Alexa Beiser

McMaster University, Hamilton, Ontario, Canada

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Publications (155)1503.46 Total impact

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    ABSTRACT: Analysis sought to determine whether Wechsler Memory Scale-Logical Memory (LM)-correct responses and errors were related to magnetic resonance imaging (MRI) brain volume measurements. The LM immediate (LM-I) and LM delay (LM-D) free recall correct responses and related and unrelated errors were scored. Principal components analysis yielded a 3-factor solution: LM-I and LM-D correct responses, LM-I and LM-D-unrelated errors, and LM-I/-D-related errors. The MRI total cerebral brain volume, frontal brain volume, temporal horn volume (THV), and white matter hyperintensities volume (WMHIV) were obtained. Increasing THV (suggesting greater regional atrophy) was associated with lower scores on the LM-correct responses factor. Extensive WMHIV was associated with higher scores on the LM-related errors factor. These results suggest that LM-correct responses could relate to emerging brain alterations. Longitudinal research might enhance the sensitivity of this test to identify preclinical impairment and persons at risk of mild cognitive impairment and dementia. © The Author(s) 2015.
    American Journal of Alzheimer s Disease and Other Dementias 03/2015; DOI:10.1177/1533317515577184 · 1.52 Impact Factor
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) is a pleiotropic peptide involved in maintaining endothelial integrity. It is unknown if circulating BDNF levels are associated with risk of cardiovascular disease (CVD). We prospectively investigated the association of circulating BDNF levels with cardiovascular events and mortality in 3687 participants (mean age 65 years, 2068 women) from the Framingham Heart Study (FHS). Using a common nonsynonomous single nucleotide polymorphism (SNP) in the BDNF gene (rs6265), we then performed a Mendelian randomization experiment in the CARDIoGRAM (Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis) consortium (>22 000 coronary artery disease [CAD] cases, >60 000 controls) to investigate whether SNP rs6265 was associated with CAD in CARDIoGRAM and, if so, whether the effect estimate differed from that predicted based on FHS data. On follow-up (median 8.9 years), 467 individuals (261 women) in FHS experienced a CVD event, and 835 (430 women) died. In multivariable-adjusted Cox regression, serum BDNF was associated inversely with CVD risk (hazard ratio [HR] per 1-SD increase 0.88, 95% CI 0.80 to 0.97, P=0.01) and with mortality (HR 0.87, 95% CI 0.80 to 0.93, P=0.0002). SNP rs6265 was associated with BDNF concentrations (0.772 ng/mL increase per minor allele copy) in FHS. In CARDIoGRAM, SNP rs6265 was associated with CAD (odds ratio 0.957, 95% CI 0.923 to 0.992), a magnitude consistent with the predicted effect (HR per minor allele copy 0.99, 95% CI 0.98 to 1.0; P=0.06 for difference between predicted and observed effect). Higher serum BDNF is associated with a decreased risk of CVD and mortality. Mendelian randomization suggests a causal protective role of BDNF in the pathogenesis of CVD. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
    Journal of the American Heart Association 02/2015; 4(3). DOI:10.1161/JAHA.114.001544
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    ABSTRACT: -Cross-sectional epidemiological and clinical research suggest lower cardiac index is associated with abnormal brain aging, including smaller brain volumes, increased white matter hyperintensities, and worse cognitive performances. Lower systemic blood flow may have implications for dementia among older adults. -1039 Framingham Offspring Cohort participants free from clinical stroke, transient ischemic attack, or dementia formed our sample (69±6 years; 53% women). Multivariable-adjusted proportional hazard models adjusting for Framingham Stroke Risk Profile score (age, sex, systolic blood pressure, anti-hypertensive medication, diabetes, cigarette smoking, cardiovascular disease [CVD] history, atrial fibrillation), education, and apolipoprotein E4 status related cardiac MRI-assessed cardiac index (cardiac output/body surface area) to incident all-cause dementia and Alzheimer's disease (AD). Over the median 7.7 year follow-up period, 32 participants developed dementia, including 26 cases of AD. Each one standard deviation unit decrease in cardiac index increased the relative risk of both dementia (HR=1.66; 95% confidence intervals [CI], 1.11-2.47; p=0.013) and AD (HR=1.65; 95% CI, 1.07-2.54; p=0.022). Compared to normal cardiac index, individuals with clinically low cardiac index had a higher relative risk of dementia (HR=2.07; 95% CI, 1.02-4.19; p=0.044). If participants with clinically prevalent CVD and atrial fibrillation were excluded (n=184), individuals with clinically low cardiac index had a higher relative risk of both dementia (HR=2.92; 95% CI, 1.34-6.36; p=0.007) and AD (HR=2.87; 95% CI, 1.21-6.80; p=0.016) compared to individuals with normal cardiac index. -Lower cardiac index is associated with an increased risk for the development of dementia and AD.
