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Mild Cognitive Impairment Represents Early-Stage Alzheimer Disease
John C. Morris, MD;
Martha Storandt, PhD;
J. Phillip Miller;
Daniel W. McKeel, MD;
Joseph L. Price, PhD;
Eugene H. Rubin, MD, PhD;
Leonard Berg, MD
Arch Neurol. 2001;58:397-405.
ABSTRACT
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Background Mild cognitive impairment (MCI) is considered to be a transitional stage
between aging and Alzheimer disease (AD).
Objective To determine whether MCI represents early-stage AD by examining its
natural history and neuropathologic basis.
Design A prospective clinical and psychometric study of community-living elderly
volunteers, both nondemented and minimally cognitively impaired, followed
up for up to 9.5 years. Neuropathologic examinations were performed on participants
who had undergone autopsy.
Setting An AD research center.
Participants All participants enrolled between July 1990 and June 1997 with Clinical
Dementia Rating (CDR) scores of 0 (cognitively healthy; n = 177; mean age,
78.9 years) or 0.5 (equivalent to MCI; n = 277; mean age, 76.9 years). Based
on the degree of clinical confidence that MCI represented dementia of the
Alzheimer type (DAT), 3 subgroups of individuals with CDR scores of 0.5 were
identified: CDR 0.5/DAT, CDR 0.5/incipient DAT, and CDR 0.5/uncertain dementia.
Main Outcome Measure Progression to the stage of CDR 1, which characterizes mild definite
DAT.
Results Survival analysis showed that 100% of CDR 0.5/DAT participants progressed
to greater dementia severity over a 9.5-year period. At 5 years, rates of
progression to a score of CDR 1 (or greater) for DAT were 60.5% (95% confidence
interval [CI], 50.2%-70.8%) for the CDR 0.5/DAT group, 35.7% (95% CI, 21.0%-50.3%)
for the CDR 0.5/incipient DAT group, 19.9% (95% CI, 8.0%-31.8%) for the CDR
0.5/uncertain dementia group, and 6.8% (95% CI, 2.2%-11.3%) for CDR 0/controls.
Progression to greater dementia severity correlated with degree of cognitive
impairment at baseline. Twenty-four of the 25 participants with scores of
CDR 0.5 had a neuropathologic dementing disorder, which was AD in 21 (84%).
Conclusions Individuals currently characterized as having MCI progress steadily
to greater stages of dementia severity at rates dependent on the level of
cognitive impairment at entry and they almost always have the neuropathologic
features of AD. We conclude that MCI generally represents early-stage AD.
INTRODUCTION
MILD COGNITIVE impairment (MCI) is conceptualized as a boundary or transitional
state between aging and dementia.1 Memory deficit
is both the usual complaint in MCI and the cardinal feature of Alzheimer disease
(AD). The major focus of MCI research has been to distinguish individuals
who will progress to AD from those who will not.1, 2, 3, 4, 5, 6, 7, 8, 9
Interest in MCI has been stimulated by the hope that pharmacologic intervention
at this stage may delay or prevent progression to AD.10
Multicenter trials of cholinesterase inhibitor drugs and other agents with
putative benefit for AD already are being conducted in individuals with MCI.
