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Loss of cognitive function is a significant challenge in aging, and developing models to understand and target cognitive decline is crucial for the development of Geroscience‐based interventions. Aged mice offer a valuable model as they share features of cognitive decline with humans. Despite numerous studies, knowledge of longitudinal age‐related cognitive changes and cognitive frailty in naturally aging mice is limited, particularly in cohorts exceeding 30 months of age, where cognitive decline is more pronounced. Moreover, the impaired physical function of aged mice is known to affect latency‐based strategies to measure cognitive performances. Here, we show a comprehensive longitudinal assessment using the Barnes Maze test in a large cohort of 424 aged (≥ 21 months) C57BL/6J mice. We introduced a new metric, the Cognitive Frailty Index (CoFI), which summarizes different age‐associated Barnes Maze parameters into a unique function. CoFI strongly associates with advancing age and mortality, offering a reliable ability to discriminate long‐ and short‐lived mice. We also established a CoFI cut‐off and a physically adjusted CoFI, both of which can distinguish between physical and cognitive frailty. This is further supported by the enhanced predictive power when physical and cognitive frailty are combined to assess short‐term mortality. Moreover, the computation method for CoFI is adaptable to various cognitive assessment tests, leveraging procedures akin to those used for calculating other frailty indices. In conclusion, through robust longitudinal tracking, CoFI has the potential to become an important ally in assessing the effectiveness of Geroscience‐based interventions to counteract age‐related cognitive impairment. Our study presents a groundbreaking longitudinal assessment of age‐related cognitive decline in a large cohort of aged mice. Through the development of the Cognitive Frailty Index (CoFI), we introduce a robust metric that correlates strongly with advancing age and mortality. Importantly, CoFI and physical frailty are distinct entities, with CoFI offering a new tool to assess cognitive impairment independently from physical decline. This adaptable tool will be valuable for testing the efficacy of innovative interventions in the field of Geroscience.

Cognitive frailty (CF) is defined by the coexistence of physical frailty and mild cognitive impairment. Malnutrition is an underlying factor of age-related conditions including physical frailty. However, the evidence associating malnutrition and cognitive frailty is limited. This cross-sectional study aimed to determine the association between malnutrition and CF in the elderly. A total of 373 participants aged 65–84 years were enrolled after excluding those who were suspected to have dementia and depression. Then, 61 CF and 45 normal participants were randomly selected to measure serum prealbumin level. Cognitive function was assessed using the Montreal Cognitive Assessment-Basic (MoCA-B). Modified Fried’s criteria were used to define physical frailty. Nutritional status was evaluated by the Mini Nutritional Assessment–short form (MNA-SF), serum prealbumin, and anthropometric measurements. The prevalence of CF was 28.72%. Malnourished status by MNA-SF category (aOR = 2.81, 95%CI: 1.18–6.67) and MNA-SF score (aOR = 0.84, 95%CI = 0.74–0.94) were independently associated with CF. However, there was no correlation between CF and malnutrition assessed by serum prealbumin level and anthropometric measurements. Other independent risk factors of CF were advanced age (aOR = 1.06, 95%CI: 1.02–1.11) and educational level below high school (aOR = 6.77, 95%CI: 1.99–23.01). Malnutrition was associated with CF among Thai elderly. High-risk groups who are old and poorly educated should receive early screening and nutritional interventions.

Background The global aging trend exacerbates the challenge of frailty and cognitive impairment in older adults, yet their combined impact on health outcomes remains under-investigated. This study aims to explore how frailty and psychometric mild cognitive impairment (pMCI) jointly affect all-cause and cardiovascular disease (CVD) mortality. Methods The cohort study we examined 2,442 participants aged ≥ 60, is the secondary analysis from the National Health and Nutrition Examination Survey (NHANES) 2011–2014. Frailty was quantified using a 49-item frailty index, while pMCI was determined by three composite cognition scores one standard deviation (SD) below the mean. The associations between frailty, pMCI, comorbidity, and mortality were assessed using weighted Cox proportional hazards models. Results Of the participants, 31.37% were frail, 17.2% had pMCI, and 8.64% exhibited both conditions. The cohort was stratified into four groups based on frailty and pMCI status. After a median follow-up period of 6.5 years, frail individuals with pMCI had the highest all-cause (75.23 per 1,000 person-years) and CVD (32.97 per 1,000 person-years) mortality rates. Adjusted hazard ratios (HRs) for all-cause (3.06; 95% CI, 2.05–4.56) and CVD (3.8; 95% CI, 2.07–6.96) mortality were highest in frail older adults with pMCI compared to those who were non-frail without pMCI. Conclusion Our study highlights the ubiquity of frailty and cognitive impairment in older adults and underscores the heightened risk of mortality associated with their coexistence. These findings suggest the critical need for proactive screening and management of frailty and cognitive function in clinical practice to improve outcomes for the older adults.

