Cognitive and functional patterns of nondemented subjects with equivocal visual amyloid PET findings.

PURPOSE: Despite good to excellent inter-reader agreement in the evaluation of amyloid load on PET scans in subjects with Alzheimer's disease, some equivocal findings have been reported in the literature. We aimed to describe the clinical characteristics of subjects with equivocal PET images. METHODS: Nondemented subjects aged 70 years or more were enrolled from the MAPT trial. Cognitive and functional assessments were conducted at baseline, at 6 months, and annually for 3 years. During the follow-up period, 271 subjects had (18)F-AV45 PET scans. Images were visually assessed by three observers and classified as positive, negative or equivocal (if one observer disagreed). After debate, equivocal images were reclassified as positive (EP+) or negative (EP-). Scans were also classified by semiautomated quantitative analysis using mean amyloid uptake of cortical regions. We evaluated agreement among the observers, and between visual and quantitative assessments using kappa coefficients, and compared the clinical characteristics of the subjects according to their PET results. RESULTS: In 158 subjects (58.30 %) the PET scan was negative for amyloid, in 77 (28.41 %) the scan was positive and in 36 (13.28 %) the scan was equivocal. Agreement among the three observers was excellent (kappa 0.80). Subjects with equivocal images were more frequently men (58 % vs. 37 %) and exhibited intermediate scores on cognitive and functional scales between those of subjects with positive and negative scans. Amyloid load differed between the EP- and negative groups and between the EP+ and positive groups after reclassification. CONCLUSION: Equivocal amyloid PET images could represent a neuroimaging entity with intermediate amyloid load but without a specific neuropsychological pattern. Clinical follow-up to assess cognitive evolution in subjects with equivocal scans is needed.

Effect of a 1-Year Nutritional Blend Supplementation on Plasma p-tau181 and GFAP Levels among Community-Dwelling Older Adults: A Secondary Analysis of the Nolan Trial.

Background: Observational studies and some randomized controlled trials have suggested that nutritional supplementation could be a possible intervention pathway to prevent cognitive decline and Alzheimer's disease (AD). As measuring amyloid-ß and tau pathophysiology by positron emission tomography (PET) or cerebrospinal fluid (CSF) analyses may be perceived as complex, plasma versions of such biomarkers have emerged as more accessible alternatives with comparable capacity of predicting cognitive impairment. Objectives: This study aimed to evaluate the effect of a 1-year intervention with a nutritional blend on plasma p-tau181 and glial fibrillary acidic protein (GFAP) levels in community-dwelling older adults. Effects were further assessed in exploratory analyses within sub-cohorts stratified according to p-tau status (with the third tertile considered as high: ≥15.1 pg/ mL) and to apolipoprotein E (APOE) ε4 allele status. Methods: A total of 289 participants ≥70 years (56.4% female, mean age 78.1 years, SD=4.7) of the randomized, double-blind, multicenter, placebo-controlled Nolan trial had their plasma p-tau181 assessed, and daily took either a nutritional blend (composed of thiamin, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folic acid, cobalamin, vitamin E, vitamin C, vitamin D, choline, selenium, citrulline, eicosapentaenoic acid - EPA, and docosahexaenoic acid - DHA) or placebo for 1 year. Results: After 1-year, both groups presented a significant increase in plasma p-tau181 and GFAP values, with no effect of the intervention (p-tau181 between-group difference: 0.27pg/mL, 95%CI: -0.95, 1.48; p=0.665; GFAP between-group difference: -3.28 pg/mL, 95%CI: -17.25, 10.69; p=0.644). P-tau-and APOE ε4-stratified analyses provided similar findings. Conclusions: In community-dwelling older adults, we observed an increase in plasma p-tau181 and GFAP levels that was not different between the supplementation groups after one year.

Omega-3 Supplementation for the Prevention of Cognitive Decline in Older Adults: Does It Depend on Homocysteine Levels?

