Extracellular microRNAs associated with psychiatric symptoms in the Normative Aging Study.

Earlier studies have revealed microRNAs (miRNAs) as potential biomarkers for neurological conditions, however, such evidence on psychiatric outcomes is limited. We utilized the Normative Aging Study (NAS) cohort to investigate the associations between extracellular miRNAs (ex-miRNA) and psychiatric symptoms among a group of older male adults, along with the targeted genes and biological pathways. We studied 569 participants with miRNA profile primarily measured in extracellular vesicles isolated from plasma, and psychiatric symptoms reported over 1996-2014 with repeated measures. Global and dimension scales of psychiatric symptoms were measured via the administration of Brief Symptom Inventory (BSI) per visit covering nine aspects of psychiatric health, such as anxiety, depression, hostility, psychoticism, etc. Ex-miRNAs were profiled using small RNA sequencing. Associations of expression of 395 ex-miRNAs (present in >70% samples) with current mental status were assessed using single-miRNA as well as Least Absolute Shrinkage and Selection Operator (LASSO)-based multi-miRNAs linear mixed effects models adjusting for key demographic and behavioral factors. Biological functions were explored using pathway analyses. We identified ex-miRNAs associated with each BSI scale. In particular, hsa-miR-320d was consistently identified for two global scales. Similar overlapping miRNAs across global and dimension scores included hsa-miR-379-3p, hsa-miR-1976, hsa-miR-151a-5p, hsa-miR-151b, hsa-miR-144-3p, etc. Top KEGG pathways for identified miRNAs included p53 signaling, Hippo signaling, FoxO signaling, protein processing in endoplasmic reticulum and several pathways related with cancer and neurological diseases. This study provided early evidence supporting the associations between extracellular miRNAs and psychiatric conditions. MiRNAs may serve as biomarkers of subclinical psychiatric illness in older adults.

Epigenome-Wide Analysis of DNA Methylation and Optimism in Women and Men.

OBJECTIVE: Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized that DNAm would differ among older individuals who are more versus less optimistic. METHODS: Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities ( n = 3816) and men (only White, n = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the individual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the "number of independent degrees of freedom" approach: effective degrees of freedom correction using the number of principal components (PCs), explaining >95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathway analyses using the Ingenuity Pathway Analysis software. RESULTS: We found that essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm-optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, and neurodevelopmental and neurodegenerative disorders. CONCLUSION: Our findings provide new insights into possible mechanisms underlying optimism and health.

Metabolomic differences in lung function metrics: evidence from two cohorts.

RATIONALE: The biochemical mechanisms underlying lung function are incompletely understood. OBJECTIVES: To identify and validate the plasma metabolome of lung function using two independent adult cohorts: discovery-the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk, n=10 460) and validation-the VA Normative Aging Study (NAS) metabolomic cohort (n=437). METHODS: We ran linear regression models for 693 metabolites to identify associations with forced expiratory volume in one second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC), in EPIC-Norfolk then validated significant findings in NAS. Significance in EPIC-Norfolk was denoted using an effective number of tests threshold of 95%; a metabolite was considered validated in NAS if the direction of effect was consistent and p<0.05. MEASUREMENTS AND MAIN RESULTS: Of 156 metabolites that associated with FEV1 in EPIC-Norfolk after adjustment for age, sex, body mass index, height, smoking and asthma status, 34 (21.8%) validated in NAS, including several metabolites involved in oxidative stress. When restricting the discovery sample to men only, a similar percentage, 18 of 79 significant metabolites (22.8%) were validated. A smaller number of metabolites were validated for FEV1/FVC, 6 of 65 (9.2%) when including all EPIC-Norfolk as the discovery population, and 2 of 34 (5.9%) when restricting to men. These metabolites were characterised by involvement in respiratory track secretants. Interestingly, no metabolites were validated for both FEV1 and FEV1/FVC. CONCLUSIONS: The validation of metabolites associated with respiratory function can help to better understand mechanisms of lung health and may assist the development of biomarkers.

Is Healthy Neuroticism Associated with Health Behaviors? A Coordinated Integrative Data Analysis.