The diagnosis of MCI is established by (1) evidence of memory impairment,
(2) preservation of general cognitive and functional abilities, and (3) absence
of diagnosed dementia.3 Mild cognitive impairment
is staged clinically at the 0.5 level on the Clinical Dementia Rating (CDR)
scale.11 Memory deficit in MCI is quantitated
by scores greater than 1.5 SDs below that of age-appropriate norms on measures
of episodic memory. However, the other MCI criteria are subjective and can
be difficult to operationalize. For example, scores in the normal range for
age on the Mini-Mental State Examination (MMSE)12
are assumed to indicate preserved general cognitive abilities, although brief
cognitive tests such as the MMSE often are insensitive to early-stage dementia.5, 13, 14 The perceptions of
a knowledgeable informant regarding an individual's cognitive abilities in
everyday functioning, on the other hand, have been shown to be sensitive and
reliable for early dementia detection.15, 16, 17, 18, 19
Overdependence on cognitive test performance and underutilization of
knowledgeable informants may result in failure to detect very mild dementia
in many individuals who nominally meet MCI criteria. Progression of patients
with MCI to "diagnosable AD" may be confounded because the threshold for dementia
diagnosis20 may vary considerably among clinicians
and may require long observation periods, since the mildest forms of AD are
marked by slow rates of cognitive decline.21, 22
Even so, MCI progresses to AD at rates of 10% to 15% per year,1, 2, 4, 5, 6, 23
suggesting that many MCI cases actually are AD. Support for this possibility
also comes from our experience with minimally impaired individuals in whom
AD almost always is the responsible neuropathologic disorder.24, 25, 26
For these reasons, we hypothesize that most MCI cases represent unrecognized
very mild AD. To test this hypothesis, we studied individuals with the CDR
0.5 level of cognitive impairment encompassed by MCI to determine their rate
of progression to more overt stages of dementia over a 9.5-year period in
comparison with nondemented older adults. We also examined the clinicopathologic
correlates of nondemented aging, MCI, and very mild AD.
SUBJECTS AND METHODS
CLINICAL DATA
Subjects were participants who enrolled in our longitudinal study (inaugurated
in 1979) of healthy aging and dementia of the Alzheimer type (DAT) between
July 1990 and June 1997 and were either nondemented or had very mild cognitive
difficulties. The period of study reflects the initiation in our protocol
in July 1990 of a classification scheme that predicts whether mildly impaired
participants will progress to greater dementia severity; eligible subjects
entered after June 1997 were not included to allow surveillance through December
1999. Individuals living in the greater St Louis, Mo, community were eligible
for enrollment. The recruitment and assessment methods have been described
previously and are based on media appeals for both healthy and cognitively
impaired persons.27, 28 All participants
are assessed annually unless prevented by death, refusal, or relocation far
from St Louis.
Four hundred four participants who met eligibility criteria and were
between the ages of 45 and 103 years were enrolled with either a CDR 0 (n
= 177) or a CDR 0.5 (n = 227) score, where CDR 0 indicates no dementia. Clinical
and neuropathologic data obtained through December 1999 were used for analysis.
All procedures were approved by the Washington University Human Studies Committee.
Data from some individuals reported herein have been included in previous
reports from our center.25, 26, 28
The inclusionary and exclusionary clinical diagnostic criteria for DAT
used in this study have been validated.29 These
criteria require the gradual onset and progression of impairment in memory
and in at least 3 other cognitive and functional domains. Other known neurologic,
medical, or psychiatric disorders with the potential to cause dementia must
be absent. These clinical diagnostic criteria are comparable to but more stringent
(because impairment in 4 domains is required) than those for "probable AD"
as reported by the work group convened by the National Institute of Neurological
and Communicative Disorders and Stroke and Alzheimer's Disease and Related
Disorders Association.30 Diagnostic accuracy
for AD with these criteria is 93% (AD confirmed histologically in 193 of 207
consecutive autopsies of individuals with DAT).28
Nondemented controls who lack known causes of dementia and have no cognitive
or functional impairment also are enrolled.
The determination of DAT or control status is based solely on clinical
methods, without reference to psychometric performance. Experienced neurologists,
psychiatrists, geriatricians, and master's-prepared nurse clinicians conduct
semistructured interviews with the participant and with a collateral source
(generally the spouse or adult child) who is knowledgeable about the participant;
a neurologic examination of the participant also is conducted. Clinicians
are assigned randomly to each assessment. At entry and every 2 years thereafter,
the assessment interviews (collateral source and participant) are videotaped
for later independent review by a second randomly chosen clinician. Examiners
and reviewers are not aware of findings from previous assessments.
The assessment protocol contains items from standard brief cognitive
batteries, including the MMSE and the Short Blessed Test (SBT),31
but the items are dispersed such that a score cannot be readily discerned.
