Effects of vitamin D3, omega-3s, and a simple strength training exercise program on bone health: the DO-HEALTH randomized controlled trial.

Evidence on the effects of Vitamin D, omega-3s, and exercise on areal bone mineral density (aBMD) in healthy older adults is limited. We examined whether vitamin D3, omega-3s, or a simple home-based exercise program (SHEP), alone or in combination, over 3 years, improve lumbar spine (LS), femoral neck (FN), or total hip (TH) aBMD assessed by DXA. Areal BMD was a secondary outcome in DO-HEALTH, a 3-year, multicenter, double-blind, randomized 2 × 2 × 2 factorial design trial in generally healthy older adults age ≥ 70 years. The study interventions were vitamin D3 (2000IU/d), omega-3s (1 g/d), and SHEP (3 × 30 min/wk), applied alone or in combination in eight treatment arms. Mixed effects models were used, adjusting for age, sex, BMI, prior fall, study site, and baseline level of the outcome. Main effects were assessed in the absence of an interaction between the interventions. Subgroup analyses by age, sex, physical activity level, dietary calcium intake, serum 25(OH)D levels, and fracture history were conducted. DXA scans were available for 1493 participants (mean age 75 years; 80.4% were physically active, 44% had 25(OH)D levels <20 ng/mL). At the LS and FN sites, none of the treatments showed a benefit. At the TH, vitamin D versus no vitamin D treatment showed a significant benefit across 3 years (difference in adjusted means [AM]: 0.0035 [95% CI, 0.0011, 0.0059] g/cm). Furthermore, there was a benefit for vitamin D versus no vitamin D treatment on LS aBMD in the male subgroup (interaction P = .003; ∆AM: 0.0070 [95% CI, 0.0007, 0.0132] g/cm). Omega-3s and SHEP had no benefit on aBMD in healthy, active, and largely vitamin D replete older adults. Our study suggests a small benefit of 2000 IU vitamin D daily on TH aBMD overall and LS aBMD among men; however, effect sizes were very modest and the clinical impact of these findings is unclear.

Vitamin D, omega-3 fatty acids (omega-3s), and strength training are simple but promising strategies to improve bone health; however, their effect in healthy older adults over a period of 3 years was unclear. In this study, we examined whether daily vitamin D supplementation (2000 IU/d), daily omega-3s supplementation (1 g/d), or a simple strength training program performed 3 times per week, either applied alone (eg, only vitamin D supplements) or in combination (eg, vitamin D and omega-3s supplements) could improve bone density at the spine, hip, or femoral neck. We included 1493 healthy older adults from Switzerland, Germany, France, and Portugal who were at least 70 years of age and who had not experienced any major health events in the 5 years before study start. Taking omega-3s supplements showed no benefit for bone density. Similarly, the simple strength exercise program showed no benefit. In contrast, participants receiving daily vitamin D supplements experienced a benefit at the hip. However, it should be noted that the effect across 3 years was very small.

Effects of vitamin D, omega-3 and a simple strength exercise programme in cardiovascular disease prevention: The DO-HEALTH randomized controlled trial.

BACKGROUND: The effects of non-pharmaceutical interventions in the prevention of cardiovascular diseases (CVD) in older adults remains unclear. Therefore, the aim was to investigate the effect of 2000 IU/day of vitamin D3, omega-3 fatty acids (1 g/day), and a simple home strength exercise program (SHEP) (3×/week) on lipid and CVD biomarkers plasma changes over 3 years, incident hypertension and major cardiovascular events (MACE). METHODS: The risk of MACE (coronary heart event or intervention, heart failure, stroke) was an exploratory endpoint of DO-HEALTH, incident hypertension and change in biomarkers were secondary endpoints. DO-HEALTH is a completed multicentre, randomised, placebo-controlled, 2 × 2 × 2 factorial design trial enrolling 2157 Europeans aged ≥70 years. RESULTS: Participants' median age was 74 [72, 77] years, 61.7% were women, 82.5% were at least moderately physically active, and 40.7% had 25(OH)D < 20 ng/mL at baseline. Compared to their controls, omega-3 increased HDL-cholesterol (difference in change over 3 years: 0.08 mmol/L, 95% CI 0.05-0.10), decreased triglycerides (-0.08 mmol/L, (95%CI -0.12 to -0.03), but increased total- (0.15 mmol/L, 95%CI 0.09; 0.2), LDL- (0.11 mmol/L, 0.06; 0.16), and non-HDL-cholesterol (0.07 mmol/L, 95%CI 0.02; 0.12). However, neither omega-3 (adjustedHR 1.00, 95%CI 0.64-1.56), nor vitamin D3 (aHR 1.37, 95%CI 0.88-2.14), nor SHEP (aHR 1.18, 95%CI 0.76-1.84) reduced risk of MACE or incident hypertension compared to control. CONCLUSION: Among generally healthy, active, and largely vitamin D replete, older adults, treatment with omega-3, vitamin D3, and/or SHEP had no benefit on MACE prevention. Only omega-3 supplementation changed lipid biomarkers, but with mixed effects. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER: NCT01745263.

