Abstract
Background
Defining the nature of the contribution of stroke to cognitive impairment remains challenging.
Methods
We randomly selected Olmsted County, MN residents aged 70–89 years on October 1, 2004 and invited eligible non-demented subjects to participate. Participants (n = 2,050) were evaluated with an informant interview, a neurological evaluation, and neuropsychological testing. Neuropsychological testing included 9 tests to assess memory, attention and executive function, visuospatial cognition and language. Subjects were diagnosed by consensus as cognitively normal, MCI (either amnestic (a-) or non-amnestic (na-)), or dementia. A history of stroke was obtained from the subject and confirmed in the medical record. We computed the odds ratios (OR) for a clinical diagnosis of MCI or for scoring in the lowest quartile on each cognitive domain.
Results
There were 1640 cognitively normal and 329 MCI subjects, 241 a-MCI and 88 na-MCI. In fully adjusted models with non-demented subjects only, a history of stroke was associated with a higher odds ratio (OR) of na-MCI (OR= 2.85, 95% CI 1.61 – 5.04) than a-MCI (OR= 1.77, 95% CI 1.14 – 2.74). A history of stroke was also associated with impaired function in each cognitive domain except memory. The association was strongest for attention and executive function (OR=2.48, 95% CI 1.73 – 3.53). APOE e4 genotype was associated only with a-MCI and with impaired memory function.
Conclusions
In this population-based sample of non-demented persons, a history of stroke was particularly associated with na-MCI and with impairment in non-memory cognition. APOE e4 genotype was associated with memory impairment and a-MCI.
INTRODUCTION
The relationship between stroke and cognitive impairment has been enigmatic. The link between large strokes that led to immediate and persistent neurological impairment has never been questioned. However, the role of single strokes that may not have produced immediate cognitive impairment is less well understood. Several prior studies have noted that subjects with a history of stroke had a higher risk of cognitive impairment or decline1–5 or dementia6 than did persons without such a history.
While the pattern of cognitive impairment associated with cerebrovascular disease in dementia is not helpful diagnostically7, the profile of strengths and weaknesses of different cognitive domains in persons who are cognitively normal or who have mild cognitive impairment (MCI) might shed some light on what brain regions are affected by cerebrovascular pathology. It may be easier to recognize the unique contribution of cerebrovascular disease in persons with the least amount of cognitive impairment compared to patients with established dementia, because the impact of Alzheimer disease (AD) may overwhelm the vascular element8. Only a few studies4, 9 have employed cognitive assessments that were of sufficient breadth and depth to explore associations between specific cognitive domains and stroke.
We had the opportunity to study the associations of prior stroke and cognition in a large, population-based sample of elderly, non-demented persons in Olmsted County Minnesota. In addition to collecting detailed information about prior stroke histories, we also collected extensive information on other vascular diseases and risk factors, and have observed associations between diabetes and cognition10 and heart disease and cognition11 in this cohort. Our objective for the present study was to examine whether a history of stroke was associated with the diagnosis of MCI or cognitive impairment determined by a battery of neuropsychological tests and independent of the categorical clinical diagnoses. We compared associations of MCI and cognitive function domains with stroke history and APOE genotype, as a proxy, albeit an imperfect one, for Alzheimer-linked pathogenic mechanisms.
METHODS
Study Subjects
Study subjects were participants in a longitudinal study designed to estimate the prevalence and incidence of mild cognitive impairment in Olmsted County. Many of the details of the study design and methodology have been previously published12. The study protocol was approved by the Institutional Review Boards of Mayo Clinic and the Olmsted Medical Center. From an enumeration of Olmsted County, MN residents aged 70 to 89 years on October 1, 2004 (n = 9953), we randomly selected 5,233 subjects and invited them to participate in the study. We offered home visits for subjects with mobility problems. We excluded subjects who died before they could be contacted (n= 263), subjects who were terminally ill and in hospice (n = 56), subjects who could not be contacted ( n = 114), and subjects who had previously been diagnosed with dementia (n = 402; confirmed by D.S.K). From an eligible cohort of 4,398 subjects invited to the study, 2,719 (61.8%) were enrolled in the study; 2,050 participated in a face-to-face evaluation. This study is based on non-demented subjects who were underwent the face-to-face evaluation.
