PET in the Evaluation of Alzheimer’s Disease and Related Disorders docx

PET in the Evaluation of Alzheimer’s Disease

and Related Disorders

Daniel H.S. Silverman

Editor

PET in the Evaluation

of Alzheimer’s Disease

and Related Disorders

Editor

Daniel H.S. Silverman, M.D., Ph.D.

Head, Neuronuclear Imaging Section

Associate Chief, Division of Biological Imaging

Associate Professor, Department of Molecular and Medical Pharmacology

Associate Director, UCLA Alzheimer’s Disease Center Imaging Core

David Geffen School of Medicine

University of California

Los Angeles, CA

USA

ISBN 978-0-387-76419-1 e-ISBN 978-0-387-76420-7

DOI 10.1007/978-0-387-76420-7

Library of Congress Control Number: 2008940848

© Springer Science + Business Media, LLC 2009

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Among all the clinical indications for which radiologists, nuclear medicine physi￾cians, neurologists, neurosurgeons, psychiatrists (and others examining disorders of

the brain) order and read brain PET scans, demand is greatest for those pertaining

to dementia and related disorders. This demand is driven by the sheer prevalence of

those conditions, coupled with the fact that the differential diagnosis for causes of

cognitive impairment is wide and often difficult to distinguish clinically.

The conceptual framework by which evaluation and management of dementia is

guided has evolved considerably during the last decade. Although we still are far

from having ideal tests or dramatic cures for any of the established causes of

dementia, our options have expanded with respect to both the diagnostic and thera￾peutic tools now available. In the first chapter of this book, the contribution and

limitations of different elements of the clinical examination for diagnosis of cogni￾tive symptoms are described, and the roles of structural and functional neuroimag￾ing in the clinical workup are given context.

The clinical utility of brain positron emission tomography (PET), as with other

imaging modalities, depends in part on how accurately and fully the information

inherently represented in the scans is appreciated and relayed in the interpretation

of the images. Even highly trained imaging specialists are challenged by this

since, for example, neuroradiologists are generally far more familiar with com￾puted tomography (CT) and magnetic resonance (MR) studies of the brain than

with PET studies, and specialists in PET and PET/CT facilities tend to be much

more experienced with oncology studies than with dedicated brain studies per￾formed for the evaluation of neurologic disorders. To help meet this challenge,

the second chapter offers practical instruction on adopting a systematic method

for visual analysis of scans, describes how quantification with clinically available

and friendly software tools can be employed to assist with analysis, and then

illustrates a straightforward approach for integrating the qualitative and quantita￾tive findings in meaningful interpretations. An Atlas in the final section of this

book complements Chapter 2 by providing interpretive practice for many real

(and clinically realistic) cases, to which the tools outlined in the second chapter

can be directly applied.

The most frequent causes of dementia are neurodegenerative disorders, with

Alzheimer’s disease being the most common. By the time patients are symptomatic

Preface

v

vi Preface

with these disorders, they have undergone significant distinct alterations in brain

metabolism. The increasing use of brain PET stems from the high sensitivity of this

imaging tool in identifying those alterations. The third chapter looks at the full

spectrum of changes in glucose metabolism detectable with PET in monitoring the

course of cognitive decline, beginning before the emergence of the first neurologic

symptoms, in people who are predisposed to developing problems, in some cases

many years into the future. Progressive changes observed with PET in the brains of

patients who experience very mild symptoms, to those who meet criteria for having

mild cognitive impairment, to those suffering from full-blown dementia, are

described, as is the role of PET in the differential diagnosis of the underlying cause

for the dysfunction.

Neurodegenerative diseases often impact not only on cognitive function, but

also on motor function. The two neurologic domains can be affected in isolation,

but frequently a mixed presentation of symptoms occurs. For example, approxi￾mately one third of Alzheimer’s patients eventually experience parkinsonian

symptoms and, conversely, a similar proportion of patients with Parkinson’s dis￾ease develop significant cognitive impairment. Other conditions, such as demen￾tia with Lewy bodies, may be characterized at an early stage by both motor and

cognitive problems. Chapter 4 examines neuronuclear imaging studies explicitly

aimed at illuminating changes in the brain associated with movement disorders.

Their potential utility with respect to drug development, as well as in direct clini￾cal application, is explained.