Cognitive impact of multidomain intervention and omega 3 according to blood Aß42/40 ratio: a subgroup analysis from the randomized MAPT trial.

BACKGROUND: In MAPT (Multidomain Alzheimer Preventive Trial), a cognitive effect of multidomain intervention (MI) was showed in non-demented subjects with positive amyloid PET. However, screening eligible patients for multidomain intervention by PET is difficult to generalize in real-world settings. METHODS: MAPT study was a 3-year, randomized, placebo-controlled trial followed by a 2-year observational and optional extension. All participants were non-demented and randomly assigned (1:1:1:1) to the MI plus omega 3, MI plus placebo, omega 3 alone, or placebo alone group. The objectives were to assess the cognitive effect of MAPT interventions (omega 3 supplementation, MI, combined intervention) in non-demented subjects according to amyloid blood status at 12, 36, and 60 months. In this subgroup analysis (n = 483), amyloid status was defined by plasma Aß42/40 ratio (cutoff ≤ 0.0107). The primary outcome measure was the change in cognitive composite score after a 1, 3, and 5-year clinical follow-up. RESULTS: The intention-to-treat (ITT) population included 483 subjects (161 positive and 322 negative amyloid participants based on plasma Aß42/40 ratio). In the positive amyloid ITT population, we showed a positive effect of MI plus omega 3 on the change in composite cognitive score in 12 (raw p = .0350, 0.01917, 95% CI = [0.0136 to 0.3699]) and 36 months (raw p = .0357, 0.2818, 95% CI = [0.0190 to 0.5446]). After correction of multiple comparisons and adjustments, these differences were not significant (adjusted p = .1144 and .0690). In the per-protocol positive amyloid group (n = 154), we observed a significant difference between the combined intervention and placebo groups at 12 (p = .0313, 0.2424, 0.0571 to 0.4276) and 36 months (p = .0195, 0.3747, 0.1055 to 0.6439) persisting after adjustment. In the ITT and per-protocol analyses, no cognitive effect was observed in the positive and negative amyloid group at 60-month visit. CONCLUSIONS: These findings suggest a benefit of MI plus omega 3 in positive blood amyloid subjects. This promising trend needs to be confirmed before using blood biomarkers for screening in preventive trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01513252 .

Development and Validation of a Cutoff for the Chair Stand Test as a Screening for Mobility Impairment in the Context of the Integrated Care for Older People Program.

BACKGROUND: The 5-repetition chair stand test (CST) is increasingly being used to assess locomotion capacity in older adults. However, there is a lack of age-stratified cutoffs for adults aged ≥70 validated against a higher risk of functional loss. METHODS: We used 2 population-based studies (Study on global AGEing and adult health in Mexico [SAGE Mexico] and Toledo Study for Healthy Aging [TSHA]) and receiver operating characteristic (ROC) analyses to develop and cross-validate age-stratified chair stand cutoffs with activities of daily living (ADL) disability as the outcome. Then, we used data from an randomized controlled trial (RCT) (Multidomain Alzheimer Preventive Trial [MAPT]) and a frailty day-hospital for external validation with cross-sectional and longitudinal measures of ADL disability. The merged sample of SAGE Mexico and TSHA was n = 1 595; sample sizes for external validation were: MAPT n = 1 573 and Frailty day-hospital n = 2 434. The Cox models for incident disability in MAPT had a mean follow-up of 58.6 months. RESULTS: Cutoffs obtained were 14 second (ages 70-79) and 16 second (ages 80+). Those cutoffs identified older adults at higher odds of incident ADL disability odds ratio (OR) = 1.72 (95% confidence interval [CI] 1.06; 2.78) for ages 70-79 and odds ratio (OR) = 2.27 (95% CI 1.07; 4.80) in those aged 80+. Being a slow chair stander according to the cut points was associated with ADL disability in cross-sectional and longitudinal measures. CONCLUSIONS: Fourteen- and 16-second cut points for the CST are suitable to identify people at higher risk of functional decline among older adults in Mexico and Toledo, Spain. Adjusting the cut point from 14 to 16 second generally improved the psychometric properties of the test. The validation of these cutoffs can facilitate the screening for limited mobility and the implementation of the Integrated Care for Older People program.

