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NT-proBNP is a biomarker of cardiovascular disease (CVD). Little is known about the heritability and genetic variants associated with NT-proBNP. Therefore, we estimated the heritability of and examined genetic associations of SNPs in the BNP gene region with circulating NT-proBNP and prevalent CVD in 4,331 participants from the Long Life Family Study (LLFS). Genotypes of 10 SNPs from the NPPB and NPPA regions that encode BNP and A-type natriuretic peptide, respectively, were tested for association with NT-proBNP and prevalent cardiovascular disease and risk factors. We performed analyses using the Sequential Oligogenic Linkage Analysis (SOLAR) program to account for family relatedness, and adjusted all models for age, sex, and field center. The mean age of the LLFS was 69.8 years (range 24-110) with 55.4% females. NT-proBNP was significantly heritable (h2 = 0.21; P = 4x10-14), and the minor alleles of rs632793 (p<0.001) and rs41300100 (p = 0.05) were independently associated with higher serum NT-proBNP levels. Additionally, the minor allele of rs632793 was significantly and consistently associated with lower prevalent CVD, including blood pressures, independent of NT-proBNP level (all P<0.05). Results for prevalent CVD, but not NT-proBNP levels, showed significant interaction by familial generation. In this family-based study of subjects with exceptional longevity, we identified several allelic variants in the BNP gene region associated with NT-pro-BNP levels and prevalent CVD.

INTRODUCTION Dementia prevalence is higher in women, in particular those of African ancestry. Reproductive health may influence dementia risk, yet data from the Caribbean are lacking. We assessed the association of reproductive health with cognition in the Tobago Women's Health Study. METHODS This population‐based study recruited middle to older aged women from the Caribbean Island of Tobago. Cognitive performance was assessed using the Digit Symbol Substitution Test (DSST). Seven indicators of reproductive health were collected via interviews. Multivariable regression models estimated the association between reproductive indicators and DSST score. RESULTS Among 776 women (mean age 55.8 ± 8.9 years), the mean number of live births was 2.83 ± 2.4, and 22% experienced at least one pregnancy complication. Later age at first live birth (mean age 22.7 ± 5.4 years) was significantly associated with higher DSST score (β = 0.35, p < 0.001), independent of other reproductive factors. DISCUSSION Older age at the time of first live birth appears protective for cognitive function among African Caribbean women. Highlights Later age at first birth is linked to better cognitive function, independent of other reproductive, demographic, and health factors. This study provides novel insights into cognitive aging among African Caribbean women, an understudied population, addressing a critical gap in research on reproductive history and cognition. This study highlights the need for further research on the longitudinal association between reproductive history and cognition, particularly in African Caribbean women.

Abstract Although the connection between type 2 diabetes (T2D) and dementia is known, it is less clear whether this relationship extends to cognitive decline. Our aim was to examine whether baseline fasting plasma glucose, insulin, HOMA-IR, and HbA1c, and T2D status predict cognitive decline in a multicenter cohort study of families with a clustering of exceptional survival. We analyzed change across five cognitive tests collected over 7.9 years: Mini-Mental State Examination, Digit Span, Logical Memory, Animal Fluency and Digit Symbol Substitution. Among 2,175 family members (mean age 63±11 years (range 32-100); 54% women), 39.8% had prediabetes and 6.8% had T2D. Multiple linear mixed models were adjusted for age, sex, field center, education, APOEε4 status, BMI and family relatedness. A trend was observed for immediate (p=0.047) and delayed (p=0.037) memory, with normal glucose tolerance (NGT) predicting increased scores, prediabetes showing no change, and T2D predicting decreased scores. Among those without T2D (N=2,026), each standard deviation (SD) higher glucose (11.5 mg/dl) was related to a greater decline in delayed memory (-0.34±0.16mg/dl; p=0.032), each SD higher HbA1c (0.32%) was related to a greater decline in immediate (-0.36±0.15 mg/dl; p=0.016) and delayed (-0.31±0.16 %; p=0.05) memory, while each SD higher HOMA-IR (1.5) was related to a greater decline in Digit Span Backwards (-0.13±0.06; p=0.047). Findings suggest that among individuals with a clustering of exceptional survival, T2D, glucose, and HbA1c may predict greater decline in episodic memory, an ability typically affected early in Alzheimer dementia. The possible mechanisms, including genetic and metabolic mediators, warrant further investigation.

