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Abstract 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.

Purpose: Cataract, the leading cause of blindness worldwide, is a multifactorial disease involving oxidative stress mechanisms. The aim of our study was to investigate the relationship between air pollution exposure and the incidence of cataract surgery., Methods: The 3C-Alienor study is a population-based cohort of residents of Bordeaux, France, aged 65 years or more, recruited in 1999-2000 and followed every 2-3 years until 2017. Cataract surgery was self-reported and checked at slit-lamp by trained professionals. Average air pollution exposure (particulate matter ≤2.5 μm (PM 2.5 ), black carbon (BC), nitrogen dioxide (NO 2 )) in the 10 years preceding baseline was estimated at the participants' geocoded residential address, using temporally adjusted land use regression. Associations of 10-year average air pollution exposure with incidence of cataract were estimated using Cox proportional hazard models adjusted for confounders., Results: The study included 829 subjects without cataract surgery prior to inclusion; the mean age at inclusion was 72.6 years (standard deviation (SD): 4.2) and 61% were women. The median (Interquartile-range (IQR)) follow-up duration was 14.1 (6.4) years during which 507 participants underwent cataract surgery. Exposure to a concentration ≥40 μg/m 3 of NO 2 (the current regulatory limit value in Europe) was associated with incident cataract surgery (HR = 1.46, CI (1.16, 1.84), p = 0.001). No statistically significant association was found with PM 2.5 and BC., Conclusion: Long-term exposure to a NO 2 concentration ≥ 40 μg/m 3 was associated with an increased incidence of cataract surgery. Complying with current European air pollution standards could reduce cataract surgery costs and improve population quality of life., (© 2024 The Author(s). Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

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 ( PM 2.5 ), nitrogen dioxide ( NO 2 ), 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) μ g / m 3 for PM 2.5 , 48.9 (14.6) μ g / m 3 for NO 2 , 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 PM 2.5 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, PM 2.5 exposure was associated with increased risk of high WMH volume in the temporal lobe, strengthening the evidence on PM 2.5 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.

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 (PM 2.5 ), black carbon (BC), nitrogen dioxide (NO 2 )) 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 PM 2.5 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 NO 2 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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cécile Delcourt : Consultant for Allergan, Bausch+Lomb, Laboratoires Théa and Novartis. Audrey Cougnard-Grégoire : Travel fees from Laboratoires Théa. Jean-François Korobelnik : Consultant pour Abbvie, Apellis, Bayer, Janssen, Nanoretina, Roche, Théa, Carl Zeiss Meditec. Membre du DSMB pour Alexion, Nonordisk. Marie-Noelle Delyfer: Consultant for AbbVie, Bayer, Horama, Horus Pharma, Novartis, Roche et Thea. Cédric Schweitzer: Consultant for Abbvie, Alcon, Glaukos, Nicox, Théa, Horus, Johnson & Johnson, Santen, Bausch & Lomb. Laure Gayraud, Marion Mortamais, Kees de Hoogh, Marie-Bénédicte Rougier, Karen Leffondré, Catherine Helmer, Danielle Vienneau, Claudine Berr : None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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 (PM 2.5 ) reductions., Results: Among 7051 participants, 789 participants developed dementia. The median PM 2.5 reduction between 1990 and 2000 was 12.2 (μg/m 3 ). 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/m 3 (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., (© 2022 the Alzheimer's Association.)

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 (PM 2.5 , NO 2 , 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 PM 2.5 compared to non-Hispanics using static measures. In contrast, Hispanics/Latinos had less exposure to PM 2.5 using dynamic measures. For all participants, higher dynamic exposure to PM 2.5 and NO 2 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 PM 2.5 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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 (PM 2.5 ), nitrogen dioxide (NO 2 ) 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 PM 2.5 exposure: one IQR increment in PM 2.5 (1.5 µg/m 3 ) was associated with accelerated decline (β: -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 PM 2.5 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 PM 2.5 effects on cognition is growing, but more research is needed on other ambient air pollutants., (Copyright © 2022. Published by Elsevier Ltd.)

