospatial impairment) that would obviously affect the ability to drive. Although some patients with mild dementia still may be safe drivers, (10) there is a clear relationship between dementia severity and unsafe driving. Driving-related practice guidelines and recommendations are available (11,12). Referral of demented drivers to an on-the-road driving evaluation program can help objectively document current driving abilities. For demented drivers who currently may be “safe,” follow-up drive evaluations (perhaps every 6 months) are indicated as all demented drivers eventually will become unsafe. Unfortunately, on-the-road evaluations can be costly and are not always available. Caregivers can periodically monitor driving ability by riding with the person with dementia. If the caregiver is hesitant to ride with the patient or to let their children or grandchildren ride with the patient because of safety concerns, the affected person probably should no longer be driving. For many reasons (loss of independence, embarrassment, lack of insight, need, etc.), driving cessation may be difficult. For some impaired drivers, no amount of discussion and reasoning will

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Table 1 Caregiver Resources Alliance for Children and Families Description: Call for a referral from a network of approximately 330 family service agencies Phone: 1-800-221-3726 Website: www.alliance1.org Alzheimer’s Association Description: Serves those affected by Alzheimer’s disease and other dementias. Core Services: Information and referral, individualized care consultation, support and educational groups, and Safe Return a national registry using identification card, bracelet or necklace. Registration for Safe Return is only available through the Alzheimer’s Association. For tracing of the lost call (800) 572-1122. Headquarter Address: 919 N. Michigan Avenue, Chicago, Illinois 60611 Phone: 1-800-272-3900 24-hour line routes to local chapter during the day and national office at night. Website: www.alz.org Alzheimer’s Disease Education and Referral Center (ADEAR) Description: The organization disseminates information about Alzheimer’s disease and related disorders and was formed by the National Institute on Aging and the National Institutes of Health. Their Website links to the National Institute on Aging (NIA)’s database on Alzheimer’s disease clinical trials and sites with details on how to participate. The Combined Health Information Database (CHID) is a medical literature database pertaining to Alzheimer’s disease and other dementias. Free publications are available. Questions can be answered through e-mail from the Website. A research newsletter is also available. Referrals to community resources for patients and caregivers are also given. Phone: 1-800-438-4380. Specialists available from 8:30 am—5:00 pm EST weekdays FAX: (301) 495-3334 E-mail: ADEAR@alzheimer’s.org Website: http://alzheimer’s.org American Association of Geriatric Psychiatry Description: Through education and research, this organization attempts to improve the practice of geriatric psychiatry. Call for a referral from a national list of geriatric psychiatrists for both Canada and the United States. Phone: (301) 654-7850, 9 am–5:30 pm EST FAX: (301) 654-4137 E-mail: [email protected] Website: www.aagp.online.org American Bar Association Description: The Website provides referrals to local bar associations and legal aid organizations. It also provides information on legal issues concerning the elderly such as guardianship and conservatorship. Website: http://www.abanet.org American Parkinson Disease Association Description: Serves those affected by Parkinson’s disease. Core Services: Offers research funding and symposia through local chapters. Also offers support groups and education. A newsletter with educational material is available through headquarter office. Headquarter Address: 1250 Hylan Blvd., Suite 4B, Staten Island, NY 10305 Phone: 1-800-223-2732, 1-888-400-2732 (CARELINK- to locate the information and referral center nearest you). FAX: 1-718-981-4399 E-mail: [email protected] Website: www.apda.parkinson.org American Stroke Association (A Division of the American Heart Association) (Continued)

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Caregiver Resources (Continued)

American Stroke Association (Contd.) Description: Provides information and referral to local chapters for stroke support groups, for educational programs, for community resources, for stroke specialists, and for questions to volunteer stroke survivors and family members. This association funds research and education initiatives. Phone: 1-888-4-STROKE (1-888-478-7653) E-mail: [email protected] Website: www.StrokeAssociation.org Centers for Medicaid and Medicare Services Description: This is a general information line concerning Medicare. Nursing home referrals and evaluations are also available. Publications and state Medicaid office referrals are available. Phone: 1-800-633-4227 Website: www.medicare.gov Children of Aging Parents Description: National information and referral for caregivers Phone: 1-800-227-7294 Website: www.caps4caregivers.org Eldercare Locator Service Description: This national service is sponsored by the Administration on Aging along with the National Association of State Units on Aging and the National Association of Area Agencies on Aging. Information and referral about services provided by state and area agencies as well as local private, nonprofit agencies in various communities are available. The financial assistance and services provided by these agencies vary from community to community. Supportive services and programs are meant to keep seniors in their own homes. Services may include meals, transportation, in-home services, adult day care, senior centers, legal assistance, and caregiver support groups. This service will make referrals to a state ombudsperson for nursing home referrals. Phone: 1-800-677-1116 Available 9 am—8 pm Eastern Standard Time, Monday–Friday Website: www.eldercare.gov Family Caregiver Alliance Description: Services as a resource in California for families of adults with brain damage and dementia. Phone: 1-800-445-8106 Website: www.caregiver.org National Academy of Elder Law Attorneys (NAELA) Description: This website provides listings for lawyers specializing in legal issues concerning the elderly. Website: www.naela.org National Adult Day Services Association Description: This association provides referrals to local chapters for assistance in locating adult day programs. Phone: 1-866-890-7357 National Association of Professional Geriatric Case Managers Description: Referrals can only be made through the Website. A directory of professionals can be obtained for $15. These professionals develop and implement individualized care plans with families. Website: http://www.caremanager.org National Family Caregivers Association Description: Provides information and referral to caregiving resources and support and advocacy for family caregivers. A caregiver can speak with a therapist, if needed. Membership is free. A newsletter is available. Phone: 1-800-896-3650 FAX: (301) 942-2302 E-mail: [email protected] Website: www.nfcacares.org (Continued)

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Social Security Administration Description: Administers Social Security benefits for retirement, for survivors, for disability, and for supplemental security income. Disability is for persons under full retirement age who have worked and have earned enough quarters of coverage. Supplemental security income is for disabled persons under age 65 or elderly persons age 65 and above with a low amount of resources and income. Medicare application, enrollment, premium collection and card issuance are handled by this agency. Referrals for Medicare claims and appeals to carriers and intermediaries are available. Referrals to local welfare departments for Medicare premium payment assistance programs and other benefits are available. Applications for some retirement claims are available online. Benefit estimates and verification as well as publications can be ordered. Phone: 1-800-772-1213 This agency prefers initial business be handled through this number with referrals to other components when needed. This line is staffed from 7 am–7 pm with automated services available 24 hours a day. Website: www.SSA.gov United States Department of Veteran Affairs Description: This agency administers disability compensation, disability pension and survivor benefits to veterans and their families. Health services include medical centers, outpatient clinics, nursing homes, home care services, adult day programs, residential care, pharmacy services, counseling, and geriatric evaluation programs. Phone: 1-800-827-1000 Website: http://www.va.gov United Way of America Description: This philanthropic organization provides financial support for local, community programs and services. This Website can direct someone to his or her local chapter for resources. Website: http://www.unitedway.org This reference list was compiled by Kathryn Lind, a MSW student at Saint Louis University School of Social Work, with assistance from her field training supervisor and our colleague, Terri Hosto, MSW, LCSW.

get them to agree to stop. In this situation, it is important for providers, caregivers, the state motor vehicle agency, law enforcement officers, insurance agents, and others to act cooperatively in stopping the individual from driving. For additional information, see the Chapter on Driving. Medication Supervision The need for medication supervision may come to the provider’s attention only after repeated office appointments or hospitalizations for problems engendered by the patient’s improper use of medications. In some instances, forgetting to take medications or inadvertent overmedication may be the presenting “symptom” of cognitive impairment. Patients with early-stage dementia may manage their own medications, often using a pillbox to assist in proper medication use. Even so, caregivers often need to provide at least minimal supervision to ensure compliance. Families should dispose of medications stored in the patient’s home that are no longer taken by the patient or have expired. If the patient lives alone, it may be safer for the caregiver to keep and dispense medications. Eventually, patients will not be able to reliably manage their medications and must depend on others for medication administration. Financial Decisions Safety concerns with finances and clutter include: inappropriate purchases (particularly from telephone solicitors, mail order, and sweepstakes), forgetting to pay bills (e.g., utilities are turned off), duplicate payment of bills, lost checks, cash, or jewelry, and piles of mail and clutter in the

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home. These signs indicate that caregivers need to take steps to prevent others from taking advantage of the patient. HEALTH MAINTENANCE Several areas of health maintenance require special attention by caregivers of patients with dementia. In this section, discussion is based on three levels of dementia severity: mild, moderate, and severe. As a rough guide, mildly impaired individuals are independent in self care; moderate impairment occurs when the patient needs assistance in carrying out activities of self-care; and severe impairment is when patients are dependent on others. Nutrition and Hydration Patients with dementia are at increased risk for nutritional imbalance, dehydration, and weight loss (13,14). Weight may fluctuate throughout the course of dementia (13). The risk of weight loss increases with the severity of dementia and is a predictor of mortality (13,14). Cholinesterase inhibitors used for the treatment of Alzheimer’s disease may decrease appetite. Maintaining adequate energy intake, restoring energy balance and maintaining skeletal muscle mass help to maintain overall nutritional status (14). The functional ability in Activities of Daily Living (ADLs) and level of energy expenditure may help to explain problems in maintaining weight and nutritional status seen in different stages of dementia (15). The patient may miss meals because they forget to eat. Problems with memory and judgment can lead to difficulties with grocery shopping, preparation of nutritious food, and meal planning. Disinhibition can be accompanied by excessive intake or unusual cravings (e.g., for sweets). Depression often accompanies dementia (16) and may result in decreased appetite or reduced initiative to prepare nutritionally balanced meals. In moderate to severe dementia, difficulties of maintaining adequate nutrition may be compounded by the psychological and behavioral symptoms of the dementing disorder. Patients may be restless or agitated, resulting in an increase in energy needs or missed calories because of being unable to sit and complete a meal. Strategies to provide calories in unconventional forms such as finger foods for “eating on the run” may be helpful. Apraxia and visuospatial changes occasionally interfere with patients’ ability to feed themselves. During the severe stage of dementia, patients may not readily take offered food. Patients may also have difficulty swallowing. It takes patience to allow an extended amount of time to eat and specialized feeding techniques to provide adequate nutrition to severely demented patients. Eating difficulties present not only practical problems, but also ethical dilemmas. For example the issue of forced nutrition (e.g., tube feeding) may arise for patients who continue to lose weight in spite of other interventions. (See the section “Artifical Hydration and Nutrition.”) Dietary Interventions Providers and caregivers should monitor the weight of the patient and address potential risk factors for malnutrition, beginning in the mild stages of dementia. Patients, particularly those who live alone, may need assistance with shopping and meal preparation. Meals delivered at home, preprepared by caregivers, or provided by a local senior citizen center can help maintain a balanced diet. Strategies to encourage healthy choices should be explored for patients who binge on sweets or other foods with low nutritional value. Reminder calls may be needed to prompt patients who forget to eat meals. In all stages of dementia, mealtime in a calm, low stress environment promotes food and fluid intake. Patients with moderate dementia are more dependent on caregivers for optimal nutritional intake. Interventions to maintain proper nourishment include: setting regular mealtimes, minimizing noise and distraction at mealtimes, providing adequate lighting, limiting food choices,

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and providing finger foods. Patients may require assistance at mealtimes. At first, it may suffice to simply cut foods to more manageable portions. Eventually patients may need cues to eat or will need to be spoon fed. Fluid intake of 6–8 glasses of water a day is important for hydration and bowel function. With progression to severe dementia, difficulties in swallowing and chewing often develop. Evaluation by a speech pathologist or barium swallow may be indicated to determine other potential etiologies of dysphagia. Instructional materials have been developed to teach specialized feeding techniques and caregivers should be referred to these as indicated. The Alzheimer’s Disease Education and Referral Center (ADEAR) is a good resource for lists of such literature, videotapes, and care guides (Table 1). Nutritional supplements may be indicated to promote nutritional adequacy but do not substitute for food and fluid. Oral Hygiene Poor oral hygiene is associated with dementia because demented patients are impaired in their ability to manage personal care and because cholinesterase inhibitors and antipsychotic medications used in dementia treatment can be associated with salivary gland dysfunction (17). The use of a soft-bristled toothbrush, frequent rinsing of the mouth with water, adequate intake of water, and sugarless hard candies to stimulate saliva flow can help decrease damage to oral tissues related to dry mouth. Caregivers need to supervise mildly demented patients who self-perform mouth care to ensure that it is done with regularity and appropriately. Routine care by dentists and dental hygienists provides the opportunity to restore and maintain the health of the mouth, teeth, and gums. This is important because oral care becomes more difficult as patients progress to more severe cognitive impairment. As dementia progresses, caregivers take on more responsibility for brushing and flossing for patients. Routine assessment for dryness and lesions of the oral cavity is needed. Regular visits to dental professionals can provide a more thorough cleaning of the teeth and gums to prevent disease. If caregivers are not denture wearers, they may need instruction on how to clean dentures and to assess that the dentures fit properly. Dentures should be removed at least 6 hours a day to rest the gums and jaw (18). Complex and time-consuming dental procedures may not be appropriate in the severe stage of dementia. The emphasis of oral care should be to prevent painful lesions and ensure adequate nutritional intake (17). Incontinence Bowel and bladder incontinence is stressful for caregivers (19). Incontinence in the mild stages of dementia is atypical. An abrupt change in the patient’s ability to maintain bowel and bladder control may signal an acute illness or a medication side effect. Short-term loss of control may relate to environmental stress. In the latter stages of dementia, incontinence is exacerbated by inappropriate reactions to the urge to urinate or defecate and by difficulty in finding the bathroom (19). Behavioral interventions such as toileting routines can be helpful. Constipation and urinary tract infections may be manifested in nonspecific behavior changes such as lethargy, decreased appetite, agitation, and catastrophic outbursts. Patients no longer monitor bowel and bladder function for themselves and will need assistance to maintain adequate diet and fluid intake. Specific interventions related to urinary continence (20) are cited in Table 2. Sleep–Rest Dementia is associated with alterations in daily sleep-wake cycles, frequent daytime napping, and nighttime wakefulness (21). To compensate for fatigue that may increase as the day progresses,

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Table 2 Progressive Functional Changes of Alzheimer’s Affecting Urinary Incontinence

Early stage: independent Mild stage: no longer independent

Incontinence

Symptoms

Interventions

None Urge type

– Difficulty with dressing

– Use of Velcrow fasteners in place of buttons, zippers, and laces Wrap-around skirts or clothes with elastic waist bands Use of a picture or color indicators on bathroom Plan for bathroom breaks Verbal prompting “reminders” Toileting schedule

Difficulty locating bathroom

Moderate stage: increasing dependence

Severe stage: complete dependence

Urge type

Total type

Not reliabily sensing the need to void Inability to recognize the toilet

Inability to inhibit spontaneous voiding No recognition of a wetting accident

Nonverbal cues such as leading to the bathroom or assisting the patient on the toilet Assist with flushing, wiping, and handwashing May need absorbant pad so as to avoid embarrassment Adequate fluid intake of at least 1500 cc/day Appropriate containment garment or devices Hygiene measures to maintain skin integrity

Source: Adapted from Ref. 20.

Hall and colleagues suggest that caregivers develop strategies to conserve energy by shortening activities and encouraging brief rest periods in the morning and afternoon (22). Normal sleep-wake cycles can be promoted by following a consistent daily routine that provides for activity as well as rest periods. A daily routine promotes a sense of security, promotes confidence promotes familiarity with surroundings and may promote behavioral maintenance. Rest periods during the day may reduce late-day confusion and night wakefulness, particularly when an easy chair or recliner is used instead of a bed (to minimize the confusion of daytime with nighttime). Additional ways of promoting normal sleep-rest cycles include: reducing environmental stimuli in the evening, avoiding caffeine and other stimulants, and establishing toileting routines. The short-term use of a hypnotic to establish a normal sleep-wake cycle may be helpful, although the benefits of the judicious use of psychotropic, sedative, and hypnotic medications must be balanced with the potential adverse effects of these medications in level of alertness and motor function.

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Patients who continue to be awake and wander at night require that the residence be safe-proofed. Offering a snack and providing calm reassurance at these times can decrease agitation and wandering. ADVANCE DIRECTIVES Advance directives ensure that the individual’s wishes are carried out in the event of mental incapacitation from an accident or illness. If not prepared earlier, documents should be completed as soon as possible after dementia onset when patients still can understand their purpose and to protect against challenges to the validity of the documents. An important directive is to establish a legally authorized representative (LAR) for the patient. The simplest LAR is realized by the patient’s appointment of a Durable Power of Attorney (DPOA) for both health-care and financial decisions. The requirements needed to establish a DPOA vary by state, but often state bar associations have DPOA forms that can be completed without the assistance of an attorney. Complicated financial and health-care arrangements, however, should prompt consultation with an attorney. Healthcare DPOA documents address issues such as who can seek appropriate medical care for the patient. It also is important to document who may provide proxy consent for research participation. The DPOA designate (surrogate decision-maker) should be someone with whom the patient shares values and who will carry out the patient’s wishes. The surrogate should discuss health care matters with the patient to appreciate the individual’s wishes (23). The discussion should include potentially difficult issues such as tube feeding and resuscitation. The principle of substituted judgment requires that the surrogate decide in accordance with the patient’s own wishes, had they been able to decide, rather than the surrogate’s own beliefs and decisions (24). For choices that have not been previously discussed with the patient, the surrogate should make determinations based on shared values. Patients lose the decisional capacity needed to complete legal documents as dementia progresses in severity. If the patient has not previously established a DPOA, a guardianship proceeding may be necessary. Guardianship proceedings can be costly and time-consuming, and the surrogate determined by the court may not be the individual the patient would have chosen when competent. In the absence of a DPOA or guardianship, the LAR for the patient may be established by state statute that typically involves next-of-kin, beginning with the spouse. However, not all states have enacted such statutes. Although next-of-kin decisions usually are accepted, contentious issues may arise in the absence of a formal designation of a LAR. For example, one family member may opt for artificial feeding in the patient’s terminal state but another member may not. If the patient’s choice is in question, the case may go to court for legal resolution. FAMILY CAREGIVER BURDEN It is important to appreciate the burden experienced by caregivers of demented patients and express support and empathy. Otherwise, caregivers may perceive physicians as non-supportive and disinterested (25). Providers also can support caregivers by making referrals to advance practice nurses, geriatric care managers, social workers, occupational, and physical therapists, psychologists, and counselors who can provide specific support services. In addition, organizations such as the Alzheimer’s Association can assist caregivers in coping with the many challenges encountered while dealing with demented patients. The Patient-Caregiver Dyad Even in the early stages when patients are independent, caregivers are instrumental in helping patients to obtain diagnosis, treatment, and to make plans for the future. Caregivers monitor the

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function of the person with dementia and assist as needed. The caregiver role may have detrimental effects on the physical and psychosocial well-being of caregivers (see chap. 22). Because of the interdependence of patients and caregivers, primary providers must not only monitor the health condition of patients but also caregivers. Caregivers often have a deep sense of duty to protect their loved one from the consequences of dementia, and thus often are unable to relax, enjoy recreational activities, or pursue health maintenance for themselves without feelings of guilt (25,26). As a result, caregivers may neglect their own health. Often the Alzheimer patient’s clinician is in the position to observe signs of caregiver stress, depression, and physical illness and may need to explicitly refer caregivers to seek health care. Referrals Caregivers more often obtain support and respite services when they are recommended by the physician than by self-referral (25). Referrals by the physician for the caregiver to seek supportive community resources should be made early in the course of the dementing illness because stressful circumstances can occur at all stages of dementia. Counseling increases the caregivers’ coping ability and appears to delay institutional placement of patients (27). Referrals to caregiver education programs (e.g., behavior management training), and respite services (e.g., adult day care, companion services), and supportive counseling reduce caregiver depression, tension, and anger, and delay nursing home placement (28). Caregiver literature and educational programs provide instruction for communication strategies and practical advice to help with ADLs, such as bathing, dressing, and toileting (Table 3). Caregivers may be reluctant to use outside resources and or believe that they are unable to afford services. Referrals often need to be reintroduced over time before caregivers act. Forewarning caregivers that a change in the needs of the patient may occur soon gives caregivers time to accept that a corresponding change for the caregiver may be required. Caregivers should become knowledgeable about potentially needed resources (e.g., nursing home placement, day care, driving evaluation) before a crisis occurs. A geriatric care manager, counselor, or an agency such as the Alzheimer’s Association can assist in operationalizing a plan of care or plan for respite services. (Table 1 lists referral sources for caregivers of demented individuals.) MAINTAINING ACTIVITY As dementia progresses, accustomed activities (e.g., work, driving, hobbies) are relinquished. Excess disability is the loss of ability greater than can be explained by the effects of the disease alone and can be reduced by participation in organized activities chosen to coincide with capabilities of the patient (29). Patients benefit from engaging in activities that promote feelings of accomplishment and allow for social interaction. Purposeful activities channel restless energy and promote feelings of usefulness. These activities should be planned based on patient strengths and interests. Caregivers should be cautioned against planning activities that are training-, task-, or completion-oriented because they can lead to frustration, anger, and reduced self-esteem (30). Patients can be assisted to maintain current activities or develop new interests and activities to replace abandoned ones. Sometimes the challenge to caregivers is to accept a new action (for example, pacing) as an activity in and of itself that meets a need. A useful tool may be to modify previously enjoyed activities (Table 4). Physical Activities Physical exercise benefits the health of older adults by minimizing the effects of chronic diseases, fostering positive mood, and maintaining strength, flexibility, and function (31). Exercise promotes

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Table 3 General Guidelines for Care of a Person with Dementia 1

2

3

4

5

6

Individualize care Learn about the patient’s past (occupation, interests, personality, etc.) Recognize strengths and current skills Focus on previously learned activities and interests Communicate effectively Approach from the front; gain eye contact Vary depending on the patient’s ability (i.e., simple sentences, repeat as necessary) Avoid abstract statements Be open and ready to listen to verbal and nonverbal language Smile Remember nonverbal language is important (smiles, cues, gestures, touch) Eliminate competing and distracting background stimuli Do not argue or confront Provide affectionate encouragement Use humor and diversion to overcome resistance Provide a safe, supportive environment Be consistent; maintain a calm, orderly routine Foster a sense of control; allow behavior that is not harmful Be flexible Provide environmental cues for orientation Provide or reduce stimuli to meet the needs of the patient at the time Be sensitive to stressors in the environment Rooms should be well lighted and uncluttered Provide a quiet area; allow for privacy Remove potentially dangerous items as required Constantly reevaluate the amount of supervision needed Provide identification to be worn by the patient Foster an active and healthy life-style Provide a nutritious, well-balanced diet Provide adequate hydration Encourage daily, routine exercise Support regular sleep-rest periods Maintain good oral hygiene Maintain dignity and high self-esteem Help maintain an appearance to be proud of Do not treat the person as a child Talk with them directly as an individual Include them in whatever is happening in the room Help preserve their social fac¸ade Provide reassurance and encouragement for actions; praise accomplishments Do not focus on failures Allow independence rather than perfection whenever possible Foster purposeful activities (provide structure as needed) Promote psychosocial health Use humor judiciously to counteract fear and anxiety Provide activities to channel restless energy Provide social interaction and activities in a non-threatening environment Provide activities that give modest stimulation (conversation, music, touch, etc.) Identify sources of anxiety; avoid situations that cause catastrophic reactions Be sensitive to mood changes Provide simple, timely explanations (Continued)

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General Guidelines for Care of a Person with Dementia (Continued)

7

Start planning now for the present and future Consider options before there is a crisis Consider available FDA-approved treatments and/ or research trials Contact a lawyer or financial advisor Discuss details with appropriate family or other sources of support Identify sources of support and respite and use them Learn all you can about the disease

retention of motor strength, skills, and balance and may help to prevent falls. Exercise also decreases the frequency of depressive manifestations and agitation (32). Providers can motivate patients and caregivers by educating them about the benefits of exercise and prescribing an exercise program. The program should be individualized for the patient’s health and safety status, time, access to means of exercise, and enjoyment (33). Activities familiar to the patient should be considered (e.g., golf, square dancing, mall walking). Patients should be encouraged to be involved in some type of daily exercise. As patients become more demented, the type of exercise and its supervision should be adjusted accordingly. Housekeeping and Meal Preparation Patients with early-stage dementia may still retain the ability to participate in cooking, cleaning, and yard work but eventually will require assistance and supervision in these tasks although still enjoy participating in them. With further progression of dementia, caregivers may need to encourage participation in simpler activities tailored to the patients’ abilities. Examples of simpler activities include: † † † † †

Providing towels and washcloths to fold and re-fold Dumping out raked leaves for re-raking Cutting out coupons from coupon booklets Providing buttons, office materials, pens, etc., to sort by size or color Sorting photographs by holiday, person, etc.

