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Mild Cognitive Impairments Predict Dementia in Nondemented Elderly Patients With Memory Loss
Andrea Bozoki, MD;
Bruno Giordani, PhD;
Judith L. Heidebrink, MD;
Stanley Berent, PhD;
Norman L. Foster, MD
Arch Neurol. 2001;58:411-416.
ABSTRACT
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Background Some elderly individuals exhibit significant memory deficits but do
not have dementia because their general intellect is preserved and they have
no impairments in everyday activities. These symptoms are often a precursor
to Alzheimer disease (AD), but sometimes dementia does not occur, even after
many years of observation. There is currently no reliable way to distinguish
between these 2 possible outcomes in an individual patient. We hypothesized
that clear impairments in at least 1 cognitive domain in addition to memory
would help identify those who will progress to AD.
Objective To determine whether nondemented patients with impairments in memory
and other domains are more likely than those with memory impairment alone
to develop AD.
Design and Methods In a retrospective study, we evaluated 48 nondemented, nondepressed
patients with clinical and psychometric evidence of memory impairment who
were followed up for 2 or more years. Age-adjusted normative criteria were
used to identify whether additional impairments were present in language,
attention, motor visuospatial function, and verbal fluency at this initial
evaluation. The presence or absence of dementia after 2 years and at the most
recent neurological evaluation was compared in subjects with normal scores
in all 4 of these cognitive areas apart from memory (M-) and those with
impairment in 1 or more of these areas (M+). Outcomes were adjusted for age,
intelligence at initial evaluation, and years of education.
Results Of the 48 nondemented patients with memory loss, 17 met M- criteria,
leaving 31 in the M+ group. Deficits in block design were the most frequent
abnormality other than memory loss. At the 2-year follow-up, 1 M- subject
(6%) had progressed to AD, whereas 15 (48%) of the M+ group had progressed
to AD (P = .003). At the most recent follow-up (mean
± SD, 4.0 ± 2.0 years), 4 (24%) of the M- patients progressed
to AD compared with 24 (77%) of the M+ patients (P<.001).
Conclusions Among nondemented elderly patients, memory loss alone rarely progresses
to dementia in the subsequent 2 years. However, the risk of dementia is significantly
increased among patients with clear cognitive impairments beyond memory loss.
Further study is needed to determine whether patients with impairments limited
to memory loss have a distinctive clinical course or pathophysiology.
INTRODUCTION
MANY OLDER adults complain of memory loss, and some show demonstrable
memory impairment. For individuals with memory impairment but preserved general
intellect and activities of daily living, prognosis is uncertain. In some
cases, this pattern of cognitive deficits may indicate the earliest symptoms
of dementia. Others will have a more benign course.
Different criteria have been used to define the features that may predict
progression to dementia. In particular, researchers have focused on declines
in episodic memory, since this cognitive system is known to be affected earliest
and most profoundly by Alzheimer disease (AD).1, 2
Memory deficits can also appear as an isolated problem in otherwise healthy
older subjects, referred to in some past studies as age-associated memory
impairment (AAMI).3, 4, 5
Since the most prominent early symptom of AD is "specific, gradual and
progressive memory loss,"6 we chose to identify
individuals with predominant difficulties in the areas of learning and immediate
memory but with intact general intellectual function. It was believed that
this classification, isolated memory impairment (IMI), would represent, in
effect, a possible pre-AD state. The IMI designation was developed in 1989
when subject enrollment began, based largely on then-prevalent AAMI criteria.
Corroborating this designation, the positron emission tomographic (PET) scans
of a group with IMI demonstrated a pattern of hypometabolism more closely
resembling that of AD patients than that of a healthy elderly control group.6, 7
In addition to the early and dramatic impairment of memory in AD, impairments
in multiple domains develop as the disease progresses, and these additional
deficits can appear early in its course. There is also evidence from PET studies
that functional changes in AD affect widespread areas of cortex, not just
the limbic system, even in what appears to be predementia states.8, 9 Therefore, we thought that consideration
of cognitive processes other than memory could improve the predictive value
of neuropsychological testing. For this study, we hypothesized that among
nondemented patients with memory complaints, measurable impairments of at
least 1 cognitive domain in addition to memory could help identify those who
would progress to AD over a few years.
SUBJECTS AND METHODS
SELECTION OF SUBJECTS
Of 196 subjects in the Michigan Alzheimer's Disease Research Center
(MADRC) database who were diagnosed as having IMI by a subspecialty-trained
neurologist on at least 1 clinic visit, we identified 53 patients who had
been evaluated for memory disturbance, met criteria for IMI at their initial
evaluation, and had repeated evaluations during at least a 2-year period.
