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Cerebrovascular and Brain Morphologic Correlates of Mild Cognitive Impairment in the National Heart, Lung, and Blood Institute Twin Study
Charles DeCarli, MD;
Bruce L. Miller, MD;
Gary E. Swan, PhD;
Terry Reed, PhD;
Philip A. Wolf, MD;
Dorit Carmelli, PhD
Arch Neurol. 2001;58:643-647.
ABSTRACT
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Objective To evaluate the relative risk (RR) of mild cognitive impairment (MCI)
associated with cerebrovascular risk factors and cerebrovascular-related brain
changes.
Design Mild cognitive impairment was determined for the subjects of the prospective
National Heart, Lung, and Blood Institute Twin Study. Quantitative measures
of brain, white matter hyperintensity, cerebral infarction, apolipoprotein
E genotype, and psychometric testing were obtained.
Results Subjects with MCI were older (73.5 ± 3.0 vs 72.1 ± 2.8
years), consumed less alcohol (3.7 ± 5.8 vs 7.0 ± 10.7 drinks
per week), had greater white matter hyperintensity volumes (0.56% ±
0.82% vs 0.25% ± 0.34% of cranial volume), and had an increased prevalance
of apolipoprotein E4 genotype (31.4% vs 19.2%) than normal subjects. White
matter hyperintensity and the presence of the apolipoprotein E4 genotype were
associated with a significantly increased risk for MCI. When all subjects
were included in the analysis, alcohol consumption was associated with a reduced
risk for MCI (RR = 0.93, P<.05). When subjects
with a history of symptomatic cerebrovascular disease were excluded from the
analysis, elevated midlife diastolic blood pressure was associated with an
increased risk for MCI (RR = 1.70, P<.05).
Conclusions Elevated midlife blood pressures, and the resulting increased white
matter hyperintensities, increase the risk for MCI in a group of community-dwelling
older men to at least the same degree as apolipoprotein E4 genotype. Given
the common occurrence of elevations in midlife blood pressure, early and effective
treatment may be warranted to prevent late-life brain abnormalities and MCI.
Moreover, since many individuals with MCI progress to clinical dementia, longitudinal
evaluations of this cohort will be important.
INTRODUCTION
SEVERAL longitudinal studies show an association between middle-age
elevations in blood pressure (BP) and impaired later-life cognition.1, 2, 3, 4, 5
The mechanisms underlying these long-term associations are unclear, but several
processes, including disturbed cerebral perfusion or reduced metabolism,6, 7, 8 abnormalities of cerebral
white matter,9 and cerebral atrophy,10 have been implicated.
Elevated BP, especially elevated systolic BP and hypertension, are associated
with an increased prevalence and extent of white matter hyperintensity (WMHI)9, 11, 12, 13, 14, 15
as well as cerebral atrophy.9, 10, 14, 15, 16
Although the impact of WMHI on memory impairment in the elderly remains uncertain,17 considerable evidence suggests that large volumes
of WMHI are associated with other impairments in cognitive performance.9, 13, 15, 18, 19, 20, 21
The extent of brain atrophy and WMHI that accompany middle-life elevations
of systolic BP also correlate with the rate of cognitive decline during 10
years.15 While these results support the notion
that brain injury in response to long-standing BP elevation can result in
mild impairment in various cognitive domains, the clinical significance of
these effects remains unclear.
Mild cognitive impairment (MCI) has become increasingly recognized as
common in later life.22 Usually defined as
isolated memory impairment in an otherwise healthy individual,22
MCI is associated with a yearly risk for Alzheimer disease (AD) that varies
from 1% to 25% per year.23 Given that cerebrovascular
risk factors, such as hypertension, are often associated with late-life brain
abnormalities and cognitive impairment, we sought to examine the relationship
between cerebrovascular risk factors, brain morphologic characteristics, and
MCI in a group of 369 nondemented, community-dwelling older men who participated
in the National Heart, Lung, and Blood Institute (NHLBI) Twin Study.
