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(Stroke. 1998;29:805-812.)
© 1998 American Heart Association, Inc.

Original Contributions

Intellectual Decline After Stroke

The Framingham Study

C. S. Kase, MD; P. A. Wolf, MD; M. Kelly-Hayes, EdD, RN; W. B. Kannel, MD; A. Beiser, PhD; R. B. D'Agostino, PhD

From the Departments of Neurology (C.S.K., P.A.W., M.K.-H.) and Medicine (W.B.K.), Boston University School of Medicine, Department of Biostatistics and Epidemiology, Boston University School of Public Health (A.B.), and Department of Mathematics, Boston University (R.B.D'A.), Boston, Mass, and the Framingham Study, National Heart, Lung, and Blood Institute, Framingham, Mass.

Correspondence to Carlos S. Kase, MD, Department of Neurology, Boston University School of Medicine, 80 East Concord St, B-605, Boston, MA 02118. E-mail cskase{at}bu.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—The causes and characteristics of cognitive decline after stroke are poorly defined, because most studies have relied on the diagnosis of dementia after stroke, without measurement of prestroke cognitive function.

Methods—The Mini-Mental State Examination (MMSE) was used to assess the cognitive performance of 74 subjects from the Framingham Study cohort who had suffered a stroke during a 13-year period. We compared their poststroke cognitive performance with the prestroke MMSE scores collected during their biennial examinations, and their prestroke/poststroke changes in MMSE score were then compared with those of 74 control subjects matched for age and sex. Cases and controls underwent testing for symptoms of depression using the Center for Epidemiologic Studies of Depression (CES-D) scale, and these findings were correlated with their cognitive performance. Changes in cognitive performance in the cases were correlated with the CT-documented characteristics of the stroke.

Results—The cases had a significantly lower mean±SE MMSE score at prestroke baseline (27.28±0.34) than did the control subjects (28.08±0.21), a difference that became more pronounced (23.57±0.92 versus 28.31±0.25; P<.001) after stroke. The poststroke decline in cognitive function in the cases was correlated only with a large, left-sided stroke on CT. The CES-D scores were significantly higher in the cases, but nondepressed cases had significantly lower MMSE scores than nondepressed controls.

Conclusions—Stroke is followed by a significant decline in cognitive performance when prestroke and poststroke measurements are compared. Although depression is more frequent in the stroke patients, their intellectual decline appears to be independent from the presence of depression.

Key Words: dementia • depression • neuropsychological tests • stroke

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The causes of dementia are varied, with Alzheimer's disease accounting for at least 50% of the cases.^{1 2} The remainder are ascribed to other mechanisms, including the so-called vascular or multi-infarct³ dementia group or a combination of the two, which contribute another 5% to 20% of the cases of dementia in a population.^{4 5} In the vascular group, the mechanism of the dementia is thought to be the cumulative effect of repeated episodes of cerebral infarction, which leads to a progressive decline in cognitive function.³ To assess the effect of stroke on cognitive performance, we systematically studied members of the Framingham Study cohort who had suffered a stroke and had been evaluated by a standardized test for cognitive function before and after the occurrence of stroke. We compared their intellectual performance with that of a control group from the same general population sample. In addition, measurements of cognitive performance of the stroke patients were correlated with the CT-documented characteristics of their stroke, and both stroke cases and controls were evaluated for the presence of symptoms of depression and their relation to changes in cognitive function.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The Framingham Study is a prospective, observational, community-based study in which participants, who were enrolled at midlife, have been followed biennially for the development of disease. Hospitalization, laboratory testing, and treatment are observed, not mandated, by the study. The conduction of the study is approved by the Institutional Review Board of Boston University, and all participants have given informed consent for their inclusion in the study. Our study population was derived as follows: of the initial Framingham Study cohort of 5209 individuals enrolled in 1949 (and followed biennially until the present), 2999 subjects were alive and stroke free on January 1, 1982. During the study period (January 1, 1982, to November 30, 1994), 251 subjects sustained a stroke. The composition of our study group, with reasons for case exclusions, is detailed in Table 1. The 74 subjects included in the study fulfilled all entry criteria: (1) one measurement of prestroke cognitive performance by a standardized test and a 6-month poststroke intellectual evaluation by the same technique, (2) absence of dementia at baseline (prestroke) evaluation, and (3) presence of a paired control from the Framingham Study cohort matched by age and sex. Stroke surveillance was done by daily monitoring of admissions to the only general hospital in the town (Columbia MetroWest Medical Center). After identification of a cohort member admitted with a neurological diagnosis, including stroke and transient ischemic attack, a study neurologist and nurse examined the subject and reviewed the results of laboratory data, including imaging studies. This clinical and laboratory information was subsequently reviewed by a panel of investigators, including two neurologists, to adjudicate the event as a stroke and in addition make a judgment about its type and severity. Sixty-one of the 74 study subjects were admitted to the hospital at the time of the stroke. The remainder were not hospitalized but were evaluated as outpatients by either emergency room physicians (n=2) or their local physicians (n=6), or they did not undergo examination at the time of the acute stroke (n=5). These 13 patients were identified as having had a stroke by their reporting it during biennial examinations or by self-report of the event, and they fulfilled all of the above entry criteria. The case patients were also tested for symptoms of depression at 3, 6, 12, and 24 months after stroke. The control subjects had tests for intellectual function and symptoms of depression performed at the 6- and 24-month points corresponding to the stroke date of their paired stroke case.

