Framingham Heart Study Research Articles

Correlation among job-induced stress, overall well-being, and cardiovascular risk in Italian workers of logistics and distribution.

Work-related stress is an occupational risk that has been linked to the development of cardiovascular disease (CVD). While previous studies have explored this association in various work contexts, none have focused specifically on logistics and distribution personnel. These workers may be exposed to significant job stress, which potentially increases the risk of CVD. In this study, we aimed to examine the relationship between work-related stress and cardiovascular risk in a sample of 413 healthy workers of a logistics and distribution company. To assess work-related stress and cardiovascular risk, we used the organisational well-being questionnaire proposed by the Italian National Anti-Corruption Authority, the Framingham Heart Study General Cardiovascular Disease (CVD) Risk Prediction Score and the WHO General Wellbeing Index (WHO-5). Our results revealed that individuals with low job support had a significantly higher CVD risk score and lower well-being index than those reporting high job support. Furthermore, workers with high-stress tasks showed higher well-being index scores than those with passive tasks. Approximately 58% of the subjects were classified as low CVD risk (CVD risk <10%), approximately 31% were classified as moderate risk (CVD risk between 10 and 20%) and 11% were considered high risk (CVD risk >20%). The overall median CVD risk for the population was moderate (6.9%), with individual scores ranging from 1 to 58%. Further analyses confirmed the protective effect of work support, also identifying physical inactivity, regular alcohol consumption and low educational level as factors contributing to an increased risk of CVD. Interestingly, factors such as job control and work support demonstrated a positive impact on psychological well-being. These results emphasise the importance of intervention strategies aimed at promoting health in the workplace. By addressing these combined factors, organisations can effectively reduce the risk of CVD and improve the general well-being of their workforce.

Association of Arterial Stiffness With Mid- to Long-Term Home Blood Pressure Variability in the Electronic Framingham Heart Study: Cohort Study.

Short-term blood pressure variability (BPV) is associated with arterial stiffness in patients with hypertension. Few studies have examined associations between arterial stiffness and digital home BPV over a mid- to long-term time span, irrespective of underlying hypertension. This study aims to investigate if arterial stiffness traits were associated with subsequent mid- to long-term home BPV in the electronic Framingham Heart Study (eFHS). We hypothesized that higher arterial stiffness was associated with higher home BPV over up to 1-year follow-up. At a Framingham Heart Study research examination (2016-2019), participants underwent arterial tonometry to acquire measures of arterial stiffness (carotid-femoral pulse wave velocity [CFPWV]; forward pressure wave amplitude [FWA]) and wave reflection (reflection coefficient [RC]). Participants who agreed to enroll in eFHS were provided with a digital blood pressure (BP) cuff to measure home BP weekly over up to 1-year follow-up. Participants with less than 3 weeks of BP readings were excluded. Linear regression models were used to examine associations of arterial measures with average real variability (ARV) of week-to-week home systolic (SBP) and diastolic (DBP) BP adjusting for important covariates. We obtained ARV as an average of the absolute differences of consecutive home BP measurements. ARV considers not only the dispersion of the BP readings around the mean but also the order of BP readings. In addition, ARV is more sensitive to measurement-to-measurement BPV compared with traditional BPV measures. Among 857 eFHS participants (mean age 54, SD 9 years; 508/857, 59% women; mean SBP/DBP 119/76 mm Hg; 405/857, 47% hypertension), 1 SD increment in FWA was associated with 0.16 (95% CI 0.09-0.23) SD increments in ARV of home SBP and 0.08 (95% CI 0.01-0.15) SD increments in ARV of home DBP; 1 SD increment in RC was associated with 0.14 (95% CI 0.07-0.22) SD increments in ARV of home SBP and 0.11 (95% CI 0.04-0.19) SD increments in ARV of home DBP. After adjusting for important covariates, there was no significant association between CFPWV and ARV of home SBP, and similarly, no significant association existed between CFPWV and ARV of home DBP (P>.05). In eFHS, higher FWA and RC were associated with higher mid- to long-term ARV of week-to-week home SBP and DBP over 1-year follow-up in individuals across the BP spectrum. Our findings suggest that higher aortic stiffness and wave reflection are associated with higher week-to-week variation of BP in a home-based setting over a mid- to long-term time span.

Association of bone fracture with 30-year body mass index (BMI) trajectories: findings from the Framingham Heart Study : Bone fracture and 30-year BMI trajectories.

