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1.
Geroscience ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654269

RESUMO

The accumulation of senescent cells in tissues is causally linked to the development of several age-related diseases; the removal of senescent glial cells in animal models prevents Tau accumulation and cognitive decline. Senescent cells can arise through several distinct mechanisms; one such mechanism is dysregulation of alternative splicing. In this study, we characterised the senescent cell phenotype in primary human astrocytes in terms of SA-ß-Gal staining and SASP secretion, and then assessed splicing factor expression and candidate gene splicing patterns. Finally, we assessed associations between expression of dysregulated isoforms and premature cognitive decline in 197 samples from the InCHIANTI study of ageing, where expression was present in both blood and brain. We demonstrate here that senescent astrocytes secrete a modified SASP characterised by increased IL8, MMP3, MMP10, and TIMP2 but decreased IL10 levels. We identified significant changes in splicing factor expression for 10/20 splicing factors tested in senescent astrocytes compared with early passage cells, as well as dysregulation of isoform levels for 8/13 brain or senescence genes tested. Finally, associations were identified between peripheral blood GFAPα, TAU3, and CDKN2A (P14ARF) isoform levels and mild or severe cognitive decline over a 3-7-year period. Our data are suggestive that some of the features of cognitive decline may arise from dysregulated splicing of important genes in senescent brain support cells, and that defects in alternative splicing or splicing regulator expression deserve exploration as points of therapeutic intervention in the future.

2.
Circulation ; 140(8): 645-657, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31424985

RESUMO

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31436047

RESUMO

BACKGROUND: A poor fat-soluble micronutrient (FMN) and a high oxidative stress status are associated with frailty. Our aim was to determine the cross-sectional association of FMNs and oxidative stress biomarkers [protein carbonyls (PrCarb) and 3-nitrotyrosine] with the frailty status in participants older than 65 years. METHODS: Plasma levels of vitamins A (retinol), D3 , E (α-tocopherol and γ-tocopherol) and carotenoids (α-carotene and ß-carotene, lycopene, lutein/zeaxanthin, and ß-cryptoxanthin), PrCarb, and 3-nitrotyrosine were measured in 1450 individuals of the FRAILOMIC initiative. Participants were classified into robust, pre-frail, and frail using Fried's frailty criteria. Associations between biomarkers and frailty status were assessed by general linear and logistic regression models, both adjusted for cohort, season of blood sampling, gender, age, height, weight, and smoking. RESULTS: Robust participants had significantly higher vitamin D3 and lutein/zeaxanthin concentrations than pre-frail and frail subjects; had significantly higher γ-tocopherol, α-carotene, ß-carotene, lycopene, and ß-cryptoxanthin concentrations than frail subjects, and had significantly lower PrCarb concentrations than frail participants in multivariate linear models. Frail subjects were more likely to be in the lowest than in the highest tertile for vitamin D3 (adjusted odds ratio: 2.15; 95% confidence interval: 1.42-3.26), α-tocopherol (2.12; 1.39-3.24), α-carotene (1.69; 1.00-2.88), ß-carotene (1.84; 1.13-2.99), lycopene (1.94; 1.24-3.05), lutein/zeaxanthin (3.60; 2.34-5.53), and ß-cryptoxanthin (3.02; 1.95-4.69) and were more likely to be in the highest than in the lowest tertile for PrCarb (2.86; 1.82-4.49) than robust subjects in multivariate regression models. CONCLUSIONS: Our study indicates that both low FMN and high PrCarb concentrations are associated with pre-frailty and frailty.

