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Phenotype-specific omic expression patterns in people with frailty could provide invaluable insight into the underlying multi-systemic pathological processes and targets for intervention. Classical approaches to frailty have not considered the potential for different frailty phenotypes. We characterized associations between frailty (with/without disability) and sets of omic factors (genomic, proteomic, and metabolomic) plus markers measured in routine geriatric care. This study was a prevalent case control using stored biospecimens (urine, whole blood, cells, plasma, and serum) from 1522 individuals (identified as robust (R), pre-frail (P), or frail (F)] from the Toledo Study of Healthy Aging (R=178/P=184/F=109), 3 City Bordeaux (111/269/100), Aging Multidisciplinary Investigation (157/79/54) and InCHIANTI (106/98/77) cohorts. The analysis included over 35,000 omic and routine laboratory variables from robust and frail or pre-frail (with/without disability) individuals using a machine learning framework. We identified three protective biomarkers, vitamin D3 (OR: 0.81 [95% CI: 0.68-0.98]), lutein zeaxanthin (OR: 0.82 [95% CI: 0.70-0.97]), and miRNA125b-5p (OR: 0.73, [95% CI: 0.56-0.97]) and one risk biomarker, cardiac troponin T (OR: 1.25 [95% CI: 1.23-1.27]). Excluding individuals with a disability, one protective biomarker was identified, miR125b-5p (OR: 0.85, [95% CI: 0.81-0.88]). Three risks of frailty biomarkers were detected: pro-BNP (OR: 1.47 [95% CI: 1.27-1.7]), cardiac troponin T (OR: 1.29 [95% CI: 1.21-1.38]), and sRAGE (OR: 1.26 [95% CI: 1.01-1.57]). Three key frailty biomarkers demonstrated a statistical association with frailty (oxidative stress, vitamin D, and cardiovascular system) with relationship patterns differing depending on the presence or absence of a disability.

International audience; ObjectivesVisual impairment and cognitive disorders are common among older people in Low-and Middle-Income Countries (LMIC). Several recent studies performed in High-Income Countries suggested that visual impairment is associated with cognitive disorders. However, no synthesis of current knowledge exists for LMIC.MethodsWe have conducted an extensive literature search combining six databases and two grey literature databases. We searched for studies assessing the link between visual and cognitive impairments carried out in LMIC. The systematic search was performed up to 14th February 2019.ResultsOverall, eight studies were included in this review. Among them, five studies were performed in Asia and seven studies had a cross-sectional design. Mean age of the participants varied from 64.2 to 76.2 years. Participants were most often females. Only three studies were specifically focused on the association between visual impairment and cognitive disorders. Out of the eight studies included, four reported a significant association; two showed a possible association and two did not retrieve any statistically significant effect. Heterogeneity in assessments of visual and cognitive impairments was high.ConclusionIn LMIC, very few studies explored the association between visual and cognitive impairments among older people. The current review seems to suggest that visual impairment is associated with cognitive disorders in LMIC. However, further studies are required to improve the knowledge on this relationship. Improving vision, in particular through optical correction and cataract surgery, could potentially be easy pathways to reduce cognitive disorders incidence and to improve quality of life of people affected by this disorder.Previous article View latest articles Next article Login options Log inShibbolethOpenAthensRestore content access Restore content access for purchases made as guest ObjectivesVisual impairment and cognitive disorders are common among older people in Low-and Middle-Income Countries (LMIC). Several recent studies performed in High-Income Countries suggested that visual impairment is associated with cognitive disorders. However, no synthesis of current knowledge exists for LMIC.MethodsWe have conducted an extensive literature search combining six databases and two grey literature databases. We searched for studies assessing the link between visual and cognitive impairments carried out in LMIC. The systematic search was performed up to 14th February 2019.ResultsOverall, eight studies were included in this review. Among them, five studies were performed in Asia and seven studies had a cross-sectional design. Mean age of the participants varied from 64.2 to 76.2 years. Participants were most often females. Only three studies were specifically focused on the association between visual impairment and cognitive disorders. Out of the eight studies included, four reported a significant association; two showed a possible association and two did not retrieve any statistically significant effect. Heterogeneity in assessments of visual and cognitive impairments was high.ConclusionIn LMIC, very few studies explored the association between visual and cognitive impairments among older people. The current review seems to suggest that visual impairment is associated with cognitive disorders in LMIC. However, further studies are required to improve the knowledge on this relationship. Improving vision, in particular through optical correction and cataract surgery, could potentially be easy pathways to reduce cognitive disorders incidence and to improve quality of life of people affected by this disorder.

International audience; IntroductionLes déficiences visuelles (DV) seraient impliquées dans la survenue des troubles cognitifs (TC) chez les personnes âgées. Cependant, aucune étude n’a exploré cette relation en population Africaine.ObjectifInvestiguer la relation entre les DV et les TC chez les personnes âgées du Congo.MéthodesLes données exploitées sont celles collectées au suivi 1 (en 2013) de la cohorte EPIDEMCA-FU qui a inclus des personnes de 65 ans et plus en République du Congo. Le diagnostic des TC (Mild Cognitive Impairment, MCI ou démences) a été établi par un neurologue suite à un examen clinique approfondi et une batterie de tests neuropsychologiques. L’acuité visuelle (AV) a été évaluée à 30 cm à l’aide de l’échelle de Parinaud pour illettrés et la DV était définie par une AV < 20/40. La relation entre les DV et les TC a été explorée en utilisant la régression logistique.RésultatsSur les 659 participants inclus dans nos analyses, 106 (57 MCI et 49 démences), soit 16,1 % avaient des TC. La prévalence de la DV était de 69 %. Les DV étaient fortement associées aux TC (OR = 3,14 ; IC 95 % : 1,38–7,17) après ajustement sur l’âge, le sexe, le niveau d’éducation, les facteurs cardiovasculaires et la présence de gêne auditive. Cependant après ajustement sur le milieu de résidence (rural, urbain), l’association n’était plus significative (OR = 1,30 ; IC 95 % : 0,51–3,35).DiscussionLes DV et les TC partagent des facteurs de risque communs et une potentielle bidirectionnalité de l’association est évoquée. En effet, les changements neurovasculaires et/ou neurophysiologiques observés dans le cerveau des personnes avec TC pourraient être l’une des conséquences des déficiences sensorielles. Aussi, leur présence peut accentuer le déclin des fonctions visuelles qui a déjà commencé avec le vieillissement. Cependant, le milieu de résidence semble influencer l’association entre DV et TC dans notre étude.ConclusionLa relation DV-TC n’est pas encore claire. Il semble donc essentiel que des études supplémentaires prenant en compte le type de population (rurale et/ou urbaine) soient conduites pour mieux expliquer le rôle du milieu de résidence dans cette relation.

