To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia.
Prospective cohort study.
Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985–1988) and were followed up prospectively for the development of AD and all-cause dementia.
Eight hundred forty (541 women, median age of 76 years) subjects participated in the study.
Main Outcome Measures
We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ε4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD.
Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00–1.66; P=.054) and AD (HR, 1.33; 95% CI, 1.00–1.76; P=.050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03–2.56; P=.04) and AD (HR, 1.87; 95% CI, 1.13–3.10; P=.01) as compared with those with values less than the median.
In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.
Previous studies have identified effects of age and vascular risk factors on brain injury in elderly individuals. We aimed to establish whether the effects of high blood pressure in the brain are evident as early as the fifth decade of life.
In an investigation of the third generation of the Framingham Heart Study, we approached all participants in 2009 to ask whether they would be willing to undergo MRI. Consenting patients underwent clinical assessment and cerebral MRI that included T1-weighted and diffusion tensor imaging to obtain estimates of fractional anisotropy, mean diffusivity, and grey-matter volumes. All images were coregistered to a common minimum deformation template for voxel-based linear regressions relating fractional anisotropy, mean diffusivity, and grey-matter volumes to age and systolic blood pressure, with adjustment for potential confounders.
579 (14·1%) of 4095 participants in the third-generation cohort (mean age 39·2 years, SD 8·4) underwent brain MRI between June, 2009 and June, 2010. Age was associated with decreased fractional anisotropy and increased mean diffusivity in almost all cerebral white-matter voxels. Age was also independently associated with reduced grey-matter volumes. Increased systolic blood pressure was linearly associated with decreased regional fractional anisotropy and increased mean diffusivity, especially in the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibres that project from the thalamus to the superior frontal gyrus. It was also strongly associated with reduced grey-matter volumes, particularly in Brodmann’s area 48 on the medial surface of the temporal lobe and Brodmann’s area 21 of the middle temporal gyrus.
Our results suggest that subtle vascular brain injury develops insidiously during life, with discernible effects even in young adults. These findings emphasise the need for early and optimum control of blood pressure.
National Institutes of Health and National Heart, Lung, and Blood Institute; National Institute on Aging; and National Institute of Neurological Disorders and Stroke.
Aging is associated with reductions in hippocampal volume (HV) that are accelerated by Alzheimer’s disease and vascular risk factors. Our genome-wide association study of dementia-free persons (n=9,232) identified 46 SNPs at four loci with p-values <4.0×10-7. Two additional samples (n=2,318) replicated associations at 12q24 within MSRB3/WIF1 (discovery + replication, rs17178006; p=5.3×10-11) and at 12q14 near HRK/FBXW8 (rs7294919; p=2.9×10-11). Remaining associations included one 2q24 SNP within DPP4 (rs6741949; p=2.9×10-7) and nine 9p33 SNPs within ASTN2 (rs7852872; p=1.0×10-7) that were also associated with HV (p<0.05) in a third younger, more heterogeneous sample (n=7,794). The ASTN2 SNP was also associated with decline in cognition in a largely independent sample (n=1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8), enzymes targeted by new diabetes medications (DPP4), and neuronal migration (ASTN2), indicating novel genetic influences that influence hippocampal size and possibly the risk of cognitive decline and dementia.
Heart failure is a risk factor for Alzheimer’s disease (AD) and cerebrovascular disease. In the absence of heart failure, we hypothesized that left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, would be associated with pre-clinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and AD in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1114 Framingham Heart Study Offspring Cohort participants free from clinical stroke or dementia (40–89 years, 67±9; 54% women). Neuropsychological and neuroimaging markers of brain aging were related to cardiac MRI-assessed LVEF. In multivariable-adjusted linear regressions, LVEF was not associated with any brain aging variable (p-values>0.15). However, LVEF quintile analyses yielded several U-shape associations. Compared to the referent (Q2–Q4), the lowest quintile (Q1) LVEF was associated with a lower mean cognitive performance, including Visual Reproduction Delayed Recall (β= −0.27, p<0.001) and Hooper Visual Organization Test (β= −0.27, p<0.001). Compared to the referent, the highest quintile (Q5) LVEF values also were associated with lower mean cognitive performances, including Logical Memory Delayed Recall (β= −0.18, p=0.03), Visual Reproduction Delayed Recall (β= −0.17, p=0.03), Trail Making Test Part B-Part A (β= −0.22, p=0.02) and Hooper Visual Organization Test (Q5 β= −0.20, p=0.02). Findings were similar when analyses were repeated excluding prevalent cardiovascular disease. In conclusion, although our observational cross-sectional data cannot establish causality, they suggest a non-linear association between LVEF and measures of accelerated cognitive aging.