Participant evaluation
Participants underwent a nurse evaluation and risk factor assessment that included the Clinical Dementia Rating scale13, a neurological evaluation performed by a study physician including a mental status examination and a structured neurological examination, and neuropsychological testing including 9 cognitive tests to assess cognitive function in memory, executive function, language, and visuospatial skills, previously described12. The data for each participant were reviewed by an expert panel of physicians, neuropsychologists, and the nurse who evaluated the participant, and a diagnosis of normal cognition, MCI or dementia was reached by consensus.
Cognitive Domains
The neuropsychological test battery consisted of subtests from the Wechsler Adult Intelligence Scale-Revised (WAIS-R)14 and the Wechsler Memory Scale-Revised (WMS-R)15 Four domains of cognitive function were evaluated: 1) Executive function - Trail Making Test B16, Digit Symbol Substitution test from the WAIS-R; 2) Language - (Boston Naming Test17, Category Fluency18; 3) Memory -Logical Memory-II (delayed recall) and Visual Reproduction-II (delayed recall) from the WMS-R, Auditory Verbal Learning Test 19; and 4) Visuospatial - (Picture Completion and Block Design from the WAIS-R). The raw scores from the neuropsychological test battery were converted to a Mayo’s Older American Normative Studies (MOANS) value that was age- and education-adjusted to norms derived from the same population and transformed to a standardized score with a mean of 10 and standard deviation of 319. Domain scores were calculated for the 4 cognitive domains, as previously described12. A z-score was generated for each domain for each subject. The average of the MOANS scaled scores in each domain represented the domain score. The values for impairment were determined by inspecting the frequency distributions of the summed scaled scores in each domain. This approach relied on previous normative work and extensive knowledge of the cognitive abilities of the population from which the ADPR participants have been drawn19–21. Typically MCI patients score between 1.0 and 1.5 SD below the mean19. Although the psychometric scores were important in the diagnostic process, the final decision about impairment made by the neuropsychologist was based on the clinical interpretation and judgment of the neuropsychologist, in the context of the entire set of data for an individual, taking into account age, level of education, and occupation.
Clinical diagnoses
Based on the face-to-face evaluation, participants were categorized as cognitively normal (controls), MCI (cases) or demented12. A diagnosis of normal cognition was assigned according to published criteria19, 22. A diagnosis of MCI was made according to published criteria: cognitive concern by a physician, patient, or nurse; impairment in 1 or more of the 4 cognitive domains; essentially normal functional activities; and not demented 22. Participants with MCI were classified as having amnestic MCI (a-MCI) if the memory domain was impaired or non-amnestic MCI (na-MCI) if there was no memory impairment. A diagnosis of dementia was made according to Diagnostic and Statistical Manual of Mental Disorders IV criteria23.
History of stroke
A history of stroke was obtained from the subject by a physician interview. Stroke was defined by standard criteria, namely that the person had suffered a focal neurological deficit consistent with ischemia in a cerebral vascular territory, the symptoms of which lasted more than 24 hours. All strokes were verified in the medical history using the medical records-linkage system24. Subjects who gave a history of stroke were also asked whether there were any changes in their thinking that accompanied their stroke.
As part of the neurological examination performed by the study physician, examination findings relevant to cerebrovascular disease were assessed, including reflex asymmetries, unilateral weakness, hemiparesis, hemianopia, unilateral Babinski signs, etc. The clinician rated these findings as indicative or not of “focal neurological signs consistent with cerebrovascular disease.”
Statistical analyses
The characteristics of study subjects are presented using descriptive statistics. Comparisons between MCI cases and controls were made using chi square tests for categorical variables or Wilcoxon rank sum test for continuous variables. Using the cognitively normal subjects as the reference group, associations between MCI and stroke were examined using bivariate and multivariable logistic regression models. The associations between MCI (any MCI, a-MCI, and na-MCI) with stroke were examined in separate logistic regression models.
