Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study.

ObjectiveDiabetic 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 methodsFramingham 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).ResultsWe 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).ConclusionsMetabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort

Association of Metabolic Dysregulation With Volumetric Brain Magnetic Resonance Imaging and Cognitive Markers of Subclinical Brain Aging in Middle-Aged Adults

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

Using Family-Based Imputation in Genome-Wide Association Studies with Large Complex Pedigrees: The Framingham Heart Study

Imputation has been widely used in genome-wide association studies (GWAS) to infer genotypes of un-genotyped variants based on the linkage disequilibrium in external reference panels such as the HapMap and 1000 Genomes. However, imputation has only rarely been performed based on family relationships to infer genotypes of un-genotyped individuals. Using 8998 Framingham Heart Study (FHS) participants genotyped with Affymetrix 550K SNPs, we imputed genotypes of same set of SNPs for additional 3121 participants, most of whom were never genotyped due to lack of DNA sample. Prior to imputation, 122 pedigrees were too large to be handled by the imputation software Merlin. Therefore, we developed a novel pedigree splitting algorithm that can maximize the number of genotyped relatives for imputing each un-genotyped individual, while keeping new sub-pedigrees under a pre-specified size. In GWAS of four phenotypes available in FHS (Alzheimer disease, circulating levels of fibrinogen, high-density lipoprotein cholesterol, and uric acid), we compared results using genotyped individuals only with results using both genotyped and imputed individuals. We studied the impact of applying different imputation quality filtering thresholds on the association results and did not found a universal threshold that always resulted in a more significant p-value for previously identified loci. However most of these loci had a lower p-value when we only included imputed genotypes with with ≥60% SNP- and ≥50% person-specific imputation certainty. In summary, we developed a novel algorithm for splitting large pedigrees for imputation and found a plausible imputation quality filtering threshold based on FHS. Further examination may be required to generalize this threshold to other studies

Interrelations Between Arterial Stiffness, Target Organ Damage, and Cardiovascular Disease Outcomes

Background-Excess transmission of pressure pulsatility caused by increased arterial stiffness may incur microcirculatory damage in end organs (target organ damage [TOD]) and, in turn, elevate risk for cardiovascular disease (CVD) events.Methods and Results-We related arterial stiffness measures (carotid-femoral pulse wave velocity, mean arterial pressure, central pulse pressure) to the prevalence and incidence of TOD (defined as albuminuria and/or echocardiographic left ventricular hypertrophy) in up to 6203 Framingham Study participants (mean age 50 +/- 15 years, 54% women). We then related presence of TOD to incident CVD in multivariable Cox regression models without and with adjustment for arterial stiffness measures. Cross-sectionally, greater arterial stiffness was associated with a higher prevalence of TOD (adjusted odds ratios ranging from 1.23 to 1.54 per SD increment in arterial stiffness measure, P<0.01). Prospectively, increased carotid-femoral pulse wave velocity was associated with incident albuminuria (odds ratio per SD 1.28, 95% CI, 1.02-1.61; P<0.05), whereas higher mean arterial pressure and central pulse pressure were associated with incident left ventricular hypertrophy (odds ratio per SD 1.37 and 1.45, respectively; P<0.01). On follow-up, 297 of 5803 participants experienced a first CVD event. Presence of TOD was associated with a 33% greater hazard of incident CVD (95% CI, 0-77%; P<0.05), which was attenuated upon adjustment for baseline arterial stiffness measures by 5-21%.Conclusions-Elevated arterial stiffness is associated with presence of TOD and may partially mediate the relations of TOD with incident CVD. Our observations in a large community-based sample suggest that mitigating arterial stiffness may lower the burden of TOD and, in turn, clinical CVD

Circulating brain‐derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community

