Association of long-term exposure to ambient air pollution with retinal neurodegeneration: the prospective Alienor study.

Chronic exposure to air pollution may have adverse effects on neurodegenerative diseases. Glaucoma, the second leading cause of blindness worldwide, is a neurodegenerative disease of the optic nerve, characterized by progressive thinning of the retinal nerve fiber layer (RNFL). We investigated the relationship of air pollution exposure with longitudinal changes of RNFL thickness in the Alienor study, a population-based cohort of residents of Bordeaux, France, aged 75 years or more. Peripapillary RNFL thickness was measured using optical coherence tomography imaging every 2 years from 2009 to 2020. Measurements were acquired and reviewed by specially trained technicians to control quality. Air pollution exposure (particulate matter ≤2.5 µm (PM2.5), black carbon (BC), nitrogen dioxide (NO2)) was estimated at the participants' geocoded residential address using land-use regression models. For each pollutant, the 10-year average of past exposure at first RNFL thickness measurement was estimated. Associations of air pollution exposure with RNFL thickness longitudinal changes were assessed using linear mixed models adjusted for potential confounders, allowing for intra-eye and intra-individual correlation (repeated measurements). The study included 683 participants with at least one RNFL thickness measurement (62% female, mean age 82 years). The average RNFL was 90 µm (SD:14.4) at baseline. Exposure to higher levels of PM2.5 and BC in the previous 10 years was significantly associated with a faster RNFL thinning during the 11-year follow-up (-0.28 µm/year (95% confidence interval (CI) [-0.44;-0.13]) and -0.26 µm/year (95% CI [-0.40;-0.12]) per interquartile range increment; p < 0.001 for both). The size of the effect was similar to one year of age in the fitted model (-0.36 µm/year). No statistically significant associations were found with NO2 in the main models. This study evidenced a strong association of chronic exposure to fine particulate matter with retinal neurodegeneration, at air pollution levels below the current recommended thresholds in Europe.

Air pollution and metabolic disorders: Dynamic versus static measures of exposure among Hispanics/Latinos and non-Hispanics.

INTRODUCTION: Exposure to air pollution disproportionately affects racial/ethnic minorities that could contribute to health inequalities including metabolic disorders. However, most existing studies used a static assessment of air pollution exposure (mostly using the residential address) and do not account for activity space when modelling exposure to air pollution. The aim of this study is to understand how exposure to air pollution impacts metabolic disorders biomarkers, how this effect differs according to ethnicity, and for the first time compare these findings with two methods of exposure assessment: dynamic and static measures. METHODS: Among the Community of Mine study, a cross-sectional study conducted in San Diego County, insulin resistance, diabetes, hypertension, obesity, dyslipidemia, and metabolic syndrome (MetS) were assessed. Exposure to air pollution (PM2.5, NO2, traffic) was calculated using static measures around the home, and dynamic measures of mobility derived from Global Positioning Systems (GPS) traces using kernel density estimators to account for exposure variability across space and time. Associations of air pollution with metabolic disorders were quantified using generalized estimating equation models to account for the clustered nature of the data. RESULTS: Among 552 participants (mean age 58.7 years, 42% Hispanic/Latino), Hispanics/Latinos had a higher exposure to PM2.5 compared to non-Hispanics using static measures. In contrast, Hispanics/Latinos had less exposure to PM2.5 using dynamic measures. For all participants, higher dynamic exposure to PM2.5 and NO2 was associated with increased insulin resistance and cholesterol levels, and increased risk of obesity, dyslipidemia and MetS (RR 1.17, 95% CI: 1.07-1.28; RR 1.21, 95% CI: 1.12-1.30, respectively). The association between dynamic PM2.5 exposure and MetS differed by Hispanic/Latino ethnicity. CONCLUSION: These results highlight the importance of considering people's daily mobility in assessing the impact of air pollution on health.

Air quality improvement and incident dementia: Effects of observed and hypothetical reductions in air pollutant using parametric g-computation.