The diagnosis of DAT is based on the clinical information (derived primarily
from the collateral source) that the participant has experienced the gradual
onset and progression of memory and other cognitive problems that represent
a decline from that individual's previous level of function and interfere,
at least to some degree, with performance of accustomed activities in the
community and at home. Support for the diagnosis is sought from the individual's
responses to relevant queries, including recall of recently experienced personal
events (eg, visit from an out-of-town relative) and of new material (eg, a
fictitious name and address); recall of highly learned personal information
(eg, name of last school attended); temporal and geographic orientation; and
abstract reasoning as measured by performance on similarities and differences,
calculations (eg, determining the number of quarters in $6.75), and problem
solving. The assessment protocol also contains visuoconstructive tasks (eg,
clock drawing), a depression inventory, aphasia battery, health history, and
medication inventory.27, 29
The CDR11, 32 is a dementia
staging instrument used to rate cognitive function along 5 levels of impairment
from none to maximal (rated as 0, 0.5, 1, 2, or 3) in each of 6 domains: memory,
orientation, judgment and problem solving, function in community affairs,
home and hobbies, and personal care. (Personal care has no 0.5 impairment
level.) Only impairment caused by cognitive dysfunction is rated. Community
affairs and home and hobbies assess instrumental activities of daily living
relevant to the individual and hence vary according to that person's accustomed
activities; examples include job performance for those who still are employed
and skills in driving, home repairs, household finances, shopping, cooking,
and card games. Personal care represents basic activities of daily living
common to almost all individuals (dressing, bathing and grooming, eating,
and continence).
Based on the collateral source and participant interviews, a global
CDR score is derived from individual ratings in each domain such that CDR
0 indicates no dementia and CDR 0.5, 1, 2, and 3 represent very mild, mild,
moderate, and severe dementia, respectively. Interrater reliability for the
CDR has been established.33, 34, 35
The CDR 0.5 stage originally was designated "questionable dementia."32 With experience, we recognized that this CDR stage
often represents the earliest symptomatic stage of AD ("very mild dementia").24 Not all domains need be rated at the same level of
impairment as the global CDR score; for example, a participant may merit a
box score of 1 for memory but scores of 0.5 or 0 for other domains and still
have a global CDR of 0.5. The individual ratings can be totaled to yield the
sum boxes,36 a more quantitative rating that
ranges from 0 (0 x 6, or no impairment in any of the 6 domains) to 18
(3 x 6, or maximal impairment in each of the 6 domains).
Beginning in July 1990, all participants with a global CDR 0.5 score
were categorized on clinical grounds into 1 of 3 groups: (1) CDR 0.5/DAT,
with impairment (0.5 or greater) in memory and at least 3 of the 5 remaining
CDR domains; (2) CDR 0.5/incipient DAT, with impairment in memory and 2 or
fewer remaining CDR domains; and (3) CDR 0.5/uncertain dementia, generally
when memory only was impaired at the 0.5 level or the impairment was doubtful
(eg, in the situation where a "worried-well" individual proclaims serious
memory loss that is inapparent to the collateral source and does not interfer
with usual function). Diagnostic confidence for DAT at the CDR 0.5 level increased
from CDR 0.5/uncertain dementia to CDR 0.5/incipient DAT to CDR 0.5/DAT. Categorization
was based on the clinician's judgment following the clinical assessment that
the participant had early-stage DAT (either CDR 0.5/DAT or CDR 0.5/incipient
DAT, depending on the number of impaired CDR domains) or that it could not
be determined whether the participant was demented or healthy (CDR 0.5/uncertain
dementia). In keeping with the expectation that CDR 0.5/DAT and CDR 0.5/incipient
DAT represented early-stage AD, these 2 groups were predicted to progress
in dementia severity with time to CDR 1 or greater. Because the CDR 0.5/incipient
DAT group was less impaired (fewer CDR domains affected), they were expected
to progress at a lesser rate than the CDR 0.5/DAT group. The CDR 0.5/uncertain
dementia participants were expected to be heterogeneous, some perhaps with
very early-stage AD and others who were cognitively normal but mildly depressed
or worried, and hence as a group were predicted not to progress or to progress
only very slowly.
