The journals of gerontology. Series A, Biological sciences and medical sciences最新文献

Background: Although the pathogenesis of delirium is poorly understood, increasing evidence supports a role for inflammation. Previously, individual inflammatory biomarkers have been associated with delirium. Aggregating biomarkers into an index may provide more information than individual biomarkers in predicting certain health outcomes (e.g., mortality); however, inflammatory indices have not yet been examined in delirium.

Methods: Four inflammatory markers, C-reactive protein, Interleukin-6, Soluble Tumor Necrosis Factor Alpha Receptor-1, and Chitinase-3 Like Protein-1 (CHI3L1), were measured preoperatively (PREOP) and on postoperative day 2 (POD2) in 548 adults aged 70+ undergoing major noncardiac surgery (mean age 76.7 [standard deviation 5.2], 58% female, 24% delirium). From these markers, four inflammatory indices were considered: 1) quartile summary score, 2) weighted summary score (WSS), 3) principal component score, 4) a well-established inflammatory (LASSO-derived) index associated with mortality. Delirium was assessed using the Confusion Assessment Method (CAM), supplemented by chart review. Generalized linear models (GLM) with a log-link term were used to determine the association between each inflammatory index and delirium incidence.

Results: Among the inflammatory indices, WSS demonstrated the strongest association with delirium: participants in WSS quartile (Q)4 had a higher risk of delirium vs. participants in Q1, after clinical variable adjustment (relative risk [RR], 95% confidence interval [CI] for PREOP: 3.07, 1.80-5.22; and POD2: 2.65, 1.63-4.30). WSS was more strongly associated with delirium than the strongest associated individual inflammatory marker (PREOP CHI3L1 [RR 2.45, 95% CI 1.53-3.92]; POD2 interleukin-6 [RR 2.39, 95% CI 1.50-3.82]).

Conclusions: A multi-protein inflammatory index using WSS provides a slight advantage over individual inflammatory markers in their association with delirium.

Background: Substantial evidence supports the relationship between peripheral insulin resistance (IR) and the development of Alzheimer's disease (AD)-dementia. However, the mechanisms explaining these associations are only partly understood. We aimed to identify a metabolic signature of IR associated with the progression from mild cognitive impairment (MCI) to AD-dementia.

Methods: This is a case-control study on 400 MCI subjects, free of type 2 diabetes, within the ACE cohort, including individuals ATN+ and ATN-. After a median of 2.1 years follow-up, 142 subjects converted to AD-dementia. IR was assessed using the HOMA-IR. A targeted multi-platform approach profiled over 600 plasma metabolites. Elastic net penalized linear regression with 10-fold cross-validation was employed to select those metabolites associated with HOMA-IR. The prediction ability of the signature was assessed using support vector machine and performance metrics. The metabolic signature was associated with AD-dementia risk using a multivariable Cox regression model. Using counterfactual-based mediation analysis we investigated the mediation role of the metabolic signature between HOMA-IR and AD-dementia. The metabolic pathways in which the metabolites were involved were identified using MetaboAnalyst.

Results: The metabolic signature comprised 18 metabolites correlated with HOMA-IR. After adjustments by confounders, the signature was associated with increased AD-dementia risk (HR 1.234; 95%CI 1.019-1.494; p<0.05). The metabolic signature mediated 35% of the total effect of HOMA-IR on AD-dementia risk. Significant metabolic pathways were related to glycerophospholipid and tyrosine metabolism.

Conclusions: We have identified a blood-based metabolic signature that reflects IR and may enhance our understanding of the biological mechanisms through which IR affects AD-dementia.

Background: Current multimorbidity measures often oversimplify complex disease interactions by assuming a merely additive impact of diseases on health outcomes. This oversimplification neglects clinical observations that certain disease combinations can exhibit synergistic effects. Thus, we aimed to incorporate simultaneous higher-order disease interactions into the validated ICD-coded multimorbidity-weighted index (MICD), to assess for model improvement.