Current literature suggests that neuroticism is positively associated with maladaptive life choices, likelihood of disease, and mortality. However, recent research has identified circumstances under which neuroticism is associated with positive outcomes. The current project examined whether "healthy neuroticism", defined as the interaction of neuroticism and conscientiousness, was associated with the following health behaviors: smoking, alcohol consumption, and physical activity. Using a pre-registered multi-study coordinated integrative data analysis (IDA) approach, we investigated whether "healthy neuroticism" predicted the odds of engaging in each of the aforementioned activities. Each study estimated identical models, using the same covariates and data transformations, enabling optimal comparability of results. These results were then meta-analyzed in order to estimate an average (N-weighted) effect and to ascertain the extent of heterogeneity in the effects. Overall, these results suggest that neuroticism alone was not related to health behaviors, while individuals higher in conscientiousness were less likely to be smokers or drinkers, and more likely to engage in physical activity. In terms of the healthy neuroticism interaction of neuroticism and conscientiousness, significant interactions for smoking and physical activity suggest that the association between neuroticism and health behaviors was smaller among those high in conscientiousness. These findings lend credence to the idea that healthy neuroticism may be linked to certain health behaviors and that these effects are generalizable across several heterogeneous samples.

Changes in Health Status in the Ft. Devens Gulf War Veterans Cohort: 1997-2017.

Gulf War veterans (GWVs) were exposed to numerous neurotoxicants during deployment. Upon returning home, many reported a multitude of symptoms including fatigue, pain, gastrointestinal and respiratory issues, and neurological, cognitive, and mood complaints, collectively termed "Gulf War Illness (GWI)." Now, nearly 30 years post-war, many GWVs continue to suffer from these symptoms, in addition to health concerns associated with normal aging. While most research on GWVs has been cross-sectional, it is important to evaluate the progression and onset of new GWI symptoms longitudinally. The current study investigated the health of GWVs 25+ years after the war by resurveying the Ft. Devens Cohort and comparing their current health to their health reported 15 to 20 years earlier. The sample consists of 317 GWVs (~54 years old at the latest survey, 38 women) who responded to both surveys (1997-1998 and 2013-2017). Multivariable regression analyses were used to assess changes in GWI symptomatology and prevalence of medical conditions. The rates of 12 of 25 health symptoms increased significantly from the prior 1997-1998 survey. Anxiety, numbness in extremities, depressed mood, and joint pain had the greatest increase in endorsement. The rates of 7 of 16 medical conditions increased significantly from the prior 1997-1998 survey. High blood pressure, diabetes, and cancer had the greatest increase in prevalence. In summary, this study demonstrates that both symptoms and physician-diagnosed medical conditions associated with GW deployment/exposure increased in prevalence. For GWVs, focus by providers on the treatment of cognitive and mental health issues as well as cardiovascular and cerebrovascular risk factors is warranted. Targeting symptom alleviation would help improve the quality of life in these veterans until treatments addressing the entire illness become available.

Personality Predicts Mortality Risk: An Integrative Data Analysis of 15 International Longitudinal Studies.

This study examined the Big Five personality traits as predictors of mortality risk, and smoking as a mediator of that association. Replication was built into the fabric of our design: we used a Coordinated Analysis with 15 international datasets, representing 44,094 participants. We found that high neuroticism and low conscientiousness, extraversion, and agreeableness were consistent predictors of mortality across studies. Smoking had a small mediating effect for neuroticism. Country and baseline age explained variation in effects: studies with older baseline age showed a pattern of protective effects (HR<1.00) for openness, and U.S. studies showed a pattern of protective effects for extraversion. This study demonstrated coordinated analysis as a powerful approach to enhance replicability and reproducibility, especially for aging-related longitudinal research.

Physical Health Conditions Among a Population-Based Cohort of Vietnam-Era Women Veterans: Agreement Between Self-Report and Medical Records.