Associations of erythrocyte omega-3 fatty acids with cognition, brain imaging and biomarkers in the Alzheimer's disease neuroimaging initiative: cross-sectional and longitudinal retrospective analyses.

BACKGROUND: The association between omega-3 (ω-3) PUFAs and cognition, brain imaging and biomarkers is still not fully established. OBJECTIVES: The aim was to analyze the cross-sectional and retrospective longitudinal associations between erythrocyte ω-3 index and cognition, brain imaging, and biomarkers among older adults. METHODS: A total of 832 Alzheimer's Disease Neuroimaging Initiative 3 (ADNI-3) participants, with a mean (SD) age of 74.0 (7.9) y, 50.8% female, 55.9% cognitively normal, 32.7% with mild cognitive impairment, and 11.4% with Alzheimer disease (AD) were included. A low ω-3 index (%EPA + %DHA) was defined as the lowest quartile (≤3.70%). Cognitive tests [composite score, AD Assessment Scale Cognitive (ADAS-Cog), Wechsler Memory Scale (WMS), Trail Making Test, Category Fluency, Mini-Mental State Examination, Montreal Cognitive Assessment] and brain variables [hippocampal volume, white matter hyperintensities (WMHs), positron emission tomography (PET) amyloid-ß (Aß) and tau] were considered as outcomes in regression models. RESULTS: Low ω-3 index was not associated with cognition, hippocampal, and WMH volume or brain Aß and tau after adjustment for demographics, ApoEε4, cardiovascular disease, BMI, and total intracranial volume in the cross-sectional analysis. In the retrospective analysis, low ω-3 index was associated with greater Aß accumulation (adjusted ß = 0.02; 95% CI: 0.01, 0.03; P = 0.003). The composite cognitive score did not differ between groups; however, low ω-3 index was significantly associated with greater WMS-delayed recall cognitive decline (adjusted ß = -1.18; 95% CI: -2.16, -0.19; P = 0.019), but unexpectedly lower total ADAS-Cog cognitive decline. Low ω-3 index was cross-sectionally associated with lower WMS performance (adjusted ß = -1.81, SE = 0.73, P = 0.014) and higher tau accumulation among ApoE ε4 carriers. CONCLUSIONS: Longitudinally, low ω-3 index was associated with greater Aß accumulation and WMS cognitive decline but unexpectedly with lower total ADAS-Cog cognitive decline. Although no associations were cross-sectionally found in the whole population, low ω-3 index was associated with lower WMS cognition and higher tau accumulation among ApoE ε4 carriers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is registered at clinicaltrials.gov as NCT00106899.

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.

Clinically meaningful change for the chair stand test: monitoring mobility in integrated care for older people.

