Multidomain Alzheimer Preventive Trial Research Articles

Defining Vitality: Associations of Three Operational Definitions of Vitality with Disability in Instrumental Activities of Daily Living and Frailty among Elderly Over a 3-Year Follow-Up (MAPT Study).

This study aimed to examine the associations of three operational definitions of vitality with variation in instrumental activities of daily living (IADL) and frailty over a 3-year follow-up among non-demented, community-dwelling elderly. Observational study. 1,679 elderly >70y (64.7% female) participants of the Multidomain Alzheimer Preventive Trial (MAPT). Vitality was defined as a psychological concept using three items from the Geriatric Depression Scale; as a physical construct using the highest quartile for hand grip strength; and as global physiological reservoir using a combination of good physical and cognitive functions. Variables were assessed at baseline, 6, 12, 24 and 36 months of follow-up. Prevalence of high vitality at baseline was 57.1%, 28.5% and 21.6% for psychological, physical, and physiological reservoir, respectively. People with high vitality presented higher IADL scores compared to people with low vitality for all definitions. Analysis from the mixed-effect model found no differences between vitality groups for IADL performance across all definitions. IADL scores improved among subjects with high vitality over time, independent on the definition; while no significant variation was observed among those with low vitality. Participants with low vitality presented 2.0 to 6.1 higher odds of having more frailty components over time (p<0.0001). High vitality defined as a concept related to psychological, physical, or physiological reservoir constructs were positively associated with better IADL performance and with reduced likelihood of frailty worsening over time.

Prospective association of white matter hyperintensity volume and frailty in older adults.

Frailty is a prevalent geriatric condition and its association with brain health is still weakly investigated. The objective of this study was to examine whether brain white matter hyperintensities (WMH) were related to longitudinal changes in frailty severity in community-dwelling older adults. 113 community-dwelling older adults, aged 70 years and over, enrolled in the placebo group from the 3-year Multidomain Alzheimer's Preventive Trial (MAPT). Frailty was assessed using Fried's frailty phenotype as an ordinal variable (range from 0 to 5, higher is worse) at baseline, 6, 12, 24 and 36 months. We obtained brain WMH data using magnetic resonance imaging (MRI) at the first and last year of the trial. The progression of WMH volume was evaluated. We included 113 baseline and 83 follow-up MRIs in this study. The median baseline WMH volume was 10.6 (6.0, 15.0) cm3 and the median progression of WMH was 1.1 (-0.3, 2.2) cm3. Our results indicate that people with higher baseline WMH had a 6% increased likelihood of increasing their frailty phenotype score (adjusted OR: 1.06, (1.00-1.12, p = 0.036)). No associations were found between the progression of WMH (slow vs. fast) volume accumulation and frailty severity. WMH were associated with frailty severity over time. Why the progression of WMH was not associated with changes in frailty severity requires further investigation.

The Association of ApoE ε4 Status with Lower Limb Function and Handgrip Strength in Older Adults.

Apolipoprotein (ApoE ε4) status has been associated with various cardiovascular diseases and Alzheimer's Disease. Some studies have found a possible relationship between the presence of an ApoE ε4 allele and the decrease of motor function in healthy older adults. The objective of this study was to measure the cross-sectional and prospective associations of ApoE ε4 status with lower limb function and handgrip strength in older adults. Longitudinal observational study using data from a randomized controlled trial. Community-dwelling older adults. 1300 older adults (≥70 years old) with ApoE ε4 status from the Multidomain Alzheimer's Preventive Trial (MAPT) were followed for three years. Lower-limb function was measured with the Short Physical Performance Battery (SPPB) and muscle strength was measured with a handgrip strength dynamometer. ApoE ε4 status was assessed with a blood draw. Mixed-effect linear regressions were used to examine cross-sectional as well as prospective associations between ApoE ε4 status and the outcomes. No significant cross-sectional or prospective associations were found between ApoE ε4 status, lower-limb function and handgrip strength in our study. ApoE ε4 status was not associated with motor function in older adults.

Is Fat Mass Cross-Sectionally Associated with Cortical Aβ Load in the Human Brain?