SUBJECTS AND METHODS
STUDY POPULATION
The NHLBI Twin Study is a longitudinal study of cardiovascular disease
and associated cardiovascular disease risk factors in 514 pairs of male twins
born between 1917 and 1927, who were 42 to 56 years old when first examined
in 1969 to 1972.24, 25 Three follow-up
examinations after 10, 16, and 25 years assessed cardiovascular disease status
and collected repeated measurements of physiological, biochemical, and psychosocial
risk factors.26 In the most recent follow-up
examination (1995-1997), brain magnetic resonance (MR) imaging was added to
the sequence of tests previously given to these subjects. Analyses in the
present study were limited to a subset of 369 individual twins who participated
in the fourth examination of this cohort and for whom MR volumetric data and
neuropsychological testing were available.
BP DETERMINATION AND DEFINITIONS OF CARDIOVASCULAR DISEASE AND RISK
FACTORS
Complete details regarding BP assessment and determination of cerebrovascular
risk factors are available elsewhere.14, 15
In brief, however, sitting BP was measured at each examination by 2 independent
examiners. Diastolic BP was recorded as the fifth phase. The slope of BP change
was determined by linear regression of each individual across the 4 measurements,
as described by DeCarli et al.14
Cardiovascular disease and risk factors were determined through medical
interviews and physical examination. Subjects' self-report of cardiovascular
events and medical procedures were confirmed with medical and hospital records.
The final diagnoses of clinical stroke, transient ischemic attack, myocardial
infarction, coronary insufficiency, and angina pectoris were determined by
trained medical staff who reviewed the medical records and physical examination
data and uniformly coded these according to standard protocols. Prevalent
coronary heart disease was ascertained on the basis of the surveillance data
and electrocardiographic data. Data on medication use were collected at each
examination by presentation of medication vials. The ankle-brachial BP ratio,
in combination with patient medical and hospital records, was used as a measure
of prevalent peripheral vascular atherosclerosis. All subjects were free of
cardiovascular disease at the first examination.
Alcohol consumption and smoking behavior were assessed at each examination.14 Alcohol consumption was defined as number of drinks
per week and cigarette use as pack-years. History of current or past cigarette
use was also determined.
CEREBRAL MR IMAGES AND IMAGE ANALYSIS
The MR (1.5-T) imaging was performed at 4 study sites by means of a
conventional spin-echo, double-echo sequence in the axial orientation with
repetition time of 2000 milliseconds, echo time of 20/100 milliseconds, 24-cm
field of view, and 5-mm contiguous slices from the vertex to the foramen magnum
imaged in a 256 x 192 matrix and interpolated to 256 x 256 with
1 excitation. The MR imaging information was transferred to a central location
for processing and analysis without knowledge of age, zygosity, and medical
history of the subjects. Image evaluation was based on a semiautomated segmentation
analysis that involves operator-guided removal of nonbrain elements as previously
described.14, 27, 28, 29
The presence of cerebral infarction on MR imaging was determined from
the size, location, and imaging characteristics of the lesion. Only lesions
3 mm or larger qualified for consideration as cerebral infarcts. Other necessary
imaging characteristics included (1) cerebrospinal fluid density on the subtraction
image and (2) if the cerebral infarct was in the basal ganglia area, distinct
separation from the circle of Willis vessels.