Although the most commonly performed clinical PET studies by far are car￾ried out with [18F]fluorodeoxyglucose (FDG) as the imaged radiotracer, substan￾tial advances have occurred in the development of other radiotracers with which

to probe brain processes associated with neurodegenerative disease. Chapter 5

describes work that is making it possible to observe and measure the molecular

participants of such processes as they accumulate, or are lost from, living brain

tissue. In the setting of Alzheimer-related changes, one molecular participant in

particular, the β-amyloid of extracellular plaques constituting one of the histo￾pathologic hallmarks of Alzheimer’s disease, has attracted substantial attention

in both industry and academic scientific settings. Following the introduction of

this area of investigation in the fifth chapter, Chapter 6 is devoted to expanding

on the scientific implications and clinical potential of radiotracers being devel￾oped to localize and measure β-amyloid deposits occurring in the brain. In the

latter chapter, particular attention is given to characterizing β-amyloid deposi￾tion in older people who would not be considered cognitively impaired by stan￾dard clinical criteria.

PET scans, particularly with FDG, have demonstrated diagnostic and prognostic

utility in evaluating patients with cognitive impairment and in distinguishing

among primary neurodegenerative disorders and other etiologies for cognitive

decline. Since the diagnostic capabilities of this medical technology have outpaced

therapeutic advances, a look into the future of PET requires concomitant consider￾ation of the future of therapeutic strategies for addressing the underlying condi￾tions. As preventive and specific disease-modifying treatments are developed, early

Preface vii

detection of accurately diagnosed neuropathologic processes, facilitated by

appropriate use of PET and other neuroimaging technologies, can be expected to

increasingly impact on the enormous human toll currently exacted by these

disorders.

Daniel H.S. Silverman, M.D., Ph.D.

There are many to whom much is owed for their roles in the creation of the present

work, moving it from the realm of abstract ideas into its present reality. I would like

to thank Rob Albano who, representing the publisher (at a time when Springer was

still Springer-Verlag), was present from its inception and first invited me to con￾sider a project along these lines. I felt fairly sure at the time that taking on this

project was a bad move, but he managed not to let me talk him (or myself) out of

it prematurely. I also wish to thank developmental editor Margaret Burns who,

working with me from almost the earliest days of the project, managed to stay

perfectly poised on the fine line between helpful prodding to keep the project mov￾ing forward and patient understanding when that forward motion may have seemed

imperceptible to an external observer (particularly as obstacles to our originally

anticipated timeline arose and had to be creatively overcome). Thanks are also due

to Springer’s book production manager Frank Ganz, and associate editor Katherine

Cacace, for ably guiding this project through the final stretch and across the finish

line. I am indebted to all of my colleagues who contributed as authors and co￾authors to the final work: my friends and colleagues at UCLA, Linda Ercoli, Gary

Small, Vladimir Kepe, Henry Huang, Saty Satyamurthy, and Jorge Barrio, with

whom I have been fortunate to collaborate over the past decade on a wide range of

imaging-related projects; Lisa Mosconi, who has shared her considerable experi￾ence on changes in brain metabolism associated with the earliest stages of

Alzheimer’s disease; John Seibyl, a friend of many years who has always sportingly

accepted my invitations to participate in any number of forums of symposia and

writing projects and has once again offered his insights into the movement side of

the neurodegenerative coin, much to the benefit of this text; Bill Klunk, for readily

agreeing at the outset to take responsibility, along with Chet Mathis and colleagues

Julie Price, Steve DeKosky, Brian Lopresti, Nicholas Tsopelas, Judith Saxton, and

Robert Nebes, for their excellent contribution on amyloid imaging; my colleague

Karl Herholz, for his insights in attempting the impossible task of forecasting the

future; and Vicky Lau, Cheri Geist, and Erin Siu, who applied their trained eyes,

creative talents, and organizational skills to successfully bringing to life reams of

clinical data and images into cogent clinical cases. Finally, I wish to express my

appreciation to those who have played roles less directly related to this actual text,

but no less important to its realization: Johannes Czernin, with whom I literally

Acknowledgments

ix

x Acknowledgments

worked alongside since my first day on the Nuclear Medicine Service at UCLA,

and Mike Phelps, whose pioneering work with PET served as a major source of my

inspiration to enter the nuclear medicine field to begin with, for the nearly one and

a half decades of friendship and support they have offered personally and, in

addition, professionally in their roles heading the Ahmanson Biological Imaging

Division, and Department of Molecular and Medical Pharmacology, respectively;

and my family—my wife Wei, our kids, our parents Donna and Robert and Pei and

Robert, and my sibs Anne, Beth, and Mikhael, whose contributions of friendship,

love, understanding of my professional commitments (and over-commitment), as

well as the many more specific roles played in day-to-day life throughout the time

that this text has been in preparation (and long before), would require another book

to fully enumerate.