The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer’s disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; N=806) and Cardiovascular Health Study (CHS; N=2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis =0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.
Heat-Shock Proteins; Alzheimer Disease; prefoldin; Genetic Association Studies
We hypothesized that inflammatory markers are cross-sectionally and longitudinally associated with neuropsychological indicators of early ischemia and Alzheimer's disease.
Framingham Offspring Study participants, free of clinical stroke or dementia (n = 1,878; 60 ± 9 years; 54% women), underwent neuropsychological assessment and ascertainment of 11 inflammatory markers. Follow-up neuropsychological assessments (6.3 ± 1.0 years) were conducted on 1,352 of the original 1,878 participants.
Multivariable linear regression related the inflammatory markers to cross-sectional performance and longitudinal change in neuropsychological performances. Secondary models included a twelfth factor, tumor necrosis factor-α (TNF-α), available on a subset of the sample (n = 1,393 cross-sectional; n = 1,213 longitudinal). Results suggest a few modest cross-sectional inflammatory and neuropsychological associations, particularly for tests assessing visual organization (C-reactive protein, p = 0.007), and a few modest relations between inflammatory markers and neuropsychological change, particularly for executive functioning (TNF-α, p = 0.004). Secondary analyses suggested that inflammatory markers were cross-sectionally (TNF-α, p = 0.004) related to reading performance.
Our findings are largely negative, but suggest that specific inflammatory markers may have limited associations with poorer cognition and reading performance among community-dwelling adults. Because of multiple testing concerns, our limited positive findings are offered as hypothesis generating and require replication in other studies.
Memory; Executive functioning; Inflammation; Cognition; WRAT-3 reading
Diabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer’s disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults.
RESEARCH DESIGN AND METHODS
Framingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998–2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C).
We observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007).
Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.
White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)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. WMH 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.
We performed a meta-analysis of genome-wide association studies (GWAS) 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.
We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs)in one locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (Pdiscovery= 4.0×10−9; Preplication =1.3×10−7; Pcombined =4.0×10−15). Other SNPs in this region also reaching genome-wide significance are rs9894383 (P=5.3×10−9), rs11869977 (P=5.7×10−9), rs936393 (P=6.8×10−9), rs3744017 (P=7.3×10−9), and rs1055129 (P=4.1×10−8). Variant alleles at these loci conferred a small increase in WMH burden (4–8% of the overall mean WMH burden in the sample).
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.
This article focuses on the effects of operational differences in case ascertainment on estimates of prevalence and incidence of cognitive impairment/dementia of the Alzheimer type. Experience and insights are discussed by investigators from the Framingham Heart Study, the East Boston Senior Health Project, the Chicago Health and Aging Project, the Mayo Clinic Study of Aging, the Baltimore Longitudinal Study of Aging, and the Aging, Demographics, and Memory Study. There is a general consensus that the single most important factor regulating prevalence estimates of Alzheimer’s disease (AD) is the severity of cognitive impairment used for case ascertainment. Studies that require a level of cognitive impairment in which persons are unable to provide self-care will have much lower estimates than studies aimed at identifying persons in the earliest stages of AD. There is limited autopsy data from the above-mentioned epidemiologic studies to address accuracy in the diagnosis of etiologic subtype, namely the specification of AD alone or in combination with other types of pathology. However, other community-based cohort studies show that many persons with mild cognitive impairment (MCI) meet pathologic criteria for AD, and a large minority of persons without dementia or MCI also meets pathologic criteria for AD, thereby suggesting that the number of persons who would benefit from an effective secondary prevention intervention is probably higher than the highest published prevalence estimates. Improved accuracy in the clinical diagnosis of AD is anticipated with the addition of molecular and structural biomarkers in the next generation of epidemiologic studies.
