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10.1146/annurev.clinpsy.1.102803.144039
Annu. Rev. Clin. Psychol. 2006. 2:379–88
doi: 10.1146/annurev.clinpsy.1.102803.144039
c 2006 by Annual Reviews. All rights reserved
Copyright MILD COGNITIVE IMPAIRMENT AND DEMENTIA
Annu. Rev. Clin. Psychol. 2006.2:379-388. Downloaded from arjournals.annualreviews.org
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Marilyn S. Albert1 and Deborah Blacker2
1
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore,
Maryland 21212; email: [email protected]
2
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School,
Boston, Massachusetts 02114; email: [email protected]
Key Words
Alzheimer’s disease, MCI, biomarkers, APOE, clinical trials
■ Abstract Mild cognitive impairment (MCI) is a clinical syndrome thought to
represent the transition between normal function and dementia. This review describes
data that support the existence of such a transitional phase, outlines the heterogeneity
of MCI and how that has influenced the evolving concept of MCI, and discusses the
impact of heterogeneity on recent MCI clinical trials.
CONTENTS
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
TRANSITION PHASE BETWEEN NORMAL FUNCTION AND DEMENTIA . . .
HETEROGENEITY OF MILD COGNITIVE IMPAIRMENT . . . . . . . . . . . . . . . . . .
CLINICAL TRIALS IN MILD COGNITIVE IMPAIRMENT . . . . . . . . . . . . . . . . . .
CONCLUSIONS AND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . .
379
380
381
384
385
INTRODUCTION
Dementia, particularly Alzheimer’s disease (AD), was first emphasized as a major
public health problem 30 years ago (Katzman 1976). This led to the development
of widely accepted clinical criteria for use in both clinical and research settings
(Am. Psychiatr. Assoc. 1994, McKhann et al. 1984). Many subsequent studies have
demonstrated that these criteria can be reliably applied across sites and that accuracy of diagnosis in comparison with pathological findings is high (e.g., Blacker
et al. 1994). A large number of clinical trials for cholinesterase inhibitors and memantine ultimately led to approval of five medications for AD. These medications
offer symptomatic relief, but do not alter the rate at which patients decline over
time.
This has increased the urgency of finding better treatments for AD, as the
demographic shift in the population toward greater life expectancy suggests geometrically increasing numbers of AD patients in the coming decades unless
more effective treatments can be developed. An improved understanding of the
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neurobiology of AD has led to optimism that disease-modifying treatments may
be on the horizon (Selkoe 2005). There is, however, concern that if disease is too
far advanced, response to these treatments may be muted. This concern, in turn,
has led to a focus on identifying patients as early as possible in the course of
disease.
Since AD was first described, it has been clear that the symptoms develop gradually over many years (Alzheimer 1907). Thus, it would seem that, by definition,
there must be a prodromal phase of disease during which symptoms are evolving
but the individual does not yet meet criteria for dementia. Various terms have been
used to describe this prodromal phase, but the term “mild cognitive impairment”
(MCI) has gained the widest recognition (Flicker et al. 1991, Petersen et al. 1999).
There has been divergence, however, in how the criteria for MCI have been applied, leading to widely varying estimates of its prevalence in the population (e.g.,
Larrieu et al. 2002, Ritchie et al. 2001) and controversy regarding its utility as a
clinical syndrome (Gauthier & Touchon 2005). The current review discusses these
issues, particularly with regard to prediction of clinical outcome and its impact on
recent clinical trials.
TRANSITION PHASE BETWEEN NORMAL FUNCTION
AND DEMENTIA
Considerable evidence supports the argument that there is a transitional phase between normal function and dementia. Neuropsychological studies of individuals
defined as neither normal nor demented demonstrate progressive declines in cognition over time. These are particularly striking in the area of episodic memory,
but other domains appear to be affected as well (Bennett et al. 2002, Storandt
et al. 2002). These findings are consistent with the fact that the clinical criteria for
dementia require impairment in two or more cognitive domains.
