Mapping Cognitive Trajectories and Detecting Early Dementia Using the Mini-Mental State Examination Cognitive Charts: Application to the French Three-City Cohort.

The Cognitive Quotient (QuoCo) classification algorithm monitoring decline on age- and education-adjusted Mini-Mental State Examination (MMSE)-derived cognitive charts has proved superior to the conventionally-used cut-off for identifying incident dementia; however, it remains to be tested in different settings. Data were drawn from the Three-City Cohort to 1) assess the screening accuracy of the QuoCo, and 2) compare its performance to that of serial MMSE tests applying different cut-offs. For the QuoCo, sensitivity was 74.2 (95% CI: 71.4-76.8) and specificity 84.1 (83.6-84.7) and for the MMSE < 24, 64.1 (61.1-67.0) and 94.8 (94.4-95.1), respectively; whereas overall accuracy and sensitivity was highest for MMSE cut-offs <25 and <26. User-friendly charts for mapping cognitive trajectories over visits with an alert for potentially 'abnormal' decline can be of practical use and encourage regular monitoring in primary care where the <24 cut-off is still widely used despite its poor sensitivity.

Comparison of ultrasensitive and mass spectrometry quantification of blood-based amyloid biomarkers for Alzheimer's disease diagnosis in a memory clinic cohort.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder with ß-amyloid pathology as a key underlying process. The relevance of cerebrospinal fluid (CSF) and brain imaging biomarkers is validated in clinical practice for early diagnosis. Yet, their cost and perceived invasiveness are a limitation for large-scale implementation. Based on positive amyloid profiles, blood-based biomarkers should allow to detect people at risk for AD and to monitor patients under therapeutics strategies. Thanks to the recent development of innovative proteomic tools, the sensibility and specificity of blood biomarkers have been considerably improved. However, their diagnosis and prognosis relevance for daily clinical practice is still incomplete. METHODS: The Plasmaboost study included 184 participants from the Montpellier's hospital NeuroCognition Biobank with AD (n = 73), mild cognitive impairments (MCI) (n = 32), subjective cognitive impairments (SCI) (n = 12), other neurodegenerative diseases (NDD) (n = 31), and other neurological disorders (OND) (n = 36). Dosage of ß-amyloid biomarkers was performed on plasma samples using immunoprecipitation-mass spectrometry (IPMS) developed by Shimadzu (IPMS-Shim Aß42, Aß40, APP669-711) and Simoa Human Neurology 3-PLEX A assay (Aß42, Aß40, t-tau). Links between those biomarkers and demographical and clinical data and CSF AD biomarkers were investigated. Performances of the two technologies to discriminate clinically or biologically based (using the AT(N) framework) diagnosis of AD were compared using receiver operating characteristic (ROC) analyses. RESULTS: The amyloid IPMS-Shim composite biomarker (combining APP669-711/Aß42 and Aß40/Aß42 ratios) discriminated AD from SCI (AUC: 0.91), OND (0.89), and NDD (0.81). The IPMS-Shim Aß42/40 ratio also discriminated AD from MCI (0.78). IPMS-Shim biomarkers have similar relevance to discriminate between amyloid-positive and amyloid-negative individuals (0.73 and 0.76 respectively) and A-T-N-/A+T+N+ profiles (0.83 and 0.85). Performances of the Simoa 3-PLEX Aß42/40 ratio were more modest. Pilot longitudinal analysis on the progression of plasma biomarkers indicates that IPMS-Shim can detect the decrease in plasma Aß42 that is specific to AD patients. CONCLUSIONS: Our study confirms the potential usefulness of amyloid plasma biomarkers, especially the IPMS-Shim technology, as a screening tool for early AD patients.

The interplay between cognition, depression, anxiety, and sleep in primary Sjogren's syndrome patients.

