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Background: The COVID-19 pandemic and lockdown have had negative effects on students' mental health. However, little information is available regarding the frequencies of depressive symptoms and suicidal ideation during the post-pandemic period. We aimed to determine whether the COVID-19 pandemic resulted in a change in the frequencies of depressive symptoms and suicidal ideation among French university students., Methods: In this comparative study, 4463 students were recruited during the pre-COVID-19 pandemic period (2013-2020) and 1768 students, during the post-COVID-19 pandemic period (2022-2023). Standardized frequencies of depressive symptoms and suicidal ideation were compared between the two time periods. Changes in the frequencies of depressive symptoms and suicidal ideation between the pre- and post-pandemic periods, were then analyzed using interrupted time series analysis., Results: Compared to participants from the pre-pandemic sample, participants from the post-pandemic sample had higher standardized rates of depressive symptoms (40.6 % vs 25.6 %) and suicidal ideation (29.3 % vs 21.1 %). Segmented logistic regression showed an about 50 % increased risk of depressive symptoms (aOR, 1.47; 95 % CI, 1.01-2.13) and a 100 % increased risk of suicidal ideation (aOR, 2.00; 95 % CI, 1.33-3.00) in the post-pandemic period. Before the pandemic, there was no significant time-trend for depressive symptoms (aOR, 1.002; 95 % CI, 0.999-1.006) and suicidal thoughts (0.999-1.006; aOR, 0.999; 95 % CI, 0.995-1.002)., Limitations: Potential biases related to self-selection of participants in the study and information bias. History of depression and suicide attempt were self-reported., Conclusions: These findings reveal an alarming deterioration of students' mental health in the post-pandemic period compared to the pre-pandemic era., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific mechanism-based treatment. We used Mendelian randomization to combine a unique cerebrospinal fluid (CSF) and plasma pQTL resource with the latest European-ancestry GWAS of MRI-markers of cSVD (white matter hyperintensities, perivascular spaces). We describe a new biological fingerprint of 49 protein-cSVD associations, predominantly in the CSF. We implemented a multipronged follow-up, across fluids, platforms, and ancestries (Europeans and East-Asian), including testing associations of direct plasma protein measurements with MRI-cSVD. We highlight 16 proteins robustly associated in both CSF and plasma, with 24/4 proteins identified in CSF/plasma only. cSVD-proteins were enriched in extracellular matrix and immune response pathways, and in genes enriched in microglia and specific microglial states (integration with single-nucleus RNA sequencing). Immune-related proteins were associated with MRI-cSVD already at age twenty. Half of cSVD-proteins were associated with stroke, dementia, or both, and seven cSVD-proteins are targets for known drugs (used for other indications in directions compatible with beneficial therapeutic effects. This first cSVD proteogenomic signature opens new avenues for biomarker and therapeutic developments., Competing Interests: Competing interests C.C. has received research support from GSK and EISAI and is a member of the advisory board of Circular Genomics and owns stocks in this company. CC is part of the scientific advisory board for ADmit. B.P. serves on the Steering Committee of the Yale Open Data Project funded by Johnson & Johnson. P.M.M. has received an honourarium as Chair of the UKRI Medical Research Council Neuroscience and Mental Health Board until March 2024. He acknowledges consultancy fees from, Biogen, Sudo. Nimbus and GSK. He has received speakers’ honoraria from Sanofi and Redburn, and has received research or educational funds from Biogen, Merck, Bristol Meyers Squibb and Nimbus. J.W declares no commercial COI; various academic research grants and is CI for LACunar Intervention Trials. The authors declared no potential conflicts of interest with respect to research, authorship, and/or publication of this article. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Objective: To assess the association between sleep irregularity, anxiety, and depression while controlling for other sleep dimensions and using a longitudinal design., Methods: Longitudinal cohort study which started in April 2020 during the first French lockdown in the general population. Follow-up questionnaires were completed in June 2020, a period without lockdown measures. Participants were asked about their sleep (regularity, duration, timing, complaints) and their anxiety (General Anxiety Disorder-7) and depressive (Patient Health Questionnaire-9) symptoms., Results: A total of 3745 participants were included (mean age: 28.9 years) with 2945 women (78.6%). At baseline, 38.1% (1428) of participants reported irregular sleep timing, 23.8% (891) anxiety and 28.9% (1081) depressive symptoms. In cross-sectional analyses, irregular sleep timing was associated with a 2.5-fold higher likelihood of anxiety and a 4-fold higher likelihood of depressive symptoms compared to regular sleepers. Associations were not explained by the other sleep dimensions and persisted in a longitudinal analysis, with irregular sleep timing at baseline being associated with anxiety (OR = 3.27[1.58-6.76]) and depressive symptoms (OR = 3.45[1.66-7.19]) during follow-up., Conclusion: The results show a strong association between sleep irregularity and mental health. Furthers studies are needed to explore how sleep regularity could promote good mental health in non-clinical populations.

Blood pressure variability (BPV) impacts brain health by influencing brain structure and cerebrovascular pathologies, though the mechanisms are poorly understood. Changes in the cerebrovasculature may lead to late-onset depression, cognitive impairment, and dementia, however the relationship between BPV with depression and anxiety remains unclear, due to methodological differences and inconsistencies in past research. This review aims to clarify the association between BPV with depression and anxiety in adults to inform understandings of the mechanisms implicating BPV in cognitive health. A systematic search from inception through to January 2024 was performed on Embase, PubMed, PsycINFO, and Web of Science. Studies that assessed BPV quantified by beat-to-beat, 24-hour, or visit-to-visit were eligible if the standardised assessment of depression and/or anxiety were reported as a linear association, or mean differences across control and affect groups. A total of 14 articles reporting on 13 samples and N = 5055 persons met the inclusion criteria (median female proportion = 61 %, range 0 % - 76 %). A meta-analysis was not possible due to methodological heterogeneity in BPV measurements and metrics across studies. Mixed results were observed across depression studies with inconsistencies and variation in the direction, strength of association, and BPV metric. There was weak evidence from only three studies to support a linear association between systolic coefficient of variation and anxiety. Collectively, the findings contribute to understanding the association between BPV and brain health, suggesting that any relationship between BPV and brain structures critical for cognitive function are independent of depression and only modestly implicate anxiety., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Mahajan has served on the advisory board of Abbott and Medtronic. The University of Adelaide reports receiving on behalf of Dr Mahajan lecture and/or consulting fees from Abbott, Bayer, Biotronik, Medtronic, and Pfizer. The University of Adelaide reports receiving on behalf of Dr Mahajan research funding from Abbott, Bayer, and Medtronic. Dr Tully reports receiving consulting fees from the Asia-Pacific Institute of Psycho-Cardiology Research., (© 2024 The Authors. Published by Elsevier B.V.)