Table 4 Activity Level Change Previous activity Woodworking

Next activity level

Mowing the lawn and lawn care

Assisting a woodworking friend or simplifying projects Playing with a friend who will assist “using orange fluorescent balls” Simplifying meals; assisting someone else to cook; frozen meals Raking the leaves and “helping out” with supervision and assistance

Secretarial work

Stuffing envelopes; routine filing

Golfing

Gourmet cooking

Next activity level Sanding pieces of wood Hitting balls in the backyard

Stirring the dough and shaping into balls Raking the leaves and sweeping the sidewalk resulting in minimal or no effectiveness “Pretend” filing

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PREPARING FOR LATE STAGE ISSUES In the terminal phases of dementia, caregivers need guidance to make the transition to a palliative care philosophy. Features of the terminal phase include loss of ability to communicate, non-ambulatory status, incontinence, and difficulty swallowing (34). The goal of care in the terminal phase is to treat patients with dignity and provide comfort and as much quality of life as possible (35). Advanced Care Planning (ACP) suggested by Ratner et al. (36) is an example of a paradigm that formalizes discussion with caregivers at a late-stage care-planning conference. Caregivers are given the opportunity to discuss their understanding of the patient’s prognosis and to address key issues that are likely to arise during end-of-life care. The purpose of this discussion is not to tell caregivers what to do, but rather to allow them the time to think, gather knowledge, and seek counseling so that when the time comes they are able to make difficult decisions based on the wishes of the patient. Some issues to be discussed in an ACP Conference are discussed below. Artificial Hydration and Nutrition Decisions about whether to artificially hydrate and feed end-stage dementia patients must be individualized. The Alzheimer’s Association Ethics Advisory Panel provides recommendations regarding prolongation of the terminal stage with tube feeding (37). Helping caregivers and others to understand that Alzheimer’s disease is a terminal illness that results in death regardless of medical intervention may help them to forgo invasive procedures such as tube feeding and focus instead on comfort measures. Acute Illness Patients may develop conditions that if left untreated can result in pain and suffering. Caregivers need to know the risk/benefit relationship of available treatment options. They may not foresee the discomfort and other untoward effects of invasive diagnostic procedures and treatments. Hospitals, focused on cure, may lack the type of care needed to assure patient comfort (38). Inpatient treatments may be necessary to maintain the patient’s comfort; however, realistically hospitalization does not assure a positive outcome in terms of survival (38,39). Acute illnesses can often be managed by the nursing home or home health care agency. Staff of these agencies often know the patient and may be best prepared to treat the acute condition, manage the effects of the dementing illness, and maintain patient comfort. Cardiopulmonary Resuscitation Caregivers may not be aware that resuscitation of patients is required by hospital and nursing home policies unless physicians write “do not resuscitate” orders. Cardiopulmonary resuscitation and the resultant hospitalization expose patients to procedures, medications, ventilators, catheters, etc. that often are not anticipated by caregivers nor wanted by patients. Hospice Care Hospice care is available and a Medicare benefit for patients with end stage dementia when death is anticipated within 6 months. The philosophy of the hospice movement, to emphasize comfort and quality of life rather than length of life, often suits the needs of patients and caregivers at this time. Providers may not realize the need for hospice care when patients are in the nursing home because comfort measures can be provided by nursing home staff. However, the attention of hospice staff with their philosophy of “comfort always” and bereavement services benefits patients and caregivers (40).

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REFERENCES 1. Alzheimer’s Association Fact Sheet. About ethical considerations: issues in diagnostic disclosure, 1997. 2. Husband HJ. Diagnostic disclosure in dementia: an opportunity for intervention? Int J Geriatr Psychiatry 2000; 15:544–547. 3. Buckles VD, Powlishta KK, Palmer JL, et al. Understanding of informed consent by demented individuals. Neurology 2003; 61:1662–1666. 4. LaBarge E, Von Dras DD, Wingbermuehle C. An analysis of themes and feelings from a support group for people with Alzheimer’s disease. Psychotherapy 1998; 35:537–544. 5. Yeh C, Truscott T, Snyder L. The benefits of a support group for persons with Alzheimer’s disease. Alzheimers Care Q 2001; 2:42–46. 6. Snyder L. Speaking our minds: personal reflections from individuals with Alzheimer’s. New York: W H Freeman and Company, 2000:1–161. 7. Lim WS, Rubin EH, Coats M, Morris JC. Early-stage Alzheimer disease represents increased suicidal risk in relation to later stages. Alzheimer Dis Assoc Disord 2005; 19:214–219. 8. Roper Starch Worldwide, Inc. for the Alzheimer’s Association. Alzheimer’s disease study: communication gaps between primary care physicians and caregivers, 2001. 9. Gitlin LN, Corcoran M. Making homes safer: environmental adaptations for people with dementia. Alzheimers Care Q 2000; 1:50–58. 10. Hunt LA, Carr D, Duchek JM, et al. Reliability and validity of the Washington University road test: a performance-based assessment for drivers with dementia of the Alzheimer type. Arch Neurol 1997; 54:707–712. 11. Dubinsky RM, Stein AC, Lyons K. Practice parameter: risk of driving and Alzheimer’s disease (an evidence-based review) report of the quality standards subcommittee of the American academy of neurology. Neurology 2000; 54:2205–2211. 12. Dobbs BM, Carr DB, Morris JC. Evaluation and management of the driver with dementia. Neurologist 2002; 8:61–70. 13. White H, Pieper C, Schmader K. The association of weight change in Alzheimer’s disease with severity of disease and mortality: a longitudinal analysis. J Am Geriatr Soc 1998; 46:1223–1227. 14. Poehlman ET, Dvorak RV. Energy expenditure, energy intake, and weight loss in Alzheimer disease. Am J Clin Nutr 2000; 71:650S–655S. 15. Riviere S, Gillette-Guyonnet S, Nourhashemi F, Vellas B. Nutrition and Alzheimer’s disease. Nutr Rev 1999; 57:363–367. 16. Rubin EH, Veiel BA, Kinscherf DA, Morris JC, Storandt M. Clinically significant depressive symptoms and very mild to mild dementia of the Alzheimer type. Int J Geriatr Psychiatry 2001; 16:694–701. 17. Ghezzi E, Ship JA. Dementia and oral health. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 89:2–5. 18. Kahn R. Renewing the commitment to oral hygiene. Geriatr Nurs 1986; 7:244–247. 19. Mace NL, Rabins PV. The 36-Hour Day. 3rd ed. Baltimore: Johns Hopkins University Press, 1999. 20. Duffy LM. Helping caregivers cope: managing urinary incontinence associated with Alzheimer’s disease. J Enterostom Ther 1990; 17:87–93. 21. Prinz PN, Peskind ER, Vitaliano PP, et al. Changes in the sleep and awakening EEG’s of nondemented and demented elderly subjects. J Am Geriatr Soc 1982; 30:86–93. 22. Hall G, Kirschling MV, Todd S. Sheltered freedom-an Alzheimer’s unit in an ICE. Geriatr Nurs 1986; 7:132–137. 23. Mitchell SL, Berkowitz RE, Lawson FME, Lipsitz LA. A cross-national survey of tube-feeding decisions in cognitively impaired older persons. J Am Geriatr Soc 2000; 48:391–397. 24. Dukoff R, Sunderland T. Durable power of attorney and informed consent with Alzheimer’s disease patients: a clinical study. Am J Psychiatry 1997; 154:1070–1075. 25. Karlin NJ, Bell PA, Noah JL. Long-term consequences of the Alzheimer’s caregiver role: a qualitative analysis. Am J Alzheimers Dis Other Demen 2001; 16:177–182. 26. Shanks-McElroy HA, Strobino J. Male caregivers of spouses with Alzheimer’s disease: risk factors and health status. Am J Alzheimers Dis Other Demen 2001; 16:167–175.

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27. Roberts J, Browne G, Milne C, et al. Problem-solving counseling for caregivers of the cognitively impaired: effective for whom? Nursing Res 1999; 48:162–172. 28. Buckwalter KC, Gerdner L, Kohout F, et al. A nursing intervention to decrease depression in family caregivers of persons with dementia. Arch Psychiatr Nurs 1999; 13:80–88. 29. Brody EM, Lkeban MH, Lawton MP, Silverman HA. Excess disabilities of mentally aged: impact of individualized treatment. Gerontologist 1971; 11:124–133. 30. Nissenboim S, Vroman C. The positive interactions program of activities for people with Alzheimer’s disease. Baltimore, Maryland: Health Professions Press, Inc, 1998:1–136. 31. Mazzeo RS, Cavanagh P, Evans WJ, et al. ACSM position stand: exercise and physical activity for older adults. Med Sci Sports Exerc 1998; 30:992–1008. 32. Powell RR. Psychological effects of exercise therapy upon institutionalized geriatric mental patients. J Gerontol 1974; 29:157–161. 33. Christmas C, Andersen AR. Exercise and older patients: guidelines for the clinician. J Am Geriatr Soc 2000; 48:318–324. 34. Alzheimer’s Association. Ethical Issues in Alzheimer’s Disease; End-of-Life Care. Chicago, IL: Alzheimer’s Association, 2000. 35. Volicer L. Care at the end of life. Alzheimers Care Q 2001; 2:59–66. 36. Ratner E, Norlander L, McSteen K. Death at home following a targeted advance-care planning process at home: the kitchen table discussion. J Am Geriatr Soc 2001; 49:778–781. 37. Alzheimer’s Association. About ethical considerations: issues in death and dying fact sheet. Chicago, IL: Alzheimer’s Association, 1997. 38. Morrison RS, Siu AL. Survival in end-stage dementia following acute illness. JAMA 2000; 284:47–52. 39. Meier DE, Ahronheim J, Morris J, Baskin-Lyons S, Morrison RS. High short-term mortality in hospitalized patients with advanced dementia: lack of benefit of tube feeding. Arch Intern Med 2001; 161:594–599. 40. Volicer L. Hospice care for dementia patients. J Am Geriatr Soc 1997; 45:1147–1149.

22 Comprehensive Review of Caregiving for the Health Care Professional Ann S. Morrison and Peter V. Rabins Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A.

OVERVIEW OF CAREGIVING In 2001 the National Alzheimer’s Association commissioned a survey to evaluate caregiver’s and physician’s perceptions of communication during clinic visits. The survey reported that 52% of caregivers want to know the effect of the disease on the patient’s ability to do daily tasks and how to cope while only 28% report that the doctor had provided this information. Physicians agreed that caregivers need this type of information (85%) and 91% of the physicians said they provide this information. The Alzheimer’s Association survey reported numerous other disconnects between what physicians said they provided and what caregivers said they received. This schism in perceptions represents difficulties in communication and problem identification (1). In spite of these communication difficulties, physicians were perceived as well informed and compassionate. Eighty percent of the caregivers indicated that physicians wanted to hear their concerns and questions and that their doctors were knowledgeable about the disease (1). Families provide care to the majority of Alzheimer’s patients. Approximately 70% of people with Alzheimer’s disease live at home (2). Caregivers can face very similar stressors with very dissimilar outcomes. They undertake tremendous responsibility and pressures while caring for their impaired relatives. As a result of their caregiving responsibilities, many suffer from depression and poor health (3). This is not the fate for all, and many caregivers emerge from their caregiving experience with significantly less negative outcomes. Women shoulder the burden of care for demented individuals. For example, Ory (4) reports that 73% of caregivers to demented patients are female. Nevertheless, each caregiver possesses a unique constellation of personal characteristics, resources, competing responsibilities, and past experiences. Knowing how these characteristics influence their abilities to operate as a caregiver enables the clinician to anticipate needs and provide an individualized plan of care (Table 1). The chronic stress associated with caregiving can mushroom across time and space. Furthermore, being a caregiver does not exist separately from coexisting problems of life. The effects of caregiving eventually effect work life, social activities, or leisure time and may create further conflict and stress (5). Accurate identification of problem areas for the caregiver improves 393

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Table 1 Characteristics that Influence Caregiver Performance Age, gender Health care status Kin relationship Racial/ethnic background

the effectiveness of interventions. Assessment includes evaluation of the caregiver, caregiving demands, secondary consequences of caregiving and the outcomes for caregivers (6). Caregivers who are elderly may have physical limitations, such as arthritis or vision problems, that impact upon their ability to carry out activities so the need for outside assistance with caregiving activities may arise earlier. In contrast, younger caregivers are more likely to face competing responsibilities. The needs of children, spouses, work, and social activities may invoke feelings of guilt or strain. Physicians can help them by planning and prioritization strategies for caregivers with busy schedules. Female caregivers report depressive symptoms and higher levels of burden in most, but not all studies (7,8). Differences in perceptions and coping strategies may explain some of the gender differences found in the literature. Elderly males may also be more hesitant to report negative emotions or caregiving difficulties. One explanation is that they equate feelings of depression with failure and conceal feelings. Gallicchio (8) suggests, that female caregivers spend more time with the patient during caregiving tasks and put forth more effort during the tasks than male caregivers. She believes this amplified level of exertion contributes to the higher levels of distress reported by women. Caregivers have more health problems than others their age because of the emotional and physical strain of caregiving. They report 46% more physician visits, use 70% more prescription drugs, and are three times more likely to become clinically depressed than their peers (1). Caregivers with poor health report even higher levels of depression and burden (3,8). Elderly caregivers have a 63% increase in mortality than other non-caregiving spouses of the same age (1). Many caregivers neglect their own needs because they simply do not have the time or energy to tend to them. In turn, the poor health of caregivers diminishes their capacity to provide care to others. Kin relationship to the care recipient is a significant factor in the caregiving experience. Caregiver spouses need to prepare themselves for some role reversal as their partners lose function. Changes in sexual intimacy between the partners are inevitable over time and social relationships in which they functioned as a couple may fade. Spouse caregivers tend to retain the caregiving role longer than adult children, and cite the bonds of the marital relationship as their motivation (9). Caregiver relatives are likely to experience competition between their obligations to their nuclear families and their care recipient. The bulk of caregivers are daughters and sons of dementia patients. In a survey by the Alzheimer’s Association 42%of caregivers were providing care to parents, 10% to parent-in-laws, 11% to grandparents compared to 9% who were caring for spouses (10). African-Americans report less overall burden than their white counterparts (11). Aranda and Knight (12) propose that African-Americans enjoy the protective benefits of ethnicity as a culture, rather than the additive effects of disadvantaged minority group status and caregiving stress. In a review of the literature, Dilworth-Anderson (13) found that caregivers to elderly minority persons use more informal support than Caucasian families. Close and distant family members as well as extended family provided the majority of this support. Explanations for the limited use of formal support include: (1) beliefs that seeking outside help indicates inadequacy as a caregiver; (2) “cultural mores” that preclude seeking help outside of the family; and (3) the perception of formal services as culturally insensitive or irrelevant.

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PROBLEMS ARISING DIRECTLY AND INDIRECTLY FROM THE CAREGIVING SITUATION Caregiving demand reflects the patient’s degree of cognitive impairment, functional level, degree of problematic behavior and patient resistance. In addition to the physical work that is generated by the caregiving demand, the emotional reactions of the caregiver to the demands is a substantial source of stress (6). Practitioners should ask the extent to which caregiving saps the energies and stamina of the caregiver. Feelings of physical exhaustion, feelings of having an excessive workload or a lack of enough time for themselves are commonly reported (Table 2). Caregivers may feel a lack of ability to lead a life of their own, feelings of being trapped by the care recipient’s illness, and wishing they could just leave. Spouse caregivers miss companionship and reciprocity with their care recipient. As the dementia patient’s abilities decrease, the caregiver’s responsibilities increase but the severity of dementia is not the most significant predictor of caregiver distress. Functional dependencies, problem behaviors and resistance to care are more relevant predictors of negative caregiver reactions (6). Therefore, even a mildly demented individual may generate a strong sense of distress in a caregiver if there are behavioral problems or if there is opposition to care. Assessment of problem behaviors should include the frequency of occurrence, and more importantly, the degree of distress generated by the problem. A daily occurrence of a minor problem, for instance, repetitive behavior, may generate a small amount of aggravation. The less frequent occurrence of paranoid or suspicious behavior or inappropriate social behavior may create significant caregiver distress. The stressors directly involved in caregiving may eventually give rise to stressors outside the boundaries of caregiving such as: family conflict, financial concerns, and constriction of social life and leisure time (Table 3). Because these activities are often part of the caregivers self-concept or identity, the inability to perform these tasks can leave the caregiver feeling that they have lost control of their lives. Many caregivers cease outside activities because of caregiving demands. The constriction of social life is one potent source of dissatisfaction. Fifty-six percent of caregivers reported less time for family as a consequence of caregiving and 53% cited giving up vacations, hobbies, or social groups (10). Work strain is a common experience for caregivers because they are likely to be employed. According to a study by the Alzheimer’s Association, almost 78% of caregivers worked outside the home (14). Fifty-seven percent reported having to go into work late, leave early, or take time off during the day to provide care. A recent study found that Alzheimer’s disease costs U.S. businesses $26 billion per year for caregiver absenteeism (15). Caregivers also report turning down promotions, transferring to a less demanding job, choosing early retirement, or quitting work altogether to solve work conflict problems. Covinsky (16) found that ethnic minorities are more likely to experience reduced employment as a result of caregiving and that a diagnosis of dementia furthered this likelihood. The presence of behavioral disturbances also was a significant predictor of reduced work hours. Covinsky (16) also found that daughters and caregivers who live with the patients are also more likely to reduce work hours in order to provide care to patients. Table 2 Stressors Arising Directly from the Caregiving Situation Degree of patient’s cognitive problems Functional ability of patient Degree of problematic behavior Degree of patient resistance Source: From Ref. 6.

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Table 3 Stressors Arising Indirectly from the Caregiving Situation Constriction of social life/leisure time Work strain Financial strain Family conflict Source: From Ref. 6.

The degree of financial strain that results from caregiving is poorly documented because caregivers often provide non-reimbursable expenses for their care recipients. In a study funded by the Alzheimer’s Association (10) seventy-eight percent of caregivers reported contributing part of their personal income or saving for their care recipient. Nonspouse caregivers who live with their care recipient spent on average $261 per mo of their own money for prescription drugs, personal care needs, and other out of pocket expenses. In this sample of caregivers 28% had income levels below $20,000, only 11% of the sample had incomes of $75,000 or more. Family dynamics can be dramatically changed when a member develops dementia. Roles and relationships need to be reconfigured. Caregiving issues can create or bring back previous family conflicts. Disagreements often reflect issues related to the nature or magnitude of a problem. Questions about what should be done to solve a problem and who should do it are common themes of family conflict.

OUTCOMES OF CAREGIVING Negative health outcomes for caregivers include problems such as depression, anger, anxiety, and poor health. Furthermore, the caregiving role changes but does not end when families use paid formal help in the home setting or choose placement into assisted living or a long-term care facility even if these options reduce stress of physical care because caregivers often take on new stressors such as arranging and negotiating care and accepting compromise. The positive aspects of caregiving are frequently overlooked. Physicians need to help caregivers identify and emphasize the positive aspects of caregiving. Cohen (17) found that 73% of the subjects in her study could state at least one positive aspect of caregiving. From within the caregiver there may be intrapersonal satisfaction, feeling that caregiving responsibilities are worthwhile activities. Caregivers also may feel good knowing that their actions are promoting positive situations or avoiding a negative situation (18). The degree of meaningfulness associated with caregiving activities was directly correlated with the presence of depression in a study by Noonan and Tennstedt (19). During subsequent visits the practitioner should help the caregiver identify healthy, positive aspects of caregiving. This can help the caregiver realistically assess their situation and provide a boost to morale. Asking the caregiver to identify positive aspects of caregiving also provides an avenue to assess mood state. Reports of poor mood state and caregiver burnout are “red flags” that deserve further assessment (Table 4). Caregiver burnout is likely when the caregiver lists few or no positive aspects of their experience. It is a strong predictor of depression (6). The evolution of depression into declining physical health has been demonstrated empirically by Pruchno (20) and Aneshensel (6). In a study by Miller (21) behavioral problems and caregiver health were the best predictors of caregiver depression in four separate caregiving populations. Depression across time is dynamic. Early in the disorder higher rates of depression in the care recipient and patient dependence are associated with rate of increases of caregiver depression (22). At the conclusion of this longitudinal study, increasing patient dependence was the only symptom

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Table 4 Factors Associated with Caregiver Burnout Feeling overwhelmed, angry, or frustrated by caregiving responsibilities Feeling frustration or angry with care recipient Feeling that life or health has suffered since becoming a caregiver Feeling that you are not doing a good enough job Feeling that your efforts do not matter or are futile

that increased the rate of caregiver depression; the effect of care recipient depression no longer had an adverse effect on caregivers. The presence of depression also negatively colors caregivers perceptions. Interestingly, caregiver depression was related to inaccurate judgments of patient’s functional ability. Exaggeration of functional loss by depressed caregivers was documented by Arguelles (23).

MODIFYING CAREGIVER DISTRESS The stress of being a caregiver can be effectively addressed when interventions align with needs. Identifying what the caregiver problems arise directly from the caregiving situation or from secondary sources enables one to pinpoint where and how to intervene. Effective interventions must reflect the caregivers needs at that point in time. Families report that physician suggestions sometimes do not target what they perceive to be the real problem. For instance, daycare may be offered as a solution to a burned out caregiver, but the caregiver may see daycare as another expense and a source of more stress. The underlying problem may be family conflict. Family members deny the illness and problems of the patient, the caregiver feels criticized, abandoned, and frustrated from lack of family support. If the source of burnout had been identified initially, a family conference, not daycare, would have been offered as a solution. Providing stage specific information, telling families what they need to know currently and in the near future, will streamline clinic visits. Short, repetitive counseling sessions are preferable since many families need to hear information more than once. Issues related to the current situation are more pressing and relevant than remote concerns of later stages. It is useful, however, to mention briefly those long-term issues that will be discussed at future visits so that caregivers can psychologically prepare for future changes. Hurried conversations may be one of the reason caregivers do not recall being taught by physicians (1). This can be addressed by providing written materials from the Alzheimer’s Association can efficiently augment patient teaching sessions. Demonstration of caregiving skills or role-play rather than explanation can hasten learning for families. Brief individual counseling that emphasizes listening and empathy can help caregivers to feel understood and cared about. Writing down suggestions bolsters the strength of the suggestion because caregivers may need to be reminded to seek treatment for their own health concerns. The future for caregivers is full of uncertainties. One fact however, is certain; their care recipient will lose abilities across time. Feelings of dread, fear, sadness and concerns about the worst-case scenario play on the emotions of many caregivers. This concern related to future events of loss is referred to as anticipatory grief. These feelings of grief weigh heavily upon caregivers (24–26). Meuser and Marwit (27) examined the grief process in spouse and adult children across time. Findings from this study indicate that distinct patterns of grief emerge. In the earliest stages of dementia spouses had more realistic appraisal of the caregiving situations and spouses were openly sad and anticipating an escalation of grief. However, adult children tended to deny cognitive losses and attribute changes to sources other than dementia.

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In the middle stages of Alzheimer’s disease (AD) spouse caregivers usually have accommodated to the increasing demands of the caregiving situation, but many report that their grief is at an apex during this stage. Because denial occurs in the earliest stages of dementia, the adult children need to rapidly expand their caregiving activities during the middle stages of the disease. Meuser and Marwit (27) report that adult children move to the point of grief quickly in this phase. In the late stages of dementia both spouse and adult children caregivers continue to express grief, with the spouses less sure that death will bring relief to their feelings of loss and sadness. STAGE SPECIFIC CAREGIVING RESPONSIBILITIES Caregivers need to focus their efforts on current problems and situations while anticipating longterm events. The physician can promote this goal by providing stage-specific information and anticipatory guidance to families (Table 5). Early Stages of Alzheimer’s Disease In the earliest stages of dementia the care recipient is most often cared for in a private residence. Accepting and learning the role of caregiver is the primary goal in this stage. Interventions emphasize education of the caregiver and family. Simple explanations of dementia followed by written material are ideal. Brochures are available from the Alzheimer’s Association for this purpose. Caregivers and families are often under stress during clinic appointments. As a result, the ability to comprehend and recall new and potentially frightening information is limited. The importance of written materials cannot be underestimated. Repetition of important information is a useful tactic to emphasize its importance and communicate complicated ideas. It is often helpful to have the caregiver re-state the information presented to assess comprehension. The health care provider should take note of the types of questions asked by the caregiver. If the questions relate to information previously discussed, they have not learned or accommodated the information. Denial can take the form of resistance to learning. Alternatively, caregiver’s questions may indicate that they are ready for further information. Caregivers should be directed to contact agencies such as the Alzheimer’s Association that provides seminars, newsletters, support groups and telephone help lines are offered by this agency. Table 5 Caregiving Responsibilities by Stage Early stages of dementia: Learns about the disorder Expands social-emotional support Obtains financial, legal planning Takes on new responsibilities Middle stages: Accepts and arranges help Addresses the living situation Extends support systems Tends to their own physical and emotional needs Final stages of dementia: Considers limiting care Completes legal paperwork Sets up hospice Bereavement: Grieves Fills new-found time

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Caregivers often need help adapting to role changes. New responsibilities are taken on as a result of caring for a demented individual. Former responsibilities may need to be shed in order to fulfill the role of caregiver. Becoming a caregiver is an unplanned, long-term event. Referrals for financial and legal counseling need to be made early in the disease so that the patient may participate in decisions. Each state has specific requirements regarding the protection of assets for caregiving families. Legal planning includes establishment of Power of Attorney and health care decision-making designees. Advance directives need to be discussed as well as reviewing wills. Caregivers need to access important legal documents such as deeds to properties, establish access to safe deposits boxes and financial accounts. Establishing support systems takes time, but is an important asset for caregivers. The mobilization of church/synagogue friends or volunteers can have a potent positive effect. Caregivers may need assistance with transportation or meals preparation. Encourage caregivers to ask family members to visit the residence and give specific suggestions as to how they can help. Middle Stages of Alzheimer’s Disease The middle stages of dementia are characterized by an inevitable expansion of caregiving demand. Equal to the rate of functional loss of the patient is the acquisition of increased care responsibilities of the caregiver. Most caregivers are faced with the difficulty of recognizing that they need substantial additional help during this stage. Accepting help is often much more difficult than recognizing the need for help. Finding and negotiating help can be as daunting a task as the caregiving load. It is not uncommon for caregivers to see this as too difficult and delay seeking help until a crisis arises. A point of transition often occurs when the patient needs round the clock care. Caregivers are then faced with major decisions about living arrangements. Providing in-home care versus placement outside of the home is one of the most difficult decisions caregivers will face. Lack of planning can lead to frantic placements, limited selection of facilities or helpers, and a more difficult adjustment to change. The decision to place a relative in a nursing home needs to be made after considering the patterns of problems and conflicts that occur within a family that lead them to decide upon nursing home placement (NHP). Simply placing the patient in a facility may not alleviate family conflict and stress that is related to factors outside of direct care. Families need to be prepared for the variation in reactions of family members to placement. This is especially true where there is minimal consensus about the need for placement. As a result, the caregiver is often caught in the cross-fire of family members who disagree. Remaining at Home One solution when round-the-clock care becomes necessary is to bring help into the home. Nonsalaried help such as family or friends may suffice. Professional help such as care aides through the department of social services (a free service in some areas). Another option is paid caregivers, which is an out-of-pocket expense for families. It is not usually necessary to hire licensed nurses for care since individuals credentialed as companions or nursing assistants often work out nicely. Respite can be obtained through the use of day-care centers. Patients often thrive in the daycare environments. Expense for this service is out of pocket. Temporary residential respite for planned hiatus of caregivers can provide both psychological and physical relief. Forms for admission can be completed in advance and serve as an emergency source of care should the caregiver become ill suddenly. Assisted Living Determining whether and when to seek assisted-living or long-term care is based upon the following considerations:

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Patient safety: Can the facility safely care for a cognitively impaired person? Many assisted-living facilities are designed to care for people with physical mobility problems. Such a facility may not be able to adequately monitor the whereabouts of a demented client. There are many dementia-specific facilities being developed to meet this special need. Physical health of patient: One of the most dramatic differences between assisted-living facilities and long-term care facilities is the level of services provided to patients. Assisted-living facilities are not able to monitor patients medically for health-related problems such as cardiac instability or glucose regulation and are staffed with nursing assistants with sparse presence of licensed nurses. Patients who require IVs, oxygen, vigilant observation and frequent phone contact to their physicians would not be candidates for this living situation. Services such as physical therapy are contracted through local agencies on an individual basis. Residents in assisted-living facilities are cared for by their private medical doctors in the community. Level of functioning and anticipated rate of decline: Most, but not all, assisted-living facilities are equipped to care for demented residents throughout the course of their disease. However, some facilities have limitations and cannot care for late stage patients. It is crucial to know what services are provided in the residence. If late stage care cannot be provided and the patient is relentlessly declining, it would not be wise to choose that particular facility. Financial status: Assisted-living facilities are almost exclusively private pay at this time. The financial status of the patient and family will determine whether assisted living is an option. Some families may choose assisted living until savings are spent down, and then move their family member to a long-term care facility. At that point the family applies for Medicaid. Philosophically, the approach in assisted living is to mimic the home environment. The approach to care represents psychological/social models of adaptation and support. Most facilities have activity programs. Dementia aside, the residents are viewed as elderly. For the well elderly this environment is safe, more relaxed and home like. Long-Term Care Long-term care facilities are able to provide a wide range of services to their residents. Both unskilled and skilled care are available. Long-term care facilities operate under medical models that provide for staffing patterns able to support more complicated medical care. For families with limited financial means, long-term care provides an avenue for uninterrupted placement. Many facilities have dementia-specific nursing units. Long-term care facilities are able to assist families with Medicaid applications. A wide range of medical services are available. Nursing home placement: Whitlach (28) found that resident adjustment to nursing home was associated with the quality of relationships between the caregiver, their care recipient, and the NH staff. Caregiver depression was associated with the caregivers age, relationship between patient and caregiver, and the caregivers interactions with staff and other families at the facility. No relationship was found between caregiver adjustment or depression and residents physical functioning or behavioral problems and caregivers visiting pattern. The importance of interpersonal relationships between the patient and caregiver as well as the relationships between nursing home staff and other resident families becomes evident. Negative interactions had stronger influence on caregiver adjustment and depression than the effects that positive interactions had on limiting negative caregiver outcomes. It is usually better to eliminate the negative than to enhance the positive but doing both is ideal since caregiver’s perception to their care recipient’s adjustment is influenced by staff remarks. Normalizing statements such as “this is common” may help the caregiver appraisal in a more positive light. If relationship was “rough” before placement, adjustment is likely to be perceived as more difficult.