4.
Nutr Metab Cardiovasc Dis ; 29(10): 1061-1067, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377184

RESUMO

BACKGROUND AND AIMS: Increased uric acid levels correlate with cardiovascular disease and cardiovascular/overall mortality. To identify a uric acid threshold above which cardiovascular mortality rises, we studied the relationship between uric acid concentration and overall/cardiovascular mortality. METHODS AND RESULTS: We analyzed data from the InCHIANTI study, a cohort study of Italian community-dwelling people with 9 years of follow-up. We selected a sample of 947 individuals over 64 years of age, free from cardio-cerebrovascular disease and with available uric acid measurement at baseline. The sample was divided according to plasma uric acid tertiles. The Hazard ratio (HR) for mortality was calculated by multivariate Cox proportional hazard model. Mean age of participants was 75.3 ± 7.3 years; the mean value of uric acid was 5.1 ± 1.4 mg/dl. Over 9-years of follow-up, 342 (36.1%) participants died, 143 deaths (15.1%) were due to cardiovascular disease. Subjects with higher uric acid concentrations presented a higher cardiovascular mortality [II (4.6-5.5 mg/dl) vs I (1.8-4.5 mg/dl) tertile HR: 1.98, 95%C.I. 1.22-3.23; III (≥5.6 mg/dl) vs I tertile HR: 1.87, 95%C.I. 1.13-3.09]. We found a non-linear association between uric acid concentrations and cardiovascular mortality with the lowest mortality for values of about 4.1 mg/dl and a significant risk increment for values above 4.3 mg/dl. CONCLUSION: In community-dwelling older individuals free from cardio-cerebrovascular events, the lowest 9-year cardiovascular mortality was observed for uric acid values far below current target values. If confirmed, these data might represent the background for investigating the efficacy of uric acid levels reduction in similar populations.

5.
Psychol Med ; : 1-12, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31409435

RESUMO

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.

6.
Biogerontology ; 20(5): 649-663, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292793

RESUMO

Dysregulation of splicing factor expression is emerging as a driver of human ageing; levels of transcripts encoding splicing regulators have previously been implicated in ageing and cellular senescence both in vitro and in vivo. We measured the expression levels of an a priori panel of 20 age- or senescence-associated splicing factors by qRT-PCR in peripheral blood samples from the InCHIANTI Study of Aging, and assessed longitudinal relationships with human ageing phenotypes (cognitive decline and physical ability) using multivariate linear regression. AKAP17A, HNRNPA0 and HNRNPM transcript levels were all predictively associated with severe decline in MMSE score (p = 0.007, 0.001 and 0.008 respectively). Further analyses also found expression of these genes was associated with a performance decline in two other cognitive measures; the Trail Making Test and the Purdue Pegboard Test. AKAP17A was nominally associated with a decline in mean hand-grip strength (p = 0.023), and further analyses found nominal associations with two other physical ability measures; the Epidemiologic Studies of the Elderly-Short Physical Performance Battery and calculated speed (m/s) during a timed 400 m fast walking test. These data add weight to the hypothesis that splicing dyregulation may contribute to the development of some ageing phenotypes in the human population.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31282535

RESUMO

BACKGROUND: Whereas the independent effects of biomarkers, including vitamin D (25(OH)D), insulin-like growth factor 1 (IGF-1), C-reactive protein (CRP) and interleukin 6 (IL-6), on gait speed in older adults have been evaluated, their joint effects on gait speed are not well understood. METHODS: Study subjects aged ≥ 65 at baseline (N = 970) were enrolled in the population-based InCHIANTI study from 1998-2000, and were followed up at 3 and 6 years. All above biomarkers and gait speed data were measured at each of the 3 time points. Using a generalized estimating equation (GEE) approach, we determined if slow gait speed (< 0.8 meter/second) was associated with the biomarkers. Further investigation was conducted for interactions between high IL-6 (≥ 2.87 pg/mL) and other biomarkers focusing on low 25(OH)D (< 20 ng/mL). RESULTS: After controlling for other biomarkers and potential confounders, IL-6 emerged as the only biomarker independently associated with gait speed. The association between high IL-6 and slow gait speed was enhanced by low 25(OH)D, with significant interaction between high IL-6 and low 25(OH)D (p = 0.038). The odds ratio of slow gait speed for low 25(OH)D and high IL-6 was 1.63 (95% C.I.: 1.15, 2.32) compared to the reference groups with both biomarker levels at the other ends. CONCLUSION: The association of low vitamin D with slow gait speed statistically interacts with high IL-6. Co-existing vitamin D insufficiency and inflammation may provide a better biomarker for identifying those at risk of developing impairments in gait speed than either factor alone.

8.
Am J Clin Nutr ; 110(2): 437-450, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31165884

RESUMO

BACKGROUND: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans. OBJECTIVE: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes. METHODS: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes. RESULTS: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs. CONCLUSIONS: We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.