Background: The ε4 allele of the apolipoprotein E gene (APOE4) plays a role in neurodegeneration and in cardiovascular disease, but findings on its association with mortality are inconsistent. We aimed to examine the association between APOE4 and mortality, and the role of dementia in this association., Methods: In this pooled analysis, data on White participants aged 45-90 years who underwent APOE genotyping were drawn from two population-based cohorts: the Whitehall II study (UK), which began in 1985 and is ongoing, and the Three-City study (France), initiated in 1999 and ended in 2012. In the Three-City study, vital status was ascertained through linkage to the national registry of death Institut National de la Statistique des Études économiques, and dementia was ascertained via a neuropsychological evaluation and validation of diagnoses by an independent committee of neurologists and geriatricians. In the Whitehall II study, vital status was ascertained through linkage to the UK national mortality register, and dementia cases were ascertained by linkage to three national registers. Participants with prevalent dementia at baseline and participants missing an APOE genotype were excluded from analyses. Cox regression proportional hazard models were used to examine the association of APOE4 with all-cause, cardiovascular, and cancer mortality. The role of dementia in the association between APOE4 status and mortality was examined by excluding participants who developed dementia during follow-up from the analyses. An illness-death model was then used to examine the role of incident dementia in these associations., Findings: 14 091 participants (8492 from the Three-City study and 5599 from the Whitehall II study; 6668 [47%] of participants were women and 7423 [53%] were men), with a median follow-up of 15·4 years (IQR 10·6-21·2), were included in the analyses. Of these participants, APOE4 carriers (3264 [23%] of the cohort carried at least one ε4 allele) had a higher risk of all-cause mortality compared with non-carriers, with hazard ratios (HR) of 1·16 (95% CI 1·07-1·26) for heterozygotes and 1·59 (1·24-2·06) for homozygotes. Compared with APOE3 homozygotes, higher cardiovascular mortality was observed in APOE4 carriers, with a HR of 1·23 (1·01-1·50) for heterozygotes, and no association was found between APOE4 and cancer mortality. Excluding cases of incident dementia over the follow-up resulted in attenuated associations with mortality in homozygotes but not in heterozygotes. The illness-death model indicated that the higher mortality risk in APOE4 carriers was not solely attributable to dementia., Interpretation: We found a robust association between APOE4 and all-cause and cardiovascular mortality but not cancer mortality. Dementia explained a significant proportion of the association with all-cause mortality for APOE4 homozygotes, while non-dementia factors, such as cardiovascular disease mortality, are likely to play a role in shaping mortality outcomes in APOE4 heterozygotes., Funding: National Institutes of Health., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AS-M reports funding from the National Institute on Aging National Institutes of Health (R01AG056477 and R01AG062553), the UK Medical Research Council (R024227 and S011676), and the Wellcome Trust (221854/Z/20/Z). BH reports grants from the Belgian National Fund for Scientific Research, the Belgian Alzheimer Research Foundation, and a WelBio Starting Grant from the WEL Research Institute; consulting fees from Biogen; honoraria for lectures from Roche; and participation on an Advisory Board for Eisai. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Evaluating whether genetic susceptibility modifies the impact of lifestyle-related factors on dementia is critical for prevention., Methods: We studied 5170 participants from a French cohort of older persons free of dementia at baseline and followed for up to 17 years. The LIfestyle for BRAin health risk score (LIBRA) including 12 modifiable factors was constructed at baseline (higher score indicating greater risk) and was related to both subsequent cognitive decline and dementia incidence, according to genetic susceptibility to dementia (reflected by the apolipoprotein E [APOE] ε4 allele and a genetic risk score [GRS])., Results: The LIBRA was associated with higher dementia incidence, with no significant effect modification by genetics (hazard ratio for one point score = 1.09 [95% confidence interval, 1.05; 1.13]) in APOE ε4 non-carriers and = 1.15 [1.08; 1.22] in carriers; P = 0.15 for interaction). Similar findings were obtained with the GRS and with cognitive decline., Discussion: Lifestyle-based prevention may be effective whatever the genetic susceptibility to dementia., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI-marker of cSVD in older age, were recently shown to be significantly associated with white matter (WM) microstructure on diffusion tensor imaging (signal-based) in young adults. To provide new insights into these early changes in WM microstructure and their relation with cSVD, we sought to explore the genetic underpinnings of cutting-edge tissue-based diffusion imaging markers across the adult lifespan. We conducted a genome-wide association study of neurite orientation dispersion and density imaging (NODDI) markers in young adults (i-Share study: N = 1 758, (mean[range]) 22.1[18-35] years), with follow-up in young middle-aged (Rhineland Study: N = 714, 35.2[30-40] years) and late middle-aged to older individuals (UK Biobank: N = 33 224, 64.3[45-82] years). We identified 21 loci associated with NODDI markers across brain regions in young adults. The most robust association, replicated in both follow-up cohorts, was with Neurite Density Index (NDI) at chr5q14.3, a known WMH locus in VCAN. Two additional loci were replicated in UK Biobank, at chr17q21.2 with NDI, and chr19q13.12 with Orientation Dispersion Index (ODI). Transcriptome-wide association studies showed associations of STAT3 expression in arterial and adipose tissue (chr17q21.2) with NDI, and of several genes at chr19q13.12 with ODI. Genetic susceptibility to larger WMH volume, but not to vascular risk factors, was significantly associated with decreased NDI in young adults, especially in regions known to harbor WMH in older age. Individually, seven of 25 known WMH risk loci were associated with NDI in young adults. In conclusion, we identified multiple novel genetic risk loci associated with NODDI markers, particularly NDI, in early adulthood. These point to possible early-life mechanisms underlying cSVD and to processes involving remyelination, neurodevelopment and neurodegeneration, with a potential for novel approaches to prevention., (© 2024. The Author(s).)

Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain., Objective: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases., Design, Setting, and Participants: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022., Exposures: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations., Main Outcomes and Measures: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses., Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke., Conclusions: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

Many studies suggest a relationship between excessive daytime sleepiness (EDS) and dementia incidence, but the underlying mechanisms remain uncertain. The study aimed to investigate the role of cardiovascular burden in the relationship between EDS and dementia incidence over a 12-year follow-up in community-dwelling older adults. We performed analyses on 6171 subjects (aged ≥65 years) free of dementia and vascular disease at baseline. Participants self-reported EDS at baseline and an expert committee validated both prevalent and incident dementia. We defined cardiovascular burden by a low Cardiovascular Health score, constructed using the American Heart Association metrics, and incident vascular events. To explore the potential role of the cardiovascular burden in the relationship between EDS and dementia, we conducted mediation analyses with inverse odds ratio-weighted estimation, using multivariable-adjusted proportional hazard Cox and logistic regression models. Subjects with EDS had a higher risk of all-cause dementia (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.13-1.69) and dementia with vascular component (DVC) (HR 2.14, 95% CI 1.30-3.51), but not Alzheimer's disease (HR 1.18, 95% CI 0.93-1.51). Cardiovascular burden explained 5% (95% CI 4.1-5.2) and 11% (95% CI 9.7-11.3) of the relationship between EDS and all-cause dementia and DVC, respectively. These findings confirm that EDS may be implicated in the development of dementia and indicate a weaker than expected role of cardiovascular burden in the relationship between EDS and DVC., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

This research explores different methodologies to modulate the effects of drowsiness on functional connectivity (FC) during resting-state functional magnetic resonance imaging (RS-fMRI). The study utilized a cohort of students (MRi-Share) and classified individuals into drowsy, alert, and mixed/undetermined states based on observed respiratory oscillations. We analyzed the FC group difference between drowsy and alert individuals after five different processing methods: the reference method, two based on physiological and a global signal regression of the BOLD time series signal, and two based on Gaussian standardizations of the FC distribution. According to the reference method, drowsy individuals exhibit higher cortico-cortical FC than alert individuals. First, we demonstrated that each method reduced the differences between drowsy and alert states. The second result is that the global signal regression was quantitively the most effective, minimizing significant FC differences to only 3.3% of the total FCs. However, one should consider the risks of overcorrection often associated with this methodology. Therefore, choosing a less aggressive form of regression, such as the physiological method or Gaussian-based approaches, might be a more cautious approach. Third and last, using the Gaussian-based methods, cortico-subcortical and intra-default mode network (DMN) FCs were significantly greater in alert than drowsy subjects. These findings bear resemblance to the anticipated patterns during the onset of sleep, where the cortex isolates itself to assist in transitioning into deeper slow wave sleep phases, simultaneously disconnecting the DMN., (© 2024. The Author(s).)

Introduction: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population-based studies using conventional T2-weighted brain magnetic resonance imaging (MRI) images., Methods: We included 8420 adults > 40 years old from three longitudinal population-based studies with brain MRI scans. We estimated and meta-analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke., Result: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13-2.68) and 1.48 (95% CI, 1.12-1.96) fold, respectively. For stroke, meta-analyses yielded HRs of 1.59 (95% CI, 1.04-2.42) for overall arteries and 2.11 (95% CI, 1.45-3.08) for basilar artery diameters > 95th percentile., Discussion: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2-weighted brain MRI-based brain diameter assessment in estimating the risk of dementia and stroke., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The closure of bars and lockdowns related to the Covid-19 pandemic changed alcohol use levels in France during the spring of 2020. We wondered whether this sudden cessation of social interactions impacted students more than non-students and what factors specific to students would explain the increase in alcohol misuse. The aims of this study were to compare self-reported changes in alcohol misuse (alcohol intake and binge-drinking frequency) during the first Covid-19 lockdown from March 17 to May 10, 2020, between French students and non-students and describe factors associated with this alcohol misuse in each subgroup., Methods: Data collected in the Confins study from April 8 to May 10, 2020, were used in cross-sectional analyses stratified by student status. Multiple logistic regression was performed to estimate the association between self-reported increase in alcohol intake or binge-drinking frequency (at least six drinks of alcohol on one occasion) and demographic, socioeconomic, and clinical factors, as well as conditions associated with the Covid-19 pandemic. The population-attributable fraction was then used to estimate the contribution of identified risk factors to increased alcohol misuse in students and non-students., Results: Among both students and non-students, a self-reported decrease or no change in alcohol intake or binge-drinking was more common than an increase. However, the risk factors explaining an increase in alcohol intake differed among students (≥ 25 years old, not working or studying in the health field, and having suicidal ideation during the last 7 days) and non-students (having a medical diagnosis of mental disorders). The risk factors explaining an increase in binge-drinking frequency were similar in the two subgroups (being a tobacco smoker before lockdown and not practicing any physical activity during the last 7 days), except suicidal thoughts, which was a risk factor for alcohol misuse specific to students., Conclusions: These results highlight the vulnerability of certain French students to alcohol misuse and the necessity of combining both mental health and substance use-related screening in the student population., (© 2024. The Author(s).)

