Does Nutritional Supplementation Have a Disease-Modifying Effect on the Alzheimer's Disease Neurodegenerative Process?

Because nutrition is one of the main factors related to Alzheimer's disease (AD), questions arise about how taking nutrients as supplements can affect its pathophysiological process. In the present study, an overview of the potential effects of nutritional supplementation on the main biomarkers related to the AD pathophysiology (i.e., amyloid-ß and tau) is explored. Trials testing the supplementation of single or combined nutrients versus placebo identified effects on some AD biomarkers, but changes were not always accompanied by positive effects on cognitive function. Differences in characteristics of studied populations (cognitive status, age, educational level), choice of nutrient combinations and doses, duration of intervention, and adjustments for potential confounders are some factors that may explain discrepancies in findings.

Effect of a 1-Year Nutritional Blend Supplementation on Plasma p-tau181 and GFAP Levels among Community-Dwelling Older Adults: A Secondary Analysis of the Nolan Trial.

Background: Observational studies and some randomized controlled trials have suggested that nutritional supplementation could be a possible intervention pathway to prevent cognitive decline and Alzheimer's disease (AD). As measuring amyloid-ß and tau pathophysiology by positron emission tomography (PET) or cerebrospinal fluid (CSF) analyses may be perceived as complex, plasma versions of such biomarkers have emerged as more accessible alternatives with comparable capacity of predicting cognitive impairment. Objectives: This study aimed to evaluate the effect of a 1-year intervention with a nutritional blend on plasma p-tau181 and glial fibrillary acidic protein (GFAP) levels in community-dwelling older adults. Effects were further assessed in exploratory analyses within sub-cohorts stratified according to p-tau status (with the third tertile considered as high: ≥15.1 pg/ mL) and to apolipoprotein E (APOE) ε4 allele status. Methods: A total of 289 participants ≥70 years (56.4% female, mean age 78.1 years, SD=4.7) of the randomized, double-blind, multicenter, placebo-controlled Nolan trial had their plasma p-tau181 assessed, and daily took either a nutritional blend (composed of thiamin, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folic acid, cobalamin, vitamin E, vitamin C, vitamin D, choline, selenium, citrulline, eicosapentaenoic acid - EPA, and docosahexaenoic acid - DHA) or placebo for 1 year. Results: After 1-year, both groups presented a significant increase in plasma p-tau181 and GFAP values, with no effect of the intervention (p-tau181 between-group difference: 0.27pg/mL, 95%CI: -0.95, 1.48; p=0.665; GFAP between-group difference: -3.28 pg/mL, 95%CI: -17.25, 10.69; p=0.644). P-tau-and APOE ε4-stratified analyses provided similar findings. Conclusions: In community-dwelling older adults, we observed an increase in plasma p-tau181 and GFAP levels that was not different between the supplementation groups after one year.

Depressive Symptoms in Older Adults via Multimodal Markers on Magnetic Resonance Imaging: A Literature Review.

Depressive symptoms the most prevalent clinical condition in the field of mood disorders in older populations. Depressive symptoms are associated to poorer morbidity and mortality, and is considered a component of frailty and intrinsic capacity. Dementia could overlap with DS in clinical and brain abnormalities. Moreover, there are sex-differences in the field of Neuro- and Gero-science. To date, no review has addressed the neuro-anatomical basis of DS in older adults using magnetic resonance imaging (MRI), neither has investigated the discrimination of dementia nor sex-differences. This narrative review investigated studies about older adults; depressive symptoms evaluation via MRI, and published in English or Spanish over the past 7 years. Moreover, it evaluated dementia discrimination and sex-related differences. The most accurate evidence showed cerebral small vessel disease as a predictor of depressive symptoms worsening. Most studies were cross-sectional, with a coarse dementia screening and sex-unrepresentative samples. Cingulate cortex and hippocampus showed a negative association to depressive symptoms, and Precuneus cortex a positive association; although these inferences require further investigation. Additional research is needed to identify the brain imaging signature of depressive symptoms in older population (if any), and if this would be associated with sex and individuals'level of frailty and intrinsic capacity.

