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).

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.

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.

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.

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.

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.

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.

MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER'S DISEASE: DESIGN AND BASELINE DATA.

OBJECTIVE: The Multidomain Alzheimer Preventive Trial (MAPT study) was designed to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multidomain intervention (consisting of nutritional counseling, physical exercise, cognitive stimulation) or a combination of the two interventions on the change of cognitive functions in frail subjects aged 70 years and older for a period of 3 years. Ancillary neuroimaging studies were additionally implemented to evaluate the impact of interventions on cerebral metabolism (FDG PET scans) and atrophy rate (MRIs), as well as brain amyloïd deposit (AV45 PET scans). DESIGN PATIENTS: 1680 subjects (mean age: 75.3 years; female: 64.8 %), enrolled by 13 memory clinics, were randomized into one of the following four groups: omega-3 supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or placebo. Participants underwent cognitive, functional and biological assessments at M6, M12, M24 and M36 visits. The primary endpoint is a change of memory function at 3 years, as assessed by the Free and Cued Selective Reminding test. All participants will be followed for 2 additional years after the 3-years intervention (MAPT PLUS extension study). INTERVENTIONS: 1/Omega-3 supplementation: two soft capsules daily as a single dose, containing a total of 400 mg docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid per day, for 3 years. 2/ Multidomain intervention: collective training sessions conducted in small groups (6-8 participants) in twelve 120-minute sessions over the first 2 months (two sessions a week for the first month, and one session a week the second month) then a 60-minute session per month in the following three areas: nutrition, physical activity, and cognition until the end of the 3 years. In addition to the collective sessions, individualized preventive outpatient visits exploring possible risk factors for cognitive decline are performed at baseline, M12 and M24. BASELINE POPULATION: For cognition, the mean MMSE at baseline was 28.1 (± 1.6). About 58% and 42% of participants had a CDR score equal to 0 and 0.5, respectively. Regarding mobility status, 200 (11.9%) had a 4-m gait speed lower or equal to 0.8 m/s. According to the Fried criteria, 673 (42.1%) participants were considered pre frail, and 51 (3.2%) frail. The red blood cell DHA content was 26.1 ± 8.1 µg/g. Five hundred and three participants underwent baseline MRI. AV45 PET scans were performed in 271 individuals and preliminary results showed that 38.0% had a cortical SUVR > 1.17, which gave an indication of significant brain amyloïd deposit. DISCUSSION: The MAPT trial is presently the first largest and longest multidomain preventive trial relevant to cognitive decline in older adults with subjective memory complaints. The multidomain intervention designed for the MAPT trial is likely to be easily implemented within the general population.

Progression of Alzheimer disease in Europe: data from the European ICTUS study.

The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North, South, West) and investigated with biannual follow-up over 2 years. Primary outcomes were cognitive, functional and behavioral measures. Caregiver burden, hospital admission and admission to nursing home were also recorded. Participant cognitive function declined non-linearly over time (MMSE: -1.5 pts/first year, -2.5 pts/second year; ADAScog: + 3.5 pts/first year, + 4.8 pts/second year), while the progression of behavioral disturbances (NPI scale) was linear. Neither scale showed regional differences, and progression of the disease was similar across Europe despite different health care systems. Functional decline (ADL, IADL) tended to progress more rapidly in Southern Europe (p=0.09), while progression of caregiver burden (Zarit Burden Interview) was most rapid in Northern Europe (5.6 pts/y, p=0.04). Incidences of hospital admission (10.44, 95%CI: 8.13-12.75, p < 0.001) and admission to nursing home (2.97, 95%CI: 1.83-4.11, p < 0.001) were lowest in Southern Europe. In general cognitive and functional decline was slower than in former cohorts. European geographical location reflecting differences in culture and in health care system does not impact on the progression of AD but does influence the management of AD subjects and caregiver burden.

End-of-life care for persons with advanced Alzheimer disease: design and baseline data from the ALFINE study.

CONTEXT: Alzheimer disease (AD) is the most common cause of dementia. Most affected individuals survive to an advanced stage of dementia, which is under-recognized as a terminal illness. OBJECTIVES: Our objectives were to better understand the clinical trajectory of advanced AD and to identify the palliative care needs of these patients. METHODS: This was an observational prospective study of AD patients in severe stage of disease included after a hospitalization in geriatric wards. They were followed up every three months during 2 years. At each visit, interviews provided data regarding: pain (Elderly Pain Caring Assessment scale), pressure ulcers, eating patterns, daily medications and use of health services. This paper describes the design of the ALFINE study and the characteristics of the recruited cohort. RESULTS: 112 patients were recruited (mean age: 84.03 + 6.96) years; 76.79% were women. Mean time since diagnosis of AD was 5.28 years. Pressure ulcers were observed in 42 patients. Pain assessment with the EPCA showed a mean score of 8.58. One third of patients with an EPCA score of more than 7 (median) had no analgesics. More than half of patients had been treated with antibiotics during the three months before inclusion in the study and 33 patients were still receiving antibiotics at inclusion. Two third of patients had been hospitalized in the month before inclusion. CONCLUSION: End-of-life care for individuals with end-stage AD is increasingly important because of the rising number of patients with this disease. Health care systems and clinicians should make efforts to ameliorate the suffering of patients and their caregivers.