Methods: Health and Retirement Study participants with linked Medicare data contributed ICD-9-CM claims, 1991-2012. Top 20 most prevalent and impactful conditions (based on associations with decline in physical functioning) were assessed through higher order interactions (two-way, three-way). We applied the least absolute shrinkage and selection operator (LASSO) and bootstrapping to identify and retain statistically significant disease interactions. We compared model fit in MICD with and without disease interactions in linear models.

Results: We analyzed 73,830 observations from 18,212 participants (training set N=14,570, testing set N=3,642). MICD without interactions produced an overall R2=0.26. Introducing two-way interactions for the top 10 most prevalent and impactful conditions resulted in a R2=0.27, while expanding to top 20 most prevalent and impactful conditions yielded a R2=0.26. When adding three-way interactions, the same top 10 conditions produced a R2=0.26, while expanding to top 20 conditions resulted in a R2=0.24.

Conclusions: We present novel insights into simultaneous higher-order disease interactions for potential integration into multimorbidity measurement. Incorporating two-way disease interactions for the top 10 most prevalent and impactful conditions showed a minimal improvement in model fit. A more precise multimorbidity index may incorporate both the main effects of diseases and their significant interactions.

Background: Little is known as to how rest-activity rhythms (RAR) are associated with frailty and how this relationship differs by sex. This study examined the relationship between RAR and frailty in a nationally representative sample of US older adults, focusing on the moderating role of sex.

Methods: 2,531 participants aged ≥60yrs [Females:55.2%; Frail:5.15% (4.02-6.29); Pre-frail:33.49% (31.29-35.68)] were included using the 2011-2014 National Health and Nutrition Examination Survey. Non-parametric RAR parameters, including inter-daily stability (IS), intra-daily variability (IV), relative amplitude (RA), most active 10-h, and least active 5-h, were estimated from wrist-worn actigraphy data. Frailty status was assessed using a modified version of frailty phenotype (range:0-5): frail (≥3), pre-frail (1-2), and non-frail (0). Multinomial logistic regression models were used to examine the interest of associations, adjusting for potential confounders.

Results: Frail and pre-frail older adults exhibited significantly lower RA, IS, higher IV, and phase delay when compared to non-frail older adults (p's<.05). Particularly, older adults with low RA had significantly greater odds of being frail and pre-frail [aOR(95%CIs); Frailty:5.60(2.61-12.04); Pre-frailty:1.58(1.13-2.20)]. Significant sex-interaction was observed (p<.01), with this association being greater in females than in males [aOR(95%CIs); Females:7.78(2.98-20.30) for frailty, 2.31(1.60-3.32) for pre-frailty; Males:4.48(1.38-14.54) for frailty, 1.12(0.61-2.07) for pre-frailty].

Conclusion: Weakened RAR strength is unfavorably associated with frailty, particularly in females. RAR may be a useful indicator associated with frailty in older adults, but sex-specific differences should be considered. Further longitudinal research is necessary to investigate the bidirectionality of their association.

Background: To describe the implementation of the ICOPE program in France using digital tool in order to: 1) describe the characteristics of people completing the screener, identifying differences across assessors (Health Care Professionals (HCP), non-HCPs or self-assessment) 2) describe the characteristics of follow-up and assessments for people with abnormal screening test 3) describe the recommendations in the intervention care plans for people with a decline in intrinsic capacity (IC).

Methods: A descriptive study, presenting the results at initial screening, as well as at assessment when needed; and the recommendations issued during Step 3. We compared these results based on whether the participant was enrolled by an HCP, by a non-HCP, or self-assessment.