Primary Sjögren's syndrome (pSS) is an autoimmune disease with frequent neurological involvement. Memory complaints are common, but their precise patterns remain unclear. We wanted to characterize patterns of neurocognitive profiles in pSS patients with cognitive complaints. Only pSS patients with memory complaints were included, prospectively. Cognitive profiles were compiled through a comprehensive cognitive evaluation by neuropsychologists. Evaluations of anxiety, depression, fatigue, sleep disorders and quality of life were performed for testing their interactions with cognitive profiles. All 32 pSS patients showed at least borderline cognitive impairment, and 17 (53%) exhibited a pathological cognitive profile: a hippocampal profile (37%), a dysexecutive profile (22%), and an instrumental profile (16%) (possible overlap). Regarding the secondary objectives: 37% of patients were depressed, and 48% exhibited a mild-to-severe anxiety trait. Sleep disorders were frequent (excessive daytime sleepiness (55%), high risk for sleep apnea (45%), and insomnia (77%)). Cognitive impairments could not be explained alone by anxiety, depression or sleep disorders. Fatigue level was strongly associated with sleep disorders. Our study highlights that cognitive complaints in pSS patients are supported by measurable cognitive impairments, apart from frequently associated disorders such as depression, anxiety or sleep troubles. Sleep disorders should be screened.

Sulcal morphology as cognitive decline predictor in older adults with memory complaints.

To determine whether sulcal morphology can predict changes in cognition, we investigated the relationship between width of 20 cerebral sulci and cognitive decline. Sulcal width was measured in T1-weighted MRI images at baseline in 433 adults aged ≥70 years with memory complaints from the MRI-Multidomain Alzheimer Preventive Trial study. Cognition was evaluated at baseline, 6, 12, 24, and 36 months of follow-up with a composite Z score. The composite score variations over time relative to the baseline sulcal width were assessed using linear mixed regression models. We observed a positive association between a greater decline in cognitive composite score and the width of the superior and the anterior inferior temporal sulci, and the cingulate anterior sulcus of the left hemisphere. Sulcal widening in the lateral temporal and the cingulate anterior areas might predict cognitive decline in individuals with memory complaints.

Exposure to ambient air pollution and cognitive decline: Results of the prospective Three-City cohort study.

BACKGROUND: Growing epidemiological evidence suggests an adverse relationship between exposure to air pollutants and cognitive decline. However, there is still some heterogeneity in the findings, with inconsistent results depending on the pollutant and the cognitive domain considered. We wanted to determine whether air pollution was associated with global and domain-specific cognitive decline. METHODS: This analysis used data from the French Three-City prospective cohort (participants aged 65 and older at recruitment and followed for up to 12 years). A battery of cognitive tests was administered at baseline and every 2 years, to assess global cognition (Mini Mental State Examination, MMSE), visual memory (Benton Visual Retention Test), semantic fluency (Isaacs Set Test) and executive functions (Trail Making Tests A and B). Exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2) and black carbon (BC) at the participants' residential address during the 5 years before the baseline visit was estimated with land use regression models. Linear mixed models and latent process mixed models were used to assess the association of each pollutant with global and domain-specific cognitive decline. RESULTS: The participants' (n = 6380) median age was 73.4 years (IQR: 8.0), and 61.5% were women. At baseline, the median MMSE score was 28 (IQR: 3). Global cognition decline, assessed with the MMSE, was slightly accelerated among participants with higher PM2.5 exposure: one IQR increment in PM2.5 (1.5 µg/m3) was associated with accelerated decline (ß: -0.0060 [-0.0112; -0.0007] standard unit per year). Other associations were inconsistent in direction, and of small magnitude. CONCLUSION: In this large population-based cohort, higher PM2.5 exposure was associated with accelerated global cognition decline. We did not detect any significant association for the specific cognitive domains or the other pollutants. Evidence concerning PM2.5 effects on cognition is growing, but more research is needed on other ambient air pollutants.