Background: Little is known about e-cigarette use in French students. Our aims were to estimate the prevalence of e-cigarette experimentation and current e-cigarette use; describe the reasons for using e-cigarettes; explore the vaping experience and identify the profiles of e-cigarette users., Methods: We used a sequential, explanatory mixed methods design in a sample of French college students. Quantitative data was collected online for a cross-sectional analysis among 1698 students. Two separate analysis based on the thematic analysis and the Grounded Theory were also performed in 20 semi-structured interviews, focusing former and current smokers also current vapers., Results: The prevalence of e-cigarette experimentation was 39.3% (95% CI: 35.2-44.0) and 5.1% (95% CI: 3.2-8.0) of students were current e-cigarette users. Experimentation was opportunistic while current usage was rational, requiring to acquire a personal electronic device, getting used to its technicality, appreciating its availability, discretion, and learning the practice. In this context, three distinct groups of e-cigarette users were identified, based on assumed identity, tobacco and e-cigarette use, the functions assigned to e-cigarettes, and intentions with regards to vaping in the future., Conclusion: Despite some limitations mainly related to the participants self-selection, this research showed that while many smokers and former smokers have tried e-cigarettes in this student population, few have continued to use them continuously. Moreover, these current e-cigarette users were a heterogeneous group. Longitudinal studies are needed in young adult smokers for a better understanding of how their tobacco and e-cigarette use affect each other and change over time., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kinouani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: While studies have demonstrated the negative impact of adverse childhood experiences (ACEs) on lifelong health, less is known about the relationship between ACEs and illegal drug use. Thus, the objective of the study was to examine the relationship between ACEs and illegal drug use among college students., Methods: French college students between 18 and 30 years enrolled in a university cohort study were eligible for inclusion. Multivariate logistic regression models were conducted for each drug., Results: Among the sample (n = 1,157), 30.6% had no ACE exposure, 29.6%, 19.2%, and 20.7% had 1, 2 and ≥ 3 ACEs, respectively. Students with ACEs had a higher likelihood of using illegal drugs (p = 0.0067). After controlling for potential confounders, having ≥ 3 ACEs increased the risk of lifetime use of multiple drugs (aOR:10.9; 95% CI: 4.6-26.0), stimulants (aOR: 3.6; 95% CI:1.7-7.7), hallucinogens (aOR: 2.0; 95% CI: 1.1-3.5), cannabis (aOR: 4.7; 95% CI: 2.7-8.0), and risky illegal drugs (e.g., higher lifetime frequency drug use) (aOR: 2.9; 95% CI: 1.5-5.8). Estimates for illegal drug use were highest with parental substance use (aOR: 2.6; 95% CI; 1.5-4.4), sexual abuse (aOR: 2.3; 95% CI; 1.4-3.8), and divorce (aOR: 1.9; 95% CI: 1.3-2.7)., Conclusions: ACEs increase the risk for lifetime illegal drug use and risky drug use in a dose-respondent fashion. These findings suggest that university students with higher levels of ACEs may benefit from additional support and services from clinical practitioners and university administrators., (© 2024. International Society of Behavioral Medicine.)

White matter hyperintensities (WMHs) are well-established markers of cerebral small vessel disease, and are associated with an increased risk of stroke, dementia, and mortality. Although their prevalence increases with age, small and punctate WMHs have been reported with surprisingly high frequency even in young, neurologically asymptomatic adults. However, most automated methods to segment WMH published to date are not optimized for detecting small and sparse WMH. Here we present the SHIVA-WMH tool, a deep-learning (DL)-based automatic WMH segmentation tool that has been trained with manual segmentations of WMH in a wide range of WMH severity. We show that it is able to detect WMH with high efficiency in subjects with only small punctate WMH as well as in subjects with large WMHs (i.e., with confluency) in evaluation datasets from three distinct databases: magnetic resonance imaging-Share consisting of young university students, MICCAI 2017 WMH challenge dataset consisting of older patients from memory clinics, and UK Biobank with community-dwelling middle-aged and older adults. Across these three cohorts with a wide-ranging WMH load, our tool achieved voxel-level and individual lesion cluster-level Dice scores of 0.66 and 0.71, respectively, which were higher than for three reference tools tested: the lesion prediction algorithm implemented in the lesion segmentation toolbox (LPA: Schmidt), PGS tool, a DL-based algorithm and the current winner of the MICCAI 2017 WMH challenge (Park et al.), and HyperMapper tool (Mojiri Forooshani et al.), another DL-based method with high reported performance in subjects with mild WMH burden. Our tool is publicly and openly available to the research community to facilitate investigations of WMH across a wide range of severity in other cohorts, and to contribute to our understanding of the emergence and progression of WMH., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Instrumental variable methods, which handle unmeasured confounding by targeting the part of the exposure explained by an exogenous variable not subject to confounding, have gained much interest in observational studies. We consider the very frequent setting of estimating the unconfounded effect of an exposure measured at baseline on the subsequent trajectory of an outcome repeatedly measured over time. We didactically explain how to apply the instrumental variable method in such setting by adapting the two-stage classical methodology with (1) the prediction of the exposure according to the instrumental variable, (2) its inclusion into a mixed model to quantify the exposure association with the subsequent outcome trajectory, and (3) the computation of the estimated total variance. A simulation study illustrates the consequences of unmeasured confounding in classical analyses and the usefulness of the instrumental variable approach. The methodology is then applied to 6224 participants of the 3C cohort to estimate the association of type-2 diabetes with subsequent cognitive trajectory, using 42 genetic polymorphisms as instrumental variables. This contribution shows how to handle endogeneity when interested in repeated outcomes, along with a R implementation. However, it should still be used with caution as it relies on instrumental variable assumptions hardly testable in practice., (© 2023 The Authors. Biometrical Journal published by Wiley-VCH GmbH.)

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets., (© 2023. The Author(s).)

In a cross sectional study of 13,837 university students, we aimed to explore the association between attention deficit hyperactivity disorder (ADHD) symptoms and lifetime psychoactive substance use (LPSU) on a wide range of illicit substances. Logistic and Hurdel multivariable regressions were used. ADHD symptoms were significantly associated with the lifetime use of ketamine, magic mushrooms, poppers, and nine other psychoactive substances. There was an association between ADHD symptoms and both LPSU and truncated count of lifetime psychoactive substance use. High levels of ADHD symptoms are associated with the use of a large variety and multiple LPSU., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Given the anatomical and functional similarities between the retina and the brain, the retina could be a "window" for viewing brain structures. We investigated the association between retinal nerve fiber layers (peripapillary retinal nerve fiber layer, ppRNFL; macular ganglion cell-inner plexiform layer, GC-IPL; and macular ganglion cell complex, GCC), and brain magnetic resonance imaging (MRI) parameters in young health adults. We included 857 students (mean age: 23.3 years, 71.3% women) from the i-Share study. We used multivariate linear models to study the cross-sectional association of each retinal nerve layer thickness assessed by spectral-domain optical coherence tomography (SD-OCT) with structural (volumes and cortical thickness), and microstructural brain markers, assessed on MRI globally and regionally. Microstructural MRI parameters included diffusion tensor imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI). On global brain analysis, thicker ppRNFL, GC-IPL and GCC were all significantly associated with patterns of diffusion metrics consistent with higher WM microstructural integrity. In regional analyses, after multiple testing corrections, our results suggested significant associations of some retinal nerve layers with brain regional gray matter occipital volumes and with diffusion MRI parameters in a region involved in the visual pathway and in regions containing associative tracts. No associations were found with global volumes or with global or regional cortical thicknesses. Results of this study suggest that some retinal nerve layers may reflect brain structures. Further studies are needed to confirm these results in young subjects., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Mental health literacy (MHL) is a determinant of psychological well-being in young people. A randomized controlled design was used to evaluate the appreciation and effectiveness of an interactive video on French University students' MHL (knowledge about depression and suicidal behavior, mental health help-seeking behaviors, stigma and misconceptions about mental health). At the baseline, all participants (n = 101) completed a questionnaire including several scales on MHL. One month after, participants were randomly assigned to two homogeneous groups (intervention, n = 50 or control, n = 51) and again completed the questionnaire on MHL. Through a mixed-methods approach, semi-structured interviews were also conducted with the intervention group to collect information on the appreciation of the interactive video. Quantitative data indicated that MHL scores increased or remained stable in the intervention group. Comparison with the control group and multivariate logistic regression models did not show statistically significant differences, due to the small sample of the study. According to qualitative data, users appreciated the content and the format of the intervention. It was suggested that the video could be disseminated in other University campuses in France and internationally to promote MHL among students., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