BACKGROUND: Clinically meaningful changes in the five-repetition chair stand test are essential for monitoring mobility in integrated care for older people. Recommendations for the clinically meaningful change of the chair stand test are not well known. Our study aimed to estimate the absolute and relative clinically meaningful changes for older adults' five-repetition chair stand test. METHODS: We applied distribution-based and anchor-based methods in addition to receiver operator characteristics analyses to a population-based study of community-dwelling adults (SAGE Mexico study, n = 897) to derive the clinically meaningful change in the chair stand test. We used three self-reported clinical anchors: moving around, vigorous activities, and walking 1 km. Our primary outcome was the incidence of disability for basic activities of daily living (ADL). Secondly, we examined our estimates of clinically meaningful change in a clinical trial population of healthy volunteers (MAPT, France, study n = 1575) concerning the risk of incident ADL disability. RESULTS: The age of SAGE Mexico participants ranged from 60 to 96 years; mean (SD) = 69.0 (6.2); 54.4% were female. Their baseline chair stand time averaged 12.1 s (SD = 3 s). Forty-eight participants (5.6%) showed incident disability over 3 years. The absolute and relative clinically meaningful change cut points found over 3 years of follow-up were 2.6 s and 27.7%, respectively. Absolute clinically meaningful change ranged from 0.5 to 4.7 s, depending on the estimation method. Relative clinically meaningful change ranged from 9.6 to 46.2%. SAGE Mexico participants with absolute and relative clinically meaningful declines (increasing 2.6 s and 27.7% from baseline time, respectively) showed an increased risk of ADL disability [aRR = 1.93; P = 0.0381; 95% CI (1.05, 3.46) and aRR = 2.27; P = 0.0157; 95% CI (1.22, 4.10)], respectively, compared with those without a clinically meaningful decline. MAPT participants [age range = 70-94; mean (SD) = 75.3 (4.4); 64.8% female; incident ADL disability over 5 years = 145(14.8%)] with a relative clinically meaningful decline (≥27.7% from baseline over 3 years) had a 74% higher risk of incident ADL disability than their counterparts [aHR = 1.74; P = 0.016; CI95% (1.11, 2.72); mean follow-up of 58 months]. CONCLUSIONS: Community-dwelling older adults with an increase of 3 s or 28% in chair stand test performance over 3 years (approximately 1 s or 10% per year) could be the target of interventions to enhance mobility and prevent incident disability.

Combined Vitamin D, Omega-3 Fatty Acids, and a Simple Home Exercise Program May Reduce Cancer Risk Among Active Adults Aged 70 and Older: A Randomized Clinical Trial.

Objective: The aim of this study was to test the individual and combined benefit of vitamin D, omega-3, and a simple home strength exercise program on the risk of any invasive cancer. Design: The DO-HEALTH trial is a three-year, multicenter, 2 × 2 × 2 factorial design double-blind, randomized-controlled trial to test the individual and combined benefit of three public health interventions. Setting: The trial was conducted between December 2012 and December 2017 in five European countries. Participants: Generally healthy community-dwelling adults ≥70 years were recruited. Interventions: Supplemental 2000 IU/day of vitamin D3, and/or 1 g/day of marine omega-3s, and/or a simple home strength exercise (SHEP) programme compared to placebo and control exercise. Main outcome: In this pre-defined exploratory analysis, time-to-development of any verified invasive cancer was the primary outcome in an adjusted, intent-to-treat analysis. Results: In total, 2,157 participants (mean age 74.9 years; 61.7% women; 40.7% with 25-OH vitamin D below 20 /ml, 83% at least moderately physically active) were randomized. Over a median follow-up of 2.99 years, 81 invasive cancer cases were diagnosed and verified. For the three individual treatments, the adjusted hazard ratios (HRs, 95% CI, cases intervention versus control) were 0.76 (0.49-1.18; 36 vs. 45) for vitamin D3, 0.70 (0.44-1.09, 32 vs. 49) for omega-3s, and 0.74 (0.48-1.15, 35 vs. 46) for SHEP. For combinations of two treatments, adjusted HRs were 0.53 (0.28-1.00; 15 vs. 28 cases) for omega-3s plus vitamin D3; 0.56 (0.30-1.04; 11 vs. 21) for vitamin D3 plus SHEP; and 0.52 (0.28-0.97; 12 vs. 26 cases) for omega-3s plus SHEP. For all three treatments combined, the adjusted HR was 0.39 (0.18-0.85; 4 vs. 12 cases). Conclusion: Supplementation with daily high-dose vitamin D3 plus omega-3s, combined with SHEP, showed cumulative reduction in the cancer risk in generally healthy and active and largely vitamin D-replete adults ≥70 years. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT01745263.

Prevalence of polypharmacy in community-dwelling older adults from seven centres in five European countries: a cross-sectional study of DO-HEALTH.