BACKGROUND: Little is known about medical morbidity among women Vietnam-era veterans, or the long-term physical health problems associated with their service. This study assessed agreement comparing data on physical health conditions from self-report and medical records from a population-based cohort of women Vietnam-era Veterans from the Health of Vietnam Era Women's Study (HealthViEWS). MATERIALS AND METHODS: Women Vietnam-era veterans (n = 4219) self-completed a survey and interview on common medical conditions. A subsample (n = 900) were contacted to provide permission to obtain medical records from as many as three of their providers. Medical record reviews were conducted using a standardized checklist. Agreement and kappa (agreement beyond chance) were calculated for physical health condition groups. RESULTS: Of the 900, 449 had medical records returned, and of those, 412 had complete surveys/interviews. The most commonly reported conditions based on self-report or medical record review included hypertension, hyperlipidemia, or arthritis. Kappa scores between self-reported conditions and medical record documentation were 0.75-0.91 for hypertension, diabetes, most cancers, and neurological conditions, but lower (k = 0.29-0.55) for cardiovascular diseases, musculoskeletal, and gastrointestinal conditions. Generally, agreement did not significantly vary by different sociodemographic groups. CONCLUSIONS: There was relatively high agreement for physical health conditions when self-report was compared with medical record review. As more women are increasingly represented in the military and more veterans in general seek care outside the Veterans Health Administration, accurate measurement of physical health conditions among population-based samples is crucial.

Telomere Length, Long-Term Black Carbon Exposure, and Cognitive Function in a Cohort of Older Men: The VA Normative Aging Study.

BACKGROUND: Long-term air pollution exposure has been associated with age-related cognitive impairment, possibly because of enhanced inflammation. Leukocytes with longer telomere length (TL) are more responsive to inflammatory stimuli, yet TL has not been evaluated in relation to air pollution and cognition. OBJECTIVES: We assessed whether TL modifies the association of 1-year exposure to black carbon (BC), a marker of traffic-related air pollution, with cognitive function in older men, and we examined whether this modification is independent of age and of C-reactive protein (CRP), a marker of inflammation. METHODS: Between 1999 and 2007, we conducted 1-3 cognitive examinations of 428 older men in the Veterans Affairs (VA) Normative Aging Study. We used covariate-adjusted repeated-measure logistic regression to estimate associations of 1-year BC exposure with relative odds of being a low scorer (≤ 25) on the Mini-Mental State Examination (MMSE), which is a proxy of poor cognition. Confounders included age, CRP, and lifestyle and sociodemographic factors. RESULTS: Each doubling in BC level was associated with 1.57 (95% CI: 1.20, 2.05) times higher odds of low MMSE scores. The BC-MMSE association was greater only among individuals with longer blood TL (5th quintile) (OR = 3.23; 95% CI: 1.37, 7.59; p = 0.04 for BC-by-TL-interaction). TL and CRP were associated neither with each other nor with MMSE. However, CRP modified the BC-MMSE relationship, with stronger associations only at higher CRP (5th quintile) and reference TL level (1st quintile) (OR = 2.68; 95% CI: 1.06, 6.79; p = 0.04 for BC-by-CRP-interaction). CONCLUSIONS: TL and CRP levels may help predict the impact of BC exposure on cognitive function in older men. Citation: Colicino E, Wilson A, Frisardi MC, Prada D, Power MC, Hoxha M, Dioni L, Spiro A III, Vokonas PS, Weisskopf MG, Schwartz JD, Baccarelli AA. 2017. Telomere length, long-term black carbon exposure, and cognitive function in a cohort of older men: the VA Normative Aging Study. Environ Health Perspect 125:76-81; http://dx.doi.org/10.1289/EHP241.

Psychological factors and DNA methylation of genes related to immune/inflammatory system markers: the VA Normative Aging Study.

