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ObjectiveWe investigated differences in the anatomical distribution of cerebral microbleeds (CMBs) on MRI, hypothesized to indicate the type of underlying cerebral small vessel disease (SVD), between Eastern and Western general populations.MethodsWe analyzed data from 11 studies identified by a PubMed search between 1996 and April 2014 according to the Preferred Reporting Items for a Systematic Review and Meta-analysis of Individual Participant Data. Study quality measures indicated low or medium risk of bias. We included stroke-free participants from populations aged between 55 and 75 years, categorized by geographic location (Eastern or Western). We categorized CMB distribution (strictly lobar, deep and/or infratentorial [D/I], or mixed [i.e., CMBs located in both lobar and D/I regions]). We tested the hypothesis that Eastern and Western populations have different anatomical distributions of CMBs using multivariable mixed effects logistic regression analyses adjusted for age, sex, and hypertension and clustering by institution.ResultsAmong 8,595 stroke-free individuals (mean age [SD] 66.7 [5.6] years; 48% male; 42% from a Western population), 624 (7.3%) had CMBs (strictly lobar in 3.1%; D/I or mixed in 4.2%). In multivariable mixed effects models, Eastern populations had higher odds of D/I or mixed CMBs (adjusted odds ratio 2.78, 95% confidence interval [CI] 1.77–4.35) compared to Western populations. Eastern populations had a higher number of D/I or mixed CMBs (adjusted prevalence ratio 2.83, 95% CI 1.27–6.31).ConclusionsEastern and Western general populations have different anatomical distributions of CMBs, suggesting differences in the spectrum of predominant underlying SVDs, with potential implications for SVD diagnosis and treatment.

Introduction We examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up. Methods Framingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified. Results Baseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion from normal cognition to MCI at 6.5-year follow-up. Annualized change rates in total cerebral brain volume and hippocampal volume were associated with conversion from normal cognition to MCI to follow-up. Discussion Baseline WMH and hippocampal volume are markers that are both associated with conversion from normal cognition to MCI, highlighting the role of both vascular lesions and neurodegeneration in MCI.

Introduction With a rapidly aging population, general practitioners are confronting the challenge of how to determine those who are at greatest risk for dementia and potentially need more specialized follow-up to mitigate symptoms early in its course. We created a practical dementia risk score and provided individualized estimates of future dementia risk. Methods Using the Framingham Heart Study data, we built our prediction model using Cox proportional hazard models and developed a point system for the risk score and risk estimates. Results The score system used total points ranging from −1 to 31 and stratifies individuals into different levels of risk. We estimated 5-, 10-, and 20-year dementia risk prediction and incorporated these into the points system. Discussion This risk score system provides a practical tool because all included predictors are easy to assess by practitioners. It can be used to estimate future probabilities of dementia for individuals.

Background The increased risk of stroke and cognitive impairment associated with atrial fibrillation (AF) is well documented. However, there is a paucity of research investigating the relations between AF and brain morphology. Objective The purpose of this study was to investigate the association between AF and brain volume measures on magnetic resonance imaging (MRI). Methods The study sample included stroke- and dementia-free participants who attended the Framingham Heart Study offspring cohort 7th examination cycle (1999–2005) and underwent contemporaneous MRI. We examined the association between prevalent AF and brain volume measures (total cerebral volume, frontal lobe volume, temporal lobe volume, temporal horn volume, hippocampal volume, and white matter hyperintensity volume) with linear regression. We first adjusted models for age and sex, and then for vascular risk factors and APOE4. Results We studied 2144 individuals (mean age 61.8 ± 9.3 years; 54% women); 73 participants (3.4%) had prevalent AF at the time of MRI. In age- and sex-adjusted models, AF was inversely associated with total cerebral brain volume, frontal brain volume, and temporal brain volume. After further adjustment for vascular risk factors and APOE4, AF remained associated with frontal brain volume. Conclusion After accounting for vascular risk factor burden, prevalent AF was associated with lobar indexes of vascular brain aging but not with expected white matter changes.

We investigated whether midlife pulse pressure is associated with brain atrophy and cognitive decline, and whether the association was modified by apolipoprotein-E ε4 (APOE-ε4) and hypertension. Participants (549 stroke-free and dementia-free Framingham Offspring Cohort Study participants, age range=55.0 to 64.9 y) underwent baseline neuropsychological and magnetic resonance imaging (subset, n=454) evaluations with 5- to 7-year follow-up. Regression analyses investigated associations between baseline pulse pressure (systolic-diastolic pressure) and cognition, total cerebral volume and temporal horn ventricular volume (as an index of smaller hippocampal volume) at follow-up, and longitudinal change in these measures. Interactions with APOE-ε4 and hypertension were assessed. Covariates included age, sex, education, assessment interval, and interim stroke. In the total sample, baseline pulse pressure was associated with worse executive ability, lower total cerebral volume, and greater temporal horn ventricular volume 5 to 7 years later, and longitudinal decline in executive ability and increase in temporal horn ventricular volume. Among APOE-ε4 carriers only, baseline pulse pressure was associated with longitudinal decline in visuospatial organization. Findings indicate arterial stiffening, indexed by pulse pressure, may play a role in early cognitive decline and brain atrophy in mid to late life, particularly among APOE-ε4 carriers.

