High intensity neutrino oscillation facilities in Europe

The EUROnu project has studied three possible options for future, high intensity neutrino oscillation facilities in Europe. The first is a Super Beam, in which the neutrinos come from the decay of pions created by bombarding targets with a 4 MW proton beam from the CERN High Power Superconducting Proton Linac. The far detector for this facility is the 500 kt MEMPHYS water Cherenkov, located in the Fréjus tunnel. The second facility is the Neutrino Factory, in which the neutrinos come from the decay of μ+ and μ− beams in a storage ring. The far detector in this case is a 100 kt magnetized iron neutrino detector at a baseline of 2000 km. The third option is a Beta Beam, in which the neutrinos come from the decay of beta emitting isotopes, in particular He6 and Ne18, also stored in a ring. The far detector is also the MEMPHYS detector in the Fréjus tunnel. EUROnu has undertaken conceptual designs of these facilities and studied the performance of the detectors. Based on this, it has determined the physics reach of each facility, in particular for the measurement of CP violation in the lepton sector, and estimated the cost of construction. These have demonstrated that the best facility to build is the Neutrino Factory. However, if a powerful proton driver is constructed for another purpose or if the MEMPHYS detector is built for astroparticle physics, the Super Beam also becomes very attractive

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

Nutrition, mode de vie et prévention du vieillissement cérébral : caractérisation de combinaisons, mécanismes et groupes à risque au moyen de l’épidémiologie moléculaire