Part I Imaging Applications in Current Clinical Practice

1 Clinical Evaluation of Dementia and

When to Perform PET .............................................................................. 3

Linda M. Ercoli and Gary W. Small

2 Clinical Interpretation of Brain PET Scans: Performing

Visual Assessments, Providing Quantifying Data,

and Generating Integrated Reports ........................................................ 33

Daniel H.S. Silverman

3 FDG PET in the Evaluation of Mild Cognitive

Impairment and Early Dementia ............................................................ 49

Lisa Mosconi and Daniel H.S. Silverman

4 PET and SPECT in the Evaluation of Patients with

Central Motor Disorders .......................................................................... 67

John P. Seibyl

Part II Emerging Approaches Using PET

5 Microstructural Imaging of Neurodegenerative Changes .................... 95

Vladimir Kepe, Sung-Cheng Huang, Gary W. Small,

Nagichettiar Satyamurthy, and Jorge R. Barrio

6 Amyloid Imaging with PET in Alzheimer’s Disease, Mild

Cognitive Impairment, and Clinically Unimpaired Subjects ............... 119

William E. Klunk, Chester A. Mathis, Julie C. Price,

Steven T. DeKosky, Brian J. Lopresti, Nicholas D. Tsopelas,

Judith A. Saxton, and Robert D. Nebes

Contents

xi

xii Contents

Part III Atlas

7 Interpretive Practice Atlas ....................................................................... 151

Daniel H.S. Silverman, Victoria Lau, Cheri Geist, and Erin Siu

Index ................................................................................................................. 211

Contributors

Jorge R. Barrio, Ph.D.

Distinguished Professor, Department of Molecular and Medical Pharmacology,

David Geffen School of Medicine, University of California, Los Angeles, CA

Steven T. DeKosky, M.D.

Professor and Chair, Department of Neurology, University of Pittsburgh,

Pittsburgh, PA

Linda M. Ercoli, Ph.D.

Assistant Clinical Professor, Department of Psychiatry and Biobehavioral

Sciences, the Semel Institute for Neuroscience and Human Behavior and the

Resnick Neuropsychiatric Hospital at the University of California,

Los Angeles, CA

Cheri Geist, B.Sc.

Research Associate, Neuronuclear Imaging Section, Department of

Molecular and Medical Pharmacology, David Geffen School of Medicine,

University of California, Los Angeles, CA

Sung-Cheng Huang, D.Sc.

Professor, Department of Molecular and Medical Pharmacology, David Geffen

School of Medicine, University of California, Los Angeles, CA

Vladimir Kepe, Ph.D.

Associate Researcher, Department of Molecular and Medical Pharmacology,

David Geffen School of Medicine, University of California, Los Angeles, CA

William E. Klunk, M.D., Ph.D.

Professor, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA

Victoria Lau, B.Sc.

Research Associate, Neuronuclear Imaging Section, Department of

Molecular and Medical Pharmacology, David Geffen School of Medicine,

University of California, Los Angeles, CA

xiii

xiv Contributors

Brian J. Lopresti, B.S.

Research Instructor, Department of Radiology, University of Pittsburgh,

PET Facility, Pittsburgh, PA

Chester A. Mathis, Ph.D.

Professor, Department of Radiology, University of Pittsburgh, Pittsburgh, PA

Lisa Mosconi, Ph.D.

Assistant Professor, Department of Psychiatry, New York University School

of Medicine, New York, NY

Robert D. Nebes, Ph.D.

Professor, Department of Psychiatry, University of Pittsburgh Medical Center,

Pittsburgh, PA

Julie C. Price, Ph.D.

Associate Professor, Department of Radiology, University of Pittsburgh,

Pittsburgh, PA

Nagichettiar Satyamurthy, Ph.D.

Professor, Department of Molecular and Medical Pharmacology,

David Geffen School of Medicine, University of California, Los Angeles, CA

Judith A. Saxton, Ph.D.

Associate Professor, Department of Neurology, University of Pittsburgh,

Pittsburgh, PA

John P. Seibyl, M.D.

Senior Scientist, Imaging Division, Institute for Neurodegenerative Disorders,

New Haven, CT

Daniel H.S. Silverman, M.D., Ph.D.

Head, Neuronuclear Imaging Section; Associate Chief, Division of

Biological Imaging; Associate Professor, Department of Molecular and

Medical Pharmacology; Associate Director, UCLA Alzheimer’s Disease

Center Imaging Core, David Geffen School of Medicine, University of

California, Los Angeles, CA

Erin Siu, B.Sc.

Research Associate, Neuronuclear Imaging Section, Department of

Molecular and Medical Pharmacology, David Geffen School of Medicine,

University of California, Los Angeles, CA

Gary W. Small, M.D.

Professor, Parlow-Solomon Professor on Aging, Department of Psychiatry,

David Geffen School of Medicine at University of California Los Angeles,

Los Angeles, CA

Nicholas Tsopelas, M.D.

Professor, Department of Psychiatry, Western Psychiatric Institute and Clinic,

University of Pittsburgh, Pittsburgh, PA