BACKGROUND: Recent evidence point towards an interaction between omega-3 (n-3) polyunsaturated fatty acids (PUFA) and plasma homocysteine (Hcy). OBJECTIVES: This study tested the hypothesis that effects of red blood cell n-3 PUFA are modified according to baseline plasma Hcy in the large Mulit-domain Alzheimer Prevention Trial (MAPT) throughout the 3-years of treatment with an additional 2 years of observational follow-up. DESIGN: Experimental study. PARTICIPANTS: From the 1680 participants that were randomized in the four groups of the MAPT study (two of which received n-3 PUFA, the other two without n-3 PUFA), 782 were selected because they had baseline data on both Hcy and n-3 PUFA. MEASUREMENTS: Cognitive performance was measured with a broad set of cognitive tests including free and total recall of the cued selective reminding test, digit symbol substitution test, category naming test and Trail-making tests (TMT-A and B) and Clinical dementia rating scale. RESULTS: We found a significant association between TMT-A and red blood cell n-3 PUFA levels in participants with Hcy values ≤16.8 µMol/L after adjustments at baseline (Estimate: -1.3, 95% CI: -2.3; -0.3, p=0.01). Additionally, participants with high Hcy values had a significant worsening after adjustments in TMT-B after a 5-year n-3 PUFA supplementation, compared to low levels of Hcy (Mean difference: 34.8, 95% CI: 7.8;61.7). CONCLUSION: This study shows that Hcy levels could modify the association between red blood cell n-3 PUFA and executive function. People with high Hcy may benefit less from a n-3 PUFA supplementation to prevent cognitive decline.

The Cost-Effectiveness of Three Prevention Strategies in Alzheimer's Disease: Results from the Multidomain Alzheimer Preventive Trial (MAPT).

BACKGROUND: To date, no curative treatment is available for Alzheimer's disease (AD). Therefore, efforts should focus on prevention strategies to improve the efficiency of healthcare systems. OBJECTIVE: Our aim was to assess the cost-effectiveness of three preventive strategies for AD compared to a placebo. DESIGN: The Multidomain Alzheimer Preventive Trial (MAPT) study was a multicenter, randomized, placebo-controlled superiority trial with four parallel groups, including three intervention groups (one group with Multidomain Intervention (MI) plus a placebo, one group with Polyunsaturated Fatty Acids (PFA), one group with a combination of PFA and MI) and one placebo group. SETTING: Participants were recruited and included in 13 memory centers in France and Monaco. PARTICIPANTS: Community-dwelling subject aged 70 years and older were followed during 3 years. INTERVENTIONS: We used data from the MAPT study which aims to test the efficacy of a MI along PFA, the MI plus a placebo, PFA alone, or a placebo alone. MEASUREMENT: Direct medical and non-medical costs were calculated from a payer's perspective during the 3 years of follow-up. The base case incremental Cost-Effectiveness Ratio (ICER) represents the cost per improved cognitive Z-score point. Sensitivity analyses were performed using different interpretation of the effectiveness criteria. RESULTS: Analyses were conducted on 1,525 participants. The ICER at year 3 that compares the MI + PFA and the MI alone to the placebo amounted to €21,443 and €21,543 respectively, per improved Z score point. PFA alone amounted to €111,720 per improved Z score point. CONCLUSION: Our study shows that ICERS of PFA combined with MI and MI alone amounted to €21,443 and €21,543 respectively per improved Z score point compared to the placebo and are below the WTP of €50,000 while the ICER of PFA alone amounted to €111,720 per improved Z score point. This information may help decision makers and serve as a basis for the implementation of a lifetime decision analytic model.

Longitudinal Course of Agitation and Aggression in Patients with Alzheimer's Disease in a Cohort Study: Methods, Baseline and Longitudinal Results of the A3C Study.

BACKGROUND: To present methodology, baseline results and longitudinal course of the Agitation and Aggression in patients with Alzheimer's Disease Cohort (A3C) study. OBJECTIVES: The central objective of A3C was to study the course, over 12 months of clinically significant Agitation and Aggression symptoms based on validated measures, and to assess relationships between symptoms and clinical significance based on global ratings. DESIGN: A3C is a longitudinal, prospective, multicenter observational cohort study performed at eight memory clinics in France, and their associated long-term care facilities. SETTING: Clinical visits were scheduled at baseline, monthly during the first 3 months, at 6 months, at 9 months and at 12 months. The first three months intended to simulate a classic randomized control trial 12-week treatment design. PARTICIPANTS: Alzheimer's Disease patients with clinically significant Agitation and Aggression symptoms lived at home or in long-term care facilities. MEASUREMENTS: Clinically significant Agitation and Aggression symptoms were rated on Neuropsychiatric Inventory (NPI), NPI-Clinician rating (NPI-C) Agitation and Aggression domains, and Cohen Mansfield Agitation Inventory. Global rating of agitation over time was based on the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. International Psychogeriatric Association "Provisional Diagnostic Criteria for Agitation", socio-demographics, non-pharmacological approaches, psychotropic medication use, resource utilization, quality of life, cognitive and physical status were assessed. RESULTS: A3C enrolled 262 AD patients with a mean age of 82.4 years (SD ±7.2 years), 58.4% women, 69.9% at home. At baseline, mean MMSE score was 10.0 (SD±8.0), Cohen Mansfield Agitation Inventory score was 62.0 (SD±15.8) and NPI-C Agitation and Aggression clinician severity score was 15.8 (SD±10.8). According to the International Psychogeriatric Association agitation definition, more than 70% of participants showed excessive motor activity (n=199, 76.3%) and/or a verbal aggression (n=199, 76.3%) while 115 (44.1%) displayed physical aggression. The change of the CMAI score and the NPI-C Agitation and Aggression at 1-year follow-up period was respectively -11.36 (Standard Error (SE)=1.32; p<0.001) and -6.72 (SE=0.77; p<0.001). CONCLUSION: Little is known about the longitudinal course of clinically significant agitation symptoms in Alzheimer's Disease about the variability in different outcome measures over time, or the definition of a clinically meaningful improvement. A3C may provide useful data to optimize future clinical trials and guide treatment development for Agitation and Aggression in Alzheimer's Disease.