We also examined associations between the z-scores of each cognitive domain and stroke. The lowest quartile was considered impaired and was compared to three higher quartiles (reference). In one set of models examining cognitive domains separately, all subjects (ie both cognitively normal subjects and MCI subjects) were included. In another set of models examining each cognitive domain separately, only subjects diagnosed as cognitively normal were included.
All multivariable models included terms for age at evaluation (< 80 vs ≥ 80), sex, and years of education (≤ 12 vs. > 12) because these variables are known to be associated with cognitive function. Confounding by diabetes (with complications), hypertension, coronary heart disease and APOE e4 genotype was assessed by including these variables in multivariate models as covariates, with each variable added separately, and with all the variables included in the model. Fourteen subjects who had insufficient information to assign a diagnosis of MCI, dementia or normal cognition, and subjects diagnosed with dementia through the in-person assessment (n=67) were excluded from the analyses.
RESULTS
There were 1640 cognitively normal and 329 MCI subjects, 241 with a-MCI and 88 with na-MCI. There were 183 subjects with a history of stroke. Table 1 describes the demographic characteristics and burden of vascular diseases of the subjects. The evaluating neurologists rated 36 (10.9%) of the MCI subjects and 67 (4.1%) of the cognitively normal subjects as having focal neurological signs consistent with cerebrovascular disease based on their neurological examination. A higher proportion of MCI subjects with a stroke history (17 of 56, 30%) reported changes in thinking following their stroke than did cognitively normal subjects with a stroke history (14 of 127, 11%).
Table 1.
Demographic Characteristics of non-demented cohort
| Variable | Cognitively Diagnosis |
|||||
|---|---|---|---|---|---|---|
| a-MCI |
na-MCI | All MCI | Cognitively Normal |
P-value | ||
| n = 241 | n = 88 | n = 329 | n = 1,640 | a-MCI vs. na-MCI | All MCI vs. Normal | |
| Age, median (Q1, Q3)*, years | 82.7 (79.0, 86.0) | 82.5 (78.4, 85.4) | 82.7 (79.0, 85.8) | 79.6 (75.1, 83.6) | 0.60 | < 0.001 |
| Sex, (% men) | 150 (62.2) | 42 (47.7) | 192 (58.4) | 810 (49.4) | 0.018 | 0.003 |
| Education, median (Q1, Q3)*, years | 12 (12, 16) | 12 (12, 14) | 12 (12, 15) | 13 (12, 16) | 0.12 | < 0.001 |
| < 9 years | 35 (14.5) | 13 (14.8) | 48 (14.6) | 92 (5.6) | 0.12 | < 0.001 |
| 9–12 years | 95 (39.4) | 45 (51.1) | 140 (42.5) | 641 (39.1) | ||
| > 12 years | 111 (46.1) | 30 (34.1) | 141 (42.9) | 907 (55.3) | ||
| Stroke, n (%) | 34 (14.1) | 22 (25.0) | 56 (17.0) | 127 (7.7) | 0.020 | <0.001 |
| Coronary heart disease†, n (%) | 83 (34.4) | 38 (43.2) | 121 (36.8) | 489 (29.8) | 0.15 | 0.013 |
| APOE ε4ε4 or ε3ε4‡, n (%) | 70 (31.5) | 19 (22.9) | 89 (27.1) | 334 (20.4) | 0.14 | 0.006 |
| BMI ≥ 30, n (%) | 51 (21.2) | 23 (26.1) | 74 (22.5) | 457 (27.9) | 0.30 | 0.06 |
| Hypertension‡, n (%) | 166 (68.9) | 68 (77.3) | 234 (71.1) | 1154 (70.4) | 0.14 | 0.79 |
| DIABETES | ||||||
| Cigarette smoking (ever) ‡, n (%) | 122 (50.6) | 43 (48.9) | 165 (50.2) | 805 (49.1) | 0.78 | 0.73 |
| Current smoker | 9 (3.7) | 4 (4.5) | 13 (4.0) | 66 (4.0) | 0.74 | 0.95 |
