Incidence of seizures following initial ischemic stroke in a community-based cohort: The Framingham Heart Study.

PURPOSE: We examined the incidence of seizures following ischemic stroke in a community-based sample. METHODS: All subjects with incident ischemic strokes in the Framingham Original and Offspring cohorts between 1982 and 2003 were identified and followed for up to 20 years to determine incidence of seizures. Seizure-type was based on the 2010 International League Against Epilepsy (ILAE) classification. Disability was stratified into mild/none, moderate and severe, based on post-stroke neurological deficit documentation according to the Framingham Heart Study (FHS) protocol and functional status was determined using the Barthel Index. RESULTS: An initial ischemic stroke occurred in 469 subjects in the cohort and seizures occurred in 25 (5.3%) of these subjects. Seizure incidence was similar in both large artery atherosclerosis (LAA) (6.8%) and cardio-embolic (CE) (6.2%) strokes. No seizures occurred following lacunar strokes. The predominant seizure type was focal seizure with or without evolution to bilateral convulsive seizure. One third of participants had seizures within the first 24h from stroke onset and half of all seizures occurred within the first 30days. On multivariate analysis, moderate and severe disability following stroke was associated with increased risk of incident seizure. CONCLUSIONS: Seizures occurred in approximately 5% of subjects after an ischemic stroke. One third of these seizures occurred in the first 24h after stroke and none followed lacunar strokes. Focal seizures with or without evolution in bilateral convulsive seizures were the most common seizure type. Moderate and severe disability was predictive of incident seizures.

Revised Framingham Stroke Risk Profile to Reflect Temporal Trends.

BACKGROUND: Age-adjusted stroke incidence has decreased over the past 50 years, likely as a result of changes in the prevalence and impact of various stroke risk factors. An updated version of the Framingham Stroke Risk Profile (FSRP) might better predict current risks in the FHS (Framingham Heart Study) and other cohorts. We compared the accuracy of the standard (old) and of a revised (new) version of the FSRP in predicting the risk of all-stroke and ischemic stroke and validated this new FSRP in 2 external cohorts, the 3C (3 Cities) and REGARDS (Reasons for Geographic and Racial Differences in Stroke) studies. METHODS: We computed the old FSRP as originally described and a new model that used the most recent epoch-specific risk factor prevalence and hazard ratios for individuals ≥55 years of age and for the subsample ≥65 years of age (to match the age range in REGARDS and 3C studies, respectively) and compared the efficacy of these models in predicting 5- and 10-year stroke risks. RESULTS: The new FSRP was a better predictor of current stroke risks in all 3 samples than the old FSRP (calibration χ2 of new/old FSRP: in men: 64.0/12.1, 59.4/30.6, and 20.7/12.5; in women: 42.5/4.1, 115.4/90.3, and 9.8/6.5 in FHS, REGARDS, and 3C, respectively). In the REGARDS, the new FSRP was a better predictor among whites compared with blacks. CONCLUSIONS: A more contemporaneous, new FSRP better predicts current risks in 3 large community samples and could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors.

Association of Physical Function with Clinical and Subclinical Brain Disease: The Framingham Offspring Study.

BACKGROUND: Handgrip strength and gait speed are simple measures of physical capability and have been associated with current and future health outcomes. However, studies on their associations with brain structure and function in middle-aged adults are lacking. OBJECTIVE: To assess the relationship of fast-paced walking speed and handgrip strength with risk of dementia, Alzheimer's disease (AD), and stroke, as well as the cross-sectional associations with cognitive and brain magnetic resonance imaging (MRI) measures in a middle-aged community sample. METHODS: Framingham Offspring (n = 2,176; mean age 62, 54% female) had physical function, brain MRI, and cognitive evaluations between 1999 and 2005 and were followed-up for incident dementia AD and stroke until 11 years later. We related walking speed and handgrip strength to incident dementia, AD, and stroke using Cox models, and to brain and cognitive measures using multivariable linear and logistic regression. Models were adjusted for age, sex, education, and vascular risk factors. RESULTS: Slow walking and weak handgrip were associated with more than 2.5-fold increase in risk of AD. Weaker handgrip was associated with an increased risk of incident stroke (HR 1.74, 95% CI: 1.12-2.70/SDU, p = 0.01) in persons ≥65 years. Both measures were associated with lower total brain volume and poorer performance on tests of visual memory, language, executive function, and visuoperceptual function. Slower gait was also related to poorer verbal memory, and weaker handgrip to poorer abstraction. CONCLUSION: Tests of walking speed and handgrip strength may serve as clinical markers of brain structure and function and may improve dementia risk prediction.