Circulating Levels of Apelin, GDF-15 and Sarcopenia: Lack of Association in the MAPT Study.

OBJECTIVES: Apelin and GDF-15 have been proposed as biomarkers of age-related sarcopenia but evidence in human models is scarce. This study aimed to explore the associations between blood apelin and GDF-15 with sarcopenia incidence and the evolution of sarcopenia components over two years in older adults >70 years. DESIGN: Secondary longitudinal analysis of the Multidomain Alzheimer Preventive Trial. PARTICIPANTS: Older adults (>70 years) attending primary care centers in France and Monaco. SETTING: Community. MEASUREMENTS: Serum Apelin (pg/mL) and plasma GDF-15 (pg/mL) were measured. Outcomes included sarcopenia defined by the European Working Group on Sarcopenia in Older People (EWGSOP) and its determinants (appendicular lean mass [ALM] evaluated through a Dual-energy X-ray Absorptiometry (DXA) scan, handgrip strength (HGS) and the 4-meter gait speed) measured over 2 years. Linear mixed models and logistic regression were used to explore the longitudinal associations. RESULTS: We included 168 subjects from MAPT (median age=76y, IQR=73-79; 78% women). Serum apelin was not significantly associated with sarcopenia incidence (OR=1.001;95%CI=1.000,1.001;p-value>0.05 in full-adjusted models) nor with ALM (ß=-5.8E-05;95%CI=-1.0E-04,2.12E-04;p>0.05), HGS (ß=-1.1E-04;95%CI=-5.0E-04,2.8E-04;p>0.05), and GS (ß=-5.1E-06;95%CI=-1.0E-05,2.0E-05;p>0.05) in fully adjusted models. Similarly, plasma GDF-15 was not associated with both the incidence of sarcopenia (OR=1.001,95%CI=1.000,1.002,p>0.05) and the evolution of its determinants ([ALM, ß=2.1E-05;95%CI=-2.6E-04,3.03E-04;p>0.05], HGS [ß=-5.9E-04;95%CI=-1.26E-03,8.1E-05; p>0.05] nor GS [ß=-2.6E-06;95%CI=-3.0E-05, 2.3E-05;p>0.05]) in fully adjusted models. CONCLUSIONS: Blood apelin and GDF-15 were not associated with sarcopenia incidence or with the evolution of sarcopenia components over a 2-year follow-up in community-dwelling older adults. Well-powered longitudinal studies are needed to confirm or refute our findings.

Nutrition-Based Approaches in Clinical Trials Targeting Cognitive Function: Highlights of the CTAD 2020.

The Clinical Trials on Alzheimer's Disease (CTAD) 2020 conference was the stage for researchers from all over the world to present their recent and ongoing research focused on potential Alzheimer's disease (AD) treatments and prevention of cognitive decline. Among a varied range of topics, nutritional aspects arose as possibilities of treatments towards the promotion of a healthy aging. Among the discussed themes, supplementation of omega-3 polyunsaturated fatty acids and multi-nutrient approaches were presented, suggesting that long-term supplementation (i.e., over 3 years) might be needed for observing positive effects on cognitive performance. Trials testing ketogenic agents and carbohydrate-restricted diet were also presented and showed promising effects on improving cognitive function of mild-cognitive impaired (MCI) and pre-diabetic individuals, respectively, in a short-term way (i.e. after 3 to 6 months). The combination of some of the nutritional approaches with physical activity interventions raises the question on whether they would individually perform in a similar way. Promising therapies involving nutrition appear to be safe and well tolerated by volunteers. Failures on achieving positive findings raise questions on whether they were driven by specific characteristics of the studied populations, insufficient doses or duration of treatment. Notwithstanding, current evidence on the applicability of nutrition-based approaches as AD treatments are encouraging but demand further research on the topic.