The size of the human head is determined by growth in the first years of life, while the rest of the body typically grows until early adulthood1. Such complex developmental processes are regulated by various genes and growth pathways2. Rare genetic syndromes have revealed genes that affect head size3, but the genetic drivers of variation in head size within the general population remain largely unknown. To elucidate biological pathways underlying the growth of the human head, we performed the largest genome-wide association study on human head size to date (N = 79,107). We identified 67 genetic loci, 50 of which are novel, and found that these loci are preferentially associated with head size and mostly independent from height. In subsequent neuroimaging analyses, the majority of genetic variants demonstrated widespread effects on the brain, whereas the effects of 17 variants could be localized to one or two specific brain regions. Through hypothesis-free approaches, we find a strong overlap of head size variants with both cancer pathways and cancer genes. Gene set analyses showed enrichment for different types of cancer and the p53, Wnt and ErbB signalling pathway. Genes overlapping or close to lead variants – such as TP53, PTEN and APC – were enriched for genes involved in macrocephaly syndromes (up to 37-fold) and high-fidelity cancer genes (up to 9-fold), whereas this enrichment was not seen for human height variants. This indicates that genes regulating early brain and cranial growth are associated with a propensity to neoplasia later in life, irrespective of height. Our results warrant further investigations of the link between head size and cancer, as well as its clinical implications in the general population.

[EN] Several studies have investigated the differential vulnerability of hippocampal subfields during aging and Alzheimer's disease (AD). Results were often contradictory, mainly because these works were based on concatenations of cross-sectional measures in cohorts with different ages or stages of AD, in the absence of a longitudinal design. Here, we investigated 327 participants from a population-based cohort of nondemented older adults with a 14-year clinical follow-up. MRI at baseline and 4 years later were assessed to measure the annualized rates of hippocampal subfields atrophy in each participant using an automatic segmentation pipeline with subsequent quality control. On the one hand, CA4 dentate gyrus was significantly more affected than the other subfields in the whole population (CA1-3: -0.68%/year; subiculum: -0.99%/year; and CA4-DG: -1.39%/year; p < 0.0001). On the other hand, the annualized rate of CA1-3 atrophy was associated with an increased risk of developing Alzheimer's clinical syndrome over time, independently of age, gender, educational level, and ApoE4 genotype (HR = 2.0; CI 95% 1.4-3.0). These results illustrate the natural history of hippocampal subfields atrophy during aging and AD by showing that the dentate gyrus is the most vulnerable subfield to the effects of aging while the cornu-ammonis is the primary target of AD pathophysiological processes, years before symptom onset., The 3C Study is conducted under a partnership agreement among the Institut National de la Sante et de la Recherche Medicale (INSERM), Bordeaux University, and Sanofi. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study is also supported by Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale, Institut de la Longevite, Conseils Regionaux d'Aquitaine et Bourgogne, Fondation de France, and the Ministry of Research-INSERM Programme "Cohortes et collections de donnees biologiques". The follow-ups have also been funded by ANR 2007LVIE 003, the "Fondation Plan Alzheimer," and the Caisse Nationale de Solidarite pour l'Autonomie (CNSA). This work benefited from the support of the project DeepvolBrain of the French National Research Agency (ANR-18-CE45-0013) and by the Spanish DPI2017-87743-R grant from the Ministerio de Economia, Industria y Competitividad of Spain. In addition, this study was achieved within the context of the Laboratory of Excellence TRAIL ANR-10-LABX-57 for the BigDataBrain project. Finally, the authors thank the Investments for the future Program IdEx Bordeaux (ANR10-IDEX-03-02, HL-MRI Project), Cluster of excellence CPU, and the CNRS. VP also received grants from Fondation Bettencourt Schueller (CCA-Inserm-Bettencourt). The sponsors did not participate in any aspect of the design or performance of the study, including data collection, management, analysis, and the interpretation or preparation, review, and approval of the manuscript.

Background Physical activity may decrease the risk of dementia; however, previous cohort studies seldom investigated the different types of physical activity and household activities. Our objective was to analyze the links between two physical activity types and dementia in older people. Methods The study used data from the prospective observational Three-city cohort and included 1550 community-dwelling individuals aged 72 to 87 without dementia at baseline. Physical activity was assessed with the Voorrips questionnaire. Two sub-scores were calculated to assess household/transportation activities and leisure/sport activities. Restricted cubic spline and proportional hazard Cox models were used to estimate the non-linear exposure-response curve for the dementia risk and the appropriate activity level thresholds. Models were adjusted for possible confounders, including socio-demographic variables, comorbidities, depressive symptoms and APOE genotype. Results The median age was 80 years, and 63.6% of participants were women. After a median follow-up of 4.6 years, dementia was diagnosed in 117 participants (7.6%). An inverse J-shaped association was found between household/transportation physical activity sub-score and dementia risk, which means that the risk is lowest for the moderately high values and then re-increases slightly for the highest values. The results remained significant when this sub-score was categorized in three classes (low, moderate, and high), with hazard ratios (95% confidence interval) of 0.55 (0.35–0.87) and 0.62 (0.38–1.01) for moderate and high activity levels, respectively. No significant effect was found for leisure/sport activities. Conclusions The 5-year risk of dementia was significantly and negatively associated with the household/transportation activity level, but not with the leisure and sport activity sub-score. This highlights the importance of considering all physical activity types in 72 years or older people.

Older persons comprise a growing proportion of the European population and may have a distinct epidemiological oral profile requiring specific preventive and curative care poorly documented. The objectives of this study were to assess the oral health status of people ≥90 years of age in France, to compare their perceived and observed oral care needs and to investigate the oral problems associated with a low oral health-related quality-of-life (OHRQoL).An oral cross-sectional study was performed during the 25th follow-up of a cohort of older persons being followed up prospectively for screening of dementia over a 15-year period in Gironde and Dordogne, France. Clinical oral indices were determined by oral examinations conducted at the participants' place of living. Cohen's Kappa coefficient was used to assess the agreement between perceived and observed oral care needs. Oral problems associated with a low OHRQoL, measured with the Geriatric Oral Health Assessment Index (GOHAI50) were investigated with logistic regression. Odds ratios (OR) were estimated with their 95% confidence intervals (CI).Data from 90 persons were analysed (76% female; median age=93 years; 20% living in an institution). Plaque and calculus were present in 93% and 58% respectively, of the 74 dentate participants. The mean number of decayed, missing, and filled teeth was 26.5 (±5.3); 66% of the participants had at least one untreated decayed tooth. Among the 85 participants with tooth loss not replaced by a fixed denture, two thirds had a removable dental prosthesis; 84% of these prostheses were considered to be maladapted. Among the 39 participants who felt unable to consult a dentist (43%), lack of transportation was the most frequently cited reason. Although 88% of the participants needed oral care, only 26% perceived that they had such a need (Kappa=0.06). Oral problems associated with a GOHAI50 were the absence of posterior occluding teeth (OR=7.15; 95%CI=1.53-33.35; P=0.012), feeling of dry mouth (OR=11.94; 95%CI=3.21-44.39; P=0.0002) and oral pain (OR=9.06; 95%CI=1.91-69.00; P=0.033).Persons ≥90 years of age have considerable preventive and curative dental care needs that impact their quality-of-life but they are rarely aware and lack transportation. NCT04065828.