INTRODUCTION: No evidence exists about the impact of air pollution reduction on incidence of dementia. The aim of this study was to quantify how air quality improvement leads to dementia-incidence benefits. METHODS: In the French Three-City cohort (12 years of follow-up), we used parametric g-computation to quantify the expected number of prevented dementia cases under different hypothetical interventions with particulate matter measuring <2.5 µm (PM2.5 ) reductions. RESULTS: Among 7051 participants, 789 participants developed dementia. The median PM2.5 reduction between 1990 and 2000 was 12.2 (µg/m3 ). Such a reduction reduced the risk of all-cause dementia (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.76 to 0.95). If all study participants were enjoying a hypothetical reduction of more than 13.10 µg/m3 (median reduction observed in the city of Montpellier), the rate difference was -0.37 (95% CI, -0.57 to -0.17) and the rate ratio was 0.67 (95% CI, 0.50 to 0.84). DISCUSSION: These findings highlight the possible substantial benefits of reducing air pollution in the prevention of dementia.

Socioeconomic inequalities in dementia risk among a French population-based cohort: quantifying the role of cardiovascular health and vascular events.

This study aimed to investigate the role of cardiovascular health (CVH) and vascular events as potential contributors to socioeconomic inequalities in dementia using causal mediation analyses. We used data from the Three-City Cohort, a French population-based study with 12 years of follow-up, with active search of dementia cases and validated diagnosis. Individual socioeconomic status was assessed using education, occupation and income. A CVH score as defined by the American Heart Association and incident vascular events were considered separately as mediators. We performed multi-level Cox proportional and Aalen additive hazard regression models to estimate the total effects of socioeconomic status on dementia risk. To estimate natural direct and indirect effects through CVH and vascular events, we applied two distinct weighting methods to quantify the role of CVH and vascular events: Inverse Odds Ratio Weighting (IORW) and Marginal Structural Models (MSM) respectively. Among 5581 participants, the risk of dementia was higher among participants with primary education (HR 1.60, 95%CI 1.44-1.78), blue-collar workers (HR 1.62, 95%CI 1.43-1.84) and with lower income (HR 1.23, 95%CI 1.09-1.29). Using additive models, 571 (95% CI 288-782) and 634 (95% CI 246-1020) additional cases of dementia per 100 000 person and year were estimated for primary education and blue-collar occupation, respectively. Using IORW, the CVH score mediate the relationship between education or income, and dementia (proportion mediated 17% and 26%, respectively). Yet, considering vascular events as mediator, MSM generated indirect effects that were smaller and more imprecise. Socioeconomic inequalities in dementia risk were observed but marginally explained by CVH or vascular events mediators.

Pesticides used in Europe and autism spectrum disorder risk: can novel exposure hypotheses be formulated beyond organophosphates, organochlorines, pyrethroids and carbamates? - A systematic review.

BACKGROUND: A growing body of evidences suggests an association between early exposure to organophosphates (OPs), organochlorines (OCs), pyrethroids or carbamates and autism spectrum disorder (ASD). However, there are limited data about the other pesticide groups, especially in Europe. OBJECTIVES: Based on a systematic review, we aimed to assess the influence of neuro- and thyrotoxic agricultural and domestic pesticides (other than OPs, OCs, pyrethroids and carbamates) authorized in Europe on risk of ASD in children or ASD behavioral phenotypes in rodents. METHODS: Pesticides were initially identified in the Hazardous Substances Data Bank. 20 currently used (10 pesticide groups) were retained based on the higher exposure potential. Epidemiological (children) and in vivo (rodents) studies were identified through PubMed, Web of Science and TOXLINE, without restriction of publication date or country (last update: November 2019). The risk of bias and level of evidence were also assessed. This systematic review is registered at the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42019145384). RESULTS: In total, two epidemiological and 15 in vivo studies were retained, focusing on the azole, neonicotinoid, phenylpyrazole and phosphonoglycine pesticide groups. No study was conducted in Europe. Glyphosate, imidacloprid, clothianidin, myclobutanil, acetamiprid, tebuconazole, thiabendazole and fipronil, globally reported an association with an increased risk of ASD in children and/or ASD behavioral phenotypes in rodents. In children, glyphosate and myclobutanil showed a "moderate level of evidence" in their association with ASD, whereas imidacloprid showed an "inadequate level of evidence". In rodents, clothianidin, imidacloprid and glyphosate showed a "high level of evidence" in their association with altered behavioral, learning and memory skills. CONCLUSION: In the framework of environmental risk factors of ASD, novel hypotheses can be formulated about early exposure to eight pesticides. Glyphosate presented the most salient level of evidence. Given their neuro- and thyrotoxic properties, additional studies are needed for the 12 other pesticides not yet studied as potential ASD risk factors according to our inclusion criteria.

