Imaging of Neurodegenerative Disorders

Best Evidence Recommendations

2nd Edition

Sangam G. Kanekar, MD

Associate Professor of Radiology and Neurology Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Seung-Ho Shin, MD

Assistant Professor of Otology
and Neurotology
Department of Otolaryngology–Head and Neck Surgery Cha University
Seongnam, Republic of Korea

1874 illustrations

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Library of Congress Cataloging-in-Publication Data

Imaging of neurodegenerative disorders / [edited by] Sangam G. Kanekar.

p. ; cm.
Includes bibliographical references and index.

ISBN 978-1-60406-854-2 (hardcover : alk. paper) – ISBN 978-1- 60406-855-9 (ebook)

I. Kanekar, Sangam G., editor.
[DNLM: 1. Neurodegenerative Diseases–diagnosis. 2. Neuroimaging–

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I dedicate this book to
“MahaSaraswati”
and to my parents Gurudas and the late Meerabai Kanekar

Contents

Foreword 1……………………………………………………………………………….. xi Foreword 2……………………………………………………………………………….xiii Preface…………………………………………………………………………………… xv Acknowledgments ………………………………………………………………………. xvii

Contributors………………………………………………………………………………xix Part I. Introduction

Chapter 1:

Chapter 2: Chapter 3: Chapter 4: Chapter 5: Chapter 6: Chapter 7:

Chapter 8: Chapter 9:

Overview of Neurodegenerative Diseases ……………………………………………… 2 Sangam G. Kanekar and Maya L. Lichtenstein

Part II. Imaging Techniques

Structural Imaging of Dementia………………………………………………………. 14 Sangam G. Kanekar and Vijay Mittal

Magnetic Resonance Spectroscopy in Neurodegenerative Disorders …………………… 24 Tushar Chandra, Suyash Mohan, Sanjeev Chawla, and Harish Poptani

SPECT and PET Imaging of Neurotransmitters in Dementia……………………………. 34 Mateen Moghbel, Andrew Newberg, Mijail Serruya, and Abass Alavi

Diffusion Tensor Imaging in Neurodegenerative Disorders…………………………….. 42 Dhiraj Baruah, Suyash Mohan, and Sumei Wang

Functional Imaging of the Brain………………………………………………………. 51 Leslie Hartman and Aaron S. Field

Role of Noninvasive Angiogram and Perfusion in the Evaluation of Neurodegenerative Disorders ……………………………………………………………………………. 60 Sangam G. Kanekar and Puneet Devgun

Part III. Normal Aging

Imaging of the Normal Aging Brain…………………………………………………… 70 Ruth A. Wood, Ludovico Minati, and Dennis Chan

Iron Accumulation and Iron Imaging in the Human Brain……………………………… 80 Stefan Ropele and Christian Langkammer

Part IV. Alzheimer’s Disease
Chapter 10: Mild Cognitive Impairment………………………………………………………….. 90

Kei Yamada and Koji Sakai

vii

Contents

viii

Chapter 11: Overview of Alzheimer’s Disease ………………………………………………….. 113 Leonardo Cruz de Souza and Marie Sarazin

Chapter 12: Genetics, Neuropathology, and Biomarkers in Alzheimer’s Disease …………………. 119 Maria Martinez-Lage Alvarez and Rashmi Tondon

Chapter 13: Imaging of Alzheimer’s Disease: Part 1…………………………………………….. 124 Donald G. McLaren, Guofan Xu, and Vivek Prabhakaran

Chapter 14: Imaging of Alzheimer’s Disease: Part 2…………………………………………….. 133 Christian La, Wolfgang Gaggl, and Vivek Prabhakaran

Chapter 15: Magnetic Resonance Imaging and Histopathological Correlation in
Alzheimer’s Disease……………………………………………………………….. 139

Mark D. Meadowcroft and Qing X. Yang

Part V. Non-Alzheimer’s Cortical Dementia
Chapter 16: Dementia with Lewy Body Disease ………………………………………………… 150

Aristides A. Capizzano and Toshio Moritani

Chapter 17: Frontotemporal Lobar Degeneration ………………………………………………. 157 Aristides A. Capizzano and Toshio Moritani

Part VI. Dementia with Extrapyramidal Syndromes

Chapter 18: Parkinson’s Disease ……………………………………………………………….. 166 Jennifer G. Goldman, John W. Ebersole, Douglas Merkitch, and Glenn T. Stebbins

Chapter 19: Atypical Parkinsonian Syndromes………………………………………………….. 180 Nicola Pavese and David J. Brooks

Chapter 20: Secondary Parkinsonism ………………………………………………………….. 186 Thyagarajan Subramanian, Kala Venkiteswaran, and Elisabeth Lucassen

Part VII. Vascular Dementia

Chapter 21: Vascular Dementia………………………………………………………………… 194 A.M. Barrett and Vahid Behravan

Chapter 22: Neuroimaging of Vascular Dementias ……………………………………………… 199 Amit Agarwal and Sangam G. Kanekar

Chapter 23: Imaging of Specific Hereditary Microangiopathies …………………………………. 210 Kenneth Lury and Mauricio Castillo

Chapter 24: Vasculitis and Dementia…………………………………………………………… 216 Sampson K. Kyere, Olaguoke Akinwande, Dheeraj Gandhi, and Gaurav Jindal

Part VIII. Infection and Inflammatory Conditions Associated with Dementia
Chapter 25: Human Immunodeficiency Virus (HIV) Dementia…………………………………… 226

Toshio Moritani, Aristides Capizzano, and Sangam G. Kanekar

Chapter 26: Non-Human Immunodeficiency Virus (HIV) Infectious Dementia …………………… 232 Krishan K. Jain, Jitendra K. Saini, and Rakesh K. Gupta

Chapter 27: Prion Disease……………………………………………………………………… 239 Toshio Moritani, Aristides Capizzano, Girish Bathla, and Yoshimitsu Ohgiya

Chapter 28: Immune-Mediated Dementias …………………………………………………….. 245 Sangam G. Kanekar, Vinod Maller, and Amit Agarwal

Part IX. Normal Pressure Hydrocephalus

Chapter 29: Normal Pressure Hydrocephalus…………………………………………………… 256 Ritu Shah, Fathima Fijula Palot Manzil, and Surjith Vattoth

Part X. Tumor-Related Cognitive Dysfunction

Chapter 30: Brain Tumors and Cognitive Dysfunction…………………………………………… 266 Sangam G. Kanekar and Hazem Matta

Chapter 31: Paraneoplastic Syndrome …………………………………………………………. 276 Toshio Moritani, Aristides A. Capizzano, and Yoshimitsu Ohgiya

Part XI. Trauma

Chapter 32: Posttraumatic Cognitive Disorders ………………………………………………… 284 Inga Koerte, Alexander Lin, Marc Muehlmann, Boris-Stephan Rauchmann, Kyle Cooper,

Michael Mayinger, Robert A. Stern, and Martha E. Shenton

Part XII. Endocrine and Toxins-Related Dementia

Chapter 33: Endocrine-, Metabolic-, Toxin-, and Drug-Related Dementia ……………………….. 296 Sangam G. Kanekar and Brian S. Bentley

Part XIII. Inborn Errors of Metabolism

Chapter 34: Inborn Errors of Metabolism ………………………………………………………. 306 Sangam G. Kanekar and Dejan Samardzic

Part XIV. Cerebellar Degeneration and Dysfunction

Chapter 35: Normal Anatomy and Pathways of Cerebellum…………………………………….. 318 Sangam G. Kanekar and Jeffrey D. Poot

Contents

Chapter 36: Imaging of Cerebellar Degeneration and Cerebellar Ataxia…………………………. 328 Sangam G. Kanekar and Kyaw Tun

Part XV. Motor Neuron Disorders

Chapter 37: Overview of Motor Neuron Disorders ……………………………………………… 340 Divisha Raheja and Zachary Simmons

Chapter 38: Neuroimaging of Motor Neuron Disorders…………………………………………. 349 Divisha Raheja and Zachary Simmons

Part XVI. Clinical Approach and Treatment

Chapter 39: Reversible versus Nonreversible Dementia: Practical Approach …………………….. 362 Sol De Jesus and Sangam G. Kanekar

Chapter 40: Advances in the Treatment of Dementia…………………………………………… 371 Madhav Thambisetty, Néstor Gálvez-Jiménez, and Thyagarajan Subramanian

Chapter 41: Imaging of Deep Brain Stimulation………………………………………………… 378 Falgun H. Chokshi

Index …………………………………………………………………………………………. 386

Foreword 1

Modern advances in extending the human lifespan are, in part, accountable for the steady rise in neurodegenerative disease worldwide. While there are many tomes written on Alzheimer’s disease and related dementias, until this one I hadn’t encountered a book that broadly emphasizes the full range of neurodegenerative syndromes, including chronic head injury, vascular causes, viral syndromes (e.g., HIV encephalopathy), prion disease, paraneoplastic syndromes, and toxin and drug-related conditions. This thoughtful and comprehensive approach has produced a unique and highly useful body of work. Over the past several decades, the imaging tools at our disposal for evaluating neurodegener- ative disorders have dramatically evolved. A half-century ago, there was no effective way to visualize the brain through an intact skull. Now, the coordinated use of structural and functional modalities permits diagnostic and prognostic assessments and provides specific biomarkers poised to monitor the success of therapeutic strategies that as yet remain largely rudimentary.

Sangam G. Kanekar’s Imaging of Neurodegenerative Dis- orders clearly fills an important gap in the literature as it uniquely offers a broader lens through to consider neurode- generative conditions. The introductory chapter, written by Dr. Kanekar and Maya L. Lichtenstein, provides the context and rationale for the work and its organizational structure. Imaging technology has contributed to discriminating

among underlying etiologies for what was previously an array of poorly understood and overlapping signs and symp- toms that affected a person’s mood, memory and personality. The integration of genetic, epidemiologic and underlying neuropathologic information is critical as well. Part II addresses imaging techniques relevant to the disorders in the book, such as diffusion tensor imaging with MRI and amyloid PET imaging. The book is grounded in the funda- mental dictum that neuroimaging evaluation of the brain requires a thorough understanding of how the brain’s appearance and physiology change with normal aging.

Dr. Kanekar has done a stellar job of gathering a large multidisciplinary group of experts from 21 institutions around the globe to contribute to this book. Dr. Kanekar is Associate Professor of Radiology and Neurology at Penn State College of Medicine and a prolific writer and editor. The enormous value of this book should be appreciated by clin- icians, students, and neuroscientists alike.

Carolyn Cidis Meltzer, MD, FACR

William P. Timmie Professor and Chair of Radiology and Imaging Sciences Emory University School of Medicine Atlanta, Georgia

Foreword 2

I have to admit that when Sangam G. Kanekar asked me to write this Foreword for his book I felt some unease about doing it. Wouldn’t it be strange to have a person who co- authored a chapter in this book praise it here? But after reading the materials that form the rest of the book, all uneasiness disappeared and I am glad to be writing this short message of introduction. Imaging neurodegenerative disorders seems to be one of the most difficult clinical neuroradiological tasks yet one that has enormous impor- tance for patients and their families. We are beginning to move beyond the limited information offered by anatomical/ structural imaging and embracing newer techniques that shed light into the physiology of these disorders, provide guidance in achieving a correct diagnosis and may even help monitor the effects of therapies. Here 41 chapters authored by 82 experts worldwide explore, explain, try to make sense of, and teach us about these devastating conditions. This book is thus, a veritable “what’s what” by “who’s who.”

A few years ago, my mother who had had multiple mye- loma for many years (basically and fortunately asymptom-

atic) developed a rapidly progressive dementia characterized by bizarre behavior. For her physicians, family and friends the situation became a true “casse-tete.” No explanation for it was ever found. I re-tell this painful episode because many if not most of us will be confronted with a loved one facing and battling a neurodegenerative disorder. Their diagnosis is slippery, their treatment is generally non-existing, and the pain and cost they result in, are enormous.

Dr. Kanekar and all of the authors in this book are to be congratulated for producing an excellent and readable oeu- vre that I hope and expect will help neuroradiologists, neu- rologists, and many others who deal with these terrible diseases to understand them better.

Mauricio Castillo, MD, FACR

Professor of Radiology Chief, Division of Neuroradiology University of North Carolina Chapel Hill, North Carolina

xiii

Preface

The World Health Organization estimated in 2010 that there were 36.5 million people worldwide living with dementia, with global cost for care of 604 billion dollars per year. A new case of dementia is diagnosed approximately every 4 sec- onds. With the continuing increase of the elderly population and a corresponding increase in neurodegenerative disor- ders, it is important for all physicians to be familiar with the various types of dementia. The diagnosis of dementia historically involved clinical suspicion alone, with, when available, confirmation via postmortem neuropathological analysis. The advancement in neuroimaging has afforded significant insight into progressive neurodegenerative disorders and their mimics. Distinguishing between prevent- able, potentially reversible, and irreversible (progressive) etiologies has serious implications for future planning in regard to the patient’s medical, social, and economic spheres.

In recent years, numerous new developments have occurred in neuroimaging. Besides improvement in structural imaging with thinner sections, 3D volume, and higher-resolution imaging, molecular and cellular imaging

have made a big impact on how we look at the brain and its function. MR spectroscopy, DTI, perfusion imaging, fMRI, and PET scans have further increased our understanding of the pathological processes of the brain, neurodegenerative dis- eases in particular. However, in spite of the wealth of new concepts that have evolved from these resources, there have been no dedicated textbooks on the imaging of neurodegen- erative diseases until now. Imaging of Neurodegenerative Disorders covers the application of these fascinating techni- ques, along with basic structural imaging in the diagnosis of various neurodegerative disorders. This book has many con- tributors who have brought fresh insights and expertise that encompass more disease entities. We attempt, at least in part, to fill the gap of knowledge that exists in the imaging and understanding of neurodegenerative diseases.

The author expects you will find this book enjoyable and educational, and hopes it guides you toward a better under- standing of neurodegenerative diseases.

Sangam G. Kanekar, MD

Acknowledgments

Working on this book with so many outstanding contributors has been an enjoyable and immensely informative experience. I thank them, the staff at Thieme Publishers Inc., and my family for their overwhelming support.

xvii

Contributors

Amit K. Agarwal, MD

Assistant Professor of Radiology
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Olaguoke Akinwande, MD

Fellow
Department of Radiology Johns Hopkins University Baltimore, Maryland

Abass Alavi, MD, PhD(Hon), DSc(Hon)

Professor of Radiology and Neurology
Director of Research Education
Department of Radiology
University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Girish Bathla, FRCR, DMRD, MMeD

Department of Radiology
University of Iowa Hospitals and Clinics Iowa City, Iowa

A. M. Barrett, MD

Director, Stroke Rehabilitation Research Kessler Foundation
Chief, Neurorehabilitation Program Innovation Kessler Institute of Rehabilitation
Professor, Physical Medicine and Rehabilitation Rutgers-New Jersey Medical School
West Orange, New Jersey

Dhiraj Baruah, MD, PDCC

Assistant Professor of Radiology Medical College of Wisconsin Milwaukee, Wisconsin

Vahid Behravan, MD

Private practice Kensington, Maryland

Brian S. Bentley, DO

Chief Resident
Department of Radiology
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

David J. Brooks, MD, DSc, FRCP FMedSci

Hartnett Professor of Neurology Department of Medicine Imperial College London London, United Kingdom

Aristides A. Capizzano, MD

Assistant Professor of Radiology University of Iowa Hospitals and Clinics Iowa City, Iowa

Mauricio Castillo, MD, FACR

Professor of Radiology
Chief, Division of Neuroradiology University of North Carolina Chapel Hill, North Carolina

Dennis Chan, MD, PhD, FRCP

University Lecturer and Honorary Consultant in Clinical Neurosciences

University of Cambridge Cambridge, United Kingdom

Tushar Chandra, MD

Pediatric Neuroradiologist Department of medical Imaging Nemours Children’s Hospital Orlando, Florida

Sanjeev Chawla, PhD

Senior Research Investigator
Department of Radiology
University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Falgun H. Chokshi, MD, MS, DABR

Department of Radiology and Imaging Sciences Emory University School of Medicine
Atlanta, Georgia

Jeffrey Kyle Cooper, BA

Harvard Medical School Boston, Massachusetts

Sol De Jesus, MD

Adjunct Clinical Post-Doctoral Associate
Center for Movement Disorders and Neurorestoration University of Florida
Gainesville, Florida

xix

Contributors

Leonardo Cruz de Souza, MD, PhD

Neurologist, Faculty of Medicine Federal University of Minas Gerais Belo Horizonte, Brazil

Puneet S. Devgun, DO

Department of Radiology
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

John W. Ebersole, MD

Resident
Department of Radiology
Rush University Medical Center Chicago, Illinois

Aaron S. Field, MD, PhD

Professor of Radiology and Biomedical Engineering Chief of Neuroradiology
School of Medicine and Public Health
University of Wisconsin

Madison, Wisconsin

Wolfgang Gaggl, PhD

Department of Radiology
School of Medicine and Public Health University of Wisconsin
Madison, Wisconsin

Néstor Gálvez-Jiménez, MD, MSc, MS(HSA), FACP

Professor of Medicine (Neurology-Florida) Cleveland Clinic Lerner College of Medicine

Chairman, Department of Neurology Director, Neurosciences Center Chief, Movement Disorders Program Cleveland Clinic

Weston, Florida

Clinical Professor and Associate Chair of Neurology Herbert Wertheim College of Medicine
Florida International University
Miami, Florida

Dheeraj Gandhi, MD

Director, Division of Interventional Neuroradiology Professor of Radiology, Neurology, and Neurosurgery University of Maryland School of Medicine Baltimore, Maryland

Jennifer G. Goldman, MD, MS

Associate Professor
Department of Neurological Sciences Rush University Medical Center Chicago, Illinois

Rakesh K. Gupta, MD

Director and Head, Department of Radiology and Imaging Fortis Memorial Research Institute
Gurgaon, Haryana, India

Leslie Hartman, MD

Department of Radiology
School of Medicine and Public Health University of Wisconsin
Madison, Wisconsin
Staff Radiologist
Regional Diagnostic Radiology
St. Cloud, Minnesota

Krishan K. Jain, MD, PDCC(Neuroradiology)

Consultant
Department of Radiology and Imaging Fortis Memorial Research Institute Gurgaon, Haryana, India

Gaurav Jindal, MD

Assistant Professor of Radiology
Division of Interventional Neuroradiology University of Maryland Medical Center Baltimore, Maryland

Sangam G. Kanekar, MD

Associate Professor of Radiology and Neurology Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Inga Katharina Koerte, MD

Professor of Neurobiological Research Department of Child and Adolescent Psychiatry,

Psychosomatic, and Psychotherapy Ludwig-Maximilian-University Munich, Germany

and

Psychiatry Neuroimaging Laboratory Department of Psychiatry
Brigham and Women’s Hospital Harvard Medical School

Boston, Massachusetts

Sampson K. Kyere, MD, PhD

Resident
Department of Radiology
University of Maryland Medical Center Baltimore, Maryland

Christian La, BA

Department of Radiology
School of Medicine and Public Health University of Wisconsin
Madison, Wisconsin

Christian Langkammer, PhD

Department of Neurology Medical University of Graz Graz, Austria

Maya Lichtenstein, MD

Clinical Fellow in Behavioral Neurology
Clinic for Alzheimer’s Disease and Related Disorders University of British Columbia
Vancouver, British Columbia, Canada

Alexander P. Lin, PhD

Director, Center for Clinical Spectroscopy Brigham and Women’s Hospital Assistant Professor of Radiology
Harvard Medical School

Boston, Massachusetts

Elisabeth B. Lucassen, MD

Assistant Professor of Neurology
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Kenneth M. Lury, MD

Assistant Professor of Radiology – Retired Division of Neuroradiology
University of North Carolina School of Medicine Chapel Hill, North Carolina

Vinod G. Maller, MD

Fellow in Interventional Radiology
University of Tennessee Health Science Center Memphis, Tennessee

Maria Martinez-Lage Alvarez, MD

Assistant Professor of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Hazem M. Matta, DO

Department of Radiology
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Michael Mayinger

Department of Child and Adolescent Psychiatry, Psychosomatic, and Psychotherapy

Ludwig-Maximilian-University Munich, Germany

Donald G. McLaren, PhD

Clinical Imaging Scientist Biospective, Inc. Montreal, Canada

Mark D. Meadowcroft, PhD

Assistant Professor of Neurosurgery and Radiology Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Douglas V. Merkitch, BA

Research Assistant
Department of Neurological Sciences Rush University Medical Center Chicago, Illinois

Ludovico Minati, PhD

Researcher
Fondazione IRCCS Istituto Neurologico Carlo Besta Milan, Italy

Vijay K. Mittal, MD

Department of Radiology
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Mateen C. Moghbel, BS

Stanford University School of Medicine Stanford, California

Suyash Mohan, MD, PDCC

Assistant Professor of Radiology
Division of Neuroradiology
Perelman School of Medicine at University of Pennsylvania Philadelphia, Pennsylvania

Toshio Moritani, MD, PhD

Department of Radiology
University of Iowa Hospitals and Clinics Iowa City, Iowa

Contributors

xxi

xxii

Contributors

Marc Mühlmann, MD

Institute for Clincal Radiology Ludwig-Maximilian-University Munich, Germany

Andrew Newberg, MD

Department of Radiology and Emergency Medicine Thomas Jefferson University
Philadelphia, Pennsylvania

Yoshimitsu Ohgiya, MD

Associate Professor of Radiology Showa University School of Medicine Tokyo, Japan

Fathima Fijula Palot Manzil, MBBS, DMRT, ABNM certified Nuclear Medicine/Clinical Imaging
Hamad Medical Corporation
Doha, Qatar

Nicola Pavese, MD, PhD

Clinical Senior Lecturer and Consultant in Neurology Neurology Imaging Unit (NIU)
Imperial College London
Division of Brain Sciences

Hammersmith Campus London, United Kingdom

Jeffrey D. Poot, DO

Diagnostic Radiology Resident Department of Radiology
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Harish Poptani, PhD

Research Associate Professor
Department of Radiology and Radiation Oncology University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Vivek Prabhakaran, MD, PhD

Assistant Professor of Radiology and Neurology School of Medicine and Public Health University of Wisconsin
Madison, Wisconsin

Divisha Raheja, MD

Assistant Professor of Neurology
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Boris-Stephan Rauchmann

Institute for Clinical Radiology Ludwig-Maximilian-University Munich, Germany

Stefan Ropele, PhD

Associate Professor of Medical Physics Department of Neurology
Medical University of Graz
Graz, Austria

Jitender Saini, MD, MBBS

Associate Professor
Department of Neuroimaging and Interventional Radiology National Institute of Mental Health and Neurosciences Bangalore, India

Koji Sakai, PhD

Associate Professor
Advanced MR Imaging Research Laboratory Department of Radiology
Graduate School of Medical Science
Kyoto Prefectural University of Medicine Kyoto, Japan

Dejan Samardzic, MD

Department of Radiology
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Marie Sarazin, MD, PhD

Professor of Neurology
Unité de Neurologie de la Mémoire et du langage Centre Hospitalier Sainte Anne
Université Paris Descartes, Sorbonne Paris Cité Paris, France

Mijail Serruya, MD, PhD

Assistant Professor of Neurology Kimmel Medical College Thomas Jefferson University Philadelphia, Pennsylvania

Ritu Shah, MD

Radiology Associates of Florida Tampa, Florida

Martha E. Shenton, PhD

Professor, Departments of Psychiatry and Radiology Director, Psychiatry Neuroimaging Laboratory Brigham and Women’s Hospital
Harvard Medical School

VA Healthcare System Boston, Massachusetts

Zachary Simmons, MD

Professor of Neurology and Humanities
Director, Neuromuscular Program and ALS Center Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Glenn T. Stebbins, PhD

Professor
Department of Neurological Sciences Rush University Medical Center Chicago, Illinois

Robert A. Stern, PhD

Professor of Neurology, Neurosurgery, and Anatomy and Neurobiology

Clinical Core Director, BU Alzheimer’s Disease Center Clinical Research Director, BU CTE Center
Boston University School of Medicine
Boston, Massachusetts

Thyagarajan Subramanian, MD

Professor of Neurology and Neural and Behavioral Sciences Director, Central PA APDA Informational Center

and Movement Disorders Program Penn State University College of Medicine Hershey, Pennsylvania

Rashmi Tondon, MD

Surgical Pathology Fellow
Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Madhav Thambisetty, MD, PhD

Clinical Investigator and Chief
Unit of Clinical and Translational Neuroscience Laboratory of Behavioral Neuroscience National Institute on Aging
National Institutes of Health
Baltimore, Maryland

Kyaw Nyan Tun, DO

Neuroradiology Fellow
Department of Radiology
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Surjith Vattoth, MD, DNB, FRCR, DABR

Senior Consultant Neuroradiologist Hamad Medical Corporation
Doha, Qatar

Kala Venkiteswaran, PhD

Assistant Professor
Departments of Neurology and Neural and

Behavioral Sciences
Milton S. Hershey Medical Center
Penn State University College of Medicine Hershey, Pennsylvania

Sumei Wang, MD

Department of Radiology
University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania

Ruth A. Wood, BM BCh, MRCP(UK)

MRC Clinical Research Training Fellow Sainsbury Wellcome Centre for Neural Circuits

and Behaviour University College London London, United Kingdom

Guofan Xu, MD

Department of Radiology
University of Wisconsin Hospital and Clinics Madison, Wisconsin

Kei Yamada, MD, PhD

Professor and Chairman
Department of Radiology
Kyoto Prefectural University of Medicine Kyoto, Japan

Qing X. Yang, PhD

Professor of Radiology, Biogengineering, Engineering Sciences, and Neurosurgery

Center for NMR Research
Department of Radiology
Penn State University College of Medicine Hershey, Pennsylvania

Contributors

xxiii

Part I Introduction

1 Overview of Neurodegene Diseases

rative

Introduction

1 Overview of Neurodegenerative Diseases

Sangam G. Kanekar and Maya L. Lichtenstein

1.1 History

Neurodegenerative diseases comprise a broad swath of differ- ent neurologic diseases, all of which have one thing in com- mon: the pathology is ultimately the loss of neurons in the central nervous system. Onset can be acute but is more often chronic, and the symptoms tend to get progressively worse over time. The diseases are difficult to talk about broadly because they manifest with such a myriad of signs and symptoms. The most common neurodegenerative disease is the dementing dis- ease of Alzheimer’s. There are many other dementing diseases as well that affect different parts of the brain, causing different symptoms. Dementia is commonly understood as the loss of function of at least two cognitive domains that is severe enough to cause loss of daily function in social or occupational spheres.1 Some neurodegenerative diseases are primarily motor disor- ders, such as Parkinson’s disease and amyotrophic lateral scle- rosis (ALS). The underlying cause of the neuronal loss that ties these diseases together is different in each case. Some diseases are caused primarily by proteins, for example through abnor- mal accumulation or misfolding. These protein accumulations disrupt the normal function of the cells and ultimately lead to cell death. Examples of these “proteinopathies” include tau, amyloid, TDP-43, and α-synuclein. Some overlap is seen between diseases and pathologies, but overall pathology is usu- ally distinctive enough for a definitive diagnosis. Other neuro- degenerative diseases are caused by inflammation or infection, toxins, or vitamin deficiencies. Some diseases are primarily genetic, caused by deletions or trinucleotide repetitions. This is where we are now in understanding these diseases.

The latter part of the 20th century up to the present has pro- vided an enormous amount of understanding of these various diseases, but much work remains to be done toward a better understanding to be able ultimately to treat the people who have these diseases more effectively. One of the biggest advances in understanding these diseases has been the role of neuroimaging. Although there was an American Society of Neu- roradiology made up of 14 neuroradiologists in 1962, before the 1970s, this field was not widely recognized.2 Skull films had been done since the advent of the roentgenogram in the early 20th century, but they could really only be used to detect skull fractures or calcifications in the head. In the early 20th century, the pneumoencephalogram was developed by Walter Dandy, but it was uncomfortable and dangerous for the patient. In the mid-20th century, angiography was developed and used by radiologists and neurosurgeons to look at the blood vessels in the brain by using contrast material injected into the arteries. Angiography has become safer in the last few decades but ini- tially carried substantial risks. These methods were invasive and did not provide a good image of the brain itself. Angiogra- phy, for example, was used not only to look at blood vessels in the brain but also to detect masses by visualizing the vessels to determine whether any had shifted from their usual locations. In 1971, the first computed tomography (CT) scan was intro- duced by Godfrey Hounsfield in a South London hospital for a woman in whom a frontal brain tumor was suspected

(▶Fig. 1.1). Since that time, the technology continues to improve, with the CT scan being used as the underlying modal- ity for positron emission tomography (PET), single-photon emission computed tomography (SPECT), and noninvasive angi- ography. However, because of the same underlying technology, there are limitations to what can be seen in the brain using a CT scan. Magnetic resonance imaging (MRI) was developed in the 1980s and has emerged as the gold standard for looking at brain structures, having increased sensitivity for brain struc- tures compared to the CT scan. Structures as small as 1 mm can be detected on MRI, and quantitative measurements can be made reliably. In addition to structural imaging, MRI can be used for functional imaging. Innovations in the field of neuro- imaging have provided ways to see neurodegenerative diseases in vivo in a way that is not possible at autopsy. Imaging also has provided a new lens for understanding and monitoring the pro- gression of these diseases, not just clinically, as in the past.

We have come a long way since the ancient Egyptians, who believed that dementia was the end result of aging, and since the Middle Ages, when health fell into the realm of the church

Fig. 1.1 Reproduction of first clinical head computed tomography scan in South London, 1971; suspected frontal brain tumor, later confirmed at biopsy, in woman. (Brain scan from Atkinson Morley Hospital, as appears in Beckmann EC. CT scanning: the early days. Br J Radiol 2006;79(937):5-8.)

and senility was considered a “fading away from spirituality.”3 The term senility, which is defined by Merriam-Webster as “the physical and mental infirmity of old age,” continues to be used casually as a synonym for dementia, although dementia is a pathology and not necessarily part of normal aging. Until rela- tively recently, in fact, Alzheimer’s was termed presenile demen- tia to set it apart from the regular dementia that any old person was expected to develop along with aging. Until the late 19th century, it was primarily through careful clinical description that individual diseases were able to be split out from the “black box” of any era’s belief about what caused any pro- gressive debilitation. James Parkinson wrote his essay on the “shaking palsy” in 1817, and some of his descriptions were observations of people walking around his neighborhood. Earlier descriptions in the literature of “rest tremor” and “festi- nation” can be found,4 but it was through Parkinson’s more detailed accounts that later investigators, importantly Jean- Martin Charcot, launched their research. Charcot was much more descriptive, naming rigidity as being a cardinal feature of the disease. He made differentiation between the features of resting versus action tremor and other features, such as pos- ture, gait, lack of actual weakness, and rigidity, which we see with what we now call Parkinson’s disease.5 Once that arche- type of the disease was confidently described, Charcot’s team could find variants of that archetype, including descriptions of what today would be called Parkinson-plus syndromes. Without any ancillary tests, these kinds of clinical observations were how diseases were described and defined. There was some gross central nervous system pathology, but no stains for neu- rons until the late 19th century, when Camillo Golgi discovered a silver stain for neurons.6 This was used by him and Santiago Ramon y Cajal for the first time to see and describe neurons, axons, dendrites, and other parts of the central nervous system, thus opening the field of neuropathology.

To give an example of the field around the turn of the 20th century, in 1894, Otto Binswanger described a case of progres- sive dementia with stroke symptoms, which he called encepha- litis subcorticalis chronica progressiva.7 His study of that patient’s brain was thereby the first to state that white matter atrophy caused by vascular insufficiency can result in dementia.

The disease was described without use of histopathology, using only gross pathology. The disease was later called Binswanger’s disease by Alzheimer, a term that is sometimes still used to refer to someone with severe vascular dementia (▶Fig. 1.2). Alois Alzheimer described a patient he saw in 1901 with short-term memory loss and behavioral disorders and was able to examine her brain after her death in 1906. He was able to identify amy- loid plaques with Nissl stain, and possibly Mann stain, and pre- sented his findings at a conference. This was one of the first clinicopathologic neurologic cases, and Emil Kraepelin named the disease after Alzheimer.8 Around the same time, Arnold Pick also described the disease later named after him on both clini- cal and pathological grounds: a patient with speech and behav- ioral problems, progressing to dementia, who had argyrophilic spherical inclusions (Pick bodies) and globose neurons on pathology.9 During this period, most dementia was considered to be due to syphilis, although there had not yet been any path- ological proof of this (this proof came in 1913 with Hideyo Noguchi’s contribution), and later Binswanger’s disease. Alz- heimer’s and Pick’s disease were considered interesting outliers of dementing illnesses. In the last 30 years, as Alzheimer’s has become recognized as the most prevalent and most studied cause of dementia, and many patients with other dementing ill- nesses are often generically labeled as having Alzheimer’s dis- ease.10 The term became the late 20th century’s version of neu- rosyphilis as a catch-all diagnosis.

The study of neurodegenerative diseases in the early 20th century did not differ much from that of the hundred years preceding it. There was no good way to differentiate some diseases in vivo and no treatment or cure for them. Dementias were classified in the back of psychiatric manuals as organic brain diseases, and no special attention was given to them. Demented people, regardless of the underlying cause or dis- ease, were often treated much the same as psychotic patients and were placed in institutions. The latter 20th century showed witnessed the advent of more refined diagnostic tools in the form of neuroimaging and neuropsychology, as well as discov- eries in molecular and cellular pathways and genetics. For example, there was the discovery of dopamine pathways and the development of levodopa in the 1960s to treat patients with

Overview of Neurodegenerative Diseases

Fig.1.2 Binswanger’sdisease.(a)Axialcomputed tomography scan shows diffuse hypodensity in the cerebral white matter (white arrows).
(b) Axial fluid-attenuated inversion recovery (FLAIR) image shows generalized prominence of convexity sulci. Diffuse hyperintensity is seen

in the cerebral white matter (white arrows), indicating small vessel disease.

Introduction

Fig. 1.3 Progressive supranuclear palsy. Sagittal T1-weighted image shows moderate atrophy of the midbrain, often called “bird’s-beak” appearance (white arrow).

Fig. 1.4 Huntington disease. Axial T2-weighted image shows atrophy of the caudate nuclei bilaterally (arrows) with dilatation of the frontal horns of the lateral ventricles.

Parkinson’s disease.11 Oliver Sacks wrote the book Awakenings about treating the institutionalized patients with levadopa and how they came to life with the medication. The drug also helped to differentiate idiopathic Parkinson’s disease from other, less typical presentations. Since the 19th century, there were descriptions from Charcot about atypical Parkinson-type patients, but only in 1964 was there a distinct clinical and path- ological entity of what is now called progressive supranuclear palsy, described by Steele-Richardson-Olszewski, differentiating this syndrome from Parkinson’s disease (▶Fig. 1.3).12 This description was not immediately accepted by all of the neuro- logic community, and the disease was considered by some to be more of a “subspecies” of Parkinson’s disease, not its own dis- ease species. The atypically presenting progressive supranu- clear palsy patients were grouped together with typical Parkin- son’s disease patients for the initial drug trials of levodopa. The drug had different effects on the two populations: it worked well for the symptoms of the idiopathic Parkinson’s diseases patients, and it worked poorly or not at all for the progressive supranuclear palsy patients.13 The logic of this finding ulti- mately allowed for wider acceptance of progressive supranu- clear palsy as a separate disease from Parkinson’s. This method of drug trial and error is still used in patients to differentiate types of underlying disease pathology that clinically may look similar.

Although Huntington’s disease had been described clinically and pathologically in 1872, and was known to be inherited in an autosomal dominant fashion, it was only in 1983 that the Huntington gene was mapped to human chromosome 4p; it was the first autosomal dominant disease to be mapped. It was

a full 10 years later that the pathogenic mutation was identified as a CAG-repeat expansion (▶Fig. 1.4).14 This mapping and identification allowed for a whole new way of studying and understanding the disease and held promise as a way for defini- tively diagnosing other diseases. Genetic testing for some dis- eases still provides some of the only other definitive diagnoses besides pathology. For example, genetics has allowed precise delineations of the myriad groups of disorders called the spino- cerebellar ataxias. Because they are caused by different genes, they can be classified as different entities, and can be studied and their courses and prognoses further elucidated with some confidence. This has helped enormously in allowing clinicians’ observations to have more definitive validation or a way to be “checked” against an objective test during the patient’s life.

Because of the advent of these diverse modalities (i.e., imag- ing, blood and fluid assays, genetics, pharmacology, immunol- ogy) and the overwhelming amount of research in these fields over the course of the 20th, and now the 21st, century, there have also been more consensus committees, standardizing test results, diagnostic criteria, and the definition of disease, so that researchers and clinicians can speak in the same language about these diseases. These tasks remains difficult because the neuro- degenerative diseases are often quite heterogeneous. Although adjuvant testing has helped to make up diagnostic criteria, many of these modalities are still in the research phase only, and the diagnoses for these diseases remain largely clinical- pathological. The role of neuroimaging in helping to differentiate and define diseases in vivo is evidenced by the fact that imaging correlates are used for diagnostic criteria of many neurodegenerative diseases.

Overview of Neurodegenerative Diseases

The aim of this book is to cover each disease as it is cur- rently understood and to show what it might look like using various techniques of neuroimaging. It is of enormous impor- tance that we start to look for not just what is there in imag- ing, but what is missing, as well to be able to see and quantify patterns of atrophy, where and why there is signal change, increased or decreased uptake, which tests are most helpful, which tests are available in research or clinically, and what tests can help differentiate between diseases. Clinically, neuroimaging is crucial for ruling out tumor, stroke, bleeding, normal-pressure hydrocephalus, or other potentially treatable or reversible causes of dementia. In the past it was thought that primary causes of dementia and other neurodegenerative diseases were progressive and relentless, and besides being used as a modality for “ruling out” other diseases, neuro- imaging did not have a role in these diseases. Increasingly, however, the role of imaging has expanded and is more acknowledged. In the clinical realm, as well as for research and knowledge for its own sake, imaging helps enormously in affirming suspicion, differentiating entities that have clinical overlap, and charting progression of neurodegenerative dis- eases. It is hoped that someday these modalities can be used to chart the effects of treatments as well. This book can be used by radiologists, neuroradiologists, neurologists, other internal medicine doctors as well as by anyone seeking to understand these diseases through the lens of the image, which is increasingly becoming more sophisticated.

1.2 Epidemiology

Recognition and diagnosis of neurodegenerative diseases are crucial because for these diseases the greatest risk factor is age, and we have an increasingly older population. As people are surviving infections, heart attacks, cancer, accidents, and other hazards of being alive, they are living longer. Along with living longer, there is an increased risk of developing a neuro- degenerative disease. This is especially true for in many low- to middle-income nations, with a major expected rise in the prev- alence of dementing illnesses in their populations in the coming years as their populations grow and more people live longer (▶Fig. 1.5).15 The difficulty in assessing the prevalence of dementia is twofold, as identified in a 2013 meta-analysis: dementia is difficult to diagnose: it often requires multi-domain specialties; batteries of tests; and, to be definite, genetic testing or autopsy, any or all of which are not always performed. Another problem has been in the study designs themselves and in misapplication of study designs involving two or more phases, which leads to underestimation of prevalence and over- precision.15 Another issue is that not all neurodegenerative dis- eases are classified primarily as dementias, and so diseases like ALS, Parkinson’s disease, and secondary causes of neuro- degenerative disease, such as alcohol or vasculitis, are often not included in those studies because they are grouped differently.

Alzheimer’s disease is the most prevalent neurodegenerative disease and accounts for 60 to 80% of all dementias. It is esti- mated that in 2010 there were 36.5 million people worldwide living with dementia. A case of dementia is diagnosed every 4 seconds.16 The World Health Organization estimated that the annual global cost for dementia in 2010 was 604 billion

dollars.15 Medical complications from neurodegenerative dis- eases are common, and these patients are hospitalized more often and for longer periods than other people in their age groups. These diseases impose an enormous burden on the economy as well as on social and family structures. As the dis- eases progress, families and caregivers must often give up their jobs to take care of the patients, and the patients often need an increased level of care in nursing homes and other assisted- living facilities.15 These costs are expected to continue to grow along with the aging population; the number of people living with dementia is predicted to double every 20 years to 65.7 million in 2030.15 Although there are variable rates of disease based on epidemiologic studies, there is not a race, country, gender, or socioeconomic class that is not at risk for developing neurodegenerative diseases.

The most common neurodegenerative disease in any age group is Alzheimer’s disease, but the proportions are different when the age for the patient is younger than 65. In one British population study, younger patients with Alzheimer’s disease accounted for only 34% of young-onset dementia. In patients younger than 65, other causes (such as those from metabolic, toxic, or systemic illnesses) are more common; but even among young-onset dementias, it seems that Alzheimer’s, fol- lowed by vascular dementia, FTD, and dementia with Lewy bodies, is the most prevalent, as is true for patients older than 65, although Lewy body dementia is the second most common cause of dementia in patients older than 65. Although there is a paucity of epidemiology relating to young-onset dementias, a British study showed an overall prevalence of 54 per 100,000 in patients age 30 to 65, and a Japanese study showed a similar overall prevalence of 43 per 100,000 in people age 18 to 65. Still, the overwhelming burden of disease is carried by the older population, with an estimated prevalence of 1 to 2%atage65,10to15%byage80,andashighas40%in 90-year-olds.1

Fig. 1.5 The growth in numbers of people with dementia in high- income (HIC) and low- and middle-income countries (LMIC). (Used with permission from Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, and Ferri CP. The global prevalence of dementia. Alzheimer Dementia 2013;9:70.)

Introduction

1.3 Clinical Approach

Neurodegenerative diseases are defined by loss of neurons, which can occur anywhere in the central nervous system: corti- cal and subcortical areas, brainstem, cerebellum, and spinal cord. It is the “where” of the neuronal loss that gives us the clin- ical presentation: both what the patient and the family notice and what we see from history and examination. The “where” can also be seen on imaging, either by injury to the area or atro- phy of the area, with concurrent loss of function.

The approach to the patient with a neurodegenerative dis- ease involves first and foremost the suspicion that this may be the cause of the patient’s complaints. The chief complaints are quite variable, and the presentations are as well: although vary- ingly acute, subacute, or chronic, they tend to be progressive, but some relapse and remit, and some seem to plateau. Because we deal with loss of neurons in the central nervous system, we expect the complaints to pertain chiefly to one or more cogni- tive functions or a motor function; included in these overbroad categories are dysfunctions that we know as clinicians to be caused by damage to a particular part of the brain, but patients do not necessarily know that memory and concentration are

two different things anatomically, or that being unsteady is not always at all a sign of being weak (▶ Table 1.1). Often there are many complaints, and they accrue over the years. Often there are disturbances that were overlooked or ignored or not consid- ered relevant by the patient or the family when the symptoms first appeared; so a careful history must be obtained, as well as a full medical and family history, and a social history that includes exposures and prior level of function. While examining the patient, the clinician will tend to concentrate on the area of chief complaint, but a full general, neurologic, and psychiatric examination also must be obtained. It is helpful for the clinician to know that many diseases may manifest with a nonspecific memory complaint or cognitive slowing. It is important to look for other neurologic signs that may help to narrow the differen- tial diagnosis. For example, a dementia with ataxia may lead the clinician to think of spinocerebellar ataxia, paraneoplastic diseases, alcoholic dementia, multiple sclerosis, prion disease, and others (▶ Fig. 1.6).17 Such an approach will help guide fur- ther testing.

In general, if the patient is older than 65 and the clinical suspicion is a primary neurodegenerative disease, such as Alzheimer’s disease, the diagnosis is clinical; but some basic

Table 1.1 Cognitive and motor complaints, with examples and differential diagnosis

Complaints Examples of symptoms Examples of possible syndromes

Cognitive

Behavior/personality

Inappropriate behavior, decline in social behavior, emotional blunting, decline in grooming, mental rigidity, hallucinations

FTD, DLB, CBS, HD, PDD, CJD, vitamin deficiency, toxins, VaD, AD

Executive skills

Problems with cooking, multi-tasking, using computer, keep- ing up with bills and finances, judgment

FTD, later-stage AD, PDD, ALS

Visual-spatial

Trouble recognizing faces, getting lost, seeing things properly, judging distances

PCA, AD

Memory

Repeating questions, forgetting appointments, no recall of events or shows/movies

AD, PD, DLB, PDD, VaD, vitamin deficiencies

Attention

Does not attend to things said, walks into rooms but doesn’t remember why/what was wanted, easily distractible

TBI, PDD, DLB, CJD, NPH

Speech/language

Speech apraxia, phoneme &/or syntax errors, poor naming, impaired comprehension, hesitant speech, severe word- finding difficulties

PPA [PNFA, SD, LPA], CBS, PSP

Praxis

Have trouble doing things on command, have trouble completing multi-step tasks in the right order, have trouble using tools, using the hands or legs properly

CBS, AD, PD, HD, PCA

Motor

Examples of symptoms

Coordination trouble with any or all of following: speech, arms, legs, gait, trunk, eye movements

Examples of possible syndromes

Flinging limb movements, tremor, jerking of limb or body (myoclonus), abnormal posturing

Masked face, decreased arm swing, less spontaneous move- ment; slow moving or talking, smaller steps.

Trouble going up or down stairs, trouble getting up from chairs, falling backward, difficulty lifting arms and holding onto objects

Dysphagia for solids or liquids, tongue weakness, decreased gag or cough reflex, changed (hoarse or quiet) voice, inappropriate emotionality

Abbreviations: AD, Alzheimer’s dementia; ALS, amyotrophic lateral sclerosis; CBD, corticobasal degeneration; CBS cortical basal syndrome, CJD, Creutzfelt-Jakob disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; HD, Huntington’s disease; LPA, logopenic aphasia; MSA, multisystem atrophy; NPH, normal pressure hydrocephalus; PCA, posterior cortical atrophy; PD, Parkinson’s disease; PDD, Parkinson’s disease with dementia; PNFA, progressive nonfluent aphasia; PSP, progressive supranuclear palsy; SCA, spinocerebellar ataxia; SD, semantic dementia; VaD, vascular disease.

Unsteadiness/ataxia Abnormal movements
Less movement/hypokinesis Weakness/falls

Bulbar problems

Vitamin deficiencies, heavy metals, toxins, SCA, HD, NPH, PD, PSP, DLB, VaD, MSA

HD, CBS, PD, CJD, SCA, heavy metal, vitamin deficiency, toxins

PD, PDD, DLB, PSP, CBS, VaD, heavy metals

VaD, PSP, PD, NPH, ALS, SCA, HD, MSA, vitamin deficiencies, toxins

VaD, ALS, MSA

Overview of Neurodegenerative Diseases

Fig. 1.6 Spinocerebellar atrophy. Axial T2-weighted image shows prominence of cerebellar folia suggestive of cerebellar atrophy. Pons is normal in morphology and signal intensity.

laboratory studies must be obtained, including complete blood cell count, complete metabolic panel, vitamin B12, and thyroid- stimulating hormone.18 Also required is an imaging study, either head CT or MRI of the brain. If the patient is younger or there is doubt about the diagnosis, further testing should be obtained (▶ Fig. 1.7). As may be indicated, appropriate labora- tory, electroencephalographic, electromyographic, sleep, and imaging studies should be obtained to confirm or rule out other possible causes of complaint.

Throughout life, however, the accumulation of clinical data tends to trump any test we do, and we often wait for families to allow pathological evidence or genetic testing for confirmation of our clinical suspicion. The hope is that we can use already developed tools more wisely, and further hope is that there continue to be more innovative approaches to diagnose more definitively and earlier in the course of disease. As research moves toward identifying diseases at earlier stages for treat- ment, we must develop new tools to identify correctly the patients and patient groups for study.

An enormously powerful tool has been and continues to be neuroimaging; it can act as a surrogate for pathology, both in the gross pathological sense in quantitative measures but also increasingly as a histopathological marker of disease in vivo. It has great advantages as well, even over pathology: images can be made showing function in different parts of the brain or highlighting loss of function; and images can be taken longitu- dinally, showing changes over time (▶Fig. 1.8). Studies can

show quantitative measures of atrophy in various parts of the brain even before a patient has clinical symptoms, such as in mild cognitive impairment. Potentially, imaging may be able to show objective efficacy of treatments.

1.4 Pathology

It would be a lot simpler if, given a thorough history and exami- nation, the astute clinician could always know what disease is causing the symptoms or, short of that, could obtain the one test that makes the diagnosis. Neurodegenerative diseases are devastating for patients and families, and often the not knowing adds to the difficulty. There is, of course, clinical overlap, and as the disease progresses, the signs and symptoms overlap even more, as more of the brain becomes engorged by disease and areas are damaged, connections are lost. A strange homogene- ity and heterogeneity can exist pathologically as well. The loss of neurons causing disease can be caused by many different processes, such as abnormal protein accumulation, vascular damage, inflammation, vitamin deficiencies, toxins, infections, or some combination thereof. These entities cause the pathol- ogy that make the disease. Pathologically, as diseases progress, there is an end pattern of neuronal and synaptic loss, as well as laminar spongiosis and astrocytosis,19 and the causative agent is not always evident. Grossly, there is often atrophy in regions typical for each disease. For example, atrophy is present in fron- tal and/or temporal regions in frontotemporal degeneration; this can be seen in imaging during life, as well as at autopsy (▶Fig. 1.9). Early in the disease, different brain regions are more affected than others, depending on the clinical subtype; for example, a substantial decrease in weight and volume in the dominant frontal lobe is expected in progressive nonfluent aphasia. As the neurodegenerative disease progresses, however, often an increase in atrophy occurs more globally, although usually the initial area remains the most affected.

Many of the neurodegenerative diseases are defined patho- logically by the type and distribution of protein accumulation. Diseases that clinically resemble one another may have a totally different underlying pathology. An example is the “Parkinson- plus” disease progressive supranuclear palsy, which clinically can resemble idiopathic Parkinson’s disease in its extrapyrami- dal rigidity, bradykinesia, and gait impairment. Although often progressive supranuclear palsy also involves dementia, bulbar palsy, and the characteristic supranuclear ophthalmoplegia, these are not always present, or at least present initially.14,15 It is certainly a disease that clinically can be confused with Par- kinson’s disease.20 At autopsy, however, the pathology of Par- kinson’s disease shows loss of dopaminergic cells in the mid- brain and Lewy body deposits made of α-synuclein. Although in progressive supranuclear palsy there is also loss of midbrain neurons and loss of substantia nigra pigment seen at autopsy, this disease also has characteristic tau pathology (▶Fig. 1.10). In contrast, some diseases have a quite different clinical presen- tation, such as in patients with ALS or FTD, who can have the same pathology in TDP-43; these patients may also share the same genetic mutation in C9ORF72.21 By no means, however, do all patients with FTD or ALS exhibit that pathology; for example, some FTDs show tau protein deposition, and other familial forms of ALS have aggregates of superoxide dismutase in cell bodies.22 The difference in protein pathology and

Introduction

Fig. 1.7 Flowchart for the assessment and investigation of young-onset dementia. This algorithm provides an overview of the diagnostic approach to patients with young-onset dementia; it is only a general guide. In amnestic young-onset dementia, first-line genetic testing is for amyloid precursor protein (APP), presenilin-1 (PSEN1), presenilin-2 (PSEN2), and prion. In behavioral cases, first-line testing is for MAPT (particularly if symmetrical atrophy on magnetic resonance imaging [MRI]) and granulin (GRN, particularly if asymmetric pattern of atrophy). Aβ, amyloid β; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CJD, Creutzfeldt-Jakob disease; EEG, electroencephalograph; FDG, fluorodeoxyglucose; FTLD, frontotemporal lobar degeneration; SPECT, single-photon emission computed tomography. VGKC, voltage-gated potassium channel. (Used with permission from Rossor MN, Fox NC, Mummery CJ, Schott JM, Warren JD. The diagnosis of young-onset dementia. Lancet Neurol 2010; 9:802.)

Fig. 1.8 Alzheimer’s disease. Coronal T1- weighted imaging shows severe atrophy of the bilateral hippocampi (arrows). There is mild generalized atrophy of the frontotemporal lobes. Coronal positron emission tomography image shows decreased uptake in the medial temporal lobes, indicating hypometabolism typical for Alzheimer’s disease.

distribution allows for definitive diagnoses to be made in many of the primary neurodegenerative diseases and has helped to differentiate and redefine some of these diseases (▶ Fig. 1.11). Pathology remains the gold standard for definitive diagnosis in many primary neurodegenerative diseases. Not all neuro-

degenerative diseases are caused by abnormal protein accumu- lation and deposits, however, and not all diseases carry a read- able “protein signature” pathologically. Some are caused by infection, inflammation, or neuronal death by direct toxic injury or less directly from ischemia or hypoxia, and other

Overview of Neurodegenerative Diseases

Fig. 1.9 Frontotemporal dementia. (a) Coronal computed tomography image shows severe atrophy of the frontal and temporal lobes bilaterally (arrows) with marked dilatation of the cerebrospinal fluid spaces. (b) Sagittal T1WI shows selective atrophy of the frontal lobe with normal parietal and occipital lobes. (c) Gross pathology of patient with pathologically proven frontotemporal dementia. Arrows indicate frontal lobe atrophy (a,b). (parts used by permission from Jennifer W. Baccon, MD, PhD, Penn State Hershey Medical Center.)

diseases have unknown causes or are caused by deleterious gain or loss of genetic function. There is a broad range of what can be seen pathologically with these diseases.

1.5 Genetics

Although it was known that there seemed to be a hereditary component to some neurodegenerative diseases, such as Hun- tington disease, which for the vast majority of cases seemed to be inherited in an autosomal dominant fashion, it was not until the 1980s and 1990s that the ability to map genes became pos- sible. Huntington disease, as mentioned earlier herein, was the first disease gene discovered. Since then, the discovery of genes that either cause, predispose to, or protect from disease has provided a whole new way of understanding and looking at dis- eases. It is important for the nongeneticist to understand a few fundamentals of the genetics behind disease. It is not always as simple as a defect in gene X causing disease Y, but this is the case in some diseases with a high degree of penetrance. In dis- eases like Huntington and the spinocerebellar ataxias, a gene

Fig. 1.10 Immunohistochemical stain for tau. (Pathology slide used by permission from Jennifer W. Baccon, MD, PhD, Penn State Hershey Medical Center)

Introduction

Fig. 1.11 The overlap between clinical and pathological descriptions of neurodegenerative diseases: Some proteinopathies and clinical entities.

mutation causes disease (▶ Table 1.2). Other genes that behave like this are the APP gene on chromosome 21 or the presenilin 1 gene on chromosome 14, both of which cause rare forms of familial Alzheimer’s disease, less than 5% of all Alzheimer’s dis- ease. These genes are also inherited in an autosomal dominant fashion. Some genes that are known to cause disease may not cause disease in each carrier, or they may cause a modified dis- ease. This is the case of the progranulin mutation, which causes FTD, in which the chance of developing the disease increases as the carrier of the mutation ages, but it is not 100% penetrant. Then there are genes that have been discovered that seem to confer a risk for developing disease, such as apolipoprotein (Apo) E4 and Alzheimer’s disease. Each person has two copies of ApoE, and it comes in three forms: E2, E3, and E4. A person with a copy of ApoE4 is considered at increased risk for devel- oping Alzheimer’s disease. A person with two copies of ApoE4 is considered to have an even greater risk and is likely to develop the disease at an earlier age14; but this is only a risk fac- tor, just as traumatic brain injury, insulin resistance, cerebral vascular disease, and smoking may be risk factors: none of these risks guarantees the development of Alzheimer’s disease. The person who has two copies of ApoE4 and is suffering from dementia might not be suffering from Alzheimer’s disease, and the reverse is also true: a person suffering from Alzheimer’s dis-

ease does not necessarily have even one copy of the ApoE4 gene. For a small subset of patients with neurodegenerative dis- eases, however, genetic testing can provide a definitive diagno- sis, and genes likely play a much greater role than we now understand in who develops disease and why.

1.6 Summary

Although it can be quite useful to have constructs in mind, it is important not to be too rigid about how we classify neuro- degenerative disorders. The definitions of these diseases and how we understand them shift like tidal sands as we learn more about each disease individually and then step back and refit our new knowledge into the greater patterns. Of course, it also depends on through which lens we are looking at them. Clinicians, geneticists, pathologists, radiologists, molecular biol- ogists, and chemists all have different ways of sorting and understanding these diseases. It is only through the effort of each part of this multidisciplinary approach that we can hope to gain a better understanding of these diseases. In doing so, we will be able to better care for and communicate with the increasing number of patients who suffer from these illnesses. The aim of this book is to develop a better understanding of neurodegenerative diseases through neuroimaging. Chapters

Overview of Neurodegenerative Diseases

Table 1.2 Overview of genetics of some established neurodegenerative diseases

Disease Gene Protein Chromosome Inheritance

Alzheimer’s

APP

A-β precursor

Dominant

APOE

Apolipoprotein E

Risk factor

PSEN1

Presenilin 1

Dominant

PSEN2

Presenilin 2

Dominant

Parkinson’s

SNCA

α-synuclein

Dominant

PRKN

Parkin

Recessive

DJ1

DJ-1

Recessive

PINK1

PTEN-induced putative kinase 1

Recessive

LRRK2

Leucine-rich repeat kinase 2; dardarin

Dominant

FTD

MAPT

Microtubule-associated protein tau

Dominant

PRG

Progranulin

Dominant

FTD with IBM and early Paget disease

VCP

Valosin-containing protein

Dominant

FTD and MND

C9ORF72

C9ORF72-encoded protein (unknown)

Dominant

ALS

SOD1

Superoxide dismutase 1

Dominant and Recessive

Huntington

ALS2

Alsin

Recessive

spinocerebellar

HTT

Huntingtin

Dominant

ataxias

ATXN I, II, and III,

Ataxin 1, 2, and 3,

6, 12, 14, respectively

Dominant

Wilson’s

ATP7B

P-type ATPase

Recessive

Prion

PRNP

Prion protein

Dominant and Risk factor

CADASIL

NOTCH3

Neurogenic locus notch homolog protein 3

Dominant

CARASIL

HTRA1

HTRA serine protease

Recessive

Abbreviations: ALS, amyotrophic lateral sclerosis; ATPase, adenosine triphosphatase; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; FTD, frontotemporal dementia; IBM, inclusion body myositis; MND, motor neuron disease.

are arranged by disease, and with a brief discussion of each dis- ease as it is now understood are the images themselves. Along with the images are discussions of what tests to order, what to look for, what is expected to be seen in each disorder, and new clinical and research modalities.

References

. [1] McKhann GM, Knopman DS, Chertkow H et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 263–269

. [2] Leeds NE, Kieffer SA. Evolution of diagnostic neuroradiology from 1904 to 1999. Radiology 2000; 217: 309–318

. [3] Albert ML, Mildworf B. The concept of dementia. J Neurolinguist 1989; 4: 301–308

. [4] Pearce JMS. Aspects of the history of Parkinson’s disease. J Neurol Neurosurg Psychiatry 1989; 52 Suppl: 6–10

. [5] Goetz CG. The history of Parkinson’s disease: early clinical descriptions and neurological therapies. Cold Spring Harb Perspect Med 2011; 1: a008862

. [6] Henry JM. Neurons and Nobel Prizes: a centennial history of neuropathology.
Neurosurgery 1998; 42: 143–156

. [7] Mast H, Tatemichi TK, Mohr JP. Chronic brain ischemia: the contributions of
Otto Binswanger and Alois Alzheimer to the mechanisms of vascular demen-
tia. J Neurol Sci 1995; 132: 4–10

. [8] Graeber MB, Kösel S, Egensperger R et al. Rediscovery of the case described
by Alois Alzheimer in 1911: historical, histological and molecular genetic
analysis. Neurogenetics 1997; 1: 73–80

. [9] Pan XD, Chen XC. Clinic, neuropathology and molecular genetics of fronto-
temporal dementia: a mini-review. Transl Neurodegener 2013; 2: 8

[10] [11] [12] [13] [14] [15]

[16] [17] [18] [19]

[20] [21] [22]

Snowden JS, Neary D, Mann DM. Frontotemporal dementia. Br J Psychiatry 2002; 180: 140–143
Hornykiewicz O. A brief history of levodopa. J Neurol 2010; 257 Suppl 2: S249–S252

Colosimo C, Bak TH, Bologna M, Berardelli A. Fifty years of progressive supra- nuclear palsy. J Neurol Neurosurg Psychiatry 2014; 85: 938–944
Daroff RB. Progressive supranuclear palsy: a brief personalized history. Yale J Biol Med 1987; 60: 119–122

Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. J Clin Invest 2005; 115: 1449–1457
Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global preva- lence of dementia: a systematic review and metaanalysis. Alzheimers Dement 2013; 9: 63–75, e2

World Health Organization. Dementia: a public health priority. http://apps. who.int/iris/bitstream/10665/75263/1/9789241564458_eng.pdf. 2012
Rossor MN, Fox NC, Mummery CJ, Schott JM, Warren JD. The diagnosis of young-onset dementia. Lancet Neurol 2010; 9: 793–806

Galasko D. The diagnostic evaluation of a patient with dementia. Continuum (Minneap Minn) 2013; 19 2 Dementia: 397–410
Duyckaerts C. Neuropathologic classification of dementias: introduction. In: Duyckaerts C, Litvan I, eds. Handbook of Clinical Neurology. Vol 89 (3rd Series) Dementias. New York, NY: Elsevier; 2008; 147–159

Bower JH, Dickson DW, Taylor L, Maraganore DM, Rocca WA. Clinical corre- lates of the pathology underlying parkinsonism: a population perspective. Mov Disord 2002; 17: 910–916
Hsiung GY, DeJesus-Hernandez M, Feldman HH et al. Clinical and patho- logical features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 2012; 135: 709–722

Mackenzie IR, Bigio EH, Ince PG et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 2007; 61: 427–434

Part II Imaging Techniques

. 2 Structural Imaging of Dementia 14

. 3 Magnetic Resonance Spectroscopy in
Neurodegenerative Disorders 24

. 4 SPECT and PET Imaging of
Neurotransmitters in Dementia 34

. 5 Diffusion Tensor Imaging in
Neurodegenerative Disorders 42

. 6 Functional Imaging of the Brain 51

. 7 Role of Noninvasive Angiogram and
Perfusion in the Evaluation of Neurodegenerative Disorders 60

Imaging Techniques

2 Structural Imaging of Dementia

Sangam G. Kanekar and Vijay Mittal

Dementia is derived from Latin as “away from the mind,” and it encompasses a vast spectrum of diseases, which can be divided into reversible and irreversible causes. Diagnosis remains a chal- lenging task to the clinician because patients with different diseases can have similar signs and symptoms. Because thera- pies have become more specific with advances in research, accurate diagnosis is paramount. Fortunately, cross-sectional imaging has evolved and has proved an invaluable tool in diag- nostic work-up. When combined with clinical signs and symp- toms, structural imaging establishes the cause of dementia and allows focused treatments.

The two most compelling arguments against routine imaging of dementia include cost and case management. Rough esti- mates of diagnostic imaging tests in dementia may range from $350 to $700 million per year in the near future.1,2,3 Use of imaging may decline if it becomes a “rule-out” tool rather than a diagnostic tool. Additionally, many findings are equivocal and therefore would not significantly change patient treatment. For example, findings of cortical atrophy on head computed tomog- raphy (CT) are problematic because the degree of atrophy has overlap with absent disease state.4 Lastly, cellular and func- tional imaging with fluorodeoxyglucose F18, single-photon emission computed tomography (SPECT) perfusion studies with technetium-hexamethylpropylenamine oxime, and magnetic resonance imaging functional studies (fMRI)—including perfu- sion MRI, blood oxygenation level–dependent fMRI, and MRI spectroscopy—are extremely resource limited and expensive. The high expense and limited availability of these functional and cellular imaging tests have resulted in their being used less often, even though they are the most sensitive tools in early diagnosis of many diseases, such as the parkinsonian syndromes.5

Structural imaging is more than an exclusionary tool, how- ever, and provides valuable diagnostic information as well. Despite the argument about equivocal imaging, CT separates normal subjects from those with true dementia with more than 89% accuracy,6 or a specificity of more than 95%.7 The identification of pseudodementia, or dementia as a symptom of depression, can indicate an easily treatable condition. Also, MRI has emerged as a more specific and sensitive modality that can provide excellent diagnostic yield. It quantifies gray and white matter structures8; for example, it has been able to quantify hippocampal volume, which is highly accurate in diagnosing Alzheimer’s disease (AD),9,10 in addition to correlating with clinical progression.4

Although routine clinical scanning of patients may not pro- vide immediate benefit, our longitudinal knowledge of various pathological processes and early alterations in brain anatomy on imaging can enable us to identify abnormalities much earlier during the clinical setting, which may benefit future at-risk patients who could undergo directed therapy. Unfortunately, postmortem examination does not allow such treatment. An example is our evolution of knowledge to distinguish AD, nor- mal pressure hydrocephalus (NPH), and microvascular disease, which have different clinical outcomes and treatments.4 Our understanding of microvascular disease, so-called unidentified

bright objects, has expanded, and we now understand that these areas of demyelination correlate with clinical signs, such as delayed reaction time or falls. Additionally, chronic micro- vascular disease can be differentiated from more acute sub- cortical infarcts by MRI.11

2.1 Imaging Modalities

A decade ago, the primary role of imaging in a suspected case of dementia or neurodegenerative disease was limited mainly to the exclusion of treatable (reversible) causes of dementia, such as tumor, subdural hematoma, infection, and stroke. With advances in technology, identifying the minute brain details at the structural and functional level has changed the role of neuroimaging (▶ Fig. 2.1). Although imaging still plays a greater role in distinguishing reversible causes from irreversible causes of dementia, this role is relatively small because reversible causes constitute only around 1% of the causes of dementia. Today, neuroimaging helps in differentiating and classifying various irreversible causes of dementia. This is even more important because concordant advances have been made in pharmaceutical, behavioral, and cognitive therapies to treat and prevent various types of dementia. Most of the functional tech- niques are new and not widely available or understood. Addi- tionally, their role in the diagnosis of neurodegenerative dis- eases is still not well established for clinical practice. Structural imaging is more readily available and easy to interpret. The development of diagnostic clinical criteria has improved diag- nostic accuracy, but these criteria are still far from perfect. For example, the accuracy of the criteria for diagnosis of AD is lim- ited and depends on the expertise of the clinical center, with specificity ranging between 76 and 88% and sensitivity between 53 and 65%. With newer structural and functional imaging techniques, the diagnosis of many dementias can be suspected or established in the early stages and helps clinicians tailor treatment as well as understand the heritance and prog- nosis of the disease, which facilitates discussion with patients and relatives.

2.1.1 Computed Tomography Versus

Magnetic Resonance Imaging

Computed tomography is fast and relatively inexpensive com- pared with MRI, and its clinical utility revolves around exclu- sion of disease rather than diagnosis. Whereas CT relies on volume changes, MRI adds soft tissue information and thus allows radiologists to assess the disease characteristics accu- rately.12 Besides the basic T1- and T2-weighted images in axial, sagittal, and coronal planes, gradient-echo T2* imaging and volumetric MRI using three-dimensional (3D) T1-weighted sequences play an important role in the evaluation of neuro- degenerative diseases. Molecular and cellular imaging tech- niques, such as diffusion tensor imaging, iron-quantifying techniques, spectroscopy, and perfusion may be added to improve the sensitivity and specificity of the diagnosis.

T1- and T2-weighted imaging is used to assess the gross anat- omy of the brain and to exclude the presence of subdural hema- toma, mass effect, hydrocephalus, or other anomalies. In addi- tion, T2-weighted sequences are sensitive to changes in tissue properties, including tissue damage, resulting from changes in the transverse magnetization or T2 decay.12 This property of T2 is helpful in evaluating neurodegenerative diseases, which are mostly characterized by cell loss, astrogliosis, microglial prolif- eration, and increased deposition of iron or other paramagnetic substances. Nonheme iron in ferritin and hemosiderin is seen as signal loss on T2-weighted imaging; this loss results from shortening of T2. The sensitivity for signal changes resulting from iron deposition in the brain can be increased by using T2*- weighted gradient-echo sequences or susceptibility-weighted imaging.12 By using an inversion pulse, the contrast of T1- weighted images can be improved, as in a magnetization- prepared rapid acquisition with gradient-echo sequence of high-resolution 3D data sets. This sequence is helpful in volu- metric analysis of the brain.

Simply put, structural imaging using MRI plays a vital role in evaluation of neurodegenerative diseases, demonstrating supe- rior ability to distinguish various degenerative diseases from each other and from age-related changes. As a prognostic tool, it estimates the future likelihood of clinical progression based on the current extent and severity of disease. Finally, it also acts as an indicator of the disease progression over time, derived from serial measurements.

2.2 Voxel-Based Methods

One of the primary findings in most neurodegenerative dis- eases on pathology is selective atrophy of a specified anatomi- cal structure early in the disease. These changes have been well studied using histopathology. Efforts are continuously being made to use imaging to quantify early neuron loss in specific

Structural Imaging of Dementia

Fig. 2.1 Coronal T2 magnetic resonance imaging through the hippocampus and entorhinal cortex. (a) Head. (b) Body. (c) Hippocampal tail. Images show: (1), hippocampus; (2), amygdala; (3), temporal horn; (red arrow), subiculum; (4), parahippocampal gyrus; (yellow arrows), entorhinal cortex; (5), fornix.

locations, which would provide the likely diagnosis. Different techniques exist, ranging from simple quantitative measures of diameter, area, and volume to the most advanced voxel-based morphometry (VBM) and voxel-based relaxometry (VBR), both of which require high-quality 3D sampling of the entire brain.13 The goal of VBM and VBR is to provide superior gray/white mat- ter differentiation, to define cortical and deep gray matter struc- tures, and to outline the cerebrospinal fluid (CSF)-filled spaces (▶ Fig. 2.2). The sequence and the slice partitions depend on the institution and capabilities of the particular scanner.

The sophistication of image-processing techniques with 3D volume acquisition has allowed accurate characterization of brain shape (deformation-based morphometry) and brain tissue composition (voxel-based morphometry) after macroscopic dif- ferences in shape have been discounted. Using these tech- niques, information about overall shape (deformation fields) and residual anatomical differences inherent in the data (nor- malized images) can be partitioned. VBM is based on coregis- tration of high-resolution 3D datasets, which are normalized to a study-specific template for detection of volume differences between two or more groups.13,14 Normalization is based on intracranial volume and has proven to reduce interindividual variations and account for gender differences. VBM involves a voxel-wise comparison of the local concentration of gray mat- ter, white matter, and CSF between two subjects. The procedure involves spatially normalizing the images, smoothing, correct- ing interindividual variations in gyral anatomy, and then voxel- wise analyzing the data. VBM has shown to be more sensitive than the normal two-dimensional measurements of structures. Although manual segmentation is time consuming and has lim- ited intraobserver and interobserver reliability, it remains the gold standard in quantitative AD imaging studies. In contrast, VBM has the advantage of being automatic, not requiring expert-dependent manual delineation of structural boundaries, and having no intraobserver and interobserver limitations.

Imaging Techniques

Fig. 2.2 Voxel-based morphometry in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In MCI, the gray matter loss is predominately seen in the medial basal and lateral temporal lobes. In AD, loss of gray matter is more extensive and involves the medial temporal lobe, basal temporal lobe, lateral temporal and parietal neocortex, posterior cingulate, temporal parietal association neocortex, and prefrontal cortex. L, left; R, right.

2.3 Structural Imaging in Aging

Differentiating normal age-related physiologic changes from early neurodegenerative disease is challenging clinically as well as on imaging. With increasing age, normal structural changes may overlap with the spectrum of neurodegenerative diseases on various imaging modalities. Common imaging and patholog- ical findings in aging include brain atrophy, white matter lesions, cerebral microbleeds, silent brain infarcts, and enlarged perivascular spaces.

Various cross-sectional imaging studies have shown smaller brain volumes with increasing age, especially in a person older than 55 years. Brain volume is expressed as a percentage of intracranial volume. A mean rate of brain volume loss of 0.4 to 0.5% per year has been described as normal.15 Hippocampal volume is shown to decline approximately 1.4 to 1.6% per year in normal aging compared with AD, which shows volume loss of 4.7% per year.16

T2-weighted hyperintense white matter changes are the most common finding in aging. These changes are due mainly to hypoxic/ischemic injury. T2*-weighted gradient-echo tech- nique allows easy identification of microbleeds. The prevalence of microbleeds has been estimated to be more than 20% in per- sons aged 60 years and older, increasing to nearly 40% in those older than 80 years.17 In the aging population, microbleeds are lobar in location. These lobar microbleeds correlate well with worse cognitive function. Lastly, dilated perivascular spaces, which can be seen at all ages, become more prominent with aging and are associated with the presence of silent brain

infarcts and hyperintense white matter changes. Dilated peri- vascular spaces are thought to be associated with cognitive deficits, independent of white matter changes and infarcts.

2.4 Role of Structural Imaging in Irreversible Dimentia

2.4.1 Mild Cognitive Impairment

Mild cognitive impairment (MCI) is defined as a mild but defi- nite decline from previous cognitive ability, confirmed by a reli- able observer and substantiated by deficits on neurocognitive testing. According to Petersen and colleagues,18 the criteria for amnestic MCI require (1) memory complaints, (2) difficulties with normal activities of daily living, (3) normal general (non- memory) cognitive function decline, (4) abnormal memory scores, and (5) no dementia. Early identification is crucial because 50 to 75% of elderly patients with MCI are at increased risk for developing of AD. Compared with normal controls, significant atrophy was identified in the hippocampus and entorhinal cortex of patients with MCI but not in the parahip- pocampal gyrus, fusiform gyri, and temporal gyri. Patients with MCI have less severe hippocampal atrophy (-12 to -14%) than those with AD (-22 to -23%), as well as less entorhinal cortex volume losses (-21%) than those with AD (-38%).19 The VBM method applied to MCI and normal groups confirmed atrophy of the hippocampus, medial temporal lobe, parahippocampal gyrus, and amygdala but also revealed differences in volumes.

Structural Imaging of Dementia

2.4.2 Alzheimer’s Disease

The main pathological features in AD are neuronal loss with gliosis in the temporal cortex, neurofibrillary tangles (NFTs) formed by tau protein aggregates, granulovacuolar degenera- tion of neurons, senile plaques, and amyloid angiopathy formed mainly by β-amyloid deposits. NFTs and neuropil threads first appear in the transentorhinal and entorhinal areas (parahippo- campal gyrus), increasing in density during the course of the disease. These changes progress to involve the hippocampus, limbic system, temporal and parietal cortices, and finally the entire neocortex.20 Historically, AD has been a clinical diagnosis that uses neuropsychiatric tests. Over the past decade, however, neuroimaging has become a more direct diagnostic tool in which specific changes may suggest the diagnosis of AD.

The findings in AD can be largely classified according to the stage of the disease. In the earliest transentorhinal stage, volume changes are confined primarily to transentorhinal and entorhinal regions, with mild involvement of the hippo- campus. During the limbic stage, the imaging and pathologic changes involve larger parts of the hippocampal formation, sub- cortical structures (thalamus, amygdala), and basal forebrain (▶ Fig. 2.3). In the later stages, there is widespread cortical atro- phy. These changes can be characterized using nonvolumetric assessment or may be quantified using newer techniques of volumetric measurements.

Early atrophic changes in the medial temporal lobe, which include the height of the hippocampal formation and the sizes of the choroidal fissure and the temporal horn, can suggest the presence of AD. The diagnostic accuracy of the visual rating was reported at 95%, which was higher than the 85% accuracy of the hippocampal volumetry in differentiating AD patients from control subjects.20 Sensitivity and specificity in distinguishing patients with AD from healthy controls are in the range of 85 and 88%, respectively.

The entorhinal cortex is affected earlier than the hippocam- pus by NFTs and has a greater potential as an early marker, but it is a more challenging region to assess on imaging. Volumetric analysis techniques have shown the reduction in entorhinal cortex volume in AD to be approximately 35 to 40% compared with healthy controls.19 Some authorities believe that the diag-

nostic accuracy of the entorhinal cortex volume alone is close to 100% and superior to the hippocampus; however, this is debat- able. In AD, hippocampal neuronal atrophy strongly correlates with NFT pathology. The percentage reduction in total number of hippocampal neurons correlates with the percentage of neu- rons with NFTs. Based on histologic volumetry, a difference of 30% between healthy controls and age-matched AD subjects was found, which correlated well with MRI volumetric studies.

As the name suggests, various parts of the limbic system show NFT and atrophic changes in the limbic stage before spreading to the neocortex. There is 20 to 33% volume reduc- tion with prolonged T2 relaxation time in the amygdala.19 T2 changes are thought to be due to increased free water content in the tissue. Changes of atrophy may also be seen in the para- hippocampal gyrus (left > right) and in the temporal gyri. Longitudinal studies have shown rapid enlargement of the ven- tricular size and evolution of brain atrophy in individuals with dementia compared with controls (▶Fig. 2.4). Using an auto- mated body substance isolation method applied to serial MRIs acquired 1 year apart, Fox and colleagues21 described median amygdala volume loss of 12.3 mL per year in the AD group and 0.3mL in controls. On fluorodeoxyglucose-positron emission tomography (FDG-PET) scan, hypometabolism is seen in the medial temporal and parietal lobes (▶ Fig. 2.5).

2.4.3 Non-Alzheimer’s Dementia Frontotemporal Degeneration

Frontotemporal degeneration (FTD) is a common cause of dementia, especially in patients younger than 70 years. It typi- cally presents between ages 45 and 65 years. Clinically, FTD can be classified into three types: frontotemporal dementia, seman- tic dementia, and nonfluent aphasia.22 FTD is characterized pathologically by extensive loss of pyramidal neurons in the frontotemporal cortex, severe gliosis within the gray and white matter, spongiosis, and the presence of argyrophilic intraneuro- nal inclusion bodies (Pick bodies). Imaging does play a role in differentiating FTD from other neurodegenerative changes. There is preferential atrophy of the frontal and anterior tempo- ral lobes, which helps distinguish it from AD.22 The three

Fig. 2.3 Alzheimer’s disease. (a) Coronal com- puted tomography scan image shows severe atrophy of amygdala and marked bilateral atro- phy of the hippocampal formations with dilata- tion of the temporal horns. There is dilatation of the lateral ventricles. (b) Axial fluid-attenuated inversion recovery (FLAIR) image of the same patients shows severe atrophy of the amygdala and head and body of the hippocampi bilaterally (arrows).

Imaging Techniques

Fig. 2.4 Serial changes in the hippocampus in patient with Alzheimer’s disease. Serial coronal magnetic resonance images of a patient with Alzheimer’s disease in (a) 2004, (b) 2006, and (c) 2008 show progressive hippocampal atrophy (arrows) with dilatation of the temporal horn. (d) Axial fluid-attenuated inversion recovery (FLAIR) image from the 2008 study shows severe atrophy of amygdala (arrows) and marked bilat- eral atrophy of the hippocampal formations (arrowheads) with dilatation of the temporal horns.

Fig. 2.5 Magnetic resonance imaging and positron emission tomography (PET) correlation in Alzheimer’s disease. (a) Coronal T1-weighted image shows moderate atrophy of the hippocampi in a 71-year-old man with memory loss, classic for Alzheimer’s disease. (b) Coronal and (c) axial fluorodeoxyglucose (FDG)-PET images of the brain show bilateral low uptake in the temporal (arrows in coronal) and parietal lobes (arrows in axial).

different types of FTD may show different appearance on MRI: (1) frontotemporal dementia is characterized clinically by behavioral disturbances, antisocial behavior, and disinhibition owing to primary involvement of the frontal lobes. There is atrophy primarily affecting the frontal lobes and anterior por- tions of the temporal lobes in the late stages of the disease (▶ Fig. 2.6). (2) Semantic dementia typically manifests with pro- gressive anomia resulting from loss of long-term memory of language comprehension and object recognition. Unlike in AD patients, short-term memory is usually intact. Structural imag- ing shows atrophy of the frontal and temporal lobes, more pro- nounced in the temporal lobes, and often asymmetric, affecting the left temporal lobe more. (3) Nonfluent progressive aphasia is characterized by the preservation of verbal comprehension with severe disruption of conversational speech, speech dysflu- ency, and phonologic errors. MRI in these patients shows atro- phy in the perisylvian regions of the frontal and temporal lobes. Severe thinning of the cortical gyri, giving a “knife-blade” appearance, is seen, especially in the anterior portion the supe- rior temporal gyrus (▶ Fig. 2.7).

Lewy Body Dementia

Lewy body dementia is a neurodegenerative disease with the histopathological hallmark of the intraneuronal aggregation of

α-synuclein protein inclusions (Lewy bodies). Patients have fluc- tuations in cognition, visual hallucinations, depression, and nighttime agitation. Antidopaminergic and anticholinergic neuroleptics may cause irreversible extrapyramidal symptoms in Lewy body dementia, making diagnosis crucial. Volumetric studies have shown that gray matter structures may be more affected than white matter structures. Conventional CT and MRI findings, although nonspecific, include atrophy of the putamen and cortical atrophy, predominantly in the occipital lobe.23,24

Corticobasal Degeneration

Corticobasal degeneration (CBD) manifests in late adulthood. Patients with CBD have asymmetric limb apraxia, rigidity, or akinesia. Severe depression and cognitive decline, leading to dementia, may also be seen. Clinically, CBD is difficult to differ- entiate from FTD and progressive supranuclear palsy (PSP). No specific imaging appearances are identified, but progressive atrophy of the parietal lobes and caudate nuclei favor CBD (▶ Fig. 2.8). The cerebral hemispheres are often asymmetric and contralateral to the clinically affected side.25 Putaminal hypoin- tensity, as well as hyperintense signal changes in the motor cor- tex or subcortical white matter on T2-weighted images, may also be seen in CBD.24 The asymmetric cerebral atrophy seen in

Structural Imaging of Dementia

Fig. 2.6 Frontotemporal dementia in patient with behavioral disturbances. Axial (a) computed tomography and (b) T2-weighted magnetic resonance images show mild frontotemporal atrophy with sparing of the occipitoparietal lobes. Sagittal (c) single-photon emission computed tomography images show hypometabolism in the frontal lobe (arrow) with normal uptake in the rest of the cerebral parenchyma.

Fig. 2.7 Frontotemporal dementia in a
61-year old patient with nonfluent aphasia. Axial (a) T2-weighted and (b) T1-weighted images show severe atrophy of the anterior temporal lobes bilaterally left more than right. There is severe thinning of the superior temporal gyrus, giving a “knife-blade” (black arrows in T2 and white arrows in FLAIR images) appearance.

CBD is believed to distinguish it from AD. However, none of these structural MRI abnormalities seems to be of diagnostic relevance for CBD.

Huntington Disease

Huntington disease is an autosomal dominant neuro- degenerative disorder that typically manifests with chorea and dementia. The classic signs of Huntington disease include cho- rea (diffuse, involuntary, rapid, irregular, jerky movements) and a gradual loss of thought processing and acquired intellectual

abilities (dementia). The neurodegeneration associated with Huntington disease affects primarily the basal ganglia (espe- cially the caudate nucleus) and the cerebral cortex. The characteristic imaging finding in Huntington disease is marked atrophy of the caudate nuclei and corpus striatum (▶ Fig. 2.9).24 The larger bicaudate and bifrontal ratios in Huntington disease patients are due to caudate atrophy and ventricular enlargement, respectively. Diffuse cerebral volume loss also may be seen and can be more pronounced in the frontal lobes than elsewhere. Preferential gray-matter atrophy also is described in the opercular cortex, hypothalamus, and right paracentral

Imaging Techniques

Fig. 2.8 Corticobasal degeneration in 65-year-old man. (a) Axial and (b) coronal T1-weighted images show symmetric atrophy of the parietal lobes (arrows).

Fig. 2.9 Huntington disease. Axial T2-weighted images reveal atrophy of the head of the caudate nuclei (white arrows), with enlargement of the frontal horns of the lateral ventricles. The right putamen is slightly atrophic (arrowheads).

lobule. Patients who have the juvenile form of Huntington disease may also demonstrate hyperintense T2 signal in the caudate nuclei and putamina.25 Simmons et al26 showed that putamena- trophy (~50.1%) exceeded caudate changes (~27.7%), and volumetric measurement of the putamen was a more sensitive indicator of brain abnormalities in patients with mild Huntington disease than were measures of caudate atrophy. Data have also suggested that putamen volume measured with MRI is a prefera- ble marker of preclinical Huntington disease.

Studies have indicated that putamen atrophy occurs first and faster in Huntington disease than does caudate atrophy. Cau- date atrophy is more prominent in the late stage of the disease.

Parkinsonian Disorders

Brain MRI techniques have more easily demarcated the lines between the various parkinsonian disorders rather than the clinical symptoms, which overlap too much and have different prognoses and management.5 The parkinsonian diseases include idiopathic Parkinson’s disease, multiple-system atrophy (MSA), PSP, CBD, and manganese-induced parkinsonism.

Idiopathic Parkinson’s Disease

Idiopathic Parkinson’s disease (IPD) is a movement disorder that is clinically characterized by resting tremor, rigidity, brady- kinesia, and postural instability resulting from loss of dopamin- ergic neurons in the substantia nigra (SN) pars compacta.27,28 Pathological characteristics include the loss of pigmented dopa- minergic neurons of the pars compacta of the SN and loss of pigmented cells of the locus ceruleus and dorsal motor nucleus of the vagus. In addition, reactive astrocytosis and intraneuro- nal aggregations of Lewy bodies are seen in the pars compacta. About 40 to 70% of patients with PD have dementia, which is mainly subcortical, resulting from dopaminergic insufficiency. The dementia in these patients is characterized predominantly by attention deficits and impairment in executive functions, whereas memory impairment may be secondary. On histology, PD patients show higher concentrations of Lewy bodies in the transrhinal and entorhinal cortices, the hippocampi, and the amygdala than do PD patients without dementia.

Although conventional MRI is usually normal in early PD, it excludes the other possible causes of secondary parkinsonism (including vascular disorders, hydrocephalus, and neoplasms). On higher magnetic fields (3 tesla [T]) right-left asymmetry of the pars compacta may be a feature in early stages of the dis- ease, especially in patients who have hemi-parkinsonism symp- toms. Narrowing of the pars compacta of the SN may be seen in patients who have long-standing PD. The normal width of the pars compacta has been reported to be 4mm, whereas in PD,

Structural Imaging of Dementia

the average width is 2.7mm.29,30 Advanced cases of PD may show distinct abnormalities of the SN, including signal increase on T2-weighted MRIs or smudging of the hypointensity in the SN toward the red nucleus. Reduction or absence of normal hypointensity on T2-weighted images is seen in the pars reticu- lata of the SN as a result of selective neuronal loss. Segmented inversion recovery ratio imaging may demonstrate a significant decrease SN:midbrain ratio. Mild, nonspecific cortical and sub- cortical volume loss is observed in some patients.

Multiple-System Atrophy

Multiple-system atrophy, characterized by autonomic dys- function, pyramidal tract dysfunction, and cerebellar ataxia,31,32 is due to neuronal loss and gliosis of the nigrostriatal tract in the MSA-parkinsonism type (MSA-P) and olivopontocerebellar tract in the MSA-cerebellar type (MSA-C).5 Pathology demon- strates glial cytoplasmic inclusion bodies. MSA is often confused with PD.

Structural MRI findings that point toward MSA-P include atrophy and signal alteration in the putamen. Putaminal hypo- intensities and putaminal rim hyperintensities (“slit-like” mar- gin) on T2-weighted imaging correspond to neuronal loss, iron deposition, and gliosis. Putaminal hyperintense rim helps to differentiate MSA from IPD, but it does not help in differentiat- ing MSA from PSP and CBD. On 3.0 T, a hyperintense putaminal rim on T2-weighted imaging is thought to be nonspecific and may be a normal finding in elderly patients. Putaminal hypoin- tensity is not unique to MSA but may rarely be seen in IPD because iron accumulation occurs in both.33,34 Specificity of these findings for differentiating MSA-P from PD and healthy controls is considered high, whereas sensitivity, especially in the early disease stages, seems insufficient. T2-weighted gradi- ent-echo putaminal hypointensity and fluid-attenuated inver- sion recovery (FLAIR) putaminal rim hyperintensity constitute the most accurate method for differentiating MSA from IPD.35

The MSA cerebellar type (MSA-C) can involve early childhood or old age. Its first sign is ataxia, first in the legs then in the arms and hands, and finally it shows bulbar manifestation.5 The primary degeneration involves pontine nuclei, with subsequent progressive antegrade degeneration of the pontocerebellar tracts and the cerebellar cortex hemispheric greater than ver- mian. Later in the disease, the inferior olive loses its normal

bulge because of neuronal loss and gliosis. MRI shows atrophy of the pons with flattening of the inferior part (loss of normal pregnant belly of pons) (▶ Fig. 2.10a).36 Atrophy of the cerebellar cortex (hemispheric greater than vermian), MCP, and inferior olives is also seen. Degeneration of pontine neurons and trans- verse pontocerebellar fibers with normal signal intensity in the surrounding parenchyma give a classic “hot-cross bun” sign of the pons on axial T2-weighted images (▶ Fig. 2.10b).37 The aver- age MCP width was significantly smaller in patients (cutoff value of 8 mm) with MSA than in those with PD or in control subjects.38

Progressive Supranuclear Palsy

Progressive supranuclear palsy occurs in late adulthood and is characterized by vertical gaze palsy, slow vertical saccades, pos- tural instability, and frequent falls. Dementia is mild and is seen in the late stages of the disease. PSP is histologically character- ized by tau-positive NFTs and glial and neuronal loss, mainly in the basal ganglia and brainstem.5 It is important to differentiate PSP from other forms of movement disorders because PSP patients typically do not respond well to dopamine replace- ment therapy.

Structural MRI findings that point toward PSP include sym- metric progressive atrophy of the midbrain, superior cerebellar peduncles, thalami, and caudate nuclei.39,40 There is associated enlargement of the third ventricle and tegmental atrophy, with increase signal intensity in the midbrain. On sagittal images, the superior contour of the midbrain may have a flattened or concave profile, a finding believed highly specific for PSP. A reduced anteroposterior midbrain diameter of less than 14 mm has been proposed to optimally separate PSP from other types of neurodegenerative parkinsonism and healthy controls.36,41 Another indirect sign of midbrain atrophy in patients with PSP is the “penguin silhouette” or “hummingbird” sign, correspond- ing to the shape of the midbrain tegmentum (the bird’s head) and pons (the bird’s body) on midsagittal MRI (▶Fig. 2.11).42 Visual assessment of atrophy of the superior cerebellar pedun- cle (SCP) can distinguish PSP patients from controls and from patients with other parkinsonian disorders, including MSA and PD, with a sensitivity of 74% and a specificity of 94%. Ratios and indices of the pons and midbrain are also used to distinguish PD, MSA, and PSP from each other. Calculation of the ratio

Fig. 2.10 Multiple-system atrophy (MSA)-cerebellar type (MSA-C). Olivopontocere- bellar degeneration. (a) Sagittal T1-weighted and (b) T2-weighted images show atrophy of the pons (white wide arrow), the middle cerebellar peduncles, and the cerebellar hemispheres (white thin arrow). Axial T2-weighted image shows classic cruciform pattern of the pontine fibers called “hot-cross bun sign” (black arrow).

Imaging Techniques

Fig. 2.11 Serial changes in the midbrain in a patient with progressive supranuclear palsy (PSP). (a) Sagittal T1-weighted image in 2009 shows mild atrophy in the midbrain, early changes of PSP. (b) Magnetic resonance imaging done in 2010 shows concave profile (white arrow) of the superior surface of the midbrain. In 2011 (c) midsagittal image shows atrophy of midbrain, dilatation of the third ventricle, and widening of the interpeduncular fossa, giving a ‘‘hummingbird’’ appearance (arrow).

between pontine and midbrain areas has been demonstrated to discriminate between PSP patients and patients with PD, MSA-P, or healthy controls. Quattrone and colleagues43 have proposed an index termed the MRI parkinsonism index (MRPI), which is calculated by multiplying the pontine:midbrain area ratio by the ratio of the MCP:SCP width (MCP/superior cerebel- lar puduncle). The MRPI is shown to be significantly larger in patients with PSP than in healthy controls or in PD and MSA-P patients. Atrophic changes are also seen in the inferior olives and frontal and temporal lobes. Atrophy of the frontal lobes is particularly seen in the orbitofrontal and medial cortex, which may help in distinguishing PSP from PD. The degree of atrophy seen in the frontal lobes correlates well with the level of behav- ioral disturbance seen clinically, as does the degree of atrophy in the caudate nuclei and brainstem with the severity of motor function impairment.

2.5 Reversible Dementia

Imaging plays an important role in diagnosing and differentiat- ing the various causes of reversible or preventable dementia. Clinical history, examinations, various laboratory tests, and imaging can easily pinpoint the diagnosis of reversible demen- tia. Medications, nutritional abnormalities, endocrine dys- function, infection and inflammatory conditions, vascular problems, and toxins are a few of the common causes of revers- ible dementia. Space-occupying lesions, such as subdural hema- toma, large intra-axial or extra-axial masses, and NPH, are well-known causes of reversible dementia and can be diag- nosed easily by imaging. Imaging findings of these pathologies are discussed in detail in subsequent chapters. Cognitive decline and dementia resulting from medications, nutritional abnor- malities, or endocrine dysfunction are predominantly sus- pected or diagnosed based on clinical history, examination, and laboratory analysis. Imaging plays a role of exclusion in the diagnosis of these conditions.

Infection and inflammatory conditions, such as human immunodeficiency (HIV) dementia, Creutzfeldt-Jakob disease

(CJD), progressive multifocal leukoencephalopathy (PML), Lyme disease, and multiple sclerosis, may be diagnosed with a combi- nation of imaging and blood and CSF examinations. HIV demen- tia (AIDS dementia complex) is caused by direct infection of the macrophages and microglia of the central nervous system by the HIV retrovirus. With the advent of highly active antiretrovi- ral therapy, there has been a significant decrease in the inci- dence of HIV dementia. Gray as well as white matter may be affected with HIV infection, leading to generalized cortical atro- phy and diffuse bilateral white-matter abnormalities. These abnormalities are seen most commonly in the peritrigonal and subinsular white matter, although they can progress to a more confluent and diffuse pattern of leukoencephalopathy. PML is seen mostly in the setting of HIV or in patients undergoing immunosuppressive therapy or who have hematologic malig- nancies. PML is caused by reactivation of the Jamestown Can- yon virus. The diagnosis of PML is confirmed by detection of JCV DNA by polymerase chain reaction in CSF. However, imag- ing, especially MRI, certainly leads to the diagnosis of PML from the pattern and distribution of the abnormality. The diagnostic hallmark of PML is the presence of multiple foci of demyelina- tion found initially sparsely distributed in the subcortical white matter but also in the cortex and deep gray structures. These lesions are frequently bilateral and multiple with involvement of the subcortical U fiber. Mass effect and hemorrhage are unusual. Demyelination is predominantly seen involving the parietal, occipital, and frontal lobes. Lesions lack enhancement and restricted diffusion. CJD is caused by a protease-resistant prion protein. Clinically, it presents with triad of myoclonus, progressive dementia, and periodic sharp-wave patterns on electroencephalography. The disease is characterized histo- pathologically by neuronal destruction, gemistocytic astrocyto- sis, spongiform changes, and prion deposition. On MRI, signal abnormalities are seen, most commonly in the gray-matter structures, including the cerebral cortex, basal ganglia, and thalami. Diffusion-weighted imaging may show restricted diffu- sion with bright signal on T2-weighted images in these areas. The variant form of CJD has a characteristic appearance on conventional MRI sequences (called the pulvinar sign), sym-

metric high signal on T2-weighted images, and FLAIR sequences in the posterior thalami.

Intracranial space-occupying lesions causing dementia are discussed in detail in Chapters 30 and 39. Cross-sectional imag- ing by either CT or MRI is sensitive and diagnostic of these con- ditions. NPH shows the classic imaging appearance of ventricu- lar dilatation out of proportion to the convexity sulci, which becomes significant with the appropriate clinical setting: the triad of dementia, recent-onset gait apraxia, and urinary incontinence. Dilation of the temporal horns occurs without the hippocampal atrophy seen in AD. Additionally, the parahippo- campal fissure is spared in NPH compared with hydrocephalus of other causes. Radioisotope cisternography demonstrates decreased CSF flow with delayed transit of the radiotracer to the subarachnoid space over the cerebral convexities. NPH can be identified on routine imaging, and patients achieve substan- tial benefit from CSF shunting.

Vascular dementia is the term used to define the cognitive impairment resulting from cerebrovascular disease and ische- mic or hemorrhagic brain injury. Pathophysiology, causes, crite- ria, and imaging findings are discussed in detail in Chapters 21 and 22.

References

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Structural Imaging of Dementia

Imaging Techniques

3 Magnetic Resonance Spectroscopy in Neurodegenerative Disorders

Tushar Chandra, Suyash Mohan, Sanjeev Chawla, and Harish Poptani

Magnetic resonance spectroscopy (MRS) has evolved as a useful technique to complement the anatomical information obtained from magnetic resonance imaging (MRI) with quantitative information on the chemical composition of brain in vivo. The fundamental theory of nuclear magnetic resonance (NMR) is the same for both MRI and MRS. MRI relies on obtaining ana- tomical information from hydrogen protons of water, whereas MRS provides information about the chemical environment of hydrogen protons of other brain metabolites. MRS has long been used in chemistry to characterize the synthesis and purity of chemical compounds; however, it has taken a long time for MRS to evolve to the extent that it can be relevant to diagnostic evaluation of patients and helpful in clinical decision-making. In current clinical practice, MRS is a useful noninvasive diagnos- tic tool to provide information about the metabolites in the brain and how they are affected in disease processes. Although the sensitivity of MRS to differentiate disease processes remains limited, it is a useful technique for complementing critical chemical information with the anatomical information obtained from MRI, and in many cases it can clinch the diagnosis.

The goal of this chapter is to familiarize readers with basic concepts of MRS and to analyze the role MRS plays in evalua- tion of the plethora of neurodegenerative disorders that affect the brain. This requires a thorough understanding of the basic principles that govern the technique, knowledge about the neu- ron-specific markers, and, most importantly, knowing how to implement the technique according to clinical requirements.

3.1 Basic Principles and Technique

Many fundamental physics concepts need to be understood before we can really look at how MRS gives us neurome- tabolic information. The first of these is the concept of nuclear magnetism.

3.1.1 Nuclear Magnetism

The basic concept of electromagnetism is that a charged particle has a magnetic field around it. This concept applies to biological tissues as well. Atoms possessing an even number of protons and neutrons are not magnetic and therefore cannot be used with this technique. The nuclei that can be used in MRS studies include hydrogen (H1), phosphorus (P31), C13, F19, and Na23; however, only H1 and P31 exist in biological tissues in high enough concentrations to obtain a spectrum. Proton spectros- copy that is based on H1, the most abundant nuclei in the body, has been most widely used to date.

3.1.2 Chemical Shift

The protons in various biological tissues are in a state of rota- tion (or precession) around an axis and get aligned to the direc- tion of the externally applied magnetic field. On application of a

radiofrequency pulse that matches the frequency of the exter- nal magnetic field, there is resonance. MRI uses this phenome- non to generate signals from protons in vivo.

The frequency of precession of an atom is given by the Lar- mor frequency, which is described by the following equation:

W 1⁄4 γBo ð3:1Þ

where γ = gyromagnetic ratio, Bo = magnetic field strength.1 For hydrogen (H1) nucleus at 1.5 tesla (T), the Larmor frequency is 63.5 MHz, whereas for phosphorus (P31), it is 25 MHz. Selec- tively applying radiofrequency pulses to match the Larmor frequency of a given nucleus allows for specific observation of different nuclei in MRS.

The magnetic field experienced by a nucleus depends not only on the external magnetic field but also on the small mag- netic fields that are generated by the electron clouds that sur- round the nucleus. These electron clouds shield the nucleus from the external magnetic field and result in a slightly differ- ent magnetic field actually experienced by the nucleus. As dif- ferent nuclei in biological tissues have different microenviron- ments (because of the electron cloud), the shielding effect is dif- ferent. Hence, based on the local chemical environment, the magnetic field experienced by the nuclei differs; the difference in local magnetic field is quite small and is called the chemical shift. This chemical shift can be expressed in terms of 1 Hz per million Hertz Hz, or simply parts per million (ppm). The chemi- cal shift specific for a given metabolite is independent of the external magnetic field strength and can help in identifying the compound on the MR spectrum. In the spectrum, the frequency characterized by chemical shift in parts per million is depicted on the x-axis, and the amplitude is depicted on the y-axis. The quantification of metabolite concentration can be made by the area under the peak.

3.1.3 Data Acquisition

Acquiring data is similar to MRI with a few additional steps. Shimming is the first step required to produce MRS data. Shim- ming refers to the process of creating a homogeneous magnetic field. The inhomogeneity can be minimized by tuning various field gradients in the x-, y-, and z-axis. This is usually done automatically but may also be done manually.

The second step is water and fat suppression. The concentra- tion of water protons is about ten thousand times the concen- tration of other metabolites in a biological tissue.2,3,4,5 The predominant spectrum, therefore, is of water; unless it is sup- pressed, the other metabolite cannot be observed to the extent of obtaining meaningful data. This can be done by adding water-suppressing pulses. Chemical shift selective water sup- pression is the most commonly applied technique for this pur- pose. Additionally, frequency-selective fat-suppression pulse is used to suppress the lipid and fat signal from the skull and marrow. Most of the lipid inside the brain is in the membrane- bound form and is not visible on in vivo MRS.

Magnetic Resonance Spectroscopy in Neurodegenerative Disorders

3.2 Techniques

Typically, MRS is performed after obtaining anatomical infor- mation by MRI. A suitable volume of interest is selected for placement of a voxel to obtain a spectrum from the region of interest.

Each of the many different MRS techniques that can be per- formed has its merits and limitations. MRS can be done using a single-voxel or multivoxel technique using short or long echo time (TE). Knowledge of these techniques and choosing the appropriate technique in a given clinical scenario are vital for successful implementation of MRS.

3.2.1 Single-Voxel Spectroscopy Versus

Chemical Shift Imaging

As the name suggests, single-voxel spectroscopy provides data from a single voxel at a time. The region of interest is selected based on the clinical question being addressed. It is highly accu- rate (with minimal partial volume) and provides good field homogeneity. The other technique is multivoxel spectroscopy, also known as chemical shift imaging or magnetic resonance spectroscopic imaging. This technique allows evaluation of a larger area of interest that encompasses multiple voxels and can be used with either a two-dimensional or three-dimen- sional technique. The tradeoff is longer acquisition time and a slightly less accurate voxel localization as the data from each voxel “bleed” into the neighboring voxel.

3.2.2 Short Versus Long Echo Time

In general, clinical MRS data vary with the choice of the TE used in the pulse sequence. Short TE techniques generally use a TE of approximately 20 to 40ms, which permits detection of additional metabolites that have a relatively short T2 compared with sequences with long TE. Furthermore, because of the lower TE value used, the signal-to-noise ratio (SNR) in these techniques is higher compared with long TE techniques;

however, the spectra can be “crowded” by the larger number of metabolite peaks. Thus, several metabolite peaks can appear as overlapping signals on short TE techniques.

Magnetic resonance spectroscopy can be performed with intermediate and long TE as well, in the range of 135 to 288 ms, which results in lesser metabolite peaks and a “cleaner” spec- trum. However, the SNR is worse compared with that with short TE techniques. An advantage of long TE techniques is that the lactate peak is inverted below the baseline in the form of a doublet at 135 to 144 ms, and this can help in separating the lipid spectrum from lactate, which remains over the baseline.

3.3 Metabolite Peaks

The following are the major metabolite peaks observed in proton MRS (▶ Fig. 3.1):
● N-acetylaspartate(NAA):NAAisthelargestmetabolitepeak

and resonates at 2.02 ppm. It is the marker of neuronal and axonal integrity. NAA is decreased in any pathological condi- tion that results in neuronal loss; hence, a decrease in NAA is seen in almost all neurodegenerative disorders. An increase in NAA is observed in Canavan’s disease (an autosomal reces- sive leukodystrophy), however, because it is caused by a defi- ciency of the enzyme aspartoacylase, which leads to elevation of NAA in the brain and urine.

● Creatine(Cr):Creatineandphosphocreatineresonateat 3.0 ppm. Cr is a marker for brain energy metabolism and is thought to be stable; it is used as an internal reference for other brain metabolites.

● Choline(Cho):Choline-containingcompounds(freecholine, phosphocholine, and glycerophosphocholine) resonate at 3.2 ppm. Cho is a constituent of cell membrane and is a marker for membrane turnover. The Cho level is increased in conditions with rapid cell membrane turnover or an increased number of cells. Cho levels are high in tumors and demyelinating conditions.

● Lipids:Lipids(orfreefattyacids)resonatefrom0.9to
1.5 ppm. Lipids are markers of severe cell stress and tissue

Fig. 3.1 Axial T1-weighted image (a) from a normal healthy subject demonstrating voxel position from right frontal lobe. Proton magnetic resonance spectra acquired with positron-resolved spectroscopy sequence using short echo time (TE; 30 ms); (b) long TE (135 ms); (c) displaying characteristic resonances: N-acetyl aspartate (NAA) (2.02 parts per million [ppm]), creatine (Cr, 3.02 ppm), choline (Cho, 3.22 ppm), glutamate (Glx, 2.35 ppm), and myo-inositol (mI, 3.56 ppm) from the voxel shown in (a). Note the spectra acquired with TE = 30 ms. (b) Broader resonances along with appreciable baseline distortion, mainly because of contamination of signals from shorter T2 components such as macromolecules. Also because of shorter T2 value of Cr than that of Cho, a higher Cho:Cr ratio is observed at longer TE spectra (c) compared with shorter TE spectra (b).

Imaging Techniques

damage, such as the liberation of membrane lipids that is seen

in the necrotic brain tumors.

● Lactate: Lactate is seen as an inverted doublet at 1.3 ppm on
MRS performed at a TE of 135 to 144 ms. At low TE values (20 to 40 ms) and higher TE values (270 ms), lactate is seen as a doublet peak above the baseline that overlaps with the lipid peak at short TE spectra. Lactate is not normally detectable in the brain spectra, and the presence of lactate signifies lack of oxidative phosphorylation and onset of anaerobic glycolysis. Increased lactate levels are seen in ischemia, hypoxia, brain tumors, and mitochondrial disorders.

● Myo-inositol (mI): mI resonates at 3.56 ppm and is seen when using a short TE; it is an osmolyte and astrocytic marker. An increase in mI is seen in Alzheimer’s disease (AD) and fronto- temporal dementias (FTDs).

● Glutamine and glutamate (Glx): These metabolites resonate from 2.2 to 2.4 ppm. Increased levels are noted in metabolic conditions resulting in hyperammonemia, such as hepatic encephalopathy.
3.4 Normal Aging
The normal process of aging induces many microstructural changes in the brain that involve both the cortex as well as the white matter. The volume of the brain decreases by approxi- mately 5% every decade after the age of 40.6 Structurally, in addition to the volume loss, there is increased iron deposition and increased white matter hyperintensities. In terms of chemi- cal composition, there is decreased brain water content and increased cerebrospinal fluid (CSF).7 Within the brain, however, not all structures are affected equally by aging. The earliest affected area is the prefrontal cortex, followed by the striatum, temporal lobe, cerebellar vermis, cerebellar hemispheres, and hippocampus. The occipital cortex is the least affected.8
Individual variations in neurometabolite levels correlate sig- nificantly with cognitive function in the elderly. Maintenance of creatine level is important in the pathophysiology of normal aging. Proton MRS studies have shown higher Cr levels in healthy aging brains compared with healthy young brains.9,10 Creatine is a sum of phosphocreatine and creatine. Phospho- creatine is converted to adenosine triphosphate by creatine kinase, an enzyme that decreases with aging. Therefore, it is logical that Cr concentration increases with age. Furthermore, increased Cr level may be a marker of decreased brain energy metabolism and may be related to age-related mild cognitive impairment or even frank dementia.11,12 Kadota et al have also demonstrated a steady and almost linear decrease in the white matter NAA:Cr ratio starting in the third decade and continuing into old age.13 No correlation has been found between NAA or Cho levels and the process of aging.
3.5 Alzheimer’s Disease
Alzheimer’s disease is the leading cause of dementia in the elderly. Typically, there is progressive dementia that most profoundly affects the declarative memory, especially early in the disease process. The disease is diagnosed based on clini- cal criteria that require exclusion of other causes of dementia and demonstration of progressive loss in more than one

domain. Clinical diagnosis of AD is currently made by the Diagnostic and Statistical Manual of Mental Disorders, 4th edi- tion text revision and the National Institute of Neurological and Communicative Disorders and Stroke Alzheimer’s Crite- ria. The definitive diagnosis of AD, however, can be made only at autopsy. Pathological changes develop first in the hip- pocampus and the entorhinal cortex and include a combina- tion of neuronal loss, amyloid deposition, glial proliferation, decreased synaptic density, and vascular changes with forma- tion of senile plaques and NFTs.14,15,16

The role of imaging in AD cases is to diagnose the condition before the onset of overt symptoms to provide a therapeutic window for drug treatment. Anatomical changes in the brain develop late in the disease process, and findings on MRI can be nonspecific. Although hippocampal atrophy is the hallmark of AD, it can be seen in various other forms of neurodegeneration.

The temporal evolution of neuropathological changes in AD is thought to follow a distinct pattern. The earliest changes of AD in the preclinical stage develop in the entorhinal cortex and hippocampus. Subsequently, there is involvement of the neo- cortex and development of overt dementia. Many studies have correlated the neuropathological findings to the development of dementia.17,18 MRS also mirrors these findings, with abnor- mal spectra from the posterior cingulate gyrus and hippocam- pus in early AD.

For a long time, MRS has been used in neurodegenerative dis- orders. Klunk et al were probably first to demonstrate decreased NAA levels on spectra from perchloric extracts in patients with AD.19 The primary neurometabolites affected in AD are NAA and mI. Because NAA is found in all neurons, a decrease in NAA is expected in any condition that involves neu- ronal loss. It is a marker of neuronal viability and functionality. Increased levels of mI reflect glial proliferation or increased glial size.20 Elevation of mI in AD is thought to represent glial activa- tion and microglial proliferation.21

The role of other neurometabolites in the diagnosis of AD is not certain. Creatine levels are used as an internal reference to calculate ratios. Regarding Cho, results have been conflicting among various studies, and no clear consensus of authorities has been established as to whether it is increased, decreased, or unchanged in AD.

The hallmark of spectroscopic alterations in AD is elevation of mI:Cr and a decrease in NAA:Cr ratios in various anatomical regions within the brain.19–23 It has also been found that mI:Cr is elevated in mild cognitive impairment and mild AD, even in the absence of a decrease in NAA:Cr.21,24 Therefore, the initial change in the progression of AD is elevation of mI:Cr, and a decrease in NAA:Cr develops later. Furthermore, the decrease in NAA:Cr correlates with dementia severity and cognitive symp- toms, indicating that decreased NAA is the marker to quantita- tively assess disease severity.25,26 MRS has not been widely used to assess treatment response, although a few single-site trials have shown improvement in NAA:Cr ratios after therapy. No multicentric data have reliably demonstrated improvement in NAA:Cr or mI:Cr ratios after drug therapy.

3.6 Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB) is the second most common cause of dementia, after AD, and it frequently coexists with AD.

Magnetic Resonance Spectroscopy in Neurodegenerative Disorders

The classic clinical picture is a triad of fluctuating cognitive impairment, recurrent visual hallucinations, and parkinsonism. The symptoms overlap with both AD and Parkinson’s disease. DLB is pathologically characterized by the finding of Lewy bod- ies in the cortex. Lewy bodies are seen in the substantia nigra in Parkinson’s disease. In patients with DLB, loss of cholinergic neurons is thought to account for degeneration of cognitive function, and the death of dopaminergic neurons appears to be responsible for degeneration of motor control.

The most important spectroscopic discriminating feature of DLB from other forms of dementias is the finding of a normal NAA:Cr ratio in the posterior cingulate gyrus. Patients with AD, FTD, or vascular dementia have decreased NAA:Cr ratios in this region.27 Molina et al demonstrated significantly lower mean NAA:Cr, Glx:Cr, and Cho:Cr ratios in the white matter in patients with DLB compared with controls.28 The spectra obtained from the gray matter were normal, suggesting involvement of white matter in DLB, a finding subsequently confirmed by diffusion tensor imaging.29,30 Kantarcki et al dem- onstrated increased Cho:Cr in the posterior cingulate gyrus in patients with DLB. The Cho level was also elevated in DLB as well as in AD.27 Xuan et al showed that patients with DLB had significantly lower NAA:Cr ratios in the bilateral hippocampi, whereas the Cho:Cr ratio did not differ from the control group.31 However, AD can coexist in many patients with DLB, and thus the hippocampal spectrum in these patients may reflect pathological changes as a result of AD rather than of DLB.

3.7 Frontotemporal Dementia

Frontotemporal dementia is a progressive neurodegenerative disorder characterized by tau- or ubiquitin-positive spherical cortical inclusions, gliosis, and microvacuolar degeneration predominantly involving the frontal and anterior temporal lobes.32,33,34,35 FTD accounts for nearly 20% of presenile demen- tia cases. The disease has three major variants: the behavioral variant, semantic dementia, and progressive nonfluent aphasia. On the basis of cognitive neuropsychological evidence, the ven- tromedial prefrontal cortex is a major locus of dysfunction early in the course of the behavioral variant of FTD.36

Proton MRS studies have demonstrated a decrease in NAA levels and an increase in Cho and mI from many sites, includ- ing the anterior and posterior cingulate cortex, medial frontal cortex, and temporal cortex. This pattern is similar to the findings observed in patients with AD, and there is consider- able overlap in the neurometabolite abnormalities observed in these conditions. Chawla et al demonstrated similar find- ings in spectra obtained from the dorsolateral prefrontral cortex as well as the motor cortex in these patients (▶ Fig. 3.2, ▶ Fig. 3.3).37 They suggested a possible association between FTD and motor neuron disease (MND) in view of the similar metabolic alterations in the motor cortex from this subset of patients. This is supported by the fact that some FTD patients with clinically normal motor examination dem- onstrate abnormal electromyography of the tongue and extremity muscles, as seen in MND.

Fig. 3.2 Proton magnetic resonance spectro- scopic imaging grids overlaid over axial T2- weighted images demonstrating the location of voxels from dorsolateral prefrontal cortex region from a frontotemporal dementia (FTD) patient (a) and from a healthy controls (b). Correspond- ing spectra (echo time [TE] = 30 ms) from the voxels demonstrating various metabolites. Note the reduced N-acetyl aspartate (NAA) and ele- vated resonances of choline (Cho) and myo- inositol (mI) in FTD patients compared with controls.

Imaging Techniques

Fig. 3.3 Proton magnetic resonance spectro- scopic imaging grids overlaid over axial T2- weighted images demonstrating the location of voxels from motor cortex region from a fronto- temporal dementia (FTD) patient (a) and from healthy controls (b). Corresponding spectra (echo time [TE] = 30 ms) from the voxels demonstrating various metabolites. Please notice reduced N- acetyl aspartate (NAA) and elevated resonances of choline (Cho) and myo-inositol (mI) in FTD patients compared with controls.

3.8 Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) is an incurable and invariably fatal neurodegenerative disease caused by infection with agents called prions. Prions are misfolded proteins, and they cause the properly folded proteins in their host to become misfolded, leading to rapid neurodegeneration. Clinical presentation is rapidly progressive dementia and myoclonus. Apart from the clinical signs and symptoms, diagnosis can be made by demon- strating characteristic triphasic spikes on electroencephalogra- phy and 14–3-3 protein in CSF analysis. The disease has four subtypes: sporadic, variant, iatrogenic, and familial. It is impor- tant to differentiate the variant form because it is transmitted by cattle infected by bovine spongiform encephalopathy virus. Variant CJD has a pathognomic “pulvinar” sign on MRI, defined as high T2 signal in the pulvinar thalami, which is higher than that in the basal ganglia. The other subtypes of the disease demonstrate high T2 signal and restricted diffusion in the stria- tum, thalamus, and cortex.

The characteristic histopathological features are spongiform degeneration of the neurons, astrocytic gliosis, amyloid plaque formation, and neuronal loss. Spongiform degeneration is seen in the cortex, putamen, caudate nucleus, thalamus, and hippo- campus. Spongiform change or vacuolization restricts free dif- fusion of protons, leading to hyperintensity of lesions on diffu- sion-weighted imaging (DWI).38 The characteristic findings are restricted diffusion in the basal ganglia and the cortex. On DWI, changes are detected earlier during the disease course com- pared with T2 and fluid-attenuated inversion recovery (FLAIR)

sequences.39,40 The disease can be followed up with serial MRI using DWI.41,42

As with all other forms of neurodegeneration, MRS demon- strates decreased NAA from the involved regions in patients with this disease. Various authorities have noted that the decrease in NAA occurs relatively late during the course of dis- ease.43 In cases of sporadic CJD, involvement of basal ganglia has been noted to correlate with rapid progression.44 Kim et al demonstrated that basal ganglia involvement was strongly associated with lower NAA:Cr ratios and shorter disease dura- tion. Therefore, NAA:Cr ratios of the affected brain at the early stage of sporadic CJD can be a useful parameter in predicting the clinical course.45

3.9 Huntington Disease

Huntington disease (HD) is a genetic neurodegenerative dis- order that affects muscle coordination and leads to cognitive decline and psychiatric symptoms. It is the most common genetic cause of involuntary writhing movements called chorea. The disease is caused by expansion of a CAG triplet repeat stretch within the HD or IT15 gene located on the short arm of chromosome 4, which encodes a protein called huntingtin. This expansion results in synthesis of an abnormal protein that causes neuronal degeneration and brain atrophy.

Striatal atrophy is considered the hallmark of pathological findings in HD.46 MRI demonstrates atrophy in the caudate nucleus and putamen, much earlier than clinical manifestations of the disease.47

Magnetic Resonance Spectroscopy in Neurodegenerative Disorders

Several investigators have shown MRS to demonstrate altera- tions in NAA and Cr levels in the striatum.48,49 A decrease in NAA corresponds to neuronal loss, and decreased Cr is consist- ent with impaired energy metabolism seen in this disease. San- chez et al demonstrated decreased Cr and NAA in the striatum in patients with HD.50 This was also confirmed by several other investigators, including a study by Bogaard et al, in which a high-field 7T magnet was used.51 Bogaard et al also demon- strated a relationship between the differences in NAA and Cr levels and clinical measures of disease severity. Therefore MRS potentially could be used to monitor the disease process.

Another postulated mechanism of development of HD is the theory of abnormal excitotoxicity of neurons, which states that abnormal activation of neurons leads to cell death.52 This event is caused by an increase in glutamate levels, which is thought to be an excitotoxic neurometabolite. Taylor et al demonstrated increased glutamate:Cr levels in HD,53 supporting this hypothe- sis; however, Bogaard et al51 found decreased glutamate levels in the striatum in patients with HD, a finding that can be explained by a decrease in the number of viable neurons to the extent that glutamate is lowered along with the neuron count.

3.10 Parkinson’s Disease

and Related Disorders

Parkinson’s disease is a progressive neurodegenerative disorder characterized by bradykinesia, rigidity, tremor, gait disorders, and cognitive dysfunction. Dementia can occur late in course of the disease. The disease is diagnosed by history and the clinical examination. The pathological hallmark of Parkinson’s disease is selective loss of dopaminergic neurons in the pars compacta of substantia nigra. As the disease progresses, there is involve- ment of the basal forebrain and the neocortex. Another impor- tant pathological feature is the presence of Lewy bodies.

Magnetic resonance spectroscopy is a powerful tool for quan- tification of brain metabolites that gives us insight into the pathophysiology of these disorders. Both proton and phospho- rus spectroscopy have been used by several authors for Parkin- son’s disease and related disorders. Mitochondrial dysfunction in the neostriatal dopaminergic neurons has been implicated in the disease pathogenesis, and MRS can target this condition.

Early studies showed no significant reduction in NAA in the striatum,54 putamen, and globus pallidus.55 Hattingen et al per- formed combined phosphorus and proton MRS in the neostria- tal region in 16 patients with early and 13 patients with advanced Parkinson’s disease and in 19 age-matched controls. They found bilateral reduction of high-energy phosphates such as adenosine triphosphate and phosphocreatine with normal levels of low-energy metabolites, such as adenosine diphosphate and inorganic phosphate.56 They concluded that mitochondrial dysfunction is an early and persistent event in the pathophysiology of dopaminergic degeneration in Parkin- son’s disease.

Recently, Zhou et al performed proton MRS in the substantia nigra in patients with Parkinson’s disease and found signifi- cantly lower NAA:Cr, NAA:Cho, NAA:(Cho + Cr) levels in Parkin- son’s disease patients compared with healthy controls. They also observed significantly lower NAA:Cr, NAA:Cho, NAA:

(Cho + Cr) in patients with severe Parkinson’s disease compared with patients with mild Parkinson’s disease.57

Clinically, diagnosis of Parkinson’s disease can be quite chal- lenging, and the differential diagnosis includes multisystem atrophy (MSA), progressive supranuclear palsy (PSP), and corti- cobasal degeneration (CBD). In MSA, the middle cerebellar peduncle and pontine nuclei are severely involved, whereas in PSP, the dentate nuclei and superior cerebellar peduncles are afflicted. In CBD, there is severe involvement of the thalamus and pontocerebellar locations. The specific diagnosis of these diseases is difficult and calls for quantitative biomarkers. MRS studies focusing on differentiating these disorders are sparse and do not provide consistent results. Further multicenter trials and prospective studies are required to evaluate the role of MRS in discriminating these disorders.

3.11 Amyotrophic Lateral

Sclerosis

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease, is a progressive neurodegenerative MND that involves the motor cortex, corticospinal tract, upper brainstem, and spinal cord anterior horn cells.58 The disease is uniformly fatal and involves both the upper motor neurons and lower motor neurons. The precise cause of this devastating neurodegenerative disorder is not yet known. The pathogenesis of this disease involves loss of neuronal integrity in the corticospinal tracts. Because NAA is a surrogate marker for neuronal integrity and viability, MRS can be helpful in providing critical information that might not be available on conventional MRI sequences (▶Fig. 3.4). Jones et al59 performed MRS on ALS and reported reduction of NAA and NAA:Cho ratios in motor cortex and adjacent cortex Many studies have shown decreased NAA:Cr ratios in areas of the brain that contribute significantly to corticospinal tracts in patients with ALS.60,61,62,63

In addition to decreased NAA, recent focus has been on the role of glutamate (glu) in the pathogenesis of ALS. The levels of glu have been found to be elevated in the plasma and CSF of patients with ALS.64,65 Glutamate is a neurometabolite that takes part in synaptic transmission. In patients with ALS, there is decreased reuptake of glu by postsynaptic receptors, which leads to increased activation of excitatory amino acid receptors, causing increased calcium ion uptake by the neurons. This is lethal for the cell and can cause activation of catabolic enzymes such as protein kinases and phospholipases that can lead to neuronal death.66

Glu and glutamine (gln) levels are thought to be relatively constant in the brain, and these metabolites appear as overlap- ping multiple peaks at 2.35 and 3.75 ppm. The combined peak from glu and gln is generally also referred to as Glx. Han at el demonstrated increased glu:Cr and Glx:Cr ratios in spectra obtained from the posterior limb of the internal capsule in patients with ALS.67

Therefore, for clinical evaluation of ALS, glu:Cr, Glx:Cr, and NAA:Cr ratios are ideal indexes. The ability of MRS to provide qualitative information that can be monitored for disease pro- gression over time makes it an ideal modality for evaluation of these patients.

Imaging Techniques

Fig. 3.4 Axial T1-weighted images demonstrat- ing region of interests from precentral gyrus (pre-CG, red), postcentral gyrus (post-CG, green), and posterior limb of internal capsule (IC, yellow) from a representative amyotrophic laterial sclerosis (ALS) patient. Occipital region (OR, orange) may be considered as an internal control as this region has been reported to be relatively spared from atrophy and abnormal glucose metabolism in ALS patients. Proton magnetic resonance spectra from these regions displaying different metabolites. Compared with occipital region, reduced NAA and elevated choline (Cho) resonances are discernible from other locations.

Fig. 3.5 Axial T2 fluid-attenuated inversion recovery (FLAIR) image demonstrating hyperintense multiple sclerosis lesions in periventricular white matter regions. A repre- sentative voxel encompassing multiple sclerosis plaque is shown, along with corresponding spectrum (echo time [TE] = 30 ms) displaying various metabolites. Please note the diminished signal from N-acetyl aspartate (NAA) and elevated signals from choline (Cho) and myo-inositol (mI). Glx, glutamate.

3.12 Multiple Sclerosis

Multiple sclerosis (MS) is the most common autoimmune neuro- degenerative/complex inflammatory disorder, especially in young adults. Most patients with MS follow a relapsing-remit- ting course characterized by relapses of variable severity fol- lowed by remissions of varying duration. An increasing body of evidence suggest sthat MS is characterized by demyelination, axonal loss, inflammation, gliosis, and edema.

Contrast-enhancing acute MS lesions typically show eleva- tions in Cho and lactate and lipid levels during the first 6 to 10 weeks after their appearance. The NAA concentration in the acute phase of lesion development is highly variable, ranging from almost no change to significant decreases. Creatine, which is generally higher in glial cells than in neurons, usually remains stable; however, significant increases68 or decreases69 have been observed in MS. These changes may be related to varying amounts of neuronal and oligodendroglial loss and astrocytic proliferation rather than altered energy metabolism. Increases have also been reported in mI levels, likely a result of microglial proliferation and in Glx levels secondary to active inflammatory infiltrates (▶ Fig. 3.5).

Acute MS plaques usually progress to chronic plaques that appear hypointense on T1-weighted images, also commonly referred to as “black holes.” These lesions harbor varying degrees of neuronal and axonal loss as inflammatory process decreases, edema resolves, and reparative mechanisms such as remyelination become active. These pathological changes can be seen as alterations in the metabolite pattern. There is a progressive return of lactate levels to normal levels within weeks, whereas Cho and lipid levels decrease for some months but do not always return to normal values. A moder- ate increase in Cr may also be observed secondary to gliosis and remyelination.70 NAA may further decrease, indicating progressive neuronal or axonal damage or show partial recovery over several months without reaching normality. Several mechanisms have been proposed to explain this behavior, such as resolution of edema and inflammation, an increase in the diameter of previously shrunken axons sec- ondary to remyelination, and reversible metabolic changes in neuronal mitochondria.71

It is now widely accepted that normal-appearing white matter (NAWM) and normal-appearing gray matter (NAGM) regions, which appear normal both macroscopically and

Magnetic Resonance Spectroscopy in Neurodegenerative Disorders

3.13 Human Immunodeficiency

Virus Infection

Involvement of the central nervous system is a common feature of human immunodeficiency virus (HIV) infection, and in par- ticular subcortical gray matter regions carry a heavy HIV load. Neurons have not been appreciably infected by HIV owing to a lack of CD4 + cell surface receptors. However, an inflammatory response involving microglial cells and perivascular macro- phages leads to neuronal dysfunction and ultimately neuronal loss. In the initial phase, brain inflammation caused by the HIV is clinically asymptomatic and turns to mild-to-advanced HIV- associated neurocognitive impairments (HNCIs) and finally in about 20% of patients to dementia or encephalopathy in the course of HIV infection.80

Several 1H MRS studies81,82,83 have reported reduced NAA suggestive of axonal loss along with increased Cho secondary to infiltration by inflammatory cells and increased mI related to gliosis from patients with HNCIs. Furthermore, abnormal metabolite pattern has also been observed, even from neuro- logically asymptomatic HIV patients who do not show any abnormalities on conventional MRI, suggesting a higher sensi- tivity of 1 H MRS in the detection of early brain damage induced by HIV (▶ Fig. 3.6). In a cohort of HIV-positive patients treated with highly active antiretroviral therapy (HAART), Roc et al84 observed elevated levels of lipids and lactate from lenticular nuclei, suggesting that HIV-induced oxidative stress and inflammation occur even after initiation of HAART. Taken

on conventional MRI, are actually not normal. Several studies72,73,74 have also reported abnormal metabolite pat- tern from NAWM and NAGM regions in MS patients com- pared with normal subjects.

To investigate the course of metabolism from MS plaques at different stages of evolutionary development, several longitudi- nal studies have been performed.70,75 A reduction in NAA:Cr ratio was reported by most of these studies during the course of the disease. A few investigators found a subsequent recovery of NAA:Cr over time, leading to the suggestion that axonal loss is not the only mechanism of reduction in the NAA:Cr ratio. An increase in the Cho:Cr and its subsequent normalization has also been reported. A small number of studies have reported that Cr concentration does not remain stable over time.70 In a study performed by Narayana et al,76 NAA levels reached their minimum value when lesion volume reached its maximum. In another serial study, increased Cho and lipid levels were observed from NAWM regions that subsequently went on to develop MRI visible lesions.77

Using whole-brain MRS, Gonen et al observed lower global NAA in MS patients compared with controls.78 This difference was greater among older than among younger subjects. Another study observed a 3.5 times faster decrease in global NAA levels compared with atrophy in MS patients, implying that neuronal cell injury precedes atrophy and that degener- ating axons may leave behind their empty myelin sheaths. This study suggests that NAA is a more sensitive indicator of disease progression than either lesion load or atrophy in MS.79

Fig. 3.6 T1-weighted images (first column) and corresponding spectra from a representative control subject (a), human immunodeficiency virus (HIV) + subsyndromic (b), HIV + sympto- matic (c) patients are shown. Proton magnetic resonance spectroscopic imaging grid is centered over subcortical gray matter region for each of the subjects. Spectra shown on the right were taken from voxels overlapping the lenticular nuclei (blue squares). The x-axis for all the spectra ranged from 0.2 to 4.3 parts per million (ppm). Spectra acquired at echo time (TE) = 135 ms (second column) and at TE = 30 m (third column) display resonances of N-acetyl aspartate (NAA, 2.02 ppm), creatine (Cr, 3.02 ppm), choline (Cho, 3.22 ppm), lactate (Lac), and lipid (Lip) at

1.33 ppm. Note that the peak of lactate is inverted below the baseline from spectra acquired at TE = 135 ms (second column).

Imaging Techniques

together, these studies suggest that quantitative 1 H MRS may play a role in the objective assessment of the presence, magni- tude, and progression of brain involvement in HIV infection.

3.14 Summary and Future

Perspectives

Magnetic resonance spectroscopy offers a noninvasive means of assessing in vivo brain function and dysfunction, both in nor- mal aging as well as in a plethora of neurodegenerative disor- ders. Studies obtained at higher field strengths have resulted in sampling of smaller tissue volumes, greater SNR, and higher metabolic spatial resolution. Despite these significant technical advancements in the acquisition and analysis of proton MRS, translation of MRS in clinical practice is still not seamless, mainly because of the lack of normative data and an insufficient understanding of the pathologic basis of proton MRS metabolite changes.

We believe further advances in these areas would expand the impact of proton MRS as a biomarker for the early detection of neurodegenerative diseases and in monitoring the potential neuroprotective effects of newer experimental therapy in this era of personalized medicine.

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[76] Narayana PA, Doyle TJ, Lai D, Wolinsky JS. Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 1998; 43: 56–71

[77] Tartaglia MC, Narayanan S, De Stefano N et al. Choline is increased in pre- lesional normal appearing white matter in multiple sclerosis. J Neurol 2002; 249: 1382–1390

[78] Gonen O, Catalaa I, Babb JS et al. Total brain N-acetylaspartate: a new mea- sure of disease load in MS. Neurology 2000; 54: 15–19

[79] Ge Y, Gonen O, Inglese M, Babb JS, Markowitz CE, Grossman RI. Neuronal cell injury precedes brain atrophy in multiple sclerosis. Neurology 2004; 62: 624–627

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[82] Meyerhoff DJ, Bloomer C, Cardenas V, Norman D, Weiner MW, Fein G. Elevated subcortical choline metabolites in cognitively and clinically asymp- tomatic HIV + patients. Neurology 1999; 52: 995–1003

[83] Suwanwelaa N, Phanuphak P, Phanthumchinda K et al. Magnetic resonance spectroscopy of the brain in neurologically asymptomatic HIV-infected patients. Magn Reson Imaging 2000; 18: 859–865

[84] Roc AC, Ances BM, Chawla S et al. Detection of human immunodeficiency virus induced inflammation and oxidative stress in lenticular nuclei with magnetic resonance spectroscopy despite antiretroviral therapy. Arch Neurol 2007; 64: 1249–1257

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. [43] Bruhn H, Weber T, Thorwirth V, Frahm J. In-vivo monitoring of neuronal loss in Creutzfeldt-Jakob disease by proton magnetic resonance spectroscopy. Lancet 1991; 337: 1610–1611

. [44] Yi SH, Park KC, Yoon SS, Kim EJ, Shin WC. Relationship between clinical course and Diffusion-weighted MRI findings in sporadic Creutzfeldt-Jakob disease. Neurol Sci 2008; 29: 251–255

. [45] Kim JH, Choi BS, Jung C, Chang Y, Kim S. Diffusion-weighted imaging and magnetic resonance spectroscopy of sporadic Creutzfeldt-Jakob disease: cor- relation with clinical course. Neuroradiology 2011; 53: 939–945

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[64] Rooney WD, Miller RG, Gelinas D, Schuff N, Maudsley AA, Weiner MW. Decreased N-acetylaspartate in motor cortex and corticospinal tract in ALS. Neurology 1998; 50: 1800–1805

[65] Rule RR, Suhy J, Schuff N, Gelinas DF, Miller RG, Weiner MW. Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study. Amyotroph Lateral Scler Other Motor Neuron Disord 2004; 5: 141–149

[66] Heath PR, Shaw PJ. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve 2002; 26: 438–458

[67] Han J, Ma L. Study of the features of proton MR spectroscopy ((1)H-MRS) on amyotrophic lateral sclerosis. J Magn Reson Imaging 2010; 31: 305–308
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[74] Inglese M, Li BS, Rusinek H, Babb JS, Grossman RI, Gonen O. Diffusely elevated cerebral choline and creatine in relapsing-remitting multiple sclerosis. Magn Reson Med 2003; 50: 190–195

[75] De Stefano N, Matthews PM, Fu L et al. Axonal damage correlates with dis- ability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 1998; 121: 1469–

Imaging Techniques

4 SPECT and PET Imaging of Neurotransmitters in Dementia

Mateen Moghbel, Andrew Newberg, Mijail Serruya, and Abass Alavi

Positron emission tomography (PET) and single-photon emis- sion computed tomography (SPECT) have contributed sub- stantially to uncovering the basis of various neuropsychiatric disorders. Our understanding of the pathophysiology and treat- ment of these complex diseases has been informed by studies on cerebral metabolism, blood flow, and neurotransmitters that have been carried out using these functional imaging modal- ities. As novel radiotracers are developed and innovative appli- cations are devised, PET and SPECT will continue to provide tre- mendous insight into the causes, diagnosis, and treatment of neurologic and psychiatric diseases. Perhaps the most common disorders studied with PET and SPECT are those that result in dementia symptoms. Thus, PET and SPECT have been used extensively in the study of Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and other related disorders. Although much of the focus has been on the evaluation of cerebral blood flow and glucose metabolism, a wide array of studies have explored various neurotransmitter systems in these disorders. This chapter reviews the current literature regarding neuro- transmitter imaging with PET and SPECT in the evaluation of dementia.

Fluorine 18 (18F)-labeled glucose is the radioligand most commonly used in clinical brain PET. Glucose is radiolabeled with 18F by substituting the hydroxyl group with 18F to create the radioligand 2-deoxy-2-fluorodeoxyglucose ([18F]FDG). [18F]FDG is taken up by brain cells in the same way as unlabeled glucose, but after phosphorylation to [18F]FDG-6-phosphate, it cannot continue glycolysis and becomes trapped in the brain cell. The PET scanner detects the amount of labeled glucose taken up by the brain because the 18F isotope, as well as the other PET isotopes, undergoes radioactive decay to emit a posi- tron and neutrino, the process of positive beta decay. The emit- ted positron travels through tissues before colliding with an electron in its path, causing both particles to be annihilated. The nuclei of positron emitters are generally rich in protons and consequently attempt to maintain stability by gaining neutrons and losing excess protons. This can be accomplished in one of two isobaric decay processes: positron emission or electron capture. The mass number in both the parent and daughter nuclei remains the same in either process. A PET scan- ner then detects the photons that are released by the annihila- tion in coincidence, forming a PET image. The resulting image is a map of the distribution of the annihilations occurring within the organ of interest. The map illustrates the particular tissues in which the tracer has become concentrated. The result is a detailed evaluation of the pattern of cerebral metabolism (▶Fig. 4.1). A nuclear medicine physician can then analyze these results in the context of the patient’s diagnosis and treat- ment plan. For brain imaging, FDG is the most common tracer for clinical purposes, but there are many experimental tracers that have been used to evaluate different neurotransmitter sys- tems in patients with neurodegenerative disorders. These trac- ers bind to specific receptors in the brain, and the amount of radioactivity detected in specific structures is correlated with the receptor availability.

For SPECT imaging, the two most common tracers are hexam- ethylpropyleneamine (HMPAO) and ethyl cysteine dimer, both of which are used for evaluating cerebral blood flow. The basic SPECT imaging technique requires injection of a gamma- emitting radioisotope combined with a particular molecule that follows some type of neurophysiologic process, including binding to neurotransmitter receptors. Subsequently, because of the gamma emission of the isotope, the ligand concentration is visualized by a gamma camera. Tomography enables the localization of radioactivity and, hence, the location of the tracer concentration. Although SPECT imaging requires longer acquisition times, has poorer spatial resolution, and has greater susceptibility to artifacts, technical advancements in the instru- ments of SPECT have begun to markedly improve these limita- tions. Most clinical SPECT systems that are used to perform patient studies still utilize scintillation cameras with NaI(Tl) (thallium-activated sodium iodide) detectors. These systems consist of one or more scintillation camera heads attached to a gantry that revolves around the patient to collect projection views. The most common configuration has two scintillation cameras that are fixed at either 90 or 180 degrees or have the capability to be positioned at selected orientations. The projec- tion information required for SPECT is acquired by gamma-ray detectors, and much of the quality of the projection depends on the properties of these detectors.

Over the years, numerous tracers have been developed for both PET and SPECT imaging for neurologic applications. After their injection into a subject, many of these experimental trac- ers function by binding to receptors for neurotransmitters, such as serotonin and dopamine. These tracers for both SPECT and PET imaging of neurotransmitters in dementia are particu- larly useful for the study of neurodegenerative disorders. This chapter reviews some of the major applications and findings of

Fig. 4.1 Normal fluorodeoxyglucose (FDG) positron emission tomog- raphy scan from a healthy control without any neuropsychiatric disorders. The scan reveals relatively uniform metabolism in all cortical and subcortical structures.

SPECT and PET Imaging of Neurotransmitters in Dementia

PET imaging in the evaluation of neurodegenerative disorders that result in dementia.

4.1 Alzheimer’s Disease

The criteria for the diagnosis of AD were originally defined by the Working Group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) in 1984.1 The criteria for the diagnosis of AD include progressive, chronic cognitive deficits in the middle-aged and elderly patients without any identifiable underlying cause. Although patients in the advanced stages of dementia can often be accu- rately diagnosed, it is a challenge to differentiate between AD and other forms of dementia in the earlier stages.2,3 With the aid of functional imaging modalities like PET, the diagnostic and etiologic questions that continue to surround AD may be answered in years to come.

Most PET studies of AD have focused on glucose metabolism and have found that whole-brain glucose metabolism (CMRGlc) is reduced in AD patients; the bilateral parietal and temporal lobes are especially affected.4,5,6,7,8,9,10 This parietal hypometab- olism (▶ Fig. 4.2) is often considered the “typical” presentation of AD and may be particularly pronounced in patients under the age of 65 years.11,12,13 Based on a large number of studies, this pattern of parietal hypometabolism carries a general sensi- tivity and specificity of approximately 85 and 60%, respectively. However, the pattern is not pathognomonic for AD and might also be observed in patients with PD, bilateral parietal subdural hematomas, bilateral parietal stroke, and bilateral parietal radi- ation therapy ports.14 It has also been reported that the magni- tude and extent of hypometabolism correlate with the severity of the dementia symptoms. Patients with moderate dementia have been found to have significant hypometabolism in the left midfrontal lobes, bilateral parietal lobes, and the superior tem- poral regions. In more advanced cases of AD, the same regions have an even greater reduction in metabolism.

Another application of PET is the measurement of changes in various neurotransmitter systems that are associated with AD. It has been reported in the literature that the neocortex, hippo- campus, and amygdala of AD patients demonstrate significantly reduced acetylcholinesterase activity, which suggests that cho- linergic innervation to the basal forebrain has been lost in these patients.15 The regions that were most affected were the tem- poral and parietal cortices. A study by Kuhl et al showed that the onset of AD before 65 years of age correlated with reduced binding of iodobenzovesamicol (an in vivo marker of the vesicu- lar acetylcholine transporter) throughout the cerebral cortex and hippocampus. However, when onset of disease occurred after age 65, binding reductions were limited to the temporal cortex and hippocampus.16

A small PET study of nine AD patients, eight patients with mild cognitive impairment (MCI), and seven age-matched healthy controls showed a significant reduction in 2-[18F]FA- 85380 BP(ND), a marker of nicotinic acetylcholine receptor activity, in typical AD-affected brain regions.17 The 2-[18F]FA- 85380 BP(ND) correlated with the severity of cognitive impair- ment, and only MCI patients who subsequently converted to AD had a reduction in 2-[18F]FA-85380 BP(ND). Thus, the nicotinic receptors in dementia may not only reflect the degree of impairment, but may also predict the clinical course of disease.

A related SPECT study investigated in vivo changes in the α4β2-nicotinic acetylcholine receptor in 16 AD patients and 16 controls.18 Subjects also underwent perfusion imaging with 99mTc-hexamethylenepropyleneamineoxime SPECT. The results showed significant bilateral reductions in nicotinic receptor binding in the frontal lobe, striatum, right medial temporal lobe, and pons in patients with AD compared with controls. However, unlike the PET study already mentioned, no signifi- cant correlations were made with clinical or cognitive mea- sures. Although this was a small sample size, both 123I-5IA- 85380 and 99mTc-HMPAO SPECT imaging demonstrated similar diagnostic performance in correctly classifying controls and patients with AD.

A study of 27 patients with mild AD underwent PET scanning with 15O-water for regional cerebral blood flow and (S)(-)[11C] nicotine for the assessment of nicotine binding.19 Mean cortical [11C]nicotine binding significantly correlated with the results of attention tests such as the Digit Symbol test and Trail Making Test A, but [11C]nicotine binding was not significantly corre- lated with the results of tests of episodic memory or visuo- spatial ability. No correlations were observed between cerebral blood flow and cognition. Thus, the cortical nicotinic receptors appear to be related to the cognitive function of attention in patients with AD.

A number of other neurotransmitter systems have also been evaluated in patients with AD. The serotonin and dopamine sys- tems have been of particular interest. For example, an early study of nine AD patients using [18F]setoperone PET revealed markedly decreased 5-hydroxytrypamine (5HT)2 binding in the temporal, frontal, parietal, and occipital cortices in patients with AD relative to control values.20 Another study on sero- tonin-2A receptors in AD patients demonstrated a temporal pattern of reduced receptor density in early stages of the dis- ease, followed by a plateauing effect as the disease progresses.21 However, studies using [11C]DASB PET have shown that this decrease in neocortical serotonin 2A receptor binding that has

Fig. 4.2 Fluorodeoxyglucose (FDG) positron emission tomography scan of an Alzheimer’s disease patient shows moderately decreased metabolism in the bilateral temporoparietal regions.

Imaging Techniques

been observed in early AD is not the result of a primary loss of serotonergic neurons or their projections.22 In yet another study, hippocampal dopamine D2 receptors density was shown to be reduced, correlating with impairments in memory in AD patients.23

Other studies have revealed decreases in postsynaptic sero- tonin receptor binding in AD patients. A study of nine AD patients and 26 controls using 123I-5-I-R91150 SPECT to evalu- ate the 5-HT2A receptors demonstrated an age-related decline of neocortical binding potential (11.6% per decade).24 Further- more, AD patients had a significant regional reduction in the 5-HT2A binding in the orbitofrontal, prefrontal, lateral frontal, cingulate, sensorimotor, parietal inferior, and occipital regions. One study using [18F]deuteroaltanserin PET showed a signifi- cant decrease in the binding potential in 5-HT2A receptors in the anterior cingulate in AD patients, but this decrease did not correlate with behavioral measures such as depressive and psy- chotic symptoms.25 Another study using [18F]altanserin and [11C]DASB PET of early AD patients and controls demonstrated a decrease of roughly 30% in cortical 5-HT2A receptor binding in patients with MCI compared with healthy controls.22 In AD patients, decreases were marked in [18F]altanserin binding but largely insignificant in [11C]DASB binding. The only exception was in the mesial temporal cortex, where a 33% reduction was observed in [11C]DASB binding.

A [18F]altanserin PET study of MCI patients and healthy age- matched controls for 2 years reported that 8 of the 14 MCI patients had progressed to probable AD by the end of the fol- low-up period.21 In patients as well as controls, no significant changes were detected in 5-HT2A receptor binding over the 2-year period. Thus, despite the marked decreases in cortical 5-HT2A receptor binding that are seen in early MCI, further reductions have not been associated with progression from MCI to AD.

One study of the 5-HT1A binding in 10 AD patients and 10 controls revealed significantly decreased 5-HT1A binding poten- tial in the right medial temporal lobe, but not in the other regions such as the frontal, lateral temporal, parietal, and cere- bellar cortices.26 Another PET study of the 5-HT1A in AD, MCI, and controls showed that significantly decreased receptor den- sities in both hippocampi and the raphe nuclei in AD patients.27 The authors also reported a strong correlation between 5-HT1A receptor decreases in the hippocampus and worsening Mini- Mental State Examination (MMSE) scores. Additionally, decreased 5-HT1A receptor measures correlated with decreased cerebral glucose metabolism as measured by FDG-PET. A separate study of 5-HT1A receptor density in the hippocampus using a voxel-based analysis revealed decreased whole-brain binding in AD brains but increased whole-brain binding in the brain of patients with amnestic MCI.28 More specifically, they noted a significant decrease of binding potential in the hippo- campus and parahippocampal gyri of AD patients, whereas there was a significant increase of binding potential in the inferior occipital gyrus in amnestic MCI patients. The authors suggest that this difference in serotonergic receptor labeling may help distinguish amnestic MCI patients from mild AD patients.

Of note, PET imaging has been useful for evaluating medica- tion for the potential treatment of AD. For example, one study used 11C-labeled WAY-100635 PET to evaluate the binding of

lecozotan, a 5-hydroxytryptamine-1A (5-HT1A) antagonist under development as therapy for AD.29 The results demon- strated that lecozotan binds to 5-HT1A receptors in the brain with a maximum observed receptor occupancy of 50 to 60% after a single 5-mg dose in elderly subjects and AD patients. Such studies can help to further identify and evaluate treatment interventions for AD and other dementing illnesses.

Another PET study assessed 5-HT4 binding and cortical Aβ burden using [11C]SB207145 and [11C]PIB, respectively.30 No significant difference in 5-HT4 receptor binding was seen between patients and healthy subjects when the diagnosis of AD was made using clinical criteria. However, when patients were assessed based on their Aβ burden, those who had posi- tive findings on Pittsburgh compound B (PIB) studies showed a 13% increase in 5-HT4 receptor binding. In summary, this study found a positive correlation between 5-HT4 receptor binding and Aβ burden in AD patients, as well as a negative correlation between 5-HT4 receptor binding and MMSE scores. The authors indicated that the data suggest that cerebral 5-HT4 receptor upregulation begins before the onset of clinical symptoms and progresses while dementia is still in its early stages. They spec- ulated that this may be a compensatory effect in response to decreased levels of interstitial 5-HT. Such a compensatory effect might help to improve cognitive function transiently, increase acetylcholine release, or counteract Aβ accumulation.