OBJECTIVE: To investigate the prevalence of polypharmacy and characteristics associated with polypharmacy in older adults from seven European cities. DESIGN: Cross-sectional study of baseline data from DO-HEALTH. SETTING AND PARTICIPANTS: DO-HEALTH enrolled 2157 community-dwelling adults age 70 and older from seven centres in Europe. Participants were excluded if they had major health problems or Mini-Mental State Examination Score <24 at baseline. PRIMARY OUTCOME MEASURES: Extensive information on prescription and over-the-counter medications were recorded. Polypharmacy was defined as the concomitant use of five or more medications, excluding vitamins or dietary supplements. Bivariate and multivariable logistic regression was used to test the association of sociodemographic factors (age, sex, years of education, living situation and city) and health-related indicators (number of comorbidities, cognitive function, frailty status, body mass index (BMI), prior fall, self-rated health and smoking status) with polypharmacy. RESULTS: 27.2% of participants reported polypharmacy ranging from 16.4% in Geneva to 60.8% in Coimbra. In the multivariable logistic regression analyses, older age (OR 1.07; 95% CI 1.04 to 1.10), greater BMI (OR 1.09; 95% CI 1.06 to 1.12) and increased number of comorbidities (OR 2.13; 95% CI 1.92 to 2.36) were associated with polypharmacy. Women were less likely to report polypharmacy than men (OR 0.65; 95% CI 0.51 to 0.84). In comparison to participants from Zurich, participants from Coimbra were more likely to report polypharmacy (OR 2.36; 95% CI 1.56 to 3.55), while participants from Geneva or Toulouse were less likely to report polypharmacy ((OR 0.36; 95% CI 0.22 to 0.59 and OR 0.64; 95% CI 0.42 to 0.96), respectively). Living situation, smoking status, years of education, prior fall, cognitive function, self-rated health and frailty status were not significantly associated with polypharmacy. CONCLUSION: Polypharmacy is common among relatively healthy older adults, with moderate variability across seven European cities. Independent of several confounders, being a woman, older age, greater BMI and greater number of comorbidities were associated with increased odds for polypharmacy. TRIAL REGISTRATION NUMBER: NCT01745263.

Effects of vitamin D, omega-3 fatty acids, and a simple home strength exercise program on fall prevention: the DO-HEALTH randomized clinical trial.

BACKGROUND: The roles of vitamin D, omega-3 fatty acids, and home exercise on fall prevention among generally healthy and active older adults are unclear. OBJECTIVES: We tested the effects of daily supplemental vitamin D, daily supplemental marine omega-3s fatty acids, and a simple home exercise program (SHEP), alone or in combination, on the incidences of total and injurious falls among generally healthy older adults. METHODS: We performed a 2 × 2 × 2 factorial-design randomized controlled trial among 2157 community-dwelling adults aged 70 years and older, who had no major health events in the 5 years prior to enrolment, recruited from Switzerland, Germany, Austria, France, and Portugal between December 2012 and November 2014. Participants were randomly assigned to supplementation with 2000 international units/day of vitamin D3 and/or 1 g/day of marine omega-3s, and/or a SHEP compared with placebo and/or control exercise over 3 years. The primary endpoint for the present fall analysis was the incidence rate of total falls. Falls were recorded prospectively throughout the trial. Since there were no interactions between treatments, the main effects are reported based on a modified intent-to-treat analysis. RESULTS: Of 2157 randomized participants, 1900 (88%) completed the study. The mean age was 74.9 years, 61.7% were women, 40.7% had a serum 25-hydroxyvitamin D concentration < 20 ng/ml, and 83% were at least moderately physically active. In total, 3333 falls were recorded over a median follow-up of 2.99 years. Overall, vitamin D and the SHEP had no benefit on total falls, whilst supplementation with omega-3s compared to no omega-3 supplementation reduced total falls by 10% (incidence rate ratio = 0.90; 95% CI, 0.81-1.00; P = 0.04). CONCLUSIONS: Among generally healthy, active, and vitamin D-replete older adults, omega-3 supplementation may have a modest benefit on the incidence of total falls, whilst a daily high dose of vitamin D or a SHEP had no benefit.

Is more always better? Dose effect in a multidomain intervention in older adults at risk of dementia.