Effects of prenatal exposure to particulate matter air pollution on corpus callosum and behavioral problems in children.

OBJECTIVE: Air pollution (AP) may affect neurodevelopment, but studies about the effects of AP on the growing human brain are still scarce. We aimed to investigate the effects of prenatal exposure to AP on lateral ventricles (LV) and corpus callosum (CC) volumes in children and to determine whether the induced brain changes are associated with behavioral problems. METHODS: Among the children recruited through a set of representative schools of the city of Barcelona, (Spain) in the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) study, 186 typically developing participants aged 8-12 years underwent brain MRI on the same 1.5 T MR unit over a 1.5-year period (October 2012-April 2014). Brain volumes were derived from structural MRI scans using automated tissue segmentation. Behavioral problems were assessed using the Strengths and Difficulties Questionnaire (SDQ) and the criteria of the Attention Deficit Hyperactivity Disorder DSM-IV list. Prenatal fine particle (PM2.5) levels were retrospectively estimated at the mothers' residential addresses during pregnancy with land use regression (LUR) models. To determine whether brain structures might be affected by prenatal PM2.5 exposure, linear regression models were run and adjusted for age, sex, intracranial volume (ICV), maternal education, home socioeconomic vulnerability index, birthweight and mothers' smoking status during pregnancy. To test for associations between brain changes and behavioral outcomes, negative binomial regressions were performed and adjusted for age, sex, ICV. RESULTS: Prenatal PM2.5 levels ranged from 11.8 to 39.5 µg/m3 during the third trimester of pregnancy. An interquartile range increase in PM2.5 level (7 µg/m3) was significantly linked to a decrease in the body CC volume (mm3) (ß = -53.7, 95%CI [-92.0, -15.5] corresponding to a 5% decrease of the mean body CC volume) independently of ICV, age, sex, maternal education, socioeconomic vulnerability index at home, birthweight and mothers' smoking status during the third trimester of pregnancy. A 50 mm3 decrease in the body CC was associated with a significant higher hyperactivity subscore (Rate Ratio (RR) = 1.09, 95%CI [1.01, 1.17) independently of age, sex and ICV. The statistical significance of these results did not survive to False Discovery Rate correction for multiple comparisons. CONCLUSIONS: Prenatal exposure to PM2.5 may be associated with CC volume decrease in children. The consequences might be an increase in behavioral problems.

Detecting cognitive changes in preclinical Alzheimer's disease: A review of its feasibility.

Significant progress has been made in characterizing the biological changes occurring in preclinical Alzheimer's disease (AD). Cognitive dysfunction has been viewed, however, as a late-stage phenomenon, despite increasing evidence that changes may be detected in the decades preceding dementia. In the absence of comprehensive evidence-based guidelines for preclinical cognitive assessment, longitudinal cohort and neuroimaging studies have been reviewed to determine the temporal order and brain biomarker correlates of specific cognitive functions. Episodic memory decline was observed to be the most salient cognitive function, correlating with high levels of amyloid deposition and hypoconnectivity across large-scale brain networks. Prospective studies point to early decline in both episodic and semantic memory processing as well as executive functions in the predementia period. The cognitive tests have, however, been principally those used to diagnose dementia. New procedures are required which target more finely the medial temporal lobe subregions first affected by clinically silent AD pathology.

Education modulates the impact of white matter lesions on the risk of mild cognitive impairment and dementia.

