Association between solar radiation and mood disorders among Gulf Coast residents.

BACKGROUND: Climate factors such as solar radiation could contribute to mood disorders, but evidence of associations between exposure to solar radiation and mood disorders is mixed and varies by region. OBJECTIVE: To evaluate the association of solar radiation with depression and distress among residents living in U.S. Gulf states. METHODS: We enrolled home-visit participants in the Gulf Long-Term Follow-up Study who completed validated screening questionnaires for depression (Patient Health Questionnaire-9, N = 10,217) and distress (Kessler Psychological Distress Questionnaire, N = 8,765) for the previous 2 weeks. Solar radiation estimates from the Daymet database (1-km grid) were linked to residential addresses. Average solar radiation exposures in the seven (SRAD7), 14 (SRAD14), and 30 days (SRAD30) before the home visit were calculated and categorized into quartiles (Q1-Q4). We used generalized linear mixed models to estimate prevalence ratios (PR) and 95% confidence intervals (CI) for associations between solar radiation and depression/distress. RESULTS: Higher levels of SRAD7 were non-monotonically inversely associated with depression [PRVs.Q1 (95%CI): Q2 = 0.81 (0.68, 0.97), Q3 = 0.80 (0.65, 0.99), Q4 = 0.88 (0.69, 1.15)] and distress [PRVs.Q1 (95%CI): Q2 = 0.76 (0.58, 0.99), Q3 = 0.77 (0.57, 1.06), Q4 = 0.84 (0.58, 1.22)]. Elevated SRAD14 and SRAD30 appeared to be associated with decreasing PRs of distress. For example, for SRAD14, PRs were 0.86 (0.63-1.19), 0.80 (0.55-1.18), and 0.75 (0.48-1.17) for Q2-4 versus Q1. Associations with SRAD7 varied somewhat, though not significantly, by season with increasing PRs of distress in spring and summer and decreasing PRs of depression and distress in fall. IMPACT STATEMENT: Previous research suffered from exposure misclassification, which impacts the validity of their conclusions. By leveraging high-resolution datasets and Gulf Long-term Follow-up Cohort, our findings support an association between increased solar radiation and fewer symptoms of mood disorders.

Plasma proteomic signature of human longevity.

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases.

Associations of Polycystic Ovary Syndrome With Indicators of Brain Health at Midlife in the CARDIA Cohort.

BACKGROUND AND OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with an adverse cardiometabolic profile early in life. Increasing evidence links cardiovascular risk factors, such as diabetes and hypertension, to accelerated cognitive aging. However, less is known about PCOS and its relationship to brain health, particularly at midlife. Our goal was to investigate possible associations between PCOS and midlife cognitive function and brain MRI findings in an ongoing prospective study. METHODS: We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a geographically diverse prospective cohort study of individuals who were 18-30 years at baseline (1985-1986) and followed for 30 years. We identified women with PCOS from an ancillary study (CARDIA Women's study (CWS); n = 1,163) as those with elevated androgen levels and/or hirsutism in conjunction with symptoms of oligomenorrhea. At year 30, participants completed cognitive testing, including the Montreal Cognitive Assessment, Rey Auditory Verbal Learning Test (RAVLT) (verbal learning and memory), Digit Symbol Substitution Test (processing speed and executive function), Stroop test (attention and cognitive control), and category and letter fluency tests (semantics and attention). A subset completed brain MRI to assess brain structure and white matter integrity. Multivariable linear regression models estimated the association between PCOS and outcomes, adjusting for age, race, education, and study center. RESULTS: Of the 1163 women in CWS, 907 completed cognitive testing, and of these, 66 (7.1%) met criteria for PCOS (age 54.7 years). Women with and without PCOS were similar for age, BMI, smoking/drinking status, and income. At year 30, participants with PCOS performed lower (mean z score; 95% CI) on Stroop (-0.323 (-0.69 to -7.37); p = 0.008), RAVLT (-0.254 (-0.473 to -0.034); p = 0.002), and category fluency (-0.267 (-0.480 to -0.040); p = 0.02) tests. Of the 291 participants with MRI, 25 (8.5%) met PCOS criteria and demonstrated lower total white matter fractional anisotropy, a measure of white matter integrity (coefficient (95% CI) -0.013 (-0.021 to -0.005); p = 0.002), though not abnormal white matter. DISCUSSION: Our results suggest that women with PCOS have lower cognitive performance and lower white matter integrity at midlife. Additional research is needed to confirm these findings and to determine potential mechanistic pathways including potential modifiable factors.