OBJECTIVES: Although psychological factors have been associated with chronic diseases such as coronary heart disease (CHD), the underlying pathways for these associations have yet to be elucidated. DNA methylation has been posited as a mechanism linking psychological factors to CHD risk. In a cohort of community-dwelling elderly men, we explored the associations between positive and negative psychological factors with DNA methylation in promoter regions of multiple genes involved in immune/inflammatory processes related to atherosclerosis. DESIGN: Prospective cohort study. SETTING: Greater Boston, Massachusetts area. PARTICIPANTS: Samples of 538 to 669 men participating in the Normative Aging Study cohort with psychological measures and DNA methylation measures, collected on 1-4 visits between 1999 and 2006 (mean age=72.7 years at first visit). OUTCOME MEASURES: We examined anxiety, depression, hostility and life satisfaction as predictors of leucocyte gene-specific DNA methylation. We estimated repeated measures linear mixed models, controlling for age, smoking, education, history of heart disease, stroke or diabetes, % lymphocytes, % monocytes and plasma folate. RESULTS: Psychological distress measured by anxiety, depression and hostility was positively associated, and happiness and life satisfaction were inversely associated with average Intercellular Adhesion Molecule-1 (ICAM-1) and coagulation factor III (F3) promoter methylation levels. There was some evidence that hostility was positively associated with toll-like receptor 2 (TLR-2) promoter methylation, and that life satisfaction was inversely associated with TLR-2 and inducible nitric oxide synthase (iNOS) promoter methylation. We observed less consistent and significant associations between psychological factors and average methylation for promoters of the genes for glucocorticoid receptor (NR3C1), interferon-γ (IFN-γ) and interleukin 6 (IL-6). CONCLUSIONS: These findings suggest that positive and negative psychological factors affect DNA methylation of selected genes involved in chronic immune/inflammatory processes and inflammation-related endothelial dysfunction. Such epigenetic changes may represent biological pathways that mediate the effects of psychological factors on CHD.

Long-term exposure to black carbon, cognition and single nucleotide polymorphisms in microRNA processing genes in older men.

INTRODUCTION: Air pollution exposure has been linked to impaired cognitive aging, but little is known about biomarkers modifying this association. MicroRNAs (miRNAs) control gene expression and neuronal programming. miRNA levels vary due to single nucleotide polymorphisms (SNPs) in genes processing miRNAs from precursor molecules. OBJECTIVES: To investigate whether SNPs in miRNA-processing genes are associated with cognition and modify the relationship between black carbon (BC), marker of traffic-related pollution, and cognitive functions. METHODS: 533 Normative Aging Study men (mean±SD 72±7years) were tested ≤4 times (mean=1.7 times) using seven cognitive tests between 1995 and 2007. We tested interactions of 16 miRNA-related SNPs with 1-year average BC from a validated land-use-regression model. We used covariate-adjusted logistic regression for low (≤25) Mini-Mental tate Examination (MMSE) and mixed-effect regression for a global cognitive score combining six other tests. RESULTS: Global cognition was negatively associated with the homozygous minor variant of rs595961 AGO1 (-0.42SD; 95%CI: (-0.71, -0.13)) relative to the major variant. BC-MMSE association was stronger in heterozygous carriers of rs11077 XPO5 (OR=1.99; 95%CI: (1.39, 2.85)) and minor variant carriers of GEMIN4 rs2740348 (OR=1.34; 95%CI: (1.05, 1.7)), compared to their major variant. The BC-global-cognition association was stronger in heterozygous carriers of GEMIN4 rs4968104 (-0.10SD; 95%CI: (-0.18, -0.02)), and GEMIN4 rs910924 (-0.09SD; 95%CI: (-0.17, -0.02)) relative to the major variant. Blood miRNA expression analyses showed associations only of XPO5 rs11077 with miR-9 and miR-96. CONCLUSIONS: Carriers of particular miRNA-processing SNPs had higher susceptibility to BC in BC-cognition associations, possibly due to influences on miRNA expression.

The Dietary Approaches to Stop Hypertension Diet and New and Recurrent Root Caries Events in Men.