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 (PM 2·5 ), nitrogen dioxide (NO 2 ), 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 NO 2 . Exposure to PM 2·5 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 PM 2.5 and NO 2 was found for the semantic fluency test (PM 2.5 4·6%, 95% CI 2·1-6·9 and NO 2 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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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 (β = -2.21, 95%CI: 4.16 to -0.27) and the first two years of life (β = -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., (Copyright © 2021. Published by Elsevier Ltd.)

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., (© 2021. The Author(s).)

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 (NO 2 ) 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 NO 2 , 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/m 3 . 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/m 3 PM2.5 increase. No association was detected between NO 2 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., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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 (β: -0.21 [95%CI: -0.68, 0.25]). For every 10 ppb increase in O3, verbal fluency and executive function worsened (β: -0.19 [95%CI: -0.34, -0.03]; β: -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.

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., Competing Interests: Declaration of competing interest The authors declare they have no actual or potential competing financial or personal interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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 (PM 2.5 ) 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 PM 2.5 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 PM 2.5 levels ranged from 11.8 to 39.5 μg/m 3 during the third trimester of pregnancy. An interquartile range increase in PM 2.5 level (7 μg/m 3 ) was significantly linked to a decrease in the body CC volume (mm 3 ) (β = -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 mm 3 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 PM 2.5 may be associated with CC volume decrease in children. The consequences might be an increase in behavioral problems., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

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., (© 2018 John Wiley & Sons, Ltd.)

Background: Traffic-related air pollution is emerging as a risk factor for Alzheimer's disease (AD) and impaired brain development. Individual differences in vulnerability to air pollution may involve the ε4 allele of Apolipoprotein E ( APOE ) gene, the primary genetic risk factor for AD., Objective: We analyzed whether the association between traffic air pollution and neurodevelopmental outcomes is modified by APOE ε4 status in children., Methods: Data on parent-reported behavior problems (total difficulties scores, Strengths and Difficulties Questionnaire), teacher-reported attention-deficit hyperactivity disorder (ADHD) symptom scores, cognitive performance trajectories (computerized tests of inattentiveness and working memory repeated 2-4 times during January 2012-March 2013), and APOE genotypes were obtained for 1,667 children age 7-11 y attending 39 schools in or near Barcelona. Basal ganglia volume (putamen, caudate, and globus pallidum) was measured in 163 of the children by MRI (October 2012-April 2014.) Average annual outdoor polycyclic aromatic hydrocarbons (PAHs), elemental carbon (EC), and nitrogen dioxide (NO 2 ) concentrations were estimated based on measurements at each school (two 1-wk campaigns conducted 6 months apart in 2012)., Results: APOE ε4 allele carriers had significantly higher behavior problem scores than noncarriers, and adverse associations with PAHs and NO 2 were stronger or limited to ε4 carriers for behavior problem scores ( P -interaction 0.03 and 0.04), caudate volume ( P -interaction 0.04 and 0.03), and inattentiveness trajectories ( P -interaction 0.15 and 0.08, respectively). Patterns of associations with the same outcomes were similar for EC., Conclusion: PAHs, EC, and NO 2 were associated with higher behavior problem scores, smaller reductions in inattentiveness over time, and smaller caudate volume in APOE ε4 allele carriers in our study population, and corresponding associations were weak or absent among ε4 noncarriers. These findings support a potential role of APOE in biological mechanisms that may contribute to associations between air pollution and neurobehavioral outcomes in children. https://doi.org/10.1289/EHP2246.