Numerous studies on the relationship between obesity and fractures have relied on body mass index (BMI) at a single time point, yielding inconclusive results. This study investigated the association of BMI trajectories over middle adulthood with fracture risk in late adulthood. This prospective cohort study analyzed 1772 qualified participants from the Framingham Original Cohort Study, with 292 (16.5%) incident fractures during an average of 17.1-year follow-up. We constructed BMI trajectories of age 35-64years based on latent class mixed modeling and explored their association with the risk of fracture after 65years using the Cox regression. The result showed that compared to the BMI trajectory Group 4 (normal to slightly overweight; see "Methods" for detailed description), Group 1 (overweight declined to normal weight) had a higher all-fracture risk after age 65 (hazard ratio [HR], 2.22, 95% CI, 1.13-4.39). The secondary analysis focusing on lower extremity fractures (pelvis, hip, leg, and foot) showed a similar association pattern. This study suggested that people whose BMI slightly increased from normal weight to low-level overweight during 30years of middle adulthood confer a significantly lower risk of fracture in later life than those whose BMI declined from overweight to normal weight. This result implies the potentially beneficial effects of avoiding weight loss to normal weight during middle adulthood for overweight persons, with reduced fracture risk in late life.

Impaired kidney function, cerebral small vessel disease and cognitive disorders: the Framingham Heart Study.

It remains unclear whether the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD), and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants. We included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain magnetic resonance imaging late in life (exam cycles 7-9), cognitive outcome data, and available interim hypertension and BP assessments. We related CKD (estimated glomerular filtration rate <60ml/min/1.73m2) and albuminuria (urine albumin-to-creatinine ratio ≥30mg/g) to CSVD markers and cognitive outcomes using multivariable regression analyses. Among 2604 participants (mean age 67.4±9.2, 64% women, 7% had CKD, and 9% albuminuria), albuminuria was independently associated with covert infarcts [adjusted OR, 1.55 (1.00-2.38); P=0.049] and incident MCI and dementia [adjusted hazard ratio (HR), 1.68 (1.18-2.41); P=0.005 and 1.71, (1.11-2.64); P=0.015, respectively]. CKD was not associated with CSVD markers but was associated with a higher risk of incident dementia [HR, 1.53 (1.02-2.29); P=0.041]. While albuminuria was predictive of the Alzheimer's disease subtype [adjusted HR=1.68, (1.03-2.74); P=0.04), CKD was predictive of vascular dementia [adjusted HR, 2.78 (1.16-6.68); P=0.023]. Kidney disease was associated with CSVD and cognitive disorders in asymptomatic community dwelling participants. The relation was independent of premorbid BP, suggesting that the link between kidney and brain disease may involve additional mechanisms beyond BP-related injury.

Gut microbiome and metabolome profiling in Framingham heart study reveals cholesterol-metabolizing bacteria

Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and invitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health.

Trends in Intracranial and Cerebral Volumes of Framingham Heart Study Participants Born 1930 to 1970

Human brain development and maintenance is under both genetic and environmental influences that likely affect later-life dementia risk. To examine environmental influences by testing whether time-dependent secular differences occurred in cranial and brain volumes and cortical thickness over birth decades spanning 1930 to 1970. This cross-sectional study used data from the community-based Framingham Heart Study cohort for participants born in the decades 1930 to 1970. Participants did not have dementia or history of stroke and had magnetic resonance imaging (MRI) obtained from March 18, 1999, to November 15, 2019. The final analysis dataset was created in October 2023. Years of birth ranging from 1925 to 1968. Cross-sectional analysis of intracranial, cortical gray matter, white matter, and hippocampal volumes as well as cortical surface area and cortical thickness. The secular measure was the decade in which the participant was born. Covariates included age at MRI and sex. The main study cohort consisted of 3226 participants with a mean (SD) age of 57.7 (7.8) years at the time of their MRI. A total of 1706 participants were female (53%) and 1520 (47%) were male. The birth decades ranged from the 1930s to 1970s. Significant trends for larger intracranial, hippocampal, and white matter volumes and cortical surface area were associated with progressive birth decades. Comparing the 1930s birth decade to the 1970s accounted for a 6.6% greater volume (1234 mL; 95% CI, 1220-1248, vs 1321 mL; 95% CI, 1301-1341) for ICV, 7.7% greater volume (441.9 mL; 95% CI, 435.2-448.5, vs 476.3 mL; 95% CI, 467.0-485.7) for white matter, 5.7% greater value (6.51 mL; 95% CI, 6.42-6.60, vs 6.89 mL; 95% CI, 6.77-7.02) for hippocampal volume, and a 14.9% greater value (1933 cm2; 95% CI, 1908-1959, vs 2222 cm2; 95% CI, 2186-2259) for cortical surface area. Repeat analysis applied to a subgroup of 1145 individuals of similar age range born in the 1940s (mean [SD] age, 60.0 [2.8] years) and 1950s (mean [SD] age, 59.0 [2.8] years) resulted in similar findings. In this study, secular trends for larger brain volumes suggested improved brain development among individuals born between 1930 and 1970. Early life environmental influences may explain these results and contribute to the declining dementia incidence previously reported in the Framingham Heart Study cohort.