The dopaminergic system has also been evaluated in AD patients. For example, one study31 investigated the relationship between striatal DA (D2) receptor availability using [11C]- raclopride PET and compared the imaging results to measures of cognition (sustained visual attention, spatial planning, word recognition) and motor (speed and dexterity) function in 24 patients with mild to moderate AD. In this study, higher D2 binding was associated with increased motor speed and, para- doxically, poorer attentional performance. The authors argued that these findings suggest that the use of DA (D2) receptor ago- nists as an adjunctive treatment in AD may have dissociable effects on cognitive function.

A study of 27 MCI patients were evaluated using PET with [11C]dihydotetrabenazine to measure striatal dopamine terminal integrity and [11C]PIB to measure cerebral amyloid burden.32 The results showed that 11 subjects were initially classified clinically as amnestic MCI, 7 as multidomain MCI, and 9 as nonamnestic MCI. At a mean follow-up of 3 years, 18 sub- jects converted to dementia with significant cerebral amyloid deposition or nigrostriatal denervation as a strong predictor of conversion to dementia. As with most of the other studies described in this chapter, there was only moderate concordance between the clinical classifications and PET-based classification of dementia subtypes.

The benzodiazepine/γ-aminobutyric (GABA) receptor system has also been evaluated in AD patients. For example, a small study33 of six early AD patients and six controls evaluated GABA binding using [11C]flumazenil PET and found decreased binding in the inferomedial temporal cortex, hippocampus, retrosple- nial cortex, and posterior perisylvian regions. In addition, [11C] flumazenil hippocampal binding correlated with memory per- formance. Interestingly, the authors report that [11C]- flumazenil binding was decreased, particularly in the brain regions with the greatest degree of neuronal loss in postmor- tem studies of early AD. The authors suggest that despite the

SPECT and PET Imaging of Neurotransmitters in Dementia

small sample size of their study, [11C]flumazenil binding could be a useful marker of neuronal loss in early AD.

However, a SPECT study using [123I]Iomazenil and [99mTc] HMPAO in 16 patients with amnestic MCI and 14 elderly control subjects revealed no significant difference in GABA binding.34 Furthermore, hypoperfusion of the precuneus and posterior cingulate cortex suggested that GABA receptors are preserved in early dementia and that functional changes precede neuronal or synaptic loss in neocortical posterior regions. Clearly, future studies are needed to better evaluate the use of GABA receptor imaging in MCI and AD.

Perhaps one of the most important potential roles for PET or SPECT imaging is in the evaluation of therapeutic interventions for AD. The relatively recent development of several pharma- ceuticals for AD provides an important area for PET imaging. Patients can be imaged before therapy to determine who might be the best candidates for therapy. Patients can also be followed up longitudinally to determine the effectiveness of the pharma- ceutical intervention. Also, PET imaging can be useful in the physiologic evaluation of various pharmacologic interventions. A PET study by Kuhl et al aimed to elucidate the pharmacologic mechanism by investigating the effects of donepezil on acetyl- cholinesterase activity.35 It was reported that donepezil hydro- chloride inhibits cerebral cortical acetylcholinesterase activity in AD patients; on average, acetylcholinesterase activity was decreased by 27%. This finding suggests that the clinical trials of donepezil are not reflecting the actual degree of pharmacologic activity and that further investigation of the effects of this drug are warranted.

A PET study of the use of tacrine in patients with AD demon- strated improvement of nicotinic receptors (measured as [11C] nicotine binding), cerebral blood flow, and cognitive tests (Trail Making Test and block design test) that preceded improve- ments in glucose metabolism.36 These improvements were observed in both short- and long-terms treatment regimens. Propentofylline (PPF) has been explored as a potential pharma- cologic intervention in patients with both vascular dementia and AD because of the elaboration of inflammatory cytokines and neurotoxic free radicals, decreased secretion of nerve growth factor by astrocytes, excess release of glutamate with associated neurotoxicity, and loss of cholinergic neurons in these two types of dementia. A phase II study using PET showed significant improvements in cerebral glucose metabolism in patients with both vascular dementia and AD after treatment with PPF. Patients treated with a placebo had significant decreases in cerebral metabolism during the same period.37

Thus, PET and SPECT imaging have been used extensively in patients with AD, both in its early stages as well as in later stages in which treatment is attempted. It is likely that as more research is performed to understand the pathophysiology and management of AD, receptor studies with PET or SPECT will play an important role.

4.2 Frontotemporal Dementia

Frontotemporal dementia is a clinical neurologic disorder that results from the degeneration of the frontal and temporal ante- rior lobes of the brain. The classification of FTD has remained controversial for years, but the current definition includes Pick

Fig. 4.3 Fluorodeoxyglucose (FDG) positron emission tomography scan of a patient with frontal lobe dementia showing hypometabolism in the bilateral frontal lobes and the anterior temporal lobes. The remainder of the cortex in this patient has preserved metabolism.

disease, primary progressive aphasia, and semantic dementia as defining characteristics. The two clinical patterns that the symptoms of FTD fall into are behavioral changes and aphasia.

Identification of the regions of the brain that are affected by FTD has been aided by FDG-PET, allowing for improved accu- racy in diagnosis. Several studies have demonstrated hypome- tabolism and deficits in perfusion, primarily in the frontal lobes of FTD patients (▶ Fig. 4.3). Diehl et al38 reported an association between FTD and metabolism in the frontal lobe. Grimmer et al39 showed that FTD patients have substantial deficits in the metabolism of the frontal cortices, as well as the caudate nuclei and the thalami.

A focal loss of serotonin receptors has been identified by PET studies as a critical aspect of the pathophysiology of FTD, a find- ing that is in line with postmortem reports. A study of 5-HT1 receptor distribution in FTD patients demonstrated marked reductions in bilateral [11C]WAY-100635 binding in the frontal, medial, and lateral temporal regions.40 Similarly, a study of 5-HT2 receptor distribution in FTD using [11C]MDL 100,907 PET demonstrated substantial decreases in binding in the orbi- tofrontal, frontal medial, and cingulate cortices.41

A PET study of four patients with frontotemporal lobar dementia (FTLD) using [11C]WAY-100635 demonstrated that the FTLD patients had significantly decreased serotonin 5-HT1A binding potential compared with controls in the frontal, temporal, and occipital regions.40 The FTLD patients had binding potential values that were 50 to 69% that of controls and suggest that profound 5-HT1A binding potential decreases may be present and contribute to the symptoms in these patients.

4.3 Parkinson’s Disease

PD is a neurologic disorder with a clinical triad of bradykinesia, tremor, and rigidity resulting from neuronal loss in the substan- tia nigra and locus ceruleus. The destruction of pigmented neu- rons in these regions leads to reduced production and storage of dopamine, as well as dysfunction of the nigrostriatal system. PD can also manifest with cognitive impairment in as many as 30% of patients.

Imaging Techniques

Fig. 4.4 A fluorodopa positron emission tomography scan of a patient with Parkinson’s disease (right scan) reveals markedly reduced uptake in the putamen and only mild uptake in the caudate nuclei compared with a healthy control subject with robust uptake throughout the basal ganglia (left scan).

Multiple PET studies in the literature report hyper- metabolism in the basal ganglia in the early stages of PD.42,43 Patients have also displayed mild and diffuse cortical hypome- tabolism that correlates with the severity of their bradykinesia. There is evidence that hemi-parkinsonism is related to hyper- metabolism in the contralateral basal ganglia.

The PET radiotracers targeting the dopaminergic system pre- synaptically and postsynaptically—through [18F]fluorodopa and 18F-N-methylspiperone, respectively—are most suitable for the diagnosis, management, and follow-up of PD and other move- ment disorders. The pathophysiology of PD is dependent on the progressive deterioration of dopaminergic neurons in the sub- stantia nigra; therefore, the uptake of [18F]fluorodopa is consis- tently reduced in the striatum (▶Fig. 4.4) and abnormal in extrastriatal regions to varying degrees.44 Whole-brain PET imaging has demonstrated additional differences in [18F]- fluorodopa uptake between PD patients and healthy controls in extrastriatal regions, which may underlie the impaired cogni- tion associated with PD. Studies have shown marked decreases in [18F]fluorodopa uptake in the frontal cortex,45 while others have reported lower uptake in the midbrain and anterior cingu- late.46 On the other hand, some studies have demonstrated that despite decreased [18F]fluorodopa uptake in the striatum, patients with early stage PD manifest substantially higher bilat- eral uptake in dorsolateral prefrontal regions.47,48

A study using FP-CIT (DaTscan) SPECT of seven patients with PD without dementia, 17 with PD plus dementia, and 18 healthy controls revealed no difference in dopamine trans- porter (DAT) binding in the striatum between PD patients with and without dementia.49 Although this sample is small, the results suggest that DAT binding is not associated with demen- tia symptoms in PD patients. A [99mC]raclopride study investi- gated the possibility that frontal lobe dysfunction is responsible for cognitive impairment in PD, either as a direct result of hin- dered transmission in the mesocortical dopaminergic system or as an indirect result of altered dopaminergic function in the substantia nigra.50 This study involved a spatial working mem- ory task (SWT) as well as a visuomotor control task (VMT). In controls, raclopride binding in the dorsal caudate was lower in SWTs than in VMTs, a finding that is consistent with the

heightened release of endogenous dopamine during executive functions. However, this difference in binding in the dorsal cauadate was not observed in PD patients. Both patients and controls demonstrated reduced racolpride binding in the ante- rior cingulate cortex during SWTs. Furthermore, dopamine release in the dorsal caudate was markedly decreased in PD patients, but it remained steady in the medial prefrontal cortex. The results of this study suggested that executive deficits in the early stages of PD are related to reduced nigrostriatal dopamin- ergic function resulting in abnormal processing in the cortico- basal ganglia circuit. However, dopaminergic transmission appears well preserved in the mesocortices of patients with early PD. This study demonstrates not only a deficit of dopamin- ergic function in PD patients but also specific effects that directly relate to cognitive impairment in these patients.

Additional studies have investigated the relationship between PD and the serotonin system. Politis et al used [11C]DASB PET to demonstrate that a progressive nonlinear reduction in serotonin transporter binding occurs in PD but is not signifi- cantly correlated with the severity of the condition.51 In con- trast, another [11C]DASB PET study showed increased serotonin transporter binding in similar patients.52

As with the other disorders, it appears that neurotransmitter studies with PET and SPECT imaging will be highly useful in both clinical and research applications in patients with PD. It is also interesting to note that neurotransmitters other than dopamine, the primary target of PD, may also be of significance in understanding the pathophysiology of the disorder, specifi- cally when it results in dementia.

4.4 Dementia With Lewy Bodies

Dementia with Lewy bodies (DLB) is a disorder that results in cognitive impairment but is found to have Lewy bodies on his- topathological evaluation, differentiating the disorder from other dementing illnesses. The dopamine receptor system is primarily affected in DLB, and it thus has been a primary focus of neuroimaging studies. For example, in a multicenter study53 using DaTscan SPECT in 326 patients with a clinical diagnosis of probable (n=94) or possible (n=57) DLB or non-DLB dementia (n=147), established by a consensus panel, the authors reported a mean sensitivity of 78% for detecting clinically probable DLB and a specificity of 90% for excluding non-DLB dementia, which was predominantly due to AD. In this study, the positive predic- tive value was 82%, and the negative predictive value was 88%. There was also relatively high inter-rater reliability in reading the scans.

A smaller study compared DaTscan and 99mTc-exametazime blood flow SPECT in 33 controls, 33 AD patients, and 28 DLB patients.54 Agreement between raters in categorizing scans was found to be “moderate” (mean kappa = 0.53) for 99mTc-exameta- zime and “excellent” (mean kappa = 0.88) for 123I-FP-CIT. In AD and DLB patients, the consensus rating was in line with the clinical diagnosis in 56% of cases using 99mTc-exametazime and 84% using 123I-FP-CIT. Receiver operator characteristic analysis revealed superior diagnostic accuracy with 123I-FP-CIT (sensitiv- ity 79%, specificity 88%) compared with occipital 99mTc-exame- tazime (sensitivity 64%, specificity 64%). Thus, this study showed that DaTscan SPECT had significantly greater diagnostic

accuracy compared with 99mTc-exametazime in the differentia- tion of DLB from AD.

A similar earlier study evaluated DaTscan in 164 older sub- jects (33 healthy older control subjects, 34 with AD, 23 with DLB, 38 with PD, and 36 with PD plus dementia).55 The results revealed a significant reduction in DAT binding in subjects with DLB compared with subjects with AD and controls but decreased binding similar to that seen in PD. Interestingly, the DLB patients had a flatter rostrocaudal (caudate-putamen) gradient compared with PD patients consistent with the patho- physiologic progression of the two disorders. The greatest loss in all three striatal regions was seen in those who had PD and dementia.

Perhaps the largest analysis to date is a systematic meta- analysis of studies in the literature that assess the accuracy of presynaptic dopaminergic imaging with 123I-FP-CIT (DaTscan) in the diagnosis of patients with DLB.56 The meta-analysis included studies in which DaTscan was performed in cases of diagnostic uncertainty and studies in which patients already had established diagnoses of DLB or non-DLB dementia or controls. Four studies with a total of 419 subjects were deemed suitable by the authors for the meta-analysis. The meta- analysis demonstrated a pooled sensitivity of DaTscan in differ- entiating DLB versus no DLB was 86.5% and a specificity of 93.6%. The authors concluded that DaTscan provided high diag- nostic accuracy for the diagnosis of DLB, especially in terms of specificity.

Another study57 compared FDG PET and 123I-β-CIT SPECT for differentiating DLB from AD and found that the most sensitive indicator (88%) was hypometabolism in the lateral occipital cortex, whereas the most specific sign (100%) was preservation of the mid or posterior cingulate gyrus. How- ever β-CIT achieved 100% accuracy and greater effect size than did [18F]FDG-PET.

Although the dopamine system has been the primary focus in DLB, other neurotransmitters are likely also affected. To investigate in vivo differences in the distribution of α4β2 sub- types of nicotinic acetylcholine receptors, one study used the ligand 123I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA- 85380) SPECT in 15 patients with DLB and 16 controls.18 Com- pared with controls, there were significant reductions in α4β2 nicotinic acetylcholine receptors in the frontal, striatal, tempo- ral, and cingulate regions in DLB patients. Also, there was increased uptake of 123I-5IA-85380 in the occipital cortex in DLB patients relative to controls. This increase was particularly noted to be associated with DLB subjects with a recent history of visual hallucinations. The authors suggested that these find- ings indicate a link between cholinergic changes in occipital lobe and visual hallucinations in DLB.

In a related study, PET imaging with N-[11C]-methyl-4- piperidyl acetate to measure brain acetylcholinesterase activity was performed in 18 patients with PD, 21 patients with PD with dementia (PDD) or DLB, and 26 healthy controls.58 The PDD/ DLB group consisted of 10 patients with PDD and 11 patients with DLB. Among the PD patients, acetylcholinesterase activity was significantly reduced in the cerebral cortex, especially in the medial occipital cortex, but it was even lower in patients with PDD/DLB. However, there was no significant difference in regional AChE activity deficits between early PD and advanced PD groups or between DLB and PDD groups.

SPECT and PET Imaging of Neurotransmitters in Dementia

Thus, neurotransmitter imaging using both PET and SPECT might be helpful in the clinical evaluation and research investi- gation of patients with DLB.

4.5 Studies Comparing Different

Dementias

In this final section, we review several studies, in addition to those described already, that specifically compare patients across multiple types of dementia. Such studies are particularly important for differentiating the disorders from one another and also helping to determine the most useful imaging studies for that purpose.

A study of 27 subjects with neurodegenerative dementia associated with parkinsonism evaluated the use of FDG-PET and DaTscan SPECT.59 The subjects were placed in groups according to their clinical diagnoses of probable AD (five sub- jects), corticobasal degeneration (six subjects), DLB (eight sub- jects), FTD (four subjects), or PD with dementia (four subjects). Using discriminant analysis of the two scans, the authors reported that 85% of the patients were correctly classified using FDG-PET alone. When DATscan was evaluated alone, 59% were correctly classified, but the combination of both DAT and nor- malized FDG uptake yielded 100% accurate classifications. The authors concluded that an automated analysis approach com- bining FDG uptake and DAT binding may be the most effective approach for classifying individual patients with dementia and parkinsonism.

To assess several different physiologic parameters in demen- tia, one study used PET with FDG, [18F]fluorodopa, and N-11C- methyl-4-piperidyl acetate (MP4A) to measure cholinergic function in eight patients with PDD, six patients with DLB, and nine patients with PD without dementia, all compared with age-matched controls.60 The results found that patients with DLB and PDD share the same profile of dopaminergic and cho- linergic deficits in the brain. The authors argued that the two disorders may represent two sides of the “same coin” in a con- tinuum of DLBs. The authors also suggested that cholinergic deficits, in addition to motor symptoms, are crucial for the development of dementia.

An interesting study of the serotonin transporter binding in the midbrain of 53 patients with PD (15), DLB (15), PSP (8), and essential tremor (15) were evaluated with FP-CIT SPECT imaging.61 Patients with PD demonstrated a moderately lower serotonin level than patients with essential tremors and con- trols. However, patients with PSP and DLB showed substantially lowered to undetectable levels of serotonin, respectively. The authors suggested that their findings indicate that the neuro- degenerative process affects serotoninergic neurons in parkin- sonian syndromes, with much more severe involvement in DLB than in PD patients, despite a comparable loss of striatal DATs.

An assessment of several different types of dementia patients demonstrated the problem in comparing clinical and imaging findings for diagnosis. In this study,62 75 subjects with mild dementia underwent a conventional clinical evalua- tion followed by PET imaging with [11C]-dihydrotetrabenazine and [11C]PIB. Based on clinical evaluation, 36 subjects were clas- sified as having AD, 25 as having FTD, and 14 as having DLB. Based on PET imaging, 47 subjects were classified as having AD,

Imaging Techniques

15 as having DLB, and 13 as having FTD. This study found that clinical consensus and neuroimaging classifications were in limited agreement in all types of dementia, with discordance of classifications occurring in approximately 35% of subjects. This study did not compare the clinical and PET findings with post- mortem diagnosis, which complicates the ability to understand the findings. However, it appears that both clinical and PET findings may be helpful in more accurately classifying dementia patients.

4.6 Conclusion

Overall, neurotransmitter imaging with PET and SPECT has been a powerful tool for evaluating patients with neurologic disorders associated with dementia. PET and SPECT imaging have shed light on the causes and pathophysiology of numerous disease processes. In the clinical settings, these functional imaging modalities prove valuable in initial diagnoses and evaluation of diseases. In the years to come, the development of radiopharmaceuticals targeting specific disorders, as well as the neurotransmitter systems they involve, will expand the scope of applications for these modalities, both clinically and in research. Moreover, functional imaging will continue to improve its abilities to assess the suitability of medical and surgical interventions for patients, to determine prognosis, and to evaluate the response to treatment. Thus, PET and SPECT imaging will continue to be a critical asset for studying the brain in patients with dementia.

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SPECT and PET Imaging of Neurotransmitters in Dementia

Imaging Techniques

5 Diffusion Tensor Imaging in Neurodegenerative Disorders Dhiraj Baruah, Suyash Mohan, and Sumei Wang

Neurodegeneration results in deterioration of neurons in the brain and spinal cord. Neurodegenerative disorder is defined as a progressive condition of the nervous system associated with destruction or loss of selective neurons associated with func- tions like movement and cognition, ultimately leading to death.1 These disorders may be hereditary or sporadic. People suffering with these conditions place a significant amount of physical and emotional burden on their family and caregivers. The increasing prevalence of neurodegenerative diseases is a major health problem that uses a significant amount of health-related expenditures.2 Depending on loss of function, neurodegenerative disorders are classified mainly into two cat- egories: affecting cognition (such as Alzheimer’s disease [AD]) and affecting movement (such as Parkinson’s disease [PD]). Although significant progress has been made in recent years for understanding the pathophysiology of these diseases, treat- ment of these conditions is still symptomatic rather than effecting a cure.

Conventional imaging techniques, including magnetic reso- nance imaging (MRI), are limited in understanding these condi- tions and usually show abnormalities only in advanced stages of the disease. Understanding the parenchymal changes in the brain at a microstructural level helps to understand the differ- ent disorders in this group and might help in developing cura- tive or preventive treatments in the future. One of these advanced imaging techniques is diffusion tensor imaging (DTI), which evaluates the microstructural changes in the brain.3,4

Our aim in this chapter is to describe the recent advances in understanding changes of white matter (WM) in patients with some common neurodegenerative disorders. Before going to the disorders, we first look at some basic facts about DTI.

5.1 DiffusionTensorImaging:

Basic Concepts

Diffusion tensor imaging uses the property of random motion (Brownian motion) of water molecules in vivo. Water diffusion in WM is constrained by the physical boundaries, including the axon sheath, leading the movement to be greater along the z (long) axis of the fiber than across it. This asymmetric property of water diffusion in WM is known as anisotropy. Color maps can be generated by using this information to localize WM tracts (▶ Fig. 5.1). Conventional DWI gives information in only one direction. DTI helps to quantify this property at the voxel level by using a tensor. Tensor is a mathematical concept that not only allows quantification of molecular motion in each direction but also gives an average magnitude of water diffusion.5

The two commonly used indices are mean diffusivity (MD) and fractional anisotropy (FA), which can be calculated using the following equations:

MD1⁄4ð!1 þ!2 þ!3Þ 3

Fig. 5.1 Diffusion tensor imaging (DTI)-based color map of a healthy subject. Colors indicate directions as follows: red, left-right; green, anterior-posterior; blue, superior-inferior. White line delineates man- ually segmented corticospinal tract (CST) (a) Reconstructed CSTs (green) are overlaid on color maps (b) (Reprinted with permission from Wang S, Poptani H, Bilello M, Wu X, Woo JH, Elman LB et al. AJNR Am J Neuroradiol. 2006 Jun-Jul;27(6):1234-8.)

vu ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi

FA1⁄4ut3 ð!1 !Þ2 þð!2 !Þ2 þð!3 !Þ2 2 !12 þ!22 þ!32

Where λ1 , λ2 , and λ3 are three eigenvalues of the diffusion ten- sor, and λ denotes the mean of the three eigenvalues. MD is a measure of the directionally averaged magnitude of diffusion and is related to the integrity of the local brain tissue. FA repre- sents the degree of anisotropy in the diffusion and reflects the degree of alignment of cellular structure. DTI indirectly assesses the integrity of tissue and could be useful in characterizing neu- rodegenerative disorders.

5.2 Aging Brain

It is important to understand normal age-related microstructural changes of WM before exploring neurodegenerative diseases, which is usually not possible with conventional MRI. Degenera- tive WM changes with normal aging include a decrease in mye- lin density and alterations in myelin structure.6,7 Conventional MRI is helpful in evaluating volumetric changes of the aging brain. Microstructural disruption of WM in the aging brain can be detected using DTI. In a study of 38 participants, Salat et al8 have shown significant age-related decline of FA in frontal WM, the posterior limb of the internal capsule, and the genu of the corpus callosum, with preservation of temporal and posterior WM. Other studies have also shown more anterior WM changes associated with the aging brain compared with posterior WM.9 The subtle and probably preclinical changes with aging seen using DTI may enable monitoring of WM recovery in normal aging, trauma, and disease.10

5.3 Alzheimer’s Disease
Alzheimer’s disease is the most common form of dementia and

has been defined pathologically by the presence of intracellular

Diffusion Tensor Imaging in Neurodegenerative Disorders

neurofibrillary tangles and extracellular neuritic plaques.

There is an accelerated loss of cortical neurons compared with

age-matched nondemented persons.11 Many authorities

have documented that changes in WM are also more pro-

nounced in patients with AD than in age-matched nonde-

mented persons.12,13 These WM changes are the focus of evalu-

ation using DTI. Studies have reported changes seen using DTI,

including decreased FA, increased MD, and decreased lattice index.14,15,16,17,18,19,20

Slight impairment of cognitive function without a full-blown picture of dementia is defined as mild cognitive impairment (MCI). Patients with MCI carry a higher risk of developing AD in later life (10 to 15% conversion rate).21 Researchers have generated in vivo quantitative DTI markers to identify patients with high risk (▶ Fig. 5.2).22,23,24 Most of the changes in MCI and AD patients are posteriorly located (involving the hippocampus, pallidum, thala- mus, and caudate), whereas changes in the normal aging brain are commonly seen anteriorly (involving frontal WM).20,25,26,27

Fig. 5.2 Results from group comparisons of fractional anisotropy (FA) and mean diffusivity (MD). The anatomical underlay is the MNI (Montreal Neurological Institute) space registered target FA image. Maps are referenced to a standard human white matter atlas (Mori et al., 2005).
The group at high risk for AD showed decreased FA (shown in red) compared with the low-risk group in a number of regions, prominently including the fornix and inferior longitudinal fasciculus (ILF) in the temporal lobe and anterior portions of the inferior fronto-occipital fasciculus (IFOF)/uncinate fasciculus (UNC) in the frontal lobe. There were no regions in which the low-risk group showed decreased FA compared with the high-risk group. Within regions of decreased FA, there were only two regions of increased MD in the high-risk group (shown in orange): the genu and the right IFOF/ILF. CING, cingulum; L, left; R, right. (Reprinted with permission from Gold BT, Powell DK, Andersen AH, Smith CD.Neuroimage. 2010 Oct 1;52(4):1487-94.)

Imaging Techniques

5.4 Dementias Other than Alzheimer’s Disease

5.4.1 Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB), also known as Lewy body variant of AD, is the second most common form of dementia in elderly patients after AD.28 The pathophysiology of DLB is likely due to neuronal synaptic dysfunction rather than to neuronal loss. Clinical differentiation between AD and DLB is not always possible. Three main clinical features described with DLB are impairment in cognitive function, visual hallucinations, and spontaneous parkinsonism.28 Posterior predominance of changes in DTI are more common in DLB than are frontal changes29; WM in the region of parieto-occipital and temporal lobes is commonly involved. As already stated, changes of FA in the posterior WM are also common in AD; however, posterior to anterior preferential involvement occurs in a significantly greater extent with DLB compared with AD. Researchers have shown significant association of decreased FA with DLB involv- ing occipital areas (precuneus) and inferior longitudinal fascicu- lus (ILF).30,31 Although preferential FA changes were seen poste- riorly in DLB, an increase in MD was rather diffuse than regional.29 Rosie et al found reduced FA in the left thalamic WM in DLB compared with that in AD patients.29

5.4.2 Frontotemporal Dementia

Frontotemporal dementia (FTD) is a neurodegenerative condi- tion that is characterized by involvement of the frontal and anterior temporal lobes.32 Depending on the predominant involvement of frontal or temporal lobe, FTD is divided into two main categories: frontal lobe variant and temporal lobe variant.33 Patients with the frontal variant of FTD usually have gradually worsening change in personality and behavior. Patients with the temporal variant of FTD have gradually wor- sening fluent aphasia.34 The first observation of decreased FA was shown in a postmortem brain by Larsson et al.35 In 36 patients with FTD, Borroni et al found significant involvement of the superior longitudinal fasciculus (SLF) with frontal variant FTD and bilateral ILF involvement in temporal variant FTD.33 Elise et al have shown decreased FA and increased radial diffu- sivity in frontotemporal WM and reduced connectivity between frontoinsula and anterior mid-cingulate cortex on resting state functional MRI in presymptomatic FTD patients years before symptom onset.36

5.5 Human Prion Disease 5.5.1 Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) was first described in the 1920s by German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob. Its pathogenesis is not completely clear; however, researchers have shown that CJD is transmissible to nonhuman primates and other animals on filtration of the inoculum, indi- cating that the agent is small and “replicating.”37 Patients with this rapidly progressive fatal neurodegenerative disease typi- cally have progressive dementia, generalized myoclonus, and

mutism. Cerebrospinal fluid examination for 14–3-3 protein is a highly sensitive and specific marker for CJD in the appropriate scenario.38 In a blinded study, Steinhoff et al have shown high diagnostic value of electroencephalography (EEG), with sensi- tivity and specificity of periodic sharp wave complexes of 67 and 86%, respectively, for the diagnosis of CJD.39 Although these laboratory examinations are helpful for diagnosis of CJD, they do not have reliable markers to assess progression of the disease.

Another option for diagnosis is brain biopsy; however, this procedure is invasive and risky. Among the routine MRI sequences, DWI is accepted as the most helpful imaging modal- ity for the diagnosis of CJD, with studies showing benefit of DWI in early stages with or without changes in EEG (▶ Fig. 5.3).40,41 Using 3-tesla (T) MRI in three patients with CJD, Fujita et al have shown significant lower MD values than those found in control patients in the striatum, caudate nucleus, puta- men, globus pallidus, and thalamus; however, they found no significant abnormality of FA compared with the control group.42

5.6 Parkinson’s and Related

Movement Disorders

Parkinson’s disease (PD) is a common chronic, progressive neu- rologic disease with classic findings including resting tremor, rigidity, bradykinesia, and postural instability. Among all the clinical symptoms, resting tremor is the most characteristic of PD.43 If tremor is absent, evaluation of conditions that can show signs of parkinsonism, including multiple system atrophy, progressive supranuclear palsy, and striatonigral degeneration, should be considered.44 Characteristic pathologic finding for the diagnosis of PD is loss of dopaminergic neurons in the pars compacta of the substantia nigra. The usefulness of positron emission tomography and single-photon emission computed tomography for the diagnosis of PD is described in the literature.45

Routine MRI is usually unremarkable in patients with PD, even in advanced stage, but it is useful for ruling out secondary causes of parkinsonism-type symptoms.46,47 Predominant fron- tal lobe atrophy has been consistently found in patients with PD without dementia, but GM volume reduction is seen in the parietal and temporal lobes more specifically associated with PD with dementia.48,49,50,51

Measurement of MD and FA using DTI helps differentiate PD patients from control groups and those with progressive supra- nuclear palsy.52,53,54 In patients with PD, decreased FA is seen in the frontal lobes, premotor areas, and cingulum.53,54 The thala- mus, globus pallidus, putamen, and caudate nucleus are com- monly involved in atypical parkinsonisms as opposed to PD.55,56 Increased diffusivity (increased MD) in the substantia nigra may be due to significant loss of dopaminergic neurons, leading to decreased cellular matrix.57 In PD patients without dementia, correlation of executive impairment with reduced FA in the parietal WM has been seen.58 FA and MD are not significantly changed in the corticospinal tract (CST) of PD patients.59,60 Although changes in the DTI parameters in the genu of corpus callosum have been described, the splenium is not involved.61 Prodoehl et al have shown that DTI of the basal ganglia and

Diffusion Tensor Imaging in Neurodegenerative Disorders

Fig. 5.3 Sporadic Creutzfeldt-Jakob disease in a 34-year-old man who had abnormal leg movement and slow thinking. (a) Axial T2-weighted magnetic resonance image shows an area of subtle abnormal signal hyperintensity in the right putamen and caudate nuclei. (b) Axial diffusion-weighted images show bilateral areas of abnormal high signal intensity at the putamen and caudate nuclei, particularly in the right. (c) Axial apparent diffusion coefficient (ADC) map from diffusion-weighted imaging demonstrates reduced ADC value.

5.8 Motor Neuron Disease 5.8.1 Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative dis- order and the most common motor neuron disease. ALS has a rapidly progressive course, usually leading to death in 2 to 3 years.80,81 Because ALS is a disease of the motor system, patients have muscle weakness and paralysis; however, cogni- tive and behavioral symptoms are also described with this motor neuron disease.82

Pathologically, ALS causes damage of upper motor neurons in the cerebral cortex and lower motor neurons in the brain- stem and spinal cord. There are different genetic subtypes.83 The familial form of ALS usually has autosomal dominant inheritance. Genetic mutations are described in familial ALS patients involving multiple locations.84 Electromyography can help identify the involvement of lower motor neurons. However, neurologic examination is the only way to detect the upper motor neuron involvement but is subjective and unreliable.

Among imaging techniques, advanced MRI, including DTI, has the potential to be used as an objective diagnostic or prognostic marker of ALS. DTI color-based map can show thinning of the CST (▶ Fig. 5.4). Reduced FA along the CST is the predominant abnormality shown in most DTI studies.85,86,87,88,89,90,91,92,93,94,95 The CST damage observed in ALS patients possibly correlates with the rate of disease progression,96 although some dis- agreement remains regarding whether the CST damage corre- lates with disease severity.97,98,99,100

Verstraete et al have shown disconnection of motor systems in patients with ALS and concluded that the disease progresses along structural brain connections rather than only through the involvement of CST.101 Moreover, ALS is a multisystem disorder. Decreased FA has also been described in areas other than motor

cerebellum is useful in classifying PD and atypical parkinsonism accurately and also in distinguishing them from nonmovement disorders.62

5.7 Huntington’s Disease

Huntington’s disease (HD) is a devastating late-onset autosomal dominant trinucleotide CAG repeat neurodegenerative disorder that involves chromosome 4, leading to abnormal elongation of the polyglutamine stretch of huntingtin, which becomes increasingly toxic. Although this mutation and resultant elon- gated huntingtin are seen in the tissues of almost all organs of HD patients, pathological changes are seen only in the brain. The main structure involved is striatum, including caudate and putamen.

Symptoms of HD depend on the length of CAG repeat, with longer CAG expansion causing earlier disease onset.63 Clinical pictures include the triad of progressive cognitive, psychiatric, and motor symptoms. Among the motor signs, chorea is consid- ered the classic manifestation of HD. Although pathological changes in HD, including neuronal loss, are described as occur- ring predominantly in the striatum, significant changes are also described in brain structures other than striatum.64,65

Studies have shown a valuable role of MRI in characterizing

changes in the brain of presymptomatic and symptomatic HD

patients.66,67,68,69 Many cross-sectional volumetric studies have

shown decreased WM volume in patients with HD.70,71,72 The

interpretation of DTI parameters is complex in HD patients

because multiple parenchymal changes occur, including demye-

lination, axon damage, neuronal loss, and gliosis.73 Decreased

FA on DTI is observed in presymptomatic patients and in

patients at early stage compared with control subjects.74,75,76 As

decreasing FA is consistently shown in patients with HD, DTI

may become an important biomarker for the early detection of HD.77,78,79

Imaging Techniques

tracts in patients with ALS by different voxel-based DTI studies. Kassubek et al have shown widespread WM involvement in ALS patients compared with control subjects, including CST, adja- cent subcortical WM, and corpus callosum (▶Fig. 5.5).93,94,102 Also, Agosto et al have shown that subtle involvement of the right uncinate fasciculus may precede the appearance of behav- ioral symptoms in patients with ALS.96

5.9 Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory immune- mediated demyelinating and neurodegenerative disease.103,104 MS is the most common cause of nontraumatic disability in young and middle-aged adults.105 The exact causes and patho- genesis of MS are not clear; however, experimental models sug- gest autoimmunity as the basis of WM injury.106 Demyelinated plaque is the predominant pathologic hallmark of MS, with a

Fig. 5.4 Diffusion tensor imaging–based color maps of a healthy subject (a) and an amyotrophic lateral sclerosis (ALS) patient (b). The left corticospinal tract (arrows) appears thinner in the ALS patient (b). (Reprinted with permission from Wang S, Poptani H, Bilello M, Wu X, Woo JH, Elman LB et al. AJNR Am J Neuroradiol. 2006 Jun-Jul;27 (6):1234-8.)

Fig. 5.5 Comparison of fractional anisotropy (FA) maps based on diffusion tensor imaging (DTI) data of 20 patients with amyotrophic lateral sclerosis (ALS) and 20 age- and gender-matched controls. Upper panel: Group-averaged FA maps of controls (left) and patients with ALS (right) in coronal (large) and axial/sagittal view. FA display threshold is 0.2. Lower left: Comparison between the ALS group and controls by whole-brain–based statistical voxel-wise comparison at group level at P < 0.05 after correction for multiple comparisons. The areas with decreased FA in ALS are displayed, with the significance of the alterations coded by temperature of the color bar. Right: Fiber tracking of the corticospinal tract (CST) in group-averaged DTI data sets. The underlying FA values were averaged and statistically compared. Differences between group-averaged ALS FA maps and group-averaged control FA maps were highly significant, as indicated. (Reprinted with permission from Kassubek J, Ludolph AC, Müller HP. Ther Adv Neurol Disord. 2012 Mar;5(2):119-27.)

special predilection for periventricular WM, corpus callosum, optic nerves, and spinal cord.106

Most patients with MS have a relapsing-remitting clinical picture with episodic onset of symptoms followed by residual deficits or full recovery. Complete recovery is common in the early stage of the disease.107 A secondary progressive course after many episodes of relapse and recovery is more common than a primary progressive course from the onset.108

Multiple sclerosis is diagnosed clinically. Because of its sensi- tivity in detection and characterization of demyelinating areas, however, MRI is integrated in the diagnostic criteria for MS.109 MRI with conventional sequences is used routinely for diagno- sis and for monitoring treatment response and disease progres- sion. Association of conventional MRI with clinical status is lim- ited, and DTI gives better information about WM damage com- pared with conventional imaging; FA and MD values are more useful in the assessment of MS patients (▶Fig. 5.6).110 DTI shows reduced FA and increased MD in MS lesions; studies have shown a reduction of FA in enhancing compared with nonen- hancing lesions.111,112,113 Although DTI shows WM damage in MS more accurately than does conventional MRI, these changes do not always correlate with clinical disability.114 Genova et al have shown a relationship between executive functioning and processing speed with changes in FA in WM regions in patients with MS.115 Moreover, the difference in WM tract disruption can be directly visualized using diffusion tensor tractography (▶ Fig. 5.7).

Diffusion Tensor Imaging in Neurodegenerative Disorders

Fig. 5.6 Axial fluid-attenuated inversion recovery (FLAIR) image (a), mean diffusivity (MD) map (b), fractional anisotropy (FA) map (c), and diffusion tensor imaging (DTI)-based color map (d) from the brain of a patient with multiple sclerosis. The lesions demonstrate increased MD value and reduced FA value.

Besides involvement of WM in the brain, involvement of the spinal cord leading to weakness and loss of proprioception fre- quently causes significant disability in patients with MS.116,117,118 In MS, spinal cord involvement is seen by conventional MRI in 80% of patients and in 99% of patients at autopsy.116,118 Conven- tional T2-weighted and contrast-enhanced MRI sequences are routinely used for diagnosis, progression, and monitoring of disease response with new treatment modalities. However, advanced imaging markers, including DTI, are more valuable in showing disease extent.

More precise DTI methods like tract-specific DTI may become helpful in assessing changes with new neuroprotec- tion and neural repair treatments, particularly in patients with progressive MS, in whom the criteria of enhancement are always useful.119

5.10 Summary

Although neurodegenerative disorders are diagnosed mainly clinically, imaging may be helpful in providing adjunctive information. Standard MRI has limited usefulness for evaluating these diseases, but microstructural information provided by DTI may impact early diagnosis and better understanding of the pathogenesis of neurodegenerative dis- eases, thus impacting the formulation of new treatment modalities.

Imaging Techniques

Fig. 5.7 Diffusion tensor tractography of corpus callosum (CC) in the same patient as in ▶ Fig. 5.6. Region of interest (ROI) is placed at the midsagittal level. Note that the fibers of CC are disrupted in the location of the lesions.

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[79] Weaver KE, Richards TL, Liang O, Laurino MY, Samii A, Aylward EH. Longitudi- nal diffusion tensor imaging in Huntington’s disease. Exp Neurol 2009; 216: 525–529

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. [81] del Aguila MA, Longstreth WT, Jr, McGuire V, Koepsell TD, van Belle G. Prog- nosis in amyotrophic lateral sclerosis: a population-based study. Neurology 2003; 60: 813–819

. [82] Phukan J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic lat- eral sclerosis. Lancet Neurol 2007; 6: 994–1003

. [83] Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol 2011; 7: 616–630

. [84] Ticozzi N, Tiloca C, Morelli C et al. Genetics of familial amyotrophic lateral sclerosis. Arch Ital Biol 2011; 149: 65–82

. [85] Cosottini M, Giannelli M, Siciliano G et al. Diffusion-tensor MR imaging of cor- ticospinal tract in amyotrophic lateral sclerosis and progressive muscular atrophy. Radiology 2005; 237: 258–264

. [86] Toosy AT, Werring DJ, Orrell RW et al. Diffusion tensor imaging detects corti- cospinal tract involvement at multiple levels in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2003; 74: 1250–1257

. [87] Abe O, Yamada H, Masutani Y et al. Amyotrophic lateral sclerosis: diffu- sion tensor tractography and voxel-based analysis. NMR Biomed 2004; 17: 411–416

. [88] Iwata NK, Aoki S, Okabe S et al. Evaluation of corticospinal tracts in ALS with diffusion tensor MRI and brainstem stimulation. Neurology 2008; 70: 528–532

. [89] Schimrigk SK, Bellenberg B, Schlüter M et al. Diffusion tensor imaging-based fractional anisotropy quantification in the corticospinal tract of patients with amyotrophic lateral sclerosis using a probabilistic mixture model. AJNR Am J Neuroradiol 2007; 28: 724–730

. [90] Senda J, Ito M, Watanabe H et al. Correlation between pyramidal tract degen- eration and widespread white matter involvement in amyotrophic lateral sclerosis: a study with tractography and diffusion-tensor imaging. Amyo- troph Lateral Scler 2009; 10: 288–294

. [91] Wang S, Poptani H, Woo JH et al. Amyotrophic lateral sclerosis: diffusion-ten- sor and chemical shift MR imaging at 3.0 T. Radiology 2006; 239: 831–838

. [92] Agosta F, Pagani E, Rocca MA et al. Voxel-based morphometry study of brain volumetry and diffusivity in amyotrophic lateral sclerosis patients with mild disability. Hum Brain Mapp 2007; 28: 1430–1438

. [93] Ciccarelli O, Behrens TE, Johansen-Berg H et al. Investigation of white matter pathology in ALS and PLS using tract-based spatial statistics. Hum Brain Mapp 2009; 30: 615–624

. [94] Sage CA, Peeters RR, Görner A, Robberecht W, Sunaert S. Quantitative diffu- sion tensor imaging in amyotrophic lateral sclerosis. Neuroimage 2007; 34: 486–499

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Functional Imaging of the Brain

6 Functional Imaging of the Brain

Leslie Hartman and Aaron S. Field

Since its discovery as a viable technique to noninvasively image the functioning brain, functional magnetic resonance imaging (fMRI) has become an increasingly popular tool for researchers, clinical neuroscientists, neuroradiologists, and others. This chapter provides an overview of the physics and technical aspects of fMRI, introduces fMRI paradigms and resting-state fMRI, reviews the advantages and disadvantages of fMRI, dis- cusses the role of fMRI in neurodegenerative disorders, and briefly touches on the future of fMRI, especially as it relates to neurodegenerative disorders.

6.1 Overview of the Physiology and Physics Underlying Functional MRI

An understanding of how fMR images are created is critical to appropriate interpretation. A complete discussion of the physi- ology and physics is beyond the scope of this introductory chapter, but excellent resources are available for a more detailed explanation, including Huettel and McCarthy (2008)1 and Jezzard et al (2001).2 The most common method for fMRI is based on the blood-oxygen-level–dependent (BOLD) contrast, the fMRI technique that is the focus of this chapter.

Understanding the physiology behind fMRI dates back to 1890 and the experiments of Roy and Sherrington at Cambridge University, where the idea that regional cerebral blood flow could reflect neuronal activity was first investigated.3 It is this basic principle that makes fMRI possible. The BOLD effect is a

complex biophysical phenomenon. The origin of BOLD fMRI signal change lies in the different magnetic properties of oxy- genated hemoglobin (O-Hb), which is diamagnetic, and deoxy- genated hemoglobin (D-Hb), which is slightly paramagnetic relative to brain tissue.4 Vessels that contain oxygenated arterial blood cause little or no distortion to the magnetic field in their vicinity, whereas field inhomogeneities resulting from the pres- ence of D-Hb lead to shortening of the T2* relaxation time and thus a reduction of signal on any MRIs sensitive to magnetic susceptibility effects (▶Fig. 6.1). As a result, the MRI signal increases with an increase in the ratio of O-Hb to D-Hb.5 In an fMRI experiment, a series of images is rapidly acquired as the subject performs a task that shifts brain activity between two or more well-defined states. Via neurovascular coupling, as the neuronal activity in a region of brain tissue increases with a specific task, there is an increase in the supply of oxygenated blood, a decrease in concentration of D-Hb, and thus an increase in MRI signal in any regions of brain associated with the task (the BOLD signal, ▶Fig. 6.1).6 Alternatively, so-called resting-state fMRI can be performed with a subject resting in the MRI scanner with eyes closed but without sleeping; in this case, BOLD signal fluctuations that demonstrate synchrony between regions are thought to reflect functional connectivity. This technique is increasingly popular and is discussed in a later section in this chapter. Additionally, many fMRI studies have demonstrated decreased task-related activity in certain brain regions, a phenomenon typically explained on the basis of a so- called default mode of resting brain activity.7,8,9,10,11

The most common MRI sequence used in BOLD fMRI is a T2* gradient-echo sequence using single-shot echo planar imaging

Fig. 6.1 Illustration of neurovascular coupling and resultant changes in the blood-oxygen-level–dependent (BOLD) signal. In the resting or basal state, there is a greater proportion of deoxyhemoglobin in capillaries and venules, which cause microscopic-field inhomogeneities that lead to decreased signal in the gradient echo magnetic resonance (MR) image (a). In the activated state, there is an increase in the flow but only a modest increase in oxygen consumption, which leads to a decrease in the concentration of deoxyhemoglobin (b). The signal difference in the gradient echo planar imaging (EPI) has been exaggerated for illustration purposes. The actual signal change is on the order of 1 to 5% at 1.5 T and 2–10% at 3.0 T and requires statistical analysis to detect. The deoxyhemoglobin is labeled as D-Hb (blue ovals) while the oxyhemoglobin is labeled as O-Hb (red ovals).

Imaging Techniques

Fig. 6.2 Example of the distortion and loss of signal in the anteroinferior temporal regions resulting from susceptibility-related field inho- mogeneities in these regions (e.g., air in the frontal sinuses, mastoid cavities). Unfortunately, blood-oxygen-level–dependent (BOLD) function- al magnetic resonance imaging (fMRI) relies on such susceptibility effects to detect regional changes in deoxyhemoglobin concentrations.

(EPI), which allows whole-brain data collection in a few sec- onds or less, as is necessary to capture brain function in near “real time.”12 This high speed comes at the expense of spatial resolution, which is substantially lower than for a conventional MRI scan, typically only 3 to 5mm.13,14 Another drawback to EPI is distortion and signal loss in the frontotemporal regions secondary to the sensitivity of EPI to magnetic susceptibility differences (▶ Fig. 6.2).

6.2 Blocked Paradigm Designs

and Postprocessing

When designing a paradigm for BOLD fMRI, tasks are chosen that can be performed in the scanner and that are expected to activate the region of interest. For example, if the concern is related to language, typically tasks that use the Broca and Wernicke areas are chosen, targeting expressive and recep- tive language, respectively. The most commonly used para- digms are “blocked” designs, in which the subject repeatedly performs a task for a specified time, resting for a similar time between repetitions (i.e., alternating “task” and “control” blocks) (▶Fig. 6.3). This repetition is required for statistical processing to detect the small signal changes that character-

ize the BOLD response, on the order of 1 to 5% at 1.5 tesla (T) or 2 to 10% at 3.0T, against a background of physiologic noise.15,16 Postprocessing of the data typically includes head motion correction and both spatial and temporal filtering of the data. Most commonly, the blocked time course of the task paradigm is convolved with a model of the hemodynamic response to generate an expected time course for BOLD signal in activated regions. Statistical tests based on the correlation or regression are then performed to identify voxels in which the signal changes over time correlate with the timing of the alternating task and control blocks, accounting for the hemo- dynamic response timing. This results in a voxel-wise statisti- cal map (e.g., t-statistic),17 to which a significance threshold is applied to determine which voxels will be considered “acti- vated” (▶Fig. 6.4). Those activated voxels are typically over- laid in color onto a higher-spatial-resolution anatomical brain image (▶ Fig. 6.5). The specifics of these postprocessing tech- niques are beyond the scope of this introductory chapter, but several excellent resources are available, including Jezzard et al (2001)2 and Huettel and McCarthy (2008).1 Several soft- ware packages are also freely available with tools for analysis of fMRI data (e.g., SPM at http://www.fil.ion.ucl.ac.uk/spm, Brain Voyager at http://www.brainvoyager.com/, AFNI at http://afni.nimh.nih.gov/afni).

Functional Imaging of the Brain

Fig. 6.3 Schematic example of a block-design functional magnetic resonance imaging (fMRI) experiment. In this case, finger tapping is used. Each block in a typical task-based fMRI experi- ment is approximately 20 to 30 seconds in duration. The “off” block is with the subject at rest; the “on” block is with the subject tapping his or her finger.

Fig. 6.4 Convolving the block design with the hemodynamic response function (HRF) yields the theoretically expected time course of signal change in an “activated” voxel. This “reference waveform” is then compared (statistically, e.g., correlation or regression analysis) to the blood- oxygen-level–dependent (BOLD) signal variations voxel by voxel; those voxels for which the similarity between the actual and expected signal changes is above the statistical threshold are considered to be activated (typically after a voxel-clustering procedure to exclude spurious “positives”).

6.3 Resting-State Functional

Magnetic Resonance Imaging and

Functional Connectivity

Interest has been increasing about using fMRI to learn how dif- ferent brain regions interact with one another, how these inter-

actions relate to observable behaviors, and how they may be compromised in various neurodegenerative or psychiatric dis- orders. Resting-state fMRI (RS-fMRI) is used to study these interactions, commonly known as functional connectivity, which is defined as the temporal dependency between spatially remote neurophysiologic events18,19; in RS-fMRI, synchronous neuronal activity between regions of the brain is sought

Imaging Techniques

Fig. 6.5 Example of overlaying thresholded functional magnetic resonance imaging (fMRI) statistical maps onto anatomical MRI. This is a resting-state fMRI obtained in a 5-year-old child under general anesthesia. The case illustrates the ability to obtain meaningful fMRI data in individuals who cannot cooperate for a task-based fMRI. (Courtesy of Dr. V. Prabhakaran, University of Wisconsin–Madison.)

through the BOLD signal at rest and is presumed to reflect func- tional connectivity.20,21,22,23 Low-frequency oscillations (~0.01 to 0.1 Hz) have been identified in the resting state (RS) that help to identify these functional networks.20,22,24 A precise neuronal basis for these low-frequency oscillations has not been eluci- dated but is presumed to exist because most RS patterns tend to occur between regions that overlap in function and neuro- anatomy.22,25,26,27 In addition, studies have shown a strong asso- ciation between spontaneous BOLD fluctuations and simulta- neously measured fluctuations in neuronal spiking.10 Other studies have illustrated an indirect association between the amplitude of RS-fMRI correlations and electrophysiologic recordings of neuronal firing.28 Commonly used methods to assess functional connectivity maps for a specific region of interest in RS-fMRI is the seed voxel approach or independent component analysis.29,30,31,32,33,34 RS-fMRI is also appealing in that it requires minimal cooperation and motivation from sub- jects and is ideal in those who cannot fully engage enough to perform task-based fMRI studies (e.g., sedated or comatose patients).

There are at least seven commonly reported, functionally linked RS networks (▶ Fig. 6.6), including the default-mode net- work (DMN), primary visual and extrastriatal visual networks, executive control network, bilateral lateralized frontoparietal networks, primary sensorimotor network, and auditory-phono- logic network.25,26,29,34,35,36,37,38,39 One of the most studied net- works is the DMN, which has been shown to have an elevated level of neuronal activity at rest normally.40,41 Connectivity and activity of the DMN have been linked to human cognitive pro- cesses, including monitoring the world around us, integration of emotional and cognitive processing, and mind-wandering with stimulus-independent thoughts.21,40,42 These findings have piqued investigators’ interest in these networks, especially the DMN, in neurologic and psychiatric brain disorders. Some of the psychiatric disorders that have been studied with fMRI include depression, schizophrenia, autism, posttraumatic syn- dromes, attention-deficit hyperactivity disorder, and dys- lexia.43,44,45,46,47,48,49 The use of fMRI in neurodegenerative dis- orders is discussed in the next section of this chapter.

6.4 Functional Magnetic Resonance Imaging in Neurodegenerative Disorders

The most common clinical application of fMRI is to localize the eloquent cortex during neurosurgical planning for intractable epilepsy or tumor resections, for example, to lateralize language before temporal lobectomy for epilepsy.50 However, many fMRI studies have sought to identify changes in brain activity in neu- rodegenerative disorders, particularly in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) in preclinical stages. fMRI has demonstrated potential in diagnosing early AD in apo- lipoprotein-E4 gene carriers without clinical symptoms and in predicting the development of AD in individuals with MCI.51,52,53 fMRI studies demonstrating a reduction in cortico- cortical connectivity in AD are supported by electrophysiologic studies, including electroencephalography (EEG) and magneto- encephalography-based studies.54 Altered levels of functional connectivity on RS-fMRI in neurodegenerative disease have been reported in the DMN and other RS networks. Some of the neurodegenerative diseases studied with RS-fMRI include AD, frontotemporal dementia, dementia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), dementia with Lewy bodies, and Huntington’s disease.55–66 Together, these studies suggest that neurodegenerative diseases target interconnected cortical networks rather than single regions within the brain.57 An example of the strength of RS functional connectivity between certain regions of the brain in association with verbal episodic memory tasks in patients with MS is illustrated in ▶ Fig. 6.7.

In addition to RS-fMRI studies, fMRI studies can demonstrate alterations in brain activity with specific tasks in ALS, AD, PD, Huntington’s disease, semantic dementia in the frontotemporal lobar degeneration spectrum, and human immunodeficiency virus positivity.52,67,68,69,70,71,72,73,74,75 For example, Tessitore et al demonstrated reduced activity in brain regions encom- passing the primary motor and premotor cortex and the right parietal association cortex but heightened activity in the

anterior putamen in an area involved in motor execution in individuals with sporadic ALS.68

Various pharmacologic agents cause changes in the physiol- ogy of the central nervous system, and this is the basis of phar- macologic fMRI (Ph-fMRI). Over the past decade, there has been increasing interest in the application of Ph-fMRI to evaluate changes in brain activity with pharmacologic agents in those

Functional Imaging of the Brain

Fig. 6.6 The most consistently reported resting-state (RS) networks with major components detailed. This is a composite from multiple RS functional magnetic resonance imaging (fMRI) studies that used different groups of subjects and acquisition protocols. Networks include the default mode network (DMN) consisting of precuneus/posterior cingulate, medial frontal, and inferior parietal cortical regions and medial temporal lobe (a); primary visual (orange) and extrastriatal visual (gold) networks comprising retinotropic occipital cortex and temporo-occipital regions (b); executive control network composed of the superior and middle prefrontal cortices, anterior cingulate, and ventrolateral prefrontal cortex (c); left and right lateralized network, including inferior and medial frontal gyri, precuneus, inferior parietal, and angular gyrus (d), primary sensorimotor network (e), and auditory- phonological network consisting of superior temporal, insular, and postcentral cortex (f).

with and without neurodegenerative disease. fMRI signal changes have been reported with administration of D-ampheta- mine, dextroamphetamine, haloperidol, and dopamine via methylphenidate, among others.76,77,78,79 Ph-fMRI has also been used to study changes in various neurodegenerative states in response to a pharmacologic agent or by using the pharmaco- logic agent as a stimulus. Examples include the use of levodopa

Imaging Techniques

Fig. 6.7 The strength of resting-state functional connectivity between the left middle frontal gyrus (posterior Brodmann area 9) and the right middle temporal gyrus is associated with peak performance on a verbal episodic memory task in patients with multiple sclerosis (peak r = 0.56, P = 1 × 10-4, corrected for multiple comparisons) (a). (b) Illustrates the strength of resting-state functional connectivity between the left middle frontal gyrus (posterior Brodmann area 9) and the anterior left middle frontal gyrus and shows an inverse association with perform- ance on a verbal episodic memory task in patients with multiple sclerosis (r = –0.63, P = 1 × 10-5, corrected for multiple comparisons). (Courtesy of Drs. M. Phillips and M. Lowe, Cleveland Clinic.)

in hemiparkinson syndrome and PD and of rivastigmine in AD, MS, and MCI.80,81,82,83,84,85,86 A study by Mattay et al in 2002 on the use of dopaminergic modulation in evaluating cortical func- tion in subjects with PD showed promising results, with evi- dence supporting that the hypodopaminergic state is associated with decreased efficiency of prefrontal cortical information processing and that dopaminergic therapy improves the physi- ologic efficiency of this region.87 A review article by Jenkins on Ph-fMRI provides a good overview of its potential uses and fac- tors to consider when designing a Ph-fMRI study and evaluating the data.88

6.5 Advantages and Limitations

Functional MRI is a powerful, noninvasive method to identify and evaluate brain responses to cognitive tasks and stimuli, to promote understanding of complex networks and the interac- tions of various brain regions, and to assess RS networks in “normal” subjects and those with neurologic and psychiatric disorders. The use of fMRI in presurgical planning is now com- monplace in the clinic. For example, in presurgical planning for intractable epilepsy or brain tumors, fMRI can lateralize lan- guage noninvasively, has a high correspondence to Wada test- ing (intracarotid sodium amobarbital procedure), and provides detailed information about the language network that the Wada test cannot provide.89,90 The advantages of fMRI have made the technique increasingly popular over the last several years, particularly given its now wide availability as a “turnkey” add-on to MRI scanners, including pulse sequences, task para- digms, devices for presentation of stimuli to subjects in the scanner, and devices to record the subject’s responses.91

The main advantages of fMRI in brain mapping are its nonin- vasiveness and relatively high spatial resolution on the order of a few millimeters, which is superior to the spatial resolution in positron emission tomography (PET).92 In addition, fMRI has a relatively high temporal resolution compared with PET, lacks ionizing radiation, and does not need external contrast agents

or tracers. BOLD sensitivity for signal change via neurovascular coupling, and thus brain activation with a specific task or at rest, is directly proportional to magnetic field strength. There- fore, a higher field strength (i.e., 3.0 T and greater) will be more sensitive than a 1.5-T scanner.16 Thus, as MRI technology continues to evolve and higher field strengths become more commonly used, BOLD sensitivity for signal change will also continue to improve.

Functional MRI has several inherent disadvantages and pit- falls that are important to understand. Some of these can be mitigated with specific techniques. One must remember that BOLD fMRI detects only changes, rather than the absolute level, of brain activity and that it does so indirectly through neu- rovascular coupling, presuming a stable relationship between neural activation and resulting changes in absolute D-Hb con- centration. Unfortunately, this coupling may be variable across individuals or across brain regions within an individual. It may be compromised by pharmacologic modulations, such as medi- cations used during anesthesia; it may change with aging; and it may be altered by the pathology under study, such as a vascu- lar tumor.93,94,95,96 There is often reduced signal intensity and geometric distortion in the frontal and temporal regions or in the vicinity of surgical changes, blood products, and so forth, secondary to magnetic susceptibility effects, potentially leading to false-negatives. Parallel acquisition techniques have been developed that not only reduce image acquisition time but also reduce susceptibility artifacts, improving signal detection in basal frontal and mesial temporal regions and benefitting stud- ies involving memory, emotion, and executive function.97 Decreasing voxel size (e.g., through decreasing slice thickness in EPI acquisitions) can decrease distortion in hippocampus and amygdala.98,99

An obvious limitation of fMRI is that MRI is contraindicated in some individuals (e.g., those with cardiac pacemaker, implanted metal, claustrophobia). BOLD fMRI is highly sensitive to head motion, including task-related head motion or motion associated with cardiac or respiratory cycles, which can cause both false-positives and false-negatives. Task-related fMRI relies on the subject to understand and to complete the required tasks, which can also lead to false-negatives if the sub- ject is unable to cooperate sufficiently. Lastly, fMRI acquisition generates loud noise, up to 120dB, which can interfere with paradigms involving auditory processing.100,101,102 One can min- imize this effect by directly reducing the source of the noise or using the hemodynamic delay of BOLD response and inserting silent periods in the acquisition process.103,104

6.6 The Future of fMRI in

Neurodegenerative Disorders

The wealth of information fMRI provides about structure- function relationships in the brain may go beyond the immedi- ate implications of identifying brain regions responsible for executing certain functions. Functional brain networks eval- uated with fMRI, including RS networks like the DMN, are emerging as potential neuroimaging biomarkers for various neurodegenerative disorders and improved early diagnosis. They are providing new insights into functional effects on the brain in different diseases and may have implications in the

development and assessment of pharmacologic therapy in neu- rodegenerative disorders. Whereas many fMRI studies have been conducted on AD, MCI, and Huntington’s disease, further fMRI research is still needed, such as in frontotemporal lobar degeneration spectrum, dementia with Lewy bodies, and PD. Several recent studies have elucidated an RS network involving the basal ganglia, promising new applications of fMRI to study neurodegenerative changes involving the basal ganglia during disease progression or pharmacologic therapy.105,106,107 Ph-fMRI methods and results will need to be considered carefully with each potential application, as there may be many confounding factors; pharmacologic effects may be direct or indirect, short- and long-term pharmacologic responses may be different, and results in study populations may not apply in individual sub- jects. Although Ph-fMRI is promising, further data are still needed to make its use clinically relevant.

Functional MRI is well-suited to identifying imaging bio- markers for longitudinal, disease-monitoring studies because it is safe and easily repeatable. Whether fMRI methods will prove successful in reliably detecting preclinical stages of various neu- rodegenerative diseases and monitoring meaningful changes are questions awaiting future studies. With ongoing advances in fMRI acquisition and analysis techniques, fMRI is likely to become an increasingly powerful tool for understanding and evaluating neurodegenerative diseases and their progressive impact on brain networks. With ultrahigh-field fMRI on the horizon, spatial resolution will likely improve to submillimeter level, and it may ultimately be possible to identify the specific cortical layer(s) altered by neurodegenerative diseases.108,109 Finally, the increasing combination of fMRI with other advanced MRI techniques (e.g., diffusion tensor imaging) and with EEG is likely to yield new insights into the structural and functional changes of neurodegenerative disorders beyond what is possible by fMRI alone.

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Functional Imaging of the Brain

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Functional Imaging of the Brain

Imaging Techniques

7 Role of Noninvasive Angiogram and Perfusion in Evaluation of Neurodegenerative Disorders

Sangam G. Kanekar and Puneet Devgun

Computed tomography (CT) and magnetic resonance (MR) angiograms are well-established noninvasive techniques in the evaluation of the intracranial and extracranial vessels. Today, accuracy in the evaluation of extracranial and medium-sized intracranial vessel pathologies is comparable to the conven- tional angiogram. Cerebral perfusion is another noninvasive technique commonly used in the evaluation of stroke that gives information regarding the structural as well as the molecular functioning of the brain tissue. CT and MR perfusion both pro- vide insight into capillary-level hemodynamics and cerebral perfusion. Compared with CT perfusion (CTP), magnetic reso- nance perfusion (MRP) does not require radiation.

Today cerebrovascular disease (CVD) is thought to be the sec- ond most common cause of dementia. There is also ongoing debate as to whether Alzheimer’s disease (AD) and vascular dementia combined are more common than AD alone. It has been suggested that CVD may play an important role in deter- mining the presence and severity of clinical symptoms of AD. Clinicians believe that the prevalence of AD with CVD is grossly underestimated. The prevalence of vascular dementia rises from 0 to 2% in the 60- to 69-year-old age group, up to 16% (3 to 6% for men) age 80 to 89.1 In addition, risk factors for vascu- lar dementia are the same as those for CVD, stroke, and white matter lesions, which include arterial hypertension, atrial fibril- lation, myocardial infarction, coronary artery disease, diabetes, generalized atherosclerosis, lipid abnormalities, smoking, family history, and specific genetic features. All this suggests the importance of vascular imaging in evaluation of a patient with dementia. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have been widely used in the evaluation of dementia patients to estimate cerebral perfusion. Over the last decade, CT and MR angiogram and perfusion techniques have also been successfully used in the evaluation of the neurodegenerative disorders, especially AD and vascular dementia. In this chapter, we discuss the prin- ciples, techniques, and applications of these noninvasive angi- ography and perfusion techniques.

7.1 Noninvasive Angiography

7.1.1 Computed Tomography

Angiography

Computed tomography angiography (CTA) is a noninvasive imaging technique typically used to evaluate large cervical and intracranial arteries. CTA is a thin-section volumetric CT exami- nation performed with intravenous contrast medium used to enhance the carotid, vertebral arteries, and the circle of Willis. CTA typically involves a volumetric helical acquisition that extends from the aortic arch to the circle of Willis (▶ Fig. 7.1). Many different scan parameters must be balanced to produce a diagnostic CTA, including contrast administration, reformatting, and reconstruction parameters. Ideal CTA imaging requires

intravenous iodinated contrast opacification of the arterial tree with no venous enhancement. The contrast opacification is dependent on the type and timing of contrast, and the optimal arterial opacification is dependent on the volume, rate, and administration of contrast. Various contrast timing strategies are available for optimal arterial opacification, including fixed delay, bolus tracking, and test bolus (GE Healthcare ).2,3,4 Fixed

Fig. 7.1 Normal neck computed tomography angiography using a bone subtracted technique reveals normal carotid and vertebral arteries in the neck.

Role of Noninvasive Angiogram and Perfusion in Evaluation

delay, the simplest of the timing strategies, uses a fixed delay from the time of contrast injection to imaging. A slightly more complex strategy is bolus tracking, where scanning starts once a pretest HU (hounsfield) opacification is reached in a vessel of interest (typically the ascending aorta). A disadvantage of this technique is the inherent lag between the time to start scan- ning to actually acquiring images. An alternative to bolus track- ing is a test bolus, in which 10 mL of contrast is injected while a region of interest (ROI) is set in the proximal internal carotid artery. Using a low-level radiation scan, the ROI is scanned con- tinuously to determine the predelay, which corresponds to 50% of the maximal test vessel opacification.

Postprocessing of the data is extremely important for correct interpretation of the images. Various techniques have been developed for postprocessing, including maximum intensity projection (MIP), multiplanar volume reformat (MPR), curved reformat (CR), shaded surface display, or volume rendering, where it is possible to evaluate the vessel in its entirety.5,6,7,8 MIP constructs a two-dimensional (2D) image by displaying only pixels with a maximum CT attenuation (▶ Fig. 7.2). Because this technique relies on detecting the highest pixel on a given ray, it is sensitive to overlap from adjacent bony and opacified venous structures. MPR, unlike MIP, constructs a 2D image from the mean of CT attenuation compared with the maximum. In the CR technique, the vessel is traced along its course, with the user selecting the pixels to display on consecutive axial images. It is mostly useful for long, tortuous vessels, such as the carotid or vertebral arteries (▶Fig. 7.3). CR is a time-consuming tech- nique and is also subject to interpretative error.

Compared with other techniques, CTA has both advantages and disadvantages. With advances in technology and multide- tector row CT (MDCT), examination can be completed in a shorter time. The vessel from the arch of the aorta to the intra- cranial arteries can be scanned in less than 15 seconds using a 64-slice MDCT. Given the speed of the examination, CTA is less prone to motion artifact and can provide true anatomical repre- sentation of stenosis, lumen diameters, and calcifications. Unlike MR, there is no restriction on patients with pacemakers, ventilators, or monitoring devices or on claustrophobic patients. The greatest disadvantages of CTA are the radiation dose and iodinated contrast.

7.1.2 Magnetic Resonance Angiography

Like CTA, magnetic resonance angiography (MRA) is a non- invasive imaging technique used to depict the extracranial and intracranial circulation. Neck and intracranial MRA can be obtained using various imaging techniques, which include time of flight (TOF), multiple overlapping thin slab acquisition (MOTSA), phase-contrast (PC), and contrast-enhanced MRA. TOF can be obtained as either a 2D or 3D TOF.9,10

Time of Flight

Time-of-flight MRA is a gradient-echo sequence that depicts vascular flow by repeatedly applying a radiofrequency (RF) pulse to a volume of tissue, followed by dephasing and rephas- ing. TOF uses the difference in longitudinal magnetization between unsaturated (high signal) and saturated spins. Station- ary tissues in this volume become saturated by the repeated RF pulses and demonstrate low signal, whereas blood flowing in vessels carries unsaturated spins and has relatively high signal intensity.9,10 2D TOF MRA is typically performed in the neck, using a large flip angle. Blood flowing perpendicular to the multiple thin slices is well imaged and produces a bright signal compared with the stationary tissue. 3D TOF MRA is performed in the head (mostly for the circle of Willis) and uses a smaller flip angle, which reduces saturation artifacts (▶Fig. 7.4). The smaller flip angle and the addition of magnetization transfer decrease the background saturation. 3D TOF, compared with 2D TOF, has better spatial resolution and better signal-to-noise res- olution, but it covers only a small volume. MOTSA is a hybrid technique between 2D and 3D TOF and has higher spatial reso- lution than 2D TOF while covering a larger area than 3D TOF MRA with less saturation artifact.

Contrast-Enhanced Magnetic Resonance Angiography

Contrast-enhanced (CE) MRA is performed with a rapid, short repetition time (TR) gradient-echo sequence (10ms) after an intravenous bolus of gadolinium. Contrast-enhanced MRA, like CTA, requires a balance of diagnostic techniques of contrast

Fig. 7.2 Normal head computed tomography angiography (CTA). Axial (a) and coronal
(b) reformatted maximum intensity projection images from CTA demonstrate normal course and caliber of intracranial vessels.

Imaging Techniques

Fig.7.3 Curved reformatted image of neck computed tomography angiography shows the course of the entire neck portion of the internal carotid artery in a single image. Large ulcerative plaque (white arrow) is seen in the distal portion of the common carotid artery.

Fig. 7.4 Maximum intensity projection images of the three-dimen- sional time-of-flight magnetic resonance angiograms of the head show normal course and caliber of intracranial vessels around the circle of Willis.

administration, reformatting, and reconstruction. Injected gad- olinium shortens the T1 to less than 10 ms so that opacified ves- sels are hyperintense.9 The timing of CE MRA can be a test bolus or automatic bolus technique, as described earlier. CE MRA can cover a much larger area of anatomy in a much shorter time and is less susceptible to motion artifact (▶ Fig. 7.5). CE MRA is obtained with intravenous contrast, which produces shortened T1, giving an anatomical representation of the vessel, whereas TOF anatomy is inferred from physiology (velocity dependent).

One of the disadvantages of CE MRA and CTA is that the data must be acquired during a narrow window of contrast enhance- ment, which relies on proper contrast bolus and image acquisi- tion. TOF and MRA can both be postprocessed into MIP images. MIP produces 3D images by a set of parallel rays drawn along the highest intensity in the source images. Multiple different projections are taken to construct a rotating 3D image.

Phase Contrast

Phase-contrast MRA is a gradient-echo sequence that depicts blood flow by quantifying the difference in the transverse mag- netization between stationary and moving tissue. After an RF pulse, a pair of symmetric but opposed phase-encoding gradi- ents are applied in one direction within the image voxel.9 The first gradient dephases, and the second rephases the transverse magnetizations. Stationary tissues have no net change in phase because they experience equal but opposite magnetic-field environments during the dephasing and then rephasing gradi- ents. Moving blood experiences different magnetic fields as each gradient is applied. The net phase shift, either positive or negative, determines the direction of flow and the amount of phase shift, which is directly proportional to the velocity of the blood flow.

Phase-contrast (PC) MRA capitalizes on the change in trans- verse magnetization (phase shift) that occurs when flowing protons encounter changes in gradient strength, produced by bipolar gradient pulses. By applying a bipolar gradient echo to the tissue, a phase shift is induced in moving spins but not in stationary tissue. PC MRA demonstrates flow directionality and

Role of Noninvasive Angiogram and Perfusion in Evaluation

7.1.3 Perfusion
Computed Tomography Perfusion

Computed tomography perfusion expands the role of CT by providing insight into capillary-level hemodynamics and the brain parenchyma. Cerebral CTP is a functional imaging tech- nique that reflects cerebral microcirculation and reveals changes in cerebral microcirculation and metabolism that can- not be detected by conventional CT or MRI scans. The general principles underlying the computation of perfusion parameters, such as cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT), are the same for both MR and CT. CTP and MR perfusion-weighted imaging (PWI) both attempt to evaluate the capillary-level hemodynamics using different tech- niques. CTP relies on direct visualization of the contrast mate- rial, whereas MR PWI techniques rely on the indirect T2* effect induced in adjacent tissues.

A basic principle in CTP is monitoring the first pass of an iodinated contrast agent through the cerebral circulation. This is accomplished by continuous cine imaging for 45 seconds over the same volume of tissue during the rapid administration of a small, high-flow contrast material. A transient hyperattenua- tion caused within the brain tissue is directly proportional to the amount of contrast material in the vessels and blood for that region. This provides insight into the delivery of blood to the brain parenchyma. The generic term cerebral perfusion refers to tissue-level blood flow in the brain. This principle is used to generate time-attenuation curves for an arterial ROI, a venous ROI, and each pixel (▶Fig. 7.6). This flow can be described using a variety of parameters, which primarily include CBF, CBV, and MTT (▶Fig. 7.7). CBV is defined as the total volume of blood in a given unit of volume of the brain, including blood in the tissues, as well as the blood in the large capacitance vessels, such as arteries, arterioles, capillaries, venules, and veins. CBF is defined as the volume of blood moving through a given unit volume of brain per unit time. MTT is defined as the average of the transit time of blood though a given brain region. The transit time of blood varies depending on the distance traveled between arterial inflow and venous outflow. MTT is related to both CBV and CBF accord- ing to the central volume principle, which states MTT=CBV/ CVF.11,12

Magnetic Resonance Perfusion

Perfusion MRI techniques include dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL). Because of the lack of radiation exposure, these techniques are usually pre- ferred in the evaluation of neurodegenerative diseases. In DSC, images are acquired dynamically before, during, and after the injection of a bolus of a gadolinium. These images are used to track the bolus and the blood in which it is dissolved as it passes through the microvasculature of the brain. In higher con- centrations, gadolinium ions confined within a cerebral blood vessel create a magnetic susceptibility effect that results in sub- stantial loss of signal on T2*-weighted images, a signal loss that extends over a distance comparable in magnitude to the diame- ter of the blood vessel.13 This allows for signal changes affecting

Fig. 7.5 Contrast-enhanced neck magnetic resonance angiography shows normal course and caliber of common carotid arteries, carotid bifurcation, and internal and external carotid arteries.

shows slowly moving blood. PC MRA can be obtained after intravenous gadolinium because PC MRA does not rely on T1 values to generate the MRA image. A major disadvantage of PC MRA is that it is a much longer sequence to acquire and there- fore more susceptible to motion artifact.

Imaging Techniques

Fig. 7.6 Time-density curves (TDCs) generated from this artery (A) and vein (V) show the arrival, peak, and passage of the contrast bolus over time. These TDCs serve as the arterial input function and the venous output for the subsequent deconvolution step to formulate color-coded computed tomography perfusion maps.

Fig. 7.7 Computed tomography perfusion colored maps calculated using deconvolution techniques show normal cerebral blood flow (a) and cerebral blood volume (b).

all of the spins in an image voxel. The technique requires a pulse sequence capable of repeatedly acquiring T2*-weighted images rapidly enough that the concentration of gadolinium within each tissue voxel can be sampled with sufficient tempo- ral resolution, preferably every 1.5 seconds or less. The sequence also needs to be multislice to cover most of the brain tissue. This is accomplished through a fast imaging technique, usually echo-planar imaging (EPI), with which interleaved images of many tissue slices can be obtained within a single TR. Both EPI spin-echo and EPI gradient-echo sequences have been used successfully for PWI.14,15 DSC provides higher spatial resolution, requires shorter scanning time, and can measure CBF, CBV, MTT, and TTP (▶ Fig. 7.8). One of the limitations of the DSC MRI perfusion is use of gadolinium contrast, which can

have potential increased risk in patients with impaired renal function.

In ASL, a preimaging RF pulse is used to magnetically label the hydrogen nuclei within water molecules in arterial blood before they flow into the imaged portion of the brain. Com- pared with a baseline image acquired without labeling, the labeling pulse attenuates the signal arising from each voxel in the brain to a degree dependent on the rate at which the labeled spins flow into the voxel.16,17 This allows for the mea- surement of regional CBF (▶ Fig. 7.9). Major advantages of ALS include lower cost and lack of adverse reactions to contrast material. One of the major limitations is that it allows only measurement of regional CBF and maps produced by ASL are noisier.

Role of Noninvasive Angiogram and Perfusion in Evaluation

Fig. 7.8 Colored maps generated from the magnetic resonance dynamic susceptibility contrast perfusion show normal cerebral blood flow (a), cerebral blood volume (b), and mean transit time (c).

Fig. 7.9 Normal arterial spin labeling. Multisection cerebral blood flow color maps representing units of mL/100 g tissue per minute.

7.2.2 Alzheimer’s Disease

Neuropathological studies suggest that evidence of AD may be present in the brain years or even decades before onset of clini- cal symptoms. Research to identify these changes is ongoing. One of the parameters under investigation to understand these neuropathological changes is by evaluation of the blood circula- tion. Fluorodeoxyglucose PET, which measures glucose metabo- lism, and HMPAO SPECT, which measures CBF, have been widely used in the evaluation of cerebral metabolism or blood flow. Today, CT or CE MRP can calculate the relative CBF, CBV, MTT, and TTP (time to peak). These techniques, which are predomi- nantly used in stroke and tumor imaging, are gaining early application in the evaluation of dementia, especially AD and vascular dementia. Although the SPECT and PET literature is more robust compared with CTP and MRP, the results are com- parable. ASL, as described above under magnetic perfusion, is another noninvasive MR technique used in evaluation of AD, MCI, and vascular dementia.

7.2 Application in Neurodegenerative Imaging

7.2.1 Changes in Perfusion Parameters in the Normal Aging Brain

In clinical practice, perfusion imaging is rarely performed to understand normal aging; however, brain and vascular changes may be appreciated while scanning the patient for other neuro- logic disorders, such as acute stroke, using CT or MRP. Various SPECT studies using technetium 99m-radiolabeled hexamethyl- propyleneamine oxime (HMPAO) have shown age-related decreases in the regional CBF compared with normal subjects.18 These changes are predominantly seen in the cingulate gyrus, frontal lobe, parietal lobe, and temporal lobe. On CT and MRP, these changes are difficult to appreciate by “eyeballing” and require a quantitative analysis, which is more of a research interest than of clinical significance (▶ Fig. 7.10).

Imaging Techniques

Fig. 7.10 Quantitative analysis of computed tomography angiography. Cerebral blood flow map from computed tomography perfusion study shows quantitative analysis of the cerebral blood flow using multiple regions of interest in the white and gray matter.

Fig. 7.11 Magnetic resonance perfusion (MRP) in vascular dementia. (a) Cerebral blood flow (CBF) map of MRP shows diffuse decrease in the CBF in the supratentorial white matter in a 60-year-old man with subcortical dementia. (b) MRP perfusion in a 43-year-old man with frontal dementia after a head injury shows an increase in the mean transit time in the bilateral frontal lobes.

Perfusion defects largely depend on the stage of the AD.19,20 In mild to moderate AD, the greatest hypoperfusion or decrease in the CBF is seen in the parietal lobes and cingulate gyri; a smaller effect may be seen in the frontal lobes. In the early stages of the disease, these deficits are asymmetric. In the later stages, characteristic hypoperfusion and hypometabolism, located mainly in the temporal, parietal, and posterior cingulate cortices, are mostly bilateral and symmetrical.21,22 It is pre- sumed that the localized hypoperfusion in the posterior cingu- late gyrus is due to hypoactivity of the posterior cingulate gyrus, caused by neuronal damage, whereas in the medial tem- poral lobe structures, it is due to loss of tight neuronal connec- tions. On MRP, decreased CBV is most pronounced in the tem- poroparietal region.23 Primary sensorimotor and primary visual cortices, as well as the striatum, thalamus, and cerebellum, are spared in AD patients. CBV decline in the frontal and parietal lobes was primarily in white matter, which was well correlated with structural damage as seen on DTI. It is documented by SPECT studies that frontal lobe deficit (at baseline) was more predictive of future cognitive decline than was that in the tem- poroparietal regions. The MTTs and TTPs of the aforementioned ROIs were significantly lower in the healthy control group than in the AD group.

The results further demonstrate that the pathological basis of AD is neuron injury due to impaired microcirculation. As the changes in hemodynamic parameters indirectly reflect physio- logic and metabolic conditions of brain tissue, the CTP scan can provide evidence for the early diagnosis of AD. Although the major pathological change of AD is cerebral neurodegeneration, there is evidence of vascular risk factors and CVD in patients with AD, which indicates that vascular-related risk factors may play important roles in the development and progression of AD.

7.2.3 Vascular Parkinsonism

The imaging modality of choice for patients with parkinsonian syndromes continues to be MRI. Imaging is primarily done to differentiate between PD and secondary parkinsonism, which also includes vascular parkinsonism (VP). Signal changes in the nigral and subcortical regions are nonspecific and non- discriminatory. Putaminal hypointensity seen on MRI is regarded as due to postsynaptic striatal dysfunction. Frontal lobe atrophy is related to the L-dopa-nonresponsive, predomi- nantly axial parkinsonian syndrome

Patients with VP may show vascular impairment in more than one vascular territory, such as periventricular and sub- cortical white matter, the basal ganglia, and the brainstem. These may be in the form of lacunar or territorial infarcts. It is well documented that dementia occurs more commonly in patients with VP than in those with PD. Although MRI is quite sensitive in detecting these abnormalities, perfusion studies, along with MRA, may be useful in identifying associated changes in the focal or generalized vascular abnormalities.

7.2.4 Vascular Dementia

Both PET and SPECT have limited roles in the evaluation of vas- cular dementia compared with degenerative dementia because vascular dementia is diagnosed with MRI in most cases. CT or MRP may show a typical perfusion defect in the cortical and subcortical structures and cerebellum, depending on the local- ization of the ischemic change. On the PET/SPECT, AD can be differentiated from the pattern of defect seen. In AD, blood flow reduction tends to be posterior predominant, whereas in vascu- lar dementia, it shows anterior predominance (▶Fig. 7.11).24

Although this defect is seen mostly in the white matter, the overlapping cortex also shows the CBF reduction secondary to disconnection between the deep cerebrum and the cortex. Sometimes these defects may be in the remote region away from the site of infarction and are believed to be caused by functional cortical-subcortical disconnections.

7.2.5 Sickle Cell Disease

vasodilation.30,31 In the nonstroke groups, CBF abnormalities were more prevalent than transcranial Doppler velocity.

7.2.6 Perfusion Changes in Normal

Pressure Hydrocephalus

Diagnosis of normal pressure hydrocephalus (NPH) is clinical, supplemented with various imaging techniques. The imaging tests fail to answer the most important question in patients with NPH, which is, which patients will benefit from ventricular shunting. Vascular imaging plays a limited role in the diagnosis of NPH. However, perfusion analysis in NPH patients using PET has shown decreased regional CBV and regional CBF.32 These parameters showed significant improvement after shunt- ing, suggesting vascular compromise within the brain paren- chyma, possibly resulting from a mass effect and raised intracranial pressure. It is also demonstrated that MRP can improve the prediction of the outcome after shunt placement in patients with NPH.

References

[1] O’Brien JT, Erkinjuntti T, Reisberg B et al. Vascular cognitive impairment. Lancet Neurol 2003; 2: 89–98

[2] Kopka L, Funke M, Fischer U, Vosshenrich R, Oestmann JW, Grabbe E. Paren- chymal liver enhancement with bolus-triggered helical CT: preliminary clinical results. Radiology 1995; 195: 282–284

[3] Puskás Z, Schuierer G. [Determination of blood circulation time for optimiz- ing contrast medium administration in CT angiography] [in German] Radiol- oge 1996; 36: 750–757

[4] Bae KT, Heiken JP, Brink JA. Aortic and hepatic contrast medium enhance- ment at CT. Part II. Effect of reduced cardiac output in a porcine model. Radi- ology 1998; 207: 657–662

[5] Napel S, Marks MP, Rubin GD et al. CT angiography with spiral CT and maxi- mum intensity projection. Radiology 1992; 185: 607–610

[6] Rubin GD, Dake MD, Napel S et al. Spiral CT of renal artery stenosis: compari- son of three-dimensional rendering techniques. Radiology 1994; 190: 181– 189

[7] Vieco PT, Morin EE, III, Gross CE. CT angiography in the examination of patients with aneurysm clips. AJNR Am J Neuroradiol 1996; 17: 455–457
[8] Kuszyk BS, Heath DG, Ney DR et al. CT angiography with volume rendering:

imaging findings. AJR Am J Roentgenol 1995; 165: 445–448
[9] Jewells V, Castillo M. MR angiography of the extracranial circulation. Magn

Reson Imaging Clin N Am 2003; 11: 585–597, vivi

Cognitive decline and dementia symptoms are not uncommon in sickle cell disease (SCD). These changes are mostly related to damage to the brain parenchyma from the various vascular insults, which include vascular endothelial damage and occlu- sion, cerebral ischemia, silent strokes, white matter (sub- cortical) changes, and intracranial hemorrhage.25 A prevalence of overt stroke in SCD is 250 times higher than in the general population.26 Overt stroke produces focal neurologic deficits that are easily diagnosed by MRI. Silent strokes occur in approx- imately 22% of children with SCD and can herald subsequent overt stroke.27 Mechanisms responsible for cerebral ischemia in SCD are complex and seem related to impaired blood flow. Blood flow abnormalities can be caused by narrowing or occlu- sion of cerebral vessels, increased viscosity, adherence of red blood cells to the vascular endothelium, and exhaustion of autoregulatory vasodilation. Detection of abnormalities of blood flow before clinical progression to stroke could be impor- tant information in helping or halting progression.

Transcranial Doppler scanning is commonly used in assess- ment of this abnormality in the CBF. Measurement of the mid- dle cerebral artery or the terminal portion of the internal carotid artery velocity is used as one of the major Doppler crite- ria. A velocity greater than 200cm/s in these vessels is more prone to overt stroke, which can be prevented by using periodic red blood cell transfusion.28 Unfortunately, Doppler has its own limitations. This technique is operator dependent, and overt strokes are seen with a velocity less than 200 cm/s.29 MRP has been used to evaluate the cerebral vascular dynamics, such as CBF and CBV, in SCD patients (▶ Fig. 7.12). MRP showed asym- metrical, elevated baseline CBF in SCD patients related to large cerebral artery stenosis, low hematocrit levels, and resultant

Role of Noninvasive Angiogram and Perfusion in Evaluation

Fig.7.12 A21-year-oldmanwithsicklecelldiseasewithearlysignsofsubcorticaldementiashows(a)adiffusedecreaseinthecerebralbloodvolume(CBV) and (b) an increase in the mean transit time in the cerebral white matter bilaterally, left more than right. (c) Intracranial time-of-flight magnetic resonance imaging shows severe narrowing of the distal internal carotid and middle cerebral arteries bilaterally, findings suggestive of moyamoya.

Imaging Techniques

. [10] Sohn CH, Sevick RJ, Frayne R. Contrast-enhanced MR angiography of the intracranial circulation. Magn Reson Imaging Clin N Am 2003; 11: 599–614

. [11] Meier P, Zierler KL. On the theory of the indicator-dilution method for mea- surement of blood flow and volume. J Appl Physiol 1954; 6: 731–744

. [12] Roberts GW, Larson KB, Spaeth EE. The interpretation of mean transit time measurements for multiphase tissue systems. J Theor Biol 1973; 39: 447–475

. [13] Rosen BR, Belliveau JW, Vevea JM, Brady TJ. Perfusion imaging with NMR
contrast agents. Magn Reson Med 1990; 14: 249–265

. [14] Speck O, Chang L, DeSilva NM, Ernst T. Perfusion MRI of the human brain
with dynamic susceptibility contrast: gradient-echo versus spin-echo tech-
niques. J Magn Reson Imaging 2000; 12: 381–387

. [15] Heiland S, Kreibich W, Reith W et al. Comparison of echo-planar sequences
for perfusion-weighted MRI: which is best? Neuroradiology 1998; 40: 216–
221

. [16] Williams DS, Detre JA, Leigh JS, Koretsky AP. Magnetic resonance imaging of
perfusion using spin inversion of arterial water. Proc Natl Acad Sci U S A
1992; 89: 212–216

. [17] Edelman RR, Siewert B, Darby DG et al. Qualitative mapping of cerebral blood
flow and functional localization with echo-planar MR imaging and signal tar-
geting with alternating radio frequency. Radiology 1994; 192: 513–520

. [18] Takahashi K, Yamaguchi S, Kobayashi S, Yamamoto Y. Effects of aging on regional cerebral blood flow assessed by using technetium Tc 99 m hexame- thylpropyleneamine oxime single-photon emission tomography with 3D stereotactic surface projection analysis. AJNR Am J Neuroradiol 2005; 26:
2005–2009

. [19] Jagust WJ. Neuroimaging in dementia. Neurol Clin 2000; 18: 885–902

. [20] Petrella JR, Coleman RE, Doraiswamy PM. Neuroimaging and early diagnosis
of Alzheimer’s disease: a look to the future. Radiology 2003; 226: 315–336

. [21] Bradley KM, O’Sullivan VT, Soper ND et al. Cerebral perfusion SPET correlated with Braak pathological stage in Alzheimer’s disease. Brain 2002;
125: 1772–1781

[22] Lee YC, Liu RS, Liao YC et al. Statistical parametric mapping of brain SPECT perfusion abnormalities in patients with Alzheimer’s disease. Eur Neurol 2003; 49: 142–145

[23] Yoshiura T, Hiwatashi A, Noguchi T et al. Arterial spin labelling at 3-T MR imaging for detection of individuals with Alzheimer’s disease. Eur Radiol 2009; 19: 2819–2825

[24] Yoshikawa T, Murase K, Oku N et al. Heterogeneity of cerebral blood flow in Alzheimer’s disease and vascular dementia. AJNR Am J Neuroradiol 2003; 24: 1341–1347

[25] Behpour AM, Shah PS, Mikulis DJ, Kassner A. Cerebral blood flow abnormali- ties in children with sickle cell disease: a systematic review. Pediatr Neurol 2013; 48: 188–199

[26] Earley CJ, Kittner SJ, Feeser BR et al. Stroke in children and sickle-cell disease: Baltimore-Washington Cooperative Young Stroke Study. Neurology 1998; 51: 169–176

[27] Pegelow CH, Macklin EA, Moser FG et al. Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease. Blood 2002; 99: 3014–3018

[28] Adams RJ, McKie VC, Brambilla D et al. Stroke prevention trial in sickle cell anemia. Control Clin Trials 1998; 19: 110–129

[29] Adams RJ, Brambilla DJ, Granger S et al. STOP Study. Stroke and conversion to high risk in children screened with transcranial Doppler ultrasound during the STOP study. Blood 2004; 103: 3689–3694

[30] Stockman JA, Nigro MA, Mishkin MM, Oski FA. Occlusion of large cerebral vessels in sickle-cell anemia. N Engl J Med 1972; 287: 846–849

[31] Gerald B, Sebes JI, Langston JW. Cerebral infarction secondary to sickle cell disease: arteriographic findings. AJR Am J Roentgenol 1980; 134: 1209–1212 [32] Walter C, Hertel F, Naumann E, Mörsdorf M. Alteration of cerebral perfusion

in patients with idiopathic normal pressure hydrocephalus measured by 3D perfusion weighted magnetic resonance imaging. J Neurol 2005; 252: 1465–1471

Part III Normal Aging

. 8 Imaging of the Normal Aging Brain 70

. 9 Iron Accumulation and Iron Imaging in
the Human Brain 80

III

Normal Aging

8 Imaging of the Normal Aging Brain

Ruth A. Wood, Ludovico Minati, and Dennis Chan

Elderly adults represent a significant and rapidly expanding proportion of the population. Some estimates state that by 2030 there will be 72 million individuals over the age of 65 years in the United States of America, constituting 19% of the population.1 Given the high prevalence of brain disorders in this population, attaining a greater understanding of the changes that occur in normal brain aging is of critical importance. Furthermore, an appreciation of such changes is a prerequisite for the identification of abnormalities associated with underly- ing pathology.

As the prevalence of many neurological diseases increases with age, it can be difficult to differentiate between the effects of aging and those of prodromal age-related disease. In addi- tion, several operational challenges exist when establishing the effects of aging on the brain. First, there is a potential ascertainment bias in the selection of individuals considered to represent “normal aging”; without exhaustive screening and follow-up, there is a risk that cohorts contain individuals with clinically silent disease. Second, most studies on normal aging are cross-sectional, with limited longitudinal data on the pro- gression of age-related changes. Third, the brain changes that occur during aging reflect a complex interaction between alter- ations of disparate physiological variables, most notably struc- ture, function, perfusion, and metabolism. Because each of these variables is evaluated using different imaging modalities, careful implementation of multimodal imaging is required to obtain a comprehensive view of aging of the brain, whereas most studies published to date have described changes as observed through single techniques applied in isolation.

This chapter provides an overview of the main brain changes associated with normal aging and the imaging modalities cur- rently used to study them. It does not intend to be a meta- analysis; the focus is on conceptual comprehensiveness rather than exhaustive comparison of published studies.

8.1 Brain Structure

8.1.1 Gray Matter Volume

Autopsy studies consistently demonstrate an age-related reduc- tion in brain weight and volume, with concomitant enlarge- ment of ventricular cerebrospinal fluid (CSF) spaces.2 These gross pathological changes correspond on a histopathological level to neuronal loss in the neocortex, hippocampus, and cere- bellum and neuronal shrinkage and loss of myelinated fibers, particularly in subcortical regions.2 Brain-volume loss observed at autopsy correlates with atrophy as determined using in vivo structural brain imaging; in addition to the use of cross- sectional imaging to identify changes at a single time point, lon- gitudinal imaging studies permit determination of change in rates of atrophy. Most of these studies use magnetic resonance imaging (MRI) techniques for their superior resolution and gray matter (GM):white matter (WM) contrast compared with com- puted tomography (CT).

The changes in brain volume over the human life span do not follow a linear trajectory. Brain volume increases in early life, followed by a plateau during which the CSF:brain volume ratio remains approximately constant.3 Brain volume then declines after the fifth decade, with progressive ventriculomegaly, sulcal expansion, and enlargement of pericerebellar subarachnoid spaces (▶ Fig. 8.1).3

Several trends emerge on more detailed scrutiny, although there is a degree of interstudy variability regarding the precise time course and spatial distribution of age-related volume changes. First, the rate of brain atrophy accelerates with age.4 Second, WM and GM are affected differently (▶ Fig. 8.2). Loss of GM occurs at an early age, and both linear and nonlinear pat- terns of correlation with age have been described (▶ Fig. 8.3),5 whereas WM volume peaks in the fifth decade before declining in older age.5

With regard to the anatomical distribution of volume loss, the regions of the cortex are affected in a non-uniform manner. Overall, there is an anteroposterior gradient of volume loss, with the earliest age-related atrophy occurring in the prefrontal cortex.6 Age-associated atrophy has also been demonstrated in the hippocampus, amygdala, striatum, and cerebellum (▶Fig. 8.4).2 Conflicting reports exist regarding age-related atrophy within the thalamus, and some regions within the basal ganglia and brainstem appear relatively unaffected.7 Although these observations are useful for understanding the aging process, it is important to keep in mind that they are the result of analyses conducted over large groups; at the single- case level, there is substantial individual variability in the extent and localization of atrophy, ranging from near absence of atrophy in comparison to a typical young brain, to moderate atrophy without any accompanying cognitive deficit.

Detailed robust understanding of the regional distribution of volume loss in normal aging is of particular relevance in view of the patterns of atrophy associated with different neuro- degenerative disorders. For example, atrophy of the medial temporal lobe is a typical early feature of Alzheimer’s disease, but this region does not exhibit significant age-related atrophy in the normal aging population.8 In frontotemporal dementia, there is asymmetrical atrophy predominantly affecting the frontal and temporal lobes, which also contrasts with the sym- metrical pattern of atrophy in normal aging.9 However, in any comparison of change between aging and neurodegenerative diseases, it is crucial to bear in mind the fact that atrophy can be absent or minimal in the preclinical and early clinical phases of most neurodegenerative disorders, making differentiation of early-stage disease from normal aging at the individual level quite difficult.

Although the association between the integrity of specific cognitive functions and regional brain atrophy in disease is widely recognized, weaker and less consistent correlations are observed between cognition and age-related atrophy.10,11 For example, reduced GM volume in the medial temporal lobe, prefrontal cortex, and posterior parietal cortex appears to be associated with lower scores on the Mini-Mental State Examination11; furthermore, there is evidence that reduced

Imaging of the Normal Aging Brain

Fig. 8.1 Axial and coronal T1-weighted magnetic resonance imaging of two representative
young (a,b) and elderly (c,d) healthy brains demonstrating global volume loss and sulcal enlargement.

Fig. 8.2 Scatterplots demonstrating the complex effect of age on white matter, gray matter, and cerebrospinal fluid volumes (CSF). (Reproduced with permission from Sowell ER, Peterson BS, Thompson PM, et al. Mapping cortical change across the human life span. Nat Neurosci. 2003;6:309–15. Copyright Nature Publishing Group, Inc.)

1.0% have been reported for most brain regions.12 In line with measurements of regional brain volume, the most prominent age-related reduction in cortical thickness is observed in the prefrontal cortex.13 Cortical thinning with age is also consis- tently found in parietal and insular regions, and in these regions, thickness measures appear more sensitive than volume measurements to age-related changes.13 Changes in cortical thickness occur in different brain regions at different times dur- ing the life span; between young adulthood and middle age, cortical thinning occurs mainly in the prefrontal cortex and at the parietal-temporal-occipital junction, whereas in the oldest

hippocampal volume is associated with poor performance on tests of episodic memory.10

Cortical Thickness

The development of automated techniques to obtain quantita- tive MRI measures has permitted the study of the effects of aging on structural parameters, such as cortical thickness (▶ Fig. 8.5), with regional changes in cortical thickness detect- able over time intervals as short as 1 year. In the normal aging population, annual reductions in cortical thickness of 0.5 to

Normal Aging

Fig. 8.3 Peak age maps showing the nonlinear effect of age on gray matter (GM). Color maps show the mean age at which peak GM density is reached for each point on the lateral, medial, and top surfaces of the brain. Shown in black are regions where the partial correlation coefficient for the nonlinear age effect did not reach statistical significance; age effects in these regions tended to decrease linearly with age rather than quadratically. (Reproduced with permission from Sowell ER, Peterson BS, Thompson PM, et al. Mapping cortical change across the human life span. Nat Neurosci 2003;6:309–315. Copyright Nature Publishing Group, Inc.)

Fig. 8.4 Coronal T1-weighted magnetic reso- nance imaging of two representative young (a) and elderly (b) healthy brains, demonstrating hippocampal atrophy, ventricular enlargement, and increased prominence of the sylvian fissures.

Fig. 8.5 Illustration of the cortical thickness measurement principle. (a) Original magnetic resonance imaging scan; (b) extraction of the cortical gray matter (GM) boundaries (yellow: white matter to GM boundary, red: cerebrospinal fluid to GM boundary); (c) thickness measurement (blue segment).

elderly, changes are most prominent in the primary sensory and motor cortices.14

The relationship between cognitive function and cortical thickness is less well established than that with cortical volumes, although some data suggest that cortical thickness correlates with performance on tests of reaction time, verbal working memory, and episodic memory.15

8.1.2 Iron Deposition in the

Extrapyramidal Nuclei

Iron accumulates in substantial quantities in the brain with normal aging, and its magnetic properties are readily detectable using MRI. MRI signal intensity changes in GM nuclei, particu- larly on gradient-echo sequences, are well described in associa- tion with normal aging and neurodegenerative disease and correlate with non-heme iron deposition as determined at autopsy (▶ Fig. 8.6).16 Iron deposits are not present at birth, and in children under the age of 10 years, the basal ganglia are hyperintense on MRI, becoming hypointense by approximately 25 years of age.16 In healthy adults, the highest iron concentra- tions are found in the globus pallidus, red nucleus, and pars reticularis of the substantia nigra.17 Deposition also occurs, albeit at a slower rate, in the cerebellum, dentate nucleus, and neostriatum.17

8.1.3 White Matter Macrostructural Lesions

Changes in WM are a common finding in cognitively intact eld- erly individuals and on T2-weighted MRI scans are visualized as hyperintense areas. These WM hyperintensities (WMHs) are classified as periventricular or deep, depending on the lesion’s proximity to the lateral ventricle (▶ Fig. 8.7). The prevalence of WMHs increases with age, and by the fifth decade, they are detectable in nearly all healthy individuals.18

Postmortem studies have identified distinct histopathological correlates for the various WMH subtypes. Periventricular WMHs are subdivided into “caps” surrounding the frontal horns of the lateral ventricles, pencil-thin lining, and halos. Pencil-thin lining and halos represent areas of demyelination

8.8).19,20
caps are associated with myelin pallor, arteriosclerosis, and

astrogliosis.20 Deep WMHs can be punctate, early confluent, or confluent. Confluent and early confluent WMHs represent a continuum of ischemic lesions; histology shows incomplete parenchymal destruction with axonal loss and astrogliosis.19 By comparison, punctate WMHs are considered more benign and correlate with regions of reduced myelination and widen- ing of Virchow-Robin perivascular spaces (▶ Fig. 8.9).19

The relationship between WMH density and cognition in normal aging remains unclear. One meta-analysis has uncov- ered limited evidence that WMHs in healthy individuals are

and subependymal

gliosis

(▶ Fig.

Periventricular

Imaging of the Normal Aging Brain

Fig. 8.6 Axial gradient-echo MRI demonstrating hypointensity of the putamina (as indicated by white arrows) in an elderly brain due to iron accumulation.

Fig. 8.7 Axial T2-weighted (a) and coronal fluid-attenuated inversion recovery (FLAIR)
(b) magnetic resonance imaging demonstrating, respectively, confluent and periventricular white matter hyperintensities, as sometimes observed in the brains of elderly patients.

Normal Aging

Fig. 8.8 Apologies, the legend is correct but does in fact refer to a different MR image which is attached. Axial T2-weighted image showing an example of nonspecific gliosis in the left frontal WM as indicated by the yellow arrow.

Fig. 8.9 Axial T2-weighted MRI demonstrating diffusely enlarged Virchow-Robin perivascular spaces in subcortical WM. An example of an enlarged Virchow Robin space is indicated by the white arrow.

associated with poor performance on tasks assessing declara- tive memory and executive function,21 whereas more recent work suggests that periventricular WMHs correlate most strongly with deficits in multiple cognitive domains.22

Microstructure

Diffusion-based MRI techniques, such as diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), and diffusion spectrum imaging (DSI), measure aspects of the diffusion of water molecules within brain tissue to probe tissue microarchi- tecture. The diffusion properties can be quantified using vari- ous parameters. Mean diffusivity (MD) is a measure of the rate at which water molecules diffuse: high MD indicates that biological barriers are sparse and indicates low tissue density. Fractional anisotropy (FA) measures the directional coherency with which diffusion occurs. In normal WM, water molecules tend to diffuse in parallel to the myelinated axon bundles, and disruption of these myelinated bundles allows water molecules to diffuse in other planes more readily, measured as a reduction in FA.

Diffusion studies can identify WM changes before the devel- opment of WMHs. In normal aging, the most consistent find- ings are reduced FA and increased MD; axonal degeneration, myelin breakdown, and glial scarring appear to be the main histopathological correlates of these changes.23 Brain regions that exhibit reduced FA with aging include the internal capsule, corpus callosum, and centrum semiovale.23 According to some

investigations, there is evidence of an anteroposterior gradient of reduced FA with aging, paralleling the changes observed using GM volumetry.24 There is limited additional evidence of a superoinferior gradient, with more marked age-related reduction of FA in dorsal fiber tracts, such as the superior longi- tudinal fasciculus.25 Aging also correlates with MD changes, although the amplitude of these changes is smaller in compari- son to changes in FA. The most consistent findings, namely, of an anteroposterior gradient of MD and of increased MD in the corpus callosum, parallel the changes observed in FA.23

There is evidence to indicate that, within the normal aging population, DTI measures are associated with cognitive func- tion. For example, FA in the body of the corpus callosum corre- lates with performance in motor skill tests, and diffusivity mea- sures in frontal regions correlate with performance on tests of verbal fluency.23

8.1.4 Cerebrovascular Changes Microbleeds

Cerebral microbleeds (CMBs) appear as small, round, homoge- neous foci of signal hypointensity on gradient-echo T2*- weighted MRI (▶ Fig. 8.10). Histopathology reveals focal depos- its of perivascular hemosiderin, suggesting that these regions represent previous microhemorrhages.26 In normal aging, CMBs do not have a specific distribution pattern and can be found in cortical and subcortical regions.27

Imaging of the Normal Aging Brain

this is not supported by the results of studies combining quan- titative perfusion with detailed structural neuroimaging, indi- cating that regional CBF reduction is not always coupled to regional brain atrophy.31,32

Cerebrovascular Reactivity

During the aging process, there is loss of elasticity, progressive fibrosis, and atherosclerosis within the cerebral vasculature.33 Macroscopic cerebrovascular reactivity (CVR), a measure of elasticity in large blood vessels, can be measured noninvasively using transcranial Doppler whereas CT, PET, and MRI-based techniques are used to assess microvascular reactivity. As age advances, macrovascular CVR declines; however, it is uncertain whether this represents a truly physiological component of aging or a reflection of underlying neurodegenerative and cere- brovascular disease.34

A reduction in microvascular CVR has also been demon- strated in association with aging in a range of studies using car- bon dioxide, breath holding, and acetazolamide challenges to assess the vasodilatory capacity of small cerebral vessels.35 A progressive attenuation of both vasodilator and vasoconstrictor responses is seen with advancing age, indicating impaired ves- sel elasticity. This reduction in CVR is more pronounced in the presence of risk factors for cardiovascular disease, for example, diabetes, smoking, and hypertension.35

8.2 Metabolism

Positron emission tomography detects gamma radiation emitted by a positron-emitting radionuclide, or tracer, linked to a biologically active molecule. Molecules like fluorodeoxy- glucose (FDG), a glucose analog, and oxygen can therefore be used to estimate differing aspects of brain metabolic activity.

Positron emission tomography studies using labeled oxygen have demonstrated an age-related decline in the global cerebral metabolic rate of oxygen (CMRO2), with one study finding a decrease in CMRO2 of 0.5% per year in certain brain regions.36 Some key trends are apparent. First, age effects on the CMRO2 are more prominent in GM than in WM.37 Second, the most marked age effects are seen in supratentorial regions, specifi- cally in the frontal, temporosylvian, and parieto-occipital corti- ces.37 In view of the correspondence with the pattern of atrophy observed in aging, it has been suggested that these PET findings occur secondary to volume loss and do not reflect true hypome- tabolism.38 Although a variety of techniques aiming to correct for the presence of atrophy now exist, many PET studies of aging predate the development of such techniques, and there- fore this issue remains contentious.38

FDG-PET studies of the normal aging population have pro- duced somewhat contradictory results.39 Although some research suggests that the aging brain becomes globally hypo- metabolic, this finding is not replicated in all studies.39,40 With regard to the cortical distribution of such changes, FDG hypometabolism is predominantly observed in the frontal lobe, particularly after the age of 60 years (▶ Fig. 8.11).41,42 Hypome- tabolism has also been reported in the temporal, parietal, and somatosensory cortices, but changes are small in magnitude compared with those observed in frontal regions.39,42

Fig. 8.10 Axial gradient-echo T2-weighted MRI showing a case of multiple cerebral microbleeds. One such microbleed is indicated by the white arrow.

It is uncertain whether CMBs are a feature of normal aging or a marker of small-vessel disease; in one study, 6.4% of healthy participants from an elderly population had at least one CMB.28 The prevalence of CMBs increases with advancing age; however, CMBs are also associated with risk factors for cerebrovascular disease, such as diabetes.27 In addition, there are correlations between the presence of CMBs and lacunar infarcts and conflu- ent WMHs, pointing to an association with vascular disease.28

The presence of CMBs correlates with cognitive impairment in patients with cerebrovascular disease, but few studies have explored this relationship in healthy elderly adults. A single study, however, has reported an association between CMBs and subjective memory impairment.29

Perfusion

Single-photon emission computed tomography (SPECT), MRI, and positron emission tomography (PET) studies have all shown that increasing age is associated with a decline in global cerebral blood flow (CBF).30,31,32 However, changes in CBF are not uniform across the brain; the most marked age effects are found in the prefrontal cortex, although decreased perfusion is also detectable in the parietal lobe, inferior temporal regions, motor cortex, and basal ganglia.30,31 Areas with relatively pre- served CBF include the occipital lobe and the posterior superior temporal lobe.30,31

The cause of age-related CBF reduction remains uncertain. The pattern of change is reminiscent of the anteroposterior gra- dient of atrophy and as a consequence led to the proposal that the reduction in CBF occurs secondary to volume loss, although

Normal Aging

Fig. 8.11 Significant areas of negative correlation between age and glucose metabolism as determined by FDG-PET in a group of males. Significant areas (p < 0.05) are overlaid on a T1-weighted MRI image. Areas with significant negative correlation in this study included (1) left superior temporal gyrus, (2) right superior temporal gyrus, (3) medial frontal gyrus, and (4) caudate/left subcallosal gyrus. The color scale denotes t value. Reproduced with permission from Shen X, Liu H, Hu Z, Hu H, Shi P. The relationship between cerebral glucose metabolism and age: report of a large brain PET data set. PLoS One. 2012; 7:e51517. Copyright Shen et al.

Imaging of the Normal Aging Brain

8.3 Brain Function

Imaging techniques used to investigate brain function at rest or in response to stimuli include PET, functional MRI (fMRI), and SPECT. In healthy adults, a transient increase in blood flow occurs locally in engaged brain regions after activation in response to task performance or internal processes. This causes an increase in the oxyhemoglobin/deoxyhemoglobin ratio and, since these two forms of hemoglobin have differing magnetic properties, a blood oxygen-level dependent (BOLD) fMRI signal is generated.43

Task-related fMRI, during which changes in the BOLD signal, as an indirect measure of brain activation, are measured during engagement in specific tasks, can be used to investigate struc- ture-function relationships. With advancing age, task-related activations tend to become weaker and more diffuse, regardless of which task is performed.23 More specifically, a reduction in functional hemispheric lateralization is seen in the prefrontal

cortex during tests of perception, episodic memory, and inhibi- tory control,23 although the explanation for this altered lateral- ization remains unclear. In some studies, reduced functional hemispheric lateralization was associated with superior per- formance on episodic, semantic, and working memory tasks, indicating a potential compensatory mechanism.44 Reduced functional hemispheric lateralization may also represent age- related loss of cortical inhibition.44

In contrast to task-related fMRI, task-free or resting-state fMRI provides information on intrinsic brain connectivity in the absence of engagement in explicit tasks.45 In normal adults, a specific network of brain regions, termed the default-mode net- work, can be prominently identified on task-free fMRI, and this encompasses the precuneus, posterior cingulate cortex, medial prefrontal cortex, and medial temporal lobe.45 In the healthy elderly population, a consistent finding is decreased functional connectivity across this network, independent of changes in brain volume (▶ Fig. 8.12).23

Fig. 8.12 Whole-brain analyses of functional connectivity using resting-state fMRI representing coherent activity in the default-mode network, comprising correlations between the posterior cingulate cortex/retrosplenial cortex and both the medial prefrontal cortex and the bilateral lateral parietal cortex, and associated decline in old age. The z value refers to the coordinate of the MRI scan along the ventral-dorsal axis according to the Talairach atlas. Reproduced with permission from Andrews-Hanna JR, Snyder AZ, Vincent JL et al. Disruption of large-scale brain systems in advanced aging. Neuron. 2007; 565:924-935. Copyright Elsevier, Inc.

Normal Aging

Table 8.1 Take-home points of the signs and symptoms generally associated with advancing age

Reduced total brain weight and volume and enlargement of CSF spaces

Reduced brain weight and volume2

Increased prevalence of white matter hyperintensities18

Reduced fractional anisotropy and increased mean diffusivity in the white matter23

Darkening of basal ganglia on T2* magnetic resonance imaging due to iron deposition23

Increased prevalence of cerebral microbleeds27

Reduced cerebral blood flow, globally but particularly in the prefrontal cortex30,31,32

Declining rate of cerebral oxygen and glucose metabolism, especially in frontal regions41,42

Decreased hemispheric lateralization of activation during performance of active tasks23

Reduced integrity of the default-mode network at rest23

8.4 Conclusions

The physiological processes associated with normal aging result in multidimensional alterations in brain structure and function, ranging from directly observable atrophy to disruption of func- tional connectivity as measured using complex analytical meth- ods (▶Table 8.1). The regional age-associated volume loss is distinct from that observed in neurodegenerative dementias. The development of lesions like WMHs and CMBs reflects a progressive accumulation of focal pathology, whereas hypoper- fusion and hypometabolism are indicative of more widespread degenerative processes.

As brain imaging techniques and associated methods of anal- ysis become increasingly sophisticated, their continued applica- tion to the study of normal aging will be a critical first step toward improved understanding of the imaging changes that accompany the diseases of later life.

8.5 Acknowledgments

The authors are grateful to Ludovico D’Incerti, MD (Neuro- radiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy), Paolo Vitali, MD (Scientific Department, Fondazione IRCCS Istituto Neurologico Mondino, Pavia, Italy), Kuven Moodley, MRCP (Brighton & Sussex Medical School, Falmer, UK), and Daniela Perani, MD (Department of Clinical Neuroscience, Università Vita-Salute e Ospedale San Raffaele, Milan, Italy), for insightful advice on previous drafts and provi- sion of part of the figures.

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Imaging of the Normal Aging Brain

Normal Aging

9 Iron Accumulation and Iron Imaging in the Human Brain

Stefan Ropele and Christian Langkammer

9.1 Iron Accumulation in the

Normal Aging Brain

Iron is an abundant trace element that is essential to the human body and has manifold functions, including blood oxygenation, conversion of blood sugar to energy, and myelin production.1 Although more than 60% of the total body iron is bound to hemoglobin, the most frequently found iron compartment in the brain is (intracellular) ferritin. Ferritin is a storage protein that keeps iron available in a nontoxic and soluble form. Each ferritin shell can host up to 5,000 iron ions. Early work using histologic Perls’ staining demonstrated that iron is not equally distributed across different brain structures; highest concentra- tions are found in deep gray matter nuclei.2 Iron accumulation in the brain is a nonlinear process. As revealed by a chemical brain analysis by Hallgren and Sourander in 1958,3 iron accu- mulates in the first four decades of life and plateaus afterward; no iron is present at birth (▶ Fig. 9.1). The reason for the accu- mulates is unclear, but it seems that iron transfer to the brain is largely one-way traffic. Throughout the brain, the highest iron concentrations can be found in the globus pallidus, red nucleus, substantia nigra, putamen, dentate nucleus, caudate nucleus, and thalamus (descending from 250 to 50 mg/kg). In contrast, cortical areas and white matter have significantly lower iron concentrations.3,4,5 Remarkably, in human brain tissue, there seems to be a baseline of iron levels of 30 mg/kg, which under- lines an essential, multifaceted role of iron and seems to reflect a minimum requirement for normal brain metabolism. Given these rather large differences of concentrations, surprisingly lit- tle is known about why iron accumulates preferably in the basal ganglia structures. Moreover, the exact mechanism of iron transfer between neurons and glia is poorly understood. Loading of intracellular ferritin may involve mitochondrial catabolism, whereas the export of ferritin from the cells to oligodendrocytes is thought to act through the mediation of ferritin receptors.

9.2 Abnormal Iron Accumulation

Although iron is an essential cofactor for many proteins and functions in the brain, iron overload is assumed to exert toxic effects as free or unbound iron ions serve as pro-oxidants.6 Ferric iron (Fe3 + ) reacts with superoxide and generates Fe2 + (Haber-Weiss reaction); ferrous iron (Fe2 + ) triggers the conver- sion of reactive oxygen species to hydroxyl radicals (Fenton reaction). Hydroxyl radicals are highly reactive oxygen species that induce oxidative stress, which may interfere with cellular signaling and lead to neuronal damage. Therefore, iron is often discussed in the context of triggering or mediating an inflam- matory or neurodegenerative cascade in many neurologic dis- eases. Increased iron levels in deep gray matter are a frequent but unspecific finding in several neurologic disorders and are frequently observed in a variety of neurodegenerative and inflammatory diseases, including Alzheimer’s disease (AD), Par- kinson’s disease (PD), Huntington’s disease, multiple sclerosis,

and amyotrophic lateral sclerosis (ALS).7,8,9,10 Besides deep gray nuclei, histologic studies in AD have found abnormally increased levels of iron in the proximity of neuritic plaques and neurofibrillary tangles.11,12 In deep gray matter and neuritic plaques, the role of iron in this context is not entirely clear, but abnormally high concentrations of iron can yield oxidative stress and induce neuronal vulnerability.13 Consequently, iron accumulation might additionally increase the toxicity of exoge- nous or endogenous toxins.

9.3 In Vivo Iron Assessment by Quantitative Magnetic Resonance Imaging

Single iron ions can be barely detected by magnetic resonance imaging (MRI), despite its high sensitivity for the underlying magnetic properties of tissues. However, the iron core of ferritin represents a highly organized structure similar to the mineral ferrihydrite (5Fe2O3 · 9H2O) and exhibits a strong paramagnetic effect that makes it detectable by MRI. This has opened a new window for the in vivo assessment of iron levels and for study- ing the pathological role of iron in the brain.

At the very beginning of clinical MRI, it was observed that the basal ganglia of healthy subjects often appeared hypoin- tense on T2-weighted spin-echo sequences (▶ Fig. 9.2). The sus- ceptibility affects scale with field strengths that make the detection of iron at high and ultrahigh field strengths more sen- sitive (▶ Fig. 9.3). Using iron staining in a histologic correlation study, it could be confirmed that the presence of iron was

Fig. 9.1 The dynamics of iron accumulation in different structures of the brain according to the study of Hallgren and Sourander. The globus pallidus shows the highest iron content and the highest rate of accumulation. The only region that does not show a plateauing effect is the thalamus, where the iron content decreases after the fourth decade of life (not shown). (From Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J Neurochem 1958; 3 (1): 41–51.)

responsible for this observation.14 Iron detection in these early studies was done using Perl’s staining, which has a moderate sensitivity for iron in white matter. More sophisticated approaches are based on diaminobenzidine-enhanced staining (▶ Fig. 9.4). Subsequent studies with visual rating of iron depo- sition in the basal ganglia followed but were limited by the intrinsically low sensitivity and a rater bias of this approach. Nowadays, quantitative MRI techniques provide sensitive mea- sures of iron content on a continuous scale, and these measure- ments are highly reproducible and comparable among subjects and scanners. The following sections of this chapter present a brief overview of proposed MR methods for iron mapping along

Iron Accumulation and Iron Imaging in the Human Brain

Fig. 9.2 Spectrum of hypointensities that can be typically observed on T2-weighted sequences in normal aging subjects as a consequence of
iron accumulation. Appearance of the dendtate nucleus (arrow, a), red nucleus and substantia nigra (arrow, b), globu spallidus, putamen, and caudate nucleus (arrow, c) in a 68-year-old healthy woman on T2-weighted spin-echo

(top rows) and corresponding fluid-attenuated inversion recovery (FLAIR, bottom rows) sequences.

with their advantages and limitations; a summary is provided in ▶ Table 9.1.

The longitudinal relaxation time T1 (also often represented by its inverse R1 = 1/T1) is only moderately affected by brain iron,15 which can be explained by a weak dipolar interaction. In contrast, the magnetic field perturbations introduced by the iron accelerate spin dephasing and, therefore, loss of transversal magnetization. In the case of a spin-echo sequence, where these field inhomogeneities are compensated by refocusing radiofre- quency pulses, some irreversible dephasing effects remain because of the stochastic nature of diffusion. This effect can be considered a series of arbitrary oriented jumps through these

Normal Aging

Fig. 9.3 Ultrahigh-field imaging allows better depiction of iron-loaded gray matter structures because of its higher sensitivity for variation of the magnetic susceptibility and its higher spatial resolution. Appear- ance of the dentate nucleus (arrows) in a formalin-fixed brain sample at 3 T (left) and 7 T (right). Images were acquired with a spoiled T2*- weighted gradient-echo sequence.

Fig. 9.4 Total nonheme iron (ferric and ferrous) can be stained with diaminobenzidine (DAB)-enhanced Perl’s (Turnbull) blue staining.14 Whereas cortical iron content is comparable to the iron content in white matter (see also ▶ Fig. 9.1), substantial variations can be observed in subcortical regions.

Table 9.1 Most relevant magnetic resonance (MR) imaging techniques proposed for the assessment of brain iron

MR method Advantages Limitations

T1 relaxometry

Robust against susceptibility artifacts

Low sensitivity for iron Time consuming

R2 relaxometry

Sequence is readily available on clinical systems Moderate sensitivity for iron
Robust against susceptibility artifacts

Moderate acquisition speed
In multislice acquisition or with fast spin-echo read- out, the observed R2 may also be affected by magnetization transfer effects

R2* relaxometry

Sequence is readily available on clinical systems
Fast 3-dimensional whole-brain acquisition (< 10 min) High sensitivity for iron

Calcifications cannot be separated from clustered iron deposits
Sensitive to macroscopic susceptibility artifacts

Phase imaging

Sequence is readily available on clinical systems High sensitivity for iron
Calcifications can be distinguished from iron deposits

Phase unwrapping and filtering needed
Not a linear measure for iron (does not reflect only local susceptibility)

Susceptibility-weighted imaging

Good sensitivity for iron
Calcifications can be distinguished from iron deposits Enhanced tissue contrast

Same as for phase imaging
Not quantitative (depends on postprocessing parameters)

Quantitative susceptibility mapping

High sensitivity for iron
Linear measure for iron
Calcifications can be distinguished from iron deposits

Extensive image postprocessing

field variations as a consequence of Brownian motion. Conse- quently, iron accelerates signal loss in spin-echo (T2) and gradi- ent-echo sequences (T2*), which in turn result in increased transverse relaxation rates R2 and R2* (R2 = 1/T2 and R2* = 1/ R2*), respectively. Both R2 and R2* relaxation rates have been proven to be sensitive and linear measures for brain iron and can be assessed using conventional MR sequences readily avail- able on clinical scanners.16,17 R2 can be measured using a spin- echo sequence and R2* using a gradient-echo sequence, both with a minimum of two acquired echoes. R2* has a higher sensi- tivity for iron than R2, allows faster acquisition of the entire brain, and can also be acquired rapidly at ultrahigh field strengths (7 tesla [T]), where specific absorption rate restric- tions are an issue. Given these advantages, R2* should be the preferred measure for brain iron in a clinical setup.5 Neverthe-

less, R2* is more prone to artifacts in the proximity of the sinus and cavities, which in turn renders R2 an interesting measure at these specific locations.18 Another related measure is R2′, which separates reversible contributions (associated with micro- structure) from total signal dephasing (R2* = R2 + R2′). R2’ is also sensitive for iron but requires a dedicated MRI sequence or, alternatively, the acquisition of both a gradient echo and a spin echo, which is time consuming in a clinical setup. Other studies have demonstrated field-dependent R2 rate increase as a means to measure brain iron, but the application of this technique in a clinical environment is complicated because it requires scan- ning of the subjects at a minimum of two different field strengths.19 Another interesting approach for iron detection is MR phase imaging.20 Phase values represent shifts in the MR frequency induced by iron (as well as other paramagnetic and

severity and progression. So far, findings have been related mostly to deep gray matter because iron mapping in the cortex suffers from the previously mentioned limitations.

Visual rating of T2-weighted images demonstrated lower sig- nal intensities (as indicative for higher iron concentration) in the putamen and red nucleus of AD patients than in healthy controls.35 In addition, R2 and R2* relaxometry demonstrated increased iron in the hippocampus,36,37 the temporal cortex,38 and the pulvinar nucleus.39 An R2* map showing increased iron deposition in the basal ganglia of an AD patient, and how this is related to a healthy control is depicted in ▶ Fig. 9.5. Extending these findings, MR phase imaging revealed higher iron con- centrations in the hippocampus, parietal cortex, putamen, cau- date nucleus, and dentate nucleus.40,41 Further evidence of increased iron levels in deep gray matter comes from magnetic field dependency studies, where iron levels in the caudate nucleus, putamen, and globus pallidus were elevated in AD patients.42,43

The affinity of iron to amyloid plaques was used to study plaque load and evolution of plaques in postmortem brains, as well as in transgenic animal models. It has been speculated that iron might be involved in the formation of amyloid because of the formation of reactive oxygen species; alterna- tively, iron might be secondarily involved in the removal of amyloid.12,44 Although the idea of depicting amyloid plaques with methods other than positron emission tomography is intriguing, MRI of these plaques is challenging because pla- que size is below the resolution of clinical MRI. Nonetheless, the plaque-attached iron causes perturbations of the mag- netic field that are strong enough to affect bulk tissue suscep- tibility and MR relaxation times.36 So far, single amyloid pla- ques have been detected by T2*-weighted imaging in human brain tissue only ex vivo.45 Unfortunately, the required sig- nal-to-noise ratio and the spatial resolution (40 μm isotropic) cannot be achieved in vivo within a clinically feasible scan time, although much hope was put on ultrahigh field scan- ners (7T and greater), which intrinsically provide a higher signal and a greater sensitivity for susceptibility changes. Consequently, a better strategy might be to use a histogram- based technique for the detection of macroscopic susceptibil- ity, changes that may reduce the need for detecting neuritic plaques on an individual basis.

9.5 Iron Mapping in Animal

Models of Alzheimer’s Disease

Small-bore systems usually operate at ultrahigh field strengths, allowing noninvasive study of the development of pathologic features in animal models at extremely high image resolution. Whereas animal models allow histologic or histo- chemical validation of MRI findings at any time point, valida- tion studies in patients with AD are obviously limited to the time point of death. This limitation hinders investigation of the disease at an early stage and also the investigation of individual therapeutic interventions. Transgenic animal mod- els have been used mostly to refine single-plaque imaging for in vivo applications.46,47

So far, only a single serial MRI study on the dynamics of plaque formation and development has been performed in a

diamagnetic compounds) and have been shown to scale with iron content.21 Owing to the fact that the MR signal represents the complex transverse magnetization, the raw-phase data obtained have 2π ambiguities, which subsequently have to be eliminated by so-called phase unwrapping algorithms.20 Spatial varying low-frequency field components can be removed by high-pass filtering.22 However, high-pass filtering substantially reduces the sensitivity for iron in a nonlinear manner, and this is why recent studies suggest that the phase-based iron content can be compared in specific brain structures only.23

Susceptibility-weighted imaging (SWI) is a related imaging modality that combines filtered phase and magnitude images to obtain images whose contrast provides a high sensitivity for iron, veins, and other paramagnetic inclusions.22,24 Because of its sensitivity for even small veins, SWI can provide valuable infor- mation for the radiologic assessment; however, SWI is not quan- titative and remains a nonlinear measure for iron content.23

The latest technique to overcome this issue is quantitative susceptibility mapping (QSM). QSM provides absolute values of the magnetic susceptibility, an intrinsic physical property of matter, rendering its results comparable when different scan- ners and field strengths are used. Although the clinical impact of QSM has not yet been fully explored, it is evident that it is a proportional and highly sensitive measure for iron.25,26,27 QSM is mathematically and computationally challenging, and the development of fast algorithms is the focus of current research.28 For practical reasons, the impact of other approaches for imaging brain iron, such as magnetic-field correlation and direct saturation imaging, remains unclear and the subject of further investigations.29,30

Although iron mapping in gray matter can be accomplished reliably, iron mapping in white matter remains challenging because myelin content and neuronal fiber orientation signifi- cantly affect the bulk susceptibility. Diamagnetic myelin coun- teracts the observed susceptibility of paramagnetic iron; in con- trast, it additively impacts relaxation rates.25,31,32 Current research focuses on disentangling these effects and providing precise individual assessment of iron and myelin content. The orientation of white matter fiber bundles with respect to the main magnetic field of the scanner also impacts the effective transverse relaxation rate R2*, gradient-echo phase, and mag- netic susceptibility.33,34 This circumstance can significantly limit comparative studies that are based on regional assessment of iron in white matter.

So far, only a limited number of MRI studies have focused on the in vivo measurement of cortical iron. Because of the thinness of the cortical layer and its relatively low iron concentration, a quite sensitive sequence is required. Unfortunately, especially MR images of the cortex are affected by artifacts of the tissue- liquor interface, which makes the application of postprocessing and correction methods essential. Therefore, current in vivo MRI studies focusing on cortical pathology are based mainly on histo- gram techniques or on an atlas-based group analyses.

9.4 Iron Mapping in Patients with

Alzheimer’s Disease

In vivo MRI studies have measured iron accumulation in the gray matter of patients with AD and related its extent to disease

Iron Accumulation and Iron Imaging in the Human Brain

Normal Aging

Fig. 9.5 Iron mapping with R2* relaxometry is a linear, sensitive, and quantitative approach in the sense that it is reproducible and comparable among subjects. Top row: Fluid-attenuated inversion recovery (FLAIR) image (left) and corresponding R2* map (right) of a 62-year-old Alzheimer’s patient. In the R2* map, a higher signal corresponds to a higher iron concentration. Lower row: FLAIR image and R2* map of a 58-year-old healthy control. Note that the windowing in both maps is identical.

transgenic mouse model at 12, 14, 16, and 18 months.48 Disease progression was reflected by an increase in the number and size of plaques. This progression was also paralleled by an increase of the R2 relaxation rate in the hippocampus and cortex of AD mice, whereas R2 in control mice remained unchanged. The association between plaque development and diffuse iron accu- mulation in gray matter needs further investigation but might offer a new way to assess plaque load and development indirectly.

In line with this finding, a study revealed elevated iron levels in the cortex in a presenilin amyloid precursor protein mouse model at an early stage of 24 weeks.49 In contrast to histo- chemical studies, this study did not find elevated iron levels in neuritic plaques using X-ray fluorescence microscopy. In this context, only neuritic plaques with iron attached seem to be detectable by MRI in a mutant APP mouse model, whereas iron- negative plaques remain invisible for T2*-weighed MRI, which highlights the pathologic role of iron in at least a certain per- centage of neuritic plaques.50

9.6 Iron Mapping in Patients with

Parkinson’s Disease

The concentration of iron in the substantia nigra (SN) is among the highest in all anatomical structures.3 This feature can be used to precisely locate the SN and adjacent regions for deep brain stimulation.51 Postmortem studies in patients with PD and related disorders, such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), consistently demonstrated elevated levels of iron in the SN.52,53,54 Although these studies additionally revealed higher iron levels in the basal ganglia of patients with PSP and MSA, the iron concentration was con- versely found to be lower in PD. In contrast, other studies sug- gested higher iron concentrations also in the basal ganglia of PD patients. Histologic investigation revealed higher iron levels in the putamen, and levels were less pronounced in the SN and the caudate nucleus55; related postmortem work found increased iron levels in the lateral segment of the globus pallidus.56

Iron Accumulation and Iron Imaging in the Human Brain

Fig. 9.6 In Parkinson’s disease, the substantia nigra is the structure with the highest disease-related iron accumulation. Although this is not obvious in conventional magnetic resonance imaging, susceptibility- weighted techniques allow a better depiction of iron-accumulating structures. (a) Fluid-attenuated inversion recovery (FLAIR) image.
(b) Corresponding R2* map.

Fig. 9.7 Tract-based spatial statistics demonstrates significant reduc- tion in fractional anisotropy (FA) (left column) and significantly increased R2* (right column) in amyotrophic lateral sclerosis patients compared with age- and sex-matched controls (significant voxels at
p < 0.05 are shown in red). The regions with decreased FA and those with increased R2* in the mesencephalic part of the corticospinal tract are closely localized. (Used with permission from Langkammer C, Enzinger C, Quasthoff S, et al. Mapping of iron deposition in conjunction with assessment of nerve fiber tract integrity in amyotrophic lateral sclerosis. J Magn Reson Imaging 2010;31(6): 1339–1345.)

In vivo MRI studies found higher R2* levels in the SN57,58,59,60 but also in the basal ganglia.61 ▶ Fig. 9.6 shows an example of the appearance of the SN on a R2* map from a patient with PD. An increase in the SN was also found using SWI62 or phase mapping.63 Another study found higher R2* rates in the lateral SN pars compacta but additionally found a correlation between the lateralized motor score from the clinically more affected side and the contralateral R2* rate in the SN.64 Additionally, increased iron levels were shown in the SN, even in patients with early untreated PD.65

Patients who developed PD along with an existing dementia showed more iron in the SN than patients with AD alone, a finding that might be relevant for differential diagnosis.66 Furthermore, MSA and PD were differentiated by using phase values from the inner region of the putamen and the pulvinar thalamus.67 Higher R2’ rates were found in the basal ganglia in patients with PSP compared with those with PD, and stepwise discriminant analysis allowed patients with PSP to be distin- guished from patients with PD and healthy controls.68

In a recent longitudinal study, patients with PD showed an increase in R2* in the SN and the putamen during a 3-year period,69 whereas these regions did not shown any change in controls. Additionally, the variation in R2* was correlated with worsening of motor symptoms of PD. These results suggest lon- gitudinal iron mapping as a tool for assessing neurodegenera- tion and monitoring treatments effects in PD.

9.7 Iron Mapping in Patients with

Motor Neuron Diseases

In amyotrophic lateral sclerosis (ALS), the focus of MRI research is mainly on the pyramidal tract of the central nervous system, starting from the spinal cord, to the corticospinal tract (CST), and extending to the motor cortex. Early work revealed a high prevalence of T2-shortening (R2 rate increase) in the precentral cortex in ALS patients, whereas this observation is rarely made in normal subjects.70 Consequently, studies on iron deposition

in ALS patients focusing on the precentral gyrus confirmed this pattern of cortical hypointensities on T2 and T2*-weighted MRI.71,72 Besides this cortical hallmark, degeneration of the CST is consistently found in ALS patients.73 Patients with ALS showed a trend for increased R2* rates along the mesencephalic CST and in the caudate nucleus compared with controls.74 Com- plementary diffusion tensor imaging revealed lower fractional anisotropy closely localized in the region of the CST, where R2* was also increased, suggesting iron mapping as a potential bio- marker paralleling neurodegeneration (▶ Fig. 9.7).

The source of T2 and T2* changes in ALS is yet not clear. An interesting study compared T2 and T2*-weighted MRI and found that the cortical hypointensities in ALS are present more often on T2- than on T2*-weighted images, which argues against elevated iron levels and suggests that other factors are more dominant.75 The observation that the occurrence of hypo- intensities in the precentral gyrus is related to normal aging also argues for microstructural tissue changes.76 On the other hand, a study that combined in vivo and postmortem MRI with subsequent histology demonstrated that cortical T2* hypoin- tensites are due to abnormally high iron deposition in deeper layers of the motor cortex in ALS.8 Additionally, histologic stain- ing of iron revealed its accumulation in microglial cells. Although the source of the signal variations has not been fully resolved, it seems that the extent and dynamics of the signal change are closely related to the disease state and progression.

Normal Aging

A longitudinal analysis of T2*-weighted images found more pronounced hypointensities in the precentral gyrus at the 6-month follow-up examination after the first evaluation,71 with the extent of the hypointensities correlated with disability as determined by the ALS functional rating scale.

9.8 Conclusion and Outlook

Iron, the most prevalent trace metal, accumulates in the human brain in the process of normal aging. However, abnormally increased iron levels in the basal ganglia are consistently found in pathogenesis, sharing a neurodegenerative and probably also an inflammatory component. Nevertheless, current knowledge about pathologically relevant iron deposition still comes mainly from histologic studies, but it is anticipated that MRI can aid in investigation of the role of iron (i.e., to clarify whether iron accumulation is secondary and reflects accumulated neurode- generation or can also trigger, or at least mediate, the neuro- degenerative cascade).

Iron has a strong paramagnetic effect in perturbing the mag- netic fields, thus rendering it detectable by MRI. Several MRI techniques and novel developments allow not only detection but also quantitative assessment of iron concentrations in the brain in vivo. Owing to the noninvasive nature of MRI, quantita- tive MRI techniques are especially promising in longitudinal studies for monitoring disease progression and possible treat- ment effects. New insight may be expected from the application of novel quantitative MR techniques and from moving to ultra- high-field-strength MRI systems.

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Part IV Alzheimer’s Disease

. 10 Mild Cognitive Impairment 90

. 11 Overview of Alzheimer’s Disease 113

. 12 Genetics, Neuropathology, and
Biomarkers in Alzheimer’s Disease 119

. 13 Imaging of Alzheimer’s Disease: Part 1 124

. 14 Imaging of Alzheimer’s Disease: Part 2 133

. 15 Magnetic Resonance Imaging and Histopathological Correlation in
Alzheimer’s Disease 139

Alzheimer’s Disease
10 Mild Cognitive Impairment

Kei Yamada and Koji Sakai

10.1 Outline of Mild Cognitive

Impairment

Mild cognitive impairment (MCI), by definition, is a state of cognitive decline in which cognitive deficits are noted but not significant enough to meet the diagnostic criteria for dementia; MCI is recognized as an intermediate state between normal cognition and dementia (▶Fig. 10.1). The original concept of MCI was proposed by Petersen et al,1 who emphasized mainly memory impairment and the status of MCI as a precursor for Alzheimer’s disease (AD). After several years, MCI was recog- nized as a concept of heterogeneous clinical presentation, cause, and prevalence2,3,4 and was expanded to be adapted to other cognitive domains, thereby extending the early detection of other dementias in their prodromal stages.5,6,7

10.2 Diagnostic Concept

and Its Evolution

The conceptual topics of MCI and MCI-related staging systems are listed in ▶ Table 10.1. As an early concept, in 1837, Prichard identified four stages of dementia: (1) impairment of recent memory with intact remote memories, (2) loss of reason, (3) incomprehension, and (4) loss of instinctive actions.8 Later, in 1962, Kral described an entity that distinguished relatively unimpaired and impaired by the terms benign senescent forget- fulness and malignant senescent forgetfulness.9 By the early 1980s, several staging systems for progressive aging and dementia associated with AD were published: Limited Cognitive Disturbance,10 Clinical Dementia Rating (CDR)11 0.5 (“questionable dementia”), and Global Deterioration Scale for

Assessment of Primary Degenerative Dementia (GDS).12 The third stage of GDS was initially termed mild cognitive decline and sub- sequently was retermed mild cognitive impairment by Reisberg and colleagues.13,14 After the late 1980s, several diagnostic crite- ria to describe cognitive decline by aging and as a precursor of dementia were proposed: age-associated memory impairment,15, aging-associated cognitive decline,16 mild cognitive disorder,17 and mild neurocognitive disorder.18 Later, in 1992, Zaudig pro- posed his own concept and definition for MCI.19 More detailed information regarding the history of MCI evolution can be found in the writings of Reisberg and colleagues.20

The current MCI concept, which has been generally accepted and referred to, was proposed by Petersen and colleagues.5,21 This concept divides MCI into four subtypes21: amnestic single- domain MCI, amnestic multidomain MCI, nonamnestic single- domain MCI, and nonamnestic multidomain MCI.

Although concerns over ambiguity and difficulty in establish- ing diagnosis remain in the current diagnostic guidelines provided by the National Institute on Aging—Alzheimer’s Asso- ciation workgroups,22,23 the term mild cognitive impairment has already been recognized as the expression of a clinical stage between normal cognitive decline and dementia.

10.3 Epidemiology
10.3.1 Mild Cognitive Impairment

Findings from epidemiologic studies have yet to provide unified information regarding the clinical aspects of MCI. Although several findings of MCI have been reported, because of differ- ing diagnostic criteria, measuring instruments, definitions of severity, and different samples based on study population

Fig. 10.1 Mild cognitive impairment as an intermediate stage in the longitudinal course of Alzheimer’s disease. (Reprinted with permission from Smith GE, Bondi MW, Mild Cognitive Impairment and Dementia, Definitions, Diagnosis, and Treatment, New York: Oxford University Press; 2013:6. Original: Petersen, 2004.)

Mild Cognitive Impairment

Table 10.1 Topics in mild cognitive impairment (MCI): concepts and criteria.

Year Study Topic

1837

Prichard8

Four stages of cognitive impairment

1962

Kral9

Benign/malignant senescent forgetfulness

1982

Gurland et al10

Limited cognitive disturbance

1982

Hughes et al11

Clinical Dementia Rating (CDR)

1982

Reisberg et al12

Global Deterioration Scale for Assessment of Primary Degenerative Dementia (GDS), (GDS 3 = mild cognitive impairment)

1986

Crook et al15

Age-associated Memory impairment (AAMI)

1992

Zaudig1,9

Zaudig’s MCI based on Diagnostic and Statistical Manual IIIR/ International Classification of Disease-10

1994

American Psychiatric Association174

Mild neurocognitive disorder (MND)

1995

Levy16

Aging-associated cognitive decline (AACD)

1995

Christensen et al17

Mild cognitive disorder (MCD)

1995

Petersen174

Petersen’s MCI (CDR = 0.5)

1995

Ebly et al173

Cognitive impairment no dementia (CIND)

2004

Petersen7

Four MCI categories

2011

Albert et al21

New criteria for MCI and biomarkers

and clinical reports, we have not established complete epide- miologic findings for MCI. Currently, several nationwide epide- miologic studies associated with the Alzheimer’s Disease Neuroimaging Initiative (ADNI)24 have been ongoing in countr- ies around the world. However, as of today, their findings, par- ticularly regarding the clinical aspects of MCI, have not been summarized to be shared with physicians worldwide. In the fol- lowing sections of this chapter, findings from epidemiologic studies are summarized.

In general, epidemiology serves a triple role in public health: descriptive, analytical, and interventional. The relationships between these roles and MCI are as follows25:

● Descriptiveepidemiology:ThemonitoringofMCIprevalence and incidence across time

● Analyticalepidemiology:Thedeterminationofriskfactors and their patterns of interaction, permitting the construction of hypothetical etiologic models of the disease process

● Interventionalepidemiology:Thedesignationofpotential intervention points for the reduction of morbidity and mortality, which may guide more targeted clinical research.
10.3.2 Descriptive Epidemiology
How widespread are both explicit and implicit MCI in the gen- eral population? The reported incidence rates for MCI vary in the literature. A variety of population-based cohort studies have reported incidence rates within their elderly populations (i.e., 65 to 75 years) to be between 14 and 111 per 1,000 patient- years26,27,28,29,30,31,32; amnestic MCI appears to occur more com- monly than nonamnestic MCI.31
10.3.3 Analytical Epidemiology
Various studies had reported that gender, race, and lower edu- cation are inconsistently associated with various MCIs.31,33,34,55, 36,37 In a community-based study (participants between 70 and 89 years),31,33 MCI was more common in men (odds ratio [OR]=1.5). In addition, elevated blood pressure, diabetes with or without symptomatic cerebrovascular disease, obesity,34,35,36, 37,38,39,40,41 cardiac disease,42 and apolipoprotein E epsilon 4 genotype43,44 were all found to be associated with higher risk of MCI or certain subtypes of MCI. Compared with normal sub- jects, MCI groups were generally seen to manifest left medial temporal lobe atrophy and smaller medical temporal lobe vol- umes.45,46 Artero and colleagues have suggested that white mat- ter lesions, particularly in periventricular areas, are associated with MCI.47 Tervo and colleagues48 examined a range of demo- graphic, vascular, and genetic factors and found the most signifi- cant risk factors to be age (OR 1.08), apolipoprotein E4 (Apo-E4) allele (OR 2.04), and medicated hypertension (OR 1.86).
▶Fig. 10.2 shows the theoretical pathways to MCI,25 which incorporate most of the known risk factors for dementia. There are, however, insufficient population data at present to permit either a statistical calculation of transition probabilities in relation to individual risk factors or a maximum likelihood

Fig. 10.2 Hypothetical etiologic model of mild cognitive impairment (black) and possible treatments (blue). (Reprinted with permission from Fig. 2 in Ritchie K. Mild cognitive impair- ment: an epidemiological perspective, Dialogues Clin Neurosci 2004;6(4): 401–408. © Les Laboratoires Servier)

Alzheimer’s Disease
calculation to assess the overall predictive value of possible

competing hypothetical general models of MCI.

10.3.4 Interventional Epidemiology

Currently, there is no clearly specified treatment for MCI. Nevertheless, it may be possible to reduce overall risk by many kinds of simple risk factor management,49 for instance, man- agement of cardiovascular and cerebrovascular risk factors, such as high blood pressure, from early adult life onward to reduce the risk of infarcts and white matter lesion accumula- tion; depression control; and the provision of adequate learning opportunities from a younger age.

10.4 Clinical Features 10.4.1 Symptoms

Patients with MCI, especially the amnestic subtypes, are known for their memory complaints; this represents a change over baseline. Subjective memory complaints have been demon- strated to predict cognitive decline, even when patients appear to be unimpaired on testing.50,51

Mood and behavioral symptoms are more common in patients with MCI than in normal subjects with intact cogni- tion.52,53,54,55 A population-based study found that apathy, agitation, anxiety, irritability, depression, and delusions were significantly more common in patients with MCI compared with those with normal cognition.54

The correlation between depression and cognitive impair- ment is complicated. Cognitive impairment may be an initial symptom of depression, so called pseudodementia. A number of population-based studies have found an association between various measures of depression and the presence of MCI.52,56,57 However, follow-up studies have yielded mixed results.52,56,61 Overall, depression is more likely to be an early manifestation of cognitive decline rather than an independent risk factor for MCI, although some studies have found disparate results.62,63

10.4.2 Subtypes

The four subtypes of MCI are based on the presence of memory impairment and the number of cognitively impaired domains: (1) amnestic MCI, single domain; (2) amnestic MCI, multidomain; (3) nonamnestic MCI, single domain; and (4) nonamnestic MCI multidomain.21 Within MCI are several types of progression to degenerative dementia other than AD, including vascular demen- tia and dementia with mental and physical causes; also, some MCI patients retain their MCI state for several years and then return to healthy condition.7 Amnestic MCI is often thought of as a precursor to AD.46 Autopsy studies of brains from MCI patients64,65 have not revealed any consistent findings regarding the neuropathological and clinical features of MCI. Therefore, it is important that MCI be recognized as “a group of patients without dementia that exhibits cognitive decline at an abnormal age, but has no difficulty during daily life.”

10.4.3 Underlying Diseases

Diseases that affect cognitive functions, such as intracranial disease, mental disorder, systematic internal disease, and medical poisoning, may all be possible underlying diseases of MCI; known disorders or conditions that can be fitted into such a category include AD, limbic neurofibrillary tangle dementia (LNTD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration (FTLD), depression, and others (▶ Table 10.2).

10.4.4 Differential Diagnosis

After excluding physiologic factors (organic factors), other pos- sible diagnoses should be considered, including depression, as well as other psychosocial factors (e.g., forfeiture of social role, loss of spouse or family member, illness). Aged patients suffer- ing from depression may display decreased cognitive perform- ance and lowered physical activity as a result of decreased attention and slower psychomotor activity, thus appearing to have dementia (hence the term pseudodementia).66 These

Table 10.2 Underlying diseases of mild cognitive impairment

Dementia Underlying disease and conditions

Dementia with degenerative disease

Frontotemporal lobar degeneration (frontotemporal dementia, semantic dementia), dementia with Lewy body, limbic system neurofibril degenerative dementia, progressive supranuclear palsy, corticobasal degeneration

Dementia with cerebrovascular disease

Cerebral infarction, bleeding cerebrally, multiple infarction dementia, Binswanger’s disease

Dementia with endocrine disease

Hypothyroidism, hypoparathyroidism, reiterate hypoglycemic attack

Dementia with trophopathy and metabolic disorder

Wernicke encephalopathy, vitamin B12 deficiency, chronic metabolic disorder (liver failure, kidney failure), hyponatremia

Dementia with hypoxic encephalopathy

Heart/lung disease, carbon monoxide poisoning

Dementia with tumor

Brain tumor (primary, metastasis), meningitis carcinomatosa, remote effect of cancer

Dementia with infectious disease

Meningitis, encephalitis, brain tumor, neurosyphilis, progressive multifocal leukoencephalopathy, AIDS

Dementia with abnormal metal metabolism

Aluminum (dialysis encephalopathy), Copper (Wilson disease)

Dementia with medical poisoning

Antineoplastic drug, antipsychotic drug, sleeping drug, anticholinergic drug, L-DOPA, cimetidine, β-blocking agents, digitalis and preparations, steroid hormone, antituberculosis drug, hypoglycemic drug, alcohol, etc.