The diagnosis of IMI is based on both clinical and psychometric evidence,
delineated below.6 In 5 patients, additional
information obtained during subsequent clinical visits indicated that an identifiable
condition accounted for the cognitive deficits (1 with a history of alcoholism,
2 with psychiatric illness, and 2 with postanoxic injury). These patients
were excluded, leaving 48 subjects.
Clinical evidence of IMI was based on the following: (1) the presence
of a memory complaint, (2) the ability to perform all instrumental activities
of daily living, (3) the absence of clinical depression, and (4) the absence
of an identifiable cause of memory impairment, such as use of a medication
known to alter memory or a significant medical or neurological illness. Standard
laboratory blood tests and structural brain imaging (computed tomography or
magnetic resonance imaging) were performed as part of this evaluation.10
The neuropsychological evidence for IMI was based on the following:
(1) normal orientation and general cognitive function as defined by a Mini-Mental
State Examination (MMSE) score of more than 23 and maintained Wechsler Adult
Intelligence Scale–Revised (WAIS-R) Full-Scale IQ (FSIQ) based on presumed
premorbid estimates, (2) a score of 9 or less on the Hamilton Depression Rating
Scale, and (3) diagnostic criteria and cognitive measures for clinical change
based on those proposed for AAMI by a National Institute of Mental Health
work group.3 These criteria used a cutoff of
1 SD below the means established for young adults as a basis for impaired
memory functions. Thus, we identified memory impairment as significant when
subjects had an immediate recall score of 6 or less on the Benton Visual Retention
Test–Revised or when the sum of scores on immediate recall of logical
memory I (LM-I) and paired associates (PA) subtests on the Wechsler Memory
Scale were 19 or less. In addition, to address concerns regarding the validity
of these historical AAMI criteria, we compared each subject's scores on LM-I
and PA to age- and education-adjusted cutoffs.11, 12
Because episodic memory ability generally declines with age, prevailing mild
cognitive impairment (MCI) criteria make use of these adjustments as a more
accurate way to identify seniors with genuine impairments.
NEUROPSYCHOLOGICAL AND NEUROLOGICAL EVALUATIONS
A neuropsychologist (B.G.) blinded to patient outcomes reviewed initial
neuropsychological testing performed in each subject and archived in the MADRC
database. We used age-adjusted normative criteria to identify the presence
or absence of impairment in the following areas: language (Boston Naming Test),
attention (WAIS-R Digit Span Forward), motor visuospatial function (WAIS-R
Block Design), and verbal fluency (Controlled Oral Word Association Test;
letters c, f, and l). (If the Controlled Oral Word Association Test was unavailable,
letter fluency on the letter d was substituted.)
For the purposes of this study, we defined impairment as performance worse
than fifth percentile or 2 SDs from the age-adjusted mean, consistent with
National Institutes of Neurological and Communicative Disorders and Stroke/Alzheimer's
Disease and Related Disorders Association criteria for dementia13
(Table 1). Subjects were then
categorized by this structured algorithm as having either normal scores in
all 4 areas (M-) or impairment in 1 or more of these areas (M+).
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Table 1. Neuropsychological Tests Used to Categorize Nondemented Subjects
With Memory Impairment
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The clinical outcome for each patient at 2 years and at the most recent
neurological examination was determined by a neurologist (A.B.) blinded to
the subject's initial neuropsychological categorization (M- or M+).
The designation of AD or continued memory impairment without dementia was
based on documentation of impaired instrumental activities of daily living
caused by cognitive impairment in the medical record by the patient's treating
neurologist. In some cases, repeated neuropsychological testing was available
to the treating physician; however, outcome in this study was based on the
physician's clinical judgment. The choice of a clinical outcome measure simulates
typical clinical decision making, given that follow-up neuropsychological
data are frequently not obtained by treating clinicians.
As an additional check on the treating physician's initial determination
of IMI, we had an assistant who was certified by the Alzheimer's Disease Cooperative
Study obtain a chart review–based Clinical Dementia Rating (CDR) score
for each subject's initial diagnostic clinic visit. Since the CDR score takes
into account only information from the history and physical sections of the
visit note, we hoped to address concerns of possible bias on the part of the
treating physician who made a determination in conjunction with neuropsychological
testing in some cases.
STATISTICAL ANALYSIS
Unadjusted statistical analyses were performed using  2
analysis for dichotomous results (Fisher exact test). Logistic regression
was used to compare outcomes in the 2 groups at 2 years, adjusted for other
prognostic factors. Kaplan-Meier curves were compared using the log-rank (Mantel-Cox)
test. To evaluate the possibility of confounding, years of education, IQ,
and age were controlled for by using a Cox regression analysis.