Frailty and cognitive impairment are critical geriatric syndromes. In previous studies, both conditions have been identified in old-age adults as increased risk factors for mortality. However, the combined effect of these two syndromes in predicting mortality among people with advanced age is not well understood. Thus, we used Chinese community cohort to determine the impact of the combined syndromes on the oldest-old people. Our present study is part of an ongoing project on Longevity and Aging in Dujiangyan, which is a community study on a 90+ year cohort in Sichuan Province in China. Participants were elderly people who completed baseline health assessment in 2005 followed by a collection of mortality data in 2009. Frailty and cognitive function were assessed with 34-item Rockwood Frailty Index and the Mini-Mental Status Examination, respectively, and the combined effect(s) of these two parameters on death was examined using the Cox proportional hazard regression model. This study consisted of a total of 705 participants (age = 93.6 ± 3.3 years; 67.4% females), of which 53.8% died during a four-year follow-up period. The prevalence of frailty, cognitive impairment, and the overlap of these two syndromes was 63.7, 74.2, and 50.3%, respectively. Our data showed that the subjects with combined frailty and cognitive impairment were associated with increased risk of death (age, gender, education level, and other potential confounders adjusted); the hazard ratio was 2.13 (95% confidence interval 1.39, 3.24), compared with the control group. However, neither frailty alone nor cognitive impairment alone increased the risk of death in these individuals. The combined frailty and cognitive impairment, other than the independently measured syndromes (frailty or cognitive impairment alone), was a significant risk factor for death among the oldest-old Chinese people.

Background The risk factors on the transition from robustness to cognitive frailty (CF), characterized by concurrent cognitive impairment and physical frailty (PF), may vary through different transition routes. Methods Data from the National Institute for Longevity Sciences-Longitudinal Study of Aging (2000−2012) were analyzed, including data for 1,061 older individuals (baseline age: 60–83 years; 51.5% men) who had a Mini-Mental State Examination (MMSE) score ≥ 24, and were dementia- and CF-free at baseline. Mild cognitive impairment (MCI) was defined as a MMSE score 24–27, PF as ≥ 1 Fried criteria, and CF as both conditions. Dietary diversity (assessed using the Quantitative Index for Dietary Diversity score; 0–1) and energy intake were categorized into sex-specific tertiles (T1–T3). Multistate modeling estimated hazard ratios of risk factors for transitions among robustness (no MCI and PF), MCI, PF, and CF states. Results At baseline, robustness, MCI, and PF proportions were 36.9%, 14.4%, and 48.7%, respectively. In robust individuals, aging increased (HR = 1.22), and high dietary diversity (HR = 0.62 for T3) and higher energy intake (HR = 0.36 for T2, 0.37 for T3) mitigated MCI risk. Conversely, obesity (HR = 1.37) and smoking (HR = 1.66) elevated, and stroke history (HR = 0.43) and high dietary diversity (HR = 0.63 for T3) lowered PF risk. Among those with MCI, female sex (HR = 1.69) and higher education (HR = 1.75 for 10−12 years, 2.19 for ≥ 13 years) facilitated recovery, while moderate energy intake impeded it (HR = 0.40 for T2). Aging (HR = 1.32), female sex (HR = 2.63), and smoking (HR = 2.91) increased CF risk, whereas moderate energy intake mitigated it (HR = 0.50 for T2). In PF participants, moderate dietary diversity (HR = 1.49 for T2), high energy intake (HR = 1.39 for T3), and alcohol consumption (HR = 1.32) promoted recovery, while depressive symptoms (HR = 0.25) and living alone (HR = 0.58) hindered it. Aging (HR = 1.28) increased CF risk, whereas higher education decreased it (HR = 0.55 for 10−12 years, 0.54 for ≥ 13 years). Conclusions Tailoring intervention strategies according to specific health statuses of older adults may prevent and delay CF onset and facilitate recovery from MCI and PF.