Effect of long-term omega-3 supplementation and a lifestyle multidomain intervention on intrinsic capacity among community-dwelling older adults: Secondary analysis of a randomized, placebo-controlled trial (MAPT study).

OBJECTIVES: To investigate the effect of omega-3 (ω-3) polyunsaturated fatty acid supplementation and a multidomain intervention (MI) (physical activity counselling, cognitive training and nutritional advice) among community-dwelling older adults on levels of intrinsic capacity (IC), a construct recently proposed by the World Health Organization. STUDY DESIGN: Secondary analysis from the factorial-design 3-year Multidomain Alzheimer Preventive Trial (MAPT) with 1445 subjects (64.2 % female, mean age 75.3 years, SD = 4.4) randomized to one group of MI plus ω-3 (800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid/day); MI plus placebo; ω-3 supplementation alone; or placebo alone. Data collection was held between 2008 and 2014. MAIN OUTCOME MEASURES: IC domains were examined with the Geriatric Depression Scale (psychological); Short Physical Performance Battery (mobility); Z-score combining four tests (cognitive function); and handgrip strength (vitality). All domains were combined into a composite IC Z-score. RESULTS: After 3 years, IC Z-score decreased among all groups when time was considered continuous (MI plus ω-3: -0.16, 95 %CI: -0.22 to -0.10; MI alone: -0.13, 95 %CI: -0.19 to -0.07; ω-3 alone: -0.19, 95 %CI: -0.25 to -0.10; placebo: -0.20, 95 %CI: -0.26 to -0.14; all p < 0.0001). There were no significant differences between groups. In a sensitivity analysis with categorical time, significant within-group declines were first identified at 24 months for all groups. CONCLUSIONS: This trial designed to improve cognitive function was unable to find effects of the intervention on the composite IC Z-score. Further investigations are needed, especially trials providing stronger interventions (such as exercise training and a controlled diet) and also embracing the sensorial domain of IC.

Red Blood Cell Omega-3 Fatty Acid Composition and Psychotropic Drug Use in Older Adults: Results from the MAPT Study.

Low docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentration has been associated with the development of some psychiatric disorders. OBJECTIVES: to assess the association between red blood cell (RBC) DHA-EPA concentration and psychotropic drug use in older adults and between the 1-year change in RBC DHA-EPA and psychotropic drug use at 12 months. DESIGN: secondary analysis of multicenter, randomized controlled trial testing multidomain intervention and/or n-3 PUFA supplement on cognitive function (MAPT study). SETTING: France, 2008-2014. PARTICIPANTS: 1680 participants ≥70 years, community-dwelling were included. MEASUREMENTS: Psychotropic drug use was self-reported during medical interviews and assessments. RBC n-3 PUFA concentration was defined by % of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) among total fatty acids. Logistic regressions models controlling for age, sex, education, depression risk and intervention group were used. RESULTS: 1594 participants had baseline DHA-EPA concentration available (mean age=75.5±4.5 years, 65% females). At baseline, participants with DHA-EPA ≤4.82% (lowest quartile) reported higher prevalence of use of overall psychotropic drugs (34.0% vs 24.4%; aOR=1.33, 95%CI=[1.03-1.72]), anxiolytic/hypnotic drugs (25.0% vs 18.2%; aOR=1.42, 95%CI=[1.07-1.89]), and antidepressants (18.3% vs 13.5%; aOR=1.25, 95%CI=[0.93-1.72]) than participants with higher DHA-EPA. Participants who experienced an increase in DHA-EPA from baseline were less likely to use a psychotropic drug at 12 months than participants with no change or a decrease (aOR=0.72, 95%CI=[0.55-0.96]). CONCLUSION: Low RBC DHA-EPA concentration was independently associated with psychotropic drug use. Future studies are needed to assess whether low RBC DHA-EPA is a risk marker for psychotropic drug use in older adults and to better understand underlying pathophysiological mechanisms. Registration number: ClinicalTrials.gov database (NCT00672685).