Air quality improvement and incident dementia: Effects of observed and hypothetical reductions in air pollutant using parametric g-computation.

INTRODUCTION: No evidence exists about the impact of air pollution reduction on incidence of dementia. The aim of this study was to quantify how air quality improvement leads to dementia-incidence benefits. METHODS: In the French Three-City cohort (12 years of follow-up), we used parametric g-computation to quantify the expected number of prevented dementia cases under different hypothetical interventions with particulate matter measuring <2.5 µm (PM2.5 ) reductions. RESULTS: Among 7051 participants, 789 participants developed dementia. The median PM2.5 reduction between 1990 and 2000 was 12.2 (µg/m3 ). Such a reduction reduced the risk of all-cause dementia (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.76 to 0.95). If all study participants were enjoying a hypothetical reduction of more than 13.10 µg/m3 (median reduction observed in the city of Montpellier), the rate difference was -0.37 (95% CI, -0.57 to -0.17) and the rate ratio was 0.67 (95% CI, 0.50 to 0.84). DISCUSSION: These findings highlight the possible substantial benefits of reducing air pollution in the prevention of dementia.

Association Between Occupational Exposure to Formaldehyde and Cognitive Impairment.

BACKGROUND AND OBJECTIVES: To our knowledge, no study has investigated the effect of exposure to formaldehyde on cognition in the general population. Our objective was to examine the association between occupational exposure to formaldehyde and cognitive impairment in middle-aged and young-old adults (≥45 years). METHODS: In the French CONSTANCES cohort, cognitive function was assessed with a standardized battery of 7 cognitive tests to evaluate global cognitive function, episodic verbal memory, language abilities, and executive functions (e.g., Digit Symbol Substitution Test [DSST]). A global cognitive score was created using principal component analysis. Cognitive impairment was assessed in reference to norms of neuropsychological battery according to age, sex, and education. Lifetime exposure to formaldehyde was assessed using a French Job Exposure Matrix created in the framework of the Matgéné project. After performing multiple imputation, separate modified Poisson regression models were used to evaluate the association between cognitive impairment (<25th percentile) and formaldehyde exposure (exposed/never exposed), exposure duration, cumulative exposure index (CEI), and combination of CEI and time of last exposure. RESULTS: Among 75,322 participants (median age 57.5 years, 53% women), 8% were exposed to formaldehyde during their professional life. These participants were at higher risk of global cognitive impairment (for global cognitive score: adjusted relative risk [aRR] 1.17; 95% confidence interval [CI] 1.11-1.23), after adjusting for confounders (age, sex, education, income, solvent exposure, Effort-Reward Imbalance, night shift, repetitive work, and noisy work). They were at higher risk of cognitive impairment for all cognitive domains explored. Longer exposure duration and high CEI were associated with cognitive impairment, with a dose-effect relationship for exposure duration. Recent exposure was associated with impairment in all cognitive domains. Time did not fully attenuate formaldehyde-associated cognitive deficits especially in highly exposed individuals (for DSST: high past exposure aRR 1.23; 95% CI 1.11-1.36; high recent exposure: aRR 1.24; 95% CI 1.13-1.35). DISCUSSION: Our findings highlight the long-term detrimental effect of formaldehyde exposure on cognitive health in a relatively young population.

Impact of multidomain preventive strategies on functional brain connectivity in older adults with cognitive complaint: Subset from the Montpellier center of the ancillary MAPT-MRI study.

Introduction: The impact of multi-domain preventive interventions on older adults, in particular on those with higher risk to develop Alzheimer's disease (AD), could be beneficial, as it may delay cognitive decline. However, the precise mechanism of such positive impact is not fully understood and may involve brain reserve and adaptability of brain functional connectivity (FC). Methods: To determine the effect of multidomain interventions (involving physical activity, cognitive training, nutritional counseling alone or in combination with omega-3 fatty acid supplementation and vs. a placebo) on the brain, longitudinal FC changes were assessed after 36 months of intervention on 100 older adults (above 70 year-old) with subjective cognitive complaints. Results: No global change in FC was detected after uni or multidomain preventive interventions. However, an effect of omega-3 fatty acid supplementation dependent on cognitive decline status was underlined for frontoparietal, salience, visual and sensorimotor networks FC. These findings were independent of the cortical thickness and vascular burden. Discussion: These results emphasize the importance of patient stratification, based on risk factors, for preventive interventions.

