Cerebrospinal fluid proteomic profile of frailty: Results from the PROLIPHYC cohort.

Frailty is a clinical state reflecting a decrease in physiological reserve capacities, known to affect numerous biological pathways and is associated with health issues, including neurodegenerative diseases. However, how global protein expression is affected in the central nervous system in frail subject remains underexplored. In this post hoc cross-sectional biomarker analysis, we included 90 adults (52-85 years) suspected of normal pressure hydrocephalus (NPH) and presenting with markers of neurodegenerative diseases. We investigated the human proteomic profile of cerebrospinal fluid associated with frailty defined by an established cumulated frailty index (FI, average = 0.32), not enriched for neurology clinical features. Using a label-free quantitative proteomic approach, we identified and quantified 999 proteins of which 13 were positively associated with frailty. Pathway analysis with the top positively frailty-associated proteins revealed enrichment for proteins related to inflammation and immune response. Among the 60 proteins negatively associated with frailty, functional pathways enriched included neurogenesis, synaptogenesis and neuronal guidance. We constructed a frailty prediction model using ridge regression with 932 standardized proteins. Our results showed that the "proteomic model" could become an equivalent predictor of FI in order to study chronological age. This study represents the first comprehensive exploration of the proteomic profile of frailty within cerebrospinal fluid. It sheds light on the physiopathology of frailty, particularly highlighting processes of neuroinflammation and inhibition of neurogenesis. Our findings unveil a range of biological mechanisms that are dysregulated in frailty, in NPH subjects at risk of neurodegenerative impairment, offering new perspectives on frailty phenotyping and prediction.

Predictive capacity of the Integrated Care for Older People (ICOPE) screening tool for intrinsic capacity impairments: results from the INSPIRE-T cohort.

BACKGROUND: The Integrated Care for Older People (ICOPE) approach was developed by the World Health Organization (WHO) aiming to shift the traditional focus of care based on diseases to a function- and person-centered approach, focused on maintaining and monitoring intrinsic capacity (IC). This study aimed to investigate the ability of the ICOPE screening tool to identify older people with clinically meaningful impairments in IC domains. METHODS: This cross-sectional analysis included 603 older adults, participants (mean age 74.7 [SD 8.8] years, women 59.0%) of the INSPIRE Translational (INSPIRE-T) cohort. Responses at screening were compared to results of the subsequent in-depth assessment (i.e., Mini Mental State Examination, Mini Nutritional Assessment, Short Physical Performance Battery, Patient Health Questionnaire-9, and clinical investigation of vision problems) to determine its predictive capacity for impairments at the IC domains (i.e., cognition, psychological, sensory (vision), vitality, and locomotion). RESULTS: The ICOPE screening items provided very high sensitivity for identifying abnormality in vision (97.2%), and varied from 42.0% to 69.6% for the other domains. High specificity (>70%) was observed for all the IC domains, except for vision (2.7%). CONCLUSIONS: The ICOPE screening tool can be a useful instrument enabling the identification of older people with impairments in IC domains, but studies with different populations are needed. It should be considered as a low-cost and simple screening tool in clinical care.

Fall risk factors among poly-medicated older Lebanese patients in primary care settings: a secondary cross-sectional analysis of the "MGPIDP-L project".