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Liberman and Fisher (29) found that NHP did not improve or change health status of caregivers over a two-year period. They support the idea that outcome for the caregiver after NHP is related to the pre-NHP family processes and relationships rather than characteristics of the patient, caregiver demographics or use of community services. Many studies document the improvement in instrumental burden after NHP, but outcomes such as health status, depression, and well being are unaffected by this change. Liberman and Fisher (29) postulate that NHP brings the further demise of the patient and eventual death to the forefront. Furthermore the loss of companionship and emotional attachment compounds the changes for spouse caregivers, who differentially reported greater decline in health and well being than adult child caregivers. Caregivers often need to be encouraged to tend to own physical and emotional needs. Often routine health care checks are viewed as just another chore. In the later middle stages of dementia going to a physician appointment for themselves requires finding care for the patient while the caregiver is away. Alternatively, the patient can accompany the caregiver, but is likely to have difficulty waiting quietly and remaining cooperative. Unless the caregiver feels sick, this is an activity many caregivers will postpone until their symptoms cannot be ignored. Final Stages of Alzheimer’s Disease In the final stages of dementia caregivers will be faced with decisions about terminal care. Caregivers trust that their physician will help them to make these difficult choices. Many families chose to limit care in some form. The short-term and long-term effects of decisions needs to be presented to families in a straightforward manner. Physicians need to help caregivers understand which health problems are reversible, which may be side effects of medications, and which problems are unlikely to change. If a family decides to limit resuscitative measures they need to understand that this decision requires legal paperwork. Counsel families to keep the paperwork accessible at all times in order to invoke their decisions in an emergency situation. Hospice is available in-home or in institutional settings. Within the home hospice volunteers and services provide guidance and support for families. Providing physical care to a dying person can be challenging. Hospice personnel and volunteers assist in problem solving and educate the family about what to expect in the final phases of life. BEREAVEMENT The period of bereavement signals the beginning of disengagement from caregiving. Aneshensel (6) found that the ability to disengage from the role of caregiver was related to the caregivers preexisting sense of loss related to the care recipient. Caregivers who recognized the loss of companionship and relationships during active caregiving experienced more depression, a negative consequence at that time. In the period of bereavement, when people deal concretely with loss, the importance of the earlier, similar experience appeared beneficial. The course of grief over the time is variable. Grief is characterized by a variety of feelings that come and go. It usually occurs suddenly in response to a reminder of the loss. Aneshensel (6) noted that grief reactions are still present even 3 years after the death. Caregivers need to be counseled that while grief reactions are expected, they may be at risk for depression. Follow-up care to evaluate mood state needs to be encouraged. CONCLUSIONS Caregivers need the support of physicians in order to continue in their role and the health care system cannot subsist without at home care providers. Since caregivers are at significant risk of

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becoming “secondary victims” to Alzheimer’s disease, identifying their specific problems and individually tailoring solutions can prevent the burgeoning effect of stress over time. Physicians need to provide medical opinions and consequences of decisions clearly. Reassurance and validation from doctors is highly valued by caregivers that can ease the demanding experience of caregiving.

APPENDIX Resources for help Alzheimer’s Association Department of Aging Local Senior Centers Department of Social Services Meals On Wheels Geriatric Case Managers Eldercare Attorneys. Internet Resources Alzheimer’s Association: www.alz.org Alzheimer’s Disease Education and Referral: www.alzheimers.org Alzheimer Page: www.biostat.wustl.edu/alzheimer Alzheimer’s.com: www.alzheimers.com ElderWeb: www.elderweb.com.

REFERENCES 1. Survey finds large communication gap between doctors and Alzheimer’s caregivers. Current news releases, Alzheimer’s association, June 7, 2001. 2. Families and long-term care; talking points on family caregivers. Alzheimer’s association web site, April 14, 2000. 3. Russo J, Vitaliano P, Brewer D, Katon W, Becker J. Psychiatric disorders in spouse caregivers of carerecipients with Alzheimer’s disease and matched controls. A diathesis-stress model of psychopathology. J Abnorm Psychol 1995; 104:197–204. 4. Ory M, Hoffman R, Yee J, Tennsted S, Schultz R. Prevalence and impact of caregiving: a detailed comparison between dementia and nondementia caregivers. Gerontologist 1999; 39:177–185. 5. Pearlin L. Conceptual strategies for the study of caregiver stress. In: Light E, Niederehe G, Lebowitz B, eds. Stress Effects on Family Caregivers of Alzheimer’s Patients. New York: Springer Publishing Co., 1994. 6. Aneshensel C, Pearlin L, Mullan J, Zarit S, Whitlatch C. Profiles in caregiving. The Unexpected Career. San Diego, CA: Academic Press, Inc. 1995. 7. Collins C, Jones R. Emotional distress and morbidity in dementia carers: a matched comparison of husbands and wives. Int J Geriatr Psych 1997; 12:1168–1173. 8. Galliccio L, Siddiqi N, Langenberg P, Baumgarten M. Gender Differences in burden and depression among informal caregivers of demented elders in the community. Int J Geriatric Psychiatry 2002; 17:154–163. 9. Montgomery RJ, Kosloski K. A longitudinal analysis of nursing home placement for dependent elders cared for by spouses versus adult children. J Gerontol 1994; 49:S62–S74.

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10. DeWine M. Letter to subcommittee on aging, committee on health, education, labor, and pensions, United States Senate. Alzheimer’s association web site, 1999. 11. Haley W, West C, m Wadley V, et al. Psychological, social, and health impact of caregiving: a comparison of black and white dementia family caregivers and noncaregivers. Psychol Aging 1995; 10:540–552. 12. Aranda M, Knight B. The influence of ethnicity and culture on the caregiver stress and coping process: a sociocultural review and analysis. Gerontologist 1997; 37:342–354. 13. Dilworth-Anderson P, Williams IC, Gibson BE. Issues of race, ethnicity, and culture in caregiving research: a 20-year review (1980–2000). Gerontologist 2002; 42:237–272. 14. Caregiving’s heavy toll on family demands a response: new study challenges private, public forces to do their part. Alzheimer’s association media news release, February 12, 1999. 15. The hidden hero’s of Alzheimer’s disease. Alzheimer’s association media news release, September 19, 1996. 16. Covinsky K, Eng C, Lui L, et al. Reduced employment in caregivers of frail elders: impact of ethnicity, patient clinical characteristics, and caregiver characteristics. J Gerontol A Biol Sci Med Sci 2001; 5611:M707–M713. 17. Cohen C, Olantonio A, Vernich L. Positive aspects of caregiving: rounding out the caregiver experience. Int J Geriatric Psychiatry 2002; 17:184–188. 18. Nolan M, Grant G, Keady J. Understanding family care. A Multidimensional model of Caring and Coping. Philadelphia: Open University Press, 1996. 19. Noonan A, Tennstedt S. Meaning in caregiving and its contribution to caregiver well being. Gerontologist 1997; 37:785–794. 20. Pruchno RA, Kleban MH, Michaels JE, Dempsey NP. Mental and physical health of caregiving spouses: Development of a causal model. J Gerontol 1990; 45:P192–P199. 21. Miller B, Townsend A, Carpenter E, Montgomery R, Still D, Young R. Social support and caregiver distress: a replication analysis. J Gerontol B Psychol Sci Soc 2001; 56:S249–S256. 22. Neundorfer MM, McClendon MJ, Smyth K, Stuckey J, Strauss M, Patterson M. A longitudinal study of the relationship between levels of depression among persons with Alzheimer’s disease and levels of depression among their family caregivers. J Gerontol B Psychol Sci Soc 2001; 56:P301–P313. 23. Arguelles S, Loewenstein D, Eisdorder C, Arguellas T. Caregivers judgements of the functional abilities of the Alzheimer’s disease patient: impact of caregivers depression and perceived burden. J Geriatr Psych Neurol Summer 2001; 14:91–98. 24. Garner J. Dementia: an intimate death. Br J Med Psychol 1997; 70:10–16. 25. Jones P, Martinson I. The experience of bereavement in caregivers of family members with Alzheimer’s disease. Image. J Nurs Scholarship 1992; 24:24–36. 26. Walker A, Pratt C. Daughters heap to mothers: intergenerational aid versus caregiving. J Marriage Fam 1991; 53:3–12. 27. Meuser YM, Marwit SJ. A comprehensive, stage-sensitive model of grief in dementia caregiving. Gerontologist 2001; 41:658–670. 28. Whitlatch C, Schur D, Noelker L, Ejaz F, Looman W. The stress process of family caregiving in institutional settings. Gerontologist 2001; 41:462–473. 29. Leiberman MA, Fisher L. The effects of nursing home placement on family caregivers of patients with Alzheimer’s disease. Gerontologist 2001; 41:819–826.

23 Pharmacology for the Cognitive Symptoms of Dementia Martin R. Farlow Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.

ALZHEIMER’S DISEASE: CURRENT THERAPEUTIC OPTIONS Alzheimer’s disease (AD) has become a major health problem in the elderly. As the population ages, AD will have an even greater impact on public health. Approximately 4.5 million people in the United States have AD (1), and AD represents the fourth leading cause of death due to disease for people over 65 years of age (2). AD is a progressive, degenerative disease that impinges on all aspects of life for both the patient and the caregiver. While the presenting symptoms may vary from one patient to the next, typically deficits in short-term memory are most prominent. The disease by definition inevitably involves loss of memory and other cognitive functions, decline in the ability to perform activities of daily living (ADL), changes in personality and behavior, and increases in resource utilization. Many individuals with AD are eventually placed in a nursing home. Neuropathologically, several processes have been identified as playing important roles as the disease progresses, including formation of amyloid plaques and neurofibrillary tangles, inflammation, free radical formation, and neuronal loss, usually in specific neurotransmitter systems. All of these mechanisms have motivated different potential drug approaches to therapy, but the best developed involves raising levels of a specific neurotransmitter, acetylcholine (ACh). AD is characterized by progressive loss of cholinergic neurons, particularly in the basal forebrain. As the illness progresses, these losses extend widely through the cerebral cortex (3). This loss of cholinergic neurons is associated with loss of the enzyme, choline acetyltransferase, which in turn reduces levels of the neurotransmitter ACh in these same brain areas (4). As the illness progresses, other neurotransmitter systems are involved including the glutaminergic, serotonergic and dopaminergic systems. However, the cholinergic deficit remains most prominent and has been associated in animal studies with deficits in learning and memory. Recognition of these cholinergic losses motivated the development of approaches to increase levels of ACh and cholinergic activity in surviving neurons in hopes of compensating for losses and improving learning and memory (cholinergic hypothesis) (5). Several approaches have been tried, including the use of ACh precursors and the development of direct agonists to different classes of cholinergic receptors 405

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(muscarinic and nicotinic). However, the most successful and to date the only proven clinically useful cholinergic approach is to block the enzyme, acetylcholinesterase (AChE), thereby increasing levels of ACh at the synapse.

TREATMENT OPTIONS Acetylcholinesterase Inhibitors Acetylcholinesterase inhibitors (AChEIs), which were the first approved AD treatments in the United States, act by increasing brain levels of ACh via blockade of AChE, the enzyme that breaks down this neurotransmitter. There are four AChEIs approved in the United States; tacrine (Cognexw), donepezil (Ariceptw), rivastigmine (Exelonw), and galantamine (originally Reminylw, now Razadynew). While these four drugs all act as AChEIs for their therapeutic mechanism of action, there are individual differences. Tacrine was the first AChEI marketed in the United States, but it is currently used only as a last-line agent because of its high incidence of hepatotoxicity and the corresponding need to carefully monitor hepatic enzymes. Because of its short half-life, tacrine must be given four times per day. For these reasons and because of the availability of other AChEIs with much better safety profiles, tacrine no longer is marketed in the United States and will not be further discussed. Donepezil Donepezil is a noncompetitive, reversible AChEI with a long half-life (approximately 70 hours), which allows for once-daily dosing of 5 or 10 mg at night (6). Donepezil was well tolerated in clinical trials, with the majority of adverse events being mild, dose-related, and gastrointestinal in nature. Some patients will have vivid dreams or sleep disorders that can be minimized by switching to morning dosing. The efficacy of donepezil has been demonstrated in a 15-week trial (7), two 24-week clinical trials (8,9), and two 52-week trials (10,11). In these studies, patients in the donepezil 5 mg and 10 mg groups showed significantly better results than the placebo group on the AD Assessment Scale-cognitive subscale (ADAS-cog), a test of cognition, and Clinicians InterviewBased Impression of Change (CIBIC-plus), a global rating scale. These effects were observed as early as Week 6 in one of the 24-week studies (9) and at Week 12 in the other (8), and differences remained statistically significant through Week 24 in both. In the two 52-week trials, a maintenance dose of donepezil 10 mg/day slowed cognitive decline by half of the rate observed in the placebo group (10), and prolonged the time to clinically assessed functional decline by 5 months (Fig. 1) (11). An open-label extension study assessed mean change from baseline in ADAS-cog scores over a period of 254 weeks and was compared to a historical placebo control (estimated from annualized changes in ADAS-cog from historical cohorts of untreated AD patients) (12). Improvement in ADAS-cog scores was maintained until Week 38 with donepezil 10 mg/day, and ADAS-cog scores declined at Week 50 and thereafter. However, year-long data from two placebo-controlled studies of donepezil, which both showed that donepezil therapy is associated with significant treatment benefits by delaying cognitive and functional decline (10,11), represent the more meaningful evidence of continued efficacy. In summary, donepezil has been shown to improve cognition over baseline in patients with mild-to-moderate AD with the ability to maintain function at or above baseline for 38 to 50 weeks. Additionally, ADLs may be partially maintained by donepezil. Donepezil is an effective, safe, and well-tolerated treatment option for cognitive deficits in AD.

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Rivastigmine Rivastigmine is a noncompetitive, reversible AChEI, as well as an inhibitor of butyrylcholinesterase (the clinical relevance of inhibiting this enzyme in the brain remains to be established) (13). Rivastigmine has a shorter half-life than donepezil; it must be given twice daily. Usual doses range from 3–12 mg/day. Gastrointestinal adverse events are relatively common, including nausea, vomiting, and anorexia (14). Slow dose escalation during titration, with increases at monthly intervals and administration after meals usually improves tolerability and allows for more effective management (15). Efficacy of rivastigmine was originally evaluated in four similarly designed, phase III studies in which patients received placebo or rivastigmine (1–4 mg/day or 6–12 mg/day) for 26 weeks (14,16,17). In the first trial, patients in the high-dose rivastigmine group showed significantly better results at Weeks 18 and 26. The magnitude of benefit was relatively large compared to previous trials with drugs in this class as might be expected since the study was designed to push patients to their maximum-tolerated dose. At Week 26, CIBIC-plus scores from both low- and high-dose rivastigmine groups were significantly improved as compared to scores from the placebo group, suggesting clinically significant benefits in global functioning (p !0.05 and p !0.01, respectively). Long-term efficacy of rivastigmine was evaluated in a 26-week, open-label extension of a previously published 26-week double-blind trial (18). For comparison, a modeling procedure was used to estimate the original placebo patients’ responses if placebo had been continued from Weeks 27 to 52 (i.e., the projected placebo group). It is important to note that treatment with rivastigmine was delayed by 6 months in those patients assigned to placebo in the original, double-blind trial. During Weeks 1 to 26, patients in the placebo group showed a progressive decline, and patients receiving rivastigmine either improved or showed less decline from baseline. Patients in the rivastigmine 6–12 mg/day group showed significantly better results on the ADAS-cog at Weeks 38, 44, and 52 when compared to both projected placebo results and to results from patients originally

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Figure 2 The above figure illustrates changes in mean ADAS-cog score from baseline over 52 weeks for groups of patients, the first receiving rivastigmine 6–12 mg/d for all 12 months, the second receiving placebo under double-blind condition for 26 weeks and then 6–12 mg/d of rivastigmine during the following 26 weeks.

on placebo who were switched to rivastigmine at 26 weeks (p !0.001). The results suggest earlier rather than later therapy may be most beneficial, and might suggest an effect of rivastigmine on disease progression (Fig. 2) (18). To summarize, rivastigmine 6–12 mg/day improves cognition and global functioning in patients with mild-to moderate AD. It has demonstrated positive effects on ADL in most studies. Although cholinergic side effects can occur at therapeutic doses, particularly during titration, rivastigmine generally is safe and well tolerated. Galantamine Galantamine is differentiated from the other cholinesterase inhibitors by its dual mechanism of action: competitive inhibition of AChE and allosteric modulation of nicotinic receptors. The clinical significance of this dual mechanism of action has not been established. However, it has been suggested that allosterically potentiating ligands like galantamine may offer a neuroprotective effect (19). Similar to rivastigmine, galantamine has a relatively short half-life, and so doses are given twice daily. An extended release preparation with once a day dosing was introduced in 2005. At the same time, galantamine ceased being marketed as Reminylw in favor of a new name, Razadynew, to minimize confusion with other drugs marketed with similarly sounding names to Reminylw. The recommended daily dose is 16 mg/day with a maximum dose of 24 mg/day (20). Adverse events associated with galantamine are similar to those seen with the other AChEIs, with the majority being gastrointestinal in nature (21). There are four published, phase III, double-blind, placebo controlled trials of galantamine (21–24). Two were conducted in the United States (21,22) and two were international (23,24). The Raskind (22) and Wilcock (23) studies were both 6 months in length and used dose escalation at 1-week intervals for 3 weeks and a fixed dose (24 mg/day or 32 mg/day) for 22 weeks versus placebo. One of these trials also included a 6-month, open-label, extension phase, in which all patients were treated with galantamine 24 mg/day (22). In the Tariot trial (21), the dose was increased at 4-week intervals, and patients received doses of placebo or galantamine 8 mg/day, 16 mg/day, or 24 mg/day for 5 months. Patients receiving galantamine 24 mg/day and 32 mg/day for 6 months showed a relatively large improvement above baseline as compared to other cholinesterase inhibitor trials and had

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significant improvements versus placebo (22). Similar improvements in ADAS-cog scores were also reported with the same doses in the Wilcock study (23). Although 32 mg/day is not an approved dose because of an increased frequency of side effects, patients in both the Raskind and Wilcock studies receiving either galantamine 24 mg/day or 32 mg/day showed statistically significantly better results on the ADAS-cog compared with patients given placebo (p ! 0.001) (22,23). In the Tariot study, both galantamine 16 mg/day and 24 mg/day produced statistically significant improvements in ADAS-cog scores versus placebo at study endpoint (p !0.001) (21). Long-term efficacy was evaluated in an open-label extension trial where patients received galantamine 24 mg/day for 6 months, regardless of initial randomization in the double-blind trial (22). The mean ADAS-cog scores for those patients receiving galantamine 24 mg/day for 12 months did not change significantly from baseline, illustrating that cognitive function was maintained (22). As was seen with rivastigmine, the data suggest starting therapy earlier in the disease course may be advantageous. ADL were measured using the ADCS/ADL (AD Cooperative Study—ADL) inventory in the Tariot study and the DAD (Disability Assessment in Dementia) scale in the Raskind study. Both of these scales re-validated measures of ADLs in patients with mild-to-moderate AD. In the Tariot study, patients taking galantamine 16 mg/day and 24 mg/day maintained ADCS/ADL scores over 5 months, and patients receiving placebo had ADCS/ADL scores that declined progressively over 5 months. As a group, patients receiving galantamine 24 mg/day for 12 months did not have significant mean change in DAD score from baseline, indicating that galantamine maintained ADL for at least 1 year (22). In comparison with the pooled placebo group, patients in the galantamine 24-mg/day group showed statistically significant benefits on ADL over 12 months (p !0.0001). In summary, galantamine demonstrated a favorable impact on cognition and ADLs in patients with mild-to-moderate AD in multiple phase III trials, prevented significant decline in baseline function for at least 12 months, and was safe and generally well tolerated. CHOLINESTERASE INHIBITORS (GENERAL FEATURES) Cholinesterase inhibitors are effective in improving cognitive and ADL deficits in some, but not all, patients with AD. All published studies consistently demonstrate efficacy for these drugs, although the degree of benefit often is small. The American Academy of Neurology’s Practice Parameter on the management of dementia recommends AChEI therapy for mild-to-moderate AD (25). In general, the higher the tolerated dose, the greater the likelihood a positive response will be achieved. Adverse effects may occur with initiation of therapy and are more likely to occur during escalating dose titration though late negative effects are also known to occur. Adverse effects predominantly are either peripheral (leg cramps, diarrhea, nasal discharge) or central cholinergic symptoms (dyspepsia, nausea, vomiting, anorexia, syncope, sleep disorders). Adverse effects may be minimized by slowing titration and or giving these drugs after meals. The length of time these drugs are effective in treatment is unknown; one study suggests that measurable benefit, albeit extremely modest, can be demonstrated after 2 years for donepezil in comparison with placebo (12). Discontinuation rarely is accompanied by withdrawal effects and clinical deterioration usually reversed by re-instituting the drug.

ALTERNATIVE TREATMENT OPTIONS Memantine Memantine is a noncompetitive N-methyl D-aspartate receptor antagonist that has been used in Germany for the treatment of dementia for over 10 years, and in 2003 was approved for treatment of AD by the U.S. Food and Drug Administration. It has a relatively long half-life but following

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previous precedents is administered twice per day. The clinical safety and efficacy of memantine have been investigated both in clinical trials and post-marketing surveillance studies (26). In a randomized, placebo-controlled, double-blind, 12-week Latvian Nursing Home Trial (NZ166), 61% of patients with severe dementia treated with memantine (10 mg/day) showed an improvement as compared with controls in global functioning, care dependence, and behavioral symptoms (27). In another 28-week, multicenter trial, patients (NZ252) with moderately severe-tosevere AD were randomized to either memantine (10 mg BID) or placebo (26). Global function was assessed by the CIBIC-plus, but cognitive function was measured by tools other than the ADAScog, in particular the Severe Impairment Battery, a test of cognitive functioning optimized to show change in patients with moderate to severe AD. Although both memantine- and placebo-treated groups demonstrated a decline in cognition and function, the group treated with memantine consistently showed less decline than those taking placebo (p !0.05) (26). In a 24-week double-blind, placebo-controlled trial in moderate to severe AD, patients on stable-doses of donepezil were treated with either placebo or 20 mg/day of memantine (28). In this 403-patient study, patients in the donepezil/memantine group had significantly better cognitive functioning at 26 weeks versus donepezil/placebo and were still above baseline at the end of the trial. Global functioning as measured by the CIBIC-plus, ADL as measured by ADCS-ADL, and psychiatric and behavioral symptoms as measured by the Neuropsychiatric Inventory were also all significantly improved in the combination group. Interestingly, significantly more patients completed the study in the combination group. Few adverse effects occurred more frequently in the memantine-treated patients compared with placebo-treated patients other than a modest increase in transient confusion, predominantly during titration. In summary, memantine has demonstrated the ability to improve cognition, ADL, and behavior in moderate-to-severe stage AD patients. The addition of memantine in moderate-to-severe AD patients treated with donepezil demonstrates benefits beyond that of donepezil alone (28). Vitamin E Vitamin E is an antioxidant that reduces neuronal damage by inhibiting the oxidation of lipids and preventing the formation of free radicals. Although vitamin E in preclinical studies has been shown to prevent oxidative damage induced by beta-amyloid in cell culture (29), only one clinical trial has investigated its use as a treatment for AD (30). This multicenter, randomized, double-blind, placebo-controlled trial compared the use of selegiline, vitamin E, or both in treating patients with moderately severe AD over a 2-year period (30). Vitamin E (2,000 IU/day) significantly delayed time to reach the primary outcome measure, which was one of the following: death, institutionalization, loss of ADL, or progression to severe dementia as compared with control patients (6 months, p !0.001) (30). Although no improvements in cognition, function, or behavior were seen in patients treated with vitamin E, beneficial treatment effects for the primary endpoint of delaying institutionalization (pZ0.003) and a secondary endpoint of decreased need for supervision (pZ0.021) were observed (30). A meta-analysis of high dose vitamin E (O400 IU/ day) in multiple conditions recently found a slight but significant risk for mortality, (31) suggesting that vitamin E therapy in AD be used judiciously, if at all, and with doses less than 400 IU/day. Ginkgo biloba A large randomized, placebo-controlled clinical trial of Ginkgo biloba investigated efficacy of this drug (120 mg/day) on cognition, social functioning, and behavior in patients with mild-to-moderate AD (NZ236) (32). Although conclusions are limited by the high dropout rate (50%) at study’s end (12 months), a modest improvement in cognitive performance as measured by ADAS-cog was seen in the Ginkgo group as compared to placebo-treated patients (32). Social functioning was also improved in the G. biloba group (32). Other studies of G. biloba and meta-analyses have reported

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similar results. However, a later Dutch study of G. biloba that was double-blind, placebo-controlled and of 24 weeks duration in 214 elderly patients with AD, vascular dementia (VaD), or age associated memory impairment failed to show any effects of treatment on neuropsychological or behavioral measures (33). These studies thus provide inconclusive evidence for a benefit of G. biloba for cognitive function; if there is an effect, it appears to be slight.