Amyloid Burden and Depressive Symptom Trajectories in Older Adults at Risk of Developing Cognitive Decline.

Objective: Little is known about the amyloid load impact on depressive symptoms or disorders, although it can modulate the cognitive trajectory in older adults. Here, we analyzed, in individuals at risk of Alzheimer's dementia, the relationship between amyloid load and depressive symptoms changes over time.Methods: This study included ≥ 70-year-old participants from the French Multidomain Alzheimer Preventive Trial (MAPT) (May 2008 to February 2011) who underwent brain amyloid load measurement by ß-amyloid-[18F] florbetapir-PET at baseline and had spontaneous memory complaints and/or limitation in 1 instrumental activity of daily living or slow walking gait (N = 264). Symptoms of depression were measured with the Geriatric Depression Scale-15 items (GDS) at baseline and 6, 12, 24, and 36 months of follow-up. Four GDS factors were determined by principal component analysis (PCA): life satisfaction, level of apathy, self-esteem, and anxiety. Amyloid positive status was defined based on the amyloid load in 6 Alzheimer's dementia-related regions. Regional amyloid load was based on 3 dimensions defined by PCA. The longitudinal links between depressive symptomatology and amyloid load (ie, cortical AV45 and amyloid load dimensions) were analyzed using linear mixed-multivariate models.Results: At baseline, 11% of participants had depressive symptoms (GDS > 5) and 34% were amyloid-positive. The global amyloid load was not associated with worsening of the total GDS score but only with the impairment of self-esteem factor during the follow-up after adjustment for age, sex, education level, and drug intake, dementia, and Mini-Mental State Examination score (ß = -0.029, 95% CI [-0.052 to -0.007], P = .003). Regional amyloid load in hippocampus and bilateral caudate nucleus protected significantly from self-esteem decrease during the 3-year follow-up.Conclusions: Although amyloid load shows no impact on GDS score in subjects at risk of Alzheimer's dementia, amyloid load may influence the progression of depressive dimension (self-esteem) with different effects according to the regional burden.Trial Registration: ClinicalTrials.gov identifier: NCT00672685.

Brief Report: Frailty in Aging People Living With HIV: A Matched Controlled Study.

BACKGROUND: We compared the prevalence of frailty among aging people living with HIV (PLHIV) with people without HIV from the ANS EP58 HAND 55-70 Study. METHODS: Cross-sectional multicentric study which consecutively included 200 PLHIV and 1000 people without HIV from the French national CONSTANCES cohort, matched on age, sex, and education level. PLHIV were aged 55-70 years, with a HIV viral load < 50 copies/mL and a lymphocyte T-CD4 level > 200 cells/µL for the last 24 and 12 months, respectively. We measured frailty (>2 items) and prefrailty (one or 2 items) using a proxy of the 5-item Fried score. Multivariate logistic regression was performed to assess the association between HIV and frailty/prefrailty, adjusting for demographic, social, behavioral, and comorbidity confounders. RESULTS: Outcome measures were available for 192 PLHIV and 822 people without HIV. The median age was 62 years, and 84.9% were men. Among PLHIV, the median CD4 cell count was 645.5 cells/µL. Prevalence of frailty/prefrailty was 5.73%/57.3% in PLHIV vs. 1.73%/52.2% in people without HIV, respectively. HIV was associated with prefrailty/frailty [odds ratio = 1.89; 95% confidence interval = 1.37 to 2.61), but after adjusting for social and behavioral factors and comorbidities, HIV was not significantly associated with prefrailty/frailty (odds ratio = 1.24; 95% confidence interval: = 0.84 to 1.81). In PLHIV only, frailty/prefrailty was associated with depressive symptomatology, kidney disease, and time since HIV infection. CONCLUSIONS: Prevalence of frailty is increased in aging PLHIV with well-controlled HIV disease, but other factors than HIV are predominant, particularly depression and comorbidities.