INTRODUCTION:Physical frailty and minimal hepatic encephalopathy (MHE) are common in advanced chronic liver disease (AdvCLD). Although the Psychometric Hepatic Encephalopathy Score is used for MHE diagnosis, its complexity limits routine use. The Stroop EncephalApp (StE) offers a simpler method for MHE diagnosis. We aimed to investigate the association between MHE using the StE and physical frailty by the Liver Frailty Index (LFI), in patients with AdvCLD.METHODS:This multicenter study analyzed data from patients with AdvCLD awaiting liver transplantation. Patients were categorized into 2 groups based on the presence or absence of MHE and compared using the LFI and its components. To identify factors influencing the various StE modalities and MHE diagnosis, we used the Spearman rank correlation coefficient and logistic regression models.RESULTS:Of the 267 patients, 73% were diagnosed with MHE, and 18% of the total cohort were classified as frail. Patients with MHE demonstrated poorer LFI scores and were more likely to be categorized as prefrail or frail. Notably, there was a significant correlation between StE time modalities, especially off-time, and the LFI score (rho = 0.438, P < 0.001). Furthermore, multivariable analyses indicated that the LFI was independently associated with MHE (OR 2.41, 95% CI 1.52–3.82).DISCUSSION:The findings suggest that the LFI score in this population reflects its ability to capture the crucial role of psychomotor speed, particularly evident in off-time performance, thus connecting neurocognitive and physical function. Further research is warranted to investigate the effectiveness of interventions targeting cognitive and physical impairments to enhance clinical outcomes in patients with AdvCLD.

Background Few studies have focused on comparing the effect of cognitive frailty (CF) with either cognitive impairment or frailty alone on fall risk. Further, studies investigating the effect of reversible cognitive frailty (RCF) or potentially reversible cognitive frailty (PRCF) on fall risk are scarce. This study aimed to investigate the influence of RCF and PRCF on falls in community-dwelling older adults of China and determine whether CF conferred a higher risk than cognitive impairment or frailty alone. Methods This study used data from five waves of the China Health and Retirement Longitudinal Study (CHARLS) conducted from 2011 to 2020. A total of 3,200 participants were divided into six groups: Healthy, cognitive impairment [subjective cognitive decline (SCD) and mild cognitive impairment (MCI)], Frailty, and CF (RCF and PRCF), according to their baseline cognitive and frailty status. A generalized estimating equation was applied to measure the association of cognitive status, frailty, and CF with risk of falls. Multivariate logistic regression models were employed to analyze potential multiplicative and additive interactions of baseline cognitive impairment and frailty on fall risk. Results Of the 3,200 participants, 17.7% and 8.3% experienced falls and fall-induced injuries, respectively, in wave 2013. After adjusting for all covariates, the participants in the PRCF group [odds ratio (OR) = 1.442, 95% confidence interval (CI): 1.179–1.922] had a higher risk of falling than those in the RCF group (OR = 1.302, 95% CI: 1.053–1.593), while cognitive impairment alone or frailty alone were not associated with increased risk. The interaction analyses revealed a lack of multiplicative (OR  =  0.952, 95% CI: 0.618–1.468) or additive [relative excess risk (RERI) =-0.043, 95% CI: -0.495–0.409; attributable proportion (AP) =-0.035, 95% CI: -0.400–0.329; synergy index (S)  =  0.840, 95% CI: 0.172–4.095] interactions of cognitive impairment and frailty for falls. Conclusions We found that the risk of falls increased in RCF and PRCF compared to either cognitive impairment or frailty alone, with PRCF being associated with a higher risk than RCF. Clinical trial number Not applicable.