To examine the relationship between adverse childhood experiences (ACEs) and Attention-deficit Hyperactivity Disorder (ADHD) among college students. We investigated the association between ACEs and ADHD symptoms among French college students enrolled in the i-Share cohort using multivariate logistic regression models. The sample comprised of 1062 participants with a mean age of 20.3 (SD = 2.3) of which 30.6% had no ACEs exposure, 29.6% had 1 ACE, 19.2% had 2 ACEs, and 20.6% had ≥ 3 ACEs. After controlling for potential confounders, every increase in ACE exposure heightened the risk of ADHD symptoms with the respective adjusted Odds Ratios and 95% confidence intervals: 1 ACE: 2.1 (0.7-6.3) / 2 ACEs: 4.5 (2.6-12.8)/ ≥ 3 ACEs: 5.2 (1.8-14.8). Estimates for ADHD symptoms were higher with sexual abuse, emotional and physical neglect, and bullying. Findings suggest that ACEs heighten the risk for developing ADHD symptoms among college students and bear important implications for prevention and clinical practice., Competing Interests: Conflict of Interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023.)

The epidemiological and societal burden of dementia is expected to increase in the coming decades due to the world population aging. In this context, the evaluation of the potential impact of intervention scenarios aiming at reducing the prevalence of dementia risk factors is an active area of research. However, such studies must account for the associated changes in mortality and the dependence between the risk factors. Using micro-simulations, this study aims to estimate the changes in dementia burden in France in 2040 according to intervention scenarios targeting the prevention or treatment of hypertension, diabetes and physical inactivity. Accounting for their communality and their effects on mortality, the results show that the disappearance of hypertension, diabetes and physical inactivity in France in 2020 could decrease dementia prevalence by 33% among men and 26% among women in 2040 and increase the life expectancy without dementia at age 65 by 3.4 years (men) and 2.6 years (women). Among the three factors, the prevention of hypertension would be the most efficient. These projections rely on current estimates of the risk of dementia and death associated with risk factors. Thanks to the R package developed they could be refined for different countries or different interventions and updated with new estimates., (© 2023. Springer Nature B.V.)

Sleep complaints and cannabis use are common among University students and are related to detrimental effects on health. The aim of this study was to explore their association. This cross-sectional study based on the i-Share e-cohort included French students between 18 and 30 years old (n = 14,787). Frequency of cannabis use was categorized into daily, weekly, monthly, and never/rarely use. Sleep complaints were defined using four items (i.e., insomnia, sleepiness, poor sleep quality, and sleep deprivation). In the whole sample (mean age: 20.4 years, 75.5% of females), 22.7% had insomnia, 18.3% had sleepiness, 22.4% had poor sleep quality, 52.5% had sleep deprivation, and 5.8% used cannabis weekly or daily. After adjustment, the likelihood of insomnia was significantly higher by 45% in cannabis users compared to non-users. The estimates steadily increased with frequency of use, reaching a 2.0-fold higher likelihood of insomnia in daily users compared to never/rarely users. Results were similar for the other sleep complaints. These findings provide support for an association between cannabis use and sleep complaints, particularly insomnia, among University students. Though direction and causality cannot be established in this setting, these results suggest warning students and health professionals about the association between cannabis use and sleep complaints., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets., (© 2023. The Author(s).)

Background: The long-term effects of traumatic brain injury (TBI) with loss of consciousness (LOC) on magnetic resonance imaging (MRI) markers of brain health and on dementia risk are still debated., Objective: To investigate the associations of history of TBI with LOC with incident dementia and neuroimaging markers of brain structure and small vessel disease lesions., Methods: The analytical sample consisted in 4,144 participants aged 65 and older who were dementia-free at baseline from the Three City -Dijon study. History of TBI with LOC was self-reported at baseline. Clinical Dementia was assessed every two to three years, up to 12 years of follow-up. A subsample of 1,675 participants <80 years old underwent a brain MRI at baseline. We investigated the associations between history of TBI with LOC and 1) incident all cause and Alzheimer's disease (AD) dementia using illness-death models, and 2) neuroimaging markers at baseline., Results: At baseline, 8.3% of the participants reported a history of TBI with LOC. In fully-adjusted models, participants with a history of TBI with LOC had no statistically significant differences in dementia risk (HR = 0.90, 95% CI = 0.60-1.36) or AD risk (HR = 1.03, 95% CI = 0.69-1.52), compared to participants without TBI history. History of TBI with LOC was associated with lower white matter volume (β= -4.58, p = 0.048), but not with other brain volumes, white matter hyperintensities volume, nor covert brain infarct., Conclusion: This study did not find evidence of an association between history of TBI with LOC and dementia or AD dementia risks over 12-year follow-up, brain atrophy, or markers of small vessel disease.

