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

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

Higher sRAGE Levels Predict Mortality in Frail Older Adults with Cardiovascular Disease.

INTRODUCTION: The evidence that blood levels of the soluble receptor for advanced glycation end products (sRAGE) predict mortality in people with cardiovascular diseases (CVD) is inconsistent. To clarify this matter, we investigated if frailty status influences this association. METHODS: We analysed data of 1,016 individuals (median age, 75 years) from 3 population-based European cohorts, enrolled in the FRAILOMIC project. Participants were stratified by history of CVD and frailty status. Mortality was recorded during 8 years of follow-up. RESULTS: In adjusted Cox regression models, baseline serum sRAGE was positively associated with an increased risk of mortality in participants with CVD (HR 1.64, 95% CI 1.09-2.49, p = 0.019) but not in non-CVD. Within the CVD group, the risk of death was markedly enhanced in the frail subgroup (CVD-F, HR 1.97, 95% CI 1.18-3.29, p = 0.009), compared to the non-frail subgroup (CVD-NF, HR 1.50, 95% CI 0.71-3.15, p = 0.287). Kaplan-Meier analysis showed that the median survival time of CVD-F with high sRAGE (>1,554 pg/mL) was 2.9 years shorter than that of CVD-F with low sRAGE, whereas no survival difference was seen for CVD-NF. Area under the ROC curve analysis demonstrated that for CVD-F, addition of sRAGE to the prediction model increased its prognostic value. CONCLUSIONS: Frailty status influences the relationship between sRAGE and mortality in older adults with CVD. sRAGE could be used as a prognostic marker of mortality for these individuals, particularly if they are also frail.

Plasma proteomic signatures predict dementia and cognitive impairment.

INTRODUCTION: Biomarker discovery of dementia and cognitive impairment is important to gather insight into mechanisms underlying the pathogenesis of these conditions. METHODS: In 997 adults from the InCHIANTI study, we assessed the association of 1301 plasma proteins with dementia and cognitive impairment. Validation was conducted in two Alzheimer's disease (AD) case-control studies as well as endophenotypes of AD including cognitive decline, brain amyloid burden, and brain volume. RESULTS: We identified four risk proteins that were significantly associated with increased odds (peptidase inhibitor 3 (PI3), trefoil factor 3 (TFF3), pregnancy associated plasma protein A (PAPPA), agouti-related peptide (AGRP)) and two protective proteins (myostatin (MSTN), integrin aVb5 (ITGAV/ITGB5)) with decreased odds of baseline cognitive impairment or dementia. Of these, four proteins (MSTN, PI3, TFF3, PAPPA) were associated cognitive decline in subjects that were cognitively normal at baseline. ITGAV/ITGB5 was associated with lower brain amyloid burden, MSTN and ITGAV/ITGB5 were associated with larger brain volume and slower brain atrophy, and PI3, PAPPA, and AGRP were associated with smaller brain volume and/or faster brain atrophy. DISCUSSION: These proteins may be useful as non-invasive biomarkers of dementia and cognitive impairment.

Anticholinergic Drug Induced Cognitive and Physical Impairment: Results from the InCHIANTI Study.

BACKGROUND: The aims of this study were to evaluate the relationship between anticholinergic drug burden (ACB) cognitive impairment, physical frailty, and cognitive frailty, and to determine if ACB is predictive of these phenotypes when modeled with biological and genomic biomarkers. METHODS: In a retrospective cohort study, a total of 1,453 adults aged 20-102 years were used to examine ACB as a predictor for cognitive impairment, physical frailty, and cognitive frailty. Anticholinergic burden is examined as a predictor for all phenotypes in a cross-sectional analysis using logistic, ordinal regression models, and Extreme Gradient Boosting for population predictive modeling. RESULTS: A significant association was found between ACB and cognitive decline (p = .02), frailty (p < .001), and cognitive frailty (p < .001). The odds of cognitive impairment increased by 1.21 (95% confidence interval [CI] = 1.06-1.37, p < .001), odds of being frail increased by 1.33 (95% CI = 1.18-1.50, p < .001), and odds of having cognitive frailty increased by 1.36 (95% CI = 1.21-1.54, p < .001). Population modeling results indicated ACB score as one of the stronger predictors for cognitive impairment, physical frailty, and cognitive frailty with area under the curves ranging from 0.81 to 0.88. CONCLUSIONS: Anticholinergic medications are a potentially modifiable risk factor for the prevention of cognitive and physical decline. Identification of reversible causes for cognitive and physical impairment is critical for the aging population. These findings encourage new research that may lead to effective interventions for deprescribing programs for the prevention of cognitive and physical decline in older adults.

