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.

Cohort Network: A Knowledge Graph toward Data Dissemination and Knowledge-Driven Discovery for Cohort Studies.

Contemporary environmental health sciences draw on large-scale longitudinal studies to understand the impact of environmental exposures and behavior factors on the risk of disease and identify potential underlying mechanisms. In such studies, cohorts of individuals are assembled and followed up over time. Each cohort generates hundreds of publications, which are typically neither coherently organized nor summarized, hence limiting knowledge-driven dissemination. Hence, we propose a Cohort Network, a multilayer knowledge graph approach to extract exposures, outcomes, and their connections. We applied the Cohort Network on 121 peer-reviewed papers published over the past 10 years from the Veterans Affairs (VA) Normative Aging Study (NAS). The Cohort Network visualized connections between exposures and outcomes across different publications and identified key exposures and outcomes, such as air pollution, DNA methylation, and lung function. We demonstrated the utility of the Cohort Network for new hypothesis generation, e.g., identification of potential mediators of exposure-outcome associations. The Cohort Network can be used by investigators to summarize the cohort's research and facilitate knowledge-driven discovery and dissemination.

Air pollution, climate conditions and risk of hospital admissions for psychotic disorders in U.S. residents.

BACKGROUND: The physical environmental risk factors for psychotic disorders are poorly understood. This study aimed to examine the associations between exposure to ambient air pollution, climate measures and risk of hospitalization for psychotic disorders and uncover potential disparities by demographic, community factors. METHODS: Using Health Cost and Utilization Project (HCUP) State Inpatient Databases (SIDs), we applied zero-inflated negative binomial regression to obtain relative risks of hospitalization due to psychotic disorders associated with increases in residential exposure to ambient air pollution (fine particulate matter, PM2.5; nitrogen dioxide, NO2), temperature and cumulative precipitation. The analysis covered all-age residents in eight U.S. states over the period of 2002-2016. We additionally investigated modification by age, sex and area-level poverty, percent of blacks and Hispanics. RESULTS: Over the study period and among the covered areas, we identified 1,211,100 admissions due to psychotic disorders. For each interquartile (IQR) increase in exposure to PM2.5 and NO2, we observed a relative risk (RR) of 1.11 (95% confidence interval (CI) = 1.09, 1.13) and 1.27 (95% CI = 1.24, 1.31), respectively. For each 1 °C increase of temperature, the RR was 1.03 (95% CI = 1.03, 1.04). Males were more affected by NO2. Older age residents (≥30 yrs) were more sensitive to PM2.5 and temperature. Population living in economically disadvantaged areas were more affected by air pollution. CONCLUSIONS: The study suggests that living in areas with higher levels of air pollutants and ambient temperature could contribute to additional risk of inpatient care for individuals with psychotic disorders.

Mild Neurocognitive Disorder, Social Engagement, and Falls Among Older Primary Care Patients.

OBJECTIVES: (1) To estimate the association between social engagement (SE) and falls; (2) To examine the relation between mild neurocognitive disorder (MNCD) and falls by different levels of SE. DESIGN: We performed a secondary data analysis using prospective cohort study design. SETTING: Primary care. PARTICIPANTS: A total of 425 older adult primary care patients at risk for mobility decline (N=425). As previously reported, at baseline, 42% of participants exhibit MNCD. MAIN OUTCOME MEASURES: The outcome variable was the number of falls during 2 years of follow-up. Exposure variables at baseline included (1) MNCD identified using a cut-off of 1.5 SD below the age-adjusted mean on at least 2 measures within a cognitive performance battery and (2) SE, which was assessed using the social component of the Late-Life Function and Disability Instrument. High SE was defined as having a score ≥ median value (≥49 out of 100). All models were adjusted for age, sex, education, marital status, comorbidities, and pain status. RESULTS: Over 2 years of follow-up, 48% of participants fell at least once. MNCD was associated with a higher rate of falls, adjusting for the covariates (Incidence Rate Ratio=1.6, 95% confidence interval: 1.1-2.3). There was no significant association between MNCD and the rate of falls among people with high SE. In participants with low SE (having a score less than 49.5 out 100), MNCD was associated with a higher rate of falls as compared with participants with no neurocognitive disorder (No-NCD). CONCLUSIONS: Among participants with low SE, MNCD was associated with a higher rate of falls, but not among participants with high SE. The findings suggest that high SE may be protective against falls among older primary care patients with MNCD.