The objective of this study was to examine the relationship of fat mass (FM) with brain amyloid (Aβ) load in older adults. Data from the Multidomain Alzheimer's Preventive Trial (MAPT) for Positron emission tomography and dual-energy X-ray absorptiometry (DXA) were used. Linear regressions controlling for appendicular muscle, age, education, clinical dementia rating scale and Apolipoprotein-E were performed to explore the relationships between FM, trunk FM and Aβ-load. Thirty-nine participants (75.7 ± 4.2 years old) with an average BMI of 27.5 ± 4.0 kg/m2 were analyzed in this study. There were significant and positive associations of both total and trunk FM with Aβ load [0.01 (0.002-0.02) and 0.02 (0.001-0.04), respectively]; however, when adding ApoE-ε4 as a confounder, associations were no longer significant. This study has found associations between FM as measured by DXA and cerebral Aβ load, suggesting that excessive FM might be involved in AD pathology.

Ready-meal consumption in older people: association with obesity and dietary intake.

To investigate ready-meal consumption trends in older French people, its association with overall diet quality and obesity. Cross-sectional analysis SETTING: Multidomain Alzheimer Preventive Trial (MAPT), France SUBJECTS: 421 MAPT participants (mean age 76.8years) who filled a food frequency questionnaire. The frequency of ready-meal consumption was low, with nearly 90% of participants declaring consuming ≤ 1 ready-meal per week. Compared to non- and low-consumers (≤ 1 ready-meal/week), regular consumers (≥ 2 ready-meals/week) were older (p < 0.01), more often frail and pre-frail (p 0.04), with impaired cognition (p = 0.02) and functional status (p = 0.02), with more depressive symptoms (p = 0.03) and more difficulties with preparing meals (p = 0.01). Results from multivariate analyses showed that regular ready-meal consumption was not associated with obesity (p = 0.26) and diet quality (p = 0.37). In our sample, few older people declared consumption of 2 or more ready-meals per week, this consumption was not associated with a higher prevalence of obesity or a lower diet quality, despite the fact that these subject were older, with a lower physical and cognitive status. These findings suggest that, for these people with difficulties in meal preparation, convenience foods consumed occasionally could help to maintain diet quality and weight status.

Anticholinergic exposure and cognitive decline in older adults: effect of anticholinergic exposure definitions in a 3-year analysis of the multidomain Alzheimer preventive trial (MAPT) study.

The aim of the present study was to assess the association between anticholinergic (atropinic) burden and cognitive decline in older adults over the course of 3years. We used data from Multidomain Alzheimer Preventive Trial (MAPT) study participants aged ≥70years and at risk of cognitive decline. Cognitive function was assessed with a composite score [Mini-Mental State Examination (MMSE) orientation, Free and Cued Selective Reminding Test, Category Naming Test, Digit Symbol Substitution Test] at 12, 24 and 36months. Participants declining by more than 0.236 points on the composite score (representing the lowest quintile of 1-year cognitive change) during any 1-year period were considered to have undergone cognitive decline. Anticholinergic exposure was defined by four methods for each of four anticholinergic scales (Anticholinergic Drug Scale, Anticholinergic Cognitive Burden, Anticholinergic Risk Scale, the Durán list). The association between cognitive decline and time-varying anticholinergic exposure [primary analysis using the Durán list and maximal anticholinergic score (0, 1 or 3)] was assessed using Cox proportional hazards models. Other cognitive decline definitions were used in sensitivity analyses. At baseline, among 1396 patients included, 7.4-23.5% were exposed to anticholinergic agents, depending on the anticholinergic scale used. Sixty-four per cent of participants experienced cognitive decline during follow-up. Regardless of the anticholinergic scale/exposure measurement used, no significant association was observed with cognitive decline {primary analysis: compared with non-anticholinergic agent users, hazard ratio [HR] = 1.14 [95% confidence interval (CI) = 0.95, 1.38] for anticholinergic score = 1; HR = 0.92 [95% CI = 0.65, 1.30] for score = 3}. Results were stable in sensitivity analyses. We found no significant association between anticholinergic exposure and cognitive decline in older adults using anticholinergic scales and definitions of exposure.

Shifting from Declines to Improvements: Associations between a Meaningful Walking Speed Change and Cognitive Evolution over Three Years in Older Adults.