Abstract 61: Differential Associations of Cardiovascular Health Factors With Vascular Health in Adults Free of Cardiovascular Disease

Background: There is limited understanding of the association of the AHA's Life's Essential 8 (LE8), reflecting cardiovascular health (CVH) behaviors and factors, with vascular stiffness and hemodynamics in adults without cardiovascular diseases (CVD). Methods: In 2330 Framingham Heart Study Offspring participants (Exam 7, 1998-2002) with applanation tonometry and LE8 data (diet, physical activity, smoking, sleep health, BMI, lipids, glucose, blood pressure), we calculated CVH scores per AHA guidelines. In multivariable linear regression analyses adjusting for CV risk factors, we analyzed LE8 as a predictor of vascular health, assessed by carotid femoral pulse wave velocity (PWV) and central pulse pressure (CPP). We examined for effect modification by age (dichotomized at median) and sex in the associations between LE8 and arterial stiffness. We set p=0.05 and p=0.10 as thresholds for significance in primary and secondary analyses, respectively. Mediation analysis was utilized to discern the indirect effects of PWV and CPP on the relationship between LE8 and both all-cause and CVD mortality. Results: In our sample (60±9 years; 57% women; LE8 = 69±12), higher LE8 indicating better CVH, was associated with lower PWV and CPP (Table). Age and sex interactions were noted for PWV (p=0.01 and 0.07, respectively). Higher LE8 was associated with lower PWV in adults ≥59 years and women but not in &lt;59 years or men (Table). With low CVH category as referent, intermediate CVH category had no significant association with PWV and high CVH category had lower PWV. CPP was lower in the intermediate and high CVH categories compared to low CVH category (Table). PWV mediated 19% and CPP 10% of the association between LE8 and CVD mortality and 17% and 15%, respectively, for all-cause mortality. Conclusion: In our community cohort, we observed age and sex differences in the relationship between CVH and vascular health. Mediation analyses revealed indirect effects on mortality, warranting further study. Table

Abstract MP19: Patterns of Early-Onset and Late-Onset Dementia Incidence in the Dementia Risk Pooling Project

Introduction: Early-onset dementia (EOD) is defined as dementia diagnosed before age 65. While much is known about late-onset dementia (LOD), research on EOD is scarce. The Dementia Risk Pooling Project (DRPP) harmonized data from nine community-based prospective studies, including under-represented racial/ethnic groups. We hypothesized that EOD incidence rates are higher for men than women, and non-Hispanic (NH) Black participants than other race/ethnicity groups. Methods: We used data from eight DRPP cohorts: Age, Gene/Environment Susceptibility-Reykjavik Study, Whitehall II study, Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Honolulu-Asia Aging Study, Multi-Ethnic Study of Atherosclerosis, Sacramento Area Latino Study on Aging, and six Framingham Heart Study cohorts. Individual data were pooled and rigorously harmonized. Race/ethnicity was categorized as self-reported Hispanic, NH White, NH Black, and NH other/unknown. Crude incidence rates and ratios were calculated per 10,000 person-years with 95% confidence intervals. Results: The analytic sample consisted of 56,607 participants, who experienced 7,504 cases of LOD and 124 cases of EOD over a median follow-up of 19.13 (IQR 10.46 - 31.11) years. EOD and LOD incidence rates per 10,000 person-years were 1.95 (95% CI 1.62 - 2.32) and 123.35 (95% CI 120.49 - 126.26), respectively. Compared to women, men had 1.17 (95% CI 0.82 - 1.66) times the rate of EOD but 0.82 (95% CI 0.79 - 0.86) times the rate of LOD. Similarly, compared to NH Whites, Hispanics and participants of other or unknown race/ethnicity had higher rates of EOD but lower rates of LOD. NH Blacks had a higher rate of both EOD and LOD compared to NH Whites, but the association with EOD was more pronounced. Conclusion: In this multi-cohort study with individual participant data, EOD and LOD incidence rates were different across sex and race/ethnicity groups. Some of these differences may be due to longer life expectancy in women and some race/ethnicity groups.