OBJECTIVES: Conflicting results have been reported regarding the association between white matter lesions (WML) and cognitive impairment. We hypothesized that education, a marker of cognitive reserve (CR), could modulate the effects of WML on the risk of mild cognitive impairment (MCI) or dementia. METHODS: We followed 500 healthy subjects from a cohort of community-dwelling persons aged 65 years and over (ESPRIT Project). At baseline, WML volume was measured using a semi-automatic method on T2-weighted MRI. Standardized cognitive and neurological evaluations were repeated after 2, 4, and 7 years. The sample was dichotomized according to education level into low (≤8 years) and high (>8 years) education groups. Cox proportional hazard models were constructed to study the association between WML and risk of MCI/dementia. RESULTS: The interaction between education level and WML volume reached significance (p = 0.017). After adjustment for potential confounders, the association between severe WML and increased MCI/dementia risk was significant in the low education group (≤8 years) (p = 0.02, hazard ratio [HR]: 3.77 [1.29-10.99]), but not in the high education group (>8 years) (p = 0.82, HR: 1.07 [0.61-1.87]). CONCLUSIONS: Severe WML significantly increases the risk of developing MCI/dementia over a 7-year period in low educated participants. Subjects with higher education levels were seen to be more likely to be resilient to the deleterious effects of severe WML. The CR hypothesis suggests several avenues for dementia prevention.

Cerebral white matter hyperintensities in the prediction of cognitive decline and incident dementia.

Cerebral white matter hyperintensities (WMH), detected in vivo with magnetic resonance imaging (MRI), are commonly used to assess cerebrovascular burden in cognitive impairment. However, the association between WMH and cognition is not consistent across the literature. The present review examines evidence from published longitudinal studies. We reviewed the PubMed data base from January 1990 to March 2013 and included studies investigating the association of WMH with (1) the risk of dementia in the general population, (2) the risk of conversion to dementia in the mild cognitive impairment (MCI) population, and (3) cognitive decline in the general population. WMH were associated with all types of dementia in the general population, but not in MCI patients. Results are discrepant for global decline. WMH appear to be early predictors of the risk of dementia, but this association appears to be modulated by cognitive reserve, age and the spatial distribution of lesions. There are, however, some limits in the use of WMH as a marker of vascular burden. In addition to their ischaemic origin, WMH may be the result of co-occurring morbidity. Further research is needed to elucidate to what extent WMH actually reflect vascular risk to evaluate the likely efficacy of interventions specifically targeting WMH reduction.

Ambient Air Pollution Exposure and Cerebral White Matter Hyperintensities in Older Adults: A Cross-Sectional Analysis in the Three-City Montpellier Study.

BACKGROUND: Growing epidemiological evidence suggests an adverse relationship between exposure to air pollutants and cognitive health, and this could be related to the effect of air pollution on vascular health. OBJECTIVE: We aim to evaluate the association between air pollution exposure and a magnetic resonance imaging (MRI) marker of cerebral vascular burden, white matter hyperintensities (WMH). METHODS: This cross-sectional analysis used data from the French Three-City Montpellier study. Randomly selected participants 65-80 years of age underwent an MRI examination to estimate their total and regional cerebral WMH volumes. Exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and black carbon (BC) at the participants' residential address during the 5 years before the MRI examination was estimated with land use regression models. Multinomial and binomial logistic regression assessed the associations between exposure to each of the three pollutants and categories of total and lobar WMH volumes. RESULTS: Participants' (n=582) median age at MRI was 70.7 years [interquartile range (IQR): 6.1], and 52% (n=300) were women. Median exposure to air pollution over the 5 years before MRI acquisition was 24.3 (IQR: 1.7) µg/m3 for PM2.5, 48.9 (14.6) µg/m3 for NO2, and 2.66 (0.60) 10-5/m for BC. We found no significant association between exposure to the three air pollutants and total WMH volume. We found that PM2.5 exposure was significantly associated with higher risk of temporal lobe WMH burden [odds ratio (OR) for an IQR increase=1.82 (95% confidence interval: 1.41, 2.36) for the second volume tercile, 2.04 (1.59, 2.61) for the third volume tercile, reference: first volume tercile]. Associations for other regional WMH volumes were inconsistent. CONCLUSION: In this population-based study in older adults, PM2.5 exposure was associated with increased risk of high WMH volume in the temporal lobe, strengthening the evidence on PM2.5 adverse effect on the brain. Further studies looking at different markers of cerebrovascular damage are still needed to document the potential vascular effects of air pollution. https://doi.org/10.1289/EHP12231.