Association of a priori dietary patterns with depressive symptoms: a harmonised meta-analysis of observational studies.

BACKGROUND: Review findings on the role of dietary patterns in preventing depression are inconsistent, possibly due to variation in assessment of dietary exposure and depression. We studied the association between dietary patterns and depressive symptoms in six population-based cohorts and meta-analysed the findings using a standardised approach that defined dietary exposure, depression assessment and covariates. METHODS: Included were cross-sectional data from 23 026 participants in six cohorts: InCHIANTI (Italy), LASA, NESDA, HELIUS (the Netherlands), ALSWH (Australia) and Whitehall II (UK). Analysis of incidence was based on three cohorts with repeated measures of depressive symptoms at 5-6 years of follow-up in 10 721 participants: Whitehall II, InCHIANTI, ALSWH. Three a priori dietary patterns, Mediterranean diet score (MDS), Alternative Healthy Eating Index (AHEI-2010), and the Dietary Approaches to Stop Hypertension (DASH) diet were investigated in relation to depressive symptoms. Analyses at the cohort-level adjusted for a fixed set of confounders, meta-analysis used a random-effects model. RESULTS: Cross-sectional and prospective analyses showed statistically significant inverse associations of the three dietary patterns with depressive symptoms (continuous and dichotomous). In cross-sectional analysis, the association of diet with depressive symptoms using a cut-off yielded an adjusted OR of 0.87 (95% confidence interval 0.84-0.91) for MDS, 0.93 (0.88-0.98) for AHEI-2010, and 0.94 (0.87-1.01) for DASH. Similar associations were observed prospectively: 0.88 (0.80-0.96) for MDS; 0.95 (0.84-1.06) for AHEI-2010; 0.90 (0.84-0.97) for DASH. CONCLUSION: Population-scale observational evidence indicates that adults following a healthy dietary pattern have fewer depressive symptoms and lower risk of developing depressive symptoms.

Development of a clinical prediction model for the onset of functional decline in people aged 65-75 years: pooled analysis of four European cohort studies.

BACKGROUND: Identifying those people at increased risk of early functional decline in activities of daily living (ADL) is essential for initiating preventive interventions. The aim of this study is to develop and validate a clinical prediction model for onset of functional decline in ADL in three years of follow-up in older people of 65-75 years old. METHODS: Four population-based cohort studies were pooled for the analysis: ActiFE-ULM (Germany), ELSA (United Kingdom), InCHIANTI (Italy), LASA (Netherlands). Included participants were 65-75 years old at baseline and reported no limitations in functional ability in ADL at baseline. Functional decline was assessed with two items on basic ADL and three items on instrumental ADL. Participants who reported at least some limitations at three-year follow-up on any of the five items were classified as experiencing functional decline. Multiple logistic regression analysis was used to develop a prediction model, with subsequent bootstrapping for optimism-correction. We applied internal-external cross-validation by alternating the data from the four cohort studies to assess the discrimination and calibration across the cohorts. RESULTS: Two thousand five hundred sixty community-dwelling people were included in the analyses (mean age 69.7 ± 3.0 years old, 47.4% female) of whom 572 (22.3%) reported functional decline at three-year follow-up. The final prediction model included 10 out of 22 predictors: age, handgrip strength, gait speed, five-repeated chair stands time (non-linear association), body mass index, cardiovascular disease, diabetes, chronic obstructive pulmonary disease, arthritis, and depressive symptoms. The optimism-corrected model showed good discrimination with a C statistic of 0.72. The calibration intercept was 0.06 and the calibration slope was 1.05. Internal-external cross-validation showed consistent performance of the model across the four cohorts. CONCLUSIONS: Based on pooled cohort data analyses we were able to show that the onset of functional decline in ADL in three years in older people aged 65-75 years can be predicted by specific physical performance measures, age, body mass index, presence of depressive symptoms, and chronic conditions. The prediction model showed good discrimination and calibration, which remained stable across the four cohorts, supporting external validity of our findings.