View this table: [in this window] [in a new window]   Table 1. Study Group Composition

The test used for measurement of cognitive function was the Mini-Mental State Examination (MMSE), introduced by Folstein and colleagues in 1975.⁶ This standardized instrument for bedside evaluation of cognitive function consists of a questionnaire with 16 items that test orientation, memory (registration and recall), attention, language, and construction functions. It produces a numerical score, with values of 24 to 30 being in the normal range, whereas values of 23 or less are generally accepted as indicative of cognitive impairment.⁶ Because the MMSE scores in a population vary according to age and educational level,^{7 8} modified "cutoff" values for the diagnosis of cognitive impairment have been suggested on the basis of these two variables.⁹ In addition to the MMSE, all subjects underwent a neuropsychological battery that included measures of memory, new learning, visuospatial and visuoconstruction skills, abstract reasoning, language, and attention. Deficits in three or more cognitive areas, including memory dysfunction, met criteria for presence of dementia. All subjects with a diagnosis of dementia met criteria specified by the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, classification. To determine whether these criteria were met, all cases were brought to a panel of neurologists and neuropsychologists for review of Framingham Study records, medical records, neurological and neuropsychological test data, and a family interview questionnaire. A detailed description of this review process was reported by Bachman et al.¹⁰

For the evaluation of symptoms of depression we used the Center for Epidemiologic Studies of Depression (CES-D) scale,¹¹ which is a questionnaire designed to elicit responses to 20 statements relating to a patient's feelings during the preceding 1-week period. Test scores range from 0 to 60: the higher the score, the greater the severity of the symptoms of depression. Scores of 16 or higher are suggestive of depression, whereas values below that figure are considered normal.¹² This scale has been extensively evaluated for reliability and validity¹² and has shown a significant correlation with a battery of measures of depression in stroke patients.¹³

Among the 74 stroke patients, 47 had CT documentation of the stroke; the remaining 27 either had a negative CT scan (n=6) or no scan was available for review (n=21). The 47 CT-documented cases constitute the subgroup used for investigation of the association between intellectual function and anatomic features of the stroke. The anatomic features of the stroke studied included laterality, size, deep versus superficial location, and the presence of associated abnormalities, such as periventricular lucencies (PVLs) and silent stroke. The stroke size was defined as small if the infarct was lacunar (15 mm in diameter) or involved less than one half of a cerebral lobe and large if it involved more than one half of a cerebral lobe. Infarcts were labeled as superficial if they affected the cerebral cortex and/or the subcortical white matter, whereas deep infarcts were those involving the basal ganglia, internal capsule, or thalamus. PVLs were defined as confluent, generally symmetrical areas of hypodensity in the periventricular white matter of the cerebral hemispheres that involved the areas of the frontal horn, body, and occipital horn of the lateral ventricle. Silent infarcts corresponded to focal areas of hypodensity in the brain substance in the territory of distribution of either cortical or perforating branches of the main cerebral arteries, without the description by the patient, family members, or medical record of a prior episode consistent with an acute stroke. In addition, an assessment of cortical atrophy on CT scan was made, and its presence was correlated with baseline MMSE scores in cases and controls; cortical atrophy was determined to be present when CT scans showed generalized dilatation of cortical sulci, with or without associated ventricular enlargement.