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.

Health symptom trajectories and neurotoxicant exposures in Gulf War veterans: the Ft. Devens cohort.

BACKGROUND: Thirty years ago, Gulf War (GW) veterans returned home with numerous health symptoms that have been associated with neurotoxicant exposures experienced during deployment. The health effects from these exposures have been termed toxic wounds. Most GW exposure-outcome studies utilize group analyses and thus individual fluctuations in symptoms may have been masked. This study investigates health symptom trajectories in the same veterans over 25 years. METHODS: Veterans were categorized into 5 a priori trajectory groups for each health symptom and Chronic Multisymptom Illness (CMI) clinical case status. Multinomial logistic regression models were used to investigate associations between these trajectories and neurotoxicant exposures. RESULTS: Results indicate that more than 21 Pyridostigmine Bromide (PB) pill exposure was associated with consistent reporting of fatigue, pain, and cognitive/mood symptoms as well as the development of six additional symptoms over time. Chemical weapons exposure was associated with both consistent reporting and development of neurological symptoms over time. Reported exposure to tent heater exhaust was associated with later development of gastrointestinal and pulmonary symptoms. Veterans reporting exposure to more than 21 PB pills were more than 8 times as likely to consistently meet the criteria for CMI over time. CONCLUSION: This study highlights the importance of the continued documentation of the health impacts experienced by GW veterans', their resulting chronic health symptoms, and the importance of exposure-outcome relationships in these veterans now 30 years post-deployment.

The impact of neurotoxicant exposures on posttraumatic stress disorder trajectories: The Ft. Devens Gulf War Veterans Cohort.

Gulf War veterans (GWVs) were exposed to neurotoxicants, including sarin nerve gas, anti-nerve agent pills, pesticides, oil well fires, and fumes from unvented tent heaters, all of which have been associated with subsequent adverse health. Posttraumatic stress disorder (PTSD) symptoms have also been associated with GW deployment; however, associations between exposures and PTSD symptoms have not been investigated. We assessed PTSD symptom trajectories and associations with neurotoxicant exposures in Ft. Devens Cohort (FDC) veterans (N = 259) who endorsed trauma exposure during deployment and completed the PTSD Checklist at three follow-ups (1992-1993, 1997-1998, 2013-2017). Results indicate that among veterans with more severe initial PTSD symptoms, symptoms remained significantly higher across follow-ups, Bs = -1.489-1.028, whereas among those with low initial PTSD symptoms, symptom severity increased significantly over time, Bs = 1.043-10.304. Additionally, neurotoxicant exposure was associated with a significant increase in PTSD symptoms, Bs = -1.870-9.003. Significant interactions between time and exposures were observed for PTSD symptom clusters, suggesting that among participants with high initial PTSD symptom, unexposed veterans experienced symptom alleviation, whereas exposed veterans' PTSD symptoms remained high. In GWVs with low initial PTSD symptoms, both unexposed and exposed veterans experienced PTSD symptom exacerbations over time; however, this occurred at a faster rate among exposed veterans. These findings suggest that in the years following deployment, GWVs who were exposed to both traumatic events and neurotoxicants may experience more severe and chronic PTSD symptoms than those without neurotoxicant exposures.

Optimism is associated with exceptional longevity in 2 epidemiologic cohorts of men and women.