| Former smoker | 113 (46.9) | 39 (44.3) | 152 (46.2) | 739 (45.1) | 0.68 | 0.70 |
| Depression‡, n (%) | 60 (24.9) | 26 (29.5) | 86 (26.1) | 182 (11.1) | 0.47 | <0.001 |
| Systolic blood pressure§‡, median (Q1, Q3) | 136 (124.8, 149) | 136 (120, 149) | 136 (123, 149) | 136 (123, 149) | 0.84 | 0.92 |
| Diastolic blood pressure§‡, median (Q1, Q3) | 70 (63, 78) | 70 (62, 79) | 70 (63, 78.5) | 70 (63, 79) | 0.67 | 0.62 |
| Focal neurological signs‡, n (%) | 21 (8.7) | 15 (17.0) | 36 (10.9) | 67 (4.1) | 0.032 | <0.001 |
| Change in thinking develop after stroke, n (% in those with stroke) | 9 (26.5) | 8 (36.4) | 17 (30.4) | 14 (11.0) | 0.040 | <0.001 |
| Hemiparesis, n (%)‡ | 12 (5.0) | 7 (8.0) | 19 (5.8) | 39 (2.4) | 0.30 | 0.001 |
Q1 = 25 percentile, Q3 = 75 percentile
Definitive or probable myocardial infarction, coronary artery bypass grafting (CABG), or percutaneous intervention (PCI), probable angina
112 normal, 19 a-MCI, and 5 na-MCI missing APOE data; 33 normal, 7a-MCI, and 4 na-MCI missing BMI data; 1 normal missing hypertension data; 1 normal missing cigarette smoking data; 2 normal missing current smoking data; 50 normal, 9 a-MCI, and 1na-MCI missing depression data; 18 normal, 3 a-MCI, and 1 na-MCI missing both systolic & diastolic blood pressure data; 4 normal missing focal neurological signs data; 4 normal, 1 a-MCI, and 1 na-MCI missing hemiparesis data.
blood pressures were the average blood pressures
Association of stroke with MCI
In models adjusting for age, sex and education, a history of stroke was associated with a higher risk of MCI (Table 2). When examined by MCI subtype there was a difference between a-MCI and na-MCI. The association of stroke with na-MCI was of greater magnitude than with a-MCI. Separate models in which diabetes (with complications), coronary heart disease, APOE genotype, and hypertension were added to the models also did not alter the differential associations between history of stroke and the MCI subtypes. Secondary analyses that excluded subjects with a history of stroke-related cognitive changes or subjects with focal neurological signs consistent with a prior stroke yielded nearly the same odds ratios.
Table 2.
Associations of stroke and APOE genotype for associations with all MCI, a-MCI and na-MCI.
| All MCI | a-MCI | na-MCI | ||||
|---|---|---|---|---|---|---|
| OR* | 95% CI | OR | 95% CI | OR | 95% CI | |
| Model 1 | ||||||
| Stroke | 2.10 | 1.48, 2.98 | 1.69 | 1.11 2.55 | 3.52 | 2.08 5.96 |
| APOE e4+ | 1.52 | 1.15, 2.01 | 1.68 | 1.23, 2.30 | 1.08 | 0.63, 1.83 |
| Model 2 | ||||||
| Stroke | 2.04 | 1.42, 2.95 | 1.74 | 1.13 2.69 | 2.97 | 1.69 5.24 |
| APOE e4+ | 1.52 | 1.14, 2.01 | 1.67 | 1.22 2.29 | 1.08 | 0.63 1.84 |
| Model 3 | ||||||
| Stroke | 2.03 | 1.40, 2.94 | 1.77 | 1.14 2.74 | 2.85 | 1.61, 5.04 |
| APOE e4+ | 1.54 | 1.16, 2.05 | 1.71 | 1.24, 2.34 | 1.06 | 0.62, 1.82 |
OR (95%CI), Odds ratios and 95% confidence intervals. Subjects who were cognitively normal were the reference group for all the analyses.
Model 1 represents associations of stroke and APOE e4 genotype with MCI in separate models, with each model controlling for age (<80 vs >=80), education (<12 vs >=12). and sex.
Model 2 includes both APOE e4 genotype and stroke history in the same model, with adjustment for age, sex and education.
