@article {1460, title = {Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study.}, journal = {Stroke}, volume = {27}, year = {1996}, month = {1996 Aug}, pages = {1274-82}, abstract = {

BACKGROUND AND PURPOSE: Our aim was to identify potential risk factors for and clinical manifestations of white matter findings on cranial MRI in elderly people.

METHODS: Medicare eligibility lists were used to obtain a representative sample of 5888 community-dwelling people aged 65 years or older. Correlates of white matter findings were sought among 3301 participants who underwent MRI scanning and denied a history of stroke or transient ischemic attack. Participants underwent extensive standardized evaluations at baseline and on follow-up, including standard questionnaires, physical examination, multiple blood tests, electrocardiogram, pulmonary function tests, carotid sonography, and M-mode echocardiography. Neuroradiologists graded white matter findings from 0 (none) to 9 (maximal) without clinical information.

RESULTS: Many potential risk factors were related to the white matter grade, but in the multivariate model the factors significantly (all P < .01) and independently associated with increased grade were greater age, clinically silent stroke on MRI, higher systolic blood pressure, lower forced expiratory volume in 1 second (FEV1), and income less than $50,000 per year. If excluded, FEV1 was replaced in the model by female sex, history of smoking, and history of physician-diagnosed hypertension at the baseline examination. Many clinical features were correlated with the white matter grade, especially those indicating impaired cognitive and lower extremity function.

CONCLUSIONS: White matter findings were significantly associated with age, silent stroke, hypertension, FEV1, and income. The white matter findings may not be considered benign because they are associated with impaired cognitive and lower extremity function.

}, keywords = {Age Factors, Aged, Aging, Blood Pressure, Brain, Cardiovascular Diseases, Cerebrovascular Disorders, Cohort Studies, Female, Humans, Ischemic Attack, Transient, Magnetic Resonance Imaging, Male, Multivariate Analysis, Risk Factors, Sex Factors}, issn = {0039-2499}, author = {Longstreth, W T and Manolio, T A and Arnold, A and Burke, G L and Bryan, N and Jungreis, C A and Enright, P L and O{\textquoteright}Leary, D and Fried, L} } @article {1491, title = {The association of antihypertensive agents with MRI white matter findings and with Modified Mini-Mental State Examination in older adults.}, journal = {J Am Geriatr Soc}, volume = {45}, year = {1997}, month = {1997 Dec}, pages = {1423-33}, abstract = {

OBJECTIVES: To examine the association of antihypertensive regimen with magnetic resonance imaging (MRI) white matter hyperintensity and with cognitive impairment in older adults.

DESIGN: Cross-sectional study.

SETTING: The Cardiovascular Health study, an observational prospective cohort study of risk factors for coronary heart disease and stroke in men and women 65 years of age and older.

PARTICIPANTS: 1268 men and women with pharmacologically treated hypertension.

MEASUREMENTS: Information on medication use, medical history, and health habits was collected at clinic examinations. Participants completed the Modified Mini-Mental State Examination (3MS) and underwent MRI examination. Without clinical information, study neuroradiologists assigned an overall grade of white matter signal intensity on MRI on a scale from 0 (no findings) to 9 (extensive findings).

RESULTS: Adjusted mean white matter grade was higher for users of calcium channel blockers (2.59, P = .007) and users of loop diuretics (2.60, P = .015) than for users of beta blockers (2.12). The association was present for both dihydropyridine and non-dihydropyridine calcium channel blockers. Adjusted mean 3MS scores were lower for users of calcium channel blockers (89.6, P < .002), especially dihydropyridines, and users of loop diuretics (89.7, P < .006) than for users of beta blockers (92.3). No statistically significant association could be shown for users of other drug regimens, including thiazides and ACE inhibitors.

CONCLUSION: In this study, users of antihypertensive regimens which included calcium channel blockers or loop diuretics had more severe white matter hyperintensity on MRI and worse performance on 3MS than users of beta blockers.

}, keywords = {Adrenergic beta-Antagonists, Aged, Aged, 80 and over, Antihypertensive Agents, Brain, Calcium Channel Blockers, Cognition, Cohort Studies, Cross-Sectional Studies, Diuretics, Female, Geriatric Assessment, Humans, Magnetic Resonance Imaging, Male, Risk Factors}, issn = {0002-8614}, author = {Heckbert, S R and Longstreth, W T and Psaty, B M and Murros, K E and Smith, N L and Newman, A B and Williamson, J D and Bernick, C and Furberg, C D} } @article {1470, title = {Clinically serious abnormalities found incidentally at MR imaging of the brain: data from the Cardiovascular Health Study.}, journal = {Radiology}, volume = {202}, year = {1997}, month = {1997 Jan}, pages = {41-6}, abstract = {

PURPOSE: To determine the prevalence of clinically serious findings unrelated to stroke on cranial magnetic resonance (MR) images in a population of community-dwelling elderly people.

MATERIALS AND METHODS: Neuroradiologists reviewed MR images of 3,672 people aged 65 years and older who were enrolled in a longitudinal, population-based study of cardiovascular and cerebrovascular disease. The neuroradiologists alerted MR imaging field centers about potentially serious abnormalities. Clinical information was obtained from clinical examinations performed before MR imaging, hospital discharge summaries, and the field centers at which MR imaging was performed.

RESULTS: On 3,672 image sets, 64 (1.74\%) clinically serious abnormalities were found. Among the presumptive diagnoses were 19 meningiomas (0.52\%), six pituitary adenomas (0.16\%), five cavernous malformations (0.14\%), eight vascular stenoses (0.22\%), four aneurysms (0.11\%), two intraventricular masses (0.05\%), two subdural fluid collections (0.05\%), and two other tumors (0.05\%). Only nine participants with these abnormalities required surgery. All but one of the meningiomas were in women, and the prevalence of the tumor decreased with increasing age.

CONCLUSION: Physicians should be alert to the possible presence of clinically serious conditions in otherwise asymptomatic elderly individuals.

}, keywords = {Aged, Aged, 80 and over, Brain, Brain Diseases, Cardiovascular Diseases, Cohort Studies, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male}, issn = {0033-8419}, doi = {10.1148/radiology.202.1.8988190}, author = {Yue, N C and Longstreth, W T and Elster, A D and Jungreis, C A and O{\textquoteright}Leary, D H and Poirier, V C} } @article {1469, title = {Sulcal, ventricular, and white matter changes at MR imaging in the aging brain: data from the cardiovascular health study.}, journal = {Radiology}, volume = {202}, year = {1997}, month = {1997 Jan}, pages = {33-9}, abstract = {

PURPOSE: To determine the distribution of changes in sulcal size, ventricular size, and white matter signal intensity depicted on cranial magnetic resonance (MR) images, with stratification according to age, race, and sex.

MATERIALS AND METHODS: Ventricular size, sulcal size, and white matter signal intensity changes were graded on cranial MR images of 3,660 community-living, elderly participants in the Cardiovascular Health Study. A healthier subgroup was also defined. Summary statistics for both groups were generated for age, race, and sex.

RESULTS: Regression models of the entire imaged cohort showed higher grades of all variables with increasing age, and higher ventricular and sulcal grades in men and in nonblack individuals. White matter grade was greater in women and in black individuals. Regression models of the healthier subgroup showed similar associations, except for a lack of association of sulcal and ventricular size with race.

CONCLUSION: Sulcal width, ventricular size, and white matter signal intensity change with age, sex, and race. Knowledge of these changes is important in appropriate interpretation of MR images of the elderly.

}, keywords = {Aged, Aged, 80 and over, Aging, Brain, Cardiovascular Diseases, Cerebral Ventricles, Cohort Studies, Continental Population Groups, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Reproducibility of Results, Sex Factors}, issn = {0033-8419}, doi = {10.1148/radiology.202.1.8988189}, author = {Yue, N C and Arnold, A M and Longstreth, W T and Elster, A D and Jungreis, C A and O{\textquoteright}Leary, D H and Poirier, V C and Bryan, R N} } @article {1517, title = {Asymptomatic internal carotid artery stenosis defined by ultrasound and the risk of subsequent stroke in the elderly. The Cardiovascular Health Study.}, journal = {Stroke}, volume = {29}, year = {1998}, month = {1998 Nov}, pages = {2371-6}, abstract = {

BACKGROUND AND PURPOSE: We sought in this study to relate carotid ultrasound findings in asymptomatic older adults to the 5-year risk of various cerebrovascular outcomes used in the Asymptomatic Carotid Atherosclerosis Study (ACAS).

METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of people 65 years and older. Analyses of internal carotid artery stenosis defined by multiple different cutoffs of peak systolic velocity, rather than one particular cutoff, were performed in the 5441 participants who underwent carotid ultrasound and lacked a history of transient ischemic attack or stroke. The 5-year risks of 7 cerebrovascular disease outcomes used in ACAS were estimated for each cutoff.

RESULTS: Associations with the 5-year risk of outcomes were substantially elevated only at cutoffs with high peak systolic velocities. In this population, the number of people with such high velocities was small. For example, with a cutoff of approximately 2.5 m/s, suggesting a stenosis of >70\%, the 5-year risk of an ipsilateral fatal or nonfatal stroke was 5\%, and only 0.5\% of the group had velocities at least this high.

CONCLUSIONS: In a group of older adults likely to participate in a screening program, as evidenced by willingness to participate in CHS, high peak systolic velocities consistent with high-grade carotid stenosis were uncommon and risk of subsequent cerebrovascular disease outcomes was relatively low. These findings do not suggest that similar populations of older adults would benefit from a program using ultrasound to screen for asymptomatic carotid stenosis.

}, keywords = {Aged, Blood Flow Velocity, Carotid Artery, Internal, Carotid Stenosis, Cerebrovascular Disorders, Cohort Studies, Female, Humans, Male, Prevalence, Risk Factors, Systole, Ultrasonography, Doppler}, issn = {0039-2499}, author = {Longstreth, W T and Shemanski, L and Lefkowitz, D and O{\textquoteright}Leary, D H and Polak, J F and Wolfson, S K} } @article {1514, title = {Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study.}, journal = {Arch Neurol}, volume = {55}, year = {1998}, month = {1998 Sep}, pages = {1217-25}, abstract = {

OBJECTIVE: To identify risk factors for and functional consequences of lacunar infarct in elderly people.

METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of people 65 years or older, in which 3660 participants underwent cranial magnetic resonance imaging (MRI). Neuroradiologists read scans in a standard fashion without any clinical information. Lacunes were defined as subcortical areas consistent with infarcts measuring 3 to 20 mm. In cross-sectional analyses, clinical correlates were contrasted among groups defined by MRI findings.

RESULTS: Of the 3660 subjects who underwent MRI, 2529 (69\%) were free of infarcts of any kind and 841 (23\%) had 1 or more lacunes without other types present, totaling 1270 lacunes. For most of these 841 subjects, their lacunes were single (66\%) and silent (89\%), namely without a history of transient ischemic attack or stroke. In multivariate analyses, factors independently associated with lacunes were increased age, diastolic blood pressure, creatinine, and pack-years of smoking (listed in descending order of strength of association; for all, P < .005), as well as maximum internal carotid artery stenosis of more than 50\% (odds ratio [OR], 1.81; P < .005), male sex (OR, 0.74; P < .005), and history of diabetes at entrance into the study (OR, 1.33; P < .05). Models for subgroups of single, multiple, silent, and symptomatic lacunes differed only minimally. Those with silent lacunes had more cognitive, upper extremity, and lower extremity dysfunction not recognized as stroke than those whose MRIs were free of infarcts.

CONCLUSIONS: In this group of older adults, lacunes defined by MRI are common and associated with factors that likely promote or reflect small-vessel disease. Silent lacunes are also associated with neurologic dysfunction.

}, keywords = {Aged, Cerebral Infarction, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Multivariate Analysis, Risk Factors}, issn = {0003-9942}, author = {Longstreth, W T and Bernick, C and Manolio, T A and Bryan, N and Jungreis, C A and Price, T R} } @article {608, title = {Clinical correlates of ventricular and sulcal size on cranial magnetic resonance imaging of 3,301 elderly people. The Cardiovascular Health Study. Collaborative Research Group.}, journal = {Neuroepidemiology}, volume = {19}, year = {2000}, month = {2000 Jan-Feb}, pages = {30-42}, abstract = {

To identify potential risk factors for and clinical manifestations of ventricular and sulcal enlargement on cranial magnetic resonance imaging (MRI), 3,301 community-dwelling people 65 years or older without a history of stroke or transient ischemic attack underwent extensive standardized evaluations and MRI. In the multivariate model, increased age and white matter grade on MRI were the dominant risk factors for ventricular and sulcal grade. For ventricular grade, other than race, for which non-Blacks had higher grades, models for men and women shared no other factors. For sulcal grades, models for men and women shared variables reflecting cigarette smoking and diabetes. Clinical features were correlated more strongly with ventricular than sulcal grade and more strongly for women than men. Significant age-adjusted correlations between ventricular grade and the Digit-Symbol Substitution Test were found for men and women. Prospective studies will be needed to extend findings of this cross-sectional analysis.

}, keywords = {Age Distribution, Age Factors, Aged, Aging, Cerebral Ventricles, Continental Population Groups, Cross-Sectional Studies, Diabetes Complications, Female, Humans, Hypertrophy, Linear Models, Magnetic Resonance Imaging, Male, Multivariate Analysis, Risk Factors, Severity of Illness Index, Sex Distribution, Sex Factors, Smoking, Stroke}, issn = {0251-5350}, doi = {10.1159/000026235}, author = {Longstreth, W T and Arnold, A M and Manolio, T A and Burke, G L and Bryan, N and Jungreis, C A and O{\textquoteright}Leary, D and Enright, P L and Fried, L} } @article {660, title = {Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults: the cardiovascular health study.}, journal = {Stroke}, volume = {32}, year = {2001}, month = {2001 Sep}, pages = {1939-46}, abstract = {

BACKGROUND AND PURPOSE: Subclinical findings on MRI of the brain are associated with poorer cognitive and neurological function among older adults. We sought to determine how alcohol consumption is related to these findings.

METHODS: As part of the Cardiovascular Health Study, 3660 adults aged 65 years and older underwent MRI of the brain from 1992 to 1994. We excluded 284 participants with a confirmed history of cerebrovascular disease. We assessed self-reported intake of beer, wine, and liquor at the annual clinic visit closest to the date of the MRI and grouped participants into 6 categories: abstainers, former drinkers, <1 drink weekly, 1 to <7 drinks weekly, 7 to <15 drinks weekly, and >/=15 drinks weekly. Neuroradiologists assessed white matter grade, infarcts, ventricular size, and sulcal size in a standardized and blinded manner. We used multivariate regression to control for sociodemographic and clinical characteristics.

RESULTS: We found a U-shaped relationship between alcohol consumption and white matter abnormalities. Compared with abstainers, individuals consuming 1 to <7 drinks had an OR of 0.68, and those consuming >/=15 drinks weekly had an OR of 0.95 (p for quadratic term=0.01). Heavier alcohol consumption was associated with a lower prevalence of infarcts (OR for >/=15 drinks weekly relative to abstainers 0.59; P for trend=0.004), but larger ventricular size (OR for >/=15 drinks weekly relative to abstainers 1.32; P for trend=0.006) and sulcal size (OR for >/=15 drinks weekly relative to abstainers 1.53; P for trend=0.007).

CONCLUSIONS: Moderate alcohol consumption is associated with a lower prevalence of white matter abnormalities and infarcts, thought to be of vascular origin, but with a dose-dependent higher prevalence of brain atrophy on MRI among older adults. The extent to which these competing associations influence overall brain function will require further study.

}, keywords = {Aged, Aging, Alcohol Drinking, Atrophy, Brain, Brain Diseases, Cerebral Infarction, Comorbidity, Demography, Female, Health Surveys, Humans, Logistic Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Odds Ratio, Prospective Studies, Sensitivity and Specificity, United States}, issn = {1524-4628}, doi = {10.1161/hs0901.095723}, author = {Mukamal, K J and Longstreth, W T and Mittleman, M A and Crum, R M and Siscovick, D S} } @article {644, title = {Cluster analysis and patterns of findings on cranial magnetic resonance imaging of the elderly: the Cardiovascular Health Study.}, journal = {Arch Neurol}, volume = {58}, year = {2001}, month = {2001 Apr}, pages = {635-40}, abstract = {

OBJECTIVE: To characterize patterns of findings on cranial magnetic resonance imaging (MRI) of the elderly using a statistical technique called cluster analysis.

SUBJECTS AND METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people 65 years and older. Of these, 3230 underwent cranial MRI scans, which were coded for presence of infarcts and grades for white matter, ventricles, and sulci. Cluster analysis separated participants into 5 clusters based solely on patterns of MRI findings. Participants comprising each cluster were contrasted with respect to cardiovascular risk factors and clinical manifestations.

RESULTS: One cluster was low on all the MRI findings (normal) and another was high on all of them (complex infarcts). Another cluster had evidence for infarcts alone (simple infarcts), whereas the last 2 clusters lacked infarcts, one having enlarged ventricles and sulci (atrophy) and the other having prominent white matter changes and enlarged ventricles (leukoaraiosis). Factors that distinguished these clusters in a discriminant analysis were age, sex, several measures of hypertension, internal carotid artery wall thickness, smoking, and prevalent claudication before the MRI. The atrophy group had the highest percentage of men and the normal group had the lowest. Cognitive and motor performance also differed across clusters, with the atrophy cluster performing better than may have been expected.

CONCLUSIONS: These MRI patterns identified participants with different vascular disease risk factors and clinical manifestations. Results of these exploratory analyses warrant consideration in other populations of elderly people. Such patterns may provide clues about the pathophysiology of structural brain changes in the elderly.

}, keywords = {Aged, Brain, Cerebral Infarction, Cerebrovascular Disorders, Cluster Analysis, Cohort Studies, Discriminant Analysis, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Risk Factors}, issn = {0003-9942}, doi = {10.1001/archneur.58.4.635}, author = {Longstreth, W T and Diehr, P and Manolio, T A and Beauchamp, N J and Jungreis, C A and Lefkowitz, D} } @article {629, title = {Frequency and predictors of stroke death in 5,888 participants in the Cardiovascular Health Study.}, journal = {Neurology}, volume = {56}, year = {2001}, month = {2001 Feb 13}, pages = {368-75}, abstract = {

BACKGROUND: Few population-based studies have examined in detail issues of stroke-related deaths in elderly people.

METHODS: Participants in the Cardiovascular Health Study (CHS) are 65 years of age or older, have had extensive baseline evaluations, and have been followed-up for fatal and nonfatal cardiovascular and cerebrovascular disease outcomes. Investigators adjudicated these outcomes and classified strokes by types and subtypes.

RESULTS: Over 7 years, 1,310 (22.2\%) of 5,888 participants died, and 455 (7.7\%) experienced incident stroke. For the 5,888, stroke mortality was 3.2 per 1,000 person-years. For the 455, it was 36.1 per 1,000 person-years, with the most lethal type being hemorrhagic and the ischemic subtype being cardioembolic. After controlling for age and stroke type, the only other independent predictor of death after any stroke was poor performance on a timed walk measured before the incident stroke. Considering only ischemic stroke, the independent predictors of death were African American race and poor performance on timed walk.

CONCLUSION: In CHS, death attributable to stroke is common. As in other studies, the most lethal stroke type was hemorrhagic, and ischemic stroke subtype, cardioembolic. Slow walking, possibly a measure of frailty, was associated with an increased risk of death of stroke. Finally, African Americans faced a greater risk of death than others after an ischemic stroke.

}, keywords = {Aged, Aged, 80 and over, Clinical Trials as Topic, Female, Humans, Longitudinal Studies, Male, Predictive Value of Tests, Stroke, Survival Analysis, United States}, issn = {0028-3878}, doi = {10.1212/wnl.56.3.368}, author = {Longstreth, W T and Bernick, C and Fitzpatrick, A and Cushman, M and Knepper, L and Lima, J and Furberg, C D} } @article {663, title = {Silent MRI infarcts and the risk of future stroke: the cardiovascular health study.}, journal = {Neurology}, volume = {57}, year = {2001}, month = {2001 Oct 09}, pages = {1222-9}, abstract = {

BACKGROUND: Silent infarcts are commonly discovered on cranial MRI in the elderly.

OBJECTIVE: To examine the association between risk of stroke and presence of silent infarcts, alone and in combination with other stroke risk factors.

METHODS: Participants (3,324) in the Cardiovascular Health Study (CHS) without a history of stroke underwent cranial MRI scans between 1992 and 1994. Silent infarcts were defined as focal lesions greater than 3 mm that were hyperintense on T2 images and, if subcortical, hypointense on T1 images. Incident strokes were identified and classified over an average follow-up of 4 years. The authors evaluated the risk of subsequent symptomatic stroke and how it was modified by other potential stroke risk factors among those with silent infarcts.

RESULTS: Approximately 28\% of CHS participants had evidence of silent infarcts (n = 923). The incidence of stroke was 18.7 per 1,000 person-years in those with silent infarcts (n = 67) compared with 9.5 per 1,000 person-years in the absence of silent infarcts. The adjusted relative risk of incident stroke increased with multiple (more than one) silent infarcts (hazard ratio 1.9 [1.2 to 2.8]). Higher values of diastolic and systolic blood pressure, common and internal carotid wall thickness, and the presence of atrial fibrillation were associated with an increased risk of strokes in those with silent infarcts (n = 53 strokes).

CONCLUSION: The presence of silent cerebral infarcts on MRI is an independent predictor of the risk of symptomatic stroke over a 4-year follow- up in older individuals without a clinical history of stroke.

}, keywords = {Aged, Cerebral Infarction, Cohort Studies, Female, Follow-Up Studies, Humans, Incidence, Magnetic Resonance Imaging, Male, Predictive Value of Tests, Risk Factors, Stroke}, issn = {0028-3878}, doi = {10.1212/wnl.57.7.1222}, author = {Bernick, C and Kuller, L and Dulberg, C and Longstreth, W T and Manolio, T and Beauchamp, N and Price, T} } @article {744, title = {A prospective analysis of risk factors for white matter disease in the brain stem: the Cardiovascular Health Study.}, journal = {Neuroepidemiology}, volume = {22}, year = {2003}, month = {2003 Sep-Oct}, pages = {275-82}, abstract = {

BACKGROUND AND PURPOSE: White matter disease (WMD) in the brain stem may be a predictor of poor clinical outcome, independent of WMD in the periventricular and subcortical areas of the brain. Many cardiovascular risk factors such as older age, hypertension, and smoking have been suggested as risk factors for WMD in the periventricular and subcortical areas of the brain. However, no epidemiologic study has examined the associations between cardiovascular risk factors and WMD in the brain stem.

METHODS: A total of 789 participants, aged 65 years or older, from the Cardiovascular Health Study constituted the present study population. WMD, defined as hyperintensive lesions on magnetic resonance imaging (MRI), in the brain stem was measured in 1992/1993 and 1997/1998.

