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<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.
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.
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.
brain ageing; brain imaging; cognition; longevity; neuropsychological testing; older people; parental longevity
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.
We include 1,965 Framingham Original and Offspring participants (age 66.5±11.0years; 54%women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (APOE) risk factors and medication use to 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 APOEε4 with lobar CMB. Additionally, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.
Novel error scores and traditional indices of executive function (EF) were related to cardiovascular risk factors (CVRF) measured 10–15 years earlier.
From 1991–1995, the Framingham Stroke Risk Profile (FSRP), a composite score of cardiovascular risk, was ascertained in 1755 Framingham Offspring participants (54% women, mean age= 54 ± 9 years). Participants were administered EF tests: FAS and Animals Fluency tests, Trail Making Test B (TrB), and Digit Span-Backwards (DS-B) in 2005–2009. Linear and logistic regression were used to relate the FSRP and its components to both error responses and traditional scores.
Consistent with previous findings, the FSRP and the individual components diabetes and sex were associated with several traditional measures of EF. Of interest were relationships between the FSRP score and TrB Total Errors (p=0.04), DS-B % Total Errors (p=0.02) and DS-B Capacity Score (p=0.03), and prevalent CVD related to making FAS Perseverations in the 75th percentile (p=0.03). By comparison, FSRP and CVD were not related to the traditional DS-B or FAS scores. Additionally, age was associated with higher Animals % Total Errors and % Perseverations among ApoE4+ individuals and with higher TrB Total Errors among ApoE4− individuals.
For those middle-aged and healthy, including those ApoE4+, CVRF are related to impairments in EF as ascertained by novel errors as well as traditional measures.
Neuropsychological assessment; Executive function; Mild cognitive impairment; ApolipoproteinE allele 4
Vascular risk factors have been associated with cognitive decline, however, it remains unclear whether apolipoprotein E (APOE) genotype modifies this relationship. We aimed to further elucidate these relationships and extend previous findings by examining data from a more comprehensive cognitive assessment than used in prior studies. 1,436 participants from the prospective Framingham Offspring Cohort Study underwent health examination from 1991-1995, followed by a baseline neuropsychological assessment (1999-2003) and a repeat neuropsychological assessment approximately eight years later (2004-2009). Multivariate linear regression analyses were performed to examine the relationship between midlife vascular risk factors, presence of the APOE ε4 allele, and cognitive change. APOE genotype significantly modified the associations between both midlife hypertension and cardiovascular disease and decline in language abilities as well as midlife diabetes and decline in verbal memory, attention, and visuospatial abilities. Associations between increased midlife vascular risk burden and greater cognitive decline were observed among APOE ε4 carriers but not non-carriers. The present findings revealed a subgroup at increased risk for cognitive decline (APOE ε4 carriers with midlife exposure to vascular risk factors) and suggest that treatment of vascular risk factors during midlife may reduce the risk of cognitive impairment later in life, particularly among APOE ε4 carriers.
Apolipoprotein E; Cognition; Vascular Risk; Aging; Diabetes; Hypertension; Cardiovascular Disease
Psychometric definitions of mild cognitive impairment (MCI) typically use cut-off levels set at 1.5 standard deviations below age- and education-adjusted norms, assuming that the education adjustment accounts for premorbid abilities. However, non-cognitive factors impact educational attainment, potentially leading to incorrect categorization as MCI. We examined whether using an adjustment based on reading performance (Wide Range Achievement Test [WRAT] Reading) improved MCI diagnostic accuracy.
935 Framingham Offspring (mean age 72 ± 5) underwent tests of Memory, Executive Function, Abstraction, Language, and Visuospatial Function as part of a neuropsychological test battery. Domain-specific test scores were regressed onto age and WRAT score, or education, to define MCI. Survival analyses were used to relate baseline MCI to incident dementia.