Vascular Age Assessed From an Uncalibrated, Noninvasive Pressure Waveform by Using a Deep Learning Approach: The AI-VascularAge Model.

BACKGROUND: Aortic stiffness, assessed as carotid-femoral pulse wave velocity, provides a measure of vascular age and risk for adverse cardiovascular disease outcomes, but it is difficult to measure. The shape of arterial pressure waveforms conveys information regarding aortic stiffness; however, the best methods to extract and interpret waveform features remain controversial. METHODS: We trained a convolutional neural network with fixed-scale (time and amplitude) brachial, radial, and carotid tonometry waveforms as input and negative inverse carotid-femoral pulse wave velocity as label. Models were trained with data from 2 community-based Icelandic samples (N=10 452 participants with 31 126 waveforms) and validated in the community-based Framingham Heart Study (N=7208 participants, 21 624 waveforms). Linear regression rescaled predicted negative inverse carotid-femoral pulse wave velocity to equivalent artificial intelligence vascular age (AI-VA). RESULTS: The AI-VascularAge model predicted negative inverse carotid-femoral pulse wave velocity with R2=0.64 in a randomly reserved Icelandic test group (n=5061, 16%) and R2=0.60 in the Framingham Heart Study. In the Framingham Heart Study (up to 18 years of follow-up; 479 cardiovascular disease, 200 coronary heart disease, and 213 heart failure events), brachial AI-VA was associated with incident cardiovascular disease adjusted for age and sex (model 1; hazard ratio, 1.79 [95% CI, 1.50-2.40] per SD; P<0.0001) or adjusted for age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, prevalent diabetes, hypertension treatment, and current smoking (model 2; hazard ratio, 1.50 [95% CI, 1.24-1.82] per SD; P<0.0001). Similar hazard ratios were demonstrated for incident coronary heart disease and heart failure events and for AI-VA values estimated from carotid or radial waveforms. CONCLUSIONS: Our results demonstrate that convolutional neural network-derived AI-VA is a powerful indicator of vascular health and cardiovascular disease risk in a broad community-based sample.

The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia.

BACKGROUND: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population. METHODS: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies. FINDINGS: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]). INTERPRETATION: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted. FUNDING: Gates Ventures.

Physical activity and diet associations with the gut microbiota in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

BACKGROUND: Gut microbiota may influence metabolic pathways related to chronic health conditions. Evidence for physical activity and diet influences on gut microbial composition exists, but data from diverse population-based cohort studies are limited. OBJECTIVES: We hypothesized that gut microbial diversity and genera are associated with physical activity and diet quality. METHODS: Data were from 537 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective cohort, who attended the year 30 follow-up examination (2015-2016; aged 47-61 y; 45% Black race/55% White race; 45% men/55% women). The 16S ribosomal RNA marker gene was sequenced from stool DNA, and genus-level taxonomy was assigned. Within-person microbial diversity (α-diversity) was assessed with Shannon diversity index and richness scores; between-person diversity (ß-diversity) measures were generated with principal coordinates analysis (PCoA). Current and long-term physical activity and diet quality measures were derived from data collected over 30 y of follow-up. Multivariable-adjusted regression analysis controlled for: sociodemographic variables (age, race, sex, education, and field center), other health behaviors (smoking, alcohol consumption, and medication use), and adjusted for multiple comparisons with the false discovery rate (<0.20). RESULTS: Based on PCoA ß-diversity, participants' microbial community compositions differed significantly (P < 0.001), with respect to both current and long-term physical activity and diet quality. α-Diversity was associated only with current physical activity (positively) in multivariable-adjusted analysis. Multiple genera (n = 45) were associated with physical activity and fewer with diet (n = 5), including positive associations with Lachnospiraceae UCG-001 and Ruminococcaceae IncertaeSedis with both behaviors. CONCLUSIONS: Physical activity and diet quality were associated with gut microbial composition among 537 participants in the CARDIA study. Multiple genera were associated with physical activity. Physical activity and diet quality were associated with genera consistent with pathways related to inflammation and short-chain fatty acid production.

Cognition and brain health among older adults in Iceland: the AGES-Reykjavik study.