Vitamin D, homocysteine and n-3PUFA status according to physical and cognitive functions in older adults with subjective memory complaint: Results from cross-sectional study of the MAPT trial.

OBJECTIVE: The aim of this study was to investigate the nutritional markers (Vitamin D, homocysteine, n-3PUFA) status of older subjects aged 70 years and older with subjective memory complaint, according to their physical and cognitive function. MAIN OUTCOME MEASURES: This study is a secondary analysis of the MAPT study. Subjects were classified into four groups: 1) Physical limitation with cognitive impairment (PLCI), 2) cognitive impairment (CI), 3) physical limitation (PL) and 4) no physical or cognitive deficits (NPCD). Baseline nutritional characteristics of the four groups according to Vitamin D (n = 732), Omega-3 polyunsaturated fatty acid (n-3PUFA) (n = 1537) and plasma total homocysteine (tHcy) (n = 729) status were investigated. Analysis was performed taking continuous and dichotomized value for Vitamin D insufficiency ([25(OH)D] < 30 ng/ml, high homocysteine level (tHcy ≥ 15 µmol/L) and low n-3PUFA (DHA + EPA ≤ 4.82%) nutritional markers for clinical relevance. RESULTS: PLCI group showed the lowest mean level of Vitamin D and highest level tHcy compared to the other groups. In multivariate analysis, taking continuous nutritional markers, only high Vitamin D was associated with reduced likelihood of PLCI (OR 0.97, 95% CI (0.95 to 0.99) P = 0.011). While taking the dichotomized values the group with low levels of n-3PUFA showed higher likelihood of PL only (OR 1.55, 95% CI (1.12 to 2.15), P = 0.009). Furthermore, our sensitivity analysis for Vitamin D with cut-off [25(OH)D] < 20 ng/ml,(i.e., Vitamin D deficiency), showed more likelihood of PL (OR 1.62, 95% CI (1.01 to 2.60) P = 0.046), CI (OR 1.90, 95% CI (1.16 to 3.10) P = 0.010), and highest likelihood of PLCI (OR 1.99, 95% CI (1.21 to 3.28) P = 0.006). CONCLUSION: In older adults with subjective memory complaints, Vitamin D deficiency status may present higher likelihood of functional deficits, including coexisting or separate physical and cognitive decline. While older adults with low level of n-3PUFA were more likely to demonstrate physical decline only.

Trajectory of the MAPT-PACC-Preclinical Alzheimer Cognitive Composite in the Placebo Group of a Randomized Control Trial: Results from the MAPT Study: Lessons for Further Trials.

Defining the primary cognitive endpoint is a major decision for Alzheimer's disease preventive trials. As an example for further trials we present in detail the three-year cognitive decline in the placebo group of MAPT trial, a randomized controlled trial (RCT) using a cognitive composite score (MAPT-PACC). Participants were dementia-free adults 70 years or older, with subjective memory complaints. Our findings as expected showed subjects with older age (>75), higher beta amyloid brain deposition, APOE-ε4 allele carriers, with low RBC DHA+EPA levels and higher CDR level are at higher risk of cognitive decline. The data presented in this paper can be useful for future preventive trials to choose the primary cognitive end point, assess the clinical relevance of cognitive changes and perform sample size calculation for several targeted population eg. ApoE4, amyloid +, oldest old, lower n3-PUFA. We believe that the trial group with CDR 0.5, without being selected by a memory test endpoint is a good target population for AD preventive trials.

Effect of Multidomain Intervention, Omega-3 Polyunsaturated Fatty Acids Supplementation or their Combinaison on Cognitive Function in Non-Demented Older Adults According to Frail Status: Results from the MAPT Study.