BACKGROUND It is unclear whether brain white matter hyperintensities (WMHI) causes or is a result of late life depression. We used the Framingham Heart Study offspring to examine whether indices of brain aging are related to incident depression in the elderly. METHODS The Center for Epidemiologic Studies Depression Scale (CES-D) was administered along with a brain MRI scan at baseline and was re-administered (n = 1212) at an average 6.6 + 0.6 year follow-up. The outcomes (i) change in CES-D scores from baseline; (ii) depression defined as CES-D ≥16; (iii) severe depression defined as CES-D ≥21; and (iv) CES-D cutoff scores and/or on antidepressant were used. RESULTS Among those who did not have depression at baseline, 9.1% (n = 110) developed depression, 4.0% (n = 48) developed severe depressive symptoms, and 11.1% (n = 135) were put on antidepressants. When depressive symptoms only was the outcome, we found that baseline WMHI was positively associated with change in CES-D scores and that those with an extensive WMHI at baseline had a high risk of developing severe depressive symptoms; the relationship was strengthened in the absence of cardiovascular diseases. In contrast, when depressive symptoms or taking antidepressant was the outcome, larger total cerebral brain volume and temporal lobe brain volume, but not WMHI, were negatively associated with the development of depression. CONCLUSIONS Brain WMHI is a probable risk factor for vascular depression in the elderly. The depression outcomes with and without antidepressant were related to different brain pathologies. Copyright © 2016 John Wiley & Sons, Ltd.

Objectives: To refine mild cognitive impairment (MCI) diagnostic criteria, we examined progression to dementia using two approaches to identifying MCI. Methods: A total of 1203 Framingham Heart Study participants were classified at baseline as cognitively normal or MCI (overall and four MCI subtypes) via conventional Petersen/Winblad criteria (single cognitive test impaired per domain, >1.5 SD below expectations) or Jak/Bondi criteria (two tests impaired per domain, >1 SD below norms). Cox proportional hazards models were constructed to examine the association between each MCI definition and incident dementia. Results: The Petersen/Winblad criteria classified 34% of participants as having MCI while the Jak/Bondi criteria classified 24% as MCI. Over a mean follow-up of 9.7 years, 58 participants (5%) developed incident dementia. Both MCI criteria were associated with incident dementia [Petersen/Winblad: hazards ratio (HR) = 2.64; p-value=.0002; Jak/Bondi: HR=3.30; p-value p-value=.008). Multi-domain amnestic and single domain non-amnestic MCI subtypes were significantly associated with incident dementia for both diagnostic approaches (all p-values Conclusions: The Jak/Bondi MCI criteria had a similar association with dementia as the conventional Petersen/Winblad MCI criteria, despite classifying ~30% fewer participants as having MCI. Further exploration of alternative methods to conventional MCI diagnostic criteria is warranted. (JINS, 2016, 22, 937–943)

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. National Foundation for Alzheimer's disease and related disorders Institut Pasteur de Lille Centre National de Genotypage Inserm FRC (fondation pour la recherche sur le cerveau) Rotary LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) MEDIALZ Project - ERDF (European Regional Development Fund) 11001003 Conseil Regional Nord Pas de Calais Fondation pour la Recherche Medicale Caisse Nationale Maladie des Travailleurs Salaries Direction Generale de la Sante MGEN Institut de la Longevite Agence Francaise de Securite Sanitaire des Produits de Sante Aquitaine and Bourgogne Regional Councils Fondation de France joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' program Eisai Wellcome Trust British Heart Foundation Chief Scientist Office of the Scottish Executive NIA N01-AG-12100 National Heart, Lung and Blood Institute Contracts 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Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 Scottish Funding Council HR03006 Academy of Finland Finnish Diabetes Research Society Folkhalsan Research Foundation Novo Nordisk Foundation Finska Lakaresallskapet Signe and Ane Gyllenberg Foundation University of Helsinki Ministry of Education Ahokas Foundation Emil Aaltonen Foundation Juho Vainio Foundation Wellcome Trust WT089062 University of Newcastle's Strategic Initiative Fund Vincent Fairfax Family Foundation Hunter Medical Research Institute Italian Ministry of Health ICS 110.1RS97.71 US National Institute on Aging N01[AG]916413 N01[AG]821336 263 MD 9164 13 263 MD 821336 Intramural Research Program, National Institute on Aging, National Institutes of Health BBSRC Royal Society Chief Scientist Office of the Scottish Government Research Into Ageing UK Biotechnology and Biological Sciences Research Council (BBSRC) Engineering and Physical Sciences Research Council (EPSRC) Economic and Social Research 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Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification.