Frequency of Conditions Associated with Declines in Intrinsic Capacity According to a Screening Tool in the Context of Integrated Care for Older People.

BACKGROUND: The screening tool of the Integrated Care for Older People (ICOPE Step 1), designed to detect declines in the domains of intrinsic capacity, has been incipiently investigated in older adult populations. OBJECTIVES: To retrospectively estimate the frequency of priority conditions associated with declines in intrinsic capacity according to an adaptation of the screening tool ICOPE Step 1 among participants of the Multidomain Alzheimer Preventive Trial (MAPT). DESIGN: A cross-sectional retrospective analysis from the baseline assessment of the MAPT. SETTING: The data was gathered during a preventive consultation for cardiovascular risk factors in memory clinics in France. PARTICIPANTS: Seven hundred fifty-nine older adults aged 70-89 years with memory complaints, allocated to the multidomain groups of the MAPT study. MEASUREMENTS: Five domains of intrinsic capacity (cognition, locomotion, nutrition, sensorial, and psychological) were assessed using a screening tool similar to the ICOPE Step 1 (MAPT Step 1). The frequency of six conditions associated with declines in intrinsic capacity (cognitive decline, limited mobility, malnutrition, visual impairment, hearing loss, and depressive symptoms) was obtained for older adults with memory complaints participating in the MAPT study. RESULTS: Overall, 89.3% of the participants had one or more conditions associated with declines in intrinsic capacity. The overall frequency of each condition was: 52.2% for cognitive decline, 20.2% for limited mobility, 6.6% for malnutrition, 18.1% for visual impairment, 56.2% for hearing loss, and 39% for depressive symptoms. CONCLUSION: After being screened with an adaptation of the ICOPE step 1 (MAPT step 1) tool, 9/10 older adults had one or more conditions associated with declines in intrinsic capacity. The relative frequency differs across conditions and could probably be lower in a population without memory complaints. The frequency of screened conditions associated with declines in IC highlights how relevant it is to develop function-centered care modalities to promote healthy aging.

Prospective Associations between Plasma Amyloid-Beta 42/40 and Frailty in Community-Dwelling Older Adults.

BACKGROUND: Brain amyloid-beta (Aß) plaques, a hallmark of the pathophysiology of Alzheimer's disease, have been associated with frailty. Whether the plasma Aß markers show similar relationship with frailty is unknown. OBJECTIVES: To investigate the prospective associations between plasma Aß42/40 ratio and overtime frailty in community-dwelling older adults. METHODS: From the 5-year Multidomain Alzheimer Preventive Trial (MAPT), we included 477 adults ≥70 years with available data on plasma Aß42/40 ratio (lower is worse). Fried frailty phenotype (robust, pre-frail and frail) was assessed at the same time-point of plasma Aß measures and after until the end of follow-up. The outcomes of interest were the change in the frailty phenotype over time (examined by mixed-effect ordinal logistic regressions) and incident frailty (examined by Cox proportional hazard models). RESULTS: Plasma Aß42/40 did not show significant associations with incident frailty; however, after adjusting for Apolipoprotein E (APOE) ε4 genotype, people in the lower quartile of plasma Aß42/40 (≤0.103) had higher risk of incident frailty (HR=2.63; 95% CI, 1.00 to 6.89), compared to those in the upper quartile (>0.123). Exploratory analysis found a significant association between the lower quartile of plasma Aß42/40 and incident frailty among APOE ε4 non-carriers (HR=3.48; 95% CI, 1.19 to 10.16), but not among carriers. No associations between plasma Aß42/40 and evolution of frailty were observed. CONCLUSION: No significant associations between plasma Aß42/40 and frailty were found when APOE ε4 status was not accounted into the model. Nevertheless, APOE ε4 non-carriers with high Aß burden might be more susceptible to develop frailty.