International audience; To examine the relationship between hearing loss and depression in older adults longitudinally. This paper uses a dimensional approach to conceptualising depression, with the aim of further enhancing understanding of this relationship. 8344 community-dwelling adults aged 65 years and above enrolled in the Three-City prospective cohort study were included. Relationships between baseline self-reported hearing loss (HL) with the trajectory of different dimensions of depression symptoms over 12 years were examined using linear mixed models. Depression dimensions were determined using the four-factor structure of the Centre for Epidemiology Studies-Depression Scale (CESD): depressed affect, positive affect, somatic symptoms and interpersonal problems. HL was associated with somatic symptoms of depression both at baseline ( = .07, = .04) and over 12 years ( = .01, = .04). HL was associated with poorer depressed affect and interpersonal problems at baseline ( = .05, = .001, = .35

We were interested in the comment from Cosson et al. (1) on our recent report about high skin autofluorescence (sAF) in hyperglycemic mothers of large-for-gestational-age (LGA) newborns (2). Several reasons can explain why Cosson et al., and previously de Ranitz-Greven et al. (3), failed to detect a relationship between sAF and macrosomia. The first explanation is the low number of participants, 100 in de Ranitz-Greven et al. (3) and 148 in Cosson et al. (1), which can lead to an underpowered study and a lack of statistical power, versus 343 …

While the neural correlates of age-related episodic memory decline have been extensively studied, the precise involvement of the Posterior Cingulate Cortex (PCC) and posterior parietal cortex (the precuneus and the angular gyrus), remains unclear. The present study examined functional and structural neural correlates of age-related episodic memory change assessed over 12 years in 120 older adults (range 76-90 years). Episodic memory performance was measured using the Free and Cued Selective Reminding Test (FCSRT); functional connectivity metrics were computed from resting-state fMRI images and structural connectivity metrics were assessed through microstructural properties of reconstructed tract using a native space pipeline. We found that FCSRT change was significantly associated with the functional connectivity between the ventral PCC and three parietal regions, the ventral superior, the inferior part of the precuneus, and the rostro dorsal part of the angular gyrus. This association was independent of hippocampal volume. In addition, we found the that change in FCSRT scores was associated with fractional anisotropy of the tract connecting the ventral PCC and the ventral superior part of the precuneus. Change in episodic memory in aging was therefore related to a combination of high functional connectivity and low structural connectivity between the ventral PCC and the ventral superior part of the precuneus.

Introduction Prodromal non-motor symptoms precede, often by decades, motor signs and diagnosis of Parkinson's disease. It is however still uncertain if cognitive changes belong to the spectrum of non-motor prodromal Parkinson's disease. Thanks to the very long-term follow-up of the PAQUID population-based cohort, we assessed trajectories of cognitive complaints and functioning over a 13-year period before the diagnosis of late onset Parkinson's disease. Methods This study relies on a matched nested case-control sample selected from the cohort. Of the 3777 initial subjects of the cohort, 43 developed incident Parkinson's disease over the follow-up. The mean age at diagnosis was 78.0 (standard deviation = 5.8) years and 46.5% were men. These cases were matched to 86 elderly control subjects. Scores of different cognitive domains, daily function, and depressive symptoms were described throughout the follow-up using mixed-effects models. Results No significant global cognitive decline preceded the diagnosis of late onset Parkinson's disease. However, psychomotor speed appeared significantly slower 2 years before the diagnosis and depressive symptoms 12 years before. Global score of instrumental activities of daily living became altered 2–3 years preceding the diagnosis of late onset Parkinson's disease, including the use of public transportation that was altered ten years before the diagnosis. Conclusion In late onset Parkinson's disease, while global cognitive functions seem preserved, psychomotor speed starts to decline 2 years before the diagnosis and activities of daily living are also impacted. Depressive symptoms appear very early in the prediagnosic phase.

In biomedical research, various longitudinal markers measuring different quantities are often collected over time. For example, repeated measures of psychometric scores are very informative about the degradation process toward dementia. These trajectories are generally nonlinear with an acceleration of the decline a few years before the diagnosis and a large heterogeneity between psychometric tests depending on the underlying cognitive function to be evaluated and the metrological properties of the test. Comparing the times of acceleration of the decline before diagnosis between cognitive tests is useful to better understand the natural history of the disease. Our objective is to propose a bivariate random changepoint model that allows for the comparison of the mean time of change between two markers. A frequentist approach is proposed that gives validated statistical tests to assess the temporal order of the changepoints. Using a spline transformation function, the model is designed to handle non-Gaussian data, that are common for cognitive scores which frequently exhibit a strong ceiling effect. The procedure is assessed through a simulation study and applied to a French cohort of elderly to identify the order of the decline of several cognitive scores. The whole methodology has been implemented in a R package freely available.

Pseudo-values provide a method to perform regression analysis for complex quantities with right-censored data. A further complication, interval-censored data, appears when events such as dementia are studied in an epidemiological cohort. We propose an extension of the pseudo-value approach for interval-censored data based on a semi-parametric estimator computed using penalised likelihood and splines. This estimator takes interval-censoring and competing risks into account in an illness-death model. We apply the pseudo-value approach to three mean value parameters of interest in studies of dementia: the probability of staying alive and non-demented, the restricted mean survival time without dementia and the absolute risk of dementia. Simulation studies are conducted to examine properties of pseudo-values based on this semi-parametric estimator. The method is applied to the French cohort PAQUID, which included more than 3,000 non-demented subjects, followed for dementia for more than 25 years.

International audience; OBJECTIVES: Previous studies have reported controversial findings regarding the association of testosterone with mortality in older men. This heterogeneity might be partially explained by comorbidities and the presence of metabolic syndrome, as well as differential associations according to causes of death.METHODS: We used data from a random subsample of the Three-City study, in which hormone levels were measured in 338 men ≥65 years without metabolic syndrome who were followed-up for 12 years. Vital status was determined for all participants from different sources. We used inverse-probability-weighted Cox regression to estimate the hazard ratios (HRs) of cause-specific mortality and 95% confidence intervals (CIs).RESULTS: Over the follow-up period, 130 men died (30 from cardiovascular disease, 45 from cancer, 55 from other causes). The association of testosterone with mortality showed significant heterogeneity across causes of death (p=0.027 and p=0.022 for total and bioavailable testosterone, respectively). Higher testosterone levels were associated with increased cardiovascular mortality (HR for 1-standard deviation increase, 1.86; 95% CI, 1.28 to 2.71 and 1.50; 95% CI, 1.04 to 2.17 for total and bioavailable testosterone, respectively). By contrast, there were no significant associations of testosterone with mortality from cancer and other causes.CONCLUSIONS: Our data suggest that the association of testosterone with mortality in men without metabolic syndrome might be differential according to the cause of death. These findings may partially explain the heterogeneity across studies on the relationship between testosterone levels and mortality.

International audience; Background:Chronic exposure to air pollution (AP) is associated with cardiovascular morbidity and mortality. Emerging epidemiological evidence suggests a relationship between exposure to various air pollutants (fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2)) and dementia. However, most of existing studies relied on population-based health administrative databases to obtain a dementia diagnosis. In a large French population-based cohort (the Three-City Study) and using state-of-the-art models for AP exposure, we aimed at assessing the effects of different air pollutants on dementia risk using reliable diagnosis tools.Methods:Participants aged ≥65 years were recruited between 1999 and 2001 and followed for 12 years. At baseline and every 2 years, dementia diagnoses were preliminary made using DSM-IV criteria and validated by an adjudication committee. Levels of NO2, O3, Black Carbon and PM2.5 were obtained at the residential addresses of participants using land-use regression models developed for Europe in the ELAPSE project (de Hoogh et al., Env Int 120 (2018) 81-92). For each year of follow-up, we estimated for each subject a 10-year moving window of mean past exposure to each pollutant. We used a Cox Proportional Hazard model where exposure to AP was included as a time-varying variable. Analyses were adjusted for individual (age, sex, education, APOE4 genotype, vascular risk factors, depression, respiratory diseases) and contextual (neighborhood’s deprivation index) level confounders.Result:At baseline, the mean (SD) age of the 7956 participants was 73.2 (5.4) years-old. Sixty-one percent of them were women. The mean time of follow-up was 9.2 (3.6) years. Over the follow-up period, the mean annual PM2.5 levels ranged from 15 to 33 µg/m3 and 910 participants developed dementia. We observed a positive association between levels of PM2.5 and dementia risk [HR=1.16, 95%CI (1.02-1.32) for a 5µg/m3 increase in PM2.5]. We did not observe any relationship between exposure to the other air pollutants and dementia risk.Conclusion:In this large cohort with reliable diagnosis of dementia and individual estimates of AP exposure, we observed that long-term exposure to PM2.5 was associated with higher dementia incidence. These results suggest that PM2.5 exposure might be a modifiable risk factor of dementia.