The two MCI definitions differed most for the lowest and highest education groups. The WRAT definition was more strongly associated with incident dementia for all five tests. MCI-level Abstraction performance was associated with incident dementia using the WRAT definition (HR = 3.20, p = .033), but not the education definition (HR = 1.19, p = .814).
The WRAT should be considered along with the standard measure of years of education, as it may be a better surrogate marker of premorbid abilities.
Mild cognitive impairment; premorbid abilities; neuropsychological assessment; Alzheimer's disease; longitudinal
Background and Purpose
BDNF, a major neurotrophin and VEGF, an endothelial growth factor 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.
In 3440 stroke/TIA-free FHS participants (mean age 65±11yrs, 56%W), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological (NP) tests available (N=1863 and 2104, respectively; mean age 61±9yrs, 55%W, in each) we related baseline BDNF and logVEGF to log-white matter hyperintensity volume (lWMHV) on brain MRI, and to visuospatial memory and executive function tests.
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 (HR comparing BDNF Q1 versus Q2–4:1.47, 95%CI:1.09–2.00, p=0.012; and HR/SD increase in logVEGF:1.21, 95%CI:1.04–1.40, p=0.012). Persons with higher BDNF levels had less lWMHV (β±SE=−0.05±0.02; p=0.025), and better visual memory (β±SE=0.18±0.07; p=0.005).
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.
BDNF; VEGF; Risk; Stroke; Brain MRI; Subclinical
Background and purpose
Exposure to vascular risk factors has a gradual deleterious effect on brain MRI and cognitive measures. We explored whether a pattern of these measures exists that predicts stroke and Alzheimer’s disease (AD) risk.
A cognitive battery was administered to 1,679 dementia and stroke-free Framingham Offspring (age>55; mean=65.7±7.0) between 1999 and 2004; participants were also free of other neurological conditions that could affect cognition and >90% also had brain MRI examination. We related cognitive and MRI measures to risks of incident stroke and AD during up to 10 years of follow-up. As a secondary analysis, we explored these associations in the FHS Original cohort (mean age 67.5±7.3 and 84.8±3.3 at the cognitive assessment and MRI examination, respectively).
A total of 55 Offspring participants sustained strokes and 31 developed AD. Offspring who scored <1.5 standard-deviations below predicted mean scores, for age and education, on an executive function test, had a higher risk of future stroke (HR=2.27;95%CI:1.06–4.85) and AD (3.60;95%CI:1.52–8.52); additional cognitive tests also predicted AD. Participants with low (<20%ile) total brain volume and high (>20%ile) white matter hyperintensity volume had a higher risk of stroke (HR=1.97;95%CI:1.03–3.77 and HR=2.74;95%CI:1.51–5.00, respectively) but not AD. Hippocampal volume at the bottom quintile predicted AD in the Offspring and Original cohorts (HR=4.41;95%CI:2.00–9.72 and HR=2.37;95%CI:1.12–5.00, respectively). A stepwise increase in stroke risk was apparent with increasing numbers of these cognitive and imagingmarkers.
Specific patterns of cognitive and brain structural measures observed even in early aging predict stroke risk and may serve as biomarkers for risk prediction.
stroke; Alzheimer’s disease; cognitive function; brain MRI
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 p < 0.05). 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 p < 0.05). 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 (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05).
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.
We aimed to examine the association of APOE ε genotype with MRI markers of cerebrovascular disease (CVD): white matter hyperintensities, brain infarcts, and cerebral microbleeds.
We performed a systematic review and meta-analysis of 42 cross-sectional or longitudinal studies identified in PubMed from 1966 to June 2012 (n = 29,965). This included unpublished data from 3 population-based studies: 3C-Dijon, Framingham Heart Study, and Sydney Memory and Ageing Study. When necessary, authors were contacted to provide effect estimates for the meta-analysis.