    Circulation 02/2015; 10(4). DOI:10.1161/CIRCULATIONAHA.114.012438 · 14.95 Impact Factor
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    ABSTRACT: -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 multi-ethnic genome-wide association studies. -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=1,943), 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 SNP 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=2.7×10(-19)) and identified novel loci on chr10q24 (p=1.6×10(-9)) and chr2p21 (p=4.4×10(-8)). In the multi-ethnic meta-analysis, we identified two additional loci, on chr1q22 (p=2.0×10(-8)) and chr2p16 (p=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer's disease (chr2p21, chr10q24), intracerebral hemorrhage (chr1q22), neuro-inflammatory diseases (chr2p21), and glioma (chr10q24, chr2p16). -We identified four novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of white matter hyperintensities in addition to previously-proposed ischemic mechanisms.
    Circulation Cardiovascular Genetics 02/2015; DOI:10.1161/CIRCGENETICS.114.000858 · 5.34 Impact Factor
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    ABSTRACT: General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C.
    Molecular Psychiatry 02/2015; DOI:10.1038/mp.2014.188 · 15.15 Impact Factor
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    ABSTRACT: We investigated the association between circulating biomarkers of inflammation and MRI markers of small vessel disease. We performed a cross-sectional study relating a panel of 15 biomarkers, representing systemic inflammation (high-sensitivity C-reactive protein, interleukin-6, monocyte chemotactic protein-1, tumor necrosis factor α, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), vascular inflammation (intercellular adhesion molecule 1, CD40 ligand, P-selectin, lipoprotein-associated phospholipase A2 mass and activity, total homocysteine, and vascular endothelial growth factor), and oxidative stress (myeloperoxidase) to ischemic (white matter hyperintensities/silent cerebral infarcts) and hemorrhagic (cerebral microbleeds) markers of cerebral small vessel disease (CSVD) on MRI in 1,763 stroke-free Framingham offspring (mean age 60.2 ± 9.1 years, 53.7% women). We observed higher levels of circulating tumor necrosis factor receptor 2 and myeloperoxidase in the presence of cerebral microbleed (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.1-4.1 and OR 1.5, 95% CI 1.1-2.0, respectively), higher levels of osteoprotegerin (OR 1.1, 95% CI 1.0-1.2), intercellular adhesion molecule 1 (OR 1.7, 95% CI 1.1-2.5), and lipoprotein-associated phospholipase A2 mass (OR 1.5, 95% CI 1.1-2.1), and lower myeloperoxidase (OR 0.8, 95% CI 0.7-1.0) in participants with greater white matter hyperintensity volumes and silent cerebral infarcts. Our study supports a possible role for inflammation in the pathogenesis of CSVD, but suggests that differing inflammatory pathways may underlie ischemic and hemorrhagic subtypes. If validated in other samples, these biomarkers may improve stroke risk prognostication and point to novel therapeutic targets to combat CSVD. © 2015 American Academy of Neurology.
