Aline Thomas

Background: Typically, e-cohorts are susceptible to low participation rates, undermining representativeness. Frequent reminders can be a cost-effective strategy to increase response rates. However, their effectiveness may vary depending on the delivery mode and message content. Objective: This study aimed to evaluate different reminder strategies (ie, emails and/or text messages with standard and/or institutional wording) and compare their effectiveness in increasing the response rate in a population-based e-cohort of healthy adults. Methods: We conducted a 4-arm parallel randomized controlled trial nested within the Le French Gut e-cohort (registration number 2021-A01439-32). In November 2024, we included participants who were enrolled online (SKEZIA platform) but were not yet active participants (ie, eligibility, consent form, and/or personal information questionnaire had not been completed). Computer-generated randomization was stratified by time since enrollment. We sent 3 reminders, 72 hours apart, following 4 experimental designs: group 1, standard emails only; group 2, text messages only; group 3, institutional emails only; and group 4, standard email, followed by a text message and an institutional email. The primary outcome was the 30-day completion rate of the personal information questionnaire. We also measured completion time (ie, time between reminder received and questionnaire fully completed), online login rate, login time, email opening, and click-through rate. Participants were unaware of the trial, and investigators were blinded to group allocation. Results: At the end of the trial, of the 20,487 eligible participants, 19,525 received at least 1 reminder (n=5225 in group 1; n=3858 in group 2, because n=1365 of the initial 5223 had no phone number and could not receive text messages; n=5222 in group 3; n=5220 in group 4). The per-protocol completion rate was 8.4%, with a higher rate in group 4 (9.4% vs 7.4%, 8.4%, and 8.3% for groups 1, 2, and 3, respectively; P <.001). Completion time was faster in group 2 (mean 6.3, SD 4.3 d) compared to groups 3 and 4 (mean 7.0, SD 3.5 and mean 7.2, SD 3.8 d, respectively; P =.003). The online login rate was higher, and the login time was faster in group 4 (login rate: 15.6% vs 12.1%, 14.3%, and 15.3% for groups 1, 2, and 3, respectively; P <.001; and login time: mean 7.1, SD 4.3 d vs mean 6.7, SD 4.3 d, mean 6.2, SD 4.6 d, mean 6.8, SD 3.9 d for groups 1, 2, and 3, respectively; P =.002). For emails, opening rates were similar ( P =.87), but the click-through rate was higher for institutional emails (23.1% vs 19.6% for standard formatting; P <.001). Conclusions: For the first time in a specifically designed randomized controlled trial, we directly compare email-only, text message–only, and a combined reminder strategy in a large e-cohort. While previous studies focused on specific populations, our work examines a general adult population, demonstrating that a mixed delivery mode strategy effectively increases response rate by 27% compared to a single-channel approach. Text messages yielded faster responses, and institutional emails, with formal wording and coordinator’s signature, seemed more appealing than less formal wording. These results provide concrete guidance for researchers seeking to improve recruitment in real-world e-cohorts.