APOE ε4 carrier status and APOE ε44 genotype were associated with increasing white matter hyperintensity burden (sample size–weighted z score meta-analysis [meta]-p = 0.0034 and 0.0030) and presence of cerebral microbleeds (meta odds ratio [OR] = 1.24, 95% confidence interval [CI] [1.07, 1.43], p = 0.004, and 1.87 [1.26, 2.78], p = 0.002), especially lobar. APOE ε2 carrier status was associated with increasing white matter hyperintensity load (z score meta-p = 0.00053) and risk of brain infarct (meta OR = 1.41[1.09, 1.81], p = 0.008).
APOE ε4 and APOE ε2 were associated with increasing burden in MRI markers for both hemorrhagic and ischemic CVD. While the association of APOE ε4 with an increased burden of CVD could be partly contributing to the relationship between APOE ε4 and AD, APOE ε2 was associated with MRI markers of CVD in the opposite direction compared to AD.
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.
discourse; naming; early markers; neuropathology; Alzheimer's disease
Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.
Methods and Results
We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).
Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.
In animal studies, brain-derived neurotrophic factor (BDNF) has been shown to impact neuronal survival and function and improve synaptic plasticity and long-term memory. Circulating BDNF levels increase with physical activity and caloric restriction, thus BDNF may mediate some of the observed associations between lifestyle and the risk for dementia. Some prior studies showed lower circulating BDNF in persons with Alzheimer disease (AD) compared with control participants; however, it remains uncertain whether reduced levels precede dementia onset.
To examine whether higher serum BDNF levels in cognitively healthy adults protect against the future risk for dementia and AD and to identify potential modifiers of this association.
DESIGN, SETTING, AND PARTICIPANTS
Framingham Study original and offspring participants were followed up from 1992 and 1998, respectively, for up to 10 years. We used Cox models to relate BDNF levels to the risk for dementia and AD and adjusted for potential confounders. We also ran sensitivity analyses stratified by sex, age, and education, as well as related BDNF genetic variants to AD risk. This community-based, prospective cohort study involved 2131 dementia-free participants aged 60 years and older (mean [SD] age, 72  years; 56% women).
MAIN OUTCOMES AND MEASURES
Ten-year incidence of dementia and AD.
During follow-up, 140 participants developed dementia, 117 of whom had AD. Controlling for age and sex, each standard-deviation increment in BDNF was associated with a 33% lower risk for dementia and AD (P = .006 and P = .01, respectively) and these associations persisted after additional adjustments. Compared with the bottom quintile, BDNF levels in the top quintile were associated with less than half the risk for dementia and AD (hazard ratio, 0.49; 95%CI, 0.28–0.85; P = .01; and hazard ratio, 0.46; 95%CI, 0.24–0.86; P = .02, respectively). These associations were apparent only among women, persons aged 80 years and older, and those with college degrees (hazard ratios for AD: 0.65, [95%CI, 0.50–0.85], P = .001; 0.63 [95%CI, 0.47–0.85], P = .002; and 0.27 [95%CI, 0.11–0.65], P = .003, respectively). Brain-derived neurotrophic factor genetic variants were not associated with AD risk.
CONCLUSIONS AND RELEVANCE
Higher serum BDNF levels may protect against future occurrence of dementia and AD. Our findings suggest a role for BDNF in the biology and possibly in the prevention of dementia and AD, especially in select subgroups of women and older and more highly educated persons.
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.
Elevated homocysteine (tHcy) is strongly associated with risk for common disorders such as stroke, cardiovascular disease and Alzheimer disease. Lowering tHcy levels has proven to have variable success in reducing clinical risk, so the question remains, “Are we correctly targeting these disorders by lowering tHcy?” Understanding folate one-carbon metabolism pathway (FOCM) genetic variation will aid us in developing new targets for therapy. The FOCM is essential in regulation of the epigenome, which controls genes in ways beyond nucleotide sequence. We present data generated from stroke-only and general populations where we identify strong association of genetic risk factors for variation in one-carbon metabolism function, characterized by the post-methionine load test. We show that GNMT harbors genetic and epigenetic differences that influence gene function, which may have downstream effects on the epigenome of the cell, affecting disease risk. We developed a genetic risk score that predicts post-methionine load homocysteine levels that may be useful in clinic. Finally, we identified a novel association between ischemic stroke and ALDH1L1, which emphasizes the clinical importance of this work. Our results highlight the importance of a concerted effort to target the FOCM (beyond tHcy) and parallel pathways in future pharmacogenetic work using the genetic variation we describe here.