Alzheimer’s disease; Dementia; Mild cognitive impairment; Cognitive impairment not dementia; Diagnostic criteria; Population-based; Prevalence, Incidence
Magnetic resonance imaging (MRI) findings of large white matter hyperintensities (LWMH), decreased brain volume and silent cerebral infarcts (SCI) are subclinical indices of brain ischemia and aging. Although the pathophysiology of these findings remains uncertain, extracellular matrix (ECM) remodeling, a process regulated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), may be implicated.
We evaluated the cross-sectional relations of circulating MMP-9 and TIMP-1 to these MRI indices in 583 stroke and dementia-free, Framingham Offspring participants (mean age 57 years, 58% women). Using multivariable regression MMP-9 (detectable versus non-detectable) and TIMP-1 (modeled as sex-specific quartiles) were related to LWMH (>1 S.D. above age-specific mean; yes/no), SCI (yes/no) and total brain volume (ratio of parenchymal to intracranial volume, TCBVr).
Mean TCBVr was 0.78 (S.D. 0.03), 13% of subjects had LWMH and 12% had SCI. Detectable MMP-9 was associated with higher prevalence of LWMH (OR 2.09, 95%confidence interval (CI) 1.00–4.37), but not with TCBVr. TIMP-1 was associated with a high prevalence of LWMH (OR for Q4 versus Q1–3: 1.83, 95%CI 1.06–3.18) and with lower mean TCBVr (Q4 associated with 0.17 S.D. units lower value relative to Q1–3; p = 0.04). Neither biomarker was associated with SCI.
Our findings are preliminary but if confirmed in further studies, suggest a pathophysiological role for the MMP/TIMP pathway in processes of brain ischemia and aging.
MMPs; Brain MRI; Framingham; Brain aging
Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease (CVD), theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with pre-clinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer’s disease in the community.
Methods and Results
Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free from clinical stroke, transient ischemic attack, or dementia (61±9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent CVD were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post-hoc comparisons revealed that participants in the bottom cardiac index tertile (values<2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values>2.92).
Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.
brain; cardiac output; epidemiology; imaging; neuropsychology
Previous studies have demonstrated an association between white matter hyperintensities (WMH) and cognitive performance primarily in Caucasian samples, limiting generalizability to other ethnic and racial groups. This study investigated the association of WMH and cognition in an ethnic and racial minority cohort (Omni) of the Framingham Heart Study and compared these results to the Caucasian (Offspring) cohort.
Quantitative brain MRI and neuropsychological evaluations were performed on stroke- and dementia-free participants. Cognitive assessment included verbal memory, visuospatial memory and organization, language, and executive functioning. Linear regression models were conducted to assess the association between WMH and cognitive function.
The Omni group presented with demographic factors that significantly differed from those of the Offspring group: they were younger, but had more stroke risk factors such as hypertension. In the Offspring group, WMH volume was significantly associated with poorer performance on tests of executive function and visual organization. No significant associations between WMH and cognitive measures were found in the Omni group, but no differences (significant interaction terms) were seen between the regression coefficients.
The Omni cohort had greater variability in factors that may mediate the association of WMH and cognition. More research is needed to investigate how stroke risk factors impact on the occurrence of WMH and its association with cognition in more diverse cohorts.
White matter hyperintensities; Cognition; Executive function; Framingham Heart Study; Magnetic resonance imaging; Cultural/ethnic diversity
Midlife obesity has been associated with an increased risk of dementia. The underlying mechanisms are poorly understood. Our aim was to examine the cross-sectional association of body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR) and CT-based measures of subcutaneous (SAT) and visceral (VAT) adipose tissue with various MRI-markers of brain aging in middle-aged community adults.
Participants from the Framingham Offspring cohort were eligible if in addition to having measures of BMI, WC, WHR, SAT and VAT, they had undergone a volumetric brain MRI scan with measures of total brain volume (TCBV), temporal horn volume (THV), white matter hyperintensity volume (WMHV) and MRI-defined brain infarcts (BI). All analyses were adjusted for age, sex and time interval between abdominal CT and brain MRI.
