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

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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

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

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

Tall 3-dwarfs: oxymoron or opportunity to increase grain yield in sorghum?

Main conclusion: Plant height was positively correlated with grain yield across a large set of 3-dwarf sorghum hybrids and production environments in north-eastern Australia. In industrialised countries, plant breeders tend to select for short plant stature in cereals like wheat, barley and rice, but also grain sorghum. This is mainly to prevent stalk lodging and to allow for machine harvesting. However, this counteracts an intrinsic positive relationship between plant height and yield potential often observed in cereals. We used data from multi-environment breeding trials comprising large sets of female sorghum lines from a range of pedigrees in hybrid combination with five different male testers. The hybrids were grown in 22 different rainfed environments in north-eastern Australia, which allowed us to thoroughly examine the relationship between plant height and yield across a range of productivity levels. Covariate analysis showed that in 38 out of the 90 tested relationships, grain yield was significantly (p < 0.05) positively and in only one case significantly negatively associated with plant height. This strong positive association between the traits was supported by the observation that 87% of the effects were either positive or zero. The effects of height on yield ranged from a decrease of 0.015 t ha−1 to an increase of 0.057 t ha−1 cm−1. The majority of the negative effects were observed in low-yielding trials and the positive effect of height tended to increase with increasing mean trial yield. Opportunities to increase yield potential by selecting for slightly taller sorghum hybrids therefore need to be explored in context with the target environments and in combination with other means to control the risks of lodging

Dietary B Vitamins and a 10-Year Risk of Dementia in Older Persons

B vitamins may lower the risk of dementia, yet epidemiological findings, mostly from countries with folic acid fortification, have remained inconsistent. We evaluated in a large French cohort of older persons the associations between dietary B vitamins and long-term incident dementia. We included 1321 participants from the Three-City Study who completed a 24 h dietary recall, were free of dementia at the time of diet assessment, and were followed for an average of 7.4 years. In Cox proportional hazards models adjusted for multiple potential confounders, including overall diet quality, higher intake of folate was inversely associated with the risk of dementia (p for trend = 0.02), with an approximately 50% lower risk for individuals in the highest compared to the lowest quintile of folate (HR = 0.47; 95% CI 0.28; 0.81). No association was found for vitamins B6 and B12. In conclusion, in a large French cohort with a relatively low baseline folate status (average intake = 278 µg/day), higher folate intakes were associated with a decreased risk of dementia