Correcting for the influence of sampling conditions on biomarkers of exposure to phenols and phthalates: a 2-step standardization method based on regression residuals.

BACKGROUND: Environmental epidemiology and biomonitoring studies typically rely on biological samples to assay the concentration of non-persistent exposure biomarkers. Between-participant variations in sampling conditions of these biological samples constitute a potential source of exposure misclassification. Few studies attempted to correct biomarker levels for this error. We aimed to assess the influence of sampling conditions on concentrations of urinary biomarkers of select phenols and phthalates, two widely-produced families of chemicals, and to standardize biomarker concentrations on sampling conditions. METHODS: Urine samples were collected between 2002 and 2006 among 287 pregnant women from Eden and Pélagie cohorts, from which phthalates and phenols metabolites levels were assayed. We applied a 2-step standardization method based on regression residuals. First, the influence of sampling conditions (including sampling hour, duration of storage before freezing) and of creatinine levels on biomarker concentrations were characterized using adjusted linear regression models. In the second step, the model estimates were used to remove the variability in biomarker concentrations due to sampling conditions and to standardize concentrations as if all samples had been collected under the same conditions (e.g., same hour of urine collection). RESULTS: Sampling hour was associated with concentrations of several exposure biomarkers. After standardization for sampling conditions, median concentrations differed by--38% for 2,5-dichlorophenol to +80 % for a metabolite of diisodecyl phthalate. However, at the individual level, standardized biomarker levels were strongly correlated (correlation coefficients above 0.80) with unstandardized measures. CONCLUSIONS: Sampling conditions, such as sampling hour, should be systematically collected in biomarker-based studies, in particular when the biomarker half-life is short. The 2-step standardization method based on regression residuals that we proposed in order to limit the impact of heterogeneity in sampling conditions could be further tested in studies describing levels of biomarkers or their influence on health.

Outdoor air pollution exposure and cognitive performance: findings from the enrolment phase of the CONSTANCES cohort.

BACKGROUND: Air pollution exposure is one of the modifiable risk factors of cognitive decline. We aimed to test the association between exposure to several outdoor air pollutants and domain-specific cognitive performance. METHODS: In this cross-sectional study, we used data from the enrolment phase of the French CONSTANCES cohort. From the 220 000 people (aged 18-69 years) randomly recruited in the French CONSTANCES cohort, participants aged 45 years old or older (104 733 people) underwent a comprehensive cognitive assessment (verbal episodic memory, language skills, and executive functions). After exclusion of those who were not suitable for our analysis, 61 462 participants with available data were included in the analyses. We used annual mean concentrations at residential addresses, derived from land-use regression models, to assign exposure to particulate matter with aerodynamic diameters less than 2·5 µm (PM2·5), nitrogen dioxide (NO2), and black carbon. We used multiple linear regression models with different covariate adjustments to test the associations between each pollutant and cognitive outcomes. We did several sensitivity analyses, including multilevel modelling, meta-analysis by centre of recruitment, and exclusion of specific population groups. FINDINGS: We found significantly poorer cognitive function, especially on semantic fluency and domains of executive functions, with an increase in exposure to black carbon and NO2. Exposure to PM2·5 was mainly significant for the semantic fluency test. We found that decrease in cognitive performance with an increase of one interquartile range of exposure ranged from 1% to nearly 5%. The largest effect size (percentage decrease) for both PM2.5 and NO2 was found for the semantic fluency test (PM2.5 4·6%, 95% CI 2·1-6·9 and NO2 3·8%, 1·9-5·7), whereas for black carbon, the largest effect size was found for the digit symbol substitution test of the domains of executive functions (4·5%, 2·7-6·3). Monotonic and linear exposure-response associations were found between air pollution exposure and cognitive performance, starting from a low level of exposures. INTERPRETATION: Significantly poorer cognitive performance was associated with exposure to outdoor air pollution even at low levels of exposure. This highlights the importance of further efforts to reduce exposure to air pollution. FUNDING: The Caisse Nationale d'Assurance Maladie, and partly funded by Merck Sharp & Dohme and L'Oréal, the French National Research Agency, and Fondation de France. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Exposure to ambient air pollution and cognitive decline: Results of the prospective Three-City cohort study.