EXPIRATION SUMMARY
In all participants who undergo autopsy, a validated retrospective postmortem
interview is conducted with the informant to assess cognitive status from
time of last assessment until death.37 Before
the results of the autopsy are known, a senior clinician reviews all clinical
assessments and the postmortem interview and generates an expiration summary.
The expiration summary yields a final CDR score and dementia diagnosis for
the participant.28
APOE GENOTYPING
Beginning in 1993, restriction enzyme isotyping of the apolipoprotein
E (APOE) allele was performed as described previously.38 Genotype results were not available to clinicians
and hence were not used diagnostically.
PSYCHOMETRICS
A 1.5-hour psychometric battery is administered to all participants
by trained psychometricians at each assessment as described in detail elsewhere.39 Testing usually takes place 1 to 2 weeks after the
clinical assessment; the psychometric results are unknown to the clinician
and do not enter into diagnosis or CDR staging. The psychometrician is unaware
of the participant's CDR score and diagnosis. The battery includes 4 measures
of episodic memory: logical memory, digit span (forward and backward), and
associate learning from the Wechsler Memory Scale (WMS)40
and the Benton Visual Retention Test,41 where
form C assesses nonverbal memory (administered according to 10-second exposure
recall instructions). Also included are 3 measures of semantic memory: the
information subtest of the Wechsler Adult Intelligence Scale (WAIS),42 the Boston Naming Test,43
and Word Fluency for S and P.44 Four speeded
measures of psychomotor and visuospatial ability address executive functions:
WAIS digit symbol, WAIS block design, Trail-Making Test part A,45
and Crossing-off.46 An attentional measure
(WMS mental control) and nontimed visuospatial measure (form D of the Visual
Retention Test) complete the battery. Scoring procedures for this battery
have been described.39
NEUROPATHOLOGY
Brains were examined by standard protocol as described previously.47, 48 Following fixation with neutral phosphate-buffered
10% formalin (3.7% formaldehyde by volume), brains were sectioned (1-cm intervals)
in the coronal plane, and tissue blocks taken from midfrontal, temporal, inferior
parietal, and occipital calcarine and visual association neocortex, hippocampal
formation, entorhinal cortex, nucleus basalis of Meynert, midbrain/substantia
nigra, pons/locus ceruleus, cerebellum, and other regions. Sections (6-µm)
from paraffin-embedded tissue blocks were stained routinely with hematoxylin-eosin
and modified Bielschowsky methods.47 Histologic
criteria reported by Khachaturian49 were used
with modification for the neuropathologic diagnosis of AD as described previously.28
STATISTICAL ANALYSIS
Progression to at least mild dementia severity, defined by a score of
CDR 1 or greater, was the primary outcome measure. Rate of progression was
estimated as a function of the length of follow-up using the Kaplan-Meier
product limit estimator. The relation of each demographic, clinical, and psychometric
measure to development of CDR 1 or greater was examined using the nonparametric
log-rank test. All calculations were performed by SAS statistical software
(SAS Institute, Cary, NC). Means are reported with SDs or 95% confidence intervals
(CIs), as appropriate.
RESULTS
BASELINE
Entry characteristics for the CDR 0/control, CDR 0.5/uncertain dementia,
CDR 0.5/incipient DAT, and CDR 0.5/DAT groups are shown in Table 1. The mean (SD) number of prescription medications used by
participants (data not shown) ranged from 2.1 (1.9) in the CDR 0/control group
to 2.4 (1.9) in the CDR 0.5/uncertain dementia group and was comparable to
the frequency of medication use in a community survey of similarly aged persons.50 Major affective disorder was excluded at entry. Depressive
features were defined by the Diagnostic and Statistical
Manual of Mental Disorders, Third Edition,20
criteria for a major depressive episode. The number of depressive features
(maximum of 9) reported by subjects was low (data not shown); the CDR 0.5/uncertain
dementia participants reported a mean of 1.5 (2.3) features, whereas the mean
for all other groups was less than 1. A greater frequency of the APOE  4 allele was found in CDR 0.5 compared with CDR 0 participants
and increased with diagnostic certainty for DAT across the CDR 0.5 groups.