Most research on exceptional longevity has investigated biomedical factors associated with survival, but recent work suggests nonbiological factors are also important. Thus, we tested whether higher optimism was associated with longer life span and greater likelihood of exceptional longevity. Data are from 2 cohorts, women from the Nurses' Health Study (NHS) and men from the Veterans Affairs Normative Aging Study (NAS), with follow-up of 10 y (2004 to 2014) and 30 y (1986 to 2016), respectively. Optimism was assessed using the Life Orientation Test-Revised in NHS and the Revised Optimism-Pessimism Scale from the Minnesota Multiphasic Personality Inventory-2 in NAS. Exceptional longevity was defined as survival to age 85 or older. Primary analyses used accelerated failure time models to assess differences in life span associated with optimism; models adjusted for demographic confounders and health conditions, and subsequently considered the role of health behaviors. Further analyses used logistic regression to evaluate the likelihood of exceptional longevity. In both sexes, we found a dose-dependent association of higher optimism levels at baseline with increased longevity (P trend < 0.01). For example, adjusting for demographics and health conditions, women in the highest versus lowest optimism quartile had 14.9% (95% confidence interval, 11.9 to 18.0) longer life span. Findings were similar in men. Participants with highest versus lowest optimism levels had 1.5 (women) and 1.7 (men) greater odds of surviving to age 85; these relationships were maintained after adjusting for health behaviors. Given work indicating optimism is modifiable, these findings suggest optimism may provide a valuable target to test for strategies to promote longevity.

Subjective well-being among male veterans in later life: the enduring effects of early life adversity.

OBJECTIVES: This study investigated the association between childhood and young adult adversities and later-life subjective well-being among older male veterans. We also explored whether early-life parent-child relationships and later-life social engagement served as moderators and mediators, respectively. METHODS: Data were from the 2008 to 2012 waves of the Health and Retirement Study for male veterans (N = 2026). Subjective well-being measures included depressive symptoms, self-rated health, and life satisfaction. Linear regression with the Process macro was employed to estimate the relationships. RESULTS: Adverse childhood experiences (ACEs) were positively associated with number of depressive symptoms and negatively related to life satisfaction. Combat exposure, a young adulthood adversity experience, was positively associated with depressive symptoms, but not with self-rated health or life satisfaction. Later-life social engagement mediated the relationship between ACEs and subjective well-being indices. Parent-child relationship quality did not moderate the association between the measures of adversity and any measure of subjective well-being. DISCUSSION: Childhood adversity and combat exposure were related to worse later life subjective well-being. Also, later-life social engagement mediated the association of two early life adversity measures and subjective well-being. Future research should examine subjective well-being and early life adversity for female veterans and should employ more detailed information about combat exposure.

Impact of Wartime Stress Exposures and Mental Health on Later-Life Functioning and Disability in Vietnam-Era Women Veterans: Findings From the Health of Vietnam-Era Women's Study.

OBJECTIVE: The effect of stress exposures and mental health sequelae on health-related outcomes is understudied among older women veterans. We examined a) the impact of wartime stress exposures on later-life functioning and disability in Vietnam-era women veterans and b) the extent to which mental health conditions known to be associated with stress-posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD)-are associated with additional later-life functioning and disability. METHODS: Data were collected in 2011 to 2012 using a mail survey and telephone interview of 4219 women veterans who were active duty during the Vietnam Era. Health functioning was assessed using the Veterans RAND 36-Item Health Survey, and disability was assessed using the World Health Organization Disability Assessment Schedule 2.0. Wartime exposures were assessed using the Women's War-Zone Stressor Scale-Revised; the Composite International Diagnostic Interview, version 3.0 was used to assess PTSD, MDD, and GAD. RESULTS: Several wartime stress exposures-including job-related pressures, dealing with death, and sexual discrimination and harassment-were associated with worse later-life health (ß ranges, -0.04 to -0.26 for functioning, 0.05 to 0.30 for disability). Current PTSD was linked with lower health functioning (physical, ß = -0.06; mental, ß = -0.15) and greater disability (ß = 0.14). Current MDD and GAD were also associated with lower mental health functioning (MDD, ß = -0.29; GAD, ß = -0.10) and greater disability (MDD, ß = 0.16; GAD, ß = 0.06). CONCLUSIONS: Results underscore the importance of detection and treatment of the potential long-term effects of wartime stressors and mental health conditions among women veterans.