International audience; Multiple system atrophy (MSA) is a rare neurodegenerative disease, with limited understanding of disease progression and prognostic factors. We leveraged the data of a large prospective cohort of MSA to study both clinical progression and survival and assess their determinants. All consecutive patients seen at the French Reference Centre for MSA since 2007 were included in a prospective cohort with an annual follow-up including the Unified MSA Rating Scale (UMSARS). We used joint models to evaluate the risk of death, the mean trajectory of each UMSARS subscale and to determine the potential factors. Investigated factors included gender, age at baseline, MSA subtype, diagnosis certainty, type of first symptoms and the duration between symptom onset and the first visit. Among the 261 MSA patients included in our cohort, the median duration of clinical follow-up was 2.1 years (up to 10.3 years) and the median survival was 4.0 years since the first visit. Main factors for poor survival were the progression over time of UMSARS score (I + II and IV) and the severity of orthostatic hypotension. MSA subtype had no effect on progression or survival. The UMSARS I + II score progressed faster over time in subjects with autonomic dysfunction as the initial feature and in women. Despite a faster progression, women and men had similar survival. From this large MSA cohort, we confirm the rapid progression and poor prognosis of MSA. We provide additional evidence for a negative impact of early autonomic dysfunction and the severity of orthostatic hypotension on both disease progression and survival.

Aim The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population-based setting. Methods Cross-sectional data were obtained from the Swedish population-based Malmo Diet and Cancer Study Re-examination 2007-2012 comprising 3001 older people (mean age 72 years). Through oral glucose tolerance testing (OGTT), fasting and post-load levels of serum insulin, plasma glucagon, serum glucose-dependent insulinotropic peptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses. Results Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B = 0.822, P = 0.004), 2-h plasma glucagon (B = 0.596, P = 0.026), 2-h serum GIP (B = 0.581, P = 0.040) and 2-h plasma GLP-1 (B = 0.585, P = 0.038), whereas negative associations were found between MMSE scores and insulin resistance (B = -0.734, P = 0.006), fasting plasma GLP-1 (B = -0.544, P = 0.033) and AGEs (B = -1.459, P = 0.030) were found. Conclusions Higher levels of insulin sensitivity, GIP and GLP-1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP-1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain Funding Agencies|Research Council of Sweden [K2011-65X-20752-04-6]; Anders Palsson Foundation; Ernhold Lundstrom Foundation; Skane County Council; Lund University; Swedish Alzheimers Foundation (Alzheimerfonden); Region Skane

Background:Given the rate of the undiagnosed cases of dementia and the consequences of inappropriate care, understanding the factors that explain the use of medical and health care in dementia is a critical concern. Our objective was to identify the psychosocial and medical determinants of use of care in dementia.Methods:The study sample consisted of 308 participants: the persons with dementia (n = 99) selected from three French population-based cohorts (i.e. PAQUID, 3C, AMI), their family caregivers (primary, n = 96, and secondary, n = 51), and their general practitioners (n = 62). Use of care in dementia was considered according to two indicators: (1) recourse to secondary care, (2) number of community and health services used.Results:Multiple logistic models including sociodemographics and psychosocial variables revealed that the determinants of nonuse of care are similar both for the recourse to secondary care and for the number of community and health services used: lack of education and the contribution of the people with dementia to the decisions regarding their own care and dementia care services in the community area. In addition, satisfaction of the primary caregiver with the services used by his/her relative is associated with non-recourse to secondary care.Conclusions:Taken together, these results highlight the predominant role of psychosocial factors in the use of care in dementia and the importance of addressing this issue through an integrative approach including psychological, social, medical, and family dimensions.

Diffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination improved the sensitivity of conventional DTI measures to detect associations between tissue-specific diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content measured along the cingulum was independently strongly associated with changes in verbal fluency. These observations suggest the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.

Background Hearing and vision (sensory) impairments are highly prevalent in people with dementia (PwD) and exacerbate the impact of living with dementia. Assessment of sensory or cognitive function may be difficult if people have concurrent dual or triple impairments. Most standard cognitive assessment tests are heavily dependent on having intact hearing and vision, and impairments in these domains may render the assessments unreliable or even invalid. Likewise, dementia may impede on the accurate reporting of symptoms that is required for most hearing and vision assessments. Thus, there is an urgent need for hearing, vision and cognitive assessment strategies to be adapted to ensure that appropriate management and support can be provided. Objective To explore the perspectives of PwD and the care partners regarding the need for accurate hearing, vision and cognitive assessments. Methods We conducted focus groups and semi-structured interviews regarding the clinical assessment for cognitive, hearing and visual impairment. Participants (n = 18) were older adults with mild to moderate dementia and a sensory impairment as well as their care partners (e.g. a family member) (n = 15) at three European sites. The qualitative material was analysed according to Mayring’s summative content analysis approach. Results Participants reported that hearing, vision and cognitive assessments were not appropriate to the complex needs of PwD and sensory comorbidity and that challenges in communication with professionals and conveying unmet needs and concerns by PwD were common in all three types of clinical assessments. They felt that information about and guidance regarding support for the condition was not adequate in the assessments and that information sharing among the professionals regarding the concurrent problems was limited. Professionals were reported as being concerned only with problems related to their own discipline and had limited regard for problems in other domains which might impact on their own assessments. Conclusions The optimal assessment and support for PwD with multiple impairments, more comprehensive, yet easy to understand, information regarding these linked to conditions and corrective device use is needed. Communication among health care professionals relevant to hearing, vision and cognition needs to be improved.

Introduction Several studies have reported disparities in the care management and survival of older cancer patients. The aim of our study was to identify determinants of treatment administration in this population of cancer patients aged over 65 years taking into account competing risks of death. Methods The INCAPAC study is a population-based study. Four cancer registries and three prospective cohort studies on older subjects (age ≥65 years) from Gironde, a French department, were merged to identify older cancer patients. We used a non-parametric multi-state model including three states (cancer, treatment and all-cause death). This model allowed studying determinants of treatment administration (all treatments including curative, symptomatic and palliative treatments) and mortality considering that patients can move from cancer state to death state, either directly or through the treatment phase. Studied variables were demographic and socioeconomic-, cancer-, health-, and geriatric-related. Results A total of 450 patients were included in the analyses. They were mainly aged 85 and over, men and educated. Among included patients, 372 (83%) received cancer treatment. In the final multivariate model, dementia was associated with a lower likelihood of receiving cancer treatment (HR = 0.68, 95% CI = 0.47–0.99). In treated patients, age, sex, comorbidities, dependency and stage at diagnosis were associated to all-cause mortality, and in untreated patients, diagnosis of dementia and stage at diagnosis were associated to mortality. Conclusion Further studies are necessary to understand the impact of geriatric impairments on treatment administration and to develop clinical practice guidelines.