RESULTS: Of the 789 participants, 212 (26.9\%) had WMD in the brain stem in 1997/1998. In multivariate logistic regression analysis, the presence of WMD in the brain stem in 1997/1998 was significantly associated with several variables measured in 1992/1993: an increase by 5 years of age (OR = 1.51, 95\% CI: 1.25-1.83), a 10-pack-years increase in smoking (OR = 1.12, 95\% CI: 1.04-1.21), a 0.1-liter increase in first-second forced expiratory volume (OR = 0.95, 95\% CI: 0.92-0.99), a 1 micromol/l increase in fibrinogen level (OR = 1.13, 95\% CI: 1.03-1.23), and MRI infarction (OR = 2.58, 95\% CI: 1.78-3.74). Excluding those (n = 167) with WMD in the brain stem in 1992/1993, the pattern remained. Hypertension was not associated with WMD in the brain stem.

CONCLUSIONS: Increased age, smoking, lower forced expiratory volume, increased fibrinogen level, and MRI infarction, but not hypertension, may be independent risk factors for WMD in the brain stem in older adults.

}, keywords = {Age Factors, Aged, Brain Diseases, Brain Infarction, Brain Stem, Cardiovascular Diseases, Female, Fibrinogen, Forced Expiratory Volume, Humans, Magnetic Resonance Imaging, Male, Prospective Studies, Regression Analysis, Risk Factors, Smoking}, issn = {0251-5350}, doi = {10.1159/000071190}, author = {Ding, Jingzhong and Nieto, F Javier and Beauchamp, Norman J and Longstreth, W T and Manolio, Teri A and Hetmanski, Jacqueline B and Fried, Linda P} } @article {729, title = {Prospective study of alcohol consumption and risk of dementia in older adults.}, journal = {JAMA}, volume = {289}, year = {2003}, month = {2003 Mar 19}, pages = {1405-13}, abstract = {

CONTEXT: Alcohol consumption has been associated with complex changes in cerebral vasculature and structure in older adults. How alcohol consumption affects the incidence of dementia is less clear.

OBJECTIVE: To determine the prospective relationship of alcohol consumption and risk of dementia among older adults.

DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study of 373 cases with incident dementia and 373 controls who were among 5888 adults aged 65 years and older who participated in the Cardiovascular Health Study, a prospective, population-based cohort study in 4 US communities. The controls were frequency-matched on age, death before 1999, and their attendance of a 1998-1999 clinic. Participants in this study underwent magnetic resonance imaging (MRI) of the brain and cognitive testing between 1992 and 1994 and were followed up until 1999.

MAIN OUTCOME MEASURES: Odds of incident dementia, ascertained by detailed neurological and neuropsychological examinations according to average alcohol consumption, assessed by self-reported intake of beer, wine, and liquor at 2 visits prior to the date of the MRI.

RESULTS: Compared with abstention, the adjusted odds for dementia among those whose weekly alcohol consumption was less than 1 drink were 0.65 (95\% confidence interval [CI], 0.41-1.02); 1 to 6 drinks, 0.46 (95\% CI, 0.27-0.77); 7 to 13 drinks, 0.69 (95\% CI, 0.37-1.31); and 14 or more drinks, 1.22 (95\% CI, 0.60-2.49; P for quadratic term =.001). A trend toward greater odds of dementia associated with heavier alcohol consumption was most apparent among men and participants with an apolipoprotein E epsilon4 allele. We found generally similar relationships of alcohol use with Alzheimer disease and vascular dementia.

CONCLUSIONS: Compared with abstention, consumption of 1 to 6 drinks weekly is associated with a lower risk of incident dementia among older adults.

}, keywords = {Aged, Alcohol Drinking, Apolipoprotein E4, Apolipoproteins E, Brain, Case-Control Studies, Dementia, Female, Humans, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Prospective Studies, Risk}, issn = {0098-7484}, doi = {10.1001/jama.289.11.1405}, author = {Mukamal, Kenneth J and Kuller, Lewis H and Fitzpatrick, Annette L and Longstreth, W T and Mittleman, Murray A and Siscovick, David S} } @article {766, title = {Cognitive impairment and decline are associated with carotid artery disease in patients without clinically evident cerebrovascular disease.}, journal = {Ann Intern Med}, volume = {140}, year = {2004}, month = {2004 Feb 17}, pages = {237-47}, abstract = {

BACKGROUND: Whether carotid artery disease is a cause of cognitive impairment in persons who have not had stroke is unknown. If this is the case, diminished performance on the Modified Mini-Mental State Examination should be more common in persons with left carotid artery disease than in those with right carotid artery disease.

OBJECTIVE: To determine whether left carotid artery disease is associated with cognitive impairment.

DESIGN: Cross-sectional and cohort study.

SETTING: Four U.S. communities participating in the Cardiovascular Health Study.

PATIENTS: 4006 right-handed men and women 65 years of age or older without history of stroke, transient ischemic attack, or carotid endarterectomy.

MEASUREMENTS: Internal carotid artery stenosis and intima-media thickness of the common carotid artery were assessed by using duplex ultrasonography. Cognitive impairment was defined as a score less than 80 on the Modified Mini-Mental State Examination, and cognitive decline was defined as an average decrease of more than 1 point annually in Modified Mini-Mental State Examination score during up to 5 years of follow-up. Multivariate logistic regression models were used to estimate the risk for cognitive impairment and decline associated with left internal carotid artery stenosis and intima-media thickness, after adjustment for measures of right-sided disease and risk factors for vascular disease.

RESULTS: After adjustment for right-sided stenosis, high-grade (> or =75\% narrowing of diameter) stenosis of the left internal carotid artery (32 patients) was associated with cognitive impairment (odds ratio, 6.7 [95\% CI, 2.4 to 18.1] compared with no stenosis) and cognitive decline (odds ratio, 2.6 [CI, 1.1 to 6.3]). Intima-media thickness of the left common carotid artery was associated with cognitive impairment and decline in univariate analysis, but this effect did not persist after adjustment.

CONCLUSIONS: Cognitive impairment and decline are associated with asymptomatic high-grade stenosis of the left internal carotid artery. The persistence of the association after adjustment for right-sided stenosis indicates that the association is not due to underlying vascular risk factors or atherosclerosis in general.

}, keywords = {Aged, Carotid Stenosis, Cognition Disorders, Cohort Studies, Cross-Sectional Studies, Female, Humans, Male, Neuropsychological Tests, Odds Ratio, Risk Factors, Tunica Intima}, issn = {1539-3704}, doi = {10.7326/0003-4819-140-4-200402170-00005}, author = {Johnston, S Claiborne and O{\textquoteright}Meara, Ellen S and Manolio, Teri A and Lefkowitz, David and O{\textquoteright}Leary, Daniel H and Goldstein, Steven and Carlson, Michelle C and Fried, Linda P and Longstreth, W T} } @article {763, title = {Plasma total homocysteine levels and cranial magnetic resonance imaging findings in elderly persons: the Cardiovascular Health Study.}, journal = {Arch Neurol}, volume = {61}, year = {2004}, month = {2004 Jan}, pages = {67-72}, abstract = {

BACKGROUND: An elevated plasma total homocysteine (tHcy) level is associated with an increased risk of vascular disease. Some studies have shown associations between tHcy level and small-vessel disease of the brain on magnetic resonance imaging (MRI).

DESIGN: In the Cardiovascular Health Study, 622 elderly participants without a history of transient ischemic attack or stroke had results for tHcy level and cranial MRI. We sought associations between tHcy level and MRI findings of ventricular grade, sulcal grade, white matter grade, and infarcts. We controlled for other factors, including levels of creatinine, folate, and vitamins B(6) and B(12) and methylenetetrahydrofolate reductase genotype.

RESULTS: After controlling for age and sex, tHcy level was not associated with the individual MRI findings. Further adjustments for other factors and other blood tests had little effect on these findings. The only significant finding was a linear trend across quintiles of tHcy level and a pattern of MRI findings combining infarcts and high white matter grade. The linear trend remained significant after controlling for other risk factors and atherosclerotic markers (top quintile vs bottom quintile odds ratio, 3.3; 95\% confidence interval, 0.96-11.20; P =.04 for linear trend) but was slightly diminished after further controlling for creatinine, folate, and vitamins B(6) and B(12) (odds ratio, 3.2; 95\% confidence interval, 0.81-13.10; P =.07 for linear trend).

CONCLUSION: We were unable to confirm the results of previous studies with respect to tHcy level and individual MRI findings, although an association was seen for an MRI pattern combining infarcts and high white matter grade.

}, keywords = {Aged, Aging, Brain, Brain Infarction, Female, Homocysteine, Humans, Magnetic Resonance Imaging, Male, Odds Ratio, Radiography, Risk Factors}, issn = {0003-9942}, doi = {10.1001/archneur.61.1.67}, author = {Longstreth, W T and Katz, Ronit and Olson, Jean and Bernick, Charles and Carr, J Jeffrey and Malinow, M Ren{\'e} and Hess, David L and Cushman, Mary and Schwartz, Stephen M} } @article {792, title = {Self-reported alcohol consumption and falls in older adults: cross-sectional and longitudinal analyses of the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {52}, year = {2004}, month = {2004 Jul}, pages = {1174-9}, abstract = {

OBJECTIVES: To assess the cross-sectional and longitudinal associations between alcohol consumption and risk of falls in older adults.

DESIGN: Cross-sectional and longitudinal analyses.

SETTING: Four U.S. communities.

PARTICIPANTS: A total of 5,841 older adults enrolled in the Cardiovascular Health Study, an ongoing, population-based, prospective cohort study, participated.

MEASUREMENTS: Self-reported alcohol consumption at baseline, self-reported frequent falls at baseline, and the 4-year risk of falls of participants who denied frequent falls at baseline.

RESULTS: Cross-sectional analysis indicated an apparent inverse association between alcohol consumption and risk of frequent falls (adjusted odds ratio in consumers of 14 or more drinks per week=0.41; 95\% confidence interval (CI)=0.14-1.17; P for trend=.06), but longitudinal analysis indicated a similar 4-year risk of falls in abstainers and light to moderate drinkers but a 25\% higher risk in consumers of 14 or more drinks per week (95\% CI=3-52\%; P for trend=.07). Similar results were found in analyses stratified by age, sex, race, and physical activity.

CONCLUSION: Consumption of 14 or more drinks per week is associated with an increased risk of subsequent falls in older adults. Cross-sectional studies may fail to identify this risk of heavier drinking, perhaps because older adults at risk for falls decrease their alcohol use over time or because heavier drinkers at risk for falls tend not to enroll in cohort studies. However, because this study relied upon annual reporting of falls, further prospective studies should be conducted to confirm these findings.

}, keywords = {Accidental Falls, Aged, Alcohol Drinking, Chi-Square Distribution, Cross-Sectional Studies, Female, Humans, Longitudinal Studies, Male, Regression Analysis, Risk Factors, Self Disclosure, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2004.52318.x}, author = {Mukamal, Kenneth J and Mittleman, Murray A and Longstreth, W T and Newman, Anne B and Fried, Linda P and Siscovick, David S} } @article {801, title = {Stroke risk factors and loss of high cognitive function.}, journal = {Neurology}, volume = {63}, year = {2004}, month = {2004 Sep 14}, pages = {793-9}, abstract = {

BACKGROUND: Modifiable stroke risk factors may contribute to age-associated declines in cognitive function. Individuals with high levels of cognitive function after midlife may have less exposure to these stroke risk factors or may be less susceptible to their effects on cognition.

METHODS: The Cardiovascular Health Study (CHS)* is a population-based, longitudinal cohort study of 5,888 people age 65 years and older. Participants (n = 4,129) who were free of dementia, stroke, or TIA at the time of baseline cranial MRI were selected for analysis. High cognitive function at baseline was defined by performance at or above midlife norms on the Modified Mini-Mental State Examination (3MS).

RESULTS: The odds of having high cognitive function at baseline decreased by quartile of stroke risk (highest vs lowest risk quartile, adjusted odds ratio [OR] 0.68; 95\% CI 0.52 to 0.88; p for trend = 0.005). Stroke risk was a predictor of decline on the 3MS in those with typical levels of cognitive function at baseline, even in the absence of incident stroke or TIA (highest vs lowest risk quartile for 3MS decline, adjusted OR 2.11; 95\% CI 1.42 to 3.13; p for trend < 0.001). In contrast, stroke risk was not associated with decline on the 3MS in those with high cognitive function at baseline (p = 0.03 for interaction).

CONCLUSIONS: In a cohort of older adults without stroke, TIA, or dementia, cognitive function and incident cognitive decline were associated with risk for stroke. Additional studies are needed to determine whether modification of stroke risk factors can reduce the cognitive decline that is often attributed to normal aging.

}, keywords = {Aged, Aged, 80 and over, Aging, Cognition Disorders, Cohort Studies, Comorbidity, Female, Follow-Up Studies, Higher Nervous Activity, Humans, Incidence, Male, Risk Assessment, Risk Factors, Sampling Studies, Sensitivity and Specificity, Severity of Illness Index, Stroke, United States}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000137014.36689.7f}, author = {Elkins, J S and O{\textquoteright}Meara, E S and Longstreth, W T and Carlson, M C and Manolio, T A and Johnston, S C} } @article {788, title = {White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke.}, journal = {Stroke}, volume = {35}, year = {2004}, month = {2004 Aug}, pages = {1821-5}, abstract = {

BACKGROUND AND PURPOSE: We have previously reported that several "silent" infarcts found on magnetic resonance imaging (MRI) were a risk factor for stroke. Several recent reports have shown that high white matter grade (WMG) and increasing WMG over time were risk factors for stroke. We tested the hypothesis that high WMG > or =2 was a predictor of risk for stroke, independent of other risk factors.

METHODS: We examined the extent of white matter hyperintensity on cranial MRI of 3293 participants from the Cardiovascular Health Study (CHS). The degree of white matter hyperintensity was graded from least severe (grade=0) to most severe (grade=9). Participants were followed-up for an average of 7 years for the occurrence of a stroke. Clinical stroke diagnoses were based on hospital records reviewed by an adjudication committee expert in stroke diagnosis. During this period, 278 strokes occurred. Results The relative risk of stroke increased significantly as the WMG increased. The risk of stroke was 2.8\% per year for participants with high WMG (grades > or =5), compared with only 0.6\% for participants with grades 0 to 1.Conclusions The risk of stroke with high WMG is independent of traditional stroke risk factors and persists when controlling for MRI infarcts, another subclinical imaging marker of cerebrovascular disease. Assessment of white matter disease may be valuable in assessing future risk of stroke.

}, keywords = {Aged, Brain, Female, Humans, Leukoaraiosis, Magnetic Resonance Imaging, Male, Radiography, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/01.STR.0000132193.35955.69}, author = {Kuller, Lewis H and Longstreth, W T and Arnold, Alice M and Bernick, Charles and Bryan, R Nick and Beauchamp, Norman J} } @article {850, title = {Alcohol use and risk of ischemic stroke among older adults: the cardiovascular health study.}, journal = {Stroke}, volume = {36}, year = {2005}, month = {2005 Sep}, pages = {1830-4}, abstract = {

BACKGROUND AND PURPOSE: The association of light to moderate alcohol consumption with risk of ischemic stroke remains uncertain, as are the roles of potentially mediating factors and modification by apolipoprotein E (apoE) genotype.

METHODS: We studied the prospective association of alcohol consumption and risk of ischemic stroke among 4410 participants free of cardiovascular disease at baseline in the Cardiovascular Health Study, a population-based cohort study of older adults from 4 US communities. Participants reported their consumption of alcoholic beverages yearly.

RESULTS: During an average follow-up period of 9.2 years, 434 cases of incident ischemic stroke occurred. Compared with long-term abstainers, the multivariate relative risks of ischemic stroke were 0.85 (95\% CI, 0.63 to 1.13), 0.75 (95\% CI, 0.53 to 1.06), 0.82 (95\% CI, 0.51 to 1.30), and 1.03 (95\% CI, 0.68 to 1.57) among consumers of <1, 1 to 6, 7 to 13, and > or =14 drinks per week (P quadratic trend 0.06). ApoE genotype appeared to modify the alcohol-ischemic stroke relationship (P interaction 0.08), with generally lower risks among drinkers than abstainers in apoE4-negative participants but higher risks among drinkers than abstainers among apoE4-positive participants. We could not identify candidate mediators among lipid, inflammatory, and prothrombotic factors.

CONCLUSIONS: In this study of older adults, the association of alcohol use and risk of ischemic stroke was U-shaped, with modestly lower risk among consumers of 1 to 6 drinks per week. However, apoE genotype may modify this association, and even moderate alcohol intake may be associated with an increased risk of ischemic stroke among apoE4-positive older adults.

}, keywords = {Aged, Alcohol Drinking, Apolipoproteins E, Brain Infarction, Brain Ischemia, Cohort Studies, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genotype, Humans, Hypertension, Inflammation, Ischemia, Lipids, Male, Middle Aged, Multivariate Analysis, Myocardial Infarction, Prospective Studies, Risk, Risk Factors, Stroke, Substance-Related Disorders, Thrombosis, Time Factors, Vascular Diseases}, issn = {1524-4628}, doi = {10.1161/01.STR.0000177587.76846.89}, author = {Mukamal, Kenneth J and Chung, Hyoju and Jenny, Nancy S and Kuller, Lewis H and Longstreth, W T and Mittleman, Murray A and Burke, Gregory L and Cushman, Mary and Beauchamp, Norman J and Siscovick, David S} } @article {862, title = {Cystatin C and subclinical brain infarction.}, journal = {J Am Soc Nephrol}, volume = {16}, year = {2005}, month = {2005 Dec}, pages = {3721-7}, abstract = {

Subclinical brain infarcts (SBI) are common in the elderly and are associated with covert neurologic and cognitive impairment. Although renal impairment is associated with accelerated cerebrovascular disease and an increased risk for clinically apparent brain infarct, few studies have examined the relationship between renal function and SBI, and these may have been limited by the inaccuracy of creatinine as a renal function marker. A cross-sectional study was performed among older adults in the Cardiovascular Health Study to examine associations between SBI and two serum markers of renal function: Serum creatinine (SCr) and cystatin C (CysC). Patients had cranial magnetic resonance imaging and renal markers measured in 1992 to 1993. Logistic regression was used to estimate the associations between renal function (estimated by 1/SCr and 1/CysC) and SBI, controlling for potential confounding factors. SBI were present in 789 (28.7\%) of 2784 participants. A linear association with SBI was observed for 1/CysC (per 1-SD decrement; odds ratio [OR] 1.20; 95\% confidence interval [CI] 1.09 to 1.32; P < 0.001) but not for 1/SCr (OR 1.08; 95\% CI 0.98 to 1.19; P = 0.14), for which a quadratic U-shaped association was suggested (P = 0.004). In a model with both markers, 1/CysC was linearly associated with SBI (OR 1.26; P < 0.001), whereas 1/SCr was not (OR 1.06; P = 0.3). The prevalence of SBI was directly associated with quintile of CysC, whereas the association between SCr and SBI was U-shaped, with greater prevalence at high and low levels. Compared with creatinine, CysC, a novel marker of renal function, has a stronger and more direct association with SBI in the elderly.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Brain Infarction, Confidence Intervals, Creatinine, Cross-Sectional Studies, Cystatin C, Cystatins, Disease Progression, Female, Geriatric Assessment, Humans, Incidence, Ischemic Attack, Transient, Magnetic Resonance Imaging, Male, Odds Ratio, Predictive Value of Tests, Prognosis, Risk Assessment, Sensitivity and Specificity, Severity of Illness Index, Sex Factors, Survival Analysis}, issn = {1046-6673}, doi = {10.1681/ASN.2005010006}, author = {Seliger, Stephen L and Longstreth, W T and Katz, Ronit and Manolio, Teri and Fried, Linda F and Shlipak, Michael and Stehman-Breen, Catherine O and Newman, Anne and Sarnak, Mark and Gillen, Daniel L and Bleyer, Anthony and Siscovick, David S} } @article {818, title = {Fish consumption and stroke risk in elderly individuals: the cardiovascular health study.}, journal = {Arch Intern Med}, volume = {165}, year = {2005}, month = {2005 Jan 24}, pages = {200-6}, abstract = {

BACKGROUND: Associations between fish consumption and stroke risk have been inconsistent, possibly because of the differences in types of fish meals consumed. Additionally, such relationships have not been specifically evaluated in the elderly, in whom disease burden may be high and diet less influential.

METHODS: Among 4775 adults 65 years or older (range, 65-98 years) and free of known cerebrovascular disease at baseline in 1989-1990, usual dietary intake was assessed using a food frequency questionnaire. In a subset, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches (fish burgers), correlated with plasma phospholipid long-chain n-3 fatty acid levels. Incident strokes were prospectively ascertained.

RESULTS: During 12 years of follow-up, participants experienced 626 incident strokes, including 529 ischemic strokes. In multivariate analyses, tuna/other fish consumption was inversely associated with total stroke (P = .04) and ischemic stroke (P = .02), with 27\% lower risk of ischemic stroke with an intake of 1 to 4 times per week (hazard ratio [HR], 0.73; 95\% confidence interval [CI], 0.55-0.98) and 30\% lower risk with intake of 5 or more times per week (HR, 0.70; 95\% CI, 0.50-0.99) compared with an intake of less than once per month. In contrast, fried fish/fish sandwich consumption was positively associated with total stroke (P = .006) and ischemic stroke (P = .003), with a 44\% higher risk of ischemic stroke with consumption of more than once per week (HR, 1.44; 95\% CI, 1.12-1.85) compared with consumption of less than once per month. Fish consumption was not associated with hemorrhagic stroke.

CONCLUSIONS: Among elderly individuals, consumption of tuna or other broiled or baked fish is associated with lower risk of ischemic stroke, while intake of fried fish or fish sandwiches is associated with higher risk. These results suggest that fish consumption may influence stroke risk late in life; potential mechanisms and alternate explanations warrant further study.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Animals, Cohort Studies, Confidence Intervals, Diet, Fatty Acids, Omega-3, Female, Fish Oils, Fishes, Humans, Incidence, Male, Multivariate Analysis, Probability, Proportional Hazards Models, Risk Assessment, Seafood, Sensitivity and Specificity, Sex Distribution, Stroke, Surveys and Questionnaires, Survival Rate, United States}, issn = {0003-9926}, doi = {10.1001/archinte.165.2.200}, author = {Mozaffarian, Dariush and Longstreth, W T and Lemaitre, Rozenn N and Manolio, Teri A and Kuller, Lewis H and Burke, Gregory L and Siscovick, David S} } @article {812, title = {Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {36}, year = {2005}, month = {2005 Jan}, pages = {56-61}, abstract = {

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) scans in the elderly commonly show white matter findings that may raise concerns. We sought to document incidence, manifestations, and predictors of worsening white matter grade on serial imaging.

METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people aged 65 years and older, of whom 1919 have had extensive initial and follow-up evaluations, including 2 MRI scans separated by 5 years. Scans were read without clinical information in standard side-by-side fashion to determine worsening white matter grade.