BACKGROUND: Growing epidemiological evidence suggests an adverse relationship between exposure to air pollutants and cognitive decline. However, there is still some heterogeneity in the findings, with inconsistent results depending on the pollutant and the cognitive domain considered. We wanted to determine whether air pollution was associated with global and domain-specific cognitive decline. METHODS: This analysis used data from the French Three-City prospective cohort (participants aged 65 and older at recruitment and followed for up to 12 years). A battery of cognitive tests was administered at baseline and every 2 years, to assess global cognition (Mini Mental State Examination, MMSE), visual memory (Benton Visual Retention Test), semantic fluency (Isaacs Set Test) and executive functions (Trail Making Tests A and B). Exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2) and black carbon (BC) at the participants' residential address during the 5 years before the baseline visit was estimated with land use regression models. Linear mixed models and latent process mixed models were used to assess the association of each pollutant with global and domain-specific cognitive decline. RESULTS: The participants' (n = 6380) median age was 73.4 years (IQR: 8.0), and 61.5% were women. At baseline, the median MMSE score was 28 (IQR: 3). Global cognition decline, assessed with the MMSE, was slightly accelerated among participants with higher PM2.5 exposure: one IQR increment in PM2.5 (1.5 µg/m3) was associated with accelerated decline (ß: -0.0060 [-0.0112; -0.0007] standard unit per year). Other associations were inconsistent in direction, and of small magnitude. CONCLUSION: In this large population-based cohort, higher PM2.5 exposure was associated with accelerated global cognition decline. We did not detect any significant association for the specific cognitive domains or the other pollutants. Evidence concerning PM2.5 effects on cognition is growing, but more research is needed on other ambient air pollutants.

Sulcal morphology as cognitive decline predictor in older adults with memory complaints.

To determine whether sulcal morphology can predict changes in cognition, we investigated the relationship between width of 20 cerebral sulci and cognitive decline. Sulcal width was measured in T1-weighted MRI images at baseline in 433 adults aged ≥70 years with memory complaints from the MRI-Multidomain Alzheimer Preventive Trial study. Cognition was evaluated at baseline, 6, 12, 24, and 36 months of follow-up with a composite Z score. The composite score variations over time relative to the baseline sulcal width were assessed using linear mixed regression models. We observed a positive association between a greater decline in cognitive composite score and the width of the superior and the anterior inferior temporal sulci, and the cingulate anterior sulcus of the left hemisphere. Sulcal widening in the lateral temporal and the cingulate anterior areas might predict cognitive decline in individuals with memory complaints.

Association between residential proximity to agricultural crops and adaptive behaviors in children with autism spectrum disorder from the French ELENA cohort.

Influences of pesticide exposures on the clinical expression of children with ASD not known. The aim of this study was to analyze the associations between early residential proximity to agricultural crops, proxy of exposure to pesticides, and adaptive behaviors in children with ASD. Children with ASD were recruited within the Etude Longitudinale de l'Enfant avec Autisme (ELENA) French cohort. Adaptive behaviors were assessed with the second edition of the Vineland Adaptive Behavior Scales (VABS-II). Baseline subscores in communication, daily living skills and socialization were considered. Residential exposure to agricultural crops was estimated by crops acreage within a 1000m radius around homes. We ran multiple linear regression models to investigate the associations between exposures to agricultural crops during the pregnancy (n = 183), the first two years of life (n = 193) and adaptive behaviors in children with ASD. The mean (SD) age of children at the inclusion in the ELENA cohort was 6.1 (3.5) years, 39% of them presented an intellectual disability (ID). The mean communication score was 73.0 (15.8). On average, the crop acreage covered 29(27)% of the acreage formed by the 1000m radius around homes. Each increase of 20% in the crop acreage was associated with a significant decrease in communication score of the VABS-II in children without ID for the pregnancy (ß = -2.21, 95%CI: 4.16 to -0.27) and the first two years of life (ß = -1.90, 95%CI: 3.68 to -0.11) periods. No association was found in children with ID. This study opens perspectives for future works to better understand ASD phenotypes.