An Exploratory Factor Analysis of Sensor-Based Physical Capability Assessment.

Physical capability (PC) is conventionally evaluated through performance-based clinical assessments. We aimed to transform a battery of sensor-based functional tests into a clinically applicable assessment tool. We used Exploratory Factor Analysis (EFA) to uncover the underlying latent structure within sensor-based measures obtained in a population-based study. Three hundred four community-dwelling older adults (163 females, 80.9 ± 6.4 years), underwent three functional tests (Quiet Stand, QS, 7-meter Walk, 7MW and Chair Stand, CST) wearing a smartphone at the lower back. Instrumented tests provided 73 sensor-based measures, out of which EFA identified a fifteen-factor model. A priori knowledge and the associations with health-related measures supported the functional interpretation and construct validity analysis of the factors, and provided the basis for developing a conceptual model of PC. For example, the "Walking Impairment" domain obtained from the 7MW test was significantly associated with measures of leg muscle power, gait speed, and overall lower extremity function. To the best of our knowledge, this is the first time that a battery of functional tests, instrumented through a smartphone, is used for outlining a sensor-based conceptual model, which could be suitable for assessing PC in older adults and tracking its changes over time.

Patterns of circulating fat-soluble vitamins and carotenoids and risk of frailty in four European cohorts of older adults.

PURPOSE: To investigate the cross-sectional and prospective associations between patterns of serum fat-soluble micronutrients and frailty in four European cohorts of older adults 65 years of age and older. METHODS: Participants from the Three-City (Bordeaux, France), AMI (Gironde, France), TSHA (Toledo, Spain) and InCHIANTI (Tuscany, Italy) cohorts with available data on serum α-carotene, ß-carotene, lycopene, cryptoxanthin, lutein + zeaxanthin, retinol, α-tocopherol, γ-tocopherol and 25-hydroxyvitamin D3 (25(OH)D) were included. A principal component (PC) analysis was used to derive micronutrient patterns. Frailty was defined using Fried's criteria. Multivariate logistic regression models adjusted for socio-demographic and health-related covariates were performed to assess the association between micronutrient patterns and prevalent frailty in 1324 participants, and the risk of frailty in 915 initially non-frail participants. RESULTS: Three different patterns were identified: the first pattern was characterized by higher serum carotenoids and α-tocopherol levels; the second was characterized by high loadings for serum vitamins A and E levels and low loadings for carotenes level; the third one had the highest loading for serum 25(OH)D and cryptoxanthin level and the lowest loading for vitamin A and E. A significant cross-sectional association was only observed between the seconnd PC and prevalent frailty (p = 0.02). Compared to the highest quartile, participants in the lowest quartile-i.e., high carotenes and low vitamins E and A levels-had higher odds of frailty (Odds ratio = 2.2; 95% confidence interval 1.3-3.8). No association with the risk of frailty was observed. CONCLUSIONS: These findings suggest that some specific micronutrient patterns are markers but not predictors of frailty in these European cohorts of older adults.

Bidirectional associations between food groups and depressive symptoms: longitudinal findings from the Invecchiare in Chianti (InCHIANTI) study.