In a sample of 733 community participants (mean age 60 years, 53% women), we observed an inverse association of BMI (estimate by standard deviation unit ± standard error =−0.27±0.12,p=0.02), WC (−0.30±0.12,p=0.01), WHR (−0.37±0.12,p=0.02), SAT (−0.23±0.11,p=0.04) and VAT (−0.36±0.12,p=0.002) with TCBV, independent of vascular risk factors. The association between VAT and TCBV was the strongest and most robust, and was also independent of BMI (−0.35±0.15,p=0.02) and insulin resistance (−0.32±0.13,p=0.01). When adjusting for C-reactive protein levels the associations were attenuated (−0.17±0.13,p=0.17 for VAT). No consistently significant association was observed between the anthropometric or CT-based abdominal fat measures and THV, WMHV or BI.
In middle-aged community participants we observed a significant inverse association of anthropometric and CT-based measures of abdominal, especially visceral, fat with total brain volume.
To determine if the presence of the apoE4 allele, a known risk factor for Alzheimer’s disease, interacts with cerebrovascular risk factors to produce a disproportionate impairment in neuropsychological performance and alterations in structural morphometry as measured by magnetic resonance imaging.
1,995 participants from the community based Framingham Offspring Cohort participants (mean age 61; 1,063 women) underwent neuropsychological testing and structural magnetic resonance imaging in 1999-2002.
Multivariate linear regression was used to estimate the relationships between Framingham Stroke Risk Profile scores, neuropsychological variables and magnetic resonance imaging measures; interaction terms were included to examine modification of these relationships by the presence of the apoE4 allele. All analyses were cross sectional.
We found significant interactions between the presence of the apoE4 allele and the top sex-specific quartile of the Stroke Risk Profile and their effects on verbal memory (p=<0.001), verbal organization (p=<0.001), non-verbal memory (p=0.015), as well as set shifting and complex attention (p=0.005). Systolic blood pressure was the only individual risk factor significantly linked to these cognitive measures. With the exception of lateral ventricular volume, there were no significant interactions between presence of apoE4, the top sex-specific quartile of the Stroke Risk Profile and any of the magnetic resonance imaging variables.
The apoE4 allele exacerbates the effects of cerebrovascular risk factors on neuropsychological function. This relationship appears to be driven by systolic blood pressure, suggesting that treatment of high systolic blood pressure could potentially reduce risk of cognitive impairment among those already at increased risk for Alzheimer’s disease.
Genome wide association studies (GWAS) have recently identified CLU, PICALM and CR1 as novel genes for late-onset Alzheimer’s disease (AD).
In a three-stage analysis of new and previously published GWAS on over 35000 persons (8371 AD cases), we sought to identify and strengthen additional loci associated with AD and confirm these in an independent sample. We also examined the contribution of recently identified genes to AD risk prediction.
Design, Setting, and Participants
We identified strong genetic associations (p<10−3) in a Stage 1 sample of 3006 AD cases and 14642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (1367 AD cases (973 incident)) with previously reported results from the Translational Genomics Research Institute (TGEN) and Mayo AD GWAS. We identified 2708 single nucleotide polymorphisms (SNPs) with p-values<10−3, and in Stage 2 pooled results for these SNPs with the European AD Initiative (2032 cases, 5328 controls) to identify ten loci with p-values<10−5. In Stage 3, we combined data for these ten loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases, 6995 controls) to identify four SNPs with a p-value<1.7×10−8. These four SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls).
Main outcome measure
We showed genome-wide significance for two new loci: rs744373 near BIN1 (OR:1.13; 95%CI:1.06–1.21 per copy of the minor allele; p=1.6×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR:1.18; 95%CI1.07–1.29; p=6.5×10−9). Associations of CLU, PICALM, BIN1 and EXOC3L2 with AD were confirmed in the Spanish sample (p<0.05). However, CLU and PICALM did not improve incident AD prediction beyond age, sex, and APOE (improvement in area under receiver-operating-characteristic curve <0.003).