Aims: Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia., Methods and Results: Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4 mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk., Conclusion: The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia., Classification of Evidence: Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo., Competing Interests: Conflict of interest: The authors report no targeted funding. R.P. is funded by the Australian National Health and Medical Research Centre Australian Dementia Centre for Research Collaboration, and Neuroscience Research Australia; Y.X. is funded by NHMRC Project Grant (APP1160373); M.W. and C.S.A. are supported by Investigator Grants (APP1174120 and GNT1175861 respectively) from the National Health and Medical Research Council (NHMRC) of Australia, and together with J.C. receive funding from an NHMRC Program Grant (APP1149987); M.W. is a consultant to Amgen, Kyowa Kirin, and Freeline; J.C. has received research grants from Servier, and from the NHMRC for both PROGRESS and ADVANCE, and honoraria from Servier for speaking about them at Scientific meetings; C.S.A. has received research grants from Penumbra, Takeda, Credit, and Genesis paid to his institution., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The use of the internet to look for information about vaccines has skyrocketed in the last years, especially with the COVID-19 pandemic. Digital vaccine literacy (DVL) refers to understanding, trust, appraisal, and application of vaccine-related information online., Objective: This study aims to develop a tool measuring DVL and assess its psychometric properties., Methods: A 7-item online questionnaire was administered to 848 French adults. Different psychometric analyses were performed, including descriptive statistics, exploratory factor analysis, confirmatory factor analysis, and convergent and discriminant validity., Results: We developed the 7-item DVL scale composed of 3 factors (understanding and trust official information; understanding and trust information in social media; and appraisal of vaccine information online in terms of evaluation of the information and its application for decision making). The mean DVL score of the baseline sample of 848 participants was 19.5 (SD 2.8) with a range of 7-28. The median score was 20. Scores were significantly different by gender (P=.24), age (P=.03), studying or working in the field of health (P=.01), and receiving regular seasonal flu shots (P=.01)., Conclusions: The DVL tool showed good psychometric proprieties, resulting in a promising measure of DVL., (©Ilaria Montagni, Aude Pouymayou, Edwige Pereira, Christophe Tzourio, Stéphane Schück, Nathalie Texier, Juan Luis González-Caballero, The CONFINS Group. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 14.12.2022.)

Purpose: The aim of this study was to (1) investigate the association of parental death and illness with suicidal ideation using a large sample of university students and (2) test whether associations were moderated by perceived family support., Methods: We used data from N = 15,008 French university students enrolled in the i-Share cohort (mean age, 20.5 years; 77% women). Students self-reported information on parental death, including the cause, parental illness (cardiovascular, stroke, cancer, depression/anxiety, alcohol abuse), and perceived family support during childhood/adolescence. Twelve-month suicidal ideation was self-reported and categorized into no, occasional, and frequent ideation., Results: Occasional and frequent suicidal ideation were, respectively, reported by 2692 (17.5%) and 699 (4.6%) students. After adjustment for age, gender, and parental education, we found associations between parental death and risk of occasional and frequent suicidal ideation (respectively, RR = 1.98 [1.81-2.17] and RR = 2.73 [2.30-3.24]). Parental deaths from illness, accidents, and suicides had the strongest associations. We also found associations for parental depression/anxiety (occasional, RR = 1.98 [1.81-2.17]; frequent, RR = 2.73 [2.30-3.24]), alcohol use problems (occasional, RR = 1.71 [1.5-1.94]; frequent, RR = 2.33 [1.89-2.87]), and cardiovascular diseases (occasional, RR = 1.22 [1.06-1.40]; frequent, RR = 1.83 [1.47-2.27]). For participants who experienced parental death and stroke, associations with occasional and frequent suicidal ideation (respectively) increased as perceived family support increased (Ps interaction  ≤ 0.005)., Conclusions: Students who experienced parental death and common parental illnesses were at risk of reporting suicidal ideation, especially if their family were perceived as an important source of support. As information on parental death or illness can be routinely collected during health visits, attention should be paid to students reporting such experiences., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Restrictive measures during the COVID-19 epidemic have led to increased levels of loneliness, especially among university students, although the influence on suicidal thoughts remains unclear. In this cross-sectional study of 1913 French university students, those with the highest level of loneliness had a fourfold increased risk of suicidal thoughts. Perceived loneliness should be incorporated into suicide risk assessment, and assistance in coping with loneliness should be considered as a means of reducing suicidal risk in vulnerable groups, like university students., (© 2022. The Author(s).)

Little is known about psychoactive substance use in students, apart from tobacco, alcohol, and cannabis. This study investigated the prevalence of substance use and overlap between various psychoactive substances in students. This cross-sectional study was conducted in 10 066 students included in the i-Share cohort between January 1, 2015, and December 31, 2017. The baseline questionnaire was the key source of information. Psychoactive substances of interest (PSI) were cannabis, cocaine, amphetamines, nitrous oxide, poppers, and MDMA. Their patterns of use were categorized as lifetime, past year, and current use. The use of other psychoactive substances including alcohol and tobacco was described in PSI users and non-users. Most participants were female (75%), and their average age was 21 years. Lifetime use of at least one PSI was reported by 65.5% of participants. Cannabis was the most frequently used substance both over lifetime (57% of students) and past year (35%), followed by poppers and nitrous oxide (28% and 26% of students over lifetime, respectively). Among polydrug users (n = 1242), 65% used only nitrous oxide and poppers, showing a strong link between these two substances. Regular alcohol use, binge drinking, and current tobacco use were higher in PSI users than in non-users. Substance use was higher than previously found in both French and European studies in young people. Nitrous oxide use was particularly high. Regular alcohol use, binge drinking, and tobacco use could be used as markers to identify students at risk of PSI use to be targeted by prevention programs., (© 2022 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Covid-19 vaccine hesitancy among young adults is a current public health issue that needs to be addressed considering the seasonally driven waves of disease and the administration of vaccine boosters. As a prevention measure, the EU Covid certificate had been implemented to increase vaccine uptake, but its application was controversial. Our study investigated students' opinions and attitudes towards Covid-19 vaccination and the EU Covid certificate through a mixed-methods design. An 18-item questionnaire was administered to 200 students during a vaccination campaign in September 2021 at the University of Bordeaux, France. Simultaneously, 30 students attended a semi-structured interview. Collected data were analyzed separately then discussed together through a parallel and convergent approach. Results showed that vaccine hesitancy was high among students, mostly from fear of short-term side effects. However, respondents decided to get vaccinated to obtain the EU Covid certificate, even if they considered it as a violation of their freedom. Straightforward communication about Covid-19 vaccination did not reach students, although this was a strong expectation from governmental and health institutions. Findings suggest that key health personnel should provide evidence-based information about vaccines in efforts of building trust with young people., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The aim of the study is to describe the use of antihypertensive and lipid-lowering drugs in post-stroke secondary prevention in France. This is a prospective cohort study based on a representative sample of the French health insurance system database. All patients aged 45 and over, hospitalized for a first stroke between 1 January 2009 and 31 December 2014 were included. For each drug class, identified using Anatomical Therapeutic Chemical (ATC) codes, patients were followed from the first drug supply after stroke until the end of study period (31 December 2017), or exit date of the database or death. Adherence was defined by the proportion of days covered and persistence by the absence of a treatment gap of more than 91 days. A total of 2674 patients were included, median age was 75.0 years (interquartile range 63.0-83.0) and 51.2% were women. For patients treated with a drug of interest after stroke, median follow-up was 4.8 years (interquartile range 3.4-6.5). Regarding antihypertensive drugs, adherence at 8 years was 84.1% and persistence was 71.0%. For lipid-lowering drugs adherence at 8 years was 68.6% and persistence was 49.4%. Adherence and persistence were lower for patients starting treatment at time of stroke (antihypertensive drugs: 70.9% for adherence and 52.6% for persistence; lipid-lowering drugs: 62.3% and 43.1%) compared to patients already treated (antihypertensive drugs: 87.2% and 75.2%; lipid-lowering drugs: 73.6% and 54.5%). In this large representative sample of patients hospitalized for a first stroke in France, post-stroke therapeutic management remains suboptimal compared to guidelines, notably regarding lipid-lowering drugs. This trend was more pronounced for newly treated patients., (© 2022 Société Française de Pharmacologie et de Thérapeutique.)