Results: 27,082 participants were enrolled. 67.9% were registered by HCPs. 90.8% participants screened positive at Step 1. Participants who completed the self-assessment were significantly younger (70.9 years versus 76.4 for HCPs or 77.9 for non-HCPs, p<0.01) and less frequently had alerts in Step 1 (83.8% versus 90.8 for HCPs or 94.8 for non-HCPs). Step 2 in-depth assessments were carried out for 8.9% of the participants. In step 2, only the SPPB showed significantly better motor abilities in individuals enrolled through self-assessment (median and IQR: 11(10 - 12) versus 10(8 - 12) for HCPs and 10(7 - 12) for non-HCPs). Prevention care plans were proposed, mainly physical activity (n=833 - 33.7%) and nutrition counseling (n=1,233 - 51.7%).

Conclusion: This study highlights the major role of HCPs in the implementation of the ICOPE program. Self-assessment enables the enrollment of more robust seniors, allowing to an early detection and treatment.

Background: Multidomain lifestyle interventions may have the potential to slow biological aging as captured by deficit accumulation frailty indices. We describe the distribution and composition of the 49-component frailty index (FI) developed by the U.S. POINTER clinical trial team of investigators and assess its cross-sectional associations with sociodemographic factors and markers chosen to be representative of behaviors targeted by the trial's multidomain interventions.

Methods: We draw baseline data from the 2111 volunteers enrolled in U.S. POINTER who were ages 60-79 years and at increased risk for cognitive decline. Frailty components were grouped into nine domains. Associations that FI scores and their domains had with behavioral markers were described with correlations and canonical correlation.

Results: The 25th, 50th, and 75th percentiles of the frailty index score distribution were 0.153, 0.189, and 0.235. Higher frailty scores tended to occur among individuals who were older, male, and living in areas of greater deprivation (all p<0.001). They were also associated with poorer self-reported diet, less physical activity, and higher Framingham risk scores (all p<0.001). Associations were diffusely distributed among the frailty component domains, indicating that no individual domain was dominating associations.

Conclusions: The U.S. POINTER deficit accumulation frailty index had expected relationships with sociodemographic factors and sensitivity to the behaviors targeted by the trial's interventions. Our analysis supports its use as a secondary outcome to assess whether the multidomain interventions differentially impact an established marker of biological aging.

Background: Patients with heart failure (HF) are at an increased risk of developing pneumonia, leading to a high mortality. A decrease in muscle strength due to aging or concomitant disease may contribute to the development of pneumonia in older adults. We sought to investigate the relationship between low muscle strength and pneumonia incidence in older patients hospitalized for worsening HF.

Methods: We carried out a sub-analysis of the FRAGILE-HF, a prospective multicenter observational study, including 1266 consecutive older (≥65 years) patients hospitalized with HF (mean age 80.2±7.8 years; 57.4% male; left ventricular ejection fraction 46±17%) and information of incident pneumonia observed after discharge. Patients were followed up for two years post-discharge.

Results: A total of 88 patients (7.0%) developed pneumonia after discharge, with an incidence of 42.7 per 1,000 person-years. A total of 893 patients with low muscle strength, defined as handgrip strength <28 kg for men and <18 kg for women according to international criteria, were more likely to develop pneumonia than those with normal muscle strength (p <0.001; log-rank test). Low muscle strength was a significant predictor of incident pneumonia (adjusted hazard ratio with 95% confidence interval: 2.65 [1.31-5.35], p=0.007). Furthermore, the mortality rates were 43.2% in patients who developed pneumonia and 19.3% in those who did not, indicating a heightened risk of death following the onset of pneumonia (adjusted hazard ratio: 4.25 [2.91-6.19], p<0.001).

Conclusions: In older patients hospitalized for HF, low muscle strength was associated with incident pneumonia after discharge.

Background: Mild cognitive impairment (MCI) and parkinsonism affect many older adults. The objective of this study was to determine the sequence of their occurrence and associated risk of death.

Methods: 1,255 community-dwelling unimpaired participants from two epidemiological cohorts were examined annually. MCI was based on neuropsychological testing, and parkinsonism was based on the motor portion of the modified Unified Parkinson's Disease Rating Scale. A multi-state Cox proportional hazards model simultaneously examined incidences of MCI, parkinsonism, and death.