Model 3 includes model 2 variables in the same model, with additional adjustment for diabetes (with complications), hypertension, and coronary heart disease.
In contrast to the pattern of association of stroke with MCI subtypes, APOE genotype was associated with a-MCI but not with na-MCI when included in a model with stroke (Table 2). Inclusion of APOE genotype and stroke in the same models, with an interaction term, revealed no significant interaction between APOE genotype and history of stroke for either a-MCI (OR=0.68, 95% CI 0.26, 1.79) or na-MCI (OR=0.58, 95% CI 0.13, 2.48). Thus, stroke was associated with both a-MCI and na-MCI, while APOE e4 genotype was associated with a-MCI but not with na-MCI.
Association of stroke with cognitive domains in all subjects
Separate analyses to investigate associations of stroke with cognitive function (assessed from the neuropsychological testing) were conducted with all 1,969 non-demented subjects included in the models (Table 3). A history of stroke was significantly associated with lower cognitive function in each cognitive domain except memory. The magnitude of the association was strongest for the executive function domain (OR = 2. 48) after adjusting for age, sex, and education, but was also elevated about 2-fold for language and visuospatial domains. Addition of diabetes, coronary heart disease, APOE genotype, and hypertension to the models had no impact on the significant associations of stroke with the 3 non-memory cognitive domains. Once again, secondary analyses that excluded subjects with a history of stroke-related cognitive changes or subjects with focal neurological signs consistent with a prior stroke yielded nearly the same odds ratios.
Table 3.
Associations of stroke and APOE genotype with all performance in each cognitive domain in non-demented subjects.
| Cognitive Domain | ||||||||
|---|---|---|---|---|---|---|---|---|
| Memory | Language | Executive | Visuospatial | |||||
| OR* | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | |
| Model 1 | ||||||||
| Stroke | 1.23 | .88, 1.74 | 1.71 | 1.21, 2.41 | 2.48 | 1.73, 3.53 | 2.15 | 1.52, 3.06 |
| APOE e4+ | 1.51 | 1.18, 1.95 | 1.21 | 0.93, 1.57 | 1.20 | 0.92, 1.58 | 1.28 | 0.99, 1.67 |
| Model 2 | ||||||||
| Stroke | 1.29 | .90, 1.86 | 1.83 | 1.27, 2.62 | 2.42 | 1.67, 3.51 | 2.12 | 1.47, 3.06 |
| APOE e4+ | 1.51 | 1.17, 1.95 | 1.21 | .93, 1.57 | 1.19 | .91, 1.57 | 1.28 | .98, 1.67 |
| Model 3 | ||||||||
| Stroke | 1.31 | 0.91, 1.88 | 1.85 | 1.29, 2.65 | 2.37 | 1.63, 3.44 | 2.14 | 1.48, 3.10 |
| APOE e4+ | 1.52 | 1.18, 1.96 | 1.21 | 0.93, 1.58 | 1.18 | 0.90, 1.56 | 1.29 | 0.99, 1.68 |
OR (95% CI), Odds ratios and 95% confidence intervals
Model 1 represents associations of stroke and APOE e4 genotype with MCI in separate models, with each model controlling for age (<80 vs >=80), education (<12 vs >=12). and sex.
Model 2 includes both APOE e4 genotype and stroke history in the same model, with adjustment for age, sex and education.
Model 3 includes model 2 variables in the same model, with additional adjustment for diabetes (with complications), hypertension, and coronary heart disease.
On the other hand, APOE e4 genotype was associated only with the memory domain (Table 3). With APOE genotype, stroke history and an interaction term for APOE and stroke history in the same model, there was no significant interaction for any of the cognitive domains. Thus, stroke was associated with poorer performance in the non-memory domains, while APOE e4 genotype was associated only with impairment in the memory domain.