The paper aimed to compare how factors previously identified as predictive factors for cognitive decline and dementia related to cognitive performance on the one hand and brain health on the other. To that aim, multiple linear regression was applied to the AGES-Reykjavik study epidemiological data. Additionally, a regression analysis was performed for change in cognition over 5 years, using the same exposure factors. The study ran from 2002 to 2011, and the sample analyzed included 1707 participants between the ages of 66 and 90. The data contains MR imaging, cognitive testing, background data, and physiological measurements. Overall, we conclude that risk factors linked to dementia relate differently to cognition and brain health. Mobility, physical strength, alcohol consumption, coronary artery disease, and hypertension were associated with cognition and brain volume. Smoking, depression, diabetes, and body fat percentage were only associated with brain volume, not cognitive performance. Modifiable factors previously linked to cognitive reserve, such as educational attainment, participation in leisure activities, multilingualism and good self-reported health, were associated with cognitive function but did not relate to brain volume. These findings show that, within the same participant pool, cognitive reserve proxy variables have a relationship with cognitive performance but have no association with relative brain volume measured simultaneously.

Facets of Personality and Risk of Cognitive Impairment: Longitudinal Findings in a Rural Community from Sardinia.

BACKGROUND: Few studies have examined the associations between personality facets and dementia risk and rarely included individuals from rural settings or with low education. OBJECTIVE: To examine the association between personality and the risk of cognitive impairment. METHODS: Participants (N = 1,668; age 50 to 94 at baseline; 56.4% women; 86.5% less than high school diploma) were from a rural region of Sardinia (Italy) who completed the Revised NEO Personality Inventory (NEO-PI-R) during the first wave (2001-2004) and the Mini-Mental State Examination (MMSE) at waves two to five (2005-2021). Cox regression was used to test personality and covariates as predictors of cognitive impairment based on MMSE education-adjusted cutoffs. RESULTS: During the up to 18-year follow-up (M = 10.38; SD = 4.76), 187 individuals (11.2%) scored as cognitively impaired. Participants with higher neuroticism (particularly the depression facet [HR = 1.22, 95% CI = 1.06-1.40]), and lower agreeableness (particularly the modesty facet [HR = 0.83, 95% CI = 0.71-0.97]) and lower conscientiousness (particularly the dutifulness facet [HR = 0.78, 95% CI = 0.67-0.92]) were at higher risk of cognitive impairment. Lower warmth ([HR = 0.75, 95% CI = 0.65-0.87], facet of extraversion) and ideas ([HR = 0.76, 95% CI = 0.65-0.89], facet of openness) were also associated with increased risk of impairment. These associations were virtually unchanged in models that accounted for other risk factors, including smoking, depression, obesity, hypertension, diabetes, and apolipoprotein E (APOE) ɛ4 carrier status. Across the five domains, sex and the APOE variant did not moderate the associations. CONCLUSION: In a sample with demographic characteristics underrepresented in dementia research, this study identifies personality domains and facets most relevant to the risk of cognitive impairment.

Association of the Gut Microbiota With Cognitive Function in Midlife.

Importance: Animal experiments and small clinical studies support a role for the gut microbiota in cognitive functioning. Few studies have investigated gut microbiota and cognition in large community samples. Objective: To examine associations of gut microbial composition with measures of cognition in an established population-based study of middle-aged adults. Design, Setting, and Participants: This cross-sectional study analyzed data from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) cohort in 4 US metropolitan centers between 2015 and 2016. Data were analyzed in 2019 and 2020. Exposures: Stool DNA were sequenced, and the following gut microbial measures were gathered: (1) ß-diversity (between-person) derived with multivariate principal coordinates analysis; (2) α-diversity (within-person), defined as richness (genera count) and the Shannon index (integrative measure of genera richness and evenness); and (3) taxonomy (107 genera, after filtering). Main Outcomes and Measures: Cognitive status was assessed using 6 clinic-administered cognitive tests: Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop, category fluency, and letter fluency. A global score measure derived using principal components analysis was also assessed; the first principal component explained 56% of variability. Results: Microbiome data were available on 597 CARDIA participants; mean (SD) age was 55.2 (3.5) years, 268 participants (44.7%) were men, and 270 (45.2%) were Black. In multivariable-adjusted principal coordinates analysis, permutational multivariate analysis of variance tests for ß-diversity were statistically significant for all cognition measures (principal component analysis, P = .001; MoCA, P = .001; DSST, P = .001; RAVLT, P = .001; Stroop, P = .007; category fluency, P = .001) with the exception of letter fluency (P = .07). After adjusting for sociodemographic variables (age, race, sex, education), health behaviors (physical activity, diet, smoking, medication use), and clinical covariates (body mass index, diabetes, hypertension), Barnesiella was positively associated with the first principal component (ß, 0.16; 95% CI, 0.08-0.24), DSST (ß, 1.18; 95% CI, 0.35-2.00), and category fluency (ß, 0.59; 95% CI, 0.31-0.87); Lachnospiraceae FCS020 group was positively associated with DSST (ß, 2.67; 95% CI, 1.10-4.23), and Sutterella was negatively associated with MoCA (ß, -0.27; 95% CI, -0.44 to -0.11). Conclusions and Relevance: In this cross-sectional study, microbial community composition, based on ß-diversity, was associated with all cognitive measures in multivariable-adjusted analysis. These data contribute to a growing body of literature suggesting that the gut microbiota may be associated with cognitive aging, but must be replicated in larger samples and further researched to identify relevant pathways.