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Table 1. Baseline Variables and Relation to Progression to a Clinical
Dementia Rating (CDR) of 1 or Greater*
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Impairment in individual cognitive domains rated by the CDR (Figure 1) showed that virtually all CDR 0.5
individuals were impaired in memory (vs none of the CDR 0 individuals); the
second most frequently impaired domain was judgment and problem solving. The
CDR 0.5/DAT participants had impairment in multiple domains (required for
DAT diagnosis) and more often had greater impairment (ie, at the 1 level)
than the CDR 0.5/incipient DAT and CDR 0.5/uncertain dementia individuals;
the greater impairment was especially notable for memory. The CDR sum boxes
(Table 1) reflect this greater
impairment. Data for personal care, which cannot be rated as 0.5, are not
shown in the Figure 1; 0%, 7%, 0%,
and 10% of the CDR 0/control, CDR 0.5/uncertain dementia, CDR 0.5/incipient
DAT, and CDR 0.5/DAT participants received a rating of 1 in personal care.
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Figure 1. Percentage of participants impaired
at baseline at the 0.5 (open portion) or 1 (shaded portion) level in Clinical
Dementia Rating (CDR) domains (memory, orientation, judgment and problem solving,
community affairs, and home and hobbies) is shown for the 4 diagnostic groups.
Con indicates CDR 0/controls; Unc, CDR 0.5/uncertain dementia group; Inc,
CDR 0.5/incipient dementia of the Alzheimer type; and DAT, CDR 0.5/dementia
of the Alzheimer type.
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The CDR and, correspondingly, the sum boxes represent the clinician's
judgment, synthesized from the informant and participant information, about
the presence or absence of cognitive impairment. Informant reports of memory
problems sufficient to interfere with performance of everyday functions were
frequent in the CDR 0.5 participants but very unusual for CDR 0 participants
(Table 1). Self-reported memory
problems occurred frequently in CDR 0 participants and hence did not reliably
distinguish the CDR 0 group from the CDR 0.5 groups.17
The SBT, which incorporates a 5-item recall of a fictitious name and address,
shows worse performance compared with controls in each of the CDR 0.5 groups.
The overall degree of impairment on the SBT was very mild for all groups.51 Performance on the SBT and on the MMSE corresponded
with the degree of diagnostic certainty about DAT, because the CDR 0.5/incipient
DAT and CDR 0.5/DAT groups performed more poorly than the CDR 0/control and
CDR 0.5/uncertain dementia groups. Even the CDR 0.5/DAT group, however, had
a mean MMSE score just at the lower range of "normal" cognitive status.4, 52, 53
Psychometric performance data for the 4 diagnostic groups also are shown
in Table 1. In a hierarchical
pattern (CDR 0.5/DAT worse than CDR 0.5/incipient DAT worse than CDR 0.5/uncertain
dementia), the CDR 0.5 participants performed more poorly than CDR 0 individuals
on measures of episodic memory (logical memory, associate learning, Visual
Retention Test form C), semantic memory (information, Boston Naming Test),
executive function (Trail-Making Test part A, digit symbol), and visuospatial
abilities (block design). Immediate memory (digit span), attentional performance
(mental control), and copying ability (Visual Retention Test form D) were
comparable across CDR 0.5 and CDR 0 groups. The CDR 0.5 groups thus demonstrate
an identical pattern of cognitive impairment, differing only in severity.
FOLLOW-UP
Figure 2 shows the survival
analysis by diagnostic group for progression to CDR 1 status or greater over
the 9.5-year observation period. Because enrollment was continuous, the period
of observation varied for participants. The sample as a whole had a mean follow-up
period of 5.1 years (2.0 years). The 5-year rates of progression to CDR 1
or greater (with 95% CIs) are 6.8% (2.2%-11.3%) for CDR 0/controls, 19.9%
(8.0%-31.8%) for CDR 0.5/uncertain dementia, 35.7% (21.0%-50.3%) for CDR 0.5/incipient
DAT, and 60.5% (50.2%-70.8%) for CDR 0.5/DAT groups. These rates are comparable
with those reported for community samples of similarly aged controls and for
patients with MCI.1, 6
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Figure 2. Rate of progression to outcome
(reaching Clinical Dementia Rating [CDR] score of  1) for each of the 4
diagnostic groups. CDR 0 indicates controls; Uncertain, participants with
uncertain dementia; Incipient, participants with incipient dementia of the
Alzheimer type; and DAT, dementia of the Alzheimer type.