This study investigated bidirectional associations between intake of food groups and depressive symptoms in 1058 Italian participants (aged 20-102 years) of the Invecchiare in Chianti study. Dietary intake, assessed with a validated FFQ, and depressive symptoms, measured with the Center for Epidemiologic Studies Depression scale (CES-D), were assessed at baseline and after 3, 6 and 9 years. Associations of repeated measurements of intakes of thirteen food groups with 3-year changes in depressive symptoms, and vice versa, were analysed using linear mixed models and logistic generalised estimating equations. Fish intake was inversely (quartile (Q)4 v. Q1, B=-0·97, 95 % CI -1·74, -0·21) and sweet food intake positively (Q4 v. Q1, B=1·03, 95 % CI 0·25, 1·81) associated with subsequent CES-D score. In the other direction, higher CES-D scores were associated with decreases in intakes of vegetables (ratio: 0·995, 95 % CI 0·990, 0·999) and red and processed meat (B=-0·006, 95 % CI -0·010, -0·001), an increase in dairy product intake (ratio: 1·008, 95 % CI 1·004, 1·013), and increasing odds of eating savoury snacks (OR: 1·012, 95 % CI 1·000, 1·024). Fruit, nuts and legumes, potatoes, wholegrain bread, olive oil, sugar-sweetened beverages, and coffee and tea were not significantly associated in either direction. Our study confirmed bidirectional associations between food group intakes and depressive symptoms. Fish and sweet food intakes were associated with 3-year improvement and deterioration in depressive symptoms, respectively. Depressive symptoms were associated with 3-year changes in vegetable, meat, dairy product and savoury snack intakes. Trials are necessary to examine the causal associations between food groups and depression.

Adherence to a Mediterranean Diet Protects from Cognitive Decline in the Invecchiare in Chianti Study of Aging.

Following a Mediterranean diet high in plant-based foods and fish, low in meat and dairy foods, and with moderate alcohol intake has been shown to promote healthy aging. Therefore, we examined the association between a Mediterranean diet and trajectories of cognitive performance in the InCHIANTI study. Subjects (N = 832) were examined every 2⁻3 years up to 18 years with an average follow-up period of 10.1 years. Cognitive performance was assessed using the Mini Mental State Examination (MMSE) at every visit. Dietary habits were assessed using a validated food frequency questionnaire and adherence to Mediterranean diet was computed on a scale of 0-9 and categorized into three groups of low (≤3), medium (4⁻5), and high (≥6). Those in the highest adherence group (OR = 0.48, 95% CI: 0.29⁻0.79) and medium adherence group (OR = 0.64, 95% CI: 0.41⁻0.99) were less likely to experience cognitive decline. The annual average decline in MMSE scores was 0.4 units, for those in the high and medium adherence group this decline was attenuated by 0.34 units (p < 0.001) and 0.16 units (p = 0.03), respectively. Our findings suggest that adherence to a Mediterranean diet can have long-lasting protective effects on cognitive decline and may be an effective strategy for the prevent or delay dementia.

An Integrated Air Monitoring Approach for Assessment of Formaldehyde in the Workplace.

The aim of this study is to validate an integrated air monitoring approach for assessing airborne formaldehyde (FA) in the workplace. An active sampling by silica gel impregnated with 2,4-dinitrophenylhydrazine, a passive solid phase microextraction technique using O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine as on-fiber derivatization reagent, an electrochemical direct-reading monitor, and an enzyme-based badge were evaluated and tested over a range of 0.020-5.12 ppm, using dynamically generated FA air concentrations. Simple linear regression analysis showed the four methods were suitable for evaluating airborne FA. Personal and area samplings in 12 anatomy pathology departments showed that the international occupational exposure limits in the GESTIS database were frequently exceeded. This monitoring approach would allow a fast, easy-to-use, and economical evaluation of both current work practices and eventual changes made to reduce FA vapor concentrations.

Assessment of occupational exposure to gaseous peracetic acid.