Validation of secondary data sources to identify Parkinson disease against clinical diagnostic criteria.

Parkinson disease (PD) is the second most common neurodegenerative disorder. Its diagnosis relies solely on a clinical examination and is not straightforward because no diagnostic test exists. Large, population-based, prospective cohort studies designed to examine other outcomes that are more common than PD might provide cost-efficient alternatives for studying the disease. However, most cohort studies have not implemented rigorous systematic screening for PD. A majority of epidemiologic studies that utilize population-based prospective designs rely on secondary data sources to identify PD cases. Direct validation of these secondary sources against clinical diagnostic criteria is lacking. The Framingham Heart Study has prospectively screened and evaluated participants for PD based on clinical diagnostic criteria. We assessed the predictive value of secondary sources for PD identification relative to clinical diagnostic criteria in the Framingham Heart Study (2001-2012). We found positive predictive values of 1.0 (95% confidence interval: 0.868, 1.0), 1.0 (95% confidence interval: 0.839, 1.0), and 0.50 (95% confidence interval: 0.307, 0.694) for PD identified from self-report, use of antiparkinsonian medications, and Medicare claims, respectively. The negative predictive values were all higher than 0.99. Our results highlight the limitations of using only Medicare claims data and suggest that population-based cohorts may be utilized for the study of PD determined via self-report or medication inventories while preserving a high degree of confidence in the validity of PD case identification.

Lipid and lipoprotein measurements and the risk of ischemic vascular events: Framingham Study.

OBJECTIVES: To examine the relationship between plasma lipid measurements and incident ischemic vascular events (ischemic stroke [IS], and as a positive control, myocardial infarction [MI]) in a community cohort. METHODS: In 6,276 stroke-free Framingham participants (aged 64 ± 10 years, 56% female), we related plasma lipid levels (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], and TC/HDL-C ratio) measured at the original cohort 15th (1977-1979) and 20th examination cycles (1986-1990) and (TC, HDL-C, TC/HDL-C ratio, triglycerides [TG], and low-density lipoprotein cholesterol [LDL-C]) measured at the offspring fourth examination (1995-1998), to 10-year risk of incident IS and MI. Utilizing genome-wide genotyping in the same subjects, we used mendelian randomization methods to assess whether observed associations were incidental or causal. RESULTS: During a mean follow-up of 9 years, 301 participants experienced incident IS. In multivariable-adjusted analyses, HDL-C ≤40 mg/dL and TC/HDL ratio ≥5 were associated with increased risk of IS (hazard ratio [95% confidence interval]: 1.59 [1.23-2.05], p < 0.001 and 1.47 [1.15-1.87], p < 0.001), but not TC or LDL-C. In adjusted analysis, a strong association between TG and IS was diminished. In the MI-free sample (n = 5,875, aged 64 ± 10 years, 58% female; 403 MI events), all lipid markers were associated with MI risk. A genetic risk score comprising 47 known determinants of circulating HDL-C was not associated with IS. CONCLUSIONS: In a middle-aged to elderly community sample, we observed that low HDL-C and high TC/HDL-C ratio, but not LDL-C or TG were associated with risk of incident IS. We observed the usual associations between lipids and risk of MI. Our findings suggest an important, but less likely causal, role of HDL-C over other lipid biomarkers for optimal stroke risk stratification.

Cognitive performance after stroke--the Framingham Heart Study.