RESULTS: Worsening was evident in 538 participants (28\%), mostly (85\%) by 1 grade. Although similar at initial scan, participants with worsening white matter grade, compared with those without, experienced greater decline on modified Mini-Mental State examination and Digit-Symbol Substitution test (both P< or =0.001) after controlling for potential confounding factors, including occurrence of transient ischemic attack or stroke between scans. Independent predictors of worsening white matter grade included cigarette smoking before initial scan and infarct on initial scan. Otherwise, predictors differed according to white matter grade on initial scan. For low initial grade, increased age, increased diastolic blood pressure, increased high-density lipoprotein cholesterol, and decreased low-density lipoprotein cholesterol were associated with increased risk of worsening. For high initial grade, any cardiovascular disease and low ankle-arm index were associated with decreased risk of worsening, whereas use of diuretics and statins were associated with increased risk.

CONCLUSIONS: Worsening white matter grade on serial MRI scans in elderly is common, is associated with cognitive decline, and has complex relations with cardiovascular risk factors.

}, keywords = {Aged, Brain, Cardiovascular Diseases, Cognition Disorders, Female, Humans, Incidence, Leukoaraiosis, Longitudinal Studies, Magnetic Resonance Imaging, Male, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/01.STR.0000149625.99732.69}, author = {Longstreth, W T and Arnold, Alice M and Beauchamp, Norman J and Manolio, Teri A and Lefkowitz, David and Jungreis, Charles and Hirsch, Calvin H and O{\textquoteright}Leary, Daniel H and Furberg, Curt D} } @article {860, title = {Vascular events, mortality, and preventive therapy following ischemic stroke in the elderly.}, journal = {Neurology}, volume = {65}, year = {2005}, month = {2005 Sep 27}, pages = {835-42}, abstract = {

BACKGROUND: The authors studied mortality, vascular events, and preventive therapies following ischemic stroke among adults aged > or =65 years.

METHODS: The authors identified 546 subjects with first ischemic stroke during 1989 to 2001 among Cardiovascular Health Study participants. Deaths, recurrent strokes, and coronary heart disease (CHD) events were identified over 3.2 years (median) follow-up.

RESULTS: During the first year of follow-up, rates were 105.4/1,000 for recurrent stroke and 59.3/1,000 for CHD. After the first year, the stroke rate was 52.0/1,000 and the CHD rate was 46.5/1,000. Cardioembolic strokes had the highest mortality (185.4/1,000) and recurrence rates (86.6/1,000). Lacunar strokes had the lowest mortality (119.3/1,000) and recurrence rates (43.0/1,000). Age and male sex predicted death and CHD, but not recurrence. Outcomes did not differ by race. Following stroke, 47.8\% used aspirin and 13.5\% used other antiplatelet agents; 52.6\% of patients with atrial fibrillation used warfarin; 31.3\% of hyperlipidemic subjects, 57.0\% of diabetic patients, and 81.5\% of hypertensive patients were drug-treated; and 40.0\% of hypertensive patients had blood pressure (BP) <140/90 mm Hg. Older subjects were less likely to use lipid-lowering therapy, women were less likely to have BP <140/90 mm Hg, and low-income subjects were less likely to use diabetes medications.

CONCLUSIONS: Recurrent strokes were nearly twice as frequent as coronary heart disease (CHD) events during the first year after initial stroke, but stroke and CHD rates were similar after the first year. Preventive drug therapies were underused, which may reflect clinical uncertainty due to the lack of clinical trials among the elderly. Utilization was lower among the oldest patients, women, and low-income individuals.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Anticoagulants, Antihypertensive Agents, Brain Ischemia, Cohort Studies, Comorbidity, Coronary Artery Disease, Drug Utilization, Female, Humans, Hyperlipidemias, Hypertension, Hypolipidemic Agents, Male, Mortality, Prospective Studies, Recurrence, Sex Factors, Stroke, Treatment Outcome}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000176058.09848.bb}, author = {Kaplan, R C and Tirschwell, D L and Longstreth, W T and Manolio, T A and Heckbert, S R and Lefkowitz, D and El-Saed, A and Psaty, B M} } @article {881, title = {Alcohol consumption and risk of coronary heart disease in older adults: the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {54}, year = {2006}, month = {2006 Jan}, pages = {30-7}, abstract = {

OBJECTIVES: To evaluate several aspects of the relationship between alcohol use and coronary heart disease in older adults, including beverage type, mediating factors, and type of outcome.

DESIGN: Prospective cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: Four thousand four hundred ten adults aged 65 and older free of cardiovascular disease at baseline.

MEASUREMENTS: Risk of incident myocardial infarction or coronary death according to self-reported consumption of beer, wine, and spirits ascertained yearly.

RESULTS: During an average follow-up period of 9.2 years, 675 cases of incident myocardial infarction or coronary death occurred. Compared with long-term abstainers, multivariate relative risks of 0.90 (95\% confidence interval (CI)=0.71-1.14), 0.93 (95\% CI=0.73-1.20), 0.76 (95\% CI=0.53-1.10), and 0.58 (95\% CI=0.39-0.86) were found in consumers of less than one, one to six, seven to 13, and 14 or more drinks per week, respectively (P for trend=.007). Associations were similar for secondary coronary outcomes, including nonfatal and fatal events. No strong mediators of the association were identified, although fibrinogen appeared to account for 9\% to 10\% of the relationship. The associations were statistically similar for intake of wine, beer, and liquor and generally similar in subgroups, including those with and without an apolipoprotein E4 allele.

CONCLUSION: In this population, consumption of 14 or more drinks per week was associated with the lowest risk of coronary heart disease, although clinicians should not recommend moderate drinking to prevent coronary heart disease based on this evidence alone, because current National Institute on Alcohol Abuse and Alcoholism guidelines suggest that older adults limit alcohol intake to one drink per day.

}, keywords = {Aged, Alcohol Drinking, Apolipoproteins E, Beer, Cohort Studies, Coronary Disease, Female, Genotype, Health Behavior, Humans, Incidence, Male, Residence Characteristics, Risk Assessment, Socioeconomic Factors, United States, Wine}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.00561.x}, author = {Mukamal, Kenneth J and Chung, Hyoju and Jenny, Nancy S and Kuller, Lewis H and Longstreth, W T and Mittleman, Murray A and Burke, Gregory L and Cushman, Mary and Psaty, Bruce M and Siscovick, David S} } @article {917, title = {Blood pressure level and outcomes in adults aged 65 and older with prior ischemic stroke.}, journal = {J Am Geriatr Soc}, volume = {54}, year = {2006}, month = {2006 Sep}, pages = {1309-16}, abstract = {

OBJECTIVES: To examine the association between blood pressure (BP) levels and long-term stroke outcomes in elderly stroke survivors.

DESIGN: Observational study.

SETTING: The Cardiovascular Health Study (CHS) of 5,888 community-dwelling adults.

PARTICIPANTS: Two hundred fifty-four adults aged 65 and older (mean age 78.6) who sustained a nonfatal first ischemic stroke.

MEASUREMENTS: BP levels assessed at prestroke and poststroke CHS visits were examined as predictors of stroke recurrence, coronary heart disease (CHD), combined vascular events (CVEs), and mortality.

RESULTS: Higher poststroke BP level, assessed 261.6 days (mean) after stroke, was associated with higher risk of stroke recurrence over 5.4 years (mean) of follow-up. The multivariate-adjusted hazard ratio for stroke recurrence was 1.42 (95\% confidence interval (CI) = 1.03-1.99) per standard deviation (SD) of systolic BP (P = .04) and 1.39 (95\% CI = 1.01-1.91) per SD of diastolic BP (P = .04). Mortality was significantly greater in patients with low or high poststroke BP than in those with intermediate BP. Poststroke BP was not associated with risk of CHD or CVE, although further analyses suggested that high systolic BP predicted CHD and CVE in younger but not older subjects. Prestroke BP did not predict poststroke outcomes.

CONCLUSION: In this observational study of adults aged 65 and older assessed approximately 8 months after stroke, low BP was associated with favorable risk of recurrent stroke, although high and low poststroke BP levels were associated with greater mortality. Long-term antihypertensive trials in older stroke survivors would increase knowledge about the benefits of lowering BP in this population.

}, keywords = {Aged, Aged, 80 and over, Blood Pressure, Brain Ischemia, Female, Follow-Up Studies, Humans, Male, Outcome Assessment, Health Care, Prospective Studies, Recurrence, Stroke, Survival Rate}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2006.00838.x}, author = {Kaplan, Robert C and Tirschwell, David L and Longstreth, W T and Manolio, Teri A and Heckbert, Susan R and LeValley, Aaron J and Lefkowitz, David and El-Saed, Aiman and Psaty, Bruce M} } @article {1002, title = {Gait variability is associated with subclinical brain vascular abnormalities in high-functioning older adults.}, journal = {Neuroepidemiology}, volume = {29}, year = {2007}, month = {2007}, pages = {193-200}, abstract = {

BACKGROUND: Gait variability is an index of how much gait parameters, such as step length, change from one step to the next. Gait variability increases with age and in individuals affected by cortical and subcortical neurodegenerative conditions, and it is associated with falls and incident mobility disability. The brain anatomical correlates of gait variability have not been studied in high-functioning community-dwelling older adults.

METHODS: Gait variability and brain MRIs were assessed in a cohort of 331 men and women (mean age = 78.3 years) free from stroke, dementia or Parkinson{\textquoteright}s disease. Gait variability was computed for spatial parameters (step length and step width) and for temporal parameters (stance time). Subclinical brain vascular abnormalities were measured on brain MRIs as infarcts and white matter hyperintensities.

RESULTS: Greater variability of step length was associated with greater prevalence of infarcts, including infarcts in the basal ganglia, and with greater white matter hyperintensities severity, independent of age, gender, cognitive function and cardiovascular disease. Weaker associations were found between the other variability measures and the MRI measures.

CONCLUSION: In this group of older adults free from neurodegenerative diseases, a greater variability of step length was associated with greater burden of subclinical brain vascular abnormalities as defined by MRI.

}, keywords = {Accidental Falls, Activities of Daily Living, Aged, Aged, 80 and over, Basal Ganglia Cerebrovascular Disease, Brain, Cerebral Infarction, Comorbidity, Female, Gait Disorders, Neurologic, Geriatric Assessment, Health Surveys, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mobility Limitation, Neurodegenerative Diseases, Neurologic Examination, Risk Factors, United States}, issn = {1423-0208}, doi = {10.1159/000111582}, author = {Rosano, Caterina and Brach, Jennifer and Studenski, Stephanie and Longstreth, W T and Newman, Anne B} } @article {977, title = {Risk factors for intracerebral hemorrhage in a pooled prospective study.}, journal = {Stroke}, volume = {38}, year = {2007}, month = {2007 Oct}, pages = {2718-25}, abstract = {

BACKGROUND AND PURPOSE: Few prospective studies have reported risk factors for intracerebral hemorrhage (ICH), and results are inconsistent. We studied risk factors for ICH in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS).

METHODS: The ARIC cohort was recruited in 1987 to 1989 and involves 15 792 men and women, aged 45 to 64 years at baseline, sampled from 4 US communities. The CHS cohort was recruited in 1989 to 1993 and involves 5888 men and women, aged 65 or over at baseline, sampled from 4 US communities. Baseline measurements included many potential vascular risk factors. The cohorts were followed for incident stroke events.

RESULTS: Over 263 489 person-years of follow-up, 135 incident ICH events occurred. In a multivariable model, age, African-American ethnicity (versus Whites), and hypertension were positively associated with incident ICH, whereas low-density lipoprotein cholesterol and triglycerides were inversely related to incident ICH. Participants with systolic blood pressure >or=160 mm Hg or diastolic blood pressure >/=110 mm Hg had 5.55 (95\% CI 3.07 to 10.0) times the rate of ICH as nonhypertensives. Sex, smoking, alcohol intake, body mass index, waist-to-hip ratio, waist circumference, and diabetes were not related to ICH.

CONCLUSIONS: In this pooled cohort the risk factors for ICH were older age, African-American ethnicity, hypertension, lower LDL-C, and lower triglycerides.

}, keywords = {African Americans, Age Distribution, Cerebral Hemorrhage, Cholesterol, LDL, Female, Follow-Up Studies, Humans, Hypertension, Incidence, Male, Middle Aged, Multivariate Analysis, Predictive Value of Tests, Prevalence, Prospective Studies, Risk Factors, Stroke, Triglycerides}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.107.487090}, author = {Sturgeon, Jared D and Folsom, Aaron R and Longstreth, W T and Shahar, Eyal and Rosamond, Wayne D and Cushman, Mary} } @article {907, title = {White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study.}, journal = {Neurobiol Aging}, volume = {28}, year = {2007}, month = {2007 Sep}, pages = {1307-15}, abstract = {

High white matter grade (WMG) on magnetic resonance imaging (MRI) is a risk factor for dementia, stroke and disability. Higher ventricular size is a marker of brain "atrophy." In the Cardiovascular Health Study (CHS) (n=3245) mean age 75 years, 50\% black and 40\% men, we evaluated WM and ventricular grade (VG), total, cardiovascular and noncardiovascular mortality and longevity before and after adjusting for numerous determinants of longevity over an approximate 10-12 years of follow-up. A low WMG and VG was a marker for low total, cardiovascular and noncardiovascular mortality and for increased longevity over 10+ years of follow-up. We estimated that a 75-year-old with WMG below median would have about a 5-6 years greater longevity and for VG about 3 years, than above the median even after adjustment for numerous risk factors. Low WMG and VG on MRI is a powerful determinant of long-term survival among older individuals.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Biomarkers, Brain, Cardiovascular Diseases, Cerebral Ventricles, European Continental Ancestry Group, Female, Geriatric Assessment, Health Status, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Retrospective Studies, Risk Factors, Sex Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2006.06.010}, author = {Kuller, Lewis H and Arnold, Alice M and Longstreth, W T and Manolio, Teri A and O{\textquoteright}Leary, Daniel H and Burke, Gregory L and Fried, Linda P and Newman, Anne B} } @article {1014, title = {Antidepressant treatment and worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {39}, year = {2008}, month = {2008 Mar}, pages = {857-62}, abstract = {

BACKGROUND AND PURPOSE: In some studies, late life depression is associated with white matter lesions on MRI. The effect of different classes of antidepressants on progression of white matter lesions is unknown. Selective serotonergic reuptake inhibitors (SSRIs) may decrease platelet aggregation. We hypothesized that Cardiovascular Health Study participants taking SSRIs would less often have worsening white matter on serial MRI than participants not on antidepressants.

METHODS: Among 1826 participants who were not using an antidepressant at initial MRI scan, we examined the association of worsening in white matter grade from initial to follow-up MRI scans, 5 years apart on average, and antidepressant use between the scans. Logistic regression models were used, controlling for a variety of potential confounding variables.

RESULTS: Use of any antidepressant during the period of study was associated with worsening white matter. In a multivariable model, risk was slightly increased, not reduced, with use of serotonergic agents (OR 1.36, 95\% CI 0.87 to 2.12) and was significantly increased with the use of tricyclic antidepressants (OR 1.77, 95\% CI 1.07 to 2.94).

CONCLUSIONS: The association between worsening white matter and use of tricyclic antidepressants was an unexpected finding that may relate to indications for use other than depression or to side effects such as hypotension. Protection against worsening was not seen with use of serotonergic agents.

}, keywords = {Aged, Antidepressive Agents, Antidepressive Agents, Tricyclic, Cohort Studies, Disease Progression, Female, Follow-Up Studies, Humans, Leukoaraiosis, Magnetic Resonance Imaging, Male, Multivariate Analysis, Risk Assessment, Serotonin Uptake Inhibitors}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.107.498097}, author = {Steffens, David C and Chung, Hyoju and Krishnan, K Ranga R and Longstreth, W T and Carlson, Michelle and Burke, Gregory L} } @article {1027, title = {Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study.}, journal = {Stroke}, volume = {39}, year = {2008}, month = {2008 Jul}, pages = {1952-9}, abstract = {

BACKGROUND AND PURPOSE: To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the C-reactive protein (CRP) and interleukin (IL)-6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study.

METHODS: Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (n=532) and Whites (n=2905).

RESULTS: Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the -174G/C promoter polymorphism was associated with an increased risk of WML (OR=1.14; 95\% CI: [1.02; 1.28]). The common haplotype tagged by the -572G/C promoter polymorphism was associated with an increased risk of BI (OR=1.57; 95\% CI: [1.15; 2.14]). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race.

CONCLUSIONS: This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.

}, keywords = {African Continental Ancestry Group, Aged, Biomarkers, Brain Infarction, C-Reactive Protein, Cohort Studies, European Continental Ancestry Group, Female, Haplotypes, Humans, Inflammation, Interleukin-6, Magnetic Resonance Imaging, Male, Polymorphism, Single Nucleotide}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.107.508135}, author = {Fornage, Myriam and Chiang, Y Aron and O{\textquoteright}Meara, Ellen S and Psaty, Bruce M and Reiner, Alexander P and Siscovick, David S and Tracy, Russell P and Longstreth, W T} } @article {1046, title = {Fish consumption and risk of subclinical brain abnormalities on MRI in older adults.}, journal = {Neurology}, volume = {71}, year = {2008}, month = {2008 Aug 05}, pages = {439-46}, abstract = {

OBJECTIVE: To investigate the association between fish consumption and subclinical brain abnormalities.

METHODS: In the population-based Cardiovascular Health Study, 3,660 participants age > or =65 underwent an MRI scan in 1992-1994. Five years later, 2,313 were scanned. Neuroradiologists assessed MRI scans in a standardized and blinded manner. Food frequency questionnaires were used to assess dietary intakes. Participants with known cerebrovascular disease were excluded from the analyses.

RESULTS: After adjustment for multiple risk factors, the risk of having one or more prevalent subclinical infarcts was lower among those consuming tuna/other fish > or =3 times/week, compared to <1/month (relative risk 0.74, 95\% CI = 0.54-1.01, p = 0.06, p trend = 0.03). Tuna/other fish consumption was also associated with trends toward lower incidence of subclinical infarcts. Additionally, tuna/other fish intake was associated with better white matter grade, but not with sulcal and ventricular grades, markers of brain atrophy. No significant associations were found between fried fish consumption and any subclinical brain abnormalities.

CONCLUSIONS: Among older adults, modest consumption of tuna/other fish, but not fried fish, was associated with lower prevalence of subclinical infarcts and white matter abnormalities on MRI examinations. Our results add to prior evidence that suggest that dietary intake of fish with higher eicosapentaenoic acid and docosahexaenoic acid content, and not fried fish intake, may have clinically important health benefits.

}, keywords = {Aged, Animals, Brain, Brain Infarction, Cooking, Cross-Sectional Studies, Diet, Female, Fish Products, Fishes, Humans, Magnetic Resonance Imaging, Male, Prospective Studies, Risk}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000324414.12665.b0}, author = {Virtanen, J K and Siscovick, D S and Longstreth, W T and Kuller, L H and Mozaffarian, D} } @article {1036, title = {Hemostatic and inflammatory risk factors for intracerebral hemorrhage in a pooled cohort.}, journal = {Stroke}, volume = {39}, year = {2008}, month = {2008 Aug}, pages = {2268-73}, abstract = {

BACKGROUND AND PURPOSE: The purpose of this study was to identify novel risk factors for intracerebral hemorrhagic stroke (ICH).

METHODS: Risk factors were assessed at baseline in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) involving 21,680 adults aged 45 or over. Over 263,489 person-years of follow-up, we identified 135 incident ICH events.

RESULTS: In multivariable models, for each SD higher baseline level of fibrinogen, the relative rate of incident ICH increased 35\% (95\% CI, 17\% to 55\%). Fibrinogen was more strongly related to ICH in ARIC than in CHS. In multivariable models, those with von Willebrand factor levels above the median were 1.72 (95\% CI, 0.97 to 3.03) times more likely to have an incident ICH as those below the median. Factor VIII was significantly positively related to ICH in ARIC (relative rate per standard deviation of 1.31; 95\% CI, 1.07 to 1.62), but not in CHS. There was no relation in multivariable models between lipoprotein (a), Factor VII, white blood cell count, or C-reactive protein and ICH.

CONCLUSIONS: Greater plasma fibrinogen and, to some degree, von Willebrand factor were associated with increased rates of ICH in these prospective studies, whereas Factor VIII was related to ICH in younger ARIC study participants only.

}, keywords = {Age Distribution, Aged, Biomarkers, C-Reactive Protein, Cerebral Hemorrhage, Cohort Studies, Factor VIII, Female, Fibrinogen, Follow-Up Studies, Humans, Leukocyte Count, Lipoprotein(a), Male, Middle Aged, Multivariate Analysis, Prevalence, Risk Factors, Stroke, United States, Vasculitis, von Willebrand Factor}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.107.505800}, author = {Sturgeon, Jared D and Folsom, Aaron R and Longstreth, W T and Shahar, Eyal and Rosamond, Wayne D and Cushman, Mary} } @article {1064, title = {Gene variants associated with ischemic stroke: the cardiovascular health study.}, journal = {Stroke}, volume = {40}, year = {2009}, month = {2009 Feb}, pages = {363-8}, abstract = {

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke.

METHODS: Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS).

RESULTS: In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90\% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90\% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10\% versus 6\%) and black (12\% versus 3\%) participants of CHS.

CONCLUSIONS: The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.

}, keywords = {African Continental Ancestry Group, Aged, Alleles, Brain Ischemia, Cardiovascular Diseases, Coronary Disease, Ethnic Groups, European Continental Ancestry Group, Female, Gene Frequency, Genetic Variation, Humans, Kaplan-Meier Estimate, Male, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Stroke, United States}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.108.521328}, author = {Luke, May M and O{\textquoteright}Meara, Ellen S and Rowland, Charles M and Shiffman, Dov and Bare, Lance A and Arellano, Andre R and Longstreth, W T and Lumley, Thomas and Rice, Kenneth and Tracy, Russell P and Devlin, James J and Psaty, Bruce M} } @article {1092, title = {Genomewide association studies of stroke.}, journal = {N Engl J Med}, volume = {360}, year = {2009}, month = {2009 Apr 23}, pages = {1718-28}, abstract = {

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.

METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95\% confidence interval [CI], 1.19 to 1.42) and 1.33 (95\% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11\% and 12\% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95\% CI, 1.01 to 1.79; P=0.04) and 1.42 (95\% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95\% CI, 1.01 to 1.37; P=0.03) and 1.19 (95\% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

}, keywords = {African Continental Ancestry Group, Aged, Chromosomes, Human, Pair 12, Cohort Studies, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Stroke}, issn = {1533-4406}, doi = {10.1056/NEJMoa0900094}, author = {Ikram, M Arfan and Seshadri, Sudha and Bis, Joshua C and Fornage, Myriam and DeStefano, Anita L and Aulchenko, Yurii S and Debette, Stephanie and Lumley, Thomas and Folsom, Aaron R and van den Herik, Evita G and Bos, Michiel J and Beiser, Alexa and Cushman, Mary and Launer, Lenore J and Shahar, Eyal and Struchalin, Maksim and Du, Yangchun and Glazer, Nicole L and Rosamond, Wayne D and Rivadeneira, Fernando and Kelly-Hayes, Margaret and Lopez, Oscar L and Coresh, Josef and Hofman, Albert and DeCarli, Charles and Heckbert, Susan R and Koudstaal, Peter J and Yang, Qiong and Smith, Nicholas L and Kase, Carlos S and Rice, Kenneth and Haritunians, Talin and Roks, Gerwin and de Kort, Paul L M and Taylor, Kent D and de Lau, Lonneke M and Oostra, Ben A and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Boerwinkle, Eric and Psaty, Bruce M and Mosley, Thomas H and van Duijn, Cornelia M and Breteler, Monique M B and Longstreth, W T and Wolf, Philip A} } @article {1085, title = {Midlife and late-life obesity and the risk of dementia: cardiovascular health study.}, journal = {Arch Neurol}, volume = {66}, year = {2009}, month = {2009 Mar}, pages = {336-42}, abstract = {

BACKGROUND: While high adiposity in middle age appears to be related to greater dementia risk, studies exploring this association in the elderly are conflicting.

OBJECTIVE: To evaluate associations between midlife and late-life obesity and risk of dementia.

DESIGN: Prospective study with mean follow-up of 5.4 years (1992-1994 through 1999).

SETTING: Community-dwelling sample in 4 US sites recruited from Medicare eligibility files.

PARTICIPANTS: A total of 2798 adults without dementia (mean age, 74.7 years; 59.1\% women) participating in the Cardiovascular Health Study who underwent magnetic resonance imaging were measured for height and weight at baseline at age 65 years or older (late life), and self-reported weight at age 50 years (midlife). Body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was calculated at both times.

MAIN OUTCOME MEASURES: Dementia, Alzheimer disease, and vascular dementia classified by a multidisciplinary committee using standardized criteria.

RESULTS: Classification resulted in 480 persons with incident dementia, 245 with Alzheimer disease (no vascular dementia), and 213 with vascular dementia (with or without Alzheimer disease). In evaluations of midlife obesity, an increased risk of dementia was found for obese (BMI >30) vs normal-weight (BMI 20-25) persons, adjusted for demographics (hazard ratio [HR], 1.39; 95\% confidence interval [CI], 1.03-1.87) and for cardiovascular risk factors (1.36; 0.94-1.95). The risk estimates were reversed in assessments of late-life BMI. Underweight persons (BMI <20) had an increased risk of dementia (1.62; 1.02-2.64), whereas being overweight (BMI >25-30) was not associated (0.92; 0.72-1.18) and being obese reduced the risk of dementia (0.63; 0.44-0.91) compared with those with normal BMI.

CONCLUSION: These results help explain the "obesity paradox" as differences in dementia risk across time are consistent with physical changes in the trajectory toward disability.

}, keywords = {Aged, Aged, 80 and over, Aging, Alzheimer Disease, Anthropometry, Body Mass Index, Dementia, Vascular, Evaluation Studies as Topic, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Obesity, Prospective Studies, Risk, Survival Analysis}, issn = {1538-3687}, doi = {10.1001/archneurol.2008.582}, author = {Fitzpatrick, Annette L and Kuller, Lewis H and Lopez, Oscar L and Diehr, Paula and O{\textquoteright}Meara, Ellen S and Longstreth, W T and Luchsinger, Jos{\'e} A} } @article {1228, title = {Albuminuria and the risk of incident stroke and stroke types in older adults.}, journal = {Neurology}, volume = {75}, year = {2010}, month = {2010 Oct 12}, pages = {1343-50}, abstract = {

BACKGROUND: The kidney biomarker that best reflects risk of stroke is unknown. We sought to evaluate the association of stroke with 3 kidney biomarkers: albuminuria, cystatin C, and glomerular filtration rate.

METHODS: These 3 biomarkers were determined in 3,287 participants without history of stroke from the Cardiovascular Health Study, a longitudinal cohort study of men and women age 65 years and older from 4 US communities. The biomarkers were albuminuria ascertained using urinary albumin-to-creatinine ratio (UACR) from morning spot urine, creatinine-based estimated glomerular filtration rate (eGFR), and cystatin C. Outcomes were incident stroke (any, ischemic, or hemorrhagic) during follow-up between 1996 and 2006.

RESULTS: A total of 390 participants had an incident stroke: 81\% ischemic, 12\% hemorrhagic, and 7\% unclassified. In adjusted Cox regression models, UACR was more strongly related to any stroke, ischemic stroke, and hemorrhagic stroke than eGFR and cystatin C. The hazard ratio (HR) of any stroke comparing the top to bottom quintile of UACR was 2.10 (95\% confidence interval [CI] 1.47-3.00), while HR for eGFR was 1.29 (95\% CI 0.91-1.84) and for cystatin C was 1.22 (95\% CI 0.85-1.74). When considering clinically relevant categories, elevated UACR was associated with increased hazard of any stroke and ischemic stroke regardless of eGFR or cystatin C categories.

CONCLUSIONS: UACR was the kidney biomarker most strongly associated with risk of incident stroke. Results in this elderly cohort may not be applicable to younger populations. These findings suggest that measures of glomerular filtration and permeability have differential effects on stroke risk.

}, keywords = {Aged, Aged, 80 and over, Albuminuria, Community Health Services, Confidence Intervals, Female, Geriatric Assessment, Glomerular Filtration Rate, Humans, Incidence, Longitudinal Studies, Male, Proportional Hazards Models, Retrospective Studies, Risk Factors, Stroke}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e3181f73638}, author = {Aguilar, M I and O{\textquoteright}Meara, E S and Seliger, S and Longstreth, W T and Hart, R G and Pergola, P E and Shlipak, M G and Katz, R and Sarnak, M J and Rifkin, D E} } @article {1212, title = {Cognition and the risk of hospitalization for serious falls in the elderly: results from the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 Nov}, pages = {1242-9}, abstract = {

BACKGROUND: Many elderly adults fall every year, sometimes resulting in serious injury and hospitalization. Although impaired cognition is a risk factor for injurious falls, little is known about cognitive decline above the threshold of impairment and risk of serious falls in community-dwelling seniors.

METHODS: In total, 702 of 5,356 older adults participating in the Cardiovascular Health Study experienced an injurious fall between 1990 and 2005, as indicated by hospitalization records. General cognition was measured annually with the Modified Mini-Mental State Examination and processing speed with the Digit Symbol Substitution Test. The Cox regression model was used to calculate hazard ratio and 95\% confidence interval with and without time-dependent covariates and adjusted for known risk factors.

RESULTS: Participants with slightly decreased Digit Symbol Substitution Test scores were at increased risk for a serious fall (hazard ratio = 1.58, 95\% confidence interval = 1.15-2.17). The risk continued to increase with each quartile decrease in Digit Symbol Substitution Test score. Participants without prevalent cardiovascular disease at baseline and decreased Modified Mini-Mental State Examination scores (80-89) had a 45\% increased risk for a serious fall and those at high risk for dementia (<80) were at twice the risk as participants scoring above 90 (hazard ratio = 2.16, 95\% confidence interval = 1.60-2.91).

CONCLUSIONS: Both decreased general cognition and decreased processing speed appear to be potential risk factors for serious falls in the elderly. When assessing the risk of serious falls in elderly patients, clinicians should consider usual factors like gait instability and sensory impairment as well as less obvious ones such as cardiovascular disease and cognitive function in nondemented adults.

}, keywords = {Accidental Falls, Aged, Aged, 80 and over, Chi-Square Distribution, Cognition Disorders, Female, Follow-Up Studies, Geriatric Assessment, Hospitalization, Humans, Male, Mental Status Schedule, Physical Examination, Proportional Hazards Models, Risk Assessment, Risk Factors, Surveys and Questionnaires}, issn = {1758-535X}, doi = {10.1093/gerona/glq115}, author = {Welmerink, Diana B and Longstreth, W T and Lyles, Mary F and Fitzpatrick, Annette L} } @article {1156, title = {Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.}, journal = {Stroke}, volume = {41}, year = {2010}, month = {2010 Feb}, pages = {210-7}, abstract = {

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4\% of whom had >or=1 MRI infarct).

RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20\%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95\% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

}, keywords = {African Americans, Aged, Brain, Brain Infarction, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.109.569194}, author = {Debette, Stephanie and Bis, Joshua C and Fornage, Myriam and Schmidt, Helena and Ikram, M Arfan and Sigurdsson, Sigurdur and Heiss, Gerardo and Struchalin, Maksim and Smith, Albert V and van der Lugt, Aad and DeCarli, Charles and Lumley, Thomas and Knopman, David S and Enzinger, Christian and Eiriksdottir, Gudny and Koudstaal, Peter J and DeStefano, Anita L and Psaty, Bruce M and Dufouil, Carole and Catellier, Diane J and Fazekas, Franz and Aspelund, Thor and Aulchenko, Yurii S and Beiser, Alexa and Rotter, Jerome I and Tzourio, Christophe and Shibata, Dean K and Tscherner, Maria and Harris, Tamara B and Rivadeneira, Fernando and Atwood, Larry D and Rice, Kenneth and Gottesman, Rebecca F and van Buchem, Mark A and Uitterlinden, Andr{\'e} G and Kelly-Hayes, Margaret and Cushman, Mary and Zhu, Yicheng and Boerwinkle, Eric and Gudnason, Vilmundur and Hofman, Albert and Romero, Jose R and Lopez, Oscar and van Duijn, Cornelia M and Au, Rhoda and Heckbert, Susan R and Wolf, Philip A and Mosley, Thomas H and Seshadri, Sudha and Breteler, Monique M B and Schmidt, Reinhold and Launer, Lenore J and Longstreth, W T} } @article {1173, title = {Intravenous tissue plasminogen activator and stroke in the elderly.}, journal = {Am J Emerg Med}, volume = {28}, year = {2010}, month = {2010 Mar}, pages = {359-63}, abstract = {

OBJECTIVE: Since publication in 1995 of the National Institute of Neurological Disorders and Stroke (NINDS) trial of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke, the benefit and frequency of use of IV tPA in the elderly have remained uncertain.

METHODS: We obtained data from the NINDS trial to summarize outcomes for randomized subjects older than 80 years. We used data from the Cardiovascular Health Study, a cohort study of 5888 elderly participants from 4 US communities followed longitudinally for stroke since 1989 to estimate the use of and hospital outcome after IV tPA in older adults following publication of the trial in 1995.

RESULTS: In the NINDS trial, 44 subjects older than 80 years were randomized, and their 3-month functional outcomes were not significantly improved with IV tPA. Of 25 randomized to IV tPA, 4 experienced symptomatic intracranial hemorrhages within 36 hours of treatment. Compared with younger patients, older patients were 2.87 times more likely to experience a symptomatic intracranial hemorrhage within 36 hours of IV tPA (95\% confidence interval, 1.04-7.93). Of 227 Cardiovascular Health Study participants hospitalized for ischemic stroke between 1995 and 2002, seven, whose mean age was 84 years, were treated with IV tPA (3.1\%; 95\% confidence interval 1.2-6.2). Two had symptomatic intracranial hemorrhages, 3 failed to improve, and 2 of the 7 had good outcomes.

CONCLUSIONS: These data highlight the need to clarify the risk-benefit profile of IV tPA in ischemic stroke victims who are older than 80 years.

}, keywords = {Aged, 80 and over, Female, Fibrinolytic Agents, Humans, Longitudinal Studies, Male, Placebos, Randomized Controlled Trials as Topic, Stroke, Tissue Plasminogen Activator, Treatment Outcome, United States}, issn = {1532-8171}, doi = {10.1016/j.ajem.2009.01.025}, author = {Longstreth, W T and Katz, Ronit and Tirschwell, David L and Cushman, Mary and Psaty, Bruce M} } @article {1233, title = {Post hoc Parkinson{\textquoteright}s disease: identifying an uncommon disease in the Cardiovascular Health Study.}, journal = {Neuroepidemiology}, volume = {35}, year = {2010}, month = {2010}, pages = {241-9}, abstract = {

BACKGROUND: Although ongoing cohort studies offer a unique opportunity to apply existing information collected prospectively to further the scientific understanding of Parkinson{\textquoteright}s disease (PD), they typically have limited information for clinical diagnosis.

METHODS: We used combinations of self-report, International Classification of Diseases - 9th edition codes and antiparkinsonian medications to identify PD in the Cardiovascular Health Study. To determine whether the expected inverse association between smoking and PD is evident using our outcome definitions, we assessed baseline smoking characteristics for various definitions of PD.

RESULTS: We identified 60 cases with prevalent PD (1.0\%; 95\% confidence interval, CI = 0.8-1.3\%) and 154 with incident PD by year 14. Clear associations were observed for current smokers (odds ratio, OR = 0.50; 95\% CI = 0.26-0.95) and for those who smoked >=50 pack-years (OR = 0.53; 95\% CI = 0.29-0.96). Estimates for smoking were similar when >=2 data sources were required. Estimates for self-report alone were attenuated towards null.

CONCLUSIONS: Using multiple data sources to identify PD represents an alternative method of outcome identification in a cohort that would otherwise not be possible for PD research. Ongoing cohort studies can provide settings in which rapid replication and explorations of new hypotheses for PD are possible.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular System, Cohort Studies, Female, Health Status, Humans, Incidence, Male, Odds Ratio, Parkinson Disease, Prevalence, Prospective Studies, Risk Factors, Smoking, Surveys and Questionnaires, United States}, issn = {1423-0208}, doi = {10.1159/000319895}, author = {Ton, T G and Jain, S and Boudreau, R and Thacker, E L and Strotmeyer, E S and Newman, A B and Longstreth, W T and Checkoway, H} } @article {1292, title = {Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults: the cardiovascular health study.}, journal = {J Am Coll Cardiol}, volume = {57}, year = {2011}, month = {2011 May 24}, pages = {2172-80}, abstract = {

OBJECTIVES: The objective of this study was to investigate the associations of mitral annular calcification, aortic annular calcification, and aortic valve sclerosis with covert magnetic resonance imaging (MRI)-defined brain infarcts.

BACKGROUND: Clinically silent brain infarcts defined by MRI are associated with increased risk for cognitive decline, dementia, and future overt stroke. Left-sided cardiac valvular and annular calcifications are suspected as risk factors for clinical ischemic stroke.

METHODS: A total of 2,680 CHS (Cardiovascular Health Study) participants without clinical histories of stroke or transient ischemic attack underwent brain MRI in 1992 and 1993, 1 to 2 years before echocardiographic exams (1994 to 1995).

RESULTS: The mean age of the participants was 74.5 {\textpm} 4.8 years, and 39.3\% were men. The presence of any annular or valvular calcification (mitral annular calcification, aortic annular calcification, or aortic valve sclerosis), mitral annular calcification alone, or aortic annular calcification alone was significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular or valve calcification remained associated with covert brain infarcts (risk ratio: 1.24; 95\% confidence interval: 1.05 to 1.47). The degree of annular or valvular calcification severity showed a direct relation with the presence of covert MRI findings.

CONCLUSIONS: Left-sided cardiac annular and valvular calcifications are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening in the progression of annular and valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk for cognitive impairment and future stroke.

}, keywords = {Aged, Aortic Valve Stenosis, Brain, Brain Infarction, Calcinosis, Cohort Studies, Female, Humans, Magnetic Resonance Imaging, Male, Mitral Valve Stenosis, Retrospective Studies}, issn = {1558-3597}, doi = {10.1016/j.jacc.2011.01.034}, author = {Rodriguez, Carlos J and Bartz, Traci M and Longstreth, W T and Kizer, Jorge R and Barasch, Eddy and Lloyd-Jones, Donald M and Gottdiener, John S} } @article {1251, title = {Association of coagulation-related and inflammation-related genes and factor VIIc levels with stroke: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {9}, year = {2011}, month = {2011 Feb}, pages = {267-74}, abstract = {

BACKGROUND: Thrombosis and inflammation are critical in stroke etiology, but associations of coagulation and inflammation gene variants with stroke, and particularly factor VII levels, are inconclusive.

OBJECTIVES: To test the associations between 736 single-nucleotide polymorphisms (SNPs) between tagging haplotype patterns of 130 coagulation and inflammation genes, and stroke events, in the 5888 participants aged >= 65 years of the observational Cardiovascular Health Study cohort.

PATIENTS/METHODS: With 16 years of follow-up, age-adjusted and sex-adjusted Cox models were used to estimate associations of SNPs and FVIIc levels with future stroke.

RESULTS: Eight hundred and fifteen strokes occurred in 5255 genotyped participants without baseline stroke (748 ischemic strokes; 586 among whites). Among whites, six SNPs were associated with stroke, with a nominal P-value of < 0.01: rs6046 and rs3093261 (F7); rs4918851 and rs3781387 (HABP2); and rs3138055 (NFKB1A) and rs4648004 (NFKB1). Two of these SNPs were associated with FVIIc levels (units of percentage activity): rs6046 (β = -18.5, P = 2.38 {\texttimes} 10(-83)) and rs3093261 (β = 2.99, P = 3.93 {\texttimes} 10(-6)). After adjustment for age, sex, race, and cardiovascular risk factors, the association of FVIIc quintiles (Q) with stroke were as follows (hazard ratio; 95\% confidence interval): Q1, reference; Q2, 1.4, 1.1-1.9); Q3, 1.1, 0.8-1.5); Q4, 1.5, 1.1-2.0); and Q5, 1.6, 1.2-2.2). Associations between SNPs and stroke were independent of FVIIc levels.

CONCLUSIONS: Variations in FVII-related genes and FVIIc levels were associated with risk of incident ischemic stroke in this elderly cohort, suggesting a potential causal role for FVII in stroke etiology.

}, keywords = {Blood Coagulation Factors, Cardiovascular Diseases, Cohort Studies, Factor VII, Female, Humans, Inflammation, Male, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Stroke}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2010.04149.x}, author = {Zakai, N A and Lange, L and Longstreth, W T and O{\textquoteright}Meara, E S and Kelley, J L and Fornage, M and Nikerson, D and Cushman, M and Reiner, A P} } @article {1331, title = {Carotid intima-media thickness, electrocardiographic left ventricular hypertrophy, and incidence of intracerebral hemorrhage.}, journal = {Stroke}, volume = {42}, year = {2011}, month = {2011 Nov}, pages = {3075-9}, abstract = {

BACKGROUND AND PURPOSE: Carotid intima-media thickness and electrocardiographic left ventricular hypertrophy are 2 subclinical cardiovascular disease measures associated with increased risk of total and ischemic strokes. Increased intima-media thickness and electrocardiographic left ventricular hypertrophy also may reflect end-organ hypertensive effects. Information is scant on the associations of these subclinical measures with intracerebral hemorrhage (ICH). We hypothesized that greater carotid intima-media thickness and the presence of electrocardiographic left ventricular hypertrophy would be independently associated with increased ICH incidence.

METHODS: Among 18,155 participants initially free of stroke in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), we assessed carotid intima-media thickness, carotid plaque, and electrocardiographic left ventricular hypertrophy. Over a median of 18 years of follow-up, 162 incident ICH events occurred.

RESULTS: After adjustment for other ICH risk factors, carotid intima-media thickness was associated positively with incidence of ICH in both ARIC and CHS. The risk was lowest in study-specific Quartile 1, elevated 1.6- to 2.6-fold in Quartiles 2 to 3, and elevated 2.5 to 3.7-fold in Quartile 4 (P<0.05 for both studies). In CHS, having a carotid plaque was associated with a 2-fold (95\% CI, 1.1-3.4) greater ICH risk than having no plaque, but only 1.2-fold (95\% CI, 0.76-2.0) greater ICH risk in ARIC. Electrocardiographic left ventricular hypertrophy carried a hazard ratio of ICH of 1.7 (95\% CI, 0.77-3.7) in CHS and 2.8 (95\% CI, 1.2-6.4) in ARIC.

CONCLUSIONS: Our data suggest that people with carotid atherosclerosis and possibly left ventricular hypertrophy are at increased risk not only of ischemic stroke, but also of ICH.

}, keywords = {Carotid Intima-Media Thickness, Cerebral Hemorrhage, Cohort Studies, Electrocardiography, Female, Follow-Up Studies, Humans, Hypertrophy, Left Ventricular, Incidence, Male, Middle Aged, Prospective Studies, Risk Factors}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.111.623157}, author = {Folsom, Aaron R and Yatsuya, Hiroshi and Psaty, Bruce M and Shahar, Eyal and Longstreth, W T} } @article {1339, title = {Fasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults.}, journal = {Stroke}, volume = {42}, year = {2011}, month = {2011 Dec}, pages = {3347-51}, abstract = {

BACKGROUND AND PURPOSE: Few studies have assessed post-glucose load measures of insulin resistance and ischemic stroke risk, and data are sparse for older adults. We investigated whether fasting and post-glucose load measures of insulin resistance were related to incident ischemic stroke in nondiabetic, older adults.

METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without prevalent diabetes or stroke at baseline, followed for 17 years for incident ischemic stroke. The Gutt insulin sensitivity index was calculated from baseline body weight and from fasting and 2-hour postload insulin and glucose; a lower Gutt index indicates higher insulin resistance.

RESULTS: Analyses included 3442 participants (42\% men) with a mean age of 73 years. Incidence of ischemic stroke was 9.8 strokes per 1000 person-years. The relative risk (RR) for lowest quartile versus highest quartile of Gutt index was 1.64 (95\% CI, 1.24-2.16), adjusted for demographics and prevalent cardiovascular and kidney disease. Similarly, the adjusted RR for highest quartile versus lowest quartile of 2-hour glucose was 1.84 (95\% CI, 1.39-2.42). In contrast, the adjusted RR for highest quartile versus lowest quartile of fasting insulin was 1.10 (95\% CI, 0.84-1.46).

CONCLUSIONS: In nondiabetic, older adults, insulin resistance measured by Gutt index or 2-hour glucose, but not by fasting insulin, was associated with risk of incident ischemic stroke.