Association of stroke with cognitive domains in cognitively normal subjects
Because the designation of cognitively normal does not imply that all “normal” subjects have equal levels of cognitive function, we were interested in assessing whether the associations of stroke with cognition could be demonstrated in participants without a diagnosis of MCI. Thus, in a final set of models, we restricted the analyses to subjects who were assigned a diagnosis of cognitively normal (Table 4). In this subset of subjects, a history of stroke was associated with lower performance in the language and executive domains. There were no interactions with APOE genotype. Addition of diabetes and hypertension did not alter the associations. Thus, even in cognitively normal subjects, stroke was associated with poorer performance in the language and executive function domains. APOE e4 genotype showed a trend only for association with poorer memory function.
Table 4.
Associations of stroke and APOE genotype with all performance in each cognitive domain in cognitively normal subjects.
| Cognitive Domain | ||||||||
|---|---|---|---|---|---|---|---|---|
| Memory | Language | Executive | Visuospatial | |||||
| OR* | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | |
| Model 1 | ||||||||
| Stroke | 1.20 | .74, 1.94 | 1.63 | 1.04, 2.54 | 1.94 | 1.23, 3.05 | 1.54 | .98, 2.42 |
| APOE e4+ | 1.37 | 0.98, 1.92 | 0.87 | 0.62, 1.22 | 0.98 | 0.69, 1.39 | 1.17 | 0.85, 1.61 |
| Model 2 | ||||||||
| Stroke | 1.33 | 0.81, 2.18 | 1.83 | 1.16, 2.89 | 1.98 | 1.23, 3.18 | 1.56 | 0.97, 2.50 |
| APOE e4+ | 1.37 | 0.98, 1.91 | 0.86 | 0.62, 1.21 | 0.97 | 0.68, 1.38 | 1.16 | 0.84, 1.60 |
| Model 3 | ||||||||
| Stroke | 1.34 | 0.82, 2.20 | 1.83 | 1.16, 2.90 | 1.94 | 1.20, 3.11 | 1.57 | 0.98, 2.53 |
| APOE e4+ | 1.37 | 0.98, 1.92 | 0.88 | 0.62, 1.23 | 0.95 | 0.67, 1.36 | 1.18 | 0.85, 1.63 |
OR (95% CI), Odds ratios and 95% confidence intervals
Model 1 represents associations of stroke and APOE e4 genotype with MCI in separate models, with each model controlling for age (<80 vs >=80), education (<12 vs >=12). and sex.
Model 2 includes both APOE e4 genotype and stroke history in the same model, with adjustment for age, sex and education.
Model 3 includes model 2 variables in the same model, with additional adjustment for diabetes (with complications), hypertension, and coronary heart disease.
DISCUSSION
We have shown using a case-control design in a population-based cohort that a history of stroke was associated with a particular pattern of cognitive impairment, based not only on the categorical diagnoses of MCI versus cognitively normal, but also on continuous measures of cognitive performance in the entire group of non-demented subjects. A history of stroke was independently associated with cognitive impairment in non-memory domains after adjustment for potential confounders. The association of a history of stroke with cognition was independent of APOE e4 genotype, and there was no interaction between the two. The association was not substantially attenuated by other vascular risk factors.
While prior studies have shown that a history of stroke was associated with cognitive impairment1–5, 9, our findings may offer the clearest view of the domain-specificity to the association. We found that the scores on Trailmaking part B and Digit Symbol Substitution (which we labeled as exemplifying the executive function domain) were most strongly linked to a history of stroke. A study from a longitudinal, population-based cohort of non-demented persons from North Manhattan found that a history of stroke was associated with cognitive decline in the form of memory impairment but not with what the authors referred to as “abstract/visuospatial performance4.” The tests underlying their assertion (similarities and nonverbal identities and oddities from Mattis Dementia Rating Scale) are similar to the tests in our language and visuospatial domains, which also showed associations with prior stroke in the current study. The one prior study of stroke and MCI9 that we are aware of also found that a history of transient ischemic attack or stroke was associated with na-MCI.