OBJECTIVES: In order to assess short-term exposure to peracetic acid (PAA) in disinfection processes, the Authors compared 4 industrial hygiene monitoring methods to evaluate their proficiency in measuring airborne PAA concentrations. MATERIAL AND METHODS: An active sampling by basic silica gel impregnated with methyl p-tolyl sulfoxide (MTSO), a passive solid phase micro-extraction technique using methyl p-tolyl sulfide (MTS) as on-fiber derivatization reagent, an electrochemical direct-reading PAA monitor, and a novel visual test strip PAA detector doped with 2,2'-azino-bis (3-ethylbenzothiazoline)-6-sulfonate were evaluated and tested over the range of 0.06-16 mg/m3, using dynamically generated PAA air concentrations. RESULTS: The linear regression analysis of linearity and accuracy showed that the 4 methods were suitable for PAA monitoring. Peracetic acid monitoring in several use applications showed that the PAA concentration (1.8 mg/m3) was immediately dangerous to life or health as proposed by the National Institute of Occupational Safety and Health, and was frequently exceeded in wastewater treatment (up to 7.33 mg/m3), and sometimes during food and beverage processes and hospital high-level disinfection operations (up to 6.8 mg/m3). CONCLUSIONS: The methods were suitable for the quick assessment of acute exposure in PAA environmental monitoring and can assist in improving safety and air quality in the workplace where this disinfectant is used. These monitoring methods allowed the evaluation of changes to work out practices to reduce PAA vapor concentrations during the operations when workers are potentially overexposed to this strong antioxidant agent. Int J Occup Med Environ Health 2018;31(4):527-535.

Predicting Trajectories of Functional Decline in 60- to 70-Year-Old People.

BACKGROUND: Early identification of people at risk of functional decline is essential for delivering targeted preventive interventions. OBJECTIVE: The aim of this study is to identify and predict trajectories of functional decline over 9 years in males and females aged 60-70 years. METHODS: We included 403 community-dwelling participants from the InCHIANTI study and 395 from the LASA study aged 60-70 years at baseline, of whom the majority reported no functional decline at baseline (median 0, interquartile range 0-1). Participants were included if they reported data on ≥2 measurements of functional ability during a 9-year follow-up. Functional ability was scored with 6 self-reported items on activities of daily living. We performed latent class growth analysis to identify trajectories of functional decline and applied multinomial regression models to develop prediction models of identified trajectories. Analyses were stratified for sex. RESULTS: Three distinct trajectories were identified: no/little decline (219 males, 241 females), intermediate decline (114 males, 158 females), and severe decline (36 males, 30 females). Higher gait speed showed decreased risk of functional limitations in males (intermediate limitations, odds ratio [OR] 0.74, 95% CI 0.57-0.97; severe limitations, OR 0.42, 95% CI 0.26-0.66). The final model in males further included the predictors fear of falling and alcohol intake (no/little decline, area under the receiver operating curve [AUC] 0.68, 95% CI 0.62-0.73; intermediate decline, AUC 0.63, 95% CI 0.56-0.69; severe decline, AUC 0.79, 95% CI 0.71-0.87). In females, higher gait speed showed a decreased risk of intermediate limitations (OR 0.51, 95% CI 0.38-0.68) and severe limitations (OR 0.18, 95% CI 0.07-0.44). Other predictors in females were age, living alone, economic satisfaction, balance, physical activity, BMI, and cardiovascular disease (no/little decline, AUC 0.80, 95% CI 0.75-0.85; intermediate decline, AUC 0.74, 95% CI 0.69-0.79; severe decline, AUC 0.95, 95% CI 0.91-0.99). CONCLUSION: Already in people aged 60-70 years, 3 distinct trajectories of functional decline were identified in these cohorts over a 9-year follow-up. Predictors of trajectories differed between males and females, except for gait speed. Identification of people at risk is the basis for targeting interventions.

Consumption of fruit and vegetables and risk of frailty: a dose-response analysis of 3 prospective cohorts of community-dwelling older adults.