Two novel genetic loci for AD are reported that for the first time reach genome-wide statistical significance; these findings were replicated in an independent population. Two recently reported associations were also confirmed, but these loci did not improve AD risk prediction, although they implicate biological pathways that may be useful targets for potential interventions.
genome-wide association study; genetic epidemiology; genetics; dementia; Alzheimer’s disease; cohort study; meta-analysis; risk
To examine whether there are sex-specific associations between brain MRI measures and neuropsychological test performance.
Differences in cardiovascular risk factors (CVRF) have been linked to decreased total cerebral brain volume (TCBV) and white matter hyperintensities (WMH). Although brain morphology has been related to cognitive performance, few studies have addressed sex-specific effects in this relationship.
Framingham Offspring who were stroke and dementia-free underwent a brain MRI scan and neuropsychological (NP) testing (n=2,085; 978 men). Factor analysis identified four domain-specific neuropsychological factors. MRI participants were divided into four MRI subgroups based on measures of TCBV and combinations of the presence of WMH and silent cerebral infarcts (≥3mm; SCI).
Overall, the relationship between MRI and NP measures was similar between the sexes. The exception was that only men showed a positive relationship between executive function (EF) and cerebrovascular disease defined as large white matter hyperintensity volume plus SCI. This finding was attributed only among men with FSRP scores > 90th percentile range (p=0.0019).
Measures of brain atrophy and subclinical markers of vascular disease showed that sex does not significantly alter the relationship between MRI and NP, except among men and women who are at high risk for stroke; these men show poorer performance on EF, whereas the women do not.
Sex; Brain MRI; Cognition; Neuropsychological tests
Data relating parental history of stroke to stroke risk in offspring remain surprisingly inconsistent, largely due to heterogeneity of study design, and the absence of verified, as opposed to historical, data on parental stroke status.
Methods and Results
We determined if 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 age 65 years), who attended the 1st, 3rd, 5th and/or 7th Offspring examinations, and were followed 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 age 65, and 128 offspring strokes (74 parental and 106 offspring strokes were ischemic). Using multivariable Cox models, adjusted for age-, sex-, sib-ship 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 (HR 2.79, 95% CI: 1.68–4.66; p<0.001 for all stroke, and HR 3.15, 95% CI: 1.69–5.88; p<0.001 for ischemic stroke). This was true for both maternal and paternal stroke.
Documented parental stroke by age 65 years was associated with a three-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.
stroke; ischemic stroke; heredity; familial aggregation
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.
Using 2.2 million genotyped and imputed SNPs, 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 ≥1 MRI-infarct.
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=4.64×10−7. Highly suggestive associations (p<1.0×10−5) were also found for 22 other SNPs in linkage disequilibrium (r2>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 African-American participants, although 4 SNPs within 200kb from rs2208454 were associated with MRI-infarcts in African-American sample.
This first community-based, genome-wide association study on covert MRI-infarcts uncovered novel associations. Although replication of the association with top SNP failed, possibly due to insufficient power, results in the African American sample are encouraging, and further efforts at replication are needed.
genome-wide association study; brain infarction; MRI; cohort study; meta-analysis
The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes β-amyloid clearance and improves memory function in animal models of aging and Alzheimer’s disease (AD).
To relate baseline circulating leptin concentrations in a dementia-free community-based sample prospectively to 1) incident dementia and AD during follow-up and 2) to MRI (magnetic resonance imaging) measures of brain aging in survivors.
Design, Setting and Participants
Plasma leptin concentrations were measured in 785 dementia-free persons (mean age 79 [SD, 5 yrs], 62% women) from the Framingham Original cohort at the 22nd examination cycle (1990–1994). A sub-sample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, the total cerebral brain volume (TCBV) and temporal horn volume (THV; inversely related to hippocampal volume) were assessed.
Main outcome measure
Incidence of dementia and AD during follow-up till December 31st, 2007.
During a median follow-up of 8.3 (range 0 to 15.5) years, 111 participants developed incident dementia, 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratios [HR] per one-SD increment in log-leptin were 0.68 [0.54–0.87] for all-cause dementia and 0.60 [0.46–0.79] for AD). This corresponds to an absolute AD risk over a 12 year follow-up of 25% for persons in the lowest quartile (Q1) versus 6% for persons in Q4 of sex-specific leptin levels. In addition, a one SD elevation in plasma leptin was associated with higher TCBV and lower THV, although the association of leptin with THV did not reach statistical significance.