La nutrition est un facteur environnemental modifiable prometteur pour la prévention du vieillissement cérébral. Une association bénéfique entre une alimentation plus saine ou des apports plus importants en certains nutriments et un moindre risque de démence ou de déclin cognitif a été suggérée dans les études épidémiologiques. Cependant, la stratégie nutritionnelle à privilégier pour la prévention reste encore mal caractérisée. Mieux décrire les mécanismes neurobiologiques chez l’Homme permettrait d’identifier les stratégies préventives les plus efficaces. L'objectif de cette thèse est d'analyser les associations épidémiologiques entre la nutrition et des marqueurs en neuro-imagerie de deux composantes physiopathologiques clés du vieillissement cérébral : la structure cérébrale et la neurodégénérescence associée d’une part, le fardeau cérébral vasculaire d’autre part. La nutrition est étudiée à travers plusieurs expositions complémentaires, du statut biologique en nutriments candidats jusqu’aux profils de consommation alimentaire. Les données proviennent de l’étude des 3-Cités, une cohorte de personnes âgées issues de la population générale. Dans une première partie, nous nous sommes intéressés à la relation entre nutrition et évolution des volumes cérébraux à l’Imagerie par Résonance Magnétique (IRM) au cours de 10 ans suivi dans la cohorte. Nous avons mis en évidence des associations entre des concentrations plasmatiques plus élevées en acides gras polyinsaturés oméga-3 (AGPI n-3) et en caroténoïdes avec une moindre atrophie du lobe temporal médian, une structure clé pour la mémoire et impliquée dans développement de la maladie d’Alzheimer. Dans une deuxième partie, une approche plus globale de l’alimentation a été adoptée avec l’évaluation de l’adhérence au Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. Ce régime alimentaire spécifiquement développé pour la santé cérébrale a été associé à un moindre risque de démence sur 16 ans de suivi et à une meilleure intégrité de la substance blanche, dégradée dans le vieillissement cérébral et dans la maladie d’Alzheimer. Dans une dernière partie, nous avons abordé la composante vasculaire de la santé cérébrale et montré une association entre une consommation de poisson plus élevée et un moindre fardeau cérébrovasculaire global, défini par la combinaison de trois marqueurs IRM : hypersignaux de la substance blanche, infarctus cérébraux silencieux et dilatations des espaces périvasculaires. Ces résultats décryptent les effets spécifiques de différentes expositions nutritionnelles sur la santé cérébrale dans le vieillissement, suggérant un rôle prépondérant des AGPI n-3 apportés par le poisson, associés à la fois à une diminution de l’atrophie et du fardeau cérébrovasculaire. Le MIND diet (intégrant le poisson et les légumes colorés, sources de caroténoïdes) était associé à une préservation globale de la microstructure cérébrale et pourrait être une stratégie de prévention efficace d’un point de vue de la santé publique.

Racial and ethnic disparities in healthy aging represent an emerging public health crisis that will only grow worse as our population grows older. Healthy lifestyle behaviors are proposed as a key strategy to promote healthy aging. However, the potential of lifestyle interventions to address aging health disparities is uncertain. We analyzed data from 42 625 adult participants (aged 20-85 years) participating in National Health and Nutrition Examination Survey (NHANES), 1999-2018 to evaluate relationships among healthy lifestyle behaviors and biological aging across White, Black, and Hispanic-identifying groups. We measured healthy lifestyle as adherence to a Mediterranean diet and level of leisure-time physical activity using established methods. We measured healthy aging using the PhenoAge biological age algorithm applied to blood chemistry data. We tested associations within each race/ethnic identity group and compared associations across groups using regression models with interaction terms. We found that within each race/ethnic identity group, greater adherence to a Mediterranean diet and higher levels of leisure-time physical activity were associated with younger biological age, independent of demographic and socioeconomic confounders, obesity, and smoking. However, these associations were stronger among White- as compared to non-Hispanic Black- and Hispanic-identifying adults. Results suggest that healthy lifestyle factors are likely to promote healthy aging across the population. However, lifestyle factors alone may not be sufficient to completely address race/ethnic disparities in healthy aging. Future studies will need to investigate additional ways to reduce racial and ethnic disparities in healthy aging.

Objective: People who eat healthier diets are less likely to develop dementia, but the biological mechanism of this protection is not well understood. We tested the hypothesis that healthy diet protects against dementia because it slows the pace of biological aging.Methods: We analyzed Framingham Offspring Cohort data. We included participants ≥60 years‐old, free of dementia and having dietary, epigenetic, and follow‐up data. We assessed healthy diet as long‐term adherence to the Mediterranean‐Dash Intervention for Neurodegenerative Delay diet (MIND, over 4 visits spanning 1991–2008). We measured the pace of aging from blood DNA methylation data collected in 2005–2008 using the DunedinPACE epigenetic clock. Incident dementia and mortality were defined using study records compiled from 2005 to 2008 visit through 2018.Results: Of n = 1,644 included participants (mean age 69.6, 54% female), n = 140 developed dementia and n = 471 died over 14 years of follow‐up. Greater MIND score was associated with slower DunedinPACE and reduced risks for dementia and mortality. Slower DunedinPACE was associated with reduced risks for dementia and mortality. In mediation analysis, slower DunedinPACE accounted for 27% of the diet‐dementia association and 57% of the diet‐mortality association.Interpretation: Findings suggest that slower pace of aging mediates part of the relationship of healthy diet with reduced dementia risk. Monitoring pace of aging may inform dementia prevention. However, a large fraction of the diet‐dementia association remains unexplained and may reflect direct connections between diet and brain aging that do not overlap other organ systems. Investigation of brain‐specific mechanisms in well‐designed mediation studies is warranted. ANN NEUROL 2024;95:1069–1079