Estrogen There are more women than men with AD, especially over the age of 65 years, suggesting an association between the decline in estrogen production during menopause and the higher prevalence of AD in women. Epidemiologic studies of estrogen use have shown that AD and related dementias occurred less in women receiving estrogen replacement therapy than those who were not (34–36). A randomized, placebo-controlled, multicenter trial (NZ120), however, reported that women (O60 years of age) with mild-to-moderate AD receiving estrogen replacement therapy (0.625 mg/day or 1.25 mg/day) for l year did not improve in global [ADCS-Clinical Global Impression of Change (CGIC) scale and CDR], cognitive (ADAS-cog), or functional outcomes (37). Similarly, a 16-week double-blind, placebo-controlled trial of unopposed estrogen in 42 women with mild to moderate AD demonstrated no improvements for women on estrogen as compared to those taking placebo (38). In women without AD who were 65 years and older, neither estrogen plus progestin therapy (39,40); or conjugated equine estrogen alone (41) protected against cognitive decline but surprisingly appeared to increase the risk for dementia. In summary, current evidence does not support a role for estrogen in treating cognitive symptoms of AD, nor does estrogen delay disease progression in women with AD. It is contra-indicated as a dementia prevention therapy in cognitively normal older women.

Nonsteroidal Antiinflammatory Drugs Epidemiologic studies, such as that by Jenkinson and colleagues (1989) (42) have reported that patients with inflammatory diseases like arthritis tend to have a reduced risk for AD (42). Others have associated the use of nonsteroidal anti-inflammatory drugs (NSAIDs)—a common treatment for patients with arthritis—with a decreased risk of AD (43,44). A prospective cohort study from Baltimore (44) also noted an increased preventive effect with the duration of use. Patients taking NSAIDs for 2 or more years had an approximately 50% lower risk for AD than those with less or no exposure to NSAIDs (44). A double-blind, placebo-controlled 6-month trial of indomethacin in 44 patients with AD demonstrated that subjects in the NSAID group at study endpoint had stable cognitive functioning as compared to significant deterioration as measured by a battery of neuropsychological tests in the placebo group. Methodology concerns and a high dropout rate particularly in the active treatment group raise questions concerning validity of the results (45). In another double-blind trial, 351 patients with AD were treated with a selective cyclooxygenase-2 inhibitor (rofecoxib) or a traditional NSAID (naproxen) or placebo for l year (46). Changes in cognitive function, ADLs and behavior were not different between either of the active drug groups and placebo at one year. Higher percentages of fatigue, dizziness, and hypertension were seen in the anti-inflammatory drug groups and more serious adverse events such as hemorrhage were also more common in the rofecoxib and naproxen groups. A similar lack of benefit for rofecoxib in mild AD has been reported recently (47). In summary, although epidemiological studies suggest NSAIDs may delay progression to AD, double-blind, placebo-controlled trials do not support use of these drugs in patients with established AD.

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ALZHEIMER’S DISEASE WITH CONCOMITANT VASCULAR DEMENTIA AND VASCULAR DEMENTIA (VaD) Galantamine has been studied in patients with mixed AD and VaD. Erkinjuntti et al. reported the results of a large, multi-site, double-blind, placebo-controlled study, where patients with VaD, and those with AD and concomitant cerebrovascular disease received galantamine 24 mg/day as part of a 6-month placebo-controlled, double-blind study followed by a 6-month open-label extension (48). Cognitive ability was maintained or improved in the galantamine treatment group as compared with placebo (63.8% vs. 50.6%, pZ0.006). The CIBIC-plus measuring overall response to therapy showed improvement in the galantamine group, 74% compared with 59% in the placebo group (pZ0.0011). Most of the adverse effects that occurred were during dose escalation and were characterized as mild to moderate and transient. The open-label extension to the initial trial demonstrated maintenance of baseline cognitive function for the entire 12-month treatment period (49–51). Galantamine was well tolerated. The evidence suggests galantamine may be effective in patients with mixed VaD and AD. Two large double-blind, placebo-controlled trials of donepezil in patients with VaD also demonstrated that the donepezil-treated groups achieved statistically significant, but modest improvements in cognitive function as measured by ADAS-cog versus placebo groups. In contrast to AD studies, the vascular placebo treated patients exhibited almost no deterioration over these 6-month trials (52,53). Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) are another approach to treating vascular abnormalities and potentially AD. Vascular disease may be stabilized or improved by the cholesterol lowering effects of these drugs. Statins also have selective antiinflammatory effects and lower levels of inflammation-associated C-reactive proteins (elevated in some patients with AD). Several retrospective epidemiological studies suggested that use of statins decreases risk of developing AD in elderly patients (54,55). Two prospective double-blind trials, however, reported no benefit of statins in preventing the onset of AD (56,57). A small pilot doubleblind, placebo-controlled 1-year trial of atorvastatin in mild to moderate AD suggested some clinical benefits (58). The role of statins in delaying disease progression in AD awaits results of larger more definitive trials. CONCLUSIONS The only proven current therapies for treating cognitive deficits of AD are symptomatic neurotransmitter-based approaches. Virtually all reported studies find that AD individuals who are treated with AChEIs or memantine have less cognitive and functional decline compared with AD individuals treated with placebo, although the magnitude of the effect is small. The slowing of progression of symptoms in AD can increase the well-being and quality of life of the patient and caregiver. Early intervention with AChEIs appears to improve treatment outcomes, which in turn depends on early diagnosis using tools for assessing cognitive, behavioral, and functional decline. Alternative non-FDA approved treatments have not been proven to be effective in treating cognitive symptoms. More placebo-controlled studies are needed to validate their potential. The recent study (28) showing benefit with the addition of memantine to donepezil suggests that future advances in therapy will involve treating patients with combinations of drugs that act by different mechanisms to more effectively improve symptoms and or delay disease progression.

REFERENCES 1. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer’s disease in the U.S. population: prevalence estimates using the 2000 census. Arch Neurol 2003; 60:1119–1122.

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2. Murphy SL. Natl Vital Stat Rep 2000; 48:1–106. 3. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR. Alzheimer’s disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 1981; 10:122–126. 4. Perry EK, Tomlinson BE, Blessed G, et al. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. BMJ 1978; 2:1457–1459. 5. Bartus RT, Dean RL, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217:408–414. 6. Ariceptw. Product Information. Teaneck, NJ: Eisai, Inc, 1998. 7. Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer’s disease: a 15-week, double-blind, placebo-controlled study. Donepezil study group. Arch Intern Med 1998; 158:1021–1031. 8. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil study group. Neurology 1998; 50:136–145. 9. Burns A, Rossor M, Hecker J, et al. The effects of donepezil in Alzheimer’s disease—results from a multinational trial. Demen Geriatr Cogn Disord 1999; 10:237–244. 10. Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001; 57:489–495. 11. Mohs RC, Doody RS, Morris JC, et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001; 57:481–488. 12. Rogers SL, Doody RS, Pratt RD, Ieni JR. Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: final analysis of a U.S. multicentre open-label study. Eur Neuropsychopharmacol 2000; 10:195–203. 13. Nordberg A, Svensson AL. Cholinesterase inhibitors in the treatment of Alzheimer’s disease: a comparison of tolerability and pharmacology. Drug Saf 1998; 19:465–480. 14. Corey-Bloom J, Anand R, Veach J. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease for the ENA 713 B352 Study Group. Int J Geriatr Psychopharmacol 1998; 1:55–65. 15. Exelon. Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation, 2001:1–19. 16. Schneider LS, Anand R, Farlow MR. Systematic review of the efficacy of rivastigmine for patients with Alzheimer’s disease. Int J Geriatr Psychopharmacol 1998; 1:S26–S34. 17. Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ 1999; 318:633–638. 18. Farlow MR, Anand R, Messina J, Hartman RC, Veach J. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol 2000; 44:236–241. 19. Maelicke A. Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer’s disease. Demen Geriatr Cogn Disord 2000; 11:11–18. 20. Reminyl. Product Information. Titusville, NJ: Janssen Pharmaceutica Products, L.P., 2001:1–6. 21. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebocontrolled trial of galantamine in AD. Neurology 2000; 54:2269–2276. 22. Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: a 6-month randomized, placebocontrolled trial with a 6-month extension. Neurology 2000; 54:2261–2268. 23. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. BMJ 2000; 321:1445–1449. 24. Rockwood K, Mintzer J, Truyen L, et al. Effects of a flexible galantamine dose in Alzheimer’s disease: a randomised, controlled trial. J Neurol Neurosurg Psychiatry 2001; 71:589–595. 25. Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review). Report of the quality standards subcommittee of the American Academy of Neurology, Guideline. Neurology 2001; 56:1154–1166. 26. Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-best study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999; 14:135–146. 27. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003; 348:1333–1341.

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24 Treatment of the Neuropsychiatric Symptoms in Alzheimer’s Disease Donna Masterman David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.

IMPORTANCE OF TREATING BEHAVIORAL DISTURBANCES IN ALZHEIMER’S DISEASE Behavioral symptoms are common in Alzheimer’s disease (AD) and represent a major source of the disease morbidity. Neuropsychiatric disturbances have been associated with more rapid cognitive decline (1), increased caregiver burden (2,3), increases in patient care costs due to earlier institutionalization of the AD patient, greater medication use and more adverse side effects and more extensive institutional staffing needs (4,5). Kaufer and colleagues (6) reported a strong correlation between the amount of neuropsychiatric disturbance as measured by the Neuropsychiatric Inventory (NPI) and the degree of caregiver distress with little relationship between the degree of impairment on the Mini-Mental State Exam (MMSE) (7) and the degree of caregiver distress. In addition, a recent cost analysis showed that AD patients with higher NPI scores (worse psychopathology) had formal costs between $3,162 and $5,919 higher than those with low NPI scores and the total direct costs between $10, 670, and $16,141 higher, depending on the severity of cognitive impairments (8). Clinical research on the treatment of these non-cognitive symptoms has only recently become a subject of major investigation. Clinical drug trials of new therapeutic agents in AD are beginning to regularly include specific scales to measure potential changes in behavioral symptoms with respect to their therapeutic interventions. In addition, an increasing number of randomized, placebo-controlled clinical trials of a wide variety of psychotropic medications to treat significant behavioral disturbances in dementia are beginning to emerge. The successful management of troublesome behaviors associated with AD can significantly improve the overall quality of life for patients and their caregivers and could result in significant relevant benefit.

THE PREVALENCE OF BEHAVIORAL SYMPTOMS IN AD A wide spectrum of behavioral changes occurs throughout the course of AD with the prevalence of certain behaviors varying widely across studies. In general, behavioral disturbances are extremely 417

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Table 1 Neuropsychiatric Symptoms and the Cholinergic Deficit in AD Anticholinergic medications produce similar neuropsychiatric symptoms Anticholinergic agents worsen AD Neuropsychiatric symptoms in AD are more marked in patients with AD with more severe cholinergic deficits Neuropsychiatric symptoms in AD reflect frontal and temporal lobe dysfunction

common in AD with overall prevalence estimates between 60–80% and a lifetime risk of 90% or greater (9,10). In one cross-sectional analysis, Mega and colleagues (11) examined the occurrence of certain common symptoms in AD across disease severity, which included changes such as personality alterations, mood disturbances, perceptual disturbances (delusions and hallucinations), vegetative symptoms, and aberrant motor disturbances (Table 1). Nearly all patients with AD develop neuropsychiatric symptoms sometime during the course of their illness with estimates of disruptive agitated behaviors ranging from 70–90% (1,12). In a longitudinal study by Devanand and colleagues, 1997, the authors found that of 235 patients with early AD, only 8.5% remained free of psychopathology during the first 3 years of follow-up. It is also not uncommon for multiple behavioral symptoms to co-exist simultaneously (13,14). In addition, many of these behavioral disturbances are episodic and in some cases may precede the diagnosis of AD (15,16). However, although behavioral symptoms may fluctuate, once present they tend to recur. This is supported by a longitudinal assessment of 181 outpatients with AD and psychosis and/or aggression by Levy and colleagues (13), where they found 95% of patients with psychosis, 93% with agitation and 85% with depression exhibited a recurrence of those symptoms during the following year. Devanand and colleagues also conducted a longitudinal study of 235 patients with early AD and followed them every 6 months for 5 years and found that 80% of patients who exhibited behavioral disturbances at one visit manifested them at the next visit (17). THE CHOLINERGIC DEFICIT IN AD AND NEUROPSYCHIATRIC SYMPTOMATOLOGY Many studies have focused on the relationship between the cholinergic deficit and cognitive impairment; however, evidence is emerging relating the cholinergic abnormalities to some of the neuropsychiatric manifestations of AD as well (Table 2). Anticholinergic toxicity is commonly accompanied by delirium with delusions and is reversible with physostigmine, a short-acting acetylcholinesterase inhibitor (AChEI). Treatment with physostigmine on psychotic symptoms was compared with haloperidol in a pilot double-blind crossover trial involving patients with probable AD (18). Reductions in psychotic symptoms were similar with the two drugs. Tacrine, the first AChEI drug approved for the symptomatic treatment of AD, was shown in two subsequent studies to also have a beneficial effect on behavioral symptomatology. In an open-label study of 28 patients with probable AD, the authors evaluated the effects of tacrine on behavioral symptoms and found a significant reduction in behavioral symptoms as measured by the NPI in response to therapy at the 120 mg/d and 160 mg/d doses. This was particularly true for symptoms of disinhibition, anxiety, and apathy (6). In a post-hoc analysis of the randomized, double-blind, placebo-controlled clinical trial data with tacrine, Raskind and coworkers (19) reported on the results of one of the secondary outcome measures in that study, the non-cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-noncog) and found that treatment resulted in stabilization or improvement in the scores for delusions, pacing, and cooperation. Cummings and colleagues (20) reported the results of a retrospective analysis of 86 patients with AD treated with open-label donepezil (another AChEI) and found behavioral improvement in

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Table 2 Neuropsychiatric Symptom Cluster in Dementia and Class of Psychopharmacologic Agent Psychosis Atypical Antipsychotic Drug

Trade name w

Risperidone Olanzapine Quetiapine Clozapine

Risperdal Zyprexaw Seroquelw Clozarilw

Starting dose

Max dose

0.5 mg/d 2.5 mg/d 12.5–25 mg/d 6.25–12.5 mg/d

1–3 mg/d 5–10 mg/d 50–150 mg/d 25–100 mg/d

Agitation/Aggression Class Antipsychotics (same as listed above) Anticonvulsant Antidepressant

Anxiolytic Other

Drug

Trade name

Depakotew Tegretolw Deserylw Paxilw Zoloftw Celexaw Busparw Ativanw Inderalw

Divalproex Carbamazepine Trazodone Paroxetine Sertraline Citalopram Buspirone Lorazepam Propranolol

Starting dose

125 bid 50–100 mg/d 25–50 mg/d 5–10 mg/d 25–50 mg/d 10–20 mg/d 5 mg bid 0.5 mg/d 10 mg bid

Max dose

1500–2000 mg/d 500–800 mg/d 200–300 mg/d 40 mg/d 150–200 mg/d 40 mg/d 45 mg/d 4–6 mg/d 50–240 mg/d

Depression Drug (Selective serotonin reuptake inhibitor) Fluoxetine Paroxetine Sertraline Citalopram Fluvoxamine (Tricyclic) Nortriptyline Desipramine (Other) Nefazodone Venlafaxine

Trade name

Starting dose

Max dose

Prozacw Paxilw Zoloftw Celexaw Luvoxw

10 mg/d 5–10 mg/d 25–50 mg/d 10–20 mg/d 50 mg/d

20–40 mg/d 40 mg/d 150–200 mg/d 40 mg/d 300 mg/d

Pamelorw

10 mg/d 50 mg/d

50–100 mg/d 150 mg/d

Serzonew Effexorw

150 mg bid 75 mg/d

600 mg/d 375 mg/d

Anxiety Drug Buspirone Lorazepam Oxazepam

Trade name w

Starting dose

Buspar Ativanw

5 mg/d 0.5 mg/d 10 mg/d

Trade name

Starting dose

Max dose 30–45 mg/d 2–6 mg/d 30 mg/d

Sleep Disturbance Drug Trazodone Zolpidem Temazepam

Deserylw Ambienw Restorilw

50 mg/d 5–10 mg/d 15 mg/d

Max dose 300 mg/d 10 mg/d 30 mg/d

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41%, which included a beneficial effect on delusions, agitation, anxiety, disinhibition, and irritability. McRae, and colleagues (21) also reported the results of another open-label study using donepezil to treat 275 patients with AD and coexisting behavioral problems for 20 weeks. These investigators found a significant improvement in overall NPI scores. More recently, the effects of donepezil on behavioral aspects of AD were evaluated as part of a 24-week, multi-centered, randomized, double-blind, placebo-controlled clinical trial involving patients with moderate to severe AD (22). This study involved 290 subjects with MMSE scores ranging from 5–17 and found significant improvement in those subjects treated with donepezil compared to placebo in the primary outcome measure, the Clinician’s Interview-Based Impression of Change with caregiver input (CIBICC) as well as in measures of cognitive function, behavior, and activities of daily living. The behavioral symptoms as measured by the NPI improved from baseline with donepezil by 4.6 points. Individual item analysis at week 24 showed a significant difference in depression/ dysphoria, anxiety, and apathy. Galantamine, a newer FDA-approved AChEI, also has been found in a randomized, doubleblind, placebo-controlled clinical trial in outpatients with mild-moderate AD to have a beneficial effect on neuropsychiatric symptoms (23). The total NPI score was improved in the group of subjects receiving galantamine compared to placebo and the specific neuropsychiatric symptoms of anxiety, disinhibition, hallucinations, and aberrant motor behavior were significantly improved and the degree of caregiver distress reduced (p!0.05). Rivastigmine, yet another FDA-approved AChEI, also has been reported to benefit the behavioral symptoms in a multi-center study of open-label rivastigmine in 173 AD patients residing in nursing homes. Cummings and colleagues (24) found that 58% demonstrated improvement in behavioral problems, which included significant responses for irritability, aberrant motor behavior, apathy, hallucinations, disruptive night-time behavior, agitation, and delusions. In another study of rivastigmine, researchers examined the effects of this compound on behavioral symptoms found in patients with dementia with Lewy bodies (DLB), another common cause of dementia with many similar features to AD (25). This placebo-controlled, double blind, multi-center study of 120 patients with DLB was conducted in Europe. Doses of rivastigmine up to 12 mg/d were compared with placebo for 20 weeks and neuropsychiatric assessments were performed using the NPI. Rivastigmine at 6–12 mg/d produced statistically and clinically significant behavioral effects showing at least a 30% improvement from baseline and was well tolerated. The effects of the irreversible AChEI, metrifonate, on behavioral symptoms in AD were evaluated prospectively in two randomized, placebo-controlled clinical trials of 672 patients. This AChEI demonstrated significant improvements in behavioral disturbances in AD as measured by the NPI showing particular benefit of symptoms of hallucinations, aggression, agitation, and aberrant motor behavior (26,27). An application to the Food and Drug Administration for metrifonate was withdrawn in 2000 because of unfavorable side effects of the drug. In a recent meta-analysis of the published literature on the effects of AChEI on behavioral symptoms, Trinh, and colleagues (28) reviewed the published literature on the topic from 1966–2001 and reported on the 29 parallel-group or crossover randomized, double-blind, placebocontrolled trials of outpatients with mild-moderate AD treated for at least a month with an AChEI. Sixteen trials included evaluations of neuropsychiatric symptoms. A small but statistically significant improvement was seen with AChEI use. In addition to the cholinesterase inhibitors, the selective muscarinic agonist, xanomeline tartrate, has been shown to improve the behavioral symptoms of AD in a randomized, double-blind, placebo-controlled trial involving 343 patients with mild-moderate AD. Dose-dependent reductions were noted in symptoms such as vocal outbursts, suspiciousness, delusions, agitation, hallucinations, wandering, fearfulness, compulsiveness, tearfulness, mood swings, and threatening behavior (29).

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While the precise neurobiology of the neuropsychiatric disturbances in AD is not fully understood, cholinergic systems appear to play a role in some of the non-cognitive manifestations of the illness. In addition, there are known alterations in several other neurotransmitter systems (such as noradrenergic, serotonergic, cholinergic, dopaminergic) that have also been implicated in the pathobiology of anxiety, mood disorders, and psychosis. Alterations in these other transmitter systems in AD may contribute in an important way to behavioral disturbances in these patients and may be a further target for improved therapies. EVALUATING BEHAVIORAL DISTURBANCES IN PATIENTS WITH DEMENTIA Critical to the initial management of these disturbances is a search for any contributing medical, medication-related, or social/environmental factors. Superimposed delirium as a cause of behavioral deterioration should always be considered. Dementia patients are more likely than nondemented elderly patients to develop an acute confusional state with toxic or metabolic insults. There should be a high index of suspicion of the presence of delirium with any acute alteration in behavior, sleep patterns, or attention, or with the onset of motor restlessness or increase in visual hallucinosis (30). Understanding the patient’s underlying needs or motivation can lead to creative interventions that diminish disturbed behaviors without drugs (31). If these approaches are not successful and behavioral disorders are severe enough to interfere with normal functioning, pharmacological therapy should be considered (Table 2). NON-PHARMACOLOGICAL BEHAVIORAL INTERVENTIONS Behavior modification treatment involves identification of the specific problem behavior and assessment of environmental factors that precipitate or reinforce the undesired behavior. The environment and actions of others are then modified to extinguish undesirable behaviors and increase desired behaviors. Operant techniques and environmental manipulation have been used to successfully reduce wandering behavior, verbal, and physical aggression, and depressive behaviors and to increase self-care skills, appropriate ambulation, and socialization (32). Caregivers and family members can benefit from education regarding the expected changes in memory, language skills, cognition, and behavior during the progressive course of AD. A wide variety of non-pharmacological interventions such as sensory intervention, environmental interventions, structured activities and behavioral therapy have been examined for their effect on unwanted behavioral symptoms in patients with dementia. For an excellent review of the literature, the reader is referred to Cohen-Mansfield (33). A large scale, multi-centered, randomized, parallel-group, placebo-controlled trial sponsored by the Alzheimer’s Disease Cooperative Study Group (ADCS) was conducted to compare the results of a behavioral intervention [behavior management techniques (BMT)] with two common pharmacologic interventions used at the time (trazodone and haloperidol) versus placebo for treating agitation in patients with AD (34). The results suggested that improvement rates were similar in all three groups (BMTZ32%, haloperidolZ32%, trazodoneZ41%, and placeboZ31%) and there were no differences in efficacy or dropout rates. There was less bradykinesia and parkinsonism in the behavioral management arm. It has been argued that one potential reason for the lack of superiority of the pharmacological interventions may have been the result of a “floor effect” with fewer patients exhibiting significant behavioral disturbances in this outpatient population compared with the more typically, acute agitation in-patients with more advanced disease in which most of the efficacy data has been reported. Also, newer atypical antipsychotic agents have since become available that appear to be better tolerated and possibly more efficacious. (See Appendix 1.)

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PHARMACOLOGICAL INTERVENTIONS Treatment of Psychosis and Agitation Psychosis (delusions and/or hallucinations) are not uncommon in dementia patients and represents a distinct clinical syndrome that may be responsive to appropriate directed pharmacologic therapy. A working definition for this has been put forth by Jeste and Finkel (35), and more recent clinical trials in dementia patients are now being conducted using this definition. Atypical Neuroleptics Although the use of typical and atypical neuroleptics in the demented elderly patient has been widely studied, many investigations have been limited by methodological flaws (i.e., heterogeneous patient populations, inadequate definition and measurement of target symptoms, lack of randomization, inadequate controls, and lack of double-blind assessment methods). In a statistical meta-analysis of controlled trials of neuroleptic treatment of agitation in patients with a primary diagnosis of dementia, Schneider, and colleagues (36) found that 18% of dementia patients derived benefit from neuroleptic treatment beyond response attributable to placebo. The placebo response was significant in many studies, varying from 0% to 67%. Kindermann and colleagues (37) conducted another recent review of the published literature from 1960 to 2000 on the treatment of psychosis, agitation, and aggression in patients with dementia. Forty-eight studies meeting their selection criteria were identified from Medline and Science Citation Index. The authors found that antipsychotic medication was generally effective for the treatment of psychosis and agitation in elderly patients with dementia and in double-blind, placebo-controlled trials in this population, mean improvement rates were 61% with antipsychotics and 35% with placebo. Potential side effects of antipsychotic drugs include sedation, orthostatic hypotension, central and peripheral anticholinergic effects, and extrapyramidal symptoms (EPS) (akathisia, parkinsonism, tardive dyskinesia, neuroleptic malignant syndrome) due to dopamine blockade. All of these side effects appear to occur with increased frequency and at lower dosage levels in elderly patients (38). The one exception is neuroleptic malignant syndrome, which is more common among younger patients. There is an increased incidence and severity of tardive dyskinesia with advancing age (39). Excessive sedation can potentially cause increased confusion and agitation. More serious consequences (e.g., hip fracture) can result from falls in elderly patients. Elderly patients are more likely to have preexisting medical conditions such as cardiac disease or prostatic hypertrophy, increasing the risk of adverse peripheral anticholinergic effects. AD patients may be more susceptible to central anticholinergic cognitive effects given the widespread cortical cholinergic deficit present in AD. Neuroleptic-induced akathisia may increase pacing and other repetitive nonaggressive behaviors. The use of atypical neuroleptics in the treatment of behavioral problems in dementia patients can be effective. In a randomized, placebo-controlled trial comparing 0.5, 1.0, and 2.0 mg per day of risperidone to placebo in treating psychosis and aggressive behavior in 625 elderly institutionalized patients with dementia, the authors found significant reductions in these behaviors as measured by the BEHAVE-AD. Seventy percent of patients completed the study and more side effects were seen in the 2 mg/d versus the 1 mg/d dose of risperidone (40). Another study in 344 nursing home patients found slightly less robust results, but efficacy was clearly demonstrated. DeDeyn and coworkers, 1999 (41) also reported on a double-blind randomized trial of 12 weeks duration of risperidone versus haloperidol in a nursing home dementia population showing an antiaggressive effect in treated patients and a superiority of risperidone over haloperidol in terms of tolerability. A more recent randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis in dementia was conducted in 337 elderly nursing home patients with dementia. Treatment with low dose risperidone (meanZ0.95 mg/day) resulted in significant reduction in aggressive behavior, agitation, and psychosis compared to placebo (42).