BACKGROUND: Little is known regarding the dose-response function in multidomain interventions for dementia prevention. METHOD: The Multidomain Alzheimer Preventive Trial is a 3-year randomized controlled trial comprising cognitive training, physical activity, nutrition, and omega-3 polyunsaturated fatty acids for at-risk older adults. The dose delivered (number of sessions attended) was modeled against global cognition, memory, and fluency in 749 participants. Interaction effects were assessed for age, sex, education, dementia score (CAIDE), frailty score, and apolipoprotein E (APOE) ε4 status. RESULTS: The dose-response models were non-linear functions indicating benefits up to about 12 to 14 training hours or 15 to 20 multidomain sessions followed by a plateau. Participants who benefited from a higher dose included women, younger participants, frail individuals, and those with lower education or lower risk of dementia. DISCUSSION: The non-linear function indicates that a higher dose is not necessarily better in multidomain interventions. The optimal dose was about half of the potentially available sessions.

Associations Between Nutritional Deficits and Physical Performance in Community-Dwelling Older Adults.

Background: Whether multiple nutritional deficiencies have a synergic effect on mobility loss remains unknown. This study aims to evaluate associations between multi-nutritional deficits and physical performance evolution among community-dwelling older adults. Methods: We included 386 participants from the Multidomain Alzheimer Preventive Trial (MAPT) (75.6 ± 4.5 years) not receiving omega-3 polyunsaturated fatty acid (PUFA) supplementation and who had available data on nutritional deficits. Baseline nutritional deficits were defined as plasma 25 hydroxyvitamin D <20 ng/ml, plasma homocysteine >14 µmol/L, or erythrocyte omega-3 PUFA index ≤ 4.87% (lower quartile). The Short Physical Performance Battery (SPPB), gait speed, and chair rise time were used to assess physical performance at baseline and after 6, 12, 24, 36, 48, and 60 months. We explored if nutrition-physical performance associations varied according to the presence of low-grade inflammation (LGI) and brain imaging indicators. Results: Within-group comparisons showed that physical function (decreased SPPB and gait speed, increased chair rise time) worsened over time, particularly in participants with ≥2 nutritional deficits; however, no between-group differences were observed when individuals without deficit and those with either 1 or ≥2 deficits were compared. Our exploratory analysis on nutritional deficit-LGI interactions showed that, among people with ≥2 deficits, chair rise time was increased over time in participants with LGI (adjusted mean difference: 3.47; 95% CI: 1.03, 5.91; p = 0.017), compared with individuals with no LGI. Conclusions: Accumulated deficits on vitamin D, homocysteine, and omega-3 PUFA were not associated with physical performance evolution in older adults, but they determined declined chair rise performance in subjects with low-grade inflammation. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT00672685], identifier [NCT00672685].

Screening for intrinsic capacity impairments as markers of increased risk of frailty and disability in the context of integrated care for older people: Secondary analysis of MAPT.

AIM: This longitudinal secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) aimed to test whether the Integrated Care for Older People (ICOPE) Step 1 screening tool is able to identify people at risk of developing frailty and disability in basic (ADL) and instrumental (IADL) activities of daily living among community-dwelling older adults. PARTICIPANTS AND SETTING: Seven hundred and fifty-nine (n = 759) non-demented participants of the MAPT aged 70-89 years were assessed in memory clinics in France between 2008 and 2013. METHODS: We measured six intrinsic capacity (IC) impairments, adapted from the ICOPE screening tool. We used Cox models to estimate the adjusted hazard ratios of incident frailty and IADL/ADL disability. Incident frailty was defined by Fried's phenotype, and incident disability was measured according to Lawton and Katz for IADLs and ADLs. RESULTS: Limited mobility (HR= 2.97, 95%CI= 1.85-4.76), depressive symptoms (HR= 2.07, 95%CI= 1.03-4.19), and visual impairment (HR= 1.70, 95%CI 1.01-2.86) were associated with a higher incidence of frailty over 5 years. Each additional IC condition demonstrated a positive association with a higher risk of incident frailty, IADL, ADL disability, with risk increased by 47%, 27%, and 23% over 5 years, respectively. CONCLUSION: Screening for IC impairments identifies older adults at higher risk of incident frailty and incident IADL/ADL disability. It is relevant to screen for these impairments together because the risk of frailty and disability increases with each additional one. ClinicalTrials.gov identifier: NCT00672685.

Associations of Omega-3 fatty acids with brain morphology and volume in cognitively healthy older adults: A narrative review.