Long-term exposure to ambient air pollution and risk of dementia: Results of the prospective Three-City Study.

BACKGROUND: Emerging epidemiological evidence suggests a relationship between exposure to air pollution and dementia. However, most of the existing studies relied on health administrative databases for the diagnosis of dementia. In a large French population-based cohort (the 3C Study), we assessed the effects of particulate matter ≤2.5 µm (PM2.5), nitrogen dioxide (NO2) and black carbon (BC) on the risk of dementia diagnosed with reliable tools. METHODS: Participants aged ≥65 years were recruited between 1999 and 2001 and followed for 12 years. At baseline and every 2 years, dementia was suspected on the basis of the neuropsychological and neurological examination and confirmed by an independent committee of clinicians. Exposure to NO2, BC and PM2.5 at the participants' residential address was estimated using land use regression models. For each pollutant and year of follow-up, the 10-year moving average of past exposure was estimated. Multilevel spatial random-effects Cox proportional hazards models were used in which exposure was included as a time-varying variable. Analyses were adjusted for individual (age, sex, education, APOE4 genotype, health behaviours) and contextual (neighbourhood deprivation index) confounders. RESULTS: At baseline, the median age of the 7066 participants was 73.4 years, and 62% were women. The median follow-up duration was 10.0 years during which 791 participants developed dementia (n = 541 Alzheimer's disease (AD) and n = 155 vascular/mixed dementia (VaD)). The 10-year moving average of PM2.5 concentrations ranged from 14.6 to 31.3 µg/m3. PM2.5 concentration was positively associated with dementia risk: HR = 1.20, 95% CI (1.08-1.32) for all-cause dementia, 1.20 (1.09-1.32) for AD, and 1.33 (1.05-1.68) for VaD per 5 µg/m3 PM2.5 increase. No association was detected between NO2 or BC exposure and dementia risk. CONCLUSION: In this large cohort of older adults, long-term PM2.5 exposure was associated with increased dementia incidence. Reducing PM2.5 emissions might lessen the burden of dementia in aging populations.

Cerebrospinal Fluid and Plasma Biomarkers do not Differ in the Presenile and Late-Onset Behavioral Variants of Frontotemporal Dementia.

BACKGROUND: Memory troubles and hippocampal atrophy are considered more frequent and focal atrophy less severe in late-onset (>65 years) than in presenile behavioral variant of frontotemporal dementia (bvFTD). OBJECTIVE: To compare cerebrospinal fluid (CSF) and plasma biomarkers in late-onset and presenile bvFTD. METHODS: Multicentric retrospective study (2007-2017) on patients with clinical diagnosis of bvFTD. RESULTS: This study included 44 patients (67%) with presenile and 22 (33%) with late-onset bvFTD (comparable mean disease duration; n = 11 with causal mutations). Hippocampal atrophy was more frequent (80% versus 25.8%) and severe in late-onset bvFTD (median Scheltens score: 3 [0-4] versus 1 [0-3]), without difference after adjustment for age. Lobar atrophy and focal hypometabolism/hypoperfusion were not different between groups. The median CSF Aß1-42 and phosphorylated tau (P-tau) concentrations were in the normal range and comparable between groups. Axonal neurodegeneration biomarkers were within the normal range (CSF T-tau; plasma T-tau in late-onset bvFTD) or higher (plasma neurofilament light chain (NFL); plasma T-tau in presenile bvFTD) than the normal values, but globally not different between bvFTD groups. Plasma glial fibrillary acid protein (GFAP) was strongly increased in both bvFTD groups compared with the values in controls of the same age. CONCLUSION: The CSF and plasma biomarker profiles did not suggest a more aggressive neurodegeneration in the presenile group (comparable T-tau, NFL, and GFAP levels) or the co-existence of Alzheimer's disease in the late-onset group (comparable and within normal range CSF Aß1-42 and P-tau). The severity of the neurodegenerative process seems comparable in presenile and late-onset bvFTD.