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The predictive value of baseline features for progression to CDR 1 or
greater status in CDR 0.5 participants is shown in Table 1. Among the clinical measures, CDR sum boxes, SBT performance,
and informant report of memory problem interfering with usual activities were
significant predictors; CDR sum boxes had the largest  2 values.
Most of the psychometric measures also were significant predictors. Logical
memory had the largest 2 value, although it should be pointed
out that all indicators were correlated.
NEUROPATHOLOGY
Table 2 shows the clinicopathologic
correlations in all participants with postmortem examinations who died on
or before December 31, 1999.
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Table 2. Clinicopathologic Correlations in 42 Cases*
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Seven of the 8 CDR 0 participants who remained nondemented at the time
of the expiration summary did not meet neuropathologic criteria for AD; the
remaining nondemented participant had histologic AD, consistent with preclinical
AD.26 Nine participants who were CDR 0 at baseline
developed dementia at the CDR 0.5 or greater level by time of death. Of these,
8 had neuropathologic AD and the remaining participant had vascular dementia
(the clinical diagnosis had been DAT).
In the CDR 0.5/uncertain dementia participants, all 6 who underwent
autopsy had neuropathologic AD, including one who, while rated CDR 0.5 at
entry, at expiration summary was considered to be nondemented (CDR 0). Seven
of the 8 CDR 0.5/incipient DAT participants with postmortem assessments had
neuropathologic AD, including 2 who remained in the incipient DAT diagnostic
category at death. The remaining participant had vascular dementia; of note,
this participant was the only CDR 0.5/incipient subject to have no memory
impairment (rated 0 in the memory domain) at entry. Eight of the 11 CDR 0.5/DAT
participants who had undergone autopsy had AD, including 8 of 10 who were
considered to be demented at death (one participant was eventually considered
to be nondemented and had a normal brain). The remaining neuropathologic diagnoses
were frontotemporal dementia in one and vascular dementia in the other. For
all participants with a CDR 0.5 score at entry, 21 (84%) had histologic AD,
2 had vascular dementia, 1 had frontotemporal dementia, and 1 had a normal
brain. Thus, 24 (96%) of the 25 CDR 0.5 participants had a dementing illness.
The AD cases frequently had associated neuropathologic findings, most commonly
cerebral infarcts but also cortical and nigral Lewy bodies, cerebral trauma,
and tumors.
COMMENT
The main finding from this study is that individuals considered by current
criteria to have only MCI in fact have very mild AD. Strong evidence supports
this conclusion. Cognitive impairment in individuals with MCI very often is
not limited to memory but involves other cognitive domains (as assessed both
clinically and psychometrically) and is sufficient to interfere with performance
of activities of daily living as reported by an informant. These individuals
thus satisfy criteria for dementia.20 Predictable
progression to more severe stages of DAT occurs in MCI at a rate that depends
on the severity of impairment at baseline21, 22;
the more impaired individuals with MCI uniformly progress in global dementia
severity within 10 years. Finally, the neuropathologic features of MCI overwhelmingly
are that of AD.