In the present historical review, we highlight several articles outlining contributions of the Framingham Heart Study over the span of nearly seven decades to our understanding of the epidemiology of blood pressure (BP), atrial fibrillation and genetic factors as they relate to cerebrovascular disease. In 1970, Framingham investigators led by William Kannel, explored the epidemiological relations of BP and its various components to risk of ischemic stroke as well as hemorrhage, and noted the greater impact of hypertension to risk of stroke compared to other cardiovascular outcomes. Framingham investigators changed the prevalent concepts in terms of the contribution of BP components to stroke risk; i.e. they showed systolic pressure to be no less important a component for stroke risk than the diastolic or mean arterial pressures. In addition, they challenged the notion that hypertension was a normal consequence of increasing age, as connoted by the term “essential” hypertension. They also refuted the idea that blood pressure elevation in the elderly is innocuous by demonstrating that increased stroke risk persisted in advanced age in hypertensive persons. Thirty years later, the Framingham Study attained long term follow up of an entire generation of participants with excellent retention to follow-up, thus providing an opportunity to study hypertension and risk of stroke in a general population sample. Framingham investigators examined the impact of various BP components over a 50-year follow-up in normotensive and untreated hypertensive individuals as regards stroke risk, and showed the long term importance of antecedent (midlife) hypertension in future stroke risk . Similarly by calling attention to the importance of chronic non-valvular atrial fibrillation as a contributor to stroke, particularly in the elderly, FHS investigators confirmed the clinical observations of the founder of stroke neurology, C. Miller Fisher, M.D., who had made the clinical and pathological association of AF to stroke. Lastly, in the dawn of the era of individualized preventive medicine, FHS is participating in the effort to further our understanding of the role of genetic factors to stroke incidence.
The contributions of the Framingham Heart Study have been many and have shaped our understanding of the relation of BP, AF and other risk factors to stroke risk, thereby setting the stage for clinical trials which demonstrated how control of these risk contributors could prevent stroke and enable stroke prevention. FHS investigators are collaborating with other geneticists and epidemiologists internationally to elucidate the role of genetic factors and stroke susceptibility, which is likely continue to shape the practice of preventive cardiovascular medicine.
Background and purpose
Parental stroke has been related to an increased risk of stroke in the offspring. This study examines whether parental stroke is also associated with increased vascular brain injury and poorer cognitive performance among offspring free of clinical stroke.
Multivariable regression analyses were used to relate parental stroke to cross-sectional and change in brain magnetic resonance imaging measures and cognitive function among the offspring, with and without adjustment for vascular risk factors.
Stroke- and dementia-free Framingham Offspring (n=1,297, age:61±9 years, 54% women) were studied. Parental stroke by age 65 years was associated with a higher baseline white matter hyperintensity volume (WMHV;β=0.17±0.08; p=0.027), and with lower visual memory performance (β =−0.80±0.34; p=0.017). During a 6 year follow-up, parental stroke was also associated with increase in WMHV (odds ratio [OR] = 1.87;95%CI:1.03–3.38) and decline in executive function (Trails B–A; OR=1.81;95%CI:1.06–3.09). The associations with WMHV and visual memory attenuated after additional adjustment for concomitant vascular risk factors.