Intrarater and interrater reliabilities for this method have been published.27, 29
APOLIPOPROTEIN E GENOTYPING
Since previous reports suggest that apolipoprotein E  4 (ApoE4) is a risk factor for MCI and
incipient AD,30, 31 ApoE genotype status categorized as a dichotomized variable (E4 present
or absent) was included in this analysis. For ApoE
structural locus genotyping, the polymerase chain reaction was used to amplify
244–base pair fragments that contain variant amino acid residues 112
(cystine  arginine = 4 allele) and 158
(arginine cystine = 2 allele). Polymerase
chain reaction products were then digested with the restriction enzyme HhaI and underwent electrophoresis on an 8% polyacrylamide
nondenaturing gel.32 In this procedure, the
most common 3 allele is cut by HhaI at position 158; the 4 allele is
cut twice by the addition of a second restriction site at position 112; and
the less frequent 2 allele lacks either recognition
site. Genotyping by using this technique was completed on 589 individual twins
of this cohort, showing allele frequencies of 2
= 0.09, 3 = 0.76, and 4 = 0.15, consistent with expected frequencies in other white populations.33 The ApoE genotypes were
available on 359 (97%) of the individuals in the subset of 369 of NHLBI twins
used in the present analysis.
DEFINITION OF MCI
Mild cognitive impairment is commonly defined
as the presence of clinically significant memory impairment in the absence
of a clinical dementia.22 Various measures
of memory performance can be used.22 For the
purpose of this analysis, we defined MCI on the basis of delayed free-recall
performance on the California Verbal Learning Test (CVLT). The CVLT34 quantifies numerous components of verbal learning
and memory and has demonstrated validity in persons with AD.35
While performance on the CVLT is affected by both age and sex,34
few normative studies have been performed on older individuals since its publication.36 Therefore, MCI was defined as a score of 4 or less,
corresponding to the lower 10th percentile of the distribution of scores or
1.4 SDs below the mean, consistent with MCI as defined by other memory tests.22 In addition, to exclude the presence of frank dementia,
subjects with a score of 24 or less on the Mini-Mental State Examination were
excluded from the analysis (n = 45).
STATISTICAL ANALYSIS
To assess validity of designating MCI on the basis of performance within
the NHLBI cohort, initial statistical analysis examined the distribution of
scores from the long-term delayed recall portion of the CVLT by means of the
SAS univariate procedure and the Kolomogorov D statistic.37
Between-group comparisons on a variety of demographic, genotypic, and cerebrovascular
risk factors were performed by means of the t test.
Forward stepwise logistic regression analysis was used to evaluate the relative
risk and 95% confidence intervals for variables significantly associated with
the presence of MCI. Because of missing ApoE data
for 3% of the cohort, the number of subjects differed slightly between the
univariate analysis, which included 369 individuals, and the logistic regression
analyses, which included 359 individuals. All analyses were conducted with
the SAS statistical package (version 6.09; SAS Institute Inc, Cary, NC). Data
are given as mean ± SD unless otherwise indicated.
RESULTS
The distribution of scores on CVLT delayed free recall are displayed
in Figure 1. Since MCI was a priori
defined as the lower 10th percentile or 1.4 SDs or more below the group mean,
37 subjects with a CVLT score of 4.0 or less were identified as having MCI.
The average performance on the delayed free recall of the CVLT across all
subjects was 8.18 ± 2.92. The mean performance for the MCI group was
2.97 ± 1.26, and for the normal memory group, 8.77 ± 2.44. Performance
on CVLT delayed free recall across all subjects was very similar to that in
other previously described elderly cohorts where individuals were between
the ages of 64 and 77 years (mean, 8.18; SD, 2.82).36
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Histogram distribution of delayed free-recall scores on the California
Verbal Learning Test for all subjects participating in this study. The heights
of the bars indicate the number of subjects at each value with that score.
The arrow indicates the cutoff score used to determine the presence of mild
cognitive impairment.
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Between-group comparisons are summarized in Table 1. Subjects with MCI were significantly older (73.5 ±
3.0 years vs 72.1 ± 2.8 years), consumed significantly less alcohol
(3.7 ± 5.8 drinks per week vs 7.0 ± 10.7 drinks per week), and
had significantly greater WMHI volumes (0.56% ± 0.82% of cranial volume
vs 0.25% ± 0.34% of cranial volume) than subjects with normal delayed
free recall.