How comparable is our sample to published MCI series, particularly because
we equate our CDR 0.5 participants to MCI without requiring quantitative memory
deficit for diagnosis? Our sample is equivalent on demographic and cognitive
features to those reported by Tierney and colleagues,4
Howieson and coworkers,23 and Devanand and
colleagues5 except that our participants were
younger than those of Howieson et al and older than those of Tierney et al
and Devanand et al. Our CDR 0/control participants are equivalent for age,
education, sex, APOE status, MMSE performance, CDR
sum boxes, and risk for development of DAT to the community-based control
sample of the Mayo Clinic MCI study.1 Our CDR
0.5/DAT participants are comparable on these same features to their category
of "AD, CDR 0.5," and our CDR 0.5/incipient DAT participants are similar to
their category of "MCI, CDR 0.5"; the Mayo Clinic investigators did not report
a category equivalent to our CDR 0.5/uncertain dementia participants. Comparison
of memory deficits, as measured by WMS logical memory, for the Mayo Clinic
subjects and our participants is indirect, since the Mayo Clinic group used
the revised version of this measure and we used the original version; also,
we measure only immediate recall, although we find performances on immediate
and delayed recall to be highly correlated.54
In our study, 7% of CDR 0, 16% of CDR 0.5/uncertain dementia, 28% of CDR 0.5/incipient
DAT, and 52% of CDR 0.5/DAT participants performed 1.5 SDs below the mean
of our CDR 0/control group on logical memory, whereas all of the Mayo Clinic
"MCI, CDR 0.5" and "AD, CDR 0.5" subjects appear to score more than 1.5 SDs
below the performance of their controls. This comparison is consistent with
the slightly lower mean MMSE score (22.6) for their "AD, CDR 0.5" group vs
the MMSE score (23.7) for our CDR 0.5/DAT group and may indicate that the
Mayo Clinic investigators used the CDR 0.5 designation for a slightly more
cognitively impaired group than do we. Our sample thus contains many participants
who meet MCI criteria (but who we already diagnose with DAT) and many others
with less cognitive impairment than is required for a diagnosis of MCI.
How can we diagnose AD in such minimally impaired participants, especially
since many physicians are uncomfortable in classifying patients with MCI as
having AD?1 First, we expect cognitive function
in truly nondemented elderly patients to be unaccompanied by substantive decline.
Rather than accepting memory failure as part of aging, in the absence of disease
we anticipate relatively stable performance over time; this expectation has
been confirmed by us and others.22, 23, 55, 56, 57
We therefore suspect even mild impairment as an abnormal rather than a benign
accompaniment of age. Second, we operationalize "impairment" as the functional
consequences of cognitively related interference with the performance of activities
of daily living. Activities need not be relinquished to meet the interference
criterion but simply performed less well than before because of cognitive
loss. Third, we rely on informant observations to identify early cognitive
change and functional impairment. Perhaps uniquely among programs investigating
aging, MCI, and early-stage AD, we keep the clinical diagnostic process independent
of neuropsychological test scores (even the SBT and MMSE) because individual
performance differences on cognitive measures may obscure the distinction
between nondemented aging and very mild DAT,14, 39, 58
whereas informant-based detection methods contrast the current and previous
cognitive abilities of the individual and are sensitive to even the mildest
stages of DAT.17
Within the 3 CDR 0.5 groups reported herein, rate of progression to
more severe stages of DAT correlated with dementia severity at entry. We predicted
that the CDR 0.5/DAT and CDR 0.5/incipient DAT groups would progress over
time (the incipient DAT group less so because it was less impaired at entry)
and that AD would be the responsible disorder for the dementia. These predictions
were correct. We predicted also that the CDR 0.5/uncertain dementia group
would be heterogeneous and would not substantially progress. Although the
rate of progression in this group is not much greater than that of control
participants, the neuropathologic findings (all 6 decedents in this group
had AD) suggest that any CDR 0.5 designation, even at the uncertain dementia
diagnostic level, may predict AD. Longer periods of observation may be necessary
to determine the rate of progression to more severe stages of DAT in very
minimally impaired individuals, but at least for some participants it appears
that the CDR 0.5/uncertain dementia classification may represent the earliest
symptomatic stage of DAT.
Selective attrition may have skewed the neuropathologic findings (eg,
participants in the CDR 0.5/uncertain dementia group with AD may be more likely
to die and undergo autopsy than those who did not have AD). Even so, in the
11 autopsy participants from all groups who were rated CDR 0.5 at expiration
summary, 9 had AD and 2 had vascular dementia. For comparison, in the 10 autopsy
participants from all groups who at expiration summary were rated CDR 0, AD
was absent in 8; the remaining 2 were considered to have preclinical AD.26 These data indicate that the CDR 0 vs CDR 0.5 distinction
is valid and further supports the conclusion that CDR 0.5 designates "very
mild dementia" rather than "questionable dementia."