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Risperidone was generally well tolerated with no increase seen in EPS, but somnolence and urinary tract infection being more common in the treated group. Olanzapine also has been shown to improve psychotic and behavioral symptoms in patients with AD in nursing care facilities. In a 6-week, double-blind, randomized, placebo-controlled trial with 206 patients which used as the primary efficacy measure the sum of the agitation/aggression, hallucinations, and delusions items of the NPI-Nursing Home version, a validated scale for use in this patient population, significant behavioral improvement was demonstrated (43). The 5 mg and 10 mg/d doses of olanzapine produced significant improvement compared with placebo in these core symptoms, but somnolence was significantly more common among treated patients and gait disturbance occurred in 19.6% and 17.0% of the 5 mg and 15 mg/d doses respectively. Quetiapine was evaluated in a prospective, open-label, 12-week pilot study in outpatients with probable AD with psychosis or aggressive behaviors and found in doses ranging from 50 to 150 mg. Patients given quetiapine showed a significant decrease of delusions, aggression, and overall behaviors based on NPI scores at 6 and 12 weeks (44,45). Larger, multi-centered, placebocontrolled trials in AD are in progress. Ziprasidone and aripiprazole are the newest atypical antipsychotics available in the United States but there is limited data regarding their use in the elderly and no reports regarding use in patients with dementia. Important side effects can occur with the atypical antipsychotics and include: ESP, tardive dyskinesia, sedation, orthostatic hypotension, falls, metabolic (weight change, hyperglycemia, dyslipidemia), QT prolongation, and cognitive toxicity, including delirium and impaired activities of daily living (See Appendix 2.) Major limitations in many of the current studies using antipsychotics in treating behavioral disturbances in dementia patients are the lack of randomized trials that extend beyond 12 weeks and the lack of long-term controlled data. To address this issue, a large, multi-centered, randomized, controlled study of the use of antipsychotics in AD sponsored by the National Institute of Mental Health is currently underway known as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Information from this study will provide useful data on the effectiveness of many of these compounds in this patient population with evaluation of more prolonged exposure (Table 3) (46). In general, atypical antipsychotics are more useful than typical antipsychotics for the treatment of agitation and psychosis in dementia but may be associated with increased risk of death (see Appendix 2) and have limitations. Patients with AD require lower doses of these drugs compared with patients with schizophrenia. Anticonvulsants The anticonvulsant Divalproate sodium is attributed to enhanced release of the inhibitory neurotransmitter, gaba-butyric acid (GABA). Several open trials (48,49) have shown divalproate sodium to be effective in managing agitation and aggression in dementia patients. In a controlled pilot study with 16 subjects, divalproate sodium was used for the treatment of agitation in dementia patients and had good efficacy and tolerability (50). The doses gradually were titrated from 500–2000 mg/d. More recently Porsteinsson and colleagues, (51) reported the results of a 6-week, placebo-controlled study of divalproex sodium for agitation in dementia in 56 nursing home patients. The brief psychiatric rating scale (BPRS), the primary outcome measure in this study, has been validated for use in this setting. The agitation score on the BPRS was significantly reduced in the treated patients compared to placebo. The Clinical Global Impression scale also showed a trend toward improvement in the treated group (pZ0.06). Divalproate sodium generally is well tolerated in the elderly but can cause gastrointestinal side effects as well as tremor and sedation. Liver function tests should be monitored.

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Table 3 Placebo-Controlled Trials in Dementia: Atypical Antipsychotics Antipsychotic Risperidone

Olanzapine Quetiapine Ziprasidone Aripriprazole

Study

N

Duration (weeks)

Results

Katz et al. (40) De Deyn et al. (41) Brodaty et al. (42) Street et al. (43) Tariot et al. (44) Scharre et al. (45) None None

625 344 337 206 333 10

12 13

Improved Improved Improved Improved Improved Improved

6 10 12

Source: Adapted from Ref. 47.

The ADCS is investigating the potential role of valproate in potentially delaying or preventing the onset of agitation in a group of patients with AD and whether it exhibits potential neuroprotective effects (52). Carbamazepine, another anticonvulsant with psychotropic properties, is effective in bipolar disorder and has also been reported to reduce emotional lability, aggression, and socially inappropriate behaviors in various brain disorders (53). Small, controlled clinical trials in dementia patients have found it efficacious in reducing irritability, hostility, agitation, and combativeness in AD patients (54,55). Carbamazepine can be started as low as 50 mg twice daily and slowly titrated upward to minimize oversedation and ataxia (56). Daily dosages used in possible AD patients have ranged from 100 to 1000 mg, and clinical improvement usually occurs within 2 to 4 weeks (57). Side effects of carbamazepine in the central nervous system are dose-related and include sedation and ataxia. Baseline complete blood count and liver function tests should be obtained. Monthly measurements are recommended for the first 6 months, with measurements repeated at 3- to 12month intervals thereafter. Gabapentin is a novel anticonvulsant that acts on the GABA system to help control seizures and has few drug-drug interactions. It is being explored as a potential useful agent in controlling difficult behaviors in dementia patients. One open-label pilot study of 12 patients (58) reported modest effectiveness; other studies are planned. Trazodone Case studies (59,60) suggest and several small studies (61,62) have shown that trazodone, a serotonin reuptake inhibitor, decreases agitation in dementia. The mechanism of the anti-agitation effect is unknown but appears to be unrelated to antidepressant or sedative properties and may be associated with calming effects observed in animal models after blockade of serotonin reuptake (57). Serotonin deficiency was shown by one group of investigators to be particularly severe in the frontal lobes in AD, and it was suggested that this neurotransmitter deficiency contributes significantly to aggressive behavior in AD patients (63). Adverse effects of trazodone include sedation, hypotension, ventricular arrhythmias, and priapism. Benzodiazepines Benzodiazepines are effective for reducing anxiety and agitation but not for reducing psychotic symptoms. Neuroleptics have greater efficacy than benzodiazepines in controlled trials of treatment of agitation. This superiority was most evident with increasing severity of dementia and agitation (48). Side effects of benzodiazepines include sedation, cognitive impairment, paradoxical disinhibition, amnestic effects, tolerance, and withdrawal syndromes. Short-acting agents such as

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lorazepam or oxazepam are preferred in elderly patients to minimize drug accumulation and drug interactions. Very small doses can be used intermittently for treatment of anxiety and mild agitation in mild AD with close monitoring of behavior and function. The literature does not support the use of benzodiazepines for agitation in patients with more severe dementia for whom atypical neuroleptics or possibly an anticonvulsant may be more efficacious (64,65). Buspirone Buspirone is a nonbenzodiazepine anxiolytic agent; its mechanism of action is unknown. There are a few case observations supporting the use of buspirone to treat agitation in AD. The binding of the drug to central dopamine receptors has raised concern about possible EPS. Beta-Adrenergic Receptor Blocking Agents In a few small clinical series, propranolol at doses ranging from 60 to 560 mg/day was successful in improving aggressive and agitated behavior in dementia patients (63). Other beta-blockers have not been extensively studied. Cardiovascular side effects may limit the use of these agents in elderly patients. Concomitant conditions such as chronic obstructive lung disease and diabetes also can preclude use of these agents in some geriatric patients. Blood pressure and pulse should be monitored closely in any dementia patient receiving beta-adrenergic blocking agents. In summary, treatment of agitation in AD patients must be individualized. Agitation should be approached initially by investigation of potentially reversible causes. Acute management may include treatment with atypical and typical neuroleptics or with short-acting benzodiazepines. Severe adverse effects and limited efficacy make these agents less useful for the management of chronic agitation. Low-dose neuroleptic therapy is useful for agitation related to psychotic symptomatology. Other available agents reported to be effective include divalproate sodium and carbamazepine. The serotonergic agent trazodone is a reasonable first-line pharmacological agent in the management of agitation because it is well tolerated (61). The antidepressant selective serotonin-reuptake inhibitors (SSRIs), which are generally well tolerated, may be helpful in treating both depressive symptoms and agitation in patients with dementia but further studies are needed. Propranolol may be helpful for aggressive, impulsive behaviors and is used in patients with behavioral disturbances resulting from head trauma. These drugs need to be used with care in the elderly since they are associated with side effects. Therapeutic approaches must be strongly influenced by consideration of potential side effects in the individual patient, and patients must be closely monitored for adverse effects. Periodic attempts should be made to reduce or discontinue any therapeutic agent. Treatment of Anxiety Anxiety is common in patients with AD (66). In AD, anxiety is inversely related to dementia severity (i.e., worse with more severe dementia), appears to be more prevalent in younger onset patients, and correlates with disability (67). No results are available from any large-scale, welldesigned, placebo-controlled trials for treatment of anxiety in this population. The treatment of anxiety with standard benzodiazepine anxiolytic agents is problematic, as discussed earlier and use of benzodiazepines must be accompanied by ongoing assessment of the risk-benefit ratio. Shorteracting benzodiazepine agents (e.g., lorazepam, oxazepam) are preferable in elderly patients. Buspirone, a nonbenzodiazepine anxiolytic that is generally well tolerated, may be effective in the treatment of anxiety in nondemented elderly patients. Because it does not appear to adversely affect cognition in young healthy persons, this agent may be helpful for the treatment of anxiety in AD (64) but well-controlled studies are needed.

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Treatment of Insomnia Sleep disturbance is common in AD. The disturbance is characterized by reduced depth and efficiency as well as increased fragmentation of sleep. With disease progression, disruption of the normal circadian rhythm is observed, with multiple periods of sleeping and waking, daytime naps, and “sundowning” (nocturnal agitation, confusion, and wandering). This disruption of the normal sleep-wake cycle in AD patients may be related to degeneration of the suprachiasmatic nucleus. The cholinergic system is important in the generation of rapid eye movement (REM) sleep, and cholinergic dysfunction in AD is likely related to sleep disturbances (68). Poor nocturnal sleep may reduce daytime alertness, aggravating cognitive impairment in AD patients and further increasing caregiver stress. A randomized, double-blind, placebo-controlled crossover trial was undertaken to test the hypothesis that slow-release exogenous melatonin 6 mg improves sleep for people with dementia. Serfaty et al. (69) examined forty-four subjects with dementia and sleep disturbance for seven weeks using wrist actigraphy. They found no evidence that two weeks of exogenous melatonin is effective in improving sleep in people with dementia. Nonpharmacological management includes optimizing sleep hygiene by limiting time in bed to 6.5 to 7 hours per night, reducing daytime naps, establishing a consistent morning awakening time, and reducing evening fluids to prevent awakening for micturation (70). The use of light therapy has also been shown to be of some benefit in dementia patients. Potentially useful medications include trazodone, temazepam, chloral hydrate, and zolpidem. Both temazepam and chloral hydrate are associated with tolerance and withdrawal syndromes. Sexual Behavior Alteration in sexual relationships can be a cause of distress for the caregiver, and these concerns should be frankly addressed. There are variable changes in libido among AD patients, ranging from loss of interest in sexual activity to increased sexual drive and disinhibition in a minority of cases. Relational changes may also make continued sexual activities distasteful to the caregiver spouse. Suggestions for redirecting undesired sexual attention or encouraging desirable physical affection may be beneficial.

CAREGIVER SUPPORT Experience with dementia patients has shown that the needs of the patient cannot be addressed in isolation from those of his or her family. Caregivers have been found to have poorer overall physical health, increased use of psychotropic medications, and more depressive symptomatology than age-matched control subjects (71,72). The proportion of caregivers with clinically-significant depression is not known, but one study found that 55% of family caregivers of AD patients had depressive symptoms (72). Caregivers should be assessed for depressive symptomatology and referred for individual therapy or medication if indicated. Participation in support groups, group therapy, or family therapy can ameliorate depressive symptoms. There is evidence that caregiver training directed at improving coping strategies and reducing psychological distress and isolation could delay nursing home placement of persons with dementia (73). The clinician should educate the caregiver regarding AD so that he or she can better understand the disease and adjust to progressive changes in the patient’s behavior and care needs (73). Several support organizations, Websites, and books are available to help family members understand the nature and course of AD. These include the Alzheimer’s Association (www.alz.org) and the books, The 36-hour Day (74) and Understanding AD (75). Some of these issues are covered in chapter 22 by Morrison and Rabins. Caregiver support groups are also an

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excellent source of information. They can increase informal support networks, enhance feelings of competence in the caregiver role, and improve psychological functioning (76). Mood and behavioral symptoms are frequently the most distressing aspects of AD for the caregiver and finding effective therapies to significantly reduce these symptoms is likely to have an important impact on patient care, caregiver distress, and the rate of institutionalization. Use of specific class of agents may be matched to particular target behavioral symptom clusters (Table 2). APPENDIX 1 Editor’s Addendum—FDA Warning Regarding Atypical Antipsychotics and Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatmentemergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. APPENDIX 2 Editor’s Addendum—FDA Public Health Advisory-Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances The FDA has determined that the treatment of behavioral disorders in elderly patients with dementia with atypical (second generations) antipsychotic medications is associated with increased mortality. Of a total of 17 placebo controlled trials performed with olanzapine (Zyprexaw), aripiprazole (Abilifyw), risperidone (Risperdalw), or quetiapine (Seroquelw) in elderly demented patients with behavioral disorders, 15 showed numerical increases in mortality in the drug-treated group compared to the placebo-treated patients. These studies enrolled a total of 5106 patients, and several analyses have demonstrated an approximately 1.6 to 1.7-fold increase in mortality in these studies. Examination of the specific causes of these deaths revealed that most were either due to heart-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia). The atypical antipsychotics fall into three drug classes based on their chemical structure. Because the increase in mortality was seen with atypical antipsychotic medications in all three chemical classes, the Agency has concluded that the effect is probably related to the common pharmacologic effects of all atypical antipsychotic medications, including those that have not been

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systematically studied in the dementia population. In addition to the drugs that were studied, the atypical antipsychotic medications include clozapine (Clozarilw) and ziprasidone (Geodonw). All of the atypical antipsychotics are approved for the treatment of schizophrenia. None, however, is approved for the treatment of behavioral disorders in patients with dementia. Because of these findings, the Agency will ask the manufacturers of these drugs to include a boxed warning in their labeling describing this risk and noting that these drugs are not approved for this indication. Symbyax, a combination product containing olanzapine and fluoxetine, approved for the treatment of depressive episodes associated with bipolar disorder, will also be included in the request. The Agency is also considering adding a similar warning to the labeling for older antipsychotic medications because the limited data available suggest a similar increase in mortality for these drugs. Source: http://www.fda.gov/cder/drug/advisory/antipsychotics.htm.

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43. Street J, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group. Arch Gen Psychiatry 2000; 57:968–976. 44. Tariot PN. Reported at 9th International Conference on Alzheimer’s Disease and Related Disorders (ICAD) in Philadelphia, 2004. 45. Scharre DW, Chang SI. Cognitive and behavioral effects of quetiapine in Alzheimer’s disease patients. Alzheimer Dis Assoc Disord 2002; 16:128–130. 46. Schneider LS, Ismail MS, Dagerman K, et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer’s disease trial. Schizophr Bull 2003; 29:57–72. 47. Schneider LA. Platform presentation at the American Association of Geriatric Psychiatry Meeting. Am J Geriatric Psychiatry 2002; 10:1–122. 48. Zayas EM, Grossberg GT. Treating the agitated Alzheimer patient. J Clin Psychiatry 1996; 57:46–51. 49. Lindenmayer JP, Kotsaftis A. Use of sodium valproate in violent and aggressive behaviors: a critical review. J Clin Psychiatry 2000; 61:123–128. 50. Herrmann N. Valproic acid treatment of agitation in dementia. Can Psychiatry 1998; 43:69–72. 51. Porsteinsson AP, Tariot PN, Erb R, et al. Placebo-controlled study of divalproex sodium for agitation in dementia. Am J Geriatr Psychiatry 2001; 9:58–66. 52. Tariot PN, Loy R, Ryan JM, et al. Mood stabilizers in Alzheimer’s disease: symptomatic and neuroprotective rationales. Adv Drug Deliv Rev 2002; 54:1567–1577. 53. Wragg RE, Jeste DV. Neuroleptics and alternative treatments: management of behavioral symptoms and psychosis in Alzheimer’s disease and related conditions. Psychiatr Clin North Am 1988; 11:195–213. 54. Leibovici A, Tariot PN. Carbamazepine treatment of agitation associated with dementia. J Geriatr Psychiatry Neurol 1988; 1:110–112. 55. Tariot PN, Erb R, Podgorski DA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998; 155:54–61. 56. Gleason RP, Schneider LS. Carbamazepine treatment of agitation in Alzheimer’s outpatients refractory to neuroleptics. J Clin Psychiatry 1990; 51:115–118. 57. Schneider LS, Sobin PB. Non-neuroleptic treatment of behavioral symptoms and agitation in Alzheimer’s disease and other dementia. Psychopharmacol Bull 1992; 28:71–79. 58. Herrmann N, Lanctot K, Myszak M. Effectiveness of gabapentin for the treatment of behavioral disorders in dementia. J Clin Psychopharmacol 2000; 20:90–93. 59. O’Neil M, Page N, Adkins WN. Tryptophane-trazodone treatment of aggressive behavior. Lancet 1986; 2:859–860. 60. Simpson DM, Foster D. Improvement in organically disturbed behavior with trazodone treatment. J Clin Psychiatry 1986; 47:191–193. 61. Sultzer DL, Gray KF, Gunay I, et al. A double-blind comparison of trazodone and haloperidol for treatment of agitation in patients with dementia. Am J Geriatr Psychiatry 1997; 5:60–69. 62. Lebert F, Stekke W, Hasenbroekx C, Pasquier F. Frontotemporal dementia: a randomized, controlled trial with trazodone. Dement Geriatr Cogn Disord 2004; 17:355–359. 63. Gottlieb GL, Kumar A. Conventional pharmacologic treatment for patients with Alzheimer’s disease. Neurology 1993; 43:S56–S63. 64. Palmer AM, Stratmann GC, Procter AW, et al. Possible neurotransmitter basis of behavioral changes in Alzheimer’s disease. Ann Neurol 1988; 23:616–620. 65. Stern RG, Duffelmeyer ME, Zemishlani Z, Davidson M. The use of benzodiazepines in the management of behavioral symptoms in demented patients. Psychiatr Clin North Am 1991; 14:375–384. 66. Mendez MF, Martin RJ, Smyth KA, et al. Psychiatric symptoms associated with Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 1990; 2:28–33. 67. Porter VR, Buxton WG, Fairbanks LA, et al. Frequency and characteristics of anxiety among patients with Alzheimer’s disease and related dementias. J Neuropsychiatry Clin Neurosci 2003; 15:180–186. 68. Culebras A. Update on disorders of sleep and the sleep-wake cycle. Psychiatr Clin North Am 1992; 15:467–489. 69. Serfaty M, Kennell-Webb S, Warner J, et al. Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia. Int J Geriatr Psychiatry 2002; 17:1120–1127.

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70. Reynolds CF, III, Hoch CC, Stack J, et al. The nature and management of sleep/wake disturbance in Alzheimer’s dementia. Psychopharmacol Bull 1988; 24:43–48. 71. Levine J, Lawlor BA. Family counseling and legal issues in Alzheimer’s disease. Psychiatr Clin North Am 1991; 14:385–396. 72. Cohen D, Eisdorfer C. Depression in family members caring for a relative with Alzheimer’s disease. J Am Geriatr Soc 1988; 36:885–889. 73. Brodaty H, McGilchrist C, Harris L, et al. Time until institutionalization and death in patients with dementia. Role of caregiver training and risk factors. Arch Neurol 1993; 50:643–650. 74. Mace NL, Rabins PV. The 36-hour day: a family guide to caring for persons with Alzheimer’s disease, related dementing illnesses, and memory loss in later life. Baltimore: Johns Hopkins University Press, 1981. 75. Aronson MK. Understanding Alzheimers disease: what it is, how to cope with it, future directions. New York: Hungry Minds, Inc, 1988. 76. Toseland RW, Rossiter CM, Labrecque MS. The effectiveness of peer-led and professionally led groups to support family caregivers. Gerontologist 1989; 29:465–471.

25 Amyloid-Based Strategies to Treat and Prevent Alzheimer’s Disease Dennis J. Selkoe Harvard Medical School, Boston, Massachusetts, U.S.A.

INTRODUCTION Few experiences in the work of a neurological diagnostician are more dispiriting than informing both patient and family that the diagnosis is Alzheimer’s disease (AD). Yet, with the remarkable rise in life expectancy and the gradual decline in competing causes of late-life brain failure, this is a diagnosis that clinicians are reaching with ever-increasing frequency. To change this scenario, we must thoroughly understand the molecular underpinnings of this complex syndrome and devise rational, mechanism-based agents for preventing it. The study of AD pathogenesis has had more than its share of controversy. Perhaps not surprisingly, it has been difficult to come to agreement about the temporal sequence of the molecular and cellular changes that lead to the dementia and which of these steps are most amenable to intervention. But in the last few years, substantial consensus has developed that certain events in the limbic and association cortices occur many years or decades prior to clinical symptoms, and a rough outline of the pathogenic cascade has emerged from the studies of many investigators. Progress in three broad areas has led to this consensus: biochemical pathology, genetics, and animal modeling. In this chapter, we will review the emerging understanding of the causes and mechanism of AD that has developed and what it is likely to mean for treating our patients.