    Neurology 01/2015; DOI:10.1212/WNL.0000000000001279 · 8.30 Impact Factor
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    ABSTRACT: 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. 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. 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. 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. © 2015 American Academy of Neurology.
    Neurology 01/2015; 84(5). DOI:10.1212/WNL.0000000000001202 · 8.30 Impact Factor
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    ABSTRACT: 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. © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    American Journal of Epidemiology 12/2014; DOI:10.1093/aje/kwu326 · 4.98 Impact Factor
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    ABSTRACT: the risk apolipoprotein E-4 (APOE4) poses for mild cognitive impairment (MCI) may vary based on the neuropsychological definition of MCI. a community-based cohort study. using two psychometric neuropsychological impairment definitions, we examined APOE4 and prevalent MCI among older adults or pre-MCI among middle-aged adults. Neuropsychological, clinical and genetic data were collected on 2,239 Framingham Offspring Cohort participants free from clinical stroke or dementia (62 ± 9 years; 54% women). Prevalent amnestic MCI was defined from neuropsychological performances ≥1.5 SD below the mean based on (i) age and education or (ii) age and Wide Range Achievement Test-3 Reading (WRAT-3 Reading) performance adjustment. in the entire sample, multivariable-adjusted logistic regressions found that APOE4 was associated with amnestic MCI when using the age and WRAT Reading definition (odds ratio [OR] = 1.7, P = 0.002) but not the age and education definition (OR = 1.0, P = 0.90). Results were modified by age, such that APOE4 was associated with amnestic MCI in participants ≥65 years using both the age and WRAT Reading definition (OR = 2.4, P < 0.001) and the age and education definition (OR = 1.7, P = 0.04). APOE4 risk for prevalent amnestic MCI varies depending on the definition of objective neuropsychological impairment for MCI. Our findings support existing literature emphasising the need to refine MCI neuropsychological profiling methods. © The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Age and Ageing 12/2014; DOI:10.1093/ageing/afu183 · 3.11 Impact Factor
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    ABSTRACT: 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. 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 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 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 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 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. 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. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: Background Detection of “any cognitive impairment” is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives. Methods We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening. Results The final Dementia Screening Indicator included age (1 point/year; ages, 65–79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m2 (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell's C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78). Conclusions The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 11/2014; DOI:10.1016/j.jalz.2013.11.006 · 14.48 Impact Factor
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    ABSTRACT: Background Plasma amyloid-β (Aβ) peptide levels have been examined as a low-cost accessible marker for risk of incident Alzheimer's disease (AD) and dementia, but results have varied between studies. We reassessed these associations in one of the largest, prospective, community-based studies to date. Methods A total of 2189 dementia-free, Framingham Study participants aged >60 years (mean age, 72 ± 8 years; 56% women) had plasma Aβ1-42 and Aβ1-40 measured and were followed prospectively (mean, 7.6 ± 3.0 years) for dementia/AD. Results Increased plasma Aβ1-42 levels were associated with lower risk of dementia (Aβ1-42: hazard ratio [HR] = 0.80 [0.71‒0.90], P < .001; Aβ1-42-to-Aβ1-40 ratio: HR = 0.86 [0.76‒0.98], P = .027) and AD (Aβ1-42: HR = 0.79 [0.69‒0.90], P < .001; Aβ1-42-to-Aβ1-40 ratio: HR = 0.83 [0.72‒0.96], P = .012). Conclusion Our results suggest that lower plasma Aβ levels are associated with risk of incident AD and dementia. They encourage further evaluation of plasma Aβ levels as a biomarker for risk of developing clinical AD and dementia.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 09/2014; DOI:10.1016/j.jalz.2014.07.001 · 14.48 Impact Factor
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    ABSTRACT: Introduction: This study incorporates unique error response analyses with traditional measures of memory to examine the association between mid-life cardiovascular risk factors and later-life memory function. Methods: The Framingham Stroke Risk Profile (FSRP), a composite score of cardiovascular risk, was assessed in 1755 Framingham Offspring participants (54% women, mean age=54+/-9 y) from 1991 to 1995. Memory tests including Logical Memory and Visual Reproductions were administered from 2005 to 2008. Linear and logistic regression examined the association between FSRP and memory measures. Interaction between the presence of the ApoE4 allele and each FSRP component on the memory measures was also assessed. Results: FSRP and the individual components of age, sex, and smoking were related to lower standard scores of memory. The new error response analyses reinforced the standard analyses and also identified new relationships. Participants with diabetes were found to make more errors on Logical Memory, and those with a history of smoking were found to make more errors on Visual Reproductions. Lastly, ApoE4+ smokers experienced significant verbal memory loss, whereas ApoE4- smokers did not. Conclusions: Middle-aged healthy adults with cardiovascular risk factors including diabetes, history of smoking, and ApoE4 positivity were found to have greater later-life memory impairments.