Background: Substantial evidence supports the benefice of healthy diet for brain aging; however, the underlying pathways remain largely unknown. Leveraging a unique cohort design with assessment of long‐term dietary habits, DNA methylation data, and 10‐year follow‐up for dementia, we evaluated the mediating role of pace of biological aging on the relationship of diet with dementia. We investigated the specificity of this pathway for brain aging, as compared to overall aging, by investigating the same mediation for the risk of all‐cause mortality.Method: We included 1,644 participants (≥60 years‐old) from the Framingham Offspring Cohort, who were free of dementia at baseline examination (exam 8 [2005‐2008]). We evaluated long‐term adherence to a Mediterranean diet (MeDi) by averaging dietary scores across four assessments (validated food frequency questionnaire at exams 5 [1991‐1995], 6 [1995‐1998], 7 [1998‐2001], and 8). Using DNA methylation data collected at baseline, we measured the pace of biological aging through the DunedinPACE epigenetic clock, which was the DNA methylation measure the most strongly associated with dementia in prior studies. Incidence of dementia and mortality was adjudicated from baseline until 2018 by expert committees. We performed mediation analyses to estimate the role of pace of biological aging on the relationship between diet and dementia or all‐cause mortality.Result: Over the follow‐up (maximum, 13.8 years), 140 (8.5%) participants developed dementia, and 471 (28.6%) died. Participants with a higher adherence to MeDi had a slower pace of biological aging, and lower risks of dementia and of all‐cause mortality (Figure). A faster pace of aging was associated with increased risks of dementia and mortality. Biological aging mediated 13% [95% CI, 0.06; 0.43] of the association between diet and dementia, and 43% [0.23; 1.08] of the association of diet with mortality.Conclusion: Part of the association of healthier diet with lower risk of dementia is mediated by a slowing of global processes of biological aging. However, this pathway does not fully explain the association of diet and dementia and the proportion mediated was three times smaller than what was observed for mortality, suggesting that other mechanisms, especially brain‐specific mechanisms, need to be further described.

INTRODUCTION We tested the hypothesis that healthy diet protects against dementia because it slows the pace of biological aging. METHODS We analyzed Framingham Offspring Cohort data (≥60y). We measured healthy diet using the Dietary Guideline for Americans (DGA, 3 visits 1991-2008), pace of aging using the DunedinPACE epigenetic clock (2005-2008), and incident dementia and mortality using records (compiled 2005-2018). RESULTS Of n=1,525 included participants (mean age 69.7, 54% female), n=129 developed dementia and n=432 died over follow-up. Greater DGA adherence was associated with slower DunedinPACE and reduced risks for dementia and mortality. Slower DunedinPACE was associated with reduced risks for dementia and mortality. Slower DunedinPACE accounted for 15% of the DGA association with dementia and 39% of the DGA association with mortality. DISCUSSION Findings suggest that slower pace of aging mediates part of the relationship of healthy diet with reduced dementia risk. Monitoring pace of aging may inform dementia prevention.

People who have a balanced diet and engage in more physical activity live longer, healthier lives. This study aimed to test the hypothesis that these associations reflect a slowing of biological processes of aging. We analyzed data from 42 625 participants (aged 20–84 years, 51% female participants) from the National Health and Nutrition Examination Surveys (NHANES), 1999–2018. We calculated adherence to a Mediterranean diet (MeDi) and level of leisure time physical activity (LTPA) using standard methods. We measured biological aging by applying the PhenoAge algorithm, developed using clinical and mortality data from NHANES-III (1988–94), to clinical chemistries measured from a blood draw at the time of the survey. We tested the associations of diet and physical activity measures with biological aging, explored synergies between these health behaviors, and tested heterogeneity in their associations across strata of age, sex, and body mass index. Participants who adhered to the MeDi and who did more LTPA had younger biological ages compared with those who had less-healthy lifestyles (high vs low MeDi tertiles: β = 0.14 standard deviation [SD] [95% confidence interval {CI}: −0.18, −0.11]; high vs sedentary LTPA, β = 0.12 SD [−0.15, −0.09]), in models controlled for demographic and socioeconomic characteristics. Healthy diet and regular physical activity were independently associated with lower clinically defined biological aging, regardless of age, sex, and BMI category.

Adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, which combines higher consumption of vegetables, berries, nuts, w

Background: The MIND diet score for brain health is a 15‐item score combining neuroprotective dietary components (e.g. green leafy vegetables, nuts, berries, whole grains, fish). A higher MIND diet score was associated with slower cognitive decline and lower risk of Alzheimer’s disease; however, its relationship with brain structure has not yet been investigated. Taking advantage of a large population‐based cohort of older adults, we constructed a MIND diet score adapted to French dietary habits and we evaluated the associations of the score with the risk of dementia and Alzheimer’s disease (AD). In a secondary analysis, we investigated the cross‐sectional relationship between the MIND diet score and gray matter structure assessed by Magnetic Resonance Imaging (MRI).Method: We included 1,412 dementia‐free participants (aged ≥65) from the Three‐City Bordeaux study. A 148‐item Food Frequency Questionnaire and a 24‐hour recall administered at home in 2001‐2002 were used to calculate a MIND diet score, adapting component thresholding to French habits and guidelines (when applicable). Incidence of dementia and its subtypes from 2001‐2002 until 2017‐2018 was adjudicated by an expert committee. A subset of 207 participants were included in an ancillary MRI study in 2010‐2011. Gray matter volume and cortical thickness within the cortical signature of AD (i.e., 9 regions with cortical thickening predictive of subsequent AD) were estimated using FreeSurfer 5.1.Result: Over a median follow‐up of 9.7 years (maximum 16.3 years), 356 participants (25.2%) were diagnosed with dementia, including 240 participants (17.0%) with AD. In multivariable Cox models, a higher MIND diet score was associated with lower risks of dementia (Hazard Ratio [HR] = 0.89 for each 1‐point increase of score; 95% Confidence Intervals [CI] = 0.83‐0.95) and AD (HR = 0.88; 95% CI = 0.81‐0.96). In the MRI sub‐study, a higher MIND diet score was significantly associated with higher total grey matter volume (β=2.54 mm³ for 1 point of score, p=0.005) and greater thickness in the AD signature (β=0.02 mm for 1 point of score, p<0.001).Conclusion: This large population‐based study provides further evidence and new mechanistic insights for the role of the MIND diet in the prevention of dementia and AD.

Background: Cerebrovascular disease (CVD), a major contributor of cognitive aging, is characterized by subclinical damage visualized on brain MRI, including covert brain infarcts, white matter hyperintensities (WMH) and dilated perivascular spaces (dPVS). Few protective factors for brain vascular health, that may help prevent stroke and dementia, have been identified so far. Fish intake may prevent ischemic events and small vessel disease. When investigating factors with a pleiotropic effect such as fish, there is interest to capture pathophysiological burden globally, combining biomarkers into a single metric. Here, we investigated the association of fish intake with a global indicator of the MRI burden of CVD among older adults.Method: This Three‐City Dijon study included 1,623 participants (≥65 years) without history of dementia, stroke or cardiovascular disease, who had completed a Food Frequency Questionnaire and underwent brain MRI with automated assessment of WMH, visual detection of covert infarcts, and grading of dPVS. A global indicator of CVD burden was estimated using a factorial analysis of mixed data; association of fish intake with the indicator was assessed by adjusted linear regression.Result: The proportions of participants consuming fish less than once a week, once a week, 2 to 3 times and more than 4 times per week were 11%, 37%, 47% and 6%, respectively. The continuous CVD burden indicator, derived from the first dimension of the factorial analysis (32.4% of explained variance), was associated with a higher WMH load, more infarcts and higher dPVS severity. Higher fish intake was associated with a lower CVD burden indicator (P for trend <0.001). Compared to participants consuming fish less than once a week, the CVD indicator decreased by ‐0.19 units (95% CI, ‐0.37; ‐0.005) for those consuming fish 2‐3 times per week and by ‐0.31 units (‐0.59; ‐0.03) for ≥4 times per week. These effect estimates of eating fish at least twice a week were equivalent to having a 4 to 5 years younger brain in terms of vascular health (β = 0.05 units (0.03; 0.06) for each one year increase of age).Conclusion: Fish consumption may promote brain vascular health before manifestation of overt brain disease.