Long-term exposure to ambient air pollution and risk of dementia: Results of the prospective Three-City Study.

BACKGROUND: Emerging epidemiological evidence suggests a relationship between exposure to air pollution and dementia. However, most of the existing studies relied on health administrative databases for the diagnosis of dementia. In a large French population-based cohort (the 3C Study), we assessed the effects of particulate matter ≤2.5 µm (PM2.5), nitrogen dioxide (NO2) and black carbon (BC) on the risk of dementia diagnosed with reliable tools. METHODS: Participants aged ≥65 years were recruited between 1999 and 2001 and followed for 12 years. At baseline and every 2 years, dementia was suspected on the basis of the neuropsychological and neurological examination and confirmed by an independent committee of clinicians. Exposure to NO2, BC and PM2.5 at the participants' residential address was estimated using land use regression models. For each pollutant and year of follow-up, the 10-year moving average of past exposure was estimated. Multilevel spatial random-effects Cox proportional hazards models were used in which exposure was included as a time-varying variable. Analyses were adjusted for individual (age, sex, education, APOE4 genotype, health behaviours) and contextual (neighbourhood deprivation index) confounders. RESULTS: At baseline, the median age of the 7066 participants was 73.4 years, and 62% were women. The median follow-up duration was 10.0 years during which 791 participants developed dementia (n = 541 Alzheimer's disease (AD) and n = 155 vascular/mixed dementia (VaD)). The 10-year moving average of PM2.5 concentrations ranged from 14.6 to 31.3 µg/m3. PM2.5 concentration was positively associated with dementia risk: HR = 1.20, 95% CI (1.08-1.32) for all-cause dementia, 1.20 (1.09-1.32) for AD, and 1.33 (1.05-1.68) for VaD per 5 µg/m3 PM2.5 increase. No association was detected between NO2 or BC exposure and dementia risk. CONCLUSION: In this large cohort of older adults, long-term PM2.5 exposure was associated with increased dementia incidence. Reducing PM2.5 emissions might lessen the burden of dementia in aging populations.

Long-Term Exposure to Ambient Air Pollution and Cognitive Function Among Hispanic/Latino Adults in San Diego, California.

BACKGROUND: Hispanics/Latinos in the United States are more likely to live in neighborhoods with greater exposure to air pollution and are projected to have the largest increase in dementia among race/ethnic minority groups. OBJECTIVE: We examined the associations of air pollution with performance on cognitive function tests in Hispanic/Latino adults. METHODS: We used data from the San Diego site of the Hispanic Community Health Study/Study of Latinos, an ongoing cohort of Hispanics/Latinos. This analysis focused on individuals ≥45 years of age who completed a neurocognitive battery examining overall mental status, verbal learning, memory, verbal fluency, and executive function (n = 2,089). Air pollution (PM2.5 and O3) before study baseline was assigned to participants' zip code. Logistic and linear regression were used to estimate the associations of air pollution on overall mental status and domain-specific standardized test scores. Models accounted for complex survey design, demographic, and socioeconomic characteristics. RESULTS: We found that for every 10µg/m3 increase in PM2.5, verbal fluency worsened (ß: -0.21 [95%CI: -0.68, 0.25]). For every 10 ppb increase in O3, verbal fluency and executive function worsened (ß: -0.19 [95%CI: -0.34, -0.03]; ß: -0.01 [95%CI: -0.01, 0.09], respectively). We did not identify any detrimental effect of pollutants on other domains. CONCLUSION: Although we found suggestions that air pollution may impact verbal fluency and executive function, we observed no consistent or precise evidence to suggest an adverse impact of air pollution on cognitive level among this cohort of Hispanic/Latino adults.

Investigating the natural history and prognostic factors of ASD in children: the multicEntric Longitudinal study of childrEN with ASD - the ELENA study protocol.