Likewise, studies of imaging and other biomarkers of AD pathology demonstrate alterations in nondemented cognitively impaired individuals that are intermediate between normal individuals and those with mild AD. This is true for
structural magnetic resonance imaging (MRI) measures of the medial temporal
lobe structures targeted by the pathology of AD (e.g., the hippocampus and entorhinal cortex), as well as for measures of whole brain atrophy (Chan et al. 2003,
Jack et al. 2000, Killiany et al. 2000). Functional imaging measures, such as single
photon emission tomography and magnetic resonance spectroscopy, show similar
findings (Johnson et al. 1998, Kantarci et al. 2000). Cerebrospinal fluid measures
of amyloid beta protein and tau in cognitively impaired nondemented individuals
are altered to a lesser degree than that seen in established AD cases (Andreason &
Blennow 2005, Blennow 2004).
Pathological findings in nondemented cognitively impaired individuals are particularly important in this context. Given the difficulty of obtaining brain tissue
at a time that individuals are not demented, it is not surprising that few published
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results are available. The largest sample comes from the Religious Order Study
and includes 37 individuals with a clinical diagnosis of MCI, 60 normal controls,
and 83 cases of AD (Bennett et al. 2005). Of the 37 MCI cases, 40% had a low
likelihood of AD based on NIA-Reagan criteria (NIA-Reagan Working Group
1997), with 60% demonstrating an intermediate or high likelihood of AD. This
was in contrast to the normals, where these proportions were reversed (60% versus
40%, respectively). Only 10% of the cases with clinically diagnosed AD had a
low likelihood of AD based on pathological criteria. A preliminary report from the
Mayo Clinic found that a minority of individuals met pathological criteria for AD
(Petersen et al. 2000). These reports contrast with the findings from Washington
University, where almost all of the cases met pathological criteria for AD (Morris
et al. 2001). This disparity suggests that there is likely variation in the clinical
criteria used to define the cases during life. It is evident that in some sets of cognitively impaired nondemented cases, the proportion of those with a high likelihood
of AD based on pathological criteria is much lower than that among individuals
who meet clinical criteria for AD; however, a substantial number of nondemented
cognitively impaired individuals do meet pathological criteria for AD. It is also
important to note that many of the cases, regardless of clinical diagnosis, had
evidence of vascular disease (Bennett et al. 2005).
Taken together, these findings indicate that it is possible to identify individuals
in a transitional state between normal function and dementia, and that such individuals have cognitive and brain changes that are consistent with a transitional
phase of disease. For research purposes, it seems important to retain the distinctiveness of this phase of disease so that the characteristics of this phase and the
effectiveness of interventions can be carefully studied. For clinical reasons, distinguishing a transitional phase of disease also seems very important, as there remains
considerable variation in the clinical outcome of individuals who are said to be
cognitively impaired but nondemented by various criteria. As discussed further below, this variation is likely the result of the heterogeneity of the population under
study.
HETEROGENEITY OF MILD COGNITIVE IMPAIRMENT
A review of the literature suggests that much of the controversy surrounding the
term “MCI” derives largely from the fact that the criteria have been implemented
in a variety of ways in research settings, while at the same time the syndrome is
more heterogeneous than originally suggested. The clinical criteria have changed
over time in recognition of this heterogeneity. However, a number of important
issues remain to be clarified.
The MCI criteria elucidated by Petersen and colleagues in 1999 implied that
cases of MCI represented a fairly uniform group of individuals (Petersen et al.
1999). These criteria were as follows: (a) memory complaint, corroborated by
an informant if possible, (b) objective memory impairment for age, (c) relatively
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preserved general cognition for age, (d) intact basic activities of daily living, (e)
not demented.
The criteria were modified to permit clinical subtypes with variable outcomes,
based on the presumed etiology underlying the disorder, following studies that
demonstrated MCI cases defined in this manner had a more variable outcome
than had been previously suggested. Based on whether a predominant memory
disorder was present or absent, two primary subtypes were delineated: amnestic
and nonamnestic MCI (Petersen 2004). The revised criteria also acknowledged
the possibility that more than one cognitive domain might be impaired within
each of these subtypes (e.g., amnestic MCI, single or multiple domains impaired).