DECIPHERING THE BIOCHEMISTRY OF THE BRAIN LESIONS YIELDS PATHOGENETIC INSIGHTS Much of the progress in elucidating the biology of both AD and frontotemporal dementia has derived from the original compositional analyses of the amyloid plaques and neurofibrillary tangles that occurred in the mid-1980s. Early efforts to identify the tangle and plaque subunit proteins were met with some skepticism. It was argued that because the plaques and tangles were end-stage 433

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lesions that appeared to represent the “tombstones” of a long process, such knowledge would provide little useful information about etiology and early pathogenesis. It has become increasingly apparent in recent years that this concern was ill founded. Neuritic (senile) plaques contain extracellular deposits of the amyloid b-proteins (Ab) (1,2) surrounded by dystrophic neurites (axons and dendrites), activated microglia and reactive astrocytes. A portion of the Ab in these deposits exists in the form of insoluble, 8–10 nm amyloid fibrils, but these are intermixed with an as yet poorly defined array of non-fibrillar forms of the peptide. Once it had been established by protein sequencing that Ab was the subunit of fibrillar amyloid, immunohistochemistry with antibodies to Ab revealed a large number of deposits in AD brain that lacked the altered microglia and astrocytes and dystrophic neurites, which characterize the neuritic plaques. Such lesions, referred to as “diffuse” plaques, represent deposits of Ab that are mostly in a non-fibrillar, apparently granular form in the neuropil (3,4). Antibodies that selectively recognize the carboxy-termini of Ab peptides have revealed that diffuse deposits are principally composed of the highly amyloidogenic 42-residue form (Ab42) (5). The compacted fibrillar cores of “mature” neuritic plaques seem to contain mixtures of Ab42 and the Ab40 peptide. The latter is the more abundant species (roughly 90%) of the Ab peptides that are produced by normal cells throughout life (see below). Importantly, Ab deposits do not occur simply in these two extreme forms (diffuse and neuritic) but rather as a continuum in which mixtures of non-fibrillar and fibrillar forms of the peptide can be associated with widely varying degrees of local neuritic and glial alteration. In regions of the Alzheimer brain that are generally not implicated in the clinical symptomatology, for example, the cerebellum and thalamus, almost all the Ab deposits are of the diffuse type, with little evidence of local gliosis and neuritic change. Likewise, the brains of aged, cognitively intact humans often contain Ab deposits, but these are overwhelmingly of the diffuse type, with relatively few neuritic plaques and neurofibrillary tangles found in the cerebral cortex. Perhaps the most frequently voiced criticism of the “amyloid hypothesis” of AD is that Ab plaques can be found in moderate or sometimes high density in the cortex of cognitively normal elderly subjects. In many but not all cases, these are diffuse plaques that appear to represent cytologically “benign” precursor lesions not associated with surrounding pathology. In this context, it is not unreasonable to draw a rough analogy to the fatty streaks observed in the arteries of individuals who have not yet experienced clinically noticeable cardiovascular events. It should also be emphasized that, despite some statements to the contrary, quantitatively significant relationships between Ab plaque burden and the extent of cognitive impairment have been established (e.g., Ref. 6), and such data have been complemented by even stronger correlations with cortical Ab levels measured biochemically (e.g., Ref. 7). Ab also accumulates within the basement membranes of cerebral capillaries, arterioles, and meningeal arterioles. Whereas Ab40 appears to be the principal subunit of these microvascular deposits, Ab42 has been shown to contribute as well, particularly in the earliest stages of amyloid angiopathy (8). The extent of microvascular b-amyloidosis often does not correlate closely with the number of Ab plaques in a brain, and its importance in contributing to the dementia remains a subject of active research. It is not yet established that AD involves a pathogenetically important alteration of blood-brain barrier function, whether in amyloid-bearing or non-amyloid-bearing vessels. The other classical lesion observed in Alzheimer’s original patient of 1906 is the neurofibrillary tangle. Tangles are generally intraneuronal cytoplasmic bundles of paired, helically-wound w10 nm filaments (PHF), sometimes interspersed with straight filaments (9). Neurofibrillary tangles usually occur in large numbers in the Alzheimer brain, particularly in the entorhinal cortex, hippocampus, amygdala, association cortices of the frontal, temporal, and parietal lobes and certain subcortical nuclei that project to these regions. The subunit protein of the PHF is the microtubule-associated protein, tau. PHF are not limited to the tangles found in the

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neuronal cell bodies, but also occur in many of the dystrophic neurites present within and outside of the amyloid plaques. Biochemical studies reveal that the tau present in PHF comprises hyperphosphorylated, insoluble forms of this normally highly soluble cytosolic protein (10–13). The insoluble tau aggregates in the tangles are often complexed with ubiquitin, a feature they share with numerous other intraneuronal proteinaceous inclusions in etiologically diverse disorders such as Parkinson’s disease and diffuse Lewy body disease. If this ubiquitination represents an attempt to remove the tau deposits by way of degradation by the proteasome, it seems to be largely unsuccessful. Phosphorylated forms of the neurofilament proteins also accumulate in tangles but are not considered to be actual subunits of the PHF. The two classical lesions of AD can occur independently of each other. Tangles composed of tau aggregates that are biochemically similar to and in some cases indistinguishable from those that occur in AD have been described in a dozen or more less common neurodegenerative diseases, in which one usually finds no Ab deposits and neuritic plaques. Conversely, Ab deposits can be seen in aged “normal” human brain in the virtual absence of tangles. There are also some cases of AD itself, which are “tangle-poor,” i.e., very few neurofibrillary tangles are observed in the neocortex despite abundant Ab plaques (14). It appears that in quite a few such cases, an alternate form of neuronal inclusion, the Lewy body (composed principally of the a-synuclein protein) is found in many cortical pyramidal neurons. In other words, the Lewy body variant of AD (not to be confused with diffuse Lewy body disease) represents a tangle-poor form of AD that is still characterized by widespread Ab plaque formation (15). The fact that neurofibrillary tangles composed of altered, aggregated forms of tau protein occur in certain disorders in the absence of Ab deposition (e.g., subacute sclerosing panencephalitis, Kuf’s disease, progressive supranuclear palsy) suggests that tangles can arise in the course of a variety of primary neuronal insults. As I shall discuss, there is growing evidence that the formation of tangles in AD represents a cytological response by neurons to the gradual accumulation of Ab and Ab-associated proteins. Ab IS GENERATED BY PROTEOLYTIC CLEAVAGES OF A LARGE PRECURSOR PROTEIN The purification and partial sequencing of the Ab protein from meningovascular amyloid deposits in AD (1) and Down’s syndrome (16) enabled the subsequent cloning of the gene encoding the b-amyloid precursor protein (APP) (2). Ab is too small to be synthesized directly on ribosomes; rather, it is derived from APP by sequential proteolytic cleavages by enzyme activities referred to as b-secretase and g-secretase (Fig. 1) (17). APP comprises a group of ubiquitously expressed polypeptides whose heterogeneity arises from both alternative splicing of exons and posttranslational modifications (e.g., the addition of N- and O-linked sugars and phosphate and sulfate groups) (17). The alternative splice forms of APP containing 751 or 770 amino acids are widely expressed in non-neuronal cells throughout the body and also occur in neurons. However, neurons express much higher levels of a 695-amino acid isoform. The difference between the 751/770- and the 695-residue forms is the presence in the former of an exon that codes for a 56-amino acid motif that is homologous to the Kunitz-type of serine protease inhibitors. This finding indicates one potential function of these longer APP isoforms. Indeed, the KPI-containing forms of APP present in human platelets serve as inhibitors of factor XIa (a serine protease) in the coagulation cascade. Nevertheless, deletion of the APP gene in mice results in neither early mortality nor appreciable morbidity; cerebral gliosis and changes in locomotor behavior occur in adult life (18), and neurons cultured at birth have diminished viability and retarded neurite outgrowth (19). The lack of a vital consequence of APP deletion in vivo may result from mammals expressing proteins closely homologous to APP—the amyloid precursor-like proteins (APLPs) (20,21). These proteins have extensive homology with APP in both the large amino-terminal ectodomain and

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Figure 1 Schematic diagrams of the b-amyloid precursor protein (APP) and its principal metabolic derivatives. The first line depicts the largest of the known APP alternate splice forms, comprising 770 amino acids. Regions of interest are indicated at their correct relative positions. A 17-residue signal peptide occurs at the N-terminus (box with vertical lines). Two alternatively spliced exons of 56 and 19 amino acids are inserted at residue 289; the first contains a serine protease inhibitor domain of the Kunitz type (KPI). A single membrane-spanning domain (TM) at amino acids 700–723 is indicated by the vertical dotted lines. The amyloid b-protein (Ab) fragment includes 28 residues just outside the membrane plus the first 12–14 residues of the transmembrane domain. In the second line, the sequence within APP that contains the Ab and transmembrane regions is expanded. The underlined residues represent the Ab1-42 peptide. The bold letters below the wildtype sequence indicate the currently known missense mutations identified in certain patients with AD and/or hereditary cerebral hemorrhage with amyloidosis. Three digit numbers Z codon number (bAPP770 isoform). In the third line, the arrow indicates the site (after residue 687) of a cleavage by asecretase that enables secretion of the large, soluble ectodomain of APP (APPs- a) into the medium and retention of the 83 residue C-terminal fragment (C83) in the membrane. C83 can undergo cleavage by the protease called g-secretase at residue 711 or residue 713 to release the p3 peptides. The fourth line depicts the alternative proteolytic cleavage after residue 671 by b-secretase that results in the secretion of the slightly truncated APPs- b molecule and the retention of a 99 residue C-terminal fragment. C99 can also undergo cleavage by g-secretase to release the Ab peptides. Cleavage of both C83 and C99 by g-secretase releases the APP intracellular domain (AICD) into the cytoplasm.

the cytoplasmic tail, but the Ab region is replaced by another hydrophobic sequence that anchors APLPs in the membrane. Thus, all members of the APP family are single transmembrane (TM) proteins, with the large N-terminal region (the ectodomain) projecting from the plasma membrane or into the lumens of certain intracellular vesicles (endoplasmic reticulum, Golgi, trans-Golgi network and endosomes) and the relatively short C-terminal region projecting into the cytoplasm (Fig. 1A). The early recognition that the last 12–14 residues of Ab derive from the membrane-anchoring region of APP gave rise to a conundrum: how could Ab be found as an intact, free peptide in the extracellular amyloid deposits? In this regard, it was generally assumed that cells would need to undergo an initial injury to their membranes to allow the unknown protease that creates the C-terminus of Ab (designated g-secretase) to access the intramembranous region of the APP

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molecule (Fig. 1). This concept meant that Ab production could not be viewed as a truly primary or initiating event in AD, since some other process would need to first injure the membrane. However, in 1992, it was discovered that Ab is constitutively secreted by healthy cells throughout life and is found in the cerebrospinal fluid (CSF) and plasma of all normal humans (22–24). Based on many subsequent studies of the proteolytic processing of APP, it has become apparent that a subset of APP holoproteins can undergo specific endoproteolytic cleavages both during and after the transport of the polypeptide through the secretory pathway to the cell surface (17). The most frequent proteolytic scission occurs between amino acids 16 and 17 of the Ab region, that is, 12 residues amino terminal to the TM sequence (Fig. 1C). This principal secretory cleavage is effected by protease(s) designated a-secretase(s). The cut creates a large, soluble ectodomain fragment (APPs-a) that is released into vesicle lumens (e.g., in the trans-Golgi network) as well as from the cell surface. This cut leaves behind a C-terminal fragment (CTF) of 83 amino acids (C83) in the membrane (Fig. 1). a-Secretase(s) are themselves membrane-anchored proteases that are capable of cleaving diverse single TM proteins. They appear to cleave APP at a specific distance from the membrane surface while showing little sequence specificity (25). The regulated a-secretase cleavage of APP (e.g., as regulated by certain muscarinic agonists) may be carried out by metalloprotease disintegrins (“ADAM” proteases) that also shed the ectodomains of other single TM proteins such as tumor necrosis factor-a (26–28). In general, a minority of APP holoproteins in the cell undergoes g-secretase cleavage. This means that any therapeutic agent that increases this scission in order to potentially “steal” APP from the b-secretase pathway (see below) would actually still leave many APP holoproteins available to be subjected to the b- and g-secretase cleavages that produce Ab. Some of those APP holoproteins that are not subjected to the a-secretase cleavage can instead be cut by b-secretase (Fig. 1D). This releases a truncated form of APPs (APPs-b) from the cell (29) and leaves a 99-residue CTF (C99) still embedded in the membrane. C99 can subsequently be cleaved by the unusual proteolytic activity referred to as g-secretase to create Ab. Also, the C83 CTF made by a-secretase can undergo cleavage by the same g-secretase to generate a peptide comprising the latter two thirds of Ab (designated p3). In summary, C99, and C83 are the immediate substrates of the g-secretase reaction that give rise to Ab and p3, respectively. Although precise quantitation is not available, a substantially smaller portion of total cellular APP undergoes cleavage by b-secretase than by a-secretase. Moreover, not all of the resultant C99 and C83 fragments are processed by g-secretase to Ab and p3; alternative proteolytic pathways can apparently fully degrade some of the CTFs in late endosomes and lysosomes. b-Secretase, which generates the amino-terminus of Ab (aspartate-1), has been identified (30–32). b-Secretase, also called BACE-1, is a single membrane-spanning aspartyl protease with its active site in its ectodomain. This architecture is consistent with what had been predicted for such an enzyme, namely that it would be membrane-anchored adjacent to its substrate (APP) and its active site would coordinate with the appropriate site in the ectodomain of its substrate to effect cleavage. The use of antisense to this novel protease has demonstrated a lowering of Ab and, at the same time, a rise in the amount a-secretase processing of APP, since more APP holoproteins are now available for this alternate cleavage (30–32). b-secretase appears to be localized to the transGolgi network and endosomal vesicles, thus placing it in subcellular loci already known to be sites of Ab generation. What are the functional consequences of the complex proteolytic processing of APP just reviewed? That question cannot yet be answered with certainty, but a variety of functions have been attributed to the APP ectodomain (principally to the APPs-a derivative). Such functions include the inhibition of certain serine proteases (in the case of the APP751/770 isoforms), enhancement of cell-cell and cell-substrate adhesion, neuritotrophic, and other growth-promoting effects, and neuroprotective properties. As regards the function of the APP holoprotein, the remarkably similar processing of APP and the Notch family of cell surface receptors (see below) has increasingly

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suggested that APP itself functions as a receptor. In this model, sequential proteolysis by a- and g-secretases releases the APP cytoplasmic domain, which can then enter the nucleus (with associated proteins, e.g., Fe65) and regulate the transcription of target genes (33–35). Both the hypothetical ligand that binds the APP ectodomain to initiate the cleavages and the downstream genes that may be activated or suppressed remain unknown. Whether such a function of APP occurs in vivo remains unclear, pending further detailed characterization of APP knock-out mice (18). No evidence has yet emerged that a fundamental cellular function of APP is lost in AD patients. Instead, APP mutations seem to act by a gain of abnormal function, namely the increased production of the potentially cytotoxic Ab fragment (see below). THE GENETICS OF AD VALIDATES Ab INHIBITION AS A PREVENTION AND TREATMENT STRATEGY It has been known for several decades that AD can occur in a familial form that appears to transmit as an autosomal dominant trait. Estimates of the portion of AD cases that are genetically based have varied widely from as low as 10% to as high as 40 or 50%, and some investigators believe that, in the fullness of time, virtually all cases will be shown to have some genetic determinants. It is difficult to settle this question in a disorder that can have very late onset in life and that was usually not explicitly diagnosed prior to the last two decades. Moreover, the discovery that the apolipoprotein 34 allele is a normal polymorphism in the population that confers increased AD risk (36) indicates that genetic factors predisposing to the disease need not occur in a simple, autosomal dominant pattern and can, therefore, be hard to recognize in genetic epidemiological studies. At this juncture, there are four well-confirmed genes in which mutations or polymorphisms result in AD, and a few other candidate genes are in various stages of confirmation. The first AD-causing gene to be identified was that encoding the precursor of Ab. Missense mutations in APP account for a tiny fraction (far less than 0.1%) of all Alzheimer’s cases, but they have proved to be highly informative as regards the pathogenic mechanism of AD in general. For example, expressing mutant APP transgenically in mice provided the first reproducible and robust animal models of the disease (37). Inheritance of one or two 34 alleles of ApoE is a far more prevalent genetic basis for AD. ApoE4 helps precipitate the disorder primarily in subjects in their sixties and seventies, thus lowering the typical age of onset of late-life AD (38). There is also evidence that an alternative ApoE allele, 32, confers some protection from the development of AD. It should be emphasized that ApoE4 is a risk factor for, not an invariant cause of, AD. Some humans homozygous for this isoform still show no Alzheimer symptoms in their ninth decade of life. The third and fourth genes implicated in familial forms of the disease are designated presenilin 1 (PS1) and presenilin 2 (PS2), because missense mutations in those highly homologous proteins result in an aggressive, early onset form of the disorder, usually beginning between ages 40 and 60 years (39–41). PS1 and PS2 are homologous polytopic proteins believed to span internal membranes of cells eight times (see below). More than 85 missense mutations have been identified in PS1 and at least six in PS2; these are scattered in the molecule but tend to cluster within and adjacent to the TM domains. Families having multiple AD members that show no linkage to any of the aforementioned four genes are also under study to identify or confirm additional genetic risk factors or autosomal dominant mutations. Within a decade or two, a sizable number of additional genes will likely be implicated, most of them probably acting as polymorphic risk factors in some populations. Despite the prominence of tau accumulation in the neurofibrillary tangles and dystrophic neurites of a very high percentage of AD cases, the tau gene has not been found to be the site of mutations in familial AD to date. Instead, mutations in tau have been discovered in families with a less common dementia, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) (42–44). The disorder is characterized by widespread neurofibrillary tangle formation

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associated with specific biochemical alterations in the microtubule-binding properties of tau (9,45), and this occurs in the absence of amyloid deposits. The discovery of tau mutations in this distinct form of dementia proves the concept that a primary alteration of tau structure and function can lead to progressive, severe neuronal degeneration and, ultimately, the death of the patient. This finding also shows that even profound neurofibrillary tangle formation does not lead to secondary accumulation of Ab as diffuse and neuritic plaques. The latter point addresses a recurring controversy in the study of AD: whether plaques or tangles have temporal precedence in the pathogenesis of the disorder. Both the APP and presenilin mutations in AD and the tau mutations in FTDP-17 support the conclusion that the tau alteration in AD follows Ab accumulation rather than the other way around.

DECIPHERING THE GENOTYPE TO PHENOTYPE CONVERSIONS OF FAMILIAL AD What do sections “Ab is Generated by Proteolytic Cleavages of a Large Precursor Protein” and “The Genetics of AD Validates Ab Inhibition as a Prevention and Treatment Strategy” in this review have to do with each other? That is, is there a relationship between the genetic factors that have been proven unequivocally to cause AD in some individuals and the production or stability of Ab? Research by many investigators worldwide during the last seven years has provided answers to this question. Both cultured cells and transgenic mice have been used to model the biochemical and neuropathological effects of each of the four genes implicated unequivocally in familial AD (Table 1). The results have been compared to the actual phenotypes observed in the brains of patients carrying the respective gene defects. In all four cases, inherited alterations in the gene products have been linked to increases in the cerebral production and/or deposition of the Ab peptides. This work has provided the strongest support for the hypothesis that cerebral Ab accumulation is an early, invariant, and necessary event in the genesis of familial AD and is thus worthy of inhibition. The APP gene can lead directly to the AD syndrome in at least two distinct ways. It can either be overexpressed owing to a gene dosage effect in trisomy 21 (Down’s syndrome), or else it can be the site of missense mutations that increase the amyloidogenic cleavages of APP at the b-secretase site (resulting in excess production of Ab40 and Ab42) or at the g-secretase site (resulting in selectively increased production of Ab42). In Down’s syndrome, a lifelong increase in APP expression and the resultant overproduction of both Ab40 and Ab42 peptides dating from birth is assumed to be responsible for the early appearance of many Ab42 diffuse plaques, which can occur

Table 1 Genetic Factors Predisposing to AD Relationships to the bamyloid phenotype chromosome

Gene defect

21

APP mutations

19

ApoE4 polymorphism

14 1

Presenilin 1 mutations Presenilin 2 mutations

Phenotype [Production of all Ab peptides or Ab42 peptides [Density of Ab plaques and vascular deposits [Production of Ab42 peptides [Production of Ab42 peptides

Source: Adapted from DJ Selkoe. Genetics and molecular pathology of Alzheimer’s disease: roles of amyloid and the presenilin. In: Neurologic Clinics: Dementia, Vol. 18; ed. DeKosky ST., Philadelphia, PA, W.B. Saunders Co., pp. 903–921.

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as soon as age 10–12 years. Down’s subjects often display diffuse plaques composed solely of Ab42 in their teens and 20s, with accrual of Ab40 peptides onto these plaques and the appearance of associated microgliosis, astrocytosis, and surrounding neuritic dystrophy beginning in their late 20s or 30s (46,47). This observation illustrates the apparent importance of Ab42 deposition as a seminal event in the development of AD-type brain pathology. The appearance of neurofibrillary tangles is also delayed until the late 20s or 30s in most Down’s patients. The gradual accrual of AD-type brain lesions in these individuals (who are retarded from birth for other reasons) appears to be associated in many cases with progressive loss of cognitive and behavioral functions after the age of 35–40 or so. There are several missense mutations in APP linked to familial AD, and these are clustered either at the b-secretase cleavage site (the so-called “Swedish” APP mutation), just after the a-secretase site or just after the g-secretase site (Fig. 1). The Swedish double mutation, just N-terminal to the b-cleavage site, induces increased cleavage by b-secretase to generate more Ab40 and Ab42 peptides. The five mutations occurring just after the g-secretase site appear in slightly different ways to selectively enhance the production of Ab species ending at residue 42 (Ab42). The mutations located internally in Ab presumably enhance the aggregational properties of all Ab species; this has been shown for the E693Q mutation that causes hereditary cerebral hemorrhage with amyloidosis of the Dutch-type (48). The internal mutation, A692G, leads to a mixed phenotype of AD-type plaque and tangle formation associated with dementia plus severe microvascular b-amyloidosis with occasional cerebral hemorrhages (49). Some of the internal mutations may also alter a-secretase processing in a way that favors the b-secretase cleavage (50). Importantly, no APP mutations away from the sites of the three secretase cleavages have been discovered in AD families despite extensive searching. If APP mutations caused AD by perturbing the normal function of the precursor, as has sometimes been hypothesized, then one would have expected AD-linked mutations to be more widely distributed in the molecule, not just at the secretase processing sites (Fig. 1). In the case of the ApoE4 polymorphism, co-expression of each of the three human ApoE alleles with APP in cultured cells produced no clear-cut change in the proteolytic processing of APP to Ab (51). Instead, the disease-promoting effect of inheriting one or two ApoE4 alleles seems to involve an enhanced aggregation and/or decreased clearance of Ab peptides (52–55). Such a mechanism is supported by studies in which mice transgenic for mutant human APP are crossed with mice in whom the endogenous ApoE gene is deleted. The resultant offspring show substantially decreased Ab burden compared to that seen in the parental APP line, and the Ab deposits that develop are overwhelmingly diffuse (non-fibrillar) (56). Moreover, mice lacking endogenous ApoE that transgenically express human ApoE3 or E4 (plus human APP) initially show even less Ab deposits than mice expressing no ApoE at all (57). But as they develop deposits with age, the presence of the E4 isoform leads to far more fibrillar (neuritic) plaques than does the E3 isoform (58). Perhaps the most intriguing genotype-to-phenotype relationship in AD involves the presenilin mutations. When PS1 and 2 were first cloned, the mechanism by which mutations in them produced the AD phenotype was an open matter and was not necessarily expected to involve enhanced Ab production. Nevertheless, assays of Ab40 and Ab42 in the plasma and the cultured skin fibroblast media of humans with these mutations soon revealed a selective w2-fold elevation of Ab42 levels (59). Extensive modeling of these mutations in cultured cells and in mice has confirmed this result. Indeed, crossing mice transgenic for mutant human APP with mice expressing a human PS1 mutation leads to a substantially accelerated AD-like phenotype, with Ab42 plaques (both diffuse and mature) occurring as early as 3–4 months of age (60). Moreover, the ability of presenilin mutations to selectively enhance Ab42 deposition in the brain has been demonstrated directly in humans bearing these mutations (61,62).

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To understand the molecular mechanism by which mutant presenilins increase the Ab42 processing event by g-secretase, we need to consider the normal biology of presenilins. PS1 and PS2 are polytopic membrane proteins that, by current evidence, cross membranes in cells eight times. Presenilin occurs largely as a heterodimer of cleaved fragments, i.e., an NTF and a CTF (63). This endoproteolysis of presenilin, conferred by a yet-unidentified protease nicknamed “presenilinase,” appears to be required for normal presenilin function. Until recently, the presenilins had been principally localized to the endoplasmic reticulum, early Golgi vesicles and vesicles shuttling in between these two. However, there is evidence that small amounts of presenilin may reach the cell surface (64). Like APP, the presenilins are expressed in virtually all cell types, and the proteins have been highly conserved during evolution. Studies in the roundworm, C. elegans, led to the recognition that the worm form of presenilin (called SEL-12) is a facilitator of the intercellular signaling pathway that uses the cell-surface receptor, Notch (65). It has become apparent that presenilin is required for the normal intramembranous cleavage of the Notch receptor following binding of its extracellular ligand (66). This cleavage releases the intracellular domain of Notch to the nucleus, where it helps to activate the transcription of a variety of downstream genes important for the proper specification of cell types, both inside and outside the nervous system (67). Deleting the PS1 gene in a mouse causes an embryonic lethal phenotype that includes severely disordered somitogenesis and axial skeletal development as well as abnormal neuronal differentiation in the forebrain (68,69). This phenotype resembles that caused by knocking out the Notch1—1 gene. Production of both Ab40 and Ab42 are markedly reduced in these PS1 knockout mice due to blocking of the g-secretase processing of APP. Precisely how presenilin regulates the g-secretase cleavage of APP and other substrates such as Notch remains a matter of debate. One theory suggests that presenilin is a key mediator of the membrane trafficking of certain proteins, presumably including APP and/or g-secretase. In this model, presenilin does not interact with APP directly but rather is responsible for its correct distribution to specific microdomains of membranous organelles (70,71). This view has been put forward by investigators who report that presenilin and APP do not interact (70). An alternative hypothesis, that presenilin is physically involved in the cleavage of APP by g-secretase, has been proposed by investigators who have detected small amounts of APP interacting with presenilin (72–74). In the context of this debate, the trafficking and maturation of APP through the secretory pathway has not been found to be noticeably altered by the complete absence of presenilin (75). These and related studies not discussed here suggested the possibility that presenilin might either be a direct and intimate co-factor of the g-secretase reaction or might actually be g-secretase itself. Evidence suggesting the latter possibility arose from the recognition that inhibiting g-secretase activity in cells by use of APP peptidomimetic compounds indicated that g-secretase might be an aspartyl protease (76). Close inspection of the presenilin amino acid sequence revealed two aspartates in adjacent TM domains of all presenilins (down to C. elegans) that flanked the site within the loop connecting these two TMs at which presenilin is normally cleaved (Fig. 2). Mutation of either of the aspartates to another amino acid completely prevented the cleavage of presenilin and simultaneously markedly inhibited the g-secretase processing of C99 to Ab and C83 to p3 (77). Furthermore, Ab could be generated in a cell-free in vitro transcription/translation reaction in the presence of membranous microsomes that contained wild-type presenilin but not those containing the aspartate-mutated presenilin, and this Ab generation only occurred at mildly acidic, not neutral, pH (77). Taken together, these results suggested the provocative possibility that presenilin is an unprecedented intramembranous aspartyl protease that might both cleave itself (an autoactivation step) and then cleave certain TM substrates, including APP and Notch. Strong support for this hypothesis has come from the demonstration that g-secretase inhibitors designed to mimic the substrate transition state between the APP cleavage site and an aspartyl protease bind directly to presenilin NTF and CTF and to no other cellular protein (78,79).

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Figure 2 Hypothetical model of the role of presenilin (PS) in Notch and APP processing based on current information. The diagram shows the predicted 8 TM domain topology of PS, which occurs principally as a cleaved heterodimer. Some Notch and APP molecules form complexes with PS. Two aspartates (D) in TM6 and TM7 of PS are required for the cleavages of Notch and APP within their TM domains, and these may align with the respective sites of cleavage in the two substrates. Following the intramembranous cleavage mediated by PS, the Notch intracellular domain is released to the nucleus to activate transcription of target genes. APP contains the Ab region (gray box), which is released into the lumen after sequential cleavages of APP by bsecretase and then g-secretase/PS.

Whether presenilin is g-secretase or an intimate and necessary cofactor for its direct involvement in Ab production, provides further strong support for the “amyloid cascade” hypothesis of AD. In other words, the most common mutations causing autosomal dominant AD occur in a critical component of the very protease that generates Ab, and mutations in either that protease or its substrate (APP) can result in a markedly accelerated and severe AD phenotype. As mutations or polymorphisms in additional genes are identified in Alzheimer families, it will be necessary to carry out the same kind of detailed genotype-to-phenotype analysis described above for the four currently confirmed genes. It will be interesting to learn whether other genetic factors linked to AD also alter the production, deposition and/or clearance of Ab in the brain.