Others

Normal pressure hydrocephalus, chronic subdural hematoma, cerebral contusion, melancholy epilepsy (hippocampal sclerosis), etc.

symptoms should be viewed separately because they may be relieved by antidepressants. On the other hand, if patients with MCI begin to develop depression, their risk of progressing to AD will be 2.6 times greater than those without depression.67 For those cases, long-term observation is important. Apart from depression, other mental disorders, such as delirium, epilepsy, and chemical-induced forgetfulness (e.g., benzodiazepine- derived medicine), should also be differentiated from MCI.

10.5 Neuropathology

Neuropathological studies suggest that MCI represents an early clinical expression of age-related neurodegenerative disease. Several autopsy studies have found that MCI patients have AD pathology that is intermediate in severity between normal and more advanced AD.44,64,68,69,70,71,72,73,74 Some stud- ies also found that pathologies consistent with other dementing processes (DLB, cerebrovascular disease) are overrepresented in MCI patients.44,46,65,75,76 Therefore, having a broad understand- ing of the knowledge and up-to-date information on AD pathol- ogy, as well as other dementing processes, is crucial to a further understanding of MCI.

A large autopsy study conducted by Schneider et al76 found that, of 134 subjects who died having a final antemortem diag- nosis of MCI, slightly more than half met the pathological crite- ria for AD. The subjects who met the pathologic criteria for “def- inite” AD were roughly equally divided between amnestic and nonamnestic MCI subtypes, along with another 20% with mixed pathologies (▶Table 10.3). Statistics indicate that MCI is a pathologically heterogeneous disorder; whether MCI was diag- nosed in its amnestic or nonamnestic form, many subjects exhibit mixed pathologies. These neuropathological findings suggest that MCI is more than a state of uncertainty for clini-

cians: the clinical syndrome of MCI may also reflect a transi- tional neuropathological process.

10.5.1 Risk Factors

The maximum risk factors for AD are recognized as aging and Apo-E4. Some studies report that most MCI patients were Apo E4 positive.77 The risk factors for angiopathy were also signifi- cant in MCI patients.78 Cholesterolemia might be associated with MCI and AD, and the latter has received much attention lately.79 Steenland et al reported that late-life depression was also strong risk factor for normal subjects progressing to MCI.80

10.5.2 Biomarkers

The annual incidence rate of AD among MCI patients is quite high, roughly estimated at around 12%,81 and a certain number of autopsies of MCI patients have shown pathological features similar to those of AD.81 Therefore, it is of pivotal importance to diagnostically predict whether or not MCI patients will proceed to AD; as a matter of fact, biomarkers aimed to distinguish pos- sible AD patients among MCI patients are still being explored continuously to this day.

In 1998, the Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and National Institute on Aging Working Group proposed a guideline for biomarkers of AD82 as follows: (1) biomarkers are able to detect a fundamental feature of Alzheimer’s neuropathology; (2) biomarkers should be validated in neuropathologically confirmed AD cases; (3) bio- markers should have preciseness (i.e., able to detect AD early in its course and distinguish it from other dementias); (4) bio- markers should be reliable; (5) biomarkers should be non- invasive; (6) biomarkers should be simple to perform; and (7) biomarkers should be inexpensive. At the moment, no bio- marker that has met all these criteria is clinically available. As diagnostic biomarkers for AD, Aβ42, Aβ40 in cerebrospinal fluid (CSF), and total tau and phosphate tau have all been recognized with clinical evidence,83 and it is expected that these biomarkers will soon be applied to MCI.

10.5.3 Current Diagnostic Guidelines

The current diagnostic guidelines for MCI, proposed by the National Institute on Aging—Alzheimer’s Association task force22 are as follows:

● Concernregardingachangeincognitionreportedbypatient
or informant or observed by clinician

● Objectiveevidenceofimpairmentinoneormorecognitive
domain, typically including memory

● Preservationofindependenceinfunctionalabilities

● Notdemented
However, the pathology of AD is a continuum of brain change, which began a long time before MCI symptoms appear; there- fore, the clear criteria that divide MCI and AD are unnatural. Nevertheless, effective treatment in the early stage of MCI requires effective criteria to divide MCI from AD. Because the current criteria for MCI are still ambiguous in the categorical distinction between MCI and dementia, overlap between MCI and mild AD can cause confusion among clinicians.23

Mild Cognitive Impairment

Table 10.3 Number and percentage of amnestic or nonamnestic MCI patients with no pathology, one type of pathology, or mixed pathology at autopsy

Presence of pathology Amnestic MCI Nonamnestic MCI (n=75) (n=59)

One pathology

41 (54.7%)

32 (54.2%)

AD diagnosis

27 (36.0%)

20 (33.9%)

NIA: high

6 (8%)

4 (6.8%)

NIA: intermediate

21 (28.0%)

16 (27.1%)

Infarcts

10 (13.3%)

11 (18.6%)

Lewy bodies

4 (5.3%)

1 (1.7%)

Mixed pathology

17 (22.7%)

9 (15.3%)

AD + infarcts

15 (20.0%)

8 (13.6%)

AD + Lewy bodies

2 (2.7%)

1 (1.7%)

AD + infarcts + Lewy bodies

Infarcts + Lewy bodies

No AD, infarcts, or Lewy bodies

17 (22.7%)

18 (30.5%)

Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impair- ment; NIA, National Institute on Aging.
Source: Table 3 in Schneider J, Arvanitakis Z, Leurgans S, et al. The neuropathology of probable Alzheimer’s disease and mild cognitive impairment. Ann Neurol 2009;66:200–208.

Alzheimer’s Disease

Fig. 10.3 An example of a diagnostic algorithm for mild cognitive impairment. AD, Alzheimer’s disease; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography. (Reprinted with permission from Mizukami K, How do we deal with mild cognitive impairment [in Japanese]. Seishin Shinkeigaku Zasshi. 2009;111(1):26-30.)

10.5.4 Diagnostic Algorithm

An example of an MCI diagnostic algorithm is as follows (▶ Fig. 10.3)84:

● Report(background,medicalorsurgicalhistory,family
history, medication) by the patient or a knowledgeable informant or observation by the clinician (refer to rating measures such as the CDR11 and Functional Assessment Staging of Alzheimer’s Disease [FAST]85

● Neuropsychiatrictest(referfortestsfordementia)

● Physicalandneurologiccheckup

● Bloodandurinetests

● Neuroimaging(computedtomography[CT],magneticreso-
nance imaging [MRI], positron emission tomography [PET]/
single-photon emission computed tomography [SPECT])

● Electroencephalography and other tests
In addition, the following should be excluded: (1) mental disor- ders, such as depression, schizophrenia, and delusional dis- order; (2) the causes of symptomatic psychosis; and (3) side effects of medicinal treatment. The ADNI items81 are helpful for tangible inspection.
10.6 Neuroimaging 10.6.1 Outline
Although the role of neuroimaging in the evaluation of MCI is yet to be clearly defined, the modalities have provided valuable

information about both healthy elderly and AD patients. There- fore, these neuroimaging studies are anticipated to provide val- uable information for clarifying MCI pathology. The main neuroimaging modalities are SPECT, PET, and MRI. The main role of neuroimaging is to undertake risk validations for MCI, as well as to rule out other types of neurodegenerative dementia. The methods of neuroimaging used to validate MCI originated from those used to validate dementia. In the following subsec- tions, validation methods and neuroimaging studies regarding MCI are summarized.

10.6.2 Nuclear Medical Imaging: Single-Photon Emission Computed Tomography and Positron Emission Tomography

Both PET and SPECT provide mapping of the accumulation of radiopharmaceutical agents at certain regions of the body. These modalities can validate blood flow and brain metabolism. The spatial resolutions, however, of PET and SPECT (3 to 6 mm) are relatively lower than those of CT and MRI (CT, 0.5 to 1.5 mm). On the other hand, the main function of CT and MRI is to depict the structure of the brain. Therefore, these neuro- imaging modalities have been combined to depict the anatomy and function simultaneously. This subsection outlines neuro- imaging studies on MCI using both single modality and mixed modalities of nuclear medicine.

has been suggested that MCI exists on a continuum between normal elderly people and patients with AD. However, it is diffi- cult to detect the hypometabolic patterns on FDG PET images by visual inspection. Therefore, statistically analyzed images have frequently been used. As shown in ▶Fig. 10.8, bilateral parietal and posterior cingulate metabolism is decreased in patients with MCI compared with healthy elderly subjects.98

In keeping with the distribution of early neurofibrillary pathology of AD, the decline in glucose metabolism involves the limbic and paralimbic cortex, as well as the temporal and parie- tal association cortex, in MCI. Longitudinal studies99 have indi- cated that FDG PET may predict the progression of MCI patients toward AD (▶ Fig. 10.9).

Regional reductions in glucose metabolism included foci in the bilateral paracampal/hippocampal cortex, right inferior pre- frontal cortex, left anterior insular cortex, left middle temporal cortex, bilateral inferior parietal cortex, and posterior cingulate cortex in a group of MCI patients who developed AD (▶Fig. 10.9a). MCI patients who did not develop AD showed only subtle abnormalities in the bilateral inferior frontal gyrus and bilateral temporal gyrus (▶ Fig. 10.9b). Compared with sta- ble MCI patients, significantly lower metabolism of the bilateral posterior cingulate cortex and right precuneus was found in the converter MCI group (▶ Fig. 10.9c).

Amyloid Imaging

A certain amount of cerebral β-amyloid (Aβ) burden has been recognized to be the primary cause of brain deterioration and cognitive decline in AD pathology.100 Therefore, amyloid imaging has rapidly become accepted as one of the central biomarkers in the study of AD progression. Among the amyloid ligands, carbon-11-labeled Pittsburgh Compound B (11C-PIB) is the most commonly studied and used tracer to date, and it appears to bind to brain fibrillar Aβ deposits with high sensitivity.101,102 As shown in ▶Fig. 10.10a, 11C-PIB PET imaging shows a clear difference in 11C-PIB uptake among non- converters to AD.103

The MCI patients showed intermediate uptake and retention between AD and nonconverters and a similar topographic

Mild Cognitive Impairment

Validation of Perfusion by Single-Photon Emission Computed Tomography

In AD pathology, from normal elderly to AD, MCI is thought to represent an intermediate stage of the decline in blood flow. Representative features of SPECT of MCI are the decline of blood flow around the association area of the posterior cerebral cor- tex (posterior cingulate gyrus, precuneus, parietotemporal lobe), and hippocampus compared with healthy elderly subjects (▶ Fig. 10.4).86

Because of the pathological variability of MCI, the patterns of blood flow are also diverse. In general, in the converter group, which shows relatively short-term progress to AD, the decline of blood flow at the region from posterior cingulate gyrus to the parietotemporal lobe is prominent compared with that seen in nonconverter groups (▶ Fig. 10.5).87,88,89,90

Furthermore, the converter group shows a significant decline of blood flow at the hippocampus.91,92 (▶ Fig. 10.6). These hypo- perfusions are noted with neurobiological knowledge of AD, specifically, that the entorhinal cortex is the earliest site to be compromised, even at a preclinical stage.93

A longitudinal follow-up study94 showed perfusion decline in an MCI group of patients in a small region of the middle and posterior cingulate and the frontal, temporal, and parietal regions. In contrast to the MCI group, the AD group showed a decline in perfusion in all cerebral lobes (▶ Fig. 10.7).

Evaluation of SPECT scans using quantitative (voxel-based statistical) analysis can potentially differentiate MCI likely to progress to AD from stable MCI with an accuracy of approxi- mately 73% before the appearance of clinical signs of significant cognitive impairment.95 Furthermore, perfusion SPECT can dif- ferentiate MCI of the AD type from other types of dementia with a sensitivity of 84% and a specificity of 89%.92,96,97 MCI patients who converted to AD showed hypoperfusion in the parahippocampal and inferior temporal gyri bilaterally.

Basal Metabolism

Based on findings and experiences with fluorodeoxyglucose (FDG) PET, which provides a measure glucose metabolism, it

Fig. 10.4 Mild cognitive impairment versus healthy control on blood flow by single-photon emission computed tomography. (Caffarra P, Ghetti C, Concari L, Venneri A, Differential patterns of hypoperfusion in subtypes of mild cognitive impairment. The Open Neuroimaging Journal 2008;2: 20–28.)

Alzheimer’s Disease

Fig. 10.5 Mild cognitive impairment (MCI) in patients who converted to Alzheimer disease compared with nonconverted MCI. Rendered brain regions indicating hypoperfusion examined by single-photon emission computed tomography. (Reprinted with permission from Park KW, Yoon HJ, Kang DY, Kim BC, Kim SY, Kim JW, Regional cerebral blood flow differences in patients with mild cogni- tive impairment between those who did and did not develop Alzheimer’s disease. Psychiatry Res Neuro- imag 2012;203:201–206.)

Fig. 10.6 Mild cognitive impairment (MCI) in patients who converted to Alzheimer disease compared with nonconverted MCI. Significant decline of blood flow at hippocampus examined by single-photon emission computed tomogra- phy. (Reprinted with permission from Habert MO, Horna JF, Sarazin M, et al. Brain perfusion SPECT with an automated quantitative tool can identify prodromal Alzheimer’s disease among patients with mild cognitive impairment. Neurobiol Aging 2011;32:15–23.)

Mild Cognitive Impairment

Fig. 10.7 Regional changes in brain perfusion between baseline and 2-year follow-up in mild cognitive impairment (a) and Alzheimer’s disease (b) groups. (Reprinted with permission from

Fig. 2 in Alegret M, Cuberas-Borrós G, Vinyes- Junqué G, et al. A two-year follow-up of cognitive deficits and brain perfusion in mild cognitive impairment and mild Alzheimer’s disease.

J Alzheimer Dis 2012;30(1):109–120. doi:10.3233/JAD-2012-111850.)

Fig. 10.8 Mild cognitive impairment versus healthy control in glucose metabolism by fluorodeoxyglucose (FDG)-positron emission tomography. (Reprinted with permission from Ishi K, PET Approaches for Diagnosis of Dementia, AJNR Am J Neuroradiol 2014;http://dx.doi.org/ 10.3174/ajnr.A3695Au: Please update with volume and page numbers.)

Alzheimer’s Disease

Fig. 10.9 Regional changes in brain metabolism between baseline and 1-year follow-up in Alzheimer’s disease (a), and healthy volunteers (b), and MCI groups (c). (Reprinted with permission from Fig. 1, Drzezga A, Lautenschlager N, Siebner H, Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer’s disease: a PET follow-up study. Eur J Nucl Med Mol Imaging 2003;30(8):1104–1113.)

Fig. 10.10 (a) Differences in 18F-florbetaben- fluorodeoxyencephalography (18F-FDG) and carbon-11-labeled Pittsburgh Compound B (11C- PIB) in a normal subject (upper row), a subject with mild cognitive impairment (MCI) (middle row) and a subject with dementia due to Alzheimer’s disease (bottom row). (b) Amyloid imaging with 18F-florbetaben in a healthy control, a participant classified as MCI, one subject with Alzheimer’s disease (AD) and one with fronto- temporal lobar degeneration (FTLD).

(Reprinted with permission from Jimenez Bonilla JF, Carril Carril JM. Molecular neuroimaging in degenerative dementias. Rev Esp Med Nucl Imag Mol 2013;32(5):301–309.) (Reprinted with per- mission from Villemagne VL, Rowe CG. Amyloid imaging. Int Psychogeriatrics 2011;23(Suppl 2): S41–S49.)

lessened the enthusiasm for cerebral Aβ (e.g., amyloid imaging) to become a stand-alone biomarker of AD.

10.6.3 Magnetic Resonance Imaging

Several MRI techniques and methods have been implemented in the diagnosis and research of MCI, including MR volumetry, structural analysis, H1 (proton) magnetic resonance spectros- copy (MRS) for metabolite evaluation, diffusion-weighted MRI for the evaluation of structure and constitution, and functional MRI (fMRI) for assessing activated brain regions in MCI patients. The following subsections summarize the validation methods based on MRI methods and MRI-based studies on MCI.

MRI Volumetry

Magnetic resonance imaging volumetry is defined as the accu- mulation of voxels or subvoxels within the region of interest (ROI) on MRI. When voxels are used for assessing morphomet- ric change of ROI, this procedure is called voxel-based morphometry (VBM). By using volumetry and VBM, volume losses in MCI patients can be observed, including regions at the hippocampus, entorhinal cortex, and amygdala. Among VBM studies, Chételat et al109 reported that significant volume loss

pattern in the posterior cingulate gyrus, anterior cingulate, and frontal cortex. Although 11C-PIB shows usability for AD diagno- sis, the radioactive decay half-life of 11C is relatively short (approximately 20 minutes) and limits its facility. To overcome this limitation, 18F-labeled Aβ imaging tracers such as 18F-flor- betaben have also been studied (18F has approximately 110 minutes of radioactive decay half-life (▶ Fig. 10.10b).104 Cortical retention of 18F-florbetaben in the frontal, posterior cingulate/precuneus, and lateral temporal areas was noted, with relative sparing of occipital and sensorimotor cortex in MCI and AD subjects. In contrast, no cortical 18F-florbetaben retention was seen in healthy controls or FTLD subjects.

As individuals progress to MCI and dementia, clinical decline and neurodegeneration accelerate and appear to proceed inde- pendently of amyloid accumulation.105 This supposition largely concurs with the model of dynamic changes proposed by Jack et al106 wherein AD biomarkers are most informative in the pre- clinical period (▶ Fig. 10.11).

In addition, findings indicate that a substantial proportion of cognitively intact elderly patients also have a significant level of Aβ plaque burden,107 further suggesting that Aβ may be necessary, but not sufficient, for AD progression.108 The lack of specificity of Aβ to predict cognitive decline, as well as its weak association with clinical symptoms and disease severity, has

Mild Cognitive Impairment

Fig. 10.11 (a) Dynamic biomarkers of the Alzheimer’s pathological cascade. (b) Positron emission tomography amyloid imaging with Pittsburgh compound B in (a) normal without atrophy on magnetic resonance imaging (MRI), (b) normal with atrophy on MRI, and (c) Alzheimer’s disease patient. (Reprinted with permission from Figs. 1 and 2 in Jack C Jr, Knopman D, Jagust W, et al, Hypothetical model of dynamic biomarkers of the Alzheimer patho- logical cascade, Lancet Neurol 2010;9(1):119— 128.)

Alzheimer’s Disease

Fig. 10.12 Atrophy on (a) mild cognitive impairment (MCI) compared with healthy control and (b) Alzheimer’s disease compared with MCI. (Reprinted with permission from Karas GB, Scheltens P, Rombouts SA, et al. Global and local gray matter loss in mild cognitive impairment and Alzheimer’s disease. Neuroimage 2004;23:708–716.)

Table 10.4 Gray matter difference in anatomical regions of normal controls versus patients with mild cognitive impairment and Alzheimer’s disease

Label Mean percentage difference

NCLR vs. MCI

MCI vs. AD

Lobes

Frontal

4.5

3.1

11.1

9.4

Temporal

1.7

0.8

10.9

11.2

Parietal

6.3

7.2

13.1

12.4

Occipital

0.5

-0.2

12.9

11.2

Medial temporal lobe, basal ganglia, and insula

Amygdala

3.3

4.1

10.7

7.6

Hippocampus

4.9

5.9

7.9

5.5

Thalamus

13.4

12.4

14.1

14.2

Caudate head

4.6

4.1

10.5

10.6

Insula

4.6

3.2

6.9

8.2

Superior temporal cortex

7.2

6.4

8.5

10.7

Cortical association areas and cingulate

Parietal association

2.3

3.0

18.7

Retrosplenial cingulate

3.1

3.5

7.3

5.9

Anterior cingulate

–0.2

1.2

9.2

8.1

Abbreviations: AD, Alzheimer’s disease; L, left; R, right; MCI, mild cognitive impairment; NCLR, normal controls.
Source: Table 4 in Karas KB, Scheltens P, Rombouts SA, et al. Global and local gray matter loss in mild cognitive impairment and Alzheimer’s disease. Neuroimage 2004;23:708–716.

100

was observed in amnestic MCI patients compared with healthy elderly subjects; these losses were seen in the hippocampus, posterior cingulate gyrus, and subcallosal area; on the other hand, compared with AD patients, the volume of gray matter at the posterior association region of the cerebellum was spared. Karas et al110 also reported that, compared with healthy elderly subjects, amnestic MCI patients exhibited significant volume loss at regions of the interior temporal lobe, insula, and thala- mus; compared with AD patients, volumes of the parietal lobe, as well as the anterior and posterior cingular gyrus, were spared (▶Fig. 10.12 and ▶Table 10.4). With these results, it was thought that amnestic MCI patients might exhibit signifi- cant brain atrophy at certain regions, although not as widely as in AD patients, especially at the interior temporal lobe region, including the hippocampus.109,110,111 Furthermore, Bell- McGinty et al112 revealed that the brain atrophy patterns differ in amnestic MCI and multiple cognitive domain MCI (▶ Fig. 10.13).

In the amnestic group, significant volume losses were noted at the left entorhinal cortex and inferior parietal lobe; in multi- ple cognitive domain MCI subjects, on the other hand, signifi- cant volume losses were noted at the right inferior frontal gyrus, right middle temporal gyrus, and bilateral superior tem- poral gyrus. These results suggest that amnestic MCI, which exhibits memory impairment as the primary feature, may be associated with medial temporal lobe atrophy, and multiple cognitive domain MCI may be associated with extensive lesions within the cerebral cortex.

Longitudinal observations also have provided valuable infor- mation and knowledge about the development of MCI. Whit- well et al113 observed prospectively 33 amnestic MCI patients

for several years until they progressed to AD, and then the investigators analyzed the patients’ longitudinal structural MRI data by VBM (▶ Fig. 10.14). At the time point of 3 years before onset of AD, significant—but not severe—volume loss was observed at the left-side–dominant amygdala, head of hippo- campi, entorhinal cortex, and fusiform gyrus; by the time point of 1 year before onset of AD, significant volume loss developed at the bilateral whole hippocampi, as well as in regions from

the posterior temporal lobe to the parietal lobe. By the time AD was diagnosed, severe volume losses involving the entire region of the temporal lobe, as well as wide-area volume loss from the temporoparietal lobe to the frontal lobe, were observed.

In these studies, compared with AD patients, wide-area atro- phy in the cerebral cortex was not observed among MCI patients. However, significant atrophy was noted in the hippo- campal region compared with healthy subjects. Furthermore,

Mild Cognitive Impairment

Fig. 10.13 Different atrophy patterns in amnestic mild cognitive impairment and multiple cognitive domain mild cognitive impairment. (Reprinted with permission from Bell-McGinty S, Lopez OL, Meltzer C, et al, Differential cortical atrophy in subgroups of mild cognitive impairment. Arch Neurol 2005;62:1393–1399.)

101

102

Alzheimer’s Disease

Fig. 10.14 Regional changes in brain atrophy between baseline and 9 to 18 months’ follow-up in patients with amnestic mild cognitive impair- ment. L, left; R, right. (Reprinted with permission from Whitwell JL, Przybelski SA, Weigand SD,
et al. 3D maps from multiple MRI illustrate changing atrophy patterns as subjects progress from mild cognitive impairment to Alzheimer’s disease. Brain 2007;130:1777–1786.)

atrophy at the hippocampal region had already begun at the early stages of MCI, and those with severe atrophy frequently progressed to AD within a short time.

Blood Flow Analysis by Arterial Spin Labeling

Neuronal activity is tightly coupled with cerebral blood flow (CBF). Therefore, one of the most reliable approaches to assess

the disease progression of MCI or AD is to measure CBF. MR- based CBF measurements have been developed to investigate hemodynamic alterations in MCI or AD, including arterial spin labeling (ASL)114 and dynamic contrast techniques.115 ASL is a noninvasive MRI technique that allows measurement of CBF without using any contrast agents. Several researchers have reported the usefulness of ASL for revealing CBF abnormalities in patients with MCI.

Mild Cognitive Impairment

Fig. 10.15 Regional perfusion abnormalities between patients with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) patients and healthy elderly controls (HC) using pulsed arterial spin labeling (PASL). L, left; R, right. (Reprinted with permission from Fig. 1 in Alexopoulos P, Sorg C, Förschler A, et al. Perfusion abnormalities in mild cognitive impairment and mild dementia in Alzheimer’s disease measured by pulsed arterial spin labeling MRI. Eur Arch Psychiatry Clin Neurosci. 2012;262(1):69–77.)

Fig. 10.16 Regional perfusion differences between (a) control, (b) mild cognitive impairment patient, and (c) Alzheimer’s disease patient on cerebral blood flow. (Reprinted with permission from Zhang Q, Stafford RB, Wang Z, et al. Microvascular perfusion based on arterial spin labeled perfusion MRI as a measure of vascular risk in Alzheimer’s disease, J Alzheimers Dis 2012;32(3):677–687. doi:10.3233/JAD-2012- 120964.)

Comparison studies of the regional perfusion abnormalities between MCI or AD patients and healthy elderly controls using pulsed ASL (PASL) have been performed116,117 and showed sig- nificant differences between healthy elderly controls and MCI and AD patients (▶ Fig. 10.15, ▶ Fig. 10.16). Lower CBF in

patients with MCI compared with healthy controls was found in the right and left superior parietal gyrus, right and left angular gyrus, left inferior parietal gyrus, left and right middle temporal gyrus, and middle occipital gyrus. Patients with AD showed lower CBF than healthy controls in the right angular gyrus, left

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and right superior parietal gyrus, left and right inferior parietal lobe, right middle occipital gyrus, left precuneus, and caudate. They concluded that PASL may be a valuable instrument for investigating perfusion changes in the transition from normal aging to dementia. Furthermore, the cross-validation studies of ASL and PET for assessing CBF on AD pathology have shown good agreement among these two modalities.118,119 Although clinical evidence of ASL on AD pathology has not been established, ASL is expected to become one of the primary measurement techniques for AD pathology because of its noninvasiveness.

1H Magnetic Resonance Spectroscopy

Proton MR spectroscopy (1H MRS) is an analytical imaging tech- nique that is sensitive to the changes in the chemical environ- ment in the brain at the cellular level. With 1H MRS, major pro- ton-containing metabolites in the brain, including N-acetyl aspartate (NAA), myo-inositol (MI), choline (Cho), and creatine (Cr), are quantitatively measured during a common data acqui- sition period as the mean values in the certain size of voxel of interest. Therefore, 1H MRS may have an important role in the clinical evaluation and monitoring of dementia in early stages of AD pathology.120

Several investigations have aimed to distinguish the behavior of brain metabolites in AD pathology from that in normal con- trols. The NAA metabolite is a marker for neuronal integrity, and it decreases in a variety of neurologic disorders, including MCI and AD.121,122 The MI spectrographic peak consists of glial metabolites that are responsible for osmoregulation.123 Elevated MI levels correlate with glial proliferation in inflammatory cen- tral nervous system demyelination124 and are higher in the 1H MRS spectra of patients with MCI and AD than in cognitively normal elderly.121 The greatest amount of Cho in the brain is bound in membrane phospholipids that are precursors of Cho and acetylcholine synthesis. It has been postulated that eleva-

tion of the Cho peak is the consequence of membrane phospha- tidylcholine catabolism to provide free Cho for the chronically deficient acetylcholine production in AD. The result is decreased NAA, whereas MI and Cho are increased in MCI rela- tive to normal values (▶Fig. 10.17).121 Furthermore, Kantarci et al125 showed that NAA:MI and hippocampal volume:total intracranial volume ratios showed an independent effect and found that low levels of the neuronal integrity marker NAA and high levels of the glial metabolite MI increased the risk for MCI. Therefore, the joint effects of these two independent parame- ters can be predictors of MCI in cognitively normal older adults.

From these mentioned studies, the observation of brain metabolites in MCI patients by using 1H MRS may provide a new differential diagnosis method based on the biochemical activity of brain. However, the values found using this method can be easily affected by the quantification method used and by the physical and chemical environment of the brain, such as temperature and hydrogen ion content (pH), and no fundamen- tal solutions have been found. Therefore, further investigation and evaluation are required for stable application in MCI and AD pathologies.

Diffusion Tensor Magnetic Resonance Imaging

Diffusion tensor imaging (DTI) is an MRI technique that allows for investigation of the microstructural integrity of white matter.126 Based on changes in translational diffusion (mean diffusivity [MD], apparent diffusion coefficient [ADC]), and directional diffusion (fractional anisotropy [FA]), structural changes in the white matter can be assessed. Furthermore, the combination of increased MD and ADC and decreased FA shows damage to white matter.

Measures of MD/ADC and FA from DTI can quantify the alter- ations in water diffusivity resulting from microscopic structural

Fig. 10.17 Brain metabolites in controls (C), mild cognitive impairment (MCI), and Alz- heimer’s disease (AD) patients. Cr, creatine; MI, myo-inositol; NAA, N-acetyl aspartate. (Reprinted with permission from Figs. 3 and 5 in Kantarci K, Jack C Jr, Xu Y, et al. Regional metabolic patterns in mild cognitive impairment and Alzheimer’s disease: a 1H MRS study, Neurology 2000;55:210–217.)

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guished from normal elderly subjects using noninvasive imag- ing techniques.132

Functional Magnetic Resonance Imaging

Functional MRI (fMRI) is a noninvasive technique used to inves- tigate the neural underpinnings of higher cognitive functions by measuring regional hemodynamic changes. These hemo- dynamic changes are thought to be linked to underlying cellular activity.133,134 The blood-oxygen-level-dependent (BOLD) signal changes detected by fMRI are thought to represent integrated synaptic activity by measuring changes in blood flow, blood volume, and the blood oxyhemoglobin:deoxyhemoglobin ratio underlying such synaptic activity.135

The pattern of activated and deactivated brain regions mod- eled in block or event-related design paradigms allows for the identification of brain regions and networks whose activity is modulated by the experimental task. By creating contrasts between disparate behavioral or cognitive conditions (e.g., fixa- tion versus memory encoding), the dynamic nature of the BOLD signal, coupled with the relatively static hemodynamic response to activity, allows for inference of which regions are selectively activated or inactivated by a task (i.e, task-positive or task-negative brain regions).136

Enriching our understanding of task-positive and task- negative brain networks are so-called task-free or resting state or functional connectivity MRI (fcMRI) studies, in which statis- tical correlations in BOLD signal dynamics while the brain is at rest have enabled identification of several large-scale neural networks composed of widely anatomically separated brain regions.137

In the following subsections, task-based and task-free fMRI studies are summarized.

Task-Activated Studies

Most studies in task-based fMRI studies have focused on inter- rogating memory functions, given the early occurrence of known AD pathologic changes in the medial temporal lobes and the reliance on these structures for learning and memory. Nevertheless, it should be noted that the specific abnormality found in a task-based fMRI study of any patient group depends greatly on the task used in the study.138 By using task- based fMRI, greater medial temporal lobe activation in MCI patients compared with controls has been demonstrated (▶ Fig. 10.20).139

As mentioned, this method, which requires cognitive tasking, allows us to observe the current status of brain functions and its relation to the function of associated regions. Therefore, if the task is successfully conducted, the results bring useful infor- mation about brain function and CBF.

Task-Free Studies

Resting-state functional MRI (rs-fMRI) is an imaging method that reflects synaptic activity through changes in blood flow and the oxyhemoglobin:deoxyhemoglobin ratio.140 By measur- ing functional connectivity between spatially distinct brain regions, rs-fMRI can be used to evaluate brain function.141,142 Several networks encompassing brain regions that display func- tional connectivity during the resting state, so-called resting

Fig. 10.18 Mean fractional anisotropy (FA) and mean diffusivity (MD) values for the genu and splenium in normal control (NC) participants and mild cognitive impairment (MCI) patients. ADC, apparent diffusion coefficient. (Reprinted with permission from Fig. 1 in Delano-Wood L, Bondi MW, Jak AJ, et al, Stroke risk modifies regional white matter differences in mild cognitive impairment. Neurobiol Aging 2010;31 (10):1721–1731.)

changes. Several researchers have revealed the difference between normal controls and MCI patients using these water diffusion–derived measures. The changes in the white matter of study participants (normal controls and MCI patients) by FA showed significant regional reductions in participants with MCI.127,128,129,130 Delano-Wood et al found that the FA value of the splenium was significantly lower in MCI patients than in normal controls, despite finding no differences in gross mor- phometry or hippocampal volumes (▶Fig. 10.18).128 Further- more, they found that MCI patients demonstrated considerably diminished white matter integrity in the posterior cingulum (PC) (▶Fig. 10.19).129 Stebbins et al131 summarized in their review that the brain lobe where MD increased and FA decreased was identified in MCI patients and that the pattern of white matter integrity disruption tends to follow an anterior to posterior gradient, with greater damage noted in posterior regions in AD and MCI patients.

As mentioned, DTI-derived measures, such as FA and ADC, have already shown their usefulness, and advances in their application should provide new insights into AD pathologies. In addition, more evolutionary techniques may bring highly accurate early identification methods for MCI patients as distin-

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Fig. 10.19 (a,b) Posterior cingulum (PC) fractional anisotropy hemispheric differences
in normal controls (NC) and mild cognitive impairment (MCI) group. (Reprinted with per- mission from Figs. 1 and 2 in Delano-Wood L, Stricker N, Sorg S, et al. Posterior cingulum white matter disruption and its associations with verbal memory and stroke risk in mild cognitive impairment. J Alzheimer Dis 2012;29:589–603.)

Fig. 10.20 A phase of compensatory hyperactivation appears to occur in the medial temporal lobe (MTL) in very mild cognitive impairment (MCI) preceding Alzheimer’s disease (AD) dementia. (Reprinted with permission from Dickerson BC, Salat DH, Greve DN, Chua EF, Rand-Giovannetti E, Rentz DM, et al. (2005). Increased hippocampal activation in mild cognitive impairment compared with normal aging and AD. Neurology 2005;65:404–411.)

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state networks.143,144,145 One network, referred to as the default

mode network (DMN), consists of the bilateral parietal cortex,

precuneus, posterior cingulate cortex, anterior cingulate

cortex, medial prefrontal cortex, hippocampus, and thalamus.

The network is active during episodic and autobiographical

memory retrieval but shows decreased activity during per-

formance of cognitive tasks that demand attention to external stimuli.136,146,147

The use of resting-state analyses to identify alterations in functional connectivity that distinguish normal aging from MCI and AD has gained momentum in recent years, although relatively few studies have thus far been completed

(▶Fig. 10.21).148 Several groups have reported finding decreased connectivity within the posterior DMN (especially the posterior cingulate cortex) in subjects with amnestic MCI compared with controls (▶ Table 10.5).149,150,151,152

As mentioned, this method, which does not required cogni- tive tasks, allows us to apply a wide variety of studies for observing default network connectivity in the brain. This possi- bility was reinforced by the recent National Institute on Aging— Alzheimer’s Association Workgroup definition of preclinical AD by Sperling et al,153 who offered the possibility that fMRI mea- surement of default network connectivity holds promise as a possible preclinical marker of AD. Further studies may reveal

Mild Cognitive Impairment

Fig. 10.21 Mean z-values from default-mode network (DMN) z-maps reveals alterations in functional connectivity in continuous MCI (cMCI) and Alzheimer’s disease (AD). HC, healthy controls. (Reprinted with permission from Fig. 4 in Binnewijzend MAA, Schoonheim MM, Sanz- Arigita E, et al. Resting-state fMRI changes in Alzheimer’s disease and mild cognitive impairment, Neurobiol Aging 2012;33:2018–2028.)

the differences in default network connectivity among normal, MCI, and AD subjects.

10.6.4 Image Analysis

Information and knowledge about MCI and AD have accumu- lated through the use of neuroimaging modalities like PET, SPECT, and MRI. Amid this accumulation of knowledge, image analysis techniques have played many important roles.

Traditionally, visual assessment has been used on a daily clinical

basis, but this method cannot produce quantitative evaluations

of pathological conditions. Therefore, manually placed ROIs

and statistics within the ROI have been applied to quantitative

analysis. However, manual ROI placement is greatly labor

intense because it requires considerable time for placing the

ROIs along the slices. Routine assessment by this manual ROI

placement method is not feasible; therefore, several semiauto-

mated and fully automated ROI analysis methods have been devised.154,155,156

In general, medical image analysis techniques can be roughly divided into morphometric analysis (morphometry) and photo- metric analysis (photometry). Recently, whole-brain image registration techniques, which provide precise anatomical compensation by linear or nonlinear transformation to the standardized template brain image, have become commonly available.154,155,156 Furthermore, automated segmentation of gray matter, white matter, and cerebrospinal fluid from the whole brain is also now possible by using software like Statisti- cal Parametric Mapping (SPM). Furthermore, MRIstudio can provide registration among variable subjects and percolated brain template for automated brain regional analysis in both morphometry and photometry.157,158 By using such software, we can obtain the volume changes and morphologic changes in subjects quantitatively. These procedures are classified as mor- phometry.159 In addition, software programs that can provide computational analysis for not only general ROI averaging but also automated statistical analysis after transformation to stan- dardized brain template (MRIstudio) are also available. Several research methods have already used such software programs to reveal regionally specific DTI in MCI and AD160 and neuro- psychiatric symptoms in MCI and AD.161 These procedures are classified as photometry. Both morphometry and photometry are based on voxel-based analysis (VBA), which is strongly affected by registration inaccuracy, moving artifacts, and imag- ing artifacts. These errors cause drawbacks in VBA and may lead to difficulty in comparing the results from different image scan- ners. To compensate for these drawbacks, large ROIs, including a large numbers of voxels, may be one solution to maintaining statisticalpower.

Table 10.5 Comparison of major findings in studies of resting-state default mode network activity in aMCI groups compared with normal controls

Subjects Present study Sorg et al1,54 Bai149 Qi et al151,6

Posterior cingulate cortex/precuneus

–B

–L

–B

Inferior parietal lobe

–R, + l

Medial temporal lobe (hippocampus, entorhinal cortex, perirhinal cortex, parahippocampal gyrus)

–L

Fusiform gyrus

–L

Lateral perifrontal cortex

–B

–R

Medial prefrontal cortex

Middle cingulate cortex

Medial temporal gyrus

–L

Angular gyrus

–R

Putamen

Abbreviations: –, decreased activities in aMCI; + , increased activities in aMCI, amnestic mild cognitive impairment; B, bilateral; L, left; R, right Source: Table 4 in Jin M, Pelak VS, Cordes D. Aberrant default mode network in subjects with amnestic mild cognitive impairment using resting-state functional MRI. Magn Reson Imaging 2012;30(1):48–61.

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Image analysis methods are under development, and many software programs are available both commercially and freely. Nevertheless, database communization for obtaining strong sta- tistical evidence by image analysis has not been realized, and differences among the different centers and different image scanners remain unresolved.

10.7 Clinical Trials

10.7.1 Medication for Mild Cognitive

Impairment

compensatory strategy, using external aids, also showed pre- liminary evidence that it improved amnestic MCI.170 Physical activity interventions are also being explored as a way to mini- mize cognitive decline in MCI. Recently, combination training with memory compensation, decision making, physical fitness, talking with others, and educational programs have been carried out, and the evaluated data showed a positive impact on patient functional outcomes. Multiple aspects of nonphar- macologic follow-up might be of benefit for MCI patients.

10.7.3 Prophylactic Follow-Up

Several prophylactic follow-ups have reported benefits in MCI prevention. One follow-up reported that individuals with habits involving intellectual activities, such as reading newspapers or magazines, playing games, doing puzzles, or visiting museums, showed a 33% decrease in the risk for dementia.171 Another follow-up reported an eightfold difference in the incidence rate between people who are single and meet other people less than once a week compared with those who live with family members and have interactions with others more than once a week.172

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At present, no medicines or nonpharmacologic therapeutic methods are available for MCI. Therefore, one of the most pro- spective therapeutic methods might be existing medicines. Sev- eral clinical trials that use cholinesterase inhibitors, such as donepezil hydrochloride, galanthamine, and rivastigmine, have been reported. In 2004, Salloway et al made the first report regarding treatment outcomes with donepezil hydrochloride for MCI.162 A significant difference was found between the med- icine and placebo; the improvement ratio was 32.6 and 24.3%, respectively, with no serious side effects reported. In 2005, Petersen et al163 also reported on the effect of donepezil hydro- chloride for treatment of MCI. This article concluded that within a year, this medicine can prevent progression to demen- tia, and after a second year, no additional positive effects to control progression are noted. On the other hand, a clinical trial for MCI with galantamine treatment reported that this agent demonstrated significant effects in preventing MCI from pro- gressing to dementia.164

10.7.2 Follow-Up Pharmacologic Follow-Up

Some authorities believe that current AD medications, namely, cholinesterase inhibitors (ChEIs), could impact the outcome for MCI patients, especially those with the amnestic subtype. On the other hand, Raschetti et al concluded from their review that “the use of cholinesterase inhibitors in MCI was not associated with any delay in the onset of AD or dementia.” Moreover, the safety profile from this review showed that risks associated with ChEls are not negligible.165 Furthermore, the British Asso- ciation for Psychopharmacology166 concluded that the medica- tions approved for AD do not demonstrate efficacy in delaying or preventing dementia in MCI patients.

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such as medial temporal regions (hippocampal formations, parahippocampal gyrus, and entorhinal cortex); consequently, episodic memory deficit is the initial symptom for most of AD patients. As the condition progresses, deficits occur in instru- mental functions (language, praxis, visuospatial abilities), which are consistent with the extension of lesions into the neo- cortical associative areas (Braak stage V).

11.2 Genetics

In most cases, AD is considered a disease with multiple causes and results from the interactions between genetic and environ- mental factors.12 The role of genetic factors in the incidence and pathogenesis of AD is complex. AD can be divided into two types according to genetic factors13: (1) familial AD, with mendelian transmission, usually early onset (before age 60 years); and (2) sporadic AD, usually with onset in older age (over 60 years), without an autosomal dominant pattern of transmission. This dichotomy should be taken with caution, however, because cases of early onset AD without evidence of autosomal dominant transmission do occur13; conversely, the importance of genetic factors in sporadic forms of the disease has been established14 by the involvement of sortilin-related receptor (SORL1).15,16,17

Familial AD with autosomal dominant transmission is rare and accounts for less than 5% of AD cases.17 Genetic studies indicate that these forms are related to three possible muta- tions17,18: (1) the gene for APP, located on chromosome 21; (2) the gene for presenilin 1 (PSEN1), located on chromosome 14; and (3) the gene for presenilin 2 (PSEN2), located on chro- mosome 1. These changes have virtually 100% penetrance by the age of 60 years. PSEN1 gene mutations are the most fre- quent (75% of cases among all cases of familial AD).17,18 By con- trast, in a whole-genome sequencing study of Icelandic people, a recent work identified a coding variant in APP that protects against AD and cognitive decline. The mutation leads to reduced production of Aβ by BACE1.19

The genetics of sporadic forms of the disease is much more complex because in most cases there is no obvious familial aggregation.18 The risk of developing AD increases from 4 to 10 times in normal subjects with a first-degree relative affected by the disease compared with patients without a family history.20

The SORL1 gene has been noted to be involved in sporadic forms of the disease.15,16,17 The SORL1 gene is located on chro- mosome 11 and is involved in intracellular trafficking of the amyloid precursor. Deletion of this gene increases the produc- tion of toxic β-amyloid peptide.15,21 However, this mutation is not present in all cases of sporadic AD.16

Among the genetic factors modulating susceptibility to AD, the polymorphism of apolipoprotein E (ApoE) is the most important. ApoE has an essential role in the regulation of lipid metabolism and is implicated in the transport, distribu- tion, endocytosis, and catabolism of lipid particles.22 It also has a role in the mechanisms of neuronal plasticity by partici- pating in synaptogenesis and the stability of synaptic con- nections.22 The mechanisms by which ApoE is involved in the

Since Alois Alzheimer’s first description of Alzheimer’s disease (AD) in 1906, the disease that was later named after him has became a major public health concern. To date, it is estimated that 24 million people worldwide have dementia, most of whom are thought to have AD.

The main risk factor for developing AD is age.1 Epidemiologic data show that the percentage of patients with AD doubles every 5 years from age 65 onward.1 Thus, the percentage of patients with AD would be of 1% for the population aged 60 years, 5% for the population aged 65 years, and about 30% for the population aged 85 years.1,2 It should be noted, however, that although AD mainly affects the elderly, it also affects an important group of young patients.2

Considering that the incidence of AD and other dementias increases with age, the prevalence of dementias is estimated to grow in the following decades worldwide as a result of the increasing longevity of populations.3 The number of people with dementia worldwide is predicted to double every 20 years, to more than 65 million in 2030 and more than 115 million in 2050.4 Besides its dramatic impact on patients and their fami- lies, AD represents an economic strain for health care systems and communities worldwide, and it is expected that the cost of caring for people with dementia in United States will grow to almost $190 billion by 2015.3

11.1 Neuropathology

Alzheimer’s disease is associated with different neuro- pathological findings, such as neuronal death and a decreased number of synapses. Its main pathological hallmarks, however, are the presence of senile plaques and neurofibrillary tangles, which reflect amyloid and tau pathology, respectively.

Extracellular amyloid plaques are formed by β-amyloid protein peptides (Aβ), which are fragments formed by the cleavage of the amyloid precursor protein (APP).5 APP is a transmembrane glycoprotein that can be processed by α- and γ-secretases, generating a nonamyloidogenic product, or by β- and γ-secretases, generating Aβ peptides, which are amyloidogenic and are prone to form plaques. However, there is no direct correlation between the number and topography of cortical senile plaques and the cognitive defi- cits in AD patients. The amount of senile plaques is not correlated with the severity of the disease, and amyloid dep- osition seems to remain stable during progression of the disease.6,7,8 Recent longitudinal imaging studies indicate that cerebral Aβ deposition precedes the clinical symptoms of AD by a decade or longer.9

Intracellular neurofibrillary tangles are formed as a result of hyperphosphorylation and oligomerization of tau, a micro- tubule-associated protein that is present mainly in the axons of neurons. The progression of tau pathology in the brain is closely correlated to clinical symptoms and to the severity of the disease10 as established by Braak and Braak.11 In the early stages of AD (Braak stages I, II, and III), neurofibrillary degener- ation can be identified in areas critical for episodic memory,

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pathophysiology of AD are not entirely clear, but ApoE seems to have an important role in the metabolism and the accumulation of Aβ.22,23

The ApoE gene is located on chromosome 19 and has three alleles (ε2, ε3, and ε4). The ε3 allele is present in 50 to 90% of individuals, the ε4 allele in 5 to 35%, and the ε2 allele in 1 to 5%.23 The risk of developing AD associated with ApoE ε4 is dose dependent: individuals carrying one ε4 allele have three times more risk of developing the disease, whereas ε4 homozygotes have 12 times more risk of developing AD than do those with ε3 homozygotes.22,23 On the other hand, the ε2 allele is associated with a reduced risk of developing AD.22,23,24,25

Recent publications showed that, in addition to autosomal dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical pheno- types and neuropathology.26

11.3 Clinical Features
11.3.1 Episodic Memory Deficits

The most prominent feature of AD is the decline in cognitive function, with an early impairment of anterograde episodic memory.17 The initial amnestic deficits with progressive wor- sening that remains predominant during the course of the dis- ease is the most frequent phenotype of AD.2 Amnestic symp- toms are characterized by memory impairment of recent events, unusual repeated omissions, and difficulty learning new information. Initially, amnestic symptoms are not associated with a loss of autonomy, and the patient remains independent for activities of daily living.

The investigation of amnestic symptoms requires formal neu- ropsychological testing to quantify and qualify the nature of the memory deficit. In fact, memory disorders are commonly observed in patients with neuropsychiatric disorders other than AD, such as as Parkinson’s disease, vascular dementia, depres- sion, or even iatrogenic conditions. Moreover, subjective memory complaints are also common in the elderly. The appropriate neu- ropsychological evaluation can distinguish genuine memory impairment (e.g., failure of information storage and new mem- ory formation) from attention or retrieval disorders (such as nor- mal aging or depression). More particularly, neuropsychological tests that provide encoding specificity are of great interest and improve the accuracy of the AD diagnosis. The Free and Cued Selective Reminding Test (FCSRT) is a neuropsychological tool in which target materials are encoded along with semantic cues. These cues are used to control for effective encoding and subse- quently are presented to optimize retrieval.27

The FCSRT can identify the so-called amnestic syndrome of the medial temporal type (or of the hippocampal type), which is defined by (1) poor free recall (as in any memory disorder) and (2) decreased total recall resulting from an insufficient effect of cueing. The low performance of total recall despite retrieval facilitation indicates poor storage of information and seems specific of a hippocampal memory disorder. The amnes- tic syndrome of the medial temporal type differs from func- tional and subcorticofrontal memory disorders, characterized by a low free recall performance with normalization (or a quasi-normalization) of the performance in total recall because of good efficacy of cueing.28 This subcortical-frontal profile of

memory impairment can be observed in depression,29 vascular dementia,30 and subcortical dementia.28

The identification of an amnestic syndrome of the medial temporal type by the FCSRT can successfully differentiate patients with AD from healthy controls, even when the disease is in an initial stage. Moreover, the FCSRT, by isolating an amnestic syndrome of the hippocampal type in subjects with mild cognitive impairment (MCI), is able to distinguish patients at an early stage of AD from those with “nonconverter” MCI with a high sensitivity (80%) and specificity (90%).31 Perform- ance of the FCSRT has been well correlated with the left medial temporal lobe volume assessed both by voxel based morphom- etry analysis and automatic volumetric method in a series of AD patients.32 These findings support considering the measure of episodic memory by the FCSRT as a useful clinical marker of medial temporal damage.

A multicenter German study comprising 185 MCI patients investigated whether the performance of the FCSRT predicts Alzheimer’s pathology.33 In this study, three different memory tests (the FCSRT, the Word List Learning Task from the Consor- tium to Establish a Registry for AD, and the Logical Memory Paragraph Recall Test from the Wechsler Memory Scale— Revised) were compared for their ability to predict a cerebro- spinal fluid (CSF) biomarker profile indicative of AD, defined by Aβ42/tau ratio.34 Their results showed that among the three memory tests, the cued recall deficits identified by the FCSRT were by far more predictive of a CSF biomarker profile indica- tive of AD pathophysiology. It should be noted, however, that the amnestic syndrome of hippocampal type may also be observed in other conditions, such as hippocampal sclerosis or behavioral variant frontotemporal dementia.35

11.3.2 Other Cognitive Deficits

Besides episodic memory deficits, temporal-spatial dis- orientation (disorientation in nonfamiliar places and difficulty in establishing a chronological order to recent events) is also present at the initial stages of AD. Patients often show difficulty orienting themselves in familiar places during intermediate stages and progress to severe disorientation in their personal residence as the disease progresses.

The progression of cognitive deficits follows extension of the underlying pathological lesions (more specifically of tau pathol- ogy) through the neocortical associative areas. Patients may develop language disorders, visuospatial and recognition defi- cits, and difficulties in executing the more complex tasks of daily living, leading to loss of autonomy and dementia.17 Patients progress from loss of higher-level activities of daily liv- ing, such as financial transactions and the use of public trans- portation, to abnormalities in the more basic activities of daily living. At severe stages of the disease, patients require contin- ued assistance for basic activities of daily living.

Aphasia may appear as the condition progresses, character- ized by decreased verbal comprehension and naming difficulty. As AD advances, all aspects of language (oral production, com- prehension, reading, and writing), can be impaired, resulting in mutism or incomprehensible language in severe cases. Gestural apraxia refers to an inability to perform learned skilled move- ments, which cannot be attributed to an alteration of judgment or to sensitive motor deficits. It is usually measured by asking

the patient to perform pantomimes of tool uses (e.g., asking the patient to imitate how to use a hammer) or symbolic gestures (asking the patient to perform a military salute) or to imitate meaningless gestures. Difficulty using objects, as well as dress- ing apraxia, is observed during moderate to severe AD.36 Patients with AD commonly show visuospatial dysfunction in the moderate stages of AD. Deficits arise first during complex tasks, which require perceptual analysis and spatial planning. Impairment in constructional ability can be easily tested by drawing and copying tasks. In typical AD, a visuoconstructive deficit predicts the development of severe dependency.37 Visual agnosia and complex visual processing dysfunction are observed in advanced stages of the disease. Patients may show impaired recognition of objects or faces.

11.3.3 Severity of the Disease

Different stages of severity are described in AD, from mild to moderate and severe (dementia) stages. According to the recently proposed AD criteria,38 the terms prodromal AD or MCI due to AD refer to early stage of the disease, which precedes the appearance of dementia.39,40 In the prodromal or MCI stage, the patient can live alone. In mild stages of AD, patients require lim- ited home care. In moderate stages, patients need supervision and regular assistance in most activities. In severe stages, resi- dential health care may be required.

The Mini-Mental State Examination (MMSE) assesses global cognitive efficiency and is generally used to evaluate dementia severity. Although the MMSE is not a specific neuro- psychological test for AD diagnosis, it is easy and quick to administer and can track the overall progression of cognitive decline. Longitudinal studies have shown that the mean annual rate of progression of cognitive impairment using MMSE is approximately 2 to 6 points. The Clinical Dementia Rating Scale, based on an overall evaluation of the patient’s condition, offers incremental stages of severity.41 Functional decline increases with disease progression.

11.3.4 Atypical Clinical Presentation

Neuropathological studies have long recognized that AD can manifest as atypical or variant syndromes without predomi- nant amnestic features.42,43,44,45 The most common variant AD phenotypes are posterior cortical atrophy (PCA), logopenic-var- iant primary progressive aphasia (lgPPA), and frontal variant AD. The new criteria for AD grouped these focal variants into atypical AD. Atypical AD is more frequent in early onset of AD.

In PCA, visuospatial deficit is the initial symptom, and then patients develop features of Bálint syndrome (ocular apraxia, optic ataxia, and simultanagnosia), Gerstmann syndrome (acal- culia, agraphia, finger agnosia, and left-right disorientation), visual agnosia, and transcortical sensory aphasia, whereas epi- sodic memory is preserved or only mildly impaired.46 Magnetic resonance imaging (MRI) and functional imaging have shown parieto-occipital localization of atrophy and hypometabolism.47

In lgPPA, language deficit is the initial symptom, character- ized by frequent pauses that disrupt the flow of conversation and the generation of phonologic errors, associated with deficit in sentence repetition. In contrast with other forms of PPA, in lgPPA, patients lack motor speech disorders or show agram-

Overview of Alzheimer’s Disease

matism as in nonfluent PPA and have less severe semantic impairments than do those with semantic variant PPA.48 Neuro- imaging showed asymmetric involvement of the temporoparie- tal junction, which is more severe in the dominant hemisphere.

The frontal variant of AD is defined by a predominant dysex- ecutive syndrome, which is frequently associated with frontal behavioral symptoms. These clinical features can lead to mis- diagnosis of frontotemporal dementia.49

11.3.5 Neuropsychiatric Features

Behavioral and neuropsychiatric symptoms associated with AD include depressive mood, apathy, agitation, and aggressivity, as well as psychotic symptoms, such as delusions and hallucina- tions.50 These manifestations tend to fluctuate over time, resulting in individual differences. The prevalence of psychosis and behavioral disturbance increases as the disease progresses and may indicate a poor prognosis.37,51

The most frequent behavioral disorder in AD is apathy, which has been found in 25 to 75% of cases.50,52 The prevalence of apa- thy also increases with the severity of dementia. It is notewor- thy that apathy should not be confounded with depression, and apathy may be present without concomitant depression.

Delusions are observed more often than hallucinations, and their frequency is estimated at 20 to 70%.52 Paranoid delusions are probably the most common type, but misidentification phe- nomena and Capgras delusion may also be observed. Hallucina- tions, commonly visual, are rare in the early stages, but they become more prevalent as the disease progresses.52 Symptoms of psychosis or agitation are associated with distress for the patient, an increased burden on caregivers, more rapid cognitive decline, and an increased likelihood of institutionalization.53

11.4 Alzheimer’s Disease Diagnosis

Until recently, the diagnosis of AD has been based on the National Institute of Neurological and Communicative Disor- ders and Stroke (NINCDS)—Alzheimer’s Disease and Related Disorders Association (ADRDA) criteria, which referred to a clin- ical dementia entity that typically manifests with a characteris- tic progressive amnestic disorder with subsequent appearance of other cognitive and neuropsychiatric changes that impair social function and activities of daily living.54 In the NINCDS– ADRDA criteria, biological investigation (blood and CSF) and neuroimaging examination (computed tomography scan or MRI) were proposed to exclude other causes of the dementia syndrome (vascular lesions, tumor, infectious or inflammatory processes).

Advances in establishing the biomarkers of AD, which pro- vide in vivo information about the pathophysiologic process associated with AD, have stimulated the proposal of new diag- nostic criteria.38,39,55,56 According to these frameworks, the diagnosis of AD is based on core clinical criteria, with the sup- port of biomarkers based on imaging and CSF measures. This combined clinical and biological approach may improve accu- racy of the diagnosis. These new diagnostic frameworks permit an earlier diagnosis of AD, before the development of dementia. Following this new perspective of a clinical-biological diagnosis approach, a consideration of preclinical stages of AD was pro- posed, according to which the pathophysiological process of the

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disease precedes the clinical manifestations.57 Whatever the stage of the disease, the new AD criteria integrated in the clini- cal approach the use of biomarkers, such as neuroimaging and biological tools.

11.4.1 Structural Brain Imaging

Brain MRI has an important role in the investigation of patients with suspected AD, that is, to detect the treatable causes of cog- nitive dysfunction, such as normal pressure hydrocephalus and subdural hematoma. Moreover, it has also been increasingly recognized that brain MRI is important in identifying the spe- cific patterns of anatomic damage associated with AD.

Atrophy of medial temporal regions, mainly the entorhinal cortex and hippocampus, is observed in early AD. There is a progression of hippocampal atrophy in AD through its different stages: hippocampal volumes of AD patients are 10 to 12% smaller than those of age-matched controls in early (prodro- mal) stages, 15 to 30% reduced in mild stages, and 30 to 40% smaller in moderate stages of the disease.58 Measurement of medial temporal lobe atrophy can distinguish AD from age- matched controls with an overall accuracy greater than 85%.59 Similarly, hippocampal measures provide sensitivity and speci- ficity of approximately 75 to 80% to predict conversion to AD in patients with MCI.58,59,60 Qualitative visual scales or volumetric measurements with specific software can be used to assess hip- pocampal atrophy.61,62 Whereas quantitative methods are restricted mainly to research centers, visual rating scales, which assess medial temporal atrophy on coronal T1-weighted MRI, are of value in clinical settings.63

In summary, hippocampal volume and medial temporal atro- phy by volumetric measures or visual rating are the best vali- dated markers of early AD. Accordingly, in the new AD criteria, loss of hippocampal volume is considered a marker of neuronal injury indirectly caused by the tau pathology.

It should be emphasized, however, that medial temporal atro- phy is not specific for AD and may be observed in other clinical situations, such as frontotemporal dementia and even depression and normal aging.58,64 On the other hand, the rate of hippocam- pal atrophy may be a better indicator of AD pathology, as the progression of hippocampal loss is approximately two to four times faster in AD patients than in healthy controls.65,66

11.4.2 Cerebrospinal Fluid Biomarkers

Biomarkers can be defined as “an objective measure of a biolog- ical or pathogenic process that can be used to evaluate disease risk or prognosis, to guide clinical diagnosis or to monitor ther- apeutic interventions.”67 In the context of AD, the development of biomarkers, especially the CSF biomarkers, opened the possi- bility of identifying in vivo a specific underlying patho- physiologic mechanism and thus leading to a redefinition of clinical diagnosis of the disease.68

The main biomarkers used in diagnosis of AD are β-amyloid peptide (Aβ42), total tau, and the isoforms of phosphorylated tau (P-tau181 and P-tau231). A series of clinicopathological studies demonstrated that these biomarkers reflect the core pathological hallmarks of AD, with CSF levels of Aβ42 reflecting the extracellular deposits of Aβ peptide and CSF levels of tau and P-tau being correlated with the amount neurofibrillary

tangles.69,70,71 CSF biomarkers may thus be considered surro- gate markers of the pathophysiologic process of AD.67

Patients with AD typically exhibit a decrease in CSF Aβ42 and an increase in CSF tau and P-tau compared with healthy con- trols.67,72,73 Each of these biomarkers differentiates AD patients from age-matched controls with 80 to 90% sensitivity and spec- ificity, but accuracy is increased by using the combined analysis of two or more of the three main AD CSF markers (total tau, P-tau, and Aβ42).

The CSF markers can also identify with high accuracy an AD pathophysiology among patients with MCI,67,74 which may be referred to as prodromal AD39 or as MCI due to AD.40 The CSF biomarkers have also been increasingly used in the differential diagnosis between AD and other dementias.75,76,77,78 The com- bined analysis of CSF biomarkers can differentiate AD from behavioral or semantic manifestations of frontotemporal lobe degenerations with high accuracy and may also identify an AD underlying mechanism in patients with atypical presentations, such as lgPPA or PCA.77,79

11.4.3 Single-Photon Emission Computed Tomography and Fluorodeoxyglucose-Positron Emission Tomography Imaging

Functional neuroimaging techniques include the measure of blood f low (technetium 99m [99mTc]-hexamethylpropylene- amine [HMPAO] or 133Xe) with single-photon emission CT (SPECT) and positron emission tomography (PET) with fluoro- deoxyglucose ([18F]-FDG). In AD, abnormalities in SPECT or [18F]-FDG-PET reflect general damage to neurons and synapses, mainly resulting from tau pathology.

The 99mTc-HMPAO SPECT is a useful neuroimaging technique for distinguishing AD from frontotemporal dementia, but a sys- tematic review reported a clinical accuracy for patients with AD versus controls of only 74%.80 On the other hand, in a group with amnestic MCI, an automated quantitative tool for brain perfusion SPECT images using the mean activity in right and left parietal cortex and hippocampus was able to distinguish patients at an early stage of AD from patients with stable MCI (sensitivity, specificity, and accuracy of 82, 90, and 89%, respectively).81

Positron emission tomography with measures of glucose metabolism has shown good accuracy in distinguishing AD patients from both normal controls and patients with non-AD dementias. A reduction in glucose metabolism in bilateral tem- poroparietal regions and in the posterior cingulate cortex is the most common finding in AD.38,40,82 However, one study showed that within different imaging markers, the largest variability of likelihood ratio for AD diagnosis was of [18F]-FDG-PET.83

Amyloid Imaging

The development of amyloid markers in molecular neuro- imaging enabled the in vivo assessment of amyloid load, a key feature in the pathophysiology of AD. The most extensively studied amyloid marker is the carbon-11-labeled Pittsburgh compound B (11C-PiB), for which a high level of correlation has been demonstrated between in vivo 11C-PIB uptake and post- mortem measures of insoluble (fibrillar) Aβ peptide deposits and plaque load.84

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Overview of Alzheimer’s Disease

A multitude of studies during the last decade showed that AD patients typically have 50 to 90% greater 11C-PIB cortical reten- tion than age-matched controls and thus discriminate AD from aged-matched controls with 80 to 100% sensitivity.85 The speci- ficity varies according to the age of the population. For instance, a high cortical 11C-PIB retention may be observed in less than 10% of asymptomatic subjects younger than 70 years but is found in up to 40% of asymptomatic subjects at the age of 80 years.86,87 A high 11C-PIB cortical uptake may also be found in cerebral amyloid angiopathy and in dementia with Lewy bod- ies.86,87Amyloid imaging by PIB-PET can also identify AD pathol- ogy in atypical clinical presentation without initial amnesia, such as PCA and lgPPA.7,88

Molecular amyloid imaging is restricted mainly to research centers, but progress in the field will likely increase the availa- bility of amyloid markers for clinical practice in the following years, especially in light of new amyloid markers that have been studied, such as 18F-florbetapir (18FAV-45) and florbetaben (18F- BAY94–9172).89

11.5 Conclusion

New proposals for the diagnosis of AD have incorporated bio- logical markers for identifying an underlying pathophysiologi- cal process. This approach allows establishment of a clinical diagnosis of AD before the dementia stage, in contrast to previ- ous diagnostic criteria published in 1984.54 According to these new frameworks, diagnosis of the disease is possible at an early stage, when the cognitive symptoms are still mild and the autonomy is preserved.

The core clinical criteria remain the main landmark of the diagnosis of AD in clinical practice, but evidence provided by biomarkers such as neuroimaging, CSF markers, and amyloid imaging is expected to increase the specificity of the diagnosis. A recent meta-analysis showed that diagnostic accuracy of imaging AD biomarkers is at least as dependent on how the bio- marker is measured as on the biomarker itself.83 Extensive work on biomarker standardization is needed before widespread adoption of these recommendations at any stage of the disease. Despite these limitations, biomarkers to improve the accuracy of the clinical diagnosis will be an essential requisite for new disease-modifying treatments that will tap into specific patho- physiologic targets.

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tive. Is radiological evaluation as good as computer-based volumetry to assess hippocampal atrophy in Alzheimer’s disease? Neuroradiology 2012; 54: 1321–1330

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[85] Noble JM, Scarmeas N. Application of pet imaging to diagnosis of Alzheimer’s disease and mild cognitive impairment. Int Rev Neurobiol 2009; 84: 133–149 [86] Herholz K, Ebmeier K. Clinical amyloid imaging in Alzheimer’s disease. Lancet

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Genetics, Neuropathology, and Biomarkers in Alzheimer’s Disease 12 Genetics, Neuropathology, and Biomarkers in

Alzheimer’s Disease Maria Martinez-Lage Alvarez and Rashmi Tondon

Alzheimer’s disease (AD) is an adult-onset, slowly progressive neurodegenerative disorder that initially affects memory and later involves other cognitive and basic neurologic functions. AD is the most common form of dementia, particularly in eld- erly adults. It is estimated that 5.2 million Americans have AD in 2014, including approximately 200,000 individuals younger than age 65.1 The pathological hallmarks of the disease found in the brain are extracellular senile plaques, composed of β- amyloid (Aβ), and intracellular neurofibrillary tangles (NFTs), composed of phosphorylated tau protein, which can also be seen in the form of neuropil threads and neurites. AD can be clinically considered as either late or early onset, depending on whether it manifests before or after age 65 years. This chapter describes the genetic aspects, neuropathological findings, and nonimaging biomarkers of AD.

12.1 Genetics of Alzheimer’s Disease

12.1.1 Late-Onset Alzheimer’s Disease

More than 95% of patients with AD have onset after the age of 65, and it is well established that the risk of developing the disease increases exponentially with age: 11% of the population age 65 years and older suffer from AD, and the prevalence is 32% for those age 85 years and older.1 The causes of AD in this sporadic (as opposed to inherited) population is undoubtedly multifactorial, likely resulting from factors like cerebrovascular disease, type 2 diabetes, or obesity. Certain genetic susceptibil- ity loci have been known for more than two decades, whereas numerous new candidates for genetic risk factors have been discovered in more recent years thanks to improved technology and increased access to genomic studies of well-selected samples.

12.1.2 Apolipoprotein E

The association of the apolipoprotein E (ApoE) ε4 allele with late-onset AD in non-Hispanic whites of European ancestry has been well known for more than a decade. ApoE is a plasma pro- tein involved in the transport of cholesterol that exists as three isoforms determined by three alleles (ε2, ε3, and ε4). A single ApoE ε4 allele conveys a twofold to threefold increase in risk of developing AD, whereas having two copies is associated with a fivefold increase, demonstrating an additive risk association.2 The ε2 allele is considered protective, also in an additive manner, so that a homozygous ε2/ε2 genotype confers a lower risk than just one ε2 allele. Not only a higher risk of developing the disease, but also an earlier age of onset, has been associated with the ε4 allele; however, the presence of ε4 is neither suffi- cient nor necessary to develop AD.

Sortilin-Related Receptor

Encoding a protein that participates in vesicle trafficking between the cell surface and Golgi apparatus, the sortilin- related receptor (SORL1) gene was chosen as a potential candi- date for AD susceptibility in an association study.3 Despite initial contradicting results from replication cohorts, sufficient evidence now supports the association of specific variants in this gene with a higher risk of developing AD, at least in the white population.4

Additional Genes Discovered in Genome-Wide Association Studies

With the advance of genome-wide technologies, it has been possible to move away from candidate gene approaches and toward unbiased assessments of the whole genome, eliminating the need to preselect candidates and opening the possibilities of detecting either novel genes or pathways not suspected to participate in a particular disorder. The effort has been tremen- dous in AD in the last several years, with collaborative studies analyzing more than 10,000 patients and more than 10,000 controls.2 Several genes have been identified with this method and replicated in diverse cohorts, making it worthwhile to mention them here. Of note, none of these other genes is simi- lar in effect to ApoE, which still remains the major genetic risk factor for late-onset AD. The most salient genes identified in these studies are listed in ▶ Table 12.1, along with their relative odds ratio values.2 Of note, these genes and their related encoded proteins can be clustered in a few functional and metabolic pathways, including lipid metabolism, innate and adaptive immunity, cell adhesion, and endocytosis, all of which are likely involved in the development of the neuropathologic substrates of AD.

12.1.3 Early-Onset Alzheimer’s Disease

The identification of families with autosomal dominant inheri- tance patterns contributed to the discovery in the late 1980s and early 1990s of three genes responsible for most early-onset AD (approximately 1% of all cases of AD). Amyloid precursor protein (APP) and presenilins 1 and 2 (PSEN1 and PSEN2 ) are involved in the processing of the Aβ molecule.5 Most mutations in these genes are autosomal dominant, albeit not always fully penetrant. These are considered causative genes because indi- viduals carrying mutations will inevitably develop the disease (except with incomplete penetrance), and detection of the mutation in an individual is diagnostic of AD.

Amyloid Precursor Protein

Located on chromosome 21q21.3, APP encodes for the amyloid precursor protein, a 110- to 130-kDa ubiquitously expressed

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Table 12.1 Molecular genetic classification of Alzheimer’s disease

Gene symbol Gene name Chromosomal Key information location

Definitive disease-causing genes (causative mutations of early onset AD)

APP

Amyloid precursor protein

21q21.3

Autosomal dominant, 25 pathogenic mutations, 16% of early-onset AD

PSEN1

Presenilin-1

14q24

Autosomal dominant, 185 pathogenic mutations, 66% of early-onset AD

PSEN2

Presenilin-2

1q31

Autosomal dominant,12 pathogenic mutations

Genes with increased susceptibility (risk variants for late-onset AD)

ApoE

Apolipoprotein E

19q13.32

ε2q13.32rot–15 ε5q13.32rotein –3

SORL1

Sortilin-related receptor

11q24.1

OR 1.08

ABCA7

Adenosing triphosphate-binding cassette, subfamily A, member 7

19p13.3

OR 1.2

BIN1

Bridging integrator 1

2q14.3

OR 1.2

CD33 (SIGLEC6)

CD33 antigen/sialic-acid binding immunoglobulin-like lectin 6

19q13.41

OR 0.9

CD2AP

CD2-associated protein

6p12.3

OR 1.1

CLU

Clusterin

8p21.1

OR 0.8

CR1

Complement component receptor 1

1q32.2

OR 1.2

EPHA1

Ephrin receptor EphA1

7q34-q35

OR 0.9

MS4A4E/MS4A6A

Membrane-spanning 4-domains, subfamily A, members 6E, 4A

11q12.2

OR 0.9

PICALM

Phosphatidylinositol-binding clathrin assembly protein

11q14.2

OR 0.8

Abbreviations: OR, odds ratio (note that an OR > 1 implies higher relative risk of disease, whereas an OR < 1 implies lower relative risk for the disease; the greater the number, the largest the size effect for that genotype).
Source: OMIM (http://omim.org/entry/104300), Schellenberg GD, Montine TJ. The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathologica 2012;124(3):305–323.

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transmembrane protein that contains an internal 39–43 amino acid sequence coding for Aβ peptides. Cleavage by β- and γ-secretases results in the formation of peptides Aβ1-40 and Aβ1-42, the major component of the hallmark senile plaques of AD.6 Up to 25 point mutations have been identified as pathogenic to date7 (see http://www.molgen.vib-ua.be/ADMu- tations). All point mutations are clustered in a 54 amino acid segment that lies within or adjacent to the sequence encoding for Aβ peptides.2 In addition to being responsible for approxi- mately 16% of cases of early-onset AD,8 mutations in the APP gene can cause autosomal dominant cerebral amyloid angiop- athy and syndromes in which the two overlap. The London mutation (V717I) is the most common APP mutation and results in increased levels of Aβ1–42 by interfering with the activity of γ-secretase. The Swedish mutation involves two different codons (K670M and N671K) and increases total levels of Aβ production. The excess of Aβ is therefore considered sufficient to cause the disease, and this has been largely supported by the observation of a high prevalence of AD neuropathological changes and increased incidence of dementia in patients with trisomy 21 (Down syndrome), who carry an extra copy of the APP gene.2 Furthermore, several gene duplication events not associated with trisomy have been recognized as pathogenic events in AD.7 Lastly, the Arctic mutation, E693G, rather than altering the total amount of Aβ or interfering with γ-secretase activity, creates a mutant peptide that is more prone to aggre- gation than is wild-type Aβ.9

Presenilins 1 and 2

Mutations in presenilin 1 (PSEN1), located in chromosome 14q24.3, are responsible for the highest percentage of auto- somal dominant early-onset AD, accounting for up to 66% of all cases.8 At least 185 pathogenic mutations have been identified to date7 (see http://www.molgen.vib-ua.be/AD mutations), all with complete penetrance by age 60 to 65 years. As is the case for APP, there is significant heterogeneity in the phenotypic characteristics of individuals with mutations in PSEN1 in terms of age of onset (as early as the late 20s), rate of progression, and severity of the disease.10 PSEN1 is the catalytic component of γ-secretase, a protein complex responsible for the cleavage of a number of membrane proteins, including APP. Normal γ-secretase activity yields mainly Aβ1–40, with smaller amounts of Aβ1–42. PSEN1 mutations alter the secretase activity,11 leading to increased ratio of Aβ1–42 to Aβ1–40, thus facilitating the depo- sition of amyloidogenic species. Presenilin 2 (PSEN2) is a highly homologous protein located in 1q31-q42, which also partici- pates in the γ-secretase complex as the catalytic domain in the absence of PSEN1. PSEN2 mutations are less common than PSEN1 variants, with only 13 pathogenic mutations known to date.7 Compared with those with PSEN1, patients with PSEN2 mutations tend to have a higher age of onset (accounting for the small number of late-onset AD cases caused by an inherited causative mutation), longer course of the disease, and more var- iable penetrance.2

Genetics, Neuropathology, and Biomarkers in Alzheimer’s Disease

12.2 Neuropathology of

Alzheimer’s Disease

The hallmark pathological features of AD include the accumula- tion of the protein fragment Aβ in extracellular “senile” plaques and other deposit and the intracellular buildup of phosphoryl- ated protein tau in the form of NFTs and neuritic threads. Other changes that are characteristic of AD include cerebral amyloid angiopathy (CAA) caused by deposition of Aβ in and around vessels, loss of synapses, neuron loss, glial activation, and ulti- mately brain atrophy. ▶Fig. 12.1 illustrates these pathological features of AD.

Amyloid precursor protein, the product of the APP gene, can be processed in two divergent pathways. When the full- length protein is cleaved by α- and γ-secretases, it results in a C-terminal fragment that is nonamyloidogenic. Conversely, when cleaved via the β- and γ-secretases, several species of Aβ fragments can occur, with Aβ1–40 the most common and Aβ1–42 being prone to aggregation (amyloidogenic). Aβ1–42 molecules form toxic oligomers, which then aggregate as extracellular insoluble fibrils with β-pleated sheet conformation, giving rise to the typical amyloid senile plaques. Aβ deposits are morpho- logically variable, ranging from the so-called neuritic plaques in which they are at the center of a cluster of tau-positive dys- trophic neurites, to diffuse (non-neuritic) plaques and diffuse

deposits known as amyloid lakes. The “amyloid cascade hypoth- esis” suggests that the accumulation of Aβ fibrils in plaques is the primary pathological event in the disease and that it leads to the formation of the other pathological features, such as NFTs, synaptic loss, neuronal degeneration, and death.12

Tau protein is associated with microtubules and is thought to participate in regulating their stability in neuronal axons. For reasons not entirely understood, tau protein becomes aber- rantly hyperphosphorylated, dissociates from microtubules, and aggregates into paired helical filaments, insoluble fibrils that then are deposited as the characteristic NFTs and neuropil threads with β-pleated sheet conformation. Studies have dem- onstrated that in at least some individuals, tau pathology appears well before β-amyloid deposits are seen, which cannot be explained in the light of the amyloid cascade hypothesis and suggests that tau pathology can be an initiating event in the disease.

The progression of AD pathology, including amyloid plaques and NFTs, follows a specific spatial and anatomical pattern, starting in the limbic cortex (entorhinal cortex and hippocam- pus) and extending toward the neocortical surface, some sub- cortical nuclei, and in some cases the brainstem. With respect to NFTs, the staging system described by Braak and Braak13 is still recommended because it reflects this pattern of progres- sion with robust reliability. It proposes six stages, but there is

Fig. 12.1 Histopathological hallmarks of Alzheimer’s disease (AD). Photomicrographs of immunohistochemical stains demonstrate the typical findings of AD and comorbid pathologies. β-amyloid immunohistochemistry highlights abundant senile plaques in the hippocampus
(a, 500x) and frontal cortex c, 100x) in this case of advanced AD. Phosphorylated tau immuno- histochemistry demonstrates neurofibrillary tangles as well as neuropil threads and neurites in the hippocampus (b, 500x; d, 200x) in the same case. Note that phosphorylated tau also labels a number of neuritic senile plaques as there are tau-positive neurites in the center of these amyloid plaques. Coexisting pathology was present in this case, as is commonly seen in AD. Lewy bodies and Lewy neurites are seen with α-synuclein immunostaining in the amygdala
(e, 200x); whereas an antibody for phosphory- lated TDP-43 also demonstrates inclusions in the same region (e, 200x).

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increased inter-rater agreement when reduced to four stages14: (1) no NFT; (2) in Braak stages I/II, NFTs are predominantly in the entorhinal cortex and closely related areas; (3) in Braak stages III/IV, NFTs are more abundant in the hippocampus and amygdala and there is slight involvement of association cortex; (4) in Braak stages V/VI, NFTs are widely distributed throughout the neocortical areas, with eventual involvement of the primary motor and sensory areas.

In addition, many but not all cases of AD will demonstrate additional coexisting non-AD-type pathology in the brain, such as Lewy body disease (LBD), vascular brain injury, hippocampal sclerosis, and TDP-43 pathology.14 Lewy bodies, composed largely of α-synuclein and characteristic of Parkinson’s disease and LBD, are commonly seen in brains with moderate to severe AD changes, not only in sporadic cases but also in some patients with PSEN1 and PSEN2 mutations.15 Cerebrovascular disease and vascular brain injury, together with CAA, are commonly identified in brains with AD changes and should be acknowl- edged. TDP-43 is the major protein present in the pathological inclusions of frontotemporal lobar degeneration not caused by tau pathology and in amyotrophic lateral sclerosis,16 and it is increasingly recognized as present in the limbic structures of brains with AD pathology, with or without coexisting hippo- campal sclerosis.

Currently, a definitive diagnosis of AD still relies on postmor- tem examination of the brain to detect the typical senile pla- ques and NFTs, which are known to correlate with the presence of clinical symptoms of AD. The guidelines for neuropathologic evaluation and assessment of AD were reviewed in a seminal consensus paper from the National Institute on Aging and the Alzheimer’s Association in 2012, 25 years after the prior con- sensus.14 The main change to the diagnostic criteria was the recognition of AD as a dynamic entity, with a prodromal asymptomatic phase during which pathology has started to accumulate but has not caused major symptoms, thus allowing for the diagnosis of AD neuropathologic changes in the absence of a clinical history of dementia and bringing to the neuro- pathology arena the concept of early and preclinical AD. The guidelines recommend documentation of the AD pathologic features as stated herein, as well as documentation of the comorbidities in the autopsy report, including LBD, vascular pathology, and TDP-43 pathology. The “ABC” staging protocol is recommended, based on the data-driven documentation of the relative amounts of each of the three morphologic characteris- tics of AD: A, Aβ/amyloid plaque score (based on Thal phases17: A0 to A3); B, NFT score (based on Braak stage13: B0, B1=I/II, B2 = III/IV, B3 = V/VI); and C, neuritic plaque score (based on Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] criteria18: C0 to C3). The combination of A, B, and C scores provides, for each case, a descriptor of “not,” “low,” “intermediate,” and “high” for AD neuropathologic change (entirely independent of clinical symptoms).14

At autopsy, patients with disease-causing mutations (APP, PSEN1, and PSEN2 ) tend to have greater amounts of neocortical senile plaques than patients who had “sporadic” AD, with no dif- ference in the amounts of tau pathology. Some mutations in these genes also result in differences in the morphology of the amyloid pathology compared with sporadic cases, such as large dense pla- ques in the APP Flemish mutation,19 ringlike plaques in the APP Arctic mutation,20 and cotton-wool plaques in PSEN1 mutations.2

12.3 Nonimaging Biomarkers in the

Diagnosis of Alzheimer’s Disease

Revised clinical criteria and guidelines for diagnosing AD were proposed and published in 201121 and recommended the con- sideration of AD as a slowly progressive disease that begins well before clinical symptoms emerge. In addition to imaging bio- markers largely discussed elsewhere, enormous efforts have been dedicated in the last two decades to the discovery of other biological biomarkers for the diagnosis of AD. As discussed earlier, a definitive diagnosis has classically been considered attainable only postmortem with the examination of the affected brain. This, however, is insufficient when we take into account the need to establish a degree of certainty both at the research level (e.g., to identify and monitor possible disease- modifying agents), as well as at the clinical level when approaching an individual patient.

12.3.1 Plasma

Plasma biomarker discovery started off with the idea of detect- ing β-amyloid in plasma. With the hypothesis that there is always an equilibrium state of Aβ production and deposition in the brain and that there is correlation with plasma levels, stud- ies were able to determine that there is an increase in plasma levels of Aβ, at least in patients with familial AD.22 Plasma level results in the general population in sporadic AD are, however, controversial and limited by complicated technological and methods problems with this test.

12.3.2 Cerebrospinal Fluid

Cerebrospinal fluid (CSF) has the potential to reflect reliably the state of chemical and cellular homeostasis in the brain, given its direct contact with the cerebral extracellular space. As such, CSF biomarkers have been incorporated into the revised research diagnostic criteria for AD since 2007,23 although they are still not largely available in community clinical practice. Levels of Aβ1–42, total tau, and phospho-tau can be used to aid in the diagnosis of AD.24 The increase in the total concentrations of tau in CSF is directly related to axonal degeneration in the cortex, whereas levels of phospho-tau are associated with NFTs. In this setting, total tau levels can increase in any process that involves cortical degeneration, such as stroke, trauma, and other neurodegenerative diseases,25 but phospho-tau is a more precise measurement associated with the underlying pathology of AD. In addition to confirmation of diagnosis in patients mani- festing full-blown symptoms, the importance of CSF AD bio- markers lies in their ability to contribute to early diagnosis, identify patients in prodromal phases (including mild cognitive impairment) that will go on to develop the disease, and select and monitor subjects for clinical trials. Because of analytical issues with the technology used (enzyme-linked immuno- sorbent assay and other immunoassay methods) across institu- tions and geographic locations, definite standardization is under way to establish homogeneity of results and improve the yield and quality of data obtained from these assays.25 Of note, CSF biomarkers are to be used in conjunction with clinical, genetic, and neuroimaging data to provide the most accurate diagnostic information.

References

. [1] Alzheimer’s Association. 2014 Alzheimer’s disease facts and figures. Alzheimers Dement 2014; 10: e47–92

. [2] Schellenberg GD, Montine TJ. The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathol 2012; 124: 305–323

. [3] Rogaeva E, Meng Y, Lee JH et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer’s disease. Nat Genet 2007; 39: 168–177

. [4] Reitz C, Cheng R, Rogaeva E et al. Genetic and Environmental Risk in Alzheimer Disease 1 Consortium. Meta-analysis of the association between variants in SORL1 and Alzheimer’s disease. Arch Neurol 2011; 68: 99–106

. [5] Reitz C, Mayeux R. Alzheimer’s disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 2014; 88: 640–651

. [6] O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 2011; 34: 185–204

. [7] Cruts M, Theuns J, Van Broeckhoven C. Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat 2012; 33: 1340–1344

. [8] Raux G, Guyant-Maréchal L, Martin C et al. Molecular diagnosis of autosomal dominant early onset Alzheimer’s disease: an update. J Med Genet 2005; 42: 793–795

. [9] Nilsberth C, Westlind-Danielsson A, Eckman CB et al. The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci 2001; 4: 887–893

. [10] Ridge PG, Ebbert MT, Kauwe JS. Genetics of Alzheimer’s disease. Biomed Res Int 2013; 2013: 254954

. [11] Chau D-M, Crump CJ, Villa JC, Scheinberg DA, Li Y-M. Familial Alzheimer’s dis- ease presenilin-1 mutations alter the active site conformation of γ-secretase. J Biol Chem 2012; 287: 17288–17296

. [12] Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297: 353–356

. [13] Braak H, Braak E. Neuropathological staging of Alzheimer-related changes.
Acta Neuropathol 1991; 82: 239–259

. [14] Hyman BT, Phelps CH, Beach TG et al. National Institute on Aging-Alzheimer’s
Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 2012; 8: 1–13

. [15] Leverenz JB, Fishel MA, Peskind ER et al. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol 2006; 63: 370–376

. [16] Neumann M, Sampathu DM, Kwong LK et al. Ubiquitinated TDP-43 in fronto- temporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006; 314: 130–133

. [17] Thal DR, Rüb U, Orantes M, Braak H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 2002; 58: 1791–1800

. [18] Mirra SS, Heyman A, McKeel D et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuro- pathologic assessment of Alzheimer’s disease. Neurology 1991; 41: 479–486

. [19] Kumar-Singh S, Cras P, Wang R et al. Dense-core senile plaques in the Flemish variant of Alzheimer’s disease are vasocentric. Am J Pathol 2002; 161: 507–520

. [20] Basun H, Bogdanovic N, Ingelsson M et al. Clinical and neuropathological fea- tures of the arctic APP gene mutation causing early-onset alzheimer disease. Arch Neurol 2008; 65: 499–505

. [21] McKhann GM, Knopman DS, Chertkow H et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alz- heimer’s disease. Alzheimers Dement 2011; 7: 263–269

. [22] Scheuner D, Eckman C, Jensen M et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996; 2: 864–870

. [23] Dubois B, Feldman HH, Jacova C et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007; 6: 734–746

. [24] Hansson O, Zetterberg H, Buchhave P et al. Prediction of Alzheimer’s disease using the CSF Abeta42/Abeta40 ratio in patients with mild cognitive impair- ment. Dement Geriatr Cogn Disord 2007; 23: 316–320

. [25] Kang JH, Korecka M, Toledo JB, Trojanowski JQ, Shaw LM. Clinical utility and analytical challenges in measurement of cerebrospinal fluid amyloid-β (1–42) and τ proteins as Alzheimer’s disease biomarkers. Clin Chem 2013; 59: 903–916

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13 Imaging of Alzheimer’s Disease: Part 1

Donald G. McLaren, Guofan Xu, and Vivek Prabhakaran

Alzheimer’s disease (AD), the most common dementia, is a pro- gressive, devastating, nonreversible, and ultimately fatal neuro- degenerative disorder that leads to loss of memory and of the ability to function independently.1 It is expected that by 2050 more than 16 million Americans and 135 million people world- wide will suffer from AD. These numbers, coupled with the fact that current treatments only slow the clinical progression of AD, necessitate the utilization and improvement of bio- markers for understanding the disease processes, improving the diagnostic accuracy, and improving treatment outcomes. Although the spatial progression of AD pathology has been understood for a number of years,2,3 the development of bio- markers to measure the spatial progression has only partially mirrored the histologic work. In 2011, the National Institute on Aging/Alzheimer’s Association Workgroup released revised criteria for the diagnosis of AD,4 which called for research on the use of abnormal levels of biomarkers in future diagnostic criteria. The workgroup concluded that advancements in bio- markers would enhance the pathophysiologic specificity of the diagnosis. Thus, this chapter focuses on structural (i.e., magnetic resonance imaging [MRI]) and metabolic or molecular imaging of AD (i.e., single photon emission tomography [SPECT] and positron emission tomography [PET]), and Chapter 14 focuses on functional neuroimaging and brain connectivity in AD (e.g., perfusion, functional MRI, and diffusion tensor imaging). It is important keep in mind that use of neuroimaging and neuroimaging biomarkers is not a replacement for neuro- psychological or neurologic assessment; rather, it complements them.

13.1 Magnetic Resonance Imaging

Magnetic resonance imaging is a noninvasive imaging tech- nique that can measure brain structure and function (see

Chapter 14). The image is typically formed by detecting the radiofrequency signal emitted by hydrogen atoms after applying a radiofrequency pulse. Different types of images are acquired by modifying the time and strength of the pulse as well as the time before detecting the emitted signal. The most common types of brain MRI are T1-weighted images, T2-weighted images, and T2*-weighted images. Some MRI scans have specific clinical uses. For example, susceptibility-weighted imaging (SWI) can be used to detect cerebral microhemorrhages.

13.1.1 T1-Weighted Imaging

T1-weighted scans provide a clear picture of the gray and white matter in the brain, which appear as gray and white on the image, respectively (▶ Fig. 13.1). T1-weighted imaging is com- monly used to assess whether a patient has normal or abnormal brain structure. In cases of cognitive impairment, it can be used to rule out strokes and tumors as well as to identify areas of atrophy in the brain. Atrophy, or brain volume loss, in the hip- pocampus, medial and lateral temporal lobes, lateral parietal lobes, and precuneus is typical in AD patients (▶ Fig. 13.2).5 A similar pattern, albeit to a lesser degree and more limited to the temporal lobes, is found in patients with mild cognitive impair- ment (MCI).5

Recently, researchers have focused on individuals with pre- clinical AD. In 2011, the National Institute on Aging and Alz- heimer’s Association Workgroup came up with three stages characterizing preclinical AD.6 Preclinical stage 1, asymptomatic amyloidosis, includes patients with high PET amyloid tracer retention or low cerebrospinal fluid (CSF) β-amyloid (Aβ)1–42. Preclinical stage 2, asymptomatic amyloidosis plus neurodegen- eration, includes patients who meet the definition for stage 1 but also have neuronal dysfunction on fluorodeoxyglucose (FDG)-PET, high CSF tau/p-tau, or cortical thinning or hippo-

Fig. 13.1 Axial, coronal, and sagittal slices of a T1-weighted magnetic resonance imaging scan showing gray matter (gray areas) and white matter (white areas). Blue crosshairs are located in the right hippocampus.

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campal atrophy on structural MRI. Preclinical stage 3, asympto- matic amyloidosis plus neurodegeneration plus subtle cognitive decline, includes patients who met the definition for stage 2 but also show subtle cognitive decline from baseline or poor performance on challenging cognitive tests and did not meet the criteria for MCI. Researchers have reported the prevalence of each of these stages in cognitively normal older adults7,8: 16% had preclinical AD stage 1, 12% had preclinical AD stage 2, and 2% had preclinical AD stage 3. Interestingly, an additional 23% of the sample had evidence of abnormal hippocampal volume or hypometabolism as measured by FDG-PET. These patients were labeled as having suspected non-AD pathology, indicating that there are other pathways to hypoperfusion and hippocam- pal volume loss. This research indicates that more research is needed into the earliest structural changes in AD.

Because of the low cost of MRI scans, large-scale research studies (e.g., Alzheimer’s Disease Neuroimaging Initiative, or ADNI) routinely collect high-resolution T1-weighted images to conduct voxel-based morphometry (VBM) and cortical thick- ness studies.9 VBM studies10 are conducted to investigate how gray matter volume changes with clinical status as well as with cognition. For example, researchers found significant correla- tions between gray matter volume in the left supramarginal gyrus, anterior cerebellum, and left superior temporal gyrus and the Free and Cued Selective Reminding Test.11 Cortical thickness studies have also investigated the relationship of cor- tical thinning to clinical status5,12,13 (▶ Fig. 13.2) and the rela- tionship between cortical thickness and cognition.14,15 In the research setting, cortical thickness can be estimated using Free- surfer (http://freesurfer.net)16; clinicians may prefer the com- mercial and Food and Drug Administration (FDA)-approved Neuroquant package from CorTech Labs (http://www.cortechs. net) for diagnostic imaging.

Large longitudinal data sets, such as ADNI, have also enabled more advanced analysis approaches of atrophy across the AD spectrum. One recent study investigated the covariation of atro- phy across brain regions in patients with MCI (▶Fig. 13.3).17

Imaging of Alzheimer’s Disease: Part 1

Fig. 13.2 Graphical representation of the cortical signature of Alzheimer’s disease (AD < controls p < 0.0001). Nodes with significant cortical thinning observed between individuals with AD and healthy controls. Data shown are on the pial surface of the FreeSurfer average brain. (Used, with permission, from Gross AL, Manly JJ, Pa J, et al; Alzheimer’s Disease Neuroimaging Initiative. Cortical signatures of cognition and their relationship to Alzheimer’s disease. Brain Imaging Behav 2012;6(4):584–598.)

This study found two patterns of atrophy related to AD bio- markers. The first pattern revealed coordinated atrophy across posterior nodes of the default-mode network, and the second pattern largely represented atrophy in the medial temporal lobe. The research indicates that there are likely to be indepen- dent, yet simultaneous disease processes causing atrophy in patients with MCI. Future longitudinal studies will likely inves- tigate the pathophysiological basis of these distinct patterns of atrophy.

13.1.2 White Matter Hyperintensities

White matter hyperintensities (WMHs) are lesions in deep white matter that are thought to reflect small-vessel disease (▶ Fig. 13.4). Current thinking is that lesions result from chronic hypoperfusion and disrupted blood-brain barrier integrity.18 WMHs appear bright on T2-weighted fluid attenuated inversion recovery (FLAIR) scans and can now be quantified with imaging software. The association between WMH and AD has been mixed, with some studies concluding that there is a relation- ship19,20 and other studies concluding that there is not a rela- tionship.21 The differences between studies likely reflect the analysis performed. In the aforementioned study showing a relationship, individuals with AD were compared with healthy controls, whereas the other study investigated whether WMHs were predictive of future AD. Yet another study revealed that individuals with high cognitive reserve may be able to cope with a greater WMH burden than those with low cognitive reserve. The implication is that cognitive reserve may be able to delay the onset of AD symptoms.22 These studies indicate that more research is needed in tracking the progression of WMHs during normal aging as well as throughout the AD pathophysio- logical process. Compared with the relationship between WMH and AD, the relationship between WMH and cognition is more established. A number of studies have reported that increased WMH burden is associated with lower cognitive perform- ance.23,24,25 Although the progression of WMHs in the course of

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Fig. 13.3 Visual depiction of the coevolution of atrophy factors related to Alzheimer’s disease (AD) biomarkers. Top row: Factor 1: Covariation of atrophy in the posterior default-mode network and hippocampus. Bottom row: Factor 3: Covariation of atrophy in medial temporal cortices. Note: Factors not related to AD biomarkers are not shown. (Modified, with permission, from Carmichael O, McLaren DG, Tommet D, Mungas D, Jones RN; for the Alzheimer’s Disease Neuroimaging Initiative. Coevolution of brain structures in amnestic mild cognitive impairment. Neuroimage 2012;66C:449–456.)

Fig. 13.4 T2 fluid-attenuated inversion recovery (FLAIR) images provide evaluation for white matter disease. White matter hyperintensities are lesions in the deep white matter that are thought to reflect small-vessel disease and indicate areas of gliosis.

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the development of AD is unknown, the risk factors for WMH are modifiable. Thus, there could be potential value in screening for WMHs clinically. Future research will likely investigate the potential value of routine WMH scans.

13.1.3 Amyloid-Related Imaging

Abnormalities

Although the assessment of amyloid-related imaging abnormal- ities (ARIA) is not useful in the diagnosis of dementia, it is critical in the development of anti-amyloid therapeutics and is potentially important in patients’ prescribed anti-amyloid therapies. ARIAs have arisen through the advent of AD thera- peutics aimed at lowering Aβ burden. Specifically, clinical trials of amyloid-lowering therapeutics revealed MRI signal changes that represent ARIA-edema or effusions (ARIA-E) and ARIA- hemosiderin deposition (ARIA-H). The observance of these abnormalities has led to new recommendations on MRI in clini- cal trials of anti-amyloid therapeutics.26

The finding of ARIA-E was an unexpected transient MRI sig- nal abnormality in several individuals undergoing anti-amyloid therapy (the highest bapineuzumab dose group [5 mg/kg], 3 of 10 patients developed ARIA-E) and was initially labeled vaso- genic edema based on MRI characteristics. Because of the scar- city of histopathological evidence that the MRI signal changes were in fact vasogenic edema, the MRI signal changes are now referred to as ARIA-E. ARIA-E is most often characterized as increased MRI signal on T2-weighted FLAIR scans in the paren- chyma, leptomeninges, or both. A low incidence of spontaneous ARIA-E has also been noted.

ARIA-H is a MRI signal abnormality that is thought to repre- sent hemosiderin deposits, including microhemorrhages and superficial siderosis. Microhemorrhages are round, focal, low- intensity lesions in the parenchyma that are detected by T2* GRE. SWI, which is essentially a T2*-gradient-echo (GRE) sequence with added susceptibility weighting, is more sensitive at detecting microhemorrhages. Not surprisingly, the size and number of microhemorrhages detected are related to the sequence resolution, sensitivity, and scanner strength. Thus, criteria for determining abnormal microhemorrhages need to be adjusted accordingly. Superficial siderois is characterized as curvilinear low intensities adjacent to the brain surface. The prevalence of microhemorrhages increases with age. The preva- lence of microhemorrhages in persons over age 80has been reported to be greater than 35% and is higher in those with hypertension and AD.26 Patients with microhemorrhages at baseline are more likely to have them during the clinical trials of anti-amyloid therapeutics.26 Work is ongoing to understand the natural progression in the increase in microhemorrhages with age and clinical status.

An Alzheimer’s Association Research Roundtable Workgroup recommends T2* GRE (due to its availability) with a slice thick- ness of 5mm or less, echo time of at least 20ms on at least a 1.5T scanner to identify ARIA-H, and a T2-weighted FLAIR sequence to identify ARIA-E.26 The following are additional rec- ommendations: more frequent scanning in phase I and early phase II clinical trials to ascertain the rates of abnormalities; considering the pharmacodynamics effects in determining the postdose time of scanning; and having short rescan intervals in individuals who develop ARIA during treatment. ARIA-E should

Imaging of Alzheimer’s Disease: Part 1

be interpreted for the severity and relevance of symptoms. Indi- viduals with more than four microhemorrhages using the afore- mentioned sequences should be excluded from clinical trials of anti-amyloid therapies. The workgroup also recommended dis- continuation from the study of individuals whose incident ARIA-H is related to significant clinical symptoms. Ongoing and future work is aimed at standardizing and reporting ARIA.27

13.2 Single-Photon Emission Computed Tomography/Positron Emission Tomography Imaging

Nuclear medicine techniques, such SPECT and PET, for imaging the central nervous system are largely different from the ana- tomical imaging methods like computed tomography (CT) and MRI. Nuclear medicine imaging relies on radiotracers that pro- vide specific molecular information about pathophysiological brain processes. Nuclear medicine imaging of dementia can be divided into two major approaches: SPECT and PET. Radio- tracers have been developed for measuring regional cerebral blood flow (rCBF), regional cerebral glucose metabolism, cere- bral amyloid deposition, neurofibrillary tangles, dopamine transporter density, and many more.

13.3 Single-Photon Emission

Computed Tomography

Brain imaging with SPECT uses lipophilic radiopharmaceuticals that cross the blood-brain barrier to measure brain perfusion. The most commonly used radiotracers include technetium- 99m-hexamethylpropyleneamine oxime [HMPAO] and 99mTc- ethylene l-cysteinate dimer [ECD]. Both these agents are injected intravenously using doses of 10 to 20 mCi (370 to 740 MBq) and are retained in brain tissue with a rapid first-pass uptake. Uptake of these radiotracers is localized in active brain tissue and reflects rCBF. SPECT images are obtained 15 to 20minutes after the tracer injection. The resolution of the SPECT perfusion image is about 1 cm. Although high-resolution imaging obtained with dedicated multidetector cameras could provide greater anatomical details, the primary purpose of SPECT imaging is to evaluate relative rCBF rather than the speci- ficity of anatomical structures.

The brain is a well perfused and regulated organ based on tight neural vascular coupling mechanisms. The rCBF reflects underlying normal physiological or pathophysiologic processes. External sensory stimuli, such as touch, sound, smell, and vision, as well as patient’s motion and cognitive activities, could all affect rCBF. In dementia patients, focal pathological pro- cesses can result in substantial neuronal loss leading to perfu- sion deficits. Specific patterns of deficits in rCBF can help diag- nosis and differentiate dementias.

As the normal distribution of perfusion agents is proportional to regional blood flow, there is approximately fourfold greater uptake in the cortical gray matter compared with white matter. Normal brain perfusion is symmetric and greater in the strip of cortex along the convexity of the frontal, parietal, temporal, and occipital lobes. Activity, and consequently uptake, is also high in the regions corresponding to subcortical gray matter, including

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the basal ganglia and the thalamus. The cortical white matter

has significantly lower activity and correspondingly low uptake. The border between the white matter and ventricles may be indistinct.

Visual interpretation of the cerebral perfusion images usually is performed by comparing both hemispheres for symmetry or by scrutinizing the continuity in the rims of cortical gray matter. The local perfusion is measured as increased, similar, or decreased relative to the perfusion in the identical area in the contralateral hemisphere. In AD patients, the most common finding using SPECT brain perfusion imaging is symmetric bilat- eral posterior temporal and parietal perfusion defects. This pat- tern of decreases has a positive predictive value of greater than 80%.28 Although the pattern has a high positive predictive value, the pattern is not pathognomonic for AD. Other pathophysio- logical processes can alter focal brain perfusion to produce a similar pattern of changes in perfusion. The pattern of deficits observed in AD has also been reported in vascular dementia, Parkinson’s disease, and various encephalopathies. Further- more, about 30% of AD patients manifest with asymmetric decreased cortical perfusion, depending on the stage of their dementia. In those cases, unilateral temporal or parietal hypo- perfusion could be seen. Frontal lobe hypoperfusion has also been seen, but with less predictive value. The negative predic- tive value of a normal SPECT perfusion scan is high for mid-to- late stage of disease.28

Clinical use of SPECT perfusion in the diagnosis of dementia is limited by its relatively low resolution, lack of anatomical specificity, and nonspecific perfusion deficit pattern among milder AD patients. However, it is a great neuroimaging research tool for dementia imaging because of its lower cost and ease of access relative to PET.

Numerous research studies have been using SPECT brain per- fusion to characterize various dementias, as well as the normal aging process and the relationship of perfusion to cognitive change.29 These research projects are usually facilitated by com- puter-aided fusion of SPECT images with corresponding CT or MRI images. A control cohort is then compiled based on high-quality “normal” brains. Finally, various advanced imaging analysis techniques, such as voxel-based analyses, three-dimen- sional stereotactic surface–based projection, and tomographic z-score mapping, greatly enhance both the sensitivity and spec- ificity of SPECT perfusion imaging in dementia characterization. Additionally, partial volume correction based on MRI anatomi- cal imaging has been reported to further improve the specificity and sensitivity in dementia characterization.29

13.4 Positron Emission

Tomography

Positron emission tomography uses positron-emitting radio- pharmaceuticals to provide spatially specific information about brain metabolism or specific molecular targets (e.g., amyloid). 2-Deoxy-2-(18F)fluoro-D-glucose, or FDG, a glucose analog that reflects glucose metabolism, is currently the most widely used PET tracer for dementia imaging in the clinic. However, there are many other emerging tracers, such as amyloid tracers, car- bon-11-labeled Pittsburgh compound B (PIB), or 18F-labeled Aβ- PET radiopharmaceuticals, to enable in vivo detection of human

brain amyloid deposition, and tau tracers, 18F-labeled T807, and 18F-labeled T808 to enable in vivo detection of hyperphosh- porylated tau proteins. These newer tracers show great poten- tial for dementia characterization. Because amyloid deposition occurs decades before symptoms, amyloid tracers could poten- tially be used for early diagnoses and to guide potential therapy for amyloid-related dementia.30

13.5 Positron Emission

Tomography: Fluorodeoxyglucose

The normal distribution of FDG in the brain is similar to those SPECT perfusion agents that have the highest uptake in cortical gray matter, basal ganglia, and thalami. This normal metabolic imaging pattern changes with aging and shows significant intersubject variations. Relatively decreased uptake has been reported to be associated with normal aging. However, the uptake within the thalamus, basal ganglia, occipital cortex, and cerebellum is usually unchanged with normal aging. The poste- rior cingulate cortex, lateral temporal lobe, posterior parietal lobes, and anterior frontal lobes generally have higher uptake related to their high resting metabolism. The regions collect- ively make up the default-mode network.31

Metabolic imaging by FDG-PET has shown usefulness in cer- tain discrete clinical settings to evaluate the cause of dementia, including AD, frontotemporal dementia, dementia with Lewy bodies, Parkinson’s disease, multi-infarct dementia, and Hun- tington disease (▶ Fig. 13.5). AD patients have reduction in both glucose metabolism and CBF in the parietotemporal association cortex. The parietotemporal involvement is usually bilateral, although asymmetry of perfusion or metabolism reduction is commonly seen. These deficits then spread to the frontal lobes as disease progresses. The primary motor, sensory, and visual cortices are typically spared until very late stage of dementia. These findings have been widely recognized as a diagnostic pat- tern for AD (▶Fig. 13.5a). As with SPECT, the FDG diagnostic pattern typical in AD is not pathognomic, although it is highly predictive.32

13.5.1 PositronEmissionTomography:

Amyloid and Tau Imaging

Many other non-FDG PET tracers show great success in charac- terizing AD by in vivo imaging of amyloid deposition. Among many of these emerging tracers, N-methyl [11C]2-(4 methylami- nophenyl)-6-hydroxy-benzothiasole (Pittsburgh compound B), named 11C-PIB, is the most successful amyloid tracer in the field of dementia neuroimaging research.33,34 It has revealed high in vivo retention that correlates with cerebral pathological changes of Alzheimer’s patients (▶ Fig. 13.6). Despite its great success of in vivo amyloid imaging, the clinical use of 11C-PIB is limited by its relatively short half-life and the limited availabil- ity of the tracer.

Another promising agent, 18F-florbetapir, also known as AV- 45 or Amyvid, has shown similar capability of in vivo mapping of beta amyloid density in the brain.35 Amyvid was recently approved by the FDA for clinical use and was selected as the amyloid imaging tracer in the anti-amyloid treatment in asymptomatic AD (A4) trial for its wide availability.

Although amyloid plaques are one of the defining pathologi- cal features of AD, normal elderly people without dementia and other patients with clinical syndromes other than dementia could have elevated levels of amyloid deposition in the brain.36 Whereas a positive amyloid scan indicates a significant amyloid burden, a negative scan carries no prognosis of future amyloid burden. Therefore, the clinical utility of amyloid PET imaging requires careful consideration to ensure its role in the proper clinical context. It is particularly important with the considera- tion of cost-effective use of limited health care resources. The current diagnostic guideline from the Amyloid Imaging Task Force does not advocate the use of such neuroimaging bio- marker tests for routine diagnostic purposes.37,38 There are sev- eral reasons for the limitation, including current clinical core criteria, which provide good diagnostic accuracy and utility in most patients; more work needs to ensure the appropriate criteria of biomarker use, limited standardization of biomarkers, and limited access to the biomarkers. Presently, the use of these advanced amyloid imaging markers may be useful only in the

Imaging of Alzheimer’s Disease: Part 1

Fig. 13.5 (a) Alzheimer’s disease (AD). A 58-year-old woman with complaints of forgetfulness and a family history of AD. Fluorodeoxyglucose (FDG) positron emission tomography (PET) shows significant hypometabolism in the bilateral parietotemporal association cortices, as well as the bilateral frontal lobes. Of note, the motor and visual cortices are spared. (b) Dementia with Lewy bodies. A 58-year-old woman with progressive cognitive decline over 2 years. FDG-PET shows significant hypometabolism in the bilateral parietotemporal association cortices, right greater than left, with metabolism deficits in the bilateral visual cortices. Of note, the bilateral frontal lobes are spared. (c) Frontotemporal dementia. A 66-year-old woman with progressive cognitive decline and memory loss for 2 years with speech difficulty. Significant FDG hypometabolism in the bilateral frontal lobes, left greater than the right. Mild hypometabolism is also seen within the bilateral temporal lobes. There is sparing of the parietal lobes and posterior cingulate cortices.

following circumstances: investigational studies, clinical trials, and as optional clinical tools where available and when deter- mined appropriate by the clinician (e.g., differentiate fronto- temporal dementia from AD).

Another investigational PET tracer, fluoroethyl methyl amino-2 napthyl ethylidene malononitrile (18F-FDDNP) appears to bind to senile plaques and neurofibrillary tangles. Thus, for imaging amyloid, the other aforementioned tracers are preferred.

Recently, novel tracers (e.g. F18-T807 and F18-T808) have been developed that are thought to bind to hyperphosphory- lated tau proteins (PHF-tau), such as neurofibrillary tangles.39,40 The tau specificity is based on co-localization of tracer uptake with immunoreactive PHF-tau pathology, but not amyloid pathology.41 Recent research in humans has shown increased tracer uptake in patients with AD.39,40 Researchers are now investigating whether this tracer can map the temporal pro- gression of tau from the entorhinal cortex to other cortical areas, as well as the clinical significance of hyperphosphory- lated tau burden.

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Fig. 13.6 Amyloid image with [11C] Pittsburgh Compound B PET scan. (a,b) Unambiguous positive amyloid binding in the cortex relative to white matter and the cerebellum. (c,d) An indeterminate classification where gray matter binding was present in the cortex of at least three lobes resembling an Alzheimer’s disease (AD) pattern but less intense and convincing than an overtly positive scan. (e,f) No cortical amyloid burden or only nonspecific white matter uptake; nonsignificant patchy or diffuse cortical gray matter binding not resembling an AD pattern (significant uptake in the basal ganglia was common and not considered in the visual rating). (Images courtesy of Dr. Sterling Johnson.)

13.6 Early Diagnosis of

Alzheimer’s Disease

Given their great sensitivity for pathophysiological abnormality in dementia patients, both SPECT perfusion and FDG-PET have been used in early AD patients or people at high risk for devel- oping AD. It is crucial to recognize their brain perfusion and metabolic abnormalities to facilitate possible intervention or disease-modifying therapy. Individuals with amnestic MCI, patients who have memory problems but do not meet the crite- ria for AD, are most likely to convert to AD in the future. Diag- nosis typically includes the following criteria: patient has mem- ory concerns, objective memory impairment for age, normal general cognitive function, capability of normal daily activity,

and not demented. Many studies have demonstrated that amnestic MCI patients have a reduction in both glucose metab- olism and CBF in the posterior cingulate cortex and precuneus. Because these brain regions have a high level of perfusion as well as metabolism in normal patients, it is quite difficult to visualize these subtle decreases in the very early stage of dis- ease onset. However, statistical analysis reveals lower metabo- lism in amnestic MCI patients relative to controls in these areas. Furthermore, reduction in metabolism and perfusion in these areas could predict a cognitive decline in asymptomatic patients (i.e., preclinical AD stage 2). The glucose hypometabo- lism seen on PET reflects projections from dysfunctional neu- rons in other brain regions, such as the hippocampus within the mesial temporal lobe. Amnestic MCI patients could poten- tially benefit more from early intervention and disease-modify-

ing therapies than could mild AD patients. The idea that AD therapies may work best early in the disease process is the premise of the A4 clinical trial. Researchers will give solanezu- mab, a monoclonal antibody-targeting amyloid, or placebo to elderly adults with amyloid (e.g., preclinical AD). The hope is that earlier treatment will be disease modifying.

13.7 Conclusions

Structural, metabolic, and molecular imaging research over the past several decades has advanced our understanding of AD pathophysiological processes, yet imaging biomarkers should not replace clinical neurologic assessments. These advances have led to an influential conceptual model for the progression of AD (biomarker) pathology.42 However, the earliest neuro- imaging biomarkers are costly, and their initiation is unknown, making it difficult to identify the earliest rise in AD risk. Future multimodal imaging research, coupled with more sensitive markers of AD pathology, will aid in identifying those at an increased risk earlier in the pathophysiological cascade. Key to this identification will be the ability to separate brain changes of normal aging from those attributable to AD-related pathol- ogy. To differentiate AD from normal or exaggerated aging, numerous studies have investigated the relationship between aging and neuroimaging findings. For example, in FDG-PET studies, the reductions most common with age were observed in the dorsolateral and medial frontal areas and the perisylvian insular cortices rather than in the default-mode network.29

The growing neuroimaging literature is focusing on investi- gating brain changes in regions affected by AD. In one study, thinner cortices in areas of atrophy in AD were associated with increased risk of conversion from normal to AD.43 Other studies have gone further to create criteria for defining abnormal bio- markers to help identify individuals in the various stages of pre- clinical AD.7,8,9 Future studies will use the preclinical AD stages to look for other subtle changes related to AD pathology. Finally, studies that investigate networks of atrophy and cortical thin- ning may have more potential to differentiate AD-related brain changes from those associated with normal aging based on the co-occurring change in spatially disparate regions.17

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Imaging of Alzheimer’s Disease: Part 2 14 Imaging of Alzheimer’s Disease: Part 2

Christian La, Wolfgang Gaggl, and Vivek Prabhakaran

As an ongoing effort toward the identification of various bio- markers and early detection of Alzheimer’s disease (AD), the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was con- ceived to help researchers and clinicians develop new treat- ments and increase the safety and efficacy of drug development. With a primary focus on structural magnetic resonance imaging (MRI) of the brain, data generated from ADNI-1 have improved the understanding of relationships between imaging and chem- ical biomarkers of AD with the acquisition of a three-dimen- sional T1-weighted magnetization-prepared rapid acquisition with gradient echo (MP-RAGE) and a dual fast spin-echo (pro- ton density/T2-weighted) sequence. As a continuation to the initiative, ADNI-GO and ADNI-2 expanded on the ADNI imaging core protocol with inclusion of resting-state functional MRI (fMRI), T2 fluid-attenuated inversion recovery (FLAIR), diffusion tensor imaging (DTI), and arterial spin-label perfusion imaging. In this chapter, we provide an overview of the research involv- ing perfusion imaging, FLAIR MRI, DTI, and magnetic resonance spectroscopy (MRS) in the AD population (▶ Table 14.1).

14.1 Perfusion-Weighted Imaging

Perfusion-weighted imaging (PWI) is an MRI sequence that is sensitive to the flow of blood in the capillaries and capillary beds, a technique that is getting more attention in the investiga- tion of AD and other neurodegenerative diseases. For the past two decades, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have served as the mainstream imaging for perfusion and metabolism and remain highly effective. Although the risk of radioactivity is rather minimal, preparation of the necessary isotopes and radioactive tracer remains a potential challenge in these nuclear medicine techniques. Only a few large-scale hospitals and research institutes have the resources to support such a

system. In contrast, PWI provides a survey of perfusion that is free of such radioactive isotopes. This method is comparatively easy to implement and is available for most commercial scan- ners used at hospitals and medical centers.

Perfusion-weighted MRI can be categorized into two general classes, depending on the method of obtaining contrast. Also called bolus-tracking MRI, dynamic-susceptibility contrast (DSC) is currently the most widely used approach. With the tracking of a bolus injection of paramagnetic, gadolinium-based contrast (GBC) agents, relative measures of regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), mean transit time (MTT), and time-to-peak (TTP) can be assessed and recorded. However, administration of GBC agents has been associated with nephrogenic systemic fibrosis in patients with significant renal insufficiency, limiting its current application. Arterial spin labeling (ASL) technique, on the other hand, makes use of endogenous arterial blood as the tracer for the quantifi- cation of blood flow. In contrast to DSC MR perfusion, which provides relative perfusion measurements, ASL MRI allows absolute quantification of perfusion as expressed in terms of milliliters per 100g per minute. The quantitative values obtained from ASL MRI offer a reliable whole-brain CBF mea- surement that is comparable to the traditional 15O-water PET perfusion imaging method,1 without the radioactivity. Its ease of acquisition, noninvasive nature, and high reproducibility over time also make it an attractive and potentially cost-effective alternative to PET.

Perfusion imaging methods have been successful in the detection of AD-related perfusion deficiencies. The pathology of AD is that of a slowly progressing neurodegenerative disorder commonly characterized by decreased rCBF. It has been previ- ously reported that patients with AD symptoms consistently show patterns of cerebral hypoperfusion, and although in such individuals a global decrease in blood flow is regularly demonstrated compared with healthy controls, CBF reduction may be more pronounced in certain regions than in others. Indeed, individuals with AD have shown a more pronounced reduction of CBF in the following regions: the precuneus, the posterior cingulate, and the lateral parietal cortices, with such findings demonstrated by DSC perfusion2 and ASL perfusion (▶Fig. 14.1).3 These perfusion abnormalities have been recorded as early as in patients with mild cognitive impair- ments (MCI) and in patients in the early preclinical phases of AD, with effects persisting well into the later stages of the dis- ease. During the preclinical stages of asymptomatic individuals, the apolipoprotein (Apo)E4 allele and family history are well- recognized risk factors for the onset of AD. Carriers of ApoE4 allele and the presence of family history, in particular maternal family history, increase the likelihood of AD-related hypoperfu- sion as tested in the asymptomatic population. Previously, the gender of the AD-affected parent has been suggested to influ- ence the risk of disease progression.4

Along with CBF deficiencies, patients even in early stages of the disease often exhibit changes in their cortical structure. Brain-volume losses are particularly prominent in the meso- temporal structures.5 The extent of atrophy in MCI patients is

Table 14.1 Magnetic resonance imaging (MRI) acquisition protocol for ADNI-1 and ADNI-GO/2

ADNI-1: (1.5-Tesla scanner) ADNI-GO/2 (3-Tesla scanner)

● Localizer

● MP-RAGE

● Sagittal MP-RAGE/IR-SPGR

● MP-RAGE (repeat)

● Accelerated sagittal MP-RAGE/IR-SPGR

● B1 calibration: head coil

● Resting-state fMRI (Philips Systems only): eyes open

● B1 calibration: body coil

● Axial T2-FLAIR

● T2 dual echo

● Axial T2

● Axial ASL perfusion (Siemens systems only) – eyes open

● Axial DTI scan (GE systems)

Abbreviations: ADNI, Alzheimer’s Disease Neuroimaging Initiative; ASL, arterial spin labeling; DTI, diffusion tensor imaging; FLAIR, fluid- attenuated inversion recovery; fMRI, functional magnetic resonance imaging; MP-RAGE, magnetization-prepared rapid acquisition with gradient echo.

Source: (http://adni.loni.usc.edu/methods/mri-analysis/mri-acquisition/).

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Fig. 14.1 Cerebral perfusion reduction in Alzheimer’s disease (AD) patients compared with healthy elderly controls. Statistical t-map of cerebral blood flow difference in AD patients and healthy elderly controls by way of arterial spin labeling perfusion magnetic resonance imaging, with activation representing areas of reduced cerebral perfusion in patients at p < 0.005 un- corrected. (Image courtesy of Ozioma C. Okonwo and the Wisconsin Alzheimer’s Disease Research Center.)

more limited. Patients with amnestic MCI who eventually prog- ress to AD have demonstrated greater susceptibility to gray matter loss in the medial and inferior temporal lobes, temporo- parietal, posterior cingulate, precuneus, anterior cingulate, and some regions of the frontal lobes compared with clinically sta- ble MCI patients.6 Despite this fact, after adjusting for brain atrophy and gray matter volume, the previously described effects of regional hypoperfusion in the posterior cingulate, the precuneus, the inferior parietal, and the lateral prefrontal corti- ces persist and cannot be explained solely by brain atrophy.3

Such hypoperfusion patterns are in line with numerous fluo- rodeoxyglucose (FDG) PET studies.7 CBF and cerebral metabo- lism are generally believed to be tightly coupled. A study com- bining FDG-PET and ASL-MR perfusion imaging in the same patients demonstrated a high degree of overlap between the two modalities of perfusion MRI and PET.8 In that study, imple- mentation of concurrent FDG-PET and ASL-MRI demonstrated not only similar regional abnormalities in AD between the two modalities, but the two modalities also provided comparable sensitivity and specificity for the detection of AD as reviewed by expert readers.8 The agreement in hypoperfusion and hypo- metabolism patterns suggests a possible sensitivity of ASL CBF toward the neurometabolic alterations among individuals with risk factors for AD.3,8

Nonetheless, despite the strong correlation between the two measures of cerebral perfusion and cerebral metabolism, some regions exhibited differential observations. Whereas the reduc- tion of CBF is somewhat consistent in the population of AD, some studies have also reported opposite findings. Such signs of hyperperfusion are discordant with the hypometabolism reported for the same regions by a number of FDG-PET studies.9 Although the explanation for this decoupling remains unclear,

it has been suggested that this increase of perfusion might be the direct or indirect result of local inflammatory response or compensatory activity in the face of neurodegeneration.10

14.2 Functional Magnetic

Resonance Imaging

A different modality that has been successfully used in the AD population, and that has been added to ADNI-2, is fMRI. Given the impairments in memory associated with progression of AD, numerous fMRI studies have focused on the functional changes in such processes. Memory issues are one of the first observable symptoms of AD, but not all memory systems are equally impaired. Episodic memory is generally the first and most affected of the memory systems. Not surprisingly, areas of the medial temporal lobe that are critical to episodic memory have been reported to sustain heavy neuronal loss, as previously stated.5 In AD, multiple regions pertaining to functional net- works subserving episodic memory sustain alterations in corti- cal activation patterns compared with age-matched healthy controls. Decreased activity from episodic memory task-fMRI has been reported in the hippocampal formation in AD patients, such as during picture encoding11 and verbal retrieval.12 Con- versely, lateral prefrontal activity has been shown to increase during verbal retrieval, suggesting the notion of a compensa- tory mechanism.12

Despite those promising results, investigations using task- evoked fMRI in the AD population are heavily confounded by individual differences and in their abilities to perform the task. Alternatively, resting-state fMRI (rs-fMRI), also called task- negative or task-free fMRI, provides an investigation of the

Imaging of Alzheimer’s Disease: Part 2

brain network free of the confounding factors associated with a task. In this context, rest refers to a constant condition without imposed stimuli. By surveying the existing spontaneous low- frequency fluctuation (SLFF) of blood-oxygen-level–dependent (BOLD) signal during rest as originally illustrated by Biswal et al,13 valuable information can be extracted. A wide array of consistent, segregated functional networks, or rs networks (RSNs), can be assessed using such a technique. Functional connectivity analysis provides an assessment of functional networks and allows for an appraisal of network integrity of specific RSNs in clinical populations compared with healthy normal persons. A survey of rs intrinsic activity might be as sig- nificant as, if not more significant than, evoked activity in terms of overall brain function.

Of particular interest is the default-mode network (DMN). Comprising primarily the precuneus/posterior cingulate, inferolateral parietal, and medial prefrontal cortices, this net- work is thought to have a role in introspection and self- reflective thinking. In normal aging, mild cognitive impair- ment, AD, and various other neurologic disorders, the DMN experiences disruption, especially in terms of functional con- nectivity (▶Fig. 14.2).14,15 Greicius et al14 demonstrated abnormality within the DMN in AD patients, with a decrease in DMN coactivity in the posterior cingulate and hippocam- pus from a study of 13 mild AD patients. These findings of reduced DMN connectivity have been replicated on multiple occasions in AD patients,16,17 in MCI patients,15 as well as in cognitively healthy older controls harboring amyloid pla- ques18,19 and in healthy older carriers of the ApoE4 allele.19 The study from Sorg et al15 additionally revealed that func- tional connectivity between both hippocampi in the medial temporal lobes and the posterior cingulate of the DMN was present in healthy controls but absent in patients, represent-

ing the effects of ongoing early neurodegeneration, possibly reflecting the later reduced integrity of the communicating fiber tract.20

Analyses of rs-fMRI have yielded consistent findings, primar- ily with a loss of intranetwork connectivity in large-scale networks in AD and MCI, including the DMN, dorsal attention network, salience network, and sensorimotor network.21 Within the DMN, patients suffer from disruption of functional connectivity spanning from the posterior to the anterior por- tions of the network.22 Although with age the anterior DMN shows increases in frontal lobe connectivity and the posterior DMN shows declines in connectivity throughout, with onset of AD pathology hastening these patterns of age-associated changes, particularly in the posterior regions.16 Furthermore, functional connectivity between regions separated by greater physical distance was markedly attenuated with increasing dis- ease severity, with such loss associated with less efficient global and nodal network topology.23

In addition to intranetwork connectivity deficiency, internet- work connectivity was also consistently disrupted.21 Studies have found decreased DMN connectivity to be associated with increased prefrontal connectivity24 and increased salience net- work connectivity,17 suggesting that the pathology of AD is associated with an alteration in large-scale functional brain net- works, which extends well beyond the DMN. Several task-fMRI studies have demonstrated decreased ability to deactivate regions irrelevant for task performance in AD and MCI popula- tions compared with the normal elderly population.25 There- fore, the ability to decrease brain activity and disengage the DMN during executive tasks is also associated with brain health. Together, these findings suggest that AD pathology is associated with widespread disruption of both intranetwork and internet- work correlations.

Fig. 14.2 Resting-state functional connectivity reduction in Alzheimer’s disease (AD) patients compared with healthy elderly controls. Statistical t-map of functional connectivity difference in AD patients and healthy elderly controls by way of seed-based approach with a seed placed in the posterior cingulate cortex (PCC) MNI [2–54 26] overlaid on an averaged anatomical brain image. Activation clusters represent areas of reduced functional connectivity with the PCC, a principal component of the default-mode network at

p < 0.005, uncorrected. (Image courtesy of Sterling C. Johnson and the Wisconsin Alzheimer’s Disease Research Center.)

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A family history of the presence of the ApoE4 allele and amy- loid aggregation, two well-accepted risk factors for AD, have been studied using such methods. Fleisher et al26 demonstrated that the high-risk population exhibited distinct characteristics compared with low-risk population. In that study, groups were defined by family history of dementia and whether or not par- ticipants were carriers of the ApoE4 allele. The two risk groups were distinguished by their activity over nine regions, including regions of the prefrontal, orbital frontal, temporal, and parietal lobes.26 In another study of cognitively normal individuals, a family history of late-onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely, the posterior cingulate and medial tempo- ral cortex,27 where amyloid deposition has been previously observed in individuals with a family history of AD, but not in those without such a history.28 As suggested by Wang et al,27 it is possible that the decreased functional connectivity may be related to amyloid deposition in an age-dependent fashion in individuals with a family history of AD.

Although much work has been dedicated toward solving the increasingly complex puzzle that constitutes AD, the relation- ship between functional-structural connectivity and metabolic measures remains to be better understood. Previously, amyloid deposition and aerobic glycolysis were demonstrated to be cor- related for both individuals with AD and for cognitively normal amyloid-positive participants, suggesting a possible association between regional aerobic glycolysis and the later development of AD pathology.29 Additionally, regions of normally high aero- bic glycolysis in healthy individuals coincides with regions of the DMN, where decreased metabolic activity, concurrent with increased amyloid deposition, is found to have occurred in AD patients. Together, this distinct pattern offers the suggestion of a particular susceptibility of these regions the pathophysiology of AD.29

From rs-fMRI, it has been demonstrated that those regions are also associated with a reduction of functional connectivity with onset of the disease. Moreover, several studies have provided evidence of decrease connectivity within the DMN in cognitively normal elderly individuals with elevated brain amy- loid.18 This discovery in cognitively normal elderly individuals supports the concept that rs-fMRI may have the ability to detect early manifestations of amyloid (Aβ) toxicity, before any appearance of clinical symptoms.

14.3 Diffusion Tensor Imaging in

Alzheimer’s Disease

The changes demonstrated in volumetric studies, fMRI and rs-fMRI, as described previously, are attributed to gray matter loss and neuronal degeneration and with it the altered connec- tivity of the functional network of the brain. More recently, white matter changes have been investigated in subjects with AD and MCI, including decreased myelin density and myelin basic protein, as well as oligodendrocyte loss. Additionally, wal- lerian degeneration is a mechanism causing axonal loss following neuronal degeneration.

A promising MRI modality for studying structural changes in white matter is DTI. Changes in diffusivity in the direction of the fiber bundles (longitudinal or axial diffusivity) are attrib-

uted primarily to axonal loss through wallerian degeneration, whereas changes in diffusivity in the direction orthogonal to the fiber bundles (transverse or radial diffusivity) have been associated with damage of cell walls and myelin sheaths. Loss of white matter fibers has been reported by Wang et al,30 who showed a decreased fractional anisotropy (FA) and increased mean diffusivity (MD) in multiple areas of the brain correlated to functional impairments as assessed using the Mini-Mental State Examination and the AD Assessment Scale. Li et al31 com- bined volumetric analysis with DTI by comparing mild AD patients with normal aging controls and demonstrated hippo- campal atrophy at the mild AD stage. A study by Solodkin et al32 suggests that DTI in the parahippocampus could be used as a biomarker of disease progression in the white matter pathology of AD. They classified MCI and AD cases using dis- criminant analysis and noted that the MCI cases identified as AD in their analysis either met the diagnostic criteria for AD or showed significant cognitive decline 1 year later. With this evidence demonstrating white matter disruption to be an important part in the pathogenesis of AD, Shu et al33 performed a systematic study of white matter changes and compared DTI at 7T and histologic images in a APP/PS1 mouse model com- pared with wild-type controls. Abnormalities of FA or axial diffusivity agreed with ultrastructural findings demonstrating histopathological changes of AD.

Methods that are investigating DTI as a marker of AD use either region-of-interest (ROI) or voxel-wise approaches. ROI approaches can rely either on manually drawn ROIs that have the advantage of being anatomically accurate in the individual subject or on template warping, which allows efficient process- ing of many subjects in group studies. Tract-based analysis poses an efficient alternative to manual ROI drawing for the individual subject. Voxel-wise approaches always rely on warp- ing of the subject anatomy to a specified template, but because of individual brain differences and imperfections of nonlinear mapping algorithms, this method is typically used for large group studies. Whether it is more effective to use whole-brain assessments or to focus on specific brain areas that have been shown to be altered by AD remains an open question. A concern regarding methods is the effect of anatomical normalization during template mapping and its effects on the scalar measures of DTI, but this has been found to be much smaller than averag- ing or blurring in ROI studies.

Several studies have documented the changes of DTI markers with AD in the hippocampus,34 the medial temporal lobe,34 the parahippocampal white matter and perforant path,35 entorhinal cortex,36 and posterior cingulum.37 Degeneration generally seems to follow the pattern of retrogenesis, where areas of late myelination during development are affected early by the dis- ease, and areas of early myelination are affected later in the progression of the disease. Compared with healthy aging, DTI changes to posterior brain structures are generally found earlier in the disease than are changes to the frontal areas.38

The DTI studies that have investigated the loss of memory, the most prevalent symptom defining AD, have focused on the area around the hippocampus and parahippocampal white matter,35 with the perforant pathway transmitting inputs into the entorhinal cortex to the hippocampus. Multiple studies found DTI changes in the perforant pathway for both AD and MCI39 compared with healthy aging, with changes in AD

generally more pronounced than in MCI. Solodkin et al32 dem- onstrated the use of DTI for in vivo assessment of parahippo- campal white matter to identify patients with MCI at risk of converting to AD.32

Furthermore, a study by Bendlin et al4 suggested that changes to white matter structure can be detected many years before detection of cognitive changes associated with AD by looking at asymptomatic patients with a family history of AD. They found that a parental family history of AD is correlated with a lowered FA value in brain areas that have been identified to be affected by the disease, including the hippocampus, corpus callosum, cingulum, uncinate fasciculus, tapetum, and neighboring white matter structures.

Although reports disagree about the structures affected by AD and MCI compared with normal aging, such as the frontal lobes and parietal lobes, most studies found consistent struc- tural changes in several brain areas using DTI metrics (typically FA and MD), reflecting the development of pathological changes with AD (▶Fig. 14.3). Differences between studies may be caused by different sensitivities of the analysis method that is used (ROI, tract, or voxel based) and the DTI sequence parame- ters chosen, such as image resolution, motion robustness, eddy current compensation, and the use of parallel imaging methods as well as technological advances in scanner hardware and DTI pulse sequences.40

14.4 Proton Magnetic Resonance

Spectroscopy

Klunk et al demonstrated that, compared to control subjects, a decrease in NAA in postmortem brain samples of AD patients correlated with the presence of plaques and neurofibrillary tangles.41

Several studies have shown MRS to be able to distinguish between AD patients and healthy controls. Whereas Klunk et al41 showed a decrease in NAA in AD patients, several investi- gators have demonstrated that NAA levels can improve in AD patients after acetylcholinesterase treatment.42 NAA has also been shown to correlate with psychiatric components of AD, where AD patients with psychosis had significantly reduced NAA levels compared with healthy controls.43

Not only does MRS hold promise of providing insight into the availability of selected metabolites as disease biomarkers, but it also provides a wide chemical spectrum of metabolites that can be used as a chemical fingerprint of the patient’s disease state.44 Together with other metrics, such as measuring the hippocam- pal volume42 and modalities like amyloid PET imaging,45 MRS can be used to provide complementary data in clinical diagno- sis. There is evidence that amyloid plaques start accumulating before behavioral symptoms of neurodegeneration can be seen: in cognitively normal older adults, the Cho:Cr and mI:Cr ratios correlated with amyloid PET imaging.45 Additionally, MRS can provide a measure of glial activity by elevation of mI in AD.46

Although there is ample evidence that adding MRS to the diagnosis and treatment of AD provides a more complete pic- ture and allows better disease monitoring and a more tailored treatment regimen, the technique has not been widely adopted for routine clinical care of AD patients. Graff-Radford and Kant- arci44 state that the primary reasons are both the lack of stan- dardization and normative data across sites and an insufficient understanding of the pathological basis of the changes observed using MRS. A practical approach would be to combine MRS with other clinical imaging techniques (e.g., volumetric MRI, DTI, functional connectivity MRI, FDG-PET).

References

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Imaging of Alzheimer’s Disease: Part 2

Fig. 14.3 Patient diagnosed with Alzheimer’s disease (right image) compared with age-matched normal subject (left image).
White matter atrophy can be observed in the splenium of the corpus callosum (yellow arrows). (Image courtesy of S. C. Johnson, University of Wisconsin-Madison.)

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Magnetic Resonance Imaging and Histopathological Correlation

15 Magnetic Resonance Imaging and Histopathological Correlation in Alzheimer’s Disease

Mark D. Meadowcroft and Qing X. Yang

Magnetic resonance imaging (MRI) presents a unique opportu- nity to noninvasively image neurodegenerative diseases and their progression. Although MRI has been extremely valuable in clinical diagnosis and treatment, currently, how MRI parameters relate to the specific pathological changes in the Alzheimer’s disease (AD) brain have not been established and validated. A gap exists between MRI contrast/metrics and the alterations in micro- and macrostructural histologic patterns of disease pathology, which results in a fundamental concern when using MRI findings in the clinical interpretation of disease processes without direct knowledge of the relationship between image contrast and disease pathology. Whereas many in vivo studies have ostensibly reported correlations of MRI contrast and metrics to AD stage, the exact anatomic-pathologic underpinnings and correlates of MRI findings remain unclear.

Advances in MRI have allowed researchers to push the boundaries of resolution constraints by using microscopic magnetic resonance imaging (μMRI). Numerous microimaging studies have been performed within the literature base, with most techniques comprising the placement of whole-tissue samples within volume or under surface radiofrequency coils, which presents difficulty in the coregistration of MR slice selec- tion with actual tissue sections cut on a cryostat or vibratome. This obstacle can be overcome by direct imaging of tissue sample slices followed by histologic staining of the tissue sec- tions, resulting in a one-to-one comparison between MRI and microscope images.1,2

The formation of beta-amyloid (Aβ) plaques remains a major neuropathological hallmark and cardinal feature of Alzheimer’s pathology. The ability to distinguish Aβ plaques with MRI has been demonstrated ex vivo with human AD tissue samples and in vivo with transgenic mice that produce amyloid plaques. These data have shown Aβ plaques as hypointensities on T2- and, to a more pronounced degree, T2*- weighted images.

The signal dropout in T2-/T2*-weighted MRIs has been attrib- uted to the iron deposition associated with amyloid plaques in human tissue samples (▶ Fig. 15.1). Homeostatic misregulation of iron is known to occur in the AD brain. The increased con- centration of iron in the brain tissue of AD patients has been well demonstrated,3,4,5 and a close association of iron with amy- loid plaques in AD tissue has been established.6,7 Aβ amyloid fibrils have a high affinity for iron, on the order of eight magni- tudes greater than transferrin for iron.8 The association with iron aids in the formation of Aβ plaque masses as the incorpora- tion of the Aβ fibrils into plaque assemblies is accelerated in an iron-enriched environment.9,10 Focal iron deposition in the form of hemosiderin, derived from ferritin protein breakdown or cerebral microbleeds, and diffuse iron are found throughout the Alzheimer’s brain parenchyma.

Microscopic MRI of tissue samples from late-stage AD tissue (Braak VI) demonstrates focal hypointensities within the gray matter in gradient-echo (GRE) images (▶ Fig. 15.2). Costaining of the same MRI tissues samples for fibrillar amyloid, with thio- flavin-S, and iron, with Perls’ stain, demonstrates that these hypointensities correspond to amyloid plaques and/or focal iron deposition. Amyloid plaques that are high in iron content exhibit a greater signal dropout on the GRE images than Aβ pla- ques that have minimal iron association (▶Fig. 15.3). Larger plaques exhibit a greater signal dropout than smaller plaques. It is apparent that the amount of signal dropout on MRI is associ- ated with the quantity of iron present at that location and the morphology of the plaques.

A similar trend in transverse relaxation is found when imaging amyloid plaques in a transgenic mouse model that harbors human mutations in amyloid precursor protein (APP) and presenilin-1 (PS1). The mice produce plaques throughout the brain in response to increased production of Aβ at approximately 9 months of age. GRE images of animal

Fig. 15.1 Iron associated with β-amyloid plaques in Alzheimer’s disease at 400x magnification. The amyloid protein is a metalloprotein with a high affinity for iron. Iron is found throughout the diffuse plaque regions as well as the highly fibrillar core. Iron within microglial cells can be viewed around the periphery of amyloid plaque mass. (a) Perls’ stain; (b) thioflavin-S amyloid stain.

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Fig. 15.2 Gradient-echo microscopic magnetic resonance images 60-μm-thick in Alzheimer’s (a) and age-matched control (b) tissue sections from the entorhinal cortex (Brodmann area 28/ 34). Cortical gray matter and subcortical white matter are clearly visible on the images at the same resolution. Alzheimer’s tissue exhibits punctate hypointensities within the cortical gray matter, which are not found within the gray matter of control tissue.

plaques demonstrate the same relationship of hypointensities with the plaques (▶Fig. 15.4). When staining is done for fibrillar amyloid and iron, a negligible amount of ferric iron is observed in plaque mass in the mouse tissue. Transverse MR relaxation measurements from regions of interest con- sisting of individual plaques and surrounding tissue demon- strate that plaques in both AD and APP/PS1 tissue have faster relaxation rates than the surrounding tissue. In comparison of plaques in AD with plaques in APP/PS1 tissue, the human plaques have shorter relaxation times (T2*) and increased relaxation rates (R2*) (▶Fig. 15.5). Although relaxation does not differ between control tissue and regions without pla- ques in AD and APP tissue, there is a significant relaxation difference between AD and APP/PS1 Aβ plaques. Histologic staining of the same tissue sections show that less iron is associated with the amyloid plaques in the APP/PS1 mouse model (▶Fig. 15.6). The decrease in iron within the trans- genic mouse plaques is congruent with the reduced R2 in pla- ques compared with AD plaques. The difference in the R2 between the AD and APP/PS1 plaques of approximately 22% is hypothesized to be due to the synergistic role that both Aβ plaques and iron have in transverse relaxation. The increased rate of relaxation in the AD plaques is predominantly a result of the summation in relaxation attributable to higher iron content in, and morphology of, the plaques. Whereas both human and transgenic mouse plaques are composed of aggregation of Aβ protein fibrils, the morphology of the transgenic plaques is quite dissimilar to that found in Alz- heimer’s tissue. APP/PS1 plaques are larger, globular shaped, and have a greater core density, with smaller extent in the surrounding diffuse halo region. Conversely, Alzheimer’s pla- ques are generally smaller, with a smaller core and a larger diffuse region. The size of the plaques plays a role in the ability to visualize them on MRI, with larger plaques more easily distinguishable. The minimal size of discernable trans- genic and AD plaques is approximately 40μm in diameter. Of note, though, plaque diameter alone does not confer the ability to visualize Aβ plaques. Alzheimer’s plaques of simi- lar size without iron are marginally discernable on MRI, whereas APP/PS1 plaques of the same size without iron are visible as hypointense spots.

The composition and morphology of the Aβ plaques are important for the interpretation of the associated changes in image contrast and parametric measurements. Immunohisto- logic staining reveals that the core of Alzheimer’s plaques is composed primarily of the 42 amino acid Aβ variant (Aβ42), whereas the coronal region is composed of Aβ40. Transgenic mouse plaques stain solely for Aβ40 in both the core and coronal regions (▶Fig. 15.7). The composition of the Aβ protein con- tains numerous hydrophobic amino-acid residues, for which Aβ42 contains two additional hydrophobic amino-acid residues compared with Aβ40.11 The increased hydrophobic nature of the Aβ42 protein is hypothesized to result in its increased amyloido- genic properties. In general, proteins centralize hydrophobic side-chains in the middle of the protein during thermal folding. The central core composition of the Alzheimer’s Aβ plaques is congruent with this notion. Conversely, the transgenic plaque cores and coronal regions are composed of less hydrophobic Aβ40.

The hypointense image contrast of transgenic mouse pla- ques is generated by the reduced mobile water content due to the aggregation of hydrophobic Aβ protein in the plaques. In addition to mobile proton (water) content, image contrast of Alzheimer’s plaques is also dependent on the amount of iron colocalized with the plaques as a result of magnetic sus- ceptibility inhomogeneities induced by iron within the pla- ques. To tease apart the synergistic effect of contrast enhancement due to iron content and plaque morphology, AD tissue samples were subjected to iron chelation with deferoxamine mesylate salt (DFO) overnight to reduce Aβ pla- que iron load. The binding affinity of DFO for Fe3 + is greater than that of Aβ, with a binding constant specific for Fe3 + (not Fe2 + ) on the order of 1030. Thioflavin-S and Perls’ staining for plaques and iron (respectively) indicate that DFO chelation reduces the amount of iron associated with the Aβ plaques (▶ Fig. 15.8). MRI of the AD tissue samples treated with DFO demonstrates that AD plaques can be discerned without iron load in the plaques (▶Fig. 15.9), congruent with the trans- genic plaques’ case, which have low iron load as well. It is also noted that MRI signal decrease in AD plaques treated with DFO is visibly less than that in untreated ones. The cor- responding R2* rate is higher in the plaques with iron than in

Magnetic Resonance Imaging and Histopathological Correlation

Fig. 15.3 T2* -weighted gradient-echo magnetic resonance imaging (MRI) (a) and histologic images of thioflavin-S staining for β-amyloid plaques (b) and Perls’ iron stain (c) of the same 60-μm-thick tissue sample from the entorhinal cortex of an Alzheimer’s disease patient. Selected hypointensities in the MRI correspond to the location of amyloid plaques (red arrows) and/or focal regions of high iron (blue arrows). The figure illustrates that the size of the β-amyloid plaque and the amount of focal iron associated with the amyloid mass are responsible for the hypointensities on the T2*-weighted images. Large plaques are more readily visible on the images, as are plaques containing a high amount of iron. β-amyloid plaques of smaller diameter and those with minimal associated iron are still visible to a reduced degree.

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Fig. 15.4 T2*-weighted image (a) and histologic thioflavin-S β-amyloid (b) and Perls’ iron (c) stains of the same 60-μm-thick slice from amyloid precursor protein(APP)/ presenilin-1 (PS1) mouse brain at –2.92 mm Bregma. Select hypointensities on the magnetic resonance imaging (MRI), which correspond to the location of β-amyloid plaques, are highlighted with red arrows. The figure illustrates that the hypointensities seen in the T2*- weighted image are in the same region as large β-amyloid plaques approximately 50 to 60 μm in diameter. Unlike the Alzheimer’s tissue, iron deposition is not present at the plaque locations. Similar to Alzheimer’s tissue, plaque diameter is an important consideration for visibility on MRI visibility, as larger plaques are more readily visible on T2*-weighted images.

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support the hypothesis that plaque size and morphology play a dominant role in their imaging, as most of the relaxation remains after iron chelation. It is interesting to note that the R2* rate in the plaques stripped of iron is still quite high compared with that of the surrounding gray matter, similar again to the transgenic mouse plaques. The plaques in both chelated and unchelated conditions have R2* values that are significantly greater than those in surrounding gray matter. The percentage of reduction in R2* after iron chelation was 14.6% for Aβ pla- ques, 17.4% for white matter, and 2.0% for gray matter. White matter is known to have large amounts of iron associated with oligodendrocytes, and iron is required for myelination. The sim- ilar reduction in R2* for white matter and Aβ plaques is indica- tive of the similar iron decrease in these tissue types. Gray mat- ter tissues have less iron, and chelation resulted in only a minor change in R2* rate in these regions.

The mechanism for T2 relaxation in Aβ plaques is multifac- eted, with iron loading in the plaques accounting for a portion of the apparent transverse relaxation. Iron is well known to perturb the local magnetic field, causing the MR signal from rapid diffusing water molecules in and near the plaques to dephase during each echo time.14 However, the morphology and composition of the plaques themselves are also synergisti- cally involved as major contributors. Several plausible mecha- nisms can lead to increased T2 relaxation rate in the transgenic mouse and human plaques without appreciable iron content. The Aβ plaque morphology revealed by the transmission elec- tron microscopy (TEM) in ▶ Fig. 15.10 provides evidence for a plausible relaxation mechanism. The transgenic mouse plaques are densely packed globular aggregates, whereas Alzheimer’s plaques appear as loosely connected patches with numerous infiltrated gaps or channels within the plaque mass. The highly compacted plaques behave similarly to a polymer-like solid. In such cases, water molecules are either repelled from the hydro- phobic moieties and/or bound to hydrophilic regions of the pla- ques. Hydrogen bonding of water molecules to the hydrophilic regions would result in a first-order cross-relaxation via pro- ton-proton magnetization exchange, leading to rapid T2 relaxa- tion. Such an effect, termed plaque dehydration, could be a sig- nificant contributor to the hypointense T2 contrast in the pla- ques. In addition, the magnetic susceptibility differences between the highly compact Aβ protein mass and surrounding tissue could induce static magnetic field inhomogeneity in con- cert with iron but to a lesser degree. The gaps and channels in the human AD plaques allow water molecules to diffuse in and out the plaques, leading to increased water molecule interac- tion with the macromolecular environment, which, in turn, would increase proton T2 relaxation. Our data suggest that pla- que dehydration appears to be a dominant factor over iron loading in the shortening T2 relaxation in the Aβ plaques. The mechanism of water dehydration can be validated by using magnetization transfer (MT) contrast imaging. When applied to AD patients, the magnetization transfer ratio (MTR) (i.e. ratio of image contrast with and without RF frequency offset) has been reported to be decreased in the whole brain.15 Regional mea- sures of MTR are reduced in the hippocampus, amygdala, and

Fig. 15.5 Transverse relaxation R2* rates from regions of interest (ROIs) with plaques and without plaques and in control tissue in human (a) and mouse (b). The R2* rate of plaque ROIs in the Alzheimer’s disease (AD) tissue is significantly greater than both regions without plaques and control tissue sections. A similar trend is found in the mouse data. The increased R2* rate for the plaque ROIs in the AD compared with the amyloid precursor protein (APP)/presenilin-1 (PS1) mouse is hypothesized to be due to higher iron in the AD plaques.

plaques without iron, similar to the comparison of AD with transgenic plaques in ▶ Fig. 15.5.