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Table 1. Univariate Comparisons of Age, Education, CVD Risk Factors,
Medical Histories, and Brain Volumes on MR Imaging in Subjects With and Without
Mild Cognitive Impairment*
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Results of stepwise logistic regression are summarized in Table 2. Since symptomatic stroke is associated with a significant
increase in risk for dementia,38 we also examined
significant risk factors for MCI for the entire subject group (model 1) and
then repeated the analysis excluding subjects with a history of any symptomatic
cerebrovascular disease (model 2). This excluded 6 subjects in the MCI group
and 37 control subjects from the model 2 analysis. Age, WMHI, and the presence
of the ApoE4 genotype were associated with a significantly
increased risk of MCI in both analytical models. Relative risk was calculated
for each year of age and percentage change in WMHI volume as a proportion
of cranial volume (eg, subjects with 1% WMHI volume were 2.31 times more likely
to have MCI than those with minimal volumes of WMHI). When all subjects were
included in the analysis (model 1), alcohol consumption (risk calculated as
drinks per day) was additionally associated with a significant risk reduction
for MCI. When subjects with a history of symptomatic cerebrovascular disease
were excluded from the analysis (model 2), diastolic BP at examination 1 (calculated
as 1 SD of the mean or 12.5 mm Hg) was additionally associated with a significantly
increased risk of MCI.
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Table 2. Adjusted RR Ratios and 95% CIs From Stepwise Logistic Regression
Analyses That Include (Model 1) and Exclude (Model 2) Subjects With Clinical
CVA*
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COMMENT
Our results show that elevations in midlife diastolic BP and WMHI volumes
are significant risk factors for MCI in a large group of community-dwelling
older men. Moreover, the relative risk for MCI related to WMHI is at least
as great as, if not greater than, the relative risk for MCI attributable to
the presence of the ApoE4 genotype. Importantly,
however, the pathophysiology of MCI caused by brain vascular disease is likely
to differ substantially from that of the more common "neurodegenerative" type22, 23 that often progresses to AD. Since
our data suggest that MCI is a heterogeneous condition, future work will be
necessary to determine the actual likelihood that MCI of the "vascular" type
might progress to clinical dementia and, if so, the type of dementia expressed
(ie, AD vs vascular dementia).
In addition to identifying factors that increase the risk for MCI, we
also found that alcohol consumption was slightly protective. This finding
supports previous data showing a positive correlation between alcohol consumption
and cognitive performance.39 This effect appeared
significant only for individuals with cerebrovascular disease, as it was not
present in model 2. How alcohol consumption might reduce the risk of later-life
MCI is presently unclear.39 Recent evidence
suggests that moderate alcohol consumption can reduce the risk of both vascular
disease and AD.40, 41 Unfortunately,
the current study was not designed to test potential causes of MCI risk reduction
due to alcohol consumption, and further research in this area is clearly necessary.
Fortunately, another clinical evaluation of this group is ongoing. Assessing
dementia incidence and type of dementia in this cohort may give some clues
to the protective effect of alcohol consumption for these individuals.
We have previously shown that midlife diastolic BP is a significant
predictor of later-life WMHI volume.14 We also
have shown that extensive WMHI volumes are significantly associated with an
increased rate of decline on measures of attention, memory, and verbal fluency.15 We believe these cognitive changes result from the
effect of elevated BP on the brain.15 Unfortunately,
the magnitude of cognitive impairment related to WMHI noted in previous studies
has been relatively small.6, 9, 13, 18, 19, 20, 21
The results of this study suggest that the impact of elevated BP and increased
WMHI may be clinically relevant in that they both increase the risk of MCI
in subjects without a history of symptomatic cerebrovascular disease.