Can We Distinguish Age-Related Frailty from Frailty Related to Diseases ? Data from the MAPT Study.

BACKGROUND: No study has tried to distinguish subjects that become frail due to diseases (frailty related to diseases) or in the absence of specific medical events; in this latter case, it is possible that aging process would act as the main frailty driver (age-related frailty). OBJECTIVES: To classify subjects according to the origin of physical frailty: age-related frailty, frailty related to diseases, frailty of uncertain origin, and to compare their clinical characteristics. MATERIALS AND METHODS: We performed a secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT), including 195 subjects ≥70 years non-frail at baseline who became frail during a 5-year follow-up (mean age 77.8 years ± 4.7; 70% female). Physical frailty was defined as presenting ≥3 of the 5 Fried criteria: weight loss, exhaustion, weakness, slowness, low physical activity. Clinical files were independently reviewed by two different clinicians using a standardized assessment method in order to classify subjects as: "age-related frailty", "frailty related to diseases" or "frailty of uncertain origin". Inconsistencies among the two raters and cases of uncertain frailty were further assessed by two other experienced clinicians. RESULTS: From the 195 included subjects, 82 (42%) were classified as age-related frailty, 53 (27%) as frailty related to diseases, and 60 (31%) as frailty of uncertain origin. Patients who became frail due to diseases did not differ from the others groups in terms of functional, cognitive, psychological status and age at baseline, however they presented a higher burden of comorbidity as measured by the Cumulative Illness Rating Scale (CIRS) (8.20 ± 2.69; vs 6.22 ± 2.02 frailty of uncertain origin; vs. 3.25 ± 1.65 age-related frailty). Time to incident frailty (23.4 months ± 12.1 vs. 39.2 ± 19.3 months) and time spent in a pre-frailty condition (17.1 ± 11.4 vs 26.6 ± 16.6 months) were shorter in the group of frailty related to diseases compared to age-related frailty. Orthopedic diseases (n=14, 26%) were the most common pathologies leading to frailty related to diseases, followed by cardiovascular diseases (n=9, 17%) and neurological diseases (n = 8, 15%). CONCLUSION: People classified as age-related frailty and frailty related to diseases presented different frailty-associated indicators. Future research should target the underlying biological cascades leading to these two frailty classifications, since they could ask for distinct strategies of prevention and management.

Effect of long-term omega-3 supplementation and a lifestyle multidomain intervention on intrinsic capacity among community-dwelling older adults: Secondary analysis of a randomized, placebo-controlled trial (MAPT study).

OBJECTIVES: To investigate the effect of omega-3 (ω-3) polyunsaturated fatty acid supplementation and a multidomain intervention (MI) (physical activity counselling, cognitive training and nutritional advice) among community-dwelling older adults on levels of intrinsic capacity (IC), a construct recently proposed by the World Health Organization. STUDY DESIGN: Secondary analysis from the factorial-design 3-year Multidomain Alzheimer Preventive Trial (MAPT) with 1445 subjects (64.2 % female, mean age 75.3 years, SD = 4.4) randomized to one group of MI plus ω-3 (800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid/day); MI plus placebo; ω-3 supplementation alone; or placebo alone. Data collection was held between 2008 and 2014. MAIN OUTCOME MEASURES: IC domains were examined with the Geriatric Depression Scale (psychological); Short Physical Performance Battery (mobility); Z-score combining four tests (cognitive function); and handgrip strength (vitality). All domains were combined into a composite IC Z-score. RESULTS: After 3 years, IC Z-score decreased among all groups when time was considered continuous (MI plus ω-3: -0.16, 95 %CI: -0.22 to -0.10; MI alone: -0.13, 95 %CI: -0.19 to -0.07; ω-3 alone: -0.19, 95 %CI: -0.25 to -0.10; placebo: -0.20, 95 %CI: -0.26 to -0.14; all p < 0.0001). There were no significant differences between groups. In a sensitivity analysis with categorical time, significant within-group declines were first identified at 24 months for all groups. CONCLUSIONS: This trial designed to improve cognitive function was unable to find effects of the intervention on the composite IC Z-score. Further investigations are needed, especially trials providing stronger interventions (such as exercise training and a controlled diet) and also embracing the sensorial domain of IC.

