Diffusion imaging genomics provides novel insight into early mechanisms of cerebral small vessel disease.

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.

Early detection of white matter hyperintensities using SHIVA-WMH detector.

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.

Factors related to increased alcohol misuse by students compared to non-students during the first Covid-19 lockdown in France: the Confins study.

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.

Adverse Childhood Experiences and Illegal Drug Use Among College Students: Findings from a French Sample.

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.

Addressing unmeasured confounders in cohort studies: Instrumental variable method for a time-fixed exposure on an outcome trajectory.

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.

Association of LIfestyle for BRAin health risk score (LIBRA) and genetic susceptibility with incident dementia and cognitive decline.

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.

Brain artery diameters and risk of dementia and stroke.

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.

Association of retinal nerve layers thickness and brain imaging in healthy young subjects from the i-Share-Bordeaux study.

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.

The role of cardiovascular health and vascular events in the relationship between excessive daytime sleepiness and dementia risk.

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.

Impact of interventions scenarios targeting three main vascular risk factors on the future burden of dementia in France.

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.

An interactive video increasing French students' mental health literacy: a mixed-methods randomized controlled pilot study.

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.

Blood pressure lowering and prevention of dementia: an individual patient data meta-analysis.

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.

Association of parental death and illness with offspring suicidal ideation: cross-sectional study in a large cohort of university students.

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 (Psinteraction ≤ 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.

Persistence of Vaccine Hesitancy and Acceptance of the EU Covid Certificate Among French Students.

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.

Measuring Digital Vaccine Literacy: Development and Psychometric Assessment of the Digital Vaccine Literacy Scale.

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.

Who is hesitant about Covid-19 vaccines? The profiling of participants in a French online cohort.

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.

Novel characterization of the relationship between verbal list-learning outcomes and hippocampal subfields in healthy adults.

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.

Evaluation of High Cholesterol and Risk of Dementia and Cognitive Decline in Older Adults Using Individual Patient Meta-Analysis.

INTRODUCTION: Although increased cholesterol level has been acknowledged as a risk factor for dementia, evidence synthesis based on published data has yielded mixed results. This is especially relevant in older adults where individual studies report non-linear relationships between cholesterol and cognition and, in some cases, find higher cholesterol associated with a lower risk of subsequent cognitive decline or dementia. Prior evidence synthesis based on published results has not allowed us to focus on older adults or to standardize analyses across studies. Given our ageing population, an increased risk of dementia in older adults, and the need for proportionate treatment in this age group, an individual participant data (IPD) meta-analysis is timely. METHOD: We combined data from 8 studies and over 21,000 participants aged 60 years and over in a 2-stage IPD to examine the relationship between total, high-density, and low-density lipoprotein (HDL and LDL) cholesterol and subsequent incident dementia or cognitive decline, with the latter categorized using a reliable change index method. RESULTS: Meta-analyses found no relationship between total, HDL, or LDL cholesterol (per millimoles per litre increase) and risk of cognitive decline in this older adult group averaging 76 years of age. For total cholesterol and cognitive decline: odds ratio (OR) 0.93 (95% confidence interval [CI] 0.86: 1.01) and for incident dementia: OR 1.01 [95% CI 0.89: 1.13]. This was not altered by rerunning the analyses separately for statin users and non-users or by the presence of an APOE e4 allele. CONCLUSION: There were no clear consistent relationships between cholesterol and cognitive decline or dementia in this older adult group, nor was there evidence of effect modification by statin use. Further work is needed in younger populations to understand the role of cholesterol across the life-course and to identify any relevant intervention points. This is especially important if modification of cholesterol is to be further evaluated for its potential influence on risk of cognitive decline or dementia.

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

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

Contributions of childhood peer victimization and/or maltreatment to young adult anxiety, depression, and suicidality: a cross-sectional study.

BACKGROUND: Childhood maltreatment and peer victimization are major risk factors for depression and suicidal behavior. Furthermore, childhood maltreatment increases the risk of peer victimization. Our objective was to distinguish between the contributions of parental maltreatment and peer victimization to the development of mental health problems in young adulthood. Specifically, we tested whether peer victimization alone or in combination with parental maltreatment before 18 years old was associated with anxiety, depression, and suicidal thoughts and behaviors at age 21 years. METHODS: We analyzed data collected from questionnaires administered in the i-Share (Internet-based Students' Health ResearchEnterprise) study in France from February 2013 to September 2019 (N = 2271 participants). We performed multinomial and binary logistic regression analyses to assess the single and combined contributions of childhood peer victimization and parental maltreatment to anxiety, depression, and suicidality in adulthood. RESULTS: Nearly one third of students (28.8%) reported at least one mental health problem; 29.8% reported peer victimization alone; 7.5% reported parental maltreatment alone; and 10.3% reported both parental maltreatment and victimization. In multivariate models, compared to participants that did not experience maltreatment or peer victimization, those that experienced peer victimization alone were more likely to report anxiety (adjusted odds ratio [aOR]: 1.90; 95% CI: 1.50-2.40), depression (aOR: 1.95; 95% CI: 1.46-2.60), or suicidal ideation, without (aOR: 1.62; 95% CI: 1.26-2.09) or with a suicide attempt (aOR: 2.70; 95% CI: 1.51-4.85). Similar associations were observed for participants that experienced maltreatment alone. Participants that experienced both maltreatment and peer victimization were at increased risk of depression (aOR: 2.63; 95% CI: 1.79-3.86) and suicidal ideation, with (aOR: 9.19; 95% CI: 4.98-16.92) and without a suicide attempt (aOR: 2.64; 95% CI: 1.86-3.76). CONCLUSIONS: Separate and combined exposures to parental maltreatment and peer victimization in childhood or adolescence were associated with increased risks of anxiety, depression, and suicidal behaviors. Peer victimization appeared to play a specific role in mental health disorders that were not otherwise explained by polyvictimization. Currently, peer victimization is a frequent, but avoidable type of child abuse; therefore, these findings have implications for policies for preventing and dealing with peer victimization.