OBJECTIVES: To examine the effect of overall dietary quality on number of teeth with new or recurrent root caries events during follow-up (root caries increment). DESIGN: Prospective study with dental examinations approximately every 3 years over 20 years. SETTING: Veterans Affairs Dental Longitudinal Study in greater Boston, Massachusetts, area. PARTICIPANTS: Men aged 47 to 90 (N = 533). MEASUREMENTS: A single calibrated examiner assessed root caries and restorations, calculus, probing pocket depth, and attachment loss on each tooth at each examination. The adjusted root caries increment (root-ADJCI) was computed from new and recurrent root caries events on teeth with recession of 2 mm or more. Dietary information was obtained from food frequency questionnaires. An adherence score was computed by comparing consumption frequency of 10 food groups (fruits, vegetables, total dairy, low-fat dairy, meat, total grains, high-fiber grains, legumes, fats, sweets) from the Dietary Approaches to Stop Hypertension (DASH) diet guidelines. Mean root-ADJCIs were compared according to DASH adherence score quartile using generalized linear negative binomial regression models, controlling for age, number of teeth at risk of root caries, time at risk of root caries, calculus, presence of removable denture, history of dental prophylaxis, body mass index, and smoking status. RESULTS: Men with DASH adherence scores in the highest quartile had a 30% lower mean root-ADJCI (1.86 teeth) than those in the lowest quartile (2.68 teeth) (P = .03). Root-ADJCI was lower with greater adherence to recommendations for vegetables and total grains and greater with greater sugar-sweetened carbonated beverage consumption. Root caries incidence rate did not vary significantly between quartiles. CONCLUSION: A higher-quality diet may reduce root caries risk in older men.

Lead exposure and tremor among older men: the VA normative aging study.

BACKGROUND: Tremor is one of the most common neurological signs, yet its etiology is poorly understood. Case-control studies suggest an association between blood lead and essential tremor, and that this association is modified by polymorphisms in the δ-aminolevulinic acid dehydrogenase (ALAD) gene. OBJECTIVE: We aimed to examine the relationship between lead and tremor, including modification by ALAD, in a prospective cohort study, using both blood lead and bone lead-a biomarker of cumulative lead exposure. METHODS: We measured tibia (n = 670) and patella (n = 672) bone lead and blood lead (n = 807) among older men (age range, 50-98 years) in the VA Normative Aging Study cohort. A tremor score was created based on an approach using hand-drawing samples. ALAD genotype was dichotomized as ALAD-2 carriers or not. We used linear regression adjusted for age, education, smoking, and alcohol intake to estimate the associations between lead biomarkers and tremor score. RESULTS: In unadjusted analyses, there was a marginal association between quintiles of all lead biomarkers and tremor scores (p-values < 0.13), which did not persist in adjusted models. Age was the strongest predictor of tremor. Among those younger than the median age (68.9 years), tremor increased significantly with blood lead (p = 0.03), but this pattern was not apparent for bone lead. We did not see modification by ALAD or an association between bone lead and change in tremor score over time. CONCLUSION: Our results do not strongly support an association between lead exposure and tremor, and suggest no association with cumulative lead biomarkers, although there is some suggestion that blood lead may be associated with tremor among the younger men in our cohort.

Associations between air pollution and perceived stress: the Veterans Administration Normative Aging Study.

BACKGROUND: There is mixed evidence suggesting that air pollution may be associated with increased risk of developing psychiatric disorders. We aimed to investigate the association between air pollution and non-specific perceived stress, often a precursor to development of affective psychiatric disorders. METHODS: This longitudinal analysis consisted of 987 older men participating in at least one visit for the Veterans Administration Normative Aging Study between 1995 and 2007 (n = 2,244 visits). At each visit, participants were administered the 14-item Perceived Stress Scale (PSS), which quantifies stress experienced in the previous week. Scores ranged from 0-56 with higher scores indicating increased stress. Differences in PSS score per interquartile range increase in moving average (1, 2, and 4-weeks) of air pollution exposures were estimated using linear mixed-effects regression after adjustment for age, race, education, physical activity, anti-depressant medication use, seasonality, meteorology, and day of week. We also evaluated effect modification by season (April-September and March-October for warm and cold season, respectively). RESULTS: Fine particles (PM2.5), black carbon (BC), nitrogen dioxide, and particle number counts (PNC) at moving averages of 1, 2, and 4-weeks were associated with higher perceived stress ratings. The strongest associations were observed for PNC; for example, a 15,997 counts/cm(3) interquartile range increase in 1-week average PNC was associated with a 3.2 point (95%CI: 2.1-4.3) increase in PSS score. Season modified the associations for specific pollutants; higher PSS scores in association with PM2.5, BC, and sulfate were observed mainly in colder months. CONCLUSIONS: Air pollution was associated with higher levels of perceived stress in this sample of older men, particularly in colder months for specific pollutants.

