Pattern of polyphenol intake and the long-term risk of dementia in older persons

International audienc

Diet-Related Metabolites Associated with Cognitive Decline Revealed by Untargeted Metabolomics in a Prospective Cohort

Scope: Untargeted metabolomics may reveal preventive targets in cognitive aging, including within the food metabolome. Methods and results: A case-control study nested in the prospective Three-City study includes participants aged &65 years and initially free of dementia. A total of 209 cases of cognitive decline and 209 controls (matched for age, gen- der, education) with slower cognitive decline over up to 12 years are contrasted. Using untargeted metabolomics and bootstrap-enhanced penalized regression, a baseline serum signature of 22 metabolites associated with subsequent cognitive decline is identified. The signature includes three coffee metabolites, a biomarker of citrus intake, a cocoa metabolite, two metabolites putatively derived from fish and wine, three medium-chain acylcarnitines, glycodeoxycholic acid, lysoPC(18:3), trimethyllysine, glucose, cortisol, creatinine, and arginine. Adding the 22 metabolites to a reference predictive model for cognitive decline (conditioned on age, gender, education and including ApoE-ε4, diabetes, BMI, and number of medications) substantially increases the predictive performance: cross-validated Area Under the Receiver Operating Curve = 75% [95% CI 70-80%] compared to 62% [95% CI 56-67%]. Conclusions: The untargeted metabolomics study supports a protective role of specific foods (e.g., coffee, cocoa, fish) and various alterations in the endogenous metabolism responsive to diet in cognitive aging

Apolipoprotein E and sex modulate fatty acid metabolism in a prospective observational study of cognitive decline

Background: Fatty acids play prominent roles in brain function as they participate in structural, metabolic and signaling processes. The homeostasis of fatty acids and related pathways is known to be impaired in cognitive decline and dementia, but the relationship between these metabolic disturbances and common risk factors, namely the ɛ4 allele of the apolipoprotein E (ApoE-ɛ4) gene and sex, remains elusive. Methods: In order to investigate early alterations associated with cognitive decline in the fatty acid-related serum metabolome, we here applied targeted metabolomics analysis on a nested case-control study (N=368), part of a prospective population cohort on dementia. Results: When considering the entire study population, circulating levels of free fatty acids, acyl-carnitines and pantothenic acid were found to be increased among those participants who had greater odds of cognitive decline over a 12-year follow-up. Interestingly, stratified analyses indicated that these metabolomic alterations were specific for ApoE-ɛ4 non-carriers and women. Conclusions: Altogether, our results highlight that the regulation of fatty acids and related metabolic pathways during ageing and cognitive decline depends on complex inter-relationships between the ApoE-ε4 genotype and sex. A better understanding of the ApoE-ɛ4 and sex dependent modulation of metabolism is essential to elucidate the individual variability in the onset of cognitive decline, which would help develop personalized therapeutic approaches

Early signature in the blood lipidome associated with subsequent cognitive decline in the elderly: A case-control analysis nested within the Three-City cohort study

Background Brain lipid metabolism appears critical for cognitive aging, but whether alterations in the lipidome relate to cognitive decline remains unclear at the system level. Methods We studied participants from the Three-City study, a multicentric cohort of older persons, free of dementia at time of blood sampling, and who provided repeated measures of cognition over 12 subsequent years. We measured 189 serum lipids from 13 lipid classes using shotgun lipidomics in a case-control sample on cognitive decline (matched on age, sex and level of education) nested within the Bordeaux study center (discovery, n = 418). Associations with cognitive decline were investigated using bootstrapped penalized regression, and tested for validation in the Dijon study center (validation, n = 314). Findings Among 17 lipids identified in the discovery stage, lower levels of the triglyceride TAG50:5, and of four membrane lipids (sphingomyelin SM40:2,2, phosphatidylethanolamine PE38:5(18:1/20:4), ether-phosphatidylethanolamine PEO34:3(16:1/18:2), and ether-phosphatidylcholine PCO34:1(16:1/18:0)), and higher levels of PCO32:0(16:0/16:0), were associated with greater odds of cognitive decline, and replicated in our validation sample. Interpretation These findings indicate that in the blood lipidome of non-demented older persons, a specific profile of lipids involved in membrane fluidity, myelination, and lipid rafts, is associated with subsequent cognitive decline. Funding The complete list of funders is available at the end of the manuscript, in the Acknowledgement section