Parental stroke by age 65 years is associated with increased vascular brain injury and lower memory in offspring equivalent to 3 and 7 years of brain aging, respectively. This may be partly attributed to inheritance of vascular risk factors.
stroke; cognitive function; brain MRI
This study aimed to determine whether relationships between obesity, as measured by waist-to-hip ratio (WHR), and cognition and brain structure were modified by the apolipoprotein epsilon 4 allele (apoE4). The sample included 1,969 stroke and dementia-free participants from the Framingham Offspring Cohort who underwent neuropsychological (NP) testing and structural Magnetic Resonance Imaging (MRI) between 1999–2002. WHR was categorized into sex-specific quartiles with those in Q4 representing central obesity. Multivariate linear regression estimated the relationships between Q4-WHR, cognitive and MRI measures; interaction terms examined modification of these relationships by the presence of apoE4. All analyses were cross sectional.
ApoE4 status significantly modified a number of associations. Specifically, we observed a significant negative relationship between Q4-WHR and a measure of executive function in the apoE4+ group but not in the apoE4− group. Similarly, we observed a stronger negative relationship between Q4-WHR and a measure of memory function for those in the apoE4+ group compared to those in the apoE4− group. Additionally, apoE4 status modified the relationship between Q4-WHR and two measures of structural brain integrity. First, a paradoxical finding of a negative association between WHR and frontal brain volume that was significant only for those in the apoE4- group, and a second finding that WHR was significantly associated with greater white matter hyperintensity volume only in the apoE4+ group.
These findings suggest that associations between central adiposity and both neuropsychological performance and underlying brain structure are highly complex and must be considered in the context of possible modifying genetic influences.
waist-to-hip ratio; apoE4; metabolic syndrome; obesity; Alzheimer’s disease
The study of Alzheimer 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 7 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.
Cohort Studies; Alzheimer's disease; Risk factors; Cerebrovascular Disorders; Genetic variation
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-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 while 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 datasets are included, stratified by age and educational achievement, for which to compare qualitative test performance of clinical and research populations.
Background and Purpose
Cerebral microbleeds (CMBs) due to cerebral amyloid angiopathy generally occur in lobar regions, while those due to hypertensive vasculopathy are deep. Inflammation may be an underlying mechanism for CMB, with varying associations according to CMB location. Lipoprotein phospholipase-A2 (Lp-PLA2) is a circulating enzyme marker of vascular inflammation associated with risk of ischemic stroke and dementia. We hypothesized that higher Lp-PLA2 levels would be related to higher prevalence of CMBs, with possible regional specificity.
Framingham Offspring participants aged ≥65 years with available Lp-PLA2 measures and brain MRI were included. Logistic regression models were used to relate Lp-PLA2 activity and mass to presence of CMBs, adjusted for age, sex, medication use (aspirin, anticoagulants, and statins), systolic blood pressure, APOE, current smoking, and diabetes.
819 participants (mean age 73 years; 53% women) were included; 106 (13%) had CMBs; 82 (10%) lobar and 27 (3%) deep. We did not observe significant associations of CMB and LpPLA2 measures in multivariable adjusted analyses. However, there was a significant interaction between APOE genotype and Lp-PLA2 activity in their relation to presence of deep CMBs (p-interaction=0.01). Among persons with APOE ε3/ε3, the OR for deep CMB was 0.95 [0.59–1.53; p=0.83], while among those with at least one ε2 or ε4 allele, OR=3.46 [1.43–8.36; p=0.006].
In our community-based sample of older adults, there was no significant association of Lp-PLA2 with total or lobar CMBs. The association of higher levels of Lp-PLA2 activity with deep CMBs among those with at least one APOE ε2 or ε4 allele merits replication.
Common carotid artery (CCA) intima-media thickness (cIMT), a measure of atherosclerosis, varies between peak-systole (PS) and end-diastole (ED). This difference might affect cardiovascular risk assessment.
Materials and methods
IMT measurements of the right and left CCA were synchronized with an electrocardiogram: R-wave for ED and T-wave for PS. IMT was measured in 2930 members of the Framingham Offspring Study. Multivariable regression models were generated with ED-IMT, PS-IMT and change in IMT as dependent variables and Framingham risk factors as independent variables. ED-IMT estimates were compared to the upper quartile of IMT based on normative data obtained at PS.