}, keywords = {Aged, Aged, 80 and over, Blood Glucose, Body Mass Index, Brain Ischemia, Fasting, Female, Humans, Incidence, Insulin Resistance, Male, Risk, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.111.620773}, author = {Thacker, Evan L and Psaty, Bruce M and McKnight, Barbara and Heckbert, Susan R and Longstreth, W T and Mukamal, Kenneth J and Meigs, James B and de Boer, Ian H and Boyko, Edward J and Carnethon, Mercedes R and Kizer, Jorge R and Tracy, Russell P and Smith, Nicholas L and Siscovick, David S} } @article {1315, title = {Gender differences in tea, coffee, and cognitive decline in the elderly: the Cardiovascular Health Study.}, journal = {J Alzheimers Dis}, volume = {27}, year = {2011}, month = {2011}, pages = {553-66}, abstract = {

Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Coffee, Cognition Disorders, Cohort Studies, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Prospective Studies, Sex Characteristics, Tea}, issn = {1875-8908}, doi = {10.3233/JAD-2011-110431}, author = {Arab, Lenore and Biggs, Mary L and O{\textquoteright}Meara, Ellen S and Longstreth, W T and Crane, Paul K and Fitzpatrick, Annette L} } @article {1298, title = {Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.}, journal = {Ann Neurol}, volume = {69}, year = {2011}, month = {2011 Jun}, pages = {928-39}, abstract = {

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 {\texttimes} 10(-9) ; p(replication) = 1.3 {\texttimes} 10(-7) ; p(combined) = 4.0 {\texttimes} 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 {\texttimes} 10(-9) ), rs11869977 (p = 5.7 {\texttimes} 10(-9) ), rs936393 (p = 6.8 {\texttimes} 10(-9) ), rs3744017 (p = 7.3 {\texttimes} 10(-9) ), and rs1055129 (p = 4.1 {\texttimes} 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8\% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

}, keywords = {Aged, Aged, 80 and over, Cerebral Cortex, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Residence Characteristics, RNA, Messenger}, issn = {1531-8249}, doi = {10.1002/ana.22403}, author = {Fornage, Myriam and Debette, Stephanie and Bis, Joshua C and Schmidt, Helena and Ikram, M Arfan and Dufouil, Carole and Sigurdsson, Sigurdur and Lumley, Thomas and DeStefano, Anita L and Fazekas, Franz and Vrooman, Henri A and Shibata, Dean K and Maillard, Pauline and Zijdenbos, Alex and Smith, Albert V and Gudnason, Haukur and de Boer, Renske and Cushman, Mary and Mazoyer, Bernard and Heiss, Gerardo and Vernooij, Meike W and Enzinger, Christian and Glazer, Nicole L and Beiser, Alexa and Knopman, David S and Cavalieri, Margherita and Niessen, Wiro J and Harris, Tamara B and Petrovic, Katja and Lopez, Oscar L and Au, Rhoda and Lambert, Jean-Charles and Hofman, Albert and Gottesman, Rebecca F and Garcia, Melissa and Heckbert, Susan R and Atwood, Larry D and Catellier, Diane J and Uitterlinden, Andr{\'e} G and Yang, Qiong and Smith, Nicholas L and Aspelund, Thor and Romero, Jose R and Rice, Kenneth and Taylor, Kent D and Nalls, Michael A and Rotter, Jerome I and Sharrett, Richey and van Duijn, Cornelia M and Amouyel, Philippe and Wolf, Philip A and Gudnason, Vilmundur and van der Lugt, Aad and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Tzourio, Christophe and Breteler, Monique M B and Mosley, Thomas H and Schmidt, Reinhold and Longstreth, W T and DeCarli, Charles and Launer, Lenore J} } @article {1289, title = {Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {42}, year = {2011}, month = {2011 Jul}, pages = {1851-6}, abstract = {

BACKGROUND AND PURPOSE: Little is known about the acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with the short-term risk of stroke.

METHODS: The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days before an incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years before stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios (ORs) and 95\% confidence intervals (95\% CIs) were calculated by conditional logistic regression. Confirmatory analyses assessed hazard ratios of stroke from Cox regression models, with hospitalization for infection as a time-varying exposure.

RESULTS: During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without a baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days before stroke, OR=3.4 (95\% CI, 1.8 to 6.5). The point estimates of risks were higher when we examined shorter intervals: for 30 days, OR=7.3 (95\% CI, 1.9 to 40.9), and for 14 days, OR=8.0 (95\% CI, 1.7 to 77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted hazard ratio=2.4 (95\% CI, 1.6 to 3.4).

CONCLUSIONS: Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.

}, keywords = {Bacterial Infections, Brain Ischemia, Cardiology, Cohort Studies, Cross-Over Studies, Female, Follow-Up Studies, Hospitalization, Humans, Male, Odds Ratio, Proportional Hazards Models, Regression Analysis, Risk, Stroke, Time Factors}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.110.608588}, author = {Elkind, Mitchell S V and Carty, Cara L and O{\textquoteright}Meara, Ellen S and Lumley, Thomas and Lefkowitz, David and Kronmal, Richard A and Longstreth, W T} } @article {1254, title = {Measures of adiposity and future risk of ischemic stroke and coronary heart disease in older men and women.}, journal = {Am J Epidemiol}, volume = {173}, year = {2011}, month = {2011 Jan 01}, pages = {10-25}, abstract = {

The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989-2007) in 3,754 community-dwelling US adults aged 65-100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (>= 30 kg/m{\texttwosuperior}) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25-29.9 kg/m{\texttwosuperior} was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95\% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95\% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.

}, keywords = {Adiposity, Age Factors, Aged, Aged, 80 and over, Brain Ischemia, Coronary Disease, Female, Humans, Incidence, Male, Middle Aged, Obesity, Prevalence, Retrospective Studies, Risk Factors, Sex Factors, United States}, issn = {1476-6256}, doi = {10.1093/aje/kwq311}, author = {Kizer, Jorge R and Biggs, Mary L and Ix, Joachim H and Mukamal, Kenneth J and Zieman, Susan J and de Boer, Ian H and Mozaffarian, Dariush and Barzilay, Joshua I and Strotmeyer, Elsa S and Luchsinger, Jos{\'e} A and Elkind, Mitchell S V and Longstreth, W T and Kuller, Lewis H and Siscovick, David S} } @article {1332, title = {Neighborhood disadvantage and ischemic stroke: the Cardiovascular Health Study (CHS).}, journal = {Stroke}, volume = {42}, year = {2011}, month = {2011 Dec}, pages = {3363-8}, abstract = {

BACKGROUND AND PURPOSE: Neighborhood characteristics may influence the risk of stroke and contribute to socioeconomic disparities in stroke incidence. The objectives of this study were to examine the relationship between neighborhood socioeconomic status and incident ischemic stroke and examine potential mediators of these associations.

METHODS: We analyzed data from 3834 whites and 785 blacks enrolled in the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ages>=65 years from 4 US counties. The primary outcome was adjudicated incident ischemic stroke. Neighborhood socioeconomic status was measured using a composite of 6 census tract variables. Race-stratified multilevel Cox proportional hazard models were constructed adjusted for sociodemographic, behavioral, and biological risk factors.

RESULTS: Among whites, in models adjusted for sociodemographic characteristics, stroke hazard was significantly higher among residents of neighborhoods in the lowest compared with the highest neighborhood socioeconomic status quartile (hazard ratio, 1.32; 95\% CI, 1.01-1.72) with greater attenuation of the hazard ratio after adjustment for biological risk factors (hazard ratio, 1.16; 0.88-1.52) than for behavioral risk factors (hazard ratio, 1.30; 0.99-1.70). Among blacks, we found no significant associations between neighborhood socioeconomic status and ischemic stroke.

CONCLUSIONS: Higher risk of incident ischemic stroke was observed in the most disadvantaged neighborhoods among whites, but not among blacks. The relationship between neighborhood socioeconomic status and stroke among whites appears to be mediated more strongly by biological than behavioral risk factors.

}, keywords = {Aged, Aged, 80 and over, Brain Ischemia, Female, Health Status Disparities, Humans, Incidence, Longitudinal Studies, Male, Poverty, Residence Characteristics, Risk, Risk Factors, Social Class, Social Environment, Socioeconomic Factors, Stroke, Urban Population}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.111.622134}, author = {Brown, Arleen F and Liang, Li-Jung and Vassar, Stefanie D and Stein-Merkin, Sharon and Longstreth, W T and Ovbiagele, Bruce and Yan, Tingjian and Escarce, Jos{\'e} J} } @article {1310, title = {Progression of magnetic resonance imaging-defined brain vascular disease predicts vascular events in elderly: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {42}, year = {2011}, month = {2011 Oct}, pages = {2970-2}, abstract = {

BACKGROUND AND PURPOSE: To determine whether progression of MRI-defined vascular disease predicts subsequent vascular events in the elderly.

METHODS: The Cardiovascular Health Study, a longitudinal cohort study of vascular disease in the elderly, allows us to address this question because its participants had 2 MRI scans≈5 years apart and have been followed for ≈9 years since the follow-up scan for incident vascular events.

RESULTS: Both MRI-defined incident infarcts and worsened white matter grade were significantly associated with heart failure, stroke, and death, but not transient ischemic attacks, angina, or myocardial infarction. Strongest associations occurred when both incident infarcts and worsened white matter grade were present for heart failure (hazard ratio, 1.79; 95\% confidence interval, 1.18-2.73), stroke (hazard ratio, 2.58; 95\% confidence interval, 1.53-4.36), death (hazard ratio, 1.69; 95\% confidence interval, 1.28-2.24), and cardiovascular death (hazard ratio, 1.97; 95\% confidence interval, 1.24-3.14).

CONCLUSIONS: Progression of MRI-defined vascular disease identifies elderly people at increased risk for subsequent heart failure, stroke, and death. Whether aggressive risk factor management would reduce risk is unknown.

}, keywords = {Aged, Brain, Disease Progression, Female, Follow-Up Studies, Heart Failure, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Predictive Value of Tests, Prognosis, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.111.622977}, author = {Longstreth, W T and Arnold, Alice M and Kuller, Lewis H and Bernick, Charles and Lefkowitz, David S and Beauchamp, Norman J and Manolio, Teri A} } @article {1297, title = {The risk of Parkinson disease associated with urate in a community-based cohort of older adults.}, journal = {Neuroepidemiology}, volume = {36}, year = {2011}, month = {2011}, pages = {223-9}, abstract = {

BACKGROUND/AIMS: Studies suggest an inverse association between urate concentration and the risk of Parkinson disease (PD). We investigated this in the Cardiovascular Health Study in an elderly community-based cohort of adults.

METHODS: The association of baseline urate ({\textmu}mol/l) and incident PD over 14 years was assessed with locally weighted scatterplot smoothing (LOESS) regression from which categories of low (<300 {\textmu}mol/l), middle (300-500 {\textmu}mol/l), and high (>500 {\textmu}mol/l) urate ranges were derived. Multivariate logistic regression models assessed the risk of PD for each urate range. Linear and quadratic terms were tested when modeling the association between urate and the risk of PD.

RESULTS: Women had significantly lower urate concentrations than did men [316.8 {\textmu}mol/l (SD 88.0) vs. 367.4 {\textmu}mol/l (SD 87.7), p < 0.0001] and in women no associations between urate and PD risk were observed. In men, LOESS curves suggested a U-shaped or threshold effect between urate and PD risk. With the middle range as reference, the risk of developing PD was significantly increased for urate <300 {\textmu}mol/l (OR 1.69, 95\% CI 1.03-2.78) but not for urate >500 {\textmu}mol/l (OR 1.55, 95\% CI 0.72-3.32) in men. A negative linear term was significant for urate <500 {\textmu}mol/l, and across the entire range a convex quadratic term was significant.

CONCLUSIONS: Results suggest a more complex relationship than previously reported between urate levels and the risk of PD in men. Low urate concentrations were associated with a higher PD risk and high urate concentrations were not associated with a further decrease in PD risk.

}, keywords = {Aged, California, Cohort Studies, Female, Humans, Male, Maryland, North Carolina, Parkinson Disease, Pennsylvania, Prospective Studies, Risk Factors, Sex Distribution, Sex Factors, Uric Acid}, issn = {1423-0208}, doi = {10.1159/000327748}, author = {Jain, S and Ton, T G and Boudreau, R M and Yang, M and Thacker, E L and Studenski, S and Longstreth, W T and Strotmeyer, E S and Newman, A B} } @article {1354, title = {Markers of inflammation in prevalent and incident Parkinson{\textquoteright}s disease in the Cardiovascular Health Study.}, journal = {Parkinsonism Relat Disord}, volume = {18}, year = {2012}, month = {2012 Mar}, pages = {274-8}, abstract = {

BACKGROUND: Studies demonstrate existence of inflammation in prevalent Parkinson{\textquoteright}s disease (PD). We assessed associations of baseline levels of inflammatory markers with prevalent PD at baseline (1989) and incident PD identified over 13 years of follow-up of the Cardiovascular Health Study.

METHODS: Blood samples at baseline were measured for fibrinogen, interleukin-6, tumor necrosis factor-α, C-reactive protein, albumin, and white blood cells. The analysis included 60 prevalent and 154 incident PD cases.

RESULTS: Risk of prevalent PD was significantly higher per doubling of IL-6 among women (odds ratio [OR]=1.5, 95\% confidence interval [CI]: 1.0, 2.4) and WBC among men (OR: 2.4, 95\% CI: 1.2, 4.9) in multivariate models. Risk of incident PD was not associated with higher levels of any biomarker after adjusting for age, smoking, African American race, and history of diabetes. Inverse associations with incident PD were observed per doubling of C-reactive protein (OR=0.9; 95\% CI: 0.8, 1.0) and of fibrinogen among women (OR=0.4; 95\% CI: 0.2, 0.8).

CONCLUSIONS: Although inflammation exists in PD, it may not represent an etiologic factor. Our findings suggest the need for larger studies that measure inflammatory markers before PD onset.

}, keywords = {Aged, Aged, 80 and over, Albumins, Biomarkers, C-Reactive Protein, Enzyme-Linked Immunosorbent Assay, Female, Fibrinogen, Humans, Incidence, Inflammation, Interleukin-6, Leukocyte Count, Male, Parkinson Disease, Prevalence, Risk Factors, Tumor Necrosis Factor-alpha}, issn = {1873-5126}, doi = {10.1016/j.parkreldis.2011.11.003}, author = {Ton, Thanh G N and Jain, Samay and Biggs, Mary L and Thacker, Evan L and Strotmeyer, Elsa S and Boudreau, Robert and Newman, Anne B and Longstreth, W T and Checkoway, Harvey} } @article {1381, title = {Risk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts.}, journal = {Ann Neurol}, volume = {71}, year = {2012}, month = {2012 Apr}, pages = {552-9}, abstract = {

OBJECTIVE: To determine whether the burden of leukoaraiosis and the number of brain infarcts, defined by magnetic resonance imaging (MRI), are prospectively and independently associated with intraparenchymal hemorrhage (IPH) incidence in a pooled population-based study.

METHODS: Among 4,872 participants initially free of clinical stroke in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, we assessed white matter grade (range, 0-9), reflecting increasing leukoaraiosis, and brain infarcts using MRI. Over a median of 13 years of follow-up, 71 incident, spontaneous IPH events occurred.

RESULTS: After adjustment for other IPH risk factors, the hazard ratios (95\% confidence intervals) across white matter grades 0 to 1, 2, 3, and 4 to 9 were 1.00, 1.68 (0.86-3.30), 3.52 (1.80-6.89), and 3.96 (1.90-8.27), respectively (p for trend <0.0001). These hazard ratios were weakened only modestly (p for trend = 0.0003) with adjustment for MRI-defined brain infarcts. The IPH hazard ratios for 0, 1, 2, or >=3 MRI-defined brain infarcts were 1.00, 1.97 (1.10-3.54), 2.00 (0.83-4.78), and 3.12 (1.31-7.43) (p for trend = 0.002), but these were substantially attenuated when adjusted for white matter grade (p for trend = 0.049).

INTERPRETATION: Greater MRI-defined burden of leukoaraiosis is a risk factor for spontaneous IPH. Spontaneous IPH should be added to the growing list of potential poor outcomes in people with leukoaraiosis.

}, keywords = {Cerebral Infarction, Cohort Studies, Female, Humans, Incidence, Intracranial Hemorrhages, Leukoaraiosis, Magnetic Resonance Imaging, Male, Middle Aged, Risk Factors}, issn = {1531-8249}, doi = {10.1002/ana.22690}, author = {Folsom, Aaron R and Yatsuya, Hiroshi and Mosley, Thomas H and Psaty, Bruce M and Longstreth, W T} } @article {6002, title = {Atrial fibrillation and cognitive decline: a longitudinal cohort study.}, journal = {Neurology}, volume = {81}, year = {2013}, month = {2013 Jul 09}, pages = {119-25}, abstract = {

OBJECTIVE: We sought to determine whether in the absence of clinical stroke, people with atrial fibrillation experience faster cognitive decline than people without atrial fibrillation.

METHODS: We conducted a longitudinal analysis in the Cardiovascular Health Study, a community-based study of 5,888 men and women aged 65 years and older, enrolled in 1989/1990 or 1992/1993. Participants did not have atrial fibrillation or a history of stroke at baseline. Participants were censored when they experienced incident clinical stroke. Incident atrial fibrillation was identified by hospital discharge diagnosis codes and annual study ECGs. The main outcome was rate of decline in mean scores on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to 9 times.

RESULTS: Analyses included 5,150 participants, of whom 552 (10.7\%) developed incident atrial fibrillation during a mean of 7 years of follow-up. Mean 3MSE scores declined faster after incident atrial fibrillation compared with no prior atrial fibrillation. For example, the predicted 5-year decline in mean 3MSE score from age 80 to age 85 was -6.4 points (95\% confidence interval [CI]: -7.0, -5.9) for participants without a history of atrial fibrillation, but was -10.3 points (95\% CI: -11.8, -8.9) for participants experiencing incident atrial fibrillation at age 80, a 5-year difference of -3.9 points (95\% CI: -5.3, -2.5).

CONCLUSIONS: In the absence of clinical stroke, people with incident atrial fibrillation are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Atrial Fibrillation, Cognition Disorders, Comorbidity, Female, Humans, Incidence, Longitudinal Studies, Luria-Nebraska Neuropsychological Battery, Male, Predictive Value of Tests}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e31829a33d1}, author = {Thacker, Evan L and McKnight, Barbara and Psaty, Bruce M and Longstreth, W T and Sitlani, Colleen M and Dublin, Sascha and Arnold, Alice M and Fitzpatrick, Annette L and Gottesman, Rebecca F and Heckbert, Susan R} } @article {6001, title = {Blood pressure variability and the risk of all-cause mortality, incident myocardial infarction, and incident stroke in the cardiovascular health study.}, journal = {Am J Hypertens}, volume = {26}, year = {2013}, month = {2013 Oct}, pages = {1210-7}, abstract = {

BACKGROUND: Recent reports have linked variability in visit-to-visit systolic blood pressure (SBP) to risk of mortality and stroke, independent of the effect of mean SBP level. This study aimed to evaluate whether variability in SBP is associated with all-cause mortality, incident myocardial infarction (MI), and incident stroke, independent of mean SBP or trends in SBP levels over time.

METHODS: The Cardiovascular Health Study is a longitudinal cohort study of vascular risk factors and disease in the elderly. Participants who attended their first 5 annual clinic visits and experienced no event before the 5th visit were eligible (n = 3,852). Primary analyses were restricted to participants not using antihypertensive medications throughout the first 5 clinic visits (n = 1,642). Intraindividual SBP variables were defined using each participant{\textquoteright}s 5-visit blood pressure measures. Cox proportional hazards models estimated adjusted hazard ratios (HRs) per SD increase in intraindividual SBP variability, adjusted for intraindividual SBP mean and change over time.

RESULTS: Over a mean follow-up of 9.9 years, there were 844 deaths, 203 MIs, and 195 strokes. Intraindividual SBP variability was significantly associated with increased risk of mortality (HR = 1.13; 95\% confidence interval (CI) = 1.05-1.21) and of incident MI (HR = 1.20; 95\%CI = 1.06-1.36), independent of the effect from adjustment factors. Intraindividual SBP variability was not associated with risk of stroke (HR = 1.03; 95\% CI = 0.89-1.21).

CONCLUSIONS: Long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and MI but not stroke. More research is needed to determine the relationship of BP variability with cardiovascular risk and the clinical implications.

}, keywords = {Aged, Blood Pressure, Cohort Studies, Female, Humans, Incidence, Longitudinal Studies, Male, Mortality, Myocardial Infarction, Risk, Stroke, United States}, issn = {1941-7225}, doi = {10.1093/ajh/hpt092}, author = {Suchy-Dicey, Astrid M and Wallace, Erin R and Mitchell, S V Elkind and Aguilar, Maria and Gottesman, Rebecca F and Rice, Kenneth and Kronmal, Richard and Psaty, Bruce M and Longstreth, W T} } @article {5856, title = {Exploring psychosocial pathways between neighbourhood characteristics and stroke in older adults: the cardiovascular health study.}, journal = {Age Ageing}, volume = {42}, year = {2013}, month = {2013 May}, pages = {391-7}, abstract = {

OBJECTIVES: to investigate whether psychosocial pathways mediate the association between neighbourhood socioeconomic disadvantage and stroke.

METHODS: prospective cohort study with a follow-up of 11.5 years.

SETTING: the Cardiovascular Health Study, a longitudinal population-based cohort study of older adults >=65 years.

MEASUREMENTS: the primary outcome was adjudicated incident ischaemic stroke. Neighbourhood socioeconomic status (NSES) was measured using a composite of six census-tract variables. Psychosocial factors were assessed with standard measures for depression, social support and social networks.

RESULTS: of the 3,834 white participants with no prior stroke, 548 had an incident ischaemic stroke over the 11.5-year follow-up. Among whites, the incident stroke hazard ratio (HR) associated with living in the lowest relative to highest NSES quartile was 1.32 (95\% CI = 1.01-1.73), in models adjusted for individual SES. Additional adjustment for psychosocial factors had a minimal effect on hazard of incident stroke (HR = 1.31, CI = 1.00-1.71). Associations between NSES and stroke incidence were not found among African-Americans (n = 785) in either partially or fully adjusted models.

CONCLUSIONS: psychosocial factors played a minimal role in mediating the effect of NSES on stroke incidence among white older adults.

}, keywords = {African Americans, Age Factors, Aged, Aged, 80 and over, Aging, Brain Ischemia, Depression, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Incidence, Linear Models, Logistic Models, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Residence Characteristics, Risk Assessment, Risk Factors, Social Support, Socioeconomic Factors, Stroke, Time Factors, United States, Vulnerable Populations}, issn = {1468-2834}, doi = {10.1093/ageing/afs179}, author = {Yan, Tingjian and Escarce, Jos{\'e} J and Liang, Li-Jung and Longstreth, W T and Merkin, Sharon Stein and Ovbiagele, Bruce and Vassar, Stefanie D and Seeman, Teresa and Sarkisian, Catherine and Brown, Arleen F} } @article {1358, title = {Height and risk of incident intraparenchymal hemorrhage: Atherosclerosis Risk in Communities and Cardiovascular Health study cohorts.}, journal = {J Stroke Cerebrovasc Dis}, volume = {22}, year = {2013}, month = {2013 May}, pages = {323-8}, abstract = {

BACKGROUND: Height is inversely associated with incident coronary disease and total stroke, but few studies have examined the association between height and intraparenchymal hemorrhage (IPH). We hypothesized that height would be inversely associated with incident IPH in the combined cohorts of the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study.

METHODS: Data on Caucasian and African American participants were used to estimate the association of height at baseline with incident IPH verified by clinician review of medical records and imaging reports. Sex-specific Cox proportional hazards regression models were used to calculate hazard ratios.