Results: Average age at baseline was 76.5 years (SD = 7.2) and 73% were female. Incident MCI occurred almost as commonly as incident parkinsonism, yet compared to no impairment, risk of death was higher for MCI (HR = 1.82, 95%CI=1.34, 2.47), but it was not different for parkinsonism (HR = 1.29; 95%CI = 0.95, 1.75). Risk of death for participants with incident MCI who progressed to parkinsonism (40%) was not significantly different from those with MCI alone (HR = 1.25, 95%CI = 0.93, 1.69). However, risk of death for participants with incident parkinsonism who progressed to MCI (51%) was significantly higher than those who did not progress (HR = 1.67, 95%CI = 1.27, 2.18), indicating that risk of death is highest with incidence of MCI.

Conclusions: The varied patterns of sequential occurrence of cognitive and motor impairment and associated risk of death suggests much greater heterogeneity than previously recognized. Further work is needed to determine the biology underlying the temporal evolution of these phenotypes, and if identification of the various subtypes improves risk stratification.

Age-related hearing loss (ARHL) or Presbycusis is the most frequent sensory deficiency in older adults and is associated with comorbidities, such as falls, cognitive decline, and frailty. Frailty is related to poor health outcomes in old age. Recent research suggested that ARHL may be a potentially modifiable risk factor for frailty, although inconclusive. The use of animal models to study the correlation between ARHL and frailty is important to test future interventions to be translated into clinical practice. The aim of this study was to determine if there is an association between ARHL and frailty in experimental animals based on the human frailty phenotype. This research studied male and female C57Bl/6J mice, at different ages (6, 14, and 22 months). Auditory steady-state responses (ASSR) threshold shifts were measured at different frequencies. To assess frailty status, we were based on the "Valence Score" which consists of measuring: weakness, weight loss, low level of activity, slowness, and little resistance. We found that hearing is significantly lower in older age groups. The mice become frail as they age. The worsening in ASSR threshold shifts with age correlates significantly with an increasing frailty. No significant differences were found between both sexes. Our research is, to our knowledge, the first carried out in experimental animals to establish the association between ARHL and frailty, which would provide a useful tool to evaluate future interventions in mice before translating them into clinical practice.

Background: Biomarkers for sarcopenia are lacking. We examined the diagnostic power of serum creatinine to cystatin C (Cr:Cyc) ratio for identifying low MRI-muscle volume and low grip strength in a large observational study of UK Biobank older adults.

Methods: Serum creatinine and cystatin C were measured via immunoassays (Beckman Coulter AU5800 and Siemens Advia 1800, respectively) and grip strength by hydraulic hand dynamometer at baseline visit (2008-2010). MRI-thigh fat-free muscle volume (FFMV) and DXA-derived appendicular lean mass were measured at imaging visit (2014-2018). Extreme outliers were removed, and covariates (demographic, lifestyle, and clinical factors, as well as time elapsed between baseline-imaging visit) were adjusted for in statistical models.

Results: 12,873 older adults (mean age: 63.5 ± 2.7 years, 44.2% women) were included for FFMV and ALM/BMI; 149,707 older adults (mean age: 64.0 ± 2.9 years, 50.5% women) for grip strength. Despite significant associations (p<0.05), in fully-adjusted models, Cr:Cyc showed poor to acceptable diagnostic power for identifying low FFMV when using cutpoints of 20th percentile (AUC: 0.577 men; 0.622 women) and T scores of -2 (AUC: 0.596 men; 0.659 women) and -2.5 (AUC: 0.609 men; 0.722 women). In fully-adjusted model, Cr:Cyc showed poor diagnostic power (AUCs: <0.70) for identifying low ALM/BMI or low grip strength irrespective of the cutpoint used.

Conclusions: Cr:Cyc may not be a suitable biomarker for identifying low muscle volume or low strength in older adults. This finding, drawn from a large sample size and the use of advanced medical imaging, marks an important contribution to the sarcopenia field.