Abstract P434: Prediabetes and Diabetes Are Associated With Distinct Gut Microbial Composition in the Framingham Heart Study

Little is known about how the gut microbiome may be associated with impaired glucose regulation (prediabetes and type 2 diabetes). Relative to normoglycemic individuals, prediabetes and diabetes will be associated with distinct microbial composition, which will provide incremental value in classifying glycemic status. We included 1265 Framingham Heart Study participants (mean age 55 yr, 56% female) with 16S rRNA gene sequencing performed on stool samples. Glycemic status was characterized as normoglycemia (&lt;100mg/dL glucose or &lt;5.7 HbA1c), prediabetes (100-125mg/dL glucose or 5.7-6.5 HbA1c), diabetes (&gt;=126mg/dL glucose, &gt;=6.5 HbA1c, or self-reported diabetes diagnosis/medication). MANOVA was used to characterize the differential abundance of microbial composition and diversity by glycemic status. Microbial diversity was characterized by α- and β-diversity (Shannon and Bray-Curtis index) and richness. We used elastic net regression and generated c-statistics to determine the utility of gut microbial composition and diversity in classifying glycemic status while adjusting for age, sex, antibiotic use, waist circumference, hypertension/lipid-lowering medication (model 1). The prevalence of prediabetes and diabetes was 368 (29%) and 113 (9%), respectively. Compared to model 1, differential abundance at the family domain was associated with a moderate improvement in classifying participants by glycemic status (c-statistic: 0.78 vs 0.80). We observed a differential abundance of 16 bacteria families between diabetes/normoglycemia, 6 between prediabetes/diabetes, and 3 between normoglycemic/prediabetes, but microbial diversity did not differ. The abundance of Ruminococcacease and Enterobacteriaceae were the top bacterial contributors to glycemic status prediction. Glycemic status was associated with distinct patterns of microbial composition. The presence of diabetes was associated with a lower abundance of butyrate-producing bacteria, which may be linked to glycemic control.

Abstract P251: Circulating Immune Cell Phenotypes Are Associated With Inflammatory Biomarkers in the Framingham Heart Study Offspring Cohort

Age-related changes in circulating immune cells have been associated with inflammation and immunosenescence, increasing susceptibility to cardiovascular disease. This study investigated the association between circulating immune cell phenotypes and inflammatory biomarkers in the Framingham Heart Study Offspring cohort. Participants (N=865, 52% female, mean age 62) were immunophenotyped using peripheral blood mononuclear cells with 37 immune cell phenotypes and 6 composite ratio measures, including T cells, B cells, NK cells, and monocytes. The inflammatory biomarkers were profiled in plasma samples using the OLINK Proteomics inflammation panel. Pairwise cross-sectional associations between 43 circulating immune cell phenotypes and 68 protein biomarkers were investigated using linear mixed-effect models accommodating familial correlations and adjusting for covariates (sex, age, number of apolipoprotein E ( APOE) ε2 and ε4 alleles, and cytomegalovirus levels), with FDR ≤0.05 to declare significant associations. Age-stratified analyses were performed to explore effect modification. CD8 T naïve cells (CD8Tn) were negatively associated with several proteins ( Figure ). Significant associations were also observed for CD4 T cell subtypes including higher levels of CD4 T helper cells associated with lower Flt3L and TNFRSF9, higher levels of CD4 T central memory (Tcm) and CD4 T effector (Teff) cells associated with lower TNFB, and higher CD4 Teff associated with lower CD40 levels. Among associations identified in the full sample, we observed a large proportion of associations between CD4 T cell subtypes and CD8 Tn in the older age group (&gt;60 years) but not the younger age group. Our results suggest that people tend to have more inflammation-associated immune responses during aging. Future studies are needed to improve understanding of the contribution of these inflammation-immune cell associations to cardiovascular disease.