RESULTS: A total of 20,983 participants initially free of stroke (11,788 women and 9195 men) were followed for an average of 15.9 years (standard deviation [SD] 5.1 years). Incident IPH occurred in 115 women and 73 men. Sex, but not age, race, study, or blood pressure, modified the association (P = .03). After adjustment for risk factors (age, systolic blood pressure, triglycerides, low-density lipoprotein cholesterol, fibrinogen, and race), among women, height was significantly inversely associated with incident IPH (hazard ratio [HR] per SD [6.3 cm] was 0.81; 95\% confidence interval [CI] 0.66-0.99; P = .04). The HR for tertile 3 vs 1 in women was 0.63 (95\% CI 0.37-1.08). Among men, height was not linearly associated with incident IPH (HR per SD [6.7 cm] was 1.09; 95\% CI 0.84-1.40; P = .52).

CONCLUSIONS: This large prospective study provides evidence that shorter height may be a risk factor for incident IPH in women.

}, keywords = {African Americans, Aged, Body Height, Cerebral Hemorrhage, European Continental Ancestry Group, Female, Humans, Incidence, Male, Middle Aged, Multivariate Analysis, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Sex Factors, Time Factors, United States}, issn = {1532-8511}, doi = {10.1016/j.jstrokecerebrovasdis.2011.09.004}, author = {Smith, Lindsay G and Yatsuya, Hiroshi and Psaty, Bruce M and Longstreth, W T and Folsom, Aaron R} } @article {5855, title = {Neighborhood socioeconomic disadvantage and mortality after stroke.}, journal = {Neurology}, volume = {80}, year = {2013}, month = {2013 Feb 05}, pages = {520-7}, chapter = {520}, abstract = {

OBJECTIVE: Residence in a socioeconomically disadvantaged community is associated with mortality, but the mechanisms are not well understood. We examined whether socioeconomic features of the residential neighborhood contribute to poststroke mortality and whether neighborhood influences are mediated by traditional behavioral and biologic risk factors.

METHODS: We used data from the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults >=65 years. Residential neighborhood disadvantage was measured using neighborhood socioeconomic status (NSES), a composite of 6 census tract variables representing income, education, employment, and wealth. Multilevel Cox proportional hazard models were constructed to determine the association of NSES to mortality after an incident stroke, adjusted for sociodemographic characteristics, stroke type, and behavioral and biologic risk factors.

RESULTS: Among the 3,834 participants with no prior stroke at baseline, 806 had a stroke over a mean 11.5 years of follow-up, with 168 (20\%) deaths 30 days after stroke and 276 (34\%) deaths at 1 year. In models adjusted for demographic characteristics, stroke type, and behavioral and biologic risk factors, mortality hazard 1 year after stroke was significantly higher among residents of neighborhoods with the lowest NSES than those in the highest NSES neighborhoods (hazard ratio 1.77, 95\% confidence interval 1.17-2.68).

CONCLUSION: Living in a socioeconomically disadvantaged neighborhood is associated with higher mortality hazard at 1 year following an incident stroke. Further work is needed to understand the structural and social characteristics of neighborhoods that may contribute to mortality in the year after a stroke and the pathways through which these characteristics operate.

}, keywords = {Aged, Female, Humans, Incidence, Kaplan-Meier Estimate, Male, Proportional Hazards Models, Residence Characteristics, Risk Factors, Socioeconomic Factors, Stroke, Vulnerable Populations}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e31828154ae}, author = {Brown, Arleen F and Liang, Li-Jung and Vassar, Stefanie D and Merkin, Sharon Stein and Longstreth, W T and Ovbiagele, Bruce and Yan, Tingjian and Escarce, Jos{\'e} J} } @article {6424, title = {Association of kidney disease measures with ischemic versus hemorrhagic strokes: pooled analyses of 4 prospective community-based cohorts.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Jul}, pages = {1925-31}, abstract = {

BACKGROUND AND PURPOSE: Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke.

METHODS: We pooled individual participant data from 4 community-based cohorts: 3 from the United States and 1 from The Netherlands. GFR was estimated using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of estimated GFR and ACR were compared for each stroke type (ischemic versus intraparenchymal hemorrhagic) using study-stratified Cox regression.

RESULTS: Among 29,595 participants (mean age, 61 [SD 12.5] years; 46\% men; 17\% black), 1261 developed stroke (12\% hemorrhagic) during 280,549 person-years. Low estimated GFR was significantly associated with increased risk of ischemic stroke, but not hemorrhagic stroke, whereas high ACR was associated with both stroke types. Adjusted hazard ratios for ischemic and hemorrhagic stroke at estimated GFR of 45 (versus 95) mL/min per 1.73 m2 were 1.30 (95\% confidence interval, 1.01-1.68) and 0.92 (0.47-1.81), respectively. In contrast, the corresponding hazard ratios for ACR of 300 (versus 5) mg/g were 1.62 (1.27-2.07) for ischemic and 2.57 (1.37-4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P=0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure.

CONCLUSIONS: Whereas albuminuria showed significant association with both stroke types, the association of decreased estimated GFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.

}, keywords = {Aged, Albuminuria, Brain Ischemia, Comorbidity, Female, Glomerular Filtration Rate, Humans, Intracranial Hemorrhages, Kidney Diseases, Male, Middle Aged, Netherlands, Proportional Hazards Models, Prospective Studies, Risk Factors, Stroke, United States}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.114.004900}, author = {Mahmoodi, Bakhtawar K and Yatsuya, Hiroshi and Matsushita, Kunihiro and Sang, Yinying and Gottesman, Rebecca F and Astor, Brad C and Woodward, Mark and Longstreth, W T and Psaty, Bruce M and Shlipak, Michael G and Folsom, Aaron R and Gansevoort, Ron T and Coresh, Josef} } @article {6548, title = {Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e99798}, abstract = {

BACKGROUND: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.

METHODS AND RESULTS: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] >= 1\%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF<= 1\% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).

CONCLUSION: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.

}, keywords = {Cell Adhesion Molecules, Neuronal, European Continental Ancestry Group, Female, Genetic Association Studies, Genetic Heterogeneity, Humans, Introns, Ischemia, Male, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies, Sequence Analysis, DNA}, issn = {1932-6203}, doi = {10.1371/journal.pone.0099798}, author = {Bis, Joshua C and DeStefano, Anita and Liu, Xiaoming and Brody, Jennifer A and Choi, Seung Hoan and Verhaaren, Benjamin F J and Debette, Stephanie and Ikram, M Arfan and Shahar, Eyal and Butler, Kenneth R and Gottesman, Rebecca F and Muzny, Donna and Kovar, Christie L and Psaty, Bruce M and Hofman, Albert and Lumley, Thomas and Gupta, Mayetri and Wolf, Philip A and van Duijn, Cornelia and Gibbs, Richard A and Mosley, Thomas H and Longstreth, W T and Boerwinkle, Eric and Seshadri, Sudha and Fornage, Myriam} } @article {6581, title = {Brain imaging findings in elderly adults and years of life, healthy life, and able life over the ensuing 16 years: the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {62}, year = {2014}, month = {2014 Oct}, pages = {1838-43}, abstract = {

OBJECTIVES: To determine whether elderly people with different patterns of magnetic resonance imaging (MRI) findings have different long-term outcomes.

DESIGN: Longitudinal cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals aged 65 and older were recruited (N = 5,888); 3,660 of these underwent MRI, and 3,230 without a stroke before MRI were included in these analyses.

MEASUREMENTS: Cluster analysis of brain MRI findings was previously used to define five clusters: normal, atrophy, simple infarct, leukoaraiosis, and complex infarct. Participants were subsequently classified as healthy if they rated their health as excellent, very good, or good and as able if they did not report any limitations in activities of daily living (ADLs). Mean years of life (YoL), years of healthy life (YHL), and years of able life (YAL) were calculated over 16 years after the MRI and compared between clusters using unadjusted and adjusted regression analyses.

RESULTS: Mean age of participants was 75.0. With 16 years of follow-up, mean YoL was 11.3; YHL, 8.0; and YAL, 8.4. Outcomes differed significantly between clusters. With or without adjustments, outcomes were all significantly better in the normal than complex infarct cluster. The three remaining clusters had intermediate results, significantly different from the normal and complex infarct clusters but not usually from one another. Over 16 years of follow-up, participants in the complex infarct cluster (n = 368) spent the largest percentage of their 8.4 years alive being sick (38\%) and not able (38\%).

CONCLUSION: Findings on MRI scans in elderly adults are associated not only with long-term survival, but also with long-term self-rated health and limitation in ADLs. The combination of infarcts and leukoaraiosis carried the worst prognosis, presumably reflecting small vessel disease.

}, keywords = {Activities of Daily Living, Aged, Atrophy, Brain, Brain Infarction, Cohort Studies, Disability Evaluation, Female, Health Status, Humans, Leukoaraiosis, Longevity, Longitudinal Studies, Magnetic Resonance Imaging, Male, Prognosis, Regression Analysis, United States}, issn = {1532-5415}, doi = {10.1111/jgs.13068}, author = {Longstreth, W T and Diehr, Paula H and Yee, Laura M and Newman, Anne B and Beauchamp, Norman J} } @article {6220, title = {Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Feb}, pages = {403-12}, abstract = {

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged >=55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3{\texttimes}10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7{\texttimes}10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Area Under Curve, Case-Control Studies, Cohort Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors, ROC Curve, Sex Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.113.003044}, author = {Ibrahim-Verbaas, Carla A and Fornage, Myriam and Bis, Joshua C and Choi, Seung Hoan and Psaty, Bruce M and Meigs, James B and Rao, Madhu and Nalls, Mike and Fontes, Jo{\~a}o D and O{\textquoteright}Donnell, Christopher J and Kathiresan, Sekar and Ehret, Georg B and Fox, Caroline S and Malik, Rainer and Dichgans, Martin and Schmidt, Helena and Lahti, Jari and Heckbert, Susan R and Lumley, Thomas and Rice, Kenneth and Rotter, Jerome I and Taylor, Kent D and Folsom, Aaron R and Boerwinkle, Eric and Rosamond, Wayne D and Shahar, Eyal and Gottesman, Rebecca F and Koudstaal, Peter J and Amin, Najaf and Wieberdink, Renske G and Dehghan, Abbas and Hofman, Albert and Uitterlinden, Andr{\'e} G and DeStefano, Anita L and Debette, Stephanie and Xue, Luting and Beiser, Alexa and Wolf, Philip A and DeCarli, Charles and Ikram, M Arfan and Seshadri, Sudha and Mosley, Thomas H and Longstreth, W T and van Duijn, Cornelia M and Launer, Lenore J} } @article {6338, title = {Separate prediction of intracerebral hemorrhage and ischemic stroke.}, journal = {Neurology}, volume = {82}, year = {2014}, month = {2014 May 20}, pages = {1804-12}, abstract = {

OBJECTIVES: To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS).

METHODS: We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45\% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38\% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41\% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions{\textquoteright} performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots.

RESULTS: High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types <0.001). For both the ICH and IS models, C statistics increased more by model extension in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Improvements in C statistics were reproduced by cross-validation. Models were well calibrated in all cohorts. Correlations between 10-year ICH and IS risks were moderate in each cohort.

CONCLUSIONS: We developed and cross-validated cumulative incidence functions for separate prediction of 10-year ICH and IS risk. These functions can be useful to further specify an individual{\textquoteright}s stroke risk.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Body Mass Index, Brain Ischemia, Cholesterol, Female, Humans, Incidence, Intracranial Hemorrhages, Male, Middle Aged, Models, Statistical, Predictive Value of Tests, Risk Assessment, Risk Factors, Stroke}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000000427}, author = {Ferket, Bart S and van Kempen, Bob J H and Wieberdink, Renske G and Steyerberg, Ewout W and Koudstaal, Peter J and Hofman, Albert and Shahar, Eyal and Gottesman, Rebecca F and Rosamond, Wayne and Kizer, Jorge R and Kronmal, Richard A and Psaty, Bruce M and Longstreth, W T and Mosley, Thomas and Folsom, Aaron R and Hunink, M G Myriam and Ikram, M Arfan} } @article {6668, title = {Association between left atrial abnormality on ECG and vascular brain injury on MRI in the Cardiovascular Health Study.}, journal = {Stroke}, volume = {46}, year = {2015}, month = {2015 Mar}, pages = {711-6}, abstract = {

BACKGROUND AND PURPOSE: Emerging evidence suggests that atrial disease is associated with vascular brain injury in the absence of atrial fibrillation.

METHODS: The Cardiovascular Health Study prospectively enrolled community-dwelling adults aged >=65 years. Among participants who underwent MRI, we examined associations of ECG left atrial abnormality with brain infarcts and leukoaraiosis. P-wave terminal force in lead V1 was the primary measure of left atrial abnormality; P-wave area and duration were secondary predictors. We excluded participants with atrial fibrillation before or on their index ECG. Primary outcomes were incident infarcts and worsening leukoaraiosis from initial to follow-up scan ≈5 years later. Secondary outcomes were prevalent infarcts and degree of leukoaraiosis on initial MRI. Relative risk (RR) and linear regression models were adjusted for vascular risk factors.

RESULTS: Among 3129 participants with >=1 scan, each SD increase in P-wave terminal force in lead V1 was associated with a 0.05-point (95\% confidence interval [CI], 0.0003-0.10) higher baseline white matter grade on a 10-point scale. P-wave terminal force in lead V1 was associated with prevalent infarcts of any type (RR per SD, 1.09; 95\% CI, 1.04-1.16) and more so with prevalent nonlacunar infarcts (RR per SD, 1.22; 95\% CI, 1.08-1.38). Among 1839 participants with 2 scans, P-wave terminal force in lead V1 was associated with worsening leukoaraiosis (RR per SD, 1.09; 95\% CI, 1.01-1.18), but not with incident infarcts (RR per SD, 1.06; 95\% CI, 0.93-1.20). Sensitivity analyses adjusting for incident atrial fibrillation found similar results. P-wave area and duration were not associated with outcomes.

CONCLUSIONS: ECG left atrial abnormality is associated with vascular brain injury in the absence of documented atrial fibrillation.

}, keywords = {Aged, Atrial Fibrillation, Brain, Brain Infarction, Cardiovascular Diseases, Cerebrovascular Trauma, Electrocardiography, Female, Heart Atria, Heart Diseases, Humans, Linear Models, Magnetic Resonance Imaging, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Regression Analysis, Risk Factors, Treatment Outcome}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.114.007762}, author = {Kamel, Hooman and Bartz, Traci M and Longstreth, W T and Okin, Peter M and Thacker, Evan L and Patton, Kristen K and Stein, Phyllis K and Gottesman, Rebecca F and Heckbert, Susan R and Kronmal, Richard A and Elkind, Mitchell S V and Soliman, Elsayed Z} } @article {6810, title = {Coagulation factor~XII genetic variation, ex~vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {13}, year = {2015}, month = {2015 Oct}, pages = {1867-77}, abstract = {

BACKGROUND: The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population-based cohorts.

OBJECTIVES: To evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex~vivo with common single-nucleotide polymorphisms (SNPs) and incident cardiovascular disease and stroke.

PATIENTS/METHODS: We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n~=~5411), both with and without inhibitory anti-factor~XIa antibody (pTG/FXIa(-) ). We evaluated their associations with ~~50~000 SNPs by using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2~years.

RESULTS: The minor allele for an SNP in the FXII gene (F12), rs1801020, was associated with lower pTG in European-Americans (β~=~-~34.2~{\textpm}~3.5~nm; P~=~3.3~{\texttimes}~10(-22) ; minor allele frequency [MAF]~=~0.23) and African-Americans (β~=~-~31.1~{\textpm}~7.9~nm; P~=~9.0~{\texttimes} 10(-5) ; MAF~=~0.42). Lower FXIa-independent pTG (pTG/FXIa(-) ) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa(-) was associated with the ABO SNP rs657152 minor allele (β~=~16.3~nm; P~=~4.3~{\texttimes}~10(-9) ; MAF~=~0.37). The risk factor-adjusted ischemic stroke hazard ratios were 1.09 (95\% confidence interval CI~1.01-1.17; P~=~0.03) for pTG, 1.06 (95\% CI~0.98-1.15; P~=~0.17) for pTG/FXIa(-) , and 1.11 (95\% CI~1.02-1.21; P~=~0.02) for FXIa-dependent pTG (pTG/FXIa(+) ), per one standard deviation increment (n~=~834 ischemic strokes). In a multicohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (β~=~-~0.02; standard error~=~0.08; P~=~0.81).

CONCLUSIONS: These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke, and indicate the importance of F12 SNPs for TG ex~vivo and in~vivo.

}, keywords = {African Americans, Age Factors, Aged, Blood Coagulation, Brain Ischemia, European Continental Ancestry Group, Factor XII, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Incidence, Male, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Assessment, Risk Factors, Stroke, Thrombin, Time Factors, United States}, issn = {1538-7836}, doi = {10.1111/jth.13111}, author = {Olson, N C and Butenas, S and Lange, L A and Lange, E M and Cushman, M and Jenny, N S and Walston, J and Souto, J C and Soria, J M and Chauhan, G and Debette, S and Longstreth, W T and Seshadri, S and Reiner, A P and Tracy, R P} } @article {6684, title = {Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Biol Psychiatry}, volume = {77}, year = {2015}, month = {2015 Apr 15}, pages = {749-63}, abstract = {

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged >=45 years. Replication of suggestive associations (p < 5 {\texttimes} 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 {\texttimes} 10(-10)) and replication cohorts (p = 5.65 {\texttimes} 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 {\texttimes} 10(-8), and rs6813517 [SPOCK3], p = 2.58 {\texttimes} 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

}, keywords = {Aged, Aged, 80 and over, Aging, Apolipoproteins E, Claudin-5, Cohort Studies, Female, Genome-Wide Association Study, Genotype, Humans, Male, Memory Disorders, Middle Aged, Polymorphism, Single Nucleotide, Proteins, Proteoglycans, Regression Analysis, Sulfotransferases, Verbal Learning}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2014.08.027}, author = {Debette, Stephanie and Ibrahim Verbaas, Carla A and Bressler, Jan and Schuur, Maaike and Smith, Albert and Bis, Joshua C and Davies, Gail and Wolf, Christiane and Gudnason, Vilmundur and Chibnik, Lori B and Yang, Qiong and DeStefano, Anita L and de Quervain, Dominique J F and Srikanth, Velandai and Lahti, Jari and Grabe, Hans J and Smith, Jennifer A and Priebe, Lutz and Yu, Lei and Karbalai, Nazanin and Hayward, Caroline and Wilson, James F and Campbell, Harry and Petrovic, Katja and Fornage, Myriam and Chauhan, Ganesh and Yeo, Robin and Boxall, Ruth and Becker, James and Stegle, Oliver and Mather, Karen A and Chouraki, Vincent and Sun, Qi and Rose, Lynda M and Resnick, Susan and Oldmeadow, Christopher and Kirin, Mirna and Wright, Alan F and Jonsdottir, Maria K and Au, Rhoda and Becker, Albert and Amin, Najaf and Nalls, Mike A and Turner, Stephen T and Kardia, Sharon L R and Oostra, Ben and Windham, Gwen and Coker, Laura H and Zhao, Wei and Knopman, David S and Heiss, Gerardo and Griswold, Michael E and Gottesman, Rebecca F and Vitart, Veronique and Hastie, Nicholas D and Zgaga, Lina and Rudan, Igor and Polasek, Ozren and Holliday, Elizabeth G and Schofield, Peter and Choi, Seung Hoan and Tanaka, Toshiko and An, Yang and Perry, Rodney T and Kennedy, Richard E and Sale, Mich{\`e}le M and Wang, Jing and Wadley, Virginia G and Liewald, David C and Ridker, Paul M and Gow, Alan J and Pattie, Alison and Starr, John M and Porteous, David and Liu, Xuan and Thomson, Russell and Armstrong, Nicola J and Eiriksdottir, Gudny and Assareh, Arezoo A and Kochan, Nicole A and Widen, Elisabeth and Palotie, Aarno and Hsieh, Yi-Chen and Eriksson, Johan G and Vogler, Christian and van Swieten, John C and Shulman, Joshua M and Beiser, Alexa and Rotter, Jerome and Schmidt, Carsten O and Hoffmann, Wolfgang and N{\"o}then, Markus M and Ferrucci, Luigi and Attia, John and Uitterlinden, Andr{\'e} G and Amouyel, Philippe and Dartigues, Jean-Fran{\c c}ois and Amieva, H{\'e}l{\`e}ne and R{\"a}ikk{\"o}nen, Katri and Garcia, Melissa and Wolf, Philip A and Hofman, Albert and Longstreth, W T and Psaty, Bruce M and Boerwinkle, Eric and DeJager, Philip L and Sachdev, Perminder S and Schmidt, Reinhold and Breteler, Monique M B and Teumer, Alexander and Lopez, Oscar L and Cichon, Sven and Chasman, Daniel I and Grodstein, Francine and M{\"u}ller-Myhsok, Bertram and Tzourio, Christophe and Papassotiropoulos, Andreas and Bennett, David A and Ikram, M Arfan and Deary, Ian J and van Duijn, Cornelia M and Launer, Lenore and Fitzpatrick, Annette L and Seshadri, Sudha and Mosley, Thomas H} } @article {6683, title = {Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.}, journal = {Circ Cardiovasc Genet}, volume = {8}, year = {2015}, month = {2015 Apr}, pages = {398-409}, abstract = {

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7{\texttimes}10(-19)) and identified novel loci on chr10q24 (P=1.6{\texttimes}10(-9)) and chr2p21 (P=4.4{\texttimes}10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0{\texttimes}10(-8)) and chr2p16 (P=1.5{\texttimes}10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

}, keywords = {Aged, Aged, 80 and over, Chromosomes, Human, Continental Population Groups, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Models, Genetic, Stroke, White Matter}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.114.000858}, author = {Verhaaren, Benjamin F J and Debette, Stephanie and Bis, Joshua C and Smith, Jennifer A and Ikram, M Kamran and Adams, Hieab H and Beecham, Ashley H and Rajan, Kumar B and Lopez, Lorna M and Barral, Sandra and van Buchem, Mark A and van der Grond, Jeroen and Smith, Albert V and Hegenscheid, Katrin and Aggarwal, Neelum T and de Andrade, Mariza and Atkinson, Elizabeth J and Beekman, Marian and Beiser, Alexa S and Blanton, Susan H and Boerwinkle, Eric and Brickman, Adam M and Bryan, R Nick and Chauhan, Ganesh and Chen, Christopher P L H and Chouraki, Vincent and de Craen, Anton J M and Crivello, Fabrice and Deary, Ian J and Deelen, Joris and De Jager, Philip L and Dufouil, Carole and Elkind, Mitchell S V and Evans, Denis A and Freudenberger, Paul and Gottesman, Rebecca F and Gu{\dh}nason, Vilmundur and Habes, Mohamad and Heckbert, Susan R and Heiss, Gerardo and Hilal, Saima and Hofer, Edith and Hofman, Albert and Ibrahim-Verbaas, Carla A and Knopman, David S and Lewis, Cora E and Liao, Jiemin and Liewald, David C M and Luciano, Michelle and van der Lugt, Aad and Martinez, Oliver O and Mayeux, Richard and Mazoyer, Bernard and Nalls, Mike and Nauck, Matthias and Niessen, Wiro J and Oostra, Ben A and Psaty, Bruce M and Rice, Kenneth M and Rotter, Jerome I and von Sarnowski, Bettina and Schmidt, Helena and Schreiner, Pamela J and Schuur, Maaike and Sidney, Stephen S and Sigurdsson, Sigurdur and Slagboom, P Eline and Stott, David J M and van Swieten, John C and Teumer, Alexander and T{\"o}glhofer, Anna Maria and Traylor, Matthew and Trompet, Stella and Turner, Stephen T and Tzourio, Christophe and Uh, Hae-Won and Uitterlinden, Andr{\'e} G and Vernooij, Meike W and Wang, Jing J and Wong, Tien Y and Wardlaw, Joanna M and Windham, B Gwen and Wittfeld, Katharina and Wolf, Christiane and Wright, Clinton B and Yang, Qiong and Zhao, Wei and Zijdenbos, Alex and Jukema, J Wouter and Sacco, Ralph L and Kardia, Sharon L R and Amouyel, Philippe and Mosley, Thomas H and Longstreth, W T and DeCarli, Charles C and van Duijn, Cornelia M and Schmidt, Reinhold and Launer, Lenore J and Grabe, Hans J and Seshadri, Sudha S and Ikram, M Arfan and Fornage, Myriam} } @article {6540, title = {Physical activity, body mass index, and brain atrophy in Alzheimer{\textquoteright}s disease.}, journal = {Neurobiol Aging}, volume = {36 Suppl 1}, year = {2015}, month = {2015 Jan}, pages = {S194-S202}, abstract = {

The purpose of this study was to use a novel imaging biomarker to assess associations between physical activity (PA), body mass index (BMI), and brain structure in normal aging, mild cognitive impairment, and Alzheimer{\textquoteright}s dementia. We studied 963 participants (mean age: 74.1 {\textpm} 4.4 years) from the multisite Cardiovascular Health Study including healthy controls (n~= 724), Alzheimer{\textquoteright}s dementia patients (n~=~104), and people with mild cognitive impairment (n~= 135). Volumetric brain images were processed using tensor-based morphometry to analyze regional brain volumes. We regressed the local brain tissue volume on reported PA and computed BMI, and performed conjunction analyses using both variables. Covariates included age, sex, and study site. PA was independently associated with greater whole brain and regional brain volumes and reduced ventricular dilation. People with higher BMI had lower whole brain and regional brain volumes. A PA-BMI conjunction analysis showed brain preservation with PA and volume loss with increased BMI in overlapping brain regions. In one of the largest voxel-based cross-sectional studies to date, PA and lower BMI may be beneficial to the brain across the spectrum of aging and neurodegeneration.