Dementia is the leading pathology of cognitive ageing. This complex syndrome results from genetic and environmental factors. Lifestyle factors, in particular nutrition, have shown robust associations with cognitive ageing in observational studies, especially when considered in combination (in the form of dietary or nutrient patterns, or lifestyle patterns more generally). However, intervention studies on nutrient supplementation, dietary or behavioral changes more generally, have been disappointing so far. One of the potential reasons for the relative failure of these studies may have been their inability to consider preventive targets in combination (particularly in the field of nutrition) or use of poorly-specified combinations (e.g., in so-called "multi-domain" prevention). In addition, the populations most likely to benefit from the intervention have often not been well characterized and the concept of "universal" prevention remains the benchmark. The general aim of this thesis was to take advantage of rich observational epidemiological data, specifically in molecular epidemiology, to help the characterization of preventive strategies for brain ageing pathologies through nutrition and lifestyle. The data comes from the 3-City (3C) study, a large multicentric cohort of elderly people in the general population. In this thesis, the first line of research aimed at identifying optimal nutritional combinations for prevention. We first targeted 3 of the most promising families of nutrients for prevention on the basis of previous knowledge (omega-3 polyunsaturated fatty acids, total carotenoids and vitamin D) and we developed a multi-micro-nutritional biological status index incorporating circulating levels of their biomarkers, associated with the risk of dementia. In practice, this index could be used to identify and provide preventive care for individuals with nutritional deficiencies who are at high risk of developing dementia. We then targeted a dementia-preventive diet developed by the scientific community, the MIND diet, and looked for a signature of the adherence to this diet in the food metabolome. The second line of research of the thesis was to explore new preventive targets by deciphering the mechanisms linking nutrition to cerebral ageing, with a particular interest in the gut-brain axis. Among 72 metabolites derived from the gut microbiota, only propionic acid was significantly associated with cognitive decline, with replication in an independent sample. Propionic acid is a short-chain fatty acid produced by the microbiota from dietary fibers, but it is also used as a food preservative, and the deleterious relationship to cognitive ageing evidenced in this work requires further investigation. Finally, in a third line of research, we investigated potential group of individuals with specific vulnerabilities that could benefit from the implementation of precision prevention in cognitive ageing. Here, we chose to broaden the scope of exposures to include, beyond nutrition, lifestyle factors as a whole. We focused on a risk score validated in the literature combining 12 modifiable factors, the LIBRA (Lifestyle for Brain health risk score), and we showed that this score was associated with the risk of dementia and cognitive decline, whatever the individual's level of genetic susceptibility (as reflected by the APOE4 allele and a genetic risk score). This latest study suggests that prevention through lifestyle modification could be effective for everyone, including among individuals who are genetically predisposed to developing dementia, which is certainly an encouraging public health message for these persons.La démence est la première pathologie associée au vieillissement cognitif. Il s’agit d’un syndrome d’étiologie complexe résultant de facteurs génétiques et environnementaux. Les facteurs de mode de vie, notamment la nutrition, ont montré des associations robustes avec le vieillissement cognitif dans les études d’observation, d’autant plus lorsqu’ils étaient considérés en combinaison (profils alimentaires ou de nutriments, profils de mode de vie plus généralement). Pour autant, les études d’intervention testant une supplémentation en nutriments, une modification du comportement alimentaire, ou intégrant plus généralement d’autres domaines du mode de vie, ont jusqu’à présent été décevantes. Une des raisons potentielles à l’échec relatif de ces études est une incapacité à considérer des cibles en combinaison (dans le domaine de la nutrition notamment) ou une mauvaise spécification des combinaisons optimales (en prévention dite « multi-domaine »). De plus, souvent, les populations les plus susceptibles de bénéficier de l’intervention n’ont pas été caractérisées et le concept de prévention « universelle » reste la référence. L’objectif général de cette thèse était de mettre à profit de riches données d’épidémiologie observationnelle, notamment moléculaires, pour affiner la caractérisation de stratégies préventives des pathologies du vieillissement cérébral par la nutrition et le mode de vie. Les données proviennent de l’étude des 3 Cités (3C), une grande cohorte multicentrique en population générale âgée. Un premier axe de recherche avait pour objectif d’identifier des combinaisons nutritionnelles optimales pour la prévention. Nous avons d’abord ciblé les 3 familles de nutriments les plus prometteuses pour la prévention sur la base des connaissances antérieures (acides gras polyinsaturés oméga-3, caroténoïdes totaux et vitamine D) et élaboré un indice de statut biologique multi-micro-nutritionnel intégrant les niveaux circulants de leurs biomarqueurs, associé au risque de démence. Cet indice pourrait permettre, en pratique, d’identifier et de prendre en charge en prévention les individus avec une déficience nutritionnelle qui sont à risque de développer une démence. Nous avons ensuite ciblé une un profil alimentaire préventif de la démence développée par la communauté scientifique, le profil MIND, et recherché une signature dans le métabolome alimentaire de l’adhésion à ce profil. Dans un deuxième axe de recherche, nous avons exploré de nouvelles cibles préventives en décryptant les mécanismes reliant la nutrition au vieillissement cérébral, avec un intérêt particulier pour l’axe intestin-cerveau. Parmi 72 métabolites dérivés du microbiote intestinal, seul l’acide propionique était significativement associé au déclin cognitif, avec réplication dans un échantillon indépendant. Il s’agit d’un acide gras à chaine courte produit par le microbiote à partir des fibres alimentaires mais qui est également utilisé comme conservateur alimentaire, et sa relation délétère au vieillissement cognitif nécessite de plus amples explorations. Enfin, dans un dernier axe, nous avons interrogé l’existence de potentiels groupes à vulnérabilité spécifique qui pourraient étayer l’implémentation d’une prévention de précision dans le vieillissement cognitif. Nous avons choisi ici d’élargir aux facteurs de mode de vie dans leur ensemble en ciblant un score combinant 12 facteurs modifiables validé dans la littérature, le LIBRA (Lifestyle for Brain health risk score), et montré que le LIBRA était associé au risque de démence et au déclin cognitif, quel que soit le niveau de susceptibilité génétique des individus (reflétée par l’allèle APOE4 et un score de risque génétique). Ce dernier travail suggère que la prévention par une modification du mode de vie pourrait être efficace chez tous, y compris chez les individus dont le profil génétique prédispose à développer une démence, ce qui constitue certainement un message encourageant pour ces personnes

A Biological Index to Screen Multi-Micronutrient Deficiencies Associated with the Risk to Develop Dementia in Older Persons from the Community