Front Cell Dev Biol

The age-associated reduction in the proliferation of neural stem cells (NSCs) has been associated with cognitive decline. Numerous factors have been shown to modulate this process, including dietary components. Frequent consumption of caffeine has been correlated with an increased risk of cognitive decline, but further evidence of a negative effect on hippocampal progenitor proliferation is limited to animal models. Here, we used a human hippocampal progenitor cell line to investigate the effects of caffeine on hippocampal progenitor integrity and proliferation specifically. The effects of five caffeine concentrations (0 mM = control, 0.1 mM ∼ 150 mg, 0.25 mM ∼ 400 mg, 0.5 mM ∼ 750 mg, and 1.0 mM ∼ 1500 mg) were measured following acute (1 day) and repeated (3 days) exposure. Immunocytochemistry was used to quantify hippocampal progenitor integrity (i.e., SOX2- and Nestin-positive cells), proliferation (i.e., Ki67-positive cells), cell count (i.e., DAPI-positive cells), and apoptosis (i.e., CC3-positive cells). We found that progenitor integrity was significantly reduced in supraphysiological caffeine conditions (i.e., 1.0 mM ∼ 1500 mg), but relative to the lowest caffeine condition (i.e., 0.1 mM ∼ 150 mg) only. Moreover, repeated exposure to supraphysiological caffeine concentrations (i.e., 1.0 mM ∼ 1500 mg) was found to affect proliferation, significantly reducing % Ki67-positive cells relative to control and lower caffeine dose conditions (i.e., 0.1 mM ∼ 150 mg and 0.25 mM ∼ 400 mg). Caffeine treatment did not influence apoptosis and there were no significant differences in any measure between lower doses of caffeine (i.e., 0.1 mM, 0.25 mM, 0.5 mM) - representative of daily human caffeine intake - and control conditions. Our study demonstrates that dietary components such as caffeine can influence NSC integrity and proliferation and may be indicative of a mechanism by which diet affects cognitive outcomes

EBioMedicine

BACKGROUND: Brain lipid metabolism appears critical for cognitive aging, but whether alterations in the lipidome relate to cognitive decline remains unclear at the system level. METHODS: We studied participants from the Three-City study, a multicentric cohort of older persons, free of dementia at time of blood sampling, and who provided repeated measures of cognition over 12 subsequent years. We measured 189 serum lipids from 13 lipid classes using shotgun lipidomics in a case-control sample on cognitive decline (matched on age, sex and level of education) nested within the Bordeaux study center (discovery, n = 418). Associations with cognitive decline were investigated using bootstrapped penalized regression, and tested for validation in the Dijon study center (validation, n = 314). FINDINGS: Among 17 lipids identified in the discovery stage, lower levels of the triglyceride TAG50:5, and of four membrane lipids (sphingomyelin SM40:2,2, phosphatidylethanolamine PE38:5(18:1/20:4), ether-phosphatidylethanolamine PEO34:3(16:1/18:2), and ether-phosphatidylcholine PCO34:1(16:1/18:0)), and higher levels of PCO32:0(16:0/16:0), were associated with greater odds of cognitive decline, and replicated in our validation sample. INTERPRETATION: These findings indicate that in the blood lipidome of non-demented older persons, a specific profile of lipids involved in membrane fluidity, myelination, and lipid rafts, is associated with subsequent cognitive decline. FUNDING: The complete list of funders is available at the end of the manuscript, in the Acknowledgement section

Nutrients

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.COGINUT : Cognition, anti-oxydants, acides gras: approche interdisciplinaire du rôle de la nutrition dans le vieillissement du cerveauHistoire naturelle du déclin cognitif et du besoin de soins chez le sujet âg

The serum metabolome mediates the concert of diet, exercise, and neurogenesis, determining the risk for cognitive decline and dementia

INTRODUCTION: Diet and exercise influence the risk of cognitive decline (CD) and dementia through the food metabolome and exercise-triggered endogenous factors, which use the blood as a vehicle to communicate with the brain. These factors might act in concert with hippocampal neurogenesis (HN) to shape CD and dementia. METHODS: Using an in vitro neurogenesis assay, we examined the effects of serum samples from a longitudinal cohort (n = 418) on proxy HN readouts and their association with future CD and dementia across a 12-year period. RESULTS: Altered apoptosis and reduced hippocampal progenitor cell integrity were associated with exercise and diet and predicted subsequent CD and dementia. The effects of exercise and diet on CD specifically were mediated by apoptosis. DISCUSSION: Diet and exercise might influence neurogenesis long before the onset of CD and dementia. Alterations in HN could signify the start of the pathological process and potentially represent biomarkers for CD and dementia.Identification of dietary modulators of cognitive ageing and brain plasticity and proof of concept of efficacy for preventing-reversing cognitive declin