Our data also confirm that MCI is likely to be a pathologically heterogeneous
disorder. Previous studies suggest that MCI is part of the continuum that
ranges from healthy aging to AD.22 The ApoE4 genotype increases both the lifetime risk of AD42 and the risk of conversion of MCI to AD,30 presumably through enhanced amyloid deposition43 or increased neuronal vulnerability.44
Our finding that ApoE4 genotype status independently
increased subject risk for MCI is consistent with these previously published
reports. The fact that both ApoE4 genotype status
and WMHI volume independently increased risk of MCI suggests the possibility
of 2 independent processes leading to MCI, supporting the notion of MCI as
a pathologically as well as clinically heterogeneous disorder.22
Importantly, there are no data yet available regarding the potential impact
of WMHI volume on the progression from MCI to clinically probable AD or other
dementia. Current ongoing work with the subjects of the NHLBI Twin Study may
allow us to directly examine the relationship between WMHI volume, current
MCI status, and dementia incidence.
It is likely that vascular risk factors, such as hypertension, cause
MCI through mechanisms different from AD. Chronic essential hypertension is
associated with age-related differences in brain structure and function,7, 9, 10, 11, 12, 13, 14
which in the presence of WMHI are associated with cognitive impairment.9, 13, 15, 18, 19, 20, 21
We have previously shown that extensive amounts of WMHI are associated with
reduced cerebral metabolism of glucose in the frontal lobes of otherwise healthy
individuals.6 This may reflect preferential
impairment of frontal-subcortical circuits by WMHI.45, 46
While frontal-subcortical circuits generally are not considered involved with
memory encoding, they may underlie working memory function.47, 48
It is possible that the CVLT is a type of task that uses these frontal circuits.49 Alternatively, recent evidence suggests that cerebrovascular
disease may interact significantly with pathologic changes of AD to enhance
the expression of clinical dementia.50 It is
possible that a similar phenomenon could occur with WMHI. Future work in this
area of research may help to define the potential interaction between these
2 very common age-related diseases.
Two important limitations to this study also should be mentioned. For
all these analyses, twin subjects were treated as individuals. First, although
we found no evidence that the twin condition affected our results, all of
the monozygotic twins and many of the dizygotic twins share ApoE4 genotype. The WMHI volumes are also highly heritable.51 Second, the NHLBI cohort is exclusively male and
mostly white. These sex and ethnic restrictions further reduce our ability
to generalize these findings. However, there is important evidence that WMHI
volumes are increased in women and African Americans,9, 12
suggesting that the impact of WMHI on MCI may be greater than that observed
with this cohort. Replication of these findings in a more representative population,
therefore, will be important to understanding the full significance of these
observations.
Finally, these observations may have therapeutic implications. If midlife
elevations of diastolic BP lead to later-life MCI and potentially cause WMHI,14 then greater awareness and treatment of midlife BP
elevations may lower the risk of later-life MCI. Our finding that the effect
of midlife diastolic BP and WMHI volumes on later-life cognition is at least
as great as that of ApoE4 genotype also suggests
that the clinical impact of this risk reduction could be considerable. Further
research into the issues of midlife BP control as it relates to later-life
cognitive function is clearly needed.
AUTHOR INFORMATION
Accepted for publication July 11, 2000.
This work was supported by grant HL51429 from the National Heart, Lung,
and Blood Institute, Bethesda, Md.
From the Department of Neurology, University of Kansas, Kansas City
(Dr DeCarli); Department of Neurology, University of California at San Francisco
(Dr Miller); Health Sciences Division, SRI International, Menlo Park, Calif
(Drs Swan and Carmelli); Department of Medical and Molecular Genetics, Indiana
University, Indianapolis (Dr Reed); and Department of Neurology, Boston University,
Boston, Mass (Dr Wolf). Dr DeCarli is now with the Department of Neurology,
University of California at Davis.
Corresponding author and reprints: Charles DeCarli, MD, Department
of Neurology, University of California at Davis, 4860 Y St, Suite 3700, Sacramento,
CA 95817 (e-mail: cdecarli{at}ucdavis.edu).
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