Although the close relationship between mobility and cognitive declines is well-known, literature has very little questioned whether improvement in walking speed over time could be associated with improvements in cognitive functions. The objective of this study was to examine the associations between a clinically meaningful improvement in walking speed and global and specific cognitive changes in older adults. Prospective cohort study. Multidomain Alzheimer Preventive Trial (MAPT) study. Three-hundred participants from the control group of the MAPT study (mean age 74.8 ± 4.2; 57% women). The 4-m usual walking speed, global cognition, memory, executive functions, and processing speed measures were collected at baseline, and at 6, 12, 24 and 36 months. Participants were categorized into three groups according to their walking speed change over the three-year study: 1/ Non-Improvers (participants not presenting an increase ≥0.05m/sec on walking speed; n=138); 2/ Improvers (increase ≥0.05m/sec; n=40); Cyclic (≥0.05m/sec improvement at some time points without maintaining it through the whole period; n=122). Adjusted mixed-effect linear regressions revealed that walking speed improvers did not significantly differ from participants who never or temporarily improved their walking speed on all of global and specific cognitive functions over three years. Nevertheless, a sensitivity analysis (excluding participants with a non-clinical walking speed improvement) indicated specific cognitive trajectories per group associated with better episodic memory scores for Improvers compared to non-improvers (β=2.41, 95% CI=.12 - 4.71; p=.039). This study found that the overtime trajectories of cognitive functions did not differ as a function of clinically meaningful walking speed changes in older adults. Nevertheless, secondary analyses provided new insights on the relationship between walking speed and specific cognitive functions. The novelty of this approach (switching from declines to improvements) should be considered in future large-scale, observational longitudinal studies.

Cross-sectional associations of plasma vitamin D with cerebral \u03b2-amyloid in older adults at risk of dementia

BackgroundVitamin D deficiency is associated with an increased risk of Alzheimer’s disease and increased beta-amyloid (Aβ) in animals. Hence we sought to investigate the relationship between plasma 25-hydroxyvitamin D (25(OH)D) and cerebral Aβ in older adults with subjective memory complaints.MethodsThis is a secondary analysis of the Multidomain Alzheimer Preventive Trial. Participants were 178 dementia-free individuals aged 70 years or older with data on plasma 25(OH)D and cerebral Aβ load assessed by [18F]-florbetapir positron emission tomography. Plasma 25(OH)D was measured at study baseline using a commercially available electro-chemiluminescence competitive binding assay. Standard uptake value ratios (SUVRs) were generated using the cerebellum as a reference. Brain regions assessed included the cortex, anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval centre and temporal cortex. Associations were explored using fully adjusted multiple linear regression models.ResultsParticipants had a mean (SD) age of 76.2 years (4.4) and 59.6% were female. The mean (SD) plasma 25(OH)D level was 22.4 ng/ml (10.8) and the mean (SD) cortical SUVR was 1.2 (0.2). We did not find any cross-sectional associations (p > 0.05) between baseline 25(OH)D levels and Aβ in any of the brain regions studied.ConclusionsThese preliminary results suggest that circulating 25(OH)D is not associated with cerebral Aβ in older adults. Further longitudinal studies with the measurement of mid-life vitamin D status are required to explore the relationship between vitamin D and Aβ accrual over time, thereby circumventing the shortfalls of a cross-sectional study.

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.

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. 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. 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. 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.

Effects of multidomain lifestyle intervention, omega-3 supplementation or their combination on physical activity levels in older adults: secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) randomised controlled trial.

to investigate the effects of a 3-year multidomain lifestyle intervention, omega-3 supplementation or both on physical activity (PA) in older adults with subjective memory complaints. the Multidomain Alzheimer Preventive Trial was a 3-year randomised controlled trial that enroled 1,680 community-dwelling adults aged 70 years or over, with subjective memory complaints. Participants were randomised to omega-3 supplementation (total daily dose of 800 mg docosahexanoic acid and up to 225 mg eicosapentanoic acid), multidomain intervention (nutritional and exercise counselling and cognitive training), omega-3 plus multidomain intervention or placebo with usual care. PA was assessed using a self-reported questionnaire. From this, global moderate-to-vigorous PA, leisure-time PA, non-leisure-time PA and light PA were measured in metabolic equivalent tasks-minutes per week (MET-min/week). in the multidomain groups, participants significantly increased their moderate-to-vigorous and leisure-time PA at 6 months (≥300 MET-min/week for both in the multidomain groups; P ≤ 0.002) before returning to baseline by the end of the trial. Activity in the placebo/usual care and omega-3/usual care groups declined overtime. Between-group differences remained significant for both multidomain groups for leisure-time physical activity at 2- and 3-year follow-ups. Compared to placebo/usual care, interventions had no significant effects on non-leisure-time PA and light PA. Omega-3 supplementation alone had no effects on PA. a multidomain intervention focused on cognitive training, and nutritional and PA counselling increased PA in the short-term and limited its decline in the long-term among older adults with memory complaints. ClinicalTrials.gov-Registration number: NCT0067268.