Statistical analysis of the data was conducted with use of two-sample t tests for continuous variables and ² analysis for categorical variables. Initial comparisons of MMSE test scores were performed for the full cohort of 74 cases and control subjects regardless of whether the index stroke was documented by CT, whereas the associations with the anatomic features of the stroke were performed in the 47 CT-documented cases with scans available for our review.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The gender distribution for the matched cases and controls was 68 men (34 cases and controls) and 80 women (40 cases and controls); the mean±SE ages were 76.0±0.7 years for men and 81.0±0.8 years for women. Other demographic data and the lag time between the prestroke and poststroke MMSE administration for cases and controls are listed in Table 2. The stroke subtypes in the 74 cases were distributed as follows: atherosclerotic brain infarction in 51 (which includes 14 of lacunar and 37 of nonlacunar subtype), cerebral embolism in 19, and intracerebral hemorrhage in 4. The location of the stroke was left hemisphere in 29 subjects, right hemisphere in 33, bilateral hemisphere in 1, pure brain stem in 1, left-sided brain stem/cerebellar in 7, and right-sided brain stem/cerebellar in 3.

View this table: [in this window] [in a new window]   Table 2. Demographic Data for Case and Control Groups

The MMSE scores of the cases and control subjects at baseline (prestroke) and after the occurrence of the stroke are shown in Table 3. The baseline prestroke scores of the cases were significantly lower than those of the controls, and the difference became more pronounced when the poststroke scores were compared. The poststroke decline in MMSE scores in the cases was significant for both left (P<.003) and right (P=.045) hemisphere locations. The poststroke cognitive impairment was characterized by significant decline in the areas of orientation and language (and nonstatistically significant decline in attention and visuoconstruction) for patients with right hemispheric strokes and for all five domains of the MMSE except memory (which showed a nonstatistically significant decline) for those with left hemispheric strokes (data not shown) (K. McNulty, R. Au, R.F. White, M. Kelly-Hayes, C.S. Kase, A. Beiser, R.B. D'Agostino, and P.A. Wolf, unpublished data, 1997). The frequency of MMSE scores in the abnormal range (<24) at baseline was 8.1% (6 of 74) for the cases and 2.7% (2 of 74) for the controls, a substantial but nonstatistically significant difference; after the stroke, the figures were 31.1% and 1.4% (P=<.001), respectively (data not shown).

View this table: [in this window] [in a new window]   Table 3. Mini-Mental Scores in Case and Control Groups at Baseline and After Stroke

In an attempt to explain the baseline differences in MMSE scores between cases and controls, we compared the risk factor profiles of both groups because it has been suggested that the presence of cardiovascular disease, and hypertension in particular, is a risk factor for cognitive dysfunction.^{14 15 16 17} We determined the "stroke risk profile" for cases and controls at biennial examination 17, before the onset of the study period (January 1, 1982), using the method of Wolf et al.¹⁸ This technique involves the calculation of a numerical value indicative of stroke risk, as determined by the addition of weighed coefficients related to stroke risk for a number of variables, including age, systolic blood pressure, use of antihypertensive therapy, diabetes, cigarette smoking, prior cardiovascular disease, atrial fibrillation, and ECG-determined left ventricular hypertrophy. The stroke risk profile, expressed as the 10-year probability of stroke, was (not unexpectedly) higher in the cases (38.4%; n=70) than in the control subjects (31.6%; n=70), but the difference was not statistically significant for men, women, or both groups combined. Furthermore, the correlation between stroke probability and MMSE score at examination 17 was also not statistically significant (r=-.02). In addition, we reviewed the CT data for all 53 stroke cases with available studies at the time of the stroke, regardless of whether the index stroke was documented (n=47) or not (n=6), to determine the frequency of preexisting abnormalities with potential impact on baseline cognitive function. These included the presence of cortical atrophy, silent strokes, and PVLs. Although the frequency of these lesions in the case group could not be compared with that in the control group because the latter did not undergo imaging studies, we assessed their potential impact on the overall baseline MMSE scores in the cases by comparing the scores of cases with and without these abnormalities. These data (Table 4) showed that none of the three CT features studied correlated with a significant difference in baseline MMSE scores. The group with cerebral atrophy had a significantly higher mean age (P=.001).