The ability to discern Aβ plaques on MRI has generally been attributed to the iron within the plaques.12,13 Microscopic MRI has provided evidence that iron is not the only cause of Aβ plaque-associated hypointensities. Our data have shown that there is a synergistic dual relaxation mechanism in play between the amount of iron integrated within the plaques and the size or morphology of the plaques. The relaxation data

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Fig.15.6 Alzheimer’s(left)andamyloidprecursor protein (APP)/presenilin-1 (PS1) transgenic (right) thioflavin-S (a,b) and Perls’ iron (c,d) stains of β-amyloid plaques at 100x magnification. The thioflavin-S stain and Perls’ stain illustrate a close relationship between β-amyloid plaques and focal iron deposition in Alzheimer’s disease (AD). The relationship between plaques and iron is not seen in the APP/PS1 animal. Differences in plaque morphology between the AD and APP/PS1 plaques are evident. The human AD plaques have a dense core of fibrillar amyloid protein with a halo of amyloid protein. APP/PS1 plaques exhibit a larger and denser thioflavin-S-positive core with a smaller halo region around them. Compared with the human AD plaques, the APP/PS1 images show a reduction in focal iron within the plaques that is diffusely found throughout the plaque.

temporal lobe of AD and mild cognitive impairment (MCI) patients compared with controls.16 A longitudinal decline in global brain MTR in AD patients over a period of 6 and 12 months has also been reported.17 The basis for the decrease in MTR has been speculated as due to microstructural changes of the gray and white matter. Specifically, it has been hypothe- sized that neurodegeneration, inflammation, gliosis, and increased interstitial fluid reduce the MT ratio. When transi- tioned to the preclinical space, it is interesting to note that stud- ies using the amyloid-generating transgenic mouse model pres- ent data that are contradictory to the MTRs seen in AD. A longi- tudinal increase in global and regional brain MTR within the APP/PS1 model compared with controls has been reported.18,19 The mechanism for the increased MTR in the APP/PSI animal models has been hypothesized to be associated with Aβ-plaque load. To better understand the cause of the paradoxical human and animal model data, it is necessary to understand the physi- cal mechanism of the MT technique. MT imaging relays infor- mation on the exchange between free and bound water mole- cules.20 The transverse relaxation for protons (water) in the direct vicinity of macromolecules or cellular structures is very short (> 1 ms) compared with free diffused water, as they are rotationally (or irrotationally) bound to the macromolecules via hydrogen bonds. As a result, through dipolar coupling or chemi- cal exchange mechanisms, the macromolecular pool is able to influence the relaxation of the free protons. Saturation of the protein-bound macromolecular pool via a radiofrequency

pulse with given frequency offset causes the net magnetization of the free water pool to decrease, resulting in an increase in the MTR.

To understand proton magnetization transfer in the direct vicinity of Aβ plaques, experiments using off-resonant satura- tion of amyloid-bound protons in 60-μm slices of Alzheimer’s tissue were undertaken. An optimal predetermined off- resonant pulse at 15 kHz (50 parts per million [ppm]) was used to saturate the amyloid-bound proton pool. Amyloid plaques are again visible with thioflavin stains and correspond to the location of hypointensities on GRE images. When plaque location is overlaid on the MTR data set, it is apparent that vox- els containing amyloid plaques have increased MTR compared with the surrounding gray matter (▶ Fig. 15.11). The increased MTR in white matter verifies the MTR calculation, as white matter is known to have an increased MTR compared to that of gray matter. Regions of interest in the plaques have significantly higher MTR than in surrounding gray matter. Following known trends on MTR values in gray and white matter, the white mat- ter has a significantly greater MTR than gray matter in the data set.

The decrease in MTR in AD plaques follows the same trend as previously published amyloid-generating mouse model data. These transgenic animals produce Aβ plaques with a moderate gliotic inflammatory response. Data from individual plaque measurements support the hypothesis that the increase in MTR for the transgenic animals is in fact due to amyloid load. The

Magnetic Resonance Imaging and Histopathological Correlation

Fig. 15.7 β-Amyloids Aβ40 and Aβ42 immunohis- tologic and thioflavin-S (Thio-S) stains of amyloid plaques at 200x magnification in Alzheimer’s (top) and amyloid precursor protein (APP)/ presenilin-1 (PS1) (bottom) tissue samples. Alzheimer’s plaques contain both 40 and 42 amino-acid β-amyloid fragments. APP/PS1 transgenic plaques contain only the 40-amino-acid variant while staining negatively for Aβ42. The figure illustrates the morphologic and compositional differences between Alzheimer’s and transgenic plaques.

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Fig. 15.8 Alzheimer’s tissue samples untreated (left) and treated (right) with deferoxamine (DFO) stained with thioflavin-S (top) and Perls’ iron (bottom) stains at 200x magnification.

The β-amyloid plaques in the DFO iron-chelated samples are stripped of iron compared with untreated plaques.

Fig. 15.9 T2*-weighted (a,d) and histologic stains for Perls’ iron (b,e) and thioflavin-S (c,f) in deferoxaminemesylate salt (DFO) untreated (left) and treated (right) Alzheimer’s entorhinal cortex tissue samples. Large plaques and those with high iron content are readily visible on magnetic resonance images of the DFO-untreated samples. Amyloid plaques in DFO-treated samples with little to no associated iron retain their discernibility on the gradient echo data sets. Chelated Alzheimer’s plaques without iron generate hypointensities on T2*-weighted images similar to amyloid precursor protein (APP)/presenilin-1 (PS1) plaques without iron. The data illustrate the ability to visualize plaques without iron and support the synergistic hypothesis that plaques are able to induce transverse proton relaxation as a result of both their association with iron and their morphology.

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plaques in the AD tissue also have an increased MTR; however, in vivo, this is hypothesized to be overshadowed by the domi- nant partial-volume decrease in MTR resulting from an increase in regional interstitial fluid.

Magnetic resonance imaging of AD and corresponding histo- logic analysis of individual Aβ plaques from the same tissue

sample have allowed the establishment of specific relationships between image metrics and disease pathology. Such relation- ships will provide a foundation for clinical interpretation of MRI findings in AD and other neurodegenerative diseases, that is, the ability of MRI to determine Aβ plaque load to aid in the diagnostic determination of AD severity.

Magnetic Resonance Imaging and Histopathological Correlation

Fig. 15.10 Transmission electron microscope im- ages of an Alzheimer’s disease (AD, left) and APP/ presenilin-1 (PS1) transgenic (right) plaque at 4,600x (top) and 22,500x (bottom) magnification. The ultrastructural composition of AD and APP/ PS1 plaques are evident in the images. The Alzheimer’s plaques exhibit a reduced density compared with the transgenic plaques, even in the condensed core of the amyloid mass (bottom). The reduced density of the Alzheimer’s plaques allows the infiltration of water (protons) into the core, which is hypothesized to aid in the increased transverse relaxation associated with Alzheimer’s plaques.

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Fig. 15.11 T2*-weighted (a), Perls’ iron stain (b), thioflavin-S stain (c), and magnetization transfer ratio (MTR) images of the same Alzheimer’s entorhinal cortex tissue sample. Hypointensities on the gradient-echo magnetic resonance image correspond to thioflavin and iron-positive amyloid plaques (arrows). Selection of these plaques on the magnetization transfer image shows that these plaques cause an increase in magnetization transfer, notwithstanding the noise present in the image. This is hypothesized to be due to the macromolecular interaction of protons in the vicinity of the amyloid mass. In addition, the known increase in MTR associated with white matter tracts can be seen on the image set.

References

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. [9] Collingwood JF, Mikhaylova A, Davidson M et al. In situ characterization and mapping of iron compounds in Alzheimer’s disease tissue. J Alzheimers Dis 2005; 7: 267–272

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Part V

Non-Alzheimer’s Cortical Dementia

16 Dementia with Lewy Body Disease 150 17 Frontotemporal Lobar Degeneration 157

Non-Alzheimer’s Cortical Dementia
16 Dementia with Lewy Body Disease

Aristides A. Capizzano and Toshio Moritani

16.1 History

Dementia with Lewy bodies (DLB) is the most recently recog- nized of the major neurodegenerative dementias. Lewy bodies (LBs) are proteinaceous cytoplasmic neuronal inclusions (▶Fig. 16.1) originally described by Friedrich Lewy in Parkin- son’s disease (PD).1 The two morphologically and molecularly distinct types of LBs are the classic brainstem and cortical LBs, both of which are immunoreactive to the presynaptic protein α-synuclein (▶Fig. 16.2).2 Therefore, from a molecular stand- point, DLB is counted among the α-synucleinopathies, together with PD and multiple-system atrophy (MSA).

A report of two cases from 1961 described two elderly men with progressive dementia and flexion contractures, who on neuropathological examination revealed extensive LBs along the neuraxis as the only pathological alteration.3 More than 30 other clinical dementia cases in which LBs with or without senile plaques and neurofibrillary tangles were the main patho- logical findings were reported by Japanese investigators over the following two decades.4 The overlap between LBs and Alzheimer’s disease (AD)-like neuropathology led to the consid- eration of DLB as a variant of AD.5

By the late 1980s, there was increased recognition of a syndrome affecting as much as 20% of the demented elderly population with confusion, hallucinations, and behavioral dis- turbances in which cortical and subcortical LBs, with variable plaque formation, heralded the pathological picture.6 This syn- drome of “senile dementia of Lewy body type” was then con- sidered within the spectrum of LB diseases, between the polar types of PD and “diffuse Lewy body disease.” Improved neuro- pathological techniques to label LBs, such as anti-ubiquitin immunohistochemistry, have been instrumental in advancing

Fig. 16.2 (a,b) α-Synuclein immunohistochemistry at 1,000x. Cortical Lewy bodies. (Courtesy Dr. Patricia Kirby, University of Iowa.)

Fig. 16.1 (a) Hematoxylin and eosin stain, 600x. Cortical Lewy body (arrow) in patient with Lewy body dementia. (b) Same Lewy body at 1,000x. (Courtesy Dr. Patricia Kirby, University of Iowa.)

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16.3 Genetics

DLB was long considered a sporadic disorder with late onset, and twin investigations of DLB did not support a major genetic cause for this disease.11 However, DLB and core clinical features thereof aggregate in families.12 A systematic review suggested a genetic overlap between familial cases of DLB and PDD.13 Fur- ther support for a genetic predisposition to DLB comes from families with combined features of dementia and parkinsonism inherited in a mendelian manner.14 The first locus for DLB was mapped on chromosome 2q35-q36 in an autosomal dominant family with autopsy-confirmed DLB,15 but in-depth molecular genetic follow-up investigations did not reveal a simple patho- genic or gene dosage mutation that cosegregated with DLB, sug- gesting that the mutation responsible for DLB in this family is complex.16 Because the current understanding of the genetics of DLB is unclear and a major DLB gene has not yet been uncov- ered, it has been suggested that mutations underlying DLB are biologically more complex than expected for monogenic disorders.14

16.4 Neuropathology

Macroscopically, the degree of cortical atrophy is variable in DLB. Given the clinical importance of distinguishing DLB from AD, some studies compared pathological and imaging changes in the hippocampal formation between the two diseases. Medial temporal lobe (including the hippocampus and parahip- pocampal gyrus) area measurements in fixed brains were significantly larger in DLB than in AD or mixed AD/DLB cases.17 Accordingly, neuron counts in the perforant pathway connect- ing the entorhinal cortex with the dentate gyrus are signifi- cantly depleted in AD compared with DLB and controls, although high variability was reported.18 An important macro- scopic feature of DLB brains is pallor of the substantia nigra and locus ceruleus, as in PD, reflecting a loss of neuromelanin. Preliminary results in PD have shown signal loss seen on in vivo heavily T1-weighted MRI in the substantia nigra compared with controls, likely reflecting a loss of paramagnetic neuromela- nin.19

Microscopically, the presence of LBs is the only histo- pathological requirement for the diagnosis of DLB.7,20 Classic brainstem and cortical LBs are best demonstrated by using immunostaining for α-synuclein21 (▶Fig. 16.2), but they con- tain a variety of other molecular components, such as ubiquitin, neurofilaments, parkin, components of the ubiquitin-protea- some system, molecular chaperones, and lipids.2 LBs likely represent a cellular response to the accumulation of abnormal proteins and undergo several phases during their formation.2 Cortical LB progression starts in the amygdala, spreads to the limbic cortex, and finally spreads to the neocortex.22 Apart from LBs, other histopathological features of DLB are Lewy-related neurites, AD-type pathology (plaques and tangles), spongiform changes, and synapse loss.7

In accord with the National Institute on Aging Reagan Criteria for diagnosis of AD,23 DLB diagnosis is related directly to the burden of LB pathology and inversely to AD pathology.8 Sub- types of DLB have been recognized in relationship to the burden

the understanding of what is now termed dementia with Lewy bodies, which accounts for approximately 15% of cases of late- onset dementia, being the second most prevalent degenerative dementia after AD.

16.2 Clinical Features

The characteristic initial symptoms and signs of DLB have been operationalized in consensus diagnostic criteria origi- nally published in 19967 and revised in 2005.8 The essential central feature is dementia, with memory deficits not neces- sarily occurring in the early stages but common with pro- gression, and particularly prominent deficits in attention, executive function, and visuospatial skills. Core features are fluctuating cognition, recurrent visual hallucinations, and spontaneous parkinsonism, and these distinguish DLB from AD. Suggestive diagnostic features are rapid eye movement sleep behavior disorder, severe neuroleptic sensitivity, and reduced dopamine transporter uptake in the basal ganglia on single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Probable DLB is diagnosed with two core features or one core and at least one suggestive feature; possible DLB is diagnosed with either one core or one or more suggestive features.8 Supportive features of the diagnosis, which are commonly present but do not have proven diagnostic specificity, are repeated falls, transient unexplained loss of consciousness, severe auto- nomic dysfunction, systematized delusions, depression, nonvisual hallucinations, relative preservation of medial temporal lobe volume on structural imaging, generalized low SPECT/PET uptake with reduced occipital activity, low 123I-metaiodobenzylguanidine (MIBG) myocardial uptake, and prominent slow-wave activity on electroencephalogra- phy with temporal lobe transient sharp waves. A diagnosis of DLB is less likely in the presence of clinical or imaging signs of cerebrovascular disease, of any other illness suffi- cient to account at least in part for the clinical picture, or if parkinsonism appears only at a stage of severe dementia.8

Men are more susceptible than women to DLB. The parkin- sonian signs are commonly bilateral, with rigidity, bradykine- sia, amimia, and slow shuffling gait. Resting tremor is less common.9 These symptoms show modest response to levo- dopa treatment. Visual hallucinations are the best clinical dis- criminator with AD, seen in up to 80% of DLB patients; they are recurrent and vivid and typically involve animals or peo- ple. Depression is commonly associated with DLB. In terms of imaging, supportive features for DLB diagnosis are lack of medial temporal atrophy (as typically seen in AD), low SPECT/ PET perfusion in the occipital lobe, and low MIBG myocardial scintigraphy.

Main differential diagnostic considerations of DLB are PD with dementia (PDD) and AD. Diagnostic criteria indicate that dementia should occur before or concurrently with parkinson- ism to diagnose DLB,8 whereas PDD is diagnosed when parkin- sonism is present for 12 months or longer before the onset of dementia.10 The arbitrariness of the distinction between DLB and PDD strongly suggests that both clinical phenotypes lie along the same pathological continuum.

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of AD-type pathology.24 The “pure” form of DLB contains LBs in only the brainstem and cerebral cortex; LBs associated with senile plaques but a low Braak tangle stage define the “com- mon” form; finally, LBs in conjunction with senile plaques and NFTs sufficient to diagnose AD are seen in the “AD form” of DLB.

16.5 Neuroimaging

16.5.1 Structural Magnetic Resonance

Imaging

In contradistinction to AD, where brain atrophy has been exten- sively reported from neuroimaging studies, atrophic changes are less conspicuous and are distributed differently in imaging studies of DLB (▶Fig. 16.3). Using voxel-based morphometry (VBM), a pattern of volume loss involving the dorsal midbrain, hypothalamus, and substantia innominata with sparing of the hippocampus and temporoparietal cortex has been proposed in DLB (▶ Fig. 16.4, ▶ Fig. 16.5).25 Furthermore, patients with a high probability of DLB on postmortem neuropathological assessment were found to have a low volume of dorsal meso- pontine gray matter with normal hippocampal volumes on antemortem MRI.26 Moreover, a high-resolution study of the medial temporal lobes with submillimiter pixel resolution27

showed that AD patients had a thinner subiculum, smaller CA1 area, and effacement of the hippocampal striation compared with DLB, features that could therefore distinguish between the two disorders. On the other hand, other studies found hippo- campal volume loss in DLB. A shape analysis of hippocampal volumes in DLB showed a differential atrophy pattern involving mostly the anterior aspect of the CA1 sector in DLB compared with AD28; hippocampal volume deficit was between 10 and 20% in DLB vs. controls (▶Fig. 16.6). More recently, using the same hippocampal radial distance technique as in the previ- ously mentioned study, DLB had left-predominant hippocampal atrophy centered at CA1 and the subiculum compared with controls, whereas no significant differences were detected between DLB and AD, although the latter may be secondary to the smaller sample size of DLB subjects.29

White matter T2 signal hyperintensities (WMSHs) are a well- known feature in the elderly and in patients with neuro- degenerative or vascular dementia; they correlate with age and history of hypertension and denote myelin loss, gliosis, and periventricular interstitial fluid accumulation. Comparison of DLB and AD showed that the results of WMSH load were inconsistent even among quantitative studies, probably reflect- ing differences in methods or subject inclusion criteria. Greater WMSHs were seen in AD than in DLB, and the latter showed WMSHs similar to those of controls30; also, similar WMSH loads

Fig. 16.3 A 75-year-old man with executive visuospatial dysfunction and visual hallucinations, rapid eye movement (REM) behavior disorder, and gait instability raising concern for dementia with Lewy bodies. (a,b) Axial T1-weighted images showing bilateral mild frontotemporal volume loss. (c) Sagittal T1-weighted with mild expansion of the sylvian fissure. (d) Axial fluid-attenuated inversion recovery with mild posterior periven- tricular leukoaraiosis.

152

in AD and DLB have been reported.31 The frequent coexistence of DLB with AD should also be considered (▶ Fig. 16.7).

Apart from the preceding differences between DLB and AD, an important comparison is the differential atrophy pattern between DLB and PDD, the main clinical phenotypes of LB pathology. Using VBM, DLB had gray matter reduction in the right superior frontal, premotor, and inferior frontal regions compared with PDD.32 Furthermore, frontal gray matter deficits in DLB correlated with attentional deficits, whereas right hip- pocampal and amygdala volumes correlated with visual mem- ory performance. In a pathologically confirmed cohort of DLB and PDD, amygdala volumes in MRI in vivo inversely corre- lated with the density of Lewy body neuropathology in the amygdala.33

16.5.2 DiffusionTensorImaging
Using tract-based spatial statistics, a voxel-wise approach to

diffusion tensor imaging (DTI) data in the style of VBM, DLB displayed lower fractional anisotropy (FA) of parieto-occipital white matter voxels compared with controls, with significantly fewer changes in frontal regions. AD subjects, on the other hand, had more diffuse reductions in FA on both sides of the central sulcus. Mean diffusivity (MD) changes were

Dementia with Lewy Body Disease

Fig. 16.4 Voxel-based morphometry-derived patterns of gray matter loss in Lewy body dementia (DLB) (left side) vs. controls (right side) and Alzheimer’s disease vs. controls (right side) corrected for multiple comparisons, p < 0.05. Gray matter loss in DLB is focused on the substantia innominata, dorsal midbrain, and hypothalamus. A, anterior; P, posterior. (Used with permission from Whitwell JL, Weigand SD, Shiung MM, et al. Focal atrophy in dementia with Lewy bodies on MRI: a distinct pattern from Alzheimer’s disease. Brain 2007;

130(Pt 3):708–719.)

widespread in both conditions. The DTI changes in DLB correlated with episodic memory, letter fluency, and parkinso- nian signs.34 A previous study demonstrated increased MD in the amygdala and reduced FA in the inferior longitudinal fascic- ulus in DLB, which correlated with parkinsonism and visual hallucinations, respectively, with a different pattern of DTI changes in AD patients who had involvement of temporoparie- tal regions and associated white matter tracts.35 Also, DLB (but not AD) patients had reduced FA compared with controls in the bilateral inferior occipitofrontal and left inferior longitudinal fasciculi, encompassing visual association areas, with both demented groups showing lower FA in the uncinate fasciculus bilaterally.36

16.5.3 Dopaminergic Imaging

Dopaminergic function in DLB using either SPECT or PET has become a suggestive feature of the diagnosis under the consen- sus criteria.7,8 DLB and PDD patients display severely reduced dopaminergic uptake in the caudate and putamen compared with controls and AD patients. [123I]N-ω-fluoropropyl-2β- carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT) SPECT has 80 to 90% sensitivity and specificity for the diagnosis of DLB and PDD,37 which becomes clinically significant for the

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Fig. 16.5 Three-dimensional surface renders showing voxel-based morphometry-derived patterns of gray matter loss in Lewy body dementia (DLB) vs. controls (left) and Alzheimer’s disease (AD) vs. controls (right) corrected for multiple comparisons; p < 0.05. DLB shows much less cortical atrophy than AD. (Used with permission from Whitwell JL, Weigand SD, Shiung MM, et al. Focal atrophy in dementia with Lewy bodies on MRI: a distinct pattern from Alzheimer’s disease. Brain 2007;130(Pt 3):708–719.)

differential diagnosis of DLB and AD. The specificity of FP-CIT scans to distinguish DLB from FTD, however, is significantly less because one-third of FTD cases also have reduced striatal dopa- mine uptake.38 The reduced dopaminergic uptake in the basal ganglia in DLB correlates with neuronal depletion in the sub- stantia nigra but not with the pathological burden of α-synu- clein, tau, or amyloid deposition, suggesting that disruption of the nigrostriatal pathway is responsible for the FP-CIT scan abnormalities in DLB.39

bution of perfusion deficits, with visual hallucinations corre- lated with parieto-occipital hypoperfusion.43 Clinical fluctua- tions, a core characteristic of DLB, correlate with brain perfu- sion changes on hexamethylpropyleneamine (HMPAO) SPECT,44 and reduced hallucinations in response to the acetylcholin- esterase inhibitor donepezil correlate with improved occipital blood flow.45

16.5.5 Management of Lewy Body

Dementia

No disease-modifying treatment is available at this point for patients with DLB. Nonpharmacologic interventions include education, reassurance, orientation and memory prompts, attentional cues, and targeted behavioral interventions.46 Par- kinsonism is treated with the lowest effective dose of levodopa because higher doses are associated with worsened confusion and hallucinations. The percentage of patients with more than 10% motor improvement is lower among DLB patients than for those with PD and PDD.47 Cholinesterase inhibitors are effective and relatively safe for treating neuropsychiatric and cognitive symptoms in DLB.48 The role of these agents in DLB may become important given the high risk of severe sensitivity reactions and cerebrovascular events with neuroleptics in these patients. However, current evidence supporting the efficacy of

16.5.4 Perfusion and Metabolism

Imaging

Occipital hypoperfusion and hypometabolism in DLB have been reported using SPECT and fluorodeoxyglucose (FDG) PET, respectively.40 In distinguishing DLB from AD, however, FP-CIT displayed better diagnostic accuracy than technetium 99m- exametazime SPECT.41 Accordingly, low SPECT/PET uptake in the occipital lobes is considered only among the supportive fea- tures of the diagnosis of DLB.8 FDG PET was shown to be more sensitive than SPECT-iodoamphetamine to the occipital and parietal changes in DLB, which may result from improved spa- tial resolution with PET over SPECT and also from higher meta- bolic than perfusion deficits in DLB.42 Furthermore, psychotic symptom clusters in DLB correlate with the anatomical distri-

Dementia with Lewy Body Disease

Fig. 16.6 A 71-year old woman with Lewy body dementia (DLB) with parkinsonism, delirium, and orthostatic hypotension. Axial fluid-attenuated inversion recovery (FLAIR) (upper row) and coronal inversion recovery (IR) T1 weighted images (lower row) displaying bilateral temporal and hippocampal atrophy without significant FLAIR hyperintensity. R, right; S, superior. (Courtesy of Dr. Kei Yamada, Kyoto Prefectural University of Medicine, Japan.)

Fig. 16.7 A 74-year-old man with a clinical picture consistent with mixed Lewy body dementia (DLB)/Alzheimer’s disease (AD) dementia. (a) Axial fluid-attenuated inversion recovery showing confluent leukoaraiosis. Oblique coronal T1-weighted (b) and T2- weighted (c,d) images perpendicular to the temporal horn display severe hippocampal atrophy and confluent

leukoaraiosis.

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cholinesterase inhibitors or the N-methyl-D-aspartate receptor

antagonist memantine in DLB remains inconclusive.49

References

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Lewy bodies: a comparative study with Alzheimer’s disease. Ann Neurol
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MRI shows stage-dependent substantia nigra signal loss in Parkinson’s dis-
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. [20] Tolnay M, Probst A. International Winter Meeting on Neuropathology and
Genetics, of Dementia. In: Neuropathology and Genetics of Dementia. Tolnay M, Probst A, eds. New York; London: Kluwer Academic/Plenum Publishers; 2001

. [21] Lowe J. Neuropathology of dementia with Lewy bodies. In: Handbook of Clin- ical Neurology: Dementias. Aminoff M, Boller F, Swaab D, eds. 3rd Series. New York: Elsevier; 2008;321–330

. [22] Marui W, Iseki E, Nakai T et al. Progression and staging of Lewy pathology in brains from patients with dementia with Lewy bodies. J Neurol Sci 2002; 195: 153–159

. [23] Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute working group on diagnostic criteria for the neuropathological assessment of Alzheimer’s disease. Neurobiol Aging 1997; 18 Suppl: S1–S2

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Kantarci K, Ferman TJ, Boeve BF et al. Focal atrophy on MRI and neuro- pathologic classification of dementia with Lewy bodies. Neurology 2012; 79: 553–560

Firbank MJ, Blamire AM, Teodorczuk A et al. High resolution imaging of the medial temporal lobe in Alzheimer’s disease and dementia with Lewy bodies. J Alzheimers Dis 2010; 21: 1129–1140
Sabattoli F, Boccardi M, Galluzzi S, Treves A, Thompson PM, Frisoni GB. Hippo- campal shape differences in dementia with Lewy bodies. Neuroimage 2008; 41: 699–705

Chow N, Aarsland D, Honarpisheh H et al. Comparing hippocampal atrophy in Alzheimer’s dementia and dementia with lewy bodies. Dement Geriatr Cogn Disord 2012; 34: 44–50
Burton EJ, McKeith IG, Burn DJ, Firbank MJ, O’Brien JT. Progression of white matter hyperintensities in Alzheimer’s disease, dementia with lewy bodies, and Parkinson’s disease dementia: a comparison with normal aging. Am J Geriatr Psychiatry 2006; 14: 842–849

Oppedal K, Aarsland D, Firbank MJ et al. White matter hyperintensities in mild lewy body dementia. Dement Geriatr Cogn Dis Extra 2012; 2: 481–495 Sanchez-Castaneda C, Rene R, Ramirez-Ruiz B et al. Correlations between gray matter reductions and cognitive deficits in dementia with Lewy Bodies and Parkinson’s disease with dementia. Mov Disord 2009; 24: 1740–1746 Burton EJ, Mukaetova-Ladinska EB, Perry RH, Jaros E, Barber R, O’Brien JT. Neuropathological correlates of volumetric MRI in autopsy-confirmed Lewy body dementia. Neurobiol Aging 2012; 33: 1228–1236

Watson R, Blamire AM, Colloby SJ et al. Characterizing dementia with Lewy bodies by means of diffusion tensor imaging. Neurology 2012; 79: 906–914 Kantarci K, Avula R, Senjem ML et al. Dementia with Lewy bodies and Alz- heimer’s disease: neurodegenerative patterns characterized by DTI. Neurol- ogy 2010; 74: 1814–1821

Kiuchi K, Morikawa M, Taoka T et al. White matter changes in dementia with Lewy bodies and Alzheimer’s disease: a tractography-based study. J Psychiatr Res 2011; 45: 1095–1100
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Morgan S, Kemp P, Booij J et al. Differentiation of frontotemporal dementia from dementia with Lewy bodies using FP-CIT SPECT. J Neurol Neurosurg Psychiatry 2012; 83: 1063–1070
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Aristides A. Capizzano and Toshio Moritani

Frontotemporal lobar degeneration (FTLD) includes different neurodegenerative disorders clinically characterized by pro- gressive behavioral changes and language disturbances. The average age at clinical onset is 50 to 60 years, and the incidence is roughly equal between men and women. Prevalence under 65 years has been reported at 15 per 100,000 inhabitants1 and is thought to approach that of presenile Alzheimer’s disease (AD). Twenty percent of FTLD patients are older than 65 at onset.2 Survival is shorter than for AD, with functional and cog- nitive decline occurring significantly more rapidly in FTLD than in AD, although there is heterogeneity depending on the partic- ular FTLD syndrome involved.3

17.1 Clinical Features

17.1.1 Frontotemporal Dementia

Syndromes

Frontotemporal dementia (FTD) syndromes encompass three clinical syndromes: behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA).4 These differentiate in clinical and anatomical terms but not in pathological substrate; although one syndrome predominates early in the disease process, with progression of brain atrophy, there is increasing clinical overlap.5

Behavioral variant FTD is characterized by profound person- ality change with disinhibition and/or apathy, blunted affect, loss of insight and empathy to others, and pressured speech. These are the characteristics of bvFTD that frequently lead to first consultation at a psychiatric clinic. Anatomically, it may involve dorsomedial or ventromedial and orbitofrontal pre- frontal areas. Cognitive deficits are less severe than the person- ality changes and involve executive tasks, with impairment in working memory, attention, set shift, verbal fluency, response inhibition, and abstract reasoning. Memory complaints are var- iable, and there is preservation of declarative verbal and visual memory in contradistinction with AD.

Semantic dementia or semantic variant of primary progres- sive aphasia (svPPA) is a disorder of progressive loss of knowledge about words and concepts associated with ante- rior temporal atrophy; the clinical manifestation depends on the side of the brain preferentially involved. Left-predomi- nant cases manifest as fluent, anomic aphasia. Patients com- plain of word-finding difficulties and trouble with naming; speech remains fluent with intact syntax and prosody. The loss of knowledge extends beyond language, with a lack of ability to put objects in their proper context. Episodic mem- ory and executive and spatial functions are preserved. Sub- jects with right-predominant temporal lobe atrophy show a behavioral syndrome with flat affect, loss of insight, and alterations of social conduct.

Progressive nonfluent aphasia, or agrammatic variant of pri- mary progressive aphasia (agPPA), is a disorder of expressive language and speech production related to left perisylvian atro- phy. Naming and repetition are impaired, but comprehension of

Frontotemporal Lobar Degeneration

17 Frontotemporal Lobar Degeneration

single words is preserved. Reading and writing are affected with errors, and speech apraxia is commonly present. PNFA may resemble logopenic aphasia (▶Fig. 17.1), in which brain atrophy involves more posterior brain regions and is thought to be associated with AD.6

Apart from the three classic syndromes outlined in the pre- ceding, there is a strong association between FTLD and amyo- trophic lateral sclerosis (ALS): half of ALS patients have cognitive impairment of the frontal type; 15% meet the criteria for FTD.7 Conversely, in a prospective study, up to 50% of FTD patients had clinical features of ALS, and 14% met the criteria for definite ALS.8 Apart from the clinical overlap, FTLD and ALS share patho- logical and genetic features that suggest that both entities con- stitute manifestations of the same disease process.9 Finally, there is also clinical overlap with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), both of which are also tauopathies, covered in Chapter 18 in this volume.

17.1.2 Inclusion and Exclusion Criteria

Consensus criteria for the core FTD syndromes have been widely used in research and clinical practice.4 For bvFTD, five core diagnostic features are required to fulfill the diagnostic criteria: insidious onset and gradual progression, early decline in social interpersonal conduct, early impairment in regulation of personal conduct, early emotional blunting, and early loss of insight.4 However, limitations of these criteria, such as ambigu- ity of some descriptors and arbitrary distinction of core and supportive features, have led to more recently revised guide- lines for diagnosis of bvFTD.10 The International Consensus Diagnostic Criteria for possible bvFTD require three of the fol- lowing symptoms: early behavioral disinhibition; early apathy or inertia; early loss of sympathy or empathy; early persevera- tive, stereotyped, or compulsive behavior; hyperorality; and a neuropsychological profile of executive deficits with sparing of memory and visuospatial functions. Probable bvFTD is diag- nosed when, apart from meeting the criteria for possible bvFTD, the following are present: significant functional decline and frontal and/or anterior temporal atrophy (on magnetic reso- nance imaging [MRI] or computed tomography [CT]) or hypo- metabolism/hypoperfusion (on positron emission tomography [PET] or single-photon emission computed tomography [SPECT]). Exclusionary criteria for bvFTD are that deficits are better accounted for by nondegenerative disorders, that behav- ioral disturbance is better accounted for by a psychiatric diag- nosis, or that biomarkers are strongly indicative of AD or other neurodegenerative process.10

17.2 Genetics

Between 35 and 50% of FTLD patients have a family history of dementia, which supports a strong genetic role in this disease, usually involving autosomal dominant inheritance.11 Approxi- mately 50% of familial cases are associated with mutations in the tau or progranulin (GRN) genes, with less than 5% of muta-

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Fig. 17.1 A 73-year-old woman with primary progressive aphasia, logopenic variant. Coronal T2-weighted images perpendicular to the temporal lobe axis (a-d) in rostrocaudal order displaying mild to moderate left temporopolar and left hippocampal atrophy.

tions occurring in the valosin-containing protein, charged mul- tivesicular body protein 2B, transactive response (TAR)-DNA binding protein (TARDP), and fused in sarcoma (FUS) genes, which illustrate the heterogeneity of FTLD.12 More than 40 mutations have been recognized in the tau gene in families with FTD and parkinsonism associated with chromosome 17q (FTDP-17), which correlate with tau neuropathology.13 The GRN gene, also on chromosome 17, like tau, has been involved in more than 60 mutations in familial FTD. GRN encodes pro- granulin, a growth factor abundantly expressed in specific neu- ronal populations. Neuropathologically, GRN mutations result in tau-inegative, ubiquitin- and TDP-43-positive inclusions with characteristic intranuclear neuronal inclusions.14 More recently, the expansion of a noncoding hexanucleotide repeat in the C9ORF72 gene on chromosome 9p was shown to be the most common genetic abnormality in familial FTD (11.7%) and famil- ial ALS (23.5%).15 Different patterns of gray matter atrophy were identified using voxel-based morphometry (VBM) among patients with C9ORF72, tau, and progranulin mutations and sporadic FTD.16

17.3 Neuropathology

Although FTLD is pathologically heterogeneous, the different subtypes share common features. An early recognized feature is gross circumscribed atrophy of the frontal or anterior temporal lobes. The early pattern of atrophy, as depicted by clinical imag- ing, determines the specific clinical syndrome. Thus, prefrontal

atrophy leads to bvFTD, anterior temporal atrophy correlates with SD, and left perisylvian atrophy correlates with PNFA. Because the sequence of atrophy in FTLD is predictable, a stag- ing system has been proposed: Initial atrophy occurs in the orbital and superior medial frontal cortices and hippocampus (stage 1), progressing to involve other anterior frontal regions, temporal cortices, and basal ganglia (stage 2), and then becom- ing diffuse with white matter loss and ventricular dilatation (stage 3) until marked atrophy is observed in all areas, includ- ing marked basal ganglia flattening resulting in concavity of the lateral ventricles (stage 4).17

Based on the types of intracellular inclusions and immuno- histochemistry, three subtypes of FTLD are recognized18: (1) tau-positive pathology with or without inclusions, (2) tau- negative ubiquitin-positive inclusions, and (3) tau-negative, ubiquitin-negative pathology.

17.3.1 Frontotemporal Lobe Degeneration-Tau: Pick’s Disease and Other Tauopathies

Named after Arnold Pick, who in 1892 reported the case of a 71-year-old man with behavioral changes and progressive aphasia with focal left temporal atrophy, Pick disease is charac- terized by Pick bodies: round/oval argyrophilic cytoplasmic neuronal inclusions (▶ Fig. 17.2). These are found in the hippo- campus, amygdala, and frontal and temporal isocortex and are readily detected with tau immunohistochemistry and stain

Frontotemporal Lobar Degeneration

on clinical CT and MRI studies that correlate with the clinical syndrome.24 In bvFTD, there is an anteroposterior gradient of atrophy involving the frontal and temporal lobes, with sparing of the parietal and occipital lobes. Although commonly bilateral, the volume loss is often asymmetrical (▶ Fig. 17.3, ▶ Fig. 17.4). A recent meta-analysis of VBM studies in bvFTD demonstrated significant gray matter loss in prefrontal regions compared with controls, with the most significant changes in the medial frontal lobes and also volume reductions in the insula and striatum.25 The earliest site of involvement is the orbitofrontal cortex, which shows sulcal widening before the mesiofrontal regions. The dorsolateral prefrontal cortex becomes involved later in the course of the disease (▶ Fig. 17.5). Hippocampal and amygdalar atrophy are also seen with bvFTD.26 Anterior mesiotemporal atrophy involving the amygdala and hippocampal head pre- dominates in FTLD and correlates with temporopolar atrophy. In the early phase of the disease, structural imaging is often normal, but most patients progress to show frontotemporal atrophy later. On 1-year follow-up, limbic and paralimbic regions, particularly the anterior cingulate cortex, exhibit pro- gressing gray matter atrophy in bvFTD.27 Furthermore, baseline determination of the site of predominant brain atrophy predicts functional decline in bvFTD, with frontal and frontotemporal predominant atrophy subtypes having faster decline compared with the temporal dominant and temporofrontal parietal sub- types.28 Behavioral deficits, such as disinhibition and apathy, are associated with right frontotemporal atrophy in patients with dementia.29

On the other hand, it has been recognized that there is a sub- group of bvFTD that does not display brain atrophy on MRI and has a significantly more benign course of the disease.30 Yet another perplexing observation is the occurrence of bvFTD symptoms in patients displaying brain sagging from intracranial hypotension,31 a potentially reversible condition, for which the name of frontotemporal brain sagging syndrome was proposed (▶Fig. 17.6). Very interestingly, the latter two groups of patients are almost exclusively males, suggesting a strong gen- der effect on the vulnerability for the clinical phenotype of bvFTD.

Semantic dementia shows consistent left anterior temporal lobe atrophy, also involving inferior and mesial temporal lobe regions, with a an anteroposterior gradient (predominant atro- phy seen anteriorly) that distinguishes SD from AD.32 The rate of volume loss over time is also more accelerated in FTD (pre- dominantly frontal atrophy) and SD (predominantly temporal atrophy) compared with AD.33

Progressive nonfluent aphasia leads to cortical thinning and atrophy of the left inferior frontal lobe, including the Broca area, superior temporal lobe, and insula (▶Fig. 17.7).6,34 Therefore, the patterns of cortical thinning differ between both variants of PPA, with more frontal and parietal atrophy in PNFA and bilateral temporal cortical atrophy in SD.34 PPA patients who show aphasia of speech, a motor speech disorder characterized by slow speaking rate, abnormal prosody, and distorted sound substitutions, additions, and repetitions have predominant atrophy in premotor and supplementary motor cortices, whereas the anterior perisylvian region correlates with nonfluent aphasia.35

Fig. 17.2 Tau immunohistochemistry at X600. Pick bodies in the dentate gyrus. (Courtesy Dr. Patricia Kirby, University of Iowa.)

variably for ubiquitin. The predominant tau isoform in Pick’s disease is 3-repeat (3R).19

17.3.2 FTLD with Ubiquitin and Transactive-Response-43 Positive Inclusions

Transactive-response DNA-binding protein of 43k Da (TDP-43) is an RNA and DNA binding protein with neuronal and glial nuclear localization that is normally involved in gene transcrip- tion regulation. TDP-43 is the main component of inclusions seen in ALS/motor neuron disease and FTLD-U, in which the protein is detected in the cytoplasm.20 There is a wide range in the morphology and distribution of ubiquitin and TDP-43- positive inclusions, with significant overlap between FTD and ALS, suggesting that these syndromes are strongly related.21

17.3.3 Dementia Lacking Distinctive

Histology

The term dementia lacking distinctive histology (DLDH) describes dementia cases with evident atrophic brain changes, but with both tau and ubiquitin immunohistochemistry being negative,22 and represents a minority of cases. Apart from FTLD-T, FTLD-U, and DLDH, which together encompass the vast majority of FTLD cases, other rare subtypes have been reported. More importantly, patients with the clinical syndromes of FTLD may present lack of FTLD neuropathology but rather have pathological findings of AD, vascular dementia, dementia with Lewy bodies (DLB), prion disease, or even normal brains on autopsy.23

17.4 Neuroimaging 17.4.1 Structural Imaging

In contradistinction to the subtle structural imaging findings of LBD, FTLD cases demonstrate characteristic atrophic patterns

159

Non-Alzheimer’s Cortical Dementia

Fig. 17.3 A 55-year-old man with apraxia, impaired visual reasoning, acalculia, deficient executive functioning, and defective speeded visual processing. He had less pronounced deficits in the areas of verbal memory, associative fluency, and verbal comprehension of complex instructions. Symptoms progressed over 7 years. (a) Right sagittal T1, (b) axial T2, (c,d) coronal T2-weighted magnetic resonance imaging.

Fig. 17.4 Same patient’s magnetic resonance imaging as ▶ Fig. 17.3. (a) Right sagittal T1 and (b) axial T2 at the corresponding levels of (a) and (b) on ▶ Fig. 17.3, respectively, but 7 years earlier, showing interval marked progression of right-predominant frontotemporal and parietal atrophy.

160

17.4.2 Diffusion Tensor Imaging and

Functional Magnetic Resonance Imaging

Diffusion tensor imaging (DTI) studies in bvFTD showed bilat- eral involvement of white matter tracts connecting the frontal lobes, such as the anterior cingulum, superior longitudinal fas- ciculus, and genu of the corpus callosum.36,37 PPA patients dis- played more focal white matter involvement than bvFTD,

patients with differential involvement in the three clinical sub- types of PPA (nonfluent, semantic, and logopenic variants).37 White matter disorganization in FTLD likely results from axonal degeneration secondary to neuronal body death, as supported by the correlation between white matter changes and cortical atrophy.

Semantic dementia patients displayed abnormal white matter on DTI analysis involving the uncinate and inferior

weighted specificity of 79.9%.40 A pattern of bilaterally reduced frontal cerebral blood flow in the absence of parietal hypoperfusion is characteristic in pathologically confirmed FTLD.41 However, there is substantial heterogeneity in the reported SPECT results. Reduced frontal and anterior tempo- ral glucose metabolism in FTD compared with controls has been reported using FDG-PET (▶ Fig. 17.8), with involvement also of the medial temporal lobes, striatum, and thalamus.42 The regions of hypometabolism in FTD correspond to those with cortical atrophy as determined with MRI using VBM analysis, whereas less congruent and asymmetric changes are seen in the temporal lobes.43

Using Pittsburgh compound-B (PiB-PET), which labels amy- loid deposits as those present in AD but not FTD neuro- pathology, PET imaging had 89.5% sensitivity and 83% specificity in distinguishing FTD from AD, with an overall simi- lar diagnostic accuracy compared with FDG-PET.44 PNFA shows reduced glucose metabolism in left frontal regions, whereas in SD the left anterior temporal lobe is hypometabolic.45 The two latter subtypes of FTLD also show less amyloid tracer uptake

longitudinal fasciculi, whereas nonfluent patients had damage of the superior longitudinal fasciculus,38 which corresponds to the topography of cortical atrophy in these disorders. White matter tract degeneration in PNFA involves primarily the left superior longitudinal fasciculus and its subcomponent the arcu- ate fasciculus, which projects to the inferior frontal lobe, with sparing of ventral tracts.38

Resting-state fMRI studies evaluating functional connectivity described reduced connectivity in the salience network (includ- ing the anterior cingulate and frontoinsular regions) in bvFTD, with increased connectivity in the default network, features which may distinguish FTLD from AD.39

17.4.3 Nuclear Medicine

Nuclear medicine clinical imaging studies in FTLD demon- strate abnormal brain perfusion and glucose metabolism using SPECT and PET, respectively. A recent meta-analysis of brain perfusion SPECT studies for differentiating AD from FTD reported pooled weighted sensitivity of 79.7% and pooled

Frontotemporal Lobar Degeneration

Fig. 17.5 A 60-year-old man with severe mixed dementia with 10 years of evolution: Alzheimer’s disease early onset, behavioral variant frontotemporal dementia. (a-d) axial computed tomography (CT), (e,f) coronal CT images with prominent bilateral anterior prefrontal cortical atrophy and marked bilateral mesial temporal atrophy (left > right) and enlargement of the third ventricle.

161

Non-Alzheimer’s Cortical Dementia

Fig. 17.6 Frontotemporal brain sagging syndro- me. A 48-year-old man with clinical diagnosis of behavior variant frontotemporal dementia and severe brain sagging on magnetic resonance imaging (MRI). (a) Sagittal T1- (b-d) axial T2- weighted MRI. Neuropathological evaluation at autopsy was negative for frontotemporal lobar dementia.

Fig. 17.7 An 84-year-old woman with progressive nonfluent aphasia. Axial fluid-attenuated inversion recovery (FLAIR) (upper row) and coronal IR T1- weighted images (lower row) with bilateral (right greater than left) perisylvian and hippocampal atrophy and FLAIR hyperintensity. (Courtesy Dr. Kei Yamada, Kyoto Prefectural University of Medicine, Japan.)

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Frontotemporal Lobar Degeneration

Fig. 17.8 Sagittal reconstructions of fluorodeoxyglucose (FDG) posi- tron emission tomography with classical findings in frontotemporal lobar dementia of marked frontal hypometabolism with preservation of occipitoparietal glucose uptake. (Courtesy Dr. Yusuf Menda, University of Iowa.)

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388–401

Part VI

Dementia with Extrapyramidal Syndromes

18 Parkinson’s Disease 166 19 Atypical Parkinsonian Syndromes 180 20 Secondary Parkinsonism 186

166

Dementia with Extrapyramidal Syndromes

18 Parkinson’s Disease
Jennifer G. Goldman, John W. Ebersole, Doug Merkitch, and Glenn T. Stebbins

Parkinson’s disease (PD) is a chronic and progressive neuro- degenerative disease that affects about 1 to 2% of the popula- tion older than 60 years. About four million people over the age of 50 have PD, and rates are expected to double by 2030.1 PD symptoms include its cardinal motor features, including brady- kinesia, resting tremor, rigidity, and gait or postural impair- ment. In addition, nonmotor features are well recognized in cognitive, behavioral, mood, sleep, autonomic, vision, and pain systems. These motor and nonmotor features can occur throughout the stages of PD, extending from premotor or early PD to moderate and advanced PD, and they affect daily func- tion, independence, and the quality of life of patients and care- givers. At present, however, no curative or neuroprotective therapies for PD have been established, but imaging and other biomarkers may play a role in the development of these therapeutics.

The diagnosis of PD has been largely clinically based, but more recently techniques like dopamine transporter imaging, transcranial ultrasound (TCS), diffusion tensor imaging (DTI), and others provide a way to detect brain changes associated with PD or parkinsonian disorders. Structural, functional, meta- bolic, and neurochemical imaging techniques may advance our understanding of the underlying neurochemistry and neuro- pathology of PD. PD is accompanied by neurodegeneration and neurotransmitter changes in the brainstem, striatal, subcortical, and cortical regions, which affect norepinephrine, serotonin, dopamine, acetylcholine, and glutamate, among others. Lewy bodies with α-synuclein staining and depigmentation of sub- stantia nigra neurons are the neuropathological hallmarks of PD. A stepwise staging system of neurodegeneration has been proposed, beginning with Lewy-related changes in the auto- nomic and olfactory systems and subsequently involving the brainstem and cortex.2,3 The field awaits in vivo imaging of α- synuclein in PD patients, although research is ongoing. This chapter discusses neuroimaging in PD as related to the diagno- sis of PD, its motor features and complications, and nonmotor issues that can occur not only in the premotor phase of PD but also in more advanced PD.

18.1 Imaging in the Diagnosis of Parkinson’s Disease

18.1.1 Early Diagnosis

The diagnosis of PD has largely relied on clinical criteria demon- strating the classic motor features of rest tremor, bradykinesia, rigidity, and gait impairment.4 However, evidence suggests that dopaminergic degeneration in the substantia nigra precedes symptom onset, with clinical symptoms not appearing until approximately 80% of striatal and 50% of nigral dopaminergic neurons are lost.5 Further, degeneration of dopaminergic neu- rons progresses most rapidly during the presymptomatic phase and the first years after symptom onset.6,7,8 Thus, early diagno- sis is critical for allowing early intervention and developing possible neuroprotective measures. Imaging techniques that

may aid in the presymptomatic or early diagnosis of PD include molecular imaging of dopamine transport proteins using single-photon emission computed tomography (SPECT) and positron emission tomography (PET), TCS, and magnetic reso- nance imaging (MRI) with techniques such as DTI. SPECT imag- ing can measure the density of transmembrane dopamine transporters (DATs) and thereby reflect presynaptic dopaminer- gic neuron integrity in vivo. [123I]FP-CIT (ioflupane I-123, DaTSCAN) and 123I-labeled-2β-carbomethoxy-3β-(4-iodo- phenyl-nortropane ([123I]-β-CIT), among others, are radiophar- maceuticals used for SPECT brain imaging.9 DAT imaging lig- ands differ in their kinetics and dopamine transporter affinity; [123I]FP-CIT has a rapid time to peak (2 to 3 hours), whereas [123I]-β-CIT has a longer time to peak (8 to 18 hours), although both have a prolonged washout phase. Studies are interpreted based on the signal shape and intensity in the striatal regions; normal studies demonstrate two symmetric, crescent-shaped regions of uptake, with distinct margins relative to surrounding brain tissue (▶Fig. 18.1), whereas abnormal studies reveal either symmetric or asymmetric decreased or absent activity in the putamen greater than caudate, such as in PD.10 SPECT imag- ing has been proposed as a highly sensitive indicator of early PD.11 [123I]-β-CIT SPECT imaging had 92% sensitivity and 100% specificity in diagnosing PD compared with the gold standard of clinical diagnosis by a movement disorder specialist.12 SPECT may have a role in ruling out PD in clinically uncertain cases.12, 13 In cases of suspected PD, DAT binding will be reduced in 90%.14 In several studies, [123I]FP-CIT has differentiated with high sensitivity and specificity, PD from essential tremor (ET), a neurologic condition characterized by postural or action trem- ors in the hands or tremors affecting the head, neck, or voice that can mimic some PD signs.15 In 2011, the United States Food and Drug Administration approved DaTSCAN using the [123I]FP- CIT ligand for use in suspected parkinsonian syndromes, based on two multicenter, phase III studies.13,16 In early parkinsonian patients with or without tremor (designated possible and prob- able PD), compared with patients with non-PD tremor and healthy controls, the DaTSCAN had 79% sensitivity and 97% specificity, whereas clinical diagnosis in early PD had 98% sensi- tivity but 67% specificity.

Positron emission tomography is an imaging modality that has been studied as an in vivo technique to measure dopamin- ergic function, cerebral blood flow, and metabolic changes. Besides dopaminergic function, there is a growing interest in radiotracers for serotonin, acetylcholine, and opioids, as well as for measuring amyloid and microglia activity in PD studies. PET can measure the ability of striatal dopaminergic neurons to take up radiolabeled levodopa or measure dopamine turnover and dopa decarboxylase activity using a variety of 11C or 18F ligands. The typical finding in PET scans in PD is asymmetric decreased uptake of the radiopharmaceutical in the putamen. The order of this decreased uptake on PET in PD occurs from rostral to cau- dal, with relative preservation of the caudate and reduced uptake progressing from the anterior to posterior putamen, in opposite direction from what is seen in normal aging.11 By the time motor symptoms develop, there is a 50% reduction in the

uptake of 6-[18F]-fluoro-L-dopa (18F-dopa), suggesting that PET may be useful in presymptomatic diagnosis and monitoring progression of PD.17 PET scans, however, have several limita- tions, including the low availability of cyclotrons, regional spec- ificity resulting from limited spatial resolution and partial vol- ume effects, longer scanning times, and radioactive ligands, despite safety monitoring and low doses. To acquire a truly quantitative measure of ligand uptake, monitoring of arterial trace elements is also required.

Transcranial ultrasound permits the visualization of the echogenicity of the substantia nigra at the level of the mes- encephalic brainstem. The typical TCS finding in PD is bilateral increased echogenicity (i.e., hyperechogenicity) of the lateral midbrain, which is present in 90% to 96% of clinically diag- nosed PD cases.18,19,20 The degree of echogenicity, however, does not correlate with severity of PD motor symptoms.18 Echogenicity of the substantia nigra may represent iron depo- sition and an increased susceptibility to PD, although the exact reason is unknown and other iron-rich brain regions do not exhibit hyperechogenicity.21 These findings, coupled with its high sensitivity, low cost, and noninvasive and readily available use, make TCS a promising potential screening tool for early PD. Drawbacks, however, include its dependence on user experience, obtaining an adequate bone window, lack of well-established cutoffs for hyperechogenicity or hypoechoge- nicity, and a fairly high rate of false-positives, particularly with ET, in which up to 16% of patients can have positive findings.22

Structural MRI in general plays a limited role in the early diagnosis of PD, aside from ruling out alternative diagnoses, such as hydrocephalus or vascular disease. Diffusion-weighted imaging, which measures the ability of water to diffuse freely in brain tissue, is highly sensitive to changes in striatal structure. Experimentation with T2 relaxometry has shown reduced T2 relaxation times in the substantia nigra in PD, possibly indicat- ing tissue destruction detectable on MRI. DTI, which provides a measure of directional diffusion and may be considered a proxy for tissue integrity (▶Fig. 18.2), has demonstrated differences in fractional ansiotropy (FA) in different cortical and subcortical regions (▶ Fig. 18.3). Decreased FA has been found in the sub- stantia nigra in all 14 newly diagnosed PD cases, compared with healthy controls, suggesting high sensitivity and specificity in this study.24 The reduced FA in the substantia nigra regions occurred particularly caudally, consistent with postmortem dopaminergic cell loss location. Magnetic resonance spectros- copy, which detects differences in the neurochemical profiles of brain structures, revealed significantly higher concentrations of γ-aminobutryic acid (GABA) in the pons and putamen of PD patients compared with healthy controls,25 suggesting involve- ment of the lower brainstem structures, similar to Braak PD staging, as well as basal ganglia in early PD.

18.1.2 Differential Diagnosis
Distinguishing idiopathic PD from other parkinsonian syn-

dromes can be difficult, especially early in the disease, when

Parkinson’s Disease

Fig. 18.1 [123I]FP-CIT (Ioflupane I-123, DaTSCAN) single-photon emission computed tomography scan of a patient with parkinsonian features. Regions of increased presynaptic dopamine transporter receptor binding in the caudate and putamen are indicated by increased signal. Note the relatively blurred margins and slightly asymmetric uptake, with caudate regions demonstrating increase uptake compared with the putamen. The color scale indicates the magnitude of ligand uptake, with lowest appearing in dark green/black and the highest in bright orange/white. The right side of the image represents the left side of the brain.

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Fig. 18.2 In diffusion tensor imaging, the application of at least six noncollinear gradients creates a 3 × 3 matrix that can be described by a mathematical construct called a tensor. From the diffusion tensor in each voxel, the three eigenvalues (λ1, λ2, and λ3) define the magnitude of the diffusion system and the three associated eigenvectors that describe the direction of the diffusion system. Based on the ratio of the three eigenvalues, the intravoxel direction of hydrogen diffusion can be determined and is termed fractional anisotropy (FA). Cerebrospinal fluid has extremely low FA values because hydrogen is free to diffuse in any direction. Gray matter has low FA because cellular structures (e.g., cell membrane, organelles) impede the free diffusion of hydrogen, but these structures do not promote organized, directional diffusion. Highly organized white matter tracts have high FA because hydrogen diffusion is directionally constrained by the tract’s cellular organization. In the figure, changes in FA across the life span can be seen as a decrease in the intensity in major white matter pathways.

Fig. 18.3 Decreases in fractional anisotropy (FA) in 20 patients with Parkinson’s disease compared with 20 age- and gender-matched normal control subjects. Significant decreases in FA were found in bilateral frontal forceps, superior longitudinal fasciculi, and the anterior and posterior limb of the internal capsule (regions in black circles). Additional regions of decreased FA were noted in the brainstem (not shown). Differences were analyzed using a two-sample t-test statistic. Significance thresholds were set for p < 0.05, corrected for multiple comparisons. Voxels evidencing significant differences between groups are displayed on representative axial sections on a canonical brain image. The color scale indicates the magnitude of t values, with lowest appearing in dark red and the highest in bright yellow/white. The left side of the images represents the left side of the brain.

168

some symptoms might not yet be present or at their fullest extent. Clinical differentiation can be unclear, leading to mis- diagnosis in up to 24% of cases.26 Other diagnoses may include atypical parkinsonian syndromes (e.g., multisystem atrophy [MSA], progressive supranuclear palsy [PSP], and corticobasal degeneration [CBD]), ET, vascular parkinsonism, and drug- induced parkinsonism. Imaging studies can aid in the differen-

tial diagnosis of these conditions and subsequently directing patient management.

In MRI studies, patients with MSA-parkinsonian type may exhibit putaminal hypointensities and a hyperintense rim along the lateral putamen on T1 images on 1.5 Tesla MRI. MRI T2 images may reveal a “hot cross bun sign” in addition to cerebel- lar atrophy in MSA cerebellar-type patients, which is thought to

indicate a loss of myelinated transverse pontocerebellar fibers. PSP patients can have midbrain and frontal lobe atrophy, as well as the “hummingbird sign” on sagittal MRI sequences as a result of midbrain atrophy and third ventricle widening.27 CBD patients may exhibit asymmetric atrophy of posterior frontal and parietal lobes on structural MRI. In several studies, appar- ent diffusion coefficient measurements on MRI scans may dif- ferentiate MSA or PSP from PD with high sensitivities and posi- tive predictive values.28,29,30 TCS also can help differentiate PD from atypical parkinsonian syndromes, with 91% sensitivity and 82% specificity and greater hyperechogenicity in atypical parkinsonism compared with PD.31

Dopamine transporter SPECT imaging does not readily distin- guish among parkinsonian syndromes, although more symmet- ric loss of the putamen and caudate may suggest an atypical parkinsonian syndrome. Approximately 10% of patients with clinically diagnosed with early PD, however, will have scans without evidence of dopaminergic deficiency (SWEDDs) on SPECT scan.32 Most SWEDD patients are unlikely to have PD at follow-up and in some cases have ET or dystonia.13 DAT SPECT scans, however, can distinguish PD from other neurologic diag- noses, such as ET, with 95% sensitivity and specificity.33 Vascu- lar parkinsonism, which manifests clinically as a “lower body” parkinsonism with prominent gait disorder and postural instability, can be accompanied by white matter ischemic changes or lacunar lesions in the basal ganglia on structural MRI, but a definitive diagnosis of vascular parkinsonism is only made at autopsy. Mean [123I]FP-CIT uptake in the basal ganglia was significantly decreased in vascular parkinsonism compared with healthy controls, and preservation of symmetri- cal uptake may help discriminate it from PD.34,35 Drug-induced parkinsonism attributable to dopamine-blocking medications (e.g., for nausea or psychiatric reasons) can clinically mimic PD. [123I]FP-CIT SPECT can differentiate these entities by showing integrity of nigrostriatal neurons in drug-induced parkinsonism versus degeneration of these neurons and reduced uptake in PD.36

Parkinson’s Disease 18.2 Imaging and Parkinson’s

Disease Motor Features 18.2.1 Motor Hallmarks

In addition to the clinical examination and rating scales used to assess the classic motor symptoms of PD, imaging techniques provide a complementary approach to understanding the struc- tural, functional, and metabolic alterations in the PD brain and how these changes relate to pathophysiology, motor pheno- type, and disease progression. This section highlights several different imaging techniques used to examine the motor fea- tures of PD (▶ Table 18.1).

Tremor

Rest tremor, one of the cardinal motor features associated with PD, occurs in about 70% of patients. Although nigrostriatal degeneration of dopaminergic neurons is a pathological hallmark of PD, tremor does not correlate with the severity of striatal dopaminergic deficit.37,38 Thus, nondopaminergic mech- anisms and circuitry extending beyond the striatum contribute to PD tremor. Studies suggest that PD tremor is mediated by an interaction of the basal ganglia, cerebellar, and thalamic circuits.39 Using combined surface electromyography and whole-head magnetoencephalography, tremor-related oscilla- tory activity was found within a cerebral network, with abnor- mal coupling in a cerebello-diencephalic-cortical loop and cor- tical motor and sensory areas contralateral to the tremor hand.40 PD patients with tremor, compared with PD patients without tremor and healthy controls, demonstrated increased imagery-related activity in the somatosensory area to a motor imagery task during functional MRI scanning. This increased activity was independent from tremor-related activity identi- fied in the motor cortex, cerebellum, and thalamic ventral inter- mediate nucleus (Vim), which is often a target for deep brain stimulation in tremor patients. In structural MRI studies using

Table 18.1 Imaging and Parkinson’s disease motor severity

Modality/analysis subjects Brain regions correlated with motor rating scales

[18F] F-DOPA PET

32 PD, assessed at baseline and mean 18 + /– 6 months

Reduced putamen > caudate uptake inversely correlated with UPDRS
Putamen with most rapid mean rate of progression (4.7% of normal mean per year)17

[18F] DOPA PET

27 nondemented PD 10 controls

Reduced putamen > caudate uptake inversely correlated with Hoehn and Yahr stage and UPDRS63

[123I] CIT SPECT

12 PD

Reduced putamen uptake inversely correlated with UPDRS, especially bradykinesia subscore145

MRI: FreeSurfer software

142 PD

Decreased cortical thickness in parietotemporal regions inversely correlated with UPDRS48

MRI-VBM gray matter

Meta-analysis of PD studies 498 PD
375 controls

Decreased gray matter volume in the left inferior frontal/ orbitofrontal gyrus inversely correlated with Hoehn and Yahr stage146

MRI-DTI region of interest approach (caudate, putamen, globus pallidus, thalamus, substantia nigra), measuring FA

151 PD
78 controls

Reduced FA in the substantia nigra inversely correlated with Hoehn and Yahr stage147

Abbreviations: CIT, carbomethoxy-iodophenyl-nortropan FA, fractional anisotropy; FDOPA, fluorodopa; MRI, magnetic resonance imaging; PD, Parkinson’s diseases; PET, positron emission tomography; SPECT, single-photon emission computed tomography; UPDRS, Unified PD Rating Scale; VBM, voxel-based morphometry.

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Fig. 18.4 Voxel-based morphometry (VBM) processing allows for comparison of individual images in a standardized coordinate system. In the process, images are first segmented into gray matter, white matter, cerebrospinal fluid (CSF), and nonbrain compartments. Then the gray matter segment is spatially normalized to a standard gray matter template using a 12-parameter affine normalization and nonlinear adjustments with 7X7X7 basis functions. The transformation parameters obtained from the gray matter normalization are then applied to the whole-brain T1-weighted volumes. Individual normalized whole-brain volumes are then segmented into gray matter, white matter, CSF, and nonbrain partitions. To correct for possible volume changes during normalization, the normalized gray and white matter segments are modulated to maintain the original non-normalized volume per voxel in the normalized gray and white matter segments. In the modulation step, voxel values are multiplied by the Jacobian determinants derived from the normalization of the T1-weighted images. The segmented, normalized, and modulated segments are then smoothed with a gaussian kernel. The smoothing step compensates for interindividual variability and conforms the data more closely to gaussian random field theory, which provides for corrected statistical inference.143,144

voxel-based morphometry (VBM) techniques (▶Fig. 18.4), PD patients with unilateral rest tremor demonstrated increased gray matter in the Vim nucleus contralateral to the side that is most affected, although no comparison group was included.41 Compared with PD patients without rest tremor, PD patients with rest tremor exhibited decreased gray matter in the poste- rior right quadrangular lobe and decline of the cerebellum.42 Using [18F]-fluorodeoxyglucose (FDG) PET, a tremor-related metabolic pattern characterized by increased activity in the cerebellum/dentate nucleus, primary motor cortex, and to some degree the striatum was detected. This pattern correlated significantly with clinical ratings of tremor but not akinesia- rigidity scores. Expression of the tremor-related metabolic pat- tern was suppressed to a greater degree by Vim rather than by subthalamic deep brain stimulation, thereby supporting the selective involvement of cerebellothalamocortical pathways in PD tremor.43 Several imaging studies suggest serotonergic

dysfunction in PD tremor. Serotonin (5HT) receptor 1A binding potential as measured by 11C-WAY 100635 PET, which is a selective antagonist for 5HT1A receptors, in the midbrain raphe was significantly reduced in PD patients compared with healthy controls. In addition, the 5HT1A binding correlated significantly with tremor rating scores but not bradykinesia or rigidity scores.44 A PET study using 11C-3- amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzo- nitrile (11C-DASB), a marker of serotonin transporter binding, revealed reduced tracer uptake in the raphe nuclei, caudate, putamen, thalamus, and motor circuitry regions in tremor- dominant PD patients, compared with akinetic-rigid PD patients and healthy controls, suggesting potential contribu- tions of presynaptic 5HT terminal dysfunction to PD tremor, although because this reduction correlated primarily with action and postural tremor, further study is needed regarding rest tremor.45

Bradykinesia and Rigidity

Bradykinesia and rigidity have been investigated in several imaging studies, either independently or in combination. Using [18F]FDG-PET, a pattern of glucose metabolism differentiated PD patients from healthy controls and MSA (striatonigral degeneration) patients.46 This PD-related motor pattern, with increased metabolic activity in the globus pallidum, putamen, and thalamus and decreased activity in the lateral frontal, para- central, interior parietal and parieto-occipital areas, signifi- cantly correlated with Unified PD Rating Scale (UPDRS) scores of bradykinesia and rigidity but not tremor ratings. The PD- related motor pattern has undergone further validation using both oxygen-15 water (H2O15) and [18F]FDG-PET scans and demonstrates high within-subject and test-retest reproducibil- ity in early and advanced stage PD patients.47 Distinct metabolic patterns such as these may have use in the diagnosis or thera- peutic monitoring. Structural MRI scans analyzed for cortical thickness revealed correlations between decreased cortical thickness in the parietotemporal sensory association areas and longer PD duration and increased motor deficits on the UPDRS, particularly bradykinesia and axial motor function48; cortical thickness in this PD sample, however, did not correlate with tremor scores. Although additional study is needed, these cortical regions overlap with those exhibiting decreased meta- bolic activity in other studies and suggest cerebral cortical dys- function in advancing PD.

Comparisons of Tremor-Dominant and Akinetic-Rigid Parkinson’s Disease Phenotypes

Some, but not all, imaging studies have identified significant differences in the neurochemistry and neural circuitry underlying tremor-dominant versus postural instability-gait impairment or akinetic-rigid motor phenotypes of PD. Tremor- dominant patients are frequently younger at onset and have a slower rate of disease progression and less cognitive decline. Using [123I]FP-CIT scans, nigrostriatal dopaminergic system impairment, even at early stages of PD, with reduced uptake in putamen and caudate regions is associated more with akinetic- rigid than tremor-dominant symptomology.49 Other [123I]FP- CIT studies, however, failed to find a significant difference in striatal dopamine transporter uptake between tremor-domi- nant and non-tremor-dominant PD subgroups.37 These studies suggest that nondopaminergic mechanisms may contribute to differences in PD motor phenotype and that further refinement of optimal methods for classification (visual morphology, semi- quantitative, other) is needed.

Because structural MRI scans of PD patients with different motor phenotypes have not revealed robust differences, studies have explored differences in blood-oxygen-level- dependent (BOLD) function on functional MRI (fMRI). BOLD activation was reduced in bilateral dorsolateral prefrontal cortex, contralateral lingual gyrus, caudate, globus pallidum interna and externa, and ispilateral thalamus in a nontremor dominant PD group compared with the tremor-dominant PD group. No significant differences were seen in gray or white matter volume between these groups as detected using

VBM.50 In another study using fMRI with regions of interest examining the striatal-thalamo-cortical and cerebello- thalamo-cortical circuits, akinetic-rigid PD patients showed more activity during a finger-tapping task in multiple corti- cal and subcortical regions, as well as striatal-thalamo- cortical and cerebello-thalamo-cortical circuits, compared with tremor-dominant PD patients; in contrast, tremor- dominant patients had greater activity in the vermis, contra- lateral cerebellar hemisphere, and ipsilateral thalamus.51 Thus, different imaging modalities may differentiate the PD subtypes and identify specific neurobiological substrates for the different motor phenotypes.

Gait Impairment

Gait and balance issues in PD are associated with morbidity, mortality, and disability and in advanced PD may respond poorly to dopaminergic treatments. Falls, start hesitation, and freezing of gait also can occur in advancing PD. Whereas imag- ing during actual gait is often impossible because most scanners require that subjects be immobile and supine, novel methods, such as motor imagery, virtual reality, or foot pedals, have been developed to simulate gait-related brain activity.

Studies using SPECT reveal that although PD patients and healthy controls have similar patterns of gait-related brain acti- vation (e.g., cortical motor regions for foot and trunk, brain- stem, and cerebellum), PD patients show significantly less regional cerebral blood flow activation in the right supplemen- tal motor area, left precuneus, and right cerebellar hemisphere. In addition, PD patients had increased activation in the lateral premotor area when visual cues are added to improve PD gait.52 Using fMRI to measure gait-related activation during mental imagery, the PD group had differences in the mean gait activa- tion pattern (i.e., hypoactivity within the parieto-occipital regions, left hippocampus, midline/lateral cerebellum, and pedunculopontine nucleus locomotor area) compared with healthy controls; activation levels in the right posterior parietal cortex correlated with severity of gait measures.53 Another fMRI study investigating gait-related activation during mental imag- ery and video stimuli of gait initiation, stepping over an obsta- cle, and gait termination found that PD patients had greater activation of visuomotor areas during the latter two mental imagery scenarios compared with healthy controls.54 Other studies suggest that gait disturbances in PD invoke nondopami- nergic and extrastriatal systems, including the cholinergic sys- tem, which is involved in locomotion and cognition. Comparing acetylcholinesterase hydrolysis rates in PD patients with a his- tory of falls to PD patients without a history of falls, thalamic acetylcholinesterase activity was reduced in the “fallers” as measured by [11C]PMP-PET; in contrast, DTZB-PET scans did not reveal significant nigrostriatal dopaminergic differences between the groups.55

Freezing of gait (FOG) is an intriguing, although not well understood, episodic gait phenomenon that occurs in moder- ate-advanced PD and is characterized by the inability to initiate and produce effective stepping or gait patterns.56 Studies have examined metabolic, functional, and structural imaging corre- lates of FOG, comparing PD patients who have FOG (FOG +) with

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those who do not FOG (FOG–). Using [18F]-6-fluoro-levodopa (FDOPA) and [18F]FDG in a small sample of PD patients, trends toward differences in striatal tracer uptake in FOG + compared with FOG– patients were noted. In FOG+patients, caudate uptake of FDOPA and FDG was reduced, whereas FDOPA decrease in the putamen was associated with FDG increases. Computer-based virtual reality paradigms have been developed to simulate FOG in the MRI environment. Processing cognitive and environmental information obtained during bipedal motor activity (i.e., using foot pedals) has been shown to induce FOG-like symptoms in PD patients who are prone to FOG epi- sodes in the “off” state.57 By using this task during fMRI, increased BOLD signal was found in the bilateral dorsolateral prefrontal cortex and posterior parietal cortices, with a concur- rent decrease in BOLD signal in bilateral sensorimotor cortices during the contrasts of the motor arrests and simulated “walk- ing.” In addition, this was also associated with significantly decreased BOLD signal in various basal ganglia and thalamic nuclei during periods of motor arrest compared with “walk- ing.”58 Several studies have examined structural gray and white matter differences associated with FOG in PD. Using VBM, greater gray matter atrophy in frontal and parietal cortices has been found in FOG+patients than in FOG– patients, sug- gesting contributions of executive dysfunction and/or altered perceptual judgment.59 Another VBM study demonstrated a predominantly posterior pattern of gray matter atrophy (i.e., cuneus, precuneus, lingual gyrus, and posterior cingulate cortex), which may implicate visuoperceptive and discrimination dysfunction in FOG.60 Using probabilistic trac- tography DTI analyses to examine the white matter con- nectivity of the pedunculopontine nucleus in a small sample of PD patients, there was decreased connectivity of the pedunculopontine nucleus and cerebellum and increased con- nectivity with the pons in FOG+patients compared to FOG– patients.61

18.3 Imaging and Parkinson’s Disease Nonmotor Features and Complications

18.3.1 Nonmotor Features

In addition to the motor features described above, nonmotor features are now recognized to accompany PD, even from early stages to more advanced disease. Early nonmotor features include decreased or loss of sense of smell (i.e., hyposmia or anosmia), depression, anxiety, constipation, cognitive impair- ment, and sleep disturbances, including dream enactment with loss of normal muscle atonia during rapid eye movement (REM) sleep (i.e., REM behavior disorder, or RBD). In moderate to advanced PD, nonmotor symptoms may include depression, anxiety, fatigue, apathy, sleep disturbances, cognitive impair- ment or dementia, and hallucinations or psychosis. Imaging studies with structural, functional, metabolic, and other tech- niques have been used to identify neurobiological substrates of various nonmotor features and to develop related biomarkers.

This section highlights imaging studies examining select olfac- tion, sleep, cognitive, and behavioral issues.

Premotor Symptoms

In recent years, the concept of a prodromal or premotor phase of PD before the onset of its classic motor features has emerged and is characterized primarily by several nonmotor features that have been associated with increased risk of developing PD.62,63,64,65 These symptoms include hyposmia or anosmia, constipation, depression, anxiety, and RBD and may be due to PD-related neurochemical and neuropathological changes in the olfactory system, gastrointestinal mucosa, and brainstem.2,3

Hyposmia or anosmia has been studied as a possible bio- marker for the development of PD in epidemiologic and imag- ing studies, in some cases in first-degree relatives of PD patients.66,67 In a prospective study of 361 asymptomatic first- degree relatives of PD patients, DaT-SPECT scanning was com- bined with olfactory testing. After 5 years, 5 of 40 hyposmic rel- atives were diagnosed by clinical criteria with PD, and all these individuals had abnormal DaT scans at baseline.67,68 In addition, several studies have focused on olfaction in already clinically diagnosed PD patients. [18F]FDG PET was used in a study of 69 Japanese, nondemented PD patients who were also evaluated for hyposmia. It found olfactory dysfunction was clinically related to cognitive dysfunction, but also to abnormal brain glu- cose metabolism in the piriform cortex and amygdala, regions involved in olfaction, memory, and emotion.69 Interestingly, activation in similar brain regions was abnormal in a small fMRI study of eight PD patients compared with controls, in which subjects rated olfactory stimuli as pleasant or unpleasant dur- ing fMRI. In PD patients, both pleasant and unpleasant smells were associated with decreased activation in the amygdalohip- pocampal complex, whereas in controls pleasant smells were associated with increased activity in the striatum and left inferior frontal gyrus and unpleasant smells with decreased activation of the ventral striatum.70 Neurochemical deficits associated with hyposmia in PD have been examined by PET scans using ligands to measure cholinergic and monoaminergic activity. In a study of nondemented PD patients who under- went [11C]-methyl-4-piperidinyl proprionate acetylcholin- esterase PET and [11C] dihydrotetrabenazine vesicular mono- amine transporter type 2 PET along with olfactory testing, smell identification scores correlated positively with acetylcholines- terease activity in the hippocampus, amygdala, and neocortex and with monoaminergic activity in the striatum.71 Some stud- ies have focused on white matter microstructural integrity of the olfactory structures. In a voxel-wise analysis, increased dif- fusivity was found in the olfactory tracts in PD patients com- pared with controls in one study.72 In another study, using tract-based spatial statistics, reduced FA was found in white matter adjacent to the gyrus rectus or in primary olfactory areas in PD patients with hyposmia or anosmia.73

Rapid eye movement behavior disorder symptoms may pre- cede PD or other synucleinopathies for up to 5 to 50 years before motor parkinsonism is seen.74,75 Similar to the olfaction imaging studies, some studies have focused on identifying brain changes associated with idiopathic RBD or development of PD,

PD dementia have focused on gray matter atrophy of the mesial temporal lobe and were based largely on manual volumetry, visual rating scales, or semiautomated techniques (whole-brain or region of interest VBM) used in the AD field.89–99 In sum- mary, these studies highlight that hippocampal atrophy occurs in PD dementia (PDD) and, in some studies, in nondemented PD patients; hippocampal or mesial temporal atrophy in PDD, however, was less severe than in AD. Some volumetric MRI studies note greater atrophy of the anterior cingulate gyrus, amygdala, or entorhinal cortex in PDD compared with cogni- tively normal or nondemented PD.93,95,98,100,101,102 Structural MRI VBM studies examining PD-MCI patients have yielded vari- able results, with some finding no gray matter differences between PD-MCI patients and controls103,104,105 but others identifying greater gray matter atrophy in temporal (e.g., hip- pocampal), parietal, and frontal (e.g., prefrontal and orbitofron- tal) lobe regions in PD-MCI patients with impaired verbal mem- ory, decision-making, and reaction time tests.103–109 A small number of studies have evaluated white matter changes, either as hyperintensities on T2-weighted or fluid-attenuated inver- sion recovery sequences using visual rating scales or semiauto- mated segmentation protocols or altered microstructural integ- rity with DTI measuring FA and MD. In some, but not all studies, PDD was associated with increased deep and periventricular white matter hyperintensities compared with cognitively nor- mal or PD-MCI patients.110,111 DTI studies using tract-based spatial statistics found reduced FA in the superior longitudinal, inferior longitudinal, fronto-occipital, and uncinate fasciculi, cingulum, and corpus callosum in patients with PDD compared with those with normal cognition; further studies are needed to determine whether there are differences in PD-MCI.105 Using [18-F]FDG-PET and a VBM modeling approach in two studies, a PD-related cognitive pattern characterized by decreased metab- olism in frontal and relatively, association areas and relative increased metabolism in the cerebellum correlated with per- formance on tests of memory and executive function and dem- onstrated progressively worse metabolic changes across the PD cognitive spectrum (from cognitively normal to single-domain PD-MCI to multiple-domain impairment PD-MCI).112,113 Because some PDD patients have comorbid AD pathology at autopsy, there has been interest in amyloid imaging with the PET tracer Pittsburgh Compound B (PIB). Results of PIB studies in PDD, however, have been somewhat variable, although sev- eral revealed increased PIB uptake or higher amyloid burden, generally to a lesser degree than that found in AD and dementia with Lewy bodies.114,115,116

Mood disorders like depression occur in about 45% of PD patients117 and may be present in premotor or early phases as well as in more advanced PD. Intrinsic neurochemical altera- tions and neurodegenerative changes in the brainstem, frontal/ limbic cortical regions, and subcortical structures likely contrib- ute. Structural MRI studies of depression, in some cases accom- panied by apathy or anxiety, yield mixed results regarding mor- phologic changes. Using VBM, one study found greater gray matter atrophy in the left orbitofrontal cortex, bilateral rectal gyrus, and right superior temporal pole,118 but another did not detect gray matter differences in PD depression.119 White matter hyperintensities as measured on T2-weighted MRI by a

whereas others have examined already diagnosed PD patients who have RBD symptoms. In a structural MRI VBM study com- paring 20 idiopathic RBD patients with controls, those with RBD had significantly decreased gray matter volume in the anterior lobes of the cerebellum bilaterally, tegmental part of the pons, and left parahippocampal gyrus.76 Brainstem white matter changes also have been found in DTI studies of idio- pathic RBD patients compared with healthy controls, with decreased FA in the midbrain tegmentum and rostral pons and increased mean diffusivity (MD) in the pontine reticular forma- tion. Interestingly, this study also detected increased gray mat- ter density in bilateral hippocampi in RBD patients, which requires further study.77 A functional connectivity study of the substantia nigra revealed different correlations using voxel- wise analyses between the left substantia nigra and left puta- men as well as in the right cuneus/precuneus and superior occipital gyrus in the RBD patients compared with PD patients and healthy controls.78 RBD patients who underwent serial dopamine transporter imaging with [123I]FP-CIT demonstrated reduced mean binding in striatal regions at baseline and after 3 years. At 3 years, three patients were diagnosed with PD; these patients also had the lowest dopamine transporter uptake at baseline and about a mean 24 to 33% reduction in striatal uptake at 3 years’ follow-up.79 Using technetium 99m ethylene cysteinate dimer (ECD) SPECT, 20 idiopathic RBD patients were examined at baseline, and 10 of these patients developed PD or dementia with Lewy bodies after 3 years; those who converted to PD or dementia with Lewy bodies had increased regional cerebral blood flow in the hippocampus at baseline compared with those who did not convert.80 In some cases, RBD has been associated with mild cognitive impairment, and perfusion changes may relate to incipient or mild cognitive deficits.81 PET studies using ligands for acetylcholine, serotonin, and mono- amines demonstrate that nondemented PD patients who have RBD symptoms have decreased neocortical, limbic, and tha- lamic cholinergic innervation compared with those without RBD symptoms, but no differences in brainstem or striatal sero- tonin transporter binding were seen.82

Cognitive and Behavioral Symptoms

Cognitive and behavioral symptoms are important contributors to PD patients’ overall function and well-being, quality of life, and outcomes. These symptoms include mild cognitive impair- ment and dementia; depression, anxiety, apathy, or other mood disorders; and hallucinations and delusions. In recent years, imaging techniques have been used to identify specific neuro- biological substrates of these issues and biomarkers suggestive of underlying neuropathology or disease progression.

Cognitive decline and dementia in PD occur in about 80% of patients as the disease progresses.83,84 Cognitive deficits that are mild but do not impair one’s ability to carry out activities of daily living have been termed mild cognitive impairment (PD- MCI).85,86 About 40% of PD patients develop dementia,87 and these patients typically have more advanced disease, older age in general, older age at PD onset, and sometimes greater poste- rior cortical neuropsychological deficits (i.e., impaired semantic fluency, visuospatial abilities).88 Many structural MRI studies of

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visual rating scale were significantly increased in periventricu- lar regions in depressed PD patients compared with nonde- pressed PD patients and healthy controls of similar age, sex, and cerebrovascular risk factors, but they did not show signifi- cant differences in other brain regions.120 In VBM studies, white matter loss in the right frontal lobe, anterior cingulate, and inferior orbitofrontal region have been detected in depressed PD patients.119 In addition, reduced FA in bilateral mediodorsal thalamic regions has been found in DTI studies of depressed PD patients compared with nondepressed PD patients.121 Resting- state fMRI studies suggest abnormal activity in the prefrontal- limbic network in depressed PD patients. In two studies, PD patients with depression, compared with those who did not have depression and with healthy controls, had reduced ampli- tudes of low-frequency fluctuations in the left orbitofrontal areas122 and dorsolateral prefrontal cortex, ventromedial pre- frontal cortex, and rostral anterior cingulate cortex.123 Abnor- malities in the serotonin system are well recognized to be asso- ciated with depression. In a PET study using [18-F]MPPF, a selec- tive 5HT1A receptor antagonist, to investigate the postsynaptic serotonergic system, depressed PD patients had reduced tracer uptake in the left hippocampus, right insula, left superior tem- poral cortex, and orbitofrontal cortex compared with nonde- pressed PD patients, thereby implicating limbic serotonergic dysfunction.124 In a study using a different serotonin ligand, [11C]DASB, depressed PD patients exhibited increased binding in the dorsolateral and prefrontal cortex compared with healthy controls.125

Psychosis in PD ranges from mild illusions to formed halluci- nations to delusions.126,127 Hallucinations occur in about one- third of PD patients treated with chronic dopaminergic therapy and are most often visual. These hallucinations may be due to medications but also may be due to disease-related factors, such as age, akinetic-rigid motor phenotype, cognitive impair- ment or impaired attention, depression, sleep disturbances, and visual problems. Structural MRI studies of visual hallucinations in PD have examined regional and global brain atrophy pat- terns. VBM studies comparing PD hallucinators with nonhallu- cinating PD patients and healthy controls demonstrate gray matter atrophy in the hippocampal, limbic, paralimbic, frontal, and neocortical regions.94,128,129,130 These studies support regional neuroanatomical changes and strong links between hallucinations and cognitive impairment but also pose potential confounds because these brain regions are implicated in cogni- tive impairment or dementia. Other VBM studies suggest tha- lamic or pedunculopontine atrophy in PD hallucinators.128,131 Given the predominant visual hallucinatory phenotype in PD, however, other VBM studies have found greater gray matter atrophy in regions associated with visual processing in PD hal- lucinators compared with nonhallucinators, including the left lingual gyrus and bilateral superior parietal lobes132 and when carefully controlling for effects of cognitive status, bilateral cunei, fusiform, middle occipital, precentral, cingulate gyri, inferior parietal lobules, right lingual gyrus, and left paracentral gyrus.133 fMRI studies in PD hallucinators demonstrate altered cortical activation patterns compared with those of PD nonhal- lucinators. Using visual stimulation fMRI paradigms (i.e., stro- boscopic and kinematic), PD hallucinators had significantly greater frontal and subcortical activation to both visual stimula-

tion paradigms and decreased cerebral activation in occipital, parietal, and temporal-parietal regions compared with nonhal- lucinators,134 thereby suggesting a disruption in normal visual processing mechanisms in the hallucinators (▶Fig. 18.5). Another study using complex visual stimuli (e.g., face recognition task) revealed significant reductions in right pre- frontal areas, including the inferior, superior, and middle frontal gyrus and anterior cingulate gyrus in PD hallucinators to the face stimulus compared with nonhallucinating PD and healthy controls.135 Further evidence for impaired visual processing in hallucinating PD comes from an fMRI study in which several seconds before an image recognition task, the nondemented, hallucinating PD patients showed reduced activation of the lat- eral occipital cortex and extrastriate temporal visual cortices compared with nonhallucinating PD patients and healthy con- trols.136 One issue with these studies is that the actual halluci- natory event is not captured during imaging. Contrasts are developed between individuals who have hallucinations by self-report and those who deny hallucinations. A recent study was able to capture BOLD activation during visual hallucina- tions in a single patient with PD. Increased activation during visual hallucinations was noted in the frontal lobes, insula, cin- gulate, thalamus, and brainstem, whereas decreased activation was found in the fusiform, inferior occipital lobe, superior tem- poral lobe, and middle frontal lobe (▶ Fig. 18.6).137 In a resting- state fMRI study, PD patients with misperceptions had decreased functional connectivity between the ventral and dor- sal attention networks, thereby implicating the role of attention in generating hallucinations.130 Decreased perfusion or glucose metabolism in predominantly posterior brain regions, fre- quently involved in visual processing, has been reported in PD hallucinators by using SPECT or PET and, in some studies, increased frontal perfusion or metabolism. Using technetium 99m-hexamethylpropyleneamine oxime (HMPAO) SPECT, hal- lucinating PD patients had decreased cerebral blood flow to temporal-occipital lobe regions138 and reduced perfusion in bilateral parieto-occipital regions in PD patients with visual hal- lucinations compared with those without hallucinations.139 Another [123I]IMP SPECT study, however, found hypoperfusion in the right fusiform gyrus but also hyperperfusion in the right superior and middle temporal gyri in PD hallucinators when covarying for Mini-Mental State Examination score and PD duration.140 Similarly, decreased metabolism in temporal- occipital-parietal regions and also increased metabolic rates in frontal regions, especially the left superior frontal gyrus, have been identified in PD hallucinators compared with nonhalluci- nators using [18F]FDG-PET.141,142

18.4 Conclusion

Neuroimaging in PD has grown tremendously over the years and has advanced our understanding of the neurobiological substrates of PD-related motor and nonmotor features. Neuroimaging biomarkers will be relevant and important for diagnosing premotor PD and, as classically defined, PD; monitoring disease progression; and measuring the effects of treatments for both PD-related motor and nonmotor symptoms.

Parkinson’s Disease

Fig. 18.5 Representative regions of significant functional magnetic resonance imaging activation during stroboscopic versus no visual stimulation in nonhallucinating Parkinson’s disease (PD) patients (top panel) and hallucinating PD patients (second panel). Note the decreased occipital lobe activation in the hallucinating patients. The two bottom panels display activation differences during apparent kinematic versus stationary visual stimulation in nonhallucinating PD patients (third panel) and hallucinating PD patients (bottom panel). Note the decreased activation in MT/V5 region and increased frontal lobe activation in the hallucinating patients. Significance thresholds were set for p < 0.001 (uncorrected for multiple comparisons) for both analyses. Voxels evidencing significant activation are displayed on representative axial sections (z = z plane Talairach coordinates) on a canonical brain image. The color scale indicates the magnitude of t values, with the lowest appearing in dark red and the highest in bright yellow/white. The left side of the images represents the left side of the brain.

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Fig. 18.6 This figure displays representative regions of significant functional magnetic resonance imaging activation in a single patient with Parkinson’s disease who experienced visual hallucinations in the scanner. This individual had frequent and brief hallucinations of African tribesmen and chimpanzees. During the scan, the patient reported 16 hallucinations interspersed with periods of no hallucinations. Voxels evidencing significant differences in activation during the hallucinations are displayed on representative sagittal, axial, coronal sections on a canonical brain image. The color scale indicates the magnitude of t values, with the lowest appearing in dark red and the highest in bright yellow/white. The left side of the images represents the left side of the brain.

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Matsui H, Nishinaka K, Oda M et al. Hypoperfusion of the visual pathway in parkinsonian patients with visual hallucinations. Mov Disord 2006; 21: 2140–2144

Oishi N, Udaka F, Kameyama M, Sawamoto N, Hashikawa K, Fukuyama H. Regional cerebral blood flow in Parkinson’s disease with nonpsychotic visual hallucinations. Neurology 2005; 65: 1708–1715
Boecker H, Ceballos-Baumann AO, Volk D, Conrad B, Forstl H, Haussermann P. Metabolic alterations in patients with Parkinson’s disease and visual halluci- nations. Arch Neurol 2007; 64: 984–988

Nagano-Saito A, Washimi Y, Arahata Y et al. Visual hallucination in Parkin- son’s disease with FDG PET. Mov Disord 2004; 19: 801–806
Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001; 14: 21–36

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Shinotoh H, Uchida Y, Ito H, Harrori T. Relationship between striatal [123I] beta-CIT binding and four major clinical signs in Parkinson’s disease. Ann Nucl Med 2000; 14: 199–203

Pan PL, Song W, Shang HF. Voxel-wise meta-analysis of gray matter abnor- malities in idiopathic Parkinson’s disease. Eur J Neurol 2012; 19: 199–206 Chan LL, Rumpel H, Yap K et al. Case control study of diffusion tensor imaging in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2007; 78: 1383–1386

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19 Atypical Parkinsonian Syndromes

Nicola Pavese and David J. Brooks

In this chapter, we discuss the different contributions of struc- tural and functional imaging to the diagnosis and management of atypical parkinsonian disorders. We focus mainly on the most common clinical conditions: multiple-system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD).

19.1 Multiple-System Atrophy

Multiple-system atrophy is a progressive neurodegenerative disorder characterized clinically by varying combinations of parkinsonism, cerebellar dysfunction, autonomic failure, and corticospinal tract dysfunction.1 Based on the predominant symptoms, MSA is classified into two subtypes, MSA with predominant parkinsonism (MSA-P) and MSA with cerebellar features (MSA-C).

The pathological hallmark of the disease is neuronal loss and gliosis in the striatal, nigral, olivo-ponto-cerebellar network, and the lateral columns of the spinal cord, with the presence of intracytoplasmic and intranuclear argyrophilic fibrillary inclu- sions containing α-synuclein in both oligodendrocytes and neurons.2 Despite the different pathology, there is a significant clinical overlap between MSA and Parkinson’s disease (PD), par- ticularly in the early stages of the disease. Three levels of diag- nostic certainty—possible, probable, and definite—have been proposed for MSA, and abnormalities in structural and func- tional imaging are indicated as features supporting (“red flags”) a diagnosis of possible MSA.1

19.1.1 Structural Imaging

Magnetic resonance imaging (MRI) with conventional sequences and, more sensitively, diffusion-weighted (DWI) and diffusion tensor imaging (DTI) have proved to have a role for discriminating MSA from typical PD and other atypical parkin- sonian syndromes.3,4 Atrophy of the putamen, the presence of a “slit” hyperintensity of the lateral margin of the putamen in T2- weighted MRI images (so called “slit sign”), and putaminal hypointesity are specific features of established MSA but are present in only around half of the cases (▶Fig. 19.1). Other

typical features (“red flags”) of MSA include atrophy of several subtentorial structures, such as the pons, the middle cerebellar peduncles, and the cerebellum, with dilatation of the fourth ventricle. In MSA-C, the severe loss of neurons and myelinated fibers at the basis pontis and the gliosis of the middle part of the reticular formation result in a characteristic cruciform hyperintensitity in the pons on T2-weighted MRI sequences, which is known as the “hot cross bun sign” (▶Fig. 19.1). The hot cross bun sign can also be seen in patients with MSA-P. Horimoto and colleagues5 performed a longitudinal MRI study to determine the exact time when the hot cross bun sign and slit sign appeared in a cohort of MSA patients. They graded the development of hot cross bun sign into six progressive stages and the slit sign into four stages. The hot cross bun sign was seen (MRI shows cross, stage IV) earlier in MSA-C than in MSA- P, often before 5 years of symptomatic disease duration. Con- versely, MSA-P showed earlier bilateral putamen changes (stage II) than MSA-C, generally before 3 years of symptoms (stage I).

Despite being highly specific for MSA (specificity > 90%), these abnormalities seen on T2-weighted MRI have not proved sensi- tive enough to be of diagnostic value (sensitivity up to 50 to 60%, with higher values of sensitivity for the basal ganglia abnormalities than for the subtentorial ones).3,4

In contrast, DWI and DTI are more sensitive to changes in putamen structure and are potentially useful for discriminating MSA from idiopathic PD. DWI MRI has been reported to detect raised water-proton apparent diffusion coefficients in the puta- men in up to 100% of patients with clinically probable MSA, whereas apparent diffusion coefficients in the putamen are normal in PD.6,7,8 An altered water diffusion signal in the middle cerebral peduncle has been reported to be useful to discrimi- nate MSA from PSP.8 A possible limitation of these studies is that they have all involved well-established atypical cases, whereas it remains to be established whether DWI MRI is also valuable to discriminate early cases where there is clinical diag- nostic uncertainty.

Voxel-based morphometry (VBM) is an MRI technique that localizes significant changes in gray and white matter density in disease. Compared with controls, MSA patients show signifi- cant reductions in the gray matter of the cerebellum and

Fig. 19.1 Details of T2 magnetic resonance imaging showing the “slit” sign (red arrow) and the “hot cross bun” sign (blue arrow). Both signs are visible on axial images.

Atypical Parkinsonian Syndromes

cerebral cortex and in the white matter of the cerebellar pedun- cles and brainstem. White matter loss along the corpus callo- sum has also been reported in MSA patients.9

Finally, transcranial sonography of brain parenchyma, which shows atypical lateral midbrain hyperechogenicity in more than 90% of patients with idiopathic PD, is normal in most MSA cases. However, MSA patients can show increased echogenicity of the lentiform nucleus, which is absent in typical PD. It has been reported that a combination of normal midbrain signal combined with lentiform nucleus hyperechogenicity separated atypical from typical PD with a sensitivity of 59% and specificity of 100% and a positive predictive value of 100%.10

19.1.2 Functional Imaging

In vivo functional neuroimaging investigations in MSA have focused on dopaminergic dysfunction in MSA-P and the changes in brain regional glucose metabolism and cerebral blood flow that occur in patients with MSA-P and MSA-C subtypes.

Both presynaptic11,12 and postsynaptic striatal dopamine deficits13,14 have been reported in MSA-P patients. Regional cerebral [18F]flurodopa (18F-dopa) uptake, expressed as an influx constant, Ki, reflects the functional integrity of monoam- inergic terminals.15 In the striatum, where dopamine innerva- tion from the midbrain substantia nigra is the major monoam- inergic component, 18F-dopa uptake reflects the integrity of dopaminergic nigrostriatal terminals and correlates well with striatal dopamine levels and also with nigrostriatal cell counts in postmortem and animal studies.16,17 MSA patients show an asymmetrically reduced striatal uptake on 18F-dopa positron emission tomography (PET) that resembles the pattern observed in patients with idiopathic PD with relatively pre- served head of caudate function. The caudate nucleus can be more severely affected in MSA than in PD, leading to a more homogeneous reduction in tracer uptake within the striatal structures (▶Fig. 19.2).11,13,18 There is, however, considerable overlap of individual levels of putamen 18F-dopa uptake in MSA and PD patients. Therefore, 18F-dopa PET is not useful in clinical practice for discriminating MSA from typical PD.19 Similar

findings have been observed in a number of PET and SPECT studies imaging the dopamine transporter (DAT), another com- monly used marker for nigrostriatal dopaminergic terminals nerve in the striatum. A recent study with 18F-FP-CIT PET reported that MSA patients showed a more prominent and ear- lier DAT loss in the ventral putamen compared with PD patients.20 Briefly, both MSA and PD groups showed similar anteroposterior gradients of putaminal DAT loss. However, the MSA group did not show the typical ventrodorsal gradient of putaminal DAT loss described in PD. In fact, there was a rela- tively even DAT loss from the ventral putamen to the posterior putamen, which could reflect the loss of striatal dopaminergic terminals that precedes nigral involvement in MSA.21 These authors suggested that the assessment of the ventrodorsal gra- dient could be useful for differentiating PD from MSA, even in the early stage.

The availability of postsynaptic D2 receptors can be evaluated using PET and SPECT benzamide tracers such as 11C-raclopride and 123I-IBZM. Both 11C-raclopride and 123I-IBZM binding is reduced in MSA patients compared with that in normal subjects and untreated PD patients, suggesting that degeneration of striatal D2 receptors occurs in this condition.22,23 Unfortunately, this finding is not sensitive enough to be used in clinical prac- tice to differentiate MSA from PD because there is an overlap of their D2 binding ranges.

18F-2-fluoro-2-deoxyglucose (FDG) PET studies of MSA patients have shown significant bilateral hypometabolism in both caudate and putamen nuclei. Further reductions have been reported in the cerebellum and in the frontal cortex.24,25,26 The same areas showed a reduction in regional cerebral blood flow with perfusion SPECT.27,28 Hypometabolism and hypoper- fusion in the cerebellum and pons are particularly prominent in MSA-C patients.29 Eckert and colleagues have reported that FDG-PET has 96% sensitivity and 99% specificity for the diagno- sis of MSA versus PD when computer-assisted methods are applied.30 This finding has been confirmed in subsequent stud- ies.31,32 Finally, network analysis of metabolic changes across the brain by spatial covariance analysis of FDG-PET scans has identified an MSA-related pattern (MSARP) characterized by

Fig. 19.2 18F-dopa positron emission tomography images in a healthy control (HC), a patient with Parkinson’s disease (PD), and a patient with multiple-system atrophy (MSA).

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covarying metabolic reductions in the putamen and the cere- bellum. MSARP values correlate with clinical ratings of motor disability and with disease duration.33 It has been suggested that the MSARP may be a useful biomarker in trials of novel neuroprotective therapies for MSA.

Despite the widespread subcortical neurodegeneration reported in postmortem studies in MSA patients, the involve- ment of extrastriatal monoaminergic and cholinergic pathways has not been extensively investigated with functional neuro- imaging in vivo. Using SPECT with 123I-β-CIT, a tropane deriva- tive with high affinity for all monoamine transporters, Scherfler et al reported decreased uptake in midbrain and pontine regions in patients with MSA-P but not in PD patients.34 In a recent study, 18F-dopa PET was used to explore changes in brain monoaminergic function in both striatal and extrastriatal areas in MSA-P. Findings in MSA-P patients were compared with those seen in idiopathic PD patients matched for disease dura- tion and healthy controls. The results of the study suggest the presence of a more widespread monoaminergic dysfunction in MSA than in PD with similar disease duration. The MSA patients showed significantly decreased 18F-dopa uptake in putamen, caudate nucleus, ventral striatum, globus pallidus externa, and red nucleus compared with that in controls, whereas PD patients showed decreased 18F-dopa uptake only in the puta- men, caudate nucleus, and ventral striatum. Additionally, in contrast to PD, no evidence was seen of early compensatory pallidal increases in regional 18F-dopa uptake in MSA patients. Interestingly, MSA cases with orthostatic hypotension had lower 18F-dopa uptake in the locus coeruleus than patients without this symptom.35

Cholinergic pathways in MSA-P patients have been investi- gated with 11C-PMP PET, a marker of acetylcholinesterase (AChE) activity. Whereas cerebral cortical cholinergic activity was decreased to a similar level in MSA-P, PD, and PSP com- pared with normal controls, thalamic and pontine cholinergic activity was significantly lower in MSA-P and PSP patients than in those with PD. Interestingly, decreased AChE activity in the brainstem and cerebellum of all three disorders correlated with disturbances of balance and gait. The authors suggest that the earlier cholinergic reductions may account for the greater gait disturbances in the early stages of MSA-P and PSP than in PD.36

Cholinesterase activity has also been evaluated with PET in a small group of patients with MSA-C,37 and these cases also showed a reduction of AChE activity in the thalamus and cere- bellum. Taken together, these findings suggest that pharmaco- logic boosting of the cholinergic system could have a role in the treatment of these conditions.

The role of neuroinflammation and microglia activation in the pathogenesis of MSA has been investigated with 11C-(R)- PK11195 PET, a selective in vivo marker of activated microglia.

Activation of microglia in response to acute and chronic brain insults occurs in order to remodel connections and clear dam- aged tissue in the affected areas. However, there is cumulative evidence suggesting that, in conditions characterized by exten- sive chronic microglial activation, cytokines and other neuro- toxic factors are released by these cells, which may promote further neurodegeneration by causing death of surrounding healthy neurons.38 Gerhard and colleagues39 have reported increased 11C-(R)-PK11195 binding in both basal ganglia (puta- men, pallidum) and extrastriatal regions (dorsolateral pre-

frontal cortex, pons, and substantia nigra) in MSA patients com- pared with normal controls, suggesting that neuroinflamma- tory responses by activated microglia occur in MSA and may contribute to the neurodegenerative process.

A prospective 48-week, randomized, double-blind, multi- national clinical trial was recently conducted to investigate the efficacy of the antibiotic minocycline, a suppressant of micro- glial activation, as a drug treatment of MSA-P patients.40 In a small subgroup of patients, 11C-(R)-PK11195-PET was per- formed to assess the effect of minocycline on activated micro- glia. This study failed to show a clinical effect of minocycline on symptom severity as assessed by clinical motor function. In the PET subgroup, however, the three patients treated with minocy- cline showed a 30% reduction in microglial activation compared with the two cases treated with placebo. These findings warrant further investigations.

Finally, MIBG SPECT and 18F-dopamine PET studies have reported that patients with idiopathic PD show a significant loss of adrenergic innervation of the heart. This loss is not seen in patients with MSA as the loss of sympathetic function is pre- synaptic rather than postsynaptic. However, up to 50% of early PD cases (Hoehn and Yahr stage I) still show normal tracer binding,41,42 so cardiac sympathetic imaging is not a sensitive discriminator of MSA from PD.

19.2 Progressive Supranuclear

Palsy

Progressive supranuclear palsy is another cause of parkinson- ism, accounting for around 5% of cases. The disease usually develops after the sixth decade of life and is characterized by a combination of symmetric parkinsonism targeting the trunk and neck, which are held extended rather than flexed, supranu- clear vertical gaze palsy, dementia of subcortical type, and pseudobulbar signs, including dysphagia, dysarthria, and emo- tional incontinence. Bradykinesia, rigidity affecting axial muscles more than the limbs, postural instability, and gait dis- turbances are the most common parkinsonian symptoms.

Pathological changes in PSP consist of decreased pigment in the substantia nigra and locus coeruleus and loss of neurons in the basal ganglia, brainstem and ocular nuclei, cerebellar nuclei, and frontal cortex. Neurofibrillary 4-repeat tau tangles are present in affected structures and frontal and midbrain atro- phy; third ventricular widening are common in advanced cases.

19.2.1 Structural Imaging

Conventional T1- and T2-weighted MRI sequences detect char- acteristic structural changes in established PSP patients.3,4 The most common MRI finding in PSP is atrophy of the midbrain and superior cerebellar peduncle with dilatation of the third ventricle. Other commonly observed findings include atrophy of the basal ganglia, frontal and temporal cortices, and increased T2 signal in the midbrain. The selective atrophy of the midbrain, along with the dilatation of the third ventricle and a relatively preserved pontine profile, creates a peculiar visual effect on midsagittal T2 MRI images, which recall the silhouette of a bird where the head of the bird is represented by the atrophied midbrain and the body by the pons, known as

with healthy controls and PD patients as a result of degenera- tion of D2 receptors.22,50

Cholinergic function has been investigated in PSP with 11C- MP4A PET, a marker of AChE activity. PSP patients showed a severe reduction of thalamic 11C-MP4A uptake,51 which is likely to reflect reduced input from the degenerating pedunculopon- tine nucleus and other brainstem cholinergic nuclei, which are the main sources of thalamic cholinergic input. The peduncolo- pontine nucleus is involved in posture and gait control, eye movements, and attention. Therefore, its dysfunction may con- tribute to the locomotor and cognitive impairment observed in PSP patients.

Finally, Gerhard and colleagues have reported widespread increases of activated microglia in basal ganglia, midbrain, frontal lobe, and cerebellum of PSP patients.52

19.3 Corticobasal Degeneration

Corticobasal degeneration is a progressive neurodegenerative disease that involves the basal ganglia and cerebral cortex. Clinically, CBD is characterized by a progressive asymmetric akinetic-rigid syndrome with apraxia, limb dystonia, myoclo- nus, and other features indicative of cortical dysfunction, such as cortical sensory loss, alien limb phenomena, and mirror movements. The neuropathological hallmarks of CBD include mild atrophy of the cortical gyri with swollen, achromatic neu- rons scattered throughout the cerebrum, particularly in the posterior frontal and inferior parietal areas, and severe neuro- nal loss within the substantia nigra. Abnormal tau accumulation in both neurons and glial cells is extensive in gray and white matter of the cortex, basal ganglia, diencephalon, and the ros- tral part of the brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques.53

19.3.1 Structural Imaging

The most common MRI finding in CBD is asymmetric cortical atrophy, although symmetric atrophy has also been reported. The cortical atrophy typically targets the parietal lobe, the para- central regions, and the frontal lobe (anterior middle and poste- rior inferior frontal lobe). Atrophy of the ipsilateral cerebral peduncle is often present in these patients. A subtle hyperin- tensity of the white matter adjacent to the areas of cortical

“the penguin” or “the hummingbird” sign and has been reported to be highly specific for PSP (▶ Fig. 19.3).43 On axial T2, the reduction of the anterior–posterior diameter of the mid- brain with selective atrophy of the midbrain tegmentum, along with the thinning of cerebral peduncle, can form the so-called “morning glory” or “Mickey mouse” sign (▶ Fig. 19.3).

Several planimetric measurements of pons, midbrain, middle, and superior cerebellar peduncles have been proposed to differ- entiate PSP from idiopathic PD and MSA. The midbrain-to-pon- tine ratio (m:p ratio) and the more complex MR parkinsonism index (MRPI)44 have been shown to have 80 to 100% diagnostic accuracy when used to differentiate PSP from controls, MSA, and idiopathic PD patients, with MRPI being more accurate to differentiate PSP from MSA-P and the m:p ratio more sensitive to differentiate PSP from PD.45

DWI MRI shows raised water-proton apparent diffusion coef- ficients in the superior rather than the middle cerebellar peduncles, caudate, putamen, globus pallidus, thalamus, pons, prefrontal white matter, and precentral white matter in PSP patients compared with controls and PD patients.7,8

Finally, in PSP patients, VBM has detected pronounced loss in the gray matter of the frontotemporal cortex, including the prefrontal and insular cortices and in the white matter of the central midbrain region and the cerebral peduncles.

19.2.2 Functional Imaging

Perfusion SPECT studies in PSP patients reveals hypoperfusion in the frontal cortex and the midbrain.18,28,46 FDG-PET studies also show areas of reduced glucose metabolism in the frontal cortex, midbrain, and striatum.47,48 Overall, these findings par- allel those observed in MSA. However, when computer-assisted methods are applied, FDG-PET has been reported to have 85% sensitivity and 99% specificity for discriminating PSP from other parkinsonisms.30

18F-dopa PET studies reveal a uniform symmetric reduction of dopamine storage in the caudate and the anterior and poste- rior putamen, in contrast to PD and MSA, where reductions are asymmetric and target putamen.11 Using a voxel-based statisti- cal parametric mapping, Tai and colleagues49 have detected reduced 18F-dopa uptake in the orbitofrontal cortex in patients with familial PSP. Striatal D2 binding measured with 11C- raclopride PET and 123I-IBZM SPECT is reduced in PSP compared

Atypical Parkinsonian Syndromes

Fig. 19.3 Details of T2 magnetic resonance imaging showing “the penguin” sign (red arrow) and the “Mickey mouse” sign (blue arrow). The penguin sign is visible on midsagittal images, whereas the Mickey mouse sign is visible on axial images.

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atrophy is detected on fluid-attenuated inversion recovery (FLAIR) image, likely to reflect demyelination secondary to axo- nal loss or dysfunction. Conversely, basal ganglia structures generally show normal volume and MRI signal in these patients.54

Using VBM, Josephs and colleagues55 analyzed antemortem MRI images of patients with subsequent autopsy-confirmed CBD. All the MRI had been performed at the first neurologic evaluation. CBD patients were divided into two groups: patients with clinically dominant dementia syndrome and pathologi- cally confirmed CBD (D-CBD) and patients with clinically domi- nant extrapyramidal features and pathologically confirmed CBD (E-CBD). They found a characteristic pattern of posterior frontal atrophy in these patients regardless of the clinical syndrome, suggesting that this finding could be a useful biomarker of CBD pathology. The middle corpus callosum and the basal ganglia, in particular the pallidum, were heavily affected, whereas there was no evidence of brainstem atrophy. The E-CBD and D-CBD subgroups differed from each other in terms of the patterns of atrophy. The D-CBD group showed more cortical gray matter atrophy yet practically no white matter atrophy, compared with the E-CBD subgroup, which had both moderate cortical gray matter and white matter atrophy.

Finally, in CBD, DTI has shown an increased water diffusion coefficient in the motor thalamus, the superior mesenteric artery (SMA), and the precentral and postcentral gyri contra- lateral to affected limbs. FA was decreased in the precentral gyrus, SMA, postcentral gyrus, and cingulum.

19.3.2 Functional Imaging

Striatal 18F-dopa uptake is asymmetrically reduced in CBD patients, targeting the caudate and putamen similarly.56 Asym- metrically decreased striatal DAT binding has also been

[3] Seppi K, Poewe W. Brain magnetic resonance imaging techniques in the diag- nosis of parkinsonian syndromes. Neuroimaging Clin N Am 2010; 20: 29–55

[4] Massey LA, Micallef C, Paviour DC et al. Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy. Mov Disord 2012; 27: 1754–1762

[5] Horimoto Y, Aiba I, Yasuda T et al. Longitudinal MRI study of multiple system atrophy – when do the findings appear, and what is the course? J Neurol 2002; 249: 847–854

[6] Schocke MF, Seppi K, Esterhammer R et al. Diffusion-weighted MRI differenti- ates the Parkinson variant of multiple system atrophy from PD. Neurology 2002; 58: 575–580

[7] Seppi K, Schocke MF, Esterhammer R et al. Diffusion-weighted imaging discriminates progressive supranuclear palsy from PD, but not from the parkinson variant of multiple system atrophy. Neurology 2003; 60: 922–927

[8] Nicoletti G, Lodi R, Condino F et al. Apparent diffusion coefficient measure- ments of the middle cerebellar peduncle differentiate the Parkinson variant of MSA from Parkinson’s disease and progressive supranuclear palsy. Brain 2006; 129: 2679–2687

[9] Minnerop M, Lüders E, Specht K et al. Callosal tissue loss in multiple system atrophy—a one-year follow-up study. Mov Disord 2010; 25: 2613–2620

[10] Walter U, Dressler D, Probst T et al. Transcranial brain sonography findings in discriminating between parkinsonism and idiopathic Parkinson’s disease. Arch Neurol 2007; 64: 1635–1640

[11] Brooks DJ, Ibanez V, Sawle GV et al. Differing patterns of striatal 18F-dopa uptake in Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990; 28: 547–555

[12] Varrone A, Marek KL, Jennings D, Innis RB, Seibyl JP. [123I]β-CIT SPECT imaging demonstrates reduced density of striatal dopamine transporters in Parkinson’s disease and multiple system atrophy. Mov Disord 2001; 16: 1023–1032

[13] Antonini A, Leenders KL, Vontobel P et al. Complementary PET studies of striatal neuronal function in the differential diagnosis between multiple system atrophy and Parkinson’s disease. Brain 1997; 120: 2187–2195

[14] Schulz JB, Klockgether T, Petersen D et al. Multiple system atrophy: natural history, MRI morphology, and dopamine receptor imaging with 123IBZM- SPECT. J Neurol Neurosurg Psychiatry 1994; 57: 1047–1056

[15] Moore RY, Whone AL, McGowan S, Brooks DJ. Monoamine neuron innerva- tion of the normal human brain: an 18F-DOPA PET study. Brain Res 2003; 982: 137–145

[16] Snow BJ, Tooyama I, McGeer EG et al. Human positron emission tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels. Ann Neurol 1993; 34: 324–330

[17] Pate BD, Kawamata T, Yamada T et al. Correlation of striatal fluorodopa uptake in the MPTP monkey with dopaminergic indices. Ann Neurol 1993; 34: 331–338

[18] Pirker W, Djamshidian S, Asenbaum S et al. Progression of dopaminergic degeneration in Parkinson’s disease and atypical parkinsonism: a longitudi- nal beta-CIT SPECT study. Mov Disord 2002; 17: 45–53

[19] Burn DJ, Sawle GV, Brooks DJ. Differential diagnosis of Parkinson’s disease, multiple system atrophy, and Steele-Richardson-Olszewski syndrome: dis- criminant analysis of striatal 18F-dopa PET data. J Neurol Neurosurg Psychia- try 1994; 57: 278–284

[20] Oh M, Kim JS, Kim JY et al. Subregional patterns of preferential striatal dopa- mine transporter loss differ in Parkinson’s disease, progressive supranuclear palsy, and multiple-system atrophy. J Nucl Med 2012; 53: 399–406

[21] Goto S, Matsumoto S, Ushio Y, Hirano A. Subregional loss of putaminal effer- ents to the basal ganglia output nuclei may cause parkinsonism in striatonig- ral degeneration. Neurology 1996; 47: 1032–1036

[22] Brooks DJ, Ibanez V, Sawle GV et al. Striatal D2 receptor status in Parkinson’s disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography. Ann Neurol 1992; 31: 184–192

[23] Plotkin M, Amthauer H, Klaffke S et al. Combined 123I-FP-CIT and 123I-IBZM SPECT for the diagnosis of parkinsonian syndromes: study on 72 patients. J Neural Transm 2005; 112: 677–692

[24] Otsuka M, Ichiya Y, Kuwabara Y et al. Glucose metabolism in the cortical and subcortical brain structures in multiple system atrophy and Parkinson’s dis- ease: a positron emission tomographic study. J Neurol Sci 1996; 144: 77–83

[25] Taniwaki T, Nakagawa M, Yamada T et al. Cerebral metabolic changes in early multiple system atrophy: a PET study. J Neurol Sci 2002; 200: 79–84

[26] Juh R, Pae C-U, Lee C-U et al. Voxel based comparison of glucose metabolism in the differential diagnosis of the multiple system atrophy using statistical parametric mapping. Neurosci Res 2005; 52: 211–219

reported in CBD patients. Postsynaptic striatal D ability may be reduced or may be preserved.57

receptor avail-

Perfusion SPECT studies have revealed asymmetric hypoper- fusion in the basal ganglia and the frontoparietal cortex. Simi- larly, FDG-PET studies have shown a characteristic pattern of reduced glucose metabolism in striatum, thalamus, and inferior parietal cortex contralateral to the most affected side. FDG-PET has been reported to have 91% sensitivity and 99% specificity for the diagnosis of CBD compared with other parkinsonisms when computer-assisted methodologies are applied.30

Evidence of microglial activation involvement in the patho- genesis of CBD has been reported.52

Finally, an fMRI study has shown decreased activation of the parietal lobe contralateral to the more affected arm in patients with early CBD, when movements, simple or complex, were performed with the hand. This finding suggests that altered higher cortical motor organization is present early in the disease.58

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1247–1255

. [42] Takatsu H, Nishida H, Matsuo H et al. Cardiac sympathetic denervation from
the early stage of Parkinson’s disease: clinical and experimental studies with
radiolabeled MIBG. J Nucl Med 2000; 41: 71–77

. [43] Kato N, Arai K, Hattori T. Study of the rostral midbrain atrophy in progressive
supranuclear palsy. J Neurol Sci 2003; 210: 57–60

[46] Johnson KA, Sperling RA, Holman BL, Nagel JS, Growdon JH. Cerebral perfu- sion in progressive supranuclear palsy. J Nucl Med 1992; 33: 704–709

[47] Karbe H, Grond M, Huber M, Herholz K, Kessler J, Heiss WD. Subcortical dam- age and cortical dysfunction in progressive supranuclear palsy demonstrated by positron emission tomography. J Neurol 1992; 239: 98–102

[48] Piccini P, de Yebenez J, Lees AJ et al. Familial progressive supranuclear palsy: detection of subclinical cases using 18F-dopa and 18fluorodeoxyglucose pos- itron emission tomography. Arch Neurol 2001; 58: 1846–1851

[49] Tai YF, Ahsan RL, de Yébenes JG, Pavese N, Brooks DJ, Piccini P. Characteriza- tion of dopaminergic dysfunction in familial progressive supranuclear palsy: an 18F-dopa PET study. J Neural Transm 2007; 114: 337–340

[50] Schwarz J, Tatsch K, Arnold G et al. 123I-iodobenzamide-SPECT in 83 patients with de novo parkinsonism. Neurology 1993; 43 Suppl 6: S17–S20

[51] Shinotoh H, Namba H, Yamaguchi M et al. Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson’s disease and progressive supra- nuclear palsy. Ann Neurol 1999; 46: 62–69

[52] Gerhard A, Trender-Gerhard I, Turkheimer F, Quinn NP, Bhatia KP, Brooks DJ. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in pro- gressive supranuclear palsy. Mov Disord 2006; 21: 89–93

[53] Kouri N, Whitwell JL, Josephs KA, Rademakers R, Dickson DW. Corticobasal degeneration: a pathologically distinct 4 R tauopathy. Nat Rev Neurol 2011; 7: 263–272

[54] Koyama M, Yagishita A, Nakata Y, Hayashi M, Bandoh M, Mizutani T. Imaging of corticobasal degeneration syndrome. Neuroradiology 2007; 49: 905–912

[55] Josephs KA, Whitwell JL, Dickson DW et al. Voxel-based morphometry in autopsy proven PSP and CBD. Neurobiol Aging 2008; 29: 280–289

[56] Sawle GV, Brooks DJ, Marsden CD, Frackowiak RS. Corticobasal degeneration. A unique pattern of regional cortical oxygen hypometabolism and striatal flu- orodopa uptake demonstrated by positron emission tomography. Brain 1991; 114 Pt 1B: 541–556

[57] Klaffke S, Kuhn AA, Plotkin M et al. Dopamine transporters, D2 receptors, and glucose metabolism in corticobasal degeneration. Mov Disord 2006; 21: 1724–1727

[58] Ukmar M, Moretti R, Torre P, Antonello RM, Longo R, Bava A. Corticobasal degeneration: structural and functional MRI and single-photon emission computed tomography. Neuroradiology 2003; 45: 708–712

Atypical Parkinsonian Syndromes

. [27] Cilia R, Marotta G, Benti R, Pezzoli G, Antonini A. Brain SPECT imaging in mul- tiple system atrophy. J Neural Transm 2005; 112: 1635–1645

. [28] Van Laere K, Casteels C, De Ceuninck L et al. Dual-tracer dopamine trans- porter and perfusion SPECT in differential diagnosis of parkinsonism using template-based discriminant analysis. J Nucl Med 2006; 47: 384–392

. [29] Shinotoh H. Neuroimaging of PD, PSP, CBD and MSA-PET and SPECT studies. J Neurol 2006; 253 Suppl 3: iii30–iii34

[44] Quattrone A, Nicoletti G, Messina D et al. MR imaging index for differentia- tion of progressive supranuclear palsy from Parkinson’s disease and the Par- kinson variant of multiple system atrophy. Radiology 2008; 246: 214–221

[45] Hussl A, Mahlknecht P, Scherfler C et al. Diagnostic accuracy of the magnetic resonance Parkinsonism index and the midbrain-to-pontine area ratio to differentiate progressive supranuclear palsy from Parkinson’s disease and the Parkinson variant of multiple system atrophy. Mov Disord 2010; 25: 2444–

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Dementia with Extrapyramidal Syndromes

20 Secondary Parkinsonism

Thyagarajan Subramanian, Kala Venkiteswaran, and Elisabeth Lucassen

In this chapter, we consider a limited set of disorders that mani- fest with clinical parkinsonism and have known secondary causes; the common clinical manifestation is secondary parkin- sonism. One simplistic but useful way to classify secondary par- kinsonism is based on the location of pathology in the central nervous system. This simplistic classification can help organize a large variety of disorders. The first group of conditions com- prises those that cause secondary parkinsonism as a result of lesions primarily at the level of the substantia nigra pars com- pacta (SNpc) neurons in the midbrain (group 1 disorders). Examples of this type of secondary parkinsonism include focal vascular malformations or ischemic infarcts in the midbrain that cause hemiparkinsonism with hemiparesis. Another exam- ple is the hemiparkinsonism-hemiatrophy syndrome, in which a developmental defect appears at the level of the SNpc and its immediate surrounding region.

The second group of conditions (group 2 disorders) manifest as secondary parkinsonism and result from lesions primarily at the level of the striatum (caudate and the putamen) or its con- nections to the remainder of the basal ganglia connectome. Examples in this category include drug-induced parkinsonism, vascular parkinsonism, Wilson’s disease, parkinsonism seen in Huntington’s disease (HD), dentatorubral-pallidoluysian atro- phy (DRPLA), pantothenate kinase–associated neurodegenera- tion (PKAN, Hallervorden-Spatz syndrome), other associated disorders included in the classification of disorders under neu- rodegeneration with brain iron accumulation (NBIA) category, and toxin-induced parkinsonism.

The final group (group 3 disorders) consists of secondary parkinsonisms that potentially involve the SNpc, their striatal targets, other basal ganglia nuclei, and diffuse pathology in the central nervous system (CNS). Examples include postinfectious parkinsonism and frontotemporal dementia with parkinsonism. Because some of these disorders are discussed in detail else- where in this book, this chapter focuses on the underlying com- mon pathology for secondary parkinsonism and more detailed discussion of four key examples: HD, DRPLA, Wilson’s disease, and vascular parkinsonism.

20.1 Pathology of Secondary

Parkinsonism

One of the key pathological mediators of secondary parkinson- ism is the dopaminergic nigrostriatal pathway and its targets in the striatum. To understand this pathology, a brief review of the basal ganglia connectome is necessary. The dopaminergic neu- rons in SNpc are located in the midbrain adjacent to the crux cerebri, the red nucleus, and the cerebral aqueduct. The long axons derived from these cell bodies terminate in the caudate nucleus and the striatum primarily, but they also have minor connections to the globus pallidus internal segment (GPi), globus pallidus external segment (GPe), thalamus, substantia nigra pars reticulata (SNr), and into the subthalamic nucleus (STN). These minor connections represent only 20% of the dopamine synthesized by the nigrostriatal pathway. Although

most of these connections are unilateral, there is evidence for interhemispheric connectivity in the nigrostriatal pathway that may be of considerable importance.1 The vast majority of dopamine secreted by the nigrostriatal pathway is used in the striatum to act on the D1-type and D2-type receptors located on the medium spiny neurons. These medium spiny neurons then send their axonal connections to either the GPi/SNr via the direct pathway or to the GPe via the indirect pathway. The GPe neurons project to the STN, which in turn projects to the GPi and SNr. The output of the GPi and SNr both project to the motor thalamus and from there to the primary motor cortex and the supplementary motor cortex. These direct and indirect pathways not only mediate motor systems, but also modulate various aspects of emotions, eye movements, and cognition and complications associated with various forms of parkinsonism.2

In secondary parkinsonism, lesions at the level of the mid- brain location of the cell bodies of the substantia nigra (group 1 disease, as defined earlier in this chapter) usually cause damage to adjacent pyramidal tracts, most frequently manifesting clini- cally as unilateral parkinsonism. Examples of this type of pathology are cavernomas that bleed, causing focal neuronal injury in the midbrain.3,4,5 Other examples include traumatic injuries and inadvertent injury during neurosurgical manipula- tions of the midbrain.6,7,8,9,10 An uncommon and rare disorder that is considered genetic or developmental in origin is the hemiatrophy-hemiparkinsonism (HA-HP) syndrome.11,12 Here the pathology is associated with developmental atrophy of the contralateral midbrain and in many cases the entire hemi- sphere. Although HA-HP is classically thought to be due to pathology that implicates the SNpc and its immediate sur- roundings, a recent report has suggested putaminal pathology that would place this condition in group 2 disorders (striatal pathology). Injury to the SNpc cell bodies has also been noted in postencephalitic parkinsonism, especially with neurotropic viruses like Japanese B, West Nile, Coxsackie, and polio infection-related encephalitis.13–17 In most of these patients, however, there is more diffuse pathology outside the SNpc. The exclusive involvement of the SNpc is rare, but when it happens, it can be dramatic. The neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) specifically causes degeneration of the SNpc and produces pathology in the nigrostriatal pathway that is similar in many ways to idiopathic PD.18 However, MPTP-induced parkinsonism produces pathology that is quite symmetric and lacks the classic α-synuclein-positive Lewy bod- ies as intracytoplasmic inclusions that are obligate in PD.19,20 Dementia with Lewy bodies is another example where the pathology is primarily presynaptic (i.e., in the SNpc and its axons).21 This entity is discussed in Chapter 16.

Secondary parkinsonism with pathology that afflicts the stri- atum is much more common (group 2 disorders). Perhaps the most common condition that presents itself as symmetric par- kinsonism is drug-induced parkinsonism.22 Here the D1-type and D2-type receptors are variably blocked, resulting in parkin- sonism; pathological studies in such patients are scant.23 In general, pathological studies in such patients do not provide

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ogy and genetics is beyond the scope of this chapter, so here we focus primarily on HD pathology.

In addition to striatal pathology, HD is associated with degen- eration of the temporal and the frontal lobes of the cerebral cor- tex, a part of the brain responsible for integrating higher mental functioning, movements, and sensations. The degenerative changes in HD primarily affect the striatal medium-sized spiny neurons that project into the GP and SNr. These spiny neurons secrete γ-aminobutyric acid as the primary neurotransmitter. One theory suggests that selective loss of these specialized cells involved in the “indirect pathway” of the basal ganglia and the relative sparing of the cells involved in the “direct pathway” of the basal ganglia result in decreased inhibition (i.e., increased activity) of the thalamus. Therefore, the thalamus increases its output to regions of the cerebral cortex involved in movement, which may be the cause of the disorganized, excessive (hyper- kinetic) movement patterns of chorea. However, as disease progresses, more and more medium-sized spiny neurons degenerate, and medium spiny neurons involved in both the direct and indirect pathways are equally involved in advanced HD; in such patients, chorea no longer occurs and is replaced by severe secondary parkinsonism. It is reported that even in advanced HD, the SNpc remains relatively spared.

Huntington’s disease is due to a mutation in a gene that is transmitted as an autosomal dominant trait. In addition, although HD usually occurs in certain families, the disorder may sometimes occur as the result of a spontaneous (sporadic) change in the gene for HD. The gene responsible for HD is known as IT15 and is located on chromosome 4. This gene regu- lates, controls, or encodes the production of a protein known as huntingtin. Mutations of the IT15 gene result in abnormally long CAG trinucleotide repeats. These expanded CAG sequences result in the production of abnormal huntingtin protein (poly- glutamine). The length of the expanded CAG repeats is thought to have some relation to the age at symptom onset. For exam- ple, those with a large number of repeats tend to develop symp- toms at an earlier age.32 Patients with CAG repeat lengths that are larger (usually > 60) manifest with symptoms in childhood or adolescence. This form of HD is called juvenile HD (Westphal variant).33

Most individuals with juvenile HD experience an age of onset that is much younger than that of their affected parents. They also often face a much more rapid progression of the disease. This occurrence is described as genetic anticipation, where a disease increases in severity in successive generations. Genetic anticipation occurs in many other genetic disorders and is not unique to HD. The molecular pathology of HD has been the focus of much research. There is clearly some commonality between other degenerative disorders in that misfolding of the huntingtin protein seems crucial for the neurodegeneration to occur in HD.34

Group 3 disorders have more widespread pathology that often involves both the SNpc cell bodies and their striatal tar- gets. Examples include postinfectious parkinsonism reported from West Nile encephalitis. Here diffuse pathology has been noted in patients who exhibited parkinsonism, which often involves multiple nuclei in the basal ganglia.35,36 Postinfectious parkinsonism has also been reported with dengue fever, Japanese B encephalitis, and in an epidemic termed encephalitis lethargica that occurred between 1915 and 1926. The validity

any specific clues except for the primary pathology for which the dopamine antagonists were used (e.g., schizophrenia) or that they have vascular lesions that predispose them to parkin- sonism.

The second most common disease that presents with sym- metric parkinsonism is vascular parkinsonism.24 Here the most frequent pathology is related to multiple lacunar infarcts bilaterally involving most frequently the lenticular-striate arteries.25 Frequently, these lacunar infarcts involve the inter- nal capsule in addition to the striatum, resulting in symmetric parkinsonism and pyramidal tract signs. It is not uncommon to find ischemic changes in the subcortical white matter. Underlying poorly treated hypertension, diabetes, and hyper- cholesterolemia-related pathology is frequently seen. Overall, atrophy of the brain and evidence of vascular lesions else- where in the brain, such as the pons and the cerebellum, are also frequent.24,25 Manganese toxicity, NBIA, and Wilson’s dis- ease are characterized by the deposition of metals in the basal ganglia and are seen clinically as mostly symmetric parkinson- ism.26,27,28,29 Manganese accumulates in the striatum and in the globus pallidus in patients environmentally or occupation- ally exposed to large quantities of manganese (e.g., in manga- nese miners). This situation can also occur in the setting of chronic liver failure resulting in a more subtle manganese deposition but causes a parkinsonian syndrome that is quite similar to other secondary parkinsonisms. Accumulation of iron in the globus pallidus is characteristic in NBIA to generate the “eye of the tiger” imaging finding on MRI along with other very characteristic imaging findings.26,27 Wilson’s disease pathology causes copper accumulation in the brain and in the eyes and in many other organs.28 The pathophysiological rea- sons for why heavy metals have a selective affinity to the basal ganglia have not been completely established. It is thought that the relative abundance of enzymes that use heavy metals in the basal ganglia may be a putative reason for the basal gan- glia to be at risk for heavy metal deposition. It is also unclear as to why this leads to parkinsonism. The best worked out molecular pathology is in the case of Wilson’s disease, where there is mutation in the Wilson’s disease protein ATP7B gene. This is an autosomal recessive genetic disorder, and it occurs when the child inherits both copies of the mutation and results in deficiency of ceruloplasmin and release of free cop- per into the serum, resulting in its widespread deposition in the body but particularly in the kidneys, eyes, and in brain. Classic Wilson’s disease pathology shows clear-cut serum deficiency of ceruloplasmin, paradoxically low serum copper (thought to be due to its deposition in tissues), excess secre- tion of copper in the urine, and deposition of copper into the cornea (KF ring) and into the basal ganglia.30

Huntington’s disease and the closely related DRPLA cause unique pathology characterized by progressive degeneration of neurons primarily in the caudate nuclei and putamen of the basal ganglia. Many other diseases can appear as HD-like sec- ondary parkinsonism. These include ataxia with oculomotor apraxia, certain spinocerebellar ataxias, PLA2G6-associated neurodegeneration, Wilson’s disease (as discussed earlier), and PKAN form of NBIA. However, the pathology that causes parkin- sonism in all these conditions appear to be centered at the level of the striatum. Most of these disorders also have associated pathology in other parts of the CNS.31 The review of all pathol-

Secondary Parkinsonism

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Dementia with Extrapyramidal Syndromes

of this later entity has been recently questioned, and the pathology in these disorders has been quite variable.14,37,38 Therefore, modern examples of postencephalitic parkinsonism that primarily show imaging abnormalities in the midbrain and basal ganglia should be distinguished from encephalitis lethargica.

20.1.1 Specific Examples of Secondary Parkinsonism

Huntington’s Disease

Huntington’s disease is a hereditary progressive neuro- degenerative disorder characterized by the development of emotional, behavioral, and psychiatric abnormalities; loss of previously acquired intellectual or cognitive functioning; and movement abnormalities.39 The classic signs of HD include the development of chorea–or involuntary, rapid, irregular, jerky dancelike movements that simultaneously afflict both proximal and distal muscles. This movement disorder may affect the face, arms, legs, or trunk. Patients also have gradual loss of thought processing and acquired intellectual abilities (dementia). There may be impairment of memory, abstract thinking, and judg- ment; disorientation; increased agitation; and personality changes. Although symptoms typically become evident during the fourth or fifth decades of life, age at onset is variable and ranges from early childhood to late adulthood. HD is transmit- ted as an autosomal dominant trait and is due to gene muta- tions on chromosome 4 (4p16.3). See details of pathology in an earlier section of this book.

The clinical course of HD can last 15 to 20 years. In the early stages, the chorea is focal and segmental but progresses to involve multiple body parts. The chorea typically peaks within 10 years and is gradually replaced by bradykinesia, rigidity, and dystonia. In a very small percentage of cases, HD may present with a parkinsonian syndrome rather than with chorea (West- phal variant).33 The latter cases typically have an early onset (e.g., <20 years). The behavioral and cognitive disturbances characteristic of HD most often account for the brunt of the patient’s disability and most of the hardship to the family. Approximately one-third develop dysthymia or an affective dis- order; one-third an intermittent explosive disorder; and the remaining third substance-abuse problems, sexual dysfunction, antisocial personality traits, or schizophreniform symptoms. Depression with suicidal tendencies is not uncommon. Even the minority who may not manifest behavioral problems ultimately succumb to dementia. Thus, secondary parkinsonism in HD is a late feature in adults patients and is an early feature in juvenile HD. This is a matter of major imaging importance when patients are referred for neuroimaging with a putative diagno- sis of HD.

The diagnosis of HD is confirmed by genetic testing. Imaging abnormalities typically involve early loss of volume in the CNS and atrophy of the caudate head in early disease (▶ Fig. 20.1). As the disease advances, there is further degeneration and atro- phy of the entire striatum and adjacent basal ganglia structures. The midbrain is relatively preserved in HD. In more advanced HD, degenerative changes in the cerebellum and more advanced cortical atrophy, especially in the prefrontal lobes, are noted.

Treatment of HD involves a multidisciplinary team that can provide social, medical, neuropsychiatric, and genetic guidance to patients and families throughout the course of the illness. Although dopamine blockers are moderately effective for cho- rea, they may aggravate bradykinesia and dystonia. Tetrabena- zine, a short-acting agent that can provide relief without high risk of causing parkinsonism, is often used to treat chorea in HD. Treatment of concomitant depression and substance abuse, if any, is critical in HD patients. From an imaging perspective, these matters need to be considered when interpreting imaging findings in HD. See Chapter 40 on advances in the treatment of dementia for details.

Dentatorubral-Pallidoluysian Atrophy

Dentatorubral-pallidoluysian atrophy is a rare subtype of type I autosomal dominant cerebellar ataxia. It is characterized by involuntary movements, ataxia, epilepsy, mental disorders, cog- nitive decline, and prominent genetic anticipation.40 The dis- ease is found most commonly in Japan, where the prevalence is estimated to be 1 in 208,000. Age of onset ranges from 1 to 60 years. The clinical symptoms are variable depending on the age of onset of the disease; myoclonus, epilepsy, and mental retardation are the main symptoms in juvenile onset, whereas cerebellar ataxia, choreoathetosis, and dementia are seen in adult onset, which is quite similar to onset in some adult HD patients. Clinical features are significantly correlated with the size of CAG repeats. Head magnetic resonance imaging (MRI) shows atrophy of cerebellum, brainstem, cerebrum, and high signal in periventricular white matter.41 T1-weighted MRI fre- quently shows cerebral atrophy, predominantly in the fronto- temporal region, with dilatation of the lateral ventricles and atrophy of the cerebellum, pons, and midbrain accompanied by dilatation of the fourth ventricle and the aqueduct (▶ Fig. 20.2).

Fig. 20.1 Coronal magnetic resonance imaging showing atrophy of the caudate and putamen in adult Huntington’s disease. There is also accompanying cortical atrophy. The loss of signals from the caudate head resulting in change of the shape and size of the lateral ventricles is classic for this diagnosis.

188

Diffuse high signal intensities throughout the periventricular white matter and centrum semiovale on T2-weighted MRI, mimicking leukoaraiosis or leukodystrophy, seem to be charac- teristic findings in DRPLA. Fluid-attenuated inversion recovery (FLAIR) images are useful for demonstrating the pathological changes in white matter more clearly than conventional T2- weighted images in DRPLA. Axial midbrain images show the signal difference between the red nucleus and the surrounding fasciculi, which has been described as a characteristic of this disease. Neuropathologically, a combined degeneration of the dentatorubral and pallidoluysian systems is a characteristic fea- ture of DRPLA.42 Neuropathological findings in DRPLA include thickening of the skull bone, atrophy of the brain, degeneration of the dentate nucleus and its afferent fibers, degeneration of the GP-STN nucleus system, atrophy of the tegmentum of the brainstem especially in the pons, degeneration of the striatum, degeneration of the superior colliculus, degeneration of the gracile nucleus, degeneration of the pyramidal tract, mild degeneration of the cerebellar cortex, mild degeneration of the cerebral cortex, and degeneration of the cerebral white matter. In juvenile type manifesting with progressive myoclonus epi- lepsy syndromes, degeneration of the GP is more severe than that of the dentate nucleus. In adult patients with cerebellar

ataxia and choreoathetoid movements without myoclonus or epilepsy, degeneration of the dentate nucleus is more severe than that of the GP.43

One clear distinction of DRPLA from other entities that have similar pathology is the preservation of SNpc in this disease.44 The pathological basis of the diffuse white matter changes seen in the subcortical white matter is unclear. Histopatholog- ical investigation has disclosed diffuse decrease of myelin sheaths and axons without gliosis and without evidence of microvascular pathology. These findings suggest that the pri- mary genetic defect may be the basis for the MRI-detected pathology in the white mater. These prominent white matter changes seen on FLAIR imaging may be quite useful because this is usually not seen in HD patients or in other forms of spi- nocerebellar atrophies that come in the differential diagnosis of DRPLA. An unstable expansion of the trinucleotide (CAG) repeats in the DRPLA gene on the short arm of chromosome 12 (ATN1 gene; 12p13.31) has been identified as causative. DRPLA progresses rather rapidly. The mean disease duration is about 13 years. Recurrent seizures and dysphagia with fre- quent fluid and food aspiration lead to bronchopneumonia and subsequent death. However, some patients can reach 60 years of age or older.

Secondary Parkinsonism

Fig. 20.2 Magnetic resonance images of patient with adult-onset DRPLA. (a–f). The T2-weighted axial images obtained from a 60-year-old patient show high-signal-intensity lesions in the middle and upper pons, midbrain tegmentum, and cerebral white matter, in addition to a left pallidal high- signal-intensity spot resulting from an old lacunar infarction (d). (f) A T1-weighted midsagittal image shows atrophy of the brainstem and cerebellum. (Used with permission from Sunami Y, Koide R, Arai N, Yamada M, Mizutani T, Oyanagi K. Radiologic and neuropathologic findings in patients in a family with dentatorubral-pallidoluysian atrophy. AJNR Am J Neuroradiol. 2011 Jan;32(1):109-14.)

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Dementia with Extrapyramidal Syndromes

Wilson’s Disease

Wilson’s disease is a rare genetic disorder of copper metabolism that leads to an excessive accumulation of copper in certain tis- sues and organs, including the liver, brain, kidneys, or corneas of the eyes. Without prompt, appropriate treatment, the disorder may result in progressive liver disease, degenerative changes of the brain, psychiatric abnormalities, and other symptoms. Neuro- logic findings may include resting, action, or postural tremor; somewhat characteristic wing-beating tremor or flapping tremor where the patient has proximal tremor at the shoulders that mimics the beating of wings of a bird; choreoathetosis; sustained muscle contractions (e.g., risus sardonicus, a forced facial gri- mace); dystonia; dysarthria; and dysphagia. Some patients may also experience increasing irritability, anxiety, severe depression, or other psychiatric symptoms. Diagnosis is via genetic testing and blood and urine chemistries to document copper abnormali- ties as detailed in the preceding pathology section. Imaging changes in Wilson disease are well described. MRI often shows T2 and FLAIR hyperintense lesions involving thalami, midbrain, and pons. These lesions are typically hypointense on T1-weighted sequence and showed no evidence of restricted diffusion. Occa- sionally, hyperintense signal on T2/FLAIR images are seen in the striatum. Involvement of the midbrain gives the appearance of the “face of the giant panda” as dorsal pontine signal abnormali- ties resemble the face of a cub panda. Face of the giant panda and her cub constitute the “double panda sign” (▶ Fig. 20.3, ▶ Fig. 20.4), which is characteristic for this disease.45

These findings are attributed to neurodegeneration and the deposition of copper into the striatum and the GP. The “face of the giant panda” sign consists of high signal intensity in the teg- mentum, preservation of signal intensity of the lateral portion of the pars reticulata of the SN and red nucleus, and hypointen- sity of the superior colliculus. The “face of panda cub” is some- times identified in the dorsal pons. “Eyes of the panda” are formed from the relative hypointensity of the central tegmental tracts, in contrast with the hyperintensity of the aqueduct opening into the fourth ventricle (“nose and mouth of the panda”) bounded inferiorly by the superior medullary velum. The panda’s “cheeks” are formed from the superior cerebellar peduncles.46 Prompt initiation of treatment as a child is often curative. The standard treatment of Wilson’s disease has evolved and is discussed in Chapter 40 in greater detail. In selected patients, liver transplantation is needed, and when successful can cure the patient.

Vascular Parkinsonism

Vascular parkinsonism frequently presents as what is classically described as lower body parkinsonism.47 The findings are that patients have disproportionate amount of parkinsonian signs and symptoms in the lower body (below the umbilicus). Symp- tom onset is insidious and can sometimes be noted as mild cog- nitive deficits. Most frequent manifestation is with slowness in walking and difficulty climbing stairs. On examination, these patients have increased tone in the lower extremities and

Fig. 20.3 T2-weighted axial MRI demonstrating the “face of the giant panda” in the midbrain (arrow). (Used with permission from Jacobs DA, Markowitz CE, Liebeskind DS, Galetta SL. The “double panda sign” in Wilson’s disease. Neurology 2003;61(7):969.)

Fig. 20.4 T2-weighted axial MRI reveals the “face of the miniature panda” in the pontine tegmentum (arrow). (Used with permission from Jacobs DA, Markowitz CE, Liebeskind DS, Galetta SL. The “double panda sign” in Wilson’s disease. Neurology 2003;61(7):969.)

190

bradykinesia seen with foot tapping and stomping with their heels. Gait is also slow, and patients have difficulty turning; some patients have a positive retropulsion test. Deep tendon jerks may be exaggerated, and a positive Babinski sign is not uncommon. Some patients have parkinsonism in the upper body as well, but this is disproportionately mild. These patients usually have other comorbid diabetes, hypertension, cardiovas- cular disorders or hypercholesterolemia. Other well-known vas- cular risk factors, like family history of strokes or cardiovascular disease, are also common, along with a history of nicotine abuse in some patients. Brain imaging frequently demonstrates lacunar infarcts in the basal ganglia (▶ Fig. 20.5), corona radiata, thalamus, or pons.48

In many patients, these lesions are silent without any known previous symptoms; others have clinical history of transient ischemic attacks or clearly documented strokes with subse- quent near complete recovery. There is also frequent report of brain volume loss and atrophy in this entity. Clinical diagnosis of concomitant Binswanger’s disease is not uncommon. Inter- estingly, imaging studies in a large series of patients diagnosed as having vascular parkinsonism failed to provide specific crite- ria for imaging abnormalities.25 Instead, a large variety of multi- focal small vascular lesions were noted. It is important to note, from an imaging perspective, that such patients are exceedingly unlikely to have imaging findings exclusive to the SNpc which is much more characteristic of idiopathic PD. However, midbrain atrophy can be frequently seen in vascular parkinsonism and is thought to be secondary to wallerian degeneration and atrophy of the crux cerbri.49

Treatment for vascular parkinsonism is primarily sympto- matic. Modest clinical improvement is noted with large doses of L-dopa given multiple times every day. Often the dose needed to get clinical benefit is in the range of 1.5 to 2 g/day of L-dopa.50 Interestingly, such patients generally do not exhibit motor fluctuations that are noted in idiopathic PD patients, and it is rare for such patients to develop drug-induced dyskine- sias.24 This is an important clinical distinction, and from an imaging perspective, the risk of involuntary movements inter- fering with imaging quality is low. Distinction between vascular parkinsonism and idiopathic PD on clinical grounds is usually not difficult. However, on occasion, this distinction can be prob- lematic in certain subtypes of idiopathic PD patients. In such patients, a dopamine transporter single-photon emission

computed tomography (SPECT) scan may be useful.51 The dif- ferential diagnosis of vascular parkinsonism always includes normal pressure hydrocephalus (NPH), and imaging studies can often be helpful, as the distinctive features of NPH, where there is more or less uniform enlargement of the entire ventricular system and accompanying brain cortical atrophy, are lacking in vascular parkinsonism. Instead, in vascular parkinsonism, there is an apparent enlargement of the lateral ventricles resulting from the loss of gray matter volume in the caudate and the putamen secondary to multiple lacunar infarcts. In some cases, however, this distinction is difficult to make on the basis of structural imaging alone. A large-volume lumbar puncture and removal of cerebrospinal fluid to determine whether the patient has tangible improvement in parkinsonism and gait is often performed as a diagnostic test. In itself, however, this test or any improvement in parkinsonism as a result of this test is not definitive.52,53 In such patients, diagnostic uncertainty remains, and often a pragmatic treatment approach that com- bines shunting with pharmacotherapy is required.

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Fig. 20.5 Magnetic resonance imaging from a patient showing vascular parkinsonism.
(a) T1-weighted image showing multiple lacunar strokes bilaterally in the putamen.
(b) Corresponding T2-weighted image. (Used with permission from Fujimoto KI. Vascular parkinsonism. J Neurol 2006;253 [Suppl 3]:III/ 16–III/21.)

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. [19] Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983; 219: 979–980

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tron emission tomographic evidence for progression of human MPTP-
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tiated by presynaptic dysfunction. Transl Neurodegener 2013; 2: 16

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tigation of vascular parkinsonism, including clinical criteria for diagnosis.
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407–414

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Part VII Vascular Dementia

. 21 Vascular Dementia 194

. 22 Neuroimaging of Vascular Dementias 199

. 23 Imaging of Specific Hereditary Microangiopathies 210

. 24 Vasculitis and Dementia 216

VII

Vascular Dementia

21 Vascular Dementia

A.M. Barrett and Vahid Behravan

A spectrum of ischemia-related cognitive problems has been identified, including vascular dementia, vascular cognitive impairment,1 multi-infarct dementia,2 and subcortical vascular dementia.3,4 The syndrome of clinical stroke or subclinical vas- cular brain injury and functionally relevant memory and cogni- tive impairment5 may have first been introduced to the field by Binswanger and Alzheimer in the 19th century.6 In contrast to dementia caused by neurodegenerative conditions affecting the brain, such as Alzheimer’s disease, frontotemporal dementia and variants (primarily cortical), Parkinson-plus syndromes, Huntington’s disease, and other neurodegenerative disorders primarily affecting the subcortical systems, vascular and ische- mic-related dementia can be considered a “secondary” form of dementia.7 These forms can be distinguished from primary neurodegenerative disorders by the mechanism of cognitive impairment: not only is there direct damage to cortical and subcortical cells and white matter circuitry, but there is indirect damage via abnormal cellular homeostasis (for example, the brain in vascular dementia may be affected by the common co- occurrence of diabetes and hyperglycemia, and the mechanics of brain perfusion may be altered related to co-occurring car- diac problems).