Background and Purpose— Cerebral microbleeds (CMB) represent a common magnetic resonance imaging marker of cerebral small vessel disease, increasingly recognized as a subclinical marker of stroke and dementia risk. CMB detection may reflect the cumulative effect of vascular risk burden and be a marker of higher mortality. We investigated the relation of CMB to risk of death in community dwelling participants free of stroke and dementia. Methods— We evaluated 1963 Framingham Original and Offspring Cohort participants (mean age 67 years; 54% women) with available brain magnetic resonance imaging and mortality data. Using Cox proportional hazards models, we related CMB to all-cause, cardiovascular, and stroke-related mortality. Results— Participants with CMB (8.9%) had higher prevalence of cardiovascular risk factors and use of preventive medications. During a mean follow-up of 7.2±2.6 years, we observed 296 deaths. In age- and sex-adjusted analysis, CMB were associated with increased all-cause mortality (hazards ratio, 1.39; 95% confidence interval 1.03–1.88), a relation that was no longer significant after adjustment for cardiovascular risk and preventive medication use (hazards ratio, 1.15; 95% confidence interval, 0.82–1.63). Conclusions— CMBs may represent the deleterious effect of cardiovascular risk factors in the cerebral vasculature. Although their presence was associated with increased all-cause mortality, the effect was no longer present after accounting for vascular risk factors and preventive treatment use. Further studies are required to clarify the role of cardiovascular preventive therapies for prevention of mortality in persons with incidental detection of CMB.

Background and Purpose— To prevent strokes that may occur as the first manifestation of atrial fibrillation (AF), screening programs have been proposed to identify patients with undiagnosed AF who may be eligible for treatment with anticoagulation. However, the frequency with which patients with AF present with stroke as the initial manifestation of the arrhythmia is unknown. Methods— We estimated the frequency with which AF may present as a stroke in 1809 community-based Framingham Heart Study participants with first-detected AF and without previous strokes, by tabulating the frequencies of strokes occurring on the same day, within 30 days before, 90 days before, and 365 days before first-detected AF. Using previously reported AF incidence rates, we estimated the incidence of strokes that may represent the initial manifestation of AF. Results— We observed 87 strokes that occurred ≤1 year before AF detection, corresponding to 1.7% on the same day, 3.4% within 30 days before, 3.7% within 90 days before, and 4.8% ≤1 year before AF detection. We estimated that strokes may present as the initial manifestation of AF at a rate of 2 to 5 per 10 000 person-years, in both men and women. Conclusions— We observed that stroke is an uncommon but measureable presenting feature of AF. Our data imply that emphasizing cost-effectiveness of population-wide AF-screening efforts will be important given the relative infrequency with which stroke represents the initial manifestation of AF.

Objective: To evaluate the possible early consequences of impaired glucose metabolism on the brain by assessing the relationship of diabetes, fasting blood glucose (FBG) levels, and insulin resistance with cognitive performance and brain integrity in healthy young and middle-aged adults. Methods: The sample included dementia-free participants (mean age 40 ± 9 years; 53% women) of the Framingham Heart Study third-generation cohort with cognitive testing of memory, abstract reasoning, visual perception, attention, and executive function (n = 2,126). In addition, brain MRI examination (n = 1,597) was used to determine white matter, gray matter, and white matter hyperintensity (WMH) volumes and fractional anisotropy measures. We used linear regression models to assess relationships between diabetes, FBG, and insulin resistance with cognition, lobar gray matter, and WMH volumes as well as voxel-based microstructural white matter integrity and gray matter density, adjusting for potential confounders. Mediating effect of brain lesions on the association of diabetes with cognitive performance was also tested. Results: Diabetes was associated with worse memory, visual perception, and attention performance; increased WMH; and decreased total cerebral brain and occipital lobar gray matter volumes. The link of diabetes with attention and memory was mediated through occipital and frontal atrophy, and the latter also through hippocampal atrophy. Both diabetes and increased FBG were associated with large areas of reductions in gray matter density and fractional anisotropy on voxel-based analyses. Conclusions: We found that hyperglycemia is associated with subtle brain injury and impaired attention and memory even in young adults, indicating that brain injury is an early manifestation of impaired glucose metabolism.