View this table: [in this window] [in a new window]   Table 4. Baseline MMSE Scores in Cases in Relation to CT-Documented Features at Presentation with Index Stroke

Further analysis of the data was undertaken to examine the observed poststroke decline in cognitive performance of the cases in relation to a number of variables. In the subgroup of 47 subjects with CT documentation of the anatomy of the stroke, we analyzed stroke laterality, size, and location (superficial versus deep), as well as the presence of preexistent silent stroke and PVLs, in relation to MMSE scores (Table 5). These data indicate a positive relationship between cognitive decline and large stroke size only, without significant differences in MMSE scores in subjects with or without the other four stroke characteristics analyzed. Furthermore, large stroke size was found to relate to significant cognitive decline in left-sided but not right-sided strokes. Finally, when we analyzed changes in mean MMSE scores in relation to ischemic stroke subtype (n=70), we found no differences in baseline MMSE scores among subjects with lacunar (n=14), thrombotic nonlacunar (n=37), or cardioembolic (n=19) strokes. When these groups were compared after stroke, the mean MMSE fell 4.0 points in the thrombotic nonlacunar group and 4.4 points in the cardioembolic group, whereas there was only a 1.4-point decline in the lacunar group (data not shown). However, the differences between groups did not reach statistical significance.

View this table: [in this window] [in a new window]   Table 5. MMSE Scores in Cases 6 Months After Stroke in Relation to CT-Documented Features of the Stroke

Scores for symptoms of depression, measured at 6 months after stroke onset in cases and at comparable intervals in controls, were significantly higher in cases (14.64±1.48) than in controls (6.22±0.75; P<.001) (Table 6). The difference in CES-D scores between cases and controls was significant in each of the two age groups compared.

View this table: [in this window] [in a new window]   Table 6. Comparison of Depression Scores (CES-D) in Case and Control Groups 6 Months After Stroke

An analysis of the CT-documented characteristics of the stroke in relation to CES-D scores in the 44 cases with data for both (Table 7) showed only a nonstatistically significant higher frequency of symptoms of depression (CES-D score of 16) in subjects with large, left-sided strokes. The CES-D scores were not significantly related to any of the CT-documented features examined in this cohort.

View this table: [in this window] [in a new window]   Table 7. Depression Scores (CES-D) in Cases 6 Months After Stroke in Relation to CT-Documented Features of the Stroke

To explore the potential association between depression and decline in MMSE scores, we analyzed the data on poststroke MMSE scores in the 41 cases and 67 control subjects who fit the category of "not depressed," with CES-D scores of <16 (Table 8). These data showed significantly (P=.036) lower poststroke MMSE scores in cases than in controls, suggesting cognitive decline in the stroke cases as a phenomenon independent from depression, although their CES-D scores were still significantly higher (P=.010) than those of controls. A similar comparison among the 25 cases and 7 controls in the "depressed" category (CES-D score of 16) also yielded significantly lower poststroke MMSE scores (P=.001) in cases than in controls (data not shown). Within this "depressed" category, mean CES-D scores were not significantly different in cases and controls.

View this table: [in this window] [in a new window]   Table 8. MMSE Scores in Case and Control Groups in the "Not Depressed" Category