Data are presented as mean ± SD.
RESULTS
We identified 48 IMI patients with 210 years of clinical follow-up (mean,
4.0 ± 2.0 years; median, 3.5 years). Their mean age was 69.4 ±
7.2 years, and years of education was 14.7 ± 3.7 (medians, 71 and 14.5,
respectively). There were 36 men and 12 women, with an overall rate of conversion
to AD of 33.3% at 2 years. In keeping with the selection criteria inherent
in the diagnosis of IMI, there was no evidence of an abnormal IQ or dementia,
with a mean FSIQ of 103.6 ± 13.3 (median, 102) and mean MMSE score
of 26.0 ± 1.7. Forty-five of 48 subjects had a CDR score of 0.5 at
their initial clinic visit. One subject had a CDR score of 0, and 2 subjects
did not have enough documented history to calculate an initial CDR score.
Of the 48 patients, 17 were considered M- and 31 were designated
M+ (Table 2). For comparison,
a review of the MADRC database as a whole revealed 108 men and 88 women with
IMI on at least one clinic visit (total, 196). Mean age for this group was
76.6 ± 7.3, with an average of 14.5 ± 3.5 years of education.
The mean FSIQ was 102.6 ± 10.6 and MMSE score was 25.5 ± 2.3.
When we examined the IMI group's initial LM-I and PA scores and compared them
with age- and education-adjusted means, we found that all M+ and all but 1
M- subject were more than 1 SD below these more restrictive measures,
currently in use for the designation of MCI. This would suggest that despite
using slightly different entry criteria, our IMI cohort is similar to MCI.
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Table 2. Summary Characteristics for Patient Groups*
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At 2-year follow-up, 1 M- subject (6%) had progressed to AD, and
15 (48%) of the M+ group had progressed to AD (P
= .003). In the logistic regression analysis adjusting for age, years of education,
and FSIQ, M+ patients were 15.7 times as likely as M- patients to progress
to dementia at 2 years (P = .02) (Figure 1). According to Kaplan-Meier estimates, at 3 years of follow-up,
the probability of progression to AD in the M+ group was 69% compared with
only 15% in the M- group. Similarly, at 5 years, the M+ groups had a
91% probability of progression, whereas the M- group reached a plateau
at 44% (Figure 2). A log-rank test
confirmed a significantly different rate of progression in the 2 groups (P<.001). A Cox proportional hazards model was then constructed
to take into account differences in age, years of education, and FSIQ. Group
differences were once again significant, with those in the M+ group having
4.6 times the risk of progression to AD (P = .01).
Age (P = .84), education (P
= .90), and FSIQ (P = .85)
were not significant independent predictors of progression; the survival estimates
by group after adjusting for these variables were essentially identical to
the Kaplan-Meier estimates.
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Figure 1. Progression of patients to Alzheimer
disease at 2 years of follow-up and at most recent follow-up. M+ indicates
impairment in 1 or more cognitive areas; M-, normal scores in all 4
cognitive areas apart from memory.
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Figure 2. Kaplan-Meier cumulative survival
plot showing years to conversion to Alzheimer disease. M+ indicates impairment
in 1 or more cognitive areas; M-, normal scores in all 4 cognitive areas
apart from memory.
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The overall progression rate of our sample was one third at 2 years,
somewhat higher than that found in several other studies14, 15, 16
of nondemented, memory-impaired subjects. (Another retrospective study, by
Bowen et al,15 found 19% progression at 2 years,
and 2 prospective studies14, 16
found 22% and 24% progression at 2 years.) Our higher rate of progression
is attributable to slightly different entry criteria and elimination of any
subjects who were subsequently found to have another explanation for their
cognitive impairment. When we consider the M+ group separately, the progression
rate was almost 50%, whereas the M- group had only a single subject
progress to dementia during that same period. Of subjects who were followed
up for at least 3 years, more than two thirds of the M+ group had converted
to AD, and at 5 years, more than 90% had. This is in stark contrast to the
M- group, in which progression occurs later and levels off at less than
50% by the same 5 years.
The FSIQ and WMS–Memory Quotient differed between the 2 groups
but were within normal limits in both. Since digit span and block design are
both WAIS subtests, on which the FSIQ is partially based, the difference in
FSIQ is understandable; in fact, no change at all from premorbid estimates
would be hard to explain in the M+ group. Because the 2 groups did not differ
in education, age at presentation, or average duration of follow-up, neither
demographic differences nor the cognitive reserve hypothesis17
is a sufficient explanation for the difference in outcome.