BACKGROUND: Falling is a major concern for the health of older adults and significantly affects their quality of life. Identifying the various risk factors and the differences between older patients can be challenging. The objective of this study was to identify the risk factors for falls among polymedicated community-dwelling older Lebanese patients following a medication review. METHODS: In this analytical cross-sectional study, we examined the risk factors for falls in 850 patients aged ≥ 65 years who were taking ≥ 5 medications daily. The study involved conducting a medication review over the course of a year in primary care settings and using multivariate logistic regression analysis to analyze the data. RESULTS: Our results showed that 106 (19.5%) of the 850 included patients had fallen at least once in the three months prior to the medication review. Loss of appetite and functional dependence were identified as the most significant predictors of falls ORa = 3.020, CI [2.074-4.397] and ORa = 2.877, CI [1.787-4.632], respectively. Other risk factors for falls included drowsiness ORa = 2.172, CI [1.499-3.145], and the use of beta-blockers ORa = 1.943, CI [1.339-2.820]. CONCLUSION: Our study highlights the importance of addressing multiple risk factors for falls among Lebanese older adults and emphasizes the need for customized interventions and ongoing monitoring to prevent falls and improve health outcomes. This study sheds light on a critical issue in the Lebanese older population and provides valuable insight into the complex nature of falls among poly-medicated Lebanese community-dwelling older adults. TRIAL REGISTRATION: 2021REC-001- INSPECT -09-04.

Visit-to-visit blood pressure variability is associated with intrinsic capacity decline: Results from the MAPT Study.

BACKGROUND: The effectiveness of the body physiological regulatory mechanisms declines in late life, and increased Blood Pressure Variability (BPV) may represent an alteration in cardiovascular homeostatic patterns. Intrinsic Capacity (IC) has been proposed by the World Health Organization as a marker of healthy aging, based on individual's functional abilities and intended at preserving successful aging. We aimed to investigate the association of visit-to-visit BPV with IC decline in a population of community-dwelling older adults. METHODS: The study population consisted of 1407 community-dwelling participants aged ≥70 years from the MAPT study evaluated during the 5-year follow-up. Systolic BPV (SBPV) and diastolic BPV (DBPV) were determined through six indicators. Cognition, psychology, locomotion and vitality constituted the four IC domains assessed. Total IC Z-score resulted from the sum of the four domains Z-scores divided by 4. The incidence of domain impairment over time was also assessed. RESULTS: Higher SBPV was significantly associated with poorer IC Z-scores in all linear mixed models [1-SD increase of CV%: ß(SE)=-0.010(0.001), p < 0.01]. Similar results were observed for DBPV [1-SD increase of CV%: ß(SE)=-0.003(0.001), p = 0.02]. Incident IC impairment was significantly higher in participants with greater SBPV, [HR=1.16 (95 % CI, 1.01-1.33), p = 0.03], while greater DBPV did not show a higher risk of incident IC impairment. CONCLUSIONS: Greater BPV is associated with IC decline over time. Our findings support BP instability as a presumable index of altered cardiovascular homeostatic mechanism, suggesting that BPV might be a clinical marker of aging and addressable risk factor for promoting healthy aging.

Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial.

