Andrea Du Preez’s research while affiliated with King's College London and other places

During pregnancy multiple biological systems undergo consistent modifications, in particular the hormonal axes and the immune system. Moreover, while it is well known that pregnant women suffering from depression show alterations in these systems, the exact underlying mechanisms are still not clear. For this reason, in this study, we explored the blood transcriptomic profile and related pathways in 41 pregnant women with a current diagnosis of depression, 23 pregnant women, who were not depressed in pregnancy but, because of a history of depressive episodes, were considered at high risk of developing antenatal depression (history-only), and 28 pregnant women who had never experienced depression in their life, including the current pregnancy. Based on resulting differentially expressed genes, we identified 28 molecular pathways modulated in depressed women compared with controls, with a main association with increased B cell activity, while history-only women showed 52 pathways differentially modulated compared with controls, involving lower cytotoxic T cell activity and higher pro-inflammatory pathways activity. Conversely, depressed women showed a differential modulation of 75 pathways, compared with history-only women, associated with increased activity of allo- and auto-immunity and pro-inflammatory pathways. Overall, our results suggest a main role of immunity within the context of perinatal depression, and of a differential modulation of specific immune processes underlying the development of depression and the associated risk.

Hippocampal neurogenesis (HN) occurs throughout the life course and is important for memory and mood. Declining with age, HN plays a pivotal role in cognitive decline (CD), dementia, and late-life depression, such that altered HN could represent a neurobiological susceptibility to these conditions. Pertinently, dietary patterns (e.g., Mediterranean diet) and/or individual nutrients (e.g., vitamin D, omega 3) can modify HN, but also modify risk for CD, dementia, and depression. Therefore, the interaction between diet/nutrition and HN may alter risk trajectories for these ageing-related brain conditions. Using a subsample (n = 371) of the Three-City cohort—where older adults provided information on diet and blood biobanking at baseline and were assessed for CD, dementia, and depressive symptomatology across 12 years—we tested for interactions between food consumption, nutrient intake, and nutritional biomarker concentrations and neurogenesis-centred susceptibility status (defined by baseline readouts of hippocampal progenitor cell integrity, cell death, and differentiation) on CD, Alzheimer’s disease (AD), vascular and other dementias (VoD), and depressive symptomatology, using multivariable-adjusted logistic regression models. Increased plasma lycopene concentrations (OR [95% CI] = 1.07 [1.01, 1.14]), higher red meat (OR [95% CI] = 1.10 [1.03, 1.19]), and lower poultry consumption (OR [95% CI] = 0.93 [0.87, 0.99]) were associated with an increased risk for AD in individuals with a neurogenesis-centred susceptibility. Increased vitamin D consumption (OR [95% CI] = 1.05 [1.01, 1.11]) and plasma γ-tocopherol concentrations (OR [95% CI] = 1.08 [1.01, 1.18]) were associated with increased risk for VoD and depressive symptomatology, respectively, but only in susceptible individuals. This research highlights an important role for diet/nutrition in modifying dementia and depression risk in individuals with a neurogenesis-centred susceptibility.

Stress exposure during the sensitive period of early development has been shown to program the brain and increases the risk to develop cognitive deficits later in life. We have shown earlier that early-life stress (ES) leads to cognitive decline at an adult age, associated with changes in adult hippocampal neurogenesis and neuroinflammation. In particular, ES has been shown to affect neurogenesis rate and the survival of newborn cells later in life as well as microglia, modulating their response to immune or metabolic challenges later in life. Both of these processes possibly contribute to the ES-induced cognitive deficits. Emerging evidence by us and others indicates that early nutritional interventions can protect against these ES-induced effects through nutritional programming. Based on human metabolomics studies, we identified various coffee-related metabolites to be part of a protective molecular signature against cognitive decline in humans. Caffeic and chlorogenic acids are coffee-polyphenols and have been described to have potent anti-oxidant and anti-inflammatory actions. Therefore, we here aimed to test whether supplementing caffeic and chlorogenic acids to the early diet could also protect against ES-induced cognitive deficits. We induced ES via the limited nesting and bedding paradigm in mice from postnatal(P) day 2–9. On P2, mice received a diet to which 0.02% chlorogenic acid (5-O-caffeoylquinic acid) + 0.02% caffeic acid (3′,4′-dihydroxycinnamic acid) were added, or a control diet up until P42. At 4 months of age, all mice were subjected to a behavioral test battery and their brains were stained for markers for microglia and neurogenesis. We found that coffee polyphenols supplemented early in life protected against ES-induced cognitive deficits, potentially this is mediated by the survival of neurons or microglia, but possibly other mechanisms not studied here are mediating the effects. This study provides additional support for the potential of early nutritional interventions and highlights polyphenols as nutrients that can protect against cognitive decline, in particular for vulnerable populations exposed to ES.