BACKGROUND: Aim: The aim of this study was to explore whether multidomain intervention (MI) and Omega-3 Polyunsaturated Fatty Acids supplementation can modify the cognitive function on elderly according to frail status. METHOD: Data are from a secondary exploratory analysis of the Multidomain Alzheimer Preventive Trial (MAPT), a French community-dwellers aged 70 or over reporting subjective memory complaints, but free from clinical dementia. The multidomain intervention consisted of 2 hours group sessions focusing on three domains (cognitive stimulation, physical activity, and nutrition) and a preventive consultation (at baseline, 12 months, and 24 months). For Omega-3 Polyunsaturated Fatty Acids supplementation, participants took two capsules of either placebo or polyunsaturated fatty acids daily. Linear mixed-model repeated-measures analyses were used including baseline, 6, 12, 24 and 36-month follow-up data to assess between-group differences in the change in cognitive tests over 36 months. RESULTS: The overall mean age of the MAPT study population was 75.25(±4.38). A tend toward significant differences in TMT-A were found for the effect of the multidomain intervention on the prefrail group compared to non-frail group. The MI and n3 PUFA program could not significantly have reduced cognitive function in a sample of pre-frailty elders. CONCLUSION: This population-based study in community-dwellers aged 70 years or over suggested that multidomain intervention and n3 PUFA supplementation have not significant effects on cognitive function change in frail older adults with memory complaints. The beneficial effect of multidomain intervention and n3 PUFA supplementation on cognitive function did not differ between frail and nonfrail participants.

The ICTUS Study: A Prospective longitudinal observational study of 1,380 AD patients in Europe. Study design and baseline characteristics of the cohort.

The long-term objective of the ICTUS study is to identify milestones in Alzheimer's disease (AD) progression and to develop a model to predict disease course in individual AD patients in Europe. The secondary objectives are to describe the patterns of prescribing, and the socioeconomic impact of AD in Europe. Between 2003 and 2005 1,380 patients with probable AD were recruited in specialised (secondary care) clinics in 12 European countries. Their mean age was 76 years and they had a mean of 8.0 +/- (SD) 4.6 years of education. Thirty-five percent were male. The mean MMSE score was 20.4 +/- (SD) 4.0. Forty-three percent had very mild dementia (CDR 0.5) and 44% had mild dementia (CDR 1). All patients completed baseline evaluation and biannual follow-up is ongoing. The goals of the current study are to describe the specific methods for recruitment in this crosscultural setting and the characteristics of the inception ICTUS cohort, including clinical features, co-morbidity, neuropsychological performance, neuropsychiatric symptoms, functional impairment and social burden.

Long-term changes in ADAS-cog: what is clinically relevant for disease modifying trials in Alzheimer?

With the development of long-term disease modifying trials, changes in ADAS-Cog at 18 months will rise certainly many questions. We decided to look in the Real.fr study at the links between changes in cognition, ADAS-Cog and function. A total of 346 Alzheimer's patients with ADAS-cog at entry and at 18 months. were eligible for this analysis. These patients were on average 77.44 years old and 254 (72.36%) were women. The great majority lived at home and about 93% were treated with a cholinesterase inhibitor at baseline. Thirty three patients (9%) had a gain of more than 2 points at the ADAS-cog at 18 months (Group I, improvement); 130 (38%) were considered as stable, the reference group (Group II ) characterized by a stability at the ADAS-cog: decline of 2 points to gain of 2 points, 112 subjects (32%) had a moderate decline between 2 and 7 at the ADAScog (Group III) and finally 71 subjects (21%) had a severe impairment more than seven points at the ADAS-cog. A loss of one Basic ADL is certainly highly relevant, and such a change was found at 18 months in more than half of the subjects, which is not surprising for a long-term evolution in mild to moderate AD. An impairment of more than 7 points at the ADAS-cog was found in 21% of the subjects at 18 months and was associated with loss.

Cognitive Changes with Omega-3 Polyunsaturated Fatty Acids in Non-Demented Older Adults with Low Omega-3 Index.