Brain imaging is a critical part of the diagnosis of vascular dementia because its constellation of cognitive symptoms can overlap with that associated with cortical dementia like Alzheimer’s disease. Although vascular dementia can com- monly be distinguished from Alzheimer’s disease by its early

deficits in motivation, initiation, and organization of thinking (subcortical deficits, sparing crystallized knowledge), one or more strokes in the posterior cortical parietal regions, either directly affecting the cortex or damaging its white matter input from the thalamus or other cortical regions, may mimic cortical neurodegenerative disease (▶ Fig. 21.1).8

21.1 Diagnostic Criteria

Although different definitions of vascular dementia have been provided by Alzheimer’s Disease Diagnostic and Treat- ment Centers (ADDTC),9 International Statistical Classifica- tion of Diseases, 10th Revision (ICD-1010), National Institute of Neurological Disorders and Stroke-Association Internatio- nale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN11), and the Hachinski ischemic score,12,13 an excellent general set of diagnostic criteria are provided by the American Psychiatric Association Diagnostic and Statisti- cal Manual (DSM, 4th edition).14 The DSM specifies vascular dementia as (1) memory impairment (impaired ability to learn new information or to recall previously learned infor- mation), required to make the diagnosis of a dementia and a prominent early symptom; and (2) one (or more) cognitive disturbances, including aphasia (language disturbance), apraxia (dysfunctional skilled learned purposive movement despite intact strength), agnosia (failure to recognize or identify faces, objects, pantomimes or other domain-specific

Fig. 21.1 Schematic coronal slice representing different pathologic syndromes in vascular dementia. Gray areas mark brain regions affected by ischemia and infarction. Multi-infarct dementia is characterized by small- and large-vessel lesions all over the gray matter (left side); strategic infarct dementia is characterized by fewer lesions in critical regions for memory function: hippocampal formation or paramedian thalamus. In subcortical vascular encephalopathy, multiple periventricular confluent white matter lesions may co-occur with small-vessel lesions. Amy, amygdala; Bgl, basal ganglia; CAI, hippocampus CA1 region; Cing, cingulate gyrus; ER, entorhinal cortex; F, frontal neocortex; Hypoth, hypothalamus; NBM, basal nucleus of Meynert; T, temporal neocortex; Thal, thalamus. (Used with permission from Thal DR, Grinberg LT, Attems J. Vascular dementia: different forms of vessel disorders contribute to the development of dementia in the elderly brain. Exp Gerontol 2012;47(11):816 –824.)

194

information despite intact sensory function), and distur- bance in executive functioning (e.g., planning, organizing, sequencing, abstracting). Anomia (pathologic difficulty pro- ducing the names of words or objects) is sufficient to meet criteria for aphasia. The cognitive deficits must cause signifi- cant impairment in social or occupational functioning and represent a significant decline from a previous level of func- tioning.

The upcoming fifth edition of the DSM is stated to propose that diagnosis of a major neurocognitive disorder of vascular origin (dementia) can involve memory; however, a minor neu- rocognitive disorder, which allows the person to continue func- tional activities but only while using compensatory measures, can be defined by a single cognitive deficit, such as executive dysfunction.

In contrast to other types of dementia, vascular dementia is defined by focal neurologic signs and symptoms (e.g., exaggera- tion of deep tendon reflexes, extensor plantar response, pseu- dobulbar palsy, gait abnormalities, weakness of an extremity) or laboratory evidence indicative of cerebrovascular disease (e.g., multiple infarctions involving cortex and underlying white matter) that are judged to be causally related to the distur- bance.8,15 Lastly, in vascular dementia, cognitive deficits and

neurologic signs may not occur exclusively during the course of the delirium.

21.2 Pathophysiology

Five different but interrelated pathologic sets of changes (▶Table 21.1) contribute to the evolution and progression of cognitive and functional deficit in this disorder.5,15,16 These changes include large-vessel embolic strokes, either of cardiac or artery-to-artery origin, and large watershed infarcts caused by brain hypoperfusion; small-vessel lacunar strokes (▶Fig. 21.2), chronic periventricular white matter ischemia (▶ Fig. 21.2), cerebral microbleeds (▶ Fig. 21.2, ▶ Fig. 21.3), and medial temporal atrophy.

Some current reviews that report the co-occurrence of medial temporal and hippocampal atrophy with pathologic evi- dence of vascular dementia have been criticized on the basis that subjects with medial temporal atrophy may have had undetected Alzheimer’s disease in addition to cerebrovascular pathology. Even if medial temporal atrophy has independent causes compared with other radiologic signs of vascular dementia, it is independently predictive of progression of cog- nitive symptoms over time.17

Vascular Dementia

Table 21.1 Pathology related to progressive cognitive impairment in vascular dementia

Pathologic disorder Cause Useful references

Large artery and watershed infarction

Embolic, hypoperfusion

Wright, 201315; Leys et al, 200540

Small artery infarctions or lacunes, counted as part of NINDS-AIREN criteria

Thrombosis affecting caudate, putamen, globus pallidus, thalamus, internal capsule, cerebellum, brainstem

Arvanitakis et al, 201141; Roman et al, 199311

Chronic subcortical ischemia affecting > 25% periventricular white matter

Cerebral vessel disease, atherosclerosis/ lipohyalinosis

Chui et al, 20009; Thal et al, 20125

Cerebral microbleeds

Cerebral vascular abnormality

Kirsch et al, 200942; Van der Flier and Cordonnier, 201236

Hippocampal atrophy and sclerosis

Neurodegeneration, presumably from metabolic insufficiency or chronic ischemia

Gorelick et al, 201143; Zarow et al, 200844

Abbreviations: NINDS-AIREN, National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences.

Fig. 21.2 (a) Brain magnetic resonance imaging illustrating periventricular white matter abnor- mality (areas of increased signal intensity, black arrows) on fluid-attenuated inversion recovery imaging. (b) Microbleeds (areas of decreased signal intensity, white arrows) are seen on T2*- weighted imaging. (Used with permission from Van der Flier WM, Cordonnier C. Microbleeds in vascular dementia: clinical aspects. Exp Gerontol 2012;47(11): 853–857.)

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Vascular Dementia

Fig. 21.3 (a) Brain magnetic resonance imaging illustrating lacunar strokes (areas of decreased signal intensity, white arrows) on fluid-attenuated inversion recovery imaging. (b) Microbleeds (areas of decreased signal intensity, white arrows) are seen on T2*-weighted imaging. (Used with permission from Van der Flier WM, Cordonnier C. Microbleeds in vascular dementia: clinical as- pects. Exp Gerontol 2012;47(11):853–857.)

21.3 Genetics

Vascular dementia genetics have codeveloped along with the genetics of Alzheimer’s disease and other primary neuro- degenerative diseases, as the distinction between these condi- tions has been clarified (▶Table 21.2). Genetic risk factors in Alzheimer’s disease have been widely studied, and these same genes, as well as different genes, have been studied in relation to the risk of development of vascular dementia.

Traditionally, to find a genetic link for a certain condition, researchers need large families or ethnicities affected with the disease. When we consider the major pathologic conditions associated with vascular dementia, genetic predictors are rele- vant to all three types: multi-infarct dementia, small-vessel and strategic infarct-type dementias, and subcortical arterioscle- rotic leukoencephalopathy (Binswanger encephalopathy). Some of the genetic associations with vascular dementia, however, may primarily reflect the genetics of Alzheimer’s disease; Alzheimer’s disease and vascular dementia co-occur in up to half of the people diagnosed with Alzheimer’s disease.15

An extensively studied gene in Alzheimer’s disease is apo- lipoprotein E (ApoE), a cholesterol carrier that supports injury repair in the brain. Polymorphic alleles of ApoE are the main genetic determinants of Alzheimer’s disease risk. The Apo-E 4 allele, which is most relevant to increased risk of Alzheimer’s disease, is also considered to increase the risk of vascular dementia.18,19,20

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is considered the most common heritable cause of stroke and vascular dementia in adults. It is a familial form of vascular dementia21,22 caused by mutations in the NOTCH3 gene located on chromosome 19 and is clinically characterized by migraines with aura, recurrent ischemic strokes, cognitive and behavior impairments, and dementia. Cerebral autosomal recessive arteriopathy with sub- cortical infarcts and leukoencephalopathy (CARASIL, also known as Maeda syndrome), is also a heritable small-vessel dis- ease clinically characterized by nonhypertensive leukoence- phalopathy associated with alopecia and spondylosis.23 Diagno- sis relies on brain MRI findings and molecular genetic testing of HTRA1 , a gene located on chromosome 10.

Other causes of hereditary cerebral vasculopathy that can lead to strokes, and potentially cognitive impairment and dementia, are less common. These causes include but are not limited to hereditary vascular retinopathy (HVR); cerebroreti- nal vasculopathy (CRV); and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS).24 HERNS is characterized by retinal capillary obliteration and CNS vascul- opathy. These patients commonly have dementia and, like patients with CADASIL, they can suffer migraine headaches. HERNS is linked to chromosome 3p21, and transmission is autosomal dominant.

Hereditary cerebral amyloid angiopathy is a condition that can cause a progressive dementia, stroke, and other neurologic problems. Many different types are associated with kindred of different nationalities. The Dutch type of hereditary cerebral amyloid angiopathy is the most common form. Flemish, Italian, Icelandic, and Arctic types of hereditary cerebral amyloid angi- opathy and two other types, known as familial British dementia (FBD) and familial Danish dementia, are known to be associated with dementia.25,26,27,28 FBD with amyloid angiopathy is an

Table 21.2 Conditions associated with subcortical, stroke-related and vascular dementia, and genetic associations. See text for details.

Condition Gene Location

Alzheimer’s disease and vascular dementia

Apolipoprotein E

Chromosome 19

CADASIL

NOTCH 3

Chromosome 19

CARASIL

HTRA1

Chromosome 10

CRV, HERNS, HVR

TREX1

Chromosome 3

HDLS

CFR1R

Chromosome 5

FBD

BRI

Chromosome 13

Hereditary cerebral amyloid angiopathy

APP, CST3,ITM2B

Chromosome 21, 20, 13

Abbreviations: CADASIL, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leu- koencephalopathy; CRV, cerebroretinal vasculopathy; FBD, familial British dementia; HDLS, hereditary diffuse leukoencephalopathy with neuroaxonal spheroids; HERNS, hereditary endotheliopathy with retin- opathy, nephopathy, and stroke; HVR, hereditary vascular retinopathy.

autosomal dominant condition characterized by vascular dementia, progressive spastic paraparesis, and cerebellar ataxia; onset is in the sixth decade of life. A point mutation in the BRI gene on chromosome 13 is the genetic abnormality.29

Other rare reported causes of vascular dementia with genetic associations include Sneddon’s syndrome (livedo reticularis with cerebrovascular disease), which causes a progressive arte- riopathy. Sneddon’s syndrome occurs sporadically, but familial cases have been reported, inherited in an autosomal dominant (with incomplete penetrance) or autosomal recessive fashion.30

Dementia has also been reported in other hereditary leu- koencephalothies, such as hereditary diffuse leukoencephalop- athy with neuroaxonal spheroids (HDLS)31 or vanishing white matter disease.32 This is relevant because neuroradiologic abnormalities in leukodystrophies of heritable or metabolic ori- gin may be mistaken for ischemic changes (▶ Fig. 21.4).33

21.4 Classification

Before computerized protocols were widely available to calcu- late the volume of brain lesions and the extent of white matter abnormality, visual rating methods were commonly used to stage ischemic injury in vascular dementia. The Fazekas scale34 rates white matter hyperintensities both generally and in periventricular regions as a marker of small-vessel disease. Scheltens et al35 suggested further modifications to quantify basal ganglia hyperintensities; however, these methods did not correlate well with computerized volumetric assessments with confirmed objective reliability and validity. Even computerized volume measurements for ischemic lesions did not correlate well with progression of cognitive and functional deficits, and therefore the value of these techniques has been questioned; because of evidence of threshold values definitely associated with cognitive deficits, however, and a stronger relation to gait and motor functional problems in small- and large-vessel ische- mia, a clinical role for these techniques still seems possible.15

Clear predictive associations with clinical diagnosis of vas- cular dementia or progression of symptoms are not yet avail- able for microbleeds. However, counting microbleed sites might be useful in the future to predict cognitive functional progression.36

Visual rating is still a widely used method for classification of medial temporal atrophy, despite the availability of computer- ized techniques. One method is a 1 to 5 scale recommended by Scheltens and colleagues.37 In Alzheimer’s disease, visual inspection for hippocampal atrophy had greater than 80% sensi- tivity and greater than 90% specificity for diagnosis.16

21.5 Additional Neuroanatomic-

Behavioral Considerations

Barrett and colleagues38 and Cramer et al39 pointed out that modality-specific outcomes accurately assess the natural evolu- tion of specific poststroke conditions, such as aphasia, spatial neglect, and limb apraxia, which are themselves tremendously disabling. A strategic infarct can affect critical regions for mem- ory and cognitive function, such as the left temporal-parietal junction. When people with preexisting aphasia, spatial neglect, or other focal cognitive syndromes develop an addi- tional, stepwise loss of functional ability, such as loss of ability to dress independently, clinicians commonly obtain a brain image to determine whether a new large-vessel stroke contrib- utes to that process. Given the potential relevance of assessing the volume of white matter lesion burden, counting lacunar lesions, assessing the volume of microbleeds, and assessing hip- pocampal atrophy in people with vascular dementia, we can expect that they may also assist with predicting progress of functional disability and the need for more aggressive manage- ment and treatment of risk factors after large-artery stroke. This means that, in the future, clinicians may routinely examine the risk of future vascular dementia in patients with a new or chronic large-artery stroke by evaluating neuroradiologic-neu- ropathologic data, making new therapies for vascular dementia more widely available as they are identified.

21.6 Acknowledgments

This work was supported by the Kessler Foundation, the National Institutes of Health, and the Department of Education/ National Institute of Disability and Rehabilitation Research (Grants K24 HD062647, H133 G120203, PI: Barrett). Study

Vascular Dementia

Fig. 21.4 Axial (a) DWI and (b) ADC images in a patient with hereditary leukoencephalopathy (HDLS) reveals increased signal intensity in both diffusion-weighted imaging (arrows in a) and on apparent diffusion coefficient mapping (arrows in b). (Used with permission from Boissé L, Islam O, Woulfe J, Ludwin SK, Brunet DG. Neurological picture: hereditary diffuse leukoencephalopathy with neuroaxonal spheroids: novel imaging find- ings. J Neurol Neurosurg Psychiatry 2010;81 (3):313–314.)

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contents do not necessarily represent the policy of the Depart- ment of Education, and one should not assume endorsement by the federal government.

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. [30] Mascarenhas R, Santo G, Gonçalo M, Ferro MA, Tellechea O, Figueiredo A. Familial Sneddon’s syndrome. Eur J Dermatol 2003; 13: 283–287

. [31] Keegan BM, Giannini C, Parisi JE, Lucchinetti CF, Boeve BF, Josephs KA. Spo- radic adult-onset leukoencephalopathy with neuroaxonal spheroids mimick- ing cerebral MS. Neurology 2008; 70: 1128–1133

. [32] Gascon-Bayarri J, Campdelacreu J, Sánchez-Castañeda C et al. Leukoencephal- opathy with vanishing white matter presenting with presenile dementia. J Neurol Neurosurg Psychiatry 2009; 80: 810–811

. [33] Boissé L, Islam O, Woulfe J, Ludwin SK, Brunet DG. Neurological picture: hereditary diffuse leukoencephalopathy with neuroaxonal spheroids: novel imaging findings. J Neurol Neurosurg Psychiatry 2010; 81: 313–314

. [34] Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnor- malities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roent- genol 1987; 149: 351–356

. [35] Scheltens P, Barkhof F, Leys D et al. A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neu- rol Sci 1993; 114: 7–12

. [36] Van der Flier WM, Cordonnier C. Microbleeds in vascular dementia: clinical aspects. Exp Gerontol 2012; 47: 853–857

. [37] Scheltens P, Leys D, Barkhof F et al. Atrophy of medial temporal lobes on MRI in “probable” Alzheimer’s disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 1992; 55: 967– 972

. [38] Barrett AM, Levy CE, Gonzalez Rothi LJ. Treatment innovation in rehabili- tation of cognitive and motor deficits after stroke and brain injury: physiological adjunctive treatments. Am J Phys Med Rehabil 2007; 86: 423–425

. [39] Cramer SC, Koroshetz WJ, Finklestein SP. The case for modality-specific out- come measures in clinical trials of stroke recovery-promoting agents. Stroke 2007; 38: 1393–1395

. [40] Leys D, Hénon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lancet Neurol 2005; 4: 752–759

. [41] Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA. Microinfarct pathology, dementia, and cognitive systems. Stroke 2011; 42: 722–727

. [42] Kirsch W, McAuley G, Holshouser B et al. Serial susceptibility weighted MRI
measures brain iron and microbleeds in dementia. J Alzheimers Dis 2009; 17:
599–609

. [43] Gorelick PB, Scuteri A, Black SE et al. American Heart Association Stroke
Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia. Vascular contributions to cogni- tive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2011; 42: 2672–2713

. [44] Zarow C, Sitzer TE, Chui HC. Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues. Curr Neurol Neurosci Rep 2008; 8: 363–370

Amit Agarwal and Sangam G. Kanekar

Vascular dementia (VaD) is the second most common cause of dementia, following Alzheimer’s disease (AD), and it remains a diagnostic challenge in clinical settings all over the world.1,2 As a clinical syndrome, VaD relates to different vascular mecha- nisms and changes in the brain and has different causes and clinical manifestations.3 VaD is not limited to multi-infarct dementia (MID), as initially proposed by Hachinski and colleagues in 1974.4 The pathophysiology of VaD indeed incor- porates interactions between vascular causes, such as cerebro- vascular diseases (CVD) and vascular risk factors; changes in the brain, such as infarcts, white matter lesions, and atrophy; host factors, such as age, education, and sex; and cognition fac- tors, such as impairments in executive functions and psycho- motor speed.1 The term vascular cognitive impairment (VCI) has been proposed as an “umbrella” term to recognize the broad spectrum of cognitive and, indeed, behavioral, changes associ- ated with vascular pathology.

The prevalence of multi-ischemic dementia in Western coun- tries has been estimated to be 7 to 10%, whereas epidemiologic data collected in Japan showed that 48.5% of individuals older than the age of 65 years had vascular dementia.5,6 Clearly, vas- cular dementia is common among the elderly population; how- ever, this type of dementia represents a diagnostic challenge because of its various clinical manifestations and different vascular causes. This challenge is illustrated by the number of clinical diagnostic criteria published and used over the past 30 years. At least eight different clinical diagnostic criteria sets for vascular dementia or multi-ischemic dementia have been used in clinical and research settings, including the original Hachinski Ischemic Scale; the criteria proposed by the Diagnos- tic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV); that proposed by the California Alzheimer’s Disease Diagnostic and Treatment Centers (CAD–DTC); the criteria of the National Institute of Neurological Disorders and Stroke-

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22 Neuroimaging of Vascular Dementias

Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS–AIREN).6 These criteria, which have been validated by some neuropathological studies and a cen- tralized imaging rater, have provided increased consistency in the diagnosis of VaD. Neuroimaging is required for confirmation of CVD in VaD and provides information about the topography and severity of the vascular lesions.7 The pathophysiology, diag- nostic criteria, genetics, and classification of VaDs are covered in depth in Chapter 21. This chapter examines the role of con- ventional and advanced neuroimaging in VaD.

22.1 Clinical Criteria

Vascular dementia is a broad term that encompasses all instan- ces of dementia associated not only with ischemic CVD but also with hemorrhagic lesions, hypoxic–ischemic cerebral lesions, such as those due to cardiac arrest, and senile leukoencephalo- pathic lesions. It excludes patients with pure asphyxia or respi- ratory failure (hypoxemic anoxia) and carbon monoxide or cya- nide poisoning (histotoxic anoxia).8 The clinical presentation of VaD varies greatly depending on the causes and location of cerebral damage. Large-vessel disease leads commonly to mul- tiple cortical infarcts and a multifocal cortical dementia syn- drome, whereas small-vessel disease, usually resulting from hypertension and diabetes, causes periventricular white matter ischemia and lacunar strokes characterized clinically by sub- cortical dementia with frontal lobe deficits, executive dys- function, slow information processing, impaired memory, inattention, depressive mood changes, slowing of motor func- tion and parkinsonian features (▶ Fig. 22.1).9,10 In the absence of biological markers to diagnose AD or VaD, clinicians must rely on clinical criteria to identify and describe dementia in these patients.

Fig. 22.1 Clinical presentation of vascular dementia varies depending on the type and location of cerebral vascular lesions. (Adapted from Román GC. Defining dementia. Acta Neurol Scand Suppl 2002;178:6–9.)

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Table 22.1 Operational definitions for the radiologic part of the NINDS-AIREN criteria (2003)

Topography Definition

Large-vessel stroke

Large-vessel stroke is an infarction defined as a parenchymal defect in an arterial territory involving the cortical gray matter
ACA: Only bilateral ACA infarcts are sufficient to meet the NINDS-AIREN criteria
PCA: Infarcts in the PCA territory can be included only when they involve the following regions:

● Paramedian thalamic infarct
● Inferior medial temporal lobe lesions
Association areas: MCA infarcts need to involve the following regions: Parietotemporal lobe (e.g., angular gyrus)
Temporo-occipital cortex:
Watershed carotid territories (between the MCA and PCA or the MCA and ACA)

Small-vessel disease

Multiple basal ganglia and frontal white matter lacunes Extensive periventricular white matter lesions (leukoaraiosis) Bilateral thalamic lesions

Severity

Large-vessel disease of the dominant hemisphere
Bilateral large-vessel hemispheric strokes
Leukoencephalopathy involving at least 25% of the total white matter

Fulfillment of radiologic criteria for probable VaD

Large-vessel disease: Both the topography and severity criteria should be met (a lesion must be scored in at least one subsection of both topography and severity)
Small-vessel disease: For white matter lesions, both the topography and severity criteria should be met

ACA, anterior cerebral artery; PCA, posterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; NINDS-AIREN, National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences; VaD, vascular dementia.

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Although their sensitivity and specificity vary, all clinical criteria (DSM-IV, NINDS, CAD-DTC) identify patients with VaD. Two tools have been used successfully, with high specificity, for the diagnosis of VaD: the criteria developed by the NINDS- AIREN8 and those of the CAD-DTC.11 Although largely based on AD-like criteria, both sets of VaD criteria have been validated neuropathologically and have been shown to exclude success- fully most patients with AD (NINDS-AIREN, 91%; CAD-DTC, 87%). Both sets of criteria outline the three critical elements necessary for the diagnosis of VaD, including dementia, CVD, and a reasonable relationship between the two.12 Finally, these two sets of VaD criteria rely on neuroimaging by com- puted tomography (CT) or magnetic resonance imaging (MRI) for confirmation of cerebrovascular lesions (although neither requires imaged lesions to correlate with cognitive or functional deficits).13

22.2 Role of Imaging

The traditional view has been that CT and MRI are performed to exclude other abnormalities that are potentially amenable to surgical treatment, such as a tumor, hematoma, or hydro- cephalus.14 However, in the recent practice parameter on the diagnosis of dementia, structural neuroimaging in the routine initial evaluation of patients with dementia is recommended as a guideline. Functional imaging provides insight into the operational aspects of the brain, and because it appears that brain pathology in dementia begins long before there is clini- cal evidence of disease, functional imaging is attractive for the early detection of dementia. Single-photon emission com- puted tomography (SPECT), positron emission tomography (PET), and functional MRI (fMRI) are becoming increasingly relevant to the study of dementia.15 The role of these imaging

techniques is discussed in detail in a previous chapter (Chap- ter 3).

Absence of vascular lesions on brain CT or MRI rules out proba- ble VaD and represents the most important element to distin- guish AD from VaD. There is no pathognomonic brain CT or MRI of VaD. Thus, correlation with the clinical evidence is mandatory.7 The NINDS-AIREN criteria provide a list of possible vascular lesions considered relevant for the pathogenesis, although with- out clearly defining their imaging criteria in terms of topography and severity of lesions. To enhance their clinical implementation, operational definitions for the radiologic part of the NINDS-AIREN criteria were subsequently defined (▶ Table 22.1).16 To be consid- ered evidence in favor of VaD (probable VaD), the radiologic find- ings should fulfill the minimum standards of the NINDS-AIREN criteria for both severity and topography (large vessel and small vessel). Imaging appearance of vascular dementia can be broadly divided into (1) large-vessel vascular dementia; (2) small-vessel vascular dementia and (3) microhemorrhage and dementia (▶ Table 22.2). Microhemorrhage and dementia are discussed in Chapter 23.

22.2.1 Large-Vessel Disease

Large-vessel VaD is broad term encompassing poststroke dementia, multi-infarct dementia, or strategic infarct dementia. The risk factors for VaD are believed to be the same as those for stroke in general. The cause and pathology of large-vessel VaD may be described considering either the type of brain lesion or the underlying type of vessel abnormality. Brain lesions mostly include large-vessel cortical–subcortical or subcortical infarcts (e.g., watershed infarcts) and hemorrhages. Vessel abnormali- ties encompass atherosclerosis and embolic sources. Vasculitis is another cause of large-vessel disease.

Neuroimaging of Vascular Dementias

Table 22.2 Neuroimaging classification of vascular dementia

Large-vessel vascular dementia

Multi-infarct dementia (multiple large complete infarcts involving cortical and subcortical areas)
Watershed infarction

Strategic single-infarct dementia Hypoperfusion and ischemic encephalopathy

Small-vessel vascular dementia

Subcortical vascular dementia Lacunes
Perivascular spaces
Silent cerebral infarcts

Microhemorrhage and dementia

CADASIL CARASIL HERNS CAA

Abbreviations: CAA, cerebral amyloid angiopathy; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leu- koencephalopathy; CARASIL, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; HERNS, hereditary endotheliopathy retinopathy and stroke.

Multi-Infarct Dementia (Poststroke Dementia)

Classic MID is characterized by multiple large and small infarcts involving the areas of major cerebral arteries: (sub)territorial lesions of variable size resulting from atherosclerosis of extrac- ranial and intracranial vessels giving rise to local thrombo- embolism or hypoperfusion and cardiac sources of cerebral emboli. Occlusion or stenosis of extracranial arteries and the major intracranial arteries can lead to MID. The thesis underly- ing the concept of “multi-infarct dementia” is that multiple lesions have a synergistic effect on mental functions, resulting in dementia, irrespective of specific location or volume. MID accounts for about 15% of VaD cases; the dominant hemisphere is more frequently involved. Medium-sized arteries in the lep-

tomeninges and proximal perforating arteries can be involved. MID cannot be linked to a specific vessel disorder. Its relation to age-related vessel disorders varies, and a combination of vascu- lar lesions is frequently seen. Atherosclerosis of cerebral arteries shows a trend to more severe lesions in the circle of Willis in VaD cases than in cognitively normal controls, suggesting that atherosclerosis-related thrombosis and embolic events are important for this type of VaD. This trend is supported by the finding that the likelihood of dementia is increased in the pres- ence of high-grade internal carotid artery (ICA) atherosclerosis. The damage can be worse depending on the presence of hyper- tension and related CVD.17

Cross-sectional imaging with CT and MRI, along with CT angiography and MR angiography, have become the imaging modalities to evaluate the patient with vascular dementia.7 These modalities are quite sensitive in confirming the size and location of symptomatic as well as asymptomatic (silent) strokes. MRI is also helpful in the diagnosis of microbleeds and anoxic or hypoxic brain injury and in identifying the changes of gliosis and encephalomalacia. The parenchymal perfusion sta- tus also may be obtained using CT or MR perfusion. Diffusion- weighted imaging (DWI)-apparent diffusion coefficient has an established role in the diagnosis of hyperacute infarction. In the subacute-chronic stage of infarction, imaging is characterized by local brain atrophy, gliosis, cavity formation, and ex vacuo dilatation of the ipsilateral ventricle. Encephalomalacia and gliosis are seen on T2 and fluid-attenuated inversion recovery (FLAIR) images as a loss of parenchymal tissue with hyperinten- sity in the infarcted and subjacent tissue with prominence of cerebrospinal fluid (CSF) space. The corticosubcortical occipito- temporal infarct shown in ▶ Fig. 22.2 is typical of cortical VaD. A lesion like this, a cerebral artery infarction that extends from the occipital to the medial temporal region, would be expected to produce symptoms of amnestic memory disorder.

Calcification and deposition of blood products (hemosiderin) may be seen on T2 and gradient echo (GRE) sequences (▶ Fig. 22.3a,b). Corticospinal tract degeneration (i.e., wallerian

Fig. 22.2 Corticosubcortical occipitotemporal infarcts in large-vessel vascular dementia. Axial fluid-attenuated inversion recovery (a,b) and coronal T2 (c) magnetic resonance images show large chronic left temporo-occipital infarct with encephalomalacia and surrounding hyperintensity resulting from gliosis. There is involvement of the left hippocampus (c, arrow) with dilation of temporal horn. Also seen is smaller right occipital cortical infarct.

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Vascular Dementia

Fig. 22.3 Large right middle cerebral artery territory infarct in a 62-year-old man with dementia. Axial T2 spin-echo (SE) (a) and susceptibility- weighted images (SWI) (b) show areas of signal dropout in the region of infarct, consistent with hemosiderin (blood products). Fluid-attenuated inversion recovery image (c) in the same patient depicts wallerian degeneration, with signal changes and atrophy of the ipsilateral brainstem and cerebral peduncle (arrow).

degeneration) is also seen with hemispheric infarction (▶Fig. 22.3c). Cortical laminar necrosis, neuronal ischemia accompanied by gliosis, and layered deposition of fat-laden macrophages may be seen in the infarcted region. Gray matter is more vulnerable to hypoxia than white matter. On MR, laminar necrosis is seen as hyperintensity in the cortex on T1-weighted and FLAIR images (▶ Fig. 22.4). These changes are visible 2 weeks after infarction and are most prominent at 1 to 3 months.

Watershed Infarcts

Watershed or border-zone infarcts are ischemic lesions that occur in characteristic locations at the junction between two main arterial territories. These lesions constitute approximately 10% of all brain infarcts and are well described in the literature. Their pathophysiology has not yet been fully elucidated, but a

commonly accepted hypothesis holds that decreased perfusion in the distal regions of the vascular territories leaves them vul- nerable to infarction. Two types of border-zone infarcts are rec- ognized: external (cortical) and internal (subcortical) (▶Fig. 22.5).18 In acute events, DWI is quite sensitive for the diagnosis of both cortical watershed infarct and internal water- shed infarct. Classically, cortical watershed infarcts appear as fan or wedge-shaped hyperintensities extending from the lat- eral margins of the lateral ventricle toward the cortex, whereas internal watershed infarcts are seen as hyperintensities running parallel to the lateral ventricles, either confluent or focal, and may be unilateral or bilateral. Anterior cortical watershed infarcts are those located between the cortical supply of the anterior cerebral artery (ACA) and middle cerebral artery (MCA) (▶Fig. 22.6a). Posterior cortical watershed infarcts are those located between the cortical supply of the MCA and the poste- rior cerebral artery (PCA) (▶Fig. 22.6b). Internal watershed

Fig. 22.4 Laminar necrosis. Axial diffusion- weighted (a) image shows acute left occipital lobe infarct. T1-weighted image (b) from 6 weeks of follow-up magnetic resonance imaging reveals hyperintensity along the gyri within the infarcted area suggestive of cortical laminar necrosis.

Neuroimaging of Vascular Dementias

Fig. 22.5 Color overlays on axial T2-weighted magnetic resonance images of normal cerebrum show probable locations of external (blue) and internal (red) border zone infarcts.

Fig. 22.6 Watershed infarct in a patient present- ing with dementia. Axial T2 magnetic resonance (MR) image (a) shows cortical watershed infarct in the right ACA/MCA (thin arrow) and middle and posterior cerebral artery territories (thick arrow). MR angiogram of the neck (b) reveals complete occlusion of the left inferior cerebral artery from its origin with poor reconstitution (arrows).

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Vascular Dementia

Fig. 22.7 Diffusion-weighted and apparent diffusion coefficient magnetic resonance images, obtained in a 52-year-old woman with cognitive decline, progressive weakness, and numbness, show multiple internal border zone infarcts in a rosary-like pattern along the left centrum semiovale.

Fig. 22.8 Strategic subcortical infarct. Axial T2-weighted (a) and fluid-attenuated inversion recovery (b) magnetic resonance images show chronic infarction of left caudate nucleus (arrow) with ex vacuo dilatation of the left lateral ventricle.

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infarcts are those located between the ACA, MCA, and PCA, and the area supplied by the Heubner, the lenticulostriate, and the anterior choroidal arteries. It can be difficult to recognize this watershed infarct from centrum ovale infarcts within the terri- tory fed by the medullary branches of the MCA. The presence of multiple rosary-like lesions highly favors the diagnosis of watershed infarct (▶Fig. 22.7). Watershed infarcts involving more than one of the border zone areas in a single hemisphere are mostly related to severe ICA stenosis or occlusion. Bilateral watershed infarcts are typically related to a profound global reduction in perfusion pressure (hypoxia, hypovolemia) or to diffuse cerebral vasculopathy.

Strategic Single-Infarct Dementia

Strategic infarct dementia is characterized by focal, ischemic lesions in areas that control or participate in cognition and behavior or higher cortical functions. Strategic cortical sites include the hippocampal formation, angular gyrus, and cingu- late gyrus; subcortical sites leading to impairment are the thala- mus, fornix, basal forebrain, caudate, globus pallidus, and the genu or anterior limb of the internal capsule.19 The mechanism by which the strategic single infarct leads to dementia is not

completely understood, but it is thought to be due to interrup- tion of frontal-subcortical circuits.20 The general organization of these circuits includes the frontal lobes, striatum, globus pal- lidus/substantia nigra, and thalamus. Neuroimaging has also helped to prove that single strategic lesions can cause dementia by disrupting communication between specific areas of the brain.

Cognitive decline and the clinical symptoms largely depend on the strategic area involved. Caudate nucleus infarctions can lead to abulia, restlessness, hyperactivity, language deficits, and poor memory (▶Fig. 22.8). The cognitive disorders seen most often in caudate infarcts are decreased problem-solving ability, impaired recent and remote memory with preservation of recognition memory, and decreased attention. Ischemic stroke or a subarachnoid hemorrhage from ruptured aneurysms involving the mesial temporal lobe and thalamus may cause memory and other cognitive deficits resulting from interrup- tion of the cholinergic projections to the cholinergic nuclei in the basal forebrain. These patients may have severe anterograde amnesia for verbal or visuospatial material, along with severe apathy, lack of initiative and spontaneity, and executive dys- function. A thalamic stroke produces a peculiar form of thalamic VaD. These patients show a depressed level of

Neuroimaging of Vascular Dementias

Fig. 22.9 Strategic single-infarct dementia.
The left-thalamic infarct shown on the axial T2 (a) and T1 sagittal image (b) is of sufficient size to disrupt the Papez circuit (frontal subcortical and eloquent behavior-related circuits). The white arrows depict the normal Papez circuit from the hippocampus (orange box) to the thalamus and to the cingulate gyrus.

Fig. 22.10 Dementia from hypoperfusion in a 59-year-old man. Single-photon emission computed tomography images after 30 minutes of acetazolamide (Diamox) injection show global hypoperfusion in the supratentorial brain. The patient returned 2 days later for a baseline study that showed no significant perfusion defect.

consciousness, impairments in attention, motivation, initiative, executive functions, and memory, as well as dramatic verbal and motor slowness and apathy. Thalamic lesions may cause thalamic amnesia as a result of damage to the mammillothala- mic tract; even small or unilateral damage to this structure may affect memory, executive functioning, and attention. The left-thalamic lesion shown in ▶ Fig. 22.9 is of sufficient size to disrupt the Papez circuit (frontal subcortical and eloquent behavior-related circuits). PCA infarcts may cause damage to the hippocampus, isthmus, entorhinal and perirhinal cortex, and parahippocampal gyrus. Therefore, the patient may mani- fest with amnesia.

Hypoperfusion and Ischemic Encephalopathy

Cerebrovascular disease is recognized as a common cause of cognitive impairment and dementia, alone or coexisting with other neurodegenerative diseases, mostly AD.21 Diseases of the large arteries and the heart can lead to cerebral hypoperfusion and have been associated with the development of dementia after stroke. Although age is one of the most important risk fac- tors for VaD, other common cardiovascular risk factors are also involved. By investigating these risk factors, a high proportion

of these cognitive disorders can be prevented or delayed. Hypo- perfusion may affect both gray and white matter. Hypoperfu- sion affecting white matter may lead to leukoaraiosis and incomplete infarction, which comprise zones of partial neuro- nal or axonal loss with demyelination, increased perivascular spaces, reactive astrocytosis, and gliosis. Hypoperfusion can also produce hippocampal neuronal loss or severe white matter changes leading to hippocampal sclerosis.22

Brain MRI is becoming the method of choice to investigate cerebral vascular pathologies. However, evaluation of the hemodynamic status of the brain requires physiologic imaging. In addition, inadequate perfusion of the brain may be caused by multiple pathophysiologic mechanisms, including cardiac dis- ease, resulting in decreased ejection fraction, atherosclerosis, or other vasculopathy and the status of collateral circulation in the brain. Identifying patients who are at increased risk for hemo- dynamic stroke is important because they may benefit from flow augmentation procedures, such as carotid endarterectomy, external carotid-internal carotid bypass, or even angioplasty. The cerebral hemodynamic status can be determined by meas- uring CBF before and after vasodilatory challenge, which can be done with either hypercapnia or acetazolamide (▶ Fig. 22.10).23 Despite this, functional imaging, such as CT and MRI perfusion

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studies, SPECT, and PET, performed in baseline conditions and/or after an acetazolamide challenge, is underused in the evaluation of VaD.21

22.2.2 Small-Vessel Disease

The prototypical presentation of poststroke dementia with sud- den onset or stepwise decline is often associated with overt stroke events, verified on imaging, but this is only the “tip of the iceberg.” An important concept that has been emerging in the field of VaD is that the CVD contributing to cognitive decline may be otherwise clinically silent. This insidious form of VaD arises from covert small-vessel pathology, which is prevalent with aging, as revealed by large population imaging studies conducted over the past 15 years. Small-vessel disease may be a final common pathway that expresses the adverse effects of vascular risk factors on the brain and may be one of the reasons that AD, stroke, and VaD share common vascular risk factors, such as aging, hypertension, elevated cholesterol, diabetes, and previous strokes.

According to the NINDS-AIREN diagnostic criteria, small- vessel VaDs are classified into two types: subcortical and cortical forms.8,16 The subcortical form is a classic subcortical VaD, whereas the cortical form is seen mostly in cerebral amy- loid angiopathy (CAA).

Subcortical Vascular Dementia

Subcortical vascular dementia (SCVD) is the most common sub- type of small-vessel VaD and constitutes approximately 50% of VaD cases.24 SCVD is attributed to small-vessel disease and is characterized by focal and diffuse ischemic white matter lesions (WMLs), lacunar infarcts, and incomplete ischemic injury. All of these disease conditions may coexist. In neuropathology literature, these lesions are described under various synonyms, such as subcortical arteriosclerotic encephalopathy (SAE) or Binswanger’s disease, diffuse white matter disease, white mat- ter lesions, leukoaraiosis, periventricular arteriosclerotic (leuko) encephalopathy or leukomalacia, subcortical vascular encephal- opathy, and periventricular lucency. With the advent of MRI, diffuse or focal white matter lesions are detected with higher sensitivity.

There are two main pathophysiologic pathways involved in SCVD. In the first, critical stenosis and hypoperfusion of multi- ple medullary arterioles cause widespread incomplete infarc- tion of deep white matter with a clinical picture of Binswanger’s disease. In the second, occlusion of the arteriolar lumen resulting from arteriolosclerosis leads to the formation of lacunes, which results in a lacunar state (état lacunaire). In practice, the two clinical pathways can overlap; lacunes and white matter lesions are often seen together, which is not sur- prising, given their common origins. In addition, a combination of small-vessel and large-vessel CVD in the same patient is not unusual. In more than half of these cases, cortical and basal ganglia microinfarctions may be present, even though these lesions are not apparent on MRI.

Neuroimaging plays an important role in diagnosis of SCVD, especially because it is a slow progressive disease. MRI can show changes before the symptoms are evident clinically. The most commonly seen abnormality on MRI is a diffuse hyperin- tensity on T2-weighted imaging, primarily in the centrum semiovale and around the ventricles.24 Confluent areas of hyperintensities (leukoaraiosis) may also be seen commonly in occipital, periventricular, and sometimes frontal white matter. On T1-weighted imaging, corresponding areas are not hypoin- tense. For the diagnosis of the Binswanger’s disease, it is impor- tant to have associated clinical cognitive decline from a previ- ously higher level of functioning in memory and two or more cognitive domains, in addition to the white matter changes on neuroimaging (▶Fig. 22.11).25 The decline must at least be severe enough to interfere with activities of daily living. With- out clinical findings, such findings on imaging are to be termed as leukoaraiosis. The second most common imaging finding seen with small-vessel disease is focal white matter lesions, found in 22% of subjects under age 40 and in 27 to 60% of those over age 65 years, whereas in patients with AD and VaD, they are detected by MR in almost 100% of patients.26 The white matter lesions can be categorized into periventricular white matter lesions, which are attached to the ventricular system, and deep white matter lesions, which are located in subcortical white matter (▶ Fig. 22.12).

Lacunae are common small, deep infarcts of the brain smaller than 2 cm in diameter, are single or multiple, and are clinically silent or less frequently symptomatic. Lacunae result from

Fig.22.11 Binswanger’sdiseaseinan83-year-old man with dementia. Axial fluid-attenuated inversion recovery magnetic resonance images show extensive symmetrical hyperintensity involving periventricular and lobar white matter. These lesions have a rather sharp outer border and show relative sparing of the U-fibers. This diffuse involvement was considered > 25% of the total white matter. There was marked worsening of white matter changes and cognitive decline within a span of 5 years (2002 and 2005).

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small-vessel disease with lumen occlusion secondary to arterio- losclerosis resulting from microatheroma and lipohyalinosis, or embolism, usually in patients with arterial hypertension. Lacu- nae are located in a territory supplied by the deep perforators such as lenticulostriate, thalamoperforating, and long medul- lary arterioles (▶Fig. 22.13 a, b).27 Therefore, lacunae can be located in the basal ganglia, the upper two-thirds of the puta- men, the internal capsule, the thalamus, the paramedian, and lateral regions of the brainstem (pontine base), corona radiata, and centrum semiovale.7 Lacunae must be distinguished from dilated periventricular spaces (état criblé). Lacunae are round, oval, or slitlike, small cavitated ischemic brain infarcts measur- ing up to 2 cm in maximum diameter, and resulting in a lacunar state or état lacunaire. Lacunar infarcts are hypodense on CT scans, hypointense on T1-weighted MRI, and hyperintense on T2-weighted MRI. In late stages, lacunae may be hypointense on FLAIR with an irregular rim of hyperintensity around. A common differential diagnosis includes Virchow-Robin spaces, which follow CSF signal on all MRI sequences (▶ Fig. 22.13). In practice, the two forms of subcortical ischemic VaD, lacunae and deep white matter lesions, are often seen together, presum- ably because of their common origin.

Perivascular Spaces

The perivascular spaces (PVSs) of the brain, also known as Virchow-Robin spaces (VRS), are pial-lined interstitial fluid -filled structures that accompany penetrating arteries and arte- rioles for a variable distance as they descend into the cerebral substance. Recent studies have shown that the PVSs are surpris- ingly complex entities with significant variability in both ultra- structure and possible function. Prominent VRS may occur in all age groups and are regarded as incidental findings without much clinical significance. However, when they are prominent in elderly patients, they indicate the shrinkage of the surround- ing white matter. On histopathology, there is no evidence of necrosis, macrophages, or tissue debris in the VRS. Occasionally, the PVSs may become strikingly enlarged, causing mass effect and assuming bizarre configurations that may be mistaken for a more ominous disease, such as a cystic neoplasm. Typical PVSs

Neuroimaging of Vascular Dementias

Fig. 22.12 Periventricular and subcortical white matter lesions in a woman with mild cognitive decline. Axial fluid-attenuated inversion recovery (a) magnetic resonance images show multiple focal hyperintensities in the periventricular and subcortical white matter. On T1-weighted images (b), corresponding areas are not hypointense.

Fig. 22.13 Lacunar infarcts versus perivascular spaces. Axial T2 and fluid-attenuated inversion recovery (FLAIR) images in lacunar infarct (a, b) and prominent perivascular space (c,d) in the basal ganglia. Enlarged perivascular spaces are isointense to the cerebrospinal fluid space on all three sequences with no hyperintense rim on FLAIR images. On the other hand, chronic lacunar infarct has a hypointense center with a hyperintense rim (arrow) on FLAIR images, an appearance that reflects gliosis.

occur in many locations. The most common site is along the lenticulostriate arteries, just above the anterior perforated sub- stance and adjacent to the anterior commissure. Less com- monly, PVSs occur along arteries that have penetrated the cere- bral cortex and extended into the white matter. Other areas where prominent PVSs can be identified include the subinsular

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region, dentate nuclei, and cerebellum. PVSs have typical MRI features (▶ Fig. 22.13c,d). They are round or oval with a well- defined, smooth margin; occur along the path of penetrating arteries; are isointense relative to CSF; and demonstrate no enhancement after contrast medium administration. When PVSs become enlarged, they are known as giant PVSs, cavernous dilatation, or expanding lacunae.28

22.2.3 Mixed Dementia

Vascular dementia secondary to CVD has been traditionally dis- tinguished from AD, which is a purely neurodegenerative form of dementia. However, CVDs such as lacunae and white matter lesions are common in patients with AD, whereas certain path- ological changes of AD, including senile plaques and tangles, are observed in elderly patients with VaD. These findings indicate that mixed vascular-degenerative dementia (MD) is the most common cause of dementia in the elderly. In the treatment and prevention of dementia, the accurate diagnosis of each individual type of dementia is vital. However, recognizing the distinction between these diseases can be difficult in clinical practice.29 Although little is known about specific risk factors for MD, these most likely include the presence of risk factors for both AD and VaD, which have been extensively studied. Vascular risk factors appear to be particularly important. Hypertension is one of the most potent risk factors for the development of VaD, but it may also increase AD risk.

Clinical criteria reflect the diversity of the MD concept. Most of these criteria remain controversial and have not been well validated by neuropathological studies. Advances in neuroimaging techniques have led to a better understanding of the features indicative of AD and VaD and may lead to improved criteria. For example, in patients with VaD, CT and MRI findings include infarctions, white matter irregular peri- ventricular hyperintensities, and hyperintense foci in the basal ganglia and thalamus. Hippocampal atrophy is most consistent with AD, although recent data suggest that it may also occur in VaD or in mixed ischemic and degenerative pathology. SPECT studies have shown that VaD patients usu- ally exhibit a diffuse and asymmetric decrease of CBF in the cerebral cortex and subcortical nuclei, with a loss of cere- bral vasomotor responsiveness. In contrast, AD patients exhibit reduced CBF in temporal and parietal areas and show preserved ability to vasodilate and increase CBF in response to various stimuli. PET reveals multiple focal metabolic defects in VaD as opposed to reduced regional metabolic rates in the temporal lobes in early AD (▶Fig. 22.14). How- ever, structural and functional neuroimaging characteristics are often unable to distinguish AD from VaD, especially in advanced cases. Unfortunately, features that might be partic- ularly suggestive of MD have not been well described, and further studies are needed to better define the potential role of neuroimaging in establishing or corroborating this diagnosis.30

Fig. 22.14 Glucose metabolism in a normal control, in a patient with vascular dementia, and in a patient with Alzheimer’s disease. The severity of dementia was comparable, and the pattern of pathologic changes differentiated these two cases: patchy metabolic defects in vascular dementia (VaD) in the frontal lobe, basal ganglia, and thalamus; hypometabolism in bilateral parietotemporal cortex and to a lesser degree in the frontal association areas in Alzheimer’s disease (AD).

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22.3 Conclusion

Currently, CVD is viewed as a distinctly secondary cause of dementia that is of uncertain importance. Although it is com- monly cited as the second leading cause of dementia, a lack of well-validated diagnostic criteria, which in turn reflects impor- tant gaps in fundamental knowledge about disease mecha- nisms, makes accurate epidemiology difficult. Distinguishing VaD from AD and other forms of dementia can be challenging because these disorders share many features. Understanding of VaD has evolved substantially in recent years, based on pre- clinical, neuropathologic, neuroimaging, physiologic, and epide- miologic studies. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowl- edge of the pathological basis of neuroimaging change and the complex interplay between vascular and AD pathologies in the evolution of clinical VaD and AD. Among the tools available to help clinicians diagnose and monitor VaD progression, neuro- imaging is especially useful for confirming the diagnosis and identifying specific VaD subtypes.

References

. [1] Erkinjuntti T. Diagnosis and management of vascular cognitive impairment and dementia. J Neural Transm Suppl 2002; 63: 91–109

. [2] Bowler JV. Criteria for vascular dementia: replacing dogma with data. Arch Neurol 2000; 57: 170–171

. [3] Erkinjuntti T, Inzitari D, Pantoni L et al. Limitations of clinical criteria for the diagnosis of vascular dementia in clinical trials: is a focus on subcortical vascular dementia a solution? Ann N Y Acad Sci 2000; 903: 262–272

. [4] Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia: a cause of mental deterioration in the elderly. Lancet 1974; 2: 207–210

. [5] Yanagihara T. Vascular dementia in Japan. Ann N Y Acad Sci 2002; 977: 24–28

. [6] Wiederkehr S, Simard M, Fortin C, van Reekum R. Validity of the clinical diagnostic criteria for vascular dementia: a critical review. Part II. J Neuro- psychiatry Clin Neurosci 2008; 20: 162–177

. [7] Guermazi A, Miaux Y, Rovira-Cañellas A et al. Neuroradiological findings in vascular dementia. Neuroradiology 2007; 49: 1–22

. [8] Román GC, Tatemichi TK, Erkinjuntti T et al. Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Work- shop. Neurology 1993; 43: 250–260

. [9] Román GC, Royall DR. Executive control function: a rational basis for the diag- nosis of vascular dementia. Alzheimer Dis Assoc Disord 1999; 13 Suppl 3: S69–S80

[10] Kurz AF. What is vascular dementia? Int J Clin Pract Suppl 2001; 120: 5–8 [11] Chui HC, Victoroff JI, Margolin D, Jagust W, Shankle R, Katzman R. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology

1992; 42: 473–480
[12] Román GC. Defining dementia: clinical criteria for the diagnosis of vascular

dementia. Acta Neurol Scand Suppl 2002; 178: 6–9
[13] Erkinjuntti T, Román G, Gauthier S, Feldman H, Rockwood K. Emerging thera-

pies for vascular dementia and vascular cognitive impairment. Stroke 2004;

35: 1010–1017
[14] van der Flier WM, Scheltens P. Use of laboratory and imaging investigations

in dementia. J Neurol Neurosurg Psychiatry 2005; 76 Suppl 5: v45–v52
[15] Tartaglia MC, Rosen HJ, Miller BL. Neuroimaging in dementia. Neurothera-

peutics 2011; 8: 82–92
[16] van Straaten EC, Scheltens P, Knol DL et al. Operational definitions for the

NINDS-AIREN criteria for vascular dementia: an interobserver study. Stroke

2003; 34: 1907–1912
[17] Jellinger KA. Pathology and pathogenesis of vascular cognitive impairment—a

critical update. Front Aging Neurosci 2013; 5: 17
[18] Mangla R, Kolar B, Almast J, Ekholm SE. Border zone infarcts: patho-

physiologic and imaging characteristics. Radiographics 2011; 31: 1201–1214 [19] Ferro JM. Hyperacute cognitive stroke syndromes. J Neurol 2001; 248: 841–

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[20] Desmond DW. Vascular dementia: a construct in evolution. Cerebrovasc Brain

Metab Rev 1996; 8: 296–325
[21] Farid K, Petras S, Ducasse V et al. Brain perfusion SPECT imaging and acetazol-

amide challenge in vascular cognitive impairment. Nucl Med Commun 2012;

33: 571–580
[22] Jellinger KA. The enigma of vascular cognitive disorder and vascular demen-

tia. Acta Neuropathol 2007; 113: 349–388
[23] Ozgur HT, Kent Walsh T, Masaryk A et al. Correlation of cerebrovascular

reserve as measured by acetazolamide-challenged SPECT with angiographic flow patterns and intra- or extracranial arterial stenosis. AJNR Am J Neurora- diol 2001; 22: 928–936

[24] Tomimoto H. Subcortical vascular dementia. Neurosci Res 2011; 71: 193– 199

[25] Bennett DA, Wilson RS, Gilley DW, Fox JH. Clinical diagnosis of Binswanger’s disease. J Neurol Neurosurg Psychiatry 1990; 53: 961–965

[26] Vernooij MW, Smits M. Structural neuroimaging in aging and Alzheimer’s disease. Neuroimaging Clin N Am 2012;22(1):33–55

[27] Leys D, Pasquier F, Lucas C, Pruvo JP. [Magnetic resonance imaging in vascular dementia] [in French] J Mal Vasc 1995; 20: 194–202

[28] Salzman KL, Osborn AG, House P et al. Giant tumefactive perivascular spaces. AJNR Am J Neuroradiol 2005; 26: 298–305

[29] Hanyu H. [Diagnosis and treatment of mixed dementia] Brain Nerve 2012; 64: 1047–1055

[30] Zekry D, Hauw JJ, Gold G. Mixed dementia: epidemiology, diagnosis, and treatment. J Am Geriatr Soc 2002; 50: 1431–1438

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23 Imaging of Specific Hereditary Microangiopathies

Kenneth Lury and Mauricio Castillo

The hereditary cerebral microangiopathies (HCM)s encom- pass a diverse group of diseases that have as common mani- festations recurring stroke symptoms, cerebral infarctions, and diffuse white matter lesions, leading to a broad spec- trum of neurologic problems and deficits. The cerebral blood vessels most often affected by HCM are the lenticulostriate arteries, pontine branches arising from the basilar artery, and thalamo-perforating arteries that arise from the P1 and P2 segments of the posterior cerebral arteries, tip of the bas- ilar artery, and posterior communicating arteries. Penetrat- ing arteries arising from leptomeningeal branches may also be affected.1

In recent years, advances in molecular genetics have identi- fied several monogenic conditions responsible for HCM. A diag- nosis of hereditary cerebral small-vessel disease has to be con- sidered in cerebrovascular disorders presenting in youth and adulthood.2 In this chapter, we address the clinical and imaging findings of the most common causes of HCM.

23.1 Fabry’s Disease

Fabry’s disease is an X-linked inherited disorder of glycosphin- golipid metabolism that results from deficient or absent lyso- somal α-galactosidase A (α-Gal A) leading to a progressive accu- mulation of globotriaosylceramide (GB3).1,2 These lipid deposits occur preferentially in the endothelial and smooth muscle cells, resulting in vascular dysfunction, tissue ischemia, and eventual vessel occlusion.3 The disease has no ethnic predilection, and its reported annual incidence is about 1:40,000 to 100,000.1,2 The classic form of the disease involves males with no detect- able α-Gal A activity. Clinical presentations include angio- keratomas, acroparesthesia, hypohidrosis, and childhood or adolescent cataracts in addition to progressive vascular disease of the heart, kidneys, and central nervous system. With advanc- ing age, progressive damage to other vital organs may lead to their failure.2 Elevated GB3 levels in the blood allow a definitive diagnosis in men. In women, however, the diagnosis can be made only by gene sequencing.1 Enzyme replacement therapy

has been shown to normalize cerebral-vessel compliance, but the influence of this treatment on clinical outcomes has not been demonstrated.3 End-stage renal disease and life-threaten- ing cardiovascular or cerebrovascular complications decrease life expectancy of untreated male and female patients by 20 and 10 years, respectively.2 Fabry’s disease should be consid- ered in the differential diagnosis in young patients with crypto- genic stroke(s) especially affecting the vertebral basilar system.3 Imaging findings are otherwise nonspecific.

23.2 CADASIL

CADASIL, or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is caused by dominant mutations in the NOTCH3 gene on chromosome 19p 13.2.2 CADASIL is the most common cause of inherited cerebral infarction(s) and vascular cognitive impairment in adults; it is characterized by five main symptoms: migraine with aura, mood disturbances, apathy, cognitive impairment, and sub- cortical ischemic strokes. The last, along with transient ischemic attacks (TIAs), are the most frequent manifestation of CADASIL and occur in 60 to 85% of patients, generally at a mean age of 49 years (range, 20 to 70 years). Territorial infarcts are rare. In most patients, there is an absence of conventional vas- cular risk factors as well as absence of involvement of other organs. At present, there is no treatment for CADASIL, either for the disease or for its symptoms. The usual preventive measures for noncardiologic embolic ischemic stroke, including the use of antiplatelet drugs rather than anticoagulants (because of the increased risk of intracerebral hemorrhage) and treatment of vascular risk factors, may offer some benefit.1,4

Although white matter abnormalities resulting from CADASIL may be indistinguishable from those found in other disorders, such as multiple sclerosis, subcortical cerebrovascular diseases, and leukodystrophies, the high frequency of early involvement of the anterior aspects of the temporal lobes and the late involvement of the external capsules are strongly suggestive of the diagnosis at different stages (▶Fig. 23.1). Other MRI

Fig. 23.1 CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). (a) Axial T2-weighted image obtained at level of the basal ganglia demonstrates extensive high signal intensity in the white matter, including the external capsule bilaterally (thick arrows) (b). Axial T2-weighted image obtained inferior to (a) shows abnormal signal in the white matter of the anterior and inferior white matter of the temporal lobes

(thin arrows).

Imaging of Specific Hereditary Microangiopathies

findings include dilated perivascular spaces that are sometimes prominent and diffuse (état criblé), diffuse white matter abnor- malities, infarctions, and atrophy.2

23.3 CARASIL

CARASIL, or cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, is an entity clini- cally similar to CADASIL that is caused by mutations in the HtrA serine protease 1 (HTRA1) gene (chromosome 10q 26.3). Serine proteases regulate cell growth by controlling the availability of insulin-like growth factors. CARASIL’s micropathological expression is distinguished from the CADASIL phenotype by absence of depositions of granular osmiophilic material in the tunica media of small arteries and arterioles in the skin as seen in CADASIL. In addition to the typical clinical features found in CADASIL, early alopecia and spondylosis are frequently present in CARASIL. This disease is rare and has been seen only in Japa- nese or Chinese families.1,5

The most characteristic brain magnetic resonance imaging (MRI) findings in patients with CARASIL are white matter lesions, more often in the periventricular and deep regions than in the superficial white matter (U-fibers) and multiple lacunar infarctions in the basal ganglia and thalamus.5

23.4 Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is an important cause of spontaneous cortical and subcortical intracranial hemorrhages (ICHs), as well as nontraumatic convexity subarachnoid hemor- rhages in normotensive elderly individuals. Microscopically, there is deposition of amyloid in the media and adventitia of small and medium-sized blood vessels of the cerebral cortex, sub- cortical regions, and leptomeninges, with sparing of similarly sized vessels in the deep white matter. Amyloid deposition engenders fibrinoid necrosis, focal vessel wall fragmentation, and microaneurysms, all of which predispose patients to repeated episodes of blood vessel leakages or frank hemorrhages.

Additionally, at sites of fibrinoid necrosis, there may be lumi- nal narrowing that can lead to ischemia. CAA is not associated

with presence of systemic amyloidosis, and both sporadic and hereditary CAA forms may occur. Hereditary CAA is rare and generally demonstrates an autosomal dominant transmission.6 Amino acid substitutions at four sites in the β-amyloid precur- sor protein, all situated within the β-amyloid peptide sequence itself, have been shown to cause heritable forms of CAA.7 Hereditary forms of CAA display a broader range of clinical manifestations than the sporadic types, which are more com- mon in the elderly and increase in both prevalence and severity with advancing age. Many patients with CAA are asymptomatic. When symptomatic, typical presentations include acute ICH, TIAs, and eventual dementia. The most common clinical presen- tation of CAA is the development of a sudden neurologic deficit secondary to acute ICH or subarachnoid hemorrhage, but these symptoms are not specific for CAA. Dementia may be seen before symptomatic ICH in 25 to 40% of patients and may be slowly progressive, similar to that seen in patients with Alz- heimer’s disease.

On imaging studies, CAA-related macrohemorrhages typi- cally exhibit irregular borders and may be associated with sub- arachnoid hemorrhage (particularly in the cerebral convexities), subdural hematomas, and less commonly, intraventricular hemorrhage. Subarachnoid and subdural hemorrhages may be due to direct extension from the cortical-subcortical hemor- rhage or may be primary in nature.

Typically, MRI obtained with blood-sensitive sequences (gra- dient-recalled echoes or susceptibility-weighted images) dem- onstrate microhemorrhages (< 5 mm), which are often clinically silent. (▶ Fig. 23.2) These microbleeds are preferentially located on the surface of the brain and the cortex and may coexist with larger acute ICHs (>5mm in diameter), which may be of varying ages and involve any lobe of the cerebral hemi- spheres but preferentially the parietal lobes and posterior regions. These larger bleeds occur in a distinctive cortical- subcortical distribution, generally sparing the basal ganglia and brainstem. The larger bleeds may show fluid levels and occasionally occur in “mirror-like” locations synchronously or metachronously. (▶ Fig. 23.3) These findings are often accompa- nied by leukoencephalopathy and diffuse cerebral atrophy (▶Fig. 23.4).6 Superficial siderosis may be seen as a conse- quence of subarachnoid bleeds and when secondary to CAA it

Fig. 23.2 Cerebral amyloid. (a) Axial T2* (gradient echo) at the level of the corona radiata demonstrates multiple areas of punctate subcortical hemorrhage, as well as blood in the subarachnoid spaces and surface of brain compatible with superficial hemosiderosis.
(b) Axial T2* (gradient echo) at level of basal ganglia in the same patient demonstrates multiple punctate hemorrhages predominantly in cortical and subcortical regions and, to a lesser degree, in the basal ganglia.

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Fig. 23.3 Cerebral amyloid. Axial fluid-attenuated inversion recovery at the level of centra semiovale demonstrates “fluid/fluid” level in an acute left parietal lobe hemorrhage as well as a subacute left frontal hemorrhage. Note also the subarachnoid spaces are high signal, indicative of acute hemorrhage.

Fig. 23.4 Cerebral amyloid. Computed tomography scan at level of the lateral ventricles shows a right frontal subarachnoid hemorrhage as well as white matter hypodensities, especially posteriorly.

Fig.23.5 Cerebralamyloid.AxialT2-weightedimageatlevelofcerebral convexities shows superficial siderosis along the convexities (arrows).

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generally affects the cerebral convexities (▶Fig. 23.5). When- ever an elderly adult presents with nontraumatic and sponta- neous subarachnoid hemorrhage in the cerebral convexities, CAA should be included in the differential diagnosis.

Currently, there is no treatment to halt or reverse CAA. Thus, attention is directed to prevention of adverse outcomes associ- ated with the natural history of CAA. Patients with a new diagnosis of CAA should have a risk:benefit evaluation before continuation of anticoagulation therapy for other disorders. Whereas hypertension is the most common cause of nontrau- matic hemorrhage in adults, the typical cortical-subcortical location of CAA-related hemorrhages is helpful in distinguish- ing them from the more common deep gray matter, cerebellar, and brainstem location of hypertensive hemorrhages.6

Occasionally, CAA may present in atypical ways. A case series of five patients with “tumefactive cerebral amyloid angiopathy” reported MRI findings that are difficult to distinguish from low-grade gliomas. These lesions were nonenhancing, nonhe- morrhagic, poorly marginated, infiltrative and masslike, with cortical swelling and variable adjacent leptomeningeal enhance- ment (▶ Fig. 23.6).8

23.5 Sickle Cell Disease

Sickle cell disease (SCD) is caused by a point mutation in the β- globin gene resulting in the mutant protein hemoglobin S (HbS) in which the sixth amino acid changes from glutamic acid to valine. The most common and severe form of SCD, homozygous

Imaging of Specific Hereditary Microangiopathies

Fig. 23.6 Cerebral infiltrative amyloid. (a) Axial noncontrast T1-weighted image at the level of cerebral convexities shows an area of low intensity and mass effect in the left frontal region. (b) Left parasagittal T1-weighted image again shows the lesion in the left frontal region. (c) Axial postgadolinium T1-weighted image at same level as (a) demonstrates leptomeningeal enhancement (arrow).

Fig. 23.7 Sickle cell disease. (a) Magnetic resonance angiography through the circle of Willis shows severe bilateral stenoses involving the anterior and middle cerebral arteries

(blue arrows) and diminished flow-related enhancement in the right posterior cerebral artery (white arrow). (b) Axial fluid-attenuated inversion recovery of the same patient at level of cerebral convexities demonstrates abnormal signal corresponding to infarction in vascular region (right parietal lobe) supplied by the right posterior cerebral artery. Note the high signal in the subarachnoid space compatible with the “ivy sign” from slow flow through collateral circulation.

HbSS, is referred to as sickle cell anemia (SCA), in which deoxy- genated HbS molecules form intracellular red blood cell poly- mers that damage the red cell membranes and increase their rigidity.9 SCD occurs most commonly in people of African, Med- iterranean, Indian, and Middle Eastern ancestry. In North Amer- ica, SCD is more frequent in African Americans, Africans, and Hispanic patients from the Caribbean and Central and South America. SCD affects about 50,000 people in the United States. Among newborn infants, SCD occurs in approximately: 1:400 African Americans, 1:36,000 Hispanics, and 1:80,000 whites. SCD is diagnosed by hemoglobin electrophoresis that identifies the abnormal hemoglobin.10 The most common histopathology abnormality related to cerebrovascular disease is damage to the endothelium of mid- to large-sized arteries, particularly at branch points, producing intimal proliferation, fibrin deposi- tion, and thrombus formation.9 The most common neurologic lesions in SCA are silent cerebral infarctions.11

Moyamoya, meaning a “hazy puff of smoke” in Japanese, is a common manifestation of cerebral SCD. Moyamoya is defined as a chronic, occlusive cerebrovascular disease with bilateral stenosis or occlusion of the terminal portions of the internal carotid arteries and/or the proximal portions of the anterior cerebral arteries and middle cerebral arteries. The “puff of

smoke” appearance is the result of small lenticulostriate arter- ies arising from the internal carotid artery terminus and proxi- mal anterior and middle cerebral arteries, forming a network of collateral circulation to bypass the narrowed or occlusive segments, moyamoya is diagnosed by MR angiography or con- ventional digital subtraction catheter angiography. The devel- opment of Moyamoya-like changes is a grave prognostic finding in patients with SCD and strokes (▶ Fig. 23.7, ▶ Fig. 23.8).9

23.6 Homocystinuria

Homocystinuria is an inherited autosomal recessive disorder in which the body is unable to process amino acids properly. Homocystinuria has multiple forms that are distinguished by their signs, symptoms, and genetic causes. Mutations in the CBS gene cause the most common form. The CBS gene is responsible for cystathionine β-synthase, an enzyme that converts homo- cysteine to cystathionine. Mutations in this gene disrupt the function of cystathionine β-synthase, preventing homocysteine from being used properly. As a result, this amino acid and its toxic byproduct substances accumulate. The most common form of homocystinuria affects 1:200,000 to 335,000 people worldwide. It is more common in Ireland (1:65,000), Germany

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Fig. 23.8 Sickle cell disease and moyamoya phenomenon. (a) Source image for time-of-flight magnetic resonance angiography of the circle of Willis shows tangles of collateral blood vessels in the sylvian regions bilaterally (arrows). (b) Digital subtraction catheter angiogram of an injection in the internal carotid artery (left posterior oblique projection) shows that some of right middle cerebral artery territory is supplied by dysplastic collaterals compatible with moyamoya vessels.

Fig. 23.9 Homocystinuria axial T2-weighted imaging through the orbits shows bilateral lens dislocation.

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(1:17,800), Norway (1:6,400), and Qatar (1:1,800) and is char- acterized by nearsightedness, dislocation of the ocular lens, an increased risk of blood clotting, arterial dissections, and osteoporosis (▶Fig. 23.9). Less common manifestations of homocystinuria include intellectual disabilities, failure to thrive, seizures, movement disorders, and megaloblastic anemia. Signs and symptoms of homocystinuria typically develop within the first year of life, although some people with a mild form of the disease might not develop these features until later in life.12 Intrauterine diagnosis of homocystinuria involves culturing amniotic cells or chorionic villi to test for cystathionine syn- thase. Although no cure exists for homocystinuria, vitamin B6 therapy can help about 50% of patients.13

23.7 Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune condition defined by arterial and venous thrombosis with persistently positive antiphospholipid antibodies (aPLs). In addition to peripheral arterial and venous thromboses affecting any size blood vessels, a variety of clinical manifestations have been reported: skin disease; cardiac, pulmonary, and renal involve- ment; hematologic manifestations; and a wide spectrum of

neurologic disorders. Cerebral involvement in APS is common and is characterized by cerebral infarctions, epilepsy, dementia, cognitive deficits, headaches, psychiatric disorders, chorea, multiple sclerosis–like disease, transverse myelitis, and ocular symptoms, any of which may be the initial features or may appear later. Headaches are a common neurologic manifesta- tion. Symptoms may result from thrombosis or direct injury to the brain. Secondary APS is seen in patients with other connec- tive tissue diseases, most often systemic lupus erythematosus. Genetic and environmental factors are involved in the causes of APS, and infections, autoimmune, and other inflammatory dis- eases and drugs and neoplasms may also induce production of aPLs. Strokes and TIAs are common as a result of arterial thromboses. Almost 20% of female stroke patients younger than 45 years of age have associated APS.

The spectrum of neuroradiologic findings in patients with APS is largely a consequence of multiple arterial or venous thromboses. Infarcts of various sizes and focal T2/fluid- attenuated inversion recovery (FLAIR)/diffusion-weighted imaging (DWI) hyperintense lesions in white matter are the most common abnormalities. Venous occlusions on magnetic resonance venogram and computed tomography venogram are typical.14

23.8 Mitochondrial

Encephalomyopathy

Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) is most commonly associated with the m.3243A > G mutation in MT-TL1, the tRNA gene responsi- ble for leucine. This condition is inherited in a maternal pattern that applies to all genes contained in mitochondrial DNA, as only egg cells contribute mitochondria to the developing embryo.15 Typically, clinical episodes begin with severe “migraine-like” headaches associated with nausea, vomiting, and sometimes seizures, followed by hemiparesis, hemianopia, and/or cortical blindness. The infarctions are often parieto- occipital and do not conform to vascular territories. Proton MR spectroscopy often demonstrates lactic acid in the basal ganglia and elsewhere (▶Fig. 23.10). Frequent comorbidities include dementia, ataxia, deafness, muscle weakness, cardiomyopathy,

23.11 Aicardi Goutières Syndrome

Aicardi Goutières syndrome (AGS) is an inherited encephalop- athy (mostly autosomal recessive) associated with mutations of four different genes. It affects newborns and usually results in severe mental and physical handicaps. There are two forms of the syndrome. The early-onset form demonstrates jittery behavior and poor feeding ability mimicking congenital viral infection. Those with later-onset type have symptoms after the first weeks or months of normal development, starting with progressive decline in head growth, weak or stiffened muscles (spasticity), and leading to moderate to severe mental and developmental retardation.19 MRI shows three features: cere- bral calcifications, white matter abnormalities, and cerebral atrophy. Calcifications are typically bilateral and located in the basal ganglia and cerebellar dentate nuclei and are best visual- ized by CT. In 50 to 70% of cases, calcifications extend to the white matter, particularly the periventricular areas.20

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[17] Gould DB, Phalan FC, van Mil SE et al. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med 2006; 354: 1489–1496

[18] COL4A1-related brain small-vessel disease. Available at: http://ghr.nlm.nih. gov/condition/col4a1-related-brain-small-vessel-disease. Accessed February 27, 2013

[19] NINDS Aicardi-Goutieres Syndrome Disorder Information Page. http://www .ninds.nih.gov/disorders/aicardi_goutieres/aicardi-goutieres.htm. Accessed Febru- ary 27, 2013

[20] Orcesi S, La Piana R, Fazzi E. Aicardi-Goutieres syndrome. Br Med Bull 2009; 89: 183–201

and diabetes.15,16 The underlying pathogenesis for the infarc- tions is not clear.1

23.9 RetinalVasculopathy+

Leukoencephalopathy

Retinal vasculopathy + leukoencephalopathy (AD-RVLC) inherited in an autosomal dominant pattern and is caused by mutations in the 3‘–5‘ DNA exonuclease TREX1. The main clini- cal manifestations are retinopathy, nephropathy, and recurrent strokes. Characteristic electron microscopic findings are described in biopsies from the brain, kidney, or skin showing multilayered basal membranes. MRI shows subcortical con- trast-enhancing lesions. In contrast to CADASIL, there is no temporal lobe disease preponderance.1

23.10 COL4A1

COL4A1-related brain small-vessel disease is very rare. It is inherited in an autosomal dominant pattern, involving muta- tions in the COL4A1 gene, which encodes for one component of a protein called type IV collagen, the main component of base- ment membranes. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Stroke is often the first symptom and typically occurs in mid- adulthood. Hemorrhagic infarction is more common than ische- mic infarction, although either type can occur. MRI may also show a diffuse leukoencephalopathy associated with dilated perivascular spaces.17,18

Imaging of Specific Hereditary Microangiopathies

Fig. 23.10 Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS), P (Proton)-magnetic resonance spectro- scopy voxel in the basal ganglia shows inverted peak at 1.3 parts per million corresponding to lactate (arrow).

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24 Vasculitis and Dementia

Sampson K. Kyere, Olaguoke Akinwande, Dheeraj Gandhi, and Gaurav Jindal

Vasculitis comprises a heterogeneous group of disorders marked by inflammation and necrosis of the vessel wall. Mani- festations of vasculitis in the central nervous system (CNS) are rare compared with those of other organ systems.1 Vasculitis- related dementia is usually of rapid progression evolving over weeks to months compared with degenerative dementia, which may take years to develop. Among the vasculitides, the pattern of cognitive decline is indistinguishable. Many of these condi- tions are treatable; therefore, a high degree of suspicion and early diagnostic evaluation of patients with signs of dementia are critical. In this chapter, we discuss the vasculitides, which may manifest with clinical dementia and the imaging findings associated with these disorders. Many of the imaging findings, both on cross-sectional imaging and digital subtraction angiog- raphy (DSA), overlap from one disorder to the next. Empiric treatment can be started if clinical suspicion warrants therapy. Biopsy also can aid in the diagnosis when equivocal.

24.1 Primary Central Nervous System Vasculitis

24.1.1 Primary Angiitis of the Central Nervous System

Causes and Histopathology

Primary angiitis of the central nervous system (PACNS) is an uncommon, heterogeneous group of vasculitides of the brain and spinal cord of unknown cause and without systemic manifestations.2 PACNS usually affects middle-aged patients at a mean of 42 years, but it can affect a wide age range of patients, from age 3 to the elderly. There is a slight male pre- dominance. Histologically, PACNS typically features a varying degree of mononuclear inflammation and necrosis of the media and adventitia of small and medium leptomeningeal and parenchymal arteries.3 Granulomatous vasculitis is the most common form (58%) of PACNS, demonstrating well- formed granulomas with multinucleated cells within vessel walls. Lymphocytic vasculitis is the second most common pattern (28%) and is marked predominantly by lymphocytic inflammation. Necrotizing vasculitis is the least common (14%) pattern, characterized by transmural necrosis associ- ated with intracranial hemorrhage.2,3 The histologic patterns remain stable over time, indicating that they do not repre- sent different phases.2

Clinical and Laboratory Features

Clinical presentations of PACNS are diverse but often marked by headache, altered cognition, focal weakness, or stroke. Spinal cord involvement is seen in 5% of cases.4 There is generally a lack of systemic constitutional symptoms, such as weight loss and fever. The course can be relapsing-remitting or slowly pro- gressive resulting in subcortical dementia. In fact, about 30% of

cases of PACNS have cognitive impairment at manifestation. Because of the potential devastating sequelae of the disease, prompt diagnosis and initiation of treatment are critical. Brain biopsy is the gold standard diagnostic tool for PACNS with a specimen consisting of dura, leptomeninges, cortex, and white matter. Sensitivity of biopsy increases to 80% if targeted to a region of radiographic abnormality.5 Because there are no systemic manifestations, blood tests are usually normal. Cere- brospinal fluid (CSF) analysis will show a mildly increased leu- kocyte count and total protein in 80 to 90% of patients without evidence of infection or malignancy. Electroencephalographic findings are nonspecific. Treatment consisting of cyclophospha- mide in combination with corticosteroids can achieve a favor- able response in most patients.6

Digital subtraction angiography offers the highest spatial resolution of the available imaging modalities and is the gold standard imaging technique for diagnosis in conjunction with both a high clinical suspicion and laboratory correlation in the absence of a brain biopsy.7 Common to most CNS vasculitides, DSA will show nonspecific alternating stenoses and dilatations primarily affecting leptomeningeal arteries or intracranial ves- sels (▶ Fig. 24.1). DSA also may be normal (▶ Fig. 24.2). Micro- aneurysms are rarely seen. Magnetic resonance angiography (MRA), although less invasive than DSA, is far less sensitive in the detection of abnormalities in small distal intracranial ves- sels. Findings on brain magnetic resonance imaging (MRI) include cortical and subcortical infarctions, parenchymal and leptomeningeal enhancement, intracranial hemorrhage, and patchy punctiform areas of subcortical enhancement (▶ Fig. 24.1, ▶Fig. 24.2). Although these findings can be nonspecific, the sensitivity of MRI exceeds CT, approaching 100% for the diagno- sis of PACNS with a high clinical suspicion.2,8 The findings on MRI can mimic those of demyelinating disease, such as multiple sclerosis (▶ Fig. 24.3).

24.2 Secondary Vasculitis

24.2.1 Systemic Lupus Erythematosus Cause and Histopathology

Systemic lupus erythematosus (SLE) is a multisystem auto- immune disorder that demonstrates neuropsychiatric symp- toms in up to 75% of cases.9 All age groups are affected, with a strong female predominance. There is a high prevalence in African American women. Focal neurologic symptoms are caused by cytokine-mediated effects on vascular endothelium, leading to complement activation and occlusive vasculopathy.10 Circulating immune complexes composed of antiphospholipid antibodies may cause thrombosis. In addition, neuronal dys- function is mediated by circulating antineuronal, antiribosomal P-protein, and anticytokine antibodies. Histologically, this results in nonspecific hyalinization, endothelial proliferation, and perivascular gliosis. Subtle cerebral edema may also be seen.

Clinical and Laboratory Features

Neurologic complications worsen the prognosis of SLE and manifest as migraines, seizures, or stroke, as well as psychosis and mood disorders. Cognitive decline affects a minority of patients but is much more common than dementia and has an insidious onset. Dementia, although rare, is virtually always preceded by clinical and laboratory manifestations of SLE. Stroke is seen in 3 to 15% of cases and is predominantly attrib- utable to cardiac embolism or an antibody-mediated hyper- coagulable state.11 Neuropsychiatric SLE can be diagnosed using a combination of CSF analysis for oligoclonal bands and elevated antineuronal antibodies, as well as serum analysis for antiribo- somal protein P antibodies.

In acute cases, MRI shows focal infarcts and swelling of the basal ganglia. Chronic neuropsychiatric SLE demonstrates generalized cerebral atrophy and nonspecific white matter

lesions.12 However, it is important to remember that a negative MRI does not exclude cerebral SLE. Single-photon emission computed tomography (SPECT) and positron emission tomog- raphy (PET) are more sensitive than MRI in mild cases of SLE, showing reduced perfusion and hypometabolism in the pari- eto-occipital regions.13,14 DSA or MRA/computed tomography angiography (CTA) rarely detects cerebral lupus vasculitis. Treatment remains a challenge because of the broad spectrum of disease manifestations and usually requires a combination of cyclophosphamide, steroids, and anticoagulation.9

24.2.2 Behçet’s Disease Cause and Histopathology

Behçet’s disease is an inflammatory disorder that was classi- cally described in 1937 as the clinical triad of oral aphthous

Vasculitis and Dementia

Fig. 24.1 A 44-year-old woman with rapid-onset dementia. (a) Axial fluid-attenuated inversion recovery magnetic resonance image (MRI) of the brain demonstrates lacunar infarction in the left basal ganglia (thin arrow) and widespread bilateral deep and periventricular white matter signal abnormality (thick arrows). (b) Axial diffusion-weighted MRI through the level of the thalami demonstrates foci of diffusion restriction (thin arrows) within the bilateral thalami consistent with acute infarctions. (c) Anteroposterior digital subtraction angiography (DSA) image, (d) lateral oblique DSA image and (e) lateral DSA image of the brain, right internal carotid artery injection, demonstrate multifocal luminal irregularity of multiple small and medium branches of the right middle and right anterior cerebral arteries (arrows). The imaging findings are consistent with primary angiitis of the central nervous system.

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Fig. 24.2 Patient is a 36-year-old pregnant white woman with confusion, memory loss, unsteady gait, headaches, and intermittent numbness in the left foot. The patient’s symptoms improved after Solu Medrol (methylprednisolone sodium succinate) treatment given after labor induction. Brain biopsy demonstrated minimal inflamma- tion in a few small vessels consistent with vasculitis status post steroid treatment.

The patient was started on prednisone and cyclophosphamide (Cytoxan). (a). Axial fluid- attenuated inversion recovery magnetic resonance image of the brain demonstrates multifocal white matter foci of abnormal signal (white arrows). (b) Diffusion-weighted axial image demonstrates multifocal diffusion

restriction compatible with small infarctions (white arrows). (c) Contrast-enhanced T1-weighted axial image demonstrates multiple leptomeningeal and parenchymal enhancing foci (white arrows). (d) Lateral view digital subtraction angiography image of the brain shows no vascular abnormalities.

ulcers, genital ulceration, and uveitis.15 The median age of inci- dence is about 40 years. About 5 to 10% of patients develop CNS involvement, which typically manifests about 5 years after onset of the aforementioned classic symptoms. CNS involve- ment has a 4:1 male predilection and is thought to be second- ary to immune-mediated small-vessel vasculitis.15

Clinical and Laboratory Features

Initial symptoms of patients with CNS involvement usually include pyramidal signs, ataxia, and hemiparesis. Symptoms tend to relapse and remit with increased frequency correlating with disease severity or prognosis.16 Up to 10% of patients with neurologic involvement manifest with dementia.15,17 Cognitive decline is usually associated with other deficits and rarely in isolation.17 Patients are also prone to developing venous sinus thrombosis.15 CSF analysis shows a pleocytosis and/or elevated protein content and may show an elevated IgG index or oligo- clonal band.16

Computed tomography (CT) imaging of the brain is usually unrevealing. MRI of the brain typically shows a prominent T2 hyperintense focus in the midbrain (most commonly) (▶ Fig. 24.4), pons, basal ganglia, thalami, and white matter.18,19 Expansion of the associated brain parenchyma may mimic a

mass (▶ Fig. 24.4). Lesions may be solitary or multifocal and are usually isointense to hypointense on T1-weighted imaging, with some lesions showing nodular or patchy enhancement. Empirical treatment with corticosteroids for acute episodes and immunosuppressive therapy for long-term therapy have been shown to be effective in improving symptomatology, although there are limited reports on the efficacy of such treatments.15

24.2.3 Sjögren’s Syndrome Cause and Histopathology

Sjögren’s syndrome is a chronic autoimmune disease that occurs in about 2 to 3% of adults, characterized as primary if occurring in isolation or secondary in patients with a preexist- ing connective tissue disorder. It is characterized by lympho- cytic infiltration and destruction of exocrine glands causing xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Predominant nervous system involvement is a peripheral neuropathy secondary to small-vessel vasculitis, whereas involvement of the CNS is less common. The prevalence of CNS involvement is controversial, as is the mechanism that has been reported to be immune mediated because of cryoglobulinemia and anti-Ro/SSA antibodies.20,21,22,23

Clinical and Laboratory Features

The reported prevalence of CNS symptoms in Sjögren’s syn- drome varies widely, ranging from 2.5 to 60.0% as a result of variability in the inclusion of psychiatric symptoms.24,25 Cases of dementia resulting from CNS involvement are rare; however, severe focal or multifocal deficits are seen in up to 10% of patients.24 Symptoms include generalized cognitive deficits, psychiatric abnormalities (most commonly depression), and migraine. Chronic encephalopathy, recurrent meningo- encephalitis, subarachnoid hemorrhage, and transverse myelitis are also seen. The disease course can be relapsing and remit- ting, mimicking multiple sclerosis. CSF analysis shows an increased immunoglobulin G (IgG) index, the presence of one or more oligoclonal bands, and elevated lymphocyte count.25

Computed tomography imaging of the brain is insensitive, whereas MRI demonstrates multiple scattered areas of hyperat-

tenuation in the subcortical and periventricular white matter on fluid-attenuated inversion recovery (FLAIR) and T2-weighted images.26 This finding is seen in patients with and without CNS impairment and may represent manifestations of ischemia or demyelination. Some patients also have brain atrophy on brain imaging. Cerebral angiography is typically performed to exclude other etiologies and is often normal, although findings of small vessel vasculitis may be seen. Empirical treatment is usually with corticosteroids and cyclophosphamide.27

24.2.4 Susac’s Syndrome Cause and Histopathology

Susac’s syndrome was first described in 1977 as the clinical triad of encephalopathy, branch retinal artery occlusions, and hearing loss.28,29 It is more common in females and occurs in a

Vasculitis and Dementia

Fig. 24.3 A 35-year-old white man with a 4-week history of confusion, urinary incontinence, and generalized weakness. (a) Sagittal T1-weighted magnetic resonance image (MRI) through the midline brain demonstrates foci of abnormal signal intensity within the corpus callosum (white arrows), similar to findings that can be seen in the setting of demyelinating disease, such as multiple sclerosis. (b) Axial FLAIR MRI of the brain demonstrates multiple foci of abnormal signal intensity (white arrows), predominantly within the white matter. (c) Axial diffusion weighted MR image of the brain demonstrates restricted diffusion in the left frontal lobe (white arrow). (d) Lateral view DSA image of the brain and (e) lateral magnified view demonstrate no angiographically visible arterial abnormalities. Brain biopsy demonstrated findings of vasculitis. The patient improved on prednisone and Cytoxan.

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Fig. 24.4 A 37-year-old white man with progressive left hemiparesis and headache. (a) Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance images (MRI) through the pons and (b) midbrain demonstrate a right brainstem hemorrhage with expansile signal abnormality involving the pons, midbrain, and right cerebral peduncle as well as right middle cerebellar peduncle (not shown). (c) Coronal T1-weighted contrast-enhanced MRI through the brainstem demonstrates enhancement of the right cerebral peduncle and right midbrain. The patient had confirmed oral aphthous ulcers as well as genital ulceration. Cerebrospinal fluid analysis demonstrated pleocytosis and an elevated protein count. The clinical and imaging findings are consistent with Behçet’s disease.

wide age range from the midteens to the early postmenopausal years. The pathogenesis is unknown, but it is thought to be autoimmune mediated. This condition is characterized by a microangiopathy affecting the precapillary arterioles of the brain, retina, and inner ear.

Clinical and Laboratory Features

Patients most commonly present with headaches, but others present with memory loss, altered mental status, and dementia. Patients can present with multiple cerebral infarcts causing cognitive decline and focal neurologic defects that may progress to dementia.

Brain MRI often shows white matter lesions with a predilection for the corpus callosum.30 For this reason, it was previously thought to represent multiple sclerosis; however, lesions in Susac’s syndrome tend to involve the central portion of the corpus callosum rather than the undersurface as seen with multiple scle- rosis. The corpus callosal lesions in Susac’s syndrome are usually small and multifocal. Basal ganglia and thalamus involvement is variable. Enhancement and restricted diffusion may occur during the acute phase. Cortical lesions are not typically seen despite findings of microinfarctions seen on histology. Leptomeningeal enhancement may occur in a small subset of patients.

Branch retinal artery occlusions are usually not seen on imag- ing but may be appreciated on funduscopic examination. Cerebral angiography is usually normal, likely because the pre- capillary arterioles are beyond the resolution of DSA. Susac’s syndrome is usually self-limited, with most patients recovering without significant residual clinical deficits. Patients who do have spontaneous improvement are usually treated with immunosuppressants.

24.2.5 Wegener’s Granulomatosis Cause and Histopathology

Wegener’s granulomatosis is an idiopathic granulomatous vasculitis that affects small and medium-sized vessels in vari- ous organs. It affects men more than women and typically occurs in patients between 40 and 65 years of age.31 CNS involvement has been reported to occur as a result of vasculi- tis; granulomatous lesions within the brain, meninges, or cranial nerves; or contiguous spread from concomitant skull base disease.32,33

Clinical and Laboratory Features

Wegener’s granulomatosis most commonly manifests with renal dysfunction (progressive glomerulonephritis), hemoptysis (resulting from pulmonary involvement), and rhinologic symp- toms. Neurologic involvement is seen in 3 to 9% of patients.32 Neurologic involvement may manifest as headache, stroke, seizures, delirium, or dementia. It tends to cause a cerebritis but may also cause peripheral and cranial neuropathies.31 The c-antineutrophil cytoplasmic antibody (c-ANCA) is highly spe- cific (> 90%), with varying reported ranges of sensitivity (40 to 90%). C-reactive protein and erythrocyte sedimentation rate are usually elevated.

Although MRI and CT studies are nonspecific, they may help localize suspected lesions when the diagnosis is sug- gested, particularly if there is meningeal, orbital, or paranasal mucosal involvement.34,35 Cerebral angiography is generally unrevealing. Treatment is with systemic corticosteroids and cyclophosphamide.

24.2.6 Polyarteritis Nodosa Cause and Histopathology

Polyarteritis nodosa is a multisystem disease characterized by hyaline-like necrosis of the media and internal elastic lamina of small and medium-sized arteries. It most commonly involves the kidneys, gastrointestinal tract, and skin, but it can affect any organ except the lungs and spleen. Polyarteritis nodosa occa- sionally causes CNS involvement resulting in cognitive decline. It tends to involve the small branches of the major cerebral arteries but occasionally may involve larger ones like the mid- dle and anterior cerebral arteries.

Clinical and Laboratory Features

Involvement of the CNS is seen in about 5% of patients and often manifests as headaches, seizures, confusion, and focal neuro- logic deficits resulting from multiple small infarcts. Reversible encephalopathy is a characteristic finding in patients with CNS involvement.36

MRI demonstrates nonspecific subcortical and white matter hyperintensities on FLAIR and T2-weighted images, some of which can be attributed to infarcts.37 Lesions have a predilec- tion for the brainstem and basal ganglia, consistent with disease propensity for small vessels. Cerebral angiography is non- specific and may show findings compatible with arteritis, including occlusion of small arteries and alternating aneurysms resulting in a “beaded” appearance. Some cases may be angio- graphically occult, as lesions affecting the small vessels can be below the resolution of DSA. Treatment is with corticosteroids and cyclophosphamide.

24.2.7 Giant Cell Arteritis Cause and Histopathology

Giant cell arteritis is a chronic granulomatous panarteritis of medium- to large-sized vessels with a predilection for the cranial vessels. In addition, small vessels, particularly those sup- plying the optic nerve, can be affected. It is rare in patients younger than age 50 and often is associated with polymyalgia rheumatica.

Clinical and Laboratory Features

Patients may manifest clinically with new-onset headache or tenderness of the temporal artery. The most common neuro- logic manifestation is visual loss, seen in 15 to 20% of patients; 80 to 90% is due to ischemic optic neuritis and the remainder to occlusion of the retinal artery.32 Additional CNS involvement manifests as ischemia in the carotid and vertebral artery terri- tories as a result of extradural involvement of the intracranial branches of the carotid and vertebral arteries.32,38 Multi-infarct

dementia occurs in 3 to 6% of patients as a result of multiple vessel involvement, stenosis, and thromboemboli.38 Laboratory findings will show elevated erythrocyte sedimentation rate and C-reactive protein.

The gold standard for diagnosis is a temporal artery biopsy demonstrating evidence of vascultis with mononucleated infil- trate or giant cells; however, the presence of skip lesions can lead to false-negatives.39 MRI has demonstrated a diagnostic sensitivity of 80.6% and specificity of 97.0% for the evaluation of mural inflammation of the superficial cranial arteries, thereby potentially guiding biopsy.40 MRI also can evaluate for intra- cranial disease. Treatment is long-term high-dose steroids to prevent progression of visual impairment.

24.2.8 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Cause and Histopathology

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant vascular dementia that is linked to a gene on chro- mosome 19. There is disproportionate cortical hypometabo- lism. Histologically, an angiopathy of small and middle-sized arteries is characteristic, without atherosclerosis or amyloid deposition.41

Clinical and Laboratory Features

Initial signs usually include recurrent transient ischemic attacks (TIAs) or strokes in multiple vascular territories and eventual dementia. Presenile dementia and migraines develop in the third to fourth decades of life. The disease has a manifestation similar to migraines and also may include auras. Depression, psychosis, pseudobulbar palsy, and focal neurologic defects are also seen.41,42 Diagnosis requires identification of the mutated gene.43 CT is nonspecific, demonstrating white matter regions of low attenuation. MRI demonstrates widespread confluent white matter hyperintensities (▶ Fig. 24.5). Focal hyperintense lesions are also seen in the basal ganglia, thalamus, and pons. Although the subcortical white matter can be diffusely involved, the frontal (93%) and temporal (86%) lobes and subinsular white matter (93%) are classic (▶Fig. 24.5).42 There is relative sparing of the occipital and orbitofrontal subcortical white matter and cortex. Cerebral microhemorrhages have been reported to occur in 25 to 70% of cases without a characteristic distribution.44 Nonspecific angiographic findings mimicking that of primary intracranial vasculitis in the setting of CADASIL have been reported in the literature.45 Typically, the disease has a variable but progressive course leading to death between 50 and 70 years of age.43

Vasculitis and Dementia

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Fig. 24.5 A 64-year-old woman with acute right arm and leg numbness. History of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). (a) Axial fluid-attenuated image recovery (FLAIR) image of the brain shows confluent diffuse white matter signal abnormality with extension into the temporal lobes along the temporal horns (arrows in b). (c) Diffusion-weighted magnetic resonance image of the superior aspects of the brain show diffusion abnormality (arrow) within the posterior right frontal lobe consistent with focal acute infarction.

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223

Part VIII

Infection and Inflammatory Conditions Associated with Dementia

. 25 Human Immunodeficiency Virus (HIV) Dementia 226

. 26 Non-Human Immunodeficiency Virus
(HIV) Infectious Dementia 232

. 27 Prion Disease 239

. 28 Immune-Mediated Dementias 245

VIII

226

Infection and Inflammatory Conditions Associated with Dementia

25 Human Immunodeficiency Virus (HIV) Dementia

Toshio Moritani, Aristides Capizzano, and Sangam G. Kanekar

25.1 Epidemiology

Initial case reports from New York and San Francisco of what would later become known as acquired immunodeficiency syndrome (AIDS) first appeared in 1981.1 Human immuno- deficiency virus type 1 (HIV-1) was first described as the puta- tive cause for AIDS in 1983.2 The HIV/AIDS pandemic has become a global tragedy. Since the first report, almost 60 mil- lion people have been infected by HIV worldwide. Of these, about 25 million have already died. It is also estimated that about 2.5 million people become newly infected with HIV-1, and 2.1 million people die of AIDS-related diseases every year.3 More than 95% of AIDS cases occur in developing countries. The epidemic is growing most rapidly in China, India, Eastern Europe, and the sub-Saharan African countries. Sub-Saharan Africa is home to two-thirds of the 33.3 million people living with HIV/AIDS worldwide.4 Most HIV-positive individuals worldwide are infected as a result of unprotected sexual intercourse; 70% acquired the infection through heterosexual intercourse. Genetic epidemiologic studies have shown poly- morphisms in genes such as cytokines and their receptors and several human leucocyte antigen alleles that influence HIV progression to AIDS.5–9 White individuals deficient in chemokine receptor type 5, one of the main chemokine receptors for HIV entry into macrophages, are resistant to HIV infection.

Human immunodeficiency virus is a single-stranded ribonu- cleic acid (RNA) retrovirus that is lymphotropic and neuro- tropic. The central nervous system (CNS) is a primary target for HIV. HIV enters the brain transiently in the early stage of infec- tion, but productive infection is rarely detectable before immu- nosuppression has developed. In 10% of all HIV-infected and AIDS patients, neurologic complaints are the initial clinical manifestation, and an additional 30% to 60% of all patients will develop neurologic symptoms during the course of the infec- tion,10 40 to 50% have an active neurologic disease, and more than 90% develop CNS involvement by the time of death. The introduction of highly active antiretroviral therapy (HAART) has resulted in profound declines in morbidity and mortality with improved immunologic status.5,6,11 Although the preva- lence of opportunistic infections decreased markedly, the effects of HAART on neurologic function have remained uncertain, and HIV-associated neurocognitive disorders (HAND) remain frequent, although typically with milder symptoms.5–9 On the other hand, antiretrovirus drug–induced toxic neuropa- thy has increased.12 Nearly 50% of HIV patients in the United States demonstrate neuropsychological testing performance below expectations compared with age-, education-, gender-, and ethnicity-matched normative groups. HAND occurs in all groups at risk of HIV infection, including children; 85% of AIDS in children is vertically transmitted from an infected mother.13 The onset of neurologic disease in children is between 2 month and 5 years. The prevalence of CNS disease in HIV-infected children ranges from 20 to 60%.

25.2 Clinical Findings

Human immunodeficiency virus involves the brain directly and leads to a subcortical dementia. The terms AIDS dementia com- plex, HIV encephalopathy, and HIV-associated dementia (HAD) have been used interchangeably to describe a clinical triad of cog- nitive, motor, and behavioral changes, typically in advanced stages of HIV infection. HIV encephalitis is the term related to neuropathlogical findings in a subgroup of the patients. Recently, nosologic and diagnostic criteria have been refined and updated. In 2007, a U.S. National Institute of Mental Health and National Institute of Neurological Disease and Stroke panel pro- posed the term HIV-associated neurocognitive disorder (HAND) for the entire spectrum of neurologic disease associated with HIV, recognizing three research diagnostic categories: (1) HAD as the most severe form of injury, (2) minor neurocognitive disorder as a milder form of impairment that still impacts daily activities of living, and (3) asymptomatic neurocognitive impairment for individuals with impairments on neuropsychological testing that do not interfere with everyday functioning.5,11,14

Typically, HAND presents as a subcortical dementia with cognitive, behavioral, and motor decline over weeks or months and cannot be explained by another preexisting neurologic disease, severe substance abuse, or another cause of demen- tia.11,15,16,17 The neurologic signs of HAND progress in more than 50% of patients not receiving any form of antiretroviral therapy.18 HAND symptoms may include asymptomatic neuro- cognitive impairment, minor cognitive disorders, or a more severe form with profound motor and behavioral and psycho- social abnormalities that disrupt work or other activities of daily living.19 Disorientation, mood disturbances, psychomotor slowing, and a decrease in attention, memory, and visuo- constructive coordination are part of the clinical picture. Motor slowing and impaired movements are due to predominant dopaminergic dysfunction. Myoclonus and tremor are rare but can occur. Cortical symptoms occur when dementia is advanced. Urinary urgency, nonspecific headache, depressive symptoms, psychosis, delirium, and seizures can also occur. HAART has decreased the severity of neurologic signs of HAND.20,21 Recently, HAD only afflicts 1 to 2% of subjects with AIDS. On the other hand, the prevalence of HAND has increased due to the longer survival and increasing age of patients.22,23 Clinical features of congenital HIV infection include microceph- aly, developmental delay, and progressive loss of developmental milestones.

Cerebrospinal fluid (CSF) analysis reveals minor mononuclear pleocytosis in 18% of asymptomatic patients and 40% of symp- tomatic patients. CSF analysis can demonstrate that HIV enters the CNS soon after exposure, even before antibodies are detect- able in blood.24,25 The diagnosis of HIV infection is made through the detection of HIV antibody using enzyme-linked immunosorbent assay and Western blot, which is usually detectable within 4 weeks of inoculation. Polymerase chain reaction–based tests measure the load of HIV-replicating

Human Immunodeficiency Virus (HIV) Dementia

virus in blood, which is useful both for testing for HIV before seroconversion and as quantitative estimate of viral load. CD4 lymphocyte count is used to stage HIV infection.

25.3 Neuropathology

In AIDS autopsy cases, HIV encephalitis (HIVE) is the productive infection of the CNS by the HIV virus and affects predominantly the white matter, basal ganglia, and brainstem and is identified in 20 to 26% in AIDS autopsy cases. Its neuropathological hall- marks are perivascular inflammation, microglial nodules, and multinucleated giant cells.26 HIVE can involve both white mat- ter (leukoencephalopathy) and gray matter (diffuse poliodys- trophy) and is characterized histopathologically by diffuse mye- lin breakdown, astrogliosis, and multinucleated giant cells with little inflammation. Frequently, individual brains show an over- lap of encephalopathy and encephalitis.27,28,29 Pathological find- ings after HAART show neuronal loss with apoptosis, astrocyto- sis, myelin pallor, and at least some activated microglia and perivascular macrophages, although the hallmarks of HIV ence- phalitis are typically absent.30,31

Immunocytochemical studies show a preponderance of HIV infection in the basal ganglia, brainstem, and deep white matter.27,32,33 Initial infection occurs in the deep brain regions from perivascular trafficking of monocytes and macrophages. HIV gains access to the CNS from the bloodstream. Circulating monocytes carry the virus across the blood-brain barrier. HIV- infected and -activated monocytes differentiate into HIV-infected and -activated macrophages and microglia. These activated cells release several potent neurotoxins, including viral gene products, such as transactivating protein of transcription (tat) and viral envelope glycoprotein gp120, and induce secretion of proinflam- matory cytokines. These toxic substances induce glutamate- induced excitotoxicity and mitochondrial dysfunction, which lead to the final stage of neuronal damage, consisting of neuronal apoptosis.5,18,34,35 The infected astrocytes, macrophages, and microglia cells serve as lifelong hosts for HIV, which causes accel- erated neurodegeneration and decreased synaptic function.5

Increased numbers of activated macrophages and activated astrocyte and macrophage-derived products most strongly correlate with dementia severity.36 The development and worsening of HAND are associated with the inflammatory response, possibly independently of viral replication.18,30,37,38,39 The severity of HAND pathology includes loss of both synaptic connections and neuronal differentiation.20 The density of apo- ptotic astrocytes and HIV-DNA-containing astrocytes correlates with rapid progression of dementia. HIV promotes neuronal apoptosis more prominently in children.40,41

25.4 Neuroimaging

Computed tomography (CT) usually demonstrates cerebral atrophy. Magnetic resonance imaging (MRI) has been shown to be a sensitive diagnostic tool in the investigation and manage- ment of HIV-related CNS disorders, not only HIVE but also opportunistic infections. T2-weighted and fluid-attenuated inversion recovery (FLAIR) images show patchy or diffuse peri- ventricular white matter ill-defined hyperintensities, with rela- tive sparing of the subcortical white matter and posterior fossa structures. There is no mass effect or contrast enhancement.42 Another typical finding is cerebral atrophy with enlarged cere- bral sulci and lateral ventricles. The degree of cerebral atrophy as quantified by MRI is correlated with the severity of demen- tia.43 In some cases, brainstem, basal ganglia, and corpus callo- sum are involved with minimal edema and mass effect, which may represent the presence of HIV. During the course of infec- tion in patients with HAND, MRI shows high signal patchy or diffuse changes in white matter.44,45 There is a significant corre- lation between MRI changes and cognitive impairment in HIV infection.24 The presence and progression of hyperintensity on T2-weighted MRI reflecting cerebral infection with HIV are significantly related to impaired immune state as measured by CD4 + cell count.24

Diffusion-weighted imaging (DWI) demonstrates high signal with increased apparent diffusion coefficient (ADC), which rep- resents T2 shine through (▶ Fig. 25.1). Diffusion tensor imaging

Fig. 25.1 Human immunodeficiency virus encephalopathy. A 45-year-old man presented with forgetfulness, memory problems, and behavioral changes 1 year after antiretroviral treatment. (a) Fluid-attenuated inversion recovery image demonstrates diffuse symmetric hyperintensity in the periventricular and deep white matter (b,c) Diffusion-weighted image shows no restricted diffusion in the areas associated with increased apparent diffusion coefficient.

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Infection and Inflammatory Conditions Associated with Dementia

Fig. 25.2 Human immunodeficiency virus encephalopathy. A 49-year-old woman presented with memory problems and behavioral changes, and dementia. (a) T2-weighted image demonstrates white matter hyperintensity
with ventriculomegaly and diffuse brain atrophy. (b) Magnetic resonance spectroscopy shows decreased N-acetyl aspartate (NAA) and increased choline and myoinositol (Minos) in the white matter abnormality.

Fig. 25.3 Progressive multifocal leukoencephal- opathy. A 42-year-old man had confusion and mental decline with human immunodeficiency virus (HIV) for 12 years. (a) Fluid-attenuated inversion recovery image shows asymmetric multiple hyperintensity lesions in the white matter extending into the U fibers. (b) Diffusion- weighted imaging demonstrates a core of increased diffusion surrounded by an area of relatively reduced diffusion consistent with progressive multifocal leukoencephalopathy.

228

(DTI)-derived variables, such as fractional anisotropy and ADC, are correlated with neuropathologic changes, dementia sever- ity, and motor-speed losses in studies of HIV-associated cogni- tive impairment.46,47,48 However, DTI may be not helpful in identifying patients with early HIV infection.49

Proton magnetic resonance spectroscopy (1H-MRS) provides a sensitive and noninvasive in vivo method to detect inflamma- tory and neuronal changes in the brain. 1H-MRS abnormalities have been reported in all stages of HIV patients, including reduced levels in the ratio of N-acetyl aspartate (NAA, a marker of neuronal integrity) to creatine (NAA/Cr), and elevations in the choline (Cho, a marker of cell membrane damage) to creatine (Cho/Cr), and myoinositol (mI, a glial cell marker) to creatine (mI:Cr) metabolic ratios (▶ Fig. 25.2).50–61 MRS changes are correlated with the severity of dementia in HIV patients. MRS is useful for evaluation of antiretroviral treatment effects.

Patients with HIV have a small but definite increased inci- dence of stroke (6 to 12%) mainly due to opportunistic varicella zoster virus infection or HIV vasculopathy.62 HIV vasculopathy was found in 5.5% of an autopsy cohort with HIV-infected patients.63 MRI with DWI is useful to detect infarctions. HIV infection is associated with many other opportunistic CNS infections, including viral infections (▶ Fig. 25.3, ▶ Fig. 25.4) as well as bacterial, fungal, and parasitic infections. Multiple

coexistent CNS infections sometimes make the interpretation of MRI findings complicated. HAART can result in clinical deterio- ration by a paradoxical activation of an inflammatory response known as immune reconstitution inflammatory syndrome (IRIS),63,64,65,66 which can be responsive to steroid therapy.

The most common abnormalities of congenital HIV CNS infection are brain atrophy and white matter disease (▶Fig. 25.5).67,68 Intracranial calcifications can be detected in 33% of HIV-infected children, which is usually not seen before 10 months of age. HIV-associated vasculitis is most commonly seen in pediatric HIV patients. An annual risk of cerebrovascular accident in HIV-positive children is 1.3%.69

25.5 Therapy

The cornerstone of treatment of HAND is HAART. The introduc- tion of aggressive treatment with HAART has been shown to improve immune recovery, delay progression to AIDS, and reduce mortality among HIV-infected patients.4,5,70 With mil- lions of replicative cycles occurring daily and a high error rate in RNA transcription of HIV, drug-resistant variants remain in the CNS unless HIV replication is suppressed completely. HIV- infected patients must continue treatment with antiretroviral therapy for their entire lives because the virus reemerges

able CNS pharmacokinetics. CNS penetration effectiveness index ranks ART regimens according to how effectively they penetrate the CNS.4,72 Drug availability, drug-drug interactions, and comorbidities are other factors to determine the ART regi- mens. Adjuvant therapy to improve cognitive function has been investigated, including paroxetine, fluconazole, and rivastig- mine.4

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Fig. 25.4 Varicella zoster virus meningoencephalitis. A 44-year-old man had altered mental status with advanced acquired immunodefficiency syndrome (AIDS). (a) Fluid-attenuated inversion recovery image shows multiple periventricular curvilinear and white matter round hyperintensity lesions. (b) Postcontrast T1-weighted image demonstrates minimal enhancement in these lesions. (c) Diffusion-weighted imaging reveals restricted diffusion in these lesions.

Fig. 25.5 Congenital human immunodeficiency virus infection in a 9- year-old boy. T2-weighted image demonstrates characteristic white matter hyperintensity with diffuse brain atrophy consistent with human immunodeficiency virus encephalopathy.

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26 Non-Human Immunodeficiency Virus (HIV) Infectious Dementia

Krishan K. Jain, Jitendra K. Saini, and Rakesh K. Gupta

Dementia is characterized by loss of cognitive abilities, decline in memory encoding and retrieval, and impairment of normal executive function in decision making, which interfere with an individual’s activities of daily living.1,2 Dementia disorders usually affect elderly individuals but may affect individuals younger than 65 years.2 In elderly patients, primary dementias like Alzheimer’s disease constitute the most common cause of memory impairments and cognitive deficits.3 Early onset and rapidly progressive dementias (RPDs) include a diverse range of conditions, from reversible to intransigent and rapidly progres- sive.1 Reversible dementias account for approximately 1.5% of all dementias.4 Depression, vitamin B12 deficiency, and hypo- thyroidism are the commonly listed reversible causes of dementia.3 Central nervous system (CNS) infections can some- times manifest with memory impairment that clinically mimics primary dementias.3 Infection represents an infrequent but important cause of RPD, as timely identification and appropri- ate treatment may produce a favorable outcome in selected instances.5 This chapter reviews neuroimaging, with an empha- sis on magnetic resonance imaging (MRI), in dementias related to infectious causes, excluding acquired immunodeficiency syndrome (AIDS)/human immunodeficiency virus (HIV) and prion disease.

26.1 Viral Infections 26.1.1 Herpes Virus Infections

Herpes simplex virus type 1 (HSV-1) remains the most common identifiable cause of acute viral encephalitis.6,7 Patients with herpes simplex encephalitis (HSE) have fever, headache, sei- zures, focal neurologic signs, impaired consciousness, and altered mental status.8 Loss of memory is frequently prominent,

along with behavioral disturbances and personality changes.6 Hokkanen et al reported findings of subcortical cognitive impairment, along with mood changes and behavioral dis- inhibition in patients with herpes zoster encephalitis (HZE).9 On MRI, HSE lesions are hyperintense on T2-weighted images and hypointense on T1-weighted imaging, predominantly involving bilateral inferior and medial aspects of the temporal lobes, and could be seen extending up to the insula. Unilateral temporal lobe involvement is also not uncommon.7,10,11 Diffu- sion-weighted imaging (DWI) is more sensitive than conven- tional T2-weighted imaging or f luid-attenuated inversion recovery (FLAIR) imaging for early detection of HSE.7,11 With progression of disease, gyriform enhancement may be observed.11 Few other rare conditions can also involve bilateral temporal lobes in similar fashion to paraneoplastic limbic ence- phalitis, Japanese encephalitis (JE), and neurosyphilis.7 In chronic cases, cerebral atrophy (▶ Fig. 26.1) is seen, along with neurologic sequelae manifesting as anterograde memory loss, anosmia, and dysphasia.11,12 Early diagnosis is critical so that acyclovir therapy can be started to improve the cognitive out- come and reduce mortality rates.13

26.1.2 Nonherpetic Viruses

Much less is known about non-HSV encephalitides, in which both mild and severe cognitive defects have been observed.14 In North America, West Nile virus (WNV) has become the most important cause of epidemic viral encephalitis. Polyomaviruses, including JC and BK viruses, frequently manifest progressive multifocal neurologic deficits or meningoencephalitis, but these do cause RPD in the immunocompromised population.15 JE is rare in Western countries; however, its neurologic, cogni- tive, and psychiatric sequelae constitute a major public health

Fig. 26.1 A 35-year-old man with chronic herpetic encephalitis with memory loss. Increased signal intensity in bilateral medial temporal lobes on axial T2-weighted (a), coronal T2-weighted (b), and axial fluid-attenuated inversion recovery (FLAIR) (c) images with features of cerebral atrophy and no focus of abnormal susceptibility on gradient image (d).

Non-Human Immunodeficiency Virus (HIV) Infectious Dementia

problem in several countries in east, southeast, and south Asia, where it is endemic.16,17 Imaging studies may be normal or may reveal T2 hyperintense signal in regions of the brain infected by the virus. Distributions of signal change can suggest specific viruses. Involvement of the thalamus or basal ganglia frequently occurs with eastern equine encephalitis, JE, and WNV.5,17

Subacute Sclerosing Panencephalitis

Viral encephalitis is sometimes insidious, manifesting with more gradual behavioral and mental status changes.15 Sub- acute sclerosing panencephalitis (SSPE) is an example of chronic viral encephalitis leading to dementia.18 It is a rare progressive neurologic disorder usually occurring in child- hood and adolescence, caused by persistent defective measles virus. Diagnosis is achieved by typical clinical findings, increased measles antibody titer in cerebrospinal fluid (CSF) and serum, and characteristic waveform in electroencepha- lography.19,20 Early-stage conventional MRI reveals no abnor- malities, but widespread periventricular hyperintensities are noted on T2-weighted imaging in late stage (▶ Fig. 26.2).20 It can be rapidly progressive, and diffuse cortical atrophy may be seen in relatively advanced cases.21 Diffusion tensor imag- ing can detect early white matter damage, even when con- ventional MRI reveals no abnormalities.22

26.2 Bacterial Infections 26.2.1 Bacterial Meningitis

Meningitis is inflammation of the dura, the leptomeninges, and the adjacent subarachnoid space. Signs and symptoms include headache, fever, neck stiffness, photophobia, vomiting, and altered consciousness. The diagnosis is usually based on a com- bination of clinical signs and symptoms along with appropriate CSF findings.7,23 Survivors of bacterial meningitis often com- plain about neurologic and neuropsychological consequences. The pattern of neuropsychological impairment resembles fea- tures observed in subcortical cognitive impairment.24 The role of imaging is primarily to confirm suspected meningitis, to

evaluate for potential complications, to rule out meningitis mimics, and to increase intracranial pressure before lumbar puncture.25

26.2.2 Spirochetes Neurosyphilis

Syphilis is a sexually transmitted disease caused by a spiro- chete, Treponema pallidum, and it can affect most organs.26 CNS involvement occurs in 5 to 30% of syphilis patients.27 Sympto- matic neurosyphilis can be divided into early and late forms. Early neurosyphilis manifests as meningitis and meningovascu- lar disease or stroke, whereas late neurosyphilis involves the meninges and brain or spinal cord parenchyma and manifests clinically as tabes dorsalis and general paresis.28,29 General paresis usually develops between 10 and 25 years after original infection; the invading spirochetes progressively destruct the neurons, resulting in impairments in memory, intellect, affect, and judgment.5,30 Imaging features are as varied as the clinical manifestations. Imaging studies may be normal in a large number of patients. Cortical cerebral atrophy is the most commonly reported finding.26,27,31 Russouw et al demonstrated correlation between atrophy and cognitive impairment, as well as between frontal lesions and overall psychiatric morbidity.32 Other radiologic findings in the general paresis stage include mesiotemporal signal changes (▶ Fig. 26.3) and hydrocephalus. Periventricular white matter changes with ventricular promi- nence can mimic the imaging features of normal pressure hydrocephalus.5,33

Lyme Disease (Neuroborreliosis)

Lyme disease is a multisystem illness caused by spirochete Bor- relia burgdorferi. CNS manifestations are rare.1,34 Lyme disease can appear as RPD and is often accompanied by cranial nerve palsies, meningitis, polyradiculopathy, depression, or psycho- sis.15 MRI abnormalities are seen in fewer than half of the patients. Foci of high T2 signal may be visualized in the cerebral white matter and brainstem.7 These lesions may mimic a demyelinating process. Other nonspecific MRI findings include

Fig. 26.2 A 9-year-old child with subacute sclerosing panencephalitis with cognitive decline and myoclonic jerks. Axial fluid-attenuated inversion recovery (FLAIR) images (a,b) showing subtle signal abnormalities In temporal and periventricular white matter. Diagnosis was confirmed with presence of measles antibody titer in cerebrospinal fluid and characteristic waveform on electroencephalography.

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Fig. 26.3 Imaging findings in patients with neurosyphilis whose initial symptoms were memory impairment and cognitive deficits. Increased signal intensity in bilateral medial temporal lobes on axial T2-weighted images (a), axial fluid-attenuated image recovery (FLAIR) (b), and coronal T2- weighted (c) images and low signal on axial T1-weighted image (d). Post-contrast T1-weighted image (e) shows no enhancement of the temporal lesions. Axial FLAIR image (f) of another patient shows a similar pattern of medial temporal lobe signal changes.

focal or diffuse leptomeningeal enhancement involving the cra- nial nerves, surface of the spinal cord, cauda equina, and spinal nerve roots.35,36

26.2.3 Central Nervous System

Tuberculosis

Tuberculosis of the CNS is commonly caused by Mycobacterium tuberculosis and constitutes 1% of all tuberculosis cases and 10% to 15% of extrapulmonary tuberculosis cases.37 Sundar et al, in their series of 76 patients younger than 65 years of age, found that 26 of 76 (34.21%) had a reversible cause of dementia with infection present in 11 of those patients. Of these 11 patients, 5had CNS tuberculosis.38 In two separate case reports, CNS tuberculosis and disseminated tuberculosis were identified as the cause of dementia.3,39 In a recently published study on tubercular meningitis, at the end of 1 year, neurologic sequelae were observed in 78.5% of patients: cognitive impairment in

55%, motor deficit in 40%, optic atrophy in 37%, and other cra- nial nerve palsy in 23%.40

Infection of the CNS manifests either in diffuse form as leptomeningitis or in localized parenchymal involvement as tuberculoma, abscess, and focal cerebritis. Tubercular menin- gitis is the most common of this type of infection, with a predilection for the meninges covering the base of the brain. The common imaging triad comprises thick enhancement in the basal cisterns, hydrocephalus (▶Fig. 26.4), and infarc- tions.7 Diagnosis is usually established via demonstration of acid-fast bacilli on smear or culture of CSF.5 CNS tubercu- lomas are commonly seen near the corticomedullary junction or in the periventricular location. The imaging appearance depends on the pathological stage of the granu- loma.41,42 A cellular component of tuberculomas will show an increased signal on T1-weighted imaging, and a greater num- ber of parenchymal lesions can be seen on magnetization transfer sequence compared with conventional spin-echo sequences.43

Non-Human Immunodeficiency Virus (HIV) Infectious Dementia

Fig. 26.4 Tubercular meningitis with cognitive decline. Axial T1-weighted (a) and T2-weighted (b) images show isointense to hyperintense lesions in the effaced basal cisterns with mild ventricular dilatation. Post-contrast T1-weighted image (c) shows enhancement of the exudates along basal cisterns and left sylvian fissure along with few ring-enhancing lesions.

26.2.4 Other Bacterial Infections

Bartonella henselae is a gram-negative bacteria that is the causative agent of cat scratch disease. Neurologic manifesta- tions are rare, usually acute encephalitis. Sometimes RPD is seen, especially in immunocompromised persons.5,15,44 Struc- tural imaging studies in Bartonella encephalitis may be normal, or it may reveal focal diffusion or T2 abnormalities.5 Infection with M. pneumoniae and neoaurum has been related to a num- ber of neurologic syndromes, including RPD. Neuroimaging can be normal or abnormal in patients with M. pneumoniae encephalitis. Multiple regions can be affected, including the thalamus, striatum, subcortical white matter, brainstem, and cerebellum.15,45,46

Whipple disease is a rare bacterial infection caused by gram- positive, acid-fast negative and periodic acid Schiff–positive bacillus Tropheryma whippelii. It often begins as a mal- absorption syndrome, but 5% of cases begin as a neurologic syn- drome with dementia, movement disorder, or psychiatric signs. Imaging with computed tomography or MRI may reveal focal areas of signal change.47

26.3 Parasitic Infections 26.3.1 Neurocysticercosis

Globally, neurocysticercosis (NCC) is one of the most common CNS parasitic infections; it is caused by the larvae of Taenia solium.42,48 Cognitive decline related to NCC is poorly character- ized and underdiagnosed. It should be considered one of the differential diagnoses in cases of dementia, especially in endemic areas.49 Brain parenchyma is the most commonly involved location in patients with NCC. On the basis of imaging and histopathology, four stages of NCC have been described, and these are grouped as vesicular or cystic, necrotic colloidal, granular nodular, and fibrocalcified stage.50 Imaging findings

vary with the stage of cyst development. Vesicular stage is typi- fied by a smooth, thin-walled T2 hyperintense cyst with small eccentric mural nodules. In the colloidal vesicular stage, cyst degeneration with pericystic edema and cyst wall enhance- ment is present.7,51 In the granular nodular stage, lesions shrink in size, cyst wall thickens, and scolex may become mineralized; edema and enhancement are persistent. In the nodular calcified stage, small calcified nodules without mass effect and enhance- ment are seen (▶ Fig. 26.5).7,42 Susceptibility-weighted imaging can demonstrate scolex in fully calcified lesions. Volumetric T2-weighted images are valuable in the demonstration of scolex in a cysticercal cyst.52,53

In around 10 to 15% of affected individuals, the parasitic cysts are located in the subarachnoid spaces and have a multilocu- lated appearance. The scolex is rarely visible in this condition.54 In large parenchymal and subarachnoid cysticercal cysts, mag- netic resonance spectroscopy shows the presence of succinate, acetate, and lactate, along with amino acids, and may help establish the diagnosis when the scolex is not demonstrable on MRI.55

26.3.2 Other Parasitic Infections

Two parasitic infections, trypanosomiasis and malaria, must be considered as the cause of RPD in returning travelers or in those who are living in endemic areas, like tropical African regions.5,15 Infection with Trypanosoma spp. causes sleeping sickness with profound neurologic consequences. Alterations in the sleep/wake cycle with progressive mental deterioration can be mistaken for neurodegenerative causes of RPD.56 Malaria infection caused by Plasmodia falciparum typically manifests with relapsing fevers and other systemic signs, but it sometimes leads to cerebral involvement. Acute losses of consciousness or convulsions are typical features of cerebral malaria. RPD is another manifestation, usually accompanied by other signs of organ involvement, including anemia, jaundice, and severe hyperpyrexia15,57,58

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Fig. 26.5 Imaging findings in a follow-up case of neurocysticercosis involving a 40-year-old man with neuropsychiatric manifestations and decreased cognitive abilities. Axial T2-weighted, fluid-attenuated inversion recovery (FLAIR), T1-weighted, and gradient images (a–d) show multiple small hypointense calcified lesions in both cerebral hemispheres with features of diffuse cerebral atrophy. A few of these lesions show minimal peripheral enhancement on post-contrast T1-weighted image (e).

Cerebral toxoplasmosis occurs primarily in immunodeficient patients, although there are rare case reports of dementia caused by Toxoplasma infection in immunocompetent individu- als.59,60 On imaging, the most common finding is single or multiple ring-enhancing lesions, some with a characteristic ‘‘eccentric target’’ appearance.61

26.4 Fungal Infections

26.4.1 Central Nervous System

Cryptococcosis

Cryptococcus neoformans infection may occur in immu- nocompetent individuals but is much more common in immunocompromised patients.7,62,63 Most patients with CNS cryptococcosis have clinical features of subacute meningitis or meningoencephalitis; however, rapidly progressive neurologic dysfunction and altered mental status may be the initial

manifestation.15,63,64 Some reports describe C. neoformans as causing rapidly progressive cognitive dysfunction, and in one case it was misdiagnosed as Alzheimer’s disease.65 Sometimes CNS cryptococcosis may initially be seen with cognitive or behavioral symptoms.66,67,68

Infection of the CNS can be either meningeal or parenchymal. Meningeal infection spreads along the base of the skull and may involve the adjacent brain parenchyma, giving rise to cryp- tococcomas, or it may extend along the perivascular spaces, which become dilated to form pseudocysts. These pseudocysts show CSF intensity on both T1- and T2-weighted imaging, which fails to enhance. Demonstration of clusters of these cysts in the basal ganglia and thalami strongly suggests cryptococcal infection.7,62,63,69 Cryptococcomas are usually seen as solid nod- ules and show hypointense signal on T1-weighted imaging and hyperintense signal on T2-weighted imaging. On DWI, crypto- coccoma will show hypointensity in the central cavity and mimic a necrotic brain tumor.63,70

Non-Human Immunodeficiency Virus (HIV) Infectious Dementia

26.5 Conclusion

Infections of the CNS should be included in the differential diag- nosis of primary dementia, especially in the presence of other clinical features related to infection. Both the clinician and radi- ologist alike should be open to the possibility of alternate diag- noses in the setting of rapidly progressive presenile dementias, particularly because several diseases within this group benefit from urgent and specific treatment. Neuroimaging can play an important role in cases with suspicion of infectious dementia because, with the help of certain imaging features, diagnosis of CNS infection can be established noninvasively, at least in a good number of cases.

26.6 References

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[29] Zetola NM, Engelman J, Jensen TP, Klausner JD. Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection. Mayo Clin Proc 2007; 82: 1091–1102

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[32] Russouw HG, Roberts MC, Emsley RA, Truter R. Psychiatric manifestations and magnetic resonance imaging in HIV-negative neurosyphilis. Biol Psychia- try 1997; 41: 467–473

[33] Fadil H, Gonzalez-Toledo E, Kelley BJ, Kelley RE. Neuroimaging findings in neurosyphilis. J Neuroimaging 2006; 16: 286–289

[34] Fernandez RE, Rothberg M, Ferencz G, Wujack D. Lyme disease of the CNS: MR imaging findings in 14 cases. AJNR Am J Neuroradiol 1990; 11: 479–481

[35] Vanzieleghem B, Lemmerling M, Carton D et al. Lyme disease in a child presenting with bilateral facial nerve palsy: MRI findings and review of the literature. Neuroradiology 1998; 40: 739–742

[36] Hattingen E, Weidauer S, Kieslich M, Boda V, Zanella FE. MR imaging in neu- roborreliosis of the cervical spinal cord. Eur Radiol 2004; 14: 2072–2075
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as rapidly progressive dementia. QJM 2014
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tuberculous meningitis: a multivariate analysis. Eur J Neurol 2007; 14: 33–37 [41] Trivedi R, Saksena S, Gupta RK. Magnetic resonance imaging in central ner-

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Clinical review of 52 cases: the SNFMI Research Group on Whipple Disease. Société Nationale Française de Médecine Interne. Medicine (Baltimore) 1997; 76: 170–184

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Part IX Normal Pressure Hydrocephalus

29 Normal Pressure Hydrocephalus 256

256

Normal Pressure Hydrocephalus

29 Normal Pressure Hydrocephalus

Ritu Shah, Fathima Fijula Palot Manzil, and Surjith Vattoth

Normal pressure hydrocephalus (NPH) is a syndrome character- ized by ventricular enlargement and a classic clinical triad of gait disturbance, urinary incontinence, and dementia. The con- dition is also sometimes described as idiopathic adult hydro- cephalus syndrome, emphasizing the fact that the intracranial pressure in NPH is not always normal. When not otherwise specified, the term NPH usually refers to the idiopathic condi- tion and contrasts with the symptomatic or secondary forms of hydrocephalus, which may develop in a setting of trauma, hemorrhage, mass lesions, infection, or aqueductal stenosis. A prompt and accurate diagnosis of NPH is critical in the treat- ment of these patients because it is one of the few causes of dementia that is potentially reversible.

29.1 Epidemiology

The incidence of NPH has been estimated in population studies to be about 5.5 per 100,000 persons in the general population or up to 1.4 to 1.5% of elderly adults. The prevalence is 21.9 per 100,000 in the general population and increases with age, rising from 3.3 per 100,000 in the age group 50 to 59 years, to 181.7 per 100,000 at 70 to 79 years of age.

29.2 Clinical Features 29.2.1 Gait Disturbance

The gait in NPH is often described as “shuffling,” “wide-based,” or “magnetic.” In the classic “magnetic apraxia” of gait, the patient has difficulty with initiation and changes in trajectory of gait and appears to be literally “stuck” to the floor. The degree of severity of magnetic apraxia can vary, with some patients only having subtle findings, particularly on turns or transfers, whereas others may be so severe that they cannot even obtain the upright position. Many patients show dis- equilibrium and slowness of gait because of short steps and gait apraxia or slowness of both the upper and lower extremities, which can improve with shunting. Appendicular tremor is seen in in 40% patients with NPH and usually does not respond to shunting.1

29.2.2 Urinary Incontinence

Most patients have urinary frequency, urgency, or frank incontinence resulting from detrusor overactivity. In a study on 42 patients with probable NPH,2 lower urinary tract symptoms were seen in 93% of the patients, with storage symptoms (93%) more common than voiding symptoms (71%). Urinary urgency (overactive bladder)/frequency (64%) is seen more frequently than urinary incontinence (57%).

29.2.3 Dementia

The dementia of NPH is characterized by subcortical cognitive deficits, involving psychomotor slowing, impaired recall, and

impaired executive functions. These deficits are often mistaken for the consequence of old age. There is a gradual decline in active retrieval from memory (immediate and delayed recall) with relatively preserved memory storage (recognition). Fur- thermore, there is a decline in executive functions and complex information processing. Sometimes deficits in visuospatial per- ception and visual construction skills are noted.3 Whereas most patients show improvement with shunting, some patients may have persistent global cognitive deficits, which often correlate with the presence of vascular risk factors.

29.3 Challenges in Diagnosis

The diagnosis of NPH requires careful exclusion of other causes of dementia, which can manifest with overlapping signs and symptoms.4 The presence of an asymmetric resting tremor, lead-pipe rigidity, or visual hallucinations may suggest demen- tia with Lewy bodies, which causes similar cognitive deficits. Depression with pseudodementia is in the differential diagnosis as well. Early presence of cortical deficits such as aphasia, apraxia, or agnosia, should raise suspicion for dementia with cortical pathology, such as Alzheimer’s disease, multi-infarct dementia, or frontotemporal dementia. In patients with pro- gressive dementia who have a normal gait, causes other than NPH should be carefully evaluated.

Some patients with NPH can also have Alzheimer’s disease as a comorbidity; both conditions are associated with hyper- tension and advanced age. Although shunting can result in improvement in gait disturbances in patients with NPH, the procedure needs careful evaluation for risks and benefits in patients with advanced dementia.

29.4 Neuroimaging

Imaging of the brain is an essential component of the evaluation when the diagnosis of NPH is considered. Magnetic resonance imaging (MRI) of the brain is the preferred radiologic examina- tion for the diagnosis of NPH, although computed tomography (CT) scanning is useful if MRI is unavailable. Both radiologic techniques require clinical correlation.

29.4.1 Ventriculomegaly

Hydrocephalus is a key finding on CT or MRI scans, where ven- triculomegaly is disproportionate to the severity of sulcal atro- phy. This “ventriculosulcal disproportion” helps differentiate NPH from ex vacuo ventriculomegly. In NPH, ventriculomegaly is prominent in all three horns of the lateral ventricles and in the third ventricle with relative sparing of the fourth ventricle (▶ Fig. 29.1).5 On MRI, the temporal horns of the lateral ventri- cles may show dilatation out of proportion to hippocampal atrophy (▶ Fig. 29.2). Evan’s index (maximal ventricular width divided by the largest biparietal distance between the inner tables of the skull) of 0.3 or greater is one criterion for probable NPH (▶ Fig. 29.3).

Normal Pressure Hydrocephalus

Fig. 29.1 Coronal reformatted computed tomography scan shows dilatation of the third and lateral ventricles out of proportion to sulcal atrophy (ventriculosulcal disproportion). Also note bilateral sylvian fissure dilatation (arrows) seen in normal pressure hydrocephalus.

Fig. 29.2 Coronal T1-weighted magnetic resonance imaging through the hippocampi shows dilatation of temporal horns of the lateral ventricles out of proportion to hippocampal atrophy.

Fig. 29.3 Axial postcontrast T1-weighted image showing an Evan’s index greater than 0.3, a criterion for probable normal pressure hydrocephalus. Evan’s index is calculated by dividing the maximal width of frontal horns (a) by the largest biparietal distance between the inner tables of the skull (b).

Fig. 29.4 Axial fluid-attenuated inversion recovery (FLAIR) image shows bilateral anterior and posterior periventricular hyperintensities indicative of transependymal edema resulting from elevated cerebro- spinal fluid pressures.

inversion recovery (FLAIR) hyperintensities on MRI indicative of transependymal edema resulting from elevated cerebrospinal fluid (CSF) pressures (▶Fig. 29.4).5,6 However, periventricular leukoencephalopathy of microangiopathic disease can also pro- duce an identical appearance.

29.4.2 Periventricular White Matter

Changes

Some patients may show frontal and occipital periventricular hypoattenuating areas on CT or contiguous T2/fluid-attenuated

257

258

Normal Pressure Hydrocephalus

Fig. 29.5 Axial T2-weighted magnetic resonance imaging through the midbrain shows a hypointense cerebrospinal fluid flow void in the cerebral aqueduct (arrow).

Fig. 29.6 Sagittal T1-weighted magnetic resonance imaging shows upward bowing and thinning of the corpus callosum (vertical arrow) with large lateral ventricles (horizontal arrow). Note that the fourth ventricle is relatively normal (arrowhead).

Cerebrospinal Fluid Flow Void Sign

The presence of a flow void at the aqueduct on axial T1- and T2-weighted images in patients with NPH has been termed the CSF flow void sign (▶Fig. 29.5). Studies have shown conflicting results in the usefulness of this sign in predicting shunt-respon- sive NPH. Bradley et al7 investigated the predictive value of CSF voids for shunt responsiveness and found a significant correla- tion; but in a later study,8 they did not find a statistically signif- icant relationship between responsiveness to CSF shunting and aqueductal flow void score.

Corpus Callosal Thinning

Corpus callosal thinning is seen as upward bowing of the corpus callosum on sagittal T1-weighted images (▶ Fig. 29.6).9 The callosal angle on coronal MRI of the posterior commissure perpendicular to the anteroposterior commissure plane may also have some diagnostic significance, although it is not accepted as a reliable criterion.10 The callosal angle was signifi- cantly smaller in NPH (mean ± standard deviation, 66 ± 14 degrees) (▶Fig. 29.7) than in Alzheimer’s disease (104 ± 15 degrees) and normal controls (112 ± 11 degrees) (▶ Fig. 29.8). Using a threshold of 90 degrees, an accuracy of 93%, a sensitiv- ity of 97%, and a specificity of 88% were observed for discrimi- nation of NPH from Alzheimer’s disease.

Cingulate Sulcus Sign

Adachi et al11 noted that on paramedian sagittal images, the cingulate sulcus appeared to be narrow and tight posteriorly in patients with NPH (▶ Fig. 29.9). The cingulate sign was seen in all 10 NPH patients in their series, but never in Alzheimer’s dis- ease or progressive supranuclear palsy (PSP), which had similar

appearance of the anterior and posterior aspects of the cingu- late sulcus (▶ Fig. 29.10).

29.4.3 Brainstem Changes

Normal pressure hydrocephalus may be associated with the “upper midbrain profile sign”; Adachi et al11 recorded this abnormality in 7 of 10 patients with NPH compared with 5 of

Fig. 29.7 Coronal T1-weighted imaging through the corpus callosum at the level of the posterior commissure, obtained perpendicular to the anterior commissure-posterior commissure. Line shows a relatively narrow callosal angle in a patient with NPH.

Normal Pressure Hydrocephalus

Fig. 29.8 (a) Sagittal T1-weighted magnetic res- onance imaging shows the plane of coronal image acquisition to calculate the callosal angle at the level of posterior commissure (vertical dotted line), which is perpendicular to the anterior commissure-posterior commissure line (horizon- tal dotted line). (b) Coronal T1-weighted magnetic resonance image obtained as shown in (a) demonstrates the wider normal callosal angle in a control subject.

Fig. 29.9 Parasagittal section of a sagittal T1-weighted magnetic resonance imaging sequence shows that the cingulate sulcus is narrow and tight posteriorly in a patient with normal pressure hydrocephalus (arrowheads), the so-called cingulate sulcus sign. Compare this with the normal-appearing cingulate sulcus in ▶ Fig. 29.10.

Fig. 29.10 Parasagittal section of a sagittal T1 weighted magnetic resonance imaging sequence shows the normal appearance of the posterior aspect of the cingulate sulcus somewhat similar to its anterior aspect (arrows) in a patient with progressive supranuclear palsy. Normal subjects also show the same pattern.

11 with Alzheimer’s disease and 3 of 5 with PSP. The upper midbrain profile sign was an abnormal appearance of the supe- rior profile of the midbrain on the midsagittal T1-weighted images.12 The profile was considered normal when it was con- vex, as represented by an imaginary curve connecting a point immediately posterior to the mammillary body and one located at the upper orifice of the aqueduct. The profile was considered abnormal when it was flat or concave, as identified by using the same imaginary line or curve (▶Fig. 29.11). This is also called “hummingbird” sign and is considered a characteristic sign of PSP, but it could also sometimes be seen in other conditions, as described earlier.

Cine Phase-Contrast Magnetic Resonance Quantification of Cerebrospinal Fuid Flow

Cine phase-contrast magnetic resonance quantification of CSF flow can measure the stroke volume (= mean volume of CSF passing through the cerebral aqueduct in systole – volume passing during diastole).8,13 Stroke volumes greater than 42 microliters may predict the likelihood of response to shunting.

259

Fig. 29.11 Sagittal T1-weighted magnetic resonance imaging shows flattening/concavity of the normally convex superior profile of the midbrain (arrow), also known as “hummingbird” sign” in a patient with normal pressure hydrocephalus.

Normal Pressure Hydrocephalus

Fig. 29.12 Sagittal cine phase-contrast magnetic resonance imaging (cerebrospinal fluid flow study) shows prominent bidirectional flow in the aqueduct (arrow).

260

In one study,8 18 of 42 patients were selected for ventriculo- peritoneal shunting based on results of flow studies, 12 of 12 patients with stroke volume > greater than 42 microliters improved versus 3 of 6 with stroke volumes less than 42 micro- liters. CSF stroke volume often increases after onset of symp- toms, plateaus after 18 to 20 months, and then declines. When sophisticated software for CSF flow quantification is not availa- ble, visual assessment of the CSF flow study should be carefully carried out to evaluate for prominent bidirectional flow in the aqueduct, which is seen in NPH (▶ Fig. 29.12).

In another CSF hydrodynamics study,14 14 shunt-responsive patients were compared with 6 nonresponders. Using a thresh- old mean CSF velocity through the aqueduct of greater than 26 millimeters per second as a predictor of responsiveness, the investigators found a sensitivity of 50%, specificity of 83.3%, positive predictive value of 87.5%, and accuracy of 70%.

Scollato et al15 described changes in aqueductal stroke vol- ume in 65 shunted patients with NPH who underwent clinical evaluation and stroke volume measurements 7 to 30 days before, and 1, 3, 6, and 12 months after, surgery. Aqueductal stroke volume decreased in all patients in whom the ventricu- loperitoneal shunt worked properly, and the rate of reduction in stroke volume correlated with clinical improvement. Post- operative rise in stroke volume indicated shunt malfunction. A precipitous drop of stroke volume after shunt may be the consequence of increased drainage and herald the occurrence of a subdural fluid collection.

29.4.4 Diffusion-Weighted Imaging

Diffusion-weighted imaging (DWI) can be useful in differentiat- ing NPH from subcortical leukoencephalopathy/Binswanger’s disease.16 Patients with Binswanger’s disease had higher appar- ent diffusion coefficient (ADC) values than those with NPH in

the periventricular and deep white matter in the frontal and occipital regions. After shunt surgery, ADC values were reduced in NPH in the frontal periventricular white matter. Increased diffusion in Binswanger’s disease may reflect irreversible break- down of axonal integrity caused by the subcortical ischemic vascular disease. Several investigators have evaluated changes in the ADC during the cardiac cycle.17,18,19 Patients with NPH show pronounced ADC changes over the cardiac cycle com- pared with either healthy controls and/or patients with ex vacuo ventricular dilatation, indicating altered biomechanical properties of intracranial tissues.

Demura et al18 measured regional fractional anisotropy and ADCs in several white matter regions before, and 24 hours after, a CSF tap test. ADC values were significantly decreased in the frontal periventricular region and the body of the corpus callo- sum in patients who showed improved neurologic status after the spinal tap, whereas no significant change was shown in the negative group. Fractional anisotropy values were significantly increased in the body of the corpus callosum in both responders and nonresponders. These findings indicate that changes in water dynamics in white matter may have a role in the mecha- nism causing symptoms of NPH.

Cerebral Perfusion Measurements Using by Dynamic Susceptibility-Contrast Magnetic Resonance Imaging

Dynamic susceptibility-contrast (DSC) MRI perfusion is a poten- tially useful diagnostic tool and a possible predictor of shunt response in NPH. In a recent study,20 DSC MRI was used to mea- sure absolute perfusion values in cortical, subcortical, and peri- ventricular regions and along the periventricular and paraven- tricular profiles in 21 cases of NPH and 16 age-matched healthy controls. Relative cerebral blood flow (rCBF), calculated with the occipital cortex as internal reference, was measured in the two groups. NPH was associated with decreased rCBF in the basal medial frontal cortex, hippocampus, lentiform nucleus, periventricular white matter (PVWM), central gray matter, and global parenchyma compared with controls. NPH patients with higher preoperative rCBF in the PVWM performed better in clinical tests. Shunt responders had higher rCBF in the basal medial frontal cortex than did nonresponders.

29.4.5 Nuclear Imaging Techniques

Nuclear imaging techniques, such as isotope cisternography and CT cisternography, have been used in NPH to evaluate CSF dynamics, such as reversal of flow (▶Fig. 29.13). These tests have generally not been found useful and have been replaced by other modalities.

Single-Photon Emission Computed Tomography

Single-photon emission computed tomography (SPECT) with technetium 99 m hexamethylpropyleneamine oxime (HMPAO) typically shows decreased rCBF in frontoparietal areas and the subcortical white matter. A combination of clinical assessment

with SPECT (with perfusion-weighted MRI) can be helpful in the preoperative selection of patients for shunting procedures with suspected NPH syndrome. Sasaki et al21 found decreased blood flow in frontal areas and around the corpus callosum, findings consistent with the deficits noted on clinical assess- ment. In another study, Kristensen et al22 described rCBF hypo- perfusion in the caudal frontal and temporal gray matter and the subcortical white matter. Removal of CSF was not accompa- nied by improvement in rCBF, indicating that the study might not provide additional information in preoperative evaluation. More recently,23 acetazolamide SPECT was found useful in iden- tifying patients who are unable to increase rCBF after acetazol- amide administration and, therefore, have a low capacity for vasodilation in the brain as a result of compression and stretch- ing by ventriculomegaly. In this study, an increase of less than 20% in preoperative acetazolamide SPECT predicted improve-

Normal Pressure Hydrocephalus

Fig. 29.13 (a) Normal indium-11-labeled diethylenetriamine pentaacetic acid (DTPA) cisternogram planar images obtained after injection into lumbar subarachnoid space. Images at 4 hours (top row) demonstrate radioactivity in the cervical spinal subarachnoid space, basal cisterns, and mild activity in the sylvian fissure and interhemispheric cisterns in a trident pattern. Images at 24 hours (bottom row) show normal ascent of activity over the cerebral convexities with relative clearing of the spinal canal and basal subarachnoid cisterns. Transient slight ventricular activity at 4 hours, disappearing at 24 hours, may be normal-variant flow pattern, but any major persistent ventricular activity is abnormal. (b) Indium-11-labeled DTPA cisternogram planar images obtained after injection into lumbar subarachnoid space in normal pressure hydrocephalus (NPH). Images at 4 hours (top row) demonstrate central heart-shaped radioactivity reflux into the lateral ventricles. Images at 24 hours (middle row) show some tracer ascending into the sylvian and interhemispheric fissures, with only faint visualization of convexity activity. Images at 48 hours (bottom row) also show stagnant radioactivity within the lateral ventricles and basal cisterns without normal significant concentration over the superior convexity/superior sagittal sinus, which would be expected by 24 hours in a normal case. ANT, anterior; L, left; LAT, lateral; R, right.

ment in cognitive impairment after surgery with 100% sensitiv- ity and 60% specificity.

Positron Emission Tomography

[18F]-flutemetamol PET scanning in patients with NPH may be useful in establishing the total burden of β-amyloid and, there- fore, the likely benefit (or lack thereof) of invasive surgical treatment of NPH, such as ventriculoperitoneal shunting in dementia. In one study, PET was used to measure cerebral retention of Pittsburgh compound B to localize or estimate β-amyloid accumulation in patients with NPH with cognitive impairment.24 Regional cerebral metabolic rate of glucose is a promising research tool to investigate regional disturbances in metabolism before and after ventricular shunt placement in idiopathic NPH.

261

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Normal Pressure Hydrocephalus

29.5 Management

Patients exhibiting a progressive decline in gait, ventricular enlargement disproportionate to the degree of atrophy, and in whom no other explanation of the gait disturbance is identified should be considered candidates for CSF shunting, even if they lack substantial dementia or urinary incontinence. Neverthe- less, the criteria for selecting patients for shunt placement are unclear, and to date, the “gold standard” for diagnosis remains clinical improvement with CSF shunting.

Patients with probable NPH25 are 40 years of age or older with insidious (nonacute) progression of symptoms over 3 months or longer and have CSF opening pressures of 70 to 245 mm H2O. MRI or CT must show an Evan’s index (maximal ventricular width divided by the largest biparietal distance between the inner tables of the skull) of 0.3, temporal horn enlargement, periventricular signal changes, periventricular edema, or an aqueductal/fourth ventricular flow void. Although a callosal angle of 40 degrees or greater was included in the guidelines, it is not a widely recognized criterion. Clinically, patients must demonstrate gait dysfunction plus either urinary or cognitive dysfunction. Abnormal urinary urgency or fre- quency is sufficient to document urinary bladder dysfunction. To meet the criteria for cognitive dysfunction, there must be impairments of two or more domains, such as psychomotor speed, fine motor speed or accuracy, attention, short-term recall, executive function, or behavioral or personality changes.

A spinal tap to remove 30 milliliters or more of CSF is an accepted method to establish the diagnosis of NPH and for pre- dicting the response to shunting. In some patients who do not show a significant response to a spinal tap, external lumbar drainage (ELD) can be useful in predicting the outcome of surgical intervention.26 For ELD, a spinal catheter is inserted into the lum- bar spine and CSF is drained at a rate of 10 to 15 milliliters per hour for 72 hours. The response to ELD can be assessed based on gait analysis or walking speed using a timed 10-meter walk before and after ELD. Nearly 85 to 90% patients who had a posi- tive test showed improvement in walking speed, whereas a third with a negative response to ELD improved after shunting. Overall, ELD provided sensitivity, specificity, positive predictive value, and negative predictive value of 95, 64, 90, and 78%, respectively. It is important to remember that a positive tap or ELD test has suffi- cient positive predictive value to recommend shunting, whereas those with a negative test should undergo a careful analysis of risk versus an estimated 20% chance of benefit.