BACKGROUND: Individuals with a high risk of stroke are also more prone to cognitive impairment perhaps because of concomitant vascular risk factors. In addition, clinical stroke increases the risk of subsequent dementia. Nevertheless, the relationship between clinical stroke and subsequent cognitive function in initially nondemented individuals remains less clear as most prior studies examined case series without controls. AIMS: To specify among nondemented individuals the cognitive domains affected by clinical stroke, independently of vascular risk factors and prestroke cognition. METHODS: One hundred thirty-two Framingham study participants (mean age = 77 ± 9 years, 54% women) with prospectively validated initial strokes, as well as age- and gender-matched controls, underwent identical cognitive evaluations ∼six-months after the stroke. Linear regression models were used to assess the differences in cognitive scores between stroke cases and controls adjusting for prestroke cognitive function as assessed by Mini-Mental State Examination scores, and with and without adjustment for vascular risk factors. RESULTS: Adjusting for prestroke cognition and vascular risk factors, persons with stroke had poorer cognitive function in the domains of immediate recall of logical and visual memories (ß = -1·27 ± 0·60, P = 0·035; ß = -1·03 ± 0·47, P = 0·028, respectively), verbal learning (paired associate test; ß = -1·31 ± 0·57, P = 0·023), language (Boston naming test; ß = -0·27 ± 0·08, P = 0·002), executive function (digit span backward; ß = -0·53 ± 0·21, P = 0·015), and visuospatial and motor skills (block design; ß = -3·02 ± 1·06, P = 0·005). CONCLUSIONS: Clinical stroke is associated with subsequent poorer performance in multiple cognitive domains. This association cannot be entirely explained by the individual's cognitive function prior to stroke or by concomitant vascular risk factor levels.

Evidence for stroke family caregiver and dyad interventions: a statement for healthcare professionals from the American Heart Association and American Stroke Association.

Stroke is a leading cause of severe, long-term disability. Most stroke survivors are cared for in the home by a family caregiver. Caregiver stress is a leading cause of stroke survivor institutionalization, which results in significant costs to the healthcare system. Stroke family caregiver and dyad intervention studies have reported a variety of outcomes. A critical analysis of 17 caregiver intervention studies and 15 caregiver/stroke survivor dyad intervention studies was conducted to provide evidence-based recommendations for the implementation and future design of stroke family caregiver and dyad interventions.

Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury: Framingham Study.

BACKGROUND AND PURPOSE: Brain-derived neurotrophic factor (BDNF), a major neurotrophin and vascular endothelial growth factor (VEGF) have a documented role in neurogenesis, angiogenesis, and neuronal survival. In animal experiments, they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample. METHODS: In 3440 Framingham Study participants (mean age, 65±11 years; 56% women) who were free of stroke/transient ischemic attack (TIA), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological tests available (n=1863 and 2104, respectively; mean age, 61±9 years, 55% women, in each), we related baseline BDNF and logVEGF to log-white matter hyperintensity volume on brain MRI, and to visuospatial memory and executive function tests. RESULTS: During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age, sex, and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (hazard ratio comparing BDNF Q1 versus Q2-Q4, 1.47; 95% confidence interval, 1.09-2.00; P=0.012 and hazard ratio/SD increase in logVEGF, 1.21; 95% confidence interval, 1.04-1.40; P=0.012). Persons with higher BDNF levels had less log-white matter hyperintensity volume (ß±SE=-0.05±0.02; P=0.025), and better visual memory (ß±SE=0.18±0.07; P=0.005). CONCLUSIONS: Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.

Transient global amnesia and neurological events: the framingham heart study.

BACKGROUND/OBJECTIVE: Transient global amnesia (TGA) is a temporary amnestic syndrome characterized by lack of other focal neurological deficits. Cerebrovascular disease, migraine and seizures have been suggested as underlying mechanisms. TGA may be a risk factor for cerebrovascular or other neurological events. We studied the relation of TGA, vascular risk factors, brain magnetic resonance imaging (MRI) indices of subclinical ischemia and neurological events in a community-based sample. DESIGN/SETTING: A total of 12 TGA cases were ascertained using standard criteria by experienced neurologists, and matched to 41 stroke- and seizure-free controls. Vascular risk factors, brain MRI findings, and subsequent cerebrovascular or seizure events were compared in cases and controls. PARTICIPANTS: Framingham Heart Study (FHS) original and offspring cohort participants were included. RESULTS: No significant differences between the groups were observed in the prevalence of vascular risk factors, or brain MRI measures. Few incident stroke/transient ischemic attacks (TIA) (one event among the cases and four in controls) or subsequent seizures occurred in either group. Head CT during the acute event (n = 11) and brain MRI (n = 7) were negative for acute abnormalities. Electroencephalograms (EEG) (n = 5) were negative for epileptiform activity. Extracranial vascular studies were negative for significant stenosis in all cases. CONCLUSION: In our community-based study TGA was not related to traditional vascular risk factors, or cerebrovascular disease. However, our study is limited by small sample size and power, and larger studies are required to exclude an association.