Metabolomic signatures of lead exposure in the VA Normative Aging Study.

BACKGROUND: Lead (Pb) is widespread and exposure to this non-essential heavy metal can cause multiple negative health effects; however the mechanisms underlying these effects remain incompletely understood. OBJECTIVES: To identify plasma metabolomic signatures of Pb exposure, as measured in blood and toenails. METHODS: In a subset of men from the VA Normative Aging Study, mass-spectrometry based plasma metabolomic profiling was performed. Pb levels were measured in blood samples and toenail clippings collected concurrently. Multivariable linear regression models, smoothing splines and Pathway analyses were employed to identify metabolites associated with Pb exposure. RESULTS: In 399 men, 858 metabolites were measured and passed QC, of which 154 (17.9%) were significantly associated with blood Pb (p < 0.05). Eleven of these passed stringent correction for multiple testing, including pro-hydroxy-pro (ß(95%CI): 1.52 (0.93,2.12), p = 7.18x10-7), N-acetylglycine (ß(95%CI): 1.44 (0.85,2.02), p = 1.12x10-6), tartarate (ß(95%CI): 0.68 (0.35,1.00), p = 4.84x10-5), vanillylmandelate (ß(95%CI): 1.05 (0.47,1.63), p = 4.44x10-7), and lysine (ß(95%CI): 1.88 (-2.8,-0.95), p = 9.10x10-5). A subset of 48 men had a second blood sample collected a mean of 6.1 years after their first. Three of the top eleven metabolites were also significant in this second blood sample. Furthermore, we identified 70 plasma metabolites associated with Pb as measured in toenails. Twenty-three plasma metabolites were significantly associated with both blood and toenail measures, while others appeared to be specific to the biosample in which Pb was measured. For example, benzanoate metabolism appeared to be of importance with the longer-term exposure assessed by toenails. DISCUSSION: Pb exposure is responsible for 0.6% of the global burden of disease and metabolomics is particularly well-suited to explore its pathogenic mechanisms. In this study, we identified metabolites and metabolomic pathways associated with Pb exposure that suggest that Pb exposure acts through oxidative stress and immune dysfunction. These findings help us to better understand the biology of this important public health burden.

Meta-analysis of epigenome-wide association studies of cognitive abilities.

Cognitive functions are important correlates of health outcomes across the life-course. Individual differences in cognitive functions are partly heritable. Epigenetic modifications, such as DNA methylation, are susceptible to both genetic and environmental factors and may provide insights into individual differences in cognitive functions. Epigenome-wide meta-analyses for blood-based DNA methylation levels at ~420,000 CpG sites were performed for seven measures of cognitive functioning using data from 11 cohorts. CpGs that passed a Bonferroni correction, adjusting for the number of CpGs and cognitive tests, were assessed for: longitudinal change; being under genetic control (methylation QTLs); and associations with brain health (structural MRI), brain methylation and Alzheimer's disease pathology. Across the seven measures of cognitive functioning (meta-analysis n range: 2557-6809), there were epigenome-wide significant (P < 1.7 × 10-8) associations for global cognitive function (cg21450381, P = 1.6 × 10-8), and phonemic verbal fluency (cg12507869, P = 2.5 × 10-9). The CpGs are located in an intergenic region on chromosome 12 and the INPP5A gene on chromosome 10, respectively. Both probes have moderate correlations (~0.4) with brain methylation in Brodmann area 20 (ventral temporal cortex). Neither probe showed evidence of longitudinal change in late-life or associations with white matter brain MRI measures in one cohort with these data. A methylation QTL analysis suggested that rs113565688 was a cis methylation QTL for cg12507869 (P = 5 × 10-5 and 4 × 10-13 in two lookup cohorts). We demonstrate a link between blood-based DNA methylation and measures of phonemic verbal fluency and global cognitive ability. Further research is warranted to understand the mechanisms linking genomic regulatory changes with cognitive function to health and disease.