Background: Anxiety is common in patients with cognitive impairment and dementia. However, whether anxiety is a risk factor for dementia is still not known. We aimed to examine the association between trait anxiety at baseline and the 10-year risk of incident dementia to determine to which extent depressive symptoms influence this relationship in the general population. Methods: Data came from 5,234 community-dwelling participants from the Three-City prospective cohort study, aged 65 years at baseline and followed over 10 years. At baseline, anxiety trait was assessed using the Spielberger State-Trait Anxiety Inventory (STAI), and depressive symptoms using Center for Epidemiologic Studies-Depression Scale (CESD). Use of anxiolytic drugs was also considered. Diagnoses of dementia were made at baseline and every 2 years. To examine the relationship between anxiety exposures and risk of incident dementia, Cox proportional hazard regression models were performed. Results: Taking anxiolytic drugs or having high trait anxiety (STAI score ≥ 44) increased the risk of dementia assessed over 10 years of follow-up [Hazard Ratio (HR) = 1.39, 95%CI: 1.08-1.80, p = 0.01 and HR = 1.26, 95%CI: 1.01-1.57, p = 0.04, respectively], independently of a large panel of socio-demographic variables, health behaviors, cardio-metabolic disorders, and additional age-related disorders such as cardiovascular diseases, activity limitations, and cognitive deficit. However, the associations were substantially attenuated after further adjustment for depressive symptoms. Conclusion: Our findings suggest that depressive symptoms shape the association between anxiety trait and dementia. Further research is needed to replicate our findings and extrapolate our results to anxiety disorders.

Background: Proponents of the biophilia hypothesis believe that contact with nature, including green spaces, has a crucial role in brain development in children. Currently, however, we are not aware of evidence linking such exposure with potential effects on brain structure., Objective: We determined whether lifelong exposure to residential surrounding greenness is associated with regional differences in brain volume based on 3-dimensional magnetic resonance imaging (3D MRI) among children attending primary school., Methods: We performed a series of analyses using data from a subcohort of 253 Barcelona schoolchildren from the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) project. We averaged satellite-based normalized difference vegetation index (NDVI) across 100-m buffers around all residential addresses since birth to estimate each participant's lifelong exposure to residential surrounding greenness, and we used high-resolution 3D MRIs of brain anatomy to identify regional differences in voxel-wise brain volume associated with greenness exposure. In addition, we performed a supporting substudy to identify regional differences in brain volume associated with measures of working memory ( d' from computerized n -back tests) and inattentiveness (hit reaction time standard error from the Attentional Network Task instrument) that were repeated four times over one year. We also performed a second supporting substudy to determine whether peak voxel tissue volumes in brain regions associated with residential greenness predicted cognitive function test scores., Results: Lifelong exposure to greenness was positively associated with gray matter volume in the left and right prefrontal cortex and in the left premotor cortex and with white matter volume in the right prefrontal region, in the left premotor region, and in both cerebellar hemispheres. Some of these regions partly overlapped with regions associated with cognitive test scores (prefrontal cortex and cerebellar and premotor white matter), and peak volumes in these regions predicted better working memory and reduced inattentiveness., Conclusion: Our findings from a study population of urban schoolchildren in Barcelona require confirmation, but they suggest that being raised in greener neighborhoods may have beneficial effects on brain development and cognitive function. https://doi.org/10.1289/EHP1876.

Background: Polycyclic aromatic hydrocarbons (PAHs) have been proposed as environmental risk factors for attention deficit hyperactivity disorder (ADHD). The effects of these pollutants on brain structures potentially involved in the pathophysiology of ADHD are unknown., Objective: The aim of this study was to investigate the effects of PAHs on basal ganglia volumes and ADHD symptoms in school children., Methods: We conducted an imaging study in 242 children aged 8-12years, recruited through a set of representative schools of the city of Barcelona, Spain. Indoor and outdoor PAHs and benzo[a]pyrene (BPA) levels were assessed in the school environment, one year before the MRI assessment. Whole-brain volumes and basal ganglia volumes (caudate nucleus, globus pallidus, putamen) were derived from structural MRI scans using automated tissue segmentation. ADHD symptoms (ADHD/DSM-IV Scales, American Psychiatric Association 2002) were reported by teachers, and inattentiveness was evaluated with standard error of hit reaction time in the attention network computer-based test., Results: Total PAHs and BPA were associated with caudate nucleus volume (CNV) (i.e., an interquartile range increase in BPA outdoor level (67pg/m 3 ) and indoor level (76pg/m 3 ) was significantly linked to a decrease in CNV (mm 3 ) (β=-150.6, 95% CI [-259.1, -42.1], p=0.007, and β=-122.4, 95% CI [-232.9, -11.8], p=0.030 respectively) independently of intracranial volume, age, sex, maternal education and socioeconomic vulnerability index at home). ADHD symptoms and inattentiveness increased in children with higher exposure to BPA, but these associations were not statistically significant., Conclusions: Exposure to PAHs, and in particular to BPA, is associated with subclinical changes on the caudate nucleus, even below the legislated annual target levels established in the European Union. The behavioral consequences of this induced brain change were not identified in this study, but given the caudate nucleus involvement in many crucial cognitive and behavior processes, this volume reduction is concerning for the children's neurodevelopment., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2016 the Alzheimer's Association. All rights reserved.)

