Vitamin D and Biomarkers of Sex Steroid Hormones Are Non-Linearly and Inversely Related to All-Cause Mortality: Results from NHANES III

Background: In men, hypovitaminosis D as well as high and low testosterone levels have been linked to adverse events, including death. A biological interaction has been previously suggested between vitamin D and androgens. In a cohort study using Third National Health and Nutrition Examination Survey data, we simultaneously investigated circulating vitamin D and biomarkers of sex steroid hormones as predictors of all-cause mortality. Methods: Age-adjusted and fully-adjusted Cox regression models were constructed to estimate hazard ratios (HR) and their 95% confidence intervals (CI). Whereas the vitamin D sufficient group (25(OH)D3 ≥30 ng/ml) was selected as a referent, biomarkers of sex steroid hormones (testosterone, estradiol, SHBG) were defined as Loge-transformed continuous variables. Results: Of 1,472 men with a mean age of 42.1 years at baseline, 382 died over a median of 192 months of follow-up. Estradiol levels were significantly higher among vitamin D deficient compared to vitamin D sufficient men and sex hormone binding globulin level was significantly higher in vitamin D sufficient compared to vitamin D insufficient or deficient groups. An inverse non-linear relationship was observed between all-cause mortality rate and levels of testosterone, estradiol and vitamin D, in fully-adjusted models. There were no significant interaction effects between vitamin D and sex steroid hormones in relation to all-cause mortality rate. Conclusions: Vitamin D and sex steroid hormones, but not sex hormone binding globulin, may be inversely and non-linearly related to all-cause mortality among adult men, after adjustment for baseline demographic, socioeconomic, lifestyle and clinical characteristics

Vitamin D receptor and megalin gene polymorphisms are associated with central adiposity status and changes among US adults

We examined longitudinal associations of vitamin D receptor (VDR) and megalin (LRP2; LDL receptor-related protein-2) gene polymorphisms with central adiposity. We used data from the Baltimore Longitudinal Study of Aging (BLSA), an ongoing prospective open cohort study. Study participants consisted of non-Hispanic white adults residing in Baltimore city, with one or more visits at age ≥50 years, and complete data (n 609–617). Repeated assessments on waist circumference (WC) and waist:hip ratio (WHR) were available. Multiple linear mixed models were used to estimate mid-follow-up age central adiposity level and annual rate of change with cut-points set at the sex-specific 80th percentile. The four binary outcomes were: ‘elevated central adiposity’ (ECA-WC and ECA-WHR) and ‘significant increase in central adiposity’ (SICA-WC and SICA-WHR). SNP for VDR (four SNP: (1) rs11568820 (CdX-2:T/C); (2) rs1544410 (BsmI:G/A); (3) rs7975232 (ApaI:A/C); (4) rs731236 (TaqI:G/A)) and Megalin (three SNP: (1) rs3755166:G/A; (2) rs2075252:C/T; (3) rs4668123:C/T) genes were selected. SNP latent classes (SNPLC) and SNP haplotypes (SNPHAP) were created. Multiple logistic regression analyses indicated that, in men, higher ECA-WHR odds were associated with SNPLC Megalin2:rs3755166[–]/rs2075252[TT]/rs4668123[T–] (v. Megalin1:rs3755166[–]/rs2075252[CC]/rs4668123[–]) (OR 2·87; 95 % CI 1·15, 7·12; P = 0·023) and that SNPLC Megalin3:rs3755166[–]/rs2075252[CT]/rs4668123[–] (v. Megalin1) was linked to lower SICA-WC odds (OR 0·48; 95 % CI 0·26, 0·88; P = 0·019) (P > 0·05 for sex × SNPLC). In women, VDR3 SNPHAP (GAA:bAT) was related to lower odds of ECA-WC (OR 0·37; 95 % CI 0·16, 0·87; P = 0·023) (P 0·05 for sex × SNPHAP). Vitamin D-related gene polymorphisms were associated with central adiposity status and change. Future mechanistic studies are needed to confirm those polymorphisms' biological significance to central adiposity

Systemic Inflammation Is Associated With Longitudinal Changes in Cognitive Performance Among Urban Adults