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
These data show that a significant decline in intellectual performance followed the occurrence of stroke when this function was measured by a simple bedside test of cognitive function administered before and after the stroke. The latter is one of the main strengths of our study, since other population studies or clinical series that have addressed the relationship between stroke and dementia^{19 20 21 22} have relied on cognitive changes first detected after the occurrence of stroke, without the benefit of knowing the patients' prestroke cognitive status. This confounds the interpretation of some of the reported data on incident dementia after stroke, because preexisting (or even "preclinical"¹⁹ ) Alzheimer's disease and dementia cannot be excluded as the explanation of dementia that is first recognized after the onset of stroke.¹⁹ In this regard, data recently reported from Rochester, Minn,²³ suggest that a 9-fold increase in the incidence of dementia detected within 1 year from a documented first ischemic stroke includes a substantial proportion of cases due to Alzheimer's disease. This study relied on retrospective chart review for the diagnosis of dementia, without the availability of standardized tests of cognitive function. Similarly, data reported by Hénon et al²⁴ indicate that through use of a standardized questionnaire to interview their closest relatives, as many as 16.3% of a group of consecutive stroke patients had evidence of dementia before stroke onset. These authors emphasize the fact that detection of an increase in the diagnosis of Alzheimer's dementia after stroke may be due in part to the recognition of these patients with prestroke dementia. We believe that our data properly addressed the prestroke/poststroke comparisons in cognitive function by use of the same standardized battery before and after the stroke. In addition, it is unlikely that a systematic bias existed in the sample by reason of case exclusion by our study design, because the exclusions resulted from a variety of reasons (see Table 1) rather than factors specifically related to the stroke, such as stroke severity or the presence of aphasia or hemineglect. On the other hand, the group of 74 cases was compiled after the subjects were evaluated in a variety of settings after their stroke, including hospital visits (n=4), clinic visits (n=46), nursing home evaluations (n=14), and home visits performed by the investigators (n=10). This procedure argues against a sample systematically biased on account of stroke features such as severity, home confinement, or institutionalization. Furthermore, comparison of the 74 cases included with the 74 who were excluded showed no statistically significant differences for age at stroke, sex distribution, level of education, or prestroke degree of independence (data not shown).

Our study documented a significant 3.7-point drop in the mean MMSE score in the stroke patients when they were tested within 6 months after stroke onset, while no change occurred in control subjects tested over similar time intervals. A potential weakness of our study is its reliance on the MMSE for detection of cognitive decline, because this widely used screening tool has its limitations. These include its dependence on verbal skills to communicate the test instructions and a different degree of sensitivity of its various subtests, although both right- and left-hemisphere functions such as orientation, visuospatial skills, memory,^{25 26} and language²⁷ are represented in the subtests. The impact of the MMSE limitations in our results was in part controlled by the use of a neuropsychological battery to determine whether the drop in MMSE score was due to true cognitive decline or merely reflected a neurological deficit (such as aphasia or hemineglect) that interfered with cognitive testing. For this reason, we believe that the presence of poststroke cognitive decline was accurately and reliably documented in this patient sample. This resulted in a diagnosis of dementia in 12.2% of the cohort (9 of 74 subjects), a figure that is substantially lower than the 16%¹⁹ and 26.3%²⁰ reported from non–population-based studies. Thus, in this prospectively studied cohort, the new onset of dementia after the initial, single, documented, symptomatic (ie, not silent) stroke occurred in slightly over 10% of the cases. This finding suggests that the reported non–population-based figures^{19 20} may be overestimates, likely the result of preexisting dementia cases being included with those of true new poststroke dementia.

Although the anatomic features of the stroke and associated abnormalities in imaging studies that relate to risk of dementia have been studied extensively, the findings have been inconsistent. In the Stroke Data Bank study, Tatemichi et al¹⁹ found a correlation of the prevalence of dementia in stroke patients with age, previous stroke and myocardial infarction, and large-artery atherothrombosis as the stroke mechanism, while the lacunar stroke subtype had the lowest prevalence of dementia. However, in a different cohort of hospitalized stroke patients, Tatemichi et al²⁰ found that lacunar infarcts were more likely to lead to dementia than was nonlacunar ischemic stroke. Although we found a more marked decline in MMSE scores in thrombotic nonlacunar and cardioembolic strokes than in lacunar strokes, the differences did not reach statistical significance. In our cohort, cognitive decline after stroke was related only to large infarcts located in the dominant hemisphere, characteristics (size and site) that were also associated with high odd ratios for dementia in the study of Tatemichi et al.²⁰ Our study failed to show a relationship between cognitive decline and other brain anatomic features, including silent stroke and PVLs. Although previous, presumably symptomatic stroke has been correlated with an increase in the risk of dementia after an index stroke,²⁰ the presence of silent stroke was not found to relate to dementia in a long-term (5-year) follow-up study.²⁸ The contribution of PVLs to cognitive dysfunction is even more difficult to assess. Although our CT-based data showed no relationship between PVLs and cognitive decline after stroke, there are abundant MRI^{29 30 31} and CT³² data relating such periventricular white matter changes to cognitive function. In a recent report from the Cardiovascular Health Study, Longstreth et al³³ found a significant correlation between MRI-detected periventricular white matter changes and cognitive performance (measured by the modified MMSE³⁴ ) in subjects aged 65 years or older who had undergone MRI as part of a longitudinal study of coronary heart disease and stroke. It is possible that the lack of an association between PVLs and cognitive decline in our cohort reflects the less-sensitive CT assessment in comparison with the higher sensitivity of MRI for the detection of more subtle and possibly clinically relevant changes in the periventricular white matter. It is also possible that the degree of severity of periventricular white matter involvement, rather than its mere presence, is determinative in its potential association with cognitive dysfunction.³⁵ Future research with use of MRI for quantitative delineation of periventricular white matter changes and the presence and characteristics of silent strokes may shed further light into the possible contribution or even interaction of these two variables in the pathogenesis of poststroke cognitive decline.