CONTEXT: Although endogenous estradiol, generally considered as the female hormone, has been little investigated in men, it could play a role in men's health, mortality in particular. The influence of estrogen receptors (ER) genetic polymorphisms on this relationship has never been studied. DESIGN AND PARTICIPANTS: The Three-City cohort study included (1999-2001) 3650 men >/=65 years who were followed for mortality over 12 years. At baseline, total estradiol (tE2) was measured and ER genotyped in a random subsample of 472 men without hormonal treatment. Free estradiol (fE2) was estimated using Vermeulen and Sodergard algorithms. MAIN OUTCOME: Mortality data were obtained from death certificates. We used inverse probability weighted Cox models to examine the association of estradiol with all-cause and cause-specific mortality and its interaction with ER genetic polymorphisms. RESULTS: 183 men died over the follow-up (cardiovascular disease (CVD), n=44; cancer, n=57; other causes, n=82). After adjustment, there was a quadratic relationship of all-cause mortality with tE2 and fE2 (p-quadratic=0.04 and 0.05, respectively), with higher mortality for the top and bottom tertiles compared to the middle one. These associations were stronger for CVD mortality (p-quadratic=0.01 and 0.02 for tE2 and fE2, respectively) and disappeared for cancer mortality. There was no evidence of an interaction of estradiol with any ER polymorphisms on all-cause mortality. CONCLUSION: In elderly men, we showed a nonlinear association of tE2 and fE2 with all-cause mortality. These quadratic relationships were stronger for CVD mortality and did not exist for cancer mortality. ER genetic polymorphisms did not modify this association. This article is protected by copyright. All rights reserved.

In line with declining trends in dementia incidence, we compared the cognitive and functional evolution of 2 "generations" of elderly individuals aged 78-88 years, who were included 10 years apart in the French Personnes Agees Quid cohort (n = 612 in 1991-1992 and n = 628 in 2001-2002) and followed-up for 12 years with assessments of cognition and disability. The impact of specific risk factors on this evolution was evaluated. Differences between the generations in baseline levels and decline over time were estimated using a joint model to account for differential attrition. Compared with the first generation, the second generation had higher performances at baseline on 4 cognitive tests (from P < 0.005). Differences in global cognition, verbal fluency, and processing speed, but not in working memory, were mostly explained by improvement in educational level. The second generation also exhibited less cognitive decline in verbal fluency and working memory. Progression of disability was less over the follow-up period for the second generation than for the first. The cognitive state of this elderly population improved, partially due to improvements in educational level.

Background Advanced glycation end-products play a role in diabetic vascular complications. Their optical properties allow to estimate their accumulation in tissues by measuring the skin autofluorescence (SAF). We searched for an association between SAF and major adverse cardiovascular events (MACE) incidence in subjects with Type 1 Diabetes (T1D) during a 7 year follow-up. Methods During year 2009, 232 subjects with T1D were included. SAF measurement, clinical [age, sex, body mass index (BMI), comorbidities] and biological data (HbA1C, blood lipids, renal parameters) were recorded. MACE (myocardial infarction, stroke, lower extremity amputation or a revascularization procedure) were registered at visits in the center or by phone call to general practitioners until 2016. Results The participants were mainly men (59.5%), 51.5 ± 16.7 years old, with BMI 25.0 ± 4.1 kg/m2, diabetes duration 21.5 ± 13.6 years, HbA1C 7.6 ± 1.1%. LDL cholesterol was 1.04 ± 0.29 g/L, estimated Glomerular Filtration Rates (CKD-EPI): 86.3 ± 26.6 ml/min/1.73 m2. Among these subjects, 25.1% were smokers, 45.3% had arterial hypertension, 15.9% had elevated AER (≥ 30 mg/24 h), and 9.9% subjects had a history of previous MACE. From 2009 to 2016, 22 patients had at least one new MACE: 6 myocardial infarctions, 1 lower limb amputation, 15 revascularization procedures. Their SAF was 2.63 ± 0.73 arbitrary units (AU) vs 2.08 ± 0.54 for other patients (p = 0.002). Using Cox-model, after adjustment for age (as the scale time), sex, diabetes duration, BMI, hypertension, smoking status, albumin excretion rates, statin treatment and a previous history of MACE, higher baseline levels of SAF were significantly associated with an increased risk of MACE during follow-up (HR = 4.13 [1.30–13.07]; p = 0.02 for 1 AU of SAF) and Kaplan–Meier curve follow-up showed significantly more frequent MACE in group with SAF upper the median (p = 0.001). Conclusion A high SAF predicts MACE in patients with T1D. Electronic supplementary material The online version of this article (10.1186/s12933-018-0718-8) contains supplementary material, which is available to authorized users.

Objectives:To examine the longitudinal risk of vision loss (VL) or hearing loss (HL) for experiencing suicidal ideation in older adults.Design:The Three-City study, examining data from three waves of follow-up (2006–2008, 2008–2010, and 2010–2012).Setting:Community-dwelling older French adults.Participants:N = 5,438 adults aged 73 years and over.Measurements:Suicidality was assessed by the Mini-International Neuropsychiatric Interview, Major Depressive Disorder module. Mild VL was defined as Parinaud of 3 or 4 and severe VL as Parinaud >4. Mild HL was self-reported as difficulty understanding a conversation and severe HL as inability to understand a conversation.Results:Severe VL was associated with an increased risk of suicidal ideation at baseline (OR = 1.59, 95% CIs = 1.06–2.38) and over five years (OR = 1.65, 95% CIs = 1.05–2.59). Mild and severe HL were associated with an increased risk of suicidal ideation, both at baseline (OR = 1.29, 95% CIs = 1.03–1.63; OR = 1.78, 95% CIs = 1.32–2.40) and over five years (OR = 1.47, 95% CIs = 1.17–1.85; OR = 1.97, 95% CIs = 1.44–2.70).Conclusion:Sensory losses in late life pose a risk for suicidal ideation. Suicidality requires better assessment and intervention in this population.