Objectives/Background: Systemic inflammation can affect cognitive performance over time. The current study examined associations between systemic inflammation and cognitive performance among African Americans and Whites urban adults, stratifying by sex, and age group and by race.Patients/Methods: Among 1,555–1,719 White and African-American urban adults [Agebase: 30–64y, 2004-2013, mean±SD follow-up time(y): 4.64 ± 0.93y], conducted linear mixed-effects regression models were conducted to test associations of inflammatory markers [C-reactive protein, Erythrocyte Sedimentation Rate (ESR), albumin, iron, and an inflammation composite score (ICS)] with longitudinal cognitive performance.Results: Among key findings, CRP was linked to poorer baseline mental status among younger women (≤50y, γ01 = –0.03 ± 0.01, p = 0.002) and poorer attention in older women (>50y, γ01 = −0.024 ± 0.007, p < 0.004) and African-Americans (γ01 = −0.029 ± 0.008, p < 0.001). ESR was related to faster decline on verbal memory among older men (>50y, γ11 = −0.008 ± 0.003, P = 0.009); with poorer performance on attention tests overall (γ01 = −0.010 ± 0.003, P = 0.003) and among African-Americans (γ01 = −0.013 ± 0.004, P = 0.002); on verbal fluency among older women (>50y,γ01 = −0.037 ± 0.013, P = 0.004) and on executive function: overall (γ01 = +0.62 ± 0.21, P = 0.004), older men (>50y, γ01 = +1.69 ± 0.53, P = 0.001) and African-Americans (γ01 = +0.84 ± 0.28, P = 0.002). Albumin was linked to slower attention decline among older men (>50y, γ11 = +0.329 ± 0.103, P = 0.009), over-time improvement in executive function overall (γ11 = −6.00 ± 2.26, P = 0.008), and better baseline psychomotor speed among African-Americans (γ01 = +0.56 ± 0.19, P = 0.003). Finally, ICS predicted faster decline on visual memory/visuo-constructive abilities among older men (>50y, γ11 = +0.17 ± 0.06, p = 0.003).Conclusion: In sum, strong associations between systemic inflammation and longitudinal cognitive performance were detected, largely among older individuals (>50y) and African-Americans. Randomized trials targeting inflammation are warranted

<span class="italic">n</span>–3 Fatty acids, hypertension and risk of cognitive decline among older adults in the Atherosclerosis Risk in Communities (ARIC) study

OBJECTIVE: Recent research indicates that n-3 fatty acids can inhibit cognitive decline, perhaps differentially by hypertensive status. DESIGN: We tested these hypotheses in a prospective cohort study (the Atherosclerosis Risk in Communities). Dietary assessment using a food-frequency questionnaire and plasma fatty acid exposure by gas chromatography were completed in 1987-1989 (visit 1), while cognitive assessment with three screening tools--the Delayed Word Recall Test, the Digit Symbol Substitution Test of the Wechsler Adult Intelligence Scale-Revised and the Word Fluency Test (WFT)--was completed in 1990-1992 (visit 2) and 1996-1998 (visit 4). Regression calibration and simulation extrapolation were used to control for measurement error in dietary exposures. SETTING: Four US communities--Forsyth County (North Carolina), Jackson (Mississippi), suburbs of Minneapolis (Minnesota) and Washington County (Maryland). SUBJECTS: Men and women aged 50-65 years at visit 1 with complete dietary data (n = 7814); white men and women in same age group in the Minnesota field centre with complete plasma fatty acid data (n = 2251). RESULTS: Findings indicated that an increase of one standard deviation in dietary long-chain n-3 fatty acids (% of energy intake) and balancing long-chain n-3/n-6 decreased the risk of 6-year cognitive decline in verbal fluency with an odds ratio (95% confidence interval) of 0.79 (0.66-0.95) and 0.81 (0.68-0.96), respectively, among hypertensives. An interaction with hypertensive status was found for dietary long-chain n-3 fatty acids (g day-1) and WFT decline (likelihood ratio test, P = 0.06). This exposure in plasma cholesteryl esters was also protective against WFT decline, particularly among hypertensives (OR = 0.51, P < 0.05). CONCLUSION: One implication from our study is that diets rich in fatty acids of marine origin should be considered for middle-aged hypertensive subjects. To this end, randomised clinical trials are needed

Dietary Antioxidant Intake and Its Association With Cognitive Function in an Ethnically Diverse Sample of US Adults

Background: Dietary antioxidants can inhibit reactions accompanying neurodegeneration and thus prevent cognitive impairment. We describe associations of dietary antioxidants with cognitive function in a large biracial population, while testing moderation by sex, race, and age and mediation by depressive symptoms. Methods: This was a cross-sectional analysis of 1274 adults (541 men and 733 women) aged 30 to 64 years at baseline (mean [standard deviation] = 47.5 [9.3]) in the Healthy Aging in Neighborhoods of Diversity Across the Lifespan Study, Baltimore city, MD. Cognitive performance in the domains of memory, language/verbal, attention, spatial, psychomotor speed, executive function, and global mental status were assessed. The 20-item Center for Epidemiologic Studies Depression Scale was used to measure depressive symptoms. Dietary intake was assessed with two 24-hour recalls, estimating daily consumption of total carotenoids and vitamins A, C, and E per 1000 kcal. Results: Among key findings, 1 standard deviation (È2.02 mg/1000 kcal) higher vitamin E was associated with a higher score on verbal memory, immediate recall (A = +0.6