INTRODUCTION: Human neurodevelopment is complete by the 4th decade of life at which point brain atrophy ensues with variable rate and regionality into old age. Literally all regions of the brain experience atrophy with older age, however the pattern and rate of atrophy can dictate the behavioral consequences (i.e., cognitive impairment, Alzheimer's disease). Substantial research has aimed to discover the reasons why some people experience greater morphologic changes that produce undesirable consequences with aging and how it may be prevented. One possible explanation is diet, particularly fish consumption and the intake of omega-3 polyunsaturated fatty acids (omega 3) concentrated in fish oil. This narrative review examines the available evidence on the association between omega-3 and brain volume in non-demented older adults. METHODS: A PubMed search of the literature was conducted in search of studies that investigated the associations of omega-3 on brain morphology and volume in cognitively intact older adults. Inclusion criteria were: populations of adults aged 45 years or over, who were cognitively intact, free of any central nervous system disease, and free of advanced structural brain atrophy. Study participants had to have DHA and EPA levels measured either by blood testing or scoring of dietary intake. There were no restrictions to dates of publication. Studies including demented participants, or participants with substantial white or grey matter atrophy visible on magnetic resonance imaging were excluded. RESULTS AND CONCLUSION: The search identified only 12 studies, 8 of which were cross-sectional observational studies, 3 longitudinal observational studies, and 1 randomized controlled trial published between 2007 and 2019. The largest amount of evidence indicated that the hippocampus was most frequently involved in this association, with a higher volume associated with higher omega-3 levels. Larger total grey matter, total brain volume, and lower white matter lesion volume were also associated with higher omega-3 among four of the reviewed studies. However, most studies reviewed provided mixed findings regarding the presence or absence of the association of interest, and the findings were observed to be brain region-dependent. Current evidence is still insufficient to formulate recommendations for omega-3 intake to support brain health specifically.

What day is today? Cognitive capacity and the risk of incident dementia in the context of integrated care for older people (ICOPE Step 1).

Based on clinical observations, our objective was to test if the older adults who failed to recall the name of the weekday, or had a higher number of mistakes in the word recall were at higher risk of mild cognitive impairment (MCI) or dementia. Longitudinal data of the Multidomain Alzheimer Preventive Trial (MAPT) was used to retrospectively measure the cognitive capacity according to the ICOPE Step 1 tool. Incident dementia was assessed by two multidisciplinary committees independent from each other. MCI was defined as Clinical Dementia Rating scale CDR = 0.5. Failure to recall the name of the weekday had a three-fold risk of incident dementia in the next 5 years (HRa = 3.11, 95%CI: 1.18-8.17). Having two or three mistakes in the word recall carried a higher risk of incident dementia, (HRa for two mistakes = 3.50, 95% CI: 1.49-8.26; HRa for three mistakes = 4.28, 95% CI: 1.60-11.46), but not MCI. People with impaired cognitive capacity according to the ICOPE Step 1 tool deserve further assessment and a closer follow-up.

DO-HEALTH: Vitamin D3 - Omega-3 - Home exercise - Healthy aging and longevity trial - Design of a multinational clinical trial on healthy aging among European seniors.

DO-HEALTH is a multi-center clinical trial among 2157 community-dwelling European men and women age 70 and older. The 2x2x2 randomized-control factorial design trial tested the individual and additive benefit, as well as the cost-effectiveness, of 3 interventions: vitamin D 2000 IU/day, omega-3 fatty acids 1000 mg/day (EPA + DHA, ratio 1:2), and a 30-minute 3 times/week home exercise (strength versus flexibility). Each treatment tested has shown considerable prior promise from mechanistic studies, small clinical trials, or large cohort studies, in the prevention of common age-related chronic diseases, but definitive data are missing. DO-HEALTH will test these interventions in relation to 6 primary endpoints (systolic and diastolic blood pressure, non-vertebral fractures, Short Physical Performance Battery score, the Montreal Cognitive Assessment, and risk of infections), plus several secondary endpoints explored in ancillary studies (i.e. rate of any falls and injurious falls, joint pain, oral health, quality of life, and incident frailty). As the 3 interventions have distinct mechanisms of action for each of the 6 primary endpoints, a maximum benefit is expected for their additive benefit as a "multi-modal" intervention. The trial duration is 3 years with in-person contacts with all participants at 4 clinical visits and by quarterly phone calls. Baseline and follow-up blood samples were collected in all participants to measure changes in 25-hydroxyvitamin D and poly-unsaturated fatty acid concentrations. Our objective was to test interventions that are expected to promote healthy aging and longer life expectancy and that can be easily and safely implemented by older community-dwelling adults.