}, keywords = {Aged, Aged, 80 and over, Aging, Alzheimer Disease, Atrophy, Biomarkers, Body Mass Index, Brain, Cognitive Dysfunction, Cross-Sectional Studies, Diffusion Magnetic Resonance Imaging, Female, Humans, Magnetic Resonance Imaging, Male, Motor Activity, Neuroimaging}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2014.05.036}, author = {Boyle, Christina P and Raji, Cyrus A and Erickson, Kirk I and Lopez, Oscar L and Becker, James T and Gach, H Michael and Longstreth, W T and Teverovskiy, Leonid and Kuller, Lewis H and Carmichael, Owen T and Thompson, Paul M} } @article {6849, title = {Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.}, journal = {JAMA Neurol}, volume = {72}, year = {2015}, month = {2015 Jul}, pages = {781-8}, abstract = {

IMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.

DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP{\textquoteright}s exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.

MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 {\texttimes} 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 {\texttimes} 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).

CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

}, keywords = {Aged, Brain Ischemia, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Muscle Proteins, National Heart, Lung, and Blood Institute (U.S.), Nuclear Proteins, Open Reading Frames, Palmitoyl-CoA Hydrolase, Stroke, United States}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2015.0582}, author = {Auer, Paul L and Nalls, Mike and Meschia, James F and Worrall, Bradford B and Longstreth, W T and Seshadri, Sudha and Kooperberg, Charles and Burger, Kathleen M and Carlson, Christopher S and Carty, Cara L and Chen, Wei-Min and Cupples, L Adrienne and DeStefano, Anita L and Fornage, Myriam and Hardy, John and Hsu, Li and Jackson, Rebecca D and Jarvik, Gail P and Kim, Daniel S and Lakshminarayan, Kamakshi and Lange, Leslie A and Manichaikul, Ani and Quinlan, Aaron R and Singleton, Andrew B and Thornton, Timothy A and Nickerson, Deborah A and Peters, Ulrike and Rich, Stephen S} } @article {6928, title = {Social Network Size and Cranial Magnetic Resonance Imaging Findings in Older Adults: The Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {63}, year = {2015}, month = {2015 Nov}, pages = {2430-2}, keywords = {Aged, Brain, Cardiovascular Diseases, Cross-Sectional Studies, Female, Geriatric Assessment, Humans, Magnetic Resonance Imaging, Male, Neuroimaging, Social Participation, Social Support}, issn = {1532-5415}, doi = {10.1111/jgs.13805}, author = {Flatt, Jason D and Rosso, Andrea L and Aizenstein, Howard J and Schulz, Richard and Longstreth, W T and Newman, Anne B and Fowler, Nicole R and Rosano, Caterina} } @article {6861, title = {White Matter Lesion Progression: Genome-Wide Search for Genetic Influences.}, journal = {Stroke}, volume = {46}, year = {2015}, month = {2015 Nov}, pages = {3048-57}, abstract = {

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.

RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5\%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5{\texttimes}10(-8)). Four loci were suggestive (P<1{\texttimes}10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46{\texttimes}10(-6)); 12q13.13 (rs4761974, P=8.71{\texttimes}10(-7)); 20p12.1 (rs6135309, P=3.69{\texttimes}10(-6)); and 4p15.31 (rs7664442, P=2.26{\texttimes}10(-6)). Variants that have been previously related to WML explained only 0.8\% to 11.7\% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.

CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

}, keywords = {Adult, Aged, Cohort Studies, Disease Progression, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Leukoencephalopathies, Male, Middle Aged, Prospective Studies, White Matter}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.115.009252}, author = {Hofer, Edith and Cavalieri, Margherita and Bis, Joshua C and DeCarli, Charles and Fornage, Myriam and Sigurdsson, Sigurdur and Srikanth, Velandai and Trompet, Stella and Verhaaren, Benjamin F J and Wolf, Christiane and Yang, Qiong and Adams, Hieab H H and Amouyel, Philippe and Beiser, Alexa and Buckley, Brendan M and Callisaya, Michele and Chauhan, Ganesh and de Craen, Anton J M and Dufouil, Carole and van Duijn, Cornelia M and Ford, Ian and Freudenberger, Paul and Gottesman, Rebecca F and Gudnason, Vilmundur and Heiss, Gerardo and Hofman, Albert and Lumley, Thomas and Martinez, Oliver and Mazoyer, Bernard and Moran, Chris and Niessen, Wiro J and Phan, Thanh and Psaty, Bruce M and Satizabal, Claudia L and Sattar, Naveed and Schilling, Sabrina and Shibata, Dean K and Slagboom, P Eline and Smith, Albert and Stott, David J and Taylor, Kent D and Thomson, Russell and T{\"o}glhofer, Anna M and Tzourio, Christophe and van Buchem, Mark and Wang, Jing and Westendorp, Rudi G J and Windham, B Gwen and Vernooij, Meike W and Zijdenbos, Alex and Beare, Richard and Debette, Stephanie and Ikram, M Arfan and Jukema, J Wouter and Launer, Lenore J and Longstreth, W T and Mosley, Thomas H and Seshadri, Sudha and Schmidt, Helena and Schmidt, Reinhold} } @article {6950, title = {Association of Smoking, Alcohol, and Obesity with Cardiovascular Death and Ischemic Stroke in Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS).}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0147065}, abstract = {

Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke and cardiovascular (CV) death. Whether modifiable lifestyle risk factors are associated with these CV outcomes in AF is unknown. Among Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS) participants with incident AF, we estimated the risk of composite endpoint of ischemic stroke or CV death associated with candidate modifiable risk factor (smoking, heavy alcohol consumption, or high body mass index [BMI]), and computed the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) of incorporating each factor into the CHA2DS2-VASc. Among 1222 ARIC (mean age: 63.4) and 756 CHS (mean age: 79.1) participants with incident AF, during mean follow-up of 6.9 years and 5.7 years, there were 332 and 335 composite events respectively. Compared with never smokers, current smokers had a higher incidence of the composite endpoint in ARIC [HR: 1.65 (1.21-2.26)] but not in CHS [HR: 1.05 (0.69-1.61)]. In ARIC, the addition of current smoking did not improve risk prediction over and above the CHA2DS2-VASc. No significant associations were observed with alcohol consumption or BMI with CVD outcomes in AF patients from either cohort. Smoking is associated with an increased risk of ischemic stroke or CV death in ARIC, which comprised mostly middle-aged to young-old (65-74 years), but not in CHS, which comprised mostly middle-old or oldest-old (>=75 years) adults with AF. However, addition of smoking to the CHA2DS2-VASc score did not improve risk prediction of these outcomes.

}, keywords = {Aged, Alcohol Drinking, Atrial Fibrillation, Cardiovascular Diseases, Female, Humans, Male, Middle Aged, Obesity, Smoking, Stroke}, issn = {1932-6203}, doi = {10.1371/journal.pone.0147065}, author = {Kwon, Younghoon and Norby, Faye L and Jensen, Paul N and Agarwal, Sunil K and Soliman, Elsayed Z and Lip, Gregory Y H and Longstreth, W T and Alonso, Alvaro and Heckbert, Susan R and Chen, Lin Y} } @article {6991, title = {Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.}, journal = {Stroke}, volume = {47}, year = {2016}, month = {2016 Feb}, pages = {307-16}, abstract = {

BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.

METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5{\texttimes}10(-6) and performed in silico association analyses in an independent sample of <=1003 cases and 7745 controls.

RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5{\texttimes}10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.

CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

}, keywords = {Adult, African Continental Ancestry Group, Age of Onset, Aged, Asian Continental Ancestry Group, Brain Ischemia, Chromosomes, Human, Pair 10, Computer Simulation, DNA, Intergenic, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Serine Endopeptidases, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.115.011328}, author = {Cheng, Yu-Ching and Stanne, Tara M and Giese, Anne-Katrin and Ho, Weang Kee and Traylor, Matthew and Amouyel, Philippe and Holliday, Elizabeth G and Malik, Rainer and Xu, Huichun and Kittner, Steven J and Cole, John W and O{\textquoteright}Connell, Jeffrey R and Danesh, John and Rasheed, Asif and Zhao, Wei and Engelter, Stefan and Grond-Ginsbach, Caspar and Kamatani, Yoichiro and Lathrop, Mark and Leys, Didier and Thijs, Vincent and Metso, Tiina M and Tatlisumak, Turgut and Pezzini, Alessandro and Parati, Eugenio A and Norrving, Bo and Bevan, Steve and Rothwell, Peter M and Sudlow, Cathie and Slowik, Agnieszka and Lindgren, Arne and Walters, Matthew R and Jannes, Jim and Shen, Jess and Crosslin, David and Doheny, Kimberly and Laurie, Cathy C and Kanse, Sandip M and Bis, Joshua C and Fornage, Myriam and Mosley, Thomas H and Hopewell, Jemma C and Strauch, Konstantin and M{\"u}ller-Nurasyid, Martina and Gieger, Christian and Waldenberger, Melanie and Peters, Annette and Meisinger, Christine and Ikram, M Arfan and Longstreth, W T and Meschia, James F and Seshadri, Sudha and Sharma, Pankaj and Worrall, Bradford and Jern, Christina and Levi, Christopher and Dichgans, Martin and Boncoraglio, Giorgio B and Markus, Hugh S and Debette, Stephanie and Rolfs, Arndt and Saleheen, Danish and Mitchell, Braxton D} } @article {6933, title = {Physical Activity and Risk of Coronary Heart Disease and Stroke in Older Adults: The Cardiovascular Health Study.}, journal = {Circulation}, volume = {133}, year = {2016}, month = {2016 Jan 12}, pages = {147-55}, abstract = {

BACKGROUND: Although guidelines suggest that older adults engage in regular physical activity (PA) to reduce cardiovascular disease (CVD), surprisingly few studies have evaluated this relationship, especially in those >75 years. In addition, with advancing age the ability to perform some types of PA might decrease, making light-moderate exercise such as walking especially important to meet recommendations.

METHODS AND RESULTS: Prospective cohort analysis among 4207 US men and women of a mean age of 73 years (standard deviation=6) who were free of CVD at baseline in the Cardiovascular Health Study were followed from 1989 to 1999. PA was assessed and cumulatively updated over time to minimize misclassification and assess the long-term effects of habitual activity. Walking (pace, blocks, combined walking score) was updated annually from baseline through 1999. Leisure-time activity and exercise intensity were updated at baseline, 1992, and 1996. Incident CVD (fatal or nonfatal myocardial infarction, coronary death, or stroke) was adjudicated using medical records. During 41,995 person-years of follow-up, 1182 CVD events occurred. After multivariable adjustment, greater PA was inversely associated with coronary heart disease, stroke (especially ischemic stroke), and total CVD, even in those >=75 years. Walking pace, distance, and overall walking score, leisure-time activity, and exercise intensity were each associated with lower risk. For example, in comparison with a walking pace <2 mph, those that habitually walked at a pace >3 mph had a lower risk of coronary heart disease (0.50; confidence interval, 0.38-0.67), stroke (0.47; confidence interval, 033-0.66), and CVD (0.50; confidence interval, 0.40-0.62).

CONCLUSIONS: These data provide empirical evidence supporting PA recommendations, in particular, walking, to reduce the incidence of CVD among older adults.

}, keywords = {Aged, Aged, 80 and over, Coronary Disease, Female, Follow-Up Studies, Health Status, Humans, Leisure Activities, Male, Motor Activity, Proportional Hazards Models, Prospective Studies, Sampling Studies, Stroke, United States, Walking}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.115.018323}, author = {Soares-Miranda, Luisa and Siscovick, David S and Psaty, Bruce M and Longstreth, W T and Mozaffarian, Dariush} } @article {6932, title = {Study of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study.}, journal = {Circulation}, volume = {133}, year = {2016}, month = {2016 Jan 12}, pages = {156-64}, abstract = {

BACKGROUND: Increasingly, the diagnostic codes from administrative claims data are being used as clinical outcomes.

METHODS AND RESULTS: Data from the Cardiovascular Health Study (CHS) were used to compare event rates and risk factor associations between adjudicated hospitalized cardiovascular events and claims-based methods of defining events. The outcomes of myocardial infarction (MI), stroke, and heart failure were defined in 3 ways: the CHS adjudicated event (CHS[adj]), selected International Classification of Diseases, Ninth Edition diagnostic codes only in the primary position for Medicare claims data from the Center for Medicare \& Medicaid Services (CMS[1st]), and the same selected diagnostic codes in any position (CMS[any]). Conventional claims-based methods of defining events had high positive predictive values but low sensitivities. For instance, the positive predictive value of International Classification of Diseases, Ninth Edition code 410.x1 for a new acute MI in the first position was 90.6\%, but this code identified only 53.8\% of incident MIs. The observed event rates for CMS[1st] were low. For MI, the incidence was 14.9 events per 1000 person-years for CHS[adj] MI, 8.6 for CMS[1st] MI, and 12.2 for CMS[any] MI. In general, cardiovascular disease risk factor associations were similar across the 3 methods of defining events. Indeed, traditional cardiovascular disease risk factors were also associated with all first hospitalizations not resulting from an MI.

CONCLUSIONS: The use of diagnostic codes from claims data as clinical events, especially when restricted to primary diagnoses, leads to an underestimation of event rates. Additionally, claims-based events data represent a composite end point that includes the outcome of interest and selected (misclassified) nonevent hospitalizations.

}, keywords = {Blood Glucose, Cardiovascular Diseases, Female, Follow-Up Studies, Health Surveys, Hospitalization, Hospitals, Veterans, Humans, Insurance Claim Review, International Classification of Diseases, Lipids, Male, Managed Care Programs, Medicare, Risk Factors, Sampling Studies, Treatment Outcome, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.115.018610}, author = {Psaty, Bruce M and Delaney, Joseph A and Arnold, Alice M and Curtis, Lesley H and Fitzpatrick, Annette L and Heckbert, Susan R and McKnight, Barbara and Ives, Diane and Gottdiener, John S and Kuller, Lewis H and Longstreth, W T} } @article {7466, title = {Blood Pressure and Heart Rate Measures Associated With Increased Risk of Covert Brain Infarction and Worsening Leukoaraiosis in Older Adults.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {37}, year = {2017}, month = {2017 Aug}, pages = {1579-1586}, abstract = {

OBJECTIVE: In people without previous stroke, covert findings on serial magnetic resonance imaging (MRI) of incident brain infarcts and worsening leukoaraiosis are associated with increased risk for ischemic stroke and dementia. We evaluated whether various measures of blood pressure (BP) and heart rate are associated with these MRI findings.

APPROACH AND RESULTS: In the CHS (Cardiovascular Health Study), a longitudinal cohort study of older adults, we used relative risk regression to assess the associations of mean, variability, and trend in systolic BP, diastolic BP, and heart rate measured at 4 annual clinic visits between 2 brain MRIs with incident covert brain infarction and worsening white matter grade (using a 10-point scale to characterize leukoaraiosis). We included participants who had both brain MRIs, no stroke before the follow-up MRI, and no change in antihypertensive medication status during follow-up. Among 878 eligible participants, incident covert brain infarction occurred in 15\% and worsening white matter grade in 27\%. Mean systolic BP was associated with increased risk for incident covert brain infarction (relative risk per 10 mm Hg, 1.28; 95\% confidence interval, 1.12-1.47), and mean diastolic BP was associated with increased risk for worsening white matter grade (relative risk per 10 mm Hg, 1.45; 95\% confidence interval, 1.24-1.69). These findings persisted in secondary and sensitivity analyses.

CONCLUSIONS: Elevated mean systolic BP is associated with increased risk for covert brain infarction, and elevated mean diastolic BP is associated with increased risk for worsening leukoaraiosis. These findings reinforce the importance of hypertension in the development of silent cerebrovascular diseases, but the pathophysiologic relationships to BP for each may differ.

}, keywords = {Age Factors, Aged, Antihypertensive Agents, Blood Pressure, Cerebral Infarction, Disease Progression, Female, Heart Rate, Humans, Hypertension, Incidence, Leukoaraiosis, Longitudinal Studies, Magnetic Resonance Imaging, Male, Prospective Studies, Pulsatile Flow, Risk Factors, Time Factors, United States}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.117.309298}, author = {Leung, Lester Y and Bartz, Traci M and Rice, Kenneth and Floyd, James and Psaty, Bruce and Gutierrez, Jose and Longstreth, W T and Mukamal, Kenneth J} } @article {7560, title = {Disability Trajectories Before and After Stroke and Myocardial Infarction: The Cardiovascular Health Study.}, journal = {JAMA Neurol}, volume = {74}, year = {2017}, month = {2017 Dec 01}, pages = {1439-1445}, abstract = {

Importance: Ischemic strokes may accelerate long-term functional decline apart from their acute effects on neurologic function.

Objective: To test whether the increase in long-term disability is steeper after than before the event for ischemic stroke but not myocardial infarction (MI).

Design, Settings, and Participants: In the population-based, prospective cohort Cardiovascular Health Study (1989-2013), longitudinal follow-up was conducted for a mean (SD) of 13 (6.2) years. Follow-up data were used until September 1, 2013; data analysis was performed from August 1, 2013, to June 1, 2016. Models based on generalized estimating equations adjusted for baseline covariates and included a test for different slopes of disability before and after the event. Participants included 5888 Medicare-eligible individuals 65 years or older who were not institutionalized, expected to reside in the area for 3 or more years, and able to provide informed consent. Exclusions were needing a wheelchair, receiving hospice care, and undergoing radiotherapy or chemotherapy.

Exposures: Ischemic stroke and MI.

Main Outcomes and Measures: Annual assessments with a disability scale (measuring activities of daily living [ADLs] and instrumental ADLs). The number of ADLs and instrumental ADLs (range, 0-12) that the participant could not perform was analyzed continuously.

Results: The mean (SD) age of the entire cohort (n = 5888) was 72.8 (5.6) years; 2495 (42.4\%) were male. During follow-up, 382 (6.5\%) participants had ischemic stroke and 395 (6.7\%) had MI with 1 or more disability assessment after the event. There was a mean of 3.7 (2.4) visits before stroke and 3.7 (2.3) visits after stroke; there was a mean of 3.8 (2.5) visits before MI and 3.8 (2.4) visits after MI. The increase in disability near the time of the event was greater for stroke (0.88 points on the disability scale; 95\% CI, 0.57 to 1.20; P < .001) than MI (0.20 points on the disability scale; 95\% CI, 0.06 to 0.35; P = .006). The annual increase in disability before stroke (0.06 points per year; 95\% CI, 0.002 to 0.12; P = .04) more than tripled after stroke (0.15 additional points per year; 95\% CI, 0.004 to 0.30; P = .04). The annual increase in disability before MI (0.04 points per year; 95\% CI, 0.004 to 0.08; P = .03) did not change significantly after MI (0.02 additional points per year; 95\% CI, -0.07 to 0.11; P = .69).

Conclusions and Relevance: In this large, population-based study, a trajectory of increasing disability became significantly steeper after stroke but not after MI. Thus, in addition to the acute brain injury and consequent impairment, ischemic stroke may also be associated with potentially treatable long-term adverse effects on the brain that lead to accelerated functional decline.

}, keywords = {Activities of Daily Living, Aged, Brain Ischemia, Cohort Studies, Disabled Persons, Disease Progression, Female, Humans, Male, Myocardial Infarction, Prospective Studies, Stroke}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2017.2802}, author = {Dhamoon, Mandip S and Longstreth, W T and Bartz, Traci M and Kaplan, Robert C and Elkind, Mitchell S V} } @article {7490, title = {Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts.}, journal = {Stroke}, volume = {48}, year = {2017}, month = {2017 Oct}, pages = {2678-2685}, abstract = {

BACKGROUND AND PURPOSE: The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke.

METHODS: We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses{\textquoteright} Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta-analysis.

RESULTS: A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95\% confidence interval [CI], 0.58-0.92) and DHA (HR, 0.80; 95\% CI, 0.64-1.00) but not eicosapentaenoic acid (HR, 0.94; 95\% CI, 0.77-1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95\% CI, 0.34-0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95\% CI, 0.37-0.92). Findings in each individual cohort were consistent with pooled results.

CONCLUSIONS: In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid.