Helicobacter pylori, persistent infection burden and structural brain imaging markers

Persistent infections, whether viral, bacterial or parasitic, including Helicobacter pylori infection, have been implicated in non-communicable diseases, including dementia and other neurodegenerative diseases. In this cross-sectional study, data on 635 cognitively normal participants from the UK Biobank study (2006–21, age range: 40–70 years) were used to examine whether H. pylori seropositivity (e.g. presence of antibodies), serointensities of five H. pylori antigens and a measure of total persistent infection burden were associated with selected brain volumetric structural MRI (total, white, grey matter, frontal grey matter (left/right), white matter hyperintensity as percent intracranial volume and bi-lateral sub-cortical volumes) and diffusion-weighted MRI measures (global and tract-specific bi-lateral fractional anisotropy and mean diffusivity), after an average 9–10 years of lag time. Persistent infection burden was calculated as a cumulative score of seropositivity for over 20 different pathogens. Multivariable-adjusted linear regression analyses were conducted, whereby selected potential confounders (all measures) and intracranial volume (sub-cortical volumes) were adjusted, with stratification by Alzheimer’s disease polygenic risk score tertile when exposures were H. pylori antigen serointensities. Type I error was adjusted to 0.007. We report little evidence of an association between H. pylori seropositivity and persistent infection burden with various volumetric outcomes (P &gt; 0.007, from multivariable regression models), unlike previously reported in past research. However, H. pylori antigen serointensities, particularly immunoglobulin G against the vacuolating cytotoxin A, GroEL and outer membrane protein antigens, were associated with poorer tract-specific white matter integrity (P &lt; 0.007), with outer membrane protein serointensity linked to worse outcomes in cognition-related tracts such as the external capsule, the anterior limb of the internal capsule and the cingulum, specifically at low Alzheimer’s disease polygenic risk. Vacuolating cytotoxin A serointensity was associated with greater white matter hyperintensity volume among individuals with mid-level Alzheimer’s disease polygenic risk, while among individuals with the highest Alzheimer’s disease polygenic risk, the urease serointensity was consistently associated with reduced bi-lateral caudate volumes and the vacuolating cytotoxin A serointensity was linked to reduced right putamen volume (P &lt; 0.007). Outer membrane protein and urease were associated with larger sub-cortical volumes (e.g. left putamen and right nucleus accumbens) at middle Alzheimer’s disease polygenic risk levels (P &lt; 0.007). Our results shed light on the relationship between H. pylori seropositivity, H. pylori antigen levels and persistent infection burden with brain volumetric structural measures. These data are important given the links between infectious agents and neurodegenerative diseases, including Alzheimer’s disease, and can be used for the development of drugs and preventive interventions that would reduce the burden of those diseases

Association of Alcohol-Induced Loss of Consciousness and Overall Alcohol Consumption With Risk for Dementia

This cohort study examines the association of overall consumption of alcohol and resultant loss of consciousness with risk for dementia. Question Are alcohol-induced loss of consciousness and heavy weekly alcohol consumption associated with increased risk of future dementia? Findings In this multicohort study of 131x202f;415 adults, a 1.2-fold excess risk of dementia was associated with heavy vs moderate alcohol consumption. Those who reported having lost consciousness due to alcohol consumption, regardless of their overall weekly consumption, had a 2-fold increased risk of dementia compared with people who had not lost consciousness and were moderate drinkers. Meaning The findings of this study suggest that alcohol-induced loss of consciousness is a long-term risk factor for dementia among both heavy and moderate drinkers. Importance Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain. Objective To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers. Design, Setting, and Participants Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131x202f;415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020. Exposures Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week. Main Outcomes and Measures Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records. Results Of the 131x202f;415 participants (mean [SD] age, 43.0 [10.4] years; 80x202f;344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96x202f;591 participants with data on loss of consciousness, 10x202f;004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (= 65 y: HR, 2.25; 95% CI, 1.38-3.66) dementia, Alzheimer disease (HR, 1.98; 95% CI, 1.28-3.07), and dementia with features of atherosclerotic cardiovascular disease (HR, 4.18; 95% CI, 1.86-9.37). The association with dementia was not explained by 14 other alcohol-related conditions. With moderate drinkers (1-14 U/wk) who had not lost consciousness as the reference group, the HR for dementia was twice as high in participants who reported having lost consciousness, whether their mean weekly consumption was moderate (HR, 2.19; 95% CI, 1.42-3.37) or heavy (HR, 2.36; 95% CI, 1.57-3.54). Conclusions and Relevance The findings of this study suggest that alcohol-induced loss of consciousness, irrespective of overall alcohol consumption, is associated with a subsequent increase in the risk of dementia.Peer reviewe