Cholesterol and depressive symptoms in older men across time.

This study aimed to examine reciprocal relations between cholesterol and depression. We assessed cholesterol and depressive symptoms twice over a 3-year interval, using 842 men from the Veterans Affairs Normative Aging Study (M = 64, standard deviation = 8). Because depressive symptoms were skewed, we used zero-inflated Poisson analyses. Cross-lagged models showed that cholesterol levels at T1 predicted the existence of depressive symptoms at T2, covarying T1 depressive symptoms, age, smoking status, body mass index, and medications. Depressive symptoms at T1 did not predict cholesterol at T2. Low cholesterol levels may be risk factors for development of depressive symptoms in late life.

Mitochondrial haplogroups modify the effect of black carbon on age-related cognitive impairment.

BACKGROUND: Traffic-related air pollution has been linked with impaired cognition in older adults, possibly due to effects of oxidative stress on the brain. Mitochondria are the main source of cellular oxidation. Haplogroups in mitochondrial DNA (mtDNA) mark individual differences in oxidative potential and are possible determinants of neurodegeneration. The aim of this study was to investigate whether mtDNA haplogroups determined differential susceptibility to cognitive effects of long-term exposure to black carbon (BC), a marker of traffic-related air pollution. METHODS: We investigated 582 older men (72 ± 7 years) in the VA Normative Aging Study cohort with ≤4 visits per participant (1.8 in average) between 1995-2007. Low (≤25) Mini Mental State Examination (MMSE) was used to assess impaired cognition in multiple domains. We fitted repeated-measure logistic regression using validated-LUR BC estimated in the year before their first visit at the participant's address. RESULTS: Mitochondrial haplotyping identified nine haplogroups phylogenetically categorized in four clusters. BC showed larger effect on MMSE in Cluster 4 carriers, including I, W and X haplogroups, [OR = 2.7; 95% CI (1.3-5.6)], moderate effect in Cluster 1, including J and T haplogroups [OR = 1.6; 95% CI: (0.9-2.9)], and no effect in Cluster 2 (H and V haplogroups) [OR = 1.1; 95% CI: (0.8-1.5)] or Cluster 3 (K and U haplogroups) [OR = 1.0; 95% CI: (0.6-1.6)]. BC effect varied only moderately across the I, X, and W haplogroups or across the J and T haplogroups. CONCLUSIONS: The association of BC with impaired cognition was worsened in carriers of phylogenetically-related mtDNA haplogroups in Cluster 4. No BC effects were detected in Cluster 2 and 3 carriers. MtDNA haplotypes may modify individual susceptibility to the particle cognitive effects.

HealthViEWS: mortality study of female US Vietnam era veterans, 1965-2010.

We conducted a retrospective study among 4,734 women who served in the US military in Vietnam (Vietnam cohort), 2,062 women who served in countries near Vietnam (near-Vietnam cohort), and 5,313 nondeployed US military women (US cohort) to evaluate the associations of mortality outcomes with Vietnam War service. Veterans were identified from military records and followed for 40 years through December 31, 2010. Information on underlying causes of death was obtained from death certificates and the National Death Index. Based on 2,743 deaths, all 3 veteran cohorts had lower mortality risk from all causes combined and from several major causes, such as diabetes mellitus, heart disease, chronic obstructive pulmonary disease, and nervous system disease relative to comparable US women. However, excess deaths from motor vehicle accidents were observed in the Vietnam cohort (standardized mortality ratio = 3.67, 95% confidence interval (CI): 2.30, 5.56) and in the US cohort (standardized mortality ratio = 1.91, 95% CI: 1.02, 3.27). More than two-thirds of women in the study were military nurses. Nurses in the Vietnam cohort had a 2-fold higher risk of pancreatic cancer death (adjusted relative risk = 2.07, 95% CI: 1.00, 4.25) and an almost 5-fold higher risk of brain cancer death compared with nurses in the US cohort (adjusted relative risk = 4.61, 95% CI: 1.27, 16.83). Findings of all-cause and motor vehicle accident deaths among female Vietnam veterans were consistent with patterns of postwar mortality risk among other war veterans.