Absence of Relationship Between Self-Reported Sleep Measures and Amyloid Load in Elderly Subjects.

Objective: To determine the relationships between self-reported sleep profile and cortical amyloid load in elderly subjects without dementia. Methods: This cross-sectional study included 143 community-dwelling participants aged ≥70 years (median: 73 years [70-85]; 87 females) with spontaneous memory complaints but dementia-free. Sociodemographic characteristics, health status, neuropsychological tests, sleep, and 18F-florbetapir (amyloid) PET data were collected. The clinical sleep interview evaluated nighttime sleep duration, but also daytime sleep duration, presence of naps, and restless leg syndrome (RLS) at time of study. Validated questionnaires assessed daytime sleepiness, insomnia, and risk of sleep apnea. The cortical standardized uptake value ratio (SUVr) was computed across six cortical regions. The relationship between sleep parameters and SUVr (cut-off ratio>1.17 and tertiles) was analyzed using logistic regression models. Results: Amyloid-PET was positive in 40.6% of participants. Almost 40% were at risk for apnea, 13.5% had RLS, 35.5% insomnia symptoms, 22.1% daytime sleepiness, and 18.8% took sleep drugs. No significant relationship was found between positive amyloid PET and nighttime sleep duration (as a continuous variable, or categorized into <6; 6-7; ≥7 h per night). Logistic regression models did not show any association between SUVr and daytime sleep duration, 24-h sleep duration, naps, RLS, daytime sleepiness, insomnia symptoms, and sleep apnea risk (before and after adjustment for APOEε4 and depressive symptoms). Conclusion: Our study did not confirm the association between amyloid-PET burden, poor sleep quantity/quality in elderly population, suggesting that the interplay between sleep, and amyloid is more complex than described.

Influence of activity space on the association between neighborhood characteristics and dementia risk: results from the 3-City study cohort.

BACKGROUND: Socioeconomic level of residential environment was found to influence cognitive performance. However, individuals from the same place of residence may be affected differently. We aim to investigate for the first time the influence of individual activity space on the association between neighborhood socioeconomic status (NSES) and the risk of dementia. METHODS: In the frame of the Three-City cohort, a French population-based study, we followed longitudinally (12 years) 7009 participants aged over 65. The activity space (i.e., the spatial area through which a person moves daily) was defined using two questions from Lawton's Instrumental Activities of Daily Living scale ("Goes shopping independently","Travels alone"), and one question about mobility restriction. The survival analysis was performed using a Cox marginal model that takes into account intra-neighborhood correlations and includes a large number of potential confounders. RESULTS: Among people with a limited activity space (n = 772, 11%), risk of dementia is increased in subjects living in a deprived area (characterized by high GINI index or low median income) compared to those living in more favored. CONCLUSION: This study shows that the individual activity space modifies the association between NSES and the risk of dementia providing a more complete picture of residential inequalities. If confirmed in different populations, these findings suggest that people with limited activity space and living in a deprived neighborhood are particularly at risk and should be targeted for prevention.

Sex-specific association between neighborhood characteristics and dementia: The Three-City cohort.

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.

Excessive Sleepiness and Longer Nighttime in Bed Increase the Risk of Cognitive Decline in Frail Elderly Subjects: The MAPT-Sleep Study.