Measurement error adjustment in essential fatty acid intake from a food frequency questionnaire: alternative approaches and methods

<p>Abstract</p> <p>Background</p> <p>We aimed at assessing the degree of measurement error in essential fatty acid intakes from a food frequency questionnaire and the impact of correcting for such an error on precision and bias of odds ratios in logistic models. To assess these impacts, and for illustrative purposes, alternative approaches and methods were used with the binary outcome of cognitive decline in verbal fluency.</p> <p>Methods</p> <p>Using the Atherosclerosis Risk in Communities (ARIC) study, we conducted a sensitivity analysis. The error-prone exposure – visit 1 fatty acid intake (1987–89) – was available for 7,814 subjects 50 years or older at baseline with complete data on cognitive decline between visits 2 (1990–92) and 4 (1996–98). Our binary outcome of interest was clinically significant decline in verbal fluency. Point estimates and 95% confidence intervals were compared between naïve and measurement-error adjusted odds ratios of decline with every SD increase in fatty acid intake as % of energy. Two approaches were explored for adjustment: (A) External validation against biomarkers (plasma fatty acids in cholesteryl esters and phospholipids) and (B) Internal repeat measurements at visits 2 and 3. The main difference between the two is that Approach B makes a stronger assumption regarding lack of error correlations in the structural model. Additionally, we compared results from regression calibration (RCAL) to those from simulation extrapolation (SIMEX). Finally, using structural equations modeling, we estimated attenuation factors associated with each dietary exposure to assess degree of measurement error in a bivariate scenario for regression calibration of logistic regression model.</p> <p>Results and conclusion</p> <p>Attenuation factors for Approach A were smaller than B, suggesting a larger amount of measurement error in the dietary exposure. Replicate measures (Approach B) unlike concentration biomarkers (Approach A) may lead to imprecise odds ratios due to larger standard errors. Using SIMEX rather than RCAL models tends to preserve precision of odds ratios. We found in many cases that bias in naïve odds ratios was towards the null. RCAL tended to correct for a larger amount of effect bias than SIMEX, particularly for Approach A.</p

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 (a-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 SNPassociations and their interactions with n-3PUFAs. 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 (P-2df = 9.4 x 10(-9) across discovery and replication cohorts). The rs11693320-A allele (frequency, similar to 80%) was associated with lower FVC (P-SNP = 2.1 x 10(-9); beta(SNP) = 2161.0 ml), and the association was attenuated by higher DHA levels (P-SNPxDHA interaction = 2.1x10(-7); beta(SNPxDHA 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

Association of Alcohol-Induced Loss of Consciousness and Overall Alcohol Consumption With Risk for Dementia

This cohort study examines the association of overall consumption of alcohol and resultant loss of consciousness with risk for dementia.Question Are alcohol-induced loss of consciousness and heavy weekly alcohol consumption associated with increased risk of future dementia? Findings In this multicohort study of 131x202f;415 adults, a 1.2-fold excess risk of dementia was associated with heavy vs moderate alcohol consumption. Those who reported having lost consciousness due to alcohol consumption, regardless of their overall weekly consumption, had a 2-fold increased risk of dementia compared with people who had not lost consciousness and were moderate drinkers. Meaning The findings of this study suggest that alcohol-induced loss of consciousness is a long-term risk factor for dementia among both heavy and moderate drinkers.Importance Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain. Objective To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers. Design, Setting, and Participants Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131x202f;415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020. Exposures Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week. Main Outcomes and Measures Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records. Results Of the 131x202f;415 participants (mean [SD] age, 43.0 [10.4] years; 80x202f;344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96x202f;591 participants with data on loss of consciousness, 10x202f;004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (= 65 y: HR, 2.25; 95% CI, 1.38-3.66) dementia, Alzheimer disease (HR, 1.98; 95% CI, 1.28-3.07), and dementia with features of atherosclerotic cardiovascular disease (HR, 4.18; 95% CI, 1.86-9.37). The association with dementia was not explained by 14 other alcohol-related conditions. With moderate drinkers (1-14 U/wk) who had not lost consciousness as the reference group, the HR for dementia was twice as high in participants who reported having lost consciousness, whether their mean weekly consumption was moderate (HR, 2.19; 95% CI, 1.42-3.37) or heavy (HR, 2.36; 95% CI, 1.57-3.54). Conclusions and Relevance The findings of this study suggest that alcohol-induced loss of consciousness, irrespective of overall alcohol consumption, is associated with a subsequent increase in the risk of dementia