Multidomain intervention and/or omega-3 in nondemented elderly subjects according to amyloid status.

INTRODUCTION: The Multidomain Alzheimer Preventive Trial (MAPT) assessed the efficacy of omega-3 fatty acid supplementation, a multidomain intervention (MI), or a combination of both on cognition. Impact according to cerebral amyloid status was evaluated by PET scan. METHODS: Participants were nondemented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. The primary outcome was a change from baseline in 36 months measured with a cognitive composite Z score. RESULTS: No effect was observed on cognition in the negative amyloid group (n = 167). In the positive amyloid group (n = 102), we observed a difference of 0.708 and 0.471 in the cognitive composite score between the MI plus omega-3 fatty acid group, the MI alone group, and the placebo group, respectively. DISCUSSION: MI alone or in combination with omega-3 fatty acids was associated with improved primary cognitive outcome in subjects with positive amyloid status. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01513252.

Implementation of the WHO integrated care for older people (ICOPE) programme in clinical practice: a prospective study.

BACKGROUND: The INSPIRE integrated care for older people (ICOPE)-CARE programme is a public health programme implementing the ICOPE health-care pathway in clinical practice. The primary objective of this study was to describe the large-scale implementation and feasibility of the INSPIRE ICOPE-CARE guidelines in clinical practice. The secondary aims were to describe the characteristics of patients who were identified as positive for abnormalities in intrinsic capacity (ie, locomotion, cognition, psychology, vitality, hearing, and vision) during step 1, and to describe the prevalence of these positive screenings. METHODS: In this prospective study, we evaluated a real-life population of users of primary care services in the Occitania region (France). Participants who were aged 60 years and older and lived in a community were eligible for inclusion in our study. Individuals aged ≥60 years were screened (step 1) by health-care providers or through self-assessments using digital tools (the ICOPE MONITOR app and the ICOPEBOT conversational robot). Our implementation strategy involved raising awareness among health-care professionals about the WHO ICOPE programme, training professionals in the ICOPE-CARE guidelines, and developing a digital infrastructure (ie, digital tools, a database, and a remote ICOPE monitoring platform). The feasibility of implementing the INSPIRE ICOPE-CARE guidelines was determined by the anticipated inclusion of ≥10 000 participants, and having a follow-up rate of over 50%. FINDINGS: Between Jan 1, 2020, and November 18, 2021, 10 903 older people (mean age 76·0, SD 10·5 years; 6627 [60·8%] of whom were women) had a baseline step 1 screening done, and 5185 (70·4%) of 7367 eligible participants had a 6-month follow-up of step 1 screening. 10 285 (94·3%) participants had a positive intrinsic capacity result during screening at baseline. 958 (9·3%) participants were evaluated with step 2 (in-depth assessments). Positive intrinsic capacity was confirmed in 865 (90·3%) participants. Most recommendations in step 3 (care plan) were related to locomotion, vitality, and cognition. INTERPRETATION: The high number of participants included in our study, as well as the high rates of follow-up, provides evidence to suggest that the large-scale implementation of ICOPE in clinical practice is feasible. The very high prevalence of positive screening for impaired intrinsic capacity during step 1, as well as the high rates of confirmed deficits in intrinsic capacity during step 2, suggest that the INSPIRE ICOPE-CARE programme is able to target individuals who are at increased risk for functional loss and disability. FUNDING: Occitania Regional Health Agency, Region Occitanie and Pyrénées-Méditerranée, European Regional Development Fund, and The Interreg Program V-A Spain-France-Andorra.

Lifelong low-phylloquinone intake is associated with cognitive impairments in old rats.

In a previous report, we showed vitamin K to preferentially accumulate in brain regions rich in white matter and to positively correlate with certain sphingolipids. In rodents, pharmacological vitamin K deficiency has resulted in behavioral perturbations. To gain insight on the role of vitamin K status on brain function, we investigated learning abilities (Morris water maze), motor activity (open field), and anxiety (elevated plus maze) in distinct groups of 6-, 12-, and 20-mo-old female Sprague-Dawley rats that had been fed diets containing low (L; ~80 µg/kg diet), adequate (A; ~500 µg/kg diet), or high (H; ~2000 µg/kg diet) levels of phylloquinone (µg/kg diet; n = 9-12/diet) since weaning. In 20-mo-old rats, sphingolipids (cerebroside, sulfatide, sphingomyelin, ceramide, and gangliosides), phylloquinone, and menaquinone-4 were also assessed in cerebellum, midbrain, pons medulla, striatum, and hippocampus. Lifetime consumption of a low-vitamin K diet resulted in cognitive deficits in the 20-mo-old rats, with those in the L group having longer latencies than those in the H group (P < 0.05); this was associated with higher concentrations of ceramides in the hippocampus (P < 0.05) and lower gangliosides in the pons medulla and midbrain (P < 0.05). The low-vitamin K diet did not affect cognition at 6 and 12 mo of age, nor did it affect motor activity or anxiety at any age. Although much remains to be elucidated about the mechanism of action of vitamin K in cognition, this report points to vitamin K as an important nutritional factor contributing to cognitive health during aging.