Biological and Neuroimaging Markers as Predictors of 5-Year Incident Frailty in Older Adults: A Secondary Analysis of the MAPT Study.

BACKGROUND: This study aims to investigate the predictive value of biological and neuroimaging markers to determine incident frailty among older people for a period of 5 years. METHODS: We included 1394 adults aged 70 years and older from the Multidomain Alzheimer Preventive Trial, who were not frail at baseline (according to Fried's criteria) and who had at least 1 post-baseline measurement of frailty. Participants who progressed to frailty during the 5-year follow-up were categorized as "incident frailty" and those who remained non-frail were categorized as "without frailty." The differences of baseline biochemical factors (25-hydroxyvitamin D, homocysteine, omega-3 index, C-reactive protein), other biological markers (Apolipoprotein E genotypes, amyloid-ß deposits), and neuroimaging data (gray matter volume, hippocampal volume, white matter hyperintensities) were compared between groups. Cox proportional hazard model was used to evaluate the associations between biomarkers and incident frailty. RESULTS: A total of 195 participants (14.0%) became frail over 5 years. Although 25-hydroxyvitamin D deficiency, homocysteine levels, low-grade inflammation (persistently increased C-reactive protein 3-10 mg/L), gray matter, and hippocampal volume were significantly associated with incident frailty in unadjusted models, these associations disappeared after adjustment for age, sex, and other confounders. Omega-3 index was the sole marker that presented a trend of association with incident frailty (hazard ratio: 0.92; 95% confidence interval: 0.83-1.01; p = .082). CONCLUSIONS: This study failed to identify biomarkers able to predict frailty incidence in community-dwelling older adults for a period of 5 years. Further longitudinal research with multiple measurements of biomarkers and frailty is needed to evaluate the long-term relationships between changes in biomarkers levels and frailty evolution.

Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial.

Importance: The benefits of vitamin D, omega-3 fatty acids, and exercise in disease prevention remain unclear. Objective: To test whether vitamin D, omega-3s, and a strength-training exercise program, alone or in combination, improved 6 health outcomes among older adults. Design, Setting, and Participants: Double-blind, placebo-controlled, 2 × 2 × 2 factorial randomized clinical trial among 2157 adults aged 70 years or older who had no major health events in the 5 years prior to enrollment and had sufficient mobility and good cognitive status. Patients were recruited between December 2012 and November 2014, and final follow-up was in November 2017. Interventions: Participants were randomized to 3 years of intervention in 1 of the following 8 groups: 2000 IU/d of vitamin D3, 1 g/d of omega-3s, and a strength-training exercise program (n = 264); vitamin D3 and omega-3s (n = 265); vitamin D3 and exercise (n = 275); vitamin D3 alone (n = 272); omega-3s and exercise (n = 275); omega-3s alone (n = 269); exercise alone (n = 267); or placebo (n = 270). Main Outcomes and Measures: The 6 primary outcomes were change in systolic and diastolic blood pressure (BP), Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates (IRs) of nonvertebral fractures and infections over 3 years. Based on multiple comparisons of 6 primary end points, 99% confidence intervals are presented and P < .01 was required for statistical significance. Results: Among 2157 randomized participants (mean age, 74.9 years; 61.7% women), 1900 (88%) completed the study. Median follow-up was 2.99 years. Overall, there were no statistically significant benefits of any intervention individually or in combination for the 6 end points at 3 years. For instance, the differences in mean change in systolic BP with vitamin D vs no vitamin D and with omega-3s vs no omega-3s were both -0.8 (99% CI, -2.1 to 0.5) mm Hg, with P < .13 and P < .11, respectively; the difference in mean change in diastolic BP with omega-3s vs no omega-3s was -0.5 (99% CI, -1.2 to 0.2) mm Hg; P = .06); and the difference in mean change in IR of infections with omega-3s vs no omega-3s was -0.13 (99% CI, -0.23 to -0.03), with an IR ratio of 0.89 (99% CI, 0.78-1.01; P = .02). No effects were found on the outcomes of SPPB, MoCA, and incidence of nonvertebral fractures). A total of 25 deaths were reported, with similar numbers in all treatment groups. Conclusions and Relevance: Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT01745263.

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 .

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.