Abstract The genetic influence on peripheral vascular health in exceptional aging has not been well-studied. Thus, we performed heritability, genome-wide linkage analyses (GWLA) and genome-wide association studies (GWAS) of ankle-brachial index (ABI) and peripheral artery disease (PAD) in 3006 individuals from the Long Life Family Study (LLFS). The LLFS is a longitudinal, family-based study including long-lived siblings and their families. ABI was measured in-home, and the minimum from both sides was used, with exclusions for ABI≥1.4 or non-compressible arteries. PAD was defined as ABI<0.9. We performed heritability and GWLA using SOLAR and GWAS using R accounting for familial relationships. Our full model was adjusted for age, sex, site, significant PCs, blood pressure, and relevant risk factors including smoking, body size, and lipids. We considered significance at a LOD≥3.0 for GWLA and at a p<5x10-8 for GWAS. The proband generation was 53.2% female, aged 88.7 and had a mean ABI of 1.06. The offspring generation was 60.1% female, aged 60.1 and had a mean ABI of 1.19. 18.2% of probands and 1.0% of offspring had PAD (7.4% overall). Residual genetic heritability was 0.12 (p=8.7x10-4) for ABI and 0.23 for PAD (p=0.0662). We found linkage with chromosome 15q12 (LOD=3.65) for ABI and association on chromosome 4q25 (rs12512857; p=6.25x10-8; ANK2; maf=0.021) for PAD. ANK2 is a gene that has been implicated in cardiac dysfunction though there have been no previous associations with ABI or PAD. This suggests that unique genetic variation is associated with peripheral vascular health in long-lived families.

Abstract Objective Skeletal muscle adiposity (SMA) increases with aging and is recognized as a major risk factor for cardiometabolic diseases, disability, and mortality among older adults. Obesity is related to dementia and cognitive decline yet the relationship between SMA and cognition remains ill defined. The objective of this study was to assess SMA and cognitive function among African Caribbean women.Design and Methods Cross-sectional analysis of 448 African Caribbean women in the Tobago Health Study (mean age, 55 years; range, 39-84 years). Cognition was assessed by the Digit Symbol Substitution Test (DSST), a test of information processing speed with a range of 0-90; higher scores suggest better cognitive function (faster information processing speed). Calf SMA (muscle density) was assessed with computed tomography (Stratec XCT-2000). Linear regression was used to assess the association of SMA with DSST adjusted for age, education, muscle area, waist circumference, alcohol intake, smoking, physical activity, diabetes, and hypertension. Results Participants had a BMI of 30.7 kg/m2. Mean (SD) DSST scores and SMA were 39.2 (13.1) and 71.7 (5.3) mg/cm3, respectively. After full adjustment, we found that one SD greater skeletal muscle adiposity was associated with a 1.40 lower DSST score (p-value=0.025). Conclusions Our findings suggest that in African Caribbean women, greater SMA is associated with slower information processing speed, an early indicator of future dementia risk. Future studies using an expanded battery of cognitive tests and longitudinal follow-up should further advance our understanding of the role of SMA and dementia risk among African ancestry populations.

Abstract Mitochondrial energy production decreases while fatigability increases with age. Genes associated with energy metabolism may contribute to fatigability. Using Long Life Family Study (LLFS), we initially assessed variants (SNPs) in 272 candidate autosomal genes involved in energy metabolism (previously associated with mitochondrial dysfunction disease) with perceived physical fatigability. Two generations of LLFS enrollees (N=2342, mean age=73.7, range 60-108 years) completed the Pittsburgh Fatigability Scale (PFS, 0-50, higher=greater fatigability) at Visit 2 (2014-2017). Physical fatigability prevalence was 42.1% (PFS≥15). Generalized linear mixed models assessed the association of each SNP with continuous PFS (GENESIS R package) adjusted for age, sex, field center, and family relatedness. We found no associations with perceived physical fatigability, all p>2.5E-7 (Bonferroni multiple comparison corrected p-value). Next steps will examine variants in the mitochondrial genome and BTBD3, another promising candidate gene recently discovered. Genetic biomarker(s) may identify individuals susceptible to greater fatigability to target for early intervention.