A genome-wide association study of depressive symptoms.

BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

Multiple biomarkers and risk of clinical and subclinical vascular brain injury: the Framingham Offspring Study.

BACKGROUND: Several biomarkers have been individually associated with vascular brain injury, but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/transient ischemic attack and the prevalence of subclinical brain injury. METHODS AND RESULTS: In 3127 stroke-free Framingham offspring (age, 59±10 years; 54% female), we related a panel of 8 biomarkers assessing inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function (homocysteine and urinary albumin/creatinine ratio) measured at the sixth examination (1995-1998) to risk of incident stroke/transient ischemic attack. In a subset of 1901 participants with available brain magnetic resonance imaging (1999-2005), we further related these biomarkers to total cerebral brain volume, covert brain infarcts, and large white-matter hyperintensity volume. During a median follow-up of 9.2 years, 130 participants experienced incident stroke/transient ischemic attack. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/transient ischemic attack and with total cerebral brain volume (P<0.05 for both) but not with covert brain infarcts or white-matter hyperintensity volume (P>0.05). In backward elimination analyses, higher log-B-type natriuretic peptide (hazard ratio, 1.39 per 1-SD increment; P=0.002) and log-urinary albumin/creatinine ratio (hazard ratio, 1.31 per 1-SD increment; P=0.004) were associated with increased risk of stroke/transient ischemic attack and improved risk prediction compared with the Framingham Stroke Risk Profile alone; when the <5%, 5% to 15%, or >15% 10-year risk category was used, the net reclassification index was 0.109 (P=0.037). Higher C-reactive protein (ß=-0.21 per 1-SD increment; P=0.008), D-dimer (ß=-0.18 per 1-SD increment; P=0.041), total homocysteine (ß=-0.21 per 1-SD increment; P=0.005), and urinary albumin/creatinine ratio (ß=-0.15 per 1-SD increment; P=0.042) were associated with lower total cerebral brain volume. CONCLUSION: In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.

Influence of age and health behaviors on stroke risk: lessons from longitudinal studies.

Stroke is a major cause of death and serious neurological disability in older adults in the United States today. The most effective means available for reducing the burden of stroke involves risk factor modification. Given the growing number of older adults at risk for stroke, it is increasingly important to identify health behaviors that can produce significant change. Ongoing longitudinal studies have identified several behavioral factors that have been shown to improve overall health and reduce the risk of stroke, including effective management of hypertension, cessation of cigarette smoking for those who smoke, and maintaining a healthy diet and active physical lifestyle. Because modification of risk factors remains a primary intervention for effective prevention of stroke, community-based studies that address and institute stroke prevention strategies have the best opportunity to reduce or postpone the devastating effect of stroke.

Health insurance and cardiovascular disease risk factors.