BACKGROUND: It is unknown whether multidomain interventions, which might preserve late-life cognition, affect Alzheimer's disease pathology. Previous studies measured cerebrospinal fluid and imaging Alzheimer's disease biomarkers in small subsamples of multidomain trial participants. Newly developed assays enable the measurement of blood-based Alzheimer's disease biomarkers in larger samples. We aimed to assess whether plasma tau phosphorylated at threonine 181 (p-tau181) was able to detect or predict 3-year multidomain intervention effects. METHODS: This is a secondary analysis of the randomised, controlled, Multidomain Alzheimer Prevention Trial (MAPT) testing a 3-year multidomain intervention, omega-3 fatty acid supplementation, or both versus placebo, in individuals aged 70 years and older in 13 memory centres in France and Monaco. Plasma p-tau181 was measured in stored blood samples in a subsample of 527 participants on an intention-to-treat basis. Changes in cognitive score were calculated as a composite measure using the average of Z scores for the following tests: Mini Mental State Examination orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency, and Digit Symbol Substitution Test. Intervention effects on 3-year change in p-tau181 concentration were estimated by use of a linear mixed model with centre-specific random intercepts. FINDINGS: Recruitment took place between May 30, 2008, and Feb 24, 2011. Median baseline plasma p-tau181 was 8·8 pg/mL (IQR 6·7-11·9) in the total sample, and significantly higher in older individuals, men, APOE ε4 carriers, and participants with renal dysfunction or a positive PET amyloid scan. During 3-year follow-up, individuals with raised baseline p-tau181 underwent greater cognitive decline (eg, mean difference in 3-year change on the composite cognitive score between control group participants with normal and abnormal baseline levels of p-tau was -0·34 [effect size -0·52; 95% CI -0·61 to 0·07] in the fully adjusted model using a 12·4 pg/mL cutoff for abnormal baseline p-tau181), but there were no intervention effects on change in p-tau181 either in this subgroup or the total population, and no effect on cognitive change in individuals with raised baseline p-tau181 (eg, in the fully adjusted model using the 12·4 pg/mL cutoff for p-tau181 abnormality, the mean difference [95% CI] in this subgroup in 3-year decline on the composite cognitive score between the control group and the multidomain + omega-3 group, the omega-3 group, and the multidomain intervention group, was, respectively: 0·13 [-0·21 to 0·47], 0·03 [-0·30 to 0·36], and 0·10 [-0·26 to 0·46]). Surprisingly, individuals with raised baseline p-tau181 showed a decrease in p-tau181 during follow-up (eg, unadjusted mean [95% CI] 3-year change was -3·01 pg/mL (-4·45 to -1·56) in control group subjects with abnormal baseline p-tau181 [using the 12·4 pg/mL abnormal p-tau cutoff]). INTERPRETATION: Our results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required. FUNDING: Toulouse Gérontopôle, French Ministry of Health and Pierre Fabre Research Institute.

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 .

Exploring the natural history of intrinsic capacity impairments: longitudinal patterns in the 10/66 study.

BACKGROUND: intrinsic capacity (IC) is a construct encompassing people's physical and mental abilities. There is an implicit link amongst IC domains: cognition, locomotion, nutrition, sensory and psychological. However, little is known about the integration of the domains. OBJECTIVES: to investigate patterns in the presentation and evolution of IC domain impairments in low-and-middle-income countries and if such patterns were associated with adverse outcomes. METHODS: secondary analyses of the first two waves of the 10/66 study (population-based surveys conducted in eight urban and four rural catchment areas in Cuba, Dominican Republic, Puerto Rico, Venezuela, Peru, Mexico and China). We applied latent transition analysis on IC to find latent statuses (latent clusters) of IC domain impairments. We evaluated the longitudinal association of the latent statuses with the risk of frailty, disability and mortality, and tested concurrent and predictive validity. RESULTS: amongst 14,923 participants included, the four latent statuses were: high IC (43%), low deterioration with impaired locomotion (17%), high deterioration without cognitive impairment (22%), and high deterioration with cognitive impairment (18%). A total of 61% of the participants worsened over time, 35% were stable, and 3% improved to a healthier status.Participants with deteriorated IC had a significantly higher risk of frailty, disability and dementia than people with high IC. There was strong concurrent and predictive validity. (Mortality Hazard Ratio = 4.60, 95%CI 4.16; 5.09; Harrel's C = 0.73 (95%CI 0.72;0.74)). CONCLUSIONS: half of the study population had high IC at baseline, and most participants followed a worsening trend. Four qualitatively different IC statuses or statuses were characterised by low and high levels of deterioration associated with their risk of disability and frailty. Locomotion and cognition impairments showed other trends than psychological and nutrition domains across the latent statuses.

Prognostication algorithm for non-cirrhotic non-B non-C hepatocellular carcinoma-a multicenter study under the aegis of the French Association of Hepato-Biliary Surgery and liver Transplantation.