These revised criteria are conceptually similar to the term “cognitive impairment
no dementia” introduced by the Canadian Study of Health and Aging (Davis &
Rockwood 2004) in that they encompass a broad range of cognitive deficits caused
by multiple etiologies.
In this context, the original clinical criteria for MCI were clearly focused on
amnestic MCI, and Petersen and colleagues were clearly attempting to focus on
individuals likely to be in the prodromal phase of AD. Their work and that of
numerous other groups has since demonstrated that amnestic MCI subjects (single
or multiple domains impaired) are at increased risk of progressing to a diagnosis
of AD over time.
Also unrecognized in the original reports was the importance of the source of
subjects as a factor in both the severity and the nature of the population under study.
In retrospect, it now seems clear that the broader one casts the net of inclusion in
a study, the more likely one is to include individuals with less severe underlying
disease. It is therefore not surprising that studies emerging from memory clinics
in tertiary care settings report the highest proportion of individuals who progress
to meet criteria for AD over time (e.g., Rubin et al. 1989), whereas studies that
recruit broadly from the community (e.g., via the media) are likely to have much
lower rates of “conversion” to AD on follow-up (e.g., Daly et al. 2000). This does
not necessarily mean that the underlying disease process is different, but rather
that the investigators have captured a different range of disease severity within
their study population.
An additional source of variation is introduced when studies are conducted in
epidemiological settings as opposed to clinical settings. In epidemiological settings, it is virtually impossible to require that each subject have an informant (as
is usually the case in clinic-based studies), as epidemiological studies seek to represent the entire range of individuals in the population. Therefore, it is necessary
to rely more heavily on neuropsychological testing as the marker of cognitive decline. This increases the importance of the particular cognitive tests that have been
selected; the reliability and validity of each of the tests is critical, as well as the
range of cognitive domains included in the test battery. For example, if tests are
selected that have a ceiling effect, it is likely that fewer individuals with impairments will be found. Likewise, if a particular cognitive domain is not included
in a test battery (e.g., executive function), it would not be possible to determine
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MCI AND DEMENTIA
383
whether the subjects would have been impaired in that domain. In order to maximize enrollment and follow-up, it is also necessary to reduce the length of the
evaluation in an epidemiological setting, as opposed to a clinical setting, resulting
in less detailed information than is optimal. These restrictions, if applied equally
to all participants, most likely influence the absolute numbers of individuals identified in a particular category (as sensitivity will vary depending on the procedures
employed), but they should not alter the relative proportion of individuals meeting
criteria or the proportion of individuals who change status over time.
As studies of nondemented cognitively impaired individuals expanded to
broader settings, it also became clear that there were substantial numbers of
individuals whose memory impairment was the predominant but not sole cognitive problem that could be seen. Many individuals with prodromal AD were
slightly impaired in other domains (e.g., language or executive function) in addition to memory. Likewise, individuals were seen whose primary cognitive impairment was in domains other than memory (e.g., attention or spatial skill). The
recent revision of the MCI criteria (Petersen 2004) recognizes these findings and
appropriately acknowledges that multiple clinical syndromes by definition must
have a transitional phase during which cognitive impairments are in evolution.
The revised criteria now describe criteria for amnestic MCI (single and multiple
domains impaired), which is thought to represent the majority of individuals who
will progress to a diagnosis of AD over time. Those with nonamnestic MCI (single and multiple domains impaired) are thought to pertain to the transitional phase
of other dementias (e.g., frontotemporal dementia, vascular dementia) as well as
psychiatric disorders (e.g., depression), though in practice these distinctions can
be blurred (e.g., Fisk et al. 2003).