Cross-Sectional Associations of Total Plasma Homocysteine with Cortical β-Amyloid Independently and as a Function of Omega 3 Polyunsaturated Fatty Acid Status in Older Adults at Risk of Dementia.

Elevated total plasma homocysteine is a risk factor for Alzheimer's disease (AD) and there is some evidence that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can modulate the effects of homocysteine-lowering B vitamins on AD related pathologies. Hence we investigated the relationship between total plasma homocysteine and cortical β-amyloid (Aβ) in older adults at risk of dementia. The role of erythrocyte membrane n-3 PUFAs (omega 3 index) on this relationship was also explored. This is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial. French community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia. Individuals were from the MAPT trial (n = 177) with data on total plasma homocysteine at baseline and cortical Aβ load. Cortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Total baseline plasma homocysteine was measured using an enzymatic cycling assay. Baseline omega 3 index was measured using gas chromatography. Cross-sectional associations were explored using adjusted multiple linear regression models. We found that total baseline plasma homocysteine was not significantly associated with cortical Aβ as demonstrated using multiple linear regression models adjusted for age, sex, education, cognitive status, time interval between baseline and PET-scan, omega-3 index, MAPT group allocation and Apolipoprotein E ε4 status (B-coefficient -0.001, 95 % CI: -0.008,0.006, p = 0.838). Exploratory analysis showed that homocysteine was however significantly associated with cortical Aβ in subjects with low baseline omega-3 index (< 4.72 %) after adjustment for Apolipoprotein E ε4 status (B-coefficient 0.041, 95 % CI: 0.017,0.066, p = 0.005, n = 10), but not in subjects with a high baseline omega-3 index (B-coefficient -0.010, 95 % CI: -0.023,0.003, p = 0.132, n = 66). The role of n-3 PUFAs on the relationship between homocysteine and cerebral Aβ warrants further investigation.

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.

Association of Cortical β-Amyloid with Erythrocyte Membrane Monounsaturated and Saturated Fatty Acids in Older Adults at Risk of Dementia.

We examined the relationships between erythrocyte membrane monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs) and cortical β-amyloid (Aβ) load in older adults reporting subjective memory complaints. This is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial. French community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia. Participants of this study were 61 individuals from the placebo arm of the MAPT trial with data on erythrocyte membrane fatty acid levels and cortical Aβ load. Cortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Fatty acids were measured in erythrocyte cell membranes using gas chromatography. Associations between erythrocyte membrane MUFAs and SFAs and cortical Aβ load were explored using adjusted multiple linear regression models and were considered significant at p ≤ 0.005 (10 comparisons) after correction for multiple testing. We found no significant associations between fatty acids and cortical Aβ load using multiple linear regression adjusted for age, sex, education, cognition, PET-scan to clinical assessment interval, PET-scan to blood collection interval and apolipoprotein E (ApoE) status. The association closest to significance was that between erythrocyte membrane stearic acid and Aβ (B-coefficient 0.03, 95 % CI: 0.00,0.05, p = 0.05). This association, although statistically non-significant, appeared to be stronger amongst ApoE ε4 carriers (B-coefficient 0.04, 95 % CI: -0.01,0.09, p = 0.08) compared to ApoE ε4 non-carriers (B-coefficient 0.02, 95 % CI: -0.01,0.05, p = 0.18) in age and sex stratified analysis. Future research in the form of large longitudinal observational study is needed to validate our findings, particularly regarding the potential association of stearic acid with cortical Aβ.

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

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. 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. French community dwellers aged 70 or over reporting subjective memory complaints, but free from clinical dementia. A subgroup of MAPT subjects in the lowest quartile of omega-3 index distribution with baseline values ≤ 4.83 % (n = 183). 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. 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. 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. 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.

Cross-sectional associations of cortical β-amyloid with erythrocyte membrane long-chain polyunsaturated fatty acids in older adults with subjective memory complaints.