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., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

There is growing evidence that vascular health plays a significant role in the etiology of clinical Alzheimer's disease (AD). Understanding the timing of vascular changes in relation to progression from cognitive impairment to AD has become of increasing importance, being both possible pre-clinical markers and potentially modifiable risk factors. White matter hyperintensities (WMH) detected in vivo with magnetic resonance imaging, are commonly used to assess cerebrovascular burden in cognitive impairment and appear to be associated with an increased risk of cognitive decline due to many causes. The present review examines specifically the association between WMH and AD and its related biomarkers. Overall, current findings across the literature suggest that WMH may predict AD at least a decade before the clinical stage of the disease, independently of biomarkers of AD pathology, thus indicating that vascular factors may constitute important targets for pre-clinical detection and intervention.

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., Competing Interests: Conflict of interest/disclosures The authors report no conflicts of interest.

Context: White matter lesions (WML) increase the risk of dementia. The relevance of WML location is less clear. We sought to determine whether a particular WML profile, based on the density and location of lesions, could be associated with an increased risk of mild cognitive impairment (MCI) or dementia over the following 7 years., Methods: In 426 healthy subjects from a cohort of community-dwelling people aged 65 years and over (ESPRIT Project), standardized cognitive and neurological evaluations were repeated after 2, 4 and 7 years. Patterns of WML were computed with a supervised data mining approach (decision trees) using the regional WML volumes (frontal, parietal, temporal, and occipital regions) and the total WML volume estimated at baseline. Cox proportional hazard models were then constructed to study the association between WML patterns and risk of MCI/dementia., Results: Total WML volume and percentage of WML in the temporal region proved to be the best predictors of progression to MCI and dementia. Specifically, severe total WML load with a high proportion of lesions in the temporal region was significantly associated with the risk of developing MCI or dementia., Conclusions: Above a certain threshold of damage, a pattern of WML clustering in the temporal region identifies individuals at increased risk of MCI or dementia. As this WML pattern is observed before the onset of clinical symptoms, it may facilitate the detection of patients at risk of MCI/dementia.

Background: Data concerning the effects of prenatal exposures to phthalates and phenols on fetal growth are limited in humans. Previous findings suggest possible effects of some phenols on male birth weight., Objective: Our aim was to assess the relationships between prenatal exposures to phthalates and phenols and fetal growth among male newborns., Methods: We conducted a case-control study on male malformations of the genitalia nested in two French mother-child cohorts with recruitment between 2002 and 2006. We measured, in maternal urinary samples collected between 6 and 30 gestational weeks, the concentrations (micrograms per liter) of 9 phenol (n = 191 pregnant women) and 11 phthalate metabolites (n = 287). Weight, length, and head circumference at birth were collected from maternity records. Statistical analyses were corrected for the oversampling of malformation cases., Results: Adjusted birth weight decreased by 77 g [95% confidence interval (CI): -129, -25] and by 49 g (95% CI: -86, -13) in association with a 1-unit increase in ln-transformed 2,4-dichlorophenol (DCP) and 2,5-DCP urinary concentrations, respectively. Benzophenone-3 (BP3) ln-transformed concentrations were positively associated with weight (26 g; 95% CI: -2, 54) and head circumference at birth (0.1 cm; 95% CI: 0.0, 0.2). Head circumference increased by 0.3 cm (95% CI: 0.0, 0.7) in association with a 1-unit increase in ln-transformed BPA concentration. For phthalate metabolites there was no evidence of monotonic associations with birth weight., Conclusions: Consistent with findings of a previous study, we observed evidence of an inverse association of 2,5-DCP and a positive association of BP3 with male birth weight.