OBJECTIVES: To investigate the changes in specific domains of cognitive function in older adults reporting subjective memory complaints with a low omega-3 index receiving omega 3 polyunsaturated fatty acid (n-3 PUFA) supplementation or placebo. DESIGN: This is a secondary exploratory analysis of the Multidomain Alzheimer Preventive Trial (MAPT) using subjects randomized to the n-3 PUFA supplementation or placebo group. SETTING: French community dwellers aged 70 or over reporting subjective memory complaints, but free from clinical dementia. PARTICIPANTS: A subgroup of MAPT subjects in the lowest quartile of omega-3 index distribution with baseline values ≤ 4.83 % (n = 183). INTERVENTION: The n-3 PUFA supplementation group consumed a daily dose of DHA (800 mg) and EPA (a maximum amount of 225 mg) for 3 years. The placebo group received identical capsules comprising liquid paraffin oil. MEASUREMENTS: Linear mixed-model repeated-measures analyses were used including baseline, 6, 12, 24 and 36-month follow-up data to assess between-group differences in the change in eight cognitive tests over 36 months. RESULTS: There was less decline on the Controlled Oral Word Association Test (COWAT) in the n-3 PUFA supplementation group compared to placebo (p = 0.009; between group mean difference over 36 months, 2.3; 95% CI, 0.6,4.0). No significant differences for any of the other cognitive tests were found, including other tests of executive functioning, although, numerically all results were in favour of the n-3 PUFA supplementation. CONCLUSIONS: We found some evidence that n-3 PUFAs might be beneficial for the maintenance of executive functioning in older adults at risk of dementia with low omega-3 index, but this exploratory finding requires further confirmation. A larger specifically designed randomised controlled trial could be merited.

The ROSAS Cohort: A Prospective, Longitudinal Study of Biomarkers for Alzheimer's Disease. Strategy, Methods and Initial Results.

OBJECTIVE: The aims of the Research Of biomarkers in Alzheimer's diseaSe (ROSAS) study were to determine the biofluid and imaging biomarkers permitting an early diagnosis of Alzheimer's disease and better characterisation of cognitive and behavioural course of the pathology. This paper outlines the overall strategy, methodology of the study, baseline characteristics of the population and first longitudinal results from the ROSAS cohort. METHODS: Longitudinal prospective monocentric observational study performed at the Alzheimer's disease Research centre in Toulouse. A total of 387 patients were studied and analyzed in 3 groups: 184 patients with dementia of Alzheimer's type, 96 patients with memory disorders without dementia (Mild Cognitive Impairment) and 107 patients without abnormal memory tests (control group), and were followed up during 4 years. Patient's sociodemographic characteristics, risk factors, medical conditions, previous and current medications, neuropsychological assessment and overall cognitive status were recorded. Blood and urine samples were collected at every year, Magnetic Resonance Imaging were performed at inclusion, after one year of follow-up and at the end of the study. RESULTS: At baseline, three different groups of the cohort differed interestingly in age, level of education, and in percentage of ApoEε4 carriers whereas the history of cardiovascular and endocrine pathologies were similar among the groups. During the follow-up period (3-4 years) 42 mild cognitive impairment patients (43.8%) progressed to dementia, 7 controls progressed into mild cognitive impairment and 1 patient in the control group converted from mild cognitive impairment group to dementia of Alzheimer's type group. During the first year of follow up, the incidence of progression from mild cognitive impairment to dementia of Alzheimer's type was 12.7 per 100, during the second year 33.9 per 100 and 46.7 per 100 for the third year. CONCLUSION: This paper presents the baseline characteristics of the unique French prospective monocenter study in which the natural course of dementia of Alzheimer's type was evaluated. Future analysis of blood and urine samples collection from the ROSAS study will permit to identify possible biofluid biomarkers predicting the early stages of the dementia of Alzheimer's type and risk of progression from Mild Cognitive Impairment to Alzheimer's disease.

Is the 25-Hydroxy-Vitamin D Serum Concentration a Good Marker of Frailty?

INTRODUCTION: The phenotype proposed by Fried and colleagues is a widely used operational definition of frailty defining such state of extreme vulnerability of older persons. Low serum 25-hydroxy-vitamin D (25(OH)D) has been suggested as biomarker of frailty in literature. STUDY DESIGN: Cross-sectional. OBJECTIVES: To explore the association of 25(OH)D concentrations with the frailty phenotype and its criteria. METHODS: 321 subjects referred by their general practitioner to a geriatric frailty clinic were assessed between January 1, 2013 and September 23, 2013. Adjusted logistic regression models were performed between serum concentrations of 25(OH)D and the frailty phenotype (global score as well as its specific criteria). Receivers operating curves were established in order to explore the existence of a possible threshold of vitamin D levels highly predictive of frailty. RESULTS: Two hundred forty-one (75%) participants had 25(OH)D levels lower than 22 ng/ml. No significant association was reported between 25(OH)D levels and frailty. Among the five criteria of frailty, 25(OH)D was only associated with sedentariness (odds ratio 0.97 [95% confidence interval 0.95-0.99]). CONCLUSION: In our sample, no association was found between 25(OH)D levels and phenotype of frailty or the different frailty criterion except for sedentariness.

Neuropsychological Profile of "Cognitive Frailty" Subjects in MAPT Study.