Late-onset stress symptomatology (LOSS) scale - short form: development and validation.

Objectives: Late-onset stress symptomatology (LOSS) is a phenomenon observed in older combat veterans who experience increased combat-related thoughts, feelings, and reminiscences corresponding with the changes and challenges of aging. Previously, we developed the LOSS Scale to assess LOSS. This paper describes the development and validation of a LOSS Scale short form (LOSS-SF) to screen veterans in various settings who may be actively re-examining their past wartime experiences. Method: Three studies examined the reliability and validity of the LOSS-SF in separate samples of male combat veterans age 55 and older (total N = 346). Veterans were administered measures via telephone and mail survey. Correlation and regression analyses examined the reliability and validity of the LOSS-SF. Results: The LOSS-SF exhibited strong internal consistency (alpha = .93), test-retest reliability (2 week interval on average; r = .88), and good concurrent validity with the LOSS Scale (r = .81). Convergent and divergent validity were supported by the pattern of correlations between the LOSS-SF and other construct measures. Conclusion: The LOSS-SF is a reliable and valid measure to quickly assess thoughts, feelings, and reminiscences about past combat experiences in older veterans and identify those veterans in distress who may benefit from psychological interventions..

The Role of Executive Functions in Object- and Action-Naming among Older Adults.

Background/Study Context: Lexical retrieval abilities and executive function skills decline with age. The extent to which these processes might be interdependent remains unknown. The aim of the current study was to examine whether individual differences in three executive functions (shifting, fluency, and inhibition) predicted naming performance in older adults. Methods: The sample included 264 adults aged 55-84. Six measures of executive functions were combined to make three executive function composites scores. Lexical retrieval performance was measured by accuracy and response time on two tasks: object naming and action naming. We conducted a series of multiple regressions to test whether executive function performance predicts naming abilities in older adults. Results: We found that different executive functions predicted naming speed and accuracy. Shifting predicted naming accuracy for both object and action naming while fluency predicted response times on both tests as well as object naming accuracy, after controlling for education, gender, age, working memory span, and speed of processing in all regressions. Interestingly, inhibition did not contribute to naming accuracy or response times on either task. Conclusion: The findings support the notion that preservation of some executive functions contributes to successful naming in older adults and that different executive functions are associated with naming speed and accuracy.

Prospective Examination of Early Associations of Iraq War Zone Deployment, Combat Severity, and Posttraumatic Stress Disorder with New Incident Medical Diagnoses.

War zone deployment and posttraumatic stress disorder (PTSD) have been associated with morbidity and mortality decades later. Less is known about the associations between these variables and the early emergence of medical disorders in war zone veterans. This prospective study of 862 U.S. Army soldiers (n = 569 deployed; n = 293 nondeployed) examined: (a) associations between Iraq War deployment status (deployed vs. nondeployed) and new medical diagnoses that emerged within six months after return from Iraq among all participants; and (b) associations between combat severity and PTSD symptoms, and new postdeployment medical diagnoses that emerged within 12 months after return from Iraq within deployed participants. New medical diagnoses were abstracted from diagnostic codes associated with clinical outpatient visits recorded within the Department of Defense Standard Ambulatory Data Record database. Combat severity was measured with the Combat Experiences module of the Deployment Risk and Resilience Inventory, and postdeployment posttraumatic stress disorder symptom severity was measured using the PTSD Checklist-Civilian. Neither deployment nor combat severity was associated with new medical diagnoses. However, among deployed soldiers, more severe PTSD symptoms were associated with increased risk for a new medical disorder diagnosis; every 10-point increase in PTSD symptoms increased odds of a new diagnosis by nearly 20% (odds ratio = 1.20). Results suggest that PTSD symptoms are associated with early morbidity in Iraq War veterans.