First-in-family (FiF) students experience significant barriers to university participation and are less likely to seek mental health help. This can contribute to increased dropouts when compared to non-FiF students. Using a mixed methods approach, we aimed to ascertain sources of mental health support and underlying factors for the preferences favoured by students from UK universities. Answers to the General Help Seeking Questionnaire (GHSQ) and to two open-ended questions were collected online. We found that FiF (n=194) students were more likely to seek help from friends relative to their non-FiF (n=134) peers. Trust was particularly important for FiF students, while for non-FiF students, the perceived benefit of talking to anyone about mental health was more relevant. Attitudes towards mental health discussion were influenced by background. Stigma and perceived burdensomeness negatively affected help-seeking among all students. Our findings suggest FiF students derive more benefits for their mental health concerns from friendship circles, implicating the importance of social integration programmes at university. Future work would benefit from evaluating mental health help-seeking intentions of students with more specific characteristics (e.g., race, gender), to better understand determinants influencing preferences and help institutions plan more fitting provisions to support students.

The microbiome is involved in nutrient metabolism and releases metabolites that can influence cognitive aging, likely through the gut‐brain axis. Human studies, generally limited in number of metabolites and follow‐up, have been inadequate to identify early metabolic alterations leading to cognitive aging. The aim of this study was to investigate the association between circulating levels of a large number of microbial metabolites in plasma and cognitive decline. We studied participants from the Three‐City study, a cohort study conducted in 3 French cities (Bordeaux, Dijon ad Montpellier). The subjects were free of dementia at the time of blood sampling and provided repeated measures of cognition over 12 subsequent years. We used a targeted metabolomic approach, combining ultra‐high performance liquid chromatography coupled to tandem mass spectrometry. We measured 77 circulating gut‐derived metabolites in a case‐control sample matched for age, sex and educational level, nested within the cohort. Associations of these metabolites to cognitive decline were investigated in the Bordeaux center (discovery sample, n = 418) using logistic regressions conditioned on matching variables. Associations with a P‐value corrected for multiple testing (False Discovery Rate [FDR]) ≤0.15 were tested for validation in the Dijon center (validation sample, n = 424). Models were subsequently adjusted for smoking, alcohol consumption and cardiometabolic health (body mass index, hypertension, hypercholesterolemia and diabetes). Higher serum levels of propionic acid, a short‐chain fatty acid, were associated with increased odds of cognitive decline (OR for 1 SD = 1.40 [95% CI 1.11, 1.75] in discovery, and = 1.26 [1.02, 1.55] in the validation stage). Associations were attenuated in the validation sample after multivariable adjustment, and additional analyses suggested mediation by hypercholesterolemia and diabetes. Moreover, propionic acid strongly correlated with blood glucose (r = 0.80) and with meat and cheese intakes (r>0.15) but not with fiber intake (r = 0.04). This exploratory study of the gut‐brain axis suggests a deleterious relationship between circulating propionic acid and cognitive decline. Our results suggest a very weak relation to pre‐biotic foods, but a possible link with processed foods, where propionic acid is often used as a preservative. Thus, the adverse impact of propionic acid on metabolism and cognition deserves further investigation.

The gut microbiome is involved in nutrient metabolism and produces metabolites that, via the gut–brain axis, signal to the brain and influence cognition. Human studies have so far had limited success in identifying early metabolic alterations linked to cognitive aging, likely due to limitations in metabolite coverage or follow-ups. Older persons from the Three-City population-based cohort who had not been diagnosed with dementia at the time of blood sampling were included, and repeated measures of cognition over 12 subsequent years were collected. Using a targeted metabolomics platform, we identified 72 circulating gut-derived metabolites in a case–control study on cognitive decline, nested within the cohort (discovery n = 418; validation n = 420). Higher serum levels of propionic acid, a short-chain fatty acid, were associated with increased odds of cognitive decline (OR for 1 SD = 1.40 (95% CI 1.11, 1.75) for discovery and 1.26 (1.02, 1.55) for validation). Additional analyses suggested mediation by hypercholesterolemia and diabetes. Propionic acid strongly correlated with blood glucose (r = 0.79) and with intakes of meat and cheese (r > 0.15), but not fiber (r = 0.04), suggesting a minor role of prebiotic foods per se, but a possible link to processed foods, in which propionic acid is a common preservative. The adverse impact of propionic acid on metabolism and cognition deserves further investigation.