Introduction De nombreuses pathologies neurologiques affectent l’hippocampe au cours du vieillissement. L’etude de la vulnerabilite des sous-champs hippocampiques peut aider a la comprehension de ces processus notamment concernant l’atteinte vasculaire cerebrale. Objectifs Etudier l’effet « pur » des dommages vasculaires independamment d’autres maladies sur l’atrophie des sous-champs hippocampiques. Patients et methodes Nous avons recrute 249 participants a partir d’une cohorte d’adultes âges non dements, apres exclusion des sujets diagnostiques avec une pathologie neurodegenerative au cours du suivi de 14 ans. En utilisant un logiciel de segmentation automatique, une IRM cerebrale 1.5 Tesla a l’inclusion et 4 ans plus tard a ete realisee en mesurant a la fois les volumes des hypersignaux de la substance blanche et les volumes des sous-champs hippocampiques. Resultats Seul le volume du Subiculum a baseline etait associe avec les hypersignaux de substance blanche qu’ils soient totaux, profonds et periventriculaires, independamment des variables demographiques et des facteurs de risque vasculaires (s = −0,17, p = 0,011 ; s = −0,25, p = 0,020 et s = −0,14, p = 0,029 respectivement). De maniere longitudinale, l’atrophie du Subiculum etait significativement plus importante parmi les sujets ayant le taux de progression d’hypersignaux profonds le plus important, independamment des facteurs confondants (s = −0,32, p = 0,014). Discussion Notre etude suggere une vulnerabilite differentielle des sous-champs a l’atteinte vasculaire cerebrale, dont les mecanismes physiopathologiques restent a preciser. Elle permet de souligner la pertinence de la distinction entre les hypersignaux periventriculaires et profonds. Les perspectives ouvertes sont nombreuses mais necessitent avant tout le developpement de protocoles harmonises de segmentation des sous-champs. Conclusion Ces resultats mettent en lumiere la vulnerabilite differentielle du Subiculum a l’atteinte vasculaire cerebrale, particulierement lorsqu’elle touche la substance blanche profonde, independamment de l’effet d’une pathologie neurodegenerative.

Objectif Etudier la relation entre la mauvaise qualite du sommeil (QS), la somnolence diurne excessive (SDE), les plaintes d’insomnie, l’usage d’hypnotiques et la survenue de demence (tout type confondu, maladie d’Alzheimer (MA), demence a composante vasculaire (DCV)) sur un suivi de 12 ans. Methodes Les analyses ont ete realisees sur 6851 participants (≥ 65 ans) non dements a l’inclusion, recrutes en population generale dans la cohorte des 3 Cites. Un interrogatoire structure et des auto-questionnaires ont ete utilises pour evaluer les plaintes de sommeil et la prise d’hypnotiques a l’inclusion. Au cours du suivi, les cas incidents de demence ont ete systematiquement depistes et diagnostiques. Des modeles de Cox multivaries ont permis d’estimer le risque de demence associe aux differentes plaintes du sommeil considere individuellement et globalement (score de severite composite). Resultats Apres ajustement sur les caracteristiques sociodemographiques, le mode de vie, l’APOE-ɛ4, les facteurs cardiovasculaires et le statut depressif, la SDE etait associee a un risque accru de 21 % de demence tout type confondu (IC95 % = 1,01-1,46) et de 58 % de DCV (IC95 %= 1,07-2,32). L’utilisation d’hypnotiques etait associee a un risque plus eleve de demence tout type confondu et, plus specifiquement a la MA (HR= 1,28 ; IC95 %= 1,04-1,58). Une interaction avec le diabete a ete detectee. Aucune association n’a ete trouvee pour la QS, les plaintes d’insomnie, ou le score composite de severite. Conclusion Les resultats suggerent un role deletere de la SDE et de l’utilisation d’hypnotiques sur le risque de demence chez le sujet âge.

Dairy products (DP) are part of a food group that may contribute to the prevention of physical frailty. We aimed to investigate DP exposure, including total DP, milk, fresh DP and cheese, and their cross-sectional and prospective associations with physical frailty in community-dwelling older adults. The cross-sectional analysis was carried out on 1490 participants from the Three-City Bordeaux cohort. The 10-year frailty risk was examined in 823 initially non-frail participants. A food frequency questionnaire was used to assess DP exposure. Physical frailty was defined as the presence of at least 3 out of 5 criteria of the frailty phenotype: weight loss, exhaustion, slowness, weakness, and low physical activity. Among others, diet quality and protein intake were considered as confounders. The baseline mean age of participants was 74.1 y and 61% were females. Frailty prevalence and incidence were 4.2% and 18.2%, respectively. No significant associations were observed between consumption of total DP or DP sub-types and frailty prevalence or incidence (OR = 1.40, 95%CI 0.65–3.01 and OR = 1.75, 95%CI 0.42–1.32, for a total DP consumption &gt, 4 times/d, respectively). Despite the absence of beneficial associations of higher DP consumption on frailty, older adults are encouraged to follow the national recommendations regarding DP.

Introduction La qualite de vie (QdV) devient un enjeu majeur dans l’etude de la progression des maladies, notamment des maladies neurologiques incurables caracterisees par une degenerescence progressive telles que l’atrophie multi-systematisee (AMS). Son etude apporte des informations cruciales sur le ressenti des patients et permet aux cliniciens de mieux les accompagner face a l’aggravation de leur etat de sante. Cependant, la QdV est un concept complique a apprehender, possiblement multidimensionnel et quantifie par un ensemble d’items categoriels. Les methodes statistiques appropriees a son etude restent encore peu diffusees en sante du fait de la complexite des donnees. Dans ce travail, nous decrivons les differentes etapes mises en œuvre pour etudier l’evolution d’une echelle de QdV au travers de l’evolution de l’echelle MSA-QoL specifique a l’AMS. Methodes Les donnees sont issues de la cohorte francaise AMS incluant plus de 600 patients diagnostiques dans le centre de reference maladie rare des CHU de Bordeaux et de Toulouse. Les patients ont un suivi annuel standardise incluant l’evaluation de la QdV par l’echelle MSA-QoL composee de 40 items, quotes de 0 a 4, evaluant les spheres motrices, non-motrices et emotionnelles/sociales. Notre methodologie s’est scindee en quatre etapes : – identifier les dimensions pertinentes mesurees par l’echelle et les items les constituants, par la methode PROMIS basee sur une analyse factorielle ; – etudier la trajectoire de chaque dimension et ses determinants par un modele IRT adapte aux donnees longitudinales ; – decrire la hierarchie d’atteintes des items de chaque dimension et la confronter a la progression de la pathologie (ici le degre de handicap) ; – quantifier l’apport de chaque item a chaque stade de la maladie par le calcul du pourcentage d’information de Fisher et identifier les plus informatifs. Resultats Nous avons identifie quatre dimensions de QdV : motrice, alimentaire, non-motrice et emotionnelle. Ces dernieres, deja partiellement atteintes en debut de suivi, s’aggravent au cours de la maladie, avec une evolution beaucoup plus rapide de la dimension motrice par rapport aux autres dimensions plus progressives. Les vitesses d’aggravation de ces dimensions different notamment selon le sexe, l’âge et les sous-diagnostics de la maladie. Enfin, l’analyse de l’information met en evidence certains items de QdV plus informatifs sur la progression de l’AMS, tels que ceux associes aux mouvements pour la dimension motrice, et la fatigue, les douleurs localisees et l’inconfort la nuit pour la dimension non-motrice. Conclusion Nous apportons avec cette etude de cas concrete, une methodologie complete permettant l’analyse de donnees longitudinales de QdV telles que rencontrees dans un nombre croissant d’etudes cliniques.