Background and Purpose— Long-term exposure to ambient air pollution is associated with cerebrovascular disease and cognitive impairment, but whether it is related to structural changes in the brain is not clear. We examined the associations between residential long-term exposure to ambient air pollution and markers of brain aging using magnetic resonance imaging. Methods— Framingham Offspring Study participants who attended the seventh examination were at least 60 years old and free of dementia and stroke were included. We evaluated associations between exposures (fine particulate matter [PM 2.5 ] and residential proximity to major roadways) and measures of total cerebral brain volume, hippocampal volume, white matter hyperintensity volume (log-transformed and extensive white matter hyperintensity volume for age), and covert brain infarcts. Models were adjusted for age, clinical covariates, indicators of socioeconomic position, and temporal trends. Results— A 2-μg/m 3 increase in PM 2.5 was associated with −0.32% (95% confidence interval, −0.59 to −0.05) smaller total cerebral brain volume and 1.46 (95% confidence interval, 1.10 to 1.94) higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 (95% confidence interval, 0.01 to 0.19) greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter. Conclusions— Exposure to elevated levels of PM 2.5 was associated with smaller total cerebral brain volume, a marker of age-associated brain atrophy, and with higher odds of covert brain infarcts. These findings suggest that air pollution is associated with insidious effects on structural brain aging even in dementia- and stroke-free persons.

Background— Cross-sectional epidemiological and clinical research suggests that 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. Methods and Results— A total of 1039 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, and dementia formed our sample (age, 69±6 years; 53% women). Multivariable-adjusted proportional hazard models adjusting for Framingham Stroke Risk Profile score (age, sex, systolic blood pressure, antihypertensive medication, diabetes mellitus, cigarette smoking, cardiovascular disease history, atrial fibrillation), education, and apolipoprotein E4 status related cardiac magnetic resonance imaging–assessed cardiac index (cardiac output divided by body surface area) to incident all-cause dementia and Alzheimer disease (AD). Over the median 7.7-year follow-up period, 32 participants developed dementia, including 26 cases of AD. Each 1-SD unit decrease in cardiac index increased the relative risk of both dementia (hazard ratio [HR]=1.66; 95% confidence interval [CI], 1.11–2.47; P =0.013) and AD (HR=1.65; 95% CI, 1.07–2.54; P =0.022). Compared with individuals with 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 cardiovascular disease 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 with individuals with normal cardiac index. Conclusion— Lower cardiac index is associated with an increased risk for the development of dementia and AD.

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.

Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD we applied a family-based paradigm to derive and characterize a set of 12 induced pluripotent stem cell (iPSC) lines from a quartet consisting of two BD-affected brothers and their two unaffected parents. Initially, no significant phenotypic differences were observed between iPSCs derived from the different family members. However, upon directed neural differentiation we observed that CXCR4 (CXC chemokine receptor-4) expressing central nervous system (CNS) neural progenitor cells (NPCs) from both BD patients compared to their unaffected parents exhibited multiple phenotypic differences at the level of neurogenesis and expression of genes critical for neuroplasticity, including WNT pathway components and ion channel subunits. Treatment of the CXCR4+ NPCs with a pharmacological inhibitor of glycogen synthase kinase 3 (GSK3), a known regulator of WNT signaling, was found to rescue a progenitor proliferation deficit in the BD-patient NPCs. Taken together, these studies provide new cellular tools for dissecting the pathophysiology of BD and evidence for dysregulation of key pathways involved in neurodevelopment and neuroplasticity. Future generation of additional iPSCs following a family-based paradigm for modeling complex neuropsychiatric disorders in conjunction with in-depth phenotyping holds promise for providing insights into the pathophysiological substrates of BD and is likely to inform the development of targeted therapeutics for its treatment and ideally prevention.

Objective: We investigated the association between circulating biomarkers of inflammation and MRI markers of small vessel disease. Methods: 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 A 2 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). Results: 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 A 2 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. Conclusions: 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.

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], p0.001 and 1.47 [1.15-1.87], p0.001), 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.