It is therefore necessary to evaluate an MCI case with the same rigor one would
bring to the diagnosis of a patient with dementia. That is, all potential medical,
psychiatric, or neurologic causes of cognitive impairment must be considered before making a diagnosis. The number of nonamnestic MCI cases that have been
followed to a diagnosis of dementia is limited. It is therefore difficult to provide much information about which specific MCI criteria they fit the best and
the numbers of subjects with various non-AD dementias or psychiatric disorders
one is likely to see within a group of MCI cases, defined broadly. There is, however, sufficient evidence to indicate that cases of depression will be included in
this group. Moreover, cases of amnestic MCI that progress to AD are also likely
to have neuropsychiatric symptoms (particularly dysphoria and irritability), thus
making the diagnostic process challenging (Copeland et al. 2003, Hwang et al.
2004).
The increasing recognition of MCI as a heterogeneous syndrome carries with
it the need to clarify the nature of what is normal. Boundary definitions of this sort
are always challenging, but this one is particularly so, since there seems little doubt
that age-related changes of cognition exist. For example, studies of animal models
(e.g., rodents and nonhuman primates) have found significant age-related change
in a number of cognitive domains that demonstrate change during prodromal AD,
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in particular episodic memory and executive function (Albert & Moss 1996). In
this context, it seems likely that differences across studies in the distribution of
neuropathological findings in MCI, as well as in normal controls, are the result of
differing definitions of what is clinically normal.
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CLINICAL TRIALS IN MILD COGNITIVE IMPAIRMENT
The heterogeneity of MCI, with respect to both clinical presentation and severity of underlying disease, has had a marked impact on recent clinical trials in
MCI. Although only a few trials have published findings, a number have reported
preliminary findings in meetings, and some general observations are therefore
possible.
Except for clinical trials of relatively short duration (e.g., 24 weeks), most of
the clinical trials in MCI have followed individuals for several (e.g., three) years
and have used a change in the rate of conversion from MCI to AD as the primary
outcome measure. That is, the primary hypothesis of each clinical trial was that
drug treatment would lower the rate at which MCI cases progressed to a diagnosis
of AD during the follow-up interval. Thus, the power of the study to determine the
efficacy of the drug was dependent on having a sufficient number of patients with
MCI who progressed to clinical dementia of the Alzheimer type during the course
of the study.
The biggest problem experienced by the MCI trials was that they varied widely
in this rate of conversion. The MCI trial of donepezil (a cholinesterase inhibitor) by
the Alzheimer’s Disease Cooperative Study (ADCS) group had a conversion rate
of 16% per year (Petersen et al. 2005). Most of the other MCI trials have reported
lower rates of conversion, with some as low as 6% per year in the treated group.
All of the trials attempted to recruit individuals who met criteria for amnestic
MCI. To better operationalize these criteria, they required that subjects fall below
a cut-off score on a test of episodic memory. The specific memory test and cut-off
score used varied across studies. For example, the donepezil trial used age and
education cut-offs for delayed recall of a story from the Wechsler Memory Scale
(WMS); the cut-offs were designed to represent 1.5 standard deviation (SD) from
the mean for each age and education grouping. The trial of rofecoxib (a COX-2
nonsteroidal anti-inflammatory) by the ADCS used performance on the Auditory
Verbal Learning Test; the criterion originally was a 1.5 SD, but this was later
changed to 1.0 SD when problems with recruitment developed (Thal et al 2005).
The Novartis trial of rivastigmine used a single cut point on recall of one of the
NYU paragraphs (Fioravanti et al 1985), as did the Johnson & Johnson trial of
galantamine (both are cholinesterase inhibitors). It seems likely that the clinical
severity of the subjects varied with the specific cut points employed, and therefore
the likelihood that the subjects would convert to AD over time also varied. This
hypothesis is supported by the fact that the Clinical Dementia Rating scale, Sum
of Boxes score (CDR-SB), a widely used measure of clinical severity, appeared to
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MCI AND DEMENTIA
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differ across the clinical trials (e.g., the mean CDR-SB was 1.8 for the donepezil
study and 1.4 for the rofecoxib study).