A robust machine learning framework to identify signatures for frailty: a nested case-control study in four aging European cohorts.

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

The impact of a multi-domain intervention on cerebral glucose metabolism: analysis from the randomized ancillary FDG PET MAPT trial.

BACKGROUND: The Multidomain Alzheimer Preventive Trial (MAPT) was designed to assess the efficacy of omega-3 fatty acid supplementation, multidomain intervention (MI), or a combination of both on cognition. Although the MAPT study was negative, an effect of MI in maintaining cognitive functions compared to placebo group was showed in positive amyloid subjects. A FDG PET study (MAPT-NI) was implemented to test the impact of MI on brain glucose metabolism. METHODS: MAPT-NI was a randomized, controlled parallel-group single-center study, exploring the effect of MI on brain glucose metabolism. Participants were non-demented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. Participants were randomly assigned (1:1) to "MI group" or "No MI group." The MI consisted of group sessions focusing on 3 domains: cognitive stimulation, physical activity, nutrition, and a preventive consultation. [18F]FDG PET scans were performed at baseline, 6 months, and 12 months, and cerebral magnetic resonance imaging scans at baseline. The primary objective was to evaluate the MI effect on brain glucose metabolism assessed by [18F]FDG PET imaging at 6 months. The primary outcome was the quantification of regional metabolism rate for glucose in cerebral regions involved early in Alzheimer disease by relative semi-quantitative SUVr (FDG-based AD biomarker). An exploratory voxel-wise analysis was performed to assess the effect of MI on brain glucose metabolism without anatomical hypothesis. RESULTS: The intention-to-treat population included 67 subjects (34 in the MI group and 33 in the No MI group. No significant MI effect was observed on primary outcome at 6 months. In the exploratory voxel-wise analysis, we observed a difference in favor of MI group on the change of cerebral glucose metabolism in limbic lobe (right hippocampus, right posterior cingulate, left posterior parahippocampal gyrus) at 6 months. CONCLUSIONS: MI failed to show an effect on metabolism in FDG-based AD biomarker, but exploratory analysis suggested positive effect on limbic system metabolism. This finding could suggest a delay effect of MI on AD progression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT01513252 .

Prescreening for European Prevention of Alzheimer Dementia (EPAD) trial-ready cohort: impact of AD risk factors and recruitment settings.

BACKGROUND: Recruitment is often a bottleneck in secondary prevention trials in Alzheimer disease (AD). Furthermore, screen-failure rates in these trials are typically high due to relatively low prevalence of AD pathology in individuals without dementia, especially among cognitively unimpaired. Prescreening on AD risk factors may facilitate recruitment, but the efficiency will depend on how these factors link to participation rates and AD pathology. We investigated whether common AD-related factors predict trial-ready cohort participation and amyloid status across different prescreen settings. METHODS: We monitored the prescreening in four cohorts linked to the European Prevention of Alzheimer Dementia (EPAD) Registry (n = 16,877; mean ± SD age = 64 ± 8 years). These included a clinical cohort, a research in-person cohort, a research online cohort, and a population-based cohort. Individuals were asked to participate in the EPAD longitudinal cohort study (EPAD-LCS), which serves as a trial-ready cohort for secondary prevention trials. Amyloid positivity was measured in cerebrospinal fluid as part of the EPAD-LCS assessment. We calculated participation rates and numbers needed to prescreen (NNPS) per participant that was amyloid-positive. We tested if age, sex, education level, APOE status, family history for dementia, memory complaints or memory scores, previously collected in these cohorts, could predict participation and amyloid status. RESULTS: A total of 2595 participants were contacted for participation in the EPAD-LCS. Participation rates varied by setting between 3 and 59%. The NNPS were 6.9 (clinical cohort), 7.5 (research in-person cohort), 8.4 (research online cohort), and 88.5 (population-based cohort). Participation in the EPAD-LCS (n = 413 (16%)) was associated with lower age (odds ratio (OR) age = 0.97 [0.95-0.99]), high education (OR = 1.64 [1.23-2.17]), male sex (OR = 1.56 [1.19-2.04]), and positive family history of dementia (OR = 1.66 [1.19-2.31]). Among participants in the EPAD-LCS, amyloid positivity (33%) was associated with higher age (OR = 1.06 [1.02-1.10]) and APOE ɛ4 allele carriership (OR = 2.99 [1.81-4.94]). These results were similar across prescreen settings. CONCLUSIONS: Numbers needed to prescreen varied greatly between settings. Understanding how common AD risk factors link to study participation and amyloid positivity is informative for recruitment strategy of studies on secondary prevention of AD.