A poor appetite or ability to eat and its association with physical function amongst community-dwelling older adults: age, gene/environment susceptibility-Reykjavik study.

A poor appetite or ability to eat and its association with physical function have not been explored considerably amongst community-dwelling older adults. The current study examined whether having an illness or physical condition affecting one's appetite or ability to eat is associated with body composition, muscle strength, or physical function amongst community-dwelling older adults. This is a secondary analysis of cross-sectional data from the age, gene/environment susceptibility-Reykjavik study (n = 5764). Illnesses or physical conditions affecting one's appetite or ability to eat, activities of daily living, current level of physical activity, and smoking habits were assessed with a questionnaire. Fat mass, fat-free mass, body mass index, knee extension strength, and grip strength were measured, and the 6-m walk test and timed up-and-go test were administered. Individuals who reported illnesses or physical conditions affecting their appetite or ability to eat were considered to have a poor appetite. The associations of appetite or the ability to eat with body composition and physical function were analysed with stepwise linear regression models. A total of 804 (14%) individuals reported having conditions affecting their appetite or ability to eat and had a significantly lower fat-free mass and body mass index, less grip strength, and poorer physical function than did those without any conditions affecting their appetite or ability to eat. Although the factors reported to affect one's appetite or ability to eat are seldom considered severe, their strong associations with physical function suggest that any condition affecting one's appetite or ability to eat requires attention.

Wave Reflection at the Origin of a First-Generation Branch Artery and Target Organ Protection: The AGES-Reykjavik Study.

[Figure: see text].

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.

CONTEXT: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. OBJECTIVE: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. DESIGN: Genetics of Obesity-associated Liver Disease Consortium. SETTING: Population-based. MAIN OUTCOME: Computed tomography measured liver attenuation. RESULTS: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. CONCLUSIONS: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.

Smoking mediates the relationship between SES and brain volume: The CARDIA study.

OBJECTIVE: Investigate whether socioeconomic status (SES) was related to brain volume in aging related regions, and if so, determine whether this relationship was mediated by lifestyle factors that are known to associate with risk of dementia in a population-based sample of community dwelling middle-aged adults. METHODS: We studied 645 (41% black) participants (mean age 55.3±3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent brain magnetic resonance imaging. SES was operationalized as a composite measure of annual income and years of education. Gray matter volume was estimated within the insular cortex, thalamus, cingulate, frontal, inferior parietal, and lateral temporal cortex. These regions are vulnerable to age-related atrophy captured by the Spatial Pattern of Atrophy for Recognition of Brain Aging (SPARE-BA) index. Lifestyle factors of interest included physical activity, cognitive activity (e.g. book/newspaper reading), smoking status, alcohol consumption, and diet. Multivariable linear regressions tested the association between SES and brain volume. Sobel mediation analyses determined if this association was mediated by lifestyle factors. All models were age, sex, and race adjusted. RESULTS: Higher SES was positively associated with brain volume (ß = .109 SE = .039; p < .01) and smoking status significantly mediated this relationship (z = 2.57). With respect to brain volume, smoking accounted for 27% of the variance (ß = -.179 SE = .065; p < .01) that was previously attributed to SES. CONCLUSION: Targeting smoking cessation could be an efficacious means to reduce the health disparity of low SES on brain volume and may decrease vulnerability for dementia.

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D.

Cellular Adhesion Molecules in Young Adulthood and Cardiac Function in Later Life.