Breathe Easy, Speak Easy: Pulmonary Function and Language Performance in Aging.

BACKGROUND: This study explored the association between pulmonary function (PF) and older adults' language performance accuracy. Study rationale was anchored in aging research reporting PF as a reliable risk factor affecting cognition among the elderly. METHODS: 180 adult English native speakers aged 55 to 84 years participated in the study. PF was measured through forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio (FFR). Language performance was assessed with an action naming test and an object naming test, and two tests of sentence comprehension, one manipulating syntactic complexity and the other, semantic negation. Greater PF was predicted to be positively associated with all tasks. RESULTS: Unadjusted models revealed FVC and FEV1 effects on language performance among older adults. Participants with higher FVC showed better naming on both tasks and those with higher FEV1 had better object naming only. In covariate-adjusted models, only a positive FVC-object naming association remained. CONCLUSION: Findings were discussed in terms of brain oxygenation mechanisms, whereby good PF may implicate efficient oxygenation, supporting neurotransmitter metabolism that protects against neural effects of cerebrovascular risk. Effects on object naming were linked to putative differential oxygenation demands across language tasks.

Associations of cumulative Pb exposure and longitudinal changes in Mini-Mental Status Exam scores, global cognition and domains of cognition: The VA Normative Aging Study.

BACKGROUND: Lead (Pb) exposure has been associated with poorer cognitive function cross-sectionally in aging adults, however the association between cumulative Pb exposure and longitudinal changes in cognition is little characterized. METHODS: In a 1993-2007 subcohort of the VA Normative Aging Study (Mini-mental status exam (MMSE) n=741; global cognition summary score n=715), we used linear mixed effects models to test associations between cumulative Pb exposure (patella or tibia bone Pb) and repeated measures of cognition (MMSE, individual cognitive tests, and global cognition summary). Cox proportional hazard modeling assessed the risk of an MMSE score falling below 25. RESULTS: Among men 51-98 at baseline, higher patella Pb concentration (IQR: 21µg/g) was associated with -0.13 lower baseline MMSE (95% CI: -0.25, -0.004) and faster longitudinal MMSE decline (-0.016 units/year, 95% CI: -0.032, -0.0004) over 15 years. Each IQR increase in patella Pb was associated with increased risk of a MMSE score below 25 (HR=1.21, 95% CI: 0.99, 1.49; p=0.07). There were no significant associations between Pb and global cognition (both baseline and longitudinal change). Patella Pb was associated with faster longitudinal decline in Word List Total Recall in the language domain (0.014 units/year, 95% CI: -0.026, -0.001) and Word List Delayed Recall in the memory domain (0.014 units/year, 95% CI: -0.027, -0.002). We found weaker associations with tibia Pb. CONCLUSIONS: Cumulative Pb exposure is associated with faster declines in MMSE and Word List Total and Delayed Recall tests. These findings support the hypothesis that Pb exposure accelerates cognitive aging.

Jump, Hop, or Skip: Modeling Practice Effects in Studies of Determinants of Cognitive Change in Older Adults.