Abstract P538: Relations of Left Ventricular Mass With Long-Term Cardiovascular and Health Outcomes: The Framingham Heart Study

Introduction: Although elevated left ventricular mass (LVM) is associated with increased risk for cardiovascular disease (CVD) events over short-term follow-up, limited data exists regarding echocardiographic assessments in relation to long-term health outcomes. Hypothesis: We assessed the associations of LVM to the risk of incident all-cause mortality, CVD, dementia, hypertension, diabetes, and chronic kidney disease (CKD) over 20 years of follow-up. Methods: We evaluated up to 3 serial echocardiographic observations (1991-2008) for up to 8218 Framingham Heart Study participants. We modeled LVM as indexed to height 2.7 , logarithmically transformed then standardized. Utilizing multivariable-adjusted time-dependent and interval-censored Cox proportional hazards models, we related log-LVMI to the incidence of CVD and other health outcomes through the end of 2019 by updating LVM and all covariates at multiple examinations. Results: Over a median follow-up of 17 years (max 29 years), our study participants (mean age 47 years, 54% women) experienced 1353 events for all-cause mortality, 948 for CVD, 293 for dementia, 1631 for hypertension, 492 for diabetes, and 627 for CKD. Higher log-LVMI was significantly associated with increased incident all-cause mortality and CVD, including its respective components: coronary heart disease, heart failure (with reduced and preserved ejection fraction), and stroke. Results were consistent for incident hard and atherosclerotic CVD. Higher LVMI was also significantly associated with increased incidence of dementia, hypertension, diabetes, and CKD (defined as eGFR&lt;60 mL/min/1.73 m 2 and defined with urine albumin-to-creatinine ratio ≥30). Conclusions: In our large prospective community-based sample higher LVMI carries an adverse prognosis for multiple health outcomes over two decades of follow-up. These findings underscore the importance of maintaining an optimal LVM over the life course with control of its key determinants such as blood pressure and glycemia.

Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.

One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.

Genetically Predicted Body Mass Index and Mortality in Chronic Obstructive Pulmonary Disease.

Rationale: Body mass index (BMI) is associated with chronic obstructive pulmonary disease (COPD) mortality, but the underlying mechanisms are unclear. The effect of genetic variants aggregated into a polygenic score may elucidate the causal mechanisms and predict risk. Objectives: To examine the associations of genetically predicted BMI with all-cause and cause-specific mortality in COPD. Methods: We developed a polygenic score (PGS) for BMI (PGSBMI) and tested for associations of the PGSBMI with all-cause, respiratory, and cardiovascular mortality in participants with COPD from the COPDGene (Genetic Epidemiology of COPD), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), and Framingham Heart studies. We calculated the difference between measured BMI and PGS-predicted BMI (BMIdiff) and categorized participants into groups of discordantly low (BMIdiff <20th percentile), concordant (BMIdiff between the 20th and 80th percentiles), and discordantly high (BMIdiff >80th percentile) BMI. We applied Cox models, examined potential nonlinear associations of the PGSBMI and BMIdiff with mortality, and summarized results with meta-analysis. Measurements and Main Results: We observed significant nonlinear associations of measured BMI and BMIdiff, but not PGSBMI, with all-cause mortality. In meta-analyses, a one-standard deviation increase in the PGSBMI was associated with an increased hazard for cardiovascular mortality (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.12-1.49), but not for respiratory or all-cause mortality. Compared with participants with concordant measured and genetically predicted BMI, those with discordantly low BMI had higher risks for all-cause mortality (HR, 1.57; 95% CI, 1.41-1.74) and respiratory death (HR, 2.01; 95% CI, 1.61-2.51). Conclusions: In people with COPD, a higher genetically predicted BMI is associated with higher cardiovascular mortality but not respiratory mortality. Individuals with a discordantly low BMI have higher all-cause and respiratory mortality rates than those with a concordant BMI.

Vascular contributions to cognitive decline: Beyond amyloid and tau in the Harvard Aging Brain Study

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau.