Another factor that likely affected rate of conversion was the apolipoprotein
E (APOE) status of the subjects. The ε4 allele of this gene is overrepresented in
AD patients compared with the general population (Saunders et al. 1993), and is
now widely recognized as a risk factor for AD. Although presence of an APOE ε4
allele was not a criterion for entry, the clinical trials varied greatly in the proportion
of individuals who were APOE ε4 positive. The donepezil study had the highest
percentage of subjects who were APOE ε4 positive (55%); this percentage was
35% in the rofecoxib trial and 40% in the rivastigmine trial. Since the APOE
ε4 allele lowers the age of onset of AD (Saunders et al. 1993), it is likely that
this variation in APOE ε4 carrier status also influenced the conversion rate of the
MCI cases across the clinical trials. One hypothesis for the high percentage of
APOE ε4–positive subjects in the donepezil study was that most of the subjects
were recruited through the Alzheimer’s Disease Centers in the United States, and
through their previous experience in studying AD patients (who are more likely to
be APOE ε4 positive than are members of the general population), the researchers
may have developed enriched samples of APOE ε4–positive MCI cases.
This experience with the MCI clinical trials confirms the importance of understanding sources of heterogeneity in MCI. Even when one classifies the syndrome
of MCI into the amnestic subtype (increasing the likelihood that dementia of the
Alzheimer type would evolve over time), there appears to remain substantial variability in outcome over a finite period (such as a three-year clinical trial). It seems
likely that this variability occurs because of differences in the severity of underlying disease rather than because the underlying disease is a different entity (i.e.,
a disorder other than AD). If MCI represents a transitional phase between normal function and dementia, then it is likely that individuals who are cognitively
impaired but not demented will differ in clinical severity across the spectrum of
mild impairment (as do patients with established AD). Those individuals who have
the most severe underlying disease will progress to dementia in the shortest time.
Those who have less severe underlying disease will take longer to progress to a
clinical diagnosis of dementia. If the focus of study is amnestic MCI, then the most
likely outcome will be AD, but the time it takes to reach this end point will vary
depending on the clinical severity of the subjects and, by extension, the underlying
degree of AD pathology.
CONCLUSIONS AND FUTURE DIRECTIONS
The lessons for future clinical trials in MCI seem clear. It will be important to
find ways of quantifying underlying disease severity with greater accuracy in
order to increase the likelihood that a sufficient number of cases will progress to a
diagnosis of AD within the follow-up period. Several options are available for such
an enrichment process, including restricting the level of clinical severity based on
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a standard clinical measure (such as the CDR-SB), including a large number of
APOE ε4 carriers in the pool of participants, or using imaging findings that suggest
greater severity of disease (such as hippocampal atrophy).
It is likely that using a high cut-off score on a difficult memory test (such as the
WMS story used by the ADCS) is the equivalent of restricting the level of clinical
severity as well as the degree of hippocampal atrophy. However, further data are
needed to determine the degree to which these variables are correlated with one
another, as well as with APOE ε4 status. The Alzheimer’s Disease Neuroimaging
Initiative (ADNI), a large multicenter study that started enrolling subjects in the
fall of 2005, will provide valuable data along these lines. The MCI cases being
recruited by ADNI are required to meet the same WMS criteria used by the ADCS.
They will also have MRI scans every six months for three years and will have
APOE ε4 genotyping. Thus, within a relatively short time the contribution of each
of these factors to the likelihood of progression from MCI to AD will become
clearer. The findings can then be used to inform the design of future clinical trials
in MCI.
It will also be important to expand studies of the transition from normal aging
to MCI. Given the neuropathological findings to date, it is evident that many cases
of amnestic MCI have widespread AD pathology. Clinical trials in AD suggest that
early intervention is important in obtaining an optimal treatment response, and this
is likely to be true for future medications as well. It will therefore be necessary
to improve our understanding of the cognitive changes among normal individuals
that are a harbinger of progression to MCI in order to determine the optimal point
at which treatments will be beneficial.