Circulating leptin is directly related to indices of brain health in asymptomatic adults and inversely related to risk of incident dementia and AD. Our findings require confirmation in independent samples.
leptin; adipokines; dementia; Alzheimer’s disease
Background and purpose
Data on the association between alcohol consumption and ischemic stroke have been inconsistent. It is not known whether allele E4 of the apolipoprotein E (apoE) gene modifies the alcohol-stroke association. We sought to examine whether E4 allele of the apoE gene influences the association between alcohol consumption and ischemic stroke or high-density lipoprotein (HDL) cholesterol.
Cohort of 7,676 person-observations of the Framingham Heart Study. Incident stroke was ascertained by standardized methods. We used Cox proportional hazard model to estimate hazard ratios of ischemic stroke.
The average age at baseline was 63 years and 55% of the participants were women. During a mean follow up of 7.4 years, 222 new cases of ischemic stroke occurred (56 embolic and 166 atherothrombotic events). Comparing current drinkers with nondrinkers, multivariable adjusted hazard ratio (95% CI) for ischemic stroke were 0.50 (0.24–1.07) in the absence of E4 allele and 0.70 (0.24–2.05) in the presence of E4 allele (p for interaction 0.64) for subjects aged <65 years. Similarly, we did not observe a statistically significant interaction between E4 allele and alcohol consumption on the risk of stroke among people 65 years and older (p for interaction 0.17). Alcohol consumption was positively associated with HDL cholesterol independent of E4 allele and age.
Our data do not provide evidence for an interaction between E4 allele and alcohol consumption on the risk of ischemic stroke in this population. Furthermore, ApoE polymorphism did no influence the alcohol-HDL relation.
Alcohol drinking; ischemic stroke; apolipoprotein E gene; lipids
Background and Purpose
Asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, is a marker of endothelial dysfunction. Elevated circulating ADMA concentrations have been associated with systemic and carotid atherosclerosis, an elevated risk of developing stroke and with MRI white matter hyperintensities (WMH). The relation of plasma ADMA to subclinical vascular brain injury has not been previously studied in a middle-aged, community-based sample.
In 2013 stroke-free Framingham Offspring (mean age 58±9.5yrs, 53% women) we related baseline plasma ADMA levels (1995–98) to subsequent brain MRI (1999–2004) measures of subclinical vascular injury: presence of silent brain infarcts (SBI) and large white matter hyperintensity volume (LWMH; defined as >1SD above age-specific mean).
Prevalence of SBI and LWMH were 10.7% and 12.6%, respectively. In multivariable analyses adjusting for age-, sex- and traditional stroke risk factors, higher ADMA levels were associated with an increased risk of prevalent SBI (OR per SD increase in ADMA: 1.16, 95%CI: 1.01–1.33, p= 0.04).We observed that participants in the upper three age-specific quartiles of plasma ADMA had an increased prevalence of SBI (OR for Q2–4 versus Q1:1.43, 95%CI: 1.00–2.04, p<0.05). Prevalence of SBI in Q1and Q2–4 was 8.3% and 11.6%, respectively. Prevalence of LWMH did not differ according to ADMA concentrations.
Higher plasma ADMA was associated with increased prevalence of SBI after adjustment for traditional stroke risk factors. Thus, ADMA may be a potentially useful new biomarker of subclinical vascular brain injury, which is an important correlate of vascular cognitive impairment and risk of stroke.
ADMA; endothelial dysfunction; silent cerebral infarct
Heritability and genetic and environmental correlations of total and regional brain volumes were estimated from a large, generally healthy, community-based sample, to determine if there are common elements to the genetic influence of brain volumes and white matter hyperintensity volume. There were 1538 Framingham Heart Study participants with brain volume measures from quantitative magnetic resonance imaging (MRI) who were free of stroke and other neurological disorders that might influence brain volumes and who were members of families with at least two Framingham Heart Study participants. Heritability was estimated using variance component methodology and adjusting for the components of the Framingham stroke risk profile. Genetic and environmental correlations between traits were obtained from bivariate analysis. Heritability estimates ranging from 0.46 to 0.60, were observed for total brain, white matter hyperintensity, hippocampal, temporal lobe, and lateral ventricular volumes. Moderate, yet significant, heritability was observed for the other measures. Bivariate analyses demonstrated that relationships between brain volume measures, except for white matter hyperintensity, reflected both moderate to strong shared genetic and shared environmental influences. This study confirms strong genetic effects on brain and white matter hyperintensity volumes. These data extend current knowledge by showing that these two different types of MRI measures do not share underlying genetic or environmental influences.