Educational Mobility, Pace of Aging, and Lifespan Among Participants in the Framingham Heart Study

People who complete more education live longer lives with better health. New evidence suggests that these benefits operate through a slowed pace of biological aging. If so, measurements of the pace of biological aging could offer intermediate end points for studies of how interventions to promote education will affect healthy longevity. To test the hypothesis that upward educational mobility is associated with a slower pace of biological aging and increased longevity. This prospective cohort study analyzed data from 3 generations of participants in the Framingham Heart Study: (1) the original cohort, enrolled beginning in 1948; (2) the Offspring cohort, enrolled beginning in 1971; and (3) the Gen3 cohort, enrolled beginning in 2002. A 3-generation database was constructed to quantify intergenerational educational mobility. Mobility data were linked with blood DNA-methylation data collected from the Offspring cohort in 2005 to 2008 (n = 1652) and the Gen3 cohort in 2009 to 2011 (n = 1449). Follow-up is ongoing. Data analysis was conducted from June 2022 to November 2023 using data obtained from the National Institutes of Health database of Genotypes and Phenotypes (dbGaP). Educational mobility was measured by comparing participants' educational outcomes with those of their parents. The pace of biological aging was measured from whole-blood DNA-methylation data using the DunedinPACE epigenetic clock. For comparison purposes, the analysis was repeated using 4 other epigenetic clocks. Survival follow-up was conducted through 2019. This study analyzed data from 3101 participants from the Framingham Heart Study; 1652 were in the Offspring cohort (mean [SD] age, 65.57 [9.22] years; 764 [46.2%] male) and 1449 were in the Gen3 cohort (mean [SD] age, 45.38 [7.83] years; 691 [47.7%] male). Participants who were upwardly mobile in educational terms tended to have slower pace of aging in later life (r = -0.18 [95% CI, -0.23 to -0.13]; P < .001). This pattern of association was similar across generations and held in within-family sibling comparisons. There were 402 Offspring cohort participants who died over the follow-up period. Upward educational mobility was associated with lower mortality risk (hazard ratio, 0.89 [95% CI, 0.81 to 0.98]; P = .01). Slower pace of aging accounted for approximately half of this association. This cohort study's findings support the hypothesis that interventions to promote educational attainment may slow the pace of biological aging and promote longevity. Epigenetic clocks have potential as near-term outcome measures of intervention effects on healthy aging. Experimental evidence is needed to confirm findings.

Factors that modulate platelet reactivity as measured by 5 assay platforms in 3429 individuals

BackgroundAssessment of platelet function is key in diagnosing bleeding disorders and evaluating antiplatelet drug efficacy. However, there is a prevailing “one-size-fits-all” approach in the interpretation of measures of platelet reactivity, with arbitrary cutoffs often derived from healthy volunteer responses. ObjectivesOur aim was to compare well-used platelet reactivity assays. MethodsBlood and platelet-rich plasma obtained from the Framingham Heart Study (N = 3429) were assayed using a range of agonists in 5 platelet assays: light transmission aggregometry, Optimul aggregometry, Multiplate impedance aggregometry (Roche Diagnostics), Total Thrombus-Formation Analysis System, and flow cytometry. Using linear mixed-effect models, we determined the contribution of preanalytical and technical factors that modulated platelet reactivity traits. ResultsA strong intra-assay correlation of platelet traits was seen in all assays, particularly Multiplate velocity (r = 0.740; ristocetin vs arachidonic acid). In contrast, only moderate interassay correlations were observed (r = 0.375; adenosine diphosphate Optimul Emax vs light transmission aggregometry large area under the curve). As expected, antiplatelet drugs strongly reduced platelet responses, with aspirin use primarily targeting arachidonic acid–induced aggregation, and explained substantial variance (β = −1.735; P = 4.59 × 10−780; variance proportion = 46.2%) and P2Y12 antagonists blocking adenosine diphosphate responses (β = −1.612; P = 6.75 × 10−27; variance proportion = 2.1%). Notably, female sex and older age were associated with enhanced platelet reactivity. Fasting status and deviations from standard venipuncture practices did not alter platelet reactivity significantly. Finally, the agonist batch, phlebotomist, and assay technician (more so for assays that require additional sample manipulation) had a moderate to large effect on measured platelet reactivity. ConclusionCaution must be exercised when extrapolating findings between assays, and the use of standard ranges must be medication-specific and sex-specific at a minimum. Researchers should also consider preanalytical and technical variables when designing experiments and interpreting platelet reactivity measures.

Adjustment for Renal Function Improves the Prognostic Performance of Urinary Thromboxane Metabolites.