Cerebrospinal fluid shunting procedures, including ventricu- loperitoneal, ventriculopleural, or ventriculoatrial shunting, can lead to significant clinical improvement in NPH symptoms in approximately 60% of patients. In a systematic review,27 data from 64 published studies on the effect of shunt procedures in idiopathic NPH were reviewed: 27 studies reported positive outcome for 1,028 of 1,446 patients 3 months after shunt; 42 studies reported positive outcome 1 year after shunt for 1,343 of 1,805 patients; 10 studies reported an improvement in 415 of 640 patients on long-term outcome (i.e., at least 3 years after the surgery). Total mortality was 1%. Common complications include subdural hemorrhage or effusion (6.3%), intracerebral hemorrhage or stroke (0.4%), infection (3%), and new-onset sei- zures (0.7%). A total of 1,401 patients had a shunt revision rate of 16% (range, 5 to 53%) as reported in 26 studies.

29.6 Conclusions

Despite major advances in clinical and diagnostic modalities, NPH remains a challenge for diagnosis and clinical manage- ment. Radiology has an important place in the diagnosis and clinical monitoring of these patients. Although the radiologic features are often not specific for NPH, a diligent and careful approach can be useful in patients with suggestive clinical signs and symptoms.

29.7 Acknowledgment

The authors thank Dr. Eva Dubowsky for providing images of the indium-11-labeled DTPA cisternogram.

References

[1] Bugalho P, Alves L, Miguel R. Gait dysfunction in Parkinson’s disease and nor- mal pressure hydrocephalus: a comparative study. J Neural Transm 2013; 120: 1201–1207

[2] Sakakibara R, Kanda T, Sekido T et al. Mechanism of bladder dysfunction in idiopathic normal pressure hydrocephalus. Neurourol Urodyn 2008; 27: 507–510

[3] Chaudhry P, Kharkar S, Heidler-Gary J et al. Characteristics and reversibility of dementia in normal pressure hydrocephalus. Behav Neurol 2007; 18: 149– 158

[4] Sorbi S, Hort J, Erkinjuntti T et al. EFNS Scientist Panel on Dementia and Cognitive Neurology. EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia. Eur J Neurol 2012; 19: 1159–1179

[5] Inatomi Y, Yonehara T, Hashimoto Y, Hirano T, Uchino M. Correlation between ventricular enlargement and white matter changes. J Neurol Sci 2008; 269: 12–17

[6] Tullberg M, Jensen C, Ekholm S, Wikkelsø C. Normal pressure hydrocephalus: vascular white matter changes on MR images must not exclude patients from shunt surgery. AJNR Am J Neuroradiol 2001; 22: 1665–1673

[7] Bradley WG, Jr, Whittemore AR, Kortman KE et al. Marked cerebrospinal fluid void: indicator of successful shunt in patients with suspected normal- pressure hydrocephalus. Radiology 1991; 178: 459–466

[8] Bradley WG, Jr, Scalzo D, Queralt J, Nitz WN, Atkinson DJ, Wong P. Normal- pressure hydrocephalus: evaluation with cerebrospinal fluid flow measure- ments at MR imaging. Radiology 1996; 198: 523–529

[9] Lee WJ, Wang SJ, Hsu LC, Lirng JF, Wu CH, Fuh JL. Brain MRI as a predictor of CSF tap test response in patients with idiopathic normal pressure hydroceph- alus. J Neurol 2010; 257: 1675–1681

[10] Ishii K, Kanda T, Harada A et al. Clinical impact of the callosal angle in the diagnosis of idiopathic normal pressure hydrocephalus. Eur Radiol 2008; 18: 2678–2683

[11] Adachi M, Kawanami T, Ohshima F, Kato T. Upper midbrain profile sign and cingulate sulcus sign: MRI findings on sagittal images in idiopathic normal- pressure hydrocephalus, Alzheimer’s disease, and progressive supranuclear palsy. Radiat Med 2006; 24: 568–572

[12] Righini A, Antonini A, De Notaris R et al. MR imaging of the superior profile of the midbrain: differential diagnosis between progressive supranuclear palsy and Parkinson’s disease. AJNR Am J Neuroradiol 2004; 25: 927–932

[13] Bradley WG. Cerebrospinal fluid dynamics and shunt responsiveness in patients with normal-pressure hydrocephalus Mayo Clinic proceedings 2002; 77: 507–508

[14] Witthiwej T, Sathira-ankul P, Chawalparit O, Chotinaiwattarakul W, Tisavipat N, Charnchaowanish P. MRI study of intracranial hydrodynamics and ventri- culoperitoneal shunt responsiveness in patient with normal pressure hydro- cephalus. J Med Assoc Thai 2012; 95: 1556–1562

[15] Scollato A, Tenenbaum R, Bahl G, Celerini M, Salani B, Di Lorenzo N. Changes in aqueductal CSF stroke volume and progression of symptoms in patients with unshunted idiopathic normal pressure hydrocephalus. AJNR Am J Neu- roradiol 2008; 29: 192–197

[16] Tullberg M, Hultin L, Ekholm S, Månsson JE, Fredman P, Wikkelsø C. White matter changes in normal pressure hydrocephalus and Binswanger’s disease: specificity, predictive value and correlations to axonal degeneration and demyelination. Acta Neurol Scand 2002; 105: 417–426

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[23] Yamada SM, Masahira N, Kawanishi Y, Fujimoto Y, Shimizu K. Preoperative acetazolamide SPECT is useful for predicting outcome of shunt operation in idiopathic normal pressure hydrocephalus patients. Clin Nucl Med 2013; 38: 671–676

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Part X

Tumor-Related Cognitive Dysfunction

30 Brain Tumors and Cognitive Dysfunction 266 31 Paraneoplastic Syndrome 276

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Tumor-Related Cognitive Dysfunction

30 Brain Tumors and Cognitive Dysfunction

Sangam G. Kanekar and Hazem Matta

Surgery, radiotherapy, and chemotherapy play important roles in the treatment of nervous system cancers (CNS) and extracerebral malignancies. These therapies have become the mainstay in treating primary or metastatic CNS and non-CNS malignancies; and with the overall improvement in survival of oncology patients, a wider spectrum of injuries involving structures of both the CNS and peripheral nervous system (PNS) are identified on routine follow-up studies. CNS neuro- toxicity of anticancer treatments has received growing inter- est in recent years among oncologists, radiologists, and other supporting staff so that treatment-induced morbidity and mortality rates can be significantly reduced with early diag- nosis and by modifying treatment regimens. Despite continu- ous improvements in cancer treatment, CNS toxicity remains an important issue.

Up to two-thirds of cancer patients experience some form of cognitive impairment during or after treatment with cancer therapy. For 35% of these patients, this deficit may persist for months or years after treatment. With more than 11 million cancer survivors in the United States, up to 3.9 million individu- als may be living with long-lasting cognitive difficulties from cancer and cancer treatments. Today various clinical as well as imaging tools are deployed to diagnose the signs and symptoms of neurotoxicity resulting from cancer therapy, so that the nec- essary dose reduction or change in the protocol may be done to avoid the long-lasting effect on the patient’s brain cells. Struc- tural and newer functional imaging techniques help in identify- ing the changes in brain volume, metabolic status, and CNS activity after treatment. Today positron emission tomography (PET) and magnetic resonance (MR), especially MR perfusion and MR spectroscopy, allow assessment of the metabolic activity and hence functioning of the brain cells. Cognitive decline and dementia resulting from intracranial tumors could be due to either direct tumor-related effects of the primary or secondary tumor or, most commonly, to treatment-related neurotoxicity.

30.1 Direct Tumor-Related

Cognitive Effects

The brain resides in the confines of the calvarium; therefore, it is susceptible to the slightest changes in pressure or volume. Symptoms depend on the histopathological characteristics of the tumor and the acuity of the disease process. For example, mass-forming tumors, such as meningiomas and metastasis, typically cause compression and mass effect and manifest with headaches and seizure,1 ultimately leading to intracranial hypertension and hydrocephalus. Alternatively, infiltrative tumors, including gliobastoma multiforme (GBM) and primary CNS lymphoma, behave more insidiously, often manifesting with slow cognitive decline despite having little or no mass effect. The extent of this cognitive impairment can be diffuse and severe, attributable to marked underestimation of paren- chymal microinvasion on current imaging techniques. The sequelae of tumor progression can involve multiple domains or

functions, depending on which neural networks are affected. Psychomotor slowness, executive dysfunction, memory impair- ment, and personality or behavior changes are the most commonly reported in infiltrative-type tumors.2

30.1.1 Cognitive Decline in Various Tumors

Meningiomas

Meningioma is one of the most commonly encountered CNS tumors, especially in the elderly population. It is a mesenchy- mal tumor, which almost always manifests as an extra-axial space-occupying mass. The vast majority of meningiomas are benign and slow growing and may manifest with seizures or focal neurologic deficits related to local brain compression. Cognitive decline as a primary clinical symptom is not uncommon and largely depends on the site and size of the meningioma. Patients with frontal meningiomas predominately show serious impairment in verbal fluency tasks and compro- mised executive functioning, found more often in left-sided meningioma. Patients with skull-base meningiomas have worse neurocognitive functioning than those with convexity meningi- omas, especially for information-processing speed and psycho- motor speed.3,4 Neuroimaging findings are classic and seen as an extra-axial intensely enhancing mass with significant com- pression of the underlying brain (▶ Fig. 30.1).

Glioblastoma Multiforme and Low-Grade Gliomas

Glioblastoma multiforme is a World Health Organization grade IV astrocytoma that is notorious for its rapid infiltration and poor prognosis. Therapy-related neurotoxicity is seldom an issue in the management of high-grade glioma patients as the mean survival is 12 to 16 months.2 Cognitive dysfunction is often the trigger for diagnostic workup and can in fact be used to predict survival.5 Parenchymal microinvasion is the key char- acteristic of this tumor that contributes to the progressive cog- nitive decline. It is challenging to estimate the entire tumor burden on routine magnetic resonance imaging (MRI), includ- ing postcontrast T1-weighted imaging (▶Fig. 30.2a,b). Today, with newer imaging techniques, such as MR spectroscopy, MR perfusion, and diffusion tensor imaging (DTI), an attempt is made to map the infiltration and extent of the tumor (▶Fig. 30.2c). A significant decline in the Mini-Mental State Examination (MMSE) scores is seen for patients with tumor progression compared with patients without tumor progres- sion. Conversely, areas of infiltrative tumors can have some pre- served function resulting from the plasticity and compensation mechanism found in the brain of tumor patients; this preserva- tion is facilitated by the slow and gradual onset of the tumor. Further decline in cognitive function is commonly seen after surgery because of the resection of the partially functional tis- sue, especially in eloquent areas.

Brain Tumors and Cognitive Dysfunction

Fig. 30.1 A 51-year-old woman with dementia and frontal lobe symptoms. (a) Axial T2 and
(b) sagittal postcontrast T1-weighted images show intensely enhancing extra-axial mass (star) causing severe compression and mass effect (arrows) on the frontal lobes bilaterally. Diffuse hyperintensity seen on T2-weighted imaging in the frontal white matter suggestive of edema (arrowhead).

Fig. 30.2 Infiltrative glioma in 64-year-old man with seizure and early symptoms of dementia. Axial (a) T2-and (b) postcontrast T1-weighted images show large necrotic mass in the right temporoparietal lobe (star) with surrounding perilesional hyperintensity (arrowheads). (c) Colored fractional anistropy map shows diffuse infiltration and disruption of the frontal and temporal lobe white matter fibers (arrows) away from the enhancing lesion.

Although low-grade gliomas are also infiltrative by nature, they have mass effect with a high incidence of focal symptoms, especially seizures. Unfortunately, controlled and uncontrolled seizures are associated with cognitive dysfunction. This effect may be further compounded by deleterious effects of surgery, radiation, and chemotherapy. Fifty percent of these patients are reported to have cognitive dysfunction in several domains, such as information-processing speed, psychomotor function, atten- tion, executive functioning, and verbal working memory.6

Metastatic Disease

The bulk of intracranial metastatic disease originates from lung carcinoma, breast cancer, and melanoma. Most patients initially have headaches nausea or vomiting, and seizures. In addition, cognitive dysfunction is common in patients with brain metas- tasis, which causes emotional difficulties, significantly decreas- ing quality of life. In a phase III study, up to 91% of 401 patients had impairment of one or more neurocognitive domains before

treatment, including memory, fine motor speed, executive function, and global neurocognitive impairment testing.7 The severity of deficit correlated with the overall tumor volume, not the number of lesions, and was predictive of survival.

Whole-brain radiation (WBRT) is the mainstay treatment, increasing median survival by 3 to 6 months.8,9 Most patients are treated with a short course of large-fraction radiation therapy (RT) (e.g., 30 Gy in 10 fractions). Large, daily RT frac- tion sizes have been reported to increase the risk of neuro- cognitive deficits. In the vast majority of patients, survival after diagnosis of brain metastasis is short, and patients do not survive long enough to develop cognitive deficits from RT. The progressive disease and large fraction size are associ- ated with higher incidence of dementia and cognitive decline. Given that the prevalence of brain metastasis far exceeds that of primary CNS tumors and prolonged life expectancy, treat- ment-related dementia poses a newly added entity that was not previously considered in the treatment of these cancer survivors.

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Tumor-Related Cognitive Dysfunction

Lymphoma

Similarly to GBM, primary CNS lymphoma is diffusely infiltra- tive; unlike other CNS tumors, however, lymphoma is poten- tially curable with possible reversibility of associated symptoms posttreatment.10 Cognitive dysfunction in primary CNS lym- phoma patients is due to multiple factors, including the effects of the tumor itself, given its infiltrative and multifocal pattern, age, and the delayed effects of WBRT and high-dose methotrex- ate-based chemotherapy (HD-MTX). Cognitive domains most likely to be impaired include attention, executive functions, memory, naming, and psychomotor speed. CNS lymphoma has a predisposition for perivascular infiltration, which may lead to a break in the blood–brain barrier, which may further potenti- ate chemotherapy (CT) and RT toxicity.10,11

30.2 Tumor Therapy-Related

Cognitive Effects

Both RT and chemotherapy are neurotoxic and cause either derangement of the cell function or cell death by various mech- anisms. Combined therapy may potentiate the effect and cause severe leukoencephalopathy and brain atrophy.

30.2.1 Radiotherapy and Dementia

Sheline12 was first to classify the RT-induced side effects according to their time of appearance after irradiation into acute disorders (days to weeks), early delayed complications (1 to 6 months), and late-delayed complications (longer than 6 months). The exact mechanisms underlying different types of RT-induced CNS effects are not clear. The mechanism of RT- induced damage to the CNS appears to be complex and likely to include a combination of vascular injury, demyelination, and neuronal damage.13 The vascular injury is thought to be partly responsible for the abnormal vasculature, thrombosis, and fibrinoid necrosis eventually leading to radiation necrosis. RT also causes cell depletion, especially oligodendrocytes, which in turn lead to demyelination and white matter necrosis. Other cells, such as neurons, astrocytes, and microglia, are also dam- aged. RT toxicity is also thought to be due to cytokines and microglial proliferation.14 Other factors that increase the risk of RT-induced toxicity are older age, concurrent diseases (such as diabetes, hypertension), vascular disease, adjuvant chemo- therapy, and genetic predisposition.

Mechanism of Radiation’s Effect on Brain

Understanding the pathophysiology and early diagnosis of these complications on imaging are of vital importance to pre- vent further damage and morbidity. This understanding also helps the clinician in modifying the regimen and the researcher to seek preventable or curable therapies.

Photon-Cell Interaction

In diagnostic radiography, where the range of radiation is around 80 to 120 kiloelectron-volts (keV), photoelectric effect

predominates. This effect rate is proportional to the cube of the atomical number of the target material. In RT, the range of photon energy is between 1 and 20 MeV.15 At this range of energy, Compton electrons cause most of the collateral radia- tion tissue damage. The occurrence of this effect is relatively independent of atomic number. The biological damage is the result of radiation interactions with the atoms forming the cells by a process called ionization. This ionization of atoms affects the molecules, which in turn affect the cells, tissues, and ulti- mately the organs and their function. The biological effects of RT are due to two mechanisms: direct and indirect effects.15,16 Direct effects refer to the absorption of radiation by DNA, pro- ducing lesions, such as base changes or damage to the sugar- phosphate backbone (▶ Fig. 30.3). This may result in single- and double-strand breaks. However, for any given cell, water makes up the most of the cell’s volume, and DNA forms a small part of the cell. Therefore, the probability of the radiation interacting with the DNA molecule is quite small. Much of the radiation (photons) interaction (ionization) takes place with the cell water, leading to a break in the water molecule bond, producing hydrogen (H) and hydroxyls (OH). Hydroxyl radicals react with cellular DNA to cause base lesions and other damage (▶ Fig. 30.3), referred to as the indirect effect; indirect effect is thought to cause about 70% of mammalian cell killing by X-rays. Double-strand breaks are the most toxic of radiation lesions. For example, 1 Gy (100 rad) of radiation produces about a thou- sand ionization tracks within a cell, resulting in about a thou- sand single-strand breaks and about 40 double-strand breaks.15,16 Repair of this double-strand break is critical for cell survival. Cells have tremendous ability to repair damage. After RT, an exposed cell may show three different effects: it may be completely repaired to function normally, it may become mutated and pass this on to the daughter cells, or, if the damage is severe, it may die.

Fig. 30.3 Illustration of radiation-induced direct and indirect effects on cellular DNA. In the direct effect, photons directly damage the DNA structure, producing a base change and/or damage to the sugar-phosphate backbone. In the indirect effects, photons cause an ionization reaction within the intracellular water, leading to a break in the oxygen-hydrogen bond, producing hydrogen (H) and hydroxyls (OH). Hydroxyl radicals react with cellular DNA to cause base lesions and other damage.

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Pathophysiology of Radiation Therapy’s Effect on Brain and Clinical Stages

In the human body, different cell systems have different sensi- tivity to RT. Cells that are actively reproducing are more sensi- tive to RT than those that are not.15 Blood cells that are con- stantly regenerating are therefore most sensitive; nerve and muscle cells are slowest to regenerate and therefore are least sensitive to radiation. Although the vascular endothelial cells and oligodendrocytes have been regarded as direct primary tar- gets of radiation, the overall effect is thought to be multi- factorial and attributed to more than one cell lineage.17

Acute changes are predominately thought to be due to RT effect on the blood–brain barrier (BBB), blood–spinal barrier, and the parenchymal CNS cells.18 Maintenance of the BBB is essential for brain homeostasis and cellular anatomic speci- ficity. RT causes disruption of the BBB through the acid sphingomyelinase pathway, leading to apoptosis of endothe- lial cells.19 BBB disruption also occurs through intercellular adhesion molecule-1 (ICAM-1)20 and tumor necrosis factor α (TNF-α) (▶Fig. 30.4a).21 Thus, the acute post-RT symptoms are thought to be due to vasogenic edema resulting from damage to the capillary endothelium, leading to cerebral edema and raised intracranial pressure.

In the delayed phase, there is also breakdown in the BBB, which is thought to be due to upregulation of hypoxia-inducible factor 1α (HIF1α) from hypoxia and ICAM-1 from vascular endothelial growth factor (VEGF) stimulation.18,22 In this phase, there is significant decrease in the mature oligodendrocytes and neural stem cells (▶Fig. 30.4b). Neuropathology reveals demyelination, astrogliosis, multifocal coagulative necrosis, and cavitations.23 Vascular changes of endothelial proliferation lead- ing to secondary ischemic changes account for most of the mentioned changes in the brain. These changes predominate in the periventricular white matter and the centrum semiovale. Later stages may show deposition of iron salts and calcium in the vessel walls as well as in the deep gray matter nuclei and subcortical tissue.

Neuroimaging

Inflammation, demyelination, and breakdown of the BBB are the underlying pathogeneses hindering the short- and long- term outcomes of cancer survivors who under go brain RT. Tra- ditional MRI can easily identify inflammation and edema in the acute phase of postradiation insult; however, it is ineffective in distinguishing between radiation-related necrosis from tumor progression. Conventional MRI and CT are also unsuccessful at demonstrating the periventricular white matter lesions that are pathologically evident in the first 12 to 18 months after com- pletion of RT.24,25 Therefore, using new techniques in neuro- imaging, such as DTI, which is the most sensitive in identifying white matter changes well before structural abnormalities manifest, can help redirect RT and salvage areas susceptible to damage. Conventional CT and MRI may be used to calculate the atrophy index in post-RT patients. However, atrophy calculated by this atrophy index often does not correlate with negative changes on cognitive testing.26 Therefore, full assessments of patients require a combination of imaging modalities and mul- tiple types of cognitive testing.

Cognitive impairment is a continuous spectrum that can range from mild dysfunction to severe dementia. As the sur- vival of cancer patients has increased, there is more and more awareness of this dysfunction. It is thought to be due to the consequences of complex interactions between preexisting cognitive abnormalities, brain tumor growth, concomitant treatments with chemotherapy, antiepileptic or psychotropic drugs, paraneoplastic encephalomyelitis, and endocrine dys- function.27,28 Several factors, such as old age (i.e., older than 60 years), large radiation doses, large irradiated brain volume, and combined treatment with chemotherapy and RT have been linked to the increased risk of leukoencephalopathy. For exam- ple, for patients treated with WBRT (40 Gray [Gy] + 14 Gy boost) and a combination of intravenous and intrathecal MTX for CNS lymphoma, the incidence of severe progressive cognitive impairment is up to 83% in patients over the age of 60 years. Even the timing of the MTX chemotherapy is important.28,29,30

Fig. 30.4 Illustration of radiation-induced changes in cerebral vascular and cellular compartments in acute (a) early delayed (b) and late delayed (c) stages of radiation-induced complications. In acute stages, radiation therapy (RT) causes increased blood–brain barrier (BBB) permeability and apoptosis of oligoprogenitor cells, mediated through the acid sphingomyelinase pathway and overexpression of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor α (TNFα). In the early delayed phase (b), there is peak production of TNFα by microglial cells and astrocytes, leading to vasogenic edema. In the late delayed phase (c), there is breakdown in the BBB due to upregulation of hypoxia-inducible factor 1α (HIF1α) due to hypoxia and ICAM-1 from vascular endothelial growth factor (VEGF) stimulation.

269

Tumor-Related Cognitive Dysfunction

The cognitive dysfunction rate is higher whenever MTX is prescribed during or after RT, and therefore this drug is given before radiation.

Radiation-Induced Mild to Moderate Cognitive Impairment

The incidence of mild to moderate cognitive dysfunction is greater than that for RT-induced dementia. Unfortunately, clear-cut definition of this condition is not achieved by the neu- rologic examinations. Clinical features include impairment of attention and short-term memory, with preservation of intel- lectual functions. Hippocampal dysfunction is one of the promi- nent features. This deficit is significant in children, especially when RT is given before 7 years of age. CT scan may show abnormal, periventricular hypodensities with or without ven- tricular enlargement. MRI is more sensitive and shows focal patchy or diffuse T2 hyperintensities in the white matter (▶Fig. 30.5).22,31,32 There may be concomitant dilatation of the ventricles. The subcortical U-fibers may be affected, but the cor- pus callosum is usually spared. Degree of the MR hyperintensities grossly correlates with neuropsychological examinations. The course of the disease is difficult to predict: some patients deterio- rate slowly, whereas most apparently remain stable. No therapy has proven beneficial for prevention, but symptomatic relief is advocated with use of methylphenidate.33 Research has shown free-radical scavengers, such as amifostin or angiotensin-convert- ing enzyme inhibitor (ACEi)34 to have a protective effect; admin- istration of erythropoietin prevents cognitive impairment.35

Radiation-Induced Dementia and Diffuse Late Atrophy

In the largest of the series, the incidence of RT-induced demen- tia was shown to be 12.3%.45 The clinical picture is character- ized by a “subcortical dementia” pattern resulting from diffuse white matter injury, which occurs in 69% of patients within 2 years of RT.27,36 Patients have progressive memory and atten- tion deficits, intellectual loss, gait abnormalities, emotional lability, apathy, and fatigue. In the later stages, patients may develop gait ataxia, incontinence, and sometimes a picture of

akinetic mutism with features of seizures, pyramidal or extrap- yramidal signs, or tremor. Neuropathology shows spongiosis of the white matter but no vascular changes, which is a hall- mark of radiation necrosis. Neuroimaging always shows diffuse white matter T2 hyperintensity associated with cortical and subcortical atrophy, as well as ventricular enlargement (▶ Fig. 30.6).37 These changes are much more diffuse in the case of WBRT. MR spectroscopy shows decrease in the peak of

Fig. 30.5 Mild to moderate cognitive dysfunction in a 57-year-old woman who was treated with whole-brain radiation therapy for brain metastasis from renal cell carcinoma. Patient had short-term memory loss. Axial T2-weighted imaging shows diffuse hyperintensity in the cerebral white matter bilaterally (arrows).

Fig. 30.6 Radiation-induced subcortical demen- tia. An 11-year-old boy treated with whole-brain radiation therapy for midbrain grade III glioma (arrows) with leptomeningeal spread showing signs and symptoms of subcortical dementia. Axial T2-weighted (a) and fluid-attenuated in- version recovery (FLAIR) (b) images show diffuse cerebral atrophy and white matter hyperintensity (arrowheads) suggestive of leukoencephalopathy.

270

Brain Tumors and Cognitive Dysfunction

Fig. 30.7 A 49-year-old man treated with intensity-modulated radiation for left frontal lobe infiltrative oligoastrocytoma. The patient had frontal dementia 6 years after completion of treatment. Axial fluid-attenuated inversion recovery (a) image from magnetic resonance imaging (MRI) dated June 28, 2006, shows an infiltrative right frontal lobe glioma (arrowhead). Axial T2-weighted imaging (b) and axial diffuse tensor imaging map (c) from MRI dated January 11, 2012, shows severe leukoencephalopathic changes and loss of white matter tracts in the bilateral frontal lobes compared with the rest of the brain.

N-acetyl aspartate (NAA), choline, and creatine, implying axonal and membrane damage. Hyperintensity changes may be local- ized to one or two lobes or to a specific region when intensity- modulated RT is given. For example, radiation injury to the frontal lobes is more prominent after treatment of olfactory neuroblastoma, which manifests with frontal lobe dementia (▶Fig. 30.7), whereas pediatric patients treated for medullo- blastoma may have ataxia from radiation-induced cerebellar atrophy (▶Fig. 30.8). In association with the white matter changes, cerebral parenchyma may also show diffuse mild to moderate cortical atrophy (▶ Fig. 30.9). The pathogenesis of the cerebral atrophy is not clear. No specific treatment is currently available for radiation-induced dementia. The occurrence of communicating dilatation of the ventricles is thought to be due to combination of radiation-induced arachnoiditis or oblitera- tion of pacchionian granulations and/or simply loss and soften- ing of cerebral white matter. It can be treated with ventriculo- peritoneal shunt, similar to normal pressure hydrocephalus.38

30.2.2 Chemotherapy and Dementia

Most chemotherapy drugs have an effect on CNS cells. It is important to identify chemotherapy-induced neurotoxicity early, either to discontinue or to change the treatment regimen so as to decrease neurotoxicity. Chemotherapy-related compli- cations can be divided into early and delayed complicatios. Common complications seen with chemotherapy include acute encephalopathy, seizure, headaches, aseptic meningitis, acute cerebellar syndrome, vasculopathy, neuropathy, visual loss, mye- lopathy, posterior reversible leukoencephalopathy syndrome (PRES), and dementia.30,31 Almost all groups of chemotherapy

271

Fig. 30.8 Radiation-induced ataxia in a 7-year-old boy treated with surgery and radiation therapy (RT) for fourth ventricular medulloblas- toma. Three years after RT, the patient had cerebellar ataxia. Axial fluid-attenuated inversion recovery image through the posterior fossa shows bilateral cerebellar atrophy (arrows) and white matter gliosis (arrowheads).

272

Tumor-Related Cognitive Dysfunction

Fig. 30.9 Radiation-induced cortical atrophy.
A 10-year-old boy previously treated with radiation therapy for pineal tumor showed cognitive dysfunction and parietal lobe syndro- me. Contrast-enhanced sagittal T1-weighted imaging (a) and axial fluid-attenuated inversion recovery image (b) show severe cortical atrophy of the bilateral frontoparietal lobes (arrows and arrowhead).

drugs can cause neurotoxicity. Broadly, these drugs are classified according to their class and mechanism of action into the follow- ing groups: anti-metabolite (methotrexate, 5-fluorouracil (5-FU)), alkylating agents (ifosfamide, cisplatin, carboplatin, carmustine and lomustine); microtubule inhibitor (vincristine, vindesine, vin- blastine, and vinorelbine); amino acid degrader (L-asparaginase); immunomodulatory agent (thalidomide); anti-inflammatory agent (corticosteroids) and hormonal agent (tamoxifen).39

The true incidence of cognitive impairment is difficult to pre- dict since there is lack of pre-chemotherapy assessments in most studies making it difficult to establish the causal relationship between cognitive dysfunction and chemotherapy. It is shown that the incidence and severity of cognitive dysfunction largely depend on the chemotherapy regimen used, and the dose and duration of chemotherapy and associated therapy.40 Most studies report an incidence between 15 and 50% in patients who received chemotherapy. Chemotherapy-induced cognitive impairment mainly involves memory and concentration.41 In contrast to RT, chemotherapy induced cognitive dysfunction appears to be transient and resolves slowly over a period of time.

Pathogenesis and Mechanisms of Chemotherapy-Induced Neurotoxicity

The exact etiology of chemotherapy-induced neurotoxicity and cognitive impairment in cancer patients is unknown but is believed to be multifactorial. Acute toxic effects of chemo- therapy are mediated through excitatory mechanisms and apo- ptotic cell death.13,18 Cognitive dysfunction is thought to be due to combination of direct neurotoxic effects of the agent; oxida- tive damage; indirect effects, such as chemotherapy-induced hormonal changes; immune dysregulation with release of cyto- kines; anemia, and to some extent genetic predisposition. Chemotherapy agents are hypothesized to affect the microglia, oligodendrocytes, and neuronal axons, causing demyelination or alterations in water content. Free radicals released from oxi- dative stress cause damage to cerebral blood vessels, while acti- vation of the immune system causes increased levels of pro- inflammatory cytokines (interleukin IL-1, IL-6, and tumor necrosis factor-alpha [TNFα]) that cross the blood–brain barrier and are associated with cognitive impairment and/or fatigue. Associated anemia in cancer patients causes decreased cerebral oxygenation, which leads to worsening of visual memory and executive function tasks.

Specific Chemotherapy-Related Complications

Discussing the CNS side effects of all the groups of chemo- therapy drugs is beyond the scope of this chapter. Methotrexate (MTX) is a dihydrofolate reductase inhibitor. Its toxic effect mainly depends on route of administration, dose, and the use of other treatment modalities, such as radiation. High-dose sys- temic MTX is associated with CNS complications like encephal- opathy and subacute stroke-like syndrome, which is character- ized by transient focal neurologic deficits, confusion, and seizures. These symptoms may resolve completely after 2 to 3 days. MTX may affect the white matter, leading to leukoence- phalopathy, an effect further enhanced by associated RT. CSF analysis is mostly unremarkable, and EEG may show diffuse nonspecific slowing typical of encephalopathy. MRI shows bilateral increased signal intensities mostly involving the supra- tentorial white matter, particularly in the centrum semiovale.23, 42,43 These areas may show restricted diffusion on DWI-ADC (▶ Fig. 30.10). Rarely, there may be florid areas of demyelination that are seen as multiple patchy/conglomerated hyperinten- sities on T2 weighted images. MTX-induced chronic leukoence- phalopathy may manifest after months to years following high- to moderate doses of MTX and presents with hemiparesis, quadriparesis, profound dementia, and coma. Less severe, but permanent, deficits include a mild to moderate dementia (▶ Fig. 30.11).23 5-Fluorouracil (5-FU), a fluorinated pyrimidine, and cytosine arabinoside (cytarabine, ara-C), a pyrimidine ana- log, both disrupt DNA synthesis. In conventional doses, neuro- toxicity is rare with these drugs. In higher doses, 5-FU crosses the BBB and is found in the highest concentration in the cere- bellum, where it is toxic to Purkinje and granule cells, leading to acute cerebellar syndrome.44 It has an acute onset, with ataxia, dysmetria, dysarthria, and nystagmus. Overall, the risk of cognitive impairment is significantly greater in patients with high doses of chemotherapy compared with the risk in control groups.

30.2.3 Combined Radiotherapy and

Chemotherapy and Dementia

The toxic effects of combined RT and chemotherapy are greater than those of single-modality treatment. These combined effects largely depend on therapeutic factors of chemotherapy

Brain Tumors and Cognitive Dysfunction

Fig. 30.10 Methotrexate (MTX)-induced acute demyelination of the cerebral white matter in a 21-year-old man treated with intrathecal MTX for leukemia. Axial diffusion-weighted imaging (DWI) (a) and apparent diffusion coefficient (b) images show bilateral areas of restricted diffusion in the centrum semiovale bilaterally resulting from acute demyelination (arrows).

Fig. 30.11 Gradually worsening atrophy and leukoencephalopathy in a 5-year-old boy treated with intrathecal and systemic methotrexate for leukemia. One year after completion of therapy (May 11, 2010), a noncontrast computed tomography scan of the brain (a) showed mild prominence of the convexity sulci and ventricular system, advanced for the age of the patient. One year later, the patient developed symptoms of fatigue and weakness. Axial T2-weighted magnetic resonance imaging (MRI) performed on March 22, 2011 (b) shows mild atrophy and leukoencephalopathic changes in the bilateral cerebral parenchyma. Two years after completion of treatment, the patient showed signs of early dementia. Axial T2-weighted MRI dated June 3, 2012 (c) showed severe diffuse atrophy with leukoencephalopathy and dilatation of the lateral ventricles.

and RT, which include the following18: (1) agent-type, dose, and schedule; (2) RT dose, fractionation rate, treatment time, treat- ment volume, and dose distribution; (3) time between chemo- therapy and RT; (4) chemical and biological dose-response modifiers (e.g., sensitizers, protectors, and immunotherapy). Some chemotherapeutic agents, such as bis-chloroethyl nitrosourea (BCNU), methotrexate, and cisplatin, are radiosen- sitizers. On the other hand, RT may induce changes in the permeability of the BBB and thus increase the delivery and con- centration and in turn toxicity of chemotherapy drugs.

The most striking toxic effect of combined therapy seen on white matter is disseminated necrotizing leukoencephalopathy. Clinically, patients may have progressive subcortical dementia, ataxia, and pyramidal and extrapyramidal syndrome, eventu- ally leading to death. Neuropathology shows combined myelin and axonal loss, spongiosis, white-matter gliosis, areas of

necrosis, and fibrotic thickening of small blood vessels in the deep white matter. MRI shows large confluent areas of hyperin- tensity on T2-weighted imaging, predominately involving the white matter. In the acute stage, these regions show restricted diffusion on DWI-ADC due to cytotoxic edema (▶ Fig. 30.12).37 Associated areas of necrosis may be seen. In the late stages, dif- fuse cortical-subcortical brain atrophy is present, with ex vacuo dilatation of ventricles.

30.2.4 Effect of Radiation

on a Pediatric Brain

The long-term survival and high rate of potential cure in the pediatric population makes awareness of the side effects of RT of great clinical significance. The clinical and imaging features

273

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Tumor-Related Cognitive Dysfunction

Fig. 30.12 Disseminated necrotizing leukoence- phalopathy. A 63-year-old woman was treated with radiation therapy and methotrexate for brain metastasis from breast cancer and developed acute-onset dementia and pyramidal signs.

Axial diffusion-weighted imaging (a), and apparent diffusion coefficient (b), show diffuse atrophy of the cerebral parenchyma with large areas of acute demyelination (arrows) in the supratentorial white matter.

of white matter injury secondary to chemotherapy and RT are not significantly different from those in adults. As in adults, the changes are divided into acute and early delayed and late delayed. Besides diffuse or patchy white matter areas of demye- lination, multiple foci of hemorrhagic lesions may be seen within the radiation portal. In the chronic stage, occult vascular malformation or cavernoma may develop. Young children are more susceptible than adults to RT-induced vascular changes, especially around the circle of Willis. Clinically, these patients may show growth retardation, cognitive impairment, strokes, and developmental delay. In addition, endocrine dysfunctions, such as growth hormone deficiency and hypothyroidism, may be noted. Overall, unmyelinated and immature white matter shows greater toxic effect of chemotherapy and RT therapy than in older children.

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[42] Lövblad K, Kelkar P, Ozdoba C, Ramelli G, Remonda L, Schroth G. Pure metho- trexate encephalopathy presenting with seizures: CT and MRI features. Pediatr Radiol 1998; 28: 86–91

[43] Chen CY, Zimmerman RA, Faro S, Bilaniuk LT, Chou TY, Molloy PT. Childhood leukemia: central nervous system abnormalities during and after treatment. AJNR Am J Neuroradiol 1996; 17: 295–310

[44] Riehl JL, Brown WJ. Acute cerebellar syndrome secondary to 5-fluorouracil therapy. Neurology 1964; 14: 961–967

[45] Crossen JR, Garwood D, Glatstein E et al. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy J Clin Oncol 1994; 12: 627–42

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31 Paraneoplastic Syndrome

Toshio Moritani, Aristides A. Capizzano, and Yoshimitsu Ohgiya

Paraneoplastic neurologic syndrome (PNS) occurs in less than 1% of cancer patients based on serologic tests without further criteria.1,2 PNS is associated with central and peripheral nervous disorders and syndromes, which include limbic ence- phalitis, cerebellar degeneration, brainstem encephalitis, stria- tal encephalitis, opsoclonus-myoclonus syndrome, myelitis, motor neuron disease, stiff-person syndrome, Lambert-Eaton syndrome, neuromyotonia, and Guillain-Barré syndrome.

Paraneoplastic and nonparaneoplastic encephalopathies are included in the category of autoimmune-mediated ence- phalopathies and are associated with various specific anti- bodies.1,3,4,5,6,7 The two main types of specific antibodies are (1) antibodies to intracellular antigens: Hu (ANNA-1, anti- neuronal nuclear antibody type 1), Ri (ANNA-2), ANNA-3, AGNA (anti-antiglial/neuronal nuclear antibody), Yo (PCA-1, Purkinje cell cytoplasmic antigen type 1), PCA-2, Ma1, Ma2, CV2/CRMP-5 (collapsing response mediator protein type 5), ZIC4 (zinc finger transcription factor), Tr, amphiphysin, and glutamic acid decarboxylase (GAD) and (2) antibodies to cell surface antigens: N-methyl-D-aspartate receptor (NMDAR), voltage-gated potassium channel (VGKC), leucine-rich, gli- oma-inactivated 1 (LGI1), contactin-associated protein 2 (CASPARS2), α-amino-3-hydroxy-5-methyl-4-isoxazole pro- pionic acid receptor (AMPAR), P/Q and N-type calcium chan- nel, neuromyelitis optica (NMO) immunoglobulin G, glycine receptor, acetylcholine receptor, γ-aminobutyric acid B1 receptor (GABABR), and metabotropic glutamate receptor-5. The common paraneoplastic and nonparaneoplastic ence- phalopathies are summarized in ▶ Table 31.1. They can also be classified according to the distribution of the lesion, usually based on the pattern of magnetic resonance imaging (MRI) findings. Early correct diagnosis is important for the appropriate treatment for either paraneoplastic or nonpara- neoplastic autoimmune-mediated encephalopathies.

31.1 Clinical Features

Paraneoplastic or nonparaneoplastic autoimmune-mediated encephalopathy is associated with a heterogeneous spectrum of clinical presentations that includes cognitive impairment, behavioral and personality changes, movement disorder, and seizures.1,3,4,5,6,7 Cognitive impairment is sometimes accompa- nied by tremor, myoclonus, ataxia, and sleep disturbance. It is often associated with some component of delirium. These dis- orders can evolve in chronic or rapidly progressive fashion. New-onset epilepsy associated with PNS is often antiepileptic drug resistant. Encephalopathy is usually progressive, may be fluctuating, or may evolve over days to several months. Neuro- logic symptoms often precede the diagnosis of underlying tumor in approximately 60% of patients.8 Cognitive and mood changes, particularly depression, are common in cancer patients and should be considered in the differential diagnosis.

Electroencephalography (EEG) typically shows diffuse slow- ing of electrical activity with or without spikes indicative of heightened cortical irritability.9 Cerebrospinal fluid (CSF) find- ings are essential to rule out infection and neoplasm. CSF find- ings of immune-mediated encephalopathy include pleocytosis in early stage and elevated protein concentrations and oligoclo- nal bands later in the illness. Fewer than 5% of the patients have completely normal CSF.10

The detection of a neural-specific antibody in serum or CSF raises the possibility of a paraneoplastic cause. However, anti- body testing does not replace clinical evaluation.5 The detection of certain paraneoplastic or nonparaneoplastic antibodies requires nonroutine laboratory analysis, frequently requiring referral to specialized centers. Patients may have more than one pathogenic antibody. All paraneoplastic and nonparaneoplastic encephalopathies can occur in the absence of, or with low titers of, known antibodies. If the paraneoplastic panel is

Table 31.1 Paraneoplastic and nonparaneoplastic immune-mediated encephalopathies

Antibody (antigen) Neoplasms (%) Common MRI patterns / Clinical syndrome

NMDAR (S)

Ovarian teratoma, testicular carcinoma (9–56%)

Normal, LE, SE, BE, cerebellitis/psychosis, memory deficits, hypoventilation

VGKC (S)

Thymoma, SCLC, prostate cancer (5–30%)

LE, SE/Morvan, neuromytonia, SIADH

AMPAR (S)

SCLC, breast (70%)

LE/agitation

GABABR (S)

SCLC (47%)

LE/epilepsy

GAD (I)

SCLC, thymoma, pancreatic/renal cell carcinoma (8%)

LE, CD/stiff-person syndrome, ataxia

Hu (I)

SCLC (98%), thymoma, neuroblastoma

LE, CD, BE, SE/sensory neuropathy, ataxia, brainstem dysfunction

Ma-2 (I)

Testicular germ cell tumor, non-SCLC, breast (96%)

LE, CD, BE/narcolepsy, hyperthermia, endocrine dysfunction

CV2/CRMP-5 (I)

SCLC, thymoma (96%)

SE, LE, BE,CD/chorea, uveitis, optic neuritis

Tr (I)

Hodgkin lymphoma

CD, BE, LE

Ri (I)

Breast, SCLC, gynecologic (97%)

BE, CD/opsoclonus-myoclonus

Yo (I)

Ovary, breast (98%)

CD/pancerebellar syndrome

Abbreviations: BE, brainstem encephalitis; CD, cerebellar degeneration; I, intracellular antigen; LE, limbic encephalitis; MRI, magnetic resonance imaging; S, cell surface antigen; SCLC, small cell lung cancer; SE, striatal encephalitis; SIADH, inappropriate antidiuretic hormone secretion syndrome.

oncologic treatment may result in improvement of PNS. Intra- venous high-dose steroids and IVIG are recommended as the first-line therapy. Plasma exchange is an additional therapeutic option. Second-line therapy usually begins after 10 days if there is no initial response. Rituximab, monoclonal antibody against CD20 protein, is recommended at treatment start. This may be combined with cyclophosphamide in adult patients. Auto- immune-mediated encephalopathy with cell surface antigens generally tends to be more responsive to treatment than that with intracellular antigens. Treatment of patients with these disorders should be based on a comprehensive clinical assess- ment, not only on antibody titers.5

31.5 Limbic Encephalitis

Limbic encephalitis is initially described as a paraneoplastic syndrome characterized by an acute or subacute onset of confu- sion, temporal lobe seizures, short-term memory loss, and psy- chiatric symptoms.19,20,21,22 Limbic encephalitis is relatively fre- quent among autoimmune encephalitis.3,20 The most common associated tumors are small cell lung cancer, breast cancer, ovarian tumor including teratoma, testicular tumor, and thymic tumor. It may be rarely associated with colon cancer, pancreatic cancer, renal cell cancer, esophageal cancer, bladder cancer, prostate cancer, neuroblastoma, melanoma, and Hodgkin and non-Hodgkin lymphoma.23 It is commonly associated with anti- bodies to intracellular antigens (anti-Ma2, Hu, CV2/CRMP-5, GAD) and neuronal surface antibodies (NMDAR, VGKC, AMPAR, GABABR) with or without tumor association.1,3,4,5,6,7,20,23

Magnetic resonance imaging contributes to the diagnosis by showing T2 and fluid-attenuated inversion recovery (FLAIR) high signal and swelling in the medial temporal lobe, which is more often bilateral than unilateral (▶ Fig. 31.1, ▶ Fig. 31.2). Sig- nificant atrophy is visible approximately 1 year after symptom onset.24 Other limbic structures, such as insular, frontal, orbital surface of the temporal lobe, anterior cingulate, and pyriform cortex, are also involved. Diffusion-weighted imaging (DWI) shows hyperintensity in the medial temporal lobe, usually with slightly increased apparent diffusion coefficient (ADC) but possibly with decreased ADC in an acute phase.18,23,25,26,27 Abnormal enhancement can be seen but is rare in limbic ence- phalitis. Differential diagnosis includes viral encephalitis, espe- cially herpes encephalitis, because of its predilection for limbic structures, postictal changes from status epilepticus, gliomato- sis cerebri, and infiltrative lymphoma (lymphomatosis).

31.6 Cerebellar Degeneration

Cerebellar dysfunction is one of the common paraneoplastic presentations. Anti-Yo (Purkinje cell cytoplasmic antibody type 1, PCA-1) antibody is most commonly associated with paraneo- plastic cerebellar degeneration with ovarian and breast carci- noma. Anti-Hu, anti-Cv2/CRMP-5, anti-Ri, and anti-VGCC (P/Q type and N-type voltage-gated calcium channel) can also be associated with paraneoplastic cerebellar degeneration with small cell lung cancer, breast cancer, and gynecologic malignan- cies.28,29,30,31 MRI shows global volume loss in both the vermis and cerebellar hemispheres, with relative sparing of the brain- stem (▶Fig. 31.3). A superior cerebellar hyperintense sign on FLAIR image has been reported.32 Differential diagnosis of

unrevealing for any specific antibody, the diagnosis is inferred when all other putative conditions are excluded.3

31.2 Pathophysiology and

Pathology

Tumor-targeted immune responses are initiated by onconeuro- nal proteins, which are expressed by neural-type tissue within a neoplasm (such as teratoma) at the plasma membrane, nucleus, cytoplasm, or nucleolus. These antigens are also expressed in neurons or glia (coincidental targets), which leads to paraneoplastic neurologic syndrome by means of immune cross-reaction.11Neuropathologic features are dominant lym- phocyte T-cell infiltration, neuronal loss, activated microglia, neuronophagia, and reactive astrocytosis. Because intracellular antigen-targeting antibodies are targeted by specific cytotoxic T cells, the histopathology is characterized by CD4 and CD8 lym- phocyte T-cell infiltration.12,13 On the other hand, such inflam- mation is less severe in patients with antibodies to cell surface or synaptic antigens, which are characterized by lymphocyte B and plasma cell infiltration, leading to antibody and comple- ment deposition.14 Thus, steroids, intravenous immunoglobulin (IVIG), or plasmapheresis would be more effective in treating patients with antibodies to cell surface or synaptic antigens than in patients with intracellular antigen-directed antibodies.

31.3 Imaging

Brain MRI is the primary neuroimaging tool for the diagnostic evaluation of paraneoplastic or nonparaneoplastic encephalo- pathies.3 MRI findings and clinical evaluations are helpful to narrow the range of tests of specific antibodies that should be ordered. MRI can be normal in any immune-mediated ence- phalopathy. The common or classic pattern of MRI findings of paraneoplastic encephalopathy includes limbic encephalitis, cerebellar degeneration, brainstem encephalitis, striatal ence- phalitis, and myelitis. However, other types have atypical or multifocal distributions.

Often PNS predates malignancy symptoms, so cost-effective screening is important.4 Recommendations for screening for tumors are different between whole-body screening for classic PNS and more localized tumor search for surface antibody syn- drome.4,15 Screening for systemic malignant tumors, such as small cell lung cancer or lymphoma, should be done by con- trast-enhanced computed tomography (CT) of the chest, abdo- men, and pelvis and/or fluorine-18-fluorodeoxyglucose (FDG) positron emission (PET)/PET-CT.16,17 If the brain MRI pattern is suggestive of specific localized tumor, mammography or scro- tal/pelvic ultrasound should be obtained.4 For ovarian teratoma, CT/MRI of pelvis/abdomen or transvaginal ultrasound has been used.

31.4 Treatment

Early treatment is critical for paraneoplastic or nonparaneo- plastic autoimmune-mediated encephalopathy.4,7,18 Vigorous antiepileptic medications and adequate support measures, including sedation and adequate ventilation, are essential for patients with seizures. Removal of tumors and appropriate

Paraneoplastic Syndrome

277

Tumor-Related Cognitive Dysfunction

Fig. 31.1 Anti-N-methyl-D-aspartate receptor (NMDAR) antibody limbic encephalitis with ovarian teratoma. A 23-year-old woman had myoclonic jerking, fever, and body aches. (a) Fluid-attenuated inversion recovery (FLAIR) image shows bilateral symmetric hyperintensity in the amygdala and hippocampi consistent with limbic encephalitis. (b) Diffusion-weighted imaging demonstrates restricted diffusion in these lesions associated with slightly decreased apparent diffusion coefficient (not shown). (c) Postcontrast computed tomography reveals a fat-contained, calcified mass consistent with an ovarian teratoma.

Fig. 31.2 Anti–voltage-gated potassium channel (VGKC) antibody limbic encephalitis (nonpara- neoplastic). A 48-year-old man was having memory problems and psychiatric symptoms. (a) Fluid-attenuated inversion recovery (FLAIR) image shows bilateral symmetric hyperintensity in the amygdala and hippocampi consistent with limbic encephalitis. (b) Diffusion-weighted imaging demonstrates no restricted diffusion in these lesions.

Fig. 31.3 Anti-Yo antibody paraneoplastic cerebellar degeneration with ovarian carcinoma. A 63-year-old woman had progressive ataxia. (a) T2- weighted image demonstrates diffuse cerebellar atrophy. (b) Postcontrast computed tomography reveals a heterogeneously enhancing mass (arrow) in the left ovary.

278

memory loss and disintegration of language, followed by decreased responsiveness with hypoventilation requiring venti- lator support, commonly ensue.14 The antibody targets NR1/ NR2 heteromers of NMDAR, an inotropic glutamate receptor expressed in the neuropil of the hippocampus and throughout the brain.38 CSF usually shows moderate lymphocytic pleocyto- sis and oligoclonal bands (> 50%).14 A characteristic EEG pattern, “extreme delta brush,” may help in the diagnosis and follow-up of this disorder48; 75% of patients have complete or near-com- plete recovery after tumor resection and immunomodulatory therapy,14,49,50 and patients in whom a tumor is not detected have worse therapy response and more frequently require second-line immunotherapy (cyclophosphamide or rituximab or both) compared with patients with tumors. Brain MRI is normal in approximately half of patients with anti-NMDAR encephalitis.

The pattern of MR findings includes limbic encephalitis, cere- bellitis, brainstem encephalitis, and striatal encephalitis (▶ Fig. 31.1); however, atypical MRI findings are common, with transient FLAIR, T2, and diffusion abnormalities outside the medial temporal lobe, sometimes with cortical enhancement.51, 52 FDG-PET can demonstrate increased glucose metabolism in the frontotemporo-occipital area.53,54

Antibody to VGKC was initially described with Isaacs syn- drome (neuromyotonia) and Morvan’s syndrome (neuromyoto- nia, dysautonomia, insomnia, and delirium).55,56,57,58,59 Other clinical presentations are peripheral nerve hyperexcitability, rapid-eye-movement sleep behavior disorder, and epilepsy. Hyponatremia from inappropriate antidiuretic hormone secre- tion syndrome (SIADH) occurs in 60% of patients.4 CNS features may be not indistinguishable from other limbic encephalitis. Recent evidence shows that the antibody is not directly binding to the Kv1.1 subunit of the potassium ion channel, but LGI1, CASPR2, or unknown protein (VGKC complex) is associated with the channel.3,4,5 Although it is typically considered nonparaneo- plastic, 5 to 30% of cases are with associated tumor (small cell lung cancer, thymoma, prostatic cancer). VGKC may have a more chronic course than other cell surface antigen encephaloi- tides. Brain MRI typically shows the pattern of limbic encepha- litis (▶ Fig. 31.2), rarely coexistent with striatal encephalitis.60 Patients with the antibody to LGI1 or CASPR2 usually have a good response to immunomodulatory treatment.5,60,61,62,63

Anti-AMPAR (Glu R1 and GluR2) encephalitis is rare and is discovered in patients with limbic encephalitis.3,64 Patients have confusion, memory disturbance, and psychiatric symptoms, with or without seizures in women, with a median age of 60 years; 70% of the patients had tumors of the lung, breast, or thymus.

Anti-GABABR encephalitis usually shows a pattern of limbic encephalitis with subacute onset of partial complex or tonic- clonic seizures,3,65 and 47% had tumors, especially small cell lung cancer. Like other cell surface antigen–mediated syn- dromes, anti-AMPAR and anti-GABABR encephalitis respond to immunotherapy. Antibodies against glycine receptors have been reported in patients with progressive rigidity, muscle spasm gaze palsies, and encephalomyelitis.

Anti-GAD antibodies are implicated in the pathogenesis of type 1 diabetes mellitus and most commonly are associated with stiff-person syndrome, nonparaneoplastic, or epilepsy- dominated limbic encephalitis.66,67,68,69,70,71

cerebellar degeneration includes alcohol and antiepileptic toxicity (predominant cerebellar vermis atrophy), and primary degenerative disorders, such as multiple system atrophy and spinocerebellar ataxia (concomitant brainstem atrophy).

31.7 Striatal Encephalitis

Striatal encephalitis is an uncommon manifestation of para- neoplastic encephalopathy. The pattern of striatal ence- phalitis is frequently seen in anti-CV2/CRMP5 encephalitis associated with small cell lung cancer and thymoma.33,34,35 However, the pattern can be seen in other paraneoplastic encephalopathies, including anti-VGKC, anti-NMDAR, and anti-Hu antibodies.36,37,38 MRI shows T2 hyperintensity in the bilateral caudate nuclei and putamina, frequently associated with limbic encephalitis and cerebellar degeneration. Reduced diffusion is usually not seen in striatal encephalitis. Differential diagnosis includes infectious encephalitis, toxic and metabolic diseases, vasculitis, demyelinating disease, Sydenham chorea, Huntington’s disease, Wilson’s disease, and Creutzfeldt-Jakob disease.

31.8 Brainstem Encephalitis

The pattern of brainstem encephalitis is commonly seen anti- Ma2 in young men with testicular cancer.39,40,41 Brainstem encephalitis can be combined with limbic and diencephalic encephalitis. Anti-Ri and anti-Hu, anti-Tr, and anti-NMDAR are less common causes of paraneoplastic brainstem encephalitis.3, 4,5,6,7,40,41,42 MRI shows FLAIR and T2 hyperintensity with or without enhancing nodules in the brainstem (▶ Fig. 31.4). Dif- ferential diagnosis includes infectious brainstem encephalitis, tumor infiltration, vasculitis, demyelinating disease, and chronic lymphocytic inflammation with pontine perivascular enhancement response to steroids (CLIPPERS).

31.9 Special Antibodies and

Paraneoplastic Encephalitis

Anti-NMDAR encephalitis is the most common autoimmune- mediated encephalopathy and was first described in 2007.43 Before this description, there were a few case reports of revers- ible encephalopathy associated with ovarian teratoma.43,44 One of the first cases reported as being Bickerstaff encephalitis may be anti-NMDAR encephalitis.41 Anti-NMDA receptor antibody is a cell-surface antibody and is often associated with an ovarian teratoma or occult ovarian teratoma found after oophorec- tomy.38 The antibody is rarely seen in association with small cell lung cancer, neuroblastoma, or Hodgkin disease3,4,14; 80% of patients with anti-NMDAR encephalitis are women, and the presence of an ovarian teratoma is more likely if the patient is older than 18 years. In children, irritability, hyperactivity, seizures, and memory change may be the first notable symp- toms.45 On the other hand, in adults, prodromal headache, psychiatric symptoms, fever, and gastrointestinal or upper res- piratory symptoms are seen in 70% of patients.46,47 Motor or complex seizures develop at early stages of the disease, and their frequency decreases with disease evolution. Short-term

Paraneoplastic Syndrome

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280

Tumor-Related Cognitive Dysfunction

Fig. 31.4 Paraneoplastic brainstem encephalitis with Hodgkin’s lymphoma. A 13-year-old girl had weight loss, ataxia, and blurred vision. (a) Fluid- attenuated inversion recovery (FLAIR) image shows hyperintense lesions in the brainstem. (b) Postcontrast computed tomography reveals enlarged mediastinal lymph nodes. (c) Whole-body positron emission tomography image demonstrates abnormal uptake in the mediastinal lymph nodes.

Anti-Hu antibody, also known as ANNA-1, was first described in 1985 associated with sensory neuropathy in patients with small cell lung carcinoma.72 Anti-Hu antibodies can be seen in patients with extrapulmonary small cell carci- noma, thymoma, or neuroblastoma. Paraneoplastic sensory neuropathy is seen in approximately 60%.72,73,74,75,76,77 Ataxia, tremor, limbic, or brainstem encephalopathy syndrome,

myelopathy, and dysautonomia (intestinal pseudoobstruc- tion) are other manifestations seen in 10 to 20% of patients. Anti-Hu encephalitis associated with intracellular antigens usually has poor response to tumor and immunomodulatory therapy.78,79,80,81 Early definitive diagnosis is important because the early stage of the disease is more responsive to treatment.

eral Hospital. Case 4–2007: a 56-year-old woman with rapidly progressive 630

vertigo and ataxia. N Engl J Med 2007; 356: 612–620

. [9] Vernino S, Geschwind M, Boeve B. Autoimmune encephalopathies. Neurolo-
gist 2007; 13: 140–147

. [10] Psimaras D, Carpentier AF, Rossi C; PNS Euronetwork. Cerebrospinal fluid
study in paraneoplastic syndromes. J Neurol Neurosurg Psychiatry 2010; 81:
42–45

. [11] Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to
synaptic and neuronal cell surface proteins. Neurology 2011; 77: 179–189

[36] Hiraga A, Kuwabara S, Hayakawa S et al. Voltage-gated potassium channel antibody-associated encephalitis with basal ganglia lesions. Neurology 2006; 66: 1780–1781

[37] Heckmann JG, Lang CJ, Druschky A, Claus D, Bartels O, Neundörfer B. Chorea resulting from paraneoplastic encephalitis. Mov Disord 1997; 12: 464–466

[38] Dalmau J, Gleichman AJ, Hughes EG et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7: 1091–1098

Paraneoplastic Syndrome

Anti CV2/CRMP-5 is associated with small cell lung carcinoma and thymoma. Limbic encephalopathy, cerebellar or brainstem syndrome, and neuropathy have been described.33,34,35,82,83,84 Movement disorder (chorea) and ocu- lar syndromes (uveitis, optic neuritis) are distinctive fea- tures. Striatal encephalitis is common. It may manifest with limbic or brainstem encephalitis or cerebellar degeneration.

Anti-Tr antibody is associated with Hodgkin’s lymphoma. Limbic encephalopathy and cerebellar or brainstem syndrome have been described.6,23

Anti-Ma2 (Ta) encephalitis usually occurs in young men with testicular germ cell tumors. MRI is abnormal in 75% and shows the pattern of limbic, diencephalic, or brainstem encephalitis. Nodular parenchymal enhancement can be seen.38,83,84

Anti-Ri antibody is associated with breast cancer, small cell lung cancer, or gynecologic malignancies. Opsoclonus–myoclo- nus syndrome, brainstem encephalitis, and paraneoplastic cere- bellar degeneration have been described.4

Anti-Yo antibody is the most common cause of paraneoplas- tic cerebellar degeneration. The anti-Yo antibody targets intra- cellular antigens in the Purkinje cells of the cerebellar cortex. The cerebellar degeneration occurs in women and is associated with ovarian or breast malignancy.2,85,86 Patients clinically pres- ent subacute pan-cerebellar symptoms, including ataxia, nys- tagmus, and dysarthria. MRI shows diffuse cerebellar atrophy without brainstem atrophy (▶Fig. 31.3). Despite tumor and immunomodulatory therapy patients often remains disabled.

31.10 Conclusions

Paraneoplastic and nonparaneoplastic encephalopathies are autoimmune-mediated encephalopathies associated with vari- ous specific antibodies. Brain MRI is the primary neuroimaging tool for the diagnostic evaluation. The pattern of MRI findings is associated with specific antibodies.

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[65] Lancaster E, Lai M, Peng X et al. Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010; 9: 67–76

[66] Baekkeskov S, Aanstoot HJ, Christgau S et al. Identification of the 64K autoan- tigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glu- tamic acid decarboxylase. Nature 1990; 347: 151–156

[67] Solimena M, De Camilli P. Autoimmunity to glutamic acid decarboxylase (GAD) in stiff-man syndrome and insulin-dependent diabetes mellitus. Trends Neurosci 1991; 14: 452–457

[68] Honnorat J, Saiz A, Giometto B et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol 2001; 58: 225–

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Receptor (NMDAR) Encephalitis Work Group. Pediatric anti-N-methyl- aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr 2013; 162: 850–856, e2

. [46] Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005; 58: 594–604

. [47] Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J. Frequency and character- istics of isolated psychiatric episodes in anti–N-methyl-D-aspartate receptor encephalitis. JAMA Neurol 2013; 70: 1133–1139[Epub ahead of print]

. [48] Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor ence- phalitis. Neurology 2012; 79: 1094–1100

. [49] Iizuka T, Sakai F, Ide T et al. Anti-NMDA receptor encephalitis in Japan: long- term outcome without tumor removal. Neurology 2008; 70: 504–511

. [50] Ishiura H, Matsuda S, Higashihara M et al. Response of anti-NMDA receptor encephalitis without tumor to immunotherapy including rituximab. Neurol- ogy 2008; 71: 1921–1923

. [51] Chan SH, Wong VC, Fung CW, Dale RC, Vincent A. Anti-NMDA receptor encephalitis with atypical brain changes on MRI. Pediatr Neurol 2010; 43: 274–278

. [52] Greiner H, Leach JL, Lee KH, Krueger DA. Anti-NMDA receptor encephalitis presenting with imaging findings and clinical features mimicking Rasmussen syndrome. Seizure 2011; 20: 266–270

[69] Alexopoulos H, Dalakas MC. A critical update on the immunopathogenesis of stiff person syndrome. Eur J Clin Invest 2010; 40: 1018–1025

[70] Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 2010; 67: 470–478

[71] Peltola J, Kulmala P, Isojärvi J et al. Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology 2000; 55: 46–50

[72] Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology 1985; 35: 538–543

[73] Graus F, Elkon KB, Cordon-Cardo C, Posner JB. Sensory neuronopathy and small cell lung cancer: antineuronal antibody that also reacts with the tumor. Am J Med 1986; 80: 45–52

[74] Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu–associated paraneo- plastic encephalomyelitis/sensory neuronopathy: a clinical study of 71 patients. Medicine (Baltimore) 1992; 71: 59–72

[75] Graus F, Keime-Guibert F, Reñe R et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124: 1138–1148 [76] Vernino S, Eggenberger ER, Rogers LR, Lennon VA. Paraneoplastic neurologi-

cal autoimmunity associated with ANNA-1 autoantibody and thymoma. Neu-

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associated paraneoplastic encephalomyelitis. Neurology 1998; 51: 1146–

Part XI Trauma

32 Posttraumatic Cognitive Disorders 284

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32 Posttraumatic Cognitive Disorders

Inga K. Koerte, Alexander Lin, Marc Muehlmann, Boris-Stephan Rauchmann, Kyle Cooper, Michael Mayinger, Robert A. Stern, and Martha E. Shenton

Mild traumatic brain injury, or mTBI, also referred to as concus- sion, is usually caused by a single event, such as a bump or blow to the head that leads to temporary alterations in the brain. Common causes include sports injuries, vehicle accidents, and falls.1 In addition to a direct impact to the head, explosions are also known to result in mTBI.2 It is estimated that at least 6 per 1,000 people experience mTBI every year.3 However, this num- ber is likely to be higher due to variations in the definition of mTBI and, more importantly, to underreporting of head injuries that occurs because many patients are not seen in medical settings after head trauma, or they are seen by private physicians.4

Based on current knowledge, the four postinjury phases of mTBI are (1) the acute phase, less than 24 hours after injury; (2) the early subacute phase from day 1 to 13; (3) the late sub- acute phase from day 14 to 20; and (4) the chronic phase after day 20. About 50% of all patients suffer from chronic symptoms lasting for up to several months postinjury in mTBI. Symptoms include irritability, personality change, insomnia, anxiety, and depression. These symptoms are typically most prominent immediately postinjury and resolve over weeks, although cog- nitive and behavioral sequelae may persist for months.5,6,7,8 Neuropsychological evaluation also demonstrates cognitive def- icits in attention, working memory, processing speed, and reaction time.9 Further, cognitive deficits are generally mild and are likely to resolve by themselves within months after the trauma.10,11 However, for a significant number of patients (15 to 20%), the so called “miserable minority,” prolonged postconcus- sive symptoms are disabling and persist longer than several months. Moreover, a small number of these patients will develop a neurodegenerative disease years or decades later in life, such as chronic traumatic encephalopathy (CTE). To date, the mechanisms leading to CTE are not understood. However, it is assumed that repetitive brain trauma (RBT) may be a neces- sary condition for developing CTE. Further, although CTE cur- rently can only be diagnosed postmortem, longitudinal studies using advanced neuroimaging may shed light on the underlying morphologic, pathophysiologic, and biochemical changes that occur in the different stages of mTBI and RBT.

32.1 Pathophysiology

Research over the last two decades has dramatically improved our understanding of the underlying pathomechanisms in mTBI. Although the precise pathomechanisms that tie frequent mTBI to neuropathological changes are not completely under- stood, they likely involve a series of multifocal mild axonal inju- ries set in motion by the initial trauma. More specifically, during mTBI, the brain undergoes shear deformation that pro- duces a stretch of axons, resulting in alterations in axonal mem- brane permeability and ionic shifts, including a massive influx of calcium into the […] cell, resulting in an accumulation in the […] mitochondria, which impairs oxidative metabolism, leading to energy failure and the breakdown of microtubules.12 Addi- tive effects may include a decrease in total cerebral blood flow,

activation of N-methyl-D-aspartate receptors, and a decrease in γ-aminobutyric acid and other inhibitory neurotransmit- ters.13,14,15 Trauma-induced metabolic changes, however, may return to baseline within a relatively short period. Nonetheless, some mTBI patients with persistent neurobehavioral and neu- rocognitive deficits demonstrate brain abnormalities that are revealed by advanced neuroimaging techniques.7,16,17,18 These advances go beyond conventional computed tomography (CT) and magnetic resonance imaging (MRI) and are reviewed below.

32.2 Imaging

32.2.1 Conventional Computed Tomography and Magnetic Resonance Imaging

Conventional CT and MRI are widely used to evaluate the acute effects of TBI and to rule out skull fracture, intracranial hemor- rhage, and brain edema. Therefore, many patients evaluated for mTBI will have undergone a CT scan or MRI or both as part of their acute evaluation. In mTBI, about 10% of the CT scans and about 30% of the conventional MRIs will show abnormalities, such as subarachnoid hemorrhage, subdural hemorrhage, or brain contusions.19,20,21

In the acute setting, conventional CT and MRI are often used to rule out severe complications of TBI, although both modal- ities have been demonstrated to lack sensitivity to detect subtle structural changes known to occur in mTBI. Moreover, these methods fail to accurately predict long-term outcome.22,23

In what follows, we review advanced neuroimaging tech- niques that are currently being used in research studies to evaluate subtle differences in the brains of patients who do not show abnormalities using conventional MRI sequences. We begin with high-resolution structural MRI, followed by a discus- sion of susceptibility-weighted imaging (SWI), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), func- tional and functional connectivity MRI, positron emission tomography (PET), and single-photon emission computer tomography (SPECT).

32.2.2 High-Resolution Structural

MR Imaging

To date, almost fully automated software tools, such as SPM and FreeSurfer,24 are available to quantify human brain volume. Region-of-interest (ROI) or voxel-based methods (VBM) also enable the characterization of specific white or gray matter structures, and they make possible comparisons between the groups. Consequently, quantitative analyses of brain volume and cortical thickness, based on high-resolution structural MRI, provide useful information for the diagnosis and prognosis of neurodegenerative diseases, such as mild cognitive impairment (MCI),25,26,27 Alzheimer’s disease (AD),27,28,29 and Parkinson’s

disease.30,31 Brain volume and cortical thickness are also known to correlate with cognitive performance.25,26,27 Moreover, a pro- nounced decrease in cortical thickness with age is thought to be a risk factor for the development of neurodegenerative dis- eases.28,29,30,31,32,33 Recent literature, in fact, suggests that the quantitative analysis of the brain’s structure, such as cortical thickness, may also be helpful in both diagnostic assessment and prognosis of mTBI.34

Studies by Lewén et al35 using animal models to investigate the effects of mTBI on cortical thickness in induced brain trauma in a murine model showed a significant increase in cor- tical thickness at the region of impact (frontoparietal cortex) at day 1, followed by a decrease in cortical thickness of 15 to 20% after 21 days. In another study,36 mice were treated with fluid percussion to induce brain trauma. Cortical thinning was found in the frontal and occipital regions of the ipsilateral hemisphere compared with a control group 17 days postinjury. These find- ings suggest a temporary swelling of the cortex directly after the trauma, followed by a decrease in cortical thickness in the chronic stage. This cortical thinning is likely due to wallerian degeneration and reactive astrogliosis.

Merkley et al37 also investigated changes in cortical thickness after TBI as a result of traffic accidents in children (age range, 9 to 16 years). In this study, widespread significant cortical thinning was found in the frontal, parietal, temporal, and occip- ital lobes at a mean postinjury scan interval of about 3 years. These investigators further report a correlation between mem- ory performance and “key regions” that have been reported to subserve working memory function.37 In a separate study, Wilde et al38 compared the cortex of 40 children with moderate to severe TBI with a control group who had orthopedic injury only. Cortical thinning was found in the frontal lobes and in the right temporal lobe in children with TBI compared with the control group. Work by Tremblay et al34 also suggests a link between a pronounced decrease in cortical thickness with age and a history of concussion in athletes participating in contact sports. The underlying mechanism is not understood, although shear injury of the axons with consecutive wallerian degenera- tion may play a role.

High-resolution structural MRI may thus be a useful tech- nique in assessment of the more chronic stages after mTBI and RBT. Future research is needed, however, to identify early changes in mTBI that may help to provide an accurate prognosis for developing neurodegenerative diseases such as CTE, as well as provide a window of opportunity for possible preventative treatment to halt the course of progressive symptoms, which are evident in a small, albeit important, cohort of patients afflicted with mTBI.

32.2.3 Susceptibility-Weighted Imaging

Susceptibility-weighted imaging (SWI) has proven an effective method for the study of brain microstructural changes and microhemorrhages that may result from acute, subacute, and chronic mTBI.39 For example, several studies have shown the positive predictive effects of SWI in pediatric patients with mTBIs of varying severity levels.40,41 These studies have also shown that a greater number and volume of microhemorrhages detected through SWI correlate with worse neuropsychological and clinical outcomes in pediatric populations. Evidence also

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supports the use of SWI as an effective tool in predicting long- term neurologic outcomes after TBI.42

Few studies have been conducted, however, to determine whether SWI is useful to detect microstructural changes in adult patients with acute and subacute mTBI. Existing studies have used SWI to determine the presence of microhemor- rhages in these patients. For example, Toth et al43 studied brain microhemorrhages in 14 patients with mTBI using DTI and SWI 72 hours and 1 month postinjury. SWI failed to detect microhemorrhages in any subjects, although signifi- cant changes in mean diffusivity (MD) and fractional anisot- ropy (FA) were detected using DTI.43 Similar studies in RBT have shown surprisingly few microhemorrhages in amateur boxers (3 of 42 studied), even though findings showed statis- tically significant differences from controls, where controls showed no microhemorrhages,44 and 2 of 21 boxers in another study showed microhemorrhages.45

However, in a more recent prospective study on the incidence of mTBIs in male and female hockey players, a new method for quantifying information from SWI was used to detect micro- structural changes in the brain during the acute and subacute phases of mTBI,46 as shown in ▶ Fig. 32.1a-c. During the season, five male and six female college-age hockey players who sus- tained a medically diagnosed concussion were tested using SWI 72 hours, 2 weeks, and 2 months postinjury. In all subjects, microhemorrhages were found. Furthermore, as noted earlier, this study used a novel measure of hypointensity burden (HIB), which showed significantly higher HIB in male hockey players compared with females, as well as between the preseason scan and 2 weeks postinjury (▶Fig. 32.1d). This may be a result of both acute damage on impact and then secondary damage in the chronic stages of injury.

Therefore, SWI may be a useful modality for detecting subtle microstructural brain changes and microhemorrhages associ- ated with postconcussive symptoms. However, to date, SWI has not been used to study patients with postconcussive symptoms. Future research is needed in this area, as early identification of these changes may help in determining patient prognosis and propensity for developing postconcussive syndrome (see review by Shenton et al16).

32.2.4 Magnetic Resonance-Diffusion

Tensor Imaging

Diffusion tensor imaging quantifies the diffusion of water mole- cules in the tissue investigated. DTI is a sensitive technique to evaluate the brain’s white matter microstructure after mTBI (for reviews see Niogi et al18 and Shenton et al16). Sensitivity of DTI for detecting subtle alterations after mTBI, compared with con- ventional CT or MRI, has been demonstrated in several stud- ies.47,48 Most studies using DTI to investigate brain alterations in mTBI and RBT have found alterations in the white matter microstructure. These alterations are thought to play a role in persistent cognitive and behavioral symptoms observed in postconcussive syndrome.

Fractional anisotropy and MD, common parameters derived from DTI, have been shown to be sensitive for detecting trau- matic axonal injury (TAI).49,50 A study by Niogi et al51 reported that 10 of 11 patients with postconcussive syndrome had a nor- mal 3 T MRI but showed decreased FA compared with a group

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Fig. 32.1 Representative (a) axial, (b) sagittal, and (c) coronal susceptibility-weighted images of a hockey player; hypointensity clusters that fall below intensity and size thresholds are overlaid in white, demonstrating exclusion of obvious blood vessels and sulci. (d) Hypointensity burden
(HIB; = [total number of voxels in accepted clusters]/[total number of brain voxels] X [volume in mm3 of one voxel]) at various time points before season (BOS), 72 hours after the start of the season, 2 weeks, 2 months, and at end of season (EOS) for both male (squares) and female (circles) patients; statistically significant differ- ence is noted at 2 weeks. (Modified, with permission, from Helmer KG, Pasternak O, Fredman E, et al. Hockey Concussion Education Project, Part 1. Susceptibility-weighted imaging study in male and female ice hockey players over a single season. J Neurosurg 2014;120 (4):864–872.)

of 26 normal controls. Interestingly, the subjects’ reaction time correlated significantly with the number of DTI lesions at least 1 month postinjury.51 In prolonged postconcussive syndrome, a decrease in FA and an increase in MD were demonstrated in the white matter tracts. Such alterations are most likely due to TAI49,50 and are most frequently found in the anterior corona radiata, the uncinate fasciculus, and the superior longitudinal fasciculus. These are all fiber tracts that represent association pathways within the same hemisphere and are most likely involved in cognitive functions like attention and memory.51 Further, commissural fibers of the corpus callosum have also been reported to be affected.50,52,53,54,55,56 The development of multitensor tractography overcomes the problem of crossing fibers and enables the tracking of fibers in the periphery until the gray/white matter border that is particularly vulnerable to TAI. ▶Fig. 32.2 shows the fiber tracts of the corpus callosum using multitensor tractography.

More recently, DTI has been used to evaluate white matter microstructure in active professional soccer players without a history of symptomatic concussion. Soccer players are at high risk for exposure to repetitive subconcussive brain trauma resulting from heading the ball with the unprotected head. Twelve male athletes trained for a career as professional soc- cer players since childhood were compared with athletes of noncontact sports.57 DTI revealed increased radial diffusivity in soccer players (▶Fig. 32.3). This finding is similar to the alterations seen in the chronic stages of mTBI and in RBT, suggesting that frequent subconcussive brain trauma may affect the brain’s microstructure.57 This hypothesis was fur- ther supported by a study of ice-hockey players who showed increased mean, radial, and axial diffusivity measure over the course of one play season.58 Three of the investigated athletes sustained a concussion, and they showed the most pro- nounced changes.

Fig. 32.2 Fiber tracts of the corpus callosum using multitensor tractography (left: coronal; right: sagittal).

A strong correlation between parameters of cognitive func- tion and alteration in white matter tracts has also been demon- strated in postconcussive syndrome.59 Specifically, in a sample of 43 mTBI patients, FA was decreased in the left anterior corona radiata compared with 23 healthy controls. Further, the decrease in FA was significantly correlated with less attentional control. Additionally, reduced FA in the uncinate fasciculus was correlated with memory performance.59 Of further note, Strain et al60 found that FA in the frontal lobe was negatively corre- lated with measures of depression. This supports the use of DTI as a biomarker of behavioral disturbance in RBT. Finally, DTI baseline evaluation in the acute phase after mTBI may be a pre- dictor of long-term outcome in cognitive and behavioral func- tion. For example, one study reported that acutely following TBI, decreased FA as well as increased MD predicted executive function at 6 months’ follow-up.61

Other advances on the horizon involve a free-water method derived from DTI.62 This method is able to separate free water that is extracellular (FW) from water that is surrounding tissue (FAt), where the former (i.e., FW) may suggest neuroinflamma- tory processes that precede neurodegeneration and the latter (FAt) may suggest neurodegeneration. This method has recently been applied to ice-hockey players, who are known to be at high risk for RBT.63 This study investigated the longitudinal course of concussion by comparing DTI in concussed ice-hockey players, before and 72 hours after a concussion. The alterations found suggest decreased extracellular space (increased FA and

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Fig. 32.3 Group comparison of diffusion tensor imaging data in 12 professional soccer players compared with eight competitive swimmers. The voxels highlighted in red demonstrate significantly increased radial diffusivity values for the soccer group compared with swimmers, indicating reduced axon diameter or myelin sheath. (Modified, with permission, from Koerte IK, Ertl-Wagner B, Reiser M, Zafonte R, Shenton ME. White matter integrity in the brains of professional soccer players without a symptomatic concussion. JAMA 2012;308(18):1859–1861.)

decreased RD) in white matter after acute concussion. This find- ing might be explained by neuroinflammation and other possi- ble alterations that occur due to concussions. The distinction between neuroinflammation and neurodegeneration might be important for identifying early stages of CTE after mTBI and RBT.

In summary, DTI is the only in vivo tool for investigating microstructural changes in white matter and is thus an impor- tant new probe for understanding diffuse axonal injuries in mTBI, the most common injuries observed in these patients. Finally, combining DTI results with other imaging information will likely also be most helpful in future studies.

32.2.5 Magnetic Resonance

Spectroscopy

Several studies have examined mTBI in the acute and subacute phases. These studies have generally demonstrated specific biochemical changes in N-acetyl aspartate (NAA, a putative neuronal marker), glutamatine and glutamine (Glx, excitatory neurotransmitter), creatinine (Cr, a marker of brain energetics), choline (Cho, marker of membrane turnover), and myoinositol (mI, a marker of glial proliferation).64 A large proportion of these studies showed consistent reductions in NAA, reflective of neuronal injury.65–70 However, findings from a study of acute to subacute mTBI in children failed to show reductions in NAA,

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suggesting that children may be protected from some neuro- logic alterations associated with TBI in adults or that other underlying biological changes predominate.71 Other studies have also demonstrated a reduction in Glx in brain gray matter along with increases in Glx and Cr in white matter. These find- ings suggest disturbances in neurotransmitter function in gray matter regions and altered energetics within white matter dur- ing the acute to subacute stages of mTBI. Evidence from these prospective studies also suggests that NAA, Cr, and Glx all return to baseline levels after adequate recovery without fur- ther TBIs.67,69 Evidence also suggests that NAA returns to nor- mal levels but may be slowed by a second episode of TBI.70 Fur- thermore, Chamard et al72 observed a significantly greater decrease in NAA/Cr over the course of a hockey season for female hockey players compared with male players, suggesting a possible difference in the effects of traumatic brain injury between sexes. Some evidence also supports the existence of abnormal levels of the glial marker mI in the acute to subacute stages of mTBI,73 although this finding has been less consistent across studies.

More recent MRS studies have also begun to focus on long- term outcomes in the chronic phase of mTBI. These studies suggest that alterations in brain metabolism may become manifest several years after the initial episode of TBI. A pri- mary finding of long-term studies of mTBI is a reduction in NAA across different brain regions, including the white mat- ter, splenium, and centrum semiovale, suggesting neuronal injury and loss.65,70,74,75,76

Other findings from these studies suggest an elevation of Cho, reflective of tissue injury or glial proliferation.65,66 It is likely that elevation of Cho in the acute phase is due to forces that cause injury to cell membranes and myelin, leading to an elevation in the amount of free Cho in the brain. On the other hand, an elevation of Cho in the chronic phase likely reflects a proliferation of glia, which is supported by increases in mI.77 These chronic findings seem to contradict the return of metab- olites to baseline values after an acute episode of mTBI. It is thus possible that these results are reflective of postconcussive syn- drome, whereby between 15 and 30% of individuals who suffer from mTBI develop symptoms that last longer than 3 months. However, most studies to date have not acquired adequate neu- ropsychological information to validate this possibility.64 Finally, Sarmento et al78 demonstrated larger reductions in NAA in individuals with chronic posttraumatic headaches com- pared with those with acute headaches, suggesting possible long-term neuronal loss. However, future prospective studies are needed to explore this possibility.

Several studies have documented reductions in NAA across brain regions in subjects exposed to RBT. A study of Iraq and Afghanistan war veterans exposed to RBT injuries showed reductions in hippocampal NAA:Cr and NAA:Cho in subjects with memory dysfunction compared with controls.79 Another study of retired boxers with parkinsonian syndrome demon- strated NAA reduction in the lentiform nucleus compared with controls and Parkinson’s disease patients, suggesting neuronal loss resulting from RBT.80 MRS has also been used to examine ice hockey and professional football players with histories of multiple concussions. These athletes exhibited increased mI in the left medial temporal lobe that correlated with episodic memory loss as well as an elevation in Cho in the prefrontal

cortex.34 Evidence also suggests that exposure to RBT can extend the time needed to fully recover NAA to baseline levels.70 Taken together, these results suggest that mTBI may lead to an extended period of brain vulnerability, which may be exacerbated by RBT.

A pilot study of RBT used a novel approach called two- dimensional correlated spectroscopy (2D-COSY), which obtains a second spectral dimension to measure additional metabolites not seen in studies using conventional MRS due to spectral overlap, as shown in ▶ Fig. 32.4. Among the changes observed in this study were statistically significant increases in Cho and Glx, consistent with excitotoxicity and axonal injury, as well as an increase in mI. 2D-COSY also showed changes in threonine, aspartate, and glutathione in the brains of these athletes, find- ings not observed using conventional MRS studies of RBT.81

32.2.6 Functional and Functional Connectivity Magnetic Resonance Imaging

Functional magnetic resonance imaging (fMRI) is an advanced MR neuroimaging that uses BOLD (blood-oxygen-level-depen- dent) contrast to distinguish between active and inactive brain regions. Compared with the previously discussed modalities, fMRI has been less frequently used in the evaluation of both the acute and chronic phase of mTBI. So far, it has been applied in research and, to lesser extent, in clinical settings.

Most fMRI studies in the field of TBI investigated the patterns of activation while subjects performed simple auditory-verbal, visual-verbal, or motor tests. Few studies applied resting-state fMRI, which has become an important area of research during the last decade.82,83,84,85,86,87 The resting-state activity of the brain, measured by means of fMRI, provides a measure of brain activation in the state of relaxed consciousness.88,89,90 In the resting awake state, the brain still uses 16% of the total body energy for neuronal firing and cycling of neurotransmitters.91 In this state, temporal synchronicity of neuronal activation pat- terns of spatially separated brain regions is detectable. The obtained data can be figured as a network of nodes and links, where the nodes are determined by voxels and the links are reflected by the degree of correlation in their activity. There is evidence that the integrity and strength of spontaneous func- tional connectivity in several networks are of behavioral and cognitive relevance (▶ Fig. 32.5)92,93,94,95,96

Between 1999 and 2006, McAllister et al performed five fMRI studies of mTBI patients and controls using auditory-verbal and visual-verbal N-back tasks. Although the analysis of the task performance revealed no group differences, the mTBI patients reported more neuropsychological symptoms. The observed activation was, however, shown to differ depending on the diffi- culty of the task variation. For example, mTBI patients showed increased activation while performing tasks of moderate diffi- culty and decreased activation when the tasks were more complex. Although four of five studies were performed with subjects who suffered from mTBI approximately 1 month before the scan, the remaining study investigated changes after the postconcussive symptoms were no longer present, at around 1 year postinjury. Although the symptoms had ceased, increased activation patterns in the right frontal lobe could still

Posttraumatic Cognitive Disorders

Fig. 32.4 Representative in vivo two-dimensional correlated spectroscopy of a human subject. Major metabolites are labeled at the diagonal; however, multiple resonances that represent cross-peaks of metabolites with additional resonances can also be observed. Color is scaled to the ratio to creatinine (Cr). Cho, choline; Glx, glutamine; mI, myoinositol; NAA, N-acetyl aspartate.

Fig. 32.5 Schematic presentation of the default mode network and its connections to dorsolateral prefrontal cortex “D.” The strength of the connectivity between cortical regions by means of correlation coefficient (r) is reflected by color. In general, an r > 0.3 is considered a threshold of valid connection; LLP, left lateral parietal; MPFC, medial prefrontal cortex; PCC, posterior cingulate cortex; RLP, right lateral parietal. (Modified, with permission, from Slobounov et al. Brain Imaging Behav 2012.)

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be observed. Therefore, it was concluded that persistent altera- tions in brain activation could be found even when postconcus- sive symptoms had abated.

In another study, Smits et al97 reported significantly lower N- back task performance in patients with postconcussive syn- drome. Additionally, positive correlations between postconcus- sive symptoms and atypical higher activation patterns were observed outside the normal activation circuit. One explanation may be that previously damaged brain areas need back up from brain areas that were previously not involved or that were involved to a lesser extent. Additionally, Gosselin et al98 reported a variety of brain regions that showed both increased and decreased brain activation in mTBI patients with more postcon- cussive symptoms, and in 2011 Matthews et al investigated mTBI patients 3 years postinjury and reported greater activation in patients with major depressive disorder in the fearful emotional face-matching task.99 In this same year, Matthews et al published a second study that compared mTBI patients who had suffered loss of consciousness with patients who had only altered con- sciousness. The time between the trauma and the investigation was again around 3 years. Participants in this second study were presented with a stop and go signal test. The fMRI analysis revealed decreased left frontal activation in the group of patients who were reported to have lost consciousness.100 Moreover, acti- vation in the left frontal area correlated with the reported symp- toms, which indicates that this area is a neural correlate of the impaired self-awareness after loss of consciousness.100

Initial studies using resting-state fMRI found activity disrup- tions within the default-mode network (DMN) in both patients with (blast-related) TBI101,102 and mTBI.103,104 A recently pub- lished study by Palacios et al102reported that increased ampli- tudes of low fluctuation are related to better neurocognitive performance in patients after TBI with chronic and severe axo- nal injury and that the loss of functional integrity in certain brain areas can lead to compensatory increases in nodes of the default-mode network (DMN). Dysfunction of the DMN in patients with mTBI compared to healthy controls was observed by Zhou et al and further investigated by Sours et al, who hypothesized that disruptions between the DMN and the task- positive network (TPN) might account for the memory dysfunc- tions observed in patients with mTBI.

The long-term effects of mTBI have been investigated by Monti et al, who compared younger and older mTBI patients with their respective age- and gender-matched controls. In accordance with previous findings, decreased bilateral hippo- campal values were observed, whereas fMRI analysis showed reduced activity of the posterior parietal cortex during a hippo- campal memory task. These findings may indicate the (func- tional) long-term significance of a previous mTBI.105

32.2.7 PositronEmissionTomography

Most positron emission tomography (PET) studies have focused on the chronic stages of mTBI as opposed to acute stage or more severe injury.106,107,108,109 Using 2-deoxy-2-(18F)-fluoro-D- glucose (FDG), studies performed in a resting state106,107 or with performance stimuli108,110 have demonstrated hypometabolism in the frontal and temporal lobes, which in some cases corre- lated with neuropsychological examinations but not with MRI or CT changes. Other studies have also shown hyper-

metabolism. This discrepancy is likely the result of differences in individual subjects, including type, rate, and time of injury, as well as differences in protocols.108,110

Two FDG-PET studies have focused on the effects of RBT in boxers111 and soldiers suffering from multiple blast expo- sures.112 Both groups showed hypometabolism in the cerebel- lum, whereas boxers showed additional changes in the poste- rior cingulate and frontal lobes, and the blast victims also showed changes in the medial temporal lobe and pons. In veter- ans, there is also the strong comorbidity of posttraumatic stress disorder (PTSD). Mendez et al113 excluded military subjects with PTSD and examined blast versus blunt head trauma. Their results showed hypometabolism in the frontotemporal regions but hypermetabolism in the caudate in soldiers with blast trauma but not blunt head trauma.

With such a small number of studies, it is difficult to draw conclusions regarding patterns of glucose metabolism. More recent studies show great promise by focusing on different aspects of RBT. The presence of tau aggregates has also been well-documented in postmortem studies of CTE.114,115 In a pre- liminary study, Small et al used 2-(1-)6-[(2-[18F] fluoroethyl) (methyl)amino]-2-naphthyl) ethylidene) malononitrile (FDDNP) for PET imaging in five retired National Football League players with history of cognitive and mood symptoms.116 FDDNP binds to both tau neurofibrillary tangles and amyloid plaque in brain tissue117 and therefore is not specific to tau, whereas tau- specific PET ligands have been developed118,119,120,121 that show great promise in characterizing tau aggregates in vivo, as opposed to postmortem. These latter, more specific tau ligands will be important in determining whether or not those with RBT are characterized more by tau pathology, which would fol- low the postmortem work of McKee et al114,115 in National Foot- ball League players and military postmortem findings of tau rather than amyloid plaque in brain tissue.

The PET ligands can also explore physiologic changes, such as neuroinflammation. By targeting peripheral benzodiazepine receptors found on activated microglia from neuroinflamma- tion, 11C-PK11195has been used to examine inflammation in chronic mTBI122 up to 17 years postinjury.123 However, 11C -PK11195has low binding specificity, such that other probes may prove to be more effective.124 Further, combining this mea- sure with a measure of free water and MRS measures sensitive to neuroinflammation, such as glutathione, described previ- ously in this chapter, would help to specify further the role of neuroinflammation in RBT and mTBI.

32.2.8 Single-Photon Emission

Computed Tomography

Single-photon emission computed tomography has been used to examine regional cerebral blood flow (rCBF) in several stud- ies of mTBI. Two studies have shown rCBF defects in the acute stage after injury including reduced perfusion of SPECT tracers in the frontal lobes of patients with mTBI. In the subacute stage, similar patterns have been observed of reduced rCBF in the frontal lobes127 as well as parietal lobe.128

In the chronic stages of mTBI, many SPECT studies focus on comparison with other imaging modalities, such as MRI and CT.128,129,130,131,132 In all studies, SPECT showed greater sensitiv- ity to detect abnormal changes compared with both imaging

methods. This is not surprising given the known lack of sensi- tivity of conventional MRI and CT. Other studies have compared SPECT findings with neuropsychological measures,130,131,133,134, 135 which have shown more mixed results, with some studies showing expected correlations with frontal brain regions and others not. This may be due to the fact that SPECT is acquired in the resting state, as opposed to the active state when patients are engaged in complex tasks and that rCBF patterns do not cor- respond with resting and activated brain states.134

With regard to RBT, studies are limited to two by the same group who studied 100 retired National Football League play- ers,136 including a subset of 30 players who underwent evalua- tion for potential treatments.137 The result of their 100-subject study revealed hypoperfusion in the prefrontal poles, temporal poles, occipital lobes, anterior and posterior cingulate gyri, and hippocampus.

Importantly, however, SPECT studies are limited by the fact that the method relies on comparison with “normal” brain regions. Given the diffuse changes that occur in mTBI, however, there may not be unaffected regions for comparison.138 Second, the observed SPECT changes are not specific to mTBI and have also been observed in chronic pain, in drug and alcohol abuse, and in headaches, many of which are comorbid issues, particu- larly in professional athletes.139 As a result, SPECT findings are not considered diagnostic of mTBI, although the absence of SPECT abnormalities is considered prognostic for good recovery.140

32.3 Summary and Future

Directions

Today, advanced multimodal neuroimaging techniques can pro- vide a diagnosis of brain injury in mTBI and RBT that goes beyond self-report and other measures, and may elucidate fur- ther the mechanisms and neurophysiology underlying mTBI. This is an important first step. More studies using multimodal imaging techniques are needed, however, as no single imaging modality captures the kind of injury extant in mTBI. There is also a need to understand mTBI and RBT in general, and to be cognizant that they are heterogeneous disorders. We need to develop individual profiles of injury. An example is the recent work by Bouix et al,141 who observed increases in gray matter in chronic mTBI using individual profiles of injury for patients, based on developing a normative atlas and comparing individ- ual patients to the atlas to develop the profile of injury. Further, future research should also include multimodal imaging to acquire different information from different modalities in the same patient to have a more complete picture of each patient’s brain alterations. Moreover, based on their enhanced sensitiv- ity, many of these newer and more advanced imaging tech- niques can be used to monitor treatment efficacy, and they may also serve as endpoints for new trials of medication aimed at neuroplasticity or reduced neuroinflammation in TBI. This is an exciting new era of discovery that has been long overdue in diagnosing mTBI on the basis of objective radiologic evidence, which sets the stage for a more complete understanding of the pathophysiological mechanisms underlying mTBI and RBT, with the hope that this understanding, including following the tra- jectory of injury and recovery, will lead to more efficacious

Posttraumatic Cognitive Disorders

treatments and to the monitoring of treatments using more sensitive imaging techniques.

32.4 Acknowledgment

The authors of this chapter wish to acknowledge the Else Kröner-Fresenius Stiftung, Germany (IK, MM). This work was also partially funded by grants from The Department of Defense (W81XWH-10-1-0835: APL; W81XWH-07-CC-CSDoD: MES; W81XWH-13-2-0063: MES), the National Institutes of Health (R01-NS078337: APL, MES; R01-NS078337), and a VA Merit Award (MES).

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[101] Han K, Mac Donald CL, Johnson AM et al. Disrupted modular organization of resting-state cortical functional connectivity in U.S. military personnel fol- lowing concussive ‘mild’ blast-related traumatic brain injury. Neuroimage 2014; 84: 76–96

[102] Palacios EM, Sala-Llonch R, Junque C et al. Resting-state functional magnetic resonance imaging activity and connectivity and cognitive outcome in trau- matic brain injury. JAMA Neurol 2013; 70: 845–851

[103] Sours C, Zhuo J, Janowich J, Aarabi B, Shanmuganathan K, Gullapalli RP. Default mode network interference in mild traumatic brain injury: a pilot resting state study. Brain Res 2013; 1537: 201–215

[104] Zhou Y, Milham MP, Lui YW et al. Default-mode network disruption in mild traumatic brain injury. Radiology 2012; 265: 882–892

[105] Monti JM, Voss MW, Pence A, McAuley E, Kramer AF, Cohen NJ. History of mild traumatic brain injury is associated with deficits in relational memory, reduced hippocampal volume, and less neural activity later in life. Front Aging Neurosci 2013; 5: 41

[106] Kato T, Nakayama N, Yasokawa Y, Okumura A, Shinoda J, Iwama T. Statistical image analysis of cerebral glucose metabolism in patients with cognitive impairment following diffuse traumatic brain injury. J Neurotrauma 2007; 24: 919–926

[107] García-Panach J, Lull N, Lull JJ et al. A voxel-based analysis of FDG-PET in trau- matic brain injury: regional metabolism and relationship between the thala- mus and cortical areas. J Neurotrauma 2011; 28: 1707–1717

[108] Gross H, Kling A, Henry G, Herndon C, Lavretsky H. Local cerebral glucose metabolism in patients with long-term behavioral and cognitive deficits fol- lowing mild traumatic brain injury. J Neuropsychiatry Clin Neurosci 1996; 8: 324–334

[109] Chen SH, Kareken DA, Fastenau PS, Trexler LE, Hutchins GD. A study of per- sistent post-concussion symptoms in mild head trauma using positron emis- sion tomography. J Neurol Neurosurg Psychiatry 2003; 74: 326–332

[110] Humayun MS, Presty SK, Lafrance ND et al. Local cerebral glucose abnormali- ties in mild closed head injured patients with cognitive impairments. Nucl Med Commun 1989; 10: 335–344

[111] Provenzano FA, Jordan B, Tikofsky RS, Saxena C, Van Heertum RL, Ichise M. F- 18 FDG PET imaging of chronic traumatic brain injury in boxers: a statistical parametric analysis. Nucl Med Commun 2010; 31: 952–957

[112] Peskind ER, Petrie EC, Cross DJ et al. Cerebrocerebellar hypometabolism asso- ciated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war veterans with persistent post-concussive symptoms. Neuroimage 2011; 54 Suppl 1: S76–S82

[113] Mendez MF, Owens EM, Reza Berenji G, Peppers DC, Liang LJ, Licht EA. Mild traumatic brain injury from primary blast vs. blunt forces: post-concussion consequences and functional neuroimaging. NeuroRehabilitation 2013; 32: 397–407

[114] McKee AC, Stern RA, Nowinski CJ et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 2013; 136: 43–64

[115] McKee AC, Cantu RC, Nowinski CJ et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 2009; 68: 709–735

[116] Small GW, Kepe V, Siddarth P et al. PET scanning of brain tau in retired National Football League players: preliminary findings. Am J Geriatr Psychia- try 2013; 21: 138–144

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Zhang W, Arteaga J, Cashion DK et al. A highly selective and specific PET tracer for imaging of tau pathologies. J Alzheimers Dis 2012; 31: 601–612 Shao X, Carpenter GM, Desmond TJ et al. Evaluation of [11C]N-methyl lanso- prazole as a radiopharmaceutical for PET imaging of tau neurofibrillary tan- gles. ACS Med Chem Lett 2012; 3: 936–941

Shoup TM, Yokell DL, Rice PA et al. A concise radiosynthesis of the tau radiopharmaceutical, [18F]T807. J Labelled Comp Radiopharm 2013; 56: 736– 740
Chien DT, Bahri S, Szardenings AK et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis 2013; 34: 457–468

Folkersma H, Boellaard R, Yaqub M et al. Widespread and prolonged increase in (R)-11C-PK11195 binding after traumatic brain injury. J Nucl Med 2011; 52: 1235–1239
Ramlackhansingh AF, Brooks DJ, Greenwood RJ et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol 2011; 70: 374–383

Yanamoto K, Yamasaki T, Kumata K et al. Evaluation of N-benzyl-N-[11C] methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([11C]DAC) as a novel translocator protein (18 kDa) radioligand in kainic acid- lesioned rat. Synapse 2009; 63: 961–971

Abu-Judeh HH, Singh M, Masdeu JC, Abdel-Dayem HM. Discordance between FDG uptake and technetium-99m-HMPAO brain perfusion in acute traumatic brain injury. J Nucl Med 1998; 39: 1357–1359
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Hofman PA, Stapert SZ, van Kroonenburgh MJ, Jolles J, de Kruijk J, Wilmink JT. MR imaging, single-photon emission CT, and neurocognitive performance after mild traumatic brain injury. AJNR Am J Neuroradiol 2001; 22: 441–449 Gray BG, Ichise M, Chung DG, Kirsh JC, Franks W. Technetium-99m-HMPAO SPECT in the evaluation of patients with a remote history of traumatic brain

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Part XII

Endocrine and Toxins-Related Dementia

33 Endocrine-, Metabolic-, Toxin-, and Drug-Related Dementia 296

XII

Endocrine and Toxins-Related Dementia

33 Endocrine-, Metabolic-, Toxin-, and Drug-Related Dementia

Sangam G. Kanekar and Brian S. Bentley

The economic burden of dementia is enormous. Establishing a precise cause of dementia whenever possible allows a more focused treatment plan and an accurate assessment of progno- sis. Reversible or preventable causes form around 15 to 20% of dementia cases. The exact incidence of dementia from endo- crine-, metabolic-, nutritional-, toxin-, and drug-related causes is difficult to estimate.

Increasingly, attention has been directed to these causes because these conditions are either preventable or reversible with appropriate treatment. Several endocrine disorders and nutritional deficiencies can masquerade as dementia and need to be investigated, especially in young patients with rapidly progressive dementias. Metabolic derangements resulting from hepatic or renal failure can lead to neuro- toxicity and cognitive decline. Several toxins, such as arsenic, mercury, aluminum, lithium, or lead, can also lead to cogni- tive decline. Other silent causes of dementia are chronic medications, particularly medicines for central nervous sys- tem (CNS) disorders (anticholinergic, antiepileptic, antipar- kinson), especially in elderly patients. In this chapter, we dis- cuss the clinical and imaging findings of various common and uncommon causes of dementia attributable to endo- crine-, metabolic-, nutritional-, toxin-, and drug-related causes (▶ Table 33.1).

Table 33.1 Common causes of irreversible dementia due to endocrine disorders, metabolic disorders, nutritional deficiencies and toxins

Endocrine dysfunction

Hypothyroidism

Hyperthyroidism

Hashimoto encephalopathy

Hypo- and hyperparathyroididsm

Pituitary insufficiency

Cushing’s disease

Addison’s disease

Hypoglycemia type 2 diabetes mellitus

Metabolic

Uremic encephalopathy

Dialysis disequilibrium syndrome

Dialysis dementia

Hepatic encephalopathy

Hepatic or portal systemic encephalopathy

Electrolyte imbalance

Porphyria

Nutritional deficiencies

Wernicke-Korsakoff syndrome

Pellagra, caused by niacin deficiency

Vitamin B12 deficiency

Toxins

Alcoholic-related dementia

Heavy metal poisoning

Carbon monoxide poisoning

Drugs and medications

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33.1 Endocrine Dysfunction

Various endocrinal abnormalities can cause derangement in the functioning of the CNS. These functional derangements could be due to either direct effects of hormones on the CNS or indirect effects through various electrolytes or immune- mediated processes.

33.1.1 Thyroid Hormones

and Cognition Disorders

Acute as well as chronic dysfunction in the thyroid gland may lead to cognitive decline and dementia. Hyperthyroidism as well as hypothyroidism can affect brain functioning at the transmitter level, leading to various neuropsychiatric and cog- nitive manifestations.1 Hyperthyroidism is more frequent in women and may manifest with myopathy, peripheral neuropa- thy, movement disorders, seizures, ophthalmoplegia, along with attention, memory, and visuospatial deficits. Hypo- thyroidism can cause peripheral neuropathy, myopathy, ataxia, cerebellar symptoms, myxedema, depression, and a dementia syndrome with a frontal-subcortical pattern. Deficits in atten- tion, recent memory, and abstract thinking may be present.

Thyroid hormones (TH) [T3 and T4] are essential for the devel- opment, maturation, and maintenance of the brain cells and cholinergic functions. THs essentially modulate all metabolic pathways through alterations in oxygen consumption and changes in protein, lipid, carbohydrates, and vitamin metabo- lism. Astrocytes display TH receptors and possess a dependency on THs for glucose transport and expression of specific struc- tural proteins. THs exert great influence on the selected brain regions, notably hippocampal (CA3 and CA2 areas of hippocam- pus), cortical, basal forebrain, and cerebellar areas, where they have influence on neurotransmitters (acetylcholine and cholin- ergic) functions and nerve growth factor.1 Deficiency in THs is shown to have a deleterious effect on synaptic connectivity and decreases myelination.

Low levels of TH are thought to increase amyloid precursor protein expression, which in turn increases the A- β production. Hypothyroidism has been considered a reversible cause of sec- ondary dementia in the elderly and therefore thyroid function tests is a must in the workup for patients with dementia.1 Com- puted tomography (CT) and magnetic resonance imaging (MRI) of the brain are usually unremarkable. Single-photon emission computed tomography (SPECT)/positron emission tomography (PET) may show frontotemporoparietal cortical hypometabo- lism (▶ Fig. 33.1). Definitive diagnosis is by hormonal assay and clinical examination.

33.1.2 Hashimoto’s Encephalopathy Hashimoto’s encephalopathy (HE) is an uncommon neurologic

syndrome associated with Hashimoto thyroiditis. The

Endocrine-, Metabolic-, Toxin-, and Drug-Related Dementia

Fig. 33.1 Hypothyroidism. Sagittal view of fluorodeoxyglucose-posi- tron emission tomography scan shows hypometabolism in the frontal lobes with normal uptake in the rest of the lobes of the cerebral parenchyma.

Fig. 33.2 Cushing’s syndrome with memory loss. Coronal T1-weighted image shows moderate atrophy of hippocampi bilaterally (arrows).

pathophysiology of HE is not entirely clear; the cause has been proposed to be autoimmune because of its association with other immunologic disorders. It is proposed that immune com- plexes deposit on vessels, causing cerebral microvasculature disruption and microscopic brain damage. HE is characterized by various neuropsychological symptoms, including cognition and/or consciousness deterioration, personality changes, sei- zures, and myoclonus. More recently, HE has gained growing attention as a cause of treatable dementias. HE has two pat- terns: acute encephalopathy (25%) manifests with focal neuro- logic deficits and a variable degree of cognitive dysfunction and consciousness impairment, whereas diffuse progressive pattern (75%) shows slow cognitive decline, dementia, and confusion.2

In approximately 50% of patients with HE, MRI may be nor- mal. In the remaining patients, MRI manifestations can vary from ischemic lesions, demyelination, and vasogenic edema to atrophy. The most commonly reported findings are generalized cerebral atrophy, diffuse increased signal on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in sub- cortical white matter and dural enhancement.3 White matter hyperintensity and atrophy may also be seen in the cerebellum. Rarely, the mesial temporal lobes and basal ganglia may be involved. Diffusion-weighted imaging (DWI) may show revers- ible areas of restricted diffusion in these regions. On magnetic resonance spectroscopy (MRS), affected areas may demonstrate reduction of N-acetyl-aspartate (NAA) and increased choline (Cho). Imaging findings may resolve with steroids or other immunosuppressant treatments. SPECT may show nonspecific patterns of reduced blood flow involving multiple regions in the brain, and PET scans may demonstrate some nonspecific hypometabolism. Diagnosis of Hashimoto’s thyroiditis is con-

firmed by the presence of elevated serums levels of antithyroid antibodies.

33.1.3 Cushing’s Syndrome

Cushing’s syndrome is an endocrine disorder characterized by sustained hypercortisolemia, either from an endogenous over- production of cortisol or treatment with exogenous steroids. In Cushing’s syndrome, the most prominent pathological change seen in the brain is atrophy.4,5 A combination of water loss as a result of alterations in vascular permeability and diuresis of sodium and water and the catabolic effects of cortisol are believed to be responsible for the reduction in brain mass. Glu- cocorticoids affect both the structure as well as the neuro- transmitter system of the brain, which are believed to suppress the myelin content in the brain, modulate neurotransmitter systems, affect serotonin biosynthesis, increase the uptake of norepinephrine, and regulate the plasticity and circuitry of many brain regions.4

Clinical presentation may include difficulty in concentration, memory difficulties, and short- and long-term logical memory deficits, as well as possible associated attention, language, visuo- spatial, and reasoning deficits. Like Cushing’s disease, patients with Addison’s syndrome can have a dementia syndrome with irritability, psychosis, apathy, fatigue, and depression.

Besides generalized atrophy on imaging, research studies have also documented hippocampal changes on MRI. In the chronic stages, MRI findings may correlate with the patho- logical findings of hippocampal sclerosis characterized by neuronal loss and gliosis in the CA-1 and subiculum of the hip- pocampus (▶Fig. 33.2). MRS may show decreased NAA:Cho

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and NAA:creatinine (Cr) levels, suggestive of neuronal changes in the temporal lobe.

33.1.4 Parathyroidism

Cognitive disturbances are seen in both hypoparathyroidism and hyperparathyroidism and are most often due to derange- ments in free calcium.5 Patients with hyperparathyroidism may have generalized weakness, fatigue, irritability, lethargy, depressed mood, and memory deficits. Hypoparathyroidism (idiopathic or acquired) and pseudohypoparathyroidism (a familial disease) are rare and mostly manifest with tetanus, seizures, extrapyramidal signs, dystonia, ataxia, and demen- tia.5 The exact biochemical mechanism responsible for the development of dementia in parathyroid dysfunction is unknown but presumed to be due to influence of calcium metabolism on higher cortical functioning. In addition, increased cerebrospinal spinal fluid concentrations of both total and ionized calcium are thought to impair blood–brain barrier (BBB) function. CT, MRI, and plain radiography of the skull reveal calcium deposits in the basal ganglia and occa- sionally in the thalamus and cerebellum (▶Fig. 33.3). Func- tional MRI has demonstrated a significant reduction in the regional cerebral blood flow in cingulate cortex, superior and inferior frontal cortex bilaterally, anterior temporal cortex, precentral gyrus, postcentral gyrus, and parietal cortex. Final diagnosis is by biochemical analysis.

33.1.5 Hypoglycemia and Type 2

Diabetes Mellitus

It is well established that the patients with diabetes mellitus are at increased risk of dementia.5 However, the exact cause and mechanism leading to this are still debatable. Hypo- glycemia is a frequent phenomenon in patients treated for dia- betes mellitus. These frequent hypoglycemic events are thought to impair nutrient delivery to the brain, downregulate different markers of neuronal plasticity, and increase the amount of neu- rotoxic glutamate. Severe hypoglycemia can result in perma- nent neurologic sequelae, including neuronal cell death, which may further accelerate the process of dementia.5 This damage

particularly impacts the neuronal receptors in the CA-1, subiculum dentate, and granule cell areas of the hippo- campus; regions that are critical for learning and memory. In addition, associated cerebrovascular disease and hyperinsuline- mia may further compound the cognitive decline.

Magnetic resonance imaging is quite sensitive in identifying the pathologic changes due to hypoglycemia. In acute stages, DWI shows areas of restricted diffusion involving the cerebral cortex, hippocampi, and deep gray matter nuclei bilaterally with corresponding apparent diffusion coefficient changes (▶ Fig. 33.4). In the later stages, these areas may show increased

Fig. 33.3 Hyperparathyroidism. Axial computed tomography image shows dense bilateral calcification of the basal ganglia, cerebellum, and left cerebral subcortical white matter (black arrows).

Fig. 33.4 Acute hypoglycemia. (a,b) Axial diffu- sion-weighted images show areas of restricted diffusion (arrows) in the left frontal, parietal, and temporal lobes, gyri, and subjacent white matter.

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signal intensity on T2 and FLAIR images, with mild to moderate changes of atrophy.

33.2 Metabolic Disorders 33.2.1 Uremic Encephalopathy

Epidemiologic data have shown the prevalence of chronic kidney disease increasing rapidly in the elderly population, with more than 25% of people over the age of 60 having stage 3 disease (National Institutes of Health, 2012).6 The rising rate of renal disease in elderly patients who may already have a pri- mary CNS impairment makes the diagnosis of uremic encephal- opathy critical. Imaging findings, along with corresponding bio- chemical changes, may be helpful in differentiating uremic encephalopathy from other neurodegenerative disorders.

The role of CT is somewhat limited when evaluating uremic encephalopathy. Imaging typically demonstrates cerebral atro- phy with secondary ventricular dilation in the setting of chronic uremia. MRI is the preferred imaging modality when assessing a patient with acute uremia, and two patterns are typically seen: cortical edema or basal ganglia edema.7 Edematous cortex and subjacent white matter show hyperintensity on T2 and FLAIR images with corresponding reversible hypointensity on T1-weighted images (▶Fig. 33.5). This appearance on MRI is somewhat similar to that seen in posterior reversible encephal- opathy syndrome (PRES) and may be related. In the basal ganglia pattern, the hyperintensity attributable to vasogenic edema is seen predominately involving bilateral corpus stria- tum and globus pallidus,8 which resolves after dialysis and is characteristic of uremic encephalopathy. Although the exact pathophysiology of both edema patterns is unclear, proposed mechanisms involve a combination of impaired cellular metab- olism from uremic toxins, such as parathyroid hormone, along with vascular territories that are vulnerable to ischemia.

33.2.2 Dialysis Disequilibrium

Syndrome

Dialysis disequilibrium syndrome (DDS) is another metabolic disorder encountered in patients with impaired kidney func-

tion who develop cerebral edema. Patients with markedly ele- vated blood urea nitrogen (BUN) levels who subsequently undergo renal replacement therapy with hemodialysis can have a rapid decrease in urea, resulting in reduced plasma osmolality and increased osmotic gradient across cell membranes. An intracellular shift of water occurs and results in reversible cere- bral edema seen on imaging. An alternative mechanism pro- poses that a reduction in intracellular pH causes increased brain osmolality and edema. Typically, DDS arises in patients at the end of, or shortly after, dialysis who complain of headache, dizziness, or vomiting. Imaging findings of DDS can range from diffuse cerebral edema to bilateral patchy T2-weighted and FLAIR white matter signal hyperintensity indicating increased brain water content.9 Incidence of DDS has improved with newer dialysis regimens; however, recognized risk factors remain older age, first dialysis treatment, preexisting neuro- logic disease, severe metabolic acidosis, and BUN lev- els > 175 mg/dl. It is important to note that DDS is separate from dialysis-associated osmotic demyelination syndrome, which may occur after rapid electrolyte shifts causing myelinolysis classically in the central pons, although extrapontine lesions are not atypical.

33.2.3 Dialysis Dementia

As patients with renal disease are living longer with dialysis, there is10 corresponding concern for increased rates of chronic dialysis-related comorbidities. Dialysis dementia was initially caused by accumulation of the dialysate phosphate binder, aluminum hydroxide, in the cortical gray matter.11 As dialysis improved and newer binding agents were developed, the rates of dialysis dementia have decreased. Cortical atro- phy is the common imaging finding seen in dialysis dementia patients (▶Fig. 33.6). Studies suggest that chronic dialysis patients experiencing cognitive impairment or movement disorders have deranged cerebral metabolite concentrations. Significant elevations of myoinositol (Myo) peak and increas- ed Myo:Cr ratio are seen in the cortical gray matter on MRS. DTI studies in these patients have demonstrated decreasing fractional anisotropy in the white matter, possibly due to microstructural distortion.12

Fig. 33.5 Uremic encephalopathy. (a,b) Axial T2- weighted images show edematous gyri with mild effacement of the sulci resulting from gyral edema (arrowheads). Similar changes are also seen along the cerebellar folia (arrow).

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Fig. 33.6 Dialysis dementia in 47-year-old man. (a) Axial T2-weighted image shows generalized prominence of convexity sulci advanced for the age of the patient. (b) Axial computed tomog- raphy image (bone window) shows diffuse thickening of the calvarium with sclerosis.

33.2.4 Hepatic Encephalopathy

Patients with advanced liver disease can experience a reversible syndrome of brain dysfunction that is characterized by neuro- psychiatric symptoms and is termed hepatic encephalopathy (HepE). HepE is thought to be due to an increase in blood ammonia levels and its associated neurotoxicity.13 Final diagno- sis is mostly by clinical and laboratory abnormalities. The most frequent imaging abnormality associated with HepE is bilateral symmetric T1-weighted hyperintensities in the basal ganglia, most commonly in the globus pallidus, secondary to manga- nese deposition and its paramagnetic effect (▶Fig. 33.7). Studies using proton MRS have demonstrated an association between the severity of HepE and the increased magnitude of the glutamine/glutamate peak,14 which reverses after treat- ment with liver transplantation. As with other metabolic neurodegenerative diseases, HepE patients are susceptible to diffuse cerebral edema and subtle shifts in the brain water content of white matter. On MRI, besides FLAIR and DWI, mag- netization transfer (MT) is quite sensitive and shows mild decreases in MT ratios, especially in the parietal and frontal lobes.15 T2 hyperintensity may also be seen along the white matter corticospinal tracts, indicative of mild edema.

33.3 Nutritional Deficiencies 33.3.1 Wernicke-Korsakoff Syndrome

Nutritional deficiencies can frequently result in neurologic sequelae. Wernicke-Korsakoff syndrome (WKS) is a relatively common illness caused by low thiamine (vitamin B1) intake, which is often associated with alcoholism. It may also be seen with malignancy, total parenteral nutrition, abdominal surgery, hyperemesis gravidarum, hemodialysis, or any situation that predisposes an individual to a chronically malnourished state. Generically, WKS encompasses two different syndromes: an acute presentation of confusion and ataxia, referred to as Wernicke encephalopathy (WE), and a chronic dementia with confabulation and psychosis known as Korsakoff syndrome (KS). Korsakoff psychosis (KP) is frequently confused with alcoholic dementia. KP is not a dementia but rather a pure amnesia with

severely impaired short-term recall but excellent long-term memory and other intellectual functions.

In a thiamine-deficient state, there is inability to regulate the osmotic gradients that disrupt the BBB, resulting in cytotoxic edema and, eventually, permanent neuronal loss in the areas with the highest metabolic demands. The classic triad of WE – ataxia, global confusion, and ophthalmoplegia – may not be present in most patients. The most common initial symptom is nonspecific mental status changes.

Fig. 33.7 Hepatic encephalopathy. Axial T1-weighted imaging shows typical diffuse hyperintensity signal in the lentiform nucleus (arrows).

In the acute setting of WE, typical imaging abnormalities are related to focally edematous lesions in the medial thalami, mammillary bodies, tectal plate, and periventricular and peria- queductal gray matter, as noted by bilateral symmetric T2- weighted and FLAIR signal hyperintensity (▶ Fig. 33.8).16 These areas may also show restricted diffusion in the acute stage of WE. The thalamus and mammillary bodies frequently display enhancement on postcontrast T1-weighted imaging; this is more often associated with alcohol-induced WE as opposed to nonalcoholic WE.17 Cerebellum may show mild atrophy with hyperintensity in the dentate nuclei.

Persistent thiamine deficiency results in disease progression leading to diffuse cerebral atrophy, enlargement of the ventri- cles, and atrophy of the mammillary bodies. Quantitative MRI may demonstrate significant regional volume deficits in KS patients involving the mammillary bodies, medial thalamus, and genu of the corpus callosum. PET and fMRI may be useful in defining the memory functions, which are disrupted in KS. 18F- fluorodeoxyglucose (FDG) PET may demonstrate significant hypometabolism in the diencephalic gray matter, suggesting interruption of the diencephalic-limbic circuit. MRS studies have revealed a low NAA:Cr ratio and an elevated lactate peak in the thalamus and cerebellum in the setting of KS.18

33.3.2 Vitamin B12 Deficiency

Deficiency of vitamin B12 (cobalamin) is seen secondary to per- nicious anemia, malabsoprtion, or a congenital defect in B12 metabolism and may manifest with neurologic symptoms, including progressive motor and sensory deficits, ataxia, and cognitive impairment. The most commonly recognized mani- festation of vitamin B12 deficiency is subacute combined degen- eration (SCD). SCD has a gradual onset of progressive extremity weakness, numbness, and paresthesias resulting from degener- ation of the posterior and lateral columns of the cord. Pathology shows swelling of the myelin sheaths, demyelination, wallerian degeneration, and gliosis. MRI of the cervical and thoracic spi- nal cord may demonstrate cord expansion early in the disease process, along with high-signal lesions on T2-weighted sequences in the dorsal and lateral columns (▶ Fig. 33.9). Brain

Endocrine-, Metabolic-, Toxin-, and Drug-Related Dementia

Fig. 33.8 Alcoholic encephalopathy. Axial
(a) fluid-attenuated inversion recovery and
(b) T2-weighted images show symmetric hyperintensity in the medial thalami (arrowhead) and mamillary bodies (arrow).

changes in B12 deficiency have not been studied extensively; however, multifocal white matter T2-weighted signal hyperin- tensities and atrophy have been identified.19 Newborns of mothers with pernicious anemia can have severe diffuse cere- bral atrophy with moderate ventricular enlargement, which is often reversible following appropriate replacement therapy.20

33.4 Toxins
33.4.1 Alcohol-Related Dementia

The current Diagnostic and Statistical Manual IV21 criteria for alcohol-related dementia (ARD) specify the persistence of cogni- tive and functional decline after the cessation of alcohol con- sumption, with all other causes of dementia excluded. The exact incidence and prevalence of ARD vary in the literature. Preva- lence studies in nursing homes have reported ARD to account for 10 to 24% of all dementias.

The clinical manifestations of alcohol dementia are similar to other types of dementia, which include memory problems, lan- guage impairment, and inability to perform complex motor tasks. ARD has a younger age of onset (< 60 years of age), is less progressive than Alzheimer’s disease, and is even potentially partially reversible. Autopsy evaluations demonstrate some degree of brain pathology in up to 78% of alcoholics.

Direct neurotoxic effect of alcohol is through glutamate exci- totoxicity, oxidative stress, and the disruption of neurogene- sis.22,23 This effect is particularly seen in binge drinking and with frequent withdrawals, which enhances the neuronal injury through increased vulnerability of upregulated N- methyl-D-aspartate (NMDA) receptors to glutamate-induced excitotoxicity. Other mechanisms attributed to the effects of alcohol on the brain include mitochondrial damage, apoptosis, and hyperhomocysteinemia leading to arterial thrombosis and strokes. In addition, hepatic encephalopathy leads to accumula- tion of ammonia and manganese in the brain, which leads interference with neurotransmitter activity and neuroprotec- tive functions. The neurotoxic effect of alcohol is particularly seen in the hippocampus, hypothalamus, and cerebellum,

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Fig. 33.9 A 51-year-old vegetarian man with progressive extremity weakness and mild cogni- tive decline. (a) Sagittal and (b) axial T2-weighted images through the cervical spine shows hyper- intensity in the posterior column (arrowheads). (c) Axial T2 image through brain shows mild atrophy of the cerebral parenchyma.

leading to impairment in memory and learning. Cholinergic neurotransmission in the basal forebrain, which plays a key role in attention, learning, and memory, also appears to be impacted by alcohol. In addition to the direct toxicity of chronic long- term deficiency of thiamine (vitamin B1), it causes development of profound memory impairment, Korsakoff syndrome.

Neuropathological studies show that loss of brain tissue largely accounts for reduction in the white matter volume.22,23 Neuronal loss is documented in cerebral cortex, especially the superior frontal cortex, Brodmann area 8, hypothalamus (supraoptic and paraventricular nuclei), and cerebellum. The frontal lobes are particularly more susceptible to damage com- pared with the rest of the brain.22,23 Neuroimaging in alcoholic dementia demonstrates typical bilateral frontal atrophy. Early changes of atrophy are seen in the frontal gyrus, which pro- ceeds to the posterior part and eventually leads to widening of sylvian fissures bilaterally (▶Fig. 33.10). There is a marked decrease in the frontal lobe white matter. In addition, there may be thinning of corpus callosum with scattered white mat- ter hyperintensities from associated hyperlipidemia.

Marchiafava-Bignami disease (MBD) is a rare disorder that results in progressive demyelination and necrosis of the corpus collosum, which is generally associated with chronic alcohol abuse. MBD is most prevalent in men between 40 and 60 years of age. The main pathologic change is in the corpus callosum, which shows demyelination accompanied by infiltration of macrophages, leading to thinning of the corpus callosum, cavity formation, and ultimately necrosis. Clinically, MBD may initially manifest either in acute form, which is often fatal, or in the chronic form, which lasts for several months or years and is

characterized by variable degrees of mental confusion, demen- tia, and impairment of gait.

Computed tomography is less sensitive and may show diffuse periventricular low-density and focal areas of low density in the genu and splenium of the corpus callosum. MRI of the brain shows areas of T1 hypointensity and T2/FLAIR hyperintensity in the corpus callosum and adjacent white matter. As the disease progresses, these areas show severe atrophy with areas of cavi- tations. MRS may show decreases in the NAA:Cr ratio during the early stages of disease as a result of secondary axonal injury after myelin degradation and prominent lactate and lipid peaks in the subacute-chronic stages from necrosis of axons and oli- godendrocytes.

33.4.2 Heavy Metal Poisoning

Exposure to large doses of heavy metals such as lead, arsenic, mercury, manganese, thallium, aluminum, toluene, bismuth, and lithium may lead to irreversible neurologic damage and dementia. This exposure may be acute or chronic. Their effect on the brain cells largely depends on permeability through the BBB.24 The diagnosis of heavy metal poisoning is mainly by clin- ical and biochemical analysis and by exclusion. Neuroimaging in these cases plays a limited role.

Lead

Chronic lead exposure is seen in both developed and underde- veloped nations. Cognitive decline is seen mostly with chronic exposure and may occur long after cessation of the exposure.

Exposure to lead may be via drinking water (lead pipes), workers inhaling larger amounts of lead fumes (e.g., at battery refinery plants), or from household paint, mainly seen in chil- dren. Lead mimics calcium in biochemical processes, crosses the BBB, and concentrates in gray matter. Lead interferes with calcium-mediated signal transduction in neurotransmitters, as it binds to synaptotagmin, a Ca2 + -binding membrane protein widely expressed in the central and peripheral nervous sys- tem.24 This protein has a much higher binding affinity for Pb2 + ion than for Ca2 + .

Mercury

Mercury in its organic and inorganic form is neurotoxic and may cause neurochemical changes similar to Alzheimer’s disease. One of the major sources of organic mercury (methyl mercury) is through the consumption of contaminated fish, and dental amal- gams are a common source of inorganic mercury. Other sources of mercury include volcanoes, mercury mines, smelters, power plants, cement factories, and crematoria. Methylmercury is slowly demethylated to inorganic mercury, most of which is excreted through the bile and then into feces. Part of inorganic mercury will cross through the BBB and gets deposited in the brain, leading to decreased performance in areas of motor func- tion and memory, and disruption of attention and verbal mem- ory observed in adults on exposure to low mercury levels.24

Manganese

Manganese toxicity is most commonly seen in welders, from inhalation of the toxic fumes. The other source for the general public is the manganese emitted by motor vehicles. Manganese may be transported across the BBB via diffusion, active trans- port, or divalent metal transport. Acute excessive manganese exposure can cause manganese madness syndrome, character- ized by hallucinations, violent acts, and irritability.24 Workers in the welding industry are also at risk of Parkinson’s disease as a result of deposition of manganese in the deep gray matter nuclei. Most of these individuals show T1 hyperintensity on MRI in the basal ganglia and other brain regions reflecting man- ganese accumulation. Long-term exposure may cause impaired

Endocrine-, Metabolic-, Toxin-, and Drug-Related Dementia

Fig. 33.10 Frontal lobes and cerebellar atrophy in a 47-year-old alcoholic patient. (a) Axial T2-weighted image shows prominence of frontal convexity sulci (black arrowheads) and decreased white matter (white arrows). (b) Coronal T1-weighted image reveals moderate prominence of cerebellar folia (arrows) suggestive of cerebellar atrophy.

manual dexterity and speed, short-term memory, and visual identification.

33.4.3 Carbon Monoxide Exposure

Carbon monoxide poisoning is not uncommon. Most of the time, carbon monoxide poisoning is mild and goes un- recognized. Carbon monoxide has an affinity to hemoglobin 200 to 250 times higher than that of oxygen, effectively displac- ing oxygen from heme-binding sites and shifting the oxygen dissociation curve to the left. The severity of symptoms largely depends on the level of carboxyhemoglobin in the blood. In the acute stage, the patient has headache, mental status changes, dyspnea, syncope, lactic acidosis, hypotension, coma, and sei- zures. Up to 30% of patients with carbon monoxide poisoning exhibit some degree of cognitive decline, ranging from subtle impairments to dementia.25 Patients may have deficits in atten- tion, concentration, executive function, visuospatial skills, ver- bal fluency, speed of information processing, and memory. Movement disorders, such as bradykinesia, masked facies, and rigidity are also seen.

The neurotoxicity of carbon monoxide is thought to be secondary to a massive release of excitatory amino acids, partic- ularly glutamate, which causes excessive calcium influx, free radical–mediated injury, and inhibition of antioxidant defenses. It also causes brain lipid peroxidation, which leads to the degra- dation of unsaturated fatty acids, reversible demyelination of CNS lipids, and vascular endothelial damage leading to neuronal cell death.25

In the acute stage, CT shows symmetric hypodensity in the medial portions of globus pallidus, with corresponding hyperintense signal on T2 and FLAIR images (▶Fig. 33.11a). The caudate nucleus, putamen, and thalamus may show simi- lar changes but less so than the globus pallidus. On DWI, these regions may show restricted diffusion from cytotoxic edema and acute tissue necrosis. Involvement of the brain- stem and cerebellum may be a reflection of more severe poisoning. Late stages show atrophy of the affected parts, predominately the globus pallidus, and diffuse brain atrophy, with corresponding movement disorders and cognitive decline (▶ Fig. 33.11b).

303

304

Endocrine and Toxins-Related Dementia

Fig. 33.11 Atrophy of globus pallidi after carbon monoxide poisoning. Axial (a) T2-weighted imaging and (b) diffusion-weighted images reveal increased signal intensity in the bilateral globus pallidi (arrows) in a 31-year-old woman with carbon monoxide poisoning. Follow-up scan after 2 years done for movement disorder shows severe atrophy (arrowheads) of the globus pallidi bilaterally on T1-weighted imaging (c).

33.4.4 Illicit Drugs and Medications

Most cases if medication toxicity result in delirium, but cog- nitive decline or dementia is not uncommon, especially in elderly patients with long-term use of medications. It has been suggested that medication toxicity could account for up to 12% of all dementia cases.26 Psychoactive drugs are reported to be among the most common cases of drug- induced cognitive impairment. Many commonly prescribed drugs for elderly patients have significant anticholinergic effects, leading to severe cognitive decline. Neuroimaging has a limited role in the diagnosis of dementia from drugs. Diagnosis in these cases is mostly by exclusion and clinical history and examination.

References

. [1] Smith JW, Evans AT, Costall B, Smythe JW. Thyroid hormones, brain function and cognition: a brief review. Neurosci Biobehav Rev 2002; 26: 45–60

. [2] Mocellin R, Walterfang M, Velakoulis D. Hashimoto’s encephalopathy: epi- demiology, pathogenesis and management. CNS Drugs 2007; 21: 799–811

[10] Okechukwu CN, Lopes AA, Stack AG, Feng S, Wolfe RA, Port FK. Impact of years of dialysis therapy on mortality risk and the characteristics of longer term dialysis survivors. Am J Kidney Dis 2002; 39: 533–538

[11] Rizzo MA, Frediani F, Granata A, Ravasi B, Cusi D, Gallieni M. Neurological complications of hemodialysis: state of the art. J Nephrol 2012; 25: 170–182

[12] Hsieh TJ, Chang JM, Chuang HY et al. End-stage renal disease: in vivo diffu- sion-tensor imaging of silent white matter damage. Radiology 2009; 252: 518–525

[13] Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neuro- toxicity. Hepatology 2006; 44: 788–794

[14] Rovira A, Alonso J, Córdoba J. MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol 2008; 29: 1612–1621

[15] Miese F, Kircheis G, Wittsack HJ et al. 1H-MR spectroscopy, magnetization transfer, and diffusion-weighted imaging in alcoholic and nonalcoholic patients with cirrhosis with hepatic encephalopathy. AJNR Am J Neuroradiol 2006; 27: 1019–1026

[16] Zuccoli G, Pipitone N. Neuroimaging findings in acute Wernicke’s encephal- opathy: review of the literature. AJR Am J Roentgenol 2009; 192: 501–508

[17] Zuccoli G, Santa Cruz D, Bertolini M et al. MR imaging findings in 56 patients with Wernicke encephalopathy: nonalcoholics may differ from alcoholics. AJNR Am J Neuroradiol 2009; 30: 171–176

[18] Jung YC, Chanraud S, Sullivan EV. Neuroimaging of Wernicke’s encephalop- athy and Korsakoff’s syndrome. Neuropsychol Rev 2012; 22: 170–180

[19] Kalita J, Misra UK. Vitamin B12 deficiency neurological syndromes: correla- tion of clinical, MRI and cognitive evoked potential. J Neurol 2008; 255: 353–

[3] Song YM, Seo DW, Chang GY. MR findings in Hashimoto encephalopathy. 359

AJNR Am J Neuroradiol 2004; 25: 807–808

. [4] Belanoff JK, Gross K, Yager A, Schatzberg AF. Corticosteroids and cognition.
J Psychiatr Res 2001; 35: 127–145

. [5] Geffken GR, Ward HE, Staab JP, Carmichael SL, Evans DL. Psychiatric morbidity
in endocrine disorders. Psychiatr Clin North Am 1998; 21: 473–489

. [6] National Institutes of Health. Kidney Disease Statistics for the United States. National Kidney and Urologic Disease Information Clearinghouse. NIH Publi- cation No. 12–3895. Available at: http://kidney.niddk.nih.gov/kudiseases/ pubs/kustats/KU_Diseases_Stats_508.pdf. Published June 2012. Accessed
September 30, 2013

. [7] Kang E, Jeon SJ, Choi SS. Uremic encephalopathy with atypical magnetic
resonance features on diffusion-weighted images. Korean J Radiol 2012; 13:
808–811

. [8] Yoon CH, Seok JI, Lee DK, An GS. Bilateral basal ganglia and unilateral cortical
involvement in a diabetic uremic patient. Clin Neurol Neurosurg 2009; 111:
477–479

. [9] Chen CL, Lai PH, Chou KJ, Lee PT, Chung HM, Fang HC. A preliminary report of
brain edema in patients with uremia at first hemodialysis: evaluation by dif- fusion-weighted MR imaging. AJNR Am J Neuroradiol 2007; 28: 68–71

[20] Korenke GC, Hunneman DH, Eber S, Hanefeld F. Severe encephalopathy with epilepsy in an infant caused by subclinical maternal pernicious anaemia: case report and review of the literature. Eur J Pediatr 2004; 163: 196–201

[21] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revison. Washington, DC: American Psychiatric Asso- ciation. 2000

[22] Namura I. Alcoholic brain damage and dementia viewed by MRI, with special consideration on frontal atrophy and white matter damage in dyslipidemic patients. Psychogeriatrics 2006; 6: 119–127

[23] Mukamal KJ, Kuller LH, Fitzpatrick AL, Longstreth WT, Jr, Mittleman MA, Sis- covick DS. Prospective study of alcohol consumption and risk of dementia in older adults. JAMA 2003; 289: 1405–1413

[24] Charleta L, Chapronb Y, Faller PC, Kirscha R,, Stoned AT, Baveyee PC. Neuro- degenerative diseases and exposure to the environmental metals Mn, Pb, and Hg. Coord Chem Rev 2012; 3: 2147–2163

[25] Choi IS. Delayed neurologic sequelae in carbon monoxide intoxication. Arch Neurol 1983; 40: 433–435

[26] Starr JM, Whalley LJ. Drug-induced dementia. Incidence, management and prevention. Drug Saf 1994; 11: 310–317

Part XIII Inborn Errors of Metabolism

34 Inborn Errors of Metabolism 306

XIII

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Inborn Errors of Metabolism

34 Inborn Errors of Metabolism

Sangam G. Kanekar and Dejan Samardzic

Inborn errors of metabolism comprise a large and heteroge- neous group of disorders. Many of these disorders affect the central nervous system (CNS) and cause white and gray matter damage and dysfunction. Although most of these disorders manifest in childhood, late-onset forms are common. The exact prevalence of these diseases causing cognitive decline is under- estimated because many are unrecognized or misdiagnosed.1 More than 750 inherited metabolic disorders are described in the literature, making it impossible to encompass them all in a single chapter. We focus on the more common inborn errors of metabolism that may manifest with cognitive decline or dementia. We discuss the clinical features, enzyme deficiency, pathogenesis, and imaging findings of the most clinically rele- vant inborn disorders.

Given the complexity of metabolic diseases, definitive classi- fication has not been established and has traditionally been based on the specific organelle involved (▶Table 34.1). Although these diseases have little in common with respect to pathogenesis, what they do share is progressive cognitive decline at a premature age. Imaging is often one of the first tests performed in patients who have inborn error of metabolism, and, therefore, radiologists are uniquely positioned to narrow the diagnostic possibilities and provide a guide for further bio- chemical workup. A combination of clinical features, imaging findings, and biochemical analysis of metabolites provides the final diagnosis, which can be confirmed via genetic testing.

34.1 Lysosomal Storage Disease

Lysosomal disorders are a group of inherited metabolic disor- ders characterized by accumulation of nonmetabolized macro- molecules leading to cellular dysfunction.2,3 Most of them are autosomal recessive, except for Fabry disease and mucopolysac- charidosis type II, which are X-linked. The initial clinical symp- toms of various subtypes depend on the extent of CNS versus visceral involvement and the specific enzymatic defect. The more common ones are described below.

34.1.1 Metachromatic Leukodystrophy

(Arylsulfatase A Deficiency)

Metachromatic leukodystrophy (MLD) is most often due to defi- ciency in the lysosomal enzyme arylsulfatase A encoded by the ARSA gene on chromosome 22q13.4,5,6,7 Deficiency of this enzyme impairs desulfation of sulfatide, a precursor to cerebro- side, and leads to accumulation of metachromatic sulfatides throughout the nervous system.4,8,9,10 This accumulation leads to a severe reduction in cerebroside content, leading to demye- lination. Demyelination starts and is most intense in the peri- ventricular area, extending into the internal capsule, cerebral peduncles, pyramidal tracts in the pons, and pyramids in the medulla, producing a white, chalky appearance of the white matter on gross examination.8 The name of this disorder comes from the deposition of metachromatically staining sulfatides in the white matter.11

The incidence of MLD is as high as 1 in 40,000.11,12,13 Depending on the age of onset, MLD is divided into four sub- types: congenital (rare), late infantile (40%, 6 months to 3 years), juvenile (40%, 4 to 16 years), and adult (20%, 16 to 30 years).11 Disease onset can be as late as the seventh decade of life.10 Clinical symptoms vary widely within each subtype, ranging from nonspecific symptoms, such as delusions, hallu- cinations, and disorganized behavior, to a gradual decline in the intellectual abilities and development of severe demen- tia.4,8 Progressive spastic paraparesis, cerebellar ataxia, extrap- yramidal symptoms, and demyelinating polyneuropathy are secondary features.1,2,14,15

Computed tomography scan shows nonspecific, symmetric, diffuse hypodensity of cerebral white matter.8 Magnetic reso- nance imaging (MRI) is more sensitive than CT and shows symmetric confluent areas of hyperintensity on T2-weighted imaging within the periventricular white matter with sparing of the subcortical U-fibers early in the disease.4,10,11,16,17 (▶ Fig. 34.1). In later stages, there is involvement of the poste- rior limb of the internal capsule, pyramidal tracts, and cere- bellar white matter with prominent atrophy of the corpus callosum.4,8 In the adult form of MLD, there is predominant involvement of the frontal white matter with diffuse cerebral atrophy.8 Proton magnetic resonance spectroscopy (MRS) reveals decreased N-acetyl aspartate (NAA), high choline- reflecting axonal damage and myelin breakdown, elevated myoinositol-reflecting gliosis, and occasionally elevated lac- tate.4,11 These changes might be seen before the abnormality is apparent on conventional MRI.

Diagnosis of MLD is suggested by the presence of high urinary excretion of sulfatides and is confirmed by molecular analysis of the ARSA gene.10 Hematopoietic stem cell transplan- tation has been successful in treating the adult-onset form of the disease and remains the mainstay of treatment.7,18,19 Enzyme replacement has been attempted with less success.4

34.1.2 Globoid Cell Leukodystrophy

(Krabbe’s Disease)

Krabbe’s disease (KD) is due to deficiency of galactocerebroside

β-galactosidase enzyme, which is coded on chromosome 14q31

in the GALC gene.20,21 Deficiency of this enzyme leads to accu-

mulation of galactosylceramide and its metabolites within

multinucleated macrophages, forming characteristic “globoid”

cells.4,9 A combination of direct destruction by these reactive

macrophages and toxic effects of accumulated galactosylcera-

mide metabolites, chiefly psychosine, results in diffuse demyeli-

nation affecting both the central and peripheral nervous systems.4,9,10,20

The incidence of KD is around 1 in 100,000, with 10% appear- ing in relatively mild form in adulthood.10 The infantile (6 months to 3 years) and juvenile (4 to 10 years) forms are rapidly progressive and lethal. Clinical symptoms include inter- mittent fevers of unknown origin, irritability, organomegaly, and hypertonicity of the lower extremities resulting from

Inborn Errors of Metabolism

Table 34.1 Organelle-based classification of inborn errors of metabolism

Lysosomal storage disorders

Defects in genes encoding myelin proteins

Metachromatic leukodystrophy

Pelizaeus-Merzbacher disease

Multiple sulfatase deficiency

18q syndrome

Krabbe’s disease

Gangliosidosis

Fabry’s disease

Fucosidosis

Mucopolysaccharidoses

Neuronal ceroid-lipofuscinoses

Peroxisomal disorders

Disorders of amino acid and organic acid metabolism

Peroxisome biogenesis defects

Phenylketonuria

Bifunctional protein deficiency

Glutaricaciduria type 1

Acyl-CoA oxidase deficiency

Propionic acidemia

X-linked adrenoleukodystrophy

Nonketotic hyperglycinemia

Adrenomyeloneuropathy

Maple syrup urine disease

Refsum’s disease

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency

Canavan’s disease

Hydroxyglutaricaciduria

Hyperhomocysteinemias

Urea cycle defects

Mitochondrial dysfunction with leukoencephalopathy

Miscellaneous

Mitochondrial myopathy
encephalopathy, lactic acidosis, and strokelike episodes

Sulfite oxidase deficiency

Myoclonic epilepsy with ragged red fibers

Galactosemia

Kearns-Sayre syndrome

Wilson’s disease

Leigh’s disease

Menkes’ disease

Carboxylase deficiency

Fragile X-associated tremor/ataxia syndrome

Cerebrotendinous xanthomatosis

Hypomelanosis of Ito

Incontinentia pigmenti

Alexander’s disease

Megalencephalic leukoencephalopathy with subcortical cysts

Congenital muscular dystrophies

Vanishing white matter disease

Leukoencephalopathy with calcifications and cysts

Hypomyelination with atrophy of the basal ganglia/cerebellum

Dentatorubral-pallidoluysian atrophy

Amyloid angiopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

Adult autosomal dominant leukoencephalopathies

Nuclear DNA repair defects

Cockayne’s syndrome

Trichothiodystrophy with photosensitivity

ease demonstrate symmetric hypodensity in the deep white matter on CT.22 On MRI, characteristic hyperintensity is seen along the corticospinal tracts on T2 and fluid-attenuated inver- sion recovery (FLAIR)-weighted imaging. These changes might be symmetric, asymmetric, or even unilateral in distribution. Hyperintensity may also involve the periventricular and pari- eto-occipital white matter, with relative sparing of the

pyramidal tract degeneration. Later symptoms include dementia, cerebellar ataxia, peripheral neuropathy, and loss of vision.20

Computed tomography reveals characteristic symmetric hyperattenuation in the bilateral thalami, corona radiata, and cerebellar dentate nuclei.20,21 This hyperdensity correlates to a high concentration of globoid cells, proliferating glia, and microcalcification seen histologically.8 Later stages of the dis-

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Inborn Errors of Metabolism

Fig. 34.1 Metachromatic leukodystrophy. Axial (a) T2 and (a) fluid-attenuated inversion recovery images show diffuse hyperintensity in the cerebral white matter with sparring of U-fibers.

Fig. 34.2 Krabbe’s disease. Axial (a) fluid- attenuated inversion recovery and (b) T2 images reveal hyperintensity in the bilateral periventricular and frontal lobes white matter. Hyperintensities near the peritrigonal regions are called flame-shaped lesions.

308

subcortical U-fibers, although these may be involved in later stages (▶ Fig. 34.2).7,8,20 Deep gray matter, cerebellar white mat- ter, and generalized atrophy may be seen in chronic stages of the disease.22,23 Enlargement and enhancement of multiple cra- nial nerves, especially the optic nerve, have been reported and are thought to be due to a combination of myelin breakdown and inflammatory response. MRS shows elevated levels of myo- inositol and choline, with a moderate increase in total creatine (Cr) (both Cr and phosphocreatine) and decreased total NAA.22, 23 Occasionally, there is a lactate peak. Diffusion tensor imaging (DTI) is useful in quantitative evaluation of white matter abnor- malities and is more sensitive than T2-weighted imaging.

Definitive diagnosis is established by demonstrating reduced galactosylceramidase activity in peripheral blood leukocytes or cultured fibroblasts and can be confirmed via gene testing.4,7,8,20 Cerebrospinal fluid (CSF) analysis is non- specific.8,20 Treatment for the adolescent-adult form of KD is mainly supportive.1,10 Stem cell bone marrow transplantation has been effective in the treatment of infantile KD but only if given in the presymptomatic stage.24

34.1.3 Fabry’s Disease

Fabry’s disease (FD) is an X-linked multisystem disorder that results from a deficiency of α-galactosidase A enzyme, which is responsible for the hydrolysis of terminal α-galactosyl residues from glycolipids and glycoproteins.10,25 Deficiency of this enzyme leads to the accumulation of neutral glycosphingolipids in the vascular endothelium, smooth muscles, and neurons. This lipid deposition in the vascular endothelium leads to thick- ening and obstruction of vessel walls resulting in infarcts. It also accumulates in the brain parenchyma predominantly in the amygdala, the leptomeninges, and the choroid stroma. Besides the CNS, lipid deposition occurs in the epithelial cells of the cornea, in renal glomeruli and tubuli, and in cardiac muscle fibers.

Early manifestations of FD include episodic extremity pain and a telangiectatic scaly maculopapular rash.25 Neurologically, patients have transient ischemic attacks or strokes in small- artery territories or in the vertebrobasilar circulation.8,10 Repeated episodes of small-vessel infarcts lead to the

Inborn Errors of Metabolism

Fig. 34.3 Fabry’s disease. Axial T1-weighted image shows hyperinten- sity in the thalami bilaterally resulting from calcification.

development of early dementia. As the disease progresses, various cardiovascular symptoms and congestive heart failure dominate.

The most characteristic finding on neuroimaging is hyper- intensity of the pulvinar nuclei (pulvinar sign) on T1- weighted imaging (▶ Fig. 34.3).26 Corresponding areas demonstrate low signal on gradient-recalled echo or suscep- tibility-weighted imaging (SWI) and hyperdensity on CT con- sistent with calcification. Similar findings can also be seen in the deep gray matter nuclei but are less specific. In addition, widespread hyperintensities are seen on T2- and FLAIR- weighted images as a result of small-vessel involvement pre-

dominantly involving periventricular white matter and basal ganglia.

Definitive diagnosis of FD is established by demonstration of a deficiency of α-galactosidase A activity in plasma, leukocytes, urine, cultured skin fibroblasts, or hair roots. Enzyme replace- ment therapy is used to slow the progression of disease; treat- ment is otherwise supportive.10

34.1.4 Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are heritable lysosomal storage disorders caused by the deficiency of specific lysosomal enzymes involved in the degradation of mucopolysaccharides (glycosaminoglycans). The MPS are classified into six groups: MPS I (Hurler), MPS II (Hunter), MPS III (Sanfilippo), MPS IV (Morquio), MPS VI (Maroteaux Lamy), and MPS VII (Sly). MPS V and MPS VIII are no longer used.27,28

All MPS are inherited by an autosomal recessive transmission, except Hunter’s disease, which is an X-linked disease. Detailed discussion of MPS is beyond the scope of this chapter. Clinical signs and symptoms vary widely with the type of MPS and severity of the deficiency of the enzyme. Definitive diagnosis of the MPS is established by enzyme assays.