heritability; quantitative MRI; brain volume; white matter hyperintensity
Background and Purpose
Carotid atherosclerosis has been associated with increased risk of stroke, and poorer cognitive performance in older adults. The relation of carotid atherosclerosis to cognitive impairment and MRI indices of ischemia and aging in midlife is less clear.
We studied 1,975 Framingham Offspring Study participants free of stroke and dementia with available carotid ultrasound, brain MRI and neuropsychological testing. We related common and internal carotid artery intima-media thickness (ICA-IMT and CCA-IMT respectively) and internal carotid stenosis (CAS) to large white matter hyperintensity (>1-SD above age-specific mean; LWMH), total brain volume (TCBV), hippocampal volume, silent cerebral infarcts (SCI) and neuropsychological measures of verbal memory, executive function and non-verbal memory measures.
We observed that ICA-IMT, but not CCA-IMT, was associated with higher prevalence of SCI (OR 1.21, 95% CI 1.03–1.43, p<0.05), LWMH (OR 1.19, 95% CI 1.03–1.38, p<0.05), lower TCBV (−0.05 per SD, p<0.05) and poorer performance in verbal memory (−0.06 per SD; p<0.05) and non-verbal memory measures (−0.08 per SD; p<0.01), but not with hippocampal volume. CAS ≥25% was associated with a higher prevalence of LWMH (adjusted OR 1.77, 95% CI 1.25–2.53) and lower TCBV (−0.11 per SD, p=0.042) but not with SCI or hippocampal volume. CAS ≥50% was associated with higher prevalence of SCI (OR 2.53, 95% CI 1.17 – 5.44), LWMH (OR 2.35, 95% CI 1.08–5.13) and poorer performance on executive function (−0.39 per SD; p<0.05) but not with TCBV or hippocampal volume.
Carotid atherosclerosis markers were associated with MRI indices of brain ischemia and aging and with cognitive impairment in a community-based sample of middle-aged adults. Our data suggest that ICA-IMT may be a better marker for cognitive impairment than CCA-IMT.
Carotid atherosclerosis; brain MRI; cognitive performance
The genes underlying the risk of stroke in the general population remain undetermined.
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.
Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5×10−8). 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.
A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.
Women have increased lifetime stroke risk and more disabling strokes compared with men. Insights into the association between menopause and stroke could lead to new prevention strategies for women. The objective of this study was to examine the association of age at natural menopause with ischemic stroke risk in the Framingham Heart Study.
Participants included women who survived stroke-free until age 60, experienced natural menopause, did not use estrogen prior to menopause, and who had complete data (n=1,430). Participants were followed until first ischemic stroke, death, or end of follow-up (2006). Age at natural menopause was self-reported. Cox proportional hazards models were used to examine the association between age at natural menopause (<42, 42-54, ≥55) and ischemic stroke risk adjusted for age, systolic blood pressure, atrial fibrillation, diabetes, current smoking, cardiovascular disease and estrogen use.
There were 234 ischemic strokes identified. Average age at menopause was 49 years (sd=4). Women with menopause at ages 42-54 (HR=0.50; 95% CI:0.29-0.89) and at ages ≥55 (HR=0.31; 95% CI:0.13-0.76) had lower stroke risk compared with those with menopause <42 years adjusted for covariates. Women with menopause before age 42 had twice the stroke risk compared to all other women (HR=2.03; 95% CI: 1.16-3.56).
In this prospective study, age at natural menopause before age 42 was associated with increased ischemic stroke risk. Future stroke studies with measures of endogenous hormones are needed to inform the underlying mechanisms so that novel prevention strategies for mid-life women can be considered.
Stroke; cerebrovascular disease; women; menopause; bone mineral density