Early Diagnosis of Alzheimer's Disease

374 Pages·2000·3.96 MB·English

by  Leonard F. M. Scinto

Early Diagnosis of
Alzheimer s
’
Disease
EDITED BY
Leonard F. M. Scinto,
PhD
Kirk R. Daffner,
MD
HUMANA PRESS
E D
ARLY IAGNOSIS
A ’ D
OF LZHEIMER S ISEASE
C C N
URRENT LINICAL EUROLOGY
Early Diagnosis of Alzheimer’s Disease, edited by Leonard F. M. Scinto
and Kirk R. Daffner,2000
Sexual and Reproductive Neurorehabilitation, edited by Mindy Aisen, 1997
E
ARLY
D
IAGNOSIS OF
A ’ D
LZHEIMER S ISEASE
Edited by
L F. M. S ,
EONARD CINTO PhD
K R. D ,
IRK AFFNER MD
Department of Neurology
Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA
Foreword by
J C. M ,
OHN ORRIS MD
Washington University School of Medicine
St. Louis, MO
H P
UMANA RESS
T , N J
OTOWA EW ERSEY
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Library of Congress Cataloging-in-Publication Data
Early diagnois of Alzheimer’s disease / edited by Leonard F. M. Scinto, Kirk R. Daffner.
p. cm. —(Current clinical neurology
Includes index.
ISBN 0-89603-452-6 (alk. paper)
1. Alzheimer’s disease–Diagnosis. I. Scinto, Leonard F. M. II. Daffner, Kirk R. III. Series.
[DNLM: 1. Alzheimer’s Disease–diagnosis. 2. Alzheimer Disease–genetics. WT 155 E125 2000]
RC523.E27 2000
616.8’31075–dc21
DNLM/DLC
for Library of Congress 99-25252
CIP
In memory of Tom A. Sandson, (1962–1999)
MD