Background: Liver resection and local ablation are the only curative treatment for non-cirrhotic hepatocellular carcinoma (HCC). Few data exist concerning the prognosis of patients resected for non-cirrhotic HCC. The objectives of this study were to determine the prognostic factors of recurrence-free survival (RFS) and overall survival (OS) and to develop a prognostication algorithm for non-cirrhotic HCC. Methods: French multicenter retrospective study including HCC patients with non-cirrhotic liver without underlying viral hepatitis: F0, F1 or F2 fibrosis. Results: A total of 467 patients were included in 11 centers from 2010 to 2018. Non-cirrhotic liver had a fibrosis score of F0 (n=237, 50.7%), F1 (n=127, 27.2%) or F2 (n=103, 22.1%). OS and RFS at 5 years were 59.2% and 34.5%, respectively. In multivariate analysis, microvascular invasion and HCC differentiation were prognostic factors of OS and RFS and the number and size were prognostic factors of RFS (P<0.005). Stratification based on RFS provided an algorithm based on size (P=0.013) and number (P<0.001): 2 HCC with the largest nodule ≤10 cm (n=271, Group 1); 2 HCC with a nodule >10 cm (n=176, Group 2); >2 HCC regardless of size (n=20, Group 3). The 5-year RFS rates were 52.7% (Group 1), 30.1% (Group 2) and 5% (Group 3). Conclusions: We developed a prognostication algorithm based on the number (≤ or >2) and size (≤ or >10 cm), which could be used as a treatment decision support concerning the need for perioperative therapy. In case of bifocal HCC, surgery should not be a contraindication.

The MGPIDP-L project: Potentially inappropriate drug prescribing and its associated factors.

OBJECTIVE: The aim of this study was to identify the prevalence of potentially inappropriate drug prescribing1 (PIDP) using a combination of explicit and implicit criteria in a sample of Lebanese older adults taking 5 or more chronic medications per day in ambulatory care settings and to identify which factors were associated with PIDP. The explicit criteria included five different lists: Beers, Laroche, European Union (EU(7)-PIM list), STOPP/ START, STOPP Frail, and Alert and Mastering of Iatrogenesis issued by the French High Authority of Health. We also performed a sensitivity analysis to compare the potentially inappropriate medications according to each criterion. METHODS: Data were collected from each patient via a face-to-face interview. Logistic regressions were conducted to evaluate both objectives. RESULTS: Many factors were positively associated with PIDP. The risk of PIDP was positively associated with age (OR =4.692, 95% CI [1.889-11.655]). Treatment for insomnia doubled the odds of PIDP (P<0.05). Participants who picked their medications from the pharmacy and had excess stock of drugs were at higher risk of having PIDP by 2.042 (95% CI [1.199-3.478]) and 2.965(95% CI [1.133-7.762]) respectively. However, patients with a perception of being heavily medicated and patients with a missed dose in the last two weeks had lower odds of PIDP. CONCLUSION: Our study showed a high prevalence of PIDP in Lebanon, which is associated with various correlates. Selecting the appropriate tools to assess PIDP and providing patient education regarding the risks associated with potentially inappropriate medications are issues to be addressed among older adults.

Using minimal clinically important differences to measure long-term transitions of osteosarcopenia: The New Mexico Aging Process Study.

BACKGROUND/OBJECTIVE: By having a better understanding of transitions in osteosarcopenia, interventions to reduce morbidity and mortality can be better targeted. The aim of this study was to show the rationale and method of using minimal clinically important differences (MCID's) to classify transitions, and the effects of demographic variables on transitions in a 9-year follow-up data from the New Mexico Aging Process Study (NMAPS). METHODS: Transitions were identified in four aspects of osteosarcopenia: bone mineral density (BMD), appendicular skeletal muscle mass/body mass index ratio (ASM/BMI), grip strength and gait speed. Transitions were identified using a MCID score. As there is currently no available MCID for BMD and ASM/BMI, those were determined using a distribution-based and an anchor-based method. Total transitions were calculated for all four measures of osteosarcopenia in all transition categories (maintaining a health status, beneficial transition, harmful transitions). Poisson regression was used to test for effects of demographic variables, including age, sex, physical activity, medication, and health status, on transitions. RESULTS: Over the 9-year follow-up, a total of 2163 MCID-derived BMD transitions were reported, 1689 ASM/BMI transitions, 2339 grip strength transitions, and 2151 gait speed transitions. Additionally, some MCID-derived transition categories were associated with sex, age, and health status. CONCLUSION: Use of MCID-derived transitions reflected the fluctuation and the dynamic nature of health in older adults. Future research should focus on transitions of modifiable markers in osteosarcopenia to design intervention trials.