BACKGROUND: Compared with those with health insurance, the uninsured receive less care for chronic conditions, such as hypertension and diabetes, and experience higher mortality. METHODS: We investigated the relations of health insurance status to the prevalence, treatment, and control of major cardiovascular disease risk factors-hypertension and elevated low-density lipoprotein (LDL) cholesterol-among Framingham Heart Study (FHS) participants in gender-specific, age-adjusted analyses. Participants who attended the seventh Offspring cohort examination cycle (1998-2001) or the first Third Generation cohort examination cycle (2002-2005) were studied. RESULTS: Among 6098 participants, 3.8% were uninsured at the time of the FHS clinic examination and ages ranged from 19 to 64 years. The prevalence of hypertension and elevated LDL cholesterol was similar for the insured and uninsured; however, the proportion of those who obtained treatment and achieved control of these risk factors was lower among the uninsured. Uninsured men and women were less likely to be treated for hypertension with odds ratios for treatment of 0.19 (95% confidence interval [CI], 0.07-0.56) for men and 0.31 (95% CI, 0.12-0.79) for women. Among men, the uninsured were less likely to receive treatment or achieve control of elevated LDL cholesterol than the insured, with odds ratios of 0.12 (95% CI, 0.04-0.38) for treatment and 0.17 (95% CI, 0.05-0.56) for control. CONCLUSION: The treatment and control of hypertension and hypercholesterolemia are lower among uninsured adults. Increasing the proportion of insured individuals may be a means to improve the treatment and control of cardiovascular disease risk factors and to reduce health disparities.

Free testosterone levels are associated with mobility limitation and physical performance in community-dwelling men: the Framingham Offspring Study.

CONTEXT: Mobility limitation is associated with increased morbidity and mortality. The relationship between circulating testosterone and mobility limitation and physical performance is incompletely understood. OBJECTIVE: Our objective was to examine cross-sectional and prospective relations between baseline sex hormones and mobility limitations and physical performance in community-dwelling older men. DESIGN, SETTING, AND PARTICIPANTS: We conducted cross-sectional and longitudinal analyses of 1445 men (mean age 61.0 +/- 9.5 yr) who attended Framingham Offspring Study examinations 7 and 8 (mean 6.6 yr apart). Total testosterone (TT) was measured by liquid chromatography tandem mass spectrometry at examination 7. Cross-sectional and longitudinal analyses of mobility limitation and physical performance were performed with continuous (per SD) and dichotomized [low TT and free testosterone (FT) and high SHBG vs. normal] hormone levels. MAIN OUTCOME MEASURES: Self-reported mobility limitation, subjective health, usual walking speed, and grip strength were assessed at examinations 7 and 8. Short physical performance battery was performed at examination 7. RESULTS: Higher continuous FT was positively associated with short physical performance battery score (beta = 0.13; P = 0.008), usual walking speed (beta = 0.02; P = 0.048), and lower risk of poor subjective health [odds ratio (OR) = 0.72; P = 0.01]. In prospective analysis, 1 SD increase in baseline FT was associated with lower risk of developing mobility limitation (OR = 0.78; 95% confidence interval = 0.62-0.97) and progression of mobility limitation (OR = 0.75; 95% confidence interval = 0.60-0.93). Men with low baseline FT had 57% higher odds of reporting incident mobility limitation (P = 0.03) and 68% higher odds of worsening of mobility limitation (P = 0.007). CONCLUSIONS: Lower levels of baseline FT are associated with a greater risk of incident or worsening mobility limitation in community-dwelling older men. Whether this risk can be reduced with testosterone therapy needs to be determined by randomized trials.

Consent for genetic research in the Framingham Heart Study.

Extensive efforts have been aimed at understanding the genetic underpinnings of complex diseases that affect humans. Numerous genome-wide association studies have assessed the association of genes with human disease, including the Framingham Heart Study (FHS), which genotyped 550,000 SNPs in 9,000 participants. The success of such efforts requires high rates of consent by participants, which is dependent on ethical oversight, communications, and trust between research participants and investigators. To study this we calculated percentages of participants who consented to collection of DNA and to various uses of their genetic information in two FHS cohorts between 2002 and 2009. The data included rates of consent for providing a DNA sample, creating an immortalized cell line, conducting research on various genetic conditions including those that might be considered sensitive, and for notifying participants of clinically significant genetic findings were above 95%. Only with regard to granting permission to share DNA or genetic findings with for-profit companies was the consent rate below 95%. We concluded that the FHS has maintained high rates of retention and consent for genetic research that has provided the scientific freedom to establish collaborations and address a broad range of research questions. We speculate that our high rates of consent have been achieved by establishing frequent and open communications with participants that highlight extensive oversight procedures. Our approach to maintaining high consent rates via ethical oversight of genetic research and communication with study participants is summarized in this report and should be of help to other studies engaged in similar types of research. Published 2010 Wiley-Liss, Inc.