OBJECTIVES: An international group proposed the existence of "cognitive frailty", a condition defined by simultaneous presence of physical frailty and cognitive impairment in the absence of dementia. The objective was to compare the neuropsychological profiles in subgroups of elders differentiated across their physical frailty (Fried phenotype) and cognitive status (Clinical Dementia Rating score) to characterize the "cognitive frailty" entity. METHOD: We studied baseline characteristics of 1,617 subjects enrolled in Multidomain Alzheimer Disease Preventive Trial (MAPT). Included subjects were aged 70 years or older and presented at least 1 of the 3 following clinical criteria: (1) Memory complaint spontaneously reported to a general practitioner, (2) limitation in one instrumental activity of daily living, (3) slow gait speed. Subjects with dementia were not included in the trial. RESULTS: "Cognitive frailty individuals" significantly differed from "individuals with cognitive impairment and without physical frailty", scoring worse at executive, and attention tests. They presented subcortico-frontal cognitive pattern different of Alzheimer Disease. Cognitive performance of subjects with 3 criteria or more of the frailty phenotype are cognitively more impaired than subjects with only one. DISCUSION: The characterization of "cognitive frailty" must be done in frail subjects to set up specific preventive clinical trials for this population.

Predictive factors of emergency hospitalisation in Alzheimer's patients: results of one-year follow-up in the REAL.FR Cohort.

OBJECTIVE: To determine the predictive factors of hospitalisation in patients with Alzheimer's disease followed in the REAL.FR cohort. METHODS: A French multicentre prospective study (REAL.FR) following 516 patients who had mild to moderate AD at inclusion. Analysis of the data after one year of follow-up. RESULTS: 139 (26,9%) of the 516 initial AD patients were hospitalized during the 1 year of follow-up. After bivariate analysis, the principal predictive factors of hospitalisation were high scores on the Reisberg scale (> or = 5: P = 0.0149) and the CDR (1: P = 0.0289; 2 or 3: P = 0.0078); > or = 2 intercurrent diseases (P = 0.00104); > or = 3 other treatments (not including specific treatments for AD) (P = 0.0026); BMI (kg/m2) between 25 and 30 (P = 0.0147); impossibility of single-leg stance (P = 0.02); > or = 1 disabilities on the ADL (P = 0.0009) and > or = 2 disabilities on the IADL (P = 0.0017); use of medical services (P = 0.0236) and of non-medical services (P = 0.0403); delirium or hallucinations (P = 0.0135), depression (P = 0.0014), or disinhibited behaviour (P = 0.0030); the gravity and frequency of behavioural symptoms (NPI freq x grav > or = 11 (median), P = 0.0012); and lastly, a score of > or = 20 for subjective caregiver burden on the Zarit scale (P < 0.0001). Multivariate analysis revealed an association between the risk of hospitalisation and the following variables : the type of centre to which the patient was admitted (neurological, psychiatric or geriatric), impaired orientation on the MMS, BMI, the number of disabilities on the ADL, and caregiver burden as evaluated by the Zarit scale. CONCLUSION: At inclusion, patients with more severe cognitive disorders, poor nutritional status and those who were the most dependent for basic activities of daily living were already at greater risk of hospitalisation. Exhaustion of the informal caregiver was an independent and supplementary predictive factor of hospitalisation.

Long-term cholinergic treatment is not associated with greater risk of weight loss during Alzheimer's disease: data from the French REAL.FR cohort.

BACKGROUND: An increased incidence of weight loss has been reported in patients with Alzheimer's disease (AD) treated with higher doses of acetylcholinesterase inhibitors (AChEI) compared with placebo patients in several clinical trials. The proportion of patients losing weight is extremely variable from one study to another and further analysis is necessary to reach a conclusion on the association of weight loss and AChEI. OBJECTIVE: This observational study was designed to investigate the potential effects of AChEI use on weight loss during AD. DESIGN: 486 patients with AD were followed for one year (initial mean age 77.3 +/- 77 years; initial mean MMS score 20.3 +/- 4.2). Comprehensive geriatric and neuropsychological assessment was conducted every 6 months. Cholinergic treatment was recorded at each visit, as well as any concomitant medication for dementia, psychotropic and other medications. We defined clinically significant weight loss as > or = 4% of the subject's initial weight based on the last measured weight. The data were initially evaluated categorically to identify those who had lost > or = 4% of their initial weight or had remained stable. RESULTS: Eighty-nine per cent of AD patients were treated with AchEI during the first year of follow-up. Twenty-one per cent experienced clinically significant weight loss during this period. Weight loss was associated with more rapid deterioration of cognitive function (Delta MMSE -2.62 +/- 3.99 versus -1.72 +/- 3.64, P = 0.014) and loss of independence in instrumental activities of daily living (Delta IADL -1.45 +/- 1.50 versus - 0.88 +/- 1.43, P = 0.002). The frequency of weight loss was similar whether AD patients were treated with AChEI or not (respectively 21.1 and 19.5%, P = 0.81). In multivariate analysis, the risk of weight loss was significantly decreased in patients taking AChEI for more than 3 months compared (OR = 0.25, 95% CI = 0.11-0.56, P = 0.0007). CONCLUSIONS: Our data suggest that long-term cholinergic treatment is not associated with greater risk of weight loss during AD and may be a protective factor. Further analysis is necessary to confirm this relation. It is obvious that the benefit observed might also be partly related to the organised non-pharmacological management provided for our patients, which included a specific care plan for each individual and facilitated response to nutritional problems as they occurred. Global care of AD patients must associate regular pluridisciplinary management with AChEI treatment.