BACKGROUND: E-selectin and intercellular adhesion molecule (ICAM)-1 are biomarkers of endothelial activation, which has been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF). However, the temporal associations between E-selectin and ICAM-1 with subclinical cardiac dysfunction are unclear. OBJECTIVES: This study sought to assess the longitudinal associations of E-selectin and ICAM-1 with subclinical alterations in cardiac function. METHODS: In the Coronary Artery Disease Risk Development in Young Adults study, a cohort of black and white young adults, we evaluated the associations of E-selectin and ICAM-1, obtained at year (Y) 7 (Y7) and Y15 examinations, with cardiac function assessed at Y30 after adjustment for key covariates. RESULTS: Higher E-selectin (n = 1,810) and ICAM-1 (n = 1,548) at Y7 were associated with black race, smoking, hypertension, and higher body mass index. After multivariable adjustment, higher E-selectin at Y7 (ß coefficient per 1 SD higher: 0.22; SE: 0.06; p < 0.001) and Y15 (ß coefficient per 1 SD higher: 0.19; SE: 0.06; p = 0.002) was associated with worse left ventricular (LV) global longitudinal strain (GLS). Additionally, higher Y15 ICAM-1 (ß coefficient per 1 SD higher: 0.18; SE: 0.06; p = 0.004) and its increase from Y7 to Y15 (ß coefficient per 1 SD higher: 0.16; SE: 0.07; p = 0.03) were also independently associated with worse LV GLS. E-selectin and ICAM-1 partially mediated the associations between higher body mass index and black race with worse GLS. Neither E-selectin nor ICAM-1 was associated with measures of LV diastolic function after multivariable adjustment. CONCLUSION: Circulating levels of E-selectin and ICAM-1 and increases in ICAM-1 over the course of young adulthood are associated with worse indices of LV systolic function in midlife. These findings suggest associations of endothelial activation with subclinical HF with preserved ejection fraction.

Childhood overweight and obesity and the risk of depression across the lifespan.

BACKGROUND: Obesity has been longitudinally associated with depression but only few studies take a life course approach. This longitudinal study investigates whether being overweight or obese at age 8 and 13 years is associated with depressive symptoms more than 60 years later and whether this association is independent of late-life body mass index (BMI). We also investigated the association of being overweight/obese at age 8 or 13 years with ever having major depressive disorder (lifetime MDD). METHOD: This analysis is based on a sub-sample of 889 AGES-Reykjavik participants with measured BMI data from early life. Late-life depressive symptoms were measured with the Geriatric Depression Scale (GDS) and lifetime MDD was assessed at late-life using the Mini International Neuropsychiatric Interview. Logistic regression analysis was used to estimate the relationships between BMI (continuous and categorical) at age 8 or 13 years, and late-life depressive symptoms (measured as GDS ≥ 5) or lifetime MDD, adjusted for sex, education, physical activity, smoking status and alcohol use. In a separate model, additional adjustments were made for late-life BMI. RESULTS: One hundred and one subjects (11%) had depressive symptoms at late-life (GDS ≥ 5), and 39 subjects (4.4%) had lifetime MDD. Being overweight or obese at age 8 or 13 years was not associated with higher depressive symptoms during late-life, irrespective of late-life BMI. Being overweight or obese at age 8 years, but not age 13 years was associated with an increased risk of lifetime MDD (Odds Ratio (OR) (95% confidence interval [CI]) for age 8 = 4.03[1.16-13.96]P = 0.03 and age 13 = 2.65[0.69-10.26] P = 0.16, respectively). CONCLUSION: Being overweight in childhood was associated with increased odds of lifetime MDD, although the magnitude of the risk is uncertain given the small numbers of participants with lifetime MDD. No clear association was observed between childhood and adolescent overweight/obesity and late-life depressive symptoms irrespective of late life BMI.

Body fat distribution on computed tomography imaging and prostate cancer risk and mortality in the AGES-Reykjavik study.