9.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
10.
BMC Geriatr ; 19(1): 179, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248370

RESUMO

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.

11.
Sensors (Basel) ; 19(10)2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091794

RESUMO

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.

12.
BMJ Open ; 9(3): e023526, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30898801

RESUMO

INTRODUCTION: The European population is rapidly ageing. In order to handle substantial future challenges in the healthcare system, we need to shift focus from treatment towards health promotion. The PreventIT project has adapted the Lifestyle-integrated Exercise (LiFE) programme and developed an intervention for healthy young older adults at risk of accelerated functional decline. The intervention targets balance, muscle strength and physical activity, and is delivered either via a smartphone application (enhanced LiFE, eLiFE) or by use of paper manuals (adapted LiFE, aLiFE). METHODS AND ANALYSIS: The PreventIT study is a multicentre, three-armed feasibility randomised controlled trial, comparing eLiFE and aLiFE against a control group that receives international guidelines of physical activity. It is performed in three European cities in Norway, Germany, and The Netherlands. The primary objective is to assess the feasibility and usability of the interventions, and to assess changes in daily life function as measured by the Late-Life Function and Disability Instrument scale and a physical behaviour complexity metric. Participants are assessed at baseline, after the 6 months intervention period and at 1 year after randomisation. Men and women between 61 and 70 years of age are randomly drawn from regional registries and respondents screened for risk of functional decline to recruit and randomise 180 participants (60 participants per study arm). ETHICS AND DISSEMINATION: Ethical approval was received at all three trial sites. Baseline results are intended to be published by late 2018, with final study findings expected in early 2019. Subgroup and further in-depth analyses will subsequently be published. TRIAL REGISTRATION NUMBER: NCT03065088; Pre-results.

13.
J Immunol Res ; 2019: 3128231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915369

RESUMO

Background: Olfactory dysfunction might unveil the association between ageing and frailty, as it is associated with declining cognitive function, depression, reduced physical performance, reduced dietary intake, and mortality; all these conditions are characterized by increased levels of inflammatory parameters. The present study is aimed at evaluating the association between olfactory dysfunction, frailty, and mortality and whether such association might be mediated by inflammation. Methods: We analysed data of 1035 participants aged 65+ enrolled in the "InCHIANTI" study. Olfactory function was tested by the recognition of the smells of coffee, mint, and air. Olfactory dysfunction was defined as lack of recognition of at least two smells. Considering the items "shrinking," "exhaustion," "sedentariness," "slowness," and "weakness" included in the Fried definition, frailty was defined as the presence of at least three criteria, prefrailty of one or two, and robustness of none. Serum interleukin-6 (IL-6) was measured in duplicate by high-sensitivity enzyme-linked immunosorbent assays. Logistic regression was adopted to assess the association of frailty with olfactory function, as well as with the increasing number of olfactory deficits. Cox regression was used to test the association between olfactory dysfunction and 9-year survival. Results: Olfactory dysfunction was associated with frailty, after adjusting (OR 1.94, 95% CI = 1.07-3.51; P = .028); analysis of the interaction term indicated that the association varied according to interleukin-6 levels (P for interaction = .005). Increasing levels of olfactory dysfunction were associated with increasing probability of being frail. Also, olfactory dysfunction was associated with reduced survival (HR 1.52, 95% CI = 1.16-1.98; P = .002); this association varied according to the presence of frailty (P for interaction = .017) and prefrailty status (P for interaction = .046), as well as increased interleukin-6 levels (P for interaction = .011). Conclusions: Impairment of olfactory function might represent a marker of frailty, prefrailty, and consequently reduced survival in an advanced age. Inflammation might represent the possible link between these conditions.