Systemic thromboxane A2 generation, assessed by quantifying the concentration of stable thromboxane B2 metabolites (TXB2-M) in the urine adjusted for urinary creatinine, is strongly associated with mortality risk. We sought to define optimal TXB2-M cutpoints for aspirin users and nonusers and determine if adjusting TXB2-M for estimated glomerular filtration rate (eGFR) in addition to urinary creatinine improved mortality risk assessment. Urinary TXB2-M were measured by competitive ELISA in 1363 aspirin users and 1681 nonusers participating in the Framingham Heart Study. Cutpoints were determined for TXB2-M and TXB2-M/eGFR using log-rank statistics and used to assess mortality risk by Cox proportional hazard modeling and restricted mean survival time. Multivariable models were compared using the Akaike Information Criterion (AIC). A cohort of 105 aspirin users with heart failure was used for external validation. Optimized cutpoints of TXB2-M were 1291 and 5609 pg/mg creatinine and of TXB2-M/eGFR were 16.6 and 62.1 filtered prostanoid units (defined as pg·min/creatinine·mL·1.73 m2), for aspirin users and nonusers, respectively. TXB2-M/eGFR cutpoints provided more robust all-cause mortality risk discrimination than TXB2-M cutpoints, with a larger unadjusted hazard ratio (2.88 vs 2.16, AIC P < 0.0001) and greater differences in restricted mean survival time between exposure groups (1.46 vs 1.10 years), findings that were confirmed in the external validation cohort of aspirin users. TXB2-M/eGFR cutpoints also provided better cardiovascular/stroke mortality risk discrimination than TXB2-M cutpoints (unadjusted hazard ratio 3.31 vs 2.13, AIC P < 0.0001). Adjustment for eGFR strengthens the association of urinary TXB2-M with long-term mortality risk irrespective of aspirin use.

Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia.

Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (β = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (β = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated (r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status. Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.

Diet, Pace of Biological Aging, and Risk of Dementia in the Framingham Heart Study.

People who eat healthier diets are less likely to develop dementia, but the biological mechanism of this protection is not well understood. We tested the hypothesis that healthy diet protects against dementia because it slows the pace of biological aging. We analyzed Framingham Offspring Cohort data. We included participants ≥60 years-old, free of dementia and having dietary, epigenetic, and follow-up data. We assessed healthy diet as long-term adherence to the Mediterranean-Dash Intervention for Neurodegenerative Delay diet (MIND, over 4 visits spanning 1991-2008). We measured the pace of aging from blood DNA methylation data collected in 2005-2008 using the DunedinPACE epigenetic clock. Incident dementia and mortality were defined using study records compiled from 2005 to 2008 visit through 2018. Of n = 1,644 included participants (mean age 69.6, 54% female), n = 140 developed dementia and n = 471 died over 14 years of follow-up. Greater MIND score was associated with slower DunedinPACE and reduced risks for dementia and mortality. Slower DunedinPACE was associated with reduced risks for dementia and mortality. In mediation analysis, slower DunedinPACE accounted for 27% of the diet-dementia association and 57% of the diet-mortality association. Findings suggest that slower pace of aging mediates part of the relationship of healthy diet with reduced dementia risk. Monitoring pace of aging may inform dementia prevention. However, a large fraction of the diet-dementia association remains unexplained and may reflect direct connections between diet and brain aging that do not overlap other organ systems. Investigation of brain-specific mechanisms in well-designed mediation studies is warranted. ANN NEUROL 2024;95:1069-1079.

Alcohol consumption as a socially contagious phenomenon in the Framingham Heart Study social network

We use longitudinal social network data from the Framingham Heart Study to examine the extent to which alcohol consumption is influenced by the network structure. We assess the spread of alcohol use in a three-state SIS-type model, classifying individuals as abstainers, moderate drinkers, and heavy drinkers. We find that the use of three-states improves on the more canonical two-state classification, as the data show that all three states are highly stable and have different social dynamics. We show that when modelling the spread of alcohol use, it is important to model the topology of social interactions by incorporating the network structure. The population is not homogeneously mixed, and clustering is high with abstainers and heavy drinkers. We find that both abstainers and heavy drinkers have a strong influence on their social environment; for every heavy drinker and abstainer connection, the probability of a moderate drinker adopting their drinking behaviour increases by 40%\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$40\\%$$\\end{document} and 18%\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$18\\%$$\\end{document}, respectively. We also find that abstinent connections have a significant positive effect on heavy drinkers quitting drinking. Using simulations, we find that while both are effective, increasing the influence of abstainers appears to be the more effective intervention compared to reducing the influence of heavy drinkers.