International audience; Several studies suggest that physical activity improves cognitive functions and reduces cognitive decline, whereas others did not find any evidence of a neuroprotective effect. Furthermore, few cohort studies have analyzed the different physical activity types and particularly household activities. Our objective was to assess the association of two physical activity types with the decline in different cognitive domains in a large prospective cohort of community-dwelling older adults from the Three-city study. Physical activity (domestic/transportation activities and leisure/sport activities) was assessed with the Voorrips questionnaire, specific for older adults. Baseline sociodemographic and health history variables as well as cognitive performance data at baseline and during the 8-year follow-up (Mini-Mental State Examination, Benton Visual Retention Test, Trail Making Tests A and B, Isaac's Set Test and Free and Cued Selective Reminding Test) were also available. Associations between physical activity scores and cognitive decline in different domains were tested using minimally- and multi-adjusted linear mixed models. The analysis included 1697 participants without dementia at baseline and with at least one follow-up visit. At baseline, participants with higher sub-scores for the two physical activity types had better cognitive performances. Interaction with time showed that decline in some cognitive scores (Trail Making Test B and Isaac's Set Test) was significantly less pronounced in participants with higher household/transportation activity sub-scores. No significant effect over time was found for leisure/sport activities. This study shows that during an 8-year follow-up, executive functions and verbal fluency were better preserved in older adults who performed household/transportation activities at moderate to high level. Participation in domestic activities and using adapted transport means could allow older adults to maintain specific cognitive abilities.

International audience; INTRODUCTION:The living environment affects general health and may influence cognitive aging; however, the relationships between neighborhood characteristics and dementia are still poorly understood.METHODS:We used data from a French population-based prospective study (the Three-City cohort) that included 7016 participants aged 65 years and older with a 12-year follow-up. We used principal components analysis of neighborhood composition indicators to construct the Three-City deprivation score. To study its impact on dementia incidence, we performed survival analyses using a marginal Cox model to take into account intraneighborhood correlations. As interaction with sex was significant, analyses were stratified by sex.RESULTS:Even after controlling on individual factors, women living in deprived neighborhoods were at higher risk of dementia (hazard ratio = 1.29, 95% confidence interval 1.00-1.67) and Alzheimer's disease (hazard ratio = 1.42, 95% confidence interval 1.09-1.84). No association was found for men.DISCUSSION:Living in a deprived neighborhood is associated with higher risk of dementia in women.

International audience; Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.

BackgroundHearing and vision impairments are among the most common and disabling comorbidities in people living with dementia. Intervening to improve sensory function could be a means by which the lives of people living with dementia may be improved. However, very few studies have tried to ameliorate outcomes in dementia by improving sensory function. This paper describes the multi-step development of a new intervention designed to support hearing and vision function in people living with dementia in their own homes. At the end of the development programme, it is anticipated that a ‘sensory support’ package will be ready for testing in a full scale randomised controlled trial.MethodsThis programme is based on the process of ‘intervention mapping’ and comprises four integrated steps, designed to address the following: (1) scoping the gaps in understanding, awareness and service provision for the hearing and/or vision impairment care needs of people with dementia using a systematic literature review and Expert Reference Group; (2) investigating the support care needs through a literature search, stakeholder surveys, focus groups, semi-structured interviews and an Expert Reference Group, leading to a prototype sensory support package; (3) refining the prototype by additional input from stakeholders using focus groups and semi-structured interviews; and (4) field testing the draft intervention using an open-labelled, non-randomised feasibility study, integrating feedback from people with dementia and their significant others to develop the final intervention ready for full scale definitive trialling. Input from the ‘patient and public voice’ is a cornerstone of the work and will interlink with each step of the development process. The programme will take place in study centres in Manchester, Nicosia and Bordeaux.DiscussionQuantitative and qualitative data analyses will be employed, dependent upon the sub-studies in question. Data from the steps will be integrated with consideration given to weighting of evidence for each step of the programme. This programme represents the logical development of a complex intervention to fulfil an unmet need. It is based on a theoretical framework and will lead to a subsequent full scale efficacy trial. The challenges in integrating the data and addressing the contextual issues across study sites will be scrutinised.

Introduction Several nutrients may predict dementia risk. We characterized nutrient biomarker patterns, which integrate the complexity of nutrient exposure and biodisponibility associated with long-term risk of dementia in a large cohort of older persons, the Three-City study. Methods We included 666 nondemented participants with plasma measurements of 22 fat-soluble nutrients at baseline, who were followed up for 12 years for dementia. Results A "deleterious" pattern combining lower blood status in vitamin D, carotenoids, and polyunsaturated fats and higher saturated fats was strongly associated with a higher risk of dementia. Compared with individuals in the first quintile of the pattern score, participants in the highest quintile of score had an approximately fourfold increased risk of dementia (hazard ratio = 4.53 [95% confidence interval 1.99, 10.32], P for trend Discussion A blood pattern reflecting lower status in several nutrients among nondemented individuals appeared strongly associated with the long-term risk of dementia in this cohort.

Introduction Chronic kidney disease (CKD) is often associated with poor hypertension control and treatment resistance, but whether CKD modifies the effect of hypertension control on outcomes is unknown. Methods We studied 10-year mortality and cardiovascular events according to hypertension control status and CKD (glomerular filtration rate

Objectives: To compare the 4-year survival, institutionalization, cognitive and functional decline of Alzheimer’s patients with specific follow-up in memory centers versus usual care. Design: Four year longitudinal follow-up. Settings: The French Network of memory centers in Alzheimer’s disease (REAL-FR study) and The French population-based study (3C study). Participants: 728 patients aged ≥ 65, living at home, meeting criteria for probable Alzheimer’s disease and having Mini Mental State Examination (MMSE) scores between 10 and 26 at baseline were included. Measurements: Cox proportional hazards models were performed to test the effectiveness of a specific follow-up in memory centers (REAL-FR study) versus usual care (3C study) on the 4-year survival and institutionalization. Linear mixed models were used to assess cognitive and functional decline in both groups. Results: After adjustment for confounding factors, the 4-year survival did not differ significantly between patients followed-up in memory centers and those who had recourse to usual care (usual care: Hazard Ratio adjusted (HRa) = 0.87, 95% confidence interval (CI) 0.53-1.43, p=0.59). Patients with a specific follow-up in memory centers had a higher risk of being institutionalized (usual care: HRa = 0.24, 95% CI 0.12-0.48, p Conclusion: Our findings failed to demonstrate any potential benefits of a specific follow-up in memory centers on clinically meaningful outcomes in the natural history of Alzheimer’s disease. Recourse to care in memory centers may have been the consequence of a faster dementia progression and a greater burden of Alzheimer’s disease, all leading to detrimental consequences on various prognostic outcomes.

Dementia is an increasing focus for policymakers, civil organizations and multidisciplinary researchers. The most recent descriptive epidemiological research into dementia is enabling investigation into how the prevalence and incidence are changing over time. To establish clear trends, such comparisons need to be founded on population-based studies that use similar diagnostic and research methods consistently over time. This narrative Review synthesizes the findings from 14 studies that investigated trends in dementia prevalence (nine studies) and incidence (five studies) from Sweden, Spain, the UK, the Netherlands, France, the USA, Japan and Nigeria. Besides the Japanese study, these studies indicate stable or declining prevalence and incidence of dementia, and some provide evidence of sex-specific changes. No single risk or protective factor has been identified that fully explains the observed trends, but major societal changes and improvements in living conditions, education and healthcare might have favourably influenced physical, mental and cognitive health throughout an individual's life course, and could be responsible for a reduced risk of dementia in later life. Analytical epidemiological approaches combined with translational neuroscientific research could provide a unique opportunity to explore the neuropathology that underlies changing occurrence of dementia in the general population.

