PET in the Evaluation of Alzheimer's Disease and Related Disorders

218 Pages·2009·4.04 MB·English

by  Linda M. Ercoli

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
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Preface
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
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.
Acknowledgments
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
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.
Contents
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
xi