Cumulative lead exposure in community-dwelling adults and fine motor function: comparing standard and novel tasks in the VA normative aging study.

BACKGROUND AND AIMS: Lead exposure in children and occupationally exposed adults has been associated with reduced visuomotor and fine motor function. However, associations in environmentally exposed adults remain relatively unexplored. To address this, we examined the association between cumulative lead exposure-as measured by lead in bone-and performance on the grooved pegboard (GP) manual dexterity task, as well as on handwriting tasks using a novel assessment approach, among men in the VA Normative Aging Study (NAS). METHODS: GP testing was done with 362 NAS participants, and handwriting assessment with 328, who also had tibia and patella lead measurements made with K-X-Ray Fluorescence (KXRF). GP scores were time (s) to complete the task with the dominant hand. The handwriting assessment approach assessed the production of signature and cursive lowercase l and m letter samples. Signature and lm task scores reflect consistency in repeated trials. We used linear regression to estimate associations and 95% confidence intervals (CI) with adjustment for age, smoking, education, income and computer experience. A backward elimination algorithm was used in the subset with both GP and handwriting assessment to identify variables predictive of each outcome. RESULTS: The mean (SD) participant age was 69.1 (7.2) years; mean patella and tibia concentrations were 25.0 (20.7)µg/g and 19.2 (14.6)µg/g, respectively. In multivariable-adjusted analyses, GP performance was associated with tibia (ß per 15µg/g bone=4.66, 95% CI: 1.73, 7.58, p=0.002) and patella (ß per 20µg/g=3.93, 95% CI: 1.11, 6.76, p=0.006). In multivariable adjusted models of handwriting production, only the lm-pattern task showed a significant association with tibia (ß per 15µg/g bone=1.27, 95% CI: 0.24, 2.29, p=0.015), such that lm pattern production was more stable with increasing lead exposure. GP and handwriting scores were differentially sensitive to education, smoking, computer experience, financial stability, income and alcohol consumption. CONCLUSIONS: Long-term cumulative environmental lead exposure was associated with deficits in GP performance, but not handwriting production. Higher lead appeared to be associated with greater consistency on the lm task. Lead sensitivity differences could suggest that lead affects neural processing speed rather than motor function per se, or could result from distinct brain areas involved in the execution of different motor tasks.

Modification by hemochromatosis gene polymorphisms of the association between traffic-related air pollution and cognition in older men: a cohort study.

BACKGROUND: Previous studies found effect modification of associations between traffic-related air pollution and cardiovascular outcomes by polymorphisms in the hemochromatosis gene (HFE). As traffic-related air pollution may impact cognition through effects on cardiovascular health or through mechanisms which may also influence cardiovascular outcomes, we hypothesized that HFE polymorphisms would also modify a previously observed association between traffic-related air pollution exposure and cognition in older men. METHODS: We considered data from 628 participants of the VA Normative Aging Study. We estimated long term exposure to black carbon (BC), a marker of traffic related air pollution, using a spatio-temporal land use regression model. We assessed cognition using the Mini-Mental State Examination (MMSE), a test of global function, and performance on a battery of other tests, covering a wide range of domains. We investigated whether variants of HFE C282Y and H63D modified the association between BC and having a low MMSE score using logistic models with generalized estimating equations and multiplicative interaction terms. Similarly, we assessed whether HFE variants modified the association between BC and performance on the cognitive battery using linear mixed models with multiplicative interaction terms. RESULTS: Our results suggest modification of the BC-cognition association by HFE C282Y, although the test of interaction did not achieve statistical significance. In multivariable-adjusted models, participants who lacked a HFE C282Y variant (CC) exhibited an adverse association between BC and total cognition z-score (beta for a doubling in BC concentration: -0.061, 95% CI: -0.115, -0.007), while we did not observe an association in participants with at least one variant genotype (CY or YY) (beta for a doubling in BC concentration: 0.073, 95% CI: -0.081, 0.228; p-value for interaction: 0.11). The pattern of association was similar for analyses considering performance on the Mini-Mental State Examination. There was little evidence to support effect modification of the BC-cognition association by the HFE H63D genotype. CONCLUSIONS: Our data suggest that older adults who lack an HFE C282Y variant may be more susceptible to an adverse effect of traffic-related air pollution exposure on cognition. This finding and the proposed biological mechanism require confirmation.