Neuroimaging changes seen in MPS are due mainly to increases in perivascular connective tissue and neuronal stor- age of mucopolysaccharides. In the early stages, imaging may be normal, but in later stages, T2-weighted images may reveal multiple small, sharply defined CSF intensity lesions dispersed throughout the white matter but most prominent in the parie- tal and occipital lobes and in the corpus callosum (▶ Fig. 34.4). These cystic areas have a radial orientation from the subepen- dymal region toward the cortex and represent dilated perivas- cular spaces filled with MPS and CSF on pathology. Other imag- ing features include cortical atrophy (▶ Fig. 34.5) and multifocal hyperintense areas on T2 and FLAIR images.29,30,31 These areas can become extensive and confluent and might resemble leuko- dystrophy. Besides white matter changes, compression of the medulla or cervical cord may be identified on sagittal T1- and T2-weighted images, believed to be due to atlantoaxial sub- luxation or diffuse thickening of the cervical dura caused by deposition of collagen and MPS. It is important to diagnose this complication to avoid myelopathic changes in the adjacent cord.

Fig. 34.4 Mucopolysaccharidoses (MPS). (a) Axial T2 and (b) sagittal T1 weighted images show multiple well-defined CSF intensity focal areas (fat arrows) in the cerebral parenchyma and corpus callosum. Axial T2-weighted image also shows bilateral frontal lobe atrophy (arrows).

309

Inborn Errors of Metabolism

Fig. 34.5 Mucopolysaccharidoses (Sanfilippo). Axial computed tomography scan image of a 10-year-old child shows generalized prominence of convexity sulci and dilation of the ventricular system, advanced for the age of the patient.

Fig. 34.6 Neuronal ceroid-lipofuscinosis (NCL). Coronal T1-weighted image shows gross prominence of convexity sulci, sylvian fissures, and severe thinning of the cortex. There is moderate dilation of the ventricular system.

310

34.1.5 Neuronal Ceroid-Lipofuscinosis

Neuronal ceroid-lipofuscinosis (NCL) is one of the most common neurodegenerative disorders of childhood, with an incidence rate of 1 in 25,000.8 NCL is due to impairment of palmitoyl protein thioesterase1 (PPT1), which leads to accumu- lation of ceroid lipopigment in lysosomes of neurons. This accu- mulation leads to neurotoxicity and neuronal death. Although NCL is a lysosomal storage disorder, unlike the classic lysosomal storage diseases, it accumulates proteins and not lipids, thus making NCL a proteinosis rather than a lipidosis. On a molecu- lar basis and according to the genetic defects, nine subtypes of NCL have been identified. At present, at least six genes (CLN 1, 2, 3, 5, 6, and 8) have been implicated in relation to these nine types of NCL.8

The first symptom of an affected child is failure of vision.8 Other symptoms may include muscular hypotonia, microceph- aly, ataxia, choreoathetosis, epilepsy, irritability, and cognitive decline. The pathologic hallmark of NCL is neuronal lipofuscin storage and neuronal loss, leading to severe atrophy of the brain with moderate to severe loss of myelin and significant astro- gliosis.

Both CT and MR of the brain show severe brain atrophy, cere- bral more severe than cerebellar8 (▶ Fig. 34.6). The periventric- ular white matter and posterior limb of the internal capsule may also show hyperintensity on T2-weighted images. These changes are thought to be due to a combination of delayed and

disturbed myelination, progressively severe gliosis, and some myelin loss. In the early stage of the disease, strikingly low sig- nal is seen in the thalamus and globus pallidus, which in the later stages demonstrate severe atrophy. Positron emission tomography scans show a severe reduction in fluorodeoxyglu- cose uptake in the cortical and subcortical regions bilaterally. Similar changes might also be seen in the cerebellum.

34.2 Mitochondrial Dysfunction

Mitochondrial disorders are the most common inborn errors of metabolism, with an estimated incidence of 1 per 10,000 live births. These disorders are due to dysfunction of pyruvic acid metabolism, the citric acid cycle, or mitochondrial respiratory chain. Thus, tissues and organs that are highly dependent on aerobic metabolism (brain and muscle) are preferentially involved. Mitochondrial disorders might be caused by defects in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA).32 nDNA defects might be inherited in an autosomal recessive or autosomal dominant manner, whereas mtDNA defects are propagated by maternal inheritance.

Clinically, mitochondrial diseases are multiple-organ disor- ders with prominent brain and muscle dysfunction. Features include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deaf- ness, optic atrophy, pigmentary retinopathy, and diabetes melli-

Inborn Errors of Metabolism

tus. The CNS findings are often fluctuating encephalopathy, seizures, dementia, migraine, strokelike episodes, ataxia, and spasticity. Chorea and dementia might also be prominent fea- tures. Imaging hallmarks of these disorders include deep gray matter involvement and diffusely elevated lactate peak on MRS, the latter of which is not seen with nonmitochondrial causes of dementia.22,23 Most are treated symptomatically. The character- istic histologic finding is accumulation of abnormal mitochon- dria that can be seen in appropriately stained muscle biopsy specimens as ragged red fibers.9,15

34.2.1 Leigh’s Disease (Subacute

Necrotizing Encephalomyelopathy)

Most prominent inborn errors in Leigh’s disease include pyru- vate dehydrogenase complex deficiency and defects in the mitochondrial electron transport chain, namely, complexes I, II, IV, and V.7,8,22 Inheritance is most commonly autosomal reces- sive, although maternal and X-linked transmissions have been identified. It is two to three times more common in males.22 Although the onset of symptoms is most often during infancy, both juvenile and adult forms also exist. The adult form may manifest with dementia, seizures, neuropathy, ataxia, and oph- thalmoplegia.33

Imaging appearance largely varies with the stage of the dis- ease. In the acute stage, lentiform, caudate, subthalamic and dentate nuclei, substantia nigra, tegmentum of pons, cerebral peduncles, periaqueductal gray, red nucleus, medulla, and other brainstem structures may show symmetric edematous changes with hyperintensity on T2 or FLAIR imaging (▶ Fig. 34.7). Rarely, edematous changes may be asymmetric. Diffusion-weighted imaging (DWI) demonstrates restricted diffusion (representing cytotoxic edema) in the involved regions. As the disease prog- resses, deep gray matter nuclei might become atrophic with cystic degeneration (▶ Fig. 34.8). In severe and advanced cases, there may be involvement of cerebral and cerebellar white matter. MRS typically demonstrates an abnormal lactate peak with a decrease in the NAA:Cr and an increase in the choline:Cr ratios predominantly in the basal ganglia and is use- ful in differentiating other nonmitochondrial processes.22 Increased levels of lactate in the blood and CSF, typical MRI

findings, and enzyme assays on fibroblasts all help to establish the diagnosis.7,15

34.2.2 Kearns-Sayre (Chronic

Progressive External Ophthalmoplegia)

Kearns-Sayre syndrome is due to macrodeletion of mitochon- drial DNA-encoding components of the electron transport chain.15 It is sporadic and characterized chiefly by external

Fig. 34.7 Acute stage of Leigh’s disease. Axial T2-weighted imaging shows bilateral symmetric hyperintensity (arrowheads) in the putamen and caudate head (corpus striatum).

Fig. 34.8 Chronic stage of Leigh’s disease. (a) Axial T2- and (b) coronal T1-weighted images reveal symmetric atrophy of the putamen with cystic degeneration (arrowheads) in a 12-year-old boy who had movement disorders.

311

312

Inborn Errors of Metabolism

Fig. 34.9 Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). (a) Axial fluid-attenuated inversion recovery (FLAIR) image shows areas of gliosis and encephalomalacia in the bilateral temporal lobes from chronic infarctions (arrows). Coronal T1-weighted imaging (b,c) shows atrophy of the right hippocampus (arrowhead) and temporal lobe (arrow).

ophthalmoplegia and retinitis pigmentosa.8,9,22 A minority of patients have onset in their second or third decade of life with dementia.9,23 Other symptoms include cardiac conduction defects, ataxia, endocrine dysfunction, paresis, neuropathy, pyramidal symptoms, and elevated CSF protein.22,23

Computed tomographic scan often reveals calcium deposits in the globus pallidus and caudate nucleus with diffuse hypo- density of the cerebral white matter and progressive atrophy.8 On MRI, T2-weighted images show bilateral symmetric hyper- intensity in the globus pallidus, caudate nucleus, substantia nigra, and thalamus.23 DWI shows high signal in the involved areas, as is usual in vacuolating myelinopathies.23 Histologically, these findings correspond to spongiosis, gliosis, and perivascu- lar calcifications in the involved areas.8 Patchy hyperintense areas are also seen in the subcortical U-fibers, with relative sparing of the periventricular white matter.7,8,23 As in most mitochondrial disorders, proton MRS shows increased lactate and decreased NAA in the affected white matter.

The combination of subcortical white matter disease com- bined with deep gray matter involvement (globi pallidi and thalami) is characteristic for Kearns-Sayre syndrome. Diagnosis, however, is based on clinical symptoms and age of onset. Some require increased CSF protein, cerebellar ataxia, and heart block as criteria for diagnosis.22 DNA analysis on leukocytes is confirmatory.7

34.2.3 Mitochrondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike Epislodes

ingly, angiographic studies do not demonstrate significant vas- cular occlusions.

Most patients have onset in the second decade of life. Signs and symptoms include visual symptoms, throbbing headache, nausea, vomiting, seizures, and multiple strokelike events.8,15 Parietal and occipital lobes are common targets in MELAS, which clinically manifests with hemiparesis and hemianopsia or cortical blindness. As a result of multifocal infarctions and loss of gray and subjacent white matter, these patients may develop significant cognitive impairment or dementia.

The strokelike events in MELAS predominantly involve the gray matter, basal ganglia, and, less likely, the underlying white matter (▶Fig. 34.9). For unknown reasons, the occipital and posterior temporal lobes are preferentially involved. The affected area demonstrates swelling and hyperintensity on T2 and FLAIR images with restricted diffusion on DWI.34 These ischemic lesions are small, often multiple, asymmetric, and importantly do not follow a vascular territorial distribution.8,9 Infarctions might also involve the thalamus, basal ganglia, and brainstem. MRI shows “migrating infarcts” with new lesions appearing next to resolving ones. Over time, this leads to pro- gressive atrophy with enlargement of the ventricular system and subarachnoid spaces. In addition, there might be diffuse cerebellar involvement and calcification of the globus pallidus and caudate nucleus. Muscle biopsy may show cyclooxygenase- positive ragged red fibers.15 The definite diagnosis is reached by molecular testing demonstrating mutations in the mitochon- drial tRNA leucine gene (MTTL1).

34.2.4 Myclonic Epilepsy with Ragged

Red Fibers

Myoclonic epilepsy with ragged red fibers (MERRF) is an extremely rare syndromic mitochondrial disorder that is most commonly caused by a mutation in mitochondrial gene A8344G, which accounts for more than 80% of the cases.7,8 This encodes for mitochondrial transfer RNA, resulting in defective

Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) is a mitochondrial disorder result- ing from decreased levels in all mitochondrially encoded pro- teins most often secondary to defective leucine tRNA.34 Defec- tive oxidative phosphorylation results in metabolic strokes that are caused by an area of brain exceeding its respiratory availability rather than by thromboembolic disease.7 Accord-

Inborn Errors of Metabolism

protein synthesis. The classic features of MERRF include myoc- lonus, epileptic seizures, ataxia, and ragged red fibers on muscle biopsy seen as late as 40 years of age.9 Less consistent clinical features include dementia, hearing loss, lactic acidosis, short stature, exercise intolerance, cardiac defects, eye abnor- malities, and speech impairment. Most of the MERRF cases are maternally inherited because of a mutation within the mitochondria.34 Imaging patterns of MERRF have not been as established as with other mitochondrial disorders. Basal ganglia calcification and atrophy, particularly in the globus pallidus, may be seen on CT and MRI. Biochemical aberrations may include elevations of serum pyruvate and lactate and reduced activities of complexes I and IV.7 Diagnosis is established via genetic testing.

34.3 Peroxisomal Defects

34.3.1 Adrenomyeloneuropathy

(Adult-Onset Adrenoleukodystrophy)

Adrenomyeloneuropathy (AMN) is an X-linked recessive dis- order resulting in accumulation of very long chain fatty acids (VLCFAs) throughout the body. AMN is thought to represent the adult-onset form of X-linked adrenoleukodystrophy.4 Both arise from mutations in the gene ABCD1 on chromosome Xq28, which encodes ALDP, a peroxisomal adenosine triphosphate- binding cassette protein that functions in transmembrane transport of VLCFAs during oxidation.35 A defect in this step is characterized by elevation of VLCFA, predominantly in the CNS white matter, peripheral nerves, adrenal cortex, and testes. Within the nervous system, elevated VLCFA levels result in inflammatory demyelination.22

Predominately, AMN affects men in the third or fourth decade of life with early-onset dementia, progressive spastic

paraparesis, and urinary incontinence.35 Adrenal insufficiency, cerebellar ataxia, and peripheral neuropathy (sensory and auto- nomic) may also be seen.8 Pathologic studies in AMN demon- strate bilateral, usually symmetric, long-tract degeneration in the spinal cord, with the most prominent involvement of the lumbar corticospinal and the cervical dorsal tracts with or without cerebral demyelination.22

If neurologic involvement is confined to the spinal cord and peripheral nerves, MRI of the brain can be normal.8 When the brain is involved, however, the abnormality is limited mainly to cerebellar white matter and brainstem corticospinal tracts. There is no inflammatory zone in AMN; therefore, there is no enhancement on postcontrast scans. Rarely, imaging findings in the brain are somewhat similar to milder forms of adreno- leukodystrophy, with symmetric T2 hyperintensity in the pyramidal tracts, posterior limb of the internal capsule, cerebel- lar white matter, and splenium or genu of the corpus callosum (▶ Fig. 34.10).36 Diagnosis of AMN is established by demonstrat- ing low NAA in the urine or via enzyme assay on fibroblasts.7

34.4 Disorders of Neurotransmitter Metabolism

34.4.1 Fragile X-Associated Tremor/

Ataxia Syndrome

Fragile X–associated tremor/ataxia syndrome (FXTAS) is an X- linked dominant disorder closely related to fragile X syndrome and resulting in progressive cognitive and cerebellar dys- function.4 In fragile X syndrome, full trinucleotide repeat muta- tion of the FMR1 gene on chromosome X involving more than 200 CGG repeats causes defective or absent production of frag- ile X mental retardation protein (FMRP), an enzyme that has

Fig. 34.10 Adrenoleukodystrophy (ALD). Axial (a) T2 and (b) fluid-attenuated inversion recovery (FLAIR) images show bilateral symmetric hyperintensity involving the corticospinal tracts (back arrowheads) and occipital and temporal white matter bilaterally (black arrows). (c) Postcontrast T1-weighted image shows lead enhancement in the area of active demyelination (arrows). Also note enhancement of the corticospinal tracts (black arrowheads).

313

Inborn Errors of Metabolism

key roles in synapse function.37,38 In FXTAS, there is a smaller number of involved trinucleotides in the premutation range of 50 to 200 CGG repeats.37 This offset in the number of tri- nucleotide repeats causes excess production of FMR1 mRNA, which exerts gradual neurotoxic effects by sequestering and perturbing the function of nuclear proteins.37 Unlike fragile X syndrome, patients with FXTAS develop symptoms later in life.

Given its variable penetrance and underdiagnosis, the num- ber of affected individuals is difficult to estimate. The disease usually manifests between the ages 50 and 80 and is more com- mon in men.4,37 Progressive cognitive and cerebellar dys- function result in early dementia, intention tremors, and ataxia. Less characteristic features include autonomic dysfunction, including hypertension, bowel and bladder dysfunction, and impotence.39 Parkinsonian features, peripheral neuropathy, and personality changes may be seen.

Magnetic resonance imaging plays an important role in the diagnosis of FXTAS. The most characteristic findings are sym- metric hyperintense lesions on FLAIR-/T2-weighted images in the middle cerebellar peduncles (MCP), known as the MCP sign.37 Signal abnormalities may also be seen in the cerebellar and deep periventricular white matter. In addition, there may be associated cerebral and cerebellar atrophy. Diagnosis is established from combination of imaging findings and clinical features. Treatment of FXTAS is mainly supportive.

34.5 Amino Acid Disorders

Aminoaciduria is defined as high levels of amino acids in the urine, which may be due to either inborn errors of metabolism or chronic liver failure or renal disorders.40 Inborn errors of metabolism related to amino acids are rare. They might be due to either inherited deficiency or altered function of an enzyme or transport system that mediates the disposition of a particular amino acid (AA). They can be classified according to disorders of AA metabolism (phenylketonuria, histidinemia, hyperproline- mia, tyrosinemia, nonketotic hyperglycinemia, and hyperhomo-

cysteinemia), defects in AA transport (cystinuria, Lowe’s syn- drome, Hartnup’s disease, iminoglycinuria), and unknown errors of metabolism.40 The final end-product of AA oxidation is ammonia, which in higher concentration is neurotoxic to the cells as well as to the neurotrasmitters. One of the major func- tions of the urea cycle is to detoxify this ammonia produced from catabolism of AA. Any defect in the urea cycle will cause hyperammonemia or elevated plasma glutamine, which leads to severe nerve cell damage.

Damage to the brain cells and its functions leading to various neurologic symptoms, including cognitive decline, largely depends on the type and the level of concentration of the toxic substrate accumulated.40 These defects may be in the urea cycle or in the degradation of the specific amino acid–like glycine in nonketotic hyperglycinemia and homocysteine in hyperhomocysteinemias. Maple syrup urine disease is caused by a deficiency of the branched chain 2-keto acid dehydrogenase, leading to abnormal oxidative decarboxylation of the branched chain AAs (BCAAs) leucine, isoleucine, and valine. The enzyme defect results in marked increases in the branched chain 2-keto acids in brain cells, causing neurotoxicity (▶ Fig. 34.11)

34.6 Miscellaneous Disorders

34.6.1 Vanishing White Matter Disease (Childhood Ataxia with Central Nervous System Hypomyelination)

Vanishing white matter disease (VWMD) is an autosomal reces- sive disorder that arises from defects in translation initiation factor eIF2B, which consists of five nonidentical subunits encoded by different genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) located on different chromosomes (12q24.3, 14q24, 1p34.1, 2p23.3, and 3q27, respectively).41 Mutations in any of these genes cause dysfunction of eIF2B, inadequate protein syn- thesis, and cell death. On pathology, the cerebral white matter shows myelin pallor, thin myelin sheaths, vacuolation, myelin

Fig. 34.11 Aminoaciduria (maple syrup urine disease). (a,b) Axial T2-weighted images show extensive bilateral edematous changes involving thalamus, globus pallidus, caudate nuclei (arrows), and frontal lobe white matter. (c) Coronal T1-weighted imaging shows diffuse hypointensity in the temporal lobe white matter (arrowheads) with mild bilateral hippocampal atrophy.

314

loss, cystic change, and rarely active demyelination. Gray matter is unaffected. The incidence of VWMD is around 1 in 40,000.40 Depending on the age of onset, VWMD is divided into three forms: classic form (2 to 6 years of age), severe infantile form (3 to 9 months), and late-onset form (10 to 21 years) of age.40,41 These patients are completely normal until adulthood, when they show psychiatric symptoms and slowly develop signs and symptoms of dementia.40 Behavioral changes may precede cog- nitive decline by several years.

On MRI, T2- and FLAIR-weighted images show symmetric and diffuse abnormal areas of hyperintensity on T2 or FLAIR images (▶ Fig. 34.12).40 As the disease progresses, there is lique- faction of the affected white matter, which is replaced by fluid- containing cysts. Patchy areas of normal white matter might be seen in a background of diffusely abnormal white matter, which gives a “stripelike” appearance on sagittal images following the corona radiata.23 In the late stages, dilation of the ventricles occurs as a result of diffuse loss of white matter. MRS shows a decrease in the heights and finally the disappearance of all the major peaks, namely, NAA, Cr, and choline. Phosphorus MRS shows a reduction in nucleoside triphosphate and inorganic phosphate with elevated phosphocreatine, suggesting a change in the energy state of the residual cells in the cerebral white matter.42

References

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adults. Neuroradiology 1991; 33: 478–493

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[7] Brodsky MC. Neuro-ophthalmologic manifestations of neurodegenerative disease in childhood. In: Pediatric Neuro-Ophthalmology. 2nd ed. New York: Springer; 2010:465–501

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[10] Sedel F, Tourbah A, Fontaine B et al. Leukoencephalopathies associated with inborn errors of metabolism in adults. J Inherit Metab Dis 2008; 31: 295–307 [11] Valk J, van der Knaap MS. Metachromatic leukodystrophy. In: Magnetic Reso-

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China: Elsevier; 2012:485–511
[16] Faerber EN, Melvin J, Smergel EM. MRI appearances of metachromatic leuko-

dystrophy. Pediatr Radiol 1999; 29: 669–672
[17] Sener RN. Metachromatic leukodystrophy: diffusion MR imaging findings.

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[18] Kidd D, Nelson J, Jones F et al. Long-term stabilization after bone marrow

transplantation in juvenile metachromatic leukodystrophy. Arch Neurol

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Inborn Errors of Metabolism

Fig. 34.12 Vanishing white matter disease. (a) Axial T2- and (b) coronal T1-weighted images show diffuse hyperintensity involving the supratentorial white matter with severe loss of white matter.

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[34] Barkovich AJ, Good WV, Koch TK, Berg BO. Mitochondrial disorders: analysis of their clinical and imaging characteristics. AJNR Am J Neuroradiol 1993; 14: 1119–1137

[35] Moser HW. Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 1997; 120: 1485–1508

[36] Barkovich AJ, Ferriero DM, Bass N, Boyer R. Involvement of the pontomedul- lary corticospinal tracts: a useful finding in the diagnosis of X-linked adreno- leukodystrophy. AJNR Am J Neuroradiol 1997; 18: 95–100

[37] Berry-Kravis E, Abrams L, Coffey SM et al. Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord 2007; 22: 2018–2030, quiz 2140

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Part XIV

Cerebellar Degeneration and Dysfunction

35 Normal Anatomy and Pathways of Cerebellum 318

36 Imaging of Cerebellar Degeneration
and Cerebellar Ataxia 328

XIV

318

Cerebellar Degeneration and Dysfunction

35 Normal Anatomy and Pathways of Cerebellum

Sangam G. Kanekar and Jeffrey D. Poot

For centuries, the cerebellum was thought to be purely a motor control device, with its major role in motor behavior and coor- dination. Over the last two decades, however, it has been increasingly recognized that the cerebellum contributes to cog- nitive processing and emotional control. Although this role has been pointed out by various anatomists and physiologists in the past, it was further solidified with advancement of molecular and functional imaging, which includes positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Functional neuroimaging showed that the various ana- tomical regions of the cerebellum were activated during higher-level tasks. The posterior lobe and lobule VI of the cere- bellum seem to be involved in higher-level tasks, such as verbal and working memory as well as executive functions. Left frontal and parietotemporal cortex hypoperfusion are interpreted to be associated with disruption of cerebellocortical connections, which can lead to cognitive problems.

Embryology and anatomy of the cerebellum remain challeng- ing because of its various nuclei and connections; however, understanding the anatomy and various tract connections has become of vital importance in the era of molecular and cellular imaging. This chapter discusses the embryology, gross anatomy with vascularity, histopathology, and nuclear and tract anat- omy, followed by state-of-the-art cross-sectional imaging.

35.1 Embryology

The cerebellum is first seen at 5 to 6 weeks as rhombic lips of the thinned roof of the fourth ventricle of the hindbrain.1,2 Rhombic lips are formed when the dorsolateral aspects of the alar plates bend medially. They compress craniocaudally to form the cerebellar plate. The cerebellar plate in a 12-week embryo demonstrates the midline vermis and the two lateral cerebellar hemispheres. The transverse fissure separates the nodule from the vermis and the lateral flocculus from the hemi- spheres. By the second month, this cerebellar plate consists of neuroepithelial (inner germinal) layer, mantle and marginal lay- ers. By 19 weeks, neuroblasts dividing in the inner germinal layer migrate to the surface, proliferate, and form the external granular (germinal) layer.1,3,4 Ultimately, these cells form a pro- liferative zone and continue to divide. The outer germinal layer produces basket, granule, and stellate cells. The inner germinal layer produces the Purkinje and Golgi cells and the cells of the deep cerebellar nuclei (dentate, globose, emboliform, and fasti- gii). Radial glial cells extend from the ventricular layer to the surface of the marginal layer and guide the migration of the developing neurons. Neuroblasts of both dividing cell layers produce glia.

35.2 Gross Anatomy

The anatomy of the cerebellum can be defined by both its struc- ture and function. The largest structure in the posterior fossa is the cerebellum. The cerebellum has a midline vermis with two lateral cerebellar hemispheres. Multiple fissures are found

within the cerebellum, with the primary fissure separating the cerebellum into anterior and posterior lobes.5 Additionally, a posterolateral fissure along the ventral inferior surface sepa- rates the posterior lobe from the flocculonodular lobe. See ▶Table 35.1 for further details of the names of the lobules, divisions, and subdivisions (▶Fig. 35.1).5,6 Along the inferior surface are cerebellar tonsils. Along the surface of the cerebel- lum, the small ridges that course medial to lateral are called folia. Three white matter peduncles attach to the dorsal aspect of the pons and medulla (▶ Table 35.1).

Regions of the cerebellum can be organized according to their function. Cerebellar pathways are involved with the articulation of speech, respiratory movements, and motor learning. The vermis is involved with medial motor systems of the trunk.5,7,8 The flocculonodular lobes are involved with balance and eye movements. The lateral cerebellar hemispheres involve the motor systems of the distal appendicular muscles and are also involved with motor planning. The three cerebellar peduncles are the superior cerebellar peduncle, also known as the brachium conjunctivum, which has mainly cerebellar outputs; the middle cerebellar peduncle, also known as brachium pontis, has mainly cerebellar inputs; and the inferior cerebellar pedun- cle, also known as the restiform body, has mainly cerebellar inputs.

The lateral hemispheres of the cerebellum involve motor plan- ning for the extremities and influence the lateral corticospinal tract.7,8,9 The intermediate hemispheres involve distal limb coor- dination and influence the lateral corticospinal and rubrospinal tracts. The vermis involves proximal limb and trunk coordina- tion and influences the anterior corticospinal, reticulospinal, vestibulospinal, and tectospinal tracts. The flocculonodular lobe involves balance and vestibulo-ocular reflexes and influences the medial longitudinal fasciculus.

The four deep cerebellar nuclei, lateral to medial, are the dentate, emboliform, globose, and fastigial nuclei. These nuclei handle all output tracts. The dentate nuclei receive input from the lateral hemispheres and are active just before voluntary movement.7,8,9 The interposed nuclei, which are made up of the emboliform and globose nuclei, receive input from the interme- diate hemispheres and are active during movements. The fastigial nuclei have input mainly from the vermis, with a small input from the flocculonodular lobe. Projections from the inferior vermis and flocculi extend to the vestibular nuclei.

35.2.1 Vascular Supply to the

Cerebellum

Three main pairs of arteries supply the cerebellum and are branches of the vertebral and basilar arteries (▶Fig. 35.2).10 First, the posterior inferior cerebellar artery (PICA) usually arises from the vertebral artery to supply the most inferior half of the cerebellum and inferior vermis as well as the lateral medulla. The anterior inferior cerebellar artery (AICA) arises from the lower basilar artery and supplies the inferior lateral pons, mid- dle cerebellar peduncles and ventral aspect of the cerebellum, including the flocculus. The superior cerebellar artery (SCA)

Normal Anatomy and Pathways of Cerebellum

Table 35.1 Anatomical nomenclature of the cerebellum according to Bolk with lobule numerals according to Larsell and classic nomenclature of the vermis and hemispheres

Hemisphere Divisions (Bolk) Fissures (Bolk) Vermis Hemispheres (Classic)

Lobule # of Larsell

Lobule name (classic)

Anterior lobe

Lingula

Vincingulum lingulae

II III

Central lobulus

Ala lobulus centralis

IV V

Culmen

Anterior quadrangular lobule

Primary fissure

Lobulus simplex

Declive

Posterior quadrangular lobule

Ansiform lobule ● CrusI

VIIA

Folium

Superior semilunar lobule

Intercrural fissure

● Crus II

Ansoparamedial fissure

Horizontal fissure

Paramedian lobule

VIIB

Tuber

Inferior semilunar Lobule

Prepyramidal fissure

Gracile lobule

VIII

Pyramis

Biventral lobule (1)

Secondary fissure

Dorsal paraflocculus

Uvula

Biventral lobule (2) Tonsil

Ventral paraflocculus

Accessory paraflocculus

Posterolateral fissure

Flocculus

Nodulus

Flocculus

arises toward the top of the basilar artery and supplies the upper lateral pons, superior cerebellar peduncles, superior half of the cerebellar hemispheres, including the deep cerebellar nuclei, and superior vermis.

The veins are located on the surface of the cerebellar hemi- spheres and generally drain into the adjacent sigmoid and transverse sinuses, with the exception of the vermian veins.10 Anatomically, they are disposed in two sets: superior and inferior (▶Fig. 35.3). The superior cerebellar veins pass partly forward and medialward, across the superior vermis, to end in the straight sinus and the internal cerebral veins, and partly lat- eralward to the transverse and superior petrosal sinuses. The inferior cerebellar veins of large size end in the transverse, superior petrosal, and occipital sinuses.

35.3 Histopathology

The three layers that make up the cerebellar cortex4,11,12 are the granule cell, Purkinje cell, and molecular layers. Within the cere- bellum are two types of synaptic inputs. Mossy fibers extend through the cerebellar white matter to form excitatory syn- apses onto granule cells. These granule cells send projections into the molecular layer, which form parallel fibers, which run perpendicular to dendritic trees of the Purkinje cells. Each parallel fiber forms excitatory synapses with multiple Purkinje cells. The axons of the Purkinje cells direct all output. These form inhibitory synapses on the deep cerebellar and vestibular nuclei. The deep cerebellar nuclei send output through the

Fig. 35.1 Sagittal T1-weighted image of midline cerebellum shows various lobes of the cerebellum. Ce, central; Cu, culmen; D, declive; F, folium; L, lingual; N, nodule; P, pyramid; T, tuber; To, tonsil; U, uvula.

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Fig. 35.2 Maximum-intensity projection from time-of-flight magnetic resonance angiography shows normal vessels of the posterior fossa: vertebral arteries (arrow), basilar artery (fat arrow), posterior cerebral arteries (thin arrows), superior cerebellar arteries (zigzag arrows), anterior inferior cerebellar arteries (arrowheads), posterior cerebellar arteries (curved arrow).

Fig. 35.3 Sagittal maximum intensity projection from time-of-flight magnetic resonance venogram shows internal cerebral veins (curved arrow), vein of Galen (arrowhead), straight sinus (fat arrow), precentral cerebellar vein (single zigzag arrow), and inferior vermian vein (double zigzag arrow).

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excitatory synapses. In addition to mossy fibers, there are also climbing fibers, which arise from the neurons of the contra- lateral inferior olivary nucleus. Climbing fibers cause a modula- tory effect on the response of Purkinje cells.

There are several inhibitory interneurons of the cerebellum. Basket and stellate cells are in the molecular layer and receive excitatory synaptic inputs from the granule cell parallel fibers. Stellate cells terminate on Purkinje cell dendrites; basket cells terminate on Purkinje cell bodies, both having a strongly inhibi- tory effect.

Golgi cells are found in the granule cell layer and receive exci- tatory inputs in the molecular layer from granule cell parallel fibers. These provide feedback inhibition on the granule cell dendrites.

In summary, mossy fibers, climbing fibers, granule cell paral- lel fibers, and deep cerebellar nuclei have excitatory synapses. Purkinje cells, stellate cells, basket cells, and Golgi cells contain inhibitory synapses.

35.3.1 Nuclear and Tract Anatomy Cerebellar Output Pathways

Coordination deficits usually occur ipsilateral to a lesion because pathways involving the cerebellum and the lateral motor systems have crossed sides twice. The first crossing occurs at the superior cerebellar peduncle, and the other occurs with the decussation of the corticospinal and rubrospinal tracts.

The lateral cerebellar hemisphere projects to the dentate nucleus. In turn, the dentate nucleus projects through the supe- rior cerebellar peduncle to the contralateral ventral lateral nucleus of the thalamus.13,14,15 Additional cerebellar outputs project to the thalamic ventral anterior and intralaminar nuclei. Additional dentate nucleus output fibers project to the rostral parvocellular division of the red nucleus, which in turn project to the inferior olive. From the ventral lateral nucleus, fibers project to motor cortex, premotor cortex, supplementary motor area, and the parietal lobe to assist in motor planning of the corticospinal systems. There are additional projections from the thalamus to the prefrontal association cortex, thought to be involved with cognitive function.

The intermediate hemisphere projects to the interposed nuclei. The interposed nuclei then project through the superior cerebellar peduncle to the contralateral ventral lateral thalamic nucleus.15,16 This projects to the motor, supplementary motor, and premotor cortex. Additional fibers project to the contra- lateral magnocellular division of the red nucleus to influence the rubrospinal tract.

Normal Anatomy and Pathways of Cerebellum

Fig. 35.4 Axial T2 image through the cerebellum at the level of pons (p) shows middle cerebellar peduncle (mc), vermis (v), and nodulus (arrow).

Fig. 35.5 Axial T2 image through the cerebellum shows inferior cerebellar peduncle (white dots), nodulus (star), uvula (u), pyramid (p), and tonsils (arrows).

The cerebellar vermis has connections from the anterior cor- ticospinal, reticulospinal, vestibulospinal, and tectospinal tracts (▶ Fig. 35.4, ▶ Fig. 35.5, ▶ Fig. 35.6).15,16 The vermis has projec- tions to the fastigial nuclei. The flocculonodular lobes and inferior vermis project mainly to the vestibular nuclei with few projections to the fastigial nuclei. Outputs from the fastigial nuclei travel along the uncinate fasciculus (fibers within the superior cerebellar peduncle), and juxtarestiform body (fibers within the inferior cerebellar peduncle). The fibers from the uncinate fasciculus ultimately influence the anterior corticospi- nal tract. The fibers from the juxtarestiform body influence the ipsilateral reticular formation, which influences the reticulospi- nal tracts and the vestibular nuclei, which in turn influences the vestibulospinal tracts. There are few direct connections to lower motor neurons via the fastigial neurons projecting to the upper cervical spinal cord.

Cerebellar Input Pathways

Inputs to the cerebellum involve multiple areas of the central nervous system. One main source of input is from the cortico- pontine fibers from the cerebral cortex that travel in the internal capsule and cerebral peduncles. Primary sensory cortex, primary motor cortex, and part of the visual cortex comprise most of the corticopontine fibers, which travel to the ipsilateral pons, synapsing in the pontine nuclei. Pontocerebel- lar fibers cross the midline to enter the contralateral middle cerebellar peduncle.

There are four spinocerebellar tracts14,15,16: the dorsal and ventral spinocerebellar tracts, which involve the lower extrem- ities; and the cuneocerebellar and rostral spinocerebellar tracts,

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Fig. 35.6 Coronal T2 image shows horizontal fissure (fat arrows), superior semilunar (single arrow), inferior semilunar (double arrow), biventer (zigzag arrow), and dentate nucleus (arrowhead).

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which involve the upper extremities and neck. Proprioception about limb movements from the lower extremities projects via the dorsal spinocerebellar tract and from the upper extremities via the cuneocerebellar tract. The activity of spinal cord inter- neurons, which reflects the magnitude of activity in descending pathways in the lower extremities, projects via the ventral spi- nocerebellar tract and in the upper extremity via the rostral spinocerebellar tract. The dorsal spinocerebellar tract ascends in the dorsolateral funiculus, entering via the dorsal roots and ascending in the gracile fasciculus. Some fibers synapse in the nucleus dorsalis of Clark, which is a long column of cells in the dorsomedial spinal cord gray matter intermediate zone from C8 to L2/L3. Fibers from the nucleus dorsalis of Clark ascend ipsi- laterally and travel to the ipsilateral cerebellar cortex via the inferior cerebellar peduncle. In the cuneocerebellar tract, fibers from the upper extremities enter the cuneate fasciculus and ascend ipsilaterally to synapse in the external cuneate nucleus, which then ascends in the inferior cerebellar peduncle to the ipsilateral cerebellum. These pathways provide rapid feedback regarding ongoing movements, allowing for fine adjustments. The ventral spinocerebellar tract arises from neurons along the outer edge of the central gray matter, then crosses the ventral commissure of the spinal cord, ascending just ventral to the dorsal spinocerebellar tract. These fibers join the superior cere- bellar peduncle and cross a second time, reaching the cerebel- lum ipsilateral to the beginning of the pathway. The rostral cer- ebellar tract is similar to the ventral spinocerebellar tract, but it involves the upper extremity and enters the cerebellum through the inferior and superior cerebellar peduncles.

The inferior olivary nuclear complex has olivocerebellar fibers, which cross the medulla to enter the contralateral cere- bellum. These form the bulk of the inferior cerebellar peduncle and terminate as climbing fibers. The parvocellular red nucleus has inputs from the contralateral dentate nucleus. A circuit is formed from the lateral cerebellar hemisphere to the dentate nucleus, to the contralateral parvocellular red nucleus, to the inferior olive via the central tegmental tract, and then back to the original cerebellar hemisphere via the inferior cerebellar peduncle. The cerebral cortex, other brainstem nuclei, and the spinal cord also send fibers to the inferior olivary nuclear com- plex. The lateral reticular nucleus receives similar inputs and projects to the cerebellum via the inferior cerebellar peduncle but gives rise to mossy fibers.

Primary vestibular nuclei project to the ipsilateral inferior cerebellar vermis and flocculonodular lobe via the juxtaresti- form body. The flocculus receives visual inputs that are impor- tant for the control of smooth pursuit eye movements. Nor- adrenergic inputs from the locus ceruleus and serotonergic inputs from the raphe nuclei project diffusely throughout the cerebellar cortex.

35.4 Diffusion Tensor Imaging of

the Cerebellum

Technical details and physics of diffusion tensor imaging (DTI) are beyond the scope of this chapter and are discussed in detail in Chapter 5. The degree of water mobility in a given brain tis- sue can be studied by adding diffusion gradients to standard magnetic resonance image (MRI) sequences.17,18 Depending on

the local microstructure, diffusion can be isotropic, which means that the magnitude of diffusion is equal in all directions, or anisotropic, which means that the magnitude of diffusion dif- fers along the various directions in space. Diffusion is typically isotropic in CSF and anisotropic along the white matter tracts. DTI allows study of the three-dimensional shape and direction of diffusion by adding diffusion gradients along multiple orthogonal directions in space. When the complete tensor of the diffusion is measured, the degree of anisotropic diffusion can be calculated (by fractional anisotropy [FA]).17,18 The degree of anisotropic diffusion can be represented as a two-dimen- sional FA map. FA values vary between 0 (maximal isotropic dif- fusion) and 1 (maximal anisotropic diffusion). High FA values are typically found along fiber tracts (e.g., corticospinal tracts, corpus callosum). Measurement of the entire diffusion tensor also provides information about the principal direction of diffu- sion within the brain. Consequently, the FA maps can be color- coded. By convention, regions with a predominant left-to-right diffusion are color-coded in red; regions with a superior- inferior diffusion direction are coded in blue; and anterior–pos- terior diffusion is color coded in green. The intensity of the color-coding is related to the magnitude of the FA value.

35.4.1 Diffusion Tensor Imaging of the Anatomy of the Brainstem and Cerebellum

Brainstem and cerebellum represent a crossroad between the fiber bundles of the spinal cord, midbrain, and cerebral hemi- spheres and vice versa.19,20 The five major white matter tract connections include the superior (SCP), middle (MCP), and inferior cerebellar peduncles (ICP), the corticospinal tract, and the medial lemniscus (ML).

The Superior Cerebellar Peduncle

The SCP is the main pathway that connects the cerebellum with the thalamus. The dentatofugal course originates from the hilus of the dentate nucleus, runs within the superior cerebellar peduncle, goes through the mesencephalic tegmentum and the red nucleus, and reaches the ventrolateral thalamus. On axial images, the SCP is identified at the dentate nucleus level, with a linear green- or blue-colored course (▶ Fig. 35.7).

Transverse Fibers and the Middle Cerebellar Peduncle

The MCP is part of the pontocerebellar tracts seen wrapping around the pons with dorsal anterior–posterior (green) and ventral left–right (red) directionality (▶Fig. 35.8).20,21,22 The transverse pontine fibers (TPFs, red) are also part of the MCP and appear on structural anisotropic axial images as large H- shaped red areas of the pons, circumscribing the two cortico- spinal tracts (▶Fig. 35.9). Morphologically, TPFs can be dis- sected into ventral transverse fibers, medial fibers, and dorsal fibers. Ventral fibers (▶Fig. 35.9) are connected to the lateral hemispheric part of lobules VIIIB, VIIIA, VII, and VI of the cere- bellum. All these fibers converge caudally and constitute part of the MCP. Their course remains ventrolateral to the ipsilateral

Normal Anatomy and Pathways of Cerebellum

Fig. 35.7 Axial diffusion tensor imaging colored maps at the level of pons shows superior cerebellar peduncle (yellow arrows), fourth ventricle (red dot), cerebellar vermis (red arrow), cerebellar hemisphere (C).

Fig. 35.8 Axial diffusion tensor imaging–colored maps at the level of pons shows middle cerebellar peduncle (yellow arrows), dentate nucleus (blue arrows), fourth ventricle (red dot), cerebellar vermis (red arrow), and cerebellar hemisphere (C).

dentate nucleus. The dorsal fibers (▶ Fig. 35.9) are more medial within the MCP and travel along the lateral border of the ipsi- lateral dentate nucleus. Most end within the anterior lobe, including its vermian, paravermian, and hemispherical parts. The medial transverse fibers between the two corticospinal tracts (▶ Fig. 35.9) are connected to the dorsolateral part of the prefrontal cortex through the rostral posterior limb of the inter- nal capsule and through the ventromedial, ipsilateral crus cere- bri. Besides the transverse pontine fibers, various other tracts connecting the cerebellum with parietal, occipital, and orbital cortex may be seen. The most complete corticopontocerebellar pathway corresponds to projections from the pericentral cortex to the hemispherical parts of the cerebellar anterior lobe (HV- VIIA) through the ipsilateral, ventromedial crus cerebri and through the rostroventral transverse fibers.

Inferior Cerebellar Peduncle

The ICP originates in the caudal medulla oblongata, traverses the pons, and sends branches into the cerebellar cortex. The tract enters the cerebellar white matter dorsal to the central tegmental tract, ventral to the superior cerebellar tract, and between the lateral wall of the fourth ventricle and the MCP. Tracts then run within the cerebellar white matter above the dentate nucleus and reach the vermis and paravermis of the cerebellar anterior lobe, especially in lobules IV-VI and IX. On axial DTI maps, the ICP is identified along the dorsal aspect

of the medulla and pons, represented by the color blue (inferior-superior direction) in its inferior half and green in its superior half.

Corticospinal (and Corticonuclear) Tract

The corticospinal and corticonuclear tracts are major descend- ing pathways connecting the motor cerebral cortex with the spinal cord (▶ Fig. 35.10).22 The course of these tracts can be fol- lowed from the sensorimotor cortex into the caudal part of the posterior limb of the internal capsule, the ventromedial part of the crus cerebri, in the pons between the ventral and dorsal segments of the transverse pontine fibers, and then into the most ventral part of the medulla oblongata in front of the inferior olivary nucleus.

Medial Lemniscus

The ML is an important pathway for ascending sensory fibers that is best seen dorsal to the dorsal transverse pontine fibers at the level of the MCP on DTI axial images (▶ Fig. 35.10).20,22 The tracts ascend within the rostromedial part of the medulla oblongata, dorsal and medial to the corticospinal tract, and spread upward and dorsal to the inferior olivary nucleus, and ventral to the central tegmental tract. At the mesencephalic level, the course is located in a ventrolateral position, dorsal to the substantia nigra and lateral to the red nucleus, and at the

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Fig. 35.9 Axial diffusion tensor imaging–colored maps at the level of midpons show the main tracts running to and fro from the cerebellum and brainstem. CST, corticospinal tract; CTT, central tegmental tract; dTF, dorsal transverse fibers (mainly connected to prefrontal fibers); LMT, longitudinal medial tract; ML, medial lemniscus; mTF medial transverse fibers; SCP, superior cerebellar peduncle rvTF, rostroventral transverse fibers.

Fig. 35.10 Axial color-coded FA maps at the level of pontomesence- phalic junction. The anatomical landmarks are labeled as follows: CST corticospinal tract, CTT central tegmental tract, ML medial lemniscus, SCP superior cerebellar peduncle, SN substantia nigra, rvTF rostro- ventral transverse fibers (mainly connected to the sensorimotor cortical fibers), vTD ventral tegmental decussation beneath the overlying red nucleus.

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telencephalic level, it terminates within the ventroposterior nucleus of the thalamus.

35.5 Magnetic Resonance

Spectroscopy

Proton magnetic resonance spectroscopy (MRS) is a non- invasive technique used for biochemical analysis of small vol- umes of interest (voxel) within the brain parenchyma. Spectros- copy measures the concentration of the particular metabolite, thus assessing the biochemical constituents of the brain tissue. Physics and the relevant technical details are discussed in detail in Chapter 3. MRS of posterior fossa is more challenging than MRS of the supratentorial area because of potential technical difficulties (e.g., field inhomogeneity) and surrounding bone; however, continuous improvement in MRS techniques has over- come these difficulties.

Calculated metabolites and their ratios depend on the metab- olite concentrations and the relaxation properties of the tissue characterized by the relaxation times T1 and T2. The cerebellar hemispheres are different from the supratentorial white and gray matter embryologically, in cytoarchitecture, and in meta- bolic activity.23,24 Embryologically, the cerebellum, which is derived from the metencephalon, originates from the rhomb-

encephalon (hindbrain), and is different from the cerebral hemispheres, which derive from the telencephalon that comes from the prosencephalon (forebrain). Most of the cerebellum is myelinated from deep to superficial white matter by 1 to 3 months after birth on T1-weighted images, whereas the cere- bral parenchyma takes almost 18 months to complete its myeli- nation. This is important to understand when reading the MRS of the cerebellum in pediatric patients.

Cerebellar MRS may be performed using either a single or multi voxel, depending on the size and the area of interest to be analyzed. Depending on the echo time, MRS can be performed using either short (<30 milliseconds [ms]), intermediate (144 ms), or long (270 ms) echo time (TE). MRS with short TE (30 ms) shows a greater number of metabolites compared with long (270 ms) or intermediate (144 ms) TE. Most prominent peaks seen on short TE are lipid (resonates at 0.9 to 1.4 parts per million [ppm]), lactate (1.3 ppm), N-acetyl aspartate (NAA) (2 ppm), glutamine/GABA (2.2 to 2.4 ppm), creatine (Cr, 3 ppm), choline (Cho, 3.2 ppm), and myoinositol (mI, 3.5 ppm). Each metabolite resonates at a specific frequency, expressed as ppm, and each one reflects specific cellular and biochemical pro- cesses. In short, NAA is a neuronal marker, Cr provides a mea- sure of energy stores, Cho is a measure of increased cellular turnover, mI is a measure of cellular signal transduction and osmoregulation, and lactate reflects anaerobic metabolism.

Normal Anatomy and Pathways of Cerebellum

35.6 Role of Cerebellum in Cognition and Neuropsychiatric Disorders

Traditionally, the role of the cerebellum was thought to be lim- ited to the coordination of voluntary movement, gait, posture, speech, and motor functions. However, during the past three decades, neuroanatomical, neuroimaging, and clinical studies have provided evidence of cerebellar involvement in cognitive and linguistic processing. Evidence that supports the idea of the cerebellum’s role in cognitive functions are neuropsychological deficits in patients with cerebellar lesions, activation of the cer- ebellum in normal subjects as they perform a cognitive task on functional MRI, and anatomical connections showing links between the cerebellum and cerebral cortex that are known or thought to be involved in cognition.27

Although the cerebellum constitutes only 10% of the total brain weight, it contains more than half of all the neurons in the brain.28 The cerebellum has 40 million nerve fibers for con- nections to neocortical areas, compared with the one million nerve fibers of the visual system. Neuroanatomical studies have shown bidirectional pathways connecting the cerebellum to important parts of the cerebral cortex involved in cognitive reg- ulation. The frontocerebellar connections consist of closed corti- cocerebellar loops in which the (dorso)lateral part of the pre- frontal cortex connects to the cerebellum via pontine nuclei, and the cerebellum sends projections back to the prefrontal cortex via the dentate nucleus and thalamus. The cerebellum is connected to the cerebrum via three cerebellar peduncles. These are connections to many brain areas relevant to cognition

35.5.1 Spectrum Analysis

Because of its different anatomical and cellular composition, the spectroscopic peaks show mild variations with respect to the cerebral parenchyma. The largest metabolic difference between the cerebellum and other brain regions is the high levels of Cr both in the vermis and in the cerebellar hemi- spheres.24,25 The exact reason for this difference is not clear but is thought to be due to the different cellular composition of cerebellar cortex compared with that of the neocortex. Compared with the six-layered neocortex, the cerebellar cor- tex has a uniform three-layer structure, consisting of a super- ficial “molecular” layer containing mainly axons and den- drites of the cerebellar neurons, a Purkinje cell layer, and a “granular” layer consisting of a multitude of densely packed small granule cells.

Anatomically, the pons is characterized by a high density of fiber bundles (i.e., white matter) and thus shows a similar spectroscopic pattern as observed in supratentorial brain white matter. It shows high levels of NAA and Cho and low levels of Cr with respect to the cerebellum. The high NAA sig- nal presumably reflects the high axonal/neuronal density of the pons. The cerebellum shows a smaller NAA:Cr ratio com- pared with the pons and the thalamus (▶ Fig. 35.11). Quanti- tative MRS shows cerebellar levels of Cho, Cr, and NAA to be 2.5, 9.1, and 9.6 mM, and for the pons, concentrations of 2.9, 6.0, and 12.1 mM, respectively.25,26 Cho:Cr is significantly greater in the vermis (0.83 ± 0.10) than in the cerebellar hemisphere (0.76 ± 0.11), and NAA:Cho was significantly lower in the vermis (1.19 ± 0.12) than in the cerebellar hemi- sphere (1.35 ± 0.16).

325

Fig. 35.11 Short echo time (TE) (30) magnetic resonance spectroscopy through the cerebellar vermis shows normal spectrum. N-acetyl aspar- tate (NAA) at two parts per million (ppm), creatine (Cr) at 3 ppm, choline (Cho) at

3.2 ppm, and myoinositol (ins) at 3.5 ppm.

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and behavior, including the dorsolateral prefrontal cortex, the medial frontal cortex, the parietal and superior temporal areas, the anterior cingulate, and the posterior hypothalamus. There are also noradrenergic, serotonergic, and dopaminergic inputs to the cerebellum from the brainstem nuclei.

Recent functional neuroimaging demonstrated that there seems to be a functional organization of the cerebellum: motor and sensorimotor tasks activate the anterior lobe, adjacent parts of lobule VI, and lobule VIII. In contrast, the posterior lobe (lobules VI and VII, in particular) is found to be involved in higher-level tasks for language, verbal working memory, and executive tasks.29 It was further shown that there is lateraliza- tion of the function within the cerebellar hemispheres; logical reasoning and language processing were predominately on the right side and visuospatial and attentional skills on the left side of the cerebellum.

Cellular as well as functional reduction is seen with the aging process. A 10 to 40% decrease in the Purkinje cell layer and a reduction in the area of the dorsal vermis have been reported with aging. Congenital and acquired lesions of the cerebellum and posterior fossa have been seen in association with various cognitive dysfunctions. Various congenital malformations may manifest with selective neuropsychological deficits involving mainly executive functions and visuospatial and linguistic abili- ties. The extent of these symptoms largely depends on the area involved and the extent of the pathology. Children with cerebel- lar hypoplasia have significant problems in attention, process- ing speed, and visuospatial functions, whereas patients with olivopontocerebellar atrophy demonstrate multiple deficits in intellect, memory, attention, language, and visuospatial and executive functions compared with a control group.30 The con- genital and early acquired cerebellar problems have a more pronounced effect on cognitive functioning than lesions acquired later in life. This observation supports the idea that the cerebellum has an important influence on the developing structures and function of the supratentorial brain, enabling the perfection of its higher-level functions.

Various acquired lesions affecting the cerebellar parenchyma, especially during childhood, also have a significant impact on cognition.31 Two major types of clinical scenarios seen with acquired lesions are the cerebellar cognitive affective syndrome (CCAS) and the posterior fossa syndrome (PFS).27 CCAS is charac- terized by executive dysfunctions, such as disturbances in plan- ning, set-shifting, abstract reasoning, and working memory; visuospatial deficits, such as impaired visuospatial organization and memory; mild language symptoms, including agramma- tism and anomia; and, finally, behavioral–affective distur- bances, consisting of blunting of affect or disinhibited and inappropriate behavior.27,32,33 Clinical analysis revealed that lesions of the posterior lobe of the cerebellum (PICA territory) result in cognitive symptoms, whereas the vermis is mostly involved in patients with behavioral–affective disturbances. Patients with superior cerebellar artery territory lesions have been reported to have clinically significant cognitive or linguis- tic disturbances.

Posterior fossa syndrome is a well-recognized clinical entity seen most commonly following posterior fossa tumor resection, but it may also be seen with trauma, vascular insults, and infec- tious causes.34 PFS is characterized by a broad spectrum of lin- guistic, cognitive, and behavioral–affective disturbances. Signs

and symptoms of this syndrome depend largely on the hemi- sphere involved. Tumors infiltrating the right cerebellar hemi- sphere are associated with difficulties in verbal processing and complex language tasks, whereas tumors of the left cerebellar hemisphere correlate with deficits in nonverbal and spatial processing. The exact pathogenesis of PFS is elusive. The hypo- thetical explanation given is that it is due to the phenomenon of cerebellocerebral diaschisis, which represents the metabolic impact of a cerebellar lesion in a distant but anatomically and functionally connected supratentorial region.35,36,37 Left cere- bellar damage was related to typical right hemispheric dysfunc- tions, such as attention deficits and visuospatial disturbances, whereas right cerebellar damage was associated with typical left-hemispheric deficits, such as disrupted language skills. PFS is also thought to be due to multiple bilateral injuries to the proximal dentate-thalamocortical pathways and/or functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles.

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36 Imaging of Cerebellar Degeneration and Cerebellar Ataxia

Sangam G. Kanekar and Kyaw Tun

Ataxia in Greek means “absence of order.” It is a movement dis- order resulting from the incoordination of movements and inadequate postural control and manifests as balance and walking disturbances. Normal motor control is the outcome of normal postural tonus, muscle coordination, and balance work- ing together in unison. Various classifications of ataxia can be found in the literature. On the basis of their clinical signs and symptoms, they can be classified into acute or chronic onset. Chronic ataxias are further divided into (1) acquired ataxias, which are due to exogenous or endogenous nongenetic causes; (2) hereditary ataxias; and (3) nonhereditary degenerative atax- ias. ▶Fig. 36.1 enumerates the common causes of cerebellar ataxia.

a history of antecedent illness. The neurologic symptoms depend largely on localization of a lesion. Hemispheric lesions result in ipsilateral limb hypotonia, dysmetria, and tremor; vermian lesions manifest with dysarthria, truncal titubation, and gait abnormalities. Neuroimaging plays an important role in identifying the pathology and associated or impending com- plications, such as upward or downward cerebellar herniation or acute hydrocephalus.

36.1.1 Cerebellar Stroke

Bland and hemorrhagic strokes cause disruption in the cerebel- lar connections and cellular dysfunction and can lead to acute- onset ataxia.

Infarct

On magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) can detect the acute infarct within the first

36.1 Acute-Onset Ataxia

Acute cerebellar ataxia is most commonly seen in younger children, between 2 and 4 years of age. In 70% of cases, there is

Fig. 36.1 Causes of chronic ataxia. CNS, central nervous system.

Imaging of Cerebellar Degeneration and Cerebellar Ataxia

Fig. 36.2 Acute right cerebellar stroke. Diffusion-weighted magnetic resonance image shows area of increased signal intensity (arrow), suggestive of cytotoxic edema from infarction.

Fig. 36.3 Acute cerebellitis. Sagittal T2-weighted imaging shows diffuse hyperintensity in the cerebellar cortex in a child with acute- onset ataxia after viral (arrows) infection.

and molecular layers of the cerebellar cortex by mature T- lymphocytes, monocytes or macrophages, and eosinophils, associated with a loss of Purkinje cells. CT is insensitive in diag- nosis of cerebellitis. MRI shows asymmetric or symmetric, bilat- eral, and diffuse T2 hyperintense signal in the cerebellar gray matter (▶ Fig. 36.3). Leptomeningeal enhancement may be seen on postcontrast scans. Rarely, subcortical areas and the deep white matter of the cerebellar hemisphere are involved.

36.1.3 Toxic Cerebellitis

Cerebellar cells, particularly Purkinje neurons and cerebellar circuits, are susceptible to toxins and poisons, such as drugs, anticonvulsant overdoses, alcohol ingestion, organic chemicals, heavy metals, and various chemotherapeutic agents. These toxins are thought to cause hypoxia or to interfere with oxida- tive metabolism, leading to a decrease in the blood oxygen level to Purkinje cells, which in turn leads to cerebellar degeneration and atrophy.2 Imaging findings are nonspecific. Brain MRI is normal in most of the cases. In a few cases, mild cortical and white matter hyperintensity is seen on T2-weighted images. In cases of chronic exposure (e.g., antiepileptic drugs), atrophy may be present (▶ Fig. 36.4).

36.2 Chronic-Onset Ataxia

Chronic-onset ataxias can be generally classified into (1) inher- ited and (2) sporadic causes. Inherited causes can be further subdivided into (a) autosomal dominant, (b) autosomal reces- sive, and (3) X-linked.

36.3 Autosomal Dominant

Inherited Type

Of the several different types of autosomal dominant central nervous system (CNS) ataxia, the two most commonly encoun- tered in clinical practice are spinocerebellar ataxia (SCA) and

6 hours after onset of symptoms. As the vasogenic edema devel- ops, an area of T2 hyperintensity is seen in this region, with or without mass effect, in the fourth ventricle, depending on the size (▶ Fig. 36.2). Magnetic resonance angiography of the head and neck can identify the associated abnormality, such as ather- osclerosis, aneurysm, dissection, or vasculitis.

Hemorrhage

Computed tomography (CT) head examination is still the first line of imaging choices in evaluating cerebellar hemorrhages. CT shows hyperdensity with a surrounding area of edema in the region of the hemorrhage. On MRI, gradient-echo or susceptibility-weighted imaging is more sensitive in detecting small hemorrhages resulting from the presence of blooming effect from the hemorrhage.

36.1.2 Cerebellitis

Cerebellitis is an important cause of acute ataxia, particularly in children and young adults, after an infectious illness, especially a viral illness. Varicella infections are the most common causes of acute cerebellar ataxia in children, sometimes referred to as post-chickenpox cerebellitis.1 Brainstem encephalitis may also involve the cerebellar tracts, resulting in ataxia. Ataxic symp- toms are thought to be due to either direct viral invasion in the cerebellum or autoimmune reaction to infectious agents. On pathology there is extensive infiltration of the leptomeninges

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Fig. 36.4 Cerebellar atrophy from chronic antiepileptic therapy. Axial computed tomographic scan of the brain shows generalized prom- inence of cerebellar folia and diffuse thickening of the calvarium.

episodic ataxia type 2. The overall prevalence of SCA is esti- mated to be about 3 per 100,000.

36.3.1 Spinocerebellar Ataxia

The SCAs are caused by expansion of CAG triplet repeats in the coding region of the disease gene, resulting in production of a mutant protein with an abnormally long polyglutamine

stretch.3 To date, 27 loci for SCAs and the gene for dentatorubral and pallidoluysian atrophy (DRPLA) have been discovered. This numbering is based on the order in which the causative genetic mutation was identified. Detail clinical, genetic, and pathoge- netic features of all the 27 SCAs are beyond the scope of this chapter. SCA shows wide ethnic and geographic variations; SCA2 is most common in Cuba, and DRPLA is most common in Japan. Worldwide, SCA3 is the most common genotype (21%), whereas SCA1 and SCA2 account for about 6% and 15% of cases, respectively.4

Clinical manifestation of SCA includes ataxia of gait, ataxia of stance, dysmetria, kinetic tremors, and nystagmus. Signs and symptoms, however, largely depend on the genetic defect and the predominate anatomical degeneration. On histopathology, besides the cerebellum, there is degeneration of the extracere- bellar structures like the cerebral cortex, basal ganglia, brain- stem, cranial nerves, and spinal cord. This degeneration shows individual variations, depending on the type of SCA; for SCA2, degeneration of the cerebellar cortex and of the pontocerebellar petal system is marked, and the dentate nucleus is spared, whereas in SCA1, the degenerative process affects mostly the spinocerebellar system, and the dentate nucleus, the Purkinje cells, and the pontocerebellar petal system are relatively spared.5,6

Differentiating various SCAs by their structural properties or even newer molecular or cellular imaging techniques (diffusion tensor imaging [DTI], magnetic resonance spectroscopy [MRS]) is not possible. On MRI, appearances are broadly divided into pure cerebellar atrophy (SCA4, SCA5, SCA8, SCA9, SCA10, SCA11, SCA14, SCA15, SCA16, SCA18, SCA21, and SCA22) (▶ Fig. 36.5), olivopontocerebellar atrophy (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA13) (▶ Fig. 36.6), and global cerebral and cerebellar atro- phy (DRPLA, SCA12, SCA17, and SCA19).7 Cellular imaging tech- niques have been used to differentiate the various types of SCAs with limited success. Proton MRS shows decreased NAA:cre- atine (Cr) ratio, N-acetyl aspartate (NAA) concentration, and choline (Cho):Cr ratio in the pons and deep cerebellum. There is a direct correlation of the severity of clinical deficit with atro- phy of the brainstem, decreased NAA:Cr ratio in the pons, and increased apparent diffusion coefficient (ADC) value in the brainstem and cerebellum in SCA1.8

Fig. 36.5 Spinocerebellar ataxia, pure cerebellar atrophy type (SCA8). (a) Sagittal T1- and (b) axial T2-weighted imaging shows diffuse prominence of the cerebellar folia. Pons is normal in size and morphology.

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36.3.2 Episodic Ataxia Type 2

Episodic ataxia type 2 (EA2) is secondary to the mutation in the CACNA1A gene in Purkinje cells that encodes α-1 subunits in neuronal calcium channels.9 This mutation is also associated with familial hemiplegic migraine and SCA6. Onset of EA2 is usually in childhood, with recurrent ataxia that may last hours to days.

In a minority of patients, MRI of EA2 shows a corticocerebel- lar atrophy (CCA) pattern; that is, atrophy of cerebellar folia without any signal changes and with normal morphology of cervical spinal cord and brainstem, although most patients have no abnormalities in the cerebellum or brainstem.10 Proton MRS shows decreased Cr concentration with normal NAA and Cho concentration in the cerebellar vermis and deep cerebellar hemispheres without cerebellar atrophy in MRI. High lactate peaks may also be observed in cerebellum and cerebrum. These findings are assumed to be attributable to early calcium channel dysfunction.10

36.4 Autosomal Recessive Ataxia 36.4.1 Friedreich’s Ataxia

Friedreich’s ataxia is the most common recessively inherited ataxia, with mean age of onset around 15 years. Clinical mani- festation includes gait ataxia, limb ataxia, dysarthria, tendon areflexia, proprioceptive loss, and Babinski sign. Most patients have an unstable expansion of a repeated trinucleotide (GAA) sequence within the first intron of the FRDA gene on chromo- some 9q13–21.1.11 Expanded GAA sequence reduces the tran- scriptional and translational efficiency, which leads to a partial deficiency of the protein frataxin. It is believed that lack of this protein can result in accumulation of iron in mitochondria, especially in the cerebellum and cortical spinal tract, which leads to atrophy and degenerative changes. As a result, the size of dentate nuclei and superior and inferior cerebellar peduncles is reduced. The corticospinal tracts are severely degenerated beyond the cervicomedullary junction, which becomes progres- sively more severe moving down the spinal cord. Loss of cells is also involved in cranial nerves VIII, X, and XII, which in turn results in facial weakness and difficulties with speech and swal- lowing.

Imaging of Cerebellar Degeneration and Cerebellar Ataxia

Fig. 36.6 Spinocerebellar ataxia, olivopontocere- bellar atrophy type (SCA3). (a) Sagittal T1- and (b) axial T2-weighted images show prominence of the cerebellar folia (cerebellar atrophy) (arrow) with atrophy of lower pons (arrowhead in a and arrow in b).

On MRI, the cervical spinal cord or, rarely, the length of the entire cord shows atrophy from degeneration, with myelin loss and gliosis of the posterior columns and roots and the spinocerebellar and corticospinal tracts (▶ Fig. 36.7). Atrophy in the cerebellum is more pronounced in the superior ver- mian and paravermian area.12 Atrophy in the cerebellum and medulla has direct correlation with the severity of ataxia, as mentioned by França et al.13 DWI and DTI show white matter signal changes or damages in inferior and superior cerebellar peduncles, corticospinal tracts along internal cap- sule, pyramids and optic radiations.14 On MRS imaging, a decreased NAA:Cr ratio with a normal Cho:Cr ratio is observed in the pons, deep cerebellar hemisphere, and cere- bral white matter.13

36.4.2 Ataxia Telangiectasia

Ataxia telangiectasia (AT) usually manifests with progressive cerebellar ataxia between the ages of 1 and 3 years. Initial signs of truncal ataxia may be seen between 6 and 12 months, and usually patients with AT become unable to walk by the age of 8 to 12 years. Telangiectasia component has later onset, usually around 3 to 6 years of age, and sometimes as late as adoles- cence. Common clinical features include choreoathetotic involuntary movement, mental retardation, endocrine abnor- malities abnormalities, such as diabetes mellitus, and recurrent respiratory tract infections that lead to bronchiectasis and chronic bronchitis. Recurrent infections are due to lymphocyto- penia and a decrease or absence of immunoglobulins A and E (IgA and IgE). The lymphocytes are also very sensitive to ioniz- ing radiation; thus, the AT patient has a high risk of lymphoma and leukemia.15 Because of the high risk of lymphoproliferative neoplasm, examination of AT patients using CT or nuclear med- icine studies should be quite restrictive, and MRI should be the mainstay of imaging evaluation.

On MRI, AT usually shows a pattern of CCA without signal changes in the brainstem and cerebellum. Atrophy of the cere- bellar vermis and cerebellar hemispheres is most pronounced because of the loss of Purkinje and granule cells from the cere- bellar cortex. Cerebellar atrophy starts from the lateral portion of the hemispheres and progresses to the inferior and superior parts and eventually to diffuse involvement of the cerebellum.15 In DWI, the ADC values are increased in the cerebellar white

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Cerebellar Degeneration and Dysfunction

Fig. 36.7 Friedreich’s ataxia. (a) Sagittal and axial T2-weighted images show mild atrophy of the cervical cord and cerebellum. (b) Axial image also shows mild increased signal intensity in the posterior columns (arrow) from myelin loss and gliosis.

Fig. 36.8 Ataxia telangiectasia. (a) Sagittal T1-weighted imaging shows moderate cerebellar atrophy. (b) Axial gradient-echo image shows multiple hypointense foci in the white matter bilaterally, probably resulting from multiple cerebral capillary telangiectasia (arrows).

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matter and cortex, with normal values in the cerebral hemispheres.16 On susceptibility-weighted or gradient echo- weighted imaging, foci of hypointensity can be observed in the cerebral parenchyma, which corresponds to capillary telangi- ectasia, especially in 3 T MRI (▶ Fig. 36.8). Proton MRS studies show a significant decrease in NAA and Cr in the cerebellar ver- mis.17 On perfusion single-photon emission computed tomog- raphy, decreased cerebellar blood flow is also documented in AT patients with cerebellar atrophy.18

36.5 Metabolic Causes

Various metabolic conditions involve the posterior fossa struc- tures and may lead to morphologic or myelination abnormali- ties, or disturbances at the neurotransmitter or disruption

pathways. Clinical symptoms and signs of metabolic diseases are nonspecific and are often challenging for the clinician. Ataxia may be an initial or an associated symptom in the vari- ous organelle-based (lysosomal, peroxisomal, mitochondrial disorders) or nonorganelle-based metabolic disorders (amino- aciduria, organic acidemia, nuclear DNA repair defects, a defect in the gene encoding myelin proteins, and miscellaneous, including primary myelin disorders [Alexander’s disease], vacuolating leukoencephalopathy [Canavan’s disease, megalen- cephalic leukoencephalopathy with subcortical cysts, vanishing white matter disease], hypomyelination with atrophy of the basal ganglia and cerebellum, and merosin-deficient congenital muscular dystrophy).19,20 Metabolic causes leading to neuro- degenerative disorders are discussed in detail in Chapter 34, Inborn Errors of Metabolism.

Imaging of Cerebellar Degeneration and Cerebellar Ataxia

36.5.1 X-Linked Inherited Ataxia Fragile X Tremor Ataxia Syndrome

Fragile X tremor ataxia syndrome (FXTAS) is an X-linked inherited disease with the mutation in fragile X mental retar- dation 1 gene (FMR1). The full mutation is an expansion of a CGG repeat in the gene to greater than 200. Usually, the normal range of CGG repeats in the FMR1 gene is less than 54. An adult man who carries a permutation in the 55 to 200 range may have cerebellar ataxia, tremor, parkinsonian features, and dementia.21 FXTAS is a late-onset neuro- degenerative disorder that predominately affects men. Clini- cal signs and symptoms include ataxia, intention tremor, rigidity, and cognitive decline.

On MRI, the main characteristic features include dis- proportionate atrophy of the cerebral and cerebellar hemi- spheres, middle cerebellar peduncles, pons, medulla, and cor- pus callosum for the age. Symmetric T1 hypointense and T2 hyperintense signals are seen in the peridentate white matter and middle cerebellar peduncles.22 Similar signal intensity changes are also seen in the cerebrum and cerebellum white matter, often bilateral, symmetric, patchy, or confluent, with involvement of the deep and periventricular white matter and with sparing of the subcortical U-fibers and cortical and deep gray matter. Diffuse atrophy of the cerebrum, particularly in the frontal and parietal lobes, with dilatation of the lateral ventricle and cerebellar atrophy, is also seen with normal pons morphology.23 A definite diagnosis is made on the basis of detection of the FMR1 permutation.

36.6 Sporadic Causes of Ataxia

36.6.1 Alcoholic Cerebellar

Degeneration

Although population-based epidemiologic studies are not avail- able, alcoholic cerebellar degeneration (ACD) is probably the most common form of chronic cerebellar ataxia. ACD is likely due to the combination of nutritional deficiency of vitamin B1, as in Wernicke’s encephalopathy, and the toxic actions of alco- hol and its derivative acetaldehyde on the neurons. Degenera- tion predominately affects the cerebellar cortex of the anterior superior vermis and adjacent hemispheres, parts of the cerebel- lum that mainly receive spinal afferents. Alcohol and acetalde- hyde, its highly toxic derivative, have various deleterious actions on central neurons, including depression of neuronal firing by interaction with γ-aminobutyric acid (GABA)-ergic inhibitory mechanisms, increased lipid peroxidation, and reduction of antioxidant concentrations.24 Wernicke’s ence- phalopathy (WE) is the clinical syndrome, with ataxia, periph- eral neuropathy, seizures, and mental confusion resulting from thiamine deficiency. Besides alcoholism, thiamine deficiency can be caused by malabsorption secondary to gastrointestinal neoplasm, bowel surgery, hyperemesis, severe malnutrition, and prolonged hyperalimentation. The neuropathological hall- marks of WE are hemorrhagic lesions that are centered on the third ventricle and affect the mammillary bodies and thalamic nuclei. If ACD and WE are on the same spectrum, WE is the acute phase that affects the cerebellum as well as other parts of

Fig. 36.9 Wernicke’s encephalopathy. (a, b) Axial fluid-attenuated inversion recovery (FLAIR) images show bilateral symmetric hyperintensity in the medial aspect of the thalami (arrows, a). Edema and hyperintensity are also seen in the mamillary bodies (fat arrow, b).

CNS, such as the mammillary bodies and thalami. ACD is the chronic variant, with cerebellar atrophy. Ataxia usually occurs subacutely in chronic alcohol users, and symptoms may stabi- lize for years. Strict abstinence improves ataxia; however, ataxia progresses in patients who continue to consume alcohol.

On MRI, the main feature of ACD is vermal cerebellar atrophy. However, many chronic alcohol users have cerebellar atrophy without ataxia.25 WE may show symmetric areas of increased T2-weighted signal intensity in mesial thalami, mammillary bodies, and periaqueductal white matter (▶ Fig. 36.9). Contrast enhancement of the thalamus and mammilary bodies is strongly associated with alcoholism. Nonalcoholic causes may have atypical findings, such as T2 hyperintensity in the cerebel- lum, cranial nerve nuclei, red nuclei, dentate nuclei, splenium, and cerebral cortex. One should remember, however, that lack of imaging abnormalities does not exclude WE.

36.6.2 Paraneoplastic Cerebellar

Degeneration

Paraneoplastic cerebellar degeneration (PCD) is an immune- mediated degenerative disorder of the cerebellar cortex that can occur in almost every neoplastic process. It is most com- monly seen with small-cell lung cancer, cancer of the breast and ovary, and Hodgkin’s lymphoma. Clinically, it may manifest as pure ataxia, or it may be associated with other syndromes, like paraneoplastic encephalomyelitis.

Approximately 50% of patients with PCD will have various antibodies in serum or cerebrospinal fluid (CSF).26 For exam- ple, anti-Yo antibody is associated with ovarian and breast cancer, anti-Tr antibody is associated with Hodgkin’s lym- phoma, and anti-CV 2 is associated with small-cell lung can- cer and malignant thymoma. The hallmark of PCD is a diffuse loss of Purkinje cells associated with inflammatory infiltrates in the cerebellar cortex, deep cerebellar nuclei, and inferior olivary nuclei.

In PCD, initial MRI is often unremarkable; however, the pres- ence of any antineuronal antibodies will confirm the diagnosis of PCD. Rarely, some cases show a transient diffuse

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Cerebellar Degeneration and Dysfunction

Fig. 36.10 Paraneoplastic syndrome. (a) Coronal T1-weighted imaging shows mild cerebellar atrophy (arrows) in a lung cancer patient with acute-onset ataxia. (b) Axial fluorodeoxyglucose (FDG) image shows intense uptake in the primary tumor (arrow) with mediastinal lymph node metastasis.

Fig. 36.11 Superficial siderosis. Axial T2-weighted imaging shows hypointense blooming strips over the cerebellar surface from hemosiderin deposition (arrows).

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cerebellar hemispheric enlargement or cortical-meningeal enhancement. During this phase, fluorodeoxyglucose (FDG)- positron emission tomography (PET) can show cerebellar hypermetabolism. In the later stages, cerebellum shows atrophy on MRI (▶ Fig. 36.10) and global decrease in FDG uptake in the cerebrum and cerebellum, with sparing of brainstem, indicating damage of cerebellar efferents to the thalamus and forearm (reverse cerebellar diaschisis).27 Generally, PCD does not respond to treatment of primary malignancy or immuno- suppressive therapy. However, in some rare cases, plasma exchange, intravenous immunoglobulins, and steroids may be helpful, especially if treatment is within the first month after manifestation of ataxia.28

36.6.3 Gluten Ataxia

Gluten ataxia is the most common clinical manifestation in patient with gluten-sensitive small bowel disorder. Diagnosis of gluten ataxia relies mainly on increased serum antigliadin anti- bodies and typical histologic findings from duodenal biopsy. Anti-gliadin antibodies target Purkinje cells and eventually lead to cerebellar cortical atrophy. However, anti-gliadin antibodies can also be found in patients with Friedreich’s ataxia and multi- system atrophy.29 The imaging pattern of gluten ataxia is non- specific. On MRI, diffuse cortical cerebellar atrophy can be seen.

On proton MRS, there is decreased NAA, NAA:Cho, and NAA:Cr ratios, with an increased Cho:Cr ratio in the deep cerebellum.

36.6.4 Siderosis of the Central Nervous

System

Superficial siderosis is characterized by deposition of free iron and hemosiderin along the pial and subpial structures in the CNS, spinal cord, and cranial nerves, especially in the second and eighth cranial nerves.30 Causes of these subarachnoid hem- orrhages may be secondary to vascular malformation, such as arteriovenous malformation and aneurysm, hemorrhagic tumor, posttraumatic or postsurgical causes. Siderosis is com- monly seen in the cerebellopontine cistern and over the cere- bellum, dependent structures in the cranial cavity. Clinical symptoms usually include progressive cerebellar ataxia, senso- rineural hearing loss, and pyramidal signs.30

In diagnosing superficial siderosis, MRI is the mainstay. T2- weighted imaging shows linear hypointensity along the surface of the brainstem, cerebellum, cranial nerves, and spinal cord in subarachnoid space (▶ Fig. 36.11). Similar changes may be also seen over the cerebral cortex. Gradient echo (T2*) and suscepti- bility-weighted imaging will show blooming artifact in the hemosiderin deposits in the subarachnoid space and further increase the sensitivity of detection.

Imaging of Cerebellar Degeneration and Cerebellar Ataxia

36.6.5 Multiple-System Atrophy

Multiple-system atrophy (MSA) is a neurodegenerative disorder with clinical symptoms of cerebellar ataxia, parkinsonism, and autonomic nervous dysfunction. MSA can be further subdivided into MSA-C, cerebellar-predominant type (formerly known as olivopontocerebellar degeneration), and MSA-P, parkinsonism type (formerly known as striatonigral degeneration). The char- acteristic pathological feature of MSA is the presence of glial cytoplasmic inclusions in oligodendroglial cells at autopsy.

The MSA-P type is characterized clinically by parkinsonian symptoms with prominence of rigidity. Unlike Parkinson’s dis- ease, however, less than 15% of MSA-P patients show response to levodopa. In MSA-P, the nigrostriatal system is the main site of disease, but less severe neurodegeneration can be wide- spread and normally includes the olivopontocerebellar system. MRI shows atrophy of the putamen, with T2 hypointense signal along posterolateral margins of putamen secondary to iron deposition. On f luid-attenuated inversion recovery (FLAIR) imaging, a hyperintense rim around the above-mentioned T2 hypointensity may be seen as a result of the accumulation of water associated with cell loss and gliosis. In addition, on DWI, abnormal increased diffusion is often observed in the putamen and middle cerebellar peduncle as a result of neuronal loss and loss of fiber tracts in this region. For similar reasons, MRS also shows a reduction in the NAA:Cr ratio within the putamen and base of the pons.

The MSA-C type usually manifests with ataxia in the lower extremities, which progresses to the upper extremities and eventually ends up with bulbar manifestation. In the MSA-C type, the olivopontocerebellar system is mainly involved, along with loss of pontine neurons and transverse pontocerebellar fibers and atrophy of middle cerebellar peduncles. The main characteristic feature in MRI is atrophy of the pons, with flat- tening of the inferior portion, which resembles “the loss of nor- mal pregnant belly of pons.” In T2-weighted imaging, atrophy of brainstem, middle cerebellar peduncles (▶ Fig. 36.12), and cere- bellum with characteristic hyperintensity in these same struc- tures may show classic “hot cross bun” sign. In DWI, there is increased diffusion in the putamen, cerebellum, and middle

cerebellar peduncles. Taoka et al report that in DTI, micro- structural change appears selectively in the middle cerebellar peduncles, with sparing of both superior and inferior cerebellar peduncles.31 Brenneis et al found that there is direct correlation between the amount of loss of the volume of the brainstem and cerebellar hemispheres and the severity of cerebellar ataxia.32 In MRS, a decrease in the NAA:Cr ratio in the lentiform nucleus was more pronounced in the MSA-P type than in the MSA-C type.33

Fig. 36.12 Multiple-system atrophy. Axial T2-weighted imaging shows mild atrophy and patchy hyperintensity in the middle cerebellar peduncles bilaterally (black arrows).

Fig. 36.13 Joubert malformation. (a) Sagittal T1-weighted imaging shows dysplastic superior vermis (arrow), enlargement of the fourth ventricle, and elongation of the interpeduncular cistern. (b) Axial T1-weighted imaging shows elongated superior cerebellar peduncles giving appearance of “molar tooth” (arrows).

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Cerebellar Degeneration and Dysfunction

36.6.6 Congenital Structural

Malformation

Cerebellar malformation can be grossly divided into hypoplasia (a small cerebellum that has fissures of normal size compared with the folia) or dysplasia (an abnormal folial pattern or the presence of heterotopic nodules of gray matter).34 These mal- formations may be either focal (localized to either a single hemisphere or the vermis) or generalized (involving both the cerebellar hemispheres and the vermis). Irrespective of the type, any type of malformation may manifest with ataxia. Asso- ciated brainstem anomalies may be seen either in association with, or isolated from, similar symptoms. Localized cerebellar hypoplasia is mostly due to prenatal disruption of the cerebellar development, usually by infarct or hemorrhage; rarely, it may be genetic. Severe generalized cerebellar hypoplasia is usually a sign of a wider disorder, including hindbrain malformations, malformations of cortical development, chromosomal abnor- malities, or a metabolic disorder of glycosylation, particularly type 1a.

Vermian dysplasias such as molar tooth–type malformation caused by mutations of primary ciliary protein genes (JSRD) and rhomboencephalosynapsis, are commonly associated with ataxia. MRI is diagnostic in such cases and shows vermis hypo- plasia with the distinctive “molar tooth” sign (▶Fig. 36.13).35 Ataxia results from abnormal function of the primary cilia, spe- cialized membrane-bound structures that project from the neu- ron and ependyma surface.35 Other imaging findings include dysmorphic midbrain, thin midbrain-pons junction, enlarged horizontal nondecussating superior cerebellar peduncles (molar tooth on axial images), and a triangular-shaped fourth ventricle (“bat wing” on axial images).

Other rare malformations that may be seen with inherited cerebellar ataxia include rhomboencephalosynapsis (character- ized by a midline continuity of the infratentorial structures, such as the deep cerebellar nuclei, superior cerebellar pedun- cles, and cerebellar hemispheres) and cerebellar cortical dys- genesis. The Dandy-Walker malformation is not a common cause of ataxia in children.

Arnold-Chiari malformation, a congenital malformation, may manifest with ataxia at a later age. Chiari type I is secondary to mismatch between the (small) posterior fossa size and normal cerebellum size.36 Symptoms are due mainly to brainstem com- pression and include hypersomnolence, central apnea, torticol- lis, ataxia, neck or back pain, or bulbar signs. On CT or MRI, cerebellar tonsils will be equal or more than 5 mm below the foramen magnum or opisthion-basion line (▶Fig. 36.14). The morphology of the tonsils is a more important factor than the extent of descent, such as pointed, triangular, or peglike rather than round. The foramen magnum will be crowded, with effacement or cisterns. On T2-weighted MRI, the tonsillar folia will be oriented in the vertical or oblique plane with or without syringohydromyelia in the cervical cord. The most important MRI sequence is phase-contrast cine MRI showing pulsatile sys- tolic tonsillar descent with obstruction of CSF flow through the foramen magnum.37

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Fig. 36.14 Chiari I malformation. Cerebellar tonsils are elongated and extend below the foramen magnum (arrow). Cervical cord shows syringohydromyelia (fat arrow).

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2007; 130: 2484–2493

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in episodic ataxia type 2: a 1H MRS study. Neurology 2005; 64: 542–544

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sound CT MR 2011; 32: 615–636

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tic cerebellar degeneration. Ann Neurol 1988; 23: 533–540
[28] David YB, Warner E, Levitan M, Sutton DM, Malkin MG, Dalmau JO. Auto- immune paraneoplastic cerebellar degeneration in ovarian carcinoma patients treated with plasmapheresis and immunoglobulin: a case report.

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Imaging of Cerebellar Degeneration and Cerebellar Ataxia

337

Part XV Motor Neuron Disorders

37 Overview of Motor Neuron Disorders 340 38 Neuroimaging of Motor Neuron

Disorders 349

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Motor Neuron Disorders

37 Overview of Motor Neuron Disorders

Divisha Raheja and Zachary Simmons

The terms motor neuron disease (MND) and amyotrophic lateral sclerosis (ALS) are often used synonymously, particularly in the United Kingdom. However, an understanding of some basic neuroanatomy will help clarify the terms upper motor neuron (UNM) and lower motor neuron (LMN) and so will facilitate a more sophisticated understanding of MNDs as a family of related disorders, ranging from pure UMN to pure LMN to mixed UMN-LMN syndromes. The role of imaging in the diag- nosis of MNDs has traditionally been limited to excluding alter- native diagnoses. However, significant advances have been made in the last few years in the development of techniques to detect early signs of UMN involvement. This chapter focuses primarily on the clinical features of MND. The role of imaging in the diagnosis and understanding of MND is discussed in detail in Chapter 38.

37.1 Upper Motor Neuron

Disorders

Upper motor neurons (▶Fig. 37.1) are neurons that have cell bodies in the primary motor cortex (Brodmann area 4) and the premotor area (Brodmann area 6) of the brain; they give rise to descending corticobulbar and corticospinal tracts that termi- nate on interneurons or motor neurons in cranial nerve motor nuclei or in spinal cord gray matter. UMN disorders are charac- terized by poor motor control, with loss of dexterity, spasticity, and pseudobulbar (spastic bulbar) palsy. Loss of muscle strength is generally mild until the disease is advanced because the LMNs are spared.

37.1.1 Primary Lateral Sclerosis

Primary lateral sclerosis (PLS) is a progressive disorder primar- ily affecting the UMNs. Originally described by Charcot in 1865 and Erb in 1875,1,2 it accounts for 3 to 5% of cases of MND.3 Symptoms in PLS usually begin in the fifth to sixth decade as a slowly evolving spastic paraparesis that spreads to the upper extremities and the bulbar muscles. Rarely, onset can be in the bulbar region, or it can ascend or descend in a hemiplegic fash- ion before progression to the other side (Mills syndrome).4,5 Progression is usually slow, over many years. The weakness is generally mild, and patients report clumsiness, a stiff and awk- ward gait, poor coordination, and loss of dexterity. Muscle atro- phy is mild, if present, generally a result of disuse, and there are no sensory symptoms. Bulbar symptoms usually begin as a mild spastic dysarthria and can progress to severe dysarthria and dysphagia associated with sialorrhea. Patients not uncommonly develop emotional lability, characterized by inappropriate laughter or crying, also known as pseudobulbar affect. Muscle cramps and spasms are common symptoms as well. Bladder function is rarely affected and is usually a late occurrence. Dementia is not a common feature, although subtle cognitive difficulties may be seen on neuropsychological testing in more than 30% of PLS patients, most commonly involving executive function.6 Patients usually do not have visual symptoms, but

eye movement abnormalities can be seen. Prognosis is signifi- cantly better than that for ALS,7 with patients demonstrating slow progression over many years.

Diagnostic criteria were proposed by Pringle et al in 1992, but specificity is low, and these criteria are no longer in wide use. The Pringle criteria required the disease to be limited to UMN findings for at least 3 years to exclude ALS.4 More recently, it has been proposed that the diagnosis of PLS should be consid- ered if the patients do not exhibit any LMN findings clinically or electrophysiologically 4 years after the onset of symptoms.3,5 Updated diagnostic criteria have been published (▶ Table 37.1).

The diagnosis is mainly clinical, with ancillary tests used to exclude other disorders. Recommended laboratory studies for assessment of UMN dysfunction include vitamin B12 levels, cop- per levels, human T-cell lymphotrophic virus (HTLV) titers, hex- osaminidase A levels (for adult-onset Tay-Sachs disease), and very-long-chain fatty acids to assess for adrenomyeloneurop- athy. Serum creatine kinase (CK) levels usually are normal and so are electrodiagnostic studies (nerve-conduction studies and needle electromyography). Historically, imaging studies have been performed to exclude mass lesions of the brain or spinal cord or to assess for other central nervous system diseases, such as multiple sclerosis, but modern imaging techniques may play a much more meaningful role. Neuroimaging techniques, including magnetic resonance imaging (MRI), magnetic reso- nance spectroscopy (MRS), positron emission tomography (PET) scans, and diffusion tensor imaging show changes along the corticospinal tracts, discussed in detail in Chapter 38.

Treatment is mainly supportive. Most recommendations for symptomatic treatment have been directed toward ALS patients, but a similar approach can be used for those with PLS. Baclofen, benzodiazepines, and tizanidine are usually the first- line drugs for treatment of spasticity. Dantrolene also is used, although less frequently, and some patients may benefit from the insertion of an intrathecal baclofen pump for spasticity that is refractory to oral agents.8,9 Botulinum toxin intramuscular injections may improve function in selected muscles. Pseudo- bulbar affect can be controlled with tricyclic antidepressants, selective serotonin reuptake inhibitors, or a combination of dextromethorphan and quinidine.10,11,12 Sialorrhea generally responds to anticholinergic agents, such as glycopyrrolate, ami- triptyline, benztropine, hyoscyamine, and transdermal scopola- mine.13,14

37.1.2 Hereditary Spastic Paraplegia

Hereditary spastic paraplegia (HSP) is a rare, genetically hetero- geneous group of disorders characterized by progressive lower extremity spasticity. The incidence has been reported to range from 3 to 10 per 100,000 population.15 Patients commonly show symptoms in the second to fourth decade of life, although juvenile onset has been reported. Retrograde “dying back” degeneration of axons of the corticospinal tracts and posterior columns is the common pathological feature.15,16 The genetics of HSP are extraordinarily heterogeneous. Although the most common mode of inheritance is autosomal dominant, it may be

Overview of Motor Neuron Disorders

Fig. 37.1 Anatomy of upper and lower motor neurons: Upper motor neurons arise from the cerebral cortex, giving rise to the corticospinal and corticobulbar tracts that terminate on cranial nerve motor nuclei in the brainstem and in the anterior horns of the spinal cord. Lower motor neurons arise from the cranial nerve nuclei in the brainstem and from the anterior horns of the spinal cord, terminating on the muscle.

Table 37.1 Diagnostic categories of primary lateral sclerosis (PLS)3

Autopsy-proven PLS

Clinically diagnosed PLS with degeneration in the motor cortex and corticospinal tracts; no loss of motor neurons in the spinal cord or brainstem; no gliosis in the anterior horn cells, and no Bunina or ubiquitinated inclusions

Clinically pure PLS

Evident UMN signs; no focal muscle atrophy or visible fasciculation; no denervation in EMG 4 yr from symptom onset; age at onset after 40 yr; secondary and mimicking conditions excluded by laboratory and neuroimaging

UMN-dominant ALS

Symptoms less than 4 yr or disability from predominantly UMN signs but with minor EMG denervation or LMN signs on examination; not sufficient to meet diagnostic criteria for ALS

PLS plus

Predominant UMN signs also with clinical, laboratory, or pathologic evidence of dementia, parkinsonism, or sensory tract abnormalities. Note: If cerebellar signs, urinary incontinence, or orthostatic hypotension are evident, multiple-system atrophy could be considered

Symptomatic lateral sclerosis

Clinically diagnosed PLS with evident possible cause (human immunodeficiency virus, paraneoplastic syndrome)

or frequency.19 Complex or complicated HSP is phenotypically diverse and manifests as spastic paraplegia in association with other neurologic abnormalities, which may include a combina- tion of ataxia, amyotrophy, pigmentary retinopathy, mental retardation, epilepsy, dementia, peripheral neuropathy, deaf- ness, and ichthyosis.15 Diagnosis is mainly clinical and is based on the individual and family history. In the absence of family history, diagnostic evaluation should be directed toward other conditions that may mimic HSP: structural causes, such as

inherited in an autosomal recessive or X-linked fashion. A total of 31 genes and 20 loci are known to be causative. Nearly 40% of the autosomal dominant families and 10% of the sporadic cases have been linked to the SPAST gene, located on chromo- some 2.17,18

Hereditary spastic paraplegia is classified as pure, or uncomplicated, when the symptoms are primarily those of lower extremity spasticity. Other features also include mild sensory loss in the distal lower extremities and urinary urgency

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Motor Neuron Disorders

hydrocephalus and myelopathy; degenerative or inflammatory processes, such as multiple sclerosis and leukodystrophies; infections, such as syphilis, HTLV, and human immuno- deficiency virus (HIV); metabolic disorders, including deficien- cies of vitamin B12, copper, and vitamin E; and paraneoplastic disorders. Electrodiagnostic studies are normal in uncompli- cated cases but may demonstrate peripheral neuropathy in some complicated cases. The primary role of imaging is to rule out other pathologies, such as multiple sclerosis or myelopathy from compressive, inflammatory, or ischemic etiologies.

Treatment is mainly supportive. Medications to reduce spas- ticity include baclofen, tizanidine, benzodiazepines, and dan- trolene. Intrathecal baclofen and botulinum toxin intra- muscular injections are alternative options if the desired effect cannot be achieved with the oral medications.

37.2 Lower Motor Neuron

Disorders

Lower motor neurons (▶Fig. 37.1) are somatic efferent neu- rons whose cell bodies are located either in cranial nerve motor nuclei or in the ventral spinal cord. These are the final pathways between the central nervous system and the skele- tal muscles. Muscle weakness, atrophy, fasciculations, and cramps are the primary clinical symptoms in LMN diseases and are the result of muscle denervation. Electrodiagnostic studies are key tests in the diagnosis of these disorders. Low- amplitude motor nerve-conduction studies with relatively preserved latencies and conduction velocities result from axonal loss. Sensory nerve-conduction studies are normal in pure LMN disorders. On needle electromyography, fibrillation potentials and positive sharp waves with or without fascicu- lation potentials can be seen, suggesting an active denervat- ing process; motor unit action potentials of large amplitude, increased duration, and increased polyphasia reflect chronic denervation and reinnervation.

Muscle biopsy may be useful when clinical and electrodiag- nostic findings are mild and nonspecific, particularly in early stages of the disease. Biopsies serve to rule out other causes of muscle weakness, such as a primary muscle disease, or an inflammatory process, such as vasculitis. When viewed under the microscope, denervated muscle fibers appear small and angulated and demonstrate dark staining on oxidative enzyme and nonspecific esterase stains. Progressive chronic denerva- tion and reinnervation usually lead to loss of randomness of the normal “checkerboard” pattern of muscle fibers, eventually resulting in groups of only one muscle fiber type, known as fiber type grouping (▶ Fig. 37.2).

37.2.1 Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) comprises a group of hereditary disorders characterized by progressive degeneration of anterior horn cells and selected brainstem motor nuclei, resulting in muscle atrophy and symmetric, predominantly proximal muscle weakness, in association with tongue fasciculations and markedly reduced to absent deep tendon reflexes.20 The first few cases of infantile, progressive weakness were described by Werdnig in 1891 and Hoffman in 1893.21,22,23 The International Consortium classified SMAs on the basis of age of onset and highest level of function (▶ Table 37.2).20 SMA I is characterized by severe, generalized muscle weakness and hypotonia at birth with rapidly progressive respiratory failure. Death usually occurs by 2 years of age.21,22 SMA II usually manifests in early childhood. These children are able to sit without assistance, but they never walk or stand unassisted. In SMA III, patients have proximal muscle weakness after the age of 18 months, are able to walk unassisted, and usually survive to adulthood.24 SMA IV has onset in adulthood and is characterized by proximal muscle weakness in a limb girdle pattern, leading to progressive diffi- culty in walking, climbing stairs, and getting up from a seated position. Life expectancy is normal.25 Fasciculations are com- monly seen in SMA types III and IV. Bulbar muscle weakness is

Fig. 37.2 Muscle biopsy from an amyotrophic lateral sclerosis (ALS) patient showing darkly staining angulated denervated muscle fibers (arrow) on nonspecific esterase staining (a). Adenosine triphosphatase stain showing fiber-type grouping and loss of randomness (arrow) of type 1 (lightly stained) and type 2 (darkly stained) fibers (b).

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Overview of Motor Neuron Disorders

Table 37.2 Classification of spinal muscular atrophy (SMA)20,21,22,24,25

SMA type Age of onset Inheritance Survival/prognosis

SMA I (Werdnig-Hoffman disease)

Infancy

Autosomal recessive

Death by 2 yr of age

SMA II

6–18 mo

Autosomal recessive

10–40 yr; may be able to stand unassisted, but never walk

SMA III (Kugelberg-Welander disease)

After 18 mo

Autosomal recessive

Able to walk; survive till adulthood

SMA IV (adult onset)

After 20 yr

Autosomal recessive

Normal life span

tion.32,33 The number of repeats has an inverse correlation with the age of onset but is unrelated to the rate of progression.33,34

Clinically, patients have progressive, painless, asymmetric, proximal muscle weakness; wasting of the facial, bulbar, and limb muscles; and endocrinologic abnormalities, such as pro- gressive testicular atrophy, azoospermia, infertility, and gyneco- mastia. Degeneration of the dorsal root ganglia results in sen- sory loss in the distal extremities. Muscle fasciculations are common, including facial and perioral fasciculations in more than 90% of patients.33,35 Muscle cramps are common as well. The disease follows a slowly progressive course, with a median survival of more than 20 years from the onset of symptoms. The average life span of patients is only minimally reduced, with a reported 10-year survival rate of 82%, compared with 95% among age-matched controls.34,36 Thus, distinguishing between Kennedy’s disease and the much more rapidly progressive ALS is critically important for patient care purposes.

The diagnostic evaluation includes molecular genetic testing for the expansion of CAG repeats on exon 1 of the androgen receptor gene. CK levels are almost always high and may be up to 10 times normal. Electrodiagnostic studies usually reveal decreased sensory and motor nerve amplitude, indicative of axonal degeneration of both sensory and motor axons.37 These findings are more severe in the upper than in the lower extremities, unlike the length-dependent process in peripheral neuropathies. Both active and chronic denervation are seen on needle electromyography examination, with chronic changes predominating. MRI may reveal decreased diameter of the cervical spinal cord.38

Treatment is supportive. Symptomatic therapy for muscle cramps and physical therapy are the mainstays. Experimental trials in animals suggested a role for androgen reduction therapy in slowing progression of the disease.39 However, randomized, placebo-controlled trials testing the androgen- reducing agents leuprorelin and dutasteride did not reveal any significant effects on swallowing and muscle strength.40,41

37.2.3 Hirayama’s Disease

Hirayama’s disease, also known as juvenile spinal muscular atro- phy of the distal upper extremity or monomelic amyotrophy, was originally described in Japan by Hirayama and colleagues in 1959.33 Most reported cases have been from Asia, particularly Japan, but additional cases have since been recognized in the western hemisphere. It is a rare disease, affecting primarily young men, most commonly between the ages of 15 and 25 years, showing insidious, asymmetric atrophy of the hand and forearm. The C7-T1 myotomes are most commonly affected, while sparing the brachioradialis muscle, but proximal weak- ness has also been noted. The weakness is predominantly uni- lateral in most affected individuals, although asymmetric and

a common feature in SMA type I but usually is not seen in the others.

Almost all cases are inherited in an autosomal recessive fash- ion. The gene responsible for SMA was identified in 1995 as the survival motor neuron gene (SMN), located on the long arm of chromosome 5.26 In humans, two forms of the SMN gene exist: SMN1 encodes for the full-length messenger RNA and hence is responsible for coding the SMN protein; SMN2 is identical to SMN1 except for a transition of cytosine to thymine at position 840 in exon 7, which results in a truncated protein that is not functional and is easily degraded. About 90% of the mRNA tran- scripts from SMN2 lack exon 7, but a small fraction can be trans- lated into normal SMN protein. In the absence of SMN1, patients are dependent for survival on SMN2 to make the SMN protein. Thus, the number of SMN2 copies has major implications for the phenotype. The larger the number of SMN2 copies, the bet- ter the prognosis.27,28

When SMA is suspected clinically, the diagnosis is confirmed by molecular genetic testing to identify homozygous deletions of the SMN gene on chromosome 5q. CK levels are usually normal in SMA I and II, although they can be elevated up to 10 times the upper limit of normal in types III and IV. Electrodiag- nostic studies and muscle biopsies demonstrate chronic dener- vation as described above.

The mainstay of treatment is supportive care, including ther- apy, nutritional support, respiratory care, orthotics, and ortho- pedic interventions. Gene therapy and stem cell therapy are under investigation.

37.2.2 Kennedy’s Disease

Kennedy’s disease, also known as bulbospinal muscular atrophy, is an X-linked recessive, adult-onset LMN disorder, described in 1968.29 Patients commonly manifest symptoms in their third or fourth decades of life with bulbar dysfunction and proximal muscle weakness. Gynecomastia is common. Although sensory symptoms are not common, sensory abnormalities have been noted on electrodiagnostic studies. Consistent with this, nerve biopsies and autopsies have revealed that there is degeneration not only of the anterior horn cells, but also of the dorsal root ganglia, resulting in sensory nerve fiber loss. This broader understanding resulted in renaming the disorder in 1982 as X-linked recessive bulbospinal neuronopathy.30

The genetic defect was recognized by La Spada et al in 1991 to be a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion within exon 1 of the androgen receptor gene located on the X chromosome.31 The number of repeats in normal indi- viduals varies between 11 and 30; the range is from 40 to 65 in symptomatic individuals. Very low repeat numbers (i.e., less than 11) are associated with mental retardation, and repeats between 30 and 40 are associated with reduced cognitive func-

343

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Motor Neuron Disorders

Fig. 37.3 Hand atrophy in an amyotrophic lateral sclerosis (ALS) patient. (a) Palmar aspect and (b) dorsal aspect representing the classic claw hand due to intrinsic hand muscle atrophy.

rarely symmetric bilateral upper extremity weaknesses have been reported. It is a benign disease, with an initial progressive course followed by stabilization after 2 to 3 years.42,43,44

The cause of the disease is unproven. It is speculated that repeated flexion and extension of the neck lead to flattening of the spinal cord secondary to microvascular ischemia. The first autopsy case was described in 1982 as demonstrating atrophic changes and gliosis in the anterior horn cells, with anteroposte- rior flattening of the cervical cord.45 MRIs have been extremely valuable in the diagnosis and are discussed in detail in Chapter 38.

Early diagnosis is important because intervention with a cer- vical collar at early stages can prevent recurrent flexion changes and prevent further progression.46,47

37.3 Disorders of Both Upper and Lower Motor Neurons

37.3.1 Amyotrophic Lateral Sclerosis

Jean-Marie Charcot first described ALS in 1869.48,49 ALS is a fatal neurodegenerative disorder affecting both the upper and lower motor neurons in the cerebral cortex, brainstem, and spinal cord. The course of the disease is inexorably progressive, result- ing in death from respiratory failure. More than 90% of the cases are sporadic (SALS). Only about 5% are familial (FALS),50 most commonly autosomal dominant. The lifetime risk of acquiring ALS by age 70 is between 1 in 400 and 1 in 1,000.51 The inci- dence of ALS worldwide is between 0.3 and 2.5 cases per 100,000 population per year.52,53 In Europe and the United States, the incidence is estimated to be 2 per 100,000 per year, with a prevalence of about 5.4 per 100,000.51,54 ALS is known by several others names, including Charcot disease (primarily in France), motor neuron disease, and (mostly in the United States) as Lou Gehrig’s disease after the famous baseball player who developed the disease in the 1930s.

Clinical Presentation and Epidemiology

Patients most commonly have a combination of UMN and LMN findings. LMN symptoms and signs include asymmetric, pain- less weakness associated with muscle atrophy ( ▶Fig. 37.3, ▶Fig. 37.4), fasciculations, and muscle cramps, whereas UMN findings usually are characterized by spasticity and brisk reflexes. Bulbar involvement is common, resulting in dysarthria and dysphagia. Bulbar onset is seen in about 25% of patients; 70% initially develop symptoms in the extremities.55 Less than 5% of the time, trunk involvement with progressive respiratory failure may be seen at onset. Patients with ALS may initially have predominantly or exclusively UMN or LMN symptoms and signs, although most eventually develop both.

The overall incidence of SALS is higher in men than in women, although there is a mild female predominance among bulbar-onset patients. FALS is equally common in men and women. The peak incidence is in the sixth to seventh decades and is about 10 years older for sporadic than familial patients. Mean survival from symptom onset to death is approximately

Fig. 37.4 Tongue atrophy in an amyotrophic lateral sclerosis (ALS) patient.

metabolism) have been implicated in both FALS and SALS. The recent connection between the open reading frame 72 gene (C9ORF72), located at 9p21, and ALS has raised new hopes for a better understanding of ALS pathophysiology because of its unique features and apparently widespread occurrence. A hexa- nucleotide (GGGGCC) repeat expansion in the noncoding pro- moter region of C9ORF72 has been identified in 24 to 46% of FALS patients and in 4 to 21% of SALS patients, making it the most commonly mutated ALS gene.74,75,76

Diagnosis

The clinical hallmark of ALS is the presence of both UMN and LMN signs at the bulbar, cervical, thoracic, and lumbar levels. Often, diagnosis is delayed because of the insidious onset of symptoms, with a median time to diagnosis from onset of symptoms of about 14 months.77 There is no single blood test, imaging study, or other biomarker that is specific for ALS. The diagnosis is based on an appropriate history and neurologic examination, supported by electrodiagnostic studies. A variety of blood tests are done to rule out ALS mimics. Examination of cerebrospinal fluid (CSF) should be performed if an infectious or infiltrative process is suspected or if an acquired demyelinat- ing polyneuropathy, such as chronic inflammatory demyelinat- ing polyneuropathy, is being considered. Other than mildly to moderately elevated serum CK levels and mildly elevated CSF protein levels, blood and CSF tests are expected to be normal in ALS. Electrodiagnostic studies are an invaluable tool in the diag- nosis of ALS. They assist the physician in assessing the extent of LMN involvement, and can be abnormal early in the course of the disease. Sensory nerve–conduction studies are invariably normal. Motor nerve–conduction studies may be normal or may reveal reduced amplitudes suggesting axonal loss. Needle examination characteristically reveals widespread active dener- vation (fibrillation potentials, positive sharp waves, and fascicu- lation potentials) and often shows chronic neurogenic changes as well, without a specific nerve root or peripheral nerve distri- bution.78 Imaging is performed primarily to exclude other structural, inflammatory, or infiltrative processes. For example, cervical stenosis with multilevel neural foraminal stenosis can result in upper motor neuron signs resulting from myelopathy and lower motor neuron findings from superimposed polyradi- culopathy. Proton density–weighted MRI may reveal hyperin- tensity within the motor tracts (specifically the internal cap- sule) in ALS patients. Newer imaging techniques, including MRS, functional MRI, PET, and diffusion tensor imaging may show early changes suggestive of UMN involvement.79 These topics are discussed in detail in Chapter 38.

The El Escorial diagnostic criteria were established by the World Federation of Neurology in 1991 and were subsequently modified to increase the sensitivity.80 Clinical, electrodiagnos- tic, and (optionally) neuropathological findings are used to arrive at a diagnosis of clinically definite, probable, laboratory- supported probable, or possible ALS based on a thorough evalu- ation at the bulbar, cervical, thoracic, and lumbar levels (▶Table 37.3). The Awaji criteria were introduced in 2008 to increase the diagnostic sensitivity. These criteria emphasized the use of electrodiagnostic findings in the clinical context and not as separate stand-alone data and thus recommended elimi- nating the category of probable laboratory-supported ALS.

3 years, but the survival curve has a relatively long tail, with one in five patients living 5 years and one in 10 patients surviv- ing 10 years or longer.53,55 Older age at onset, early respiratory muscle dysfunction, and bulbar onset are associated with shorter survival. Fatigue and decreased exercise capacity are common symptoms in ALS, and ultimately most patients require assistance with activities of daily living. Dysphagia eventually occurs in most patients, placing them at risk for weight loss and malnutrition, further compromising the prog- nosis. Respiratory dysfunction usually presents with exertional dyspnea and orthopnea. Eventually, progressive weakening of the respiratory muscles leads to respiratory failure and death. Cognitive impairment, usually in the form of frontotemporal dysfunction, occurs in 30 to 50% of patients, with about 15% developing a full-blown frontotemporal dementia (FTD).56,57,58

Cause, Pathogenesis, and Genetics

The cause of ALS remains unknown. The pathophysiological mechanisms underlying the disease process appear to involve a complex interaction of genetic and molecular pathways. Vari- ous mechanisms, including viral infections, activation of the immune system, exogenous toxins, mitochondrial dysfunction, neuroinflammation, oxidative stress, axonal transport, and pro- tein misfolding and degradation, have been considered and investigated over the years.59,60,61 The incidence of ALS has been noted to be higher in football players, smokers, and personnel who served in armed forces.62,63,64 The role of androgen toxicity and protective effect of estrogens have been speculated as con- tributing to higher incidence of the disease in men.65,66 Gluta- mate-induced neurotoxicity has also been implicated in the pathogenesis. Neurotoxins like β-methyl-amino-L-alanine have been associated with the epidemic of ALS and parkinsonism on the island of Guam, although there is not universal agreement about this.67,68,69

The discovery of mutations in the superoxide dismutase 1 (SOD1) gene in patients with FALS by Siddique and colleagues was a landmark in the history of ALS research.70 This gene, located on chromosome 21, encodes for the enzyme Cu-Zn superoxide dismutase, and variants of it are responsible for up to 20% of FALS cases. SOD1 mutations have also been identified in about 1 to 4% of sporadic cases.71 Cu-Zn superoxide dismut- ase catalyzes the dismutation of superoxide (O2-), resulting in oxygen and hydrogen peroxide. Mutations in SOD1 result in a toxic gain of function of the enzyme, leading to the generation of free radicals and causing progressive neuronal death. SOD1- associated FALS is usually inherited in an autosomal dominant fashion, although recessive transmission has been described in patients from Sweden and Finland.61,72 The transactive response TAR-DNA binding protein (TARDP) gene codes for the TDP-43 protein, which normally is localized in the nucleus; however, the cleaved form can be seen in the cytoplasm in pathological conditions. This TDP-43 protein is the major disease protein in ubiquitin-positive, tau-negative, and α- synuclein negative frontotemporal dementia (FTD) and is also present as cytoplasmic inclusions in almost all patients with ALS, strongly suggesting an overlap between FTD and ALS.73 Mutations in the TARDP gene account for 5 to 10% of FALS cases and are found in up to 2% of patients with SALS.53,55,71 Various other genes, including OPTN, FUS, and ANG (involved in RNA

Overview of Motor Neuron Disorders

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Motor Neuron Disorders

Table 37.3 Revised El Escorial criteria81

The diagnosis of ALS requires:

(A) The presence of:

● (A:1) Evidence of LMN degeneration by
clinical, electrophysiological or
neuropathologic examination

● (A:2) Evidence of UMN degeneration by
clinical examination, and

● (A:3) Progressive spread of symptoms or signs
within a region or to other regions, as determined by history or examination, together with (B).

(B) The absence of:

● (B:1) Electrophysiologic or pathological
evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration, and

● (B:2) Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs

The clinical diagnosis of ALS, without patho- logical confirmation, may be categorized into various levels of certainty:

● Clinically definite ALS: UMN and LMN signs in three regions

● Clinically probable ALS: UMN and LMN signs in at least two regions with UMN signs rostral to LMN signs

● Clinically probable ALS: Laboratory- supported: clinical signs of UMN and LMN dysfunction in only one region or UMN signs alone in one region, and LMN signs defined by EMG criteria in at least two limbs, with proper application of neuroimaging and clinical laboratory protocols to exclude other
causes

● Possible ALS: UMN and LMN signs in one region, UMN signs alone in two or more regions, or LMN signs above UMN signs

Abbreviations: EMG, electromyography; LMN, lower motor neuron; UMN, upper motor neuron.
Source: Modified and reprinted with permission. Copyright © 2000 by Informa Healthcare.
Source: Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1(5):293–299

346

The Awaji criteria also recommended that fasciculation poten- tials be taken as evidence of lower motor neuron dysfunction, thus eliminating the often-challenging need to find fibrillation potentials and positive sharp waves, particularly in cranial nerve innervated muscles or clinically unaffected limb muscles.81,82

Treatment

The mainstay of treatment for ALS patients is supportive, and thus palliative care and maximizing quality of life are the focus of management.83,84 Riluzole, an inhibitor of glutamate release, is the only approved drug for ALS. It is a disease-modifying drug that has been shown to prolong survival, on average, by 2 to 3 months.85 Symptomatic treatment includes management of muscle cramps, spasticity, sialorrhea, constipation, depression, anxiety, and pseudobulbar affect. Assistive devices and durable medical equipment eventually fill the homes of most patients with ALS, including orthotics, pivot discs, transfer boards, walkers, wheelchairs, and smaller devices for assistance with activities of daily living.86 Respiratory support in the form of noninvasive ventilation is recommended when patients develop orthopnea, dyspnea on exertion, or morning headaches or when the forced vital capacity is less than 50% of the pre- dicted value.87 Randomized controlled trials have shown that noninvasive ventilation prolongs survival and improves quality of life in patients without severe bulbar dysfunction and also improves some quality-of-life indices, such as sleep.13,88 Most

patients eventually require tracheostomy and mechanical ven- tilation to sustain life, but less than 10% choose this option in most Western countries.89 Malnutrition negatively affects prog- nosis and quality of life. A gastrostomy tube is recommended when weight loss exceeds 10% of body weight or the body mass index is less than 20 kg/m2 and is best done when the forced vital capacity is greater than 50% of predicted.13,90 The care of ALS patients is highly complex and best served by a multidisci- plinary approach in specialized ALS centers with neurologists, nurse coordinators, respiratory therapists, nutritionists, physi- cal and occupational therapists, and social workers. Such care can improve quality of life and prolong survival.91,92

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Divisha Raheja and Zachary Simmons

The diagnosis of motor neuron disorders (MNDs) is based on evidence of upper motor neuron (UMN) or lower motor neuron (LMN) dysfunction or both. LMN signs, such as muscle atrophy and fasciculations, are relatively easy to recognize clinically and are further aided by electrodiagnostic studies, which can often identify denervation and reinnervation of muscle before the development of symptoms or of abnormalities on neurologic examination. Thus, these studies have become standard, clini- cally useful instruments in the neurologist’s armamentarium. In contrast, UMN dysfunction is diagnosed by clinical examina- tion alone. The lack of objective markers for UMN involvement, particularly before such findings are clinically apparent, delays the diagnosis in many patients and precludes early initiation of neuroprotective treatment and the inclusion of these patients in clinical treatment trials. Electrodiagnosis has been used in an attempt to address this gap. However, transcranial magnetic stimulation (TMS) lacks sensitivity for subclinical UMN deficits. The triple stimulation technique (TST) combines collision stud- ies with TMS and has shown some promise, but the sensitivity is also low. For example, in patients who went on to develop amyotrophic lateral sclerosis (ALS), but who did not meet the criteria for definite or probable ALS at testing, the TST was abnormal in only 4 of 18 patients.1

Traditionally, the role of neuroimaging has been to exclude “ALS mimic” syndromes; from the clinician’s perspective, this means that MNDs are diagnosed using clinical and electrodiag- nostic means and that imaging findings in these patients are expected to be normal or nonspecifically abnormal. However, several advanced MR-based and functional neuroimaging tech- niques have substantially increased our knowledge about the pathophysiology of, and the dynamic changes that occur in, the human brain in MNDs. These techniques show promise for aiding clinical diagnosis and monitoring clinical progression in MNDs. This chapter focuses on these newer imaging techniques in ALS and other MNDs.

38.1 Conventional Magnetic

Resonance Imaging

Conventional magnetic resonance imaging (MRI) is routinely used to look for other pathologies, such as cerebral mass lesions, multiple sclerosis, cervical spondylotic myelopathy, conus lesions, or lumbosacral radiculopathy. In patients with ALS, a few subtle changes have been reported on T1-weighted, T2-weighted, proton density, and fluid-attenuated inversion recovery images (FLAIR), which are not diagnostic but are sup- portive of the diagnosis of a MND in patients with high clinical suspicion.

Hyperintensities of the corticospinal tract (CST) in ALS have been reported by some as best detected on T2-weighted images and by others as best seen on proton density or FLAIR sequences.2 They are most readily identified in the posterior limb of internal capsule and are best monitored on the coronal images from centrum semiovale to the brainstem (▶ Fig. 38.1a, b). Increased T2 signal is also seen in the extramotor frontotem-

Neuroimaging of Motor Neuron Disorders

38 Neuroimaging of Motor Neuron Disorders

poral regions (▶ Fig. 38.1 c). The sensitivity of these changes in patients with ALS and primary lateral sclerosis (PLS) ranges from 15 to 76% in various studies, with a reported sensitivity close to 62% with combined application of all three sequences.3, 4 Specificity for ALS is not high, however, as these changes can be seen in normal healthy individuals, in other diseases, such as leukodystrophies, or after liver transplantation. There is no relationship between the degree of CST hyperintensity and the severity of clinical UMN involvement.5

The precentral cortex can appear as a hypointense rim on T2- weighted and FLAIR images in patients with ALS (▶ Fig. 38.1 d). The mechanism has been thought to be a T2 shortening effect that results from excessive iron accumulation, fibrillary gliosis, or macrophage infiltration,6,7 but this is neither specific nor sensitive for ALS pathology. Hyperintensity of the anterolateral columns of the cervical cord has been observed on T2-weighted images in patients with ALS, consistent with the degeneration of the CST at autopsy, and is more specific than signal changes in the brain.2,8,9,10 A recent study with 7 T MRI revealed similar T2 hyperintensities in bilateral lateral segments of the spinal cord.11

Spinal cord imaging may be abnormal in some non-ALS MNDs. Cervical cord imaging findings have been described in detail in patients with Hirayama’s disease. These include loss of attachment of the dura to the lamina, asymmetric lower spinal cord atrophy, spinal cord T2 hyperintensity, loss of cervical lordosis in the neutral position, and forward displacement of the dura with flexion MRI (▶Fig. 38.2).12,13,14 Flexion MRI should be considered in patients with a high clinical suspicion of Hirayama’s disease to increase the sensitivity. Loss of attach- ment of the dura is described as the most specific finding, with a sensitivity of 70 to 90%13,15 Reduced diameters of the cervical and thoracic spinal cords can be seen in patients with Ken- nedy’s disease,16 and spinal cord atrophy is a common feature in patients with pure or complicated hereditary spastic paraple- gia (HSP).17,18

38.2 Voxel-Based Morphometry

Voxel-based morphometry (VBM) is an automated statistical approach that is used to detect the regional differences in brain tissue density and tissue amount. The technique typically uses T1-weighted volumetric MRI scans and performs statistical tests across all voxels in the image to identify volume differ- ences between groups.19

Global atrophy, as noted by reduced brain parenchymal frac- tion (BPF) in comparison to healthy control subjects, has been reported in some studies of patients with ALS.20 Regional gray matter (GM) atrophy of not only the motor cortex, but also the frontotemporal and parietal regions, has been noted in patients with ALS without cognitive impairment (▶ Fig. 38.3).20,21 Atrophy of the frontal regions has been noted to be severe in patients with ALS and frontotemporal dementia (FTD). ALS patients with mild cognitive impairment without evidence of frank FTD have also demonstrated gray matter loss in the frontal, parietal, and limbic regions compared with patients with no cognitive loss.3,22

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Fig. 38.1 Brain magnetic resonance imaging findings in amyotrophic lateral sclerosis (ALS). (a,b) Hyperintensity in the subcortical white matter on axial and sagittal fluid-attenuated inversion recovery images (arrows) in a 43-year- old woman with ALS. (c,d) T2-weighted images obtained from a 58-year-old patient with ALS with dementia show symmetric hyperintensity in the anterior temporal subcortical white matter (arrows) (c) and hypointensity along

the precentral cortices (arrowheads, d). (Re- printed with permission from the American Society of Neuroradiology and Agosta F, Chiò a, Cosottini M, et al. The present and the future of neuroimaging in amyotrophic lateral sclerosis. AJNR. Am J Neuroradiol 2010;31(10):1769– 1777.)

Fig. 38.2 Magnetic resonance imaging of the cervical spine in an 18-year-old man with Hirayama’s disease. (a) Axial T2-weighted image demonstrates loss of attachment at the C5 level (arrow). (b) Neutral-position T2-weighted image demonstrates subtle atrophy at C5-C6 (arrow). (c) Flexion T2- weighted image demonstrates 6 mm of anterior dural shift with near-complete obliteration of the subarachnoid space at C5–C6 (arrow). (Reprinted with permission from the American Society of Neuroradiology, Lehman VT, Luetmer PH, Sorenson EJ, et al. Cervical spine MR imaging findings of patients with Hirayama disease in North America: a multisite study. AJNR Am J Neuroradiol 2013;34(2):451–456.)

350

Because N-acetyl aspartate (NAA) is primarily found in neurons, whereas creatine (Cr) and choline (Cho) can be derived from all brain cells, the absolute concentration of NAA and the NAA/Cr and NAA/Cho ratios are considered markers of neuronal struc- tural integrity. MRS studies can be performed from a single voxel using a single-voxel spectroscopy technique or using a chemical-shift imaging technique in which multiple voxels can be studied simultaneously.

Proton MRS studies reveal reduced concentrations of NAA or reduced NAA:Cr, NAA:Cho, and NAA:Cr+Cho ratios in the motor cortex in ALS and PLS patients (▶Fig. 38.4).29,30,31,32,33 These changes are most prominent in the precentral gyrus and the corona radiata, but they can also be seen in the premotor regions, primary sensory cortex, and extramotor frontal regions, with relative sparing of the parietal lobes. Similar changes are also seen in the brainstem, primarily in the pons and upper medulla of patients with prominent UMN or bulbar signs.34

Reduced concentrations of NAA correlate with disease sever- ity in patients with ALS as measured with the ALS Functional Rating Scale-Revised and with UMN signs.29,35,36 Bulbar onset patients tend to have a lower NAA:Cr+Cho ratio than limb- onset patients, and the frontal NAA:Cr ratio correlates well with cognitive dysfunction.34,37,38 Myo-inositol, another spectro- scopic biomarker for glial activity, is also noted to be increased in the motor cortices of patients with ALS.

VBM studies have also provided evidence of white matter (WM) atrophy in extramotor areas, such as the corpus callosum, cere- bellum, frontotemporal and occipital regions, supporting the theory that ALS is a multisystem disease and suggesting that extramotor involvement may be seen early in the disease.20,23,24 A few longitudinal studies have looked at the progression of GM loss and have demonstrated greater GM atrophy in the motor and extramotor frontal regions with disease progression, more pronounced in rapidly progressing cases.25,26

Global and regional atrophy in the precentral cortex and the corpus callosum have been reported in patients with PLS com- pared with controls.27 Regional GM and WM atrophy, mainly in the pericentral regions and specifically the precentral gyrus have been reported in patients with HSP, correlating with the most affected cortical region (i.e., the motor cortex). These changes are more prominent in patients with complicated than pure HSP. Corpus callosum thinning has been noted to be a common feature in patients with complicated HSP.28

38.3 Magnetic Resonance

Spectroscopy

Magnetic resonance spectroscopy (MRS) is a noninvasive tech- nique to evaluate the chemical environment of the brain.

Neuroimaging of Motor Neuron Disorders

Fig. 38.3 Regional gray matter atrophy in the brains of amyotrophic lateral sclerosis (ALS) patients compared with controls. Atrophy of the gray matter is present in the precentral and postcentral gyri, extending from the primary motor cortex to premotor, parietal, and frontal regions in a group of 17 ALS patients compared with controls. The differences between groups are superimposed on a standard normalized T1-weighted image. (Image reprinted with permission from the American Society of Neuroradiology, Agosta F, Chiò A, Cosottini M, et al. The present and the future of neuroimaging in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol 2010;31(10):1769–1771.)

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Fig. 38.4 Two-dimensional multivoxel spectroscopy of the motor cortex in a control subject (a–c) and a patient with amyotrophic later sclerosis (ALS) patient (d–f). Axial T2-weighted image shows the grid and the volume of interest (solid white rectangle, a and d). Reduced NAA/Cr and NAA/Cho ratios are demonstrated in the ALS patient (e, f) compared with the control subject (b,c). (Image reprinted with permission from John Wiley & Sons, Wang S, Melhem ER. Amyotrophic lateral sclerosis and primary lateral sclerosis: The role of diffusion tensor imaging and other advanced MR-based techniques as objective upper motor neuron markers. Ann NY Acad Sci 2005;1064:61–77.)

38.4 DiffusionTensorImaging

Diffusion tensor imaging (DTI) is a relatively new MR-based

technique that allows estimation of the orientation of white

matter fiber bundles based on the diffusion characteristics of

water. This technique permits the detection of brain injuries

earlier than they can be detected by conventional imaging

techniques. Diffusivity of water is generally higher along the

direction of the fiber tracts than perpendicular to them. A

quantitative measure of the overall presence of obstacles to

diffusion is called mean diffusivity (MD). The MD is a measure

of diffusivity of water molecules irrespective of the direction

and hence is higher in less restricted environments, such as

cerebrospinal fluid. The directionality of diffusion can be

quantified by fractional anisotropy (FA), which ranges from

zero (no directional dependence of diffusion) to one (diffusion

along a single direction). Thus, any structural change in the

white matter or axonal loss would affect the diffusion charac-

teristics and lead to an increase in the MD and a decrease in FA.39,40,41

Increased MD and decreased FA along the CST have been reported in multiple studies as a measure of UMN dysfunction in patients with ALS and PLS (▶Fig. 38.5).41,42,43,44 These

changes are thought to be secondary to loss of pyramidal motor neurons in the primary motor cortex and axonal degeneration of the CST, together with the proliferation of glial cells, extracel- lular matrix expansion, and intraneuronal abnormalities.7,41 The posterior limb of the internal capsule (PLIC) is predomi- nantly involved, although changes have been reported in the corpus callosum and in subcortical regions beneath the motor and premotor cortex. Patients with bulbar-onset ALS have the most significant decrease in FA (▶ Fig. 38.6).41 Decreased FA has been correlated with severity and disease progression in ALS patients in some studies, but other studies have failed to con- firm this finding.2,45 A few studies have focused on differences in white matter involvement in patients with ALS and PLS, sug- gesting different pathology of the two diseases. Patients with PLS are noted to have decreased FA along the whole length of CST from the primary motor cortex to the medullary pyramids. The rostral part of the CST is significantly involved in patients with PLS, specifically, the corpus callosum and the subcortical regions underlying the primary motor cortices. In contrast, although ALS patients also are noted to have decreased FA along the CST, the rostral portions of the CST and the callosal fibers are not as involved as in patients with PLS. The extent of these changes does not correlate with the duration of the disease in

Neuroimaging of Motor Neuron Disorders

Fig. 38.5 Graphs of mean fractional anisotropy (FA) in the right (Mean_R) and left (Mean_L) corticospinal tracts and in the left and right precentral (Pre_L and Pre_R) and postcentral (Post_L and Post_R) regions of 28 ALS patients (green) and 26 healthy controls (blue). Mean values shown with SDs (black lines). Significant parameters marked by a red asterisk (p < 0.0041 on left and p < 0.001 on right); ns indicates not significant. CT = controls; PA = ALS patients. (Image reprinted with permission from Sage CA, Peeters RR, Görner A, Robberecht W, Sunaert S. Quantitative diffusion tensor imaging in amyo- trophic lateral sclerosis. Neuroimage 2007;34 (2):486–99).

Fig. 38.6 Diffusion tensor imaging in 15 ALS patients compared with controls demonstrating reduced fractional anisotropy in the pyramidal tract, corpus callosum, and thalamus (a,b), and under the motor and premotor cortex (c,d). (Images reprinted with permission from Oxford University Press, Sach M, Winkler G, Glauche V, et al. Diffusion tensor MRI of early upper motor neuron involvement in amyotrophic lateral scle- rosis. Brain 2004;127(Pt 2):340–350.)

approach also have shown extramotor involvement in the cor- pus callosum, premotor white matter, prefrontal white matter, and temporal regions.48,49

Patients with progressive muscular atrophy (PMA) usually do not demonstrate these changes, as would be expected from lack of UMN involvement in these patients.50 However, a few studies have revealed that patients with PMA who demonstrated decreased FA values in PLIC similar to those seen in patients

PLS patients, but it tends to worsen with the disease duration and severity in ALS patients.44,46

Cervical cord FA has been reported to be decreased in patients with ALS compared with controls and to correlate with disease severity.47 Longitudinal follow-up of these patients demonstrates a significant decrease in the cord FA and an increase in the MD over time, despite the stability of the brain CST FA and MD.45 DTI studies recorded with a voxel-based

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Fig. 38.7 Diffusion tensor tractography of a control subject (a) compared with patient with amyotrophic lateral sclerosis (ALS). (b). Reduced fiber density of the corticospinal tract (green) is demonstrated in the ALS patient. (Images re- printed with permission from John Wiley & Sons, Wang S, Melhem ER. Amyotrophic lateral scle- rosis and primary lateral sclerosis: the role of diffusion tensor imaging and other advanced MR- based techniques as objective upper motor neuron markers. Ann NY Acad Sci 2005;1064:61– 77.)

with UMN signs eventually developed ALS, suggesting a role for DTI as an early marker of UMN involvement.42,43

Diffusion tensor imaging also allows interregional fiber track- ing. Known as diffusion tensor tractography, this technique allows identification of major white matter tracts as they course through the brain. Further quantification of the white matter tracts can be performed using a region-based approach. A decreased number of CST fibers is seen in patients with ALS and PLS with severe clinical deficits compared with normal sub- jects (▶ Fig. 38.7).7,48

38.5 MagnetizationTransfer

Imaging

Magnetization transfer ratio (MTR) is an MR-based parameter that measures the exchange of magnetization between free protons (water molecules) and those bound to macromolecules and is thus thought to reflect alterations in macromolecular structures. Reduced MTR values are indicative of inability of neuronal macromolecules to exchange magnetization with the surrounding free water molecules, which correlates with axonal degeneration and demyelination.51 MT imaging also improves the visibility of gadolinium-enhancing lesions by suppressing the surrounding normal brain parenchyma and leading to contrast augmentation.

Reduced MTR values are seen along the CST and in the pre- central gyrus in patients with ALS, consistent with the pathol- ogy of the disease. This reduction has been reported in two dif- ferent studies as ranging from 2.6 to 20% compared with con- trols.52,53 Hyperintensity along the CST has been reported in a single study using T1-weighted MT contrast images in 80% of ALS patients compared with controls.54 Reduced MTR values also have been reported in the nonprimary motor cortices, including the premotor cortex (superior and middle frontal gyri) and the motor-related parietal cortices. Prefrontal and temporal lobes demonstrate MTR reductions in patients with or without frontotemporal dementia, suggesting extramotor involvement in ALS patients, in line with neuropathological findings and with other nuclear imaging studies, such as func- tional MRIs and PET scans.55 It is not clear whether these changes correlate with the severity of the disease. Longitudinal studies are needed to establish the utility of the MT imaging as a surrogate marker for disease severity and evolution.

38.6 Functional Imaging
38.6.1 PositronEmissionTomography

Positron emission tomography allows noninvasive quantifica- tion of cerebral blood flow, metabolism, and receptor binding. It uses positron-emitting radioisotopes as molecular probes to assess biochemical processes in vivo. The typical agents used for PET studies are fluorodeoxyglucose (FDG), carbon 11- labeled deoxyglucose, or methionine. Different analogs, such as dopamine, amyloid, and benzodiazepine receptor ligands, have been used with radioactive fluorine, oxygen, or carbon to analyze activity in neurologic patients.

Positron emission tomography studies have been described at rest and during motor activation tasks in patients with ALS, PMA, and controls. Reduced global cerebral blood flow suggest- ing hypometabolism has been reported in some studies of patients with ALS56,57 but not in others.58 In contrast, regional cerebral blood flow (rCBF) has been consistently noted to be reduced in those with ALS. In the resting state, the reduction is mainly in the primary sensorimotor cortex and the adjacent premotor, parietal, and insular cortices.58,59 PET studies of patients with ALS during a motor activation task reveal reduced rCBF in the medial prefrontal cortex, anterior cingulate gyrus, and parahippocampal gyrus. These changes beyond the primary sensorimotor cortices during performance of a simple motor task likely demonstrate the neural plasticity and the development of new synapses and pathways to compensate for the loss of pyramidal neurons. These rCBF changes were not demonstrated in patients with primary LMN disorders, such as PMA.56,60

The presence or absence of cognitive deficits in patients with ALS leads to different findings on PET. Studies of ALS patients with cognitive deficits or of nondemented patients with impaired verbal fluency revealed impaired activation in the cortical and subcortical regions, including the dorsolateral pre- frontal cortex, premotor cortex, insular cortex, and anterior thalamic nuclear groups compared with cognitively intact patients.59,61

Ligand-based PET studies have been performed using 11C-flu- mazenil, which binds to the gamma-aminobutyric acid A (GABA A) receptor, thought to serve as a marker for neuronal loss. These studies show reduced binding of 11C-flumazenil in not only the motor/premotor regions, but also the association corti- ces, specifically the prefrontal cortex (▶Fig. 38.8).62 ALS

Neuroimaging of Motor Neuron Disorders

Fig. 38.8 Relative decreases in 11C-flumazenil binding in ALS patients (a) compared to controls (b). Regions of decreased binding are superimposed on an average MRI constructed from spatially normalized MRI data of normal control subjects. (Image reprinted with permission from Lloyd CM, Richardson MP, Brooks DJ, Al-Chalabi A, Leigh PN. Extramotor involvement in ALS: PET studies with the GABA(A) ligand 11Cflumazenil. Brain. 2000;123: 2289–96)

38.6.2 Functional Magnetic Resonance

Imaging

Functional MRI (fMRI) is a noninvasive tool based on the blood- oxygen–dependent contrast method, relying on the T2 effect of deoxyhemoglobin in the tissues. Patients with ALS have been noted to demonstrate increased activation of the premotor cor- tex, supplementary motor area, basal ganglia, and cerebellum during simple motor tasks, such as finger tapping.65,66,67,68 This shift of activity with upper limb movement and the increased

patients with poor verbal fluency demonstrate decreased 11C- flumazenil binding in the right inferior frontal gyrus, superior temporal gyrus and the anterior insula. The left inferior and middle frontal gyrus and the cuneus were noted to be involved in patients with poor performance on confrontation naming tests.63 A recent study using [18F]FDG PET revealed large hypo- metabolic areas in the frontal and parietal regions bilaterally in bulbar-onset patients compared to control subjects and to spi- nal-onset onset patients, associated with lower neuro- psychological testing scores in bulbar patients (▶ Fig. 38.9).64

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Fig. 38.9 Positron emission tomography studies showing (in red) areas in which there is increased [18F]fluorodeoxyglucose (FDG) uptake in control subjects as compared to patients with bulbar amyotrophic lateral sclerosis (ALS). These areas include bilateral prefrontal cortex, premotor cortex, right insula, anterior cingulate gyrus and inferior parietal lobes patients. (Image reprinted with permission from Cistaro A, Valentini MC, Chiò A, et al. Brain hypermetabolism in amyo- trophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset. Eur J Nucl Med Mol Imaging 2012;39(2):251–259.)

ipsilateral involvement of the sensorimotor cortex support the concept of functional reorganization to compensate for the loss of pyramidal neurons.65,66,67,69 fMRI studies during a motor imagery task also revealed increased activation of the premotor areas, a finding that became more prominent with longer dis- ease duration.70 Another fMRI study of ALS patients during motor imagery tasks revealed reduced activation of the parietal and medial frontal regions, areas that are usually involved in motor imagery tasks. This finding suggests reduced activation of the usual networks, possibly related to involvement of the prefrontal cortex by the underlying disease (▶Fig. 38.10).71 Impaired activation of the middle and inferior frontal gyri,

anterior cingulate gyrus, and the parietal and temporal lobes has been demonstrated in ALS patients during letter fluency and confrontation naming tasks, corresponding to clinical defi- cits in these spheres by the patients.72

38.7 Conclusion

Although imaging studies have traditionally served a negative (“rule-out”) rather than a positive (“rule in”) role in MNDs, this is changing. Voxel-based morphometry, magnetic reso- nance spectroscopy, diffusion tensor imaging, magnetization transfer imaging, and functional studies all show promise in

Neuroimaging of Motor Neuron Disorders

Fig. 38.10 Functional magnetic resonance imaging demonstrating areas of activation during motor imagery in healthy controls (a) and in amyotrophic lateral sclerosis (ALS) patients (b). Areas of significantly reduced activation during motor imagery in ALS patients compared with healthy controls are demonstrated in (c). (Image reprinted with permission from Elsevier, Stanton BR, Williams VC, Leigh PN, et al. Cortical activation during motor imagery is reduced in amyotrophic lateral sclerosis. Brain Res 2007;1172:145–151.)

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Part XVI Clinical Approach and Treatment

39 Reversible versus Nonreversible
Dementia: Practical Approach 362

40 Advances in the Treatment of Dementia 371 41 Imaging of Deep Brain Stimulation 378

XVI

362

Clinical Approach and Treatment

39 Reversible versus Nonreversible Dementia: Practical Approach

Sol De Jesus and Sangram Kanekar

The advancement of neuroimaging has afforded significant insight into progressive neurodegenerative disorders and their mimics. Many primary and secondary disease entities can man- ifest with memory dysfunction. Although Alzheimer’s disease (AD) remains the most common primary type of dementia, the clinician must consider many preventable disorders before making a final diagnosis of AD. Distinguishing between a pre- ventable, potentially reversible cause and an irreversible (pro- gressive) cause has serious implications for future planning in regard to the patient’s medical, social, and economic spheres. The diagnosis of dementia has historically involved clinical sus- picion alone and, when available, confirmation via postmortem neuropathological analysis. Although the diagnosis of dementia remains largely clinical, neuroimaging can help direct the diag- nostic workup. This chapter concentrates on summarizing pre- ventable and potentially reversible presentations of memory dysfunction. The reader is referred to previous chapters in this text for discussion of primary progressive and more common reversible types.

39.1 Prevalence

Aging is the most significant risk factor for dementia. Most individuals will age successfully. As the population ages, how- ever, the risk for dementia also inevitably increases. The Fed- eral Interagency Forum on Aging-Related Statistics reports that the older population considered age 65 and older, is expected to double by 2030.1 The World Health Organization (WHO)2,3 estimates that 35.6 million individuals worldwide suffer from dementia, with 7.7 million new cases per year. Dementia prevalence may be as high as 40% in people age 90 and older, whereas it is only 1 to 2% at age 65.4 The Aging, Demographic and Memory Study (ADAMS), published in 2007, attempted to estimate the prevalence in the United States of AD, vascular dementia, and other dementias, includ- ing the reversible dementia types. In a sample of more than 800 patients, ADAMS estimated prevalence at 12.7% for the reversible dementia syndromes.5 This number will vary from 1 to 30%, depending on the population studied.6,7,8,9 Most available studies are retrospective, and prevalence will vary depending on the specialties involved, the difference in classi- fication of reversible disease entities between studies, and the study setting. The statistics presented do not take into account the percentage of dementia patients who may have concomitant reversible causes or the duration of the disease process and its association with reversibility.

39.2 Diagnostic Evaluation

The initial clinical symptoms of dementia are variable and may include the presence of impaired memory with an associated decline in one or more cognitive memory, (language, executive function, visual spatial, attention, and praxis), or behavior and

personality changes.10 These deficits must impair the individu- al’s overall functional state in the context of daily living.

The recommended diagnostic evaluation for suspected dementia includes complete history, physical, and neurologic examination, bedside cognitive screen (Mini-Mental State Examination, Montreal Cognitive Assessment), serum studies (complete blood cell count, basic metabolic panel, vitamin B12, thyroid-stimulating hormone, liver function tests), and imaging (computed tomography [CT] and/or magnetic resonance imag- ing [MRI]).11,12,13 The American Academy of Neurology (AAN) latest practice parameters now recommend neuroimaging as an important diagnostic ancillary tool.13 This initial screening is helpful in capturing possible dementia mimics. For atypical and unclear presentations, such as early onset (< 65 years of age) or rapidly progressive deterioration, it is necessary to expand the basic screening. Neuroimaging modalities used in dementia include CT, MRI, positron emission tomography (PET), single- photon emission computed tomography (SPECT), and func- tional MRI (fMRI). The role of each imaging modality, whether it is clinical or research based, and its use in dementia and dementia mimics are summarized in (▶ Table 39.1). In clinical

Table 39.1 Utility of different imaging modalities in the evaluation of cognitive dysfunction26,58

Imaging Type of imaging Utility Study in Dementia modality Evaluation

X-ray: structural

Rule out space-occupying lesions (hemorrhage, tumors, ventricular dilation) and assess generalized atrophy

MRI

Electromagnetic: structural

Sequence dependent:

● T1: anatomy and atrophy
assessment

● T2-FLAIR: atrophy and small
vessel cerebrovascular disease
burden

● Gradient echo: visualization of
microhemorrhages, which may be associated with amyloid angiopathy

PET

Gamma rays: functional

Provides supporting information regarding regional cerebral metabolism changes

SPECT

Gamma rays: functional

Provides supporting information regarding cerebral function via blood flow measurement

fMRI

Electromagnetic: functional

Mostly research based, providing information regarding cortical connectivity and synaptic dysfunction

Abbreviations: CT, computed tomography; fMRI, functional magnetic resonance imaging; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

Reversible versus Nonreversible Dementia: Practical Approach

Fig. 39.1 Algorithm for reversible and preventable dementia. HIV, human immunodeficiency virus; MS, multiple sclerosis; NPH, normal pressure hydrocephalus; SDH, subdural hematoma. SLE, systemic lupus erythematosus; vit, vitamin. This simple guide does not include all the possible reversible entities.

treating symptoms. In 2002, Hejl et al14 defined potentially reversible types of dementia as arrestable spontaneously or via treatment or a disease entity that may be contributing to the memory complaints or dementia. True reversibility of many of these disease types remains unclear.15,16,17,18

39.3.1 Preventable Entities

Obstructive sleep apnea has been linked to memory dys- function. If screened appropriately, it may be readily identified in individuals who snore and complain of excessive daytime sleepiness, mood changes, and difficulty maintaining attention. These individuals tend to be younger than the typical dementia patient, being diagnosed during middle age. Diagnosis is con- firmed via polysomnography when breathing is interrupted for longer than 10 seconds, 5 or more times per hour. Studies have shown anatomical brain changes in patients with chronic untreated sleep apnea.19 Brain structural changes affecting white matter were further delineated by Macey et al20 in a 2008 report using diffusion tensor imaging modalities. The question remains whether true reversibility is obtainable if the destruc- tion seen in imaging occurs from intermittent periods of hypoxia.21,22

Pseudodementia was introduced in 1961 by Leslie Kiloh. The term has been reserved for the manifestation of memory dys- function as consequence of psychiatric disorder, traditionally depression.23 The incidence of depression is high in the aging population, and depression often manifests with cognitive symptoms.24 The Geriatric Depression Scale and formal neuropsychiatric testing, along with basic dementia screening, have been useful in identifying this cohort of patients.25 Neuro- imaging is an ancillary tool to exclude underlying structural changes that explain the neuropsychiatric changes. Most imag- ing cases will be unremarkable. However, nonspecific changes have been cited in the literature to include white matter

practice, CT and MRI are sufficient for the initial investigations; however, the increase in the availability of PET and SPECT has also made these imaging modalities an option in clinical prac- tice to support a suspected diagnosis.

Close attention to the temporal course of the memory dys- function, focal neurologic examination findings, fluctuation of symptoms, and comorbid conditions can direct the clinician to the appropriate investigation and help delineate a precise cause between reversible and irreversible. Dementia and the demen- tia mimics can manifest as acute, subacute, or chronic. Memory dysfunction may be the main initial symptom, or it may be an accompanying symptom with a medical illness or other pri- mary cause. Medical illnesses may exacerbate baseline neuro- logic deficits that will then uncover a primary progressive neu- rodegenerative disease state, as seen in metabolic encephalop- athy. Although the underlying disorder may not be reversible, all attempts should be made to address the concomitant disease exacerbating the baseline neurologic deficits. The differential diagnosis for reversible dementia can be daunting and can be subdivided into the categories of vascular, infectious, traumatic, autoimmune, metabolic, toxic, idiopathic, neoplasms, and others (▶ Fig. 39.1).

39.3 Reversible versus Irreversible

Causes of Dementia

Primary neurodegenerative diseases involving memory dys- functions are progressive in nature. There is continued degen- eration of cellular networks and brain substance either by misfolded protein accumulation, poor synaptic transmission, or abnormal metabolism/neurotransmitter levels. The course of these illnesses is complicated by concomitant medical disease, which may delay or cloud the final diagnosis. As there are no known disease-modifying therapies, efforts are directed at

363

Clinical Approach and Treatment

Fig. 39.2 Vascular dementia. (a) Axial diffusion- weighted imaging (November 2004) shows a large area of restricted diffusion in the right parietal lobe (arrow), suggestive of hyperacute stroke. Within 4 months, this patient had signs and symptoms of dementia. (b) Axial computed tomography scan image (February 2005) shows a large area of hypodensity in the right frontopar- ietal lobe (arrowheads) with ex vacuo dilatation of the lateral ventricle suggestive of encephaloma- lacia and loss of parenchyma.

lesions.26 Once the psychiatric disorder is treated, memory complaints are expected to reverse, although they may do so in a delayed fashion. Dementia may also be accompanied by depression, and treating the depression may restore some func- tion but will not reverse underlying pathology.17

Small vessel, lacunar disease, and vascular dementia represent the second most common type of dementia (▶ Fig. 39.2). Vascu- lar dementia is irreversible and progressive; however, there is a theoretical stage of preventability if risk factors are addressed before evidence of irreversible ischemic change is seen. The National Institute of Neurological and Communicative Disor- ders and Stroke (NINDS)/Association Internationale pour la Recherche et l’Enseignement en Neurosciences (AIREN) crite- ria27 for vascular dementia require evidence of cerebrovascular disease by CT or MRI. These changes include diffuse white matter small-vessel disease or focal large-vessel ischemic changes involving strategic memory pathways or brain struc- tures. The risk factors for vascular dementia are similar to those for vascular and cardiac disease and include hypertension, hyperlipidemia, diabetes mellitus, obesity, smoking, and homo- cysteinuria.28 Multiple scales have attempted to correlate the degree of white matter changes to the degree of small-vessel disease and cognitive impairment. Whereas significant territo- rial infarcts have been identified, such as thalamic lacunar infarct and associated higher degree of cognitive impairment, overall there is no single scale that is used uniformly to quantify the degree of tissue involvement.29,30,31 Imaging correlates for vascular changes are summarized in ▶ Table 39.226,32; refer to Chapter 21 for more extensive discussion.

39.4 Potentially Reversible

Entities

Many different approaches have been designed to further clas- sify the potentially reversible disease types, including associa- tion with other medical diseases or other neurologic signs. The following sections comprise a straightforward collection of the different possible potential reversible entities and the most common neuroimaging correlates available.

39.4.1 Structural

Because the brain is encased within the skull, pressure changes via intracranial hemorrhage or structural lesions will cause destruction to local cell bodies and their connections. Clinical changes secondary to a bleed or structural lesion (neoplasm) can manifest with memory dysfunction and/or a state of confu- sion. Additional neurologic symptoms, history of trauma, and rate of progression may provide further clues as to location and suspected injury.

Intracranial Hemorrhage

There are different types of intracranial hemorrhages (sub- arachnoid, subdural, epidural, lobar), and manifestation varies based on the type of bleed. The subdural hematoma has been considered one of the most likely to mimic dementia. At-risk populations include elderly adults, alcoholics, those with gener- alized atrophy, and those with iatrogenic (postprocedural) causes. Generalized atrophy results in stretching of bridging veins, which may cause spontaneous or posttraumatic bleeding

Table 39.2 Imaging correlates for vascular changes in the different imaging modalities26,32

Computed Magnetic resonance SPECT tomography imaging

Hypoattenuation of subcortical regions

T1: hypointensities and enlarged perivascular spaces

Used as an ancillary tool when diagnosis is unclear; seen as a patchy reduction in blood flow dependent on the site of the lesion

Enlarged perivascular spaces (lacunae)

T2/FLAIR: hyperinten- sities involving periventricular white matter, subcortical deep gray nuclei

Abbreviations: FLAIR, fluid-attenuated inversion recovery; SPECT, single-photon emission computed tomography.