Incidence and predictive factors of depressive symptoms in Alzheimer's disease: the REAL.FR study.

BACKGROUND: Many patients develop psychiatric and behavioral disturbances in the course of Alzheimer's disease (AD). Among these disturbances, depressive symptoms are frequent and affect nearly 40% of patients. The natural history and course of such symptoms in AD, and in particular the predictive factors, are little known. We studied the incidence and risk factors for the development of the first depressive symptoms in AD. DESIGN: Multicenter prospective study. PARTICIPANTS: Three hundred twelve AD patients from the French Network on AD (REAL.FR) without depression and without antidepressant treatment at baseline were followed up and assessed every 6 months for 4 years. During follow-up, all events occurring between two visits were carefully recorded. MEASUREMENTS: We used the Neuropsychiatric Inventory (NPI) for comprehensive evaluation of behavioral and psychological symptoms and depressive symptoms in particular. A multivariate analysis was performed using a backward stepwise Cox proportional hazards model. RESULTS: The incidence of depressive symptoms was 17.45% person/years, 95%CI (13.88-21.02). Among non-time dependent variables, duration of disease (RR=0.51; 95%CI: 0.30-0.85, p=0.0102) and the number of comorbid conditions (RR=0.45; 95%CI: 0.24-0.83, p=0.0115) were protective factors against the development of depressive symptoms. Agitation/aggression (RR=1.96; 95%CI: 1.19-3.23, p=0.0078) and sleep disturbances (RR=2.65; 95%CI: 1.40-5.00, p=0.0026) were time-dependent variables predictive of depressive symptoms. CONCLUSION: Better knowledge of predictive factors of mood disturbances in AD will enable clinicians to set up appropriate management of their patients. As published longitudinal studies are few, further works should be carried out to improve knowledge of the pattern and course of depression and depressive symptoms in AD.

How should we deal with missing data in clinical trials involving Alzheimer's disease patients?

Missing data are frequent in Alzheimer's disease (AD) trials due to the age of participants and the nature of the disease. This can lead to bias and decreased statistical power. We assessed the level and causes of missing data in a 2-year randomised trial of an AD patient management program (PLASA study), and conducted sensitivity analyses on the primary endpoint (functional decline), using various methods for handling missing data: complete case, LOCF, Z-score LOCF, longitudinal mixed effects model, multiple imputation. By 2 years, 32% of the 1131 subjects had dropped out, with the commonest reasons being death (28% of dropouts) and refusal (22%). Baseline cognitive and functional status were predictive of dropout. All sensitivity analyses led to the same conclusion: no effect of the intervention on the rate of functional decline. All analyses demonstrated significant functional decline over time in both groups, but the magnitude of decline and between-group (intervention versus usual care) differences varied across methods. In particular, the LOCF analysis substantially underestimated 2-year decline in both groups compared to other methods. Our results suggest that data were not "missing completely at random", meaning that the complete case method was unsuitable. The LOCF method was also unsuitable since it assumes no decline after dropout. Methods based on the more plausible "missing at random" hypothesis (multiple imputation, longitudinal mixed effects models, z-score LOCF) appeared more appropriate. This work highlights the importance of considering the validity of the underlying hypotheses of methods used for handling missing data in AD trials.

Differences in resource use and costs of dementia care between European countries: baseline data from the ICTUS study.

OBJECTIVES: This study aimed to estimate the costs of formal and informal care of patients with Alzheimer's disease, to compare care costs across European countries and identify potential differences in cost patterns between countries and regions. SETTING: The ICTUS study is a prospective, naturalistic observational study conducted in specialised memory clinics in 12 European countries. In total, 1385 patients diagnosed with Alzheimer's disease were enrolled at baseline. All subjects had a reliable informant (primary caregiver) and informed consent was obtained from patients or their primary caregiver. MAIN OUTCOME MEASURES: Resource utilization data was captured with the RUD Lite (Resource Utilization in Dementia) instrument and caregiver burden with the Zarit Burden Interview (ZBI). Patient disease severity was measured with the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog), Katz´ index (PADL), Instrumental activities of daily living (IADL) scale and Neuropsychiatric inventory (NPI). RESULTS: The mean annual cost of care per patient was estimated to €7,820 (95% CI: €7,194-€8,446), whereof 54% were costs of informal care, 16% direct medical costs and 30% community care costs. There were substantial differences in total resource utilization and also in the balance between formal and informal care between Northern, Western and Southern Europe. PADL scores were strongly associated with formal care costs while IADL scores correlated strongly with informal care costs. CONCLUSIONS: Costs of Alzheimer's disease are high across European countries. Activities of daily living is an important determinant of care costs. Formal care service use is lower and informal care higher in Southern Europe compared to Western and Northern Europe. Differences in resource utilization patterns are important to consider in international studies of dementia care costs as well as in economic evaluations of new treatments for dementia.