THE COMPLEX PATHOGENETIC CASCADE OF AD Although genetic evidence has strongly favored the concept that Ab production and accumulation are early and essential features of AD, there remains considerable debate about whether and how this can explain the full Alzheimer phenotype (Fig. 3). Gradual and chronic elevation of Ab42 in brain interstitial fluid and [perhaps also inside neurons (80,81)] caused by mutations in APP or presenilin is assumed to lead gradually to oligomerization of some of the peptide and then, eventually, its fibrillization (i.e., amyloid fibril formation). There is a growing interest in the possibility that diffusable oligomers of Ab could represent potentially neurotoxic species and that the abundant Ab fibrils, which occur in mature plaques, represent a relatively inert reservoir of Ab that is in equilibrium with these smaller, biologically active oligomers (82). Based on the evolution of Ab-related pathology in Down’s syndrome and in transgenic mice that overexpress mutant APP and/or PS1, it has been shown that Ab42 accumulation and diffuse plaque formation gradually become associated with local microglial activation, cytokine release, reactive astrocytosis, an acute phase protein response and a multi-cellular and multi-protein inflammatory process (83–85). This

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Figure 3 Ab cascade hypothesis.

inflammatory process apparently includes the binding of the initial component of the classical complement cascade, C1q, by Ab (86) and the triggering of the full complement cascade (87). Whether Ab oligomers trigger synaptic dysfunction via such an intermediate inflammatory process and/or whether they produce direct synaptotoxic effects by subtly disrupting macromolecules (receptors, channel proteins, etc.) on the synaptic plasma membrane (88) remains a subject for further work. There is considerable evidence that the effects of an Ab-initiated inflammatory and neurotoxic process include excessive generation of free radicals and peroxidative injury to proteins and other macromolecules and neurons [see e.g., (89,90)]. In this context, a therapeutic trial of the antioxidant vitamin E appeared to slow the clinical progression of AD, although actual amnestic and cognitive symptoms were not noticeably improved (91). Among the many possible metabolic consequences of Ab accumulation and oligomerization, altered ionic homeostasis, particularly excessive calcium entry into neurons, may well contribute to selective neuronal dysfunction and death, based on culture studies of the effects of aggregated Ab (92–94). Establishing definitively that Ab accumulation triggers the dissociation of tau from microtubules, its hyperphosphorylation and its assembly into PHF (45,95) awaits further research. However, the offspring of human mutant tau transgenic mice crossed with mutant human APP transgenic mice show an accelerated accumulation and deposition of altered forms of tau, including in tangle-like lesions (96). Thus, a “plaque-plus-tangle” phenotype was generated in these doubly transgenic mice that more closely resembles the AD state than do APP transgenic mice alone.

QUESTIONS ABOUND Although genetic, neuropathological, cell culture and animal modeling studies all support an Abmediated cytopathological cascade along the lines of that suggested in the previous section (Fig. 3), many questions remain unanswered. One would like to know the relative contributions of extracellular and intraneuronal Ab accumulation in potentially initiating neurotoxicity. Whereas immunohistochemistry has traditionally shown only abundant extracellular Ab deposits in AD brain,

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recent evidence suggests the detection of some Ab42 interneuronally in AD brain sections (97). Furthermore, small amounts of stable Ab dimers have been visualized inside both neuronal and certain non-neuronal cells in culture (81). A related question is whether Ab fibrils are the principal toxic moiety in the disease, or do smaller oligomeric assemblies serve as the microglia-activating and neuron-injuring species? One would also like to know whether apoptosis of neurons is an important part of the pathogenetic cascade that, if inhibited, would slow or prevent brain dysfunction. Although both of the presenilins (particularly mutant PS2) have been associated with enhanced apoptosis in cell culture studies [e.g., (98)], expression of AD-causing mutations in presenilin by knock-in techniques in mice has not yet produced evidence that the mutations enhance neuronal apoptosis in vivo (99). How a putative pro-apoptotic function of presenilin relates to the likelihood that presenilin is an aspartyl protease that processes APP, Notch, and other intramembranous substrates needs to be clarified. The presence of innumerable tangle-bearing neurons in the AD brain that still show relatively well preserved organelle structure by EM, coupled with evidence that mutations in tau lead to accelerated tangle formation and ultimately neuronal death, indicates that a nonapoptotic neuronal dysfunction (i.e., the tau alteration/tangle formation process) can clearly precede neuronal death, which might finally occur by apoptosis. What about the selective vulnerability of neuronal populations to the Alzheimer process? Local and regional differences in the pathogenic process arise on at least two broad levels. First, Ab42 can accumulate chronically in some brain regions (e.g., cerebellum, striatum, and thalamus) with very little evolution to fibril-rich amyloid plaques and little associated neuritic and glial cytopathology. This finding suggests the possible existence of pro- or anti-aggregating factors that vary among brain regions and that enable Ab to proceed into oligomeric forms or else prevent it from doing so. Second, even in regions where abundant Ab oligomerization/fibrillization can occur (e.g., the cerebral cortex), some surrounding neurons and their processes appear to undergo few or no cytopathological changes. This raises the prospect of an intrinsic ability on the part of certain neurons to resist Ab-mediated cytotoxicity. In the final analysis, the multifaceted molecular and cellular events that appear to occur downstream of Ab accumulation (Fig. 3) may be difficult to place into a detailed temporal sequence. It is likely that microglia, astrocytes, and neurites may all respond to the disease process simultaneously and that the response of one cell type can adversely affect another. As a result, interfering with early steps in the process, such as Ab production or Ab assembly, may prove a more tractable therapeutic strategy than attempting to block the multiple downstream cellular effects of the peptide and its many associated proteins. The progress in illuminating the role of the presenilins in the proteolytic processing of APP, Notch, and other important cellular proteins leads to a new way of thinking about the origin of Alzheimer’s disease. It appears that the presenilins and, in particular, their two TM aspartate residues, were conserved during evolution because they confer a strong developmental advantage in mediating the processing of Notch, which is vital for life in all multicellular animals. Stable complexes between Notch and presenilin in cells (64) are more readily detectable than stable complexes between APP and presenilin, although the latter are also observed (73). Therefore, Notch appears to be a kinetically favored substrate of presenilin (100), but lower-level cleavage of an alternate substrate, APP, leads to the gradual accumulation of its particularly hydrophobic fragment, Ab42, over time. From this vantage point, Alzheimer’s disease has emerged as a side product of a highly advantageous enzymatic machine that produces ill consequences only when humans survive late into postreproductive life. An exception to the late nature of the ill effect is represented by the inheritance of missense mutations in the substrate (APP) or the protease (presenilin) of the g-secretase reaction, in the sense that such mutations biochemically accentuate the cleavage process and thus accelerate the production of Ab42.

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THERAPEUTIC OPPORTUNITIES PROVIDED BY THE Ab CASCADE Regardless of such interesting theoretical considerations, sufficient progress in delineating the disease cascade has now been achieved to envision several discrete targets for treatment. Inhibitors of Ab production, that is, small compounds that cross the blood-brain barrier and decrease but do not eliminate either b- or g-secretase activity, could be therapeutic in the early clinical phases of the disease, particularly in patients with mild cognitive impairment, as well as in non-demented (presymptomatic) subjects. In the case of g-secretase inhibitors, these could be designed to decrease Ab production by some 30–40% or so, hopefully without interfering in a quantitatively important way with Notch processing. The fact that very small amounts of the Notch intracellular fragment are apparently sufficient to activate signaling in cells (101) may mean that some decrease in Notch proteolysis can be tolerated, particularly in Alzheimer patients, in whom developmental issues are not at stake. Whether such a beneficial therapeutic index for a g-secretase inhibitor can be achieved—by targeting either the active site (presenilin) or one of the associated proteins (e.g., nicastrin)—will require further preclinical and clinical research. In regard to b-secretase (BACE-1), far fewer inhibitors of this protease have emerged from highthroughput compound screening on Ab-secreting cells than is the case for g-secretase. This probably signifies that it is more difficult to find small organic compounds that adequately block the active site of b-secretase. However, the fact that the crystal structure of BACE-1 has been solved (102) indicates that it should be possible to design inhibitory compounds that will block the active site. If this can be accomplished, such inhibitors may have a better therapeutic index than those of g-secretase, in view of the finding that completely inactivating BACE-1 (by knocking out its gene) leads to no deleterious phenotype in mice. The latter observation suggests that mechanism-based toxicity may not be encountered with BACE-1 inhibitors, although non-mechanism based side effects of a particular inhibitor certainly remain a possibility. An alternate and attractive approach to secretase inhibition would be to use small molecules to bind Ab monomers and prevent their assembly into potentially neurotoxic oligomers. However, if an anti-aggregating compound solely blocked amyloid fibril formation, this could actually allow increased accumulation of metastable intermediates such as oligomers and protofibrils and might thus actually aggravate the disease (88). One advantage of an anti-oligomer strategy is that one would be targeting what is believed to be a purely pathological event in the disease, rather than interfering with normal metabolic reactions such as those of b- and g-secretase. An immunological approach to lowering brain levels of Ab monomers, oligomers, and higher aggregates is supported by a large number of studies in APP transgenic mice. Parenteral immunization with synthetic human Ab peptides was initially shown to lead to a humoral immune response that is associated with striking clearance of pre-existing Ab deposits, or their actual prevention if the mice are immunized early in life (103). Subsequent studies have confirmed and extended this approach, showing that Ab immunization can not only lower brain Ab burden but also improve learning deficits in the mice (104,105). A mucosal (intranasal) route of Ab administration has also been found to reduce plaque numbers and the associated gliosis and neuritic dystrophy, as well as lower brain Ab levels in transgenic mice (106). Furthermore, passive administration of Ab antibodies can also induce the Ab-clearing effect (107). At least two general mechanisms for the Ab-lowering effects of active and passive immunization have been proposed. First, the anti-Ab antibodies may cross the blood-brain barrier in small amounts and bind to Ab, followed by gradual clearing of the resultant Ab-antibody complexes by local microglia (107). Second, the high titers of anti-Ab antibodies in the peripheral circulation may sequester Ab in that compartment, resulting in a redistribution of Ab from brain parenchyma to CSF to plasma (108). Whether one or both of these mechanisms—or yet another—is operative remains unclear. No untoward antigen-antibody

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reaction was reported in the mouse models, i.e., the peri-plaque inflammatory cytopathology in the mouse was prevented rather than aggravated (103,106). However, the administration of an Ab1-42 peptide vaccine (with an adjuvant) to humans with mild to moderate AD resulted in a small but unacceptable number of cases of a serious inflammatory reaction in the CNS that seems to resemble a post-vaccinal meningoencephalitis. This adverse was probably caused by a T-cell reaction to the Ab1-42 vaccine that is directed at the C-terminus of Ab, and some older humans appear to have a pre-existing T-cell responsiveness to this epitope (109). As a result of this reaction, two alternative immune-based therapeutics have been evaluated pre-clinically, a short (N-terminal) Ab fragment as an active vaccine, and an antibody to Ab as a passive vaccine, and the latter agent has recently entered clinical trials (110). Another Ab-based approach to the treatment of AD would be to administer anti-inflammatory drugs that could interfere with aspects of the microglial, astrocytic, and cytokine responses that have been shown to occur in the AD brain. The epidemiologic evidence that consumption of nonsteroidal anti-inflammatory drugs for other purposes (e.g., chronic arthritis) may be associated with a somewhat lower likelihood of developing AD could potentially be explained on this basis (111). However, it would presumably be best to design novel compounds that interfere with one or more specific steps in the Ab-induced inflammatory cascade in the brain, rather than relying on conventional anti-inflammatory drugs that have considerable potential gastrointestinal and other toxicities, particularly in older patients. Finally, one could use a variety of anti-oxidants, free radical scavengers, calcium channel blockers, metal chelators or modulators of certain signal transduction pathways that might serve to protect neurons from the downstream effects of the accumulation of Ab. The problem with such approaches may turn out to be that there are multiple ways in which neurons respond to Ab and the associated inflammatory process, and blocking one or two of these response pathways might not significantly decrease overall neuronal dysfunction and loss. One could also envision the use of neurorestorative factors, e.g., neurotrophins, and small compounds mimicking their actions, that might rescue synapses and cell bodies undergoing active injury. However, this approach would need to operate in the face of ongoing new injury from the putative cytotoxic effects of Ab oligomers. Because the success of any one of the above strategies cannot be predicted and because two or more approaches might ultimately be combined, all such efforts and others not reviewed here need to be vigorously pursued. Current, largely symptomatic treatments aimed at enhancing the level of depleted neurotransmitters, particularly acetylcholine, may continue to be useful, even if more specific, Ab-based treatments aimed at early steps in the disease are forthcoming. In the future, it is likely that individuals reaching their 50s or beyond will be offered a specific risk-assessment profile to determine their likelihood of developing AD. Such an assessment, modeled on that now widely used to judge the risk of serious atherosclerotic disease, could include inquiry about a positive family history of AD, identification of specific predisposing genetic factors, structural, and functional brain imaging to detect evidence of presymptomatic lesions, and measurement of Ab42, tau, and other markers of the neuropathology in CSF and perhaps (in the case of Ab) in blood. Based on further epidemiologic experience with such assessment measures in large populations of healthy elderly, MCI, and AD subjects, it should be possible to estimate—first crudely and later more accurately—the likelihood that an individual will develop AD. If this can be accomplished, then those at particularly high risk could be offered preventative treatments with one or more of the agents contemplated in the previous paragraphs. Although the achievement of an integrated diagnostic and therapeutic approach to this complex and devastating disorder may seem remote, the current rate of scientific progress and the likelihood of further clinical trials in the near future indicates that some level of practical success may come sooner than one might think.

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94. Lorenzo A, Yankner B. b-amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc Natl Acad Sci USA 1994; 91:12243–12247. 95. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 1999; 402:615–622. 96. Lewis J, Dickson DW, Lin WL, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001; 293:1487–1491. 97. Gouras GK, Tasi J, Naslund J, et al. Intraneuronal Ab42 accumulation in human brain. Am J Pathol 2000; 156:15–20. 98. Wolozin B, Iwasaki K, Vito P, et al. Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. Science 1996; 274:1710–1713. 99. Siman R, Reaume AG, Savage MJ, et al. Presenilin-1 P264L knock-in mutation: differential effects on abeta production, amyloid deposition, and neuronal vulnerability. J Neurosci 2000; 20:8717–8726. 100. Berezovska O, Jack C, Deng A, Gastineau N, Rebeck GW, Hyman BT. Notch1 and amyloid precursor protein are competitive substrates for presenilin1-dependent gamma-secretase cleavage. J Biol Chem 2001; 276:30018–30023. 101. Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 1998; 393:382–386. 102. Hong L, Koelsch G, Lin X, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 2000; 290:150–153. 103. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-b attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400:173–177. 104. Janus C, Pearson J, McLaurin J, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 2000; 408:979–982. 105. Morgan D, Diamond DM, Gottschall PE, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 2000; 408:982–985. 106. Weiner HL, Lemere CA, Maron R, et al. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol 2000; 48:567–579. 107. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer’ disease. Nat Med 2000; 6:916–919. 108. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2001; 98:8850–8855. 109. Monsonego A, Zota V, Karni A, et al. Increased T cell reactivity to amyloid b-protein in older humans and patients with Alzheimer’s disease. J Clin Invest 2003; 12:415–422. 110. Selkoe DJ, Schenk D. Alzheimer’s Disease: Molecular understanding predicts amyloid-based therapeutics. Ann Rev Pharmacol Toxicol 2003; 43:545–584. 111. McGeer PL, McGeer EG. Inflammation, autotoxicity and Alzheimer’ disease. Neurobiol Aging 2001; 22:799–809.

26 Prevention Strategies for Alzheimer’s Disease Marı´a M. Corrada and Claudia H. Kawas Departments of Neurology, Neurobiology and Behavior, University of California Irvine, Irvine, California, U.S.A.

PUBLIC HEALTH IMPORTANCE AND PREVENTION In the past century, life expectancy has increased more than 27 years. As the number of elderly persons has dramatically increased, Alzheimer’s disease (AD) has become one of the major public health problems in the United States and the entire developed world. The “prevalence and malignancy of AD,” as described in a two-page editorial written in 1976 by Dr. Robert Katzman (1), has become well known to physicians as well as the lay public. In the editorial, Katzman estimated the prevalence and mortality due to AD, and placed AD as a leading cause of death in the United States. Hebert has shown that the impact of AD will be ever more dramatic over the next 50 years as the numbers of very elderly in the population rise at an accelerated rate (2). Projecting age-specific prevalence data for AD to the population distributions obtained from the U.S. Census Bureau, there were 4.5 million cases of AD in the United States in the year 2000 and there will be 13.2 million in the year 2050. At present, AD is the third most expensive disease in the United States costing approximately $100 billion each year (3). Patients suffering from AD eventually become completely dependent and rely on relatives for care or are placed in nursing homes. Costs for the disease thus include direct (nursing home care, hospitalizations, physician visits, social services including adult day care, and medications) as well as indirect costs (loss of productivity and premature death). Given the increasingly aging population, the costs associated with the disease will certainly grow and will very likely make AD the most expensive disease in the United States within the next decades. Preventing or even delaying the onset of the disease will certainly have an enormous impact on society. Considerable attention has been given to primary prevention strategies such as the so-called “vaccinations” for AD that rely on antibodies to amyloid b (Ab), or drugs that act as inhibitors of b- and g- secretase (anti-amyloid therapies, see Chap. 25 by Dr. D. Selkoe). However, despite potential promise for the future with these approaches, it may be that compounds already in existence can also serve to significantly reduce the age-associated incidence of AD. This chapter summarizes some of these promising approaches, including several that are currently being investigated in randomized clinical trials. 453

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TYPES OF PREVENTION Opportunities for prevention of AD can be illustrated within a model of AD as a chronic disease (Fig. 1) (4). Although this model describes a continuous process, three stages can be identified that explain conceptually different events throughout the disease process. In a chronic disease, there is typically an initial latent period, which may even last for several decades, before any clinical symptoms are evident. During this stage the pathologic process is initiated, likely due to one or more initiating factors. In AD, diffuse and neuritic plaques may begin to appear during this early stage of the disease (5). In the later prodromal (or preclinical) stage, mild clinical symptoms begin to appear as the disease process continues. During this stage, events leading to the development of neuritic degeneration, neurofibrillary tangles, and synaptic loss also begin. In the final expression (or clinical) stage, damage to the brain accumulates to such a degree that clinical symptoms are clearly evident in the form of cognitive and functional disability severe enough to warrant a diagnosis of Alzheimer’s Dementia. These different stages of the Alzheimer’s disease process provide a variety of opportunities for intervention in the hopes of halting or altering the natural progression of the disease. Primary prevention strategies would act during the early latent stage to eliminate or reduce exposure to factors in order to prevent the transition into the pathologic process. Secondary prevention would act during the prodromal stage to delay the clinical manifestation of the disease. Finally, tertiary prevention would be applied during the expression stage of the disease in hopes of slowing or halting the progression of the dementia severity. When considering the utility of compounds for the “prevention” of AD in this model, it is crucial to remember that drugs or interventions that have a role in one stage of prevention may have no effect on other stages. For example, approaches that are useful for preventing the occurrence of strokes (anti-hypertensive drugs, cholesterol lowering agents, etc.) are of little utility for the tertiary prevention or treatment of the stroke once it has occurred. Similarly, it is likely that the primary and secondary prevention of AD will require different strategies than ones that may be useful for tertiary prevention (treatment). Studies that have suggested that certain compounds may be useful for the treatment of AD (6–16), do not give us clues regarding the potential utility in primary prevention. The biological processes that are targeted by any particular agent may no longer be operative once the disease process has reached these later stages. Current available treatments for AD act only during the expression phase, and thus deal with tertiary prevention. The only FDA-approved drugs that are currently available for treating the primary symptoms of AD are aimed at symptomatically improving cognition or functional STAGES OF DISEASE

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Figure 1 Alzheimer’s disease as a chronic disease. Source: Adapted from Ref. 4.

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ability (see Chap. 23 by Dr. M. Farlow). It is not known whether these drugs may also slow down the pathological progression of the disease. Moreover, the demonstrated effects of these drugs have been modest. This symptomatic approach may help maintain the overall intellectual ability of the patient for a period of time, however, if these drugs do indeed affect disease progression and mortality, they may in the long run extend the duration of the disease, thus increasing its prevalence. The other available treatments for AD deal with relief of behavioral symptoms such as aggression, hallucinations, depression, irritability, and delusions (see Chap. 24). This type of therapy is beneficial in terms of maintaining the quality of life of patients and caregivers, but again, acts only after the disease is clinically evident. Secondary prevention is also not ideal because it, too, is based on altering a disease process already established. In the long run, the opportunity for primary prevention of AD is considerably more appealing to the individual and to public health than are symptomatic therapies that may prolong the illness and hence actually increase the burden of disease. Primary prevention thus seems like the most effective course of action since it deals with preventing or slowing down the pathological process that will lead to expression of clinical symptoms. There are three main types of observational study designs that are traditionally used in epidemiologic research when attempting to identify risk and protective factors in the development of a disease: case-control, cross-sectional, and cohort studies. Case-control studies are generally the first studies to be performed for the purpose of identifying risk or protective factors because they are generally conducted quickly and are relatively inexpensive. In cross-sectional studies, information about disease and exposure is obtained at a single point in time. Case-control studies and cross-sectional studies have similar disadvantages with respect to AD. While cost- and laborefficient, these studies rely on recall of lifetime exposures. In the case of AD, this information is generally dependent on surrogate informants, such as spouses or children, who may not know the information of interest. Since case-control and cross-sectional studies consist of existing cases (prevalent cases), it is often difficult to interpret the results of these studies as it is unclear whether the exposure or the disease occurred first. A further complication may arise if physicians tend to prescribe certain medications more frequently if a subject is demented, which would result in an apparent increase in risk. Conversely, physicians may stop or not prescribe medications because a patient has dementia, which would result in an apparent decreased risk. To circumvent these problems, case-control or cross-sectional studies are generally followed by cohort studies. These investigations begin with participants that do not have the disease of interest and are followed up over time to identify newly diagnosed cases (incident cases). In these studies, exposure information is collected prospectively before the development of disease and is generally obtained uniformly for all members of the cohort and directly from the subjects themselves. These investigations provide invaluable information regarding potential agents, which can then be tested in clinical trials as preventive strategies against AD. In the following sections, we review these three types of studies but we concentrate on prospective investigations, that provide the strongest evidence short of a randomized clinical trial.

POTENTIAL PREVENTIVE INTERVENTIONS Pharmacological Interventions Over the past several years, certain factors have been described in numerous observational studies that may protect against the development of AD or may delay its onset. These potentially neuroprotective agents have been suggested as possible strategies that may be useful to delay or prevent the onset of AD. Potential agents have included hormonal replacement therapy, nonsteroidal antiinflammatory drugs, antioxidants, folate, Ginkgo biloba and cholesterol-lowering agents. The evidence for each of these approaches is discussed below.

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Estrogens Potential mechanisms: Estrogens affect numerous biological processes relevant for brain health and for AD. Among other activities, they are known to affect regulation of acetylcholine and nerve growth factor, to exhibit antioxidant activity, to inhibit apolipoprotein E levels in plasma, and to affect vasculature. These potential mechanisms have been reviewed in several publications (17–19). Estrogens occur naturally in several forms, including estradiol, estrone, and estriol. Of these, estradiol has the highest potency at the receptor and may possibly be the most relevant for brain functioning. In the past, the most commonly prescribed form of estrogen replacement therapy consisted of conjugated equine estrogens (a mixture of numerous estrogens) without progestin. More recently, women with a uterus have been prescribed estrogen in combination with progestin. The effect of each of these preparations, however, may not be the same. The observational studies cited below generally grouped together all forms of estrogen. Evidence from observational studies: Figure 2 shows the results from observational studies of estrogen use and AD that have been published to date. The results from many retrospective studies of estrogen and AD have been inconclusive. Two studies (20,21) found a statistically significant decrease in risk of AD with the use of estrogen replacement therapy. Other retrospective studies, however, have found a non-significant decrease in risk (22,23), no association (24,25) or a non-significant increase in risk (26,27). A cross-sectional study (28) has also looked at the association between use of estrogen and AD with results suggesting a protective effect of estrogen on AD. In 1994, Paganini-Hill and Henderson (29) published the first study of estrogen and AD where information of estrogen use was collected prospectively. The authors studied a large cohort of women from the Leisure World retirement community and, using a nested case-control design, found that AD and related dementias in these women occurred less often in estrogen users relative to nonusers. Moreover, their study demonstrated both a dose and a duration effect, with the risk of AD decreasing with increasing dose and duration of estrogen use. Subsequently, several other prospective studies have found similar results. Greater protective effects of estrogen in postmenopausal women were also found in the North Manhattan Study (30), in the Baltimore Longitudinal Study of Aging (31), in studies performed with patients at the Mayo clinic (32), and in the CacheCounty Study (33). Data from this last study also showed that increased duration of use afforded greater protection primarily in women with prior, rather than current, use. Not all prospective studies, however, have found the use of estrogens to be protective. Studies in the United Kingdom (34) and Canada (35) have failed to find an association. In 1998, Yaffe and colleagues (17) performed a meta-analysis of all studies of ERT and AD that had been published up to that date. The authors did not find a significant reduction in risk when combining eight case-control studies [odds ratio (OR)Z0.80, 95% confidence interval (CI)Z0.5–1.28] but found a 52% reduction in risk of AD among estrogen users when they combined the results of two prospective studies (ORZ0.48, 95% CIZ0.29–0.81). Although outside the scope of this chapter, estrogen has also been studied intensively in regards to cognitive performance (36–42), with several observational studies suggesting that it may enhance cognitive, particularly verbal abilities. Moreover, the improvement in cognition found in observational studies has been supported by a number of randomized clinical trials where the use of estrogens appeared to show improvements in certain cognitive abilities (43–45). Some observational studies (36,42) as well as randomized trials, however, (46–48) have failed to replicate the findings. Anti-Inflammatory Drugs Potential mechanisms: Neuritic plaques, a hallmark of AD pathology, have been associated with a host of proteins and acute-phase reactants, activated microglia, and complement

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Prevalent Cases _____________ Heyman (26) Amaducci (27) Broe (22) Graves (24) Brenner (25) Henderson (20) Mortel (23) Lerner (21) Baldereschi (28) Incident Cases ____________ Paganini-Hill (29) Tang (30)

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Figure 2 Observational studies of the effect of estrogen use on the risk of AD. Abbreviations: yr, year; mos, months.

activation, which are evidence of local inflammation. McGeer and colleagues (49,50) have extensively reviewed the biological mechanisms that link AD to inflammatory processes. From these observations, it follows that pharmacological suppression of inflammation may slow the rate of AD pathology. Anti-inflammatory drugs are inhibitors of the cyclooxygenase (COX) enzymes. Both isoforms of COX, COX1, and COX2, have been identified in the brain and have been suggested as potential targets for suppressing inflammatory reactions associated with AD. COX 1 is constitutive and its inhibition most likely mediates gastric and renal toxicities. COX 2 in most of the body is inducible, but appears to be constitutive in neurons. In addition, it has been noted to be upregulated in neurodegenerative models and in AD. It is not yet clear which of these isoforms is most relevant for the pathology associated with AD. Most anti-inflammatory drugs that have been available to date are non-selective inhibitors of both isoforms of the COX enzymes. However, selective COX 2 inhibitors have been developed recently and are also being tested in AD. More recently, an in vitro study observed that a subset of NSAIDs (ibuprofen, sulindac, and

