OBJECTIVE:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor neuron with very few known risk factors. We conducted a spatial epidemiologic analysis of ALS incidence in Denmark to assess the contribution of sociodemographic determinants to geographic variation. METHODS:We analyzed 4249 ALS cases (1982-2013), each with 100 controls matched on sex and birth year. Odds ratio and 95% confidence bands at birth and diagnosis/index locations were calculated using generalized additive models. We included a bivariate spatial smooth for location in our conditional logistic regression adjusted for socioeconomic status and marital status. We also conducted analyses adjusted for both birth and diagnosis addresses to separate location effects. RESULTS:We observed significantly elevated ALS odds near Copenhagen for both the birth and diagnosis period analyses. Sociodemographic factors did not explain the observed patterns. When we further adjusted our spatial analyses by including both birth and diagnosis addresses, the significant area of elevated male ALS odds by birth address shifted to northwest Denmark away from Copenhagen, and there was little evidence of variation among women. Geographic variation at diagnosis differed between male and females, suggesting that patterns are not just due to regional variation in case ascertainment. CONCLUSION:ALS incidence in Denmark is associated with both location at birth and diagnosis, suggesting that geographic variation may be due to exposures occurring at birth or closer to diagnosis, although the latter could relate to case ascertainment issues.

Background: The C8 Health Project was established in 2005 to collect data on perfluorooctanoic acid (PFOA, or C8) and human health in Ohio and West Virginia communities contaminated by a fluoropolymer production facility. Objective: We assessed PFOA exposure via contaminated drinking water in a subset of C8 Health Project participants who drank water from private wells. Methods: Participants provided demographic information and residential, occupational, and medical histories. Laboratory analyses were conducted to determine serum-PFOA concentrations. PFOA data were collected from 2001 through 2005 from 62 private drinking water wells. We examined the relationship between drinking water and PFOA levels in serum using robust regression methods. As a comparison with regression models, we used a first-order, single-compartment pharmacokinetic model to estimate the serum: drinking-water concentration ratio at steady state. Results: The median serum PFOA concentration in 108 study participants who used private wells was 75.7 mu g/L, approximately 20 times greater than the levels in the U. S. general population but similar to those of local residents who drank public water. Each 1 mu g/L increase in PFOA levels in drinking water was associated with an increase in serum concentrations of 141.5 mu g/L (95% confidence interval, 134.9-148.1). The serum: drinking-water concentration ratio for the steady-state pharmacokinetic model was 114. Conclusions: PFOA-contaminated drinking water is a significant contributor to PFOA levels in serum in the study population. Regression methods and pharmacokinetic modeling produced similar estimates of the relationship.

Introduction

We examined the association between endogenous sex hormones and both objective and subjective measures of cognitive function.

Methods

We followed 3044 women up to 23 years in a prospective cohort study. We measured plasma levels of estrone, estrone sulfate, estradiol, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) in 1989-1990, conducted neuropsychologic testing in 1999-2008, and inquired about subjective cognition in 2012.

Results

Overall, we observed little relation between plasma levels of hormones and either neuropsychologic test performance or subjective cognition. However, after adjustment for age and education, we observed a borderline significant association of higher levels of plasma estrone with higher scores for both overall cognition (P trend = .10) and verbal memory (P trend = .08).

Discussion

There were no clear associations of endogenous hormone levels at midlife and cognition in later life, although a suggested finding of higher levels of plasma estrone associated with better cognitive function merits further research.

Cognitive function at middle age is of particular public health interest, as it strongly predicts later dementia. Children who have experienced abuse subsequently have worse cognitive function than those who have not. However, it remains unclear whether the association of abuse with cognitive function persists into middle age. In 2014-2016, 14,151 women ages 49-69 years who had previously responded to a childhood abuse questionnaire completed a cognitive battery. In models adjusted for childhood socioeconomic status and head trauma, combined physical, emotional, and sexual abuse was associated with lower scores on both Learning/Working Memory (severe abuse, lower scores similar to that observed in women 4.8 years older in our data) and Psychomotor Speed/Attention (severe abuse, lower scores similar to that observed in women to 2.9 years older in our data). Adjustment for adulthood socioeconomic status and health factors (e.g., smoking, hypertension) slightly attenuated associations. In exploratory analyses further adjusted for psychological distress, associations were attenuated. Women exposed versus unexposed to childhood abuse had poorer cognitive function at mid-life. Associations were particularly strong for learning and working memory and were not accounted for by adulthood health factors. Childhood abuse should be investigated as a potential risk factor for cognitive decline and dementia in old age.

Background

Lead is a ubiquitous toxicant following three compartment kinetics with the longest half-life found in bones. Patella and tibia lead levels-validated measures of cumulative exposure-require specialized X-ray-fluorescence-spectroscopy available only in a few centers worldwide. We developed minimally invasive biomarkers reflecting individual cumulative lead exposure using blood DNA methylation profiles-obtainable via Illumina 450K or IlluminaEPIC bead-chip assays.

Methods

We developed and tested two methylation-based biomarkers from 348 Normative Aging Study (NAS) elderly men. We selected methylation sites with strong associations with bone lead levels via robust regressions analysis and constructed the biomarkers using elastic nets. Results were validated in a NAS subset, reporting specificity, and sensitivity.