Associations Between Multidomain Lifestyle Interventions and Intrinsic Capacity Domains During Aging: A Narrative Review.

Background: Recently, the World Health Organization defined five domains of intrinsic capacity (IC), composed of physical and mental capacities linked to body functions, and that contribute to healthy aging: locomotion, cognition, psychological, vitality and sensorial. In the past decade, studies investigating the effects of concomitant lifestyle interventions (also called multidomain interventions) on one or several IC domains have been developed. The aim of this study is to synthetize the scientific literature about the associations between multidomain lifestyle interventions and IC domains. Methods: We conducted a narrative review of randomized controlled trials examining the effects of multidomain lifestyle interventions on at least one IC domain among older people. Multidomain intervention was defined as the presence of at least two of the following lifestyle interventions: physical activity/exercise, nutrition, cognitive stimulation, and management of cardiovascular risk factors (eg, smoking, alcohol consumption). Results: Multidomain interventions were associated with improvements on locomotion (as measured by performance-based tests of lower-limb function) and vitality (as measured by handgrip strength); benefits on cognitive function were also found, in particular among populations at increased risk of dementia and when operationalizing strong multidomain interventions (eg, using regular exercise training instead of physical activity advices). No study investigated the effects of multidomain lifestyle interventions on the sensorial domain (hearing and/or vision). The modalities composing the multidomain interventions and intervention length, as well as study population, substantially varied across studies; the most common combination of interventions was physical activity- and nutritional-related interventions. Conclusion: Available evidence is still limited, but literature suggests a positive effect of multidomain lifestyle interventions on IC domains, in particular locomotion. Further studies are still needed on this topic, in particular, studies exploring the effects of multidomain lifestyle interventions on the sensorial domain, as well as on a composite measurement of all IC domains.

Defining Vitality Using Physical and Mental Well-Being Measures in Nursing Homes: A Prospective Study.

OBJECTIVES: To propose an objective definition of vitality and to evaluate its predictive value regarding the evolution of functional ability, as well as the risk of hospitalization and mortality in very old NH residents. DESIGN: Observational study. SETTINGS: Nursing homes. PARTICIPANTS: 541 participants. MEASUREMENTS: We operationalized tree definitions of vitality (binary variables discriminating vital from non-vital individuals): Mental vitality, assessed using three items of the geriatric depression scale; Physical vitality measured through hand grip strength test; and combined vitality, which combined mental and physical vitality definitions. Outcome measures were the 1-year evolution of functional ability as measured by a scale of activities of daily living (ADL) (score from 0 to 6) and the incidence of hospitalizations and mortality (time-to-event). RESULTS: First, 204 (37.7%) residents were defined as mentally vital. Second, 139 (27.5%) residents were defined as physically vital. And 52 (9.6%) were defined as vital when combining physical and. Combined vitality was associated with a reduced risk of hospitalization compared to combined non-vitality. Physically vital residents were associated with a reduced risk of mortality. No prospective associations were found between vital and non-vital individuals on the evolution of ADL scores across the three vitality definitions. But mentally vital individuals were associated with a worsening of ADL score. CONCLUSIONS: Better combined vitality seems to be associated with a reduced risk for hospitalizations, but more studies are needed to confirm a valid measurement of vitality in people living in NH in regards to ADL and mortality.

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

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

Body mass index growth trajectories associated with the different parameters of the metabolic syndrome at adulthood.