    Alzheimer Disease and Associated Disorders 09/2014; DOI:10.1097/WAD.0000000000000059 · 2.69 Impact Factor
  • Alzheimer's and Dementia 07/2014; 10(4):P432. DOI:10.1016/j.jalz.2014.05.568 · 17.47 Impact Factor
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    ABSTRACT: 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.AimsTo 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.ResultsAdjusting 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 (β = −1·27 ± 0·60, P = 0·035; β = −1·03 ± 0·47, P = 0·028, respectively), verbal learning (paired associate test; β = −1·31 ± 0·57, P = 0·023), language (Boston naming test; β = −0·27 ± 0·08, P = 0·002), executive function (digit span backward; β = −0·53 ± 0·21, P = 0·015), and visuospatial and motor skills (block design; β = −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.
    International Journal of Stroke 05/2014; DOI:10.1111/ijs.12275 · 4.03 Impact Factor
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    ABSTRACT: Cerebral microbleeds (CMBs) are associated with increased risk of stroke and poor cognition. Vascular risk factors and medications used for stroke prevention may increase the risk of CMB. We examined the prevalence of CMB and the association of these risk factors with CMB, postulating that risk factors for cerebral amyloid angiopathy would be associated with lobar CMB and markers of hypertensive vasculopathy with deep CMB. We include 1965 Framingham Original and Offspring participants (age, 66.5±11.0 years; 54% women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (apolipoprotein E [APOE]) risk factors and medication use to the presence of CMB overall and stratified by brain location (deep, lobar, or mixed). CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age (P<0.0001) and was higher in men (P<0.001). Hypertension increased risk of any CMB, and in deep and mixed locations (P<0.05), and low total cholesterol and APOE ε4 increased risk of lobar CMB (P<0.05). Statin use increased risk of lobar and mixed location CMB (P<0.05). The latter association was not affected by adjustment for cholesterol levels or concomitant medication use. We observed the expected association of hypertension with deep CMB and low cholesterol and APOE ε4 with lobar CMB. In addition, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.
    Stroke 04/2014; 45(5). DOI:10.1161/STROKEAHA.114.004130 · 6.02 Impact Factor
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    ABSTRACT: To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages. Dementia-free Framingham participants from generation 1 (n = 789, age 79 ± 4 years, 64% women) and generation 2 (n = 2,793, age 61 ± 9 years, 55% women; total = 3,582, age 65 ± 11 years, 57% women) had serum IGF-1 measured in 1990-1994 and 1998-2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999-2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE ε4, plasma homocysteine, waist-hip ratio, and physical activity. Mean IGF-1 levels were 144 ± 60 μg/L in generation 1 and 114 ± 37 μg/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 ± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14-2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (β/SD increment in IGF-1 was 0.55 ± 0.24, p = 0.025; and 0.26 ± 0.06, p < 0.001, for generations 1 and 2, respectively). Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.