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Subcortical brain structures play a key role in pathological processes of age-related neurodegenerative disorders. Mounting evidence also suggests that early-life factors may have an impact on the development of common late-life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration., Methods: Using large population-based brain imaging datasets across the lifespan (N ≤ 40,628), we aimed to 1) estimate the heritability of subcortical volumes in young (18-35 years), middle (35-65 years), and older (65+ years) age, and their genetic correlation across age groups; 2) identify whether genetic loci associated with subcortical volumes in older persons also show associations in early adulthood, and explore underlying genes using transcriptome-wide association studies; and 3) explore their association with neurological phenotypes., Results: Heritability of subcortical volumes consistently decreased with increasing age. Genetic risk scores for smaller caudate nucleus, putamen, and hippocampus volume in older adults were associated with smaller volumes in young adults. Individually, 10 loci associated with subcortical volumes in older adults also showed associations in young adults. Within these loci, transcriptome-wide association studies showed that expression of several genes in brain tissues (especially MYLK2 and TUFM) was associated with subcortical volumes in both age groups. One risk variant for smaller caudate nucleus volume (TUFM locus) was associated with lower cognitive performance. Genetically predicted Alzheimer's disease was associated with smaller subcortical volumes in middle and older age., Conclusions: Our findings provide novel insights into the genetic determinants of subcortical volumes across the lifespan. More studies are needed to decipher the underlying biology and clinical impact., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: To report the characteristics of vaccine-hesitant individuals in a French-speaking adult population in the context of the SARS-CoV-2 pandemic; and to identify predictors of hesitancy about Covid-19-related vaccines., Methods: Between April and May 2020, 1640 French-speaking adults participating in an online cohort were classified according to their attitudes towards vaccination as: "hesitant", "anti-vaccination", and "pro-vaccination". Descriptive statistics, univariate multinomial regression models and multivariate analyses were compiled and carried out., Results: At the time of inclusion, compared to pro-vaccination participants, hesitant participants were more frequently females (p=0.044), not annually vaccinated against flu (p=0.026), less optimistic about the discovery of a treatment against Covid-19 in a few months (p<0.001), less ready to undergo this treatment (p<0.001), presenting less trust in the ability of public health authorities to control the pandemic (p=0.036) and reporting lower scores on knowledge-related scales (p values from <0.001 to 0.002). Univariate analyses confirmed these results with odds ratios ranging from 1.51 [1.05-2.17] to 2.19 [1.56-3.07]. In the multivariate models, the remaining variables associated with hesitant compared to pro-vaccination attitudes were discovery of a treatment against Covid-19 in a few months (OR=2.57 [1.73-3.81]), being ready to undergo this treatment (OR=7.07 [4.89-10.22]), digital vaccine literacy (OR=1.70 [1.14-2.54]) and general health literacy (OR=1.49 [1.03-2.15])., Discussion: In a continuum of relative acceptance of Covid-19-related vaccines, hesitant individuals were situated in between the behaviours and characteristics of pro-vaccination and anti-vaccination groups. While their characteristics were in line with the literature, this study was the first to report data on health literacy, digital vaccine literacy and capacity to detect fake news associated with vaccine hesitancy., Conclusions: While failing to identify straightforward predictors, findings suggest that continued education and communication campaigns focused on improving vaccine literacy, particularly among women younger than 35 years, could heighten the proportion of persons accepting vaccination., Competing Interests: Declaration of interest statement We wish to confirm that there are no known conflicts of interest associated with this publication and that there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background and Objectives: Fish intake may prevent cerebrovascular disease (CVD), yet the mechanisms are unclear, especially regarding its impact on subclinical damage. Assuming that fish may have pleiotropic effect on cerebrovascular health, we investigated the association of fish intake with global CVD burden based on brain MRI markers., Methods: This cross-sectional analysis included participants from the Three-City Dijon population-based cohort (age ≥65 years) without dementia, stroke, or history of hospitalized cardiovascular disease who underwent brain MRI with automated assessment of white matter hyperintensities, visual detection of covert infarcts, and grading of dilated perivascular spaces. Fish intake was assessed through a frequency questionnaire, and the primary outcome measure was defined as the first component of a factor analysis of mixed data applied to MRI markers. The association of fish intake with the CVD burden indicator was studied with linear regressions., Results: In total, 1,623 participants (mean age 72.3 years, 63% women) were included. The first component of factor analysis (32.4% of explained variance) was associated with higher levels of all 3 MRI markers. Higher fish intake was associated with lower CVD burden. In a model adjusted for total intracranial volume, compared to participants consuming fish <1 time per week, those consuming fish 2 to 3 and ≥4 times per week had a β = -0.19 (95% confidence interval -0.37 to -0.01) and β = -0.30 (-0.57 to -0.03) lower indicator of CVD burden, respectively ( p trend < 0.001). We found evidence of effect modification by age such that the association of fish to CVD was stronger in younger participants (65-69 years) and not significant in participants ≥75 years of age. For comparison, in the younger age group, consuming fish 2 to 3 times a week was roughly equivalent (in the opposite direction) to the effect of hypertension., Discussion: In this large population-based study, higher frequency of fish intake was associated with lower CVD burden, especially among participants <75 years of age, suggesting a beneficial effect on brain vascular health before manifestation of overt brain disease., Classification of Evidence: This study provides Class II evidence that in individuals without stroke or dementia, higher fish intake is associated with lower subclinical CVD on MRI., (© 2021 American Academy of Neurology.)