BACKGROUND: Growth trajectories have shown to be related to obesity and metabolic risks in later life, however body mass index (BMI) trajectories according to the presence or absence of metabolic syndrome (MS) and its parameters in adulthood are scarce in literature. OBJECTIVES: To investigate BMI trajectories during childhood in relation to MS and its parameters in adult age. METHODS: A total of 1919 subjects (43.4% male, 20-60 y) participated in this retrospective cohort study. Height, weight, waist circumference (WC), blood glucose, high-density lipoprotein cholesterol, triglycerides and blood pressure were measured at adulthood. Childhood weight and height were collected retrospectively from health booklets. Differences between BMI growth curves of subjects with and without MS were assessed using mixed models for correlated data. RESULTS: BMI trajectories differed according to the presence or not of MS at adulthood, from the age of 4 years forward (all P<0.05), to the presence or not of hypertriglyceridemia from 1.5 years forward (all P<0.05), and to WC>94 cm (men) / 80 cm (women) compared to lower WC, at all ages (all P<0.05). CONCLUSIONS: BMI growth curves differ according to the presence or not of MS at adulthood, but differences only appeared after the age of 4 years. Changes vary according to the MS parameters considered. Deviation of the MS-associated BMI curve from normal pattern could correspond to alteration in body composition. These differences in BMI trajectories during childhood support the theory of an early origin of the MS, justifying early prevention.

Comparisons of physical activity, adipokines, vitamin D status and dietary vitamin D intake among adolescents.

BACKGROUND: Considering that lifestyle and diet are key factors responsible for the increases in adiposity in youth, it is important to understand how vitamin D, adipokines and markers of glucose metabolism are related to physical activity level (PAL) during growth. The present study aimed to investigate associations between physical activity level, adiponectin/leptin ratio, vitamin D status and dietary vitamin D intake among adolescents. METHODS: A cross-sectional study was conducted with adolescents aged 14-18 years old who were living in São Paulo, Brazil. Serum 25 hydroxyvitamin D [25(OH)D], adiponectin (A), leptin (L), glucose and insulin were obtained after 12 h of fasting. Dietary calcium and vitamin D intake were measured by 24-h food record, as repeated in 62.6% of the sample. PAL was measured by the International Physical Activity Questionnaire (IPAQ). Pearson's chi-square test, Pearson correlation and linear regression analysis were performed. RESULTS: A total of 198 subjects, mean (SD) age 16.3 (1.4) years, 51% male, were enrolled in the study. Some 9% of participants were sedentary, 22% were insufficiently active (IA), 51% were active and 18% were very active (VA). The A/L ratio was lower among sedentary/IA subjects [2.2 (4.0) versus 5.6 (12.3); P = 0.01] compared to active/VA subjects. PAL was not associated with vitamin D status or markers of glucose metabolism. Serum 25(OH)D positively associated with vitamin D intake, after adjusting for sex, sun exposure and season of the year in regression analysis (partial r2 =0.026, P = 0.02). CONCLUSIONS: Low PAL was associated with a lower A/L ratio. Vitamin D status was not associated with sun exposure habits, although it was positively correlated with vitamin D intake.

Oral information in orthopaedics: how should the patient's understanding be assessed?

INTRODUCTION: Patient information is governed by recommendations of best practices required from any healthcare professional. The aim of this study was to design a tool to measure patient comprehension of the information provided during a surgical consultation before a scheduled surgery. MATERIAL AND METHODS: This was a single-center prospective study of 21 patients using a rating scale-type visual analog scale. Each patient was interviewed and asked to score his or her understanding of the information provided. The investigator checked the external validity of the tool using questions to assess patient's understanding level. RESULTS: The results show that there is a tendency to overvalue some information (reasons for the intervention and alternatives to surgery) and that certain information is not understood (risks and complications) or not provided (postoperative follow-up). CONCLUSION: This study confirms that a rating scale can measure the understanding of information and there is a variation between perceived and actual understanding.