Biomarkers of mitochondrial dysfunction and inflammaging in older adults and blood pressure variability.

Most physiopathological mechanisms underlying blood pressure variability (BPV) are implicated in aging. Vascular aging is associated with chronic low-grade inflammation occurring in late life, known as "inflammaging" and the hallmark "mitochondrial dysfunction" due to age-related stress. We aimed to determine whether plasma levels of the pleiotropic stress-related mitokine growth/differentiation factor 15 (GDF-15) and two inflammatory biomarkers, interleukin 6 (IL-6) and tumor necrosis factor receptor 1 (TNFR-1), are associated with visit-to-visit BPV in a population of community-dwelling older adults. The study population consisted of 1096 community-dwelling participants [median age 75 (72-78) years; 699 females, 63.7%] aged ≥ 70 years from the MAPT study. Plasma blood sample was collected 12 months after enrolment and BP was assessed up to seven times over a 4-year period. Systolic (SBPV) and diastolic BPV (DBPV) were determined through several indicators taking into account BP change over time, the order of measurements and formulas independent of mean BP levels. Higher values of GDF-15 were significantly associated with increased SBPV (all indicators) after adjustment for relevant covariates [adjusted 1-SD increase in GDF-15: ß (SE) = 0.07 (0.04), p < 0.044, for coefficient of variation%]. GDF-15 levels were not associated with DBPV. No significant associations were found between IL-6 and BPV, whereas TNFR1 was only partially related to DBPV. Unlike inflammation biomarkers, higher GDF-15 levels were associated with greater SBPV. Our findings support the age-related process of mitochondrial dysfunction underlying BP instability, suggesting that BPV might be a potential marker of aging.

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.

Telephone and Smartphone-Based Interventions for Cognitive and Cardio-Metabolic Health in Middle-Aged and Older Adults: A Systematic Review.

Purpose: Dementia and cardio-metabolic diseases share many risk factors. Management of these risk factors could contribute to successful aging, including the prevention of cardio-metabolic disease and dementia. The increasing use of smartphones offers an opportunity for remote preventive interventions. We provided a systematic review of telephone and smartphone-based interventions targeting the prevention of cognitive decline, dementia cardio-metabolic diseases or their risk factors among adults aged over 50 years. Patients and Methods: We searched Pubmed and the International Clinical Trials Registry Platform for experimental studies. We used the Cochrane risk-of-bias tool (Version 2) for randomized trials or TREND (Transparent Reporting of Evaluations with Nonrandomized Designs) checklists to assess study quality for completed studies. Results: We analyzed 21 completed (3 for cognition, 18 for cardio-metabolic outcomes) and 50 ongoing studies (23 for cognition, 27 for cardio-metabolic outcomes). Smartphone interventions were used in 26 studies (3 completed, 23 ongoing). Other interventions involved telephone vocal support and text messaging. Few studies were at low risk of bias. There were heterogeneous cognitive and cardio-metabolic outcomes. The highest quality studies found no significant effects on cognition, and inconsistent results for HbA1c, blood pressure or physical activity. The lower quality-studies found effects on global cognition, working memory, memory and language and inconsistent results for clinical, biological or behavioral cardio-metabolic outcomes. Conclusion and Implications: Despite the large number of commercially available mobile health applications, the magnitude of the scientific evidence base remains very limited. Based on published studies, the added value of telephone and smartphone tools for the prevention of cardio-metabolic diseases, cognitive decline or dementia is currently uncertain, but, there are several ongoing studies expected to be completed in the coming years.