The association between non-memory cognitive impairment and cerebrovascular disease other than prior stroke is a recurrent theme25. Clinically diagnosed “vascular dementia” has been associated with executive dysfunction26. Imaging studies of subjects with white matter hyperintensity have found that non-memory cognitive dysfunction was more prominent than anterograde amnesia27–29. Analyses of patients with lacunar infarcts and extensive white matter hyperintensity burden also have found more prominent associations between evidence of infarction and non-amnesic cognitive functions than with memory impairment30. Disruption of subcortical white matter pathways linking frontal cortex to other regions by ischemic mechanisms is an attractive explanation as it accounts for both the clinical observations in the present study as well as the evidence from imaging linking white matter hyperintensities and lacunar infarcts to executive deficits27, 31.
The impact of stroke on cognition was subclinical because the majority of subjects in our study had no cognitive consequences of their stroke, and moreover, associations between stroke history and cognition were observed in our cognitively normal subjects. There are several possible subclinical mechanisms that could account for the cumulative rather than apoplectic development of dementia due to cerebrovascular disease. One is that prior strokes, in causing brain injury, reduce brain reserve, which allows the impact of subsequent diseases such as Alzheimer disease to be manifested clinically at an earlier time point32. A second explanation posits that overt strokes are associated with progressive cerebral microvascular disease, with the latter leading to ongoing brain injury and eventually dementia. Both could conceivably account for the predilection for executive, non-memory dysfunction. While the brain reserve and microvascular mechanisms are not mutually exclusive, they have rather different implications for potential interventions. The first one views the cerebrovascular event as an insult occurring at one point in time, whereas the latter hypothesizes a vascular process that is insidious and cumulative. Both, however, go well beyond the concept of vascular dementia as a disease that is exclusively due to overt, large infarcts.
The lack of attenuation of associations between stroke and cognitive impairment by other vascular risk factors has not been previously commented upon. A history of stroke was independently associated with cognitive impairment, even with diabetes (with complications), hypertension or coronary heart disease in the models. On the other hand, diabetes with complications10 and certain types of coronary heart disease11 were also independently associated with na-MCI, when stroke history was in the model. This implies that there either are other pathways for cerebrovascular disease besides stroke, that are correlated with diabetes or heart disease. Alternatively, these latter diseases might have a direct link with neurodegenerative disease.
APOE e4 genotype behaved quite differently as a risk factor than stroke history. It was more strongly associated with both a-MCI and with poor memory domain performance but not with impairment in any other cognitive domain. The association of APOE e4 genotype with subsequent risk of AD is well established33, 34. The differential associations of a history of stroke with impairment in non-memory cognition and APOE e4 genotype with memory dysfunction suggest that the pathophysiological processes driven by cerebrovascular disease and APOE genotype are distinct.
The strengths of our study were that we derived our observations from a population-based cohort of persons who were not demented. The cognitive status of our subjects was evaluated with neuropsychological testing and clinical evaluation by a physician. The history of stroke was verified in the medical records of subjects using he medical records-linkage system for Olmsted County residents. The weaknesses of our study were that it was cross-sectional and used prevalent cases of MCI; therefore, the temporality of exposure and disease is not clear. We did not have imaging data on the location of the strokes. More precise definitions of the strokes might have substantially increased the specificity of the estimates of association.
Acknowledgments
Funding/Support: This work is supported by grants from the National Institute on Aging (P50 AG16574 and U01 AG06786), the National Institute of Mental Health (K01 MH68351), the National Institute of Aging (K01 AG028573), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR30582), and by the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program.
Footnotes
Author Contributions:
Study concept and design: Knopman, Roberts, Petersen
Acquisition of data: Knopman, Petersen, Boeve, Tangalos, Geda
Analysis and interpretation of data: Knopman, Roberts, Petersen
Drafting of the manuscript: Knopman
Critical revision of the manuscript for important intellectual content: Knopman, Roberts, Petersen, Boeve, Tangalos, Geda
Statistical analysis: Pankratz, Cha
Study supervision: Knopman, Roberts, Petersen
Financial Disclosure: Dr. Knopman has served on a Data Safety monitoring board for Sanofi-Aventis and will serve on a Data Safety Monitoring board for Lilly. He is also an investigator in a clinical trial sponsored by Elan Pharmaceuticals. Dr. Petersen has been a consultant to GE HealthCare, Servier and Elan Pharmaceuticals. The remaining authors have reported no conflicts of interest.
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