    Neurology 04/2014; 82(18). DOI:10.1212/WNL.0000000000000382 · 8.30 Impact Factor
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    ABSTRACT: Studies of clinical and community cohorts have shown that antemortem imaging measures of hippocampal volume have correlated with postmortem Alzheimer pathology. Fewer studies have examined the relationship between both Alzheimer and cerebrovascular pathology, and antemortem brain imaging. The aim of this study was to correlate antemortem brain magnetic resonance imaging (MRI) volumes with postmortem brain pathology (both Alzheimer-related and cerebrovascular) in a community-derived cohort from the Framingham Heart Study. Participants (n=59) from the Framingham Heart Study were included if they were enrolled in the brain autopsy program and underwent antemortem clinical evaluation, neuropsychological testing, and brain MRI. Cortical neurofibrillary tangle pathology correlated with lower total cerebral brain (β±SE=-0.04±0.01, P=0.004) and hippocampal volumes (β±SE=-0.03±0.02, P=0.044) and larger temporal horns (log-transformed, β±SE=0.05±0.01, P=0.001). Similar findings were seen between total/cortical neuritic plaques and total cerebral brain and temporal horn volume. White matter hyperintensities (also log-transformed) were best predicted by the presence of deep nuclei microinfarcts (β±SE=0.53±0.21, P=0.016), whereas hippocampal volume was significantly decreased in the presence of hippocampal sclerosis (β±SE=-1.23±0.30, P<0.001). This study showed that volumetric MRI measures correlated with postmortem Alzheimer-related and cerebrovascular neuropathology in this community-derived cohort, confirming that these MRI measures are important antemortem surrogates for these dementia-related pathologies.
    Alzheimer disease and associated disorders 03/2014; DOI:10.1097/WAD.0000000000000032 · 2.88 Impact Factor
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    ABSTRACT: Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60×10-63], CBS [p = 3.15×10-26], CPS1 [p = 9.10×10-13], ALDH1L1 [p = 7.3×10-13] and PSPH [p = 1.17×10-16]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.
    PLoS Genetics 03/2014; 10(3):e1004214. DOI:10.1371/journal.pgen.1004214 · 8.17 Impact Factor
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    ABSTRACT: 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. 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. 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=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-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)). 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.
    Stroke 01/2014; DOI:10.1161/STROKEAHA.113.003044 · 6.02 Impact Factor

Publication Stats

12k Citations
1,503.46 Total Impact Points

Top Journals

Institutions

  • 2015
    • McMaster University
      Hamilton, Ontario, Canada
  • 2003–2015
    • National Heart, Lung, and Blood Institute
      • Division of Cardiovascular Sciences (DCVS)
      베서스다, Maryland, United States
  • 2014
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 1998–2014
    • Boston University
      • • Department of Neurology
      • • Department of Biostatistics
      • • Section of Preventive Medicine and Epidemiology
      • • Department of Mathematics and Statistics
      Boston, Massachusetts, United States
    • University at Buffalo, The State University of New York
      Buffalo, New York, United States
  • 2013
    • University of Helsinki
      • Institute of Behavioural Sciences
      Helsinki, Province of Southern Finland, Finland
  • 2002–2013
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
    • National Institutes of Health
      Maryland, United States
  • 2012
    • University of California, Davis
      • Department of Neurology
      Davis, CA, United States
    • Erasmus Universiteit Rotterdam
      • Department of Epidemiology
      Rotterdam, South Holland, Netherlands
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
  • 2011
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2009
    • Erasmus MC
      • Department of Epidemiology
      Rotterdam, South Holland, Netherlands
  • 2006
    • University of Northern Iowa
      سدار فالز، آیووا, Iowa, United States
    • Morehouse School of Medicine
      Atlanta, Georgia, United States
  • 2004
    • University of Alberta
      • Department of Medicine
      Edmonton, Alberta, Canada