Randomised controlled trials for the prevention of cognitive decline or dementia: A systematic review.

Dementia prevention research has progressed rapidly in recent years, with publication of several large lifestyle intervention trials, and renewed interest in pharmacological interventions, notably for individuals with Alzheimer's disease biomarkers, warranting an updated review of results and methodology. We identified 112 completed trials testing the efficacy of single-domain pharmacological (n = 33, 29%), nutritional (n = 27, 24%), physical activity (n = 18, 16%) and cognitive stimulation (n = 13, 12%), or multidomain (n = 22, 20%) interventions on incident dementia, or a relevant intermediate marker (e.g. cognitive function, biomarkers or dementia risk scores) in people without dementia. The earliest trials tested pharmacological interventions or nutritional supplements, but lifestyle interventions predominated in the last decade. In total, 21 (19%) trials demonstrated a clear beneficial effect on the pre-specified primary outcome (or all co-primary outcomes), but only two (10%) were large-scale (testing blood pressure lowering (Syst-Eur) or multidomain (FINGER) interventions on incident dementia and cognitive change in cognitive function, respectively). Of the 116 ongoing trials, 40% (n = 46) are testing multidomain interventions. Recent methodological shifts concern target populations, primary outcome measures, and intervention design, but study design remains constant (parallel group randomised controlled trial). Future trials may consider using adaptive trials or interventions, and more targeted approaches, since certain interventions may be more effective in certain subgroups of the population, and at specific times in the life-course. Efforts should also be made to increase the representativeness and diversity of prevention trial populations.

A 1-year randomized controlled trial of a nutritional blend to improve nutritional biomarkers and prevent cognitive decline among community-dwelling older adults: The Nolan Study.

Introduction: This study aimed to test the efficacy of a nutritional blend (NB) in improving nutritional biomarkers and preventing cognitive decline among older adults. Methods: A 1-year randomized, double-blind, multicenter, placebo-controlled trial with 362 adults (58.6% female, mean 78.3 years, SD = 4.8) receiving an NB or placebo. Erythrocyte ω-3 index and homocysteine concentrations were primary outcomes. Other outcomes included Patient-Reported Outcomes Measurement Information System (PROMIS) Applied Cognition-Abilities, composite cognitive score (CCS), Cognitive Function Instrument (CFI) self-assessment and study partner, hippocampal volume (HV), and Alzheimer's disease signature cortical thickness (CT). Results: A total of 305 subjects completed the follow-up. Supplementation increased ω-3 index and decreased homocysteine, but did not affect CCS, CFI self-assessment, HV, and CT. Placebo improved and treatment did not change PROMIS at 1 month. Intervention showed a positive effect on CFI study partner. Discussion: Although improving nutritional biomarkers, this 1-year trial with a multi-nutrient novel approach was not able to show effects on cognitive outcomes among older adults.

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.

Nutrition state of science and dementia prevention: recommendations of the Nutrition for Dementia Prevention Working Group.

Observational studies suggest that nutritional factors have a potential cognitive benefit. However, systematic reviews of randomised trials of dietary and nutritional supplements have reported largely null effects on cognitive outcomes and have highlighted study inconsistencies and other limitations. In this Personal View, the Nutrition for Dementia Prevention Working Group presents what we consider to be limitations in the existing nutrition clinical trials for dementia prevention. On the basis of this evidence, we propose recommendations for incorporating dietary patterns and the use of genetic, and nutrition assessment tools, biomarkers, and novel clinical trial designs to guide future trial developments. Nutrition-based research has unique challenges that could require testing both more personalised interventions in targeted risk subgroups, identified by nutritional and other biomarkers, and large-scale and pragmatic study designs for more generalisable public health interventions across diverse populations.