In vivo pharmacological profile of S 38093, a novel histamine H3 receptor inverse agonist.

S 38093, a novel histamine H3 receptor inverse agonist, was tested in a series of neurochemical and behavioral paradigms designed to evaluate its procognitive and arousal properties. In intracerebral microdialysis studies performed in rats, S 38093 dose-dependently increased histamine extracellular levels in the prefrontal cortex and facilitated cholinergic transmission in the prefrontal cortex and hippocampus of rats after acute and chronic administration (10mg/kg i.p.). Acute oral administration of S 38093 at 0.1mg/kg significantly improved spatial working memory in rats in the Morris water maze test. The compound also displayed cognition enhancing properties in the two-trial object recognition task in rats, in a natural forgetting paradigm at 0.3 and 1mg/kg p.o. and in a scopolamine-induced memory deficit situation at 3mg/kg p.o. The property of S 38093 to promote episodic memory was confirmed in a social recognition test in rats at 0.3 and 1mg/kg i.p. Arousal properties of S 38093 were assessed in freely moving rats by using electroencephalographic recordings: at 3 and 10mg/kg i.p., S 38093 significantly reduced slow wave sleep delta power and induced at the highest dose a delay in sleep latency. S 38093 at 10mg/kg p.o. also decreased the barbital-induced sleeping time in rats. Taken together these data indicate that S 38093, a novel H3 inverse agonist, displays cognition enhancing at low doses and arousal properties at higher doses in rodents.

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.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: 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. FUNDING: French Ministry of Health, Pierre Fabre Research Institute, Gerontopole, Exhonit Therapeutics, Avid Radiopharmaceuticals.

Effects of long-term vitamin K (phylloquinone) intake on retina aging.

Emerging evidence suggests neuroprotective functions of vitamin K and/or vitamin K-dependent proteins. We investigated the effect of dietary vitamin K on retina aging (thinning). Female Sprague-Dawley rats were maintained from weaning on low (80 microg kg(-1) diet), adequate (500 microg kg(-1) diet) or high (2000 microg kg(-1) diet) levels of vitamin K1 (phylloquinone). Relative concentrations of brain vitamin K associated with these diets were 1: 3.3: 25 (K1) and 1: 2.7: 9.0 (menaquinone-4). Histomorphometry of old (21 month) rats revealed positive associations between vitamin K and thickness of retina layers, especially in the equatorial/peripheral retina. No association of diet and retina thickness was detected among young (6 month) animals. The sparing effect of vitamin K in the retina was most evident in the inner plexiform layer and in the photoreceptor inner and outer segments. Surprisingly, we observed no effect of vitamin K on the age-dependent loss of photoreceptor cells, interneurons or ganglion cells. These data suggest a role for vitamin K in maintaining the aging retina and suggest that the sparing effect of vitamin K does not reflect the survival-promoting (anti-apoptotic) activities of vitamin K-dependent proteins.

Menaquinone-4 concentration is correlated with sphingolipid concentrations in rat brain.

Studies with animals support a role for vitamin K (VK) in the biosynthesis of sphingolipids, a class of complex lipids present in high concentrations in the brain. In mice and rats, VK deficiency decreases levels of brain sulfatides and causes behavioral alterations. In light of its heterogeneity and to better understand the role of VK in the brain, we characterized the distribution of the two main VK vitamers, phylloquinone (K1) and menaquinone-4 (MK-4), in nine distinct brain regions. Weaning female Sprague-Dawley rats (n=5/dietary group) were fed diets containing either low (L, 80 microg/kg diet), adequate (A, 500 microg/kg diet) or high (H, 2000 microg/kg diet) levels of K1 for 6 mo. The main form of VK in the brain was MK-4, and it was present in significantly higher concentrations in myelinated regions (the pons medulla and midbrain) than in nonmyelinated regions. Both regional K1 and MK-4 increased with K1 intake (P<0.05). Sphingolipid distribution varied across brain regions (P<0.001) but was not affected by K1 intake. In the L and A groups but not the H group, brain MK-4 concentration was positively correlated with the concentrations of sulfatides (L, r=0.518; A, r=0.479) and sphingomyelin (L, r=0.515; A, r=0.426), and negatively correlated with ganglioside concentration (L, r=-0.398); A, r=-0.353). Sphingolipids are involved in major cellular events such as cell proliferation, differentiation and survival. The strong associations reported here between brain MK-4 and sphingomyelin, sulfatides and gangliosides suggest that this vitamer may play an important role in the brain.