Objective: To identify self-reported sleep-wake disturbances that increase the risk of cognitive decline over 1-year follow-up in frail participants. Background: Risk factors for cognitive impairment need to be better identified especially at earliest stages of the pathogenesis. Sleep-wake disturbances may be critical factors to consider and were thus being assessed in this at-risk population for cognitive decline. Methods: Frail elderly participants aged ≥70 years were selected from a subsample of the Multi-domain Alzheimer Preventive Trial (MAPT) for a sleep assessment (MAPT-sleep study) at 18-month follow-up (M18). Sleep-wake disturbances were evaluated using a clinical interview (duration of daytime and nighttime sleep, time in bed, number of naps, and presence of clinically-defined sleep disorders) and numerous validated questionnaires [Epworth Sleepiness Scale for excessive daytime sleepiness (EDS), Insomnia Severity Scale and Berlin Questionnaire]. Cognitive decline was defined as a difference between the MMSE and cognitive composite scores at M24 and M36 that was ranked in the lowest decile. Multivariate logistic regression models adjusted for several potential confounding factors were performed. Results: Among the 479 frail participants, 63 developed MMSE-cognitive decline and 50 cognitive composite score decrease between M24 and M36. Subjects with EDS had an increased risk of MMSE decline (OR = 2.46; 95% CI [1.28; 4.71], p = 0.007). A longer time spent in bed during night was associated with cognitive composite score decline (OR = 1.32 [1.03; 1.71], p = 0.03). These associations persisted when controlling for potential confounders. Patients with MMSE score decline and EDS had more naps, clinically-defined REM-sleep Behavior Disorder, fatigue and insomnia symptoms, while patients with cognitive composite score decline with longer time in bed had increased 24-h total sleep time duration but with higher wake time after onset. Conclusions: The risk of cognitive decline is higher in frailty subjects with EDS and longer nighttime in bed. Early detection of sleep-wake disturbances might help identifying frail subjects at risk of cognitive decline to further propose sleep health strategies to prevent cognitive impairment. http://www.clinicaltrials.gov NCT00672685; Date of registration May, 2nd 2008.

Nutrition and mortality in the elderly over 10 years of follow-up: the Three-City study.

In the last 20 years, many prospective cohort studies have assessed the relationships between food consumption and mortality. Result interpretation is mainly hindered by the limited adjustment for confounders and, to a lesser extent, the small sample sizes. The aim of this study was to investigate the association between dietary habits and all-cause mortality in a multicentre prospective cohort that included non-institutionalised, community-based elderly individuals (Three-City Study). A brief FFQ was administered at baseline. Hazard ratios (HR) and 95 % CI for all-cause mortality were estimated relative to the consumption frequency of several food groups, using Cox proportional hazards models adjusted for sex, centre, socio-demographic characteristics and health status indicators. Among the 8937 participants (mean age: 74·2 years, 60·7 % women), 2016 deaths were recorded during an average follow-up of 9 years. The risk of death was significantly lower among subjects with the highest fruit and vegetable consumption (HR 0·90; 95 % CI 0·82, 0·99, P=0·03) and with regular fish consumption (HR 0·89; 95 % CI 0·81, 0·97, P=0·01). The benefit of olive oil use was found only in women (moderate olive oil use: HR 0·80; 95 % CI 0·68, 0·94, P=0·007; intensive use: HR 0·72; 95 % CI 0·60, 0·85, P=0·0002). Conversely, daily meat consumption increased the mortality risk (HR 1·12; 95 % CI, 1·01, 1·24, P=0·03). No association was found between risk of death and diet diversity and use of various fats. These findings suggest that fruits/vegetables, olive oil and regular fish consumptions have a beneficial effect on the risk of death, independently of the socio-demographic features and the number of medical conditions.

Working Memory Deficit as a Risk Factor for Severe Apathy in Schizophrenia: A 1-Year Longitudinal Study.