Omega-3 (n-3) and 6 (n-6) polyunsaturated fatty acids (PUFAs) have been associated with reduced cognitive decline in observational studies. Hence, we examined the cross-sectional associations between cortical β-amyloid (Aβ) and erythrocyte membrane PUFAs in 61 non-demented elderly individuals reporting subjective memory complaints from the Multidomain Alzheimer Preventive Trial placebo arm. Cortical-to-cerebellar standard uptake value ratios were obtained using [18 F] florbetapir positron emission tomography. Fatty acids were measured in erythrocyte membranes by gas chromatography. Associations were explored using adjusted multiple linear regression models and were considered significant at p≤0.005 after correction for multiple testing (10 comparisons). We found no significant associations between cortical Aβ and erythrocyte membrane PUFAs. The associations closest to significance after adjustment were those between Aβ and erythrocyte membrane arachidonic acid (without apolipoprotein E status adjustment: B-coefficient, 0.03; CI, 0.01, 0.05; p=0.02. Including Apolipoprotein E adjustment: B-coefficient, 0.03; CI, 0.00, 0.06; p=0.04) and Aβ and erythrocyte membrane linoleic acid (without apolipoprotein E status adjustment: B-coefficient, -0.02; CI, -0.04, 0.00; p=0.02. Including Apolipoprotein E adjustment: B-coefficient, -0.02; CI, -0.04, 0.00; p=0.09). Furthermore, the association between Aβ and erythrocyte membrane arachidonic acid seemed to be specific to Apolipoprotein E ε4 non-carriers (B-coefficient 0.03, CI: 0.00, 0.06, p=0.03, n=36). In contrast, no association was found between Aβ and erythrocyte membrane linoleic acid in Apolipoprotein E ε4 stratified analysis. Investigating the relationships between Aβ and PUFAs longitudinally would provide further evidence as to whether fatty acids, particularly arachidonic acid and linoleic acid, might modulate cognition through Aβ-dependent mechanisms.

Cognitive Event-Related Potential, an Early Diagnosis Biomarker in Frail Elderly Subjects: The ERP-MAPT-PLUS Ancillary Study.

By analyzing brain synaptic function, cognitive event-related potentials (ERPs) could provide powerful and innovative tools for early Alzheimer's disease (AD) diagnosis. We investigated the relevance of the ERP-P300 component as a potential diagnosis marker in elderly subjects at risk of developing AD. ERP-P300 was analyzed on 85 subjects recruited from the Multidomain Alzheimer Preventive Trial (MAPT). PET-AV45 brain imaging was available from 36 subjects. Two ERP-P300 subgroups were identified according to their PET-AV45 status: PET-Aβ positive (n = 15) and PET-Aβ negative (n = 21). In the amyloid positive group, we observed a highly significant increase in P3b latency in parietal brain regions (p = 0.0052). P3b in parietal regions correctly categorized 69.4% elderly subjects from the P300-PET Aβ positive group. Combined analysis of parietal P3b latencies and category fluency correctly classified 75% subjects from the P300-PET Aβ positive group. The P300 ERP presents good predictive measure of brain amyloid load and has the potential to be used as a screening instrument for preclinical AD. The incorporation of P3b latency may be used as an adjunctive tool with neuropsychological assessment (i.e., verbal category fluency) as a specific and sensitive method for preclinical assessment of AD.

Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial

No large trials have been done to investigate the efficacy of an intervention combining a specific compound and several lifestyle interventions compared with placebo for the prevention of cognitive decline. We tested the effect of omega 3 polyunsaturated fatty acid supplementation and a multidomain intervention (physical activity, cognitive training, and nutritional advice), alone or in combination, compared with placebo, on cognitive decline. The Multidomain Alzheimer Preventive Trial was a 3-year, multicentre, randomised, placebo-controlled superiority trial with four parallel groups at 13 memory centres in France and Monaco. Participants were non-demented, aged 70 years or older, and community-dwelling, and had either relayed a spontaneous memory complaint to their physician, limitations in one instrumental activity of daily living, or slow gait speed. They were randomly assigned (1:1:1:1) to either the multidomain intervention (43 group sessions integrating cognitive training, physical activity, and nutrition, and three preventive consultations) plus omega 3 polyunsaturated fatty acids (ie, two capsules a day providing a total daily dose of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid), the multidomain intervention plus placebo, omega 3 polyunsaturated fatty acids alone, or placebo alone. A computer-generated randomisation procedure was used to stratify patients by centre. All participants and study staff were blinded to polyunsaturated fatty acid or placebo assignment, but were unblinded to the multidomain intervention component. Assessment of cognitive outcomes was done by independent neuropsychologists blinded to group assignment. The primary outcome was change from baseline to 36 months on a composite Z score combining four cognitive tests (free and total recall of the Free and Cued Selective Reminding test, ten Mini-Mental State Examination orientation items, Digit Symbol Substitution Test, and Category Naming Test) in the modified intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT00672685). 1680 participants were enrolled and randomly allocated between May 30, 2008, and Feb 24, 2011. In the modified intention-to-treat population (n=1525), there were no significant differences in 3-year cognitive decline between any of the three intervention groups and the placebo group. Between-group differences compared with placebo were 0·093 (95% CI 0·001 to 0·184; adjusted p=0·142) for the combined intervention group, 0·079 (-0·012 to 0·170; 0·179) for the multidomain intervention plus placebo group, and 0·011 (-0·081 to 0·103; 0·812) for the omega 3 polyunsaturated fatty acids group. 146 (36%) participants in the multidomain plus polyunsaturated fatty acids group, 142 (34%) in the multidomain plus placebo group, 134 (33%) in the polyunsaturated fatty acids group, and 133 (32%) in the placebo group had at least one serious emerging adverse event. Four treatment-related deaths were recorded (two in the multidomain plus placebo group and two in the placebo group). The interventions did not raise any safety concerns and there were no differences between groups in serious or other adverse events. The multidomain intervention and polyunsaturated fatty acids, either alone or in combination, had no significant effects on cognitive decline over 3 years in elderly people with memory complaints. An effective multidomain intervention strategy to prevent or delay cognitive impairment and the target population remain to be determined, particularly in real-world settings. French Ministry of Health, Pierre Fabre Research Institute, Gerontopole, Exhonit Therapeutics, Avid Radiopharmaceuticals.