Aging leads to declines in physical and cognitive functions, with NLRP3-associated neuroinflammation playing a key role. While physical frailty quantifies age-related physiological decline, the concept of cognitive frailty, integrating physical frailty and cognitive impairment, remains underexplored. The relationship between NLRP3-driven neuroinflammation and functional deterioration is not fully understood. Lipopolysaccharide (LPS)-induced systemic inflammation mimics features of cognitive and physical impairment, highlighting its potential as an experimental model for cognitive frailty. This study aims to characterize physical and cognitive frailty phenotypes in aging and inflammation and explore the association between frailty and NLRP3 inflammasome signaling in the mouse brain. Adult, aged, and LPS-treated adult male mice were subjected to a battery of behavioral tests over five consecutive days. Physical frailty was evaluated using the Clinical Frailty Index (CFI), the Eight-item Frailty Index (FI), and the Frailty Phenotype (FP). Mild cognitive impairment was assessed separately, and a novel Cognitive Frailty Index (CogFI), integrating both physical and cognitive parameters, was proposed. Senescent cells were quantified by counting β-galactosidase+ cells. Levels of NLRP3-associated markers were measured in the hippocampus and amygdala. Behavioral assessments revealed that aging leads to heterogeneous declines in physical and cognitive performance, whereas LPS induced a more uniform and severe phenotype 5 days postinjection (dpi). The proposed CogFI effectively captured the variability in age-related behavioral decline. LPS administration did not increase the number of β-galactosidase+ cells, unlike natural aging. Furthermore, only aging induced sustained NLRP3 expression in the hippocampus. Correlational analyses demonstrated strong associations between hippocampal Caspase-1 levels and all frailty indices, including CogFI ( r  > 0.83), and between NLRP3 levels and both CFI and CogFI ( r  > 0.56). Notably, the cognitive component alone did not correlate significantly with any NLRP3 pathway markers in either the hippocampus or the amygdala. This study introduces a novel, quantitative measure of cognitive frailty in mice and establishes NLRP3 inflammasome activation as a relevant molecular correlate of frailty. While LPS-induced inflammation models certain severe aspects of cognitive frailty at 5 dpi, it does not recapitulate the full molecular complexity of natural aging. These findings underscore the importance of distinguishing between induced and intrinsic aging processes in the study of frailty.

IntroductionFrailty is strongly associated with the clinical course of cognitive impairment and dementia, thus arguing for the need of its assessment in individuals affected by cognitive deficits. This study aimed to retrospectively evaluate frailty in patients aged 65 years and older referred to two Centers for Cognitive Decline and Dementia (CCDDs).MethodsA total of 1256 patients consecutively referred for a first visit to two CCDDs in Lombardy (Italy) between January 2021 to July 2022 were included. All patients were evaluated by an expert physician in diagnosis and care of dementia according to a standardized clinical protocol. Frailty was assessed using a 24-items Frailty Index (FI) based on routinely collected health records, excluding cognitive decline or dementia, and categorized as mild, moderate, and severe.ResultsOverall, 40% of patients were affected by mild frailty and 25% of the sample has moderate to severe frailty. The prevalence and severity of frailty increased with decreasing Mini Mental State Examination (MMSE) score and advancing age. Frailty was also detected in 60% of patients with mild cognitive impairment.ConclusionFrailty is common in patients referring to CCDDs for cognitive deficits. Its systematic assessment using a FI generated with readily available medical information could help develop appropriate models of assistance and guide personalization of care.

The “very old intensive care patients” (abbreviated to VOPs; greater than 80 years old) are probably the fastest expanding subgroup of all intensive care unit (ICU) patients. Up until recently most ICU physicians have been reluctant to admit these VOPs. The general consensus was that there was little survival to gain and the incremental life expectancy of ICU admission was considered too small. Several publications have questioned this belief, but others have confirmed the poor long-term mortality rates in VOPs. More appropriate triage (resource limitation enforced decisions), admission decisions based on shared decision-making and improved prediction models are also needed for this particular patient group. Here, an expert panel proposes a research agenda for VOPs for the coming years.