BACKGROUND: Consuming fruit and vegetables (FVs) may protect against frailty, but to our knowledge no study has yet assessed their prospective dose-response relation. OBJECTIVE: We sought to examine the dose-response association between FV consumption and the risk of frailty in older adults. DESIGN: Data were taken from 3 independent cohorts of community-dwelling older adults: the Seniors-ENRICA (Study on Nutrition and Cardiovascular Risk Factors in Spain) cohort (n = 1872), Three-City (3C) Bordeaux cohort (n = 581), and integrated multidisciplinary approach cohort (n = 473). Baseline food consumption was assessed with a validated computerized diet history (Seniors-ENRICA) or with a food-frequency questionnaire (3C Bordeaux and AMI). In all cohorts, incident frailty was assessed with the use of the Fried criteria. Results across cohorts were pooled with the use of a random-effects model. RESULTS: During a mean 2.5-y follow-up, 300 incident frailty cases occurred. Fully adjusted models showed that the pooled ORs (95% CIs) of incident frailty comparing participants who consumed 1, 2, or ≥3 portions of fruit/d to those with no consumption were, respectively, 0.59 (0.27, 0.90), 0.58 (0.29, 0.86), and 0.48 (0.20, 0.75), with a P-trend of 0.04. The corresponding values for vegetables were 0.69 (0.42, 0.97), 0.56 (0.35, 0.77), and 0.52 (0.13, 0.92), with a P-trend < 0.01. When FVs were analyzed together, the pooled ORs (95% CIs) of incident frailty were 0.41 (0.21, 0.60), 0.47 (0.25, 0.68), 0.36 (0.18, 0.53), and 0.31 (0.13, 0.48), with a P-trend < 0.01 for participants who consumed 2, 3, 4, or ≥5 portions/d, respectively, compared with those who consumed ≤1 portion/d. An inverse dose-response relation was also found between the baseline consumption of fruit and risk of exhaustion, low physical activity, and slow walking speed, whereas the consumption of vegetables was associated with a decreased risk of exhaustion and unintentional weight loss. CONCLUSIONS: Among community-dwelling older adults, FV consumption was associated with a lower short-term risk of frailty in a dose-response manner, and the strongest association was obtained with 3 portions of fruit/d and 2 portions of vegetables/d.

The association between dietary patterns derived by reduced rank regression and depressive symptoms over time: the Invecchiare in Chianti (InCHIANTI) study.

This study aimed to identify dietary patterns using reduced rank regression (RRR) and to explore their associations with depressive symptoms over 9 years in the Invecchiare in Chianti study. At baseline, 1362 participants (55·4 % women) aged 18-102 years (mean age 68 (sd 15·5) years) were included in the study. Baseline data collection started in 1998 and was repeated after 3, 6 and 9 years. Dietary intake information was obtained using a country-specific, validated FFQ with 188 food items. For baseline diet, dietary pattern scores in quartiles (Q) were derived using RRR with the nutrients EPA+DHA, folate, Mg and Zn as response variables. Continuous depression scores from the Centre for Epidemiologic Studies Depression (CES-D) scale were used for assessing depressive symptoms. The derived dietary pattern was rich in vegetables, olive oil, grains, fruit, fish and moderate in wine and red and processed meat, and was labelled as 'typical Tuscan dietary pattern'. After full adjustment, an inverse association was observed between this dietary pattern and depressive symptoms at baseline (Q1 v. Q4, B -2·77; 95 % CI -4·55, -0·98). When examining the relationship between the above-mentioned dietary pattern at baseline and depressive symptoms over 9 years, a similar association was found after full adjustment for confounding factors (Q1 v. Q4, B -1·78; 95 % CI -3·17, -0·38). A diet rich in vegetables, olive oil, grains, fruits, fish and moderate in wine and red and processed meat was consistently associated with lower CES-D scores over a 9-year period in the Tuscan population.