We compared performance on the 4 tests used to discriminate M-
from M+ to examine differences between M+ patients who converted to AD during
follow-up and those who did not. Of these, block design was the most frequently
abnormal in both groups (63% in converters and 57% in nonconverters). The
most discriminating test was the Boston Naming Test, on which 42% of converters
had abnormal results, but only 14% of nonconverters had abnormal results.
However, no single test was able to distinguish those among the M+ group who
progressed to AD from those who did not. Only when the results of 2 or more
tests were abnormal could the groups be distinguished (P=.03) (Table 3).
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Table 3. M+ Subjects With Abnormal Results on Each of the 4 Tests*
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COMMENT
Our results demonstrate that consideration of cognitive domains other
than memory can significantly improve the predictive value of neuropsychological
testing in nondemented patients with a memory complaint. These results follow
from the hypothesis that subjects with evidence of impairments extending beyond
memory are more likely to have AD than those with only memory deficits. Several
studies18, 19 have demonstrated
that cognitive deficits roughly parallel histopathologic abnormalities at
autopsy. Consequently, we expect that M+ subjects have neuropathological changes
whose functional consequences already extend beyond the hippocampus and entorhinal
cortex. In this study, we chose tests looking at 4 anatomically separate domains
to maximize the likelihood of capturing a region clinically affected by the
distribution of neuronal pathologic features, should that subject actually
have early AD. By this method, we determined that nondemented patients with
mild cognitive impairments in several domains including memory were more than
twice as likely as those with memory impairment alone to develop AD over a
period of 2 to 5 years. Furthermore, 50% of this group progressed from the
category of M+ to AD at 2 years. This figure was significantly higher than
any previously clinically identified "at-risk" population3, 14
and similar to the yield obtained with expensive and frequently unavailable
fluorine 18–labeled deoxyglucose (FDG)–PET imaging in a similar
population (70% at 3 years).6 Our results are
also significantly different from those found in studies of AAMI patients,
due to the more inclusive nature of the original AAMI criteria, which have
since been criticized for a high "misidentification rate" of healthy elderly
patients. One study5 found that only 29 (16.5%)
of 176 of subjects followed up prospectively with an initial diagnosis of
AAMI had progressed to dementia or MCI at an average of 3.6 years of follow-up.
The corollary to our hypothesis that subjects classified as M+ are more
likely to have AD than those classified as M- is that patients presenting
with memory deficits alone are less likely to have neuronal pathologic features
of the AD type, at least outside limbic regions. Certainly, many of these
subjects simply have neuropathological changes limited to hippocampus and
entorhinal cortex (Braak and Braak stages I through IV) as suggested by postmortem
examinations in patients with questionable dementia.20, 21
However, a subset of these patients may have a fundamentally different response
to the process that in others more rapidly evolves to AD, such as resistance
to disease progression or a better ability to compensate for deficits. In
other cases, the M- group may have a form of cognitive reserve not accounted
for by controlling for age, education, and FSIQ. Still others may have a disorder
distinct from AD or have no significant brain pathologic condition, merely
meeting IMI criteria on the basis of memory scores that are different than
those of young adults.
The most convincing evidence that some M- subjects do not have
AD is the strikingly different clinical course many experience. As in some
prospective studies, we found that some who develop clear-cut memory impairment
in later life maintain a circumscribed memory deficit without dementia throughout
many years.5 Since it should be easier to develop
impairment of a single cognitive domain on the basis of factors other than
degenerative disease, the consideration of additional domains acts as a "check"
on the diagnosis of incipient dementia. We note that although these patients
do not become demented, progressive amnesia may ensue, eventually leading
to a complete inability to learn new information or to recall previously learned
information. This is difficult to differentiate from AD on a clinical examination
and may explain why it has not been widely recognized to date. Hippocampal
sclerosis is one pathologic substrate that might account for this more benign
course.22, 23 FDG-PET showing a
more limited pattern of hypometabolism or functional magnetic resonance imaging
demonstrating intact nonmemory neural networks are other potential ways to
distinguish such an amnestic disorder from AD.
In our study, the subset of subjects who were followed up for more than
5 years is too small to determine whether there is truly a plateau in the
number of M- subjects who develop AD, although the trend is clearly
in that direction. Further studies are needed to determine whether this group
that does not develop dementia represents a completely different disease process
from that affecting the M+ group. Psychological criteria such as we have used
have not been applied in available autopsy studies of nondemented but memory-impaired
individuals. These studies18, 24
have primarily found pathologic features typical of AD.