Background: Stroke and transient ischemic attack confer greater risk of cognitive decline and dementia., Aims: We used data from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a blood pressure-lowering randomized controlled trial in stroke/transient ischemic attack. We evaluated overall and sex-specific differences in treatment effects for cognitive decline/dementia, as well as associations with vascular and stroke-specific predictors,considering death as a competing risk., Methods: Multinomial logistic regression was used to estimate overall and sex-specific odds ratios (OR) (95% confidence intervals (CI)) for treatment effects and predictors associated with the risk of cognitive decline/dementia, and the women-to-men ratio of odds ratio (RORs)., Results: Over a median four years, 763 cognitive decline/dementia (30.9% women) were recorded in 5888 participants. Women had lower odds of cognitive decline/dementia than men (OR 0.78, 95%CI 0.63-0.95). Active treatment was associated with lower odds of cognitive decline/dementia (0.84, 0.72-0.98), with no evidence of sex difference. Higher education (0.96,0.94-0.98 (per year)) and baseline Mini-Mental State Examination (MMSE)) were associated with lower odds of cognitive decline/dementia (0.84,0.82-0.86 (per point higher)). Higher diastolic blood pressure (1.11,1.02-1.20 (per 10 mmHg)), low estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m 2 (1.27,1.03-1.58), and peripheral arterial disease (1.78,1.26-2.52) were associated with higher odds of cognitive decline/dementia. APOE ɛ4 was not associated with cognitive decline/dementia (1.05 (0.85-1.30)). Low eGFR was more strongly associated with cognitive decline/dementia in women than men (RORs, 1.60 (1.03-2.48)). Diabetes was more strongly associated with men than women., Conclusions: Several risk factors were associated with cognitive decline/dementia in people with prior stroke/transient ischemic attack, with notable sex differences. Long-term cognitive sequelae of stroke should be considered to strengthen joint prevention strategies for stroke, cognitive decline, and dementia. Trial Registration: This trial was not registered because enrolment began before 1 July 2005.

Previous studies have shown the negative impact of the COVID-19 epidemic on students' mental health. It is, however, uncertain whether students are really at higher risk of mental health disturbances than non-students and if they are differentially impacted by lockdown periods over time. The objective of our study was to compare the frequency of depressive symptoms, anxiety, and suicidal thoughts in students and non-students enrolled in the same study in France and during the same key periods of the COVID-19 epidemic. Using a repeated cross-sectional design, we collected data from a sample of 3783 participants in the CONFINS study during three recruitment waves between March 2020 and January 2021. Multivariate logistic regression models, adjusted for potential confounding factors, showed that students were more likely to have high scores of depressive symptoms and anxiety more frequently than non-students. These differences were particularly strong during the first (depressive symptoms: adjusted odds ratio aOR 1.59, 95% CI 1.22-2.08; anxiety: aOR 1.63, 95% CI 1.22-2.18) and second lockdowns (depressive symptoms: aOR 1.80, 95% CI 1.04-3.12; anxiety: aOR 2.25, 95% CI 1.24-4.10). These findings suggest that the restrictive measures-lockdown and curfew-have an alarmingly stronger negative impact on students than on non-students and underline the frailty of students' mental health and the need to pay greater attention to this population in this epidemic-related context., (© 2021. The Author(s).)

[Figure: see text].

The relationship between hippocampal subfield volumetry and verbal list-learning test outcomes have mostly been studied in clinical and elderly populations, and remain controversial. For the first time, we characterized a relationship between verbal list-learning test outcomes and hippocampal subfield volumetry on two large separate datasets of 447 and 1,442 healthy young and middle-aged adults, and explored the processes that could explain this relationship. We observed a replicable positive linear correlation between verbal list-learning test free recall scores and CA1 volume, specific to verbal list learning as demonstrated by the hippocampal subfield volumetry independence from verbal intelligence. Learning meaningless items was also positively correlated with CA1 volume, pointing to the role of the test design rather than word meaning. Accordingly, we found that association-based mnemonics mediated the relationship between verbal list-learning test outcomes and CA1 volume. This mediation suggests that integrating items into associative representations during verbal list-learning tests explains CA1 volume variations: this new explanation is consistent with the associative functions of the human CA1., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

[Figure: see text].

Functional connectivity analyses of fMRI data have shown that the activity of the brain at rest is spatially organized into resting-state networks (RSNs). RSNs appear as groups of anatomically distant but functionally tightly connected brain regions. Inter-RSN intrinsic connectivity analyses may provide an optimal spatial level of integration to analyze the variability of the functional connectome. Here we propose a deep learning approach to enable the automated classification of individual independent-component (IC) decompositions into a set of predefined RSNs. Two databases were used in this work, BIL&GIN and MRi-Share, with 427 and 1811 participants, respectively. We trained a multilayer perceptron (MLP) to classify each IC as one of 45 RSNs, using the IC classification of 282 participants in BIL&GIN for training and a 5-dimensional parameter grid search for hyperparameter optimization. It reached an accuracy of 92 %. Predictions for the remaining individuals in BIL&GIN were tested against the original classification and demonstrated good spatial overlap between the cortical RSNs. As a first application, we created an RSN atlas based on MRi-Share. This atlas defined a brain parcellation in 29 RSNs covering 96 % of the gray matter. Second, we proposed an individual-based analysis of the subdivision of the default-mode network into 4 networks. Minimal overlap between RSNs was found except in the angular gyrus and potentially in the precuneus. We thus provide the community with an individual IC classifier that can be used to analyze one dataset or to statistically compare different datasets for RSN spatial definitions., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

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).)

Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures., Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk., Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition., Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)