Background We investigated how body weight affects survival after stroke, leveraging the availability of multiple prestroke body mass index (BMI) measurements and using a nested case‐control design in a community‐based sample. Methods and Results We compared all‐cause mortality in participants stratified by prestroke weight. Separate analyses were performed for ischemic stroke and all stroke and for age‐, sex‐, and BMI category‐matched stroke‐free controls. Participants were grouped into BMI categories and followed for up to 10 years. Differences in survival were tested for interaction by case status. In sensitivity analysis, to exclude those with prestroke weight loss, we restricted the reference group to participants with 2 consistently normal BMI measurements within 10 years before stroke/matching. There were 782 stroke cases (age 71±9, 51% female participants, 87% ischemic stroke) and 2346 controls (age 72±9, 51% female participants). Overweight participants with ischemic stroke had a lower mortality compared with those with normal weight (hazard ratio [HR]=0.70, 95%CI 0.55‐0.90, P =0.005). The association of reduced mortality with BMI ≥25, compared with normal‐weight BMI 18.5 to P =0.051 and P =0.130, respectively). Compared with participants with stable normal weight, moderately increased weight was protective after ischemic stroke (overweight HR=0.72, 95%CI 0.53‐0.99, P =0.041). Conclusions Overweight and mildly obese participants had better 10‐year survival after ischemic stroke compared with normal‐weight participants, even after excluding persons with recent prestroke weight loss. There may be unknown protective factors associated with a moderately increased body weight before stroke.

Background: the risk apolipoprotein E-4 (APOE4) poses for mild cognitive impairment (MCI) may vary based on the neuropsychological definition of MCI. Setting: a community-based cohort study. Methods: 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. Results: 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). Conclusion: 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.

Studies of clinical and community cohorts have shown that antemortem imaging measures of hippocampal volume have correlated with postmortem Alzheimer's pathology. Fewer studies have examined the relationship between both Alzheimer's 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 (FHS). Participants (n=59) from the FHS 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 (beta±SE=−0.04±0.01, p=0.004) and hippocampal volumes (beta±SE=−0.03±0.02, p=0.044) and larger temporal horns (log-transformed, beta±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 (beta±SE=0.53±0.21, p=0.016), whereas hippocampal volume was significantly decreased in the presence of hippocampal sclerosis (beta±SE =−1.23±0.30, p

International audience; BACKGROUND: Gender-specific risks for dementia and Alzheimer's disease (AD) starting in midlife remain largely unknown. METHODS: Prospectively ascertained dementia/AD and cause-specific mortality in Framingham Heart Study (FHS) participants was used to generate 10- to 50-year risk estimates of dementia/AD on the basis of the Kaplan-Meier method (cumulative incidence) or accounting for competing risk of death (lifetime risk [LTR]). RESULTS: Overall, 777 cases of incident dementia (601 AD) occurred in 7901 participants (4333 women) over 136,266 person-years. Whereas cumulative incidences were similar in women and men, LTRs were higher in women older than 85 years of age. LTR of dementia/AD at age 45 was 1 in 5 in women and 1 in 10 in men. Cardiovascular mortality was higher in men with rate ratios decreasing from approximately 6 at 45 to 54 years of age to less than 2 after age 65. CONCLUSION: Selective survival of men with a healthier cardiovascular risk profile and hence lower propensity to dementia might partly explain the higher LTR of dementia/AD in women.

Background: offspring of long-lived individuals have lower risk for dementia. We examined the relation between parental longevity and cognition and subclinical markers of brain ageing in community-dwelling adult offspring. Methods: offspring participants with both parents in the Framingham Heart Study, aged ≥55 years and dementia-free underwent baseline and repeat neuropsychological (NP) testing and brain magnetic resonance imaging (MRI). Parental longevity was defined as having at least one parent survive to age ≥85 years. To test the association between parental longevity and measures of cognition and brain volumes, we used multivariable linear and logistic regression adjusting for age, sex, education and time to NP testing or brain MRI. Results: of 728 offspring (mean age 66 years, 54% women), 407 (56%) had ≥1 parent achieve longevity. In cross-sectional analysis, parental longevity was associated with better scores on attention (beta 0.21 ± 0.08, P = 0.006) and a lower odds of extensive white matter hyperintensity on brain MRI (odds ratio 0.59, 95% CI: 0.38, 0.92, P = 0.019). The association with white matter hyperintensity was no longer significant in models adjusted for cardiovascular risk factors and disease. In longitudinal analysis (6.7 ± 1.7 years later), offspring with parental longevity had slower decline in attention (0.18 ± 0.08, P = 0.038), executive function (beta 0.19 ± 0.09, P = 0.031) and visual memory (beta −0.18 ± 0.08, P = 0.023), and less increase in temporal horn volume (beta −0.25 ± 0.09, P = 0.005). The associations persisted in fully adjusted models. Conclusion: parental longevity is associated with better brain ageing in middle-aged offspring.