Recent data on the natural history of Alzheimer's disease: results from the REAL.FR Study.

OBJECTIVES: This paper aims to present the changes observed in the evolution of Alzheimer's disease (AD) in the cohort REAL.FR after one year by taking account new treatments and improved management. METHODS: Four hundred and ninety-eight patients recruited for the REAL.FR study were followed for one year with a standardized case report filled for each patient every 6 months. Changes in the status of these patients were evaluated on various levels: cognitive, functional, behavioural, global, nutritional, social, medical and caregiver burden. Specific treatments were also recorded. RESULTS: A high proportion of patients received specific treatment for AD throughout the year (86%), mainly acetylcholinesterase inhibitors (AChEI) . As expected we observed statistically significant changes in cognitive function (MMS: -1.93 +/- 3.74, p < 0.0001 and ADAS-cog: +2.40 +/- 3.74, p < 0.0001), an overall loss of autonomy (ADL: -0.56 +/- 1.05, p < 0.0001 and IADL: -1.00 +/- 1.46, p < 0.0001), worsening of behavioral disturbances (NPI: +1.85 +/- 14.83, p=0.0047) and a deterioration of general status (CDRSB: +1.63 +/- 2.55, p< 0.0001). Even if the MNA score decreased not significantly, the loss was close to the threshold of significativity (MNA: -0.31 +/- 3.07, p=0.0531). CONCLUSION: We observed a statistically significant change for the worse in most parameters. However, it appears that this deterioration had been relatively slowed by non-pharmacological management and the specific AD treatments. This resulted in stability or improvement of the condition in 63.4% of patient at 1 year. The management proposed (including prescription of AChEI) seemed to have a real impact on the course of the disease during this first year of follow-up.

Living alone with Alzheimer's disease: cross-sectional and longitudinal analysis in the REAL.FR Study.

OBJECTIVES: The purpose of this study was to examine the characteristics of Alzheimer's disease (AD) patients living alone and to describe the rate of cognitive and functional impairment after a one-year follow-up. DESIGN AND SETTING: In a prospective longitudinal study conducted by the French network on Alzheimer's disease (the REAL.FR study), 677 older community-dwelling AD patients were interviewed and completed questionnaires and evaluation scales every 6 months during a one-year follow-up. MEASUREMENTS: All patients were assessed by trained staff who collected data on neuropsychological status using the Mini Mental State Examination (MMSE), behavioural disturbances with the Neuropsychiatric Inventory (NPI) and nutritional status with the Mini Nutritional Assessment (MNA). Patients were assessed for current mobility and function in activities of daily living (ADL) and instrumental activities of daily living (IADL). RESULTS: At inclusion, 28% of the 677 non-institutionalised individuals with AD lived alone. Those who lived alone were significantly older than those who did not, and among them the percentage of women was significantly higher. Patients living alone were at increased risk of malnutrition and were more likely to have a low income than those living with others. Persons with AD living alone made greater use of health services. Dementia stage evaluated by cognitive impairment (MMSE) and ADL disabilities was similar in both groups. At one-year follow-up, the mortality rate was significantly higher in AD patients living with others. Institutionalisation and hospitalisation rates were similar. CONCLUSION: These results draw attention to the fact that elderly persons with AD living alone are a subpopulation with specific needs which require the development of targeted interventions. Further investigation of the factors associated with the lower mortality rate in AD patients living alone is necessary, and the results of long-term follow-up in this prospective study should shed light on this question.