}, keywords = {Adult, Aged, Aged, 80 and over, Biomarkers, Brain Ischemia, Cardiovascular Diseases, Case-Control Studies, Cohort Studies, Fatty Acids, Omega-3, Female, Follow-Up Studies, Humans, Incidence, Intracranial Arteriosclerosis, Intracranial Embolism, Intracranial Thrombosis, Male, Middle Aged, Prospective Studies, Random Allocation, Risk Factors, Stroke, United States}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.117.018235}, author = {Saber, Hamidreza and Yakoob, Mohammad Yawar and Shi, Peilin and Longstreth, W T and Lemaitre, Rozenn N and Siscovick, David and Rexrode, Kathryn M and Willett, Walter C and Mozaffarian, Dariush} } @article {8632, title = {Coagulation factor VIII, white matter hyperintensities and cognitive function: Results from the Cardiovascular Health Study.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0242062}, abstract = {

OBJECTIVE: To investigate the relationship between high FVIII clotting activity (FVIII:C), MRI-defined white matter hyperintensities (WMH) and cognitive function over time.

METHODS: Data from the population-based Cardiovascular Health Study (n = 5,888, aged >=65) were used. FVIII:C was measured in blood samples taken at baseline. WMH burden was assessed on two cranial MRI scans taken roughly 5 years apart. Cognitive function was assessed annually using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST). We used ordinal logistic regression models adjusted for demographic and cardiovascular factors in cross-sectional and longitudinal WMH analyses, and adjusted linear regression and linear mixed models in the analyses of cognitive function.

RESULTS: After adjustment for confounding, higher levels of FVIII:C were not strongly associated with the burden of WMH on the initial MRI scan (OR>p75 = 1.20, 95\% CI 0.99-1.45; N = 2,735) nor with WMH burden worsening over time (OR>p75 = 1.18, 95\% CI 0.87-1.59; N = 1,527). High FVIII:C showed no strong association with cognitive scores cross-sectionally (3MSE>p75 β = -0.06, 95\%CI -0.45 to 0.32, N = 4,005; DSST>p75 β = -0.69, 95\%CI -1.52 to 0.13, N = 3,954) or over time (3MSE>p75 β = -0.07,95\% CI -0.58 to 0.44, N = 2,764; DSST>p75 β = -0.22, 95\% CI -0.97 to 0.53, N = 2,306) after confounding adjustment.

INTERPRETATION: The results from this cohort study of older adult participants indicate no strong relationships between higher FVIII:C levels and WMH burden or cognitive function in cross-sectional and longitudinal analyses.

}, keywords = {Aged, Blood Coagulation, Cognition, Cross-Sectional Studies, Factor VIII, Female, Humans, Logistic Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mental Status and Dementia Tests, Up-Regulation, White Matter}, issn = {1932-6203}, doi = {10.1371/journal.pone.0242062}, author = {Rohmann, Jessica L and Longstreth, W T and Cushman, Mary and Fitzpatrick, Annette L and Heckbert, Susan R and Rice, Kenneth and Rosendaal, Frits R and Sitlani, Colleen M and Psaty, Bruce M and Siegerink, Bob} } @article {9095, title = {Longitudinal Changes in Hearing and Visual Impairments and Risk of Dementia in Older Adults in the United States.}, journal = {JAMA Netw Open}, volume = {5}, year = {2022}, month = {2022 05 02}, pages = {e2210734}, abstract = {

Importance: Hearing and vision problems are individually associated with increased dementia risk, but the impact of having concurrent hearing and vision deficits, ie, dual sensory impairment (DSI), on risk of dementia, including its major subtypes Alzheimer disease (AD) and vascular dementia (VaD), is not well known.

Objective: To evaluate whether DSI is associated with incident dementia in older adults.

Design, Setting, and Participants: This prospective cohort study from the Cardiovascular Health Study (CHS) was conducted between 1992 and 1999, with as many as 8 years of follow-up. The multicenter, population-based sample was recruited from Medicare eligibility files in 4 US communities with academic medical centers. Of 5888 participants aged 65 years and older in CHS, 3602 underwent cranial magnetic resonance imaging and completed the modified Mini-Mental State Examination in 1992 to 1994 as part of the CHS Cognition Study. A total of 227 participants were excluded due to prevalent dementia, leaving a total of 3375 participants without dementia at study baseline. The study hypothesis was that DSI would be associated with increased risk of dementia compared with no sensory impairment. The association between the duration of DSI with risk of dementia was also evaluated. Data analysis was conducted from November 2019 to February 2020.

Exposures: Hearing and vision impairments were collected via self-report at baseline and as many as 5 follow-up visits.

Main Outcomes and Measures: All-cause dementia, AD, and VaD, classified by a multidisciplinary committee using standardized criteria.

Results: A total of 2927 participants with information on hearing and vision at all available study visits were included in the analysis (mean [SD] age, 74.6 [4.8] years; 1704 [58.2\%] women; 455 [15.5\%] African American or Black; 2472 [85.5\%] White). Compared with no sensory impairment, DSI was associated with increased risk of all-cause dementia (hazard ratio [HR], 2.60; 95\% CI, 1.66-2.06; P < .001), AD (HR, 3.67; 95\% CI, 2.04-6.60; P < .001) but not VaD (HR, 2.03; 95\% CI, 1.00-4.09; P = .05).

Conclusions and Relevance: In this cohort study, DSI was associated with increased risk of dementia, particularly AD. Evaluation of hearing and vision in older adults may help to identify those at high risk of developing dementia.

}, keywords = {Aged, Alzheimer Disease, Cohort Studies, Female, Hearing, Hearing Loss, Humans, Male, Medicare, Prospective Studies, United States, Vision Disorders}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2022.10734}, author = {Hwang, Phillip H and Longstreth, W T and Thielke, Stephen M and Francis, Courtney E and Carone, Marco and Kuller, Lewis H and Fitzpatrick, Annette L} } @article {9291, title = {Association of Obesity With Cognitive Decline in Black and White Americans.}, journal = {Neurology}, volume = {100}, year = {2023}, month = {2023 Jan 10}, pages = {e220-e231}, abstract = {

BACKGROUND AND OBJECTIVES: There are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts.

METHODS: We pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55\% female, 24\% Black, and 29\% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant{\textquoteright}s first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15).

RESULTS: Obese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, -0.36 [95\% CI, -0.46 to -0.17]; < 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, -0.19 [95\% CI, -0.39 to 0.002]; = 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95\% CI, -0.009 to 0.03]; = 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95\% CI, 0.01 to 0.05]; < 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline ( = 0.34).

DISCUSSION: These results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.

}, keywords = {Aged, Black or African American, Cognition, Cognitive Dysfunction, Female, Humans, Male, Middle Aged, Obesity, Risk Factors, United States, White}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000201367}, author = {Quaye, Emmanuel and Galecki, Andrzej T and Tilton, Nicholas and Whitney, Rachael and Brice{\~n}o, Emily M and Elkind, Mitchell S V and Fitzpatrick, Annette L and Gottesman, Rebecca F and Griswold, Michael and Gross, Alden L and Heckbert, Susan R and Hughes, Timothy M and Longstreth, W T and Sacco, Ralph L and Sidney, Stephen and Windham, B Gwen and Yaffe, Kristine and Levine, Deborah A} } @article {9451, title = {Plasma Trimethylamine--Oxide and Incident Ischemic Stroke: The Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis.}, journal = {J Am Heart Assoc}, volume = {12}, year = {2023}, month = {2023 Aug 15}, pages = {e8711}, abstract = {

Background The association of circulating trimethylamine--oxide (TMAO) with stroke has received limited attention. To address this gap, we examined the associations of serial measures of plasma TMAO with incident ischemic stroke. Methods and Results We used a prospective cohort design with data pooled from 2 cohorts. The settings were the CHS (Cardiovascular Health Study), a cohort of older adults, and the MESA (Multi-Ethnic Study of Atherosclerosis), both in the United States. We measured plasma concentrations of TMAO at baseline and again during the follow-up using high-performance liquid chromatography and mass spectrometry. We assessed the association of plasma TMAO with incident ischemic stroke using proportional hazards regression adjusted for risk factors. The combined cohorts included 11 785 participants without a history of stroke, on average 73 (CHS) and 62 (MESA) years old at baseline, including 60\% (CHS) and 53\% (MESA) women. We identified 1031 total incident ischemic strokes during a median 15-year follow-up in the combined cohorts. In multivariable analyses, TMAO was significantly associated with incident ischemic stroke risk (hazard ratios comparing a doubling of TMAO: 1.11 [1.03-1.18], =0.004). The association was linear over the range of TMAO concentrations and appeared restricted to those without diagnosed coronary heart disease. An association with hemorrhagic stroke was not found. Conclusions Plasma TMAO levels are associated with incident ischemic stroke in a diverse population. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, keywords = {Aged, Atherosclerosis, Female, Humans, Ischemic Stroke, Methylamines, Oxides, Prospective Studies, Risk Factors, Stroke, United States}, issn = {2047-9980}, doi = {10.1161/JAHA.122.029230}, author = {Lemaitre, Rozenn N and Jensen, Paul N and Wang, Zeneng and Fretts, Amanda M and Sitlani, Colleen M and Nemet, Ina and Sotoodehnia, Nona and de Oliveira Otto, Marcia C and Zhu, Weifei and Budoff, Matt and Longstreth, W T and Psaty, Bruce M and Siscovick, David S and Hazen, Stanley L and Mozaffarian, Dariush} } @article {9972, title = {Cumulative Systolic Blood Pressure and Incident Stroke Type Variation by Race and Ethnicity.}, journal = {JAMA Netw Open}, volume = {7}, year = {2024}, month = {2024 May 01}, pages = {e248502}, abstract = {

IMPORTANCE: Stroke risk varies by systolic blood pressure (SBP), race, and ethnicity. The association between cumulative mean SBP and incident stroke type is unclear, and whether this association differs by race and ethnicity remains unknown.

OBJECTIVE: To examine the association between cumulative mean SBP and first incident stroke among 3 major stroke types-ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH)-and explore how these associations vary by race and ethnicity.

DESIGN, SETTING, AND PARTICIPANTS: Individual participant data from 6 US longitudinal cohorts (January 1, 1971, to December 31, 2019) were pooled. The analysis was performed from January 1, 2022, to January 2, 2024. The median follow-up was 21.6 (IQR, 13.6-31.8) years.

EXPOSURE: Time-dependent cumulative mean SBP.

MAIN OUTCOMES AND MEASURES: The primary outcome was time from baseline visit to first incident stroke. Secondary outcomes consisted of time to first incident IS, ICH, and SAH.

RESULTS: Among 40 016 participants, 38 167 who were 18 years or older at baseline with no history of stroke and at least 1 SBP measurement before the first incident stroke were included in the analysis. Of these, 54.0\% were women; 25.0\% were Black, 8.9\% were Hispanic of any race, and 66.2\% were White. The mean (SD) age at baseline was 53.4 (17.0) years and the mean (SD) SBP at baseline was 136.9 (20.4) mm Hg. A 10-mm Hg higher cumulative mean SBP was associated with a higher risk of overall stroke (hazard ratio [HR], 1.20 [95\% CI, 1.18-1.23]), IS (HR, 1.20 [95\% CI, 1.17-1.22]), and ICH (HR, 1.31 [95\% CI, 1.25-1.38]) but not SAH (HR, 1.13 [95\% CI, 0.99-1.29]; P = .06). Compared with White participants, Black participants had a higher risk of IS (HR, 1.20 [95\% CI, 1.09-1.33]) and ICH (HR, 1.67 [95\% CI, 1.30-2.13]) and Hispanic participants of any race had a higher risk of SAH (HR, 3.81 [95\% CI, 1.29-11.22]). There was no consistent evidence that race and ethnicity modified the association of cumulative mean SBP with first incident stroke and stroke type.

CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that cumulative mean SBP was associated with incident stroke type, but the associations did not differ by race and ethnicity. Culturally informed stroke prevention programs should address modifiable risk factors such as SBP along with social determinants of health and structural inequities in society.

}, keywords = {Adult, Aged, Black or African American, Blood Pressure, Cerebral Hemorrhage, Ethnicity, Female, Hispanic or Latino, Humans, Hypertension, Incidence, Ischemic Stroke, Longitudinal Studies, Male, Middle Aged, Racial Groups, Risk Factors, Stroke, Subarachnoid Hemorrhage, United States, White, White People}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2024.8502}, author = {Johnson, Kimson E and Li, Hanyu and Zhang, Min and Springer, Mellanie V and Galecki, Andrzej T and Whitney, Rachael T and Gottesman, Rebecca F and Hayward, Rodney A and Sidney, Stephen and Elkind, Mitchell S V and Longstreth, W T and Heckbert, Susan R and Gerber, Yariv and Sullivan, Kevin J and Levine, Deborah A} } @article {9706, title = {Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia.}, journal = {JAMA Netw Open}, volume = {7}, year = {2024}, month = {2024 May 01}, pages = {e2412824}, abstract = {

IMPORTANCE: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain.

OBJECTIVE: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases.

DESIGN, SETTING, AND PARTICIPANTS: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022.

EXPOSURES: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations.

MAIN OUTCOMES AND MEASURES: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses.

RESULTS: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9\% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95\% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95\% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4\% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95\% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95\% CI, 1.03-1.06; P = 1.9 {\texttimes} 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke.

CONCLUSIONS: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Blood Pressure, Cerebral Small Vessel Diseases, Dementia, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Prospective Studies, Risk Factors, Stroke}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2024.12824}, author = {Sargurupremraj, Muralidharan and Soumar{\'e}, A{\"\i}cha and Bis, Joshua C and Surakka, Ida and J{\"u}rgenson, Tuuli and Joly, Pierre and Knol, Maria J and Wang, Ruiqi and Yang, Qiong and Satizabal, Claudia L and Gudjonsson, Alexander and Mishra, Aniket and Bouteloup, Vincent and Phuah, Chia-Ling and van Duijn, Cornelia M and Cruchaga, Carlos and Dufouil, Carole and Chene, Genevi{\`e}ve and Lopez, Oscar L and Psaty, Bruce M and Tzourio, Christophe and Amouyel, Philippe and Adams, Hieab H and Jacqmin-Gadda, H{\'e}l{\`e}ne and Ikram, Mohammad Arfan and Gudnason, Vilmundur and Milani, Lili and Winsvold, Bendik S and Hveem, Kristian and Matthews, Paul M and Longstreth, W T and Seshadri, Sudha and Launer, Lenore J and Debette, Stephanie} } @article {9982, title = {Albuminuria, structural brain findings and Circulating biomarkers of brain injury in older adults.}, journal = {Sci Rep}, volume = {15}, year = {2025}, month = {2025 Jul 01}, pages = {22172}, abstract = {

Albuminuria reflects systemic endothelial dysfunction, but its relationships with subclinical brain abnormalities have not been comprehensively catalogued. The Cardiovascular Health Study recruited older adults from four US communities, beginning in 1989-1990. Systematic measurements of albuminuria were performed in 1996-1997; two brain MRIs, in 1992-1994 and 1997-1999; and serum neurofilament light chain (NfL) measurements from 1996-1997 stored samples. We examined the associations of albuminuria with longitudinal progression of white matter hyperintensities (WMH) and ventricular size, incident infarcts, and cross-sectional quantitative brain volumes and circulating biomarkers of neuronal injury (n = 834-1950). Albuminuria was positively associated with ventricular grade worsening (odds ratio per doubling 1.10, 95\% confidence interval (CI) 1.01-1.19) and with circulating NfL levels (2\% higher per doubling, 95\% CI 1-4\%), even after adjustment for vascular risk factors. Albuminuria was also associated with worsening of WMH, incident infarcts, and quantitative WMH and hippocampal volumes, but these latter associations appeared to reflect burden of cardiovascular risk factors. Albuminuria is independently associated with worsening ventricular size and circulating NfL, suggesting a specific role of microvascular dysfunction in brain atrophy. It also reflects cardiovascular risk factor burden on markers of vascular brain injury. These results highlight the diverse associations of albuminuria with common brain abnormalities of aging.

}, keywords = {Aged, Aged, 80 and over, Albuminuria, Biomarkers, Brain, Brain Injuries, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Neurofilament Proteins, Risk Factors, White Matter}, issn = {2045-2322}, doi = {10.1038/s41598-025-06448-1}, author = {Horn, Jens W and Fohner, Alison and Tracy, Russell and Adams, Hieab H H and Djouss{\'e}, Luc and Romundstad, Solfrid and Janszky, Imre and Longstreth, W T and Mukamal, Kenneth J} } @article {9913, title = {Circulating non-esterified fatty acids, risk of dementia and cognitive decline: The cardiovascular health study and multi-ethnic study of atherosclerosis.}, journal = {Neurobiol Aging}, volume = {148}, year = {2025}, month = {2025 Apr}, pages = {71-79}, abstract = {

Circulating non-esterified fatty acids (NEFAs) have toxic effects on a variety of organs central to cardiometabolic disease and can cross the blood-brain barrier. Whether NEFAs associate with cognitive decline or dementia remains unknown. Circulating total NEFA levels were measured in 3242 participants without dementia among older adults of the Cardiovascular Health Study (CHS) and related to adjudicated dementia over 6 years (n = 456 cases) and annually assessed cognitive decline. For confirmation, we related circulating NEFAs to cognition assessed 10 years later among 4361 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). In CHS participants, each SD higher NEFA levels were associated with a hazard ratio (HR) for all-cause dementia of 1.11 (95 \% CI: 1.01; 1.22). Baseline NEFA levels were also associated with more rapid decline in cognition over 6 years of follow-up. In MESA, circulating NEFA measurements were associated with lower cognitive scores measured 10 years later.{\textquoteright}

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Cognition, Cognitive Dysfunction, Cohort Studies, Dementia, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Male, Middle Aged, Risk, Risk Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2025.01.009}, author = {Moseholm, Kristine F and Jensen, Majken K and B{\r u}zkov{\'a}, Petra and Aroner, Sarah A and Fitzpatrick, Annette L and Longstreth, W T and Lopez, Oscar and Siscovick, David S and Kizer, Jorge R and Ix, Joachim H and Hughes, Timothy M and Hayden, Kathleen M and Nomura, Sarah and Tsai, Michael Y and McClelland, Robyn and Djouss{\'e}, Luc and Mukamal, Kenneth J} } @article {9898, title = {Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.}, journal = {Genome Med}, volume = {17}, year = {2025}, month = {2025 Mar 21}, pages = {27}, abstract = {

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595).

RESULTS: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15\% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95\% confidence interval [CI]: 0.54-0.81, p = 6.1 {\texttimes} 10) and coronary artery disease (OR: 0.74, 95\%CI: 0.63-0.87, p = 2.9 {\texttimes} 10) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.

CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

}, keywords = {Aged, Cardiovascular Diseases, Chemokine CCL2, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Monocytes, Receptors, CCR2}, issn = {1756-994X}, doi = {10.1186/s13073-025-01456-2}, author = {Georgakis, Marios K and Malik, Rainer and Bounkari, Omar El and Hasbani, Natalie R and Li, Jiang and Huffman, Jennifer E and Shakt, Gabrielle and Tack, Reinier W P and Kimball, Tamara N and Asare, Yaw and Morrison, Alanna C and Tsao, Noah L and Judy, Renae and Mitchell, Braxton D and Xu, Huichun and Montasser, May E and Do, Ron and Kenny, Eimear E and Loos, Ruth J F and Terry, James G and Carr, John Jeffrey and Bis, Joshua C and Psaty, Bruce M and Longstreth, W T and Young, Kendra A and Lutz, Sharon M and Cho, Michael H and Broome, Jai and Khan, Alyna T and Wang, Fei Fei and Heard-Costa, Nancy and Seshadri, Sudha and Vasan, Ramachandran S and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Yanek, Lisa R and Kral, Brian G and Becker, Lewis C and Peyser, Patricia A and Bielak, Lawrence F and Ammous, Farah and Carson, April P and Hall, Michael E and Raffield, Laura M and Rich, Stephen S and Post, Wendy S and Tracy, Russel P and Taylor, Kent D and Guo, Xiuqing and Mahaney, Michael C and Curran, Joanne E and Blangero, John and Clarke, Shoa L and Haessler, Jeffrey W and Hu, Yao and Assimes, Themistocles L and Kooperberg, Charles and Bernhagen, J{\"u}rgen and Anderson, Christopher D and Damrauer, Scott M and Zand, Ramin and Rotter, Jerome I and de Vries, Paul S and Dichgans, Martin} } @article {9940, title = {Selected social and lifestyle correlates of brain health markers: the Cross-Cohort Collaboration Consortium.}, journal = {Alzheimers Dement}, volume = {21}, year = {2025}, month = {2025 Apr}, pages = {e70148}, abstract = {

INTRODUCTION: To investigate the associations of education level, marital status, and physical activity with dementia risk and brain MRI markers.

METHODS: Data from six community-based samples from the Cross-Cohort Collaboration Consortium were analyzed. Self-reported education level, marital status, and physical activity at age 60 to 75 years were harmonized. Subsamples of participants with brain MRI markers at time of exposure were selected. Associations with dementia risk and cross-sectional MRI markers were meta-analyzed.

RESULTS: Higher education level was associated with lower dementia risk (hazard ratio [HR]~=~0.65, 95\% confidence interval [CI]~=~0.59; 0.72~vs low level) but not significantly with brain MRI markers. Compared with being unmarried, being married was only associated with higher total brain and hippocampal volumes. Being physically active was associated with lower dementia risk (HR~=~0.73, 95\% CI~=~0.52; 1.04), as well as larger total brain volume and smaller white matter hyperintensity volume.

DISCUSSION: This study provides further evidence regarding the contribution of education level and physical activity to dementia resilience.

HIGHLIGHTS: Education level, marital status, and physical activity are thought to contribute to resilience against ADRD. We used random-effects meta-analysis to summarize results from six community-based samples from the CCC. In this cross-cohort meta-analysis, higher education level and being physically active were associated with lower risk of dementia. In cross-sectional analyses, being married was associated with larger TBV and HV, while being physically active was associated with larger TBV and lower WMHV.

}, keywords = {Aged, Brain, Cohort Studies, Cross-Sectional Studies, Dementia, Educational Status, Exercise, Female, Humans, Life Style, Magnetic Resonance Imaging, Male, Marital Status, Middle Aged, Risk Factors}, issn = {1552-5279}, doi = {10.1002/alz.70148}, author = {Grasset, Leslie and Bis, Joshua C and Frenzel, Stefan and Kojis, Daniel and Simino, Jeannette and Yaqub, Amber and Beiser, Alexa and Berr, Claudine and Bressler, Jan and B{\"u}low, Robin and DeCarli, Charles S and Fohner, Alison E and Harrington, Laura B and Helmer, Catherine and Ikram, M Arfan and Lemaitre, Rozenn N and Lopez, Oscar L and Longstreth, W T and Neitzel, Julia and Odden, Michelle C and Palta, Priya and Schmidt, Carsten O and Talluri, Rajesh and Vernooij, Meike W and V{\"o}lzke, Henry and Voortman, Trudy and Whalen, Quest and Wittfeld, Katharina and Grabe, Hans J and Mosley, Thomas H and Psaty, Bruce M and Wolters, Frank J and Seshadri, Sudha and Dufouil, Carole} }