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indomethacin) were able to decrease levels of amyloidogenic Ab-42 peptide in cultured cells, and that this effect was not mediated by COX activity inhibition (51). Subsequently, researchers from the Rotterdam study reported that the observed decrease in AD risk among NSAID users was restricted to that same subset of NSAIDs (52). Evidence from observational studies: Since an initial observation by Jenkinson and colleagues (53), numerous epidemiological studies have reported a reduced risk of AD in patients with inflammatory diseases such as arthritis (22,54–56). It is not clear, however, whether these patients have a reduced risk because of the anti-inflammatory treatments taken for these conditions or whether persons with a predisposition, either genetic or environmental, to inflammatory diseases also have a predisposition toward a reduced risk of AD. Many case-control and cross-sectional studies have looked at the association between use of steroids (24,55–57) or NSAIDs (56–60) and the risk of AD. In a review article by McGeer and colleagues (61), the combined odd ratios were estimated for case-control studies that looked at steroids or NSAIDs as protective factors for AD. For both types of studies the combined odds ratio indicated a significantly reduced risk among users of either steroids (combined ORZ0.66, 95% CIZ0.43–0.999) or among users of NSAIDs (combined ORZ0.50, 95% CIZ0.34–0.72). Figure 3 shows results from observational studies that have investigated AD and NSAID use. Several prospective studies have also explored this association but not all have found a protective effect of NSAIDs against dementia or AD. In a population sample in southwest France, there was no difference in the risk of dementia between users and non-users of NSAIDs after a 2-year follow-up (62). Similarly, in a community survey conducted in Australia, no association was found between NSAID use and development of dementia after an average of 3.6 years of follow-up (63). A nested case-control study done at the Mayo clinic found a non-significant protective effect of NSAIDs among men and no effect among women (64). Nonetheless, prospective studies with longer follow-up and larger numbers of subjects have tended to suggest a protective effect. Most studies that show an effect of NSAIDs on the risk of AD generally report about a 50% reduction in risk. In addition, most prospective studies have found increased protection against AD with increased duration of use. Subjects in the Baltimore Longitudinal Study of Aging (65) who had two or more years of exposure to NSAIDs, had approximately one-half the risk of AD than did subjects who reported no exposure, while subjects with less than two years of exposure had a non-significant reduced risk. This result was also demonstrated in a large population sample in the Netherlands, where exposure to NSAIDs was determined by pharmacy records (66). Subjects in this study who had taken NSAIDs for two or more years appeared to have a reduction in the incidence of AD while those who had used these drugs for less time did not show a reduction. Similar results with duration of use were found in the Cache County Study (67), where in addition former use was associated with a reduced risk of AD while current use was not. In 2003, Etminan and colleagues (68) performed a meta-analysis of nine observational studies of the effect of NSAIDs on AD published up to that date. The study found greater protection against AD with long term use [O2 years, relative risk (RR)Z0.27, 95% CIZ0.13–0.58] rather than intermediate use (!2 years, RRZ0.83, 95% CIZ0.65–1.06). The effect of NSAIDs has also been examined in relation to cognitive decline in older persons. Some studies have reported an improvement in cognition with NSAID use (69,70) while others have found a significant worsening in cognition among users of NSAIDs (62,71). Vitamins B Vitamins Potential mechanisms: Several potential mechanisms, some of which may be related to homocysteine, have been suggested to link the intake of B-vitamins, particularly folate, to the

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Figure 3 Observational studies of the effect of nonsteroidal anti-inflammatory drug use on the risk of AD. Abbreviations: yr, year; mos, months.

development of AD. Intake of folate and other B-vitamins is associated to homocysteine levels, a well-known risk factor for vascular disease (72–77). Studies that show a relation between vascular disease and AD (78–80) support the notion that homocysteine levels may contribute to vascular disease through a direct effect on vascular endothelial cells (81). However, even in the absence of significant cerebrovascular disease or atherosclerosis, homocysteine has been shown to be a risk factor in patients with neuropathologically confirmed AD (82). Non-vascular mechanisms have also been suggested to explain the link between folate intake and AD. Animal studies provide evidence that folic acid deficiency and homocysteine may be directly related to amyloid toxicity (83) or may cause direct toxicity to neuronal cells (84). Non-homocysteine mechanisms involving methylation reactions in the brain (85) have also been postulated to explain the association between folate intake and AD development. Of interest, two studies have associated atrophy in different areas of the brain to serum folate levels (86) or homocysteine levels, (82) but the mechanisms for these results are not known.

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Evidence from observational studies: Most studies reporting on the association between AD and B-vitamins have looked at plasma or serum levels of the vitamins or homocysteine. In particular, one prospective study showed increased levels of plasma homocysteine as a strong risk factor for AD (87) and another smaller prospective study (88) found that subjects with low serum levels of folate or vitamin B12 had double the risk of an AD diagnosis 3 years later. Several small case-control studies (82,89–92) have also looked at this association. One of these studies reported a lower intake of folate in AD cases as compared to controls (92). To our knowledge, the only prospective study of the association between folate intake and AD is our own investigation in the Baltimore Longitudinal Study of Aging (93). In that study, subjects with a total folate intake (diet plus supplements) above the recommended dietary allowance (RDA) of 400 mg had a 55% decrease in risk compared to those below the RDA after an average follow-up of 9.3 years. Antioxidants Potential mechanisms: Free radicals are chemical species that play normal roles in the body’s metabolism but can cause damage to the cell when present in excess. Antioxidants such as vitamin E, vitamin C, b-carotene, selenium, and a-lipoic acid, among others, can protect cells from damage by scavenging free radicals. When the balance between antioxidants and free radicals is broken in favor of free radicals, oxidative stress occurs. The effects of oxidative stress can accumulate over the years and could account in part for the late-life onset and the slowly progressive nature of AD and other neurodegenerative diseases. Moreover, aging itself is associated with a decreased ability to defend against the accumulation of free radicals (94). Experiments suggest that oxidative processes may be related to Ab aggregation, microglial stimulation, damage to mitochondrial and nuclear DNA, as well as protein and lipid peroxidation. Evidence for the oxidative stress hypothesis in AD has been thoroughly reviewed by Markesbery (95) and more recently by Christen (96). Evidence from observational studies: A few case-control studies have reported that antioxidant levels are significantly lower in AD patients compared to controls. These studies have observed that, compared to controls, AD patients may have lower vitamin C plasma levels (97), lower vitamin E serum levels (98,99), or lower vitamin E CSF levels (99). However, not all studies have been able to replicate these results (97,100). Figures 4 and 5 shows results from prospective studies of vitamins E and C and risk of AD. Summarizing the results from these prospective studies is difficult because of the different sources of antioxidants (supplements, dietary, dietary plus supplements) in each study. Results have been conflicting, with a protective effect against AD in some (101,102) but not all studies (103,104). In the East Boston Study (101), data obtained from a medication questionnaire showed that none of the vitamin E or vitamin C supplement users developed AD after an average follow-up period of 4.3 years. In the Cache County Study, (102) use of vitamin E and vitamin C supplements in combination, but not individually, was associated with a lower incidence of AD. In contrast, the Honolulu Asian Aging Study did not find an association between use of vitamin E or C supplements after 3 to 5 years of follow-up (103). These antioxidants, however, were found to be protective against vascular dementia and mixed or other dementias. Finally, the Washington Heights-Inwood Columbia Aging Project (WHICAP) in northern Manhattan (104) found no association between supplement intake of vitamin C, or vitamin E and the incidence of AD after a 4-year follow-up. Studies of dietary intake have also produced conflicting evidence. The Rotterdam Study (105) followed 5,395 subjects for an average of 6 years and found a significant decrease in AD risk in subjects with a high daily dietary intake of vitamin E and vitamin C. The Chicago Health and Aging project (CHAP) (106) reported on 815 subjects who were followed for an average of 3.9 years. The authors found that higher vitamin E intake from diet was associated with a reduced risk of AD but found no association with total intake of vitamin E (diet plus supplements), or with vitamin C

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__________ Supplements non sign.

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(diet or total intake). Last, the WHICAP study reported no association between dietary or total (diet plus supplements) intake of vitamin C or vitamin E and the incidence of AD in 980 subjects followed for an average of 4 years (104). In our studies in the Baltimore Longitudinal Study of Aging, total intake of vitamin E appeared to reduce the risk of AD. However, when vitamin E total intake was simultaneously analyzed with other vitamins, only total folate intake was significantly related to a decrease in risk of AD (93). Many studies have also reported on the association between scores in cognitive tests and antioxidants, either from plasma levels, dietary intake, or supplement use. There is much literature on this association between antioxidants and cognitive performance in the elderly, but the evidence has yielded contradictory results (103,107–112). Ginkgo Biloba Potential mechanisms: The extract of the leaves of this ancient tree has long been used for medicinal purposes particularly in Asia, and more recently, in Europe (especially Germany).

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Figure 5 Observational studies of the effect of vitamin C on the risk of AD. Abbreviations: T, tertile; Q, quartile; Qi, quintile; sign, significant; RDA, recommended dietary allowance.

Considered a dietary supplement, it is available in the United States without prescription in a variety of formulations. Ginkgo biloba extracts are, besides vitamins, the most widely used form of alternative medicine to improve patients’ memory (113,114). Although, there is little evidence that gingko can delay or prevent the onset of AD, it has been heavily promoted through the media and appears to be in wide usage in the United States for this purpose. G. biloba is often prescribed as an agent to treat memory disorders including AD, vascular, and mixed dementias in several European countries (115). The effect of G. biloba as a preventive agent seems biologically plausible due to the properties of several of its components. The currently used extracts, the most common being “Egb 761” contains organic acids, flavonoids, and terpenoids (bilobilide and ginkolides). G. biloba components have antagonistic effects on platelet-activating factor, anti-inflammatory effects, impact on the cholinergic neurotransmitter system, and antioxidant and free radical scavenger properties (116). G. biloba has also been observed to inhibit neuronal death induced by Ab (117) as well as inhibit Ab aggregation (118).

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Evidence from observational studies: Most of the evidence for the association between G. biloba and AD has come from animal laboratory studies, and treatment trials of demented patients. Most of the research on the effect of G. biloba has been published in European countries, particularly Germany, where G. biloba is frequently prescribed to treat memory disorders. To our knowledge, only one observational study has explored the association between G. biloba and the risk of AD. A report from a nested case-control study in France with a 7-year follow-up reported a non-significant decreasing risk of AD with increasing number of exposures to G. biloba (119). Statins Potential mechanisms: Statins are a type of drug prescribed for the lowering of serum cholesterol levels. These drugs work by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA), the rate-limiting enzyme in cholesterol synthesis. There is increasing evidence linking cholesterol levels (120,121) and atherosclerotic cardiovascular disease (79,122) to AD pathogenesis. Proposed mechanisms include that elevations in cholesterol may reduce the levels of the soluble form of Ab in the brain or somehow be linked through the role of apolipoprotein E in regulating cholesterol supply to neurons that produce Ab. It is postulated that statins may help prevent against AD directly by reducing high cholesterol levels or indirectly by reducing cardiovascular disease. It is also possible that statins have effects on AD due to their antiinflammatory properties. Evidence from observational studies: Only a handful of observational studies have looked at risk of AD and statins. In a cross-sectional study, Wolozin and colleagues (123) found that users of statins identified from hospital records had a lower prevalence of AD (60% to 73% lower) than non-users. The reduction was apparent only with two types of statins (lovastatin and pravastatin) but not with a third type (simvastatin). Jick and colleagues (124) found similar results for all dementias combined in a study from the General Practice Research Database in the United Kingdom. In the Canadian Study of Health and Aging (125) the use of statins was also noted to be more common among controls than among cases of AD but only in subjects younger than 80 years of age. Non-Pharmacological Interventions Other factors, besides the pharmacological agents described in the previous sections, have been implicated as potentially beneficial against the development of dementia and AD. Among these are participation in physical activities and in cognitively demanding activities. Below we describe the available evidence for each of these. Exercise Potential mechanisms: Physical activity and exercise may be beneficial in reducing the risk of AD through a variety, or perhaps combination, of mechanisms. These mechanisms include lowering of blood pressure and serum lipids, as well as effects on cerebral blood flow and platelet aggregation (126–128). Alternatively, increased physical activity may affect AD indirectly by resulting in improved cardiovascular and cerebrovascular health, both of which have been associated with the clinical expression of AD (78,129). Evidence from observational studies: Several case-control studies have explored the association between physical activity and AD. Some studies found a reduction in risk with increased activity (22,127,130), while others were not able to replicate the results (131). Prospective studies have also looked at the association, also with conflicting results. Studies from the Leisure World Retirement Community (29,132), a small prospective study in Australia (Sydney Older Persons Study) (133), a prospective study of dementia in the elderly of Shanghai (134), and a

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recent report from the Chicago Health and Aging Study (135) have all failed to find an association between physical exercise and risk of dementia or AD. Other prospective studies have found a significant reduction in risk with increased physical activity. A 3-year follow-up study in China (136) reported that subjects limited to indoor activities were at an increased risk of dementia compared to those without such limitations. The association was corroborated in a prospective study of residents of Hisayama, Japan (126), where after 7 years of follow-up, regular moderate physical activity was protective against AD but not vascular dementia. In the Canadian Study of Health and Aging (128) an association was observed between moderate or high levels of physical activity and a decreased risk of AD and dementia of any type. In addition, the authors observed a significant decreasing risk with increasing level of physical activity. In a community-based cohort study of Northern Manhattan residents, participation in physical activities such as walking for pleasure, going on an excursion, and physical conditioning, was associated with a 20% reduction in the risk of dementia (137). An association has also been found between increased physical activity and slower cognitive decline (128,138). Social and Leisure Activities Potential mechanisms: It is hypothesized that involvement in cognitively stimulating activities might delay the onset of dementia by increasing or maintaining brain reserve (139). In this hypothesis, the number of synapses between neurons increases due to increased cognitive stimulation. Therefore, an individual with higher cognitive reserve will cross the threshold at which dementia would be diagnosed at a later time than would an individual with lower cognitive reserve. It is possible, however, that decreased participation in leisure activities is a sign of early disease rather than a risk factor. If this is the case, subjects in early stages of dementia, even if not clinically apparent, would tend to participate less in these activities because of their incipient cognitive impairment. It is hard to distinguish between these two hypotheses especially when we consider the evidence that describes AD as a disease that may begin many years before symptoms are clinically apparent (140–142). Randomized trials would be the only way to obtain the information necessary to definitively distinguish between these two competing hypotheses. Evidence from observational studies: Cross-sectional studies have reported an association between participation in social or leisure activities and development of dementia or AD (127,143) but the most compelling evidence comes from prospective studies. In a population-based cohort in France (PAQUID Study) (144) after a follow-up of at least 3 years a significant decrease in risk (about 50%) was observed among subjects participating in activities like traveling, odd jobs, knitting, or gardening. A study in Shanghai (134) observed that after 5 and 10 years of follow-up a lack of participation in leisure activities such as gardening, touring, or group activities increased the risk for AD. In a community-based cohort study of Northern Manhattan residents (137), risk of dementia decreased (about 40%) in subjects with high participation in leisure activities. The leisure activities most strongly associated with a decreased risk were reading, visiting friends or relatives, going to movies or restaurants, walking for pleasure, or going for an excursion. In two separate studies conducted by the same group of researchers, the Religious Orders Study (135) and the CHAP (145), the risk of developing AD decreased with increased participation in common cognitive activities, such as watching television, reading newspapers, and playing games. More recently, in a prospective study of twins from the Swedish Twin Registry (146) who were followed for at least 30 years, participation in a greater overall number of activities was protective against AD. When stratified by gender, however, overall activity as well as participation in intellectual-cultural activities was protective for women but not men.

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1 Temporal Relationship 2 Biological Plausibility 3 Consistency or Replication of Findings 4 Absence of Confounding or Alternate Explanations 5 Dose-Response Relationship 6 Strength of the Association 7 Cessation of Exposure 8 Specificity of the Association

Figure 6 Criteria for judging whether an association is causal. Source: Adapted from Ref. 147.

CAUSALITY All of the evidence presented above is encouraging for a potential causal relationship between these protective factors and the development of AD. The real issue is: can these agents or interventions, if used, prevent the development of AD? In the long run, a causal relationship between these and AD will depend on the demonstration of several criteria (Fig. 6). While there is evidence for many of the criteria for causality in the prospective studies conducted to date, randomized clinical trials are critical to complete the story. This is particularly important when trying to ensure the absence of potential confounders, many of which are likely to be unknown. The evidence from prospective observational studies although strong, is not conclusive, alternative explanations are still possible. In randomized trials, however, randomization assures that on average, known and unknown confounding factors are equally distributed between intervention and non-intervention groups, so any effect seen on the intervention group is attributed to the intervention itself and not to other factors. Fortunately, several randomized prevention trials are currently underway, which will help establish these causal relationships. (For a discussion of causal criteria see Gordis, 2000 (147) or Rothman and Greenland, 1998 (148).

PRIMARY AND SECONDARY PREVENTION TRIALS In the model of AD as a chronic disease, interventions done in subjects with mild cognitive impairment (MCI) (149) can be considered a form of secondary prevention. Subjects with MCI have cognitive deficits that are not severe enough to meet the clinical criteria for AD. These subjects are at a higher risk of developing AD and are often at the initial pathological stages of the disease. Prevention trials done at this stage are important because of the benefits of potentially halting the disease process at a stage when people have mild symptoms and signs. It is also possible that if MCI precedes AD in the disease process, trials can be done at this stage that will require fewer subjects, would be done faster, and would be less costly than primary prevention trials (150). However, an intervention that works at this stage may not work at an earlier stage when the disease process is not as far along. Biological processes may change between the latent and prodromal stages. Thus, although important in their own right, secondary prevention trials would still not answer the question of primary prevention or vice versa. In the long run, primary prevention trials would be expected to have the most public health impact. As we discussed above, randomized trials of primary prevention are crucial to determine if the use of putative protective agents will, in fact, prevent AD. Starting long after the initiation of primary prevention trials for heart disease and cancer, the first prevention trials in AD began only in the past few years. These landmark studies are presently underway and others are being proposed.

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Hopefully the success of these studies will usher in a new era of prevention trials in AD. Many questions remain to be answered and ultimately primary trials are the only scientifically plausible way to demonstrate utility of putative protective factors in the prevention of AD and other dementias.

Primary Prevention Trials in AD Success of primary prevention trials in AD depends on building a successful infrastructure for the recruitment and follow-up of normally aging individuals. In general these studies require thousands of subjects who are followed for several years. These studies are labor intensive and costly, but the potential savings to society would be substantial should one of the studies prove effective in the delay in onset or prevention of AD. For information about active trials in your area check the ADEAR (AD Education and Research) Web site (http://www.alzheimers.org/trials/index.html). Estrogens In the United States, two clinical trials were initiated to examine estrogens for the prevention of AD: the Women’s Health Initiative Memory Study (WHIMS) and the Preventing Postmenopausal Memory Loss and Alzheimer’s with Replacement Estrogens study (PREPARE). WHIMS is a component of the NIH-funded Women’s Health Initiative. In this study, over 7000 women aged 65–79 were randomized to estrogen alone, estrogen plus progestin, or to placebo and followed for the development of dementia, memory loss, and other outcomes. In 2003 the study reported that women in the estrogen plus progestin group had twice the risk of developing dementia when compared to the placebo group. AD was the most common type of dementia diagnosed in that study. Early in 2004, the estrogen-only arm of the study was prematurely discontinued because of an increase in the risk of stroke as compared to the placebo group. Preliminary results suggested no difference in the two groups with respect to development of dementia. WHIMS thus provided data to suggest that estrogen in combination with progestin (or perhaps progestin alone) may increase the risk of AD. It did not, however, answer if estrogens alone are related to the risk. The PREPARE study was also designed to examine the utility of conjugated estrogens, with or without progestin, to delay AD and memory loss in women 65 years or older with a family history of AD in a first-degree relative. Due to the findings in WHIMS, the trial was prematurely halted, but it is following the enrolled participants without revealing the treatment assignment in order to determine if there is a benefit with remote exposure. Reconciling the results from observational studies and randomized trials of estrogen has been difficult. Numerous observational trials of estrogen have suggested a protective effect against AD. These studies investigated different populations, different types of estrogen preparations (conjugated estrogens, estrogen with and without progestin, estradiol, etc.), and involved different ages of exposure. It should be noted that most of the observational studies involved women on unopposed estrogens (i.e., no progestin). The results from a randomized trial of estrogen, however, suggested that, at least in combination with progestin, estrogen might actually increase the risk of dementia. It is possible that the positive association between estrogen and the development of AD applies only to unopposed estrogens or, alternatively that it was confounded in the observational studies. Self-selection of estrogen therapy by women and their physicians is not random and may identify individuals who are, in fact, protected in other ways. Alternatively, certain forms of estrogen at certain times may have value in the protection against AD and further research in the laboratory may yield additional clues to ways in which hormone replacement may be useful. At this time, however, estrogen cannot be recommended in the context of AD prevention.

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Nonsteroidal Anti-Inflammatory Drugs The National Institute on Aging funded the first primary prevention trial in AD to examine nonsteroidal anti-inflammatory drugs in 1999. The AD Anti-inflammatory Prevention Trial is being conducted at Johns Hopkins University, Sun Health Research Institute, Boston University, University of Rochester, and the University of Washington. This study is investigating the utility of naproxen as well as the selective COX2 inhibitor, celecoxib for the prevention of AD and cognitive decline in about 1000 subjects 70 years or older with a family history of dementia. This trial no longer gives mediation to subjects because of safety concerns, but subjects continue to be followed. More information about the study can be obtained by calling their toll free number 1-8662STOPAD (1-866-278-6723) or on their Web site (http://www.2stopad.org). Ginkgo Biloba In 1999, the National Center for Complementary and Alternative Medicine in collaboration with the National Institute on Aging requested applications to study the potential efficacy of G. biloba for the prevention of AD in subjects aged 75 or older. The funding for this study, which has been named GEM (Ginkgo Evaluation of Memory Study), was awarded to a consortium of sites in Pennsylvania, Maryland, North Carolina, and California. In 2002, this placebo-controlled trial completed recruitment of over 3000 subjects who were randomized to 240 mg/day of G. biloba or placebo. In addition to the development of dementia, participants are monitored for other outcomes, including mortality, functional disability, and hospitalizations. Potential modifiers such as APOE genotype, education, depression, cardiovascular, and cerebrovascular disease are also being considered. It is anticipated that completion of the study will be in 2009. More information can be found on the study’s Web site (http://nccam-ginkgo.org/aboutginkgo.aspx). Potential Future Trials As we continue the search for strategies to delay or prevent AD and other dementias, additional trials will undoubtedly be initiated. At present antioxidants (of various types), folic acid, and statins are among the more promising agents for further investigation in a primary prevention trial. Secondary Prevention Trials Antioxidants, cholinergic agents, and nonsteroidal anti-inflammatory drugs are among the agents currently under investigation for the secondary prevention of AD. These studies typically involve subjects with MCI. The Alzheimer’s Disease Cooperative Study (ADCS), an NIH-funded consortium of investigators, recently completed a randomized, double-blind, placebo-control trial that evaluated the safety and efficacy of vitamin E and donepezil, a cholinesterase inhibitor, to delay clinical progression of elderly subjects from MCI to AD. Results from the trial, which enrolled approximately 720 participants aged 55 to 90 across the United States and Canada, were published in the New England Journal of Medicine in 2005 (www.nejm.org 10.1056/NEJMoa050151). PUBLIC HEALTH IMPACT OF DELAYING THE ONSET OF AD Primary prevention trials are costly, complex, and require a long time before completion. The cost and labor involved, however, are justified given the impact that those interventions could have in reducing the overall burden of the disease. Several authors have considered the potential impact of interventions to prevent or delay the onset of AD (151,152). Since the incidence of AD doubles with every five years of age after 65 years, a delay in onset of 5 years would reduce the age-specific incidence of AD by half. In 1998 Brookmeyer and colleagues (152) quantified the reduction in the number of cases of AD and the monetary savings associated with various delays in the onset of AD

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0 .5 1

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Delay (years)

0 2037 2047 2017 2027 2007 Year 1997

Figure 7 Potential impact of interventions to delay onset of AD. Source: Adapted from Ref. 152.

(Fig. 7). The number of people suffering from AD was conservatively estimated at 8 million by the year 2047. An intervention that would delay the onset of AD by 5 years would result in a 50% reduction in age-adjusted risk. Such a delay would reduce the number of prevalent cases by 1.15 million and 4.04 million respectively after 10 and 50 years. Even a modest delay in onset of 6 months would decrease the number of affected people by 100,000 and 380,000 after 10 and 50 years respectively. This modest delay would translate to annual savings of $4.7 billion (10 years) and $18 billion (50 years). Delays of 2 to 3 years, consistent with the observational reduction of AD by estrogens and nonsteroidals, would have even a greater effect. If any of the ongoing studies described above have positive results, the goal of reducing the incidence and delaying the onset of AD by several years may be realistic and could have significant public health impact. SUMMARY At present, no approach has been proven to prevent or delay the development of dementia or AD. Observational studies, however, have identified numerous putative protective factors in recent years. These potentially modifiable factors include hormonal replacement therapies, antiinflammatory compounds, cholesterol-lowering agents, ginkgo biloba, antioxidants, such as Vitamins E and C, and folic acid. Non-pharmacologic approaches under investigation include physical exercise and involvement in cognitively demanding activities. Primary prevention trials are necessary to determine if any of these strategies have a role in the prevention of AD. WHIMS, the only trial completed to date, showed that hormonal replacement with estrogen and progestin appeared to increase the risk of dementia. Randomized trials of non-steroidal anti-inflammatory drugs and gingko biloba are currently in progress. Hopefully, additional trials will soon follow for other potentially promising agents, including antioxidants, folic acid and statins. Although it is costly to conduct primary prevention studies, the public health impact of even modest delays can be substantial. The exciting progress of the past few years will hopefully translate during the coming decade into proven prevention strategies. REFERENCES 1. Katzman R. The prevalence and malignancy of Alzheimer’s disease: a major killer. Arch Neurol 1976; 33:217–218. 2. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the U.S. population: prevalence estimates using the 2000 census. Arch Neurol 2003; 60:1119–1122.

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