Ancient pigs reveal a near-complete genomic turnover following their introduction to Europe

Archaeological evidence indicates that pig domestication had begun by ~10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ~8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local Euro-pean wild boars, although it is also possible that European wild boars were domesticated independently without any genetic con-tribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process

Epidemiological study of the relationship between the food exposome and brain aging : from candidate nutrient to holistic approaches

L’alimentation représente une piste prometteuse pour la prévention des pathologies du vieillissement cérébral, en particulier la démence et sa principale cause, la maladie d’Alzheimer, pour lesquelles il n’existe aucun traitement étiologique. La recherche épidémiologique nutritionnelle a traditionnellement reposé sur une approche par nutriment candidat, ignorant les effets additifs et potentiellement synergiques entre composés alimentaires, pourtant consommés ensemble dans l’alimentation. La combinaison nutritionnelle optimale pour la prévention du déclin cognitif et de la démence reste encore inconnue. L’objectif principal de ce travail de thèse était d’identifier de nouvelles cibles préventives pour le vieillissement cérébral via une approche holistique de l’exposition nutritionnelle, combinant des méthodes semi-confirmatoires (par profils de nutriments candidats) et des approches plus exploratoires (profilage métabolomique) dans la cohorte de personnes âgées des Trois-Cités (3C), Bordeaux. Dans une première partie semiconfirmatoire, deux profils multi-nutriments associés au risque de démence au cours de 12 ans de suivi, ont été identifiés par une méthode de réduction de dimension supervisée : un profil d’apports alimentaires en polyphénols (combinant principalement des composés phénoliques du vin rouge, des agrumes et des noix) et une combinaison de biomarqueurs nutritionnels (vitamine D, caroténoïdes et acide gras polyinsaturés). Dans une seconde partie exploratoire, des profils en métabolomique non-ciblée, analysés par régression pénalisée, ont mis en évidence une relation entre le métabolome alimentaire (métabolites dérivés du café, des agrumes, du chocolat, du poisson, du vin rouge) et le déclin cognitif. Des altérations du métabolome endogène ont également été observées, suggérant l’implication du statut cardiométabolique (phospholipides, acylcarnitines, acides biliaires, triméthyllysine, glucose) et du microbiote (acides biliaires secondaires, triméthyllysine) dans le vieillissement cérébral. Enfin, une analyse du lipidome a permis d’identifier une signature lipidique du déclin cognitif, validée dans un échantillon externe issu de 3C Dijon. Cette étude suggérait des modifications précoces des lipides membranaires au cours du vieillissement cérébral.Diet is a promising strategy for the prevention of brain aging, including dementia and its main form Alzheimer’s disease, for which no cure currently exists. Traditional nutritional epidemiology is based on a candidate-nutrient approach that ignores additive effects and potential synergies between dietary compounds, though consumed together in the diet. The optimal combination of nutrients for the prevention of cognitive decline and dementia remains unknown. The objective of this thesis was to identify new preventive targets for brain aging through a holistic approach of nutritional exposures, including semiconfirmatory (patterns of candidate-nutrients) and exploratory methods (metabolomics profiling) applied to older people from the Three-City (3C) study, Bordeaux. In a first part (semi-confirmatory), we investigated combinations of nutrients best associated with the risk of dementia over 12 years, using partial least square regression. We identified two multinutrient patterns: a pattern of polyphenols intake (mainly composed of polyphenols from red wine, citrus and nuts) and a nutrient biomarker pattern (including vitamin D, carotenoids and polyunsaturated fatty acids). In a second part (exploratory), we discovered, using untargeted metabolomics and penalized regression, associations between the food metabolome (metabolites derived from coffee, citrus, chocolate, fish and red wine) and cognitive decline. Other metabolic alterations involved the endogeneous metabolome, including metabolites related to cardiometabolic status (phospholipids, acylcarnitines, bile acids, trimethyllysine, glucose) and to gut microbiota (secondary bile acids, trimethyllysine). Finally, the study of the lipidome revealed a lipid signature of cognitive decline, validated in an external sample from 3C Dijon, which suggested early change in membrane lipids over the course of brain aging