BACKGROUND/STUDY CONTEXT: Studies have found that executive functioning is affected early in the pathophysiological processes associated with Alzheimer's disease and vascular dementia. There also exists a range of functioning on executive tasks during normal aging. Although qualitative data are commonly utilized in clinical practice for evaluating subtle changes in cognitive functioning and diagnostic discernment, it is not clear whether error responses used in clinical practice are also evident as normative behavior.As part of an extensive battery of neuropsychological tests, executive functioning measures (i.e., Trail Making Test Part B, Similarities and Verbal Fluency tests) were administered via standardized administration prescript. Regression analyses were used to determine associations between vascular aging indices and qualitative performance measures. Descriptive statistics are included for 1907 cognitively normal individuals.Results suggest that although qualitative errors do occur, they are relatively infrequent within a presumably cognitively normal sample. Error commission rates on executive functioning tests are significantly associated with both age and education.Provided is a baseline profile of errors committed on tests of executive function across a range of age and educational levels. The normative data sets are included, stratified by age and educational achievement, for which to compare qualitative test performance of clinical and research populations.

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 (β±SE=−0.05±0.02; P =0.025), and better visual memory (β±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.

We examined the progression of lexical-retrieval deficits in individuals with neuropathologically determined Alzheimer's disease (AD; n = 23) and a comparison group without criteria for AD (n = 24) to determine whether linguistic changes were a significant marker of the disease. Our participants underwent multiple administrations of a neuropsychological battery, with initial administration occurring on average 16 years prior to death. The battery included the Boston Naming Test (BNT), a letter fluency task (FAS) and written description of the Cookie Theft Picture (CTP). Repeated measures analysis revealed that the AD-group showed progressively greater decline in FAS and CTP lexical performance than the comparison group. Cross-sectional time-specific group comparisons indicated that the CTP differentiated performance between the two groups at 7-9 years prior to death and FAS and BNT only at 2-4 years. These results suggest that lexical-retrieval deficits in written discourse serve as an early indicator of AD.

To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging.Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998-2001) and brain MRI and cognition (1999-2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively).Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p0.05).Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.

Objective: We related a panel of inflammatory biomarkers to risk of incident ischemic stroke (IIS) in a community-dwelling sample. Methods: Stroke-free Framingham offspring attending examination cycle 7 (1998–2001) had 15 circulating inflammatory biomarkers measured. Cox proportional hazard models were used to calculate the hazard ratios (HRs) of IIS per SD increment of each biomarker. Model 1 included age and sex. Model 2 additionally adjusted for systolic blood pressure, hypertension treatment, current smoking, diabetes, cardiovascular disease, and atrial fibrillation. The continuous net reclassification improvement was used to assess the improvement in IIS risk prediction of statistically significant biomarkers from our main analysis over traditional stroke risk factors. Results: In 3,224 participants (mean age 61 ± 9 years, 54% women), 98 experienced IIS (mean follow-up of 9.8 [±2.2] years). In model 1, ln–C-reactive protein (ln-CRP) (HR 1.28, 95% confidence interval [CI] 1.04–1.56), ln–tumor necrosis factor receptor 2 (ln-TNFR2) (HR 1.33, 95% CI 1.09–1.63), ln–total homocysteine (ln-tHcy) (HR 1.32, 95% CI 1.11–1.58), and vascular endothelial growth factor (VEGF) (HR 1.25, 95% CI 1.07–1.46) were associated with risk of IIS. All associations, except for ln-CRP, remained significant in model 2 (ln-TNFR2: HR 1.24, 95% CI 1.02–1.51; ln-tHcy: HR 1.20, 95% CI 1.01–1.43; and VEGF: HR 1.21, 95% CI 1.04–1.42). The addition of these 4 biomarkers to the clinical Framingham Stroke Risk Profile score improved stroke risk prediction (net reclassification improvement: 0.34, 0.12–0.57; p Conclusions: Higher levels of 4 biomarkers—CRP, tHcy, TNFR2, and VEGF—increased risk of IIS and improved the predictive ability of the Framingham Stroke Risk Profile score. Further research is warranted to explore their role as potential therapeutic targets.

Elevated blood glucose and the apolipoprotein (APOE) e4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer’s disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE e4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE e4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.