Our study has the typical shortcomings of a retrospective study, with
concerns regarding enrollment, selective loss to follow-up, and inherent limitations
in the measures of change. A larger, prospective study extending 5 years or
longer is needed. Clinical definitions that include information gained with
longitudinal observation may better define both the mildest forms of AD and
similar but more benign conditions. It is interesting to note that men make
up most of our cohort, both in our selected group of 48 subjects and in the
total group of 196 subjects ever identified with IMI at our institution. Further
studies will be needed to determine whether this represents referral bias
or has biological significance. As in most dementia clinics, women constitute
most of our patients overall, and the predominance of men in the IMI category
is unexpected.
We adopted cutoff scores for psychological tests based on criteria recommended
for AAMI by a consensus conference. The AAMI criteria were proposed to describe
the "clear, age-related memory deficit" that could occur in healthy, elderly
individuals.3 Specifically, the recommendation
was to include anyone older than 50 years who had a secondary memory test
performance at least 1 SD below the mean established for young adults. These
criteria are rigorous and do not take into account the substantial cohort
effects that can occur when different age groups are compared cross-sectionally
instead of being followed longitudinally. To address this concern, we examined
each subject's memory scores (LM-I and PA) with an age- and education-adjusted
cutoff, such as is used in the modern MCI definition. We found that all but
1 subject met these more lenient criteria, supporting the observation that
our IMI cohort is similar to the current MCI group, despite being originally
selected using AAMI criteria.
By choosing a very lenient cutoff for defining our M+ population (2
SDs below age-adjusted means), we gave subjects the "benefit of the doubt"
in terms of labeling them as sufficiently cognitively impaired to be at high
risk of progression (ie, marginally impaired subjects fell into the M-
group). Since the null hypothesis was that the rates of conversion of the
2 groups, M- and M+, were equal, by leaving more patients in the M-
group, we risked having a larger percentage of supposedly nonprogressing patients
progress, approximating the rate within the M+ group. Since our results were
still statistically significant, we believe that this choice of cutoff only
strengthens our conclusions.
One of the goals of the clinical neurologist is to predict which mildly
impaired individuals will develop a clear dementia, based on characteristics
of that person's presentation. Improving our ability to predict the appearance
of dementia at an earlier stage and with greater accuracy could not only reassure
many, but could also spare patients and their families the heightened anxiety
that accompanies years of watchful waiting and would allow interventions targeted
at secondary prevention to be applied with far better specificity and earlier
in the disease process than is currently feasible. Medications currently considered
too toxic or risky to be given to the very broad category of "people older
than 60 years with reduced memory efficiency" might be used if the population
to be treated was deemed to be more clearly at risk. Because of its significant
emotional and financial implications, until reliable criteria are established,
AD should only be diagnosed when dementia is clearly present.
AUTHOR INFORMATION
Accepted for publication July 11, 2000.
The study was supported by the MADRC (National Institutes of Health
grant P50-AG08671).
We acknowledge the data collection and management efforts of Jodie Carr,
without whom this study would have been much more difficult to perform.
From the Departments of Neurology (Drs Bozoki, Heidebrink, and Foster)
and Psychiatry (Drs Giordani and Berent), University of Michigan Medical Center,
and Geriatric Research Education and Clinical Center, Ann Arbor Veterans Affairs
Medical Center (Dr Heidebrink), Ann Arbor.
Corresponding author and reprints: Andrea Bozoki, MD, Department
of Neurology, University of Michigan, TC1913A, 1500 E Medical Center Dr, Ann
Arbor, MI 48109-0322 (e-mail: abozoki{at}med.umich.edu).
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Neuropsychological Markers of Progression From Mild Cognitive Impairment to Alzheimer's Disease
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Self-Administered Screening for Mild Cognitive Impairment: Initial Validation of a Computerized Test Battery
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Dementia Assessment in Primary Care: Results From a Study in Three Managed Care Systems
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Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2004;59:M621-M626.
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Mild cognitive impairment: prevalence and incidence according to different diagnostic criteria: Results of the Leipzig Longitudinal Study of the Aged (LEILA75+)
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Mild cognitive impairment can be detected by multiple assessments in a single day
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Low Cognitive Performance, Comorbid Disease, and Task-Specific Disability: Findings From a Nationally Representative Survey
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Is Mild Cognitive Impairment Prodromal for Vascular Dementia Like Alzheimer's Disease?
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Stroke 2002;33:1981-1985.
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Natural history of mild cognitive impairment in older persons
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