Parental occurrence of stroke and risk of stroke in their children: the Framingham study.

BACKGROUND: Data relating parental history of stroke to stroke risk in offspring remain surprisingly inconsistent, largely because of heterogeneity of study design and the absence of verified, as opposed to historical, data on parental stroke status. METHODS AND RESULTS: We determined whether prospectively verified parental occurrence of stroke increased incident stroke risk among offspring in a community-based sample by studying 3443 stroke-free Framingham offspring (53% female; mean age, 48+/-14 years) with verified parental stroke status (by 65 years of age) who attended the first, third, fifth, and/or seventh offspring examinations and were followed up for up to 8 years after each baseline examination. Over up to 11,029 such person-observation periods (77,534 person-years), we documented 106 parental strokes by 65 years of age and 128 offspring strokes (74 parental and 106 offspring strokes were ischemic). Using multivariable Cox models adjusted for age, sex, sibship, and baseline stroke risk factors, we observed that parental stroke, both all stroke generally and ischemic stroke specifically, was associated with an increased risk of incident stroke of the same type in the offspring (hazard ratio, 2.79; 95% confidence interval, 1.68 to 4.66; P<0.001 for all stroke; and hazard ratio, 3.15; 95% confidence interval, 1.69 to 5.88; P<0.001 for ischemic stroke). This was true for both maternal and paternal stroke. CONCLUSIONS: Documented parental stroke by 65 years of age was associated with a 3-fold increase in risk of offspring stroke. This increased risk persisted after adjustment for conventional stroke risk factors. Thus, verified parental stroke may serve as a clinically useful risk marker of an individual's propensity to stroke.

A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.

BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity. METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort. RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage. CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

Association of MRI markers of vascular brain injury with incident stroke, mild cognitive impairment, dementia, and mortality: the Framingham Offspring Study.

BACKGROUND AND PURPOSE: White matter hyperintensities and MRI-defined brain infarcts (BIs) have individually been related to stroke, dementia, and mortality in population-based studies, mainly in older people. Their significance in middle-aged community-dwelling persons and the relative importance of these associations remain unclear. We simultaneously assessed the relation of white matter hyperintensities and BI with incident stroke, mild cognitive impairment, dementia, and mortality in a middle-aged community-based cohort. METHODS: A total of 2229 Framingham Offspring Study participants aged 62+/-9 years underwent volumetric brain MRI and neuropsychological testing (1999 to 2005). Incident stroke, dementia, and mortality were prospectively ascertained and for 1694 participants in whom a second neuropsychological assessment was performed (2005 to 2007), incident mild cognitive impairment was evaluated. All outcomes were related to white matter hyperintensities volume (WMHV), age-specific extensive WMHV and BI adjusting for age and gender. RESULTS: Extensive WMHV and BI were associated with an increased risk of stroke (hazard ratio [HR]=2.28, 95% CI: 1.02 to 5.13; HR=2.84, 95% CI: 1.32 to 6.10). WMHV, extensive WMHV, and BI were associated with an increased risk of dementia (HR=2.22, 95% CI: 1.32 to 3.72; HR=3.97, 95% CI: 1.10 to 14.30; HR=6.12, 95% CI: 1.82 to 20.54) independently of vascular risk factors and interim stroke. WMHV and extensive WMHV were associated with incident amnestic mild cognitive impairment in participants aged > or = 60 years only (OR=2.47, 95% CI: 1.31 to 4.66 and OR=1.49, 95% CI: 1.14 to 1.97). WMHV and extensive WMHV were associated with an increased risk of death (HR=1.38, 95% CI: 1.13 to 1.69; HR=2.27, 95% CI: 1.41 to 3.65) independent of vascular risk factors and of interim stroke and dementia. CONCLUSIONS: In a large community-based sample of middle-aged adults, BI predicted an increased risk of stroke and dementia independent of vascular risk factors. White matter hyperintensities portended an increased risk of stroke, amnestic mild cognitive impairment, dementia, and death independent of vascular risk factors and interim vascular events.

Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.

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.