F
OREWORD
Dramatic increases in the life expectancy in the United States and other developed
countries have resulted in unprecedented numbers and proportions of older adults in the
population. This demographic evolution in turn has fueled growing interest in age-
associated dementing illnesses, particularly Alzheimer’s disease. The prevalence of
Alzheimer’s disease, by far the leading cause of dementia in the United States, doubles
every 5 years after age 65 such that perhaps as many as one-half of all individuals age 85
years or older are demented.
Much has been learned about Alzheimer’s disease since two milestone events
occurred in 1984. First, uniform clinical diagnostic criteria were introduced by the Work
Group convened by the National Institute on Neurological and Communicative Disor-
ders and Stroke and the Alzheimer’s Disease and Related Disorders Association (1) and
provided the basis for the accurate recognition of the disorder. Second, Glenner and
Wong isolated the beta amyloid peptide from meningeal vessels in Alzheimer’s disease
brain (2), thus ushering in an era of remarkable progress in deciphering the neurobiologic
mechanisms underlying Alzheimer’s disease and in developing drug therapies. The pace
of scientific advance has been so rapid that it is easy to forget that only two decades ago
the major issue regarding dementia was not therapy or biology, but simply whether it was
possible to clinically differentiate Alzheimer’s disease from other forms of “senile brain
degeneration” and vascular dementia. Use of accurate clinical criteria with quantitative
postmortem assessment, coincident with a reduction in vascular dementia owing to
improved stroke prevention measures, now firmly establish Alzheimer’s disease as the
predominant cause of “senile” dementia.
There remain difficulties in dementia classification, however. In particular, it has not
been possible to resolve whether aging and Alzheimer’s disease are continuous or cat-
egorical processes because the clinical and pathological boundaries between the two
conditions often are indistinct. The difficulty in distinguishing aging and Alzheimer’s
disease is underscored by the plethora of terms that have been introduced to characterize
borderzone states in which the individual is neither clearly normal nor clearly demented:
“benign senescent forgetfulness,” “age-associated memory impairment,” “pathological
aging,” “cognitive impairment, no dementia,” and “mild cognitive impairment.” At the
same time, there is accumulating evidence to suggest that truly healthy brain aging can
occur into the ninth and tenth decades of life and may be associated with less cognitive
decline (3,4) and neuropathological changes (5) than usually are assumed. Such evidence
indicates that more than minimal cognitive decline may not be “normal” for age and that
much (perhaps most) of what presently is described as mild cognitive impairment (6) and
similar states may represent incipient or very mild Alzheimer’s disease.
It was not uncommon years ago to reserve the diagnosis of Alzheimer’s disease for
moderate-to-severe stages of dementia, a practice that reflected both uncertainty about
distinguishing mild dementia from normal aging and the lack of incentive to make an
“early” diagnosis when there was little to offer the patient. This attitude has been replaced
by growing interest in diagnosing the disorder at earlier and earlier stages, stimulated by
the advent of approved drugs for the symptomatic treatment of Alzheimer’s disease (7)
and the promise of newer agents that may halt dementia progression or even prevent the
disease. Thus, therapeutic nihilism is being dispelled. Impetus for detection of early-
vii
viii Foreword
stage Alzheimer’s disease also comes from the realization that investigations of proposed
causative mechanisms and putative biomarkers should not be limited to advanced dis-
ease, in which critical findings that distinguish disease from aging may be obscured.
This volume on the early diagnosis of Alzheimer’s disease is both timely and compel-
ling. It offers contributions from a superb group of experts who have helped define the
relevant issues and led critical clinical and scientific advances in early-stage diagnosis.
The first three chapters justify the importance of accurate diagnosis and describe the
clinical and pathological phenotypes for early-stage Alzheimer’s disease. Chapter 4
provides a masterful review of the molecular pathology of the disorder and proposes a
schema for its initiating pathophysiologic events. Chapters 5 and 12 cogently discuss the
current state of knowledge for the genetics of Alzheimer’s disease as well as the important
implications of genetic testing for early diagnosis and presymptomatic detection. The
encouraging potential roles for structural and functional neuroimaging as tools for diag-
nosis and for monitoring response in therapeutic trials of antidementia agents are re-
viewed in Chapters 6 and 7. The clinical utility of cognitive testing in detecting and
predicting early-stage Alzheimer’s disease is cogently discussed in Chapter 8. Chapters
9 and 10 comprehensively review the promise and limitations of proposed biomarkers for
Alzheimer’s disease. Chapter 11 summarizes the status of currently approved therapies
for Alzheimer’s disease and convincingly argues that early-stage illness should be a
target for intervention.
The editors are to be commended for the extraordinarily high quality of the contrib-
uting authors and the chapters and for focusing attention on the topic of early-stage
Alzheimer’s disease. As we move into the next century, I predict that the early diagnosis
of Alzheimer’s disease will become a dominant issue for clinicians, patients, and their
families as new therapies are developed and new research discoveries occur. This volume
not only serves as a testimonial to the value of early diagnosis, but provides clinicians and
scientists with the basis to appreciate ongoing developments in this emerging and impor-
tant field.
John C. Morris, MD
References
1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease:
Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task
Force on Alzheimer’s disease. Neurology 1984;34:939–944.
2. Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel
cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885–890.
3. Rubin EH, Storandt M, Miller JP, Kinscherf DA, Grant EA, Morris JC, et al. A prospective study of cognitive function
and onset of dementia in cognitively healthy elders. Arch Neurol 1998;55:395–401.
4. Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role of APOE (cid:161)4 in modulating effects of other risk
factors for cognitive decline in elderly persons. JAMA 1999;282:40–46.
5. Price JL, Morris JC. Tangles and plaques in nondemented aging and preclinical Alzheimer’s disease. Ann Neurol
1999;45:358–368.
6. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment. Arch Neurol
1999;56:303–308.
7. Knopman D, Morris LC. An update on primary drug therapies for Alzheimer’s disease. Arch Neurol 1997;54:1406–
1409.
P
REFACE
As the population ages, an increasing number of individuals are at risk for degenerative
diseases such as Alzheimer’s disease (AD). Early Diagnosis of Alzheimer’s Disease has
been written out of the conviction that without an understanding of the complex issues
surrounding the search for early markers for Alzheimer’s disease, the prospects for early
diagnosis and, consequently, the development of new interventions for the disease will,
at best, be delayed. In the past few years, we have seen a proliferation of research on
methods to detect Alzheimer’s disease early in its course. It is an excellent time to take
stock of the progress of this rapidly expanding field.
The chapters in Early Diagnosis of Alzheimer’s Disease review the most promising
approaches in current research on early diagnostic markers for AD. These approaches
include the elucidation of changes in the brain as seen in structural and functional neuroim-
aging, characteristic patterns of cognitive decline as documented by sensitive neuropsycho-
logical tests, various genetic markers, and a wide array of biological assays. We have placed
these different approaches to early diagnosis within a broader context by also reviewing
current clinical practice in diagnosing AD, major theories about its pathophysiology, and
the therapeutic and ethical implications of early diagnosis. Each of the areas explored in
Early Diagnosis of Alzheimer’s Disease holds promise for contributing to the development
of strategies for meeting the diagnostic and therapeutic challenge posed by AD.
Early Diagnosis of Alzheimer’s Disease is addressed to a broad audience within the
biomedical research and clinical communities. It should be of interest to clinicians who
endeavor to care for an aging population, researchers working in the area of new thera-
peutic approaches to the disease, and policymakers who are concerned about the impli-
cations surrounding early diagnosis and the delivery of health care. Although the work
gathered here provides a timely summary of different approaches for the early diagnosis
of AD, we hope it will make a more lasting contribution in setting a framework for future
research and critical thinking on the many issues surrounding early diagnosis. We are
grateful to our fellow authors who have contributed their time and expertise to this work.
Such a cooperative effort by many scholars from a variety of disciplines serves as a model
for how important questions concerning diagnosis and therapy will need to be pursued
to find adequate solutions to the puzzle of AD.
We thank the staff at Humana Press for their patience and care in the production of this
volume. We appreciate the effort of Barbara Vericker during the planning and execution
of this work. Her talents have added immeasurably to its successful completion.
Leonard F. M. Scinto, PhD
Kirk R. Daffner, MD
ix