BACKGROUND: The World Cancer Research Fund classifies as "strong evidence" the link between obesity and the risk of advanced prostate cancer. In light of the different hormonal profiles associated with where adipose is stored, this study investigated the role of objectively measured body fat distribution and the risk of clinically relevant prostate cancer. METHODS: This was a prospective study of 1832 men in the Age, Gene/Environment Susceptibility-Reykjavik study. From 2002 to 2006, participants underwent baseline computed tomography imaging of fat deposition, bioelectric impedance analysis, and measurement of body mass index (BMI) and waist circumference. Men were followed through linkage with nationwide cancer registries for the incidence of total (n = 172), high-grade (Gleason grade ≥8; n = 43), advanced (≥cT3b/N1/M1 at diagnosis or fatal prostate cancer over follow-up; n = 41), and fatal prostate cancer (n = 31) through 2015. Cox regression was used to evaluate the association between adiposity measures and prostate cancer outcomes. RESULTS: Among all men, visceral fat (hazard ratio [HR], 1.31 per 1-standard deviation [SD] increase; 95% confidence interval [CI], 1.00-1.72) and thigh subcutaneous fat (HR, 1.37 per 1-SD increase; 95% CI, 1.00-1.88) were associated with risk of advanced and fatal disease, respectively. Among men who were leaner based on BMI, visceral fat was associated with both advanced and fatal disease. BMI and waist circumference were associated with a higher risk of advanced and fatal disease. No adiposity measures were associated with total or high-grade disease. CONCLUSIONS: Specific fat depots as well as BMI and waist circumference were associated with the risk of aggressive prostate cancer, which may help to elucidate underlying mechanisms and target intervention strategies.

Cigarette smoking and gray matter brain volumes in middle age adults: the CARDIA Brain MRI sub-study.

Cigarette smoking has been associated with dementia and dementia-related brain changes, notably gray matter (GM) volume atrophy. These associations are thought to reflect the co-morbidity of smoking and vascular, respiratory, and substance use/psychological conditions. However, the extent and localization of the smoking-GM relationship and the degree to which vascular, respiratory, and substance use/psychological factors influence this relationship remain unclear. In the Coronary Artery Risk Development in Young Adults CARDIA cohort (n = 698; 52% women; 40% black participants; age = 50.3 (SD = 3.5)), we examined the associations of smoking status with total GM volume and GM volume of brain regions linked to neurocognitive and addiction disorders. Linear regression models were used to adjust for vascular, respiratory, and substance use/psychological factors and to examine whether they modify the smoking-GM relationship. Compared to never-smokers, current smokers had smaller total GM volume (-8.86 cm3 (95%CI = -13.44, -4.29). Adjustment for substance use/psychological - but not vascular or respiratory - factors substantially attenuated this association (coefficients = -5.54 (95% CI = -10.32, -0.76); -8.33 (95% CI = -12.94, -3.72); -7.69 (95% CI = -6.95, -4.21), respectively). There was an interaction between smoking and alcohol use such that among alcohol non-users, smoking was not related to GM volumes and among alcohol users, those who currently smoked had -12 cm3 smaller total GM, specifically in the frontal and temporal lobes, amygdala, cingulate, and insula. Results suggest a large-magnitude association between smoking and smaller GM volume at middle age, accounting for vascular, respiratory, and substance use/psychological factors, and that the association was strongest in alcohol users. Regions suggested to be most vulnerable are those where cognition and addiction processes overlap.

Cigarette smoking and cerebral blood flow in a cohort of middle-aged adults.

Cigarette smoking is often associated with dementia. This association is thought to be mediated by hypoperfusion; however, how smoking behavior relates to cerebral blood flow (CBF) remains unclear. Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort (mean age = 50; n = 522), we examined the association between smoking behavior (status, cumulative pack-years, age at smoking initiation, and years since cessation) and CBF (arterial spin labeling) in brain lobes and regions linked to dementia. We used adjusted linear regression models and tested whether associations differed between current and former-smokers. Compared to never-smokers, former-smokers had lower CBF in the parietal and occipital lobes, cuneus, precuneus, putamen, and insula; in contrast, current-smokers did not have lower CBF. The relationship between pack-years and CBF was different between current and former-smokers (p for interaction < 0.05): Among current-smokers, higher pack-years were associated with higher occipital, temporal, cuneus, putamen, insula, hippocampus, and caudate CBF; former-smokers had lower caudate CBF with increasing pack-years. Results show links between smoking and CBF at middle-age in regions implicated in cognitive and compulsive/addictive processes. Differences between current and former smoking suggest that distinct pathological and/or compensatory mechanisms may be involved depending on the timing and history of smoking exposure.

Omega-3 Fatty Acids and Genome-Wide Interaction Analyses Reveal DPP10-Pulmonary Function Association.

RATIONALE: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. METHODS: Associations of n-3 PUFA biomarkers (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs. RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df = 9.4 × 10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency, ∼80%) was associated with lower FVC (PSNP = 2.1 × 10-9; ßSNP = -161.0 ml), and the association was attenuated by higher DHA levels (PSNP×DHA interaction = 2.1 × 10-7; ßSNP×DHA interaction = 36.2 ml). CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.