Improvements in cognitive test scores upon repeated assessment due to practice effects (PEs) are well documented, but there is no empirical evidence on whether alternative specifications of PEs result in different estimated associations between exposure and rate of cognitive change. If alternative PE specifications produce different estimates of association between an exposure and rate of cognitive change, this would be a challenge for nearly all longitudinal research on determinants of cognitive aging. Using data from 3 cohort studies-the Three-City Study-Dijon (Dijon, France, 1999-2010), the Normative Aging Study (Greater Boston, Massachusetts, 1993-2007), and the Washington Heights-Inwood Community Aging Project (New York, New York, 1999-2012)-for 2 exposures (diabetes and depression) and 3 cognitive outcomes, we compared results from longitudinal models using alternative PE specifications: no PEs; use of an indicator for the first cognitive visit; number of prior testing occasions; and square root of the number of prior testing occasions. Alternative specifications led to large differences in the estimated rates of cognitive change but minimal differences in estimated associations of exposure with cognitive level or change. Based on model fit, using an indicator for the first visit was often (but not always) the preferred model. PE specification can lead to substantial differences in estimated rates of cognitive change, but in these diverse examples and study samples it did not substantively affect estimated associations of risk factors with change.

Cognitive function and short-term exposure to residential air temperature: A repeated measures study based on spatiotemporal estimates of temperature.

Few studies have examined the association between ambient temperature and cognitive function, or used exposure to temperature at a given address instead of a single stationary monitor. The existing literature on the temperature-cognition relationship has mostly consisted of experimental studies that involve a small sample size and a few specific temperature values. In the current study, we examined the association between residential air temperature and Mini-Mental State Examination (MMSE) scores, a quantitative measurement of cognitive function, in a longitudinal cohort of elderly men. Residential air temperature was estimated by a novel spatiotemporal approach that incorporates satellite remote sensing, land use regression, meteorological variables and spatial smoothing in the Northeastern USA. We then applied logistic regression generalized estimating equations to examine the relationship between residential temperature (range: -5.8-25.7°C), and the risk of low MMSE scores (MMSE scores ≤25) among 594 elderly men (1085 visits in total) from the Veterans Affairs Normative Aging Study, 2000-2008. Sensitivity analysis on visits wherein subjects lived within 30km of the clinic center in Massachusetts or aged ≥70 years was also evaluated. A statistically significant, U-shaped association between residential air temperature and low MMSE score (p-value=0.036) was observed. Sensitivity analysis suggested that the estimated effect remains among individuals aged ≥70 years. In conclusion, the data suggest that risk of low MMSE scores is highest when temperature is either high or low, and lowest when ambient temperature is approximately within 10-15°C in a cohort of elderly men. Further research is needed to confirm our findings and assess generalizability to other populations.

APOE ε4 allele modifies the association of lead exposure with age-related cognitive decline in older individuals.

BACKGROUND: Continuing chronic and sporadic high-level of lead exposure in some regions in the U.S. has directed public attention to the effects of lead on human health. Long-term lead exposure has been associated with faster cognitive decline in older individuals; however, genetic susceptibility to lead-related cognitive decline during aging has been poorly studied. METHODS: We determined the interaction of APOE-epsilon variants and environmental lead exposure in relation to age-related cognitive decline. We measured tibia bone lead by K-shell-x-ray fluorescence, APOE-epsilon variants by multiplex PCR and global cognitive z-scores in 489 men from the VA-Normative Aging Study. To determine global cognitive z-scores we incorporated multiple cognitive assessments, including word list memory task, digit span backwards, verbal fluency test, sum of drawings, and pattern comparison task, which were assessed at multiple visits. We used linear mixed-effect models with random intercepts for individual and for cognitive test. RESULTS: An interquartile range (IQR:14.23µg/g) increase in tibia lead concentration was associated with a 0.06 (95% confidence interval [95%CI]: -0.11 to -0.01) lower global cognition z-score. In the presence of both ε4 alleles, one IQR increase in tibia lead was associated with 0.57 (95%CI: -0.97 to -0.16; p-value for interaction: 0.03) lower total cognition z-score. A borderline association was observed in presence of one ε4 allele (Estimate-effect per 1-IQR increase: -0.11, 95%CI: -0.22, 0.01) as well as lack of association in individuals without APOE ε4 allele. CONCLUSIONS: Our findings suggest that individuals carrying both ε4 alleles are more susceptible to lead impact on global cognitive decline during aging.