Apathy, described as impaired motivation and goal-directed behavior, is a common yet often overlooked multidimensional psychopathological state in schizophrenia. Its underlying cognitive processes remain largely unexplored. Data was drawn from a longitudinal hospital study of patients with a DSM-IV diagnosis of schizophrenia; 137 (82.5%) participated at the 1-month follow-up and 81 (59.1%) at the 1-year follow-up. Apathy was assessed with the Lille Apathy Rating Scale, validated in French and in schizophrenia. Severe apathy, overall (total score > -13) and on 4 previously identified distinct dimensions, was considered. Episodic verbal learning was assessed with the California Verbal Learning Test, executive functioning with the Trail Making Test, the Six Element Test and the Stop Signal Paradigm and working memory with the Letter-Number Sequencing Test. After controlling for confounding variables, only episodic verbal learning was associated with severe overall apathy in the cross-sectional study. At 1 year, working memory was associated with an increased risk of severe overall apathy, adjusting for baseline apathy. Using a dimensional approach to apathy, specific types of cognition were found to be associated with specific dimensions of apathy. Our findings confirm the need for a multidimensional approach of negative symptoms in schizophrenia. Moreover, cognitive functioning could be a risk factor for developing severe apathy. Cognitive remediation may thus be a useful non-pharmacological intervention for treating apathy in schizophrenia patients.

Palmomental Reflex a Relevant Sign in Early Alzheimer's Disease Diagnosis?

BACKGROUND: Sophisticated and expensive biomarkers are proposed for the diagnostic of Alzheimer's disease (AD). The amyloid process seems to be early in AD, and brain amyloid load affects the frontal lobe. OBJECTIVE: To determine if certain simple clinical signs, especially frontal-related signs, could help reach an earlier and better diagnosis. METHODS: In the frame of the 3-City cohort, we conducted a nested case-control study comparing incident cases of AD to controls matched for age, gender, and education. The standardized neurological exam included extrapyramidal signs (akinesia, rigidity, rest tremor), pyramidal symptoms (spastic rigidity, Babinski reflex), primitive reflexes (snout, palmomental reflex grasping), and tremor (essential, intentional, head) at the time of diagnosis and two years before. RESULTS: We compared 106 incident AD subjects (mean age at diagnosis 82.2 (SD = 5.9); median MMSE at diagnosis = 23) to 208 matched controls. In patients younger than 80, palmomental reflexes were more frequent in AD than controls, two years before diagnosis (25.0 versus 7.0% , p = 0.03) and at time of diagnosis (30.3 versus 12.3% , p = 0.02). No difference was observed for other signs two years before diagnosis or for patients older than 80. CONCLUSION: Before diagnosis, the clinical examination of AD patients is not strictly normal; the primitive reflexes appear to be pathological. It might be in connection with the frontal amyloid load at an early stage of the disease. Clinical examination can reveal simple and interesting signs that deserve consideration as well as the other more invasive and expensive biomarkers.

Plasma ß-amyloid 40 levels are positively associated with mortality risks in the elderly.

BACKGROUND: We evaluated if plasma ß-amyloid (Aß) levels were associated with mortality risks in a subsample of the French Three-City (3C) prospective cohort study. METHODS: Analyses were based on 1254 participants randomly selected from the initial 3C cohort stratified by center, sex, and age in the context of a nested case-cohort study to investigate biological variables. Associations between plasma Aß and mortality were assessed with the Cox regression model with delayed entry including various potential confounding factors and testing possible mediators. RESULTS: A relationship between high plasma Aß1-40 concentrations and risk of mortality (hazards ratio, 1.15; 95% confidence interval, 1.01-1.31, P = .03) was unveiled independently of age, educational level, vascular risk factors, diet, physical activity, cognitive impairment, or frailty status. It was only modified when we included cystatin C levels. CONCLUSIONS: Further investigations are needed to determine precisely the pathophysiological roles of plasma Aß1-40 and cystatin C and before envisioning any future clinical applications.