The Annual Review of Clinical Psychology is online at
http://clinpsy.annualreviews.org
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Annual Review of Clinical Psychology
Volume 2, 2006
Annu. Rev. Clin. Psychol. 2006.2:379-388. Downloaded from arjournals.annualreviews.org
by American University of Beirut on 02/02/10. For personal use only.
CONTENTS
THE HISTORY AND EMPIRICAL STATUS OF KEY PSYCHOANALYTIC
CONCEPTS, Lester Luborsky and Marna S. Barrett
DOCTORAL TRAINING IN CLINICAL PSYCHOLOGY, Richard M. McFall
METHODOLOGICAL AND CONCEPTUAL ISSUES IN FUNCTIONAL
MAGNETIC RESONANCE IMAGING: APPLICATIONS TO
SCHIZOPHRENIA RESEARCH, Gregory G. Brown and Lisa T. Eyler
THE USE OF STRUCTURAL ANALYSIS OF SOCIAL BEHAVIOR (SASB) AS
AN ASSESSMENT TOOL, Lorna Smith Benjamin, Jeffrey Conrad
Rothweiler, and Kenneth L. Critchfield
1
21
51
83
REINTERPRETING COMORBIDITY: A MODEL-BASED APPROACH TO
UNDERSTANDING AND CLASSIFYING PSYCHOPATHOLOGY,
Robert F. Krueger and Kristian E. Markon
WOMEN’S MENTAL HEALTH RESEARCH: THE EMERGENCE OF A
BIOMEDICAL FIELD, Mary C. Blehar
POSTTRAUMATIC STRESS DISORDER: ETIOLOGY, EPIDEMIOLOGY, AND
TREATMENT OUTCOME, Terence M. Keane, Amy D. Marshall,
and Casey T. Taft
111
135
161
THE PSYCHOPATHOLOGY AND TREATMENT OF BIPOLAR DISORDER,
David J. Miklowitz and Sheri L. Johnson
199
ATTEMPTED AND COMPLETED SUICIDE IN ADOLESCENCE,
Anthony Spirito and Christianne Esposito-Smythers
ENDOPHENOTYPES IN THE GENETIC ANALYSES OF MENTAL
DISORDERS, Tyrone D. Cannon and Matthew C. Keller
SCHIZOTYPAL PERSONALITY: NEURODEVELOPMENTAL AND
PSYCHOSOCIAL TRAJECTORIES, Adrian Raine
AUTISM FROM DEVELOPMENTAL AND NEUROPSYCHOLOGICAL
PERSPECTIVES, Marian Sigman, Sarah J. Spence, and A. Ting Wang
OBESITY, Anthony N. Fabricatore and Thomas A. Wadden
MILD COGNITIVE IMPAIRMENT AND DEMENTIA,
Marilyn S. Albert and Deborah Blacker
237
267
291
327
357
379
vii
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viii
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Annual Reviews
AR271-FM
CONTENTS
COGNITION AND AGING IN PSYCHOPATHOLOGY: FOCUS ON
SCHIZOPHRENIA AND DEPRESSION, Philip D. Harvey, Abraham
Reichenberg, and Christopher R. Bowie
CONTINGENCY MANAGEMENT FOR TREATMENT OF SUBSTANCE
ABUSE, Maxine Stitzer and Nancy Petry
PERSONALITY AND RISK OF PHYSICAL ILLNESS, Timothy W. Smith and
Justin MacKenzie
Annu. Rev. Clin. Psychol. 2006.2:379-388. Downloaded from arjournals.annualreviews.org
by American University of Beirut on 02/02/10. For personal use only.
RECOVERED MEMORIES, Elizabeth F. Loftus and Deborah Davis
389
411
435
469
INDEX
Subject Index
ERRATA
An online log of corrections to Annual Review of Clinical Psychology chapters
(if any) may be found at http://www.AnnualReviews.org
499