BACKGROUND: Low blood status in several nutritional compounds, including long-chain omega-3 fatty acids (LC n-3 PUFA), carotenoids, and vitamin D, have been associated with a higher risk to develop dementia. Nutritional deficiencies may potentiate each other regarding dementia risk; yet the association of multiple nutritional deficiencies with dementia has been little explored. OBJECTIVE: To develop an index of micronutritional biological status (MNBS) for the screening of multi-micronutritional deficiencies associated with the risk of dementia in a prospective population-based cohort of older persons. METHODS: We included participants from the Bordeaux Three-City study, who were free of dementia at baseline, had blood measurements of LC n-3 PUFA, carotenoids, and 25(OH)D, and who were followed for up to 18 years for dementia. We used penalized splines in Cox models to model dose-response relationships of each nutritional component with the risk of dementia and construct a risk index. RESULTS: 629 participants with an average age of 73.1 years were included in the study. Each increase of 1 SD of the MNBS index was associated with a 46%higher risk of dementia (HR = 1.46, 95%CI 1.23; 1.73). Participants with highest index ([mean+1SD; max]) had a 4-fold increased risk of dementia compared with participants with a low index ([min; mean-1SD]) (HR = 4.17, 95%CI 2.30; 7.57). CONCLUSION: This index of assessment of micronutritional biological status is a practical tool that may help identify populations with inadequate nutritional status, screen eligible individuals for nutritional prevention in primary care, or for supplementation in preventive trials of dementia

A Mediterranean Diet-Based Metabolomic Score and Cognitive Decline in Older Adults: A Case-Control Analysis Nested within the Three-City Cohort Study

International audienceEvidence on the Mediterranean diet (MD) and age-related cognitive decline (CD) is still inconclusive partly due to self-reported dietary assessment. The aim of the current study is to develop an MD- metabolomic score (MDMS) and investigate its association with CD in community-dwelling older adults. This study includes participants from the Three-City Study from the Bordeaux (n = 418) and Dijon (n = 422) cohorts who are free of dementia at baseline. Repeated measures of cognition over 12 years are collected. An MDMS is designed based on serum biomarkers related to MD key food groups and using a targeted metabolomics platform. Associations with CD are investigated through conditional logistic regression (matched on age, sex, and education level) in both sample sets. The MDMS is found to be inversely associated with CD (odds ratio [OR] [95% confidence interval (CI)] = 0.90 [0.80-1.00]; p = 0.048) in the Bordeaux (discovery) cohort. Results are comparable in the Dijon (validation) cohort, with a trend toward significance (OR [95% CI] = 0.91 [0.83-1.01]; p = 0.084). A greater adherence to the MD, here assessed by a serum MDMS, is associated with lower odds of CD in older adults

Exploration of the Gut-Brain Axis through Metabolomics Identifies Serum Propionic Acid Associated with Higher Cognitive Decline in Older Persons

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 investigatio

Exploration of the Gut–Brain Axis through Metabolomics Identifies Serum Propionic Acid Associated with Higher Cognitive Decline in Older Persons

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

High intensity neutrino oscillation facilities in Europe (vol 16, 021002, 2013)

The EUROnu project has studied three possible options for future, high intensity neutrino oscillation facilities in Europe. The first is a Super Beam, in which the neutrinos come from the decay of pions created by bombarding targets with a 4 MW proton beam from the CERN High Power Superconducting Proton Linac. The far detector for this facility is the 500 kt MEMPHYS water Cherenkov, located in the Fréjus tunnel. The second facility is the Neutrino Factory, in which the neutrinos come from the decay of μ+ and μ- beams in a storage ring. The far detector in this case is a 100 kt Magnetised Iron Neutrino Detector at a baseline of 2000 km. The third option is a Beta Beam, in which the neutrinos come from the decay of beta emitting isotopes, in particular 6He and 18Ne, also stored in a ring. The far detector is also the MEMPHYS detector in the Fréjus tunnel. EUROnu has undertaken conceptual designs of these facilities and studied the performance of the detectors. Based on this, it has determined the physics reach of each facility, in particular for the measurement of CP violation in the lepton sector, and estimated the cost of construction. These have demonstrated that the best facility to build is the Neutrino Factory. However, if a powerful proton driver is constructed for another purpose or if the MEMPHYS detector is built for astroparticle physics, the Super Beam also becomes very attractive