The average age of our population was 57.9 years. Average difference in IMT during the cardiac cycle was 0.037 mm (95% CI: 0.035–0.038 mm). ED-IMT and PS-IMT had similar associations with Framingham risk factors (total R2= 0.292 versus 0.275) and were significantly associated with all risk factors. In a fully adjusted multivariable model, a thinner IMT at peak-systole was associated with pulse pressure (p < 0.0001), LDL-cholesterol (p = 0.0064), age (p = 0.046), and no other risk factors. Performing ED-IMT measurements while using upper quartile PS-IMT normative data lead to inappropriately increasing by 42.1% the number of individuals in the fourth IMT quartile (high cardiovascular risk category).
The difference in IMT between peak-systole and end-diastole is associated with pulse pressure, LDL-cholesterol, and age. In our study, mean IMT difference during the cardiac cycle lead to an overestimation by 42.1% of individuals at high risk for cardiovascular disease.
Ultrasonics; Risk Factors; Carotid Arteries; Blood Pressure; systole; diastole
While the Clock Drawing Test (CDT) is a popular tool used to assess cognitive function, limited normative data on CDT performance exists. The objective of the current study was to provide normative data on an expanded version of previous CDT scoring protocols from a large community-based sample of middle to older adults (aged 43 to 91) from the Framingham Heart Study.
The CDT was administered to 1476 Framingham Heart Study Offspring Cohort participants using a scoring protocol that assigned error scores to drawn features. Total error scores were computed, as well as for subscales pertaining to outline, numeral placement, time-setting, center, and “other.”
Higher levels of education were significantly associated with fewer errors for time-setting (Command: p<.001; Copy: p=.003), numerals (Command: p<.001) and “other” (Command: p<.001) subscales. Older age was significantly associated with more errors for time-setting (Command: p<.001; Copy: p=.003), numeral (Command: p<.001) and “other” (Command: p<.001) subscales. Significant differences were also found between education groups on the Command condition for all but the oldest age group (75+).
Results provide normative data on CDT performance within a community-based cohort. Errors appear to be more prevalent in older compared with younger individuals, and may be less prevalent in individuals who completed at least some college compared with those who did not. Future studies are needed to determine whether this expanded scoring system allows detection of preclinical symptoms of future risk for dementia.
Clock Drawing Test; Normal aging; Scoring methods; Neuropsychological tests; Dementia; Cognitive screening
Background/objective: Transient global amnesia (TGA) is a temporary amnestic syndrome characterized by lack of other focal neurological deficits. Cerebrovascular disease, migraine and seizures have been suggested as underlying mechanisms. TGA may be a risk factor for cerebrovascular or other neurological events. We studied the relation of TGA, vascular risk factors, brain magnetic resonance imaging (MRI) indices of subclinical ischemia and neurological events in a community-based sample.
Design/setting: A total of 12 TGA cases were ascertained using standard criteria by experienced neurologists, and matched to 41 stroke- and seizure-free controls. Vascular risk factors, brain MRI findings, and subsequent cerebrovascular or seizure events were compared in cases and controls.
Participants: Framingham Heart Study (FHS) original and offspring cohort participants were included.
Results: No significant differences between the groups were observed in the prevalence of vascular risk factors, or brain MRI measures. Few incident stroke/transient ischemic attacks (TIA) (one event among the cases and four in controls) or subsequent seizures occurred in either group. Head CT during the acute event (n = 11) and brain MRI (n = 7) were negative for acute abnormalities. Electroencephalograms (EEG) (n = 5) were negative for epileptiform activity. Extracranial vascular studies were negative for significant stenosis in all cases.
Conclusion: In our community-based study TGA was not related to traditional vascular risk factors, or cerebrovascular disease. However, our study is limited by small sample size and power, and larger studies are required to exclude an association.
transient global amnesia; cerebrovascular disease; stroke; TIA; Brain MRI