364

Reversible versus Nonreversible Dementia: Practical Approach

Fig. 39.3 Subdural hematoma in 61-year-old man with dementia. (a) Axial computed tomography and (b) axial T2-weighted imaging show left holohemispheric subdural hematoma (arrowheads) causing effacement and compression of the cortical sulci and left cerebral parenchyma.

within the subdural space. The cognitive and neurologic changes from the compression unilaterally or bilaterally, depending on the degree of cerebral atrophy, may vary in clini- cal signs and symptoms. CT scan is the imaging modality of choice for identification of acute ICH, revealing a crescent- shaped collection with a subdural hematoma (▶ Fig. 39.3). MRI can provide further information about the age of bleed. It is expected that, with evacuation of blood and relief of pressure on cortical structures, cognitive symptoms improve. Brand et al33 described cognitive impairment as an expected sequel within their cohort of patients who had subarachnoid, sub- dural, and intracerebral hemorrhage at 6 months’ follow-up. Improvement was variable, and full reversibility is not men- tioned.

Normal Pressure Hydrocephalus

Normal pressure hydrocephalus (NPH) is identified by the clini- cal triad of cognitive dysfunction, urinary incontinence, and gait abnormalities (described as a “magnetic gait”). Memory complaints tend to be seen later in the disease course. Neuro- imaging reveals enlarged ventricles out of proportion to the degree of atrophy (▶ Fig. 39.4). NPH is described as a communi- cating hydrocephalus, and presumed pathophysiology is impaired cerebrospinal fluid (CSF) absorption, as evident in radionuclide cisternography and MRI CSF flow studies. Clinical response to shunting procedures and serial lumbar punctures is variable in patients with idiopathic NPH.6 Cognitive deficits are the least likely to show any major improvement, although over- all long-term improvement was seen in as many as 75% of patients who did have the shunting procedure.34 Duration of symptoms before intervention may correlate with the degree of response. NPH must be distinguished from hydrocephalus ex vacuo.

Meningioma

Meningiomas are dural-based, nonglial tumors that arise from arachnoid cap cells. They exhibit indolent growth and cause neurologic symptoms by compression of localized tissue and

Fig. 39.4 Axial computed tomography scan of the head
shows moderate dilatation of the lateral ventricles out of proportion to the convexity sulci, suggestive of normal pressure hydrocephalus.

increased intracranial pressure. Peak incidence occurs in the sixth and seventh decade of life; however, they may be seen at any age. The tumor is a homogeneous mass that is easily identi- fied by the dural tail on enhanced imaging (▶Fig. 39.5). Total resection of tumor in elderly patients is associated with increased morbidity and mortality, but significant cognitive improvement has been seen.35,36

365

366

Clinical Approach and Treatment

Fig. 39.5 Sagittal T1-weighted imaging shows an extraxial mass (star) centered over the planum sphenoidale causing severe mass effect on the frontal lobes (arrow).

Fig. 39.7 A 63-year-old uremic man with impairment of higher cortical functions. Axial fluid-attenuated inversion recovery (FLAIR) image shows mild expansion of the cortical gyri with bright signal intensity suggestive of cortical edema (white arrows). Focal hyperintensity is seen in the occipital cortex (black arrows) and subjacent white matter bilaterally resulting from associated posterior reversible encephalop- athy syndrome.

39.4.2 Systemic Metabolic and

Toxic Disorders

Systemic manifestations of metabolic and toxic disorders may include alteration of consciousness, encephalopathy, decreased arousal, and deficits involving the different cognitive domains. Electrolyte abnormalities and organ failure will lead to abnor- malities in brain metabolism and injury to cognitive pathways in a localized or diffuse fashion.

Hepatic disease (chronic liver disease, Wilson’s disease) on MRI reveals T1/T2 hyperintensities along the deep gray matter structures (▶Fig. 39.6), which have been shown to regress in follow-up imaging after liver transplantation.37,38 Uremic patients can also present with impairment of higher cortical

functions. When uremia is severe, a posterior reversible leu- koencephalopathy or cerebral cytotoxic and vasogenic edema on MRI can be seen (▶ Fig. 39.7).39

Toxic effects of alcohol or inhalant abuse, heavy metal expo- sure, and malnutrition involve all the major organs, including

Fig. 39.6 Chronic liver failure with cognitive decline. (a) Axial T1 image shows symmetric hyperintensity in the globus pallidus bilaterally. This region shows normal signal intensity on (b) fluid-attenuated inversion recovery images.

Reversible versus Nonreversible Dementia: Practical Approach

Table 39.3 Systemic (metabolic/toxic) disease entities and their imaging correlates17,40,41,42,43,44,59,60

Disease entity

Imaging correlates

Alcohol/vitamin deficiency

Marchiafava-Bignami disease

Generalized atrophy, T2 hyperintensities involving corpus callosum or T1 hypointensities along same region suggestive of cavitation

Acquired hepatocellular degeneration

Diffuse microcavitation at gray/white matter junction

Wernicke-Korsakoff (thiamine deficiency)

T2/FLAIR and diffusion hyperintensities involving mammillary bodies, thalamus, cerebral aqueduct/third ventricle, fornix Atrophy of mammillary bodies

Methanol poisoning

Bilateral putaminal hemorrhagic necrosis

Cerebellar degeneration

Cerebellar cortical atrophy

Heavy metal

Iron/manganese

T1 hyperintensities within basal ganglia

Lead

T2 hyperintensities within basal ganglia, hypothalamus, and pons

Other substances

Inhaled toluene

Diffuse white matter changes: toxic leukoencephalopathy

Abbreviation: FLAIR, fluid-attenuated inversion recovery.

the central nervous system (CNS). Acutely, exposure to these toxins may cause cognitive changes that are potentially revers- ible; however, correlation between the exposure period or the pattern of ingestion and the likelihood of reversibility remains unclear. Long-term alcohol use leads to direct end-organ altera- tions (Marchiafava-Bignami disease, acquired hepatocerebral degeneration, Korsakoff ’s syndrome, cerebellar degeneration) and changes to physiologic homeostasis by malnutrition and vitamin deficiency (Marchiafava-Bignami disease, pellagra, Wernike’s encephalopathy).40 The same disease entities may have direct influence on, or lead to, nutritional deficiencies, which ultimately have an end-organ effect.40 As summarized by Bjork and Gilman41, functional neuroimaging modalities such as fMRI, diffusion tensor imaging, magnetic resonance spectros- copy, and PET are aiding in our understanding of the effects of acute alcohol exposure in resting-state connections, alcohol’s influence on the composition of brain tissue, regional changes, and dopamine involvement.41 Brain lesions are varied to include decreased brain volume, which is now another area of interest that uses voxel-based morphometry.42,43,44 Imaging correlates for systemic disease entities are summarized in (▶ Table 39.3).

To complete the discussion of toxic exposure manifesting as cognitive deficits, it is important to consider medication effects and polypharmacy. Medications like benzodiazepines and the combination of medications, especially in elderly patients, may be a simple reversible inciting factor for the signs of memory dysfunction. Other medications to consider as possible offend- ing agents include antibiotics, chemotherapeutic agents (especially those introduced intrathecally), anticonvulsants, and psychiatric agents.

39.4.3 Infectious Causes HIV–Associated Neurocognitive Disorder

As highlighted in the 2013 Conference on Retroviruses and Opportunistic Infections human immunodeficiency virus (HIV) CNS-associated changes remain poorly understood.45 HIV- associated neurocognitive disorder (HAND) is considered a milder form of cognitive dysfunction seen in early infection and in the age of antiretroviral therapy (ART) has been a topic of great interest. It has been difficult to ascertain whether

cognitive dysfunction is from direct neuroinvasion, neuro- toxicity from ART therapy, or an immune response to retroviral treatment, aging of the HIV population, comorbid factors, or (a more likely explanation) a combination thereof. Although highly active antiretroviral therapy has been noted to decrease the progression to AIDS dementia, it does not appear to reverse injury present before initiation of retroviral therapies or to halt fully any further neurocognitive changes.46 Imaging studies reveal global brain atrophy, white matter changes, and basal ganglia signal changes in patients with HAND.47

Whipple’s Disease, Chronic Meningitis, and Central Nervous System Lyme Disease

Whipple’s disease, a systemic disorder, can lead to cognitive dys- function. Associated CNS involvement varies from 6 to 63%, depending on the study, although it is rare to have isolated CNS Whipple’s disease.48,49 Whipple’s disease should be considered in the setting of progressive cognitive dysfunction with associ- ated gastrointestinal disturbances. Imaging may be nonspecific and can show focal or diffuse gadolinium-enhancing lesions, mostly within white matter, but meningeal involvement is also seen.50 Follow-up imaging may be useful in assessing for the resolution of lesions once treatment has been started or in cases where recurrence is a possibility.

Chronic meningitis is defined as meningeal inflammation with abnormal CSF findings lasting more than 4 weeks.51,52,53 Numerous infectious and noninfectious causes for chronic men- ingitis are possible; however, in up to one-third of patients, the cause remains unclear.53 Imaging findings reveal pachymenin- geal enhancement, and hydrocephalus as a complication of the inflammatory response.

Lyme disease involves the central nervous system in 10 to 20% of patients during the acute disseminated phase of the infection.54 Cognitive changes seen in Lyme encephalopathy are suspected to occur in response to the inflammatory changes and not irreversible cellular injury. Lyme remains a clinical diagnosis with supporting serologic studies and or spinal fluid testing when CNS is involved. Imaging changes are nonspecific and include T2/fluorescent-attenuated inversion recovery (FLAIR) hyperintensities. Clinical response to antibiotic therapy continues to be excellent.54,55

367

Clinical Approach and Treatment

Fig. 39.8 8 Limbic encephalitis from ovarian cancer in 59-year-old woman. Axial fluid-attenuated inversion recovery image shows symmetrical hyperintensity in the hippocacampi bilaterally.

Fig. 39.9 Algorithm for irreversible dementia. AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CBDG, corticobasal degeneration; FTLD, frontotemporal dementia; MCI, mild cognitive impairment; MSA, multiple system atrophy; PSP, progressive supranuclear palsy. This simple guide does not include all possible irreversible entities.

368

39.4.4 Inflammatory

Limbic encephalitis clinically manifests as a subacute dementia with associated psychiatric symptoms. It is a paraneoplastic or autoimmune-associated disorder that requires investiga- tion for possible underlying neoplasm. MRI findings include T2/FLAIR hyperintensities with predilection for the temporal lobe; however, the lentiform nucleus can also be involved (▶Fig. 39.8).17,56 Reversibility of symptoms with removal of neoplasm, if present, or immunosuppression has been documented.57

39.4.5 Neurodegenerative Dementias

Neurodegenerative dementias are covered extensively in previ- ous chapters. ▶Fig. 39.9 provides the most common primary progressive neurodegenerative disorders divided by cortical, subcortical, and mixed dementia types. Brain CT, MRI, and func- tional imaging will allow for further supportive evidence via classic imaging correlates as described in ▶ Table 39.4 for some of the primary neurodegenerative dementias.

39.5 Conclusion

This chapter briefly summarizes reversible and irreversible dementias and neuroimaging. The differential diagnosis for memory dysfunction is vast and complex because they exist as primary conditions or as manifestations of underlying medical illness. Obtaining comprehensive history, complete neurologic examination, and baseline medical screen in accordance with neuroimaging may guide diagnosis and treatment. True revers- ibility of dementia mimics remains unclear and will require

using structural and functional imaging modalities for earlier 394

identification of anatomical changes and biomarkers in the pur- suit of neuroprotective therapies that eventually might lead to potential cures.

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Table 39.4 Progressive neurodegenerative disorders and most commonly associated imaging correlates12,26,58,61–66

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Alzheimer’s disease

CT/MRI

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SPECT/ FDG-PET

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[61] Agosta F, Caso F, Filippi M. Dementia and neuroimaging. J Neurol 2013; 260:

685–691
[62] Haines A, Katona C. Dementia in old age. Occas Pap R Coll Gen Pract 1992:

62–66
[63] Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST

Report of the Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: early detection of dementia: mild cogni- tive impairment (an evidence-based review). Neurology 2001; 56: 1133–

[64] Murray AD. Imaging approaches for dementia. AJNR Am J Neuroradiol 2012; 33: 1836–1844

[65] Degnan AJ, Levy LM. Neuroimaging of rapidly progressive dementias, part 1: neurodegenerative etiologies. AJNR Am J Neuroradiol 2014; 35: 418–423
[66] Degnan AJ, Levy LM. Neuroimaging of rapidly progressive dementias, part 2:

prion, inflammatory, neoplastic, and other etiologies. AJNR Am J Neuroradiol 2014; 35: 424–431

drome. Alcohol Alcohol 2009; 44: 155–165
[45] Spudich SS, Ances BM. Neurologic complications of HIV infection: highlights 1142

from the 2013 Conference on Retroviruses and Opportunistic Infections. Top

Antivir Med 2013; 21: 100–108

. [46] Spudich S. HIV and neurocognitive dysfunction. Curr HIV/AIDS Rep 2013; 10:
235–243

. [47] Steinbrink F, Evers S, Buerke B et al. German Competence Network HIV/AIDS.
Cognitive impairment in HIV infection is associated with MRI and CSF pattern of neurodegeneration. Eur J Neurol 2013; 20: 420–428

Dementias can be broadly classified as reversible and nonrever- sible. This classification is bound to change over time as disease pathology becomes more clear-cut, and newer modalities of treatment that target the pathology are discovered, and dis- eases that were considered nonreversible are likely to become reversible. For now, however, this classification structure is useful, to enhance our understanding and explore imaging consequences as well as opportunities.

40.1 Treatment of Reversible

Dementias

Conventional treatment strategies continue to be the mainstays in the treatment of reversible dementias. These include identifi- cation of reversible causes and prompt initiation of treatment. Examples include vitamin B12 replenishment in the case of B12 deficiency via parenteral administration initially and then fur- ther correction using appropriate investigations. The imaging finding in patients with dementia in the case of B12 deficiency is that of subacute combined degeneration, classically seen pre- dominantly in the spinal cord. These changes completely reverse in 3 to 4 months if treatment is initiated promptly.1,2,3 Nitrous oxide use in anesthesia can potentially exacerbate pre- vious borderline cases of B12 deficiency. Therefore, imaging hall- marks of the B12 deficiency characterized in cross-section images by bilateral paired areas of T2 hyperintensity, seen as an “inverted V” or “inverted rabbit ears” in the expected anatomi- cal location of the dorsal columns, is often considered pathog- nomonic for B12 deficiency, even in the absence of classic neuro- logic deficits on clinical testing. These changes are reversible with proper initiation of treatment. Recent work also suggests that diffusion tensor imaging (DTI) may be useful as a technique to detect changes resulting from B12 deficiency in the brain.4 However, the use of DTI in monitoring treatment efficacy with B12 repletion is unknown.

Correcting hypothyroidism and treating infectious causes of dementia (human immunodeficiency virus and syphilis) also alter imaging pathology, although neurosyphilis-induced imag- ing changes are only partially altered by treatment. Normal pressure hydrocephalus (NPH) is treated with surgical place- ment of a ventriculoperitoneal or lumboperitoneal shunts. Bet- ter shunt designs have allowed minimization of the complica- tions caused by excess removal of cerebrospinal fluid (CSF) after the placement of shunts. Understanding the fluid mechanics of CSF drainage in NPH and the prudent use of improved technol- ogy have allowed this complication to be minimized.5

40.1.1 Wilson’s Disease
New treatment regimens are in place for Wilson’s disease,

which is reversible if recognized and treated early. The mag- netic resonance imaging (MRI) findings in Wilson’s disease are discussed elsewhere in this book (Chapter 20). Here we discuss the new treatment protocols, their rationale, and imaging consequences. The new regimen avoids D-penicillamine or

Advances in the Treatment of Dementia

40 Advances in the Treatment of Dementia

Madhav Thambisetty, Néstor Gálvez-Jiménez, and Thyagarajan Subramanian

triamterene alone. The use of these compounds by themselves has produced numerous complications, including potentially lethal status dystonicus, which is associated with acute-onset thalamic, tegmentum, and brainstem MRI findings (▶ Fig. 40.1) within 2 weeks of starting therapy in some patients.6 Although this change in MRI can be reversed in some patients while treatment is continued further on D-penicillamine, these reports of severe complications have led to the development of safer new regimens. The new regimen that has become stan- dardized uses zinc and triamterene in combination initially for 3 months, and then if there is satisfactory reduction in copper excretion in the urine and sufficient zinc in the measured urine samples, patients may continue on zinc alone. From an imaging standpoint, patients can be followed up by using periodic MRI to determine whether the copper deposits in the basal ganglia are clearing. However, the radiologic outcomes suggest better chelation with D-penicillamine as opposed to treatment with zinc.7 To date, zinc does not appear in imaging studies as abnor- mal signals. Nevertheless, most treatment protocols in contem- porary medicine tend to initiate treatment with zinc and triam- terene. In addition to chelation, many Wilson’s disease patients require anti-parkinsonian medications, botulinum toxin ther- apy for focal dystonia, and medications for psychiatric symptom management.

40.2 Nonreversible Dementias

A number of antioxidants and free radical scavengers have been investigated as either common preventative or ameliorative therapies for all neurodegenerative disorders. This sweeping approach, although it has a strong scientific basis, has not had positive results in clinical research testing. The number of agents in this category that have undergone testing is beyond the scope of this chapter. Some examples include coenzyme Q10, several vitamins, and several natural products. To date, none of these agents has shown proven benefits and none is recommended as standard treatment. Health care providers must be aware, however, that some patients take these medica- tions as nutritional aids and nutraceuticals. Ongoing research efforts continue to explore this overarching approach to all neu- rodegenerative disorders. An example of recent success is the use of vitamins B6, B12, and folic acid in combination in patients with elevated homocysteine to prevent brain cortical atrophy as evidenced by serial MRI studies.8 Whereas the vast majority of these vitamin and herbal agents, antioxidants, and free radi- cal scavengers have no deleterious consequences, some do and can actually cause rare imaging changes.

40.2.1 Alzheimer’s Disease

Two types of medications are used to treat the symptoms of Alzheimer’s disease (AD),9 and a useful treatment schematic drawing that summarizes current strategies and their basis is shown in ▶Fig. 40.2. First, to enhance cerebral cholinergic activity in AD, anticholinesterases have been used. There is con- sistent evidence from numerous trials that, on average, subjects

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Fig. 40.1 Axial fluid attenuated inversion recovery (FLAIR) images (b), in Wilson disease patient with chelation-induced dystonia, show increased areas of high signal intensity in the bilateral thalami, tegmentum, pons, upper medulla, and adjacent cerebellum after treatment with trientine, compared with (a) MRI performed 4 months earlier. (Reprinted with permission from Kim B, Chung SJ, Shin H-W. J Clin Neurosci 2013;20:606–608.)

treated with these medications show statistically significant improvements (versus placebo) on measures of cognition (the cognitive subscale of the Alzheimer’s Disease Assessment Scale [ADAS] and the Mini-Mental State Examination), as well as on measures of overall improvement from the clinician and care- giver in all stages of AD.10 However, the magnitude of benefit on the cognitive scales is minimal. Many patients have claimed significant subjective improvement. The ADAS-cog is an approximately 70-point scale, however, and the 2- to 4-point improvement from treatment results in modest “real-life” change. From a neuroimaging standpoint, measuring the effects of treatment using structural imaging remains a work in

progress. Several methods, including manual or automated measurement of the hippocampus or the ventricles, are being tested and with refinement of techniques will become available in the near future. Needless to say, these methods will prove of great value in treating AD patients and monitoring AD clinical symptoms.11 Another important issue in imaging is a safety issue related to the transdermal formulation of rivastigmine. Local burns are possible because of the small metal content in the patches. Because patients with dementia might not remem- ber that they have a patch on or that a patch has not been removed, it is important to instruct caregivers and to also check patients’ skin for any transdermal patches of rivastigmine.

Second, modulation of the N-methyl-D-aspartate (NMDA) receptor with the use of memantine, a noncompetitive NMDA receptor antagonist, is standard therapy for most AD patients. It is not clear how this medication causes an improvement in cognition. Like the cholinesterase inhibitors, memantine has shown a statistically significant benefit on measures of cognition and global impression in moderate to severe AD. There is evi- dence that the combination of both medications may be better than either alone. Again, the effect is modest at best. Because of the modest effects and relatively high cost of the medications, resource utilization will likely become an even greater issue in treatment considerations than it is at present.

Advances in the Treatment of Dementia

Fig. 40.2 Mechanism of action of cholinesterase inhibitors. (Modified with permission from Hanson MR, Galvez-Jimenez N. Cleve Clin J Med 2000;67 (6):441–448.)

In addition to cognitively directed medical treatment, the occurrence of emotional changes and depression in AD is high. These result from progressive deterioration of affective systems and can be intermixed with behavioral changes (e.g., aggres- siveness, psychosis) as the disease progresses. Selective sero- tonin reuptake inhibitors (SSRIs) are a viable initial treatment for emotional changes and depressive symptoms. Novel approaches to the treatment of AD include the development of an AD vaccine by immunizing against the β-amyloid (Aβ) protein.12 Although initial trials have not been successful, the concept of developing a vaccine to retard AD pathology is intriguing, and several lines of research are pursuing this idea.

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Another notion is to modulate the neuroimmune system to mit- igate and perhaps retard neurodegeneration. Strategies include development of a specific set of antibodies and novel gene therapy that targets the immune system to clear pathological proteins from the brain.13 Finally, the gene therapy approach using growth factor injection into the brain has been attempted with limited success but has not met the standards for wide- spread application. These experimental strategies remain of interest as future AD therapies. The availability of good imaging surrogates for AD has been a major advance in facilitating research into AD experimental therapeutics.

The recent incorporation of neuroimaging as well as CSF bio- markers in the revised diagnostic criteria for AD14 reflects the considerable advances in our knowledge about their association with disease onset, severity, and progression. Moreover, their usefulness in defining a “preclinical” stage of AD15 is likely to accelerate the development of disease-modifying treatments in at-risk older individuals before the onset of clinical symptoms. The neuroimaging methods specified by the revised criteria to define the presence of an “AD pathophysiological process” include positive positron emission tomography (PET) amyloid imaging, decreased16 fluorodeoxyglucose uptake on PET in the temporoparietal cortex, and disproportionate atrophy on struc- tural MRI in the medial, basal, and lateral temporal lobes and medial parietal cortex.17 It is worth noting in this context that the Food and Drug Administration recently approved florbeta- pir (Amyvid; Eli Lilly, Indianapolis, IN), the first radioligand for in vivo imaging of brain amyloid burden in humans by PET18 and other similar applications.16

40.2.2 Parkinson’s Disease

Advances in the treatment of Parkinson’s disease (PD), PD-plus syndromes, secondary parkinsonisms, and complications of these disorders have been major accomplishments in the past decade.19 Besides the use of levodopa in combination with car- bidopa or benseraside (dopa decarboxylase inhibitors), several additional pharmacologic agents have been approved as medi- cations for parkinsonism. One class of agents is the dopamine agonists. Although this class has been used for treating PD for many years, several new developments have occurred in this field over the past several years. Two previously extensively used dopamine agonists, bromocriptine and pergolide, have been abandoned as treatments for parkinsonism because their use has been associated with high risk for cardiac valvular dis- ease.20 This risk is attributed to the ergot-like properties of these agents. Lisuride, another ergot-like dopamine agonist, is not available in the United States, but it is widely used in Asia and in the European Union. Two well-established nonergot dopamine agonists, ropinirole and pramipexole, are mainstays in the treatment of PD. They are of much less use in other forms of parkinsonism and need to be avoided in patients with Lewy body dementia because they cause a significant increase in the risk for hallucinations. These long-acting agents are also to be avoided in PD patients with dementia. Two nonenteral dopa- mine agonists are also available. Rotigotine is available as a once a day transdermal patch, and apomorphine is available as a subcutaneous injection. These agents are of putative benefit in patients who may have significant trouble with oral drugs or as adjuncts to other ongoing PD therapies. Another class of agents

routinely used are the monoamine-oxidase B inhibitors. Selegi- line, a drug introduced in the early 1990s, and rasagiline, a more recent introduction, are both useful in the treatment of PD. These medications are both used in early disease for mild symptoms and in more advanced disease as adjunct therapy to other anti-parkinsonian medications to minimize complica- tions. Examples of such complications include drug-induced dyskinesias and end-of-dose wearing off. Finally, carboxy-O- methyltransferase inhibitors remain available as adjunct agents to enhance the action of levodopa in patients with more advanced disease. Two agents, entacapone and talcapone, are available, although talcapone requires careful hepatic monitor- ing and hence is not often used. There has been a major reduc- tion in the use of anticholinergic agents in the treatment of PD. Previous mainstays, benztropine and trihexyphenidyl (Artane) are no longer considered effective choices in most PD patients because their risks outweigh their benefits, as it is being increasingly recognized that there are long-term complications of chronic use of anticholinergic agents, especially in terms of causing cognitive side effects. In general, the modern approach to PD therapy is via rational polypharmacy in which neurologists use a prudent combination of two or more medi- cations to manage the symptoms optimally while minimizing side effects.

40.2.3 Parkinson-Plus and Secondary

Parkinsonisms

Parkinson-plus and secondary parkinsonisms require quite dif- ferent therapeutic approaches, often comprising much larger doses of levodopa. For example, multiple-system atrophy (MSA) patients frequently need 3 to 4 times the mean daily dose of levodopa compared with a PD patient with a similar degree of parkinsonism. The rationale for this increased need is based in the pathology of secondary parkinsonism, where there is damage to the dopaminergic targets and hence a higher dose is needed. It is also important to note that most dopamine ago- nists have a minimal role in the treatment of secondary parkin- sonisms. A rare complication of the use of large doses of levo- dopa is caused by its abrupt withdrawal. The syndrome of acute levodopa withdrawal resembles neuroleptic malignant syn- drome, which clinically manifests with hyperthermia, tachycar- dia, generalized stiffness, and occasionally dystonia. Imaging shows cerebellar white matter signal abnormalities that reverse when the patient is successfully treated by restoring dopamine and shares some features of posterior reversible encephalop- athy syndrome (PRES) (▶ Fig. 40.3). From an imaging perspec- tive, this condition must be kept in mind when a parkinsonian patient presents with findings that resemble PRES.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the globus pallidus internal segment (GPi) and lesioning of the STN or GPi have been shown to be effective in ameliorating PD symptoms in patients who are unable to get satisfactory relief with pharmacotherapy or who experience unacceptable side effects from pharmacotherapy. DBS has not been helpful in most patients with secondary parkinsonism. DBS is being investigated in other neurodegenerative disorders and is a major advancement in the field. The imaging aspects of DBS are discussed in Chapter 41.

The imaging implications of the therapies discussed so far for PD and related disorders are the following: in PD patients with drug-induced dyskinesias, the choreiform movements cause major motion artifacts during imaging. Because drug-induced dykinesias are uniquely temporally related to the short-acting levodopa formulation, a short-term withholding of levodopa overnight is generally a safe practice and will abolish the drug- induced dyskinesias to permit imaging. This short-term medi- cation withdrawal should not be prolonged beyond what is nec- essary to obtain a good imaging study to avoid the risk of neu- roleptic malignant syndrome (discussed earlier). Amantadine, a drug with multiple sites of action, can be effective to mitigate dyskinesias. This could be a strategy to suppress drug-induced dyskinesias to facilitate imaging. Another imaging implication applies to patients who are NPO (i.e., not taking any food or liquids orally) in preparation for surgery or anesthesia. In such patients, the lack of dopaminergic medications will cause their symptoms to be become more manifest. Specifically, resting tremor, significant bradykinesia, and dystonia could be appar- ent in PD patients who are NPO before surgery. These symp- toms could compromise quality of brain imaging. Although gen- eral anesthesia may solve the positioning of a parkinsonian patient with significant resting tremor this option might not be available and is associated with considerable risk. In this sce- nario, the use of injectable apomorphine along with an anti- nausea agent may provide excellent short-term relief of symp- toms for approximately 1 to 2 hours, enabling a high-quality imaging study to be accomplished. Another, less-effective option is the use of the rotigotine patch, although the patch will need to be removed immediately before the beginning of the imaging study. These options may be of particular benefit in patients who are undergoing DBS surgery and are NPO in prep- aration for such surgery. Sedation in such patients interferes with the ability of the neurologist to perform intraoperative neurophysiologic monitoring until the sedation wears off. This delay could potentially be avoided with the use of parenteral dopaminergic agents.

Many new approaches to pharmacotherapy in PD are in development and have been recently reviewed.21 These experi- mental approaches include new medications to mitigate drug- induced dyskinesias, methods to prolong the effective duration

Advances in the Treatment of Dementia

Fig. 40.3 Imaging changes in acute L-dopa withdrawal-induced neuroleptic malignant syndrome (NMS).

of action of L-dopa formulations, and novel methods to deliver L-dopa. One novel method that is in advanced stages of testing is a levodopa formulation that is administered into the duode- num via a subcutaneous pump.22 This technology is in advanced clinical trials and is expected to reach patients in the next few years. Levodopa formulations that have longer half-lives and novel routes of delivery (intranasal) are also under investiga- tion. Two multicenter research studies to investigate gene ther- apy using recombinant adenoassociated virus to modulate either the subthalamic nucleus or the striatal expression of aromatic amino acid decarboxylase are in advanced stages of testing. A European effort to evaluate the use of fetal tissue transplants in PD patients is also under way. Many novel small molecules and natural products for PD are also in advanced stages of testing. Targeted therapeutic agents that attempt to reverse the primary pathology in PD are also under investiga- tion. There is now compelling evidence that protein repair in degenerating dopaminergic neurons is faulty and that patho- logically misfolded proteins can potentially spread disease in a prion-like fashion within the brain. So efforts are being made to intervene therapeutically at multiple molecular targets and at secondary gial response to the primary pathology. Each of these studies will benefit from a reliable imaging biomarker; hence, there is a worldwide effort to discover reliable biomarkers for disease identification and disease progression in PD.

Huntington’s disease (HD) therapy has made some incre- mental gains in the past few decades with the acceptance of tetrabenazine as a suitable choice of treatment for HD chorea. Tetrabenazine is extremely short acting and has little risk of causing drug-induced parkinsonism in HD patients, unlike the older medications used in the treatment of chorea, like haloper- idol and risperidone (Resperidal). These antidopaminergic medications frequently caused secondary drug-induced parkin- sonism that worsened disability in HD patients and accelerated mortality. Therefore, traditional typical antipsychotic agents are avoided; tetrabenazine or, if needed, atypical antipsychotic agents are used to control chorea in HD. Neuropsychiatric complications of HD are also treated with alternative medica- tions like propranolol for anxiety and impulse control or pru- dent use of selective serotonin reuptake inhibitors that have adjunct antianxiety benefits. Rarely, HD patients may be on a

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combination therapy of tetrabenazine and an antiparkinsonian medication. In such patients, if motion artifacts from chorea are of concern, brief discontinuation of the antiparkinsonian medi- cation while continuing the tetrabenazine may provide sufficient suppression of movement without interfering with cognitive function, as is associated with other methods of phar- macologic immobilization of patients, like using conscious sedation or deeper forms of anesthesia. Chorea in HD may also benefit from amantadine treatment or, in selected patients, riluzole. Less commonly, nabilone, a synthetic cannabinoid, is prescribed for chorea.23

The juvenile form of HD (Westphal variant) manifests with akinesia and rigidity but not chorea. These patients are treated with high doses of levodopa, similarly to how other secondary forms of parkinsonism are treated. Patients with both the adult form and the juvenile form of HD benefit from cognitive thera- pies. So choline esterase inhibitors and memantine appear to benefit symptomatic cognitive decline in HD patients.

New experimental therapeutic approaches in development for HD include gene therapy using anti-sense RNA technology to silence the trinucleotide repeats or other approaches to negate the deleterious effects of the huntingtin protein. Although such exciting new possibilities are in development, thhe current approach is to use evidence-based pragmatic treatments that provide comfort and symptom management in HD.24

Amyotrophic lateral sclerosis (ALS) is extensively covered elsewhere in this book. However, its treatment remains a chal- lenge.25 Riluzole has become standard treatment for ALS, but its effects are minimal in mitigating the symptoms. ALS manage- ment has remained largely symptomatic and to provide relief from pain and suffering. A promising ALS stem cell trial that attempts to diminish the inflammation in the spinal cord using stem cell transplants directly placed surgically is ongoing. This experimental approach has strong preclinical and clinical safety data and holds much promise.26

Degenerative disorders of the cerebellum remain an area of active preclinical research but without much clinical relief to patients. Advances in understanding the genetics of these dis- eases are likely to inspire the discovery of new treatments in the near future.

Other advances in pharmacologic approaches are in the symptomatic treatment of comorbidities in degenerative disor- ders. Sialorrhea, a major feature of many neurodegenerative disorders like PD, AD, MSA, HD, and ALS, is effectively treated with the injection of salivary glands with botulinum toxins. Periodic botulinum toxin injection is also effective in treating focal cervical dystonia, which accompanies many degenerative disorders (e.g., retrocollis in progressive supranuclear palsy, anterocollis in MSA and foot dystonia in PD). Botulinum toxin injections also provide relief for focal dystonia in pyknodysosto- sis (PKND). The feature of pseudobulbar affect seen in many neurodegenerative disorders like vascular dementias, parkin- sonism, AD, and rarely ALS now has a newly approved treat- ment using dextromethorphan hydrobromide and quinidine sulfate as a combined formulation. Although the effects from this treatment have been modest, a new option to treat this symptom that can be quite disabling and socially embarrassing is now available. Depression, hallucinations, and sleep distur- bances are now more frequently recognized as comorbid

illnesses in many neurodegenerative disorders. The approval and availability of a wide array of atypical antipsychotic agents (e.g., Quetiapine and clozapine) that do not cause extrapyrami- dal side effects has been a major advancement in treating such symptoms.

40.3 Summary

In this chapter, we review a broad range of treatments for dementias that may have relevance to the imaging sciences. The key issue is whether treatments alter imaging or pose unique opportunities and challenges to neuroimaging. Some well-known examples of imaging findings after treatment are considered, and rarer examples are provided as a window to the future. Disease entities and treatment entities we consider here are the broad categories of progressive dementias, revers- ible dementias, and symptomatic treatments.

References

[1] Gürsoy AE, Kolukısa M, Babacan-Yıldız G, Celebi A. Subacute combined degeneration of the spinal cord due to different etiologies and improvement of MRI findings. Case Rep Neurol Med 2013; 2013: 159649

[2] Naidich MJ, Ho SU. Case 87: Subacute combined degeneration. Radiology 2005; 237: 101–105

[3] Pittock SJ, Payne TA, Harper CM. Reversible myelopathy in a 34-year-old man with vitamin B12 deficiency. Mayo Clin Proc 2002; 77: 291–294

[4] Gupta PK, Gupta RK, Garg RK et al. DTI correlates of cognition in conventional MRI of normal-appearing brain in patients with clinical features of subacute combined degeneration and biochemically proven vitamin B12 deficiency. AJNR Am J Neuroradiol 2014; 35: 872–877

[5] Mpakopoulou M, Brotis AG, Gatos H, Paterakis K, Fountas KN. Ten years of clinical experience in the use of fixed-pressure versus programmable valves: a retrospective study of 159 patients. Acta Neurochir Suppl (Wien) 2012; 113: 25–28

[6] Huang CC, Chu NS. Acute dystonia with thalamic and brainstem lesions after initial penicillamine treatment in Wilson’s disease. Eur Neurol 1998; 39: 32–37

[7] da Costa MdoD, Spitz M, Bacheschi LA, Leite CC, Lucato LT, Barbosa ER. Wilson’s disease: two treatment modalities. Correlations to pretreatment and posttreatment brain MRI. Neuroradiology 2009; 51: 627–633

[8] Douaud G, Refsum H, de Jager CA et al. Preventing Alzheimer’s disease- related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A 2013; 110: 9523–9528

[9] Farrimond LE, Roberts E, McShane R. Memantine and cholinesterase inhibitor combination therapy for Alzheimer’s disease: a systematic review. BMJ Open 2012; 2: 8

[10] Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 2006: CD005593

[11] Filippi M, Agosta F, Frisoni GB et al. Magnetic resonance imaging in Alzheimer’s disease: from diagnosis to monitoring treatment effect. Curr Alzheimer Res 2012; 9: 1198–1209

[12] Morgan D, Diamond DM, Gottschall PE et al. A beta peptide vaccination pre- vents memory loss in an animal model of Alzheimer’s disease. Nature 2000; 408: 982–985

[13] Sabbagh JJ, Kinney JW, Cummings JL. Animal systems in the development of treatments for Alzheimer’s disease: challenges, methods, and implications. Neurobiol Aging 2013; 34: 169–183

[14] Jack CR, Jr, Albert MS, Knopman DS et al. Introduction to the recommenda- tions from the National Institute on Aging-Alzheimer’s Association work- groups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 257–262

[15] Sperling RA, Aisen PS, Beckett LA et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 280–292

. [16] Bertelson JA, Ajtai B. Neuroimaging of dementia. Neurol Clin 2014; 32: 59–93

. [17] McKhann GM, Knopman DS, Chertkow H et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for
Alzheimer’s disease. Alzheimers Dement 2011; 7: 263–269

. [18] Yang L, Rieves D, Ganley C. Brain amyloid imaging—FDA approval of florbeta-
pir F18 injection. N Engl J Med 2012; 367: 885–887

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pharmacological options for treating advanced Parkinson’s disease. Clin Ther
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[22] Nyholm D, Klangemo K, Johansson A. Levodopa/carbidopa intestinal gel infusion long-term therapy in advanced Parkinson’s disease. Eur J Neurol 2012; 19: 1079–1085

[23] Armstrong MJ, Miyasaki JM American Academy of Neurology. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology 2012; 79: 597–603

[24] Mestre TA, Ferreira JJ. An evidence-based approach in the treatment of Huntington’s disease. Parkinsonism Relat Disord 2012; 18: 316–320

[25] Gibson SB, Bromberg MB. Amyotrophic lateral sclerosis: drug therapy from the bench to the bedside. Semin Neurol 2012; 32: 173–178

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41 Imaging of Deep Brain Stimulation

Falgun H. Chokshi

Deep brain stimulation (DBS) has revolutionized the treatment of treatment-refractory movement disorders. It has also rejuve- nated the field of functional neurosurgery by allowing precise anatomical neuromodulation of select intracranial nuclei.1

Historically, DBS probes were placed via burr holes and local anesthesia, using only surgical anatomical landmarks and radi- ography for guidance.2,3 Subsequent work by Horsley estab- lished the foundations of the stereotactic technique,4 which led to development of several stereotactic atlases.1 Next came the era of stereotactic technique combined with ventriculography, which was brought to surgical practice in 1947.5 It was not until the advent of magnetic resonance imaging (MRI) that DBS, and functional neurosurgery at large, matured significantly further, with better localization of target nuclei.

The role of the neuroradiologist is crucial in the screening, presurgical imaging, and postsurgical evaluation of patients receiving DBS. As an important member of the multidiscipli- nary team, a neuroradiologist often works closely with the neurologist and neurosurgeon to treat the patient.

The purpose of this chapter is to discuss the underlying imag- ing and management principles of DBS, including basal ganglia anatomy, indications for DBS, techniques for target visualiza- tion, and postoperative evaluation. Furthermore, we briefly discuss the role of MRI risk and safety as they relate to DBS.

41.1 Anatomy of Target Nuclei

Three nuclei have historically been targeted for DBS in move- ment disorders: (1) the ventral intermediate nucleus (VIM) of the thalamus, (2) globus pallidus interna (GPi), and (3) subtha-

lamic nucleus (STN).6 Methods for targeting these nuclei are discussed later in the section on techniques.

The VIM is anatomically located in the cephalad-lateral por- tion of the thalamus. Adjacent structures include the ventral lateral nucleus anteriorly, the ventral posteromedial and pos- terolateral nuclei posteriorly, the posterior limb of the internal capsule laterally, and the medial thalamic nuclei medially.

The basal ganglia are paired structures and comprise the caudate nuclei (CN), putamena (PN), and globus pallidi (GP) (▶ Fig. 41.1). They play a fundamental role in integrating complex movement, having connections with almost all parts of the brain.7,8 The STN and substantia nigra (SN) are considered by some, including our group, to be part of the basal ganglia.7,9,10 These five deep gray nuclei are metabolically quite active, have high energy demands, and are susceptible to both systemic diseases and those altering cerebral perfusion and/or oxygenation.7,8,9,11

The CN, PN, and GP are grouped into the corpus striatum; and the CN, PN, and nucleus accumbens (NA) are called the striatum (or neostriatum). These classifications are due to neuro- chemical, histologic, and connectional similarities among the nuclei.7,10

Five nuclei constitute the basal ganglia, but only two are rou- tinely targeted for DBS: (1) the GP (GPi) and (2) the STN (▶ Fig. 41.2). The GPi is in the medial portion of the GP (laterally is the GP externa). It lies medial to the lamina interna and lateral to the internal capsule.12 The STN is located in the rostral midbrain and lies posterior and medial to the cerebral pedun- cles (crus cerebri). Each STN is a small biconvex structure whose orientation is oblique, with the superior pole located posterior and lateral to the inferior pole.12,13

Fig. 41.1 Cross-sectional anatomy of the basal ganglia and their associated structures. VA/VL, ventral anterior/ventral lateral thalamic nucleus. (Illustration by Eric Jablonowski.)

41.2 Indications for Deep Brain

Stimulation

Common indications for DBS include Parkinson’s disease (PD),14 essential tremor (ET),15 chronic pain,16 and dystonia.17,18 Initial work on the effects of DBS focused on chronic stimulation of the VIM of the thalamus in patients with PD or ET, with some subjects showing complete relief from tremor.19 Subsequently, DBS was used in patients with severe akinetic-rigid PD and motor fluctuations, where the STN was stimulated.19 Patients showed a reproducible diminishment of their symptoms.14 Eventually, the Food and Drug Administration approved DBS of the bilateral STN in patients with advanced PD in 2002 and GPi stimulation in 2003.6

41.3 Techniques

Imaging techniques for DBS fall into one of three main catego- ries: (1) screening for potential DBS patients; (2) targeting of nuclei, namely, the GPi and STN; and (3) postoperative lead placement confirmation and complication assessment.

41.3.1 Screening of Patients

Patients who are clinically deemed candidates for DBS (usually for advanced PD) typically undergo a screening brain MRI to exclude other causes for their symptoms (e.g., thalamic tumor causing PD-like symptoms). The presence of leukoencephalop-

Imaging of Deep Brain Stimulation

Fig. 41.2 Deep brain stimulation (DBS) device and targets. (a) Diagrammatic representation of the DBS device showing both intracranial and extracranial components. (b) Coronal depiction of globus pallidus (GP) targeting by DBS lead. (c) Coronal depiction of subthalamic nucleus targeting by DBS lead. (Illustration by Eric Jablonowski.)

athy, severe brain atrophy, multiple lacunar infarcts, severe ventriculomegaly, and mass, such as atrioventricular mal- formation or tumor, along the expected path of the lead, are all contraindications to DBS (▶ Fig. 41.3).20,21,22

At our institution, all patients considered for DBS are screened using a standard noncontrast protocol comprising five sequences (▶Table 41.1). A detailed report is transcribed, which helps the neurosurgical team in treatment planning.

41.3.2 Nuclei Targeting

Currently, the vast majority of nuclei targeting focuses on the GPi and the STN,6 which is the focus of this section. This is a critical part of the patient’s treatment plan, with the outcome of the DBS placement hinging on the proper presurgical plan- ning of the trajectory.20

Targeting of nuclei can be indirect (statistically determined coordinates relative to the anterior-posterior commissure line and related to known anatomical atlases) (▶ Fig. 41.4) or direct (direct visualization via MRI) and using an MRI-computed tomography (CT) fusion technique incorporating a stereotactic atlas.6

At our institution, a “homegrown” hybrid targeting system has been developed (unpublished data), encompassing the information provided by a Talaraich atlas and via three- dimensional (3D) T1-weighted images of the brain during pre- operative evaluation. Additionally, an abbreviated preoperative MRI of the brain is performed on the day of surgery, as described in ▶ Table 41.1.

379

Clinical Approach and Treatment

Fig. 41.3 Screening magnetic resonance imaging (MRI) showing thalamic tumor causing parkinso- nian symptoms. (a) Axial T1 magnetization- prepared rapid acquisition gradient echo (MP RAGE) and (b) axial fluid-attenuated inversion recovery (FLAIR) images show an expansile lesion (white arrows) in the left thalamus, which was thought to cause the patient’s parkinsonian symptoms. DBS surgery was not scheduled.

Table 41.1 Deep brain stimulation magnetic resonance imaging (MRI) protocols at Emory Neuroradiology

Screening MRI

1.5 T MRI with transmit-receive head coil only protocol

Volumetric axial T1-weighted
Reformed to coronal and sagittal planes

Volumetric axial T1-weighted inversion recovery

Axial DWI and ADC maps

Axial T2-weighted GRE

Axial FLAIR

Axial T2-weighted FSE

Preoperative MRI

Post-contrast volumetric axial T1-weighted

Post-contrast volumetric axial T1-weighted inversion recovery

Postoperative MRI

Volumetric axial T1-weighted

Volumetric axial T1-weighted inversion recovery

Axial T2-weighted GRE

Axial FLAIR

Axial T2-weighted FSE

Abbreviations: ADC, apparent diffusion coefficient; DWI, diffusion- weighted imaging; FLAIR, fluid-attenuated inversion recovery; FSE, fast spin echo; GRE, gradient echo.

380

Historically, many centers have used microelectrode record- ing (MER) of neurons along the path of the implant lead to identify the signature of groups of neurons, thereby using this method to localize target nuclei. A detailed discussion of this technique is beyond the scope of this chapter, and the reader is referred to select publications.23,24,25

Subthalamic Nucleus

Using the anterior-posterior commissure (AC-PC) line, some authorities have reported the coordinates of the STN as 12 mm

lateral, 3 mm posterior, and 3 mm inferior to the mid-commis- sural point26; 9 to 12 mm lateral, 1 to 2 mm posterior, and 5 mm inferior to the mid AC-PC line27; 12.12mm lateral, 2.41mm posterior, and 2.39 mm relative to the mid-commissural point (▶ Fig. 41.5).28

Direct targeting of the STN is also used, first described using coronal T2-weighted images.23 The STNs are visible as hypoin- tense structures having biconvex shapes, placed in the upper midbrain.29 Additionally, these authorities used the red nucleus as an internal reference point to determine the anteroposterior orientation and location of the STN. Additionally, Dormont and colleagues30 showed that the anatomical location of the STN had corresponding iron deposition, explaining the T2-hypoin- tense signal of this nucleus.

Various studies have examined STN visualization at 3 T mag- netic field strength (▶Fig. 41.6). Slavin and colleagues found that high-resolution contiguous T2-weighted fast spin echo images allowed direct visualization of the STN.27 A multi- gradient-echo fast low-angle shot technique also allowed simultaneous acquisition of 3D T1-weighted images for stereo- tactic use and T2* contrast to detect the STN.31 Some authori- ties have relied on the red nucleus as an internal landmark, also showing that 3D reconstruction of images aids targeting better than 2D images.32 Liu and colleagues have found that quantita- tive susceptibility weighted imaging (SWI) at 3 T field strength is significantly better at visualizing the STN compared with con- ventional T2-weighted fast spin-echo imaging.33

Globus Pallidus Interna

Initial work on direct targeting of the GPi focused on using axial turbo-spin echo proton attenuation-weighted images, described by Hirabayashi and colleagues as accurate in 71% of the 48 patients they imaged.34 Subsequent studies corroborated the value of this sequence in targeting the GPi in children with dystonia, showing clear visualization of the internal and external pallidum, the putamen, and the pallidocapsular

Imaging of Deep Brain Stimulation

Fig. 41.4 Anterior-posterior commissure (AC-PC) line. Sagittal postcontrast magnetization- prepared rapid acquisition gradient echo (MPRAGE) image showing the anatomical relationships between the AC and PC, with delineation of the AC-PC line (white solid arrows). The midpoint of the AC-PC line is conventionally the coordinate (0, 0, 0).

Fig. 41.5 Hybrid targeting of the subthalamic nucleus (STN). Hybrid targeting system at Emory Neurosurgery showing atlas-based regions superimposed on three-dimensional magnetic resonance images. Sagittal (a), coronal (b) and axial (c) images show that the STN (red), thalami (green), caudate (blue), and zona incerta (yellow) are highlighted.

border.35 In this study, targeting was typically aimed for the posteroventral pallidum. Additionally, in children, direct MR targeting of the GPi was shown to be superior to atlas-based targeting.36

At our institution, as discussed, we use a hybrid system to localize the GPi (▶ Fig. 41.7). Coordinates that we use for the GPi are 21 mm lateral to the AC-PC line, 1 mm posterior to

the AC-PC line midpoint, and 4 mm inferior to the AC-PC line midpoint.

41.4 Postoperative Imaging

Postoperative imaging of DBS evaluates (1) early and late opera- tive complications and (2) implantable lead positioning relative

381

Clinical Approach and Treatment

to the intended target. Both CT and MRI are useful. ▶ Table 41.1 lists the MRI protocol at our institution.

41.4.1 Complications

Complications can be divided into early and late. Early compli- cations mainly involve ischemia and intracranial hemorrhage (▶Fig. 41.8), namely, intraparenchymal hematoma, subdural hematoma, and epidural hematoma.37,38 Some studies suggest age, bleeding disorders, gender, and hypertension as predispos- ing factors.39,40 The risk of bleeding using single-electrode ver- sus multielectrode recording (MER) is controversial.40,41 Of note, seizures following DBS are rare,42 prompting a noncontrast head CT evaluation to assess for hemorrhage.42,43

Late complications predominantly include infection, which ranges from 1 to 22.2% in incidence.44,45 Infection in a DBS patient can result in prolonged hospitalization, long-term antibiotic therapy, or even removal of the leads.23 Antibiotic- containing cement has shown some success in blocking microbacterial proliferation.45 Lead migration is another com- plication, for which the published incidence to date is 4 to 5%.42 Frank electrode breakage is rare (▶ Fig. 41.9), usually associated with connecting the lead and extension behind the ear instead of the calvarium.42,46,47

41.4.2 Lead Placement Confirmation

Confirmation of DBS lead positioning is a key step in identifying the relationship between the electrode and target and to validate the precision of targeting. Various approaches to this assessment have been published, but no single approach is

Fig. 41.6 Subthalamic nucleus (STN) on susceptibility-weighted imaging (SWI). Axial SWI image showing that the STNs (black arrows) are lateral and posterior to the substantia nigra (white arrows), lateral to the symmetric red nuclei (dashed arrows).

Fig. 41.7 Hybrid targeting of the globus pallidus interna (GPi). Hybrid targeting system at Emory Neurosurgery showing atlas-based regions superimposed on three-dimensional magnetic resonance images. Sagittal (a), coronal (b) and axial (c) images show that the GPi (red), GP externa (GPe, green), putamen/caudate (blue), and anterior commissure (yellow) are highlighted.

382

Imaging of Deep Brain Stimulation

Fig. 41.8 Early complication, brainstem hemor- rhage. Axial noncontrast computed tomography (CT) image of the head immediately following bilateral deep brain stimulation (DBS) lead placement (black arrows on scout image (a)

and axial image (b). Acute intraparenchymal hematoma (white arrows) surrounding the right lead tip, extending into the right side of the brainstem (c,d).

Fig. 41.10 Confirmation of deep brain stimulation (DBS) leads in subthalamic nucleus (STN), magnetic resonance imaging (MRI).
(a) coronal and (b) parasagittal T1 inversion recovery (IR) three- dimensional images of the brain show proper placement of DBS leads in the subtemporal nucleus bilaterally (white arrows).

Fig. 41.9 Deep brain stimulation lead fracture evaluation by computed tomography (CT). Oblique coronal maximum intensity projection (MIP) image of patient suspected of lead fracture. The image supports that the leads are intact and tips are in the region of the subthalamic nucleus bilaterally.

universally accepted (▶ Fig. 41.10). For example, Yelnik and col- leagues reported using the Schaltenbrand and Wharen atlas fused onto anatomical MRI to show differences in the effect of DBS in patients with akinesia and rigidity of stimulation based on lead placement in the internal versus external GP.48

Using a 3D atlas and MR fusion method in a group of DBS patients with STN targeting, Yelnik and colleagues were also able to show that stimulation of the zona incerta and the lentic- ular fasciculus around the STN allowed amelioration of PD

383

384

Clinical Approach and Treatment

symptoms.49 Many other atlas and MR fusion-based evaluation methods have also been studied.13,50

Postoperative MRI is quite helpful when DBS failure occurs. In a study of 41 patients with suboptimal DBS results, Okun and colleagues51 found the main causes for failures to be suboptimal medical treatment (73%), suboptimal pacemaker programming (54%), and suboptimal lead placement (46%). In another study, by Anheim and colleagues,52 the precise localization of elec- trode placement in the STN is necessary for proper response to DBS.

41.5 Risk and Safety of Magnetic

Resonance Imaging

Whereas CT can detect most DBS-related complications, such as acute intracranial hemorrhage and lead fracture, we believe that MRI is the modality of choice to assess for both complica- tions and lead placement confirmation.6 However, there is a risk of electrode element heating due to energy deposition dur- ing radiofrequency electromagnetic pulse generation.53,54,55,56

After such risks were reported, the manufacturer of the DBS system updated the safety guidelines in November 2005. The major parts of this update include (1) the pacemaker device must be “off,” 2) use a 1.5-T MR system, 3) use of a transmit- receive-type radiofrequency head coil that does not cover the chest area, and (4) optimization of MR parameters to keep the specific absorption rate (SAR) below 0.1 W/kg in the head.6

These guidelines pose a set of dilemmas for both the neuro-

radiologist and the referring physician. For example, without

the availability of a transmit-only head coil, DBS patients can-

not undergo MRI using these guidelines. In fact, they cannot

have an MRI safely on any other part of the body once the leads

are in place, according to the manufacturer’s guideline.6 Addi-

tionally, variability in SAR has been shown, to the point where

some authorities question the need for such a strict cutoff for the SAR.57,58,59

41.6 Summary

Deep brain stimulation continues to evolve as a novel means of restoring functionality and decreasing morbidity in patients with movement disorders resistant to medical therapy. Rapid development of DBS targeting and postoperative evaluation techniques is under way, with ever-emerging indications for DBS coming to light, including for major depression, obsessive- compulsive disorder, and anorexia nervosa. The integral roles of neuroimaging and the neuroradiologist are paramount in the pre- and post-DBS periods and will continue to grow.

41.7 Acknowledgments

Thanks to Mark E. Mullins, MD, PhD, for editorial assistance and guidance and Eric Jablonowski for medical illustrative services.

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Index

Note: Page numbers set bold or italic indicate headings or figures, respectively.

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency 307

5-fluorouracil 272

18-q syndrome 307 A

ABCA7 gene 120
Abnormal movement complaints 6 ACD, see Alcoholic cerebellar

degeneration (ACD) Acetylcholinesterase (AChE) activity
– in dementia with Lewy bodies 39
– in multiple-system atrophy 182
– in Parkinson’s disease 171
– in progressive supranuclear palsy 183 Acquired hepatocellular

degeneration 367
Acyl-CoA oxidase deficiency 307 Addison syndrome 296, 297 Adenosing triphosphate-binding

cassette 120 Adrenomyeloneuropathy (AMN) 307,

313, 313, 340
Adult autosomal dominant

leukoencephalopathies 307 Aging brain

– as primary dementia risk factor 362

– brain function in 77, 77

– cerebrospinal fluid in 26, 70, 71

– cerebrovascular changes in 74, 75

– cerebrovascular reactivity in 75

– cortical thickness in 71, 72

– creatine levels in 26

– diffusion tensor imaging in 42, 168

– fractional anisotropy 168

– functional magnetic resonance
imaging in 77, 77

– gray matter in 70, 71–72

– iron deposition in 73, 73, 80, 80, 81

– magnetic resonance spectroscopy

Alexander disease 307, 332 Alkylating agents 272
ALS, see Amyotrophic lateral sclerosis

(ALS)
ALS2 gene 11
Alsin 11
Alzheimer, Alois 3, 113 Alzheimer’s disease (AD)
– amyloid deposition in 36, 83, 98,

113, 121, 121, 128, 130, 139, 139,

140, 141, 145–148
– animal model of, amyloid plaques

in 139, 142–144
– antidepressants in 373
– apathy in 115
– aphasia in 114–115
– atypical presentation of 115
– biomarkers in 93, 99, 116, 122
– cerebrovascular disease and 60
– cholesterolemia and 93
– cholinesterase inhibitors in 373
– clinical features of 114
– clinical overlaps with 10
– cognitive deficits in 114
– cortical signature of 124–125, 125 – delusions in 115
– dementia with Lewy bodies vs. 44,

151–153, 155
– diagnosis of 115, 130
– diffusion tensor imaging in 42, 43 – dopamine system in 35
– dopaminergic system in 36
– early diagnosis of 130
– early-onset 119
– familial autosomal dominant 113 – frontal variant 115
– functional magnetic resonance

imaging in 54, 134, 135
– GABA system in 36–37
– genetics in 9, 11, 113, 119, 120 – gray matter in 100, 139, 140
– hallucinations in 115
– in epidemiology of

neurodegenerative diseases 5 – in genome-wide association

studies 119
– in history of neurodegenerative

disease 3
– increase in 113
– iron accumulation in 80, 139 –– animal models of 83

– mild cognitive impairment vs. 100 – neurofibrillary tangles in 113, 121 – neuropathology of 113, 121, 121
– neuropsychiatric features of 115

– paranoia in 115
– patient complaints in 6
– perfusion in 65, 66
– perfusion-weighted imaging in 133,

134

– plasma biomarkers of 122
– positron emission tomography

in 35, 37, 116, 127–128, 129–130 – posterior cortical atrophy

variant 115
– preclinical 124
– prodromal 115–116
– serotonin system in 35–36
– severity of 115
– single photon emission computed

tomography in 35, 116, 127
– structural imaging in 17, 17, 18, 116 – tacrine in 37
– tau protein in 121, 128, 130
– therapeutic evaluation in 37
– treatments for 371
– vascular dementia vs. 66
– white matter in 125, 126, 153, 155 Amantadine 375–376
American Society of Neuroradiology 2 Amino acid (AA) disorders
– as inborn errors of metabolism 307,

314, 314
– clinical overlaps with 10
Amino acid degrader 272 Aminoaciduria 314, 314
AMN, see Adrenomyeloneuropathy (AMN) Amnesia
– in Alzheimer’s disease 114
– in mild cognitive impairment 100, 101 – in normal pressure

hydrocephalus 256
– in prion disease 239
– in strategic single-infarct

dementia 204
– in voltage-gated potassium channel

encephalopathy 250 – in Wernicke-Korsakoff

syndrome 300
Amyloid angiopathy 307
Amyloid deposition
– in Alzheimer’s disease 36, 83, 98,

113, 121, 121, 128, 130, 139, 139,

140, 141, 145–148
– in animal model of Alzheimer’s

disease 139, 142–144
– in Creutzfeldt-Jakob disease 28, 240 – in frontotemporal lobar

degeneration 98
– in mild cognitive impairment 95,

98–99
– in prion disease 240
– iron and 83, 143
– magnetization transfer ratio

and 144, 148
– morphology of 147
– on MRI 143
Amyloid precursor protein (APP) 9, 11,

119, 120, 121, 140, 142–145

Amyloid-related imaging abnormalities (ARIAs), in Alzheimer’s disease 127

Amyotrophic lateral sclerosis (ALS)
– cause of 345
– clinical presentation of 344, 344
– corticospinal tract in 45–46, 46, 349 – diagnosis of 345, 346

– diffusion tensor imaging in 45, 46, 352, 353–354

– epidemiology of 344
– familial 344
– frontotemporal dementia vs. 7
– frontotemporal lobar degeneration

and 157
– functional magnetic resonance

imaging in 355, 357
– genetics in 11, 345
– iron mapping in 85, 85
– magnetic resonance imaging in 349,

350

– magnetic resonance spectroscopy in 29, 30, 351, 352

– magnetization transfer ratio in 354 – patient complaints in 6
– positron emission tomography

in 354, 355–356
– sporadic 344
– treatment of 346, 376
– voxel-based morphometry in 349, 351 Amyvid tracer 128
Angiography, see Computed

tomography angiography (CTA), Digital subtraction angiography (DSA), Magnetic resonance angiography (MRA)

Animal models, of Alzheimer’s disease – amyloid plaques in 139, 142–144
– iron mapping in 83
Anosmia

– in herpes simplex encephalitis 232 – in Parkinson’s disease 172 Anterior inferior cerebellar artery

(AICA) 318, 320
Anterior-posterior commissure (AC-PC)

line 381
Anti-AMPAR encephalitis 279 Anti-CV2/CRMP-5 encephalitis 281 Anti-GABABR encephalitis 279 Anti-GAD encephalitis 279 Anti-glutamic acid decarboxylase

syndrome 245
Anti-Hu encephalitis 280
Anti-Ma2 encephalitis 281 Anti-NMDARencephalitis 279 Anti-Ri encephalitis 281
Anti-Tr encephalitis 281
Anti-VGKC encephalitis 279 Anti-voltage-gated potassium channel

encephalopathy 250, 250 Anti-Yo encephalitis 281 Antibodies
– in celiac disease 247

– in gluten sensitivity dementia 247 – in immune-mediated

dementias 245, 245
– in limbic encephalitis 277
– in paraneoplastic syndrome 20,

276–277, 279

in 26

– metabolism in 75, 76

– microbleeds in 74, 75

– perfusion changes in 65, 66, 75

– positron emission tomography
in 75, 76

– signs and symptoms associated with

– structural changes in 70, 71–75

– structural imaging in 16

– volume changes in 70, 71–72

– white matter in 42, 71, 73, 73, 74 AICA, see Anterior inferior cerebellar

– – – –

–

– – –

–

iron mapping in 83, 84
late-onset 119
Lewy bodies in 151 logopenic-variant primary progressive aphasia variant of 115 magnetic resonance imaging in 124, 124, 126, 133

magnetic resonance spectroscopy in 26, 137
magnetization transfer ratio in 144, 148

memory deficits in 114 metabolism in 128, 129, 134 microscopic magnetic resonance imaging in 139, 139, 140–148
mild cognitive impairment and 93, 93, 93, 115–116

artery (AICA)
Aicardi Goutiers syndrome (AGS) 215 Alcoholic cerebellar degeneration

(ACD) 328, 333, 333 Alcoholicencephalopathy 301 Alcoholic-related dementia (ARD) 301,

303

211, 211

Index

– insystemiclupus erythematosus 248

Antidepressants
– in Alzheimer’s disease 373
– in motor neuron disease 340 Antiphospholipid syndrome (APS) 214 Apathy, in Alzheimer’s disease 115 Aphasia, see Logopenic aphasia (LPA),

Primary progressive aphasia (PPA), Progressive nonfluent aphasia (PNFA)

– in Alzheimer’s disease 114–115

– in frontotemporal dementia 37, 44

– in vascular dementia 195
Apo E4
– in Alzheimer’s disease 93, 133
– in mild cognitive impairment 93 ApoE gene 10, 11, 113, 119, 120 Apolipoprotein E 11, 196 Apomorphine 374–375
APP gene 9, 11, 119, 120, 121–122, 196 – SeealsoAmyloidprecursorprotein
(APP)
APS, see Antiphospholipid syndrome
(APS)
ARD, see Alcoholic-related dementia
(ARD)
Argyrophilic fibrillary inclusions

– in frontotemporal degeneration 17

– in frontotemporal lobar
degeneration 158, 159

– in multiple-system atrophy 180

– in neurodegenerative disease 3 Arnold-Chiari malformation 336 Artane 374
Arterial spin labeling (ASL) 64, 65, 102,
103
Arylsulfatase A deficiency 306, 307–
308
ASL, see Arterial spin labeling (ASL) Ataxia
– cerebellar

–– acute-onset 328, 329–330

–– autosomal dominant inherited 329,
330–331

–– autosomal recessive 331, 332

–– causes of 328

–– chronic 328, 329

–– defined 328

–– in gluten sensitivity 247

–– in prion disease 239

–– inherited 328, 330–331

–– metabolic 332

–– sporadic 328

– drug-induced 328

– Friedreich 328, 331, 332

– gluten 328, 334

– in fragile X-associated tremor/ataxia
syndrome 307, 313, 328, 333

– spinocerebellar 330

–– genetic testing with 4

–– genetics in 11, 330

–– in classification of cerebellar ataxia 328

–– magnetic resonance spectroscopy in 330

–– patient complaints in 6
Ataxia telangiectasia (AT) 328, 331, 332 Ataxins 11
ATP7B gene 11
Attention complaints 6
ATXN genes 11
AV-45 tracer 128

Bacterial infections 233, 234–235 Bacterial meningitis 233
Bálint syndrome 115
Bartonella henselae 235

Basal ganglia
– in aging brain 78, 80
– in Alzheimer’s disease 83, 100, 128 – in Behçet disease 251
– in CADASIL 210, 221
– in CARASIL 211
– in cerebral amyloid angiopathy
– in children 73
– in corticobasal degeneration 183
– in Creutzfeldt-Jakob disease 28
– in deep brain stimulation 378
– in dementia with Lewy bodies 151,

154
– in frontotemporal lobar

degeneration 158
– in functional magnetic resonance

imaging 57
– in HIV infection 227
– in Huntington disease 19, 187–188 – in hyperparathyroidism 298
– in Leigh disease 311
– in MELAS 215, 215, 312
– in mixed dementia 208
– in multiple-system atrophy 180
– in myoclonic epilepsy with ragged

red fibers 313
– in parathyroidism 298, 298
– in Parkinson’s disease 38, 84, 169
– in Parkinson’s diseases 38
– in polyarteritis nodosa 221
– in primary angiitis of central nervous

system 217
– in prion disease 240, 241
– in progressive supranuclear

palsy 21, 182
– in secondary parkinsonism 186–187 – in systemic lupus

erythematosus 217
– in vascular parkinsonism 191, 191,

194, 200, 206, 207–208
Basilar artery 320
Behavior complaints 6
Behavioral variant frontotemporal

dementia (bvFTD) 157–159 Behçet disease 217, 220, 250 Benseraside 374 Benzodiazepines 367 Benztropine 374

Bifunctional protein deficiency 307 BIN1 gene 120
Binswanger’s disease 3, 3 Biomarkers

– in Alzheimer’s disease 93, 99, 116 – in mild cognitive impairment 93 BK virus 233
Blood-brain barrier (BBB)

– in combined radiotherapy and computed tomography dementia 273

– in lead toxicity 302
– in manganese toxicity 303
– in mercury toxicity 303
– in parathyroidism 298
– in radiotherapy 269, 269
– in thiamine deficiency 300 Blood-oxygen-level-dependent (BOLD)

contrast 51, 51, 171–172

– SeealsoFunctionalmagnetic resonance imaging (fMRI) BOLD, see Blood-oxygen-level-

dependent (BOLD) contrast Borrelia burgdorferi 233 Botulinum toxin 376 Bradykinesia, in Parkinson’s

disease 38, 171
Brain sagging 159, 162
Brain tumors
– chemotherapy for, dementia

and 271, 273
– cognitive effects of 266
– metastatic 267
– radiotherapy for
–– blood-brain barrier in 269, 269 –– computed tomography and,

dementia in combined 272, 274 –– dementia and, for brain

tumors 268, 270, 270, 271–272 –– diffuse late atrophy in 270
–– imaging of effects of 269
–– in pediatric patients, brain effects

of 273
–– mechanism of brain effects in 268,

268, 269
–– photon-cell interaction in 268, 268,

269

– treatment of 266
– whole-brain radiation for 267 Brainstem
– anatomy, diffusion tensor imaging

of 322, 323–324
– in Alzheimer’s disease 121
– in amyotrophic lateral sclerosis 45 – in Arnold-Chiari malformation 336 – in ataxia telangiectasia 331
– in Behçet disease 220, 251, 251
– in carbon monoxide exposure 303 – in dementia with Lewy bodies 150–

151
– in dentatorubral-pallidoluysian

atrophy 189, 189
– in HIV infection 227
– in Leigh disease 311
– in Lyme disease 233
– in multiple-system atrophy 335 – in normal pressure

hydrocephalus 258, 259
– in paraneoplastic cerebellar

degeneration 281
– in Parkinson’s disease 173 – in progressive supranuclear

palsy 21, 183
– in spinal muscular atrophy 342 – in spinocerebellar ataxia 330 Brainstem encephalitis, in

paraneoplastic syndrome 279, 280 Breast cancer 276, 277
Bridging integrator 1 120 Bromocriptine 374

Brownian motion 42
Bulbar problems 6
Bulbospinal muscular atrophy 343 bvFTD, see Behavioral variant

frontotemporal dementia (bvFTD)

C9ORF72 gene 11, 158
C11-PIB tracer 128, 130 CADASIL, see Cerebral autosomal

dominant arteriopathy (CADASIL)

Canavan disease 25, 307, 332 CARASIL, see Cerebral autosomal

recessive arteriopathy (CARASIL) Carbidopa 374
Carbon monoxide exposure 303, 304 Carboplatin 272 Carboxy-O-methyltransferase

inhibitors 374
Carboxylase deficiency 307 Carmustine 272
Cat scratch disease 235
Caudate nuclei (CN) 378, 378
CBD, see Corticobasal degeneration

(CBD)
CCA, see Corticocerebellar atrophy

(CCA)
CD, see Celiac disease (CD)
CD-2 associated protein 120 CD2AP gene 120
CD33 antigen 120
CD33 gene 120
Celiac disease (CD) 247, 248, 334 Central nervous system tumors, see

Brain tumors
Cerebellar ataxia
– acute-onset 328, 329–330
– autosomal dominant inherited 329,

330–331
– autosomal recessive 331, 332
– causes of 328
– chronic 328, 329
– defined 328
– in gluten sensitivity 247
– in prion disease 239
– inherited 328, 330–331
– metabolic 332
– sporadic 328
Cerebellar degeneration
– alcoholic 328, 333, 333
– in toxic cerebellitis 329
– paraneoplastic 277, 278, 281, 328,

333, 334
Cerebellar embryology 318 Cerebellar hemorrhage 329 Cerebellar infarct 328, 329
– SeealsoInfarct(s)
Cerebellar input pathways 321 Cerebellar output pathways 320, 321 Cerebellar stroke 328, 329 Cerebellitis
– acute 329, 329
– toxic 329, 330
Cerebellum
– congenital malformations of 335–

336, 336
– diffusion tensor imaging of 322,

323–324
– gross anatomy of 318, 319
– histopathology of 319, 321
– magnetic resonance spectroscopy

of 324, 325
– vascular supply of 318, 320 Cerebral amyloid angiopathy

(CAA) 211, 211, 212 Cerebral autosomal dominant

arteriopathy (CADASIL)
– as inborn error of metabolism 307 – genetics in 11, 196, 196
– imaging of 210, 210
– in classification of vascular

dementia 201
– vasculitis in 221, 222
– white matter in 210, 210

387

388

Index

Cerebral autosomal recessive arteriopathy (CARASIL) 201

– as inborn error of metabolism 307

– genetics in 11, 196, 196

– imaging of 211
Cerebral blood flow, see Perfusion Cerebral microbleeds (CMBs), in aging
brain 74, 75
Cerebral peduncles 378
– in Behçet disease 220
– in corticobasal degeneration 183
– in multiple-system atrophy 180, 183 Cerebroretinal vasculopathy
(CRV) 196, 196 Cerebrospinal fluid (CSF)

– in aging 26, 70, 71

– in Alzheimer’s disease 93, 114, 116,
122, 124

– in amyotrophic lateral sclerosis 29,
345

– in Behçet disease 218

– in Creutzfeldt-Jakob disease 28, 239,
240

– in HIV infection 226

– in mucopolysaccharidoses 309, 309

– in normal pressure
hydrocephalus 23, 257, 257

–– cine phase-contrast magnetic
resonance quantification of flow
in 259, 260

–– flow void sign in 258, 258

–– shunting 262

– in paraneoplastic cerebellar
degeneration 333

– in paraneoplastic syndrome 276,
279

– in primary angiitis of central nervous
system 216

– in progressive multifocal
leukoencephalopathy 23

– in sarcoidosis 252

– in Sjögren syndrome 219, 249

– in voltage-gated potassium channel
encephalopathy 250

– in voxel-based morphometry 15,
170 Cerebrotendinousxanthomatosis 307 Cerebrovascular disease (CVD) 60, 206,
209
– SeealsoVasculardementia(VaD) Cerebrovascular reactivity (CVR), in
aging brain 75
Charcot, Jean-Martin 3
Charged multivesicular body protein
2B 157
Chemical-shift imaging 25 Chemotherapy, dementia and 271, 273 – Seealsospecificagents
Childhood ataxia with central nervous
system hypomyelination 314, 315 Cholesterolemia
– Alzheimer’s disease and 93
– mild cognitive impairment and 93 Choline (Cho)

– in Alzheimer’s disease 26

– in dementia with Lewy bodies 27

– in frontotemporal dementia 27, 27–
28

– in gluten sensitivity 247

– in HIV infection 31

– in multiple sclerosis 30–31

– in traumatic brain injury 287,
289

– peak,inmagneticresonance spectroscopy 25, 25

Cholinesterase inhibitors
– in Alzheimer’s disease 373
– in dementia with Lewy bodies 156
– in mild cognitive impairment 108 Chronic lymphocyte inflammation with

pontine perivascular enhancement

response to steroids (CLIPPERS) 279 Chronic traumatic encephalopathy

(CTE) 284
Cisplatin 272
Cisternography, in normal pressure

hydrocephalus 260, 261
CJD, see Creutzfeldt-Jakob disease (CJD) Climbing fibers 320
Clinical approach 6, 6, 7–8
CLIPPERS, see Chronic lymphocyte

inflammation with pontine perivascular enhancement response to steroids (CLIPPERS)

CLU gene 120
Clusterin 120
CMB, see Cerebral microbleeds (CMBs) CN, see Caudate nuclei (CN) Cobalamin deficiency 301, 302 Cockayne syndrome 307
Cognitive complaints 6
Cognitive impairment, see Mild

cognitive impairment (MCI)
– in Alzheimer’s disease 114
– in amyotrophic lateral sclerosis 345 – in Behçet disease 251
– in brain tumor therapy 268
– in brain tumors 266
– in chemotherapy 272
– in meningioma 266
– in multiple sclerosis 245, 246–247 – in normal pressure

hydrocephalus 365
– in Parkinson’s disease 38 – in sarcoidosis 252
– in Sjögren syndrome 249 – in systemic lupus

erythematosus 248
– in vascular dementia 364
– radiation-induced 270, 270
– with chemotherapy 272 COL4A1-related brain small vessel

disease 215
Complaints, patient, in presentation of

neurodegenerative disease 6 Complement component receptor

1 120
Computed tomography (CT)
– hemorrhage on 329
– in dementia evaluation 362 – in dementia imaging 14
– in frontotemporal lobar

degeneration 161
– in history of neuroimaging 2, 2 – in hyperparathyroidism 298
– in Kearns-Sayre disease 312
– in Krabbe disease 307
– in normal pressure

hydrocephalus 257
– in Sjögren syndrome 250
– in traumatic brain injury 284 – radiotherapy and, dementia in

combined 272, 274
Computed tomography angiography

(CTA) 60, 60, 61–62
– multidetector row 61

– postprocessing in 61, 61
Computed tomography cisternography,

in normal pressure

hydrocephalus 260, 261 Computed tomography perfusion

(CTP) 63, 64
Concussion 284
– SeealsoTraumaticbraininjury(TBI) Congenital cerebellar

malformations 335–336, 336 Copper accumulation, in Wilson

disease 187
Corpus callosum, thinning, in normal

pressure hydrocephalus 258, 258 Cortical basal syndrome (CBS), patient

complaints in 6
Cortical thickness
– in aging brain 71, 72
– in Alzheimer’s disease 125
– in Parkinson’s disease 171
– in Parkinson’s diseases 169
– in traumatic brain injury 285 Corticobasal degeneration (CBD)
– clinical overlaps with 10
– functional imaging in 184
– magnetic resonance imaging in 183 – Parkinson’s disease vs. 29
– patient complaints in 6
– single photon emission computed

tomography in 184
– structural imaging in 18, 20, 183
– voxel-based morphometry in 184 Corticocerebellar atrophy (CCA) 331 Corticonuclear tract 323, 324 Corticospinal tract (CST)
– in adrenoleukodystrophy 313
– in amyotrophic lateral sclerosis 45–

46, 46, 349, 353–354
– in cerebellar anatomy 323, 324
– in Friedreich ataxia 331, 332
– in hepatic encephalopathy 300
– in hereditary spastic paraplegia 340 – in Krabbe disease 307
– in motor neuron anatomy 341
– in primary lateral sclerosis 341
– in vascular dementia 201, 202
CR1 gene 120
Creatine (Cr)
– in Alzheimer’s disease 26, 104
– in Creutzfeldt-Jakob disease 28
– in dementia with Lewy bodies 27
– in HIV infection 31
– in Huntington disease 29
– in Krabbe disease 308
– in Marchiafava-Bignami disease 302 – in mild cognitive impairment 104
– in multiple sclerosis 31
– in normal aging 26
– in traumatic brain injury 287, 289
– in Wernicke-Korsakoff

syndrome 301
– peak, in magnetic resonance

spectroscopy 25, 25 Creutzfeldt-Jakob disease (CJD), see

Prion diseases
– diagnosis of 239, 239, 240
– diffusion tensor imaging in 44, 45 – diffusion weighted imaging in 28,

44, 45
– genetic 239
– iatrogenic 239
– magnetic resonance imaging in 44,

45, 239, 239, 240, 240, 241–242

– magnetic resonance spectroscopy in 28

– patient complaints in 6
– positron emission tomography

in 243
– single photon emission computed

tomography in 242
– sporadic 239
– structural imaging in 23
– thalamic involvement in 242, 242 – variant 239
Cryptococcosis 236
CSF, see Cerebrospinal fluid (CSF) CST, see Corticospinal tract (CST)
CT, see Computed tomography (CT) CTA, see Computed tomography

angiography (CTA)
CTE, see Chronic traumatic

encephalopathy (CTE)
CTP, see Computed tomography

perfusion (CTP)
Cushing syndrome 297, 297
CVD, see Cerebrovascular disease (CVD) CVR, see Cerebrovascular reactivity

(CVR)
Cyclophosphamide, in primary angiitis

of the central nervous system 216,

218
Cysticercosis 235, 236 Cytosine arabinoside 272

D-Penicillamine, in Wilson disease treatment 371

Dandy, Walter 2
Dandy-Walker malformation 336 Dardarin 11
DATs, see Dopamine transporters

(DATs)
DaTSCAN 166
DDS, see Dialysis disequilibrium

syndrome (DDS)
Deep brain stimulation (DBS)
– anatomy in 378
– complications in 382, 383
– electrode breakage in 382, 383
– history of 378
– in secondary parkinsonism 374
– indications for 379
– infection in 382
– iron mapping and 84
– lead placement confirmation in 382,

383
– magnetic resonance imaging in 380,

383, 384
– nuclei targeting in 379, 381–382
– patient screening for 379, 380
– techniques in 379, 381–382
Deep cerebellar nuclei 318
Default mode network (DMN) 54, 55,

135
Delusions, in Alzheimer’s disease

(AD) 115
Dementia, see specific dementias
– chemotherapy and 271, 273
– cost of, global 5
– defined 2
– diagnostic evaluation in 362, 362 – flowchart for assessment and

investigation of 8
– in history of neurodegenerative

disease 2–3

– in normal pressure hydrocephalus 256

– potentially reversible 364

– prevalence of 362

– preventable 363

– radiotherapy and 268, 270, 270,
271–272

– reversible vs. irreversible 363

– senility vs. 2

– structural imaging of
–– arguments against 14
–– computed tomography in 14
–– in aging 16
–– modalities in 14
–– MRI in 14, 14, 15
–– voxel-based methods in 15, 16
– treatmentof
–– nonreversible 45
–– reversible 371
– vasculitis and 217–220, 222 Dementia lacking distinctive histology
(DLDH) 159
Dementia with Lewy bodies (DLB)

– acetylcholinesterase activity in 39

– Alzheimer’s disease vs. 44, 151–153,
155

– clinical features of 151

– clinical overlaps with 10

– cortical atrophy in 151

– diagnosis of 151

– differential diagnosis of 151

– diffusion tensor imaging in 44, 153

– dopamine system in 38

– dopaminergic imaging in 153

– frontotemporal dementia vs. 154

– genetics of 151

– hippocampus in 152, 155

– history of 150

– Lewy bodies in 151

– magnetic resonance imaging in 152,
152, 153–155

– magnetic resonance spectroscopy
in 26

– management of 154

– metabolism in 154

– neuropathology of 151

– nicotinic acetylcholine receptors
in 39

– Parkinson’s disease and 39, 150, 153

– patient complaints in 6

– perfusion in 154

– positron emission tomography
in 38, 154

– possible 151

– probable 151

– single photon emission computed
tomography in 38, 154

– structural imaging in 18, 152, 152,
153–155

– volume loss in 152, 153–154

– white matter in 153, 155 Dengue fever 188
Dentate nucleus 318, 320, 321, 322,
323

– in Alzheimer’s disease 83

– in Friedreich ataxia 331

– iron deposition in 73, 80, 82, 83 Dentatorubral-pallidoluysian atrophy
(DRPLA) 186–187, 188, 189, 307, 328 Depression
– in aging 364
– in Alzheimer’s disease 373
– in CADASIL 221

– in corticobasal degeneration 18
– in Cushing syndrome 297
– in dementia with Lewy bodies 18,

151
– in Huntington disease 188
– in Lyme disease 233
– in mild cognitive impairment 92
– in paraneoplastic syndrome 276
– in Parkinson’s disease 172–173
– in Sjögren syndrome 219
– in traumatic brain injury 284, 287 – in voltage-gated potassium channel

encephalopathy 250
– in Wilson disease 190
– pseudodementia in 14, 363 Diabetes mellitus 298, 298
– Alzheimer’s disease and 119
– ataxia telangiectasia and 331
– cerebral microbleeds in 75
– MELAS and 215
– mild cognitive impairment and 91 – paraneoplastic syndrome and 279 – secondary parkinsonism and 187 – small-vessel disease and 206, 364 – vascular dementia and 194 Dialysis dementia 299, 300
Dialysis disequilibrium syndrome

(DDS) 299
Diffuse late atrophy, radiation-

induced 270
Diffusion tensor imaging (DTI), see

Fractional anisotropy (FA), Mean

diffusivity (MD)
– basic concepts in 42, 96–97
– diffusion weighted imaging vs. 42 – in aging brain 42, 168
– in Alzheimer’s disease 42, 43
– in amyotrophic lateral sclerosis 45,

46, 353–354
– in Creutzfeldt-Jakob disease 44, 45 – in dementia with Lewy bodies 44,

153
– in frontotemporal dementia 44 – in frontotemporal lobar

degeneration 160
– in HIV infection 228
– in Huntington disease 45
– in mild cognitive impairment 104,

105–106
– in motor neuron disease 45, 46–47,

352, 353–354
– in multiple sclerosis 46, 47–48, 246 – in multiple-system atrophy 180
– in Parkinson’s disease 44, 167
– in Parkinson’s diseases 168
– in progressive supranuclear palsy 44 – in traumatic brain injury 285, 286–

287
– of brainstem 322, 323
– of cerebellum 322, 323–324
– white matter in 42
Diffusion weighted imaging (DWI)
– diffusion tensor imaging vs. 42
– in cerebellar infarct 328, 329
– in Creutzfeldt-Jakob disease 28, 44, 45 – in HIV infection 227, 227
– in hyperglycemia 298, 299
– in limbic encephalitis 277
– in multiple-system atrophy 180
– in normal pressure

hydrocephalus 260
– in progressive supranuclear

palsy 183

Digital subtraction angiography (DSA), in primary angiitis of central nervous system 216, 217–219

Disseminated necrotizing leukoencephalopathy 273

DJ1 gene 11
DLB, see Dementia with Lewy bodies

(DLB)
DMN, see Default mode network

(DMN)
Donepezil hydrochloride, for mild

cognitive impairment 108 Dopamine agonists 374
Dopamine system
– in Alzheimer’s disease 35
– in dementia with Lewy bodies 38,

151
– in Parkinson’s disease 38 Dopamine transporters (DATs), in

Parkinson’s disease 166 Dopaminergic system
– in Alzheimer’s disease 36
– in dementia with Lewy bodies 153 – in Parkinson’s disease 38, 169
– in secondary parkinsonism 186 Dorsal fibers 322
Dorsal spinocerebellar tracts 321 DRPLA, see Dentatorubral-

pallidoluysian atrophy (DRPLA) Drug-induced ataxia 328 Drug-induced cerebellitis 329, 330 Drug-induced dementia 304 Drug-induced parkinsonism 169

– SeealsoParkinsonism,Secondary parkinsonism

DSA, see Digital subtraction angiography (DSA)

DSC, see Dynamic susceptibility contrast (DSC)

DWI, see Diffusion weighted imaging (DWI)

Dynamic susceptibility contrast (DSC) – in Alzheimer’s disease 133
– in normal cerebral blood flow 65
– in normal pressure

hydrocephalus 260 – mechanism of 63

Echo planar imaging (EPI), in fMRI 52,

Electroencephalography (EEG)
– in Creutzfeldt-Jakob disease 44
– in paraneoplastic syndrome 276
– in prion disease 239
– in prion disease transmission 239 Emboliform nucleus 318 Embryology, of cerebellum 318 Encephalitis lethargica 188 Endocrine-related dementia
– Cushing syndrome in 297, 297
– Hashimoto encephalopathy in 296 – hyperglycemia in 298, 298
– parathyroidism in 298, 298
– thyroid hormones in 296, 297
– type 2 diabetes in 298, 298 Entacapone 374
Ephrin receptor EphA1 120
EPI, see Echo planar imaging (EPI) Epidemiology, of neurodegenerative

diseases 5, 5
Episodic ataxia type 2 (EA2) 328, 331

Essential tremor (ET)
– deep brain stimulation for 379 – Parkinson’s disease vs. 39, 166 ET, see Essential tremor (ET) Executive skills complaints 6 External lumbar drainage (ELD), in

normal pressure hydrocephalus 262

FA, see Fractional anisotropy (FA) Fabry disease 210, 307, 308, 309 Familial British dementia (FBD) 196,

196

Fastigial nucleus 318
Fat suppression 24
Fatal familial insomnia (FFI) 239 FBD, see Familial British dementia

(FBD)
FCSRT, see Free and Cued Selective

Reminding Test (FCSRT)
Fenton reaction 80
FFI, see Fatal familial insomnia (FFI) Fiber type grouping 342, 342 Fluorine 18 (18F)-labeled glucose 34 Fluoroethyl methyl amino-2 naphthyl

ethylidene malononitrile (18F-

DDNP) 129
fMRI, see Magnetic resonance imaging

(MRI)
FOG, see Freezing of gait (FOG)
Folia 7, 318
Fractional anisotropy (FA) 42
– See also Diffusion tensor imaging (DTI) – defined 42
– equation for 42
– in aging 168
– in Alzheimer’s disease 43
– in amyotrophic lateral sclerosis 352,

353

– in cerebellum 322
– in dementia with Lewy bodies 153 – in glioblastoma multiforme 267
– in motor neuron disease 352
– in multiple sclerosis 246
– in Parkinson’s disease 167
– in Parkinson’s diseases 168–169
– in traumatic brain injury 287 Fragile X-associated tremor/ataxia

syndrome (FXTAS) 307, 313, 328, 333 Free and Cued Selective Reminding Test

(FCSRT) 114
Freezing of gait (FOG), in Parkinson’s

disease 171
Friedreich’s ataxia 328, 331, 332 Frontal variant Alzheimer’s

disease 115 Frontotemporal brain sagging

syndrome 159, 162 Frontotemporal dementia (FTD)
– amyotrophic lateral sclerosis vs. 7 – behavioral variant 157–159
– dementia with Lewy bodies vs. 154 – diffusion tensor imaging in 44
– familial 158
– genetics in 11
– magnetic resonance spectroscopy

in 27, 27, 28
– motor neuron disease and 27 – patient complaints in 6
– positron emission tomography

in 37, 37
– serotonin system in 37

Index

389

390

Index

– structural imaging in 17, 19
– syndromes 157, 158
– variants of 27
Frontotemporal lobar degeneration

(FTLD)

– age at onset 157

– amygdala in 159

– amyloid imaging in 98

– amyotrophic lateral sclerosis
and 157

– clinical features of 157, 158

– clinical overlaps with 10

– computed tomography in 161

– dementia lacking distinctive
histology in 159

– diagnosis of 157

– diffusion tensor imaging in 160

– exclusion criteria for 157

– functional magnetic resonance
imaging in 160

– genetics in 157

– hippocampus in 159

– inclusion criteria for 157

– magnetic resonance imaging in 160,
162

– neuropathology of 158

– Pick disease in 158, 159

– positron emission tomography
in 37, 161, 163

– prevalence of 157

– single photon emission computed
tomography in 161

– structural imaging of 159, 160–162

– subtypes of 158

– tau 158, 159

– volume loss in 159, 160

– with ubiquitin and transactive-
response-43 positive inclusions 159 FTD, see Frontotemporal dementia
(FTD)
FTLD, see Frontotemporal lobar
degeneration (FTLD) Fucosidosis 307
Functional magnetic resonance
imaging (fMRI)

– activation in 52, 53

– advantages of 56

– blocked paradigm designs in 52, 53

– blood-oxygen-level-dependent
contrast in 51, 51

– default mode network in 54, 55, 135

– disadvantages of 56

– echo planar imaging in 52, 52

– future of 56

– in aging brain 77, 77

– in Alzheimer’s disease 54, 134, 135

– in amyotrophic lateral sclerosis 355,
357

– in frontotemporal lobar degeneration 160

– in mild cognitive impairment 54, 105, 106–107

– in motor neuron disease 355, 357

– in multiple sclerosis 54, 56

– in neurodegenerative disorders 54,
56, 56

– in parathyroidism 298

– in Parkinson’s disease 171, 174

– in Parkinson’s diseases 175–176

– in traumatic brain injury 288, 289

– networks in 53, 55

– pharmacological 55, 57

– physics of 51

– physiology of 51
– positron emission tomography in 56 – postprocessing in 52
– resting-state 51, 53, 55
Fungal infections 236
FUS gene 157

GABA, see Gamma-aminobutyric (GABA) system

Gait impairment
– in normal pressure

hydrocephalus 256, 365
– in Parkinson’s disease 171 Galactosemia 307 Galanthamine, for mild cognitive

impairment 108 Gamma-aminobutyric (GABA) system – in alcoholic cerebellar

degeneration 333
– in Alzheimer’s disease 36–37 Gangliosidosis 307
GB3, see Globotriaosylceramide (GB3) GBM, see Glioblastoma multiforme

(GBM)
Gene therapy
– for Huntington disease 376 – in Alzheimer’s disease 374 – in Parkinson’s disease 375 Genetic testing, in history of

neurodegenerative disease 4 Genetics

– in adrenomyeloneuropathy 313 – in Alzheimer’s disease 9, 11, 113,

119, 120
– in amyotrophic lateral sclerosis 345 – in dementia with Lewy bodies 151 – in dentatorubral-pallidoluysian

atrophy 189
– in fragile X-associated tremor/ataxia

syndrome 313, 333
– in Friedreich ataxia 331 – in frontotemporal lobar

degeneration 157
– in hereditary spastic paraplegia 341 – in Huntington disease 9, 11, 187
– in Kennedy disease 343
– in myoclonic epilepsy with ragged

red fibers 312
– in prion diseases 11, 240
– in spinal muscular atrophy 343 – in vanishing white matter

disease 314
– in vascular dementia 196, 196
– of neurodegenerative disease 9
– of spinocerebellar ataxia 330 Genome-wide association studies, of

Alzheimer’s disease 119 Gerstmann-Straussler-Scheinker

disease (GSS) 239, 242
Giant cell arteritis 221
Glioblastoma multiforme (GBM) 266,

267
Glioma, low-grade 266, 267 Global cerebral and cerebellar

atrophy 330
Globoid cell leukodystrophy 306, 308 Globose nucleus 318 Globotriaosylceramide (GB3) 210 Globus pallidi (GP) 378, 378
Globus pallidus interna (GPi) 378–379,

380, 382

Glucose metabolism, see Metabolism Glutamate excitotoxicity, with

alcohol 301
Glutamine and glutamate (Glx)
– in amyotrophic lateral sclerosis 29 – in dementia with Lewy bodies 27 – in Huntington disease 29
– in traumatic brain injury 287, 289 – peak, in magnetic resonance

spectroscopy 25, 26 Glutaricaciduria type 1 307
Gluten sensitivity 245, 247, 248, 328,

334

Glx, see Glutamine and glutamate (Glx) Golgi cells 320
GP, see Globus pallidi (GP)
Granule cell

– chemotherapy and 272
– in ataxia telangiectasia 331
– in cerebellar histology 319
– in hypoglycemia 298
Gray matter
– in aging brain 70, 71–72
– in Alzheimer’s disease 100, 139, 140 – in mild cognitive impairment 100
– normal-appearing, in multiple

sclerosis 30
GRN gene 157
GSS, see Gerstmann-Straussler-

Scheinker disease (GSS)

HA-HP, see Hemiatrophy- hemiparkinsonism (HA-HP) syndrome

Haber-Weiss reaction 80 Hallervorden-Spatz syndrome 186 Hallucinations
– in Alzheimer’s disease (AD) 115
– in dementia with Lewy bodies 151 – in Parkinson’s disease 174

– in Parkinson’s diseases 175 Haloperidol 55, 376
HAND, see HIV-associated

neurocognitive disorders (HAND) Hashimoto encephalopathy (HE) 245,

296

HD, see Huntington disease (HD) HDLS, see Hereditary diffuse

leukoencephalopathy with

neuroaxonal spheroids (HDLS) HE, see Hashimoto encephalopathy

(HE)
Heavy metal poisoning 302, 367 Hemiatrophy-hemiparkinsonism (HA-

HP) syndrome 186 Hemiparkinsonism with

hemiparesis 186
Hemorrhage
– cerebellar 329
– intracranial 364, 365, 382, 383 Hemosiderin 15, 74, 127, 139, 201,

202, 334, 334
Hepatic disease 366
Hepatic encephalopathy (HepE) 300,

300

Hereditary cerebral amyloid angiopathy 196, 196

Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) 196, 197, 197

Hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS) 196, 196, 201

Hereditary spastic paraplegia (HSP) 340, 349

Hereditary vascular retinopathy (HVR) 196, 196

HERNS, see Hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS)

Herpes simplex encephalitis (HSE) 232, 232

Hexamethylpropylene amine oxime (HMPAO) 34

HIF1α, see Hypoxia-inducible factor 1α (HIF1α)

Hirayama disease 343, 349, 350 History, of neurodegenerative

diseases 2, 2, 3–4
HIV, see Human immunodeficiency

virus (HIV) HIVencephalitis(HIVE) 226–227 HIV-associated neurocognitive

disorders (HAND) 367
– as term 226
– incidence of 226
– symptoms of 226
– treatment of 228 HIV-associated neurocognitive

impairments (HNCIs) 31 HMPAO, see Hexamethylpropylene

amine oxime (HMPAO) HNCIs, see HIV-associated

neurocognitive impairments (HNCIs) Hockey-stick sign 242, 242
Hodgkin lymphoma 276, 277, 279, 280,

281, 333
Homocystinuria 213, 214, 364 Hounsfield, Godfrey 2
HSE, see Herpes simplex encephalitis

(HSE)
HSP, see Hereditary spastic paraplegia

(HSP)
HTRA serine protease 11
HTRA1 gene 11
HTT gene 11
Human immunodeficiency virus (HIV),

see entries at HIV
– history of 226
– infection
–– cerebrospinal fluid in 226
–– congenital, CNS infection in 228,

229

–– in brain 227
–– magnetic resonance spectroscopy

in 31, 31, 228, 228
–– opportunistic CNS infections

in 228, 228–229
– overviewof 226
– structural imaging in 22 Huntington disease (HD) 4
– cerebral cortex in 187
– course of 188
– diagnosis of 188
– gene therapy for 376
– genetics in 9, 11, 187
– in diffusion tensor imaging 45 – in history of neurodegenerative

disease 4
– in magnetic resonance

spectroscopy 28
– in secondary parkinsonism 187, 188 – magnetic resonance imaging in 188

– – – –

– – –

– –

–

amino acid disorders as 314, 314 classification of 307
Fabry disease as 308, 309
globoid cell leukodystrophy as 306, 308

Kearns-Sayre syndrome as 311 Leigh disease as 311, 311 lysosomal storage disease as 306, 307–311

MELAS as 312, 312
metachromatic leukodystrophy
as 306, 307–308
mitochondrial dysfunction as 310, 311–312
mucopolysaccharidoses as 309, 309, 310
myoclonic epilepsy with ragged red fibers as 312
neuronal ceroid-lipofuscinosis
as 310, 311
peroxisomal disorders as 313, 313, 314–315
vanishing white matter disease
as 314, 315

Incontinence, urinary
– in adrenomyeloneuropathy 313 – in normal pressure

hydrocephalus 256 Incontinentiapigmenti 307
Infarct(s), see Vascular dementia (VaD) – cerebellar 328, 329
– in antiphospholipid syndrome 214 – in Behçet disease 251
– in CADASIL 210, 210
– in CARASIL 211
– in COL4A1 small-vessel disease 215 – in dementia with Lewy bodies 93
– in Fabry disease 309
– in HIV vasculopathy 228
– in MELAS 214, 312
– in multi-infarct dementia 194, 201,

201, 202
– in sickle cell disease 213, 213
– in Sjögren syndrome 249
– in strategic-infarct dementia 194,

204, 204, 205
– in systemic lupus

erythematosus 249
– in tuberculosis 234
– lacunar 217, 364, 379
– watershed 202, 203–204
Infectious dementia, see HIV-associated

neurocognitive disorders (HAND)
– bacterial infections in 233, 234–235 – bacterial meningitis in 233
– cryptococcosis in 236
– cysticercosis in 235, 236
– fungal 236
– herpes simplex encephalitis in 232,

232
– herpes virus in 232, 232 – Lyme disease in 233
– parasitic 235, 236
– syphilis in 233, 234
– tuberculosis in 234, 235 – viral 232, 232, 233

Index

– patient complaints in 6
– structural imaging in 19, 20
– treatment of 375
– white matter in 45
Huntington protein 11 Hydroxyglutaricaciduria 307 Hyperhomocysteinemias 301, 307, 314 Hyperparathyroidism 298, 298 Hypoglycemia 298, 298
– SeealsoDiabetesmellitus Hypokinesis complaints 6 Hypomelanosis of Ito 307 Hypomyelination with atrophy basal

ganglia/cerebellum 307 Hypoperfusion encephalopathy 205,

205

Hyposmia, in Parkinson’s disease 172 Hypothyroidism 296, 296–297, 371 Hypoxia-inducible factor 1α

(HIF1α) 269, 269

Iatrogenic Creutzfeldt-Jakob disease (iCJD) 239

– SeealsoCreutzfeldt-Jakobdisease (CJD)

iCJD, see Iatrogenic Creutzfeldt-Jakob disease (iCJD)

ICP, see Inferior cerebellar peduncle (ICP)

Idiopathic Parkinson’s disease (IPD) 20 – SeealsoParkinson’sdisease(PD) Ifosfamide 272
Illicit drugs 304

Imaging, see specific modalities – in clinical approach 6–7, 8
– structural

–– in Alzheimer’s disease 17, 17, 18,
116

–– in corticobasal degeneration 18, 20

–– in Creutzfeldt-Jakob disease 23

–– in dementia with Lewy bodies 18

–– in frontotemporal dementia 17, 19

–– in history of neurodegenerative
disease 2, 2

–– in HIV dementia 22

–– in Huntington disease 19, 20

–– in idiopathic Parkinson’s disease 20

–– in mild cognitive impairment 16,
21

–– in multiple-system atrophy 21

–– in normal pressure
hydrocephalus 23

–– in Parkinsonian disorders 20, 21–22

–– in progressive multifocal
leukoencephalopathy 22

–– in progressive supranuclear
palsy 21

–– in reversible dementia 22

–– of dementia
––– arguments against 14
––– computed tomography in 14 ––– modalities in 14
––– MRI in 14, 14, 15
Immune reconstitution inflammatory
syndrome (IRIS) 228 Immune-mediated dementia

– anti-voltage-gated potassium
channel encephalopathy in 250

– antibodies in 245, 245

– Behçet disease in 250

– categories of 245, 245

– celiac disease in 247
– multiple sclerosis in 245
– sarcoidosis in 251
– Sjögren encephalopathy in 249 – systemic lupus erythematosus

in 248
Inborn errors of metabolism

Inferior cerebellar peduncle (ICP) 323 Inferior cerebellar veins 319
Inferior vermian vein 320 Intercellular adhesion molecule-1

(ICAM-1) 269, 269
Internal capsule 378
Intracranial hemorrhage 364, 365, 382,

383

Intracranial hypotension 159 IRIS, see Immune reconstitution

inflammatory syndrome (IRIS) Iron accumulation
– abnormal 80
– amyloid plaques and 143
– assessment of, with quantitative

magnetic resonance imaging 80, 81–

82
– in aging brain 73, 73, 80, 80, 81
– in Alzheimer’s disease 80, 83, 84, 139 –– animal models of 83
– in motor neuron diseases 85, 85
– in multiple-system atrophy 84
– in Parkinson’s disease 84
– in Parkinson’s diseases 85
– in progressive supranuclear palsy 84 – in secondary parkinsonism 186
– in substantia negra 85, 85
Ischemic encephalopathy 205, 205

Japanese B encephalitis 188, 233 JC virus 233
Joubert malformation 335
Juvenile spinal muscular atrophy of

distal upper extremity 343 K

KD, see Krabbe disease (KD) Kearns-Sayre syndrome 307, 311 Kennedy disease 343
Korsakoff psychosis (KP) 300 Korsakoff syndrome (KS) 300

– SeealsoWernicke-Korsakoff syndrome

KP, see Korsakoff psychosis (KP) Krabbe disease (KD) 306, 307–308 KS, see Korsakoff syndrome (KS) Kugelberg Welander disease 343 Kuru 239

– SeealsoCreutzfeldt-Jakobdisease (CJD), Prion diseases

L-asparaginase 272
Lactate peak
– in alcoholic-related dementia 301 – in episodic ataxia type 2 331
– in HIV infection 31
– in Leigh disease 311
– in magnetic resonance

spectroscopy 25, 25, 26 – in mitochondrial

encephalomyopathy 215
– in multiple sclerosis 30 Lacunar infarct 189, 217, 364, 379 – See also Infarct(s)
Language complaints 6
– See also Aphasia
Larmor frequency 24
LE, see Limbic encephalitis (LE)

Lead poisoning 302, 367
Leigh disease 307, 311, 311
Levodopa
– in dementia with Lewy bodies 151, 154 – in history of neurodegenerative

disease 4
– in Huntington disease 376
– in multiple-system atrophy 374
– in Parkinson’s disease 374
– in vascular parkinsonism 191
– subcutaneous pump 375
– withdrawal 374, 375
Lewy bodies (LBs)
– classical brainstem 150
– cortical 150, 150
– defined 150
– in Alzheimer’s disease 121, 122, 151 – in dementia with Lewy bodies 27,

151
– in diagnosis of dementia with Lewy

bodies 151
– in mild cognitive impairment 93 – in Parkinson’s disease 20, 166
– in Parkinson’s diseases 7
– in secondary parkinsonism 186 – types of 150, 150
Lewy body dementia, see Dementia

with Lewy bodies (DLB)
Limbic encephalitis (LE) 250, 277, 278,

368, 368
Lipid peak, see Magnetic resonance

spectroscopy (MRS)
– in HIV infection 31
– in magnetic resonance

spectroscopy 25
– in Marchiafava-Bignami disease 302 – in multiple sclerosis 30
Lisuride 374
Lithium toxicity 328
Liver failure 366
Logopenic aphasia (LPA)
– as Alzheimer’s disease variant 115 – patient complaints in 6
Lomustine 272
Low-grade glioma 266, 267
LPA, see Logopenic aphasia (LPA) LRRK2 gene 11
Lung cancer 277, 279–280
Lyme disease 233, 367
Lymphoma 268, 276, 277, 279, 280,

333
Lysosomal storage disorders 306, 307–

311
– See also Inborn errors of metabolism

Maeda syndrome, see Cerebral autosomal recessive arteriopathy (CARASIL)

Magnetic resonance angiography (MRA)

– contrast-enhanced 61, 63
– phase contrast 62
– time of flight 61, 62
Magnetic resonance imaging (MRI), see

Imaging
– amyloid plaques on 143
– fragile X-associated tremor/ataxia

syndrome in 314
– functional
–– activation in 52, 53 –– advantages of 56

391

392

Index

blocked paradigm designs in 52, 53 blood-oxygen-level-dependent contrast in 51, 51
default mode network in 54, 55, 135

disadvantages of 56
echo planar imaging in 52, 52 future of 56
in aging brain 77, 77
in Alzheimer’s disease 54, 134, 135 in amyotrophic lateral
sclerosis 355, 357
in frontotemporal lobar degeneration 160
in mild cognitive impairment 54, 105, 106–107
in motor neuron disease 355, 357 in multiple sclerosis 54, 56
in neurodegenerative disorders 54, 56, 56
in parathyroidism 298
in Parkinson’s disease 171, 174
in Parkinson’s diseases 175–176
in traumatic brain injury 288, 289 networks in 53, 55 pharmacological 55, 57
physics of 51
physiology of 51
positron emission tomography
in 56
postprocessing in 52
resting-state 51, 53, 55

– in hepatic encephalopathy 300, 300 – in herpes simplex encephalitis 232 – in history of neuroimaging 2
– in Huntington disease 188

– in Kearns-Sayre syndrome 312
– in Krabbe disease 308, 308
– in Leigh disease 311, 311
– in limbic encephalitis 277, 278
– in maple syrup urine disease 314
– in Marchiafava-Bignami disease 302 – in MELAS 312, 312

– in meningioma 267 – in metachromatic

leukodystrophy 306, 308
– in mild cognitive impairment 99
–– volumetry 99, 99, 100–102
– in motor neuron disease 349, 350
– in mucopolysaccharidoses 309, 309 – in multiple sclerosis 246, 246–247 – in multiple-system atrophy 21, 168,

180, 180, 335, 335 – in neuronal ceroid-

lipofuscinosis 310, 311 – in neurosyphilis 234
– in normal pressure

hydrocephalus 257–258
– in paraneoplastic cerebellar

degeneration 333, 334
– in paraneoplastic syndrome 277,

278, 279
– in Parkinson’s disease 167 – in progressive supranuclear

palsy 22, 22, 182, 183
– in sarcoidosis 252, 252–253
– in siderosis of central nervous

system 334, 334
– in striatal encephalitis 279 – in subacute sclerosing

panencephalitis 233 – in systemic lupus

erythematosus 248–249
– in traumatic brain injury 284
– in uremic encephalopathy 299, 299 – in vascular dementia 195–196, 201–

202
– in vascular parkinsonism 169, 191 – in voltage-gated potassium channel

encephalopathy in 250, 250 – in Wilson disease 190
– iron imaging with 80, 81–82 – microscopic, in Alzheimer’s

disease 139, 139, 140–148
– perfusion-weighted 63, 65
–– in Alzheimer’s disease 133, 134 Magnetic resonance spectroscopy

(MRS)
– chemical shift in 24
– data acquisition in 24
– fat suppression in 24
– future perspectives in 32
– in aging 26
– in Alzheimer’s disease 26, 137
– in amyotrophic lateral sclerosis 29,

30, 351, 352
– in ataxia telangiectasia 332
– in Creutzfeldt-Jakob disease 28
– in Cushing syndrome 298
– in dementia with Lewy bodies 26 – in dialysis dementia 299
– in episodic ataxia type 2 331
– in Friedreich ataxia 331
– in frontotemporal dementia 27, 27,

– in gluten ataxia 334
– in gluten sensitivity 247
– in Hashimoto encephalopathy 297 – in hepatic encephalopathy 300
– in HIV infection 31, 31, 228, 228
– in Huntington disease 28
– in Krabbe disease 308
– in Leigh disease 311
– in Marchiafava-Bignami disease 302 – in MELAS 215
– in metachromatic

leukodystrophy 306
– in mild cognitive impairment 104,

104
– in motor neuron disease 351, 352 – in multiple sclerosis 30, 30, 246
– in multiple-system atrophy 335
– in Parkinson’s disease 29
– in primary lateral sclerosis 351
– in radiation-induced dementia 271 – in spinocerebellar ataxia 330
– in thiamine deficiency 301
– in traumatic brain injury 287, 289 – in vanishing white matter

disease 315
– metabolite peaks in 25, 25
– nuclear magnetism in 24
– of cerebellum 324, 325
– shimming in 24
– short versus long echo time in 25 – single-voxel spectroscopy versus

chemical-shift imaging in 25
– techniques 25
– water suppression in 24 Magnetization transfer ratio (MTR)
– amyloid plaques and 144, 148
– in Alzheimer’s disease 144, 148
– in amyotrophic lateral sclerosis 354 – in hepatic encephalopathy 300
– in motor neuron disease 354 Malaria 235
Manganese toxicity 187, 303, 367 Maple syrup urine disease 307, 314,

314
MAPT gene 11 Marchiafava-Bignami disease

(MBD) 302, 367
MBD, see Marchiafava-Bignami disease

(MBD)
MCI, see Mild cognitive impairment

(MCI)
MCP sign 314
MD, see Mean diffusivity (MD), Mixed

dementia (MD)
Mean diffusivity (MD), see Diffusion

tensor imaging (DTI)
– defined 42
– equation for 42
– in Alzheimer’s disease 43
– in amyotrophic lateral sclerosis 353 – in dementia with Lewy bodies 153 – in motor neuron disease 352
– in multiple sclerosis 246
Medial fibers 322
Medial lemniscus (ML) 323, 324 Medial transverse fibers 322 Medication effects 367
Medication toxicity 304 Megalencephalic leukoencephalopathy

with calcifications and cysts 307 MELAS, see Mitochondrial myopathy,

encephalopathy, lactic acidosis, and strokelike episodes (MELAS)

Memantine 156 Membrane-spanning 4-domains

subfamily A 120
Memory, see Amnesia
– in Alzheimer’s disease 114
– in mild cognitive impairment 100,

101

– in normal pressure hydrocephalus 256

Meningioma 266, 267, 365, 366 Meningitis
– bacterial 233
– chronic 367

– tubercular 234, 235
Menkes disease 307
Mercury poisoning 303
MERRF, see Myoclonic epilepsy with

ragged red fibers (MERRF) Metabolic-related dementia
– as potentially-reversible 366
– dialysis dementia in 299, 300
– dialysis disequilibrium syndrome

in 299
– hepatic encephalopathy in 300, 300 – uremic encephalopathy in 299, 299 Metabolism, see Inborn errors of

metabolism, Positron emission

tomography (PET)
– in aging brain 75, 76
– in Alzheimer’s disease 128, 129, 134 – in dementia with Lewy bodies 154 – in mild cognitive impairment 95, 98 – in multiple-system atrophy 181
– in traumatic brain injury 290 Metachromatic leukodystrophy

(MLD) 306, 307–308, 328 Metastatic disease 267
Methanol poisoning 367 Methotrexate (MTX) 268, 270, 272,

273

Microscopic magnetic resonance imaging (μMRI), see Magnetic resonance imaging (MRI), microscopic

Microtubule inhibitors 272 Microtubule-associated protein tau 11 MID, see Multi-infarct dementia (MID) Middle cerebellar peduncles

(MCP) 314, 322, 324
Mild cognitive impairment (MCI)
– Alzheimer’s disease and 93, 93, 93,

115–116
– Alzheimer’s disease vs. 100
– amnesic 100, 101
– amyloid imaging in 95, 98–99
– analytical epidemiology of 91, 91 – Apo E4 and 93
– arterial spin labeling in 102, 103 – as intermediate state between

normal cognition and dementia 90
– biomarkers in 93
– cholesterolemia and 93
– clinical features of 92, 92
– clinical trials for 108
– descriptive epidemiology of 91
– diagnostic algorithm for 94, 94
– diagnostic concept and evolution 90,

– diagnostic guidelines for 93
– differential diagnosis of 92
– diffusion tensor imaging in 104,

105–106
– epidemiology of 90, 91

–– ––

––

–– –– –– –– –– ––

–– ––

–– –– ––

–– –– –– –– –– –– –– –– ––

injury 284

– in adrenomyeloneuropathy 313, 313

– in alcoholic cerebellar
degeneration 333

– in Alzheimer’s disease 124, 124, 126,
133

– in aminoaciduria 314, 314

– in amyotrophic lateral sclerosis 349,
350

– in anti-NMDAR encephalitis 279

– in Arnold-Chiari malformation 336,
336

– in ataxia telangiectasia 331

– in Behçet disease 251, 251

– in CADASIL 210

– in cerebellitis 329, 329
–– toxic 329, 330

– in cerebral amyloid angiopathy 211,
211–212

– in corticobasal degeneration 183

– in Creutzfeldt-Jakob disease 44, 45,
239, 239, 240, 240, 241–242

– in deep brain stimulation 380, 383,
384

– in dementia evaluation 362

– in dementia structural imaging 14,
14, 15

– in dementia with Lewy bodies 152,
152, 153–155

– in dentatorubral-pallidoluysian
atrophy 189

– in Fabry disease 309, 309

– in fragile X tremor ataxia
syndrome 333

– in Friedreich ataxia 331, 332

– in frontotemporal lobar
degeneration 160, 162

– in glioblastoma multiforme 267

– in gluten sensitivity 247

– in Hashimoto encephalopathy 297

––
––
– high-resolution, in traumatic brain

– follow-up for 108

– functional magnetic resonance
imaging in 54, 105, 106–107

– gray matter in 100

– image analysis in 107

– in Parkinson’s disease 173

– in single photon emission computed
tomography 95, 95, 96–97

– interventional epidemiology of 92

– Lewy bodies in 93

– magnetic resonance imaging in 99 –– volumetry 99, 99, 100–102

– magnetic resonance spectroscopy
in 104, 104

– medication for 108

– metabolism in 95, 98

– neuropathology of 92–93, 93, 94

– outline of 90

– perfusion in 95, 95, 96–97, 102, 103

– positron emission tomography
in 95, 98

– prevention of 108

– radiation-induced 270, 270

– risk factors for 93

– structural imaging in 16

– subtypes of 92

– symptoms of 92

– underlying diseases with 92, 92 Mild traumatic brain injury (mTBI)
284
– SeealsoTraumaticbraininjury(TBI) Mini-Mental State Examination
(MMSE) 115, 266
Mitochondrial dysfunction 310, 311–
312
Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) 214, 215, 307, 312, 312
Mixed dementia (MD) 208, 208 ML, see Medial lemniscus (ML) MLD, see Metachromatic
leukodystrophy (MLD)
MND, see Motor neuron disease (MND) Molar tooth-type malformation 335,
336
Molecular layers, in cerebellar
histology 319
Monomelic amyotrophy 343 Mood disorders, in Parkinson’s
disease 173
– SeealsoDepression
Motor complaints 6
Motor neuron anatomy 341 Motor neuron disease (MND), see
Amyotrophic lateral sclerosis (ALS),
Multiple sclerosis (MS)

– clinical overlaps with 10

– diffusion tensor imaging in 45, 46–
47, 352, 353–354

– frontotemporal dementia and 27

– functional magnetic resonance
imaging in 355, 357

– genetics in 11

– iron mapping in 85, 85

– lower

–– Hirayama disease in 343

–– Kennedy disease in 343

–– spinal muscular atrophy in 342,
343

–– upper vs. 340
– magnetic resonance imaging in 349,
350

– magnetic resonance spectroscopy in 351, 352

– magnetization transfer ratio in 354 – positron emission tomography

in 354, 355–356 – upper

–– hereditary spastic paraplegia in 340

–– lower vs. 340
–– primary lateral sclerosis in 340, 341 – voxel-based morphometry in 349,

351

Moyamoya, in sickle cell disease 213,

213–214
MPS, see Mucopolysaccharidoses (MPS) MRA, see Magnetic resonance

angiography (MRA)
MRI, see Magnetic resonance imaging

(MRI)
MRI parkinsonism index (MRPI) 22 MRS, see Magnetic resonance

spectroscopy (MRS)
MS4A4E gene 120
MS4A6A gene 120
MSA, see Multiple-system atrophy

(MSA)
mTBI, see Mild traumatic brain injury

(mTBI)
MTR, see Magnetization transfer ratio

(MTR)
MTX, see Methotrexate (MTX) Mucopolysaccharidoses (MPS) 307,

309, 309, 310
Multi-infarct dementia (MID) 194, 201,

201, 202
Multiple sclerosis (MS)
– as immune-mediated 245
– cognitive dysfunction in 245, 246–

247
– diffusion tensor imaging in 46, 47–

48, 246
– functional magnetic resonance

imaging in 54, 56
– magnetic resonance imaging in 246,

246–247
– magnetic resonance spectroscopy

in 30, 30, 246
– normal-appearing gray matter in 30 – normal-appearing white matter

in 30
– positron emission tomography

in 246
– single photon emission computed

tomography in 246
– Sjögren syndrome vs. 249
– spinal cord involvement in 47
– subtypes of 245
– white matter in 47, 47–48
– whole-brain atrophy in 246, 247
– “black holes” in 30
Multiple sulfatase deficiency 307 Multiple-system atrophy (MSA) 335 – acetylcholinesterase activity in 182 – argyrophilic fibrillary inclusions

in 180
– C-type 21, 335
– clinical overlaps with 10
– dementia with Lewy bodies and

150
– diffusion tensor imaging in 180
– diffusion weighted imaging in 180 – functional imaging in 181, 181
– iron accumulation in 84

– magnetic resonance imaging in 21, 168, 180, 180

– metabolism in 181
– microglia in 182
– olivo-ponto-cerebellar network

in 180
– P-type 335
– Parkinson’s disease vs. 29, 168, 180,

182
– patient complaints in 6
– positron emission tomography

in 181, 181
– progressive supranuclear palsy

vs. 183
– structural imaging in 21, 21, 180,

180

– transcranial ultrasound in 181
– voxel-based morphometry in 180 Multitensor tractography, in traumatic

brain injury 286, 286
Myo-inositol (mI)
– in Alzheimer’s disease 26, 104
– in dialysis dementia 299
– in frontotemporal dementia 27, 27–

– in magnetic resonance spectroscopy 25, 26

– in mild cognitive impairment 104, 104

Myoclonic epilepsy with ragged red fibers (MERRF) 307, 312

N-acetyl aspartate (NAA)
– in Alzheimer’s disease 26, 137
– in amyotrophic lateral sclerosis 29,

351
– in Creutzfeldt-Jakob disease 28
– in dementia with Lewy bodies 27
– in frontotemporal dementia 27, 27–

– in gluten sensitivity 247 – in HIV infection 31, 31
– in Krabbe disease 308
– in magnetic resonance

spectroscopy 25, 25
– in Marchiafava-Bignami disease 302 – in metachromatic

leukodystrophy 306
– in mild cognitive impairment 104,

104

– in motor neuron disease 351 – in multiple sclerosis 30–31 – in normal aging 26
– in Parkinson’s disease 29

– in traumatic brain injury 287, 289 – in Wernicke-Korsakoff

syndrome 301
NAA, see N-acetyl aspartate (NAA) NAGM, see Normal-appearing gray

matter (NAGM)
National Institute of Neurological

Disorders and Stroke-Association Internationale and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS– AIREN) 199–200

NAWM, see Normal-appearing white matter (NAWM)

NBIA, see Neurodegeneration with brain iron accumulation (NBIA) NCC, see Neurocysticercosis (NCC)

NCL, see Neuronal ceroid-lipofuscinosis (NCL)

Neuroblastoma 276, 280 Neuroborreliosis 233 Neurocysticercosis (NCC) 235, 236 Neurodegeneration with brain iron

accumulation (NBIA) 186–187 – SeealsoIronaccumulation Neurodegenerative diseases
– clinical approach in 6, 6, 7–8 – defined 42

– epidemiology of 5, 5
– genetics of 9
– history of 2, 2, 3–4
– pathology in 7, 9–10 Neurofibrillary tangles (NFTs), see Tau

protein
– in Alzheimer’s disease 80, 95, 113,

116, 121, 121, 129, 137
– in dementia with Lewy bodies 150 – in progressive supranuclear

palsy 182
– in repetitive brain trauma 290 Neurogenic locus notch homolog

protein 3 11
Neuroimaging, see Imaging Neuronal ceroid-lipofuscinosis

(NCL) 307, 310, 311 Neurosarcoidosis 245, 251, 252–253 Neurosyphilis 3, 233, 234, 342, 371 Nicotinic acetylcholine receptors, in

dementia with Lewy bodies 39 NINDS-AIREN, see National Institute of

Neurological Disorders and Stroke- Association Internationale and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS– AIREN)

Nitrous oxide 371
Noguchi, Hideyo 3 Nonketotichyperglycinemia 307 Normal pressure hydrocephalus (NPH) – as potentially-reversible

dementia 365
– brainstem changes in 258, 259
– cerebrospinal fluid in 23, 257, 257 –– cine phase-contrast magnetic

resonance quantification of flow

in 259, 260
–– flow void sign in 258, 258
–– in normal pressure hydrocephalus ––– cinephase-contrastmagnetic

resonance quantification of flow

in 259, 260
––– flow void sign in 258, 258
–– shunting 262
– cingulate nucleus sign in 258, 259 – clinical features of 256
– corpus callosal thickening in 258,

258
– dementia in 256
– diagnosis of 256, 262
– diffusion weighted imaging in 260 – dynamic susceptibility contrast

MRI 260
– epidemiology of 256
– external lumbar drainage in 262 – gait disturbance in 256
– imaging in 256, 257–261
– management of 262
– nuclear imaging in 260, 261
– patient complaints in 6
– perfusion in 67

Index

393

394

Index

– periventricular white matter changes in 257, 257, 258–259

– positron emission tomography in 261

– shunting in 262

– single photon emission computed
tomography in 260

– spinal tap in 262

– structural imaging in 23

– urinary incontinence in 256

– vascular parkinsonism vs. 191

– ventriculomegaly in 256, 257 Normal-appearing gray matter
(NAGM), in multiple sclerosis 30 Normal-appearing white matter
(NAWM), in multiple sclerosis 30 NOTCH3 gene 11
NPH, see Normal pressure
hydrocephalus (NPH) Nuclear magnetism 24 Nutritional-deficiency related
dementia

– vitamin B12 deficiency in 301, 302

– Wernicke-Korsakoff syndrome
in 300, 301 O
Obstructive sleep apnea 363 Olfaction, see Anosmia, Hyposmia Olivocerebellar fibers 322 Olivopontocerebellar atrophy 21, 326,
330, 331, 335
Ovarian teratoma 276, 277, 279 Overlap, clinical 7, 10
P
PACNS, see Primary angiitis of the central nervous system (PACNS)
Pancreatic carcinoma 276 Pantothenate kinase-associated
neurodegeneration (PKAN) 186–187 Parallel fibers 319
Paraneoplastic cerebellar degeneration
(PCD) 281, 328, 333, 334 Paraneoplastic encephalitis 279 Paraneoplastic syndrome (PNS) – antibodies in 20, 276, 279
– brainstem encephalitis in 279, 280 – cerebellar degeneration in 277, 278 – clinical features of 276
– electroencephalography in 276
– imaging in 277
– limbic encephalitis in 277, 278 – pathology of 277
– pathophysiologyof 277
– screening for 277
– striatal encephalitis in 279
– treatment of 277
Parasitic infections 235, 236 Parathyroidism 298, 298
Parkin 11
Parkinson, James 2 Parkinsonism, see Secondary
parkinsonism

– drug-induced 169

– postinfectious 187

– vascular
–– in magnetic resonance
imaging 169, 191
–– in secondary parkinsonism 187, 190

–– lacunar infarcts in 187
–– normal pressure hydrocephalus

vs. 191
–– perfusion in 66
–– treatment of 191
Parkinson’s disease (PD), see Vascular

parkinsonism (VP)
– akinetic-rigid 171
– anosmia in 172
– behavioral symptoms in 173
– bradykinesia in 171
– cognitive symptoms in 173
– dementia with Lewy bodies and 39,

150
– depression in 173
– diagnosis of
–– differential 167
–– early 166
–– imaging in 166
– differential diagnosis in 29
– diffusion tensor imaging in 44, 167 – dopamine system in 38
– dopaminergic system in 38, 169
– essential tremor vs. 39, 166
– fractional anisotropy in 167
– freezing of gait in 171
– functional magnetic resonance

imaging in 171, 174
– gait impairment in 171
– hallucinations in 174
– hyposmia in 172
– imaging
–– in diagnosis 166
–– of motor hallmarks 169
–– of nonmotor features 172
– iron mapping in 84
– Lewy bodies in 20, 166
– magnetic resonance imaging in 167 – magnetic resonance spectroscopy

in 29
– mild cognitive impairment in 173
– mood disorders in 173
– multiple-system atrophy vs. 29, 168,

180, 182
– positron emission tomography

in 37, 166
– premotor symptoms in 172
– progressive supranuclear palsy

vs. 44, 183
– psychosis in 174
– rapid eye movement behavior

disorder in 172
– rest tremor in 169
– rigidity in 171
– secondary parkinsonism vs. 20, 66 – serotonin system in 38–39, 170
– single photon emission computed

tomography in 166, 169, 171, 174 – transcranial ultrasound in 167
– treatments for 374
– tremor-dominant 171 Parkinson’s disease dementia (PDD)

– atrophies in 173

– dementia with Lewy bodies vs. 151,
153

– white matter hyperintensities
in 173
Parkinson’s diseases (PD)

– diagnosis of
–– early 167–168
–– imaging in 167–168
– diffusion tensor imaging in 168 – fractional anisotropy in 168–169

– FreeSurfer software in 169
– functional magnetic resonance

imaging in 176
– genetics in 11
– hallucinations in 175
– imaging
–– in diagnosis 167–168
–– of motor hallmarks 169–170 –– of nonmotor features 175–176 – in history of neurodegenerative

disease 3
– iron mapping in 85
– Lewy bodies in 7
– positron emission tomography

in 38, 169
– progressive supranuclear palsy vs. 7 – single photon emission computed

tomography in 167, 169
– substantia negra in 169
– supranuclear palsy vs. 7
– voxel-based morphometry in 169–

170

Parkinson’s diseases dementia (PDD) – clinical overlaps with 10
– patient complaints in 6
PARKN gene 11

Pathology, in neurodegenerative disease 7, 9–10

Patient complaints 6
PCA, see Posterior cortical atrophy

(PCA)
PCD, see Paraneoplastic cerebellar

degeneration (PCD)
Pediatric patients
– congenital HIV in 228
– magnetic resonance spectroscopy

in 324
– radiotherapy brain effects in 271,

273

Pelizaeus-Merzbacher disease 307 Perfusion
– arterial spin labeling for 64, 65 – computed tomography 63, 64

– dynamic susceptibility contrast for 63, 65

– in aging 65, 66, 75
– in Alzheimer’s disease 65, 66
– in dementia with Lewy bodies 154
– in mild cognitive impairment 95, 95,

96–97, 102, 103
– in normal pressure hydrocephalus 67

– in sickle cell disease 67, 67
– in vascular dementia 66, 66
– in vascular parkinsonism 66
– magnetic resonance 63, 65 Perfusion-weighted imaging (PWI), in

Alzheimer’s disease 133, 134 Pergolide 374
Perivascular spaces (PVSs) 207, 207 Peroxisomal disorders 307, 313, 313,

314–315
Peroxisome biogenesis defects 307 PET, see Positron emission tomography

(PET)
Phenylketonuria 307, 314
Phenytoin toxicity 328 Phosphatidylinositol-binding clathrin

assembly protein 120 Photon-cell interaction, in

radiotherapy 268, 268, 269
PICA, see Posterior inferior cerebellar

artery (PICA)

PICALM gene 120
Pick bodies 159
– SeealsoArgyrophilicfibrillary

inclusions
Pick disease 158, 159
– in frontotemporal dementia 37 – in history of neurodegenerative

disease 3
PKAN, see Pantothenate kinase-

associated neurodegeneration

(PKAN)
Plasma biomarkers, in Alzheimer’s

disease 122
PLS, see Primary lateral sclerosis (PLS) PML, see Progressive multifocal

leukoencephalopathy (PML) Pneumoencephalogram 2 PNFA, see Progressive nonfluent

aphasia (PNFA)
PNS, see Paraneoplastic syndrome

(PNS)
Polyarteritis nodosa 221 Polyomavirus 233
Polypharmacy 367
Positron emission tomography (PET),

see Metabolism
– fluorine 18 (18F)-labeled glucose

in 34
– functional magnetic resonance

imaging vs. 56
– importance of 34
– in aging brain 75, 76
– in Alzheimer’s disease 35, 35, 116,

127–128, 129–130
– in amyotrophic lateral sclerosis 354,

355–356
– in dementia evaluation 362
– in dementia with Lewy bodies 38,

154
– in frontotemporal dementia 37, 37 – in frontotemporal lobar

degeneration 37, 161, 163
– in hypothyroidism 296, 297
– in mild cognitive impairment 95, 98 – in motor neuron disease 354, 355–

356

– in multiple sclerosis 246
– in multiple-system atrophy in 181,

181

– in normal pressure hydrocephalus 261

– in paraneoplastic cerebellar degeneration 334, 334

– in Parkinson’s disease 37, 166 – in Parkinson’s diseases 38, 169 – in prion disease 243
– in progressive supranuclear

palsy 183
– in traumatic brain injury 290
– mechanism of 34
Posterior cortical atrophy (PCA)
– as Alzheimer’s disease variant 115 – patient complaints in 6
Posterior inferior cerebellar artery

(PICA) 318, 320
Posterior reversible encephalopathy

syndrome (PRES) 299, 366, 374 Postinfectious parkinsonism 187 PPA, see Primary progressive aphasia

(PPA)
Pramipexole 374
Praxis complaints 6 Precentral cerebellar vein 320

240

Index

PRES, see Posterior reversible encephalopathy syndrome (PRES)

Presenelin 1 11, 113, 120, 120 Presenelin 2 11, 113, 120, 120
PRG gene 11
Primary angiitis of the central nervous

system (PACNS) 216, 217–219, 245 Primary lateral sclerosis (PLS) 340,

341, 349, 351, 352–353, 354 Primary progressive aphasia (PPA)
– in frontotemporal dementia 37
– language deficit 115
– patient complaints in 6
– semantic variant 115, 157
Prion diseases, see Creutzfeldt-Jakob

disease (CJD)

– acquired 239

– clinical features of 239

– genetic 239

– genetics in 11, 240

– imaging in 240, 241–243

– incidence of 239

– neuropathology of

– sporadic 239
Prion protein 11 PRNP gene 11 Progranulin 11, 157 Progressive multifocal
leukoencephalopathy (PML)

– in HIV infection 228

– structural imaging in 22 Progressive muscular atrophy
(PMA) 353
Progressive nonfluent aphasia (PNFA)

– frontal lobe in 7

– in frontotemporal degeneration 18,
27, 157

– in magnetic resonance imaging 159,
162

– neuropathology of 158

– patient complaints in 6 Progressive supranuclear palsy (PSP)

– cholinergic function in 183

– clinical overlaps with 10

– diffusion weighted imaging in 183

– functional imaging in 183

– iron accumulation in 84

– magnetic resonance imaging in 182,
183

– multiple-system atrophy vs. 183

– neurofibrillary tangles in 182

– Parkinson’s disease vs. 44, 183

– Parkinson’s diseases vs. 7

– patient complaints in 6

– positron emission tomography
in 183

– serotonin system in 39

– structural imaging in 21, 182, 183

– voxel-based morphometry in 183 Propionic acidemia 307
Propranolol 376
Prostate cancer 276
PSEN1 gene 11, 113, 120, 120
PSEN2 gene 11, 113, 120, 120 Pseudodementia 14, 92, 256, 363
PSP, see Progressive supranuclear palsy
(PSP)
Pulvinar sign 242, 242
Pure cerebellar atrophy 330, 330 Purkinje cell
– 5-Fluorouracil and 272
– in ataxia telangiectasia 331
– in celiac disease 247, 334

– in cerebellar histology 319 – in cerebellitis 329
– in paraneoplastic cerebellar

degeneration 281, 333
– in toxic cerebellitis 329
Putamena 378, 378
PVSs, see Perivascular spaces (PVSs) PWI, see Perfusion-weighted imaging

(PWI)

QSM, see Quantitative susceptibility mapping (QSM)

Quantitative susceptibility mapping (QSM) 83

Radiotherapy
– blood-brain barrier in 269, 269 – computed tomography and,

dementia in combined 272, 274
– dementia and, for brain tumors 268,

270, 270, 271–272
– diffuse late atrophy in 270
– imaging of effects of 269
– in pediatric patients, brain effects

of 273
– mechanism of brain effects in 268,

268, 269
– photon-cell interaction in 268, 268,

269

Rapid eye movement behavior disorder (RBD), in Parkinson’s disease 172

Rasagiline 374
RBD, see Rapid eye movement behavior

disorder (RBD)
RBT, see Repetitive brain trauma (RBT) Refsum disease 307, 328
Renal cell carcinoma 276, 277 Repetitive brain trauma (RBT) 284,

288, 290
– SeealsoTraumaticbraininjury(TBI) Rest tremor, in Parkinson’s disease 169 Retinal vasculopathy +

leukoencephalopathy 215 Reversible dementia, structural

imaging in 22
Rhombic lips 318 Rhomboencephalosynapsis 336 Riluzole 346, 376
Risperidone 376
Rituximab 277
Rivastigmine 56, 108, 229, 372 Ropinirole 374
Rotigotine 374–375

Sacks, Oliver 4
Sarcoidosis 245, 251, 252–253 SCA, see Superior cerebellar artery

(SCA)
Scans without evidence of

dopaminergic deficiency (SWEDDs),

in Parkinson’s disease 169 SCD, see Sickle cell disease (SCD),

Subacute combined degeneration

(SCD)
sCJD, see Sporadic Creutzfeldt-Jakob

disease (sCJD)

SD, see Semantic dementia (SD) Secondary parkinsonism, see

Parkinsonism, Vascular

parkinsonism (VP)
– dentatorubral-pallidoluysian

atrophy as 186–187, 188
– Huntington disease as 188
– Parkinson’s disease vs. 20, 66 – pathology of 186
– substantia nigra pars compacta

in 186
– treatments for 374
– Wilson disease as 190
Selective serotonin reuptake inhibitors

(SSRIs), in Alzheimer’s disease 373 Selegiline 374
Semantic dementia (SD)
– anterior temporal atrophy in 158
– as frontotemporal syndrome 157
– magnetic resonance imaging in 159 – patient complaints in 6

Semantic variant of primary progressive aphasia (svPPA) 115, 157

Senility 2
Serotonin system
– in Alzheimer’s disease 35–36
– in frontotemporal dementia 37
– in Parkinson’s disease 38–39, 170,

174
– in progressive supranuclear palsy 39 Shimming 24
Shunting, in normal pressure

hydrocephalus 67, 258–260, 262,

371
Sialic-acid binding immunoglobulin-

like lectin 6 120 Sialorrhea 340, 376
Sickle cell disease (SCD)
– imaging in 212, 213–214 – perfusion in 67, 67 Siderosis of central nervous

system 127, 211–212, 218, 328, 334,

334

SIGLEC6 gene 120
Single photon emission computed

tomography (SPECT)
– Alzheimer’s disease in 35, 116, 127 – corticobasal degeneration in 184
– dementia with Lewy bodies in 38,

154

– frontotemporal lobar degeneration in 161

– importance of 34
– mechanism of 34
– mild cognitive impairment in 95, 95,

96–97
– multiple sclerosis in 246
– normal pressure hydrocephalus

in 260
– Parkinson’s disease in 166, 169, 171,

174
– Parkinson’s diseases in 167, 169 – prion disease in 242
– Sjögren syndrome in 249
– traumatic brain injury in 290
– vascular dementia in 205 Single-voxel spectroscopy 25 Sjögren encephalopathy

dementias 245, 249
Sjögren syndrome (SS) 218, 249, 250 SLE, see Systemic lupus erythematosus

(SLE)

Sleep apnea 363
SMA, see Spinal muscular atrophy

(SMA)
Smell, see Anosmia, Hyposmia SN, see Substantia nigra (SN) SNCA gene 11
SNpc, see Substantia nigra pars

compacta (SNpc)
Solvent toxicity 328
SORL1 gene 113, 119, 120 Sortilin-related receptor 113, 119, 120 SPECT, see Single photon emission

computed tomography (SPECT) Spectroscopy, see Magnetic resonance

spectroscopy (MRS), Two- dimensional correlated spectroscopy (2D-COSY)

Speech complaints 6
– SeealsoAphasia
Spinal cord
– in adrenomyeloneuropathy 313
– in amyotrophic lateral sclerosis 45,

349
– in Friedreich ataxia 331
– in hereditary spastic paraplegia 349 – in Hirayama disease 344
– in Kennedy disease 343
– in Lyme disease 234
– in motor neuron disease 349
– in multiple sclerosis 47
– in multiple-system atrophy 180
– in neurosyphilis 233
– in primary angiitis of central nervous

system 216
– in superficial siderosis 334
– in vitamin B12 deficiency 301 Spinal muscular atrophy (SMA) 342,

343

Spinocerebellar ataxias 330
– genetic testing with 4
– genetics in 11, 330
– in classification of cerebellar

ataxia 328
– magnetic resonance spectroscopy

in 330
– patient complaints in 6 Spinocerebellar atrophy 7 Spinocerebellar tracts 321 Spirochetes 233, 234
Sporadic Creutzfeldt-Jakob disease

(sCJD) 239
– SeealsoCreutzfeldt-Jakobdisease

(CJD)
SS, see Sjögren syndrome (SS) Stellate cells 320
Stiff-person syndrome 276, 276,

279
STN, see Subthalamic nucleus (STN) Strategic-infarct dementia 194, 204,

204, 205
Striatal encephalitis, in paraneoplastic

syndrome 279
Stroke, cerebellar 328, 329
– See also Infarct(s)
Structural imaging, see Imaging Subacute combined degeneration

(SCD), in vitamin B12 deficiency 301 Subacute sclerosing panencephalitis

(SSPE) 233, 233 Subcortical vascular

encephalopathy 194 Substantia nigra (SN)
– in deep brain stimulation 378

395

396

Index

– in Parkinson’s disease early diagnosis 166

– in Parkinson’s diseases 169

– in secondary parkinsonism 186

– iron accumulation in 85, 85 Substantia nigra pars compacta
(SNpc) 186–187, 378
Substantia nigra pars reticulata 378 Subthalamic nucleus (STN) 378, 378,
379, 380, 381–382
Sulfite oxidase deficiency 307 Superficial siderosis 127, 211–212,
218, 328, 334, 334
Superior cerebellar artery (SCA) 318,
320
Superior cerebellar peduncle 322, 323 Superior cerebellar veins 319 Superoxide dismutase 1 11
Susac syndrome 219 Susceptibility-weighted imaging
(SWI) 83

– in Alzheimer’s disease 127

– in Fabry disease 309

– in multi-infarct dementia 202

– in traumatic brain injury 285, 286

– subthalamic nucleus in 382 SWEDDs, see Scans without evidence of
dopaminergic deficiency (SWEDDs) SWI, see Susceptibility-weighted
imaging (SWI)
Syphilis 3, 233, 234, 342, 371 Systemic lupus erythematosus
(SLE) 216, 245, 248, 248, 249, 363
T
Tacrine, in Alzheimer’s disease 37 Taenia solium 235, 236 Talcapone 374
Tamoxifen 272
Tau bodies 158, 159
Tau imaging 128, 129
Tau protein, see Neurofibrillary tangles
(NFTs)

– in Alzheimer’s disease 114, 116,
121, 121, 122, 124, 128, 129, 130

– in corticobasal degeneration 183

– in frontotemporal dementia 27

– in frontotemporal lobar
degeneration 157–158

– in mild cognitive impairment 93

– in Pick disease 159

– in progressive supranuclear
palsy 182

– in repetitive brain trauma 290

– in traumatic brain injury 290 Tay-Sachs disease 328, 340
TBI, see Traumatic brain injury (TBI) TDP-43 protein 345
Testicular cancer 276, 277, 279 Tetrabenazine 375–376
TG, see Transglutaminase (TG) Thalamic tumor 380
Thalidomide 272
Thiamine deficiency 300, 301, 367 Thymoma 276, 280
Thyroid hormones 296, 297
TNF-α, see Tumor necrosis factor α
(TNF-α)
Toluene inhalation 302, 367
Toxic cerebellitis 329, 330 Toxin-related dementias
– alcoholic-related dementia in 301

– carbon monoxide exposure in 303, 304

– heavy metal poisoning in 302, 367 – medications in 304
Toxoplasmosis 236
Transactive response-DNA binding

protein (TARDP) 157, 159 Transcranial ultrasound
– in multiple-system atrophy 181
– in Parkinson’s disease 166–167 Transglutaminase (TG) antibodies 247 Transverse pontine fibers (TPFs) 322–

323
Traumatic brain injury (TBI)
– chronic traumatic encephalopathy

in 284
– computed tomography in 284
– diffusion tensor imaging in 285,

286–287
– functional magnetic resonance

imaging in 289
– magnetic resonance imaging in 284 –– high-resolution 284
– magnetic resonance spectroscopy

in 287, 289
– metabolism in 290
– mild 284
– pathophysiology of
– patient complaints in 6
– positron emission tomography

in 290
– repetitive brain injury in 284
– single-photon emission computed

tomography in 290
– susceptibility-weighted imaging

in 285, 286
Tremor, see Essential tremor (ET), Rest

tremor
Triamterene 371 Trichothiodystrophy with

photosensitivity 307 Trihexyphenidyl 374 Tropherymawhippelii 235 Trypanosomiasis 235
Tuberculosis 234, 235
Tumor necrosis factor α (TNF-α) 252,

269, 269, 272
Tumors, see Brain tumors,

Paraneoplastic syndrome (PNS),

specific cancers Two-dimensional correlated

spectroscopy (2D-COSY) 288 Type 2 diabetes mellitus 298,

298

– See also Diabetes mellitus U

Ubiquitin inclusions
– in frontotemporal dementia

27
– in frontotemporal lobar

degeneration 159
– in Lewy bodies 151
Ultrasound, transcranial
– in multiple-system atrophy 181 – in Parkinson’s disease 166–167 Urea cycle defects 307
Uremic encephalopathy 299, 299 Urinary incontinence
– in adrenomyeloneuropathy 313 – in normal pressure

hydrocephalus 256

VaD, see Vascular dementia (VaD) Valosin-containing protein 11, 157 Vanishing white matter disease

(VWMD) 314, 315
Variant Creutzfeldt-Jakob disease

(vCJD) 239
– SeealsoCreutzfeldt-Jakobdisease

(CJD) Varicella zoster

meningoencephalitis 229 Vascular dementia (VaD)
– Alzheimer’s disease vs. 66
– as preventable 364
– classification of 197, 201
– clinical criteria for 199, 199
– cortical 199
– defined 23
– diagnostic criteria for 194
– genetics in 196, 196
– hypoperfusion encephalopathy

in 205, 205
– imaging in 200, 200, 201
– in Diagnostic and Statistical

Manual 194
– ischemic encephalopathy in 205,

205
– large-vessel 200, 201–202
– magnetic resonance imaging

in 195–196, 201–202
– mixed dementia in 208, 208 – neuroanatomic-behavior

considerations in 197
– pathologic syndromes in 194
– pathophysiology of 195, 195, 196 – patient complaints in 6
– perfusion in 66, 66
– perivascular spaces in 207, 207
– single photon emission computed

tomography in 205
– small-vessel 201, 206, 206, 207 – subcortical 199
– watershed infarcts in 202,

203–204
Vascular endothelial growth factor

(VEGF) 269, 269
Vascular parkinsonism (VP), see

Secondary parkinsonism
– in secondary parkinsonism 187, 190 – lacunar infarcts in 187
– magnetic resonance imaging in 169,

191

– normal pressure hydrocephalus vs. 191

– perfusion in 66
– treatment of 191 Vasculitis
– in Behçet disease 217, 220 – in CADASIL 221, 222
– in giant cell arteritis 221
– in polyarteritis nodosa 221 – in Sjögren syndrome 218 – in Susac syndrome 219
– in systemic lupus

erythematosus 216
– in Wegener granulomatosis 219 – primary central nervous

system 216, 217–219
– secondary 216, 220, 222
vCJD, see Variant Creutzfeldt-Jakob

disease (vCJD) VCP gene 11

VEGF, see Vascular endothelial growth factor (VEGF)

Vein of Galen 320
Ventral intermediate nucleus

(VIM) 378
Ventral spinocerebellar tracts 321 Ventral transverse fibers 322 Ventriculomegaly, in normal pressure

hydrocephalus 256, 257
Vermian dysplasia 336
Vertebral arteries 320
VGKC-E, see Voltage-gated potassium

channel encephalopathy (VGKC-E) VIM, see Ventral intermediate nucleus

(VIM)
Vinblastine 272
Vincristine 272
Vindesine 272
Vinorelbine 272
Viral encephalitides 232, 232, 233 Virchow-Robin spaces (VRSs) 207, 207 Visual complaints 6
Vitamin B1 deficiency 300, 301 Vitamin B12 deficiency 301, 302, 371 Vitamin deficiencies, patient

complaints in 6
Vitamin E deficiency 328 Voltage-gated potassium channel

encephalopathy (VGKC-E) 250, 250,

279
Voxel-based morphometry (VBM) 15 – in Alzheimer’s disease 125, 125
– in amyotrophic lateral sclerosis 349,

351

– in corticobasal degeneration 184
– in dementia imaging 15, 16
– in dementia with Lewy bodies 152,

153–154
– in mild cognitive impairment 16,

99–100, 100, 102
– in motor neuron disease 349, 351 – in multiple-system atrophy 180 – in Parkinson’s diseases 169–170 – in primary lateral sclerosis 351
– in progressive supranuclear

palsy 183
Voxel-based relaxometry (VBR), in

dementia imaging 15
VP, see Vascular parkinsonism (VP) VRSs, see Virchow-Robin spaces (VRSs) VWMD, see Vanishing white matter

disease (VWMD)

Watershed infarcts 202, 203–204 WBRT, see Whole-brain radiation

(WBRT)
Weakness, as complaint 6
Wegener granulomatosis 219 Werdnig-Hoffman disease 343 Wernicke encephalopathy (WE) 300,

333
Wernicke-Korsakoff syndrome

(WKS) 300, 301, 367
West Nile encephalitis 187, 233 Whipple disease 235, 367
White matter (WM)
– in aging brain 42, 71, 73, 73, 74 – in CADASIL 210, 210
– in Huntington disease 45
– in mucopolysaccharidoses 309 – in multiple sclerosis 47, 47–48

284

– in normal pressure hydrocephalus 257, 257, 258–259

– macrostructural lesions in, in aging brain 73, 73

– microstructural changes in, in aging brain 74

– normal-appearing, in multiple sclerosis 30

– water diffusion in 42
White matter hyperintensities (WMHs)

– in Alzheimer’s disease 125, 126, 153,
155

– in dementia with Lewy bodies 152, 155

– in Parkinson’s disease dementia 173 Whole-brain radiation (WBRT) 267 Wilson disease 187, 190, 190, 307, 366

– genetics in 11
– in secondary parkinsonism 186 – treatment of 371
WKS, see Wernicke-Korsakoff

syndrome
WM, see White matter (WM) WMHs, see White matter

hyperintensities (WMHs)

X-linked adrenoleukodystrophy 307 Z

Zinc, in Wilson disease treatment 371

α-galactosidase A (α-Gal A) 210, 306, 308

α-synuclein, see Lewy bodies (LBs)
– in amyotrophic lateral sclerosis 345 – in dementia with Lewy bodies 18,

150, 150, 151, 154
– in multiple-system atrophy 180 – in neurodegenerative disease 2 – in Parkinson’s disease 11, 186
– in Parkinson’s diseases 7

“

“Black holes”, in multiple sclerosis 30

“Double panda” sign 190

“Face of the giant panda” sign 190

“Face of the miniature panda” sign 190

“Hot cross bun” sign 168, 180 “Hummingbird” sign 21, 22,

259
“Mickey mouse” sign 183 “Morning glory” sign 183 “Penguin silhouette” 21, 22,

183

“Proteinopathies” 2
“Slit” sign 180
“Upper midbrain profile sign” 258,

259

Index

397

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