BACKGROUND: Brain‐derived neurotrophic factor (BDNF) is a pleiotropic peptide involved in maintaining endothelial integrity. It is unknown if circulating BDNF levels are associated with risk of cardiovascular disease (CVD). METHODS AND RESULTS: We prospectively investigated the association of circulating BDNF levels with cardiovascular events and mortality in 3687 participants (mean age 65 years, 2068 women) from the Framingham Heart Study (FHS). Using a common nonsynonomous single nucleotide polymorphism (SNP) in the BDNF gene (rs6265), we then performed a Mendelian randomization experiment in the CARDIoGRAM (Coronary ARtery DIsease Genome‐Wide Replication And Meta‐Analysis) consortium (>22 000 coronary artery disease [CAD] cases, >60 000 controls) to investigate whether SNP rs6265 was associated with CAD in CARDIoGRAM and, if so, whether the effect estimate differed from that predicted based on FHS data. On follow‐up (median 8.9 years), 467 individuals (261 women) in FHS experienced a CVD event, and 835 (430 women) died. In multivariable‐adjusted Cox regression, serum BDNF was associated inversely with CVD risk (hazard ratio [HR] per 1‐SD increase 0.88, 95% CI 0.80 to 0.97, P=0.01) and with mortality (HR 0.87, 95% CI 0.80 to 0.93, P=0.0002). SNP rs6265 was associated with BDNF concentrations (0.772 ng/mL increase per minor allele copy) in FHS. In CARDIoGRAM, SNP rs6265 was associated with CAD (odds ratio 0.957, 95% CI 0.923 to 0.992), a magnitude consistent with the predicted effect (HR per minor allele copy 0.99, 95% CI 0.98 to 1.0; P=0.06 for difference between predicted and observed effect). CONCLUSION: Higher serum BDNF is associated with a decreased risk of CVD and mortality. Mendelian randomization suggests a causal protective role of BDNF in the pathogenesis of CVD

Circulating ceramide ratios and risk of vascular brain aging and dementia

BACKGROUND: We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer\u27s disease (AD) dementia in a large, community-based sample. METHODS: We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. RESULTS: During a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox-proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56-0.96) and AD dementia (HR 0.73, 95% CI 0.53-1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57-0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53-1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross-sectionally associated with lower white matter hyperintensity burden on MRI (-0.05 ± 0.02, P = 0.02; -0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. CONCLUSIONS: Higher plasma ratios of very long-chain to long-chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community-based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults

Atrial fibrillation without comorbidities: Prevalence, incidence and prognosis (from the Framingham Heart Study)

BACKGROUND: The epidemiology of atrial fibrillation (AF) without comorbidities, known as \u27lone AF\u27, is uncertain. Although it has been considered a benign condition, we hypothesized that it confers a worse prognosis compared with a matched sample without AF. METHODS: We described the proportion of AF without comorbidities (clinical, subclinical cardiovascular disease and triggers) among the entire AF sample in Framingham Heart Study (FHS). We compared AF without comorbidities with typical AF, and age-, sex- and cohort-matched individuals without AF, using Cox proportional hazards analysis in relation to combined cardiovascular events (stroke, heart failure, myocardial infarction), and mortality. RESULTS: Of 10,311 FHS participants, 1,961 were diagnosed with incident AF, among which 173 individuals had AF without comorbidities (47% women, mean age 71+/-12 years). AF without comorbidities had a prevalence of 1.7% of the entire cohort, and an annual incidence of 0.5 per 1000 person-years. During a median follow-up of 9.7 years after initial AF, 137 individuals with AF without comorbidities (79.2%) died and 141 individuals developed cardiovascular events (81.5%). AF without comorbidities had significantly lower mortality (HR 0.67, 95%CI 0.55-0.81, P \u3c .001) and total cardiovascular events (HR 0.66, 95% CI 0.55-0.80, P \u3c .001) compared with typical AF. However, mortality (HR1.43, 95% CI 1.18-1.75, P \u3c .001) and risk of total cardiovascular events (HR 1.73, 95% CI 1.39-2.16, P \u3c .001) were higher than age-, sex-, and cohort-matched individuals without AF. CONCLUSIONS: The risk of cardiovascular outcomes and mortality among individuals with AF without comorbidities is lower than typical AF, but is significantly elevated compared with matched individuals without AF

Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging:The Cross-Cohort Collaboration

Background and purpose:Prior studies reported conflicting findings regarding the association of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis with measures of brain health. We examined whether NAFLD and liver fibrosis are associated with structural brain imaging measures in middle- and old-age adults. Methods: In this cross-sectional study among dementia- and stroke-free individuals, data were pooled from the Offspring and Third Generation cohorts of the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Study of Health in Pomerania. NAFLD was assessed through abdominal imaging. Transient hepatic elastography (FibroScan) was used to assess liver fibrosis in FHS and RS. Linear regression models were used to explore the relation of NAFLD and liver fibrosis with brain volumes, including total brain, gray matter, hippocampus, and white matter hyperintensities, adjusting for potential confounders. Results were combined using fixed effects meta-analysis. Results:In total, 5660 and 3022 individuals were included for NAFLD and liver fibrosis analyses, respectively. NAFLD was associated with smaller volumes of total brain (β = −3.5, 95% confidence interval [CI] = −5.4 to −1.7), total gray matter (β = −1.9, 95% CI = −3.4 to −0.3), and total cortical gray matter (β = −1.9, 95% CI = −3.7 to −0.01). In addition, liver fibrosis (defined as liver stiffness measure ≥8.2 kPa) was related to smaller total brain volumes (β = −7.3, 95% CI = −11.1 to −3.5). Heterogeneity between studies was low. Conclusions:NAFLD and liver fibrosis may be directly related to brain aging. Larger and prospective studies are warranted to validate these findings and identify liver-related preventive strategies for neurodegeneration.</p

Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes

BACKGROUND:Cardiovascular disease (CVD) and its most common manifestations - including coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) - are major causes of morbidity and mortality. In many industrialized countries, cardiovascular disease (CVD) claims more lives each year than any other disease. Heart disease and stroke are the first and third leading causes of death in the United States. Prior investigations have reported several single gene variants associated with CHD, stroke, HF, and AF. We report a community-based genome-wide association study of major CVD outcomes.METHODS:In 1345 Framingham Heart Study participants from the largest 310 pedigrees (54% women, mean age 33 years at entry), we analyzed associations of 70,987 qualifying SNPs (Affymetrix 100K GeneChip) to four major CVD outcomes: major atherosclerotic CVD (n = 142; myocardial infarction, stroke, CHD death), major CHD (n = 118; myocardial infarction, CHD death), AF (n = 151), and HF (n = 73). Participants free of the condition at entry were included in proportional hazards models. We analyzed model-based deviance residuals using generalized estimating equations to test associations between SNP genotypes and traits in additive genetic models restricted to autosomal SNPs with minor allele frequency [greater than or equal to]0.10, genotype call rate [greater than or equal to]0.80, and Hardy-Weinberg equilibrium p-value [greater than or equal to] 0.001.RESULTS:Six associations yielded p <10-5. The lowest p-values for each CVD trait were as follows: major CVD, rs499818, p = 6.6 x 10-6; major CHD, rs2549513, p = 9.7 x 10-6; AF, rs958546, p = 4.8 x 10-6; HF: rs740363, p = 8.8 x 10-6. Of note, we found associations of a 13 Kb region on chromosome 9p21 with major CVD (p 1.7 - 1.9 x 10-5) and major CHD (p 2.5 - 3.5 x 10-4) that confirm associations with CHD in two recently reported genome-wide association studies. Also, rs10501920 in CNTN5 was associated with AF (p = 9.4 x 10-6) and HF (p = 1.2 x 10-4). Complete results for these phenotypes can be found at the dbgap website http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:No association attained genome-wide significance, but several intriguing findings emerged. Notably, we replicated associations of chromosome 9p21 with major CVD. Additional studies are needed to validate these results. Finding genetic variants associated with CVD may point to novel disease pathways and identify potential targeted preventive therapies

Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts

Introduction: Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease. Methods: We studied eight prospective cohorts with 22,623 participants profiled by n