Background Carotid atherosclerosis is associated with subclinical ischemic cerebrovascular disease, but its role in hemorrhage‐prone small vessel disease—represented by cerebral microbleed ( CMB )—is unclear, although vascular risk factors underlie both conditions. We hypothesized that persons with carotid atherosclerosis would have higher risk of CMB , particularly in deep regions. Methods and Results We studied 1243 participants in the Framingham Offspring Study (aged 56.9±8.8 years; 53% women) with carotid ultrasound available on 2 occasions (1995–1998 and 2005–2008) prior to brain magnetic resonance imaging. Using multivariable logistic regression, we related baseline carotid stenosis, baseline intima–media thickness, and site‐specific carotid intima–media thickness progression (at internal and common carotid locations) to the prevalence and location (lobar or deep plus mixed) of CMB . In addition, we assessed effect modification by lipid levels and use of statin and antithrombotic medications. Carotid stenosis ≥25% (a marker of cerebrovascular atherosclerosis) was associated with presence of CMB overall (Odds Ratio 2.20, 95% CI 1.10–4.40) and at deep and mixed locations (odds ratio 3.60, 95% CI 1.23–10.5). Baseline carotid intima–media thickness was not associated with CMB . Progression of common carotid artery intima–media thickness among persons on hypertension treatment was associated with lower risk of deep and mixed CMB (odds ratio per SD 0.41, 95% CI 0.18–0.96). Conclusions Cumulative vascular risk factor exposure may increase the risk of CMB , especially in deep regions. The apparent paradoxical association of carotid intima–media thickness progression with lower risk of CMB may reflect benefits of intensive vascular risk factor treatment among persons with higher cardiovascular risk and deserves further investigation. If replicated, the results may have potential implications for assessment of preventive and therapeutic interventions for subclinical cerebral hemorrhage.

The study of Alzheimer's disease (AD) in the Framingham Heart Study (FHS), a multi-generational, community-based population study, began nearly four decades ago. In this overview, we highlight findings from seven prior publications that examined lifetime risk estimates for AD, environmental risk factors for AD, circulating and imaging markers of aging-related brain injury, and explorations on the genetics underlying AD. First, we describe estimations of the lifetime risk of AD. These estimates are distinguished from other measures of disease burden and have substantial public health implications. We then describe prospective studies of environmental AD risk factors: one examined the association between plasma levels of omega-3 fatty-acid and risk of incident AD, the other explored the association of diabetes to this risk in subsamples with specific characteristics. With evidence of inflammation as an underlying mechanism, we also describe findings from a study that compared the effects of serum cytokines and spontaneous production of peripheral blood mononuclear cell cytokines on AD risk. Investigating AD related endophenotypes increases sensitivity in identifying risk factors and can be used to explore pathophysiologic pathways between a risk factor and the disease. We describe findings of an association between large volume of white matter hyperintensities and a specific pattern of cognitive deficits in non-demented participants. Finally, we summarize our findings from two genetic studies: The first used genome-wide association (GWA) and family-based association methods to explore the genetic basis of cognitive and structural brain traits. The second is a large meta-analysis GWA study of AD, in which novel loci of AD susceptibility were found. Together, these findings demonstrate the FHS multi-directional efforts in investigating dementia and AD.

Background Common carotid artery intima-media thickness (IMT), a measure of atherosclerosis, varies between peak systole and end-diastole. This difference might affect cardiovascular risk assessment. Methods IMT measurements of the right and left common carotid arteries were synchronized with an electrocardiogram, using the R wave for end-diastole and the T wave for peak systole. IMT was measured in 2,930 members of the Framingham Offspring Study. Multivariate regression models were generated with end-diastolic IMT, peak systolic IMT, and change in IMT as dependent variables and Framingham risk factors as independent variables. End-diastolic IMT estimates were compared with the upper quartile of IMT on the basis of normative data obtained at peak systole. Results The average age of the study population was 57.9 years. The average difference in IMT during the cardiac cycle was 0.037 mm (95% confidence interval, 0.035–0.038 mm). End-diastolic IMT and peak systolic IMT had similar associations with Framingham risk factors (total R 2 = 0.292 vs 0.275) and were significantly associated with all risk factors. In a fully adjusted multivariate model, thinner IMT at peak systole was associated with pulse pressure ( P P = .0064), age ( P = .046), and no other risk factors. Performing end-diastolic IMT measurements while using upper quartile peak systolic IMT normative data led to inappropriately increasing by 42.1% the number of individuals in the fourth IMT quartile (high cardiovascular risk category). Conclusion The difference in IMT between peak systole and end diastole is associated with pulse pressure, low-density lipoprotein cholesterol, and age. In this study, the mean IMT difference during the cardiac cycle led to an overestimation by 42.1% of individuals at high risk for cardiovascular disease.

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 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 15% 10-year risk category was used, the net reclassification index was 0.109 ( P =0.037). Higher C-reactive protein (β=−0.21 per 1-SD increment; P =0.008), D-dimer (β=−0.18 per 1-SD increment; P =0.041), total homocysteine (β=−0.21 per 1-SD increment; P =0.005), and urinary albumin/creatinine ratio (β=−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.

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10 -8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10 -11), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10 -12), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10 -3 for 6q22 and 1.2 × 10 -3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size. © 2012 Nature America, Inc. All rights reserved.

OBJECTIVE 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). RESULTS 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). CONCLUSIONS Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.