The finding of lower prestroke MMSE scores in our cases is intriguing and remains unexplained. Our attempts to relate it to either measures of general cardiovascular health or prestroke brain changes detected on CT scan did not provide an answer. Among these factors, hypertension,^{14 15 16 17} silent strokes, periventricular white matter changes,^{29 30} and ventricular enlargement³¹ are thought to be associated with cognitive dysfunction either at baseline or after the occurrence of subsequent stroke. The lack of such associations in our population may reflect our use of CT rather than MRI, but other unexplored factors, such as concomitant illness and the use of medications with central nervous system effects, may have played a role as well. Further analysis of these factors in the case and control subjects at baseline may be required to clarify the meaning of this observation.

The independent role of depression in poststroke cognitive decline is difficult to assess. Although the frequency,^{36 37} clinical course,^{38 39} relation to lesion location,^{40 41} and prognosis⁴² of poststroke depression have been defined, the magnitude of its impact on intellectual performance remains uncertain. Robinson and colleagues^{43 44} have reported significantly lower levels of cognitive performance, measured by either the MMSE⁴³ or a more extensive neuropsychological battery,^{44 45} in patients with major depression and left hemisphere strokes. They found that all 11 such patients had abnormally low MMSE scores (mean, 13.0±5.8), whereas only about 40% of nondepressed patients with left-sided strokes had low MMSE scores. Furthermore, when they matched patients with and without major depression for size and location of lesion,⁴⁶ they found significantly lower MMSE scores in the depressed group, leading to the suggestion that major poststroke depression may be responsible for impaired intellectual performance. In agreement with these data, we found an excess of cases with symptoms of depression in comparison with controls at 6 months after stroke in all age categories (Table 6), but the relation of symptoms of depression with large, left-sided strokes, although present, did not reach statistical significance (Table 7). In addition, nondepressed cases showed significantly lower MMSE scores than nondepressed controls, suggesting that their intellectual decline was independent of the presence of symptoms of depression. However, these results need to be interpreted with caution, because our diagnosis of symptoms of depression depended heavily on one single measure, the CES-D scale, which relies on self-reporting of symptoms and is thus subject to error. Our conclusions regarding the interaction of measures of depression with cognitive performance need to be tested further with the use of more complete neuropsychological tools.

In conclusion, we have presented data that document a significant decline in intellectual performance in subjects who sustained a stroke and underwent measurement of cognitive function with the same standardized test before and after the stroke. This change in cognitive performance was correlated only with large, left-sided strokes detected by CT scan. An MRI analysis of other anatomic brain changes possibly related to cognitive decline as well as detailed measurements of depression will be needed to assess the magnitude of their impact in poststroke intellectual decline.

	Acknowledgments

 
This study was supported by grants from the National Institute of Neurological Disorders and Stroke (2-RO1-NS-17950-15; Dr Wolf), the National Institute of Aging (2-RO1-AG08122-08; Dr Wolf), and the Framingham Heart Study of the National Heart, Lung, and Blood Institute (supported by NIH/NHLBI contract NO1-HC-38038; Dr Wolf). The authors are grateful to Deborah A. Foulkes of The Framingham Study for her assistance in the preparation of the manuscript.

Received December 12, 1997; accepted January 13, 1998.

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