Background Physical activity may decrease the risk of dementia; however, previous cohort studies seldom investigated the different types of physical activity and household activities. Our objective was to analyze the links between two physical activity types and dementia in older people.Methods The study used data from the prospective observational Three-city cohort and included 1550 community-dwelling individuals aged 72 to 87 without dementia at baseline. Physical activity was assessed with the Voorrips questionnaire. Two sub-scores were calculated to assess household/transportation activities and leisure/sport activities. Restricted cubic spline and proportional hazard Cox models were used to estimate the non-linear exposure-response curve for the dementia risk and the appropriate activity level thresholds. Models were adjusted for possible confounders, including socio-demographic variables, comorbidities, depressive symptoms and APOE genotype.Results The median age was 80 years, and 63.6% of participants were women. After a median follow-up of 4.6 years, dementia was diagnosed in 117 participants (7.6%). An inverse J-shaped association was found between household/transportation physical activity sub-score and dementia risk. The results remained significant when this sub-score was categorized in three classes (low, moderate, and high), with hazard ratios (95% confidence interval) of 0.55 (0.35-0.87) and 0.62 (0.38-1.01) for moderate and high activity levels, respectively. No significant protective effect was found for leisure/sport activities.Conclusions The 5-year risk of dementia was significantly and negatively associated with the household/transportation activity level, but not with the leisure and sport activity sub-score. This highlights the importance of considering all physical activity types in 72 years or older people.

International audience; Diabetes is associated with a higher dementia and mortality risk. However, few studies have accounted for death when estimating the association between diabetes and dementia. We estimated absolute and relative risks of all-cause dementia according to diabetes exposure status in older adults while accounting for competing risk of death using illness-death models. Effect modification by specific characteristics (age, gender, education, cardiovascular risk factors, body mass index, cardiovascular history, depressive symptomatology, impaired renal function, and APOEɛ4 genotype) was also investigated. We analyzed the Three-City study data, a French population-based cohort of adults aged 65 years and above who were followed up for 12 years from 1999-2001. Among 8,328 participants selected in the analytical sample (median age, 73.3 years; 60.3% women), 809 (9.3%) presented with diabetes at baseline. Over a median follow-up period of 8.3 years, 836 participants developed incident dementia. Baseline diabetes was associated with a higher risk of dementia: hazard ratio, 1.79 [95% confidence interval, 1.46-2.19]. No effect modification was shown. Diabetes was associated with a higher 12-year absolute risk of dementia and a lower dementia-free life expectancy (e.g., 14.5% [11.2-18.1] versus 8.7% [7.6-10.2], and 13.4 [12.7-14.1] years versus 16.5 [16.0-17.1] years, respectively, for a 70-year-old woman with the highest level of education). These findings support the potential impact of preventing diabetes on reducing dementia risk in older adults, with a 2-3-year higher dementia-free life expectancy for individuals without diabetes, and inform the design of future interventional trials.

International audience; It is currently unknown whether brain atrophy subtypes defined in Alzheimer's disease are clinically relevant during aging. We investigated participants (n = 368) from a population-based cohort of non-demented older adults who received longitudinal neuropsychological assessments during 12 years. Magnetic resonance imaging scans at baseline and 4 years later were used to define participants with "hippocampal predominant atrophy," "cortical predominant atrophy," "homogenous atrophy," and "no evidence of brain subtype atrophy" based on the dynamics of hippocampal-to-cortical volume ratio evolution. After adjustment on age, gender, educational level, and ApoE4 genotype, participants with "hippocampal predominant atrophy" declined faster regarding global cognition, verbal fluency, and verbal episodic memory. In Cox proportional-hazards models, "hippocampal predominant atrophy" was associated with an increased risk of developing Alzheimer's clinical syndrome over time (hazard ratio = 5.73; 95% CI 2.71e12.15), independently of age and ApoE4 genotype, the 2 other significant predictive factors. As a possible surrogate of confined tauopathy and early Alzheimer's disease pathology, future studies should consider the definition of "hippocampal predominant atrophy" based on hippocampal-to-cortical volume ratio evolution rather than hippocampal volume alone.

Hearing loss (HL) is highly common in older adulthood, constituting the third most prevalent chronic health condition in this population. In addition to posing a substantial burden to disease and negatively impacting quality of life, an emerging literature highlights that HL is associated with unipolar depression including among older adults. This review outlines evidence examining the HL and depression relationship as well as clinical implications for assessment and treatment of comorbid depression and HL. Although prevalence estimates of comorbid depression in HL vary, as many as 1 in 5 experience clinically relevant depression symptoms. Both cross-sectional and longitudinal studies indicate that HL is related to increased unipolar depression symptoms, although the strength of the association varies between studies. A range of methodological variations, such as inclusion age, severity of HL and assessment of depression, likely underpin this heterogeneity. Overall, however, the evidence clearly points to an association of HL with clinically relevant depression symptoms. The association with the diagnosis of major depression disorder remains less clear and under-researched. HL is also associated with a range of other poor mental health outcomes in older adults, including anxiety and suicidal ideation, and predicts poorer cognitive functioning. Accordingly, assessment and treatment of comorbid depression in HL is pertinent to promote mental well-being among older adults. Currently, evidence regarding best practice for treating depression in HL remains scant. Preliminary evidence indicates that audiological rehabilitation, including use of hearing aids, as well as community-based hearing interventions can also improve mental health. Psychological intervention that enhances communication skills and addresses coping strategies might also be beneficial for this population. Additionally, evidence suggests that online interventions are feasible and may circumvent communication difficulties in therapy associated with HL. Due to poor help-seeking among this population, an enhanced focus on specific and targeted assessment and treatment is likely necessary to ensure reduced mental health burden among older adults with HL.

Background: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. Methods: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). Results: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. Conclusions: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

International audience; BACKGROUND:Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.OBJECTIVE:We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.METHODS:Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.RESULTS:There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.CONCLUSIONS:Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.

There is a growing interest in developing tailored non-pharmacological strategies to face patients’ needs in dementia. Occupational therapy (OT) may contribute to promote self-empowerment of both patients and caregivers. France has implemented nationwide OT over a short-term period of 3/4 months. The main objective of the MatheoAlz study is to measure the impact of maintaining OT over 4 supplementary months on patients’ neuropsychiatric symptoms. The MatheoAlz trial (Maintenance of Occupational Therapy in Alzheimer’s disease) is a multi-center, pragmatic randomized controlled trial testing maintenance of OT over 4 supplementary months compared to routine OT delivered as recommended. This paper describes the study protocol. MatheoAlz plans to enroll 240 dyads, i.e. dementia patients and caregivers, whose main inclusion criteria are: prescription for routine OT, patients with mild or moderate dementia, living at home, receiving support from an informal caregiver. The study will compare a control group of patients benefiting from 12 to 15 initial sessions of OT over 3/4 months and an intervention group of patients benefiting from these initial sessions plus 8 extra home sessions over 4 supplementary months. The main outcome is the patient’s neuropsychiatric symptoms assessed by the Neuropsychiatric Inventory at 8 months. Several clinical outcomes and economic consequences are measured at 4, 8 and 12 months. This is the first trial designed to assess the specific impact of the maintaining OT on the patients’ neuropsychiatric symptoms burden. The results will inform policymakers on strategies to implement in the near future. This trial was registered at ClinicalTrials.gov on February 16, 2018, identifier: NCT03435705 .