INTRODUCTION: There is global concern about the increasing prevalence of autism spectrum disorders (ASDs), which are early-onset and long-lasting disorders. Although ASDs are considered to comprise a unique syndrome, their clinical presentation and outcome vary widely. Large-scale and long-term cohort studies of well-phenotyped samples are needed to better understand the course of ASDs and their determinants. The primary objective of the multicEntric Longitudinal study of childrEN with ASD (ELENA) study is to understand the natural history of ASD in children and identify the risk and prognostic factors that affect their health and development. METHODS AND ANALYSIS: This is a multicentric, longitudinal, prospective, observational cohort in which 1000 children with ASD diagnosed between 2 and 16 years of age will be recruited by 2020 and followed over 6 years. The baseline follow-up starts with the clinical examination to establish the ASD diagnosis. A battery of clinical tools consisting of the Autism Diagnostic Observation Schedule, the revised version of the Autism Diagnostic Interview, measures of intellectual functioning, as well as large-scale behavioural and developmental measurements will allow us to study the heterogeneity of the clinical presentation of ASD subtypes. Subsequent follow-up at 18 months and at 3, 4.5 and 6 years after the baseline examination will allow us to explore the developmental trajectories and variables associated with the severity of ASD. In addition to the children's clinical and developmental examinations, parents are invited to complete self-reported questionnaires concerning perinatal and early postnatal history, congenital anomalies, genetic factors, lifestyle factors, medical and psychiatric comorbidities, and the socioeconomic environment. As of 1 November 2018, a total of 766 participants have been included. ETHICS AND DISSEMINATION: Ethical approval was obtained through the Marseille Mediterranean Ethics Committee (ID RCB: 2014-A01423-44), France. We aim to disseminate the findings through national and international conferences, international peer-reviewed journals, and social media. TRIAL REGISTRATION NUMBER: NCT02625116; Pre-results.

The Effects of Air Pollution on the Brain: a Review of Studies Interfacing Environmental Epidemiology and Neuroimaging.

PURPOSE OF REVIEW: An emerging body of evidence has raised concern regarding the potentially harmful effects of inhaled pollutants on the central nervous system during the last decade. In the general population, traffic-related air pollution (TRAP) exposure has been associated with adverse effects on cognitive, behavior, and psychomotor development in children, and with cognitive decline and higher risk of dementia in the elderly. Recently, studies have interfaced environmental epidemiology with magnetic resonance imaging to investigate in vivo the effects of TRAP on the human brain. The aim of this systematic review was to describe and synthesize the findings from these studies. The bibliographic search was carried out in PubMed with ad hoc keywords. RECENT FINDINGS: The selected studies revealed that cerebral white matter, cortical gray matter, and basal ganglia might be the targets of TRAP. The detected brain damages could be involved in cognition changes. The effect of TRAP on cognition appears to be biologically plausible. Interfacing environmental epidemiology and neuroimaging is an emerging field with room for improvement. Future studies, together with inputs from experimental findings, should provide more relevant and detailed knowledge about the nature of the relationship between TRAP exposure and cognitive, behavior, and psychomotor disorders observed in the general population.

Sparse multiple factor analysis to integrate genetic data, neuroimaging features, and attention-deficit/hyperactivity disorder domains.

OBJECTIVES: We proposed the application of a multivariate cross-sectional framework based on a combination of a variable selection method and a multiple factor analysis (MFA) in order to identify complex meaningful biological signals related to attention-deficit/hyperactivity disorder (ADHD) symptoms and hyperactivity/inattention domains. METHODS: The study included 135 children from the general population with genomic and neuroimaging data. ADHD symptoms were assessed using a questionnaire based on ADHD-DSM-IV criteria. In all analyses, the raw sum scores of the hyperactivity and inattention domains and total ADHD were used. The analytical framework comprised two steps. First, zero-inflated negative binomial linear model via penalized maximum likelihood (LASSO-ZINB) was performed. Second, the most predictive features obtained with LASSO-ZINB were used as input for the MFA. RESULTS: We observed significant relationships between ADHD symptoms and hyperactivity and inattention domains with white matter, gray matter regions, and cerebellum, as well as with loci within chromosome 1. CONCLUSIONS: Multivariate methods can be used to advance the neurobiological characterization of complex diseases, improving the statistical power with respect to univariate methods, allowing the identification of meaningful biological signals in Imaging Genetic studies.