Abstract Skeletal muscle fat infiltration (myosteatosis) leads to poorer muscle quality and function with aging, and is emerging as a predictor of skeletal muscle strength, mobility, and metabolic disorders. Few studies investigated the association of physical activity (PA) and sedentary behavior (SB) with myosteatosis, especially in African Caribbeans, a vastly under-studied, rapidly growing population. We examined the associations of objectively measured PA and SB (Bodymedia SenseWear Armbands) worn over 7 days with calf muscle density (mg/cm3), a marker of intra-muscular fat (Stratec XCT-2000), in older adult African Caribbean men (N=355, mean age 62 years) and women (N=682, mean age 59 years) of the Tobago Health Study. Compared to men, women were younger with higher BMI, more SB, less light (LPA) and moderate to vigorous PA (MVPA), and lower muscle density (p< 0.05, age-adjusted). Meeting MVPA guidelines (150 min MVPA/week) was associated with greater muscle density in obese men and women (p=0.03, p=0.09 respectively, age-adjusted). Adjusting for age, BMI, smoking, diabetes, hypertension, and lipid-lowering treatment, we assessed sex stratified partial spearman correlations between PA and SB and muscle density. MVPA was more strongly correlated with greater muscle density in men (r=0.15, p=0.01) than in women (r=0.07, p=0.09), while SB was associated with lower muscle density in women (r=-0.08, p=.044), but not significantly in men (r=-0.10, p=0.12). Our novel findings indicate that the association between PA and SB with myosteatosis may differ by sex. These findings may have important implications for sex specific activity guidelines related to skeletal muscle health in African Caribbeans.

Abstract Atherosclerotic occlusion of peripheral arteries is a major contributor to morbidity and mortality in older adults. Our aim was to describe the epidemiology of peripheral artery disease (PAD) and other peripheral vascular disease (OPD) in the LLFS. 3248 individuals from 509 families (1182 probands, mean age 89; 2066 offspring, mean age 60) had doppler ankle-brachial index (ABI) assessment. Measures were performed twice for each posterior tibial artery and minimum of the mean ABI was used. PAD was defined as any ABI<0.9. OPD was defined as any ABI >1.4 or ≥1 non-compressible artery. Stepwise linear or logistic regression determined significant independent clinical and demographic predictors (P<0.05) after adjustment for age, sex, study center, and familial relatedness. Overall, ABI had a median of 1.2 with 7.4% PAD (18.1% probands, 1.2% offspring; P<0.001). OPD prevalence was 10.6% and was more common than PAD in offspring (8.1%). Age-adjusted OPD was higher in men (13.3%) than women (8.3%, P<0.001), while age-adjusted PAD did not did not differ by sex (P=0.45). Predictors of PAD included greater age and systolic blood pressure, lower diastolic blood pressure, prevalent kidney disease, antihypertensive use, and current smoking. Predictors of OPD included greater age, male sex, and current smoking. In these exceptionally long-lived families, PAD was low compared to other epidemiologic studies. However, OPD including non-compressible arteries, a marker of arterial stiffness, was more prevalent than PAD. These findings in long-lived families highlight a need for more epidemiologic research in other peripheral vascular disease in adults from the general population.

Abstract Gait speed is a predictor of overall health and mortality in older adults. Metabolomics may provide insights into biological mechanisms underlying gait speed. Herein, we examined the association between 193 lipid metabolites with gait speed in 1,717 adults (52.1% women) aged 82.0 ± 14.5. Lipidomic analysis was performed using liquid chromatography-mass spectrometry. Gait speed was measured over 4-meters and slowness was defined as <0.8m/s. Logistic regression, adjusted for age, sex, field center, height, fasting-duration and familial-relatedness, were used to examine the association between log-transformed metabolites with slowness. A false discovery rate (FDR) of p<0.05 was employed to account for multiple comparisons. Gait speed was 0.83 ± 0.32 and 53.4% had slowness. Three lipid metabolites were significantly associated with lower odds of slowness: an acylcarnitine, sphingomyelin and a ceramide non-hydroxy fatty acid-sphingosine. Our results potentially link lipids involved with mitochondrial beta-oxidation and nerve signal transduction to gait speed in older adults.

Abstract We tested the association of lipid metabolites with ankle-brachial index (ABI) in the LLFS. Minimum ABI from doppler was used. Participants underwent phlebotomy after >8 hours fasting. Plasma metabolites were isolated via solid phase extraction. Lipid metabolites (N=193) were measured using RPLC-MS and corrected for batch effects in 948 participants. We used linear mixed models adjusted for age, sex, site, fasting, and relatedness. Twenty metabolites were associated with ABI (FDR P<0.05), of which 17/20 were triacyclglycerol (TAG) species, plus cholesterol ester (22:6), phosphatidylcholine (35:7), and phosphatidylethanolamine (38:7). After additional adjustment for traditional ABI risk factors, only two TAGs (50:1, 42:0) were significantly associated after multiple testing correction. While not significant in the base model, the metabolite lysophosphatidylcholine (18:3) demonstrated a marginally significant protective association after full adjustment (P=0.014). While triglycerides are known correlates of atherosclerotic deposition, these findings may identify novel metabolic correlates of peripheral vascular health in long-lived individuals.