Assuntos
Envelhecimento/fisiologia , Fragilidade/epidemiologia , Transtornos do Olfato/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Fragilidade/mortalidade , Humanos , Inflamação , Interleucina-6/sangue , Itália/epidemiologia , Masculino , Transtornos do Olfato/mortalidade , Estudos Prospectivos
14.
Clin Nutr ; 2019 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-30850268

RESUMO

BACKGROUND & AIMS: PUFA intake is associated with reduced cardiovascular and all-cause mortality in the general population; however, evidence about this association in older adults is controversial. The objective of this study was to evaluate the relationship between PUFA intake and serum concentration, and the association of these variables with all-cause and cardiovascular mortality. METHODS: in this cohort study, we selected 927 community dwelling adults aged ≥65 years enrolled in the InCHIANTI study from 1998 to 2000 and followed-up for 9 years. The association between PUFA intake and serum concentration was evaluated using scatterplot and Pearson correlation test; all-cause and cardiovascular mortality was analyzed using the Kaplan-Meier method and Cox regressions adjusted for potential confounders. RESULTS: mean age of the population was 75 years (SD 7.3), 55% were women. There was no association between overall PUFAs, linolenic and linoleic acid intake and their serum concentration. There was no association between quartiles (Q) of PUFA intake and all-cause mortality: compared to Q1 of PUFA intake, the adjusted HR (95% CI) for overall mortality were: 1.05 (0.74-1.50) in Q2, 1.10 (0.76-1.58) in Q3, and 0.98 (0.68-1.41) in Q4; this lack of association was confirmed for cardiovascular mortality. Compared to Q1, participants in the fourth quartile of PUFA serum concentration had lower risk of all-cause mortality (adjusted HR [95%CI]: Q2 1.10 [0.79-1.53], Q3 0.84 [0.60-1.19], Q4 0.66 [0.44-0.995]), no association was found for cardiovascular mortality. CONCLUSIONS: In our sample of community-dwelling older adults, PUFA intake is not associated with PUFA serum concentration. Interventions to modulate PUFA concentration based on dietary intake may not be effective in preventing mortality in this population.

15.
J Am Med Dir Assoc ; 20(8): 1026-1031, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30772170

RESUMO

OBJECTIVES: Frailty phenotype (FP) has low sensitivity toward the identification of older people who will lose 1 or more activities of daily living. Nevertheless, the definition of disability in terms of activities of daily living may not resemble the pattern of functional impairment occurring during aging. The aim of this study was to examine the discriminative capacity of the FP toward the identification of patterns of disabilities in an extended list of tasks, identified among community-dwelling older people. DESIGN: Longitudinal cohort study. SETTING AND PARTICIPANTS: We included 997 persons age 65 years and older selected from the Invecchiare in Chianti (InCHIANTI) Study population. MEASURES: Using latent class analysis, we assessed the pattern of 3-year changes in 24 functional tasks. Then, we calculated the discriminative capacity of the FP for each pattern of disability. Analyses were stratified by sex. RESULTS: In both men and women, we recognized 3 classes: stable function; disability in complex tasks; and global functional disability. Among women, ability of FP to identify persons in global functional disability showed sensitivity = 0.42, specificity = 0.98, positive and negative predictive values 0.75 and 0.91; the corresponding values for prediction of disability in complex tasks were 0.13, 0.98, 0.68, and 0.75. Similar results were obtained among men. CONCLUSIONS/IMPLICATIONS: Over 3 years, older people of the InCHIANTI population remained largely functional stable, some persons developed deficiency in complex tasks, and a minority developed global functional disability. Trying to predict these 3 patterns may be useful for the care of older people in order to promote individualized interventions to reduce the burden of disabilities and their consequences. To this purpose, FP showed a fairly good capacity to identify people at risk of functional decline, but further studies are needed to identify instruments with better prognostic capacity.

16.
Dig Liver Dis ; 51(9): 1330-1336, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30808572

RESUMO

BACKGROUND: The relation between liver fibrosis scores and health outcomes in older people has been barely investigated. We aimed to evaluate the association of four liver fibrosis scores (fibrosis-4 -FIB-4-, NAFLD fibrosis score -NFS-, BARD and aspartate aminotransferase/alanine aminotransferase ratio -AST/ALT-) with mortality and incident disability at 6 years in an older population. METHODS: We studied 962 individuals aged ≥65 (mean age 74.4; female 55.5%) with a mean follow-up of 95.7 months, enrolled in the InCHIANTI study. The relationship between liver fibrosis scores and mortality and disability was assessed through Cox and log-binomial regressions. RESULTS: NFS and FIB-4 were associated with higher overall (aHR ranging 1.38-1.78 for intermediate risk of fibrosis and 1.60-2.02 for high risk) and cardiovascular (aHR ranging 1.76-2.90 for intermediate and 2.22-2.42 for high risk) mortality. AST/ALT and BARD were only associated with overall mortality. Only NFS and FIB-4 high risk classes were associated with incident disability (aRR ranging 1.93-2.76). Despite poor sensitivity, all scores showed high specificity (ranging 0.88-0.95). CONCLUSION: Higher risk of liver fibrosis is associated with higher risk of poor health outcomes. Liver fibrosis scores may help to stratify the risk and, mainly, identify elderly patients with favorable prognosis.