Air pollution and DNA methylation: interaction by psychological factors in the VA Normative Aging Study.

DNA methylation is a potential pathway linking air pollution to disease. Studies indicate that psychological functioning modifies the association between pollution and morbidity. The authors estimated the association of DNA methylation with ambient particulate matter less than 2.5 µm in diameter (PM(2.5)) and black carbon, using mixed models. DNA methylation of the inducible nitric oxide synthase gene, iNOS, and the glucocorticoid receptor gene, GCR, was measured by quantitative polymerase chain reaction pyrosequencing of 1,377 blood samples from 699 elderly male participants in the VA Normative Aging Study (1999-2009). The authors also investigated whether this association was modified by psychological factors including optimism or pessimism, anxiety, and depression. iNOS methylation was decreased after acute exposure to both black carbon and PM(2.5). A 1-µg/m(3) increase in exposure to black carbon in the 4 hours preceding the clinical examination was associated with a 0.9% decrease in 5-methylcytosine (95% CI: 0.4, 1.4) in iNOS, and a 10-µg/m(3) increase in exposure to PM(2.5) was associated with a 0.6% decrease in 5-methylcytosine (95% CI: 0.03, 1.1) in iNOS. Participants with low optimism and high anxiety had associations that were 3-4 times larger than those with high optimism or low anxiety. GCR methylation was not associated with particulate air pollution exposure.

Lifestyle change and high-density lipoprotein change: the US Department of Veterans Affairs Normative Aging Study.

BACKGROUND: We sought to determine whether lifestyle modifications are associated with high-density lipoprotein cholesterol (HDL-C) change in a cohort with long-term follow-up. HYPOTHESIS: Changes in alcohol consumption, smoking, or body mass index (BMI) are associated with within-individual changes in HDL-C. METHODS: We selected 1420 men with ≥2 HDL-C measurements from the US Department of Veterans Affairs Normative Aging Study (NAS). Changes in HDL-C (in milligrams/deciliter) over a 3-year period were calculated for each pair of exams. For each interval of HDL-C change, lifestyle exposures were categorized: participants maintained a stable BMI >25 kg/m(2) (reference) or ≤25 kg/m(2) since the previous exam, or increased or decreased BMI; participants were actively smoking at both exams (reference), nonsmokers at both exams, quit, or initiated smoking between exams; and participants maintained alcohol intake of <2 (reference) or ≥2 drinks daily since the previous exam, or increased or decreased alcohol intake. Longitudinal analysis was used to examine the relationship between the lifestyle change categories and 3-year change in HDL-C for each interval, adjusting for comorbidities, lipids, and cholesterol medication. RESULTS: Participants were followed for approximately 14.3 years. Increases in HDL-C were associated with maintaining alcohol intake of ≥2 drinks daily (mean HDL-C increase, 0.86; P = 0.02), increasing alcohol intake from <2 to ≥2 drinks daily (mean, 2.53; P = 0.0003), and with maintaining a BMI of ≤25 kg/m(2) (mean, 0.71; P = 0.04). CONCLUSIONS: Increases in alcohol consumption, maintaining moderate alcohol intake, and maintaining BMI ≤25 kg/m(2) were associated with significant 3-year increases in HDL-C.