Brain Amyloid Deposition Is Associated With Lower Instrumental Activities of Daily Living Abilities in Older Adults. Results From the MAPT Study.

Brain amyloid deposition is one of the key pathological hallmarks underlying the cognitive changes associated with Alzheimer's disease. Growing interest has been given to the earliest clinical manifestations of amyloid plaques. However, the relationship between amyloid status and activities of everyday function remains largely unknown. In the present study, we examined the relationship between instrumental activities of daily living performance (using the ADL-PI score) and amyloid status in older adults. Cross-sectional analyses of data from the Multidomain Alzheimer Preventive Trial (MAPT) were performed. Volunteers underwent a brain 18F-AV45 positron emission tomography examination. Bivariate analysis and regression models were conducted to study the relationships between brain amyloid deposition and the total ADL-PI score. We included 271 participants (women = 60%; age = 76±4 years). Amyloid positron emission tomography was positive (standard uptake value ≥1.17) for 103 participants (38%). The ADL-PI score was lower in amyloid positive participants than in their amyloid negative counterparts (38.8 vs 40.3, p = .007). This association was also confirmed in regression models adjusted for age, gender, and familial history of Alzheimer's disease (odds ratio = 0.94; 95% confidence interval 0.89-0.99; p = .02). This finding was consistent in cognitively normal individuals and in those with mild cognitive impairment, using the clinical dementia rating scale. This study highlighted an association between early functional limitations and brain amyloid deposition in elderly subjects. These symptoms could be the clinical manifestations of amyloid plaques even in the absence of overt dementia. Further prospective studies are warranted for examining the evolution of ADL-PI score over the course of Alzheimer's disease.

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 &gt; 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.

Recruitment strategies for preventive trials. The MAPT study (MultiDomain Alzheimer Preventive Trial).

1680 participants were randomized over the recruitment period in MAPT study. A total of 1290 participants were recruited in the 7 University Hospital centers, and 390 participants in the 6 memory clinics around Toulouse Gerontopole / Alzheimer Disease research clinical center. The first randomization was on May 30, 2008, and the targeted number of randomized participants was reached on February 24, 2011; 2595 subjects were finally screened, of which 1680 fulfilled the eligibility criteria which represents 64.8%. Approximately, one quarter of screened people refused to participate after the detailed presentation of the study and 4.3% were still interested in participating but missed for unknown reasons the baseline visit even after repeated contacts. Of the 1810 subjects who signed the consent for participating to the study at the baseline visit, 130 (7.1%) were excluded because one of the eligibility criteria was not satisfied. Interestingly, the higher percentage of randomizations compared to screened participants is the personal contact source; almost 85 % of screened participants entered in the study. In an equivalent way, Medias and conferences are efficient recruiting sources to enrol volunteers in the study. Unexpectedly, only about 60% of screened participants from the hospital and GP sources were randomized and 33.2% from health care services. Almost a quarter of the randomized participants come from the hospital outpatients clinics and approximately 20% from public conferences. A total of 1128 contacts yielded to 556 screened volunteers and 345 randomized participants in the coordinating center of Toulouse. Thus, 30 % of contacts were recruited.