17.
Br J Nutr ; 121(4): 439-450, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30588894

RESUMO

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.

18.
Artigo em Inglês | MEDLINE | ID: mdl-30507519

RESUMO

Assessing the risk to develop a specific disease is the first step towards prevention, both at individual and population level. The development and validation of Risk Prediction Models (RPMs) is the norm within different fields of medicine but still underused in psychiatry, despite the global impact of mental disorders. In particular, there is a lack of RPMs to assess the risk of developing depression, the first worldwide cause of disability and harbinger of functional decline in old age. We present DRAT-up, the first prospective RPM to identify late life depression among community-dwelling subjects aged 60 to 75. The development of DRAT-up was based on appraisal of relevant literature, extraction of robust risk estimates and integration into model parameters. A unique feature is the ability to estimate risk even in the presence of missing values. To assess the properties of DRAT-up a validation study was conducted on three European cohorts, namely ELSA, InCHIANTI and TILDA, with 20206, 1359, and 3124 eligible samples, respectively. The model yielded accurate risk estimation in the three datasets from a small number of predictors. The Brier scores were 0.054, 0.133, and 0.041, while the values of Area Under the Curve (AUC) were 0.761, 0.736, and 0.768, respectively. Sensitivity analyses suggest robustness to missing values: setting any individual feature to unknown caused Brier scores to increase of 0.004, and AUCs to decrease of 0.045 in the worst cases. DRAT-up can be readily used for clinical purposes and to aid policy making in the field of mental health.

19.
Artigo em Inglês | MEDLINE | ID: mdl-30590397

RESUMO

Background: The aims of this study were to evaluate the relationship between anticholinergic drug burden (ACB) cognitive impairment, physical frailty and cognitive frailty, and 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 was 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 = 0.02), frailty (p <.001) and cognitive frailty (p <.001). The odds of cognitive impairment increased by 1.21 (95% 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 AUCs ranging from 0.81-0.88. 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.

20.
Clin Epigenetics ; 10(1): 161, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587240

RESUMO

BACKGROUND: Most research into myocardial infarctions (MIs) have focused on preventative efforts. For survivors, the occurrence of an MI represents a major clinical event that can have long-lasting consequences. There has been little to no research into the molecular changes that can occur as a result of an incident MI. Here, we use three cohorts to identify epigenetic changes that are indicative of an incident MI and their association with gene expression and metabolomics. RESULTS: Using paired samples from the KORA cohort, we screened for DNA methylation loci (CpGs) whose change in methylation is potentially indicative of the occurrence of an incident MI between the baseline and follow-up exams. We used paired samples from the NAS cohort to identify 11 CpGs which were predictive in an independent cohort. After removing two CpGs associated with medication usage, we were left with an "epigenetic fingerprint" of MI composed of nine CpGs. We tested this fingerprint in the InCHIANTI cohort where it moderately discriminated incident MI occurrence (AUC = 0.61, P = 6.5 × 10-3). Returning to KORA, we associated the epigenetic fingerprint loci with cis-gene expression and integrated it into a gene expression-metabolomic network, which revealed links between the epigenetic fingerprint CpGs and branched chain amino acid (BCAA) metabolism. CONCLUSIONS: There are significant changes in DNA methylation after an incident MI. Nine of these CpGs show consistent changes in multiple cohorts, significantly discriminate MI in independent cohorts, and were independent of medication usage. Integration with gene expression and metabolomics data indicates a link between MI-associated epigenetic changes and BCAA metabolism.


Assuntos
Metilação de DNA , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla/métodos , Leucócitos/química , Infarto do Miocárdio/genética , Idoso , Ilhas de CpG , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Fatores de Risco
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