Elevated plasma total homocysteine (tHcy) level is an established risk factor for cardiovascular disease. The relationship between tHcy and carotid artery intima-media thickness (IMT) at the internal carotid artery (ICA)/bulb-IMT and common carotid artery (CCA)-IMT had not been systematically studied, however. Because the ICA/bulb segment is more prone to plaque formation than the CCA segment, differential associations with tHcy at these sites might suggest mechanisms of tHcy action. We examined the cross-sectional segment-specific relationships of tHcy to ICA/bulb-IMT and CCA-IMT in 2499 participants from the Framingham Offspring Study who were free of cardiovascular disease. In multivariate linear regression analysis, ICA/bulb-IMT was significantly higher in the fourth tHcy quartile category compared with the other quartile categories, in both the age- and sex-adjusted and the multivariate-adjusted models ( P for trend P =.03) and thus stratified the analyses by median age (58 years). A significant positive trend between tHcy and ICA/bulb-IMT was seen in individuals age ≥58 years ( P for trend P for trend=.24) in multivariate-adjusted models. For CCA-IMT, no significant trends were observed in any of the analyses. The segment-specific association between elevated tHcy level and ICA/bulb-IMT suggests an association between tHcy and plaque formation.

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.

Background/Aims: We hypothesized that inflammatory markers are cross-sectionally and longitudinally associated with neuropsychological indicators of early ischemia and Alzheimer’s disease. Methods: 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. Results: 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. Conclusions: 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.

Background and Purpose— 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. Methods — 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). Results — CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age ( P P P APOE ε4 increased risk of lobar CMB ( P P Conclusions — 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.

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.

Objective: To examine whether there are sex-specific associations between brain magnetic resonance imaging (MRI) measures and neuropsychologic (NP) test performance. Background: Differences in cardiovascular risk factors have been linked to decreased total cerebral brain volume and white matter hyperintensities (WMHs). Although brain morphology has been related to cognitive performance, few studies have addressed sex-specific effects in this relationship. Methods: Framingham Offspring who were stroke and dementia-free underwent a brain MRI scan and NP testing (n = 2085; 978 men). Factor analysis identified 4 domain-specific NP factors. MRI participants were divided into 4 MRI subgroups based on measures of total cerebral brain volume and combinations of the presence of WMH and silent cerebral infarcts (≥ 3 mm). Results: 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 and cerebrovascular disease defined as large WMH volume plus silent cerebral infarct. This finding was attributed only among men with Framingham Stroke Risk Profile scores > 90th percentile range (P = 0.0019). Conclusions: 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 executive function, whereas the women do not.

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 P 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.

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Background Data on the association between alcohol consumption and ischemic stroke have been inconsistent. It is not known whether allele ɛ 4 of the apolipoprotein E (apoE) gene modifies the alcohol-stroke association. We sought to examine whether ɛ 4 allele of the apoE gene influences the association between alcohol consumption and ischemic stroke or high-density lipoprotein (HDL) cholesterol. Methods We examined a cohort of 7676 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. Results 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% confidence interval) for ischemic stroke was 0.50 (0.24-1.07) in the absence of ɛ 4 allele and 0.70 (0.24-2.05) in the presence of ɛ 4 allele ( P for interaction=.64) for those younger than 65 years. Similarly, we did not observe a statistically significant interaction between ɛ 4 allele and alcohol consumption on the risk of stroke among people aged 65 years and older ( P for interaction=.17). Alcohol consumption was positively associated with HDL cholesterol independent of ɛ 4 allele and age. Conclusions Our data do not provide evidence for an interaction between ɛ 4 allele and alcohol consumption on the risk of ischemic stroke in this population. Furthermore, apoE polymorphism did not influence the alcohol-HDL relation.

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. Methods— We studied 1975 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 and internal carotid stenosis to large white matter hyperintensity (>1 SD above age-specific mean), total brain volume, hippocampal volume, silent cerebral infarcts, and neuropsychological measures of verbal memory, executive function, and nonverbal memory measures. Results— We observed that internal carotid artery intima-media thickness, but not common carotid artery intima-media thickness, was associated with higher prevalence of silent cerebral infarcts (OR, 1.21; 95% CI, 1.03–1.43; P P P P P P =0.042) but not with silent cerebral infarcts or hippocampal volume. Internal carotid stenosis ≥50% was associated with higher prevalence of silent cerebral infarcts (OR, 2.53; 95% CI, 1.17–5.44), large white matter hyperintensity (OR, 2.35; 95% CI, 1.08–5.13), and poorer performance on executive function (−0.39 per SD; P Conclusions— 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 internal carotid artery intima-media thickness may be a better marker for cognitive impairment than common carotid artery intima-media thickness.