Environmental factors like diet have been linked to depression and/or relapse risk in later life. This could be partially driven by the food metabolome, which communicates with the brain via the circulatory system and interacts with hippocampal neurogenesis (HN), a form of brain plasticity implicated in depression aetiology. Despite the associations between HN, diet and depression, human data further substantiating this hypothesis are largely missing. Here, we used an in vitro model of HN to test the effects of serum samples from a longitudinal ageing cohort of 373 participants, with or without depressive symptomology. 1% participant serum was applied to human fetal hippocampal progenitor cells, and changes in HN markers were related to the occurrence of depressive symptoms across a 12-year period. Key nutritional, metabolomic and lipidomic biomarkers (extracted from participant plasma and serum) were subsequently tested for their ability to modulate HN. In our assay, we found that reduced cell death and increased neuronal differentiation were associated with later life depressive symptomatology. Additionally, we found impairments in neuronal cell morphology in cells treated with serum from participants experiencing recurrent depressive symptoms across the 12-year period. Interestingly, we found that increased neuronal differentiation was modulated by increased serum levels of metabolite butyrylcarnitine and decreased glycerophospholipid, PC35:1(16:0/19:1), levels – both of which are closely linked to diet – all in the context of depressive symptomology. These findings potentially suggest that diet and altered HN could subsequently shape the trajectory of late-life depressive symptomology.

Introduction et but de l’étude Le microbiote intestinal (MI) participe à la digestion et au métabolisme de nombreux nutriments en libérant des métabolites dans le tube digestif, dont certains gagnent la circulation sanguine et traversent la barrière hémato-encéphalique, interagissant ainsi directement avec le cerveau. Cependant, les connaissances sur le lien entre MI et santé cérébrale sont en grande partie précliniques, et peu d’études ont porté sur les métabolites microbiotiques circulants et le vieillissement cognitif chez l’homme. L’objectif de cette étude était d’analyser et de valider, dans un cas-témoin niché dans une grande cohorte de sujets âgés, l’association entre des dizaines de métabolites sanguins dérivés du MI et le déclin cognitif au long cours. Matériel et méthodes Cette étude met à profit les données de la cohorte des trois-cités (3C, Bordeaux, Dijon et Montpellier) chez des personnes âgées de 65 ans ou plus à l’inclusion. Les participants non déments au moment du prélèvement sanguin et dont la cognition a été mesurée de façon répétée au cours des 12 années suivantes étaient éligibles pour le cas-témoin niché. Un échantillon de découverte a été défini dans 3C Bordeaux, incluant les 209 participants avec la pente de déclin cognitif la plus importante, appariés à 209 témoins avec une cognition plus stable (pente > pente médiane) et de même âge, sexe et niveau d’études. Un échantillon de validation a été défini de façon similaire dans 3C Dijon (210 paires cas-témoin). Une analyse en métabolomique ciblée a permis de quantifier 76 métabolites liés à l’alimentation et potentiellement dérivés du MI. L’association entre chaque métabolite et le déclin cognitif a été étudiée dans l’échantillon de découverte en utilisant des régressions logistiques conditionnelles. Les métabolites dont la P-valeur corrigée pour les tests multiples (FDR) était ≤ 0,15 ont été testés pour réplication. Résultats et analyse statistique 7 métabolites étaient associés au déclin cognitif avec une P-FDR ≤ 0,15 dans l’échantillon de découverte : la phénylacétylglutamine, l’acide indole-lactique, l’acide kynurénique, la bétaïne, la vitamine B5, le propionate et le 3,4-DHPV-S. Seul le propionate était répliqué (OR = 1,26, 95 % IC [1,02 ;1,55]). Cette association était atténuée de façon importante après ajustement sur les facteurs de risque cardiométaboliques dans l’échantillon de validation (une population à risque vasculaire plus important que la population de découverte). Conclusion Cette étude suggère une relation délétère entre l’acide propionique circulant et le déclin cognitif. Le rôle de la santé cardiométabolique dans cette relation mérite d’être approfondi.