Findings

Participants were 73 years old on average (standard deviation, SD = 6), with moderate lead levels of (mean ± SD patella: 27 ± 18 µg/g; tibia:21 ± 13 µg/g). Methylation-based biomarkers for lead in patella and tibia included 59 and 138 DNA methylation sites, respectively. Estimated lead levels were significantly correlated with actual measured values, (r = 0.62 patella, r = 0.59 tibia) and had low mean square error (MSE) (MSE = 0.68 patella, MSE = 0.53 tibia). Means and distributions of the estimated and actual lead levels were not significantly different across patella and tibia bones (p > 0.05). Methylation-based biomarkers discriminated participants highly exposed (>median) to lead with a specificity of 74 and 73% for patella and tibia lead levels, respectively, with 70% sensitivity.

Interpretation

DNA methylation-based lead biomarkers are novel tools that can be used to reconstruct decades' worth of individual cumulative lead exposure using only blood DNA methylation profiles and may help identify the consequences of cumulative exposure.

Data indicate that the prevalence of autism spectrum disorder (ASD) may be increasing and that it varies geographically. We investigated associations between residential location and ASD in the children of Nurses' Health Study II (United States) participants in order to generate hypotheses about social and environmental factors related to etiology or diagnosis. Analyses included data on 13,507 children born during 1989-1999 (486 with ASD). We explored relationships between ASD and residential location both at birth and at age 6 years (i.e., closer to average age at diagnosis). Generalized additive models were used to predict ASD odds across the United States. Children born in New England were 50% more likely to be diagnosed with ASD compared with children born elsewhere in the United States. Patterns were not explained by geographic variation in maternal age, birth year, child's sex, community income, or prenatal exposure to hazardous air pollutants, indicating that spatial variation is not attributable to these factors. Using the residential address at age 6 years produced similar results; however, areas of significantly decreased ASD odds were observed in the Southeast, where children were half as likely to have ASD. These results may indicate that diagnostic factors are driving spatial patterns; however, we cannot rule out the possibility that other environmental factors are influencing distributions.

Background

Aging-related cognitive decline is an early symptom of Alzheimer's disease and other dementias, and on its own can have substantial consequences on an individual's ability to perform important everyday functions. Despite increasing interest in the potential roles of extracellular microRNAs (miRNAs) in central nervous system (CNS) pathologies, there has been little research on extracellular miRNAs in early stages of cognitive decline. We leverage the longitudinal Normative Aging Study (NAS) cohort to investigate associations between plasma miRNAs and cognitive function among cognitively normal men.

Methods

This study includes data from up to 530 NAS participants (median age: 71.0 years) collected from 1996 to 2013, with a total of 1,331 person-visits (equal to 2,471 years of follow up). Global cognitive function was assessed using the Mini-Mental State Examination (MMSE). Plasma miRNAs were profiled using small RNA sequencing. Associations of expression of 381 miRNAs with current cognitive function and rate of change in cognitive function were assessed using linear regression (N = 457) and linear mixed models (N = 530), respectively.

Results

In adjusted models, levels of 2 plasma miRNAs were associated with higher MMSE scores (p < 0.05). Expression of 33 plasma miRNAs was associated with rate of change in MMSE scores over time (p < 0.05). Enriched KEGG pathways for miRNAs associated with concurrent MMSE and MMSE trajectory included Hippo signaling and extracellular matrix-receptor interactions. Gene targets of miRNAs associated with MMSE trajectory were additionally associated with prion diseases and fatty acid biosynthesis.

Conclusions

Circulating miRNAs were associated with both cross-sectional cognitive function and rate of change in cognitive function among cognitively normal men. Further research is needed to elucidate the potential functions of these miRNAs in the CNS and investigate relationships with other neurological outcomes.

Background

Prior work has suggested relationships between prenatal intake of certain nutrients and autism.

Objectives

We examined a broad set of prenatal nutrients and foods using a Bayesian modeling approach.

Methods

Participants were drawn from the Early Autism Risks Longitudinal Investigation (n = 127), a cohort following women with a child with autism through a subsequent pregnancy. Participants were also drawn from the Nurses' Health Study II (NHSII, n = 713), a cohort of United States female nurses, for comparison analyses. In both studies, information on prospectively reported prenatal diet was drawn from food frequency questionnaires, and child autism-related traits were measured by the Social Responsiveness Scale (SRS). Bayesian kernel machine regression was used to examine the combined effects of several nutrients with neurodevelopmental relevance, including polyunsaturated fatty acids (PUFAs), iron, zinc, vitamin D, folate, and other methyl donors, and separately, key food sources of these, in association with child SRS scores in crude and adjusted models.

Results

In adjusted analyses, the overall mixture effects of nutrients in Early Autism Risks Longitudinal Investigation and foods in both cohorts on SRS scores were not observed, though there was some suggestion of decreasing SRS scores with increasing overall nutrient mixture in NHSII. No associations were observed with folate within the context of this mixture, but holding other nutrients fixed, n-6 PUFAs were associated with lower SRS scores in NHSII. In both cohorts, lower SRS scores were observed with higher intake of some groupings of vegetables, though for differing types of vegetables across cohorts, and some vegetable groups were associated with higher SRS scores in NHSII.

Conclusions

Our work extends prior research and suggests the need to further consider prenatal dietary factors from a combined effects perspective. In addition, findings here point to potential differences in nutrient associations based on a family history of autism, which suggests the need to consider gene interactions in future work.