Our study has limitations. It was restricted to individuals in whom
the diagnostic distinction was between nondemented aging and DAT, and thus
we cannot address MCI caused by other conditions. Our informant-based assessment
methods may not be applicable in all situations, such as population surveys
where a reliable informant cannot be ensured for all individuals. As with
any volunteer cohort, there may be selection biases in our sample. Our participants,
however, were drawn from the community rather than by referral from memory
disorder clinics and have attributes identical to those reported for free-living
older adults, including the frequency of prescription medication use,50 the rate at which nondemented participants develop
AD,1 and the presence of comorbid disorders
at autopsy. Thus, there is no obvious reason to consider this sample as any
different from other longitudinal samples of aging and very mild dementia.
The unique aspects of this study relate to the long surveillance period (9.5
years) and the extensive clinicopathologic data.
The implications of our major finding, that MCI represents early-stage
AD, potentially are enormous. Two large population-based studies of older
adults indicate that the prevalence of MCI is more than double that of dementia.
The Canadian Study of Health and Aging59 reported
the prevalence of "cognitive impairment, no dementia" to be 16.8% in individuals
older than 64 years, whereas the Italian Longitudinal Study on Aging60 found the prevalence of "cognitive impairment, no
dementia" to be 10.7% and of "age related cognitive decline" to be 7.5% in
subjects aged 65 to 84 years. The prevalence of dementia in these studies
was 8% and 5.5%, respectively. Combined with our findings that many individuals
labeled as having MCI have diagnosable DAT, these data suggest that the true
prevalence of AD may be much greater than is appreciated.
This study also demonstrates that DAT can be diagnosed at earlier stages
than currently is practiced. Early recognition of dementia may alleviate uncertainty
by patients and their families as to the true cause of the perceived cognitive
decline, permit patients to participate in planning for their future at a
stage when decision-making capacity is only minimally affected, and allow
early access to dementia therapy with the goal of maximizing a period of relatively
good function, although it is not yet proven that currently available cholinesterase
inhibitor drugs benefit very mild DAT as they do mild-moderate DAT. Finally,
future clinical trial designs for antidementia agents that incorporate a placebo
treatment arm will need to consider the ethical and practical implications
of withholding active treatment from individuals with very mild DAT.61
AUTHOR INFORMATION
Accepted for publication November 14, 2000.
This study was supported by grants AG 03991 and AG 05681 from the National
Institute on Aging, Bethesda, Md.
A preliminary version of this study was presented at the Second Annual
Leonard Berg Symposium, St Louis, Mo, September 30 and October 1, 1999. (The
Berg Symposium was supported by an unrestricted educational grant from Eisai
Inc, Teaneck, NJ, and Pfizer Inc, New York, NY.)
We are indebted to Elizabeth A. Grant, PhD, and Jack Baty, BA, for data
analysis; Alison Goate, DPhil, for APOE data; the investigators
and staff of the Memory and Aging Project for clinical and psychometric assessments;
and Robert Schmidt, MD, Arie Perry, MD, and Kevin Roth, MD, of the Department
of Pathology, Washington University, St Louis, Mo, for postmortem assessments.
The manuscript was expertly prepared by Nancy J. Ogle and Virginia Buckles,
PhD.
From the Departments of Neurology (Drs Morris, Storandt, and Berg),
Psychology (Dr Storandt), Pathology (Drs Morris and McKeel), Anatomy and Neurobiology
(Dr Price), and Psychiatry (Dr Rubin), Division of Biostatistics (Mr Miller),
and Alzheimer's Disease Research Center (Drs Morris, Storandt, McKeel, Price,
Rubin, and Berg and Mr Miller), Washington University, St Louis, Mo.
Corresponding author and reprints: John C. Morris, MD, Alzheimer's
Disease Research Center, Washington University School of Medicine, 4488 Forest
Park Ave, Suite 130, St Louis, MO 63178.
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