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Frailty complicates the care of individuals with dementia, increasing their vulnerability to adverse outcomes. This Personal View presents expert recommendations for managing frailty in individuals with dementia, aimed at health-care providers, particularly those in primary care. We conducted a rapid literature review followed by a consensus process involving 18 international experts on dementia and frailty. The experts identified key areas, including diagnosis of frailty, assessment of nutritional status and nutritional management, physical activity, prevention of falls, and polypharmacy management. The recommendations emphasise early identification of frailty and a comprehensive, interdisciplinary approach to care that aims to maintain the individual's daily functioning, quality of life, and independence. The recommendations highlight the importance of tailored interventions, regular monitoring, and the integration of psychosocial support into the therapeutic approach. These recommendations address a crucial gap in existing clinical guidelines, offering practical guidance for clinicians managing frailty in individuals with dementia., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: An accessible marker of both biological age and dementia risk is crucial to advancing dementia prevention and treatment strategies. Although frailty is a candidate for that role, the nature of the relationship between frailty and dementia is not well understood., Objective: To clarify the temporal relationship between frailty and incident dementia by investigating frailty trajectories in the years preceding dementia onset., Design, Setting, and Participants: Participant data came from 4 prospective cohort studies: the English Longitudinal Study of Ageing, the Health and Retirement Study, the Rush Memory and Aging Project, and the National Alzheimer Coordinating Center. Data were collected between 1997 and 2024 and were analyzed from July 2023 to August 2024. The settings were retirement communities, national-level surveys, and a multiclinic-based cohort. Included individuals were 60 years or older and without cognitive impairment at baseline. Included individuals also had data on age, sex, education level, and ethnicity and a frailty index score calculated at baseline., Exposure: Frailty was the main exposure, with participants' degrees of frailty quantified using retrospectively calculated frailty index scores., Main Outcomes and Measures: Incident all-cause dementia ascertained through physician-derived diagnoses, self- and informant-report, and estimated classifications based on combinations of cognitive tests., Results: The participant number before exclusions was 87 737. After exclusions, data from 29 849 participants (mean [SD] age, 71.6 [7.7] years; 18 369 female [62%]; 257 963 person-years of follow-up; 3154 cases of incident dementia) were analyzed. Bayesian generalized linear mixed regression models revealed accelerations in frailty trajectories 4 to 9 years before incident dementia. Overall, frailty was positively associated with dementia risk (adjusted hazard ratios [aHRs] ranged from 1.18; 95% CI, 1.13-1.24 to 1.73; 95% CI, 1.57-1.92). This association held among participants whose time between frailty measurement and incident dementia exceeded the identified acceleration period (aHRs ranged from 1.18; 95% CI, 1.12-1.23 to 1.43; 95% CI, 1.14-1.80)., Conclusions and Relevance: These findings suggest that frailty measurements may be used to identify high-risk population groups for preferential enrolment into clinical trials for dementia prevention and treatment. Frailty itself may represent a useful upstream target for behavioral and societal approaches to dementia prevention.

The concept of frailty, now being adopted in most medical disciplines, is attracting growing interest in neurology. Every day, most neurologists care for patients with varying degrees of frailty, from very mild to very severe. Frailty exacerbates patients' health needs, complicates clinical decision making, and negatively affects their health outcomes. Increasing evidence suggests that frailty affects the risk, clinical presentation, and course of common age-related neurological disorders, including dementia, Parkinson's disease, stroke, and multiple sclerosis. Most neurologists should become familiar with assessing and measuring frailty. Doing so can provide information that is crucial for diagnosis, prognostication, and care planning. Consideration of frailty can help to elucidate the pathophysiological underpinnings of age-related neurological disorders, clarify the clinical validity and utility of candidate biomarkers, and identify novel therapeutic targets. Randomised controlled trials investigating late-life neurological diseases that address frailty have the potential to provide insight into these complex disorders., Competing Interests: Declaration of interests KR currently serves on a data safety monitoring board for EIP Pharma. KR has served as a member of the ADMET-2 advisory board (Johns Hopkins), and the Wake Forest University Medical School Centre advisory board. KR has received honoraria for invited lectures, rounds, and academic symposia on frailty from Burnaby Family Practice, Chinese Medical Association, University of Nebraska-Omaha, the Australia New Zealand Society of Geriatric Medicine, the Atria Institute, University of British Columbia, McMaster University, and the Fraser Health Authority. KR has asserted copyright over the Clinical Frailty Scale and (with a colleague) the Pictorial Fit-Frail Scale, which are made freely available for non-commercial education and research, as well as non-profit health care with completion of a permission agreement stipulating users will not change, charge for, or commercialise the scales. For-profit entities pay a licencing fee, 15% of which is retained by the Dalhousie University Office of Commercialization and Innovation Engagement. After taxes, the remainder of the licence fees are donated to the Dalhousie Medical Research Foundation. Licences have been negotiated with Rebibus Therapeutics, Cook Research, W L Gore Associates, Pfizer, Cellcolabs, AstraZeneca, Qu Biologics, Biotest, BioAge Labs, Congenica, and Icosavax. KR is co-founder of Ardea Outcomes (DGI Clinical until 2021), which has had contracts with pharmaceutical and device manufacturers Danone, Hollister, INmune, Novartis, and Takeda on individualised outcome measurement. On behalf of Ardea Outcomes, KR attended an advisory board meeting with Nutricia on dementia. KR is named on a US patent application submitted by Ardea Outcomes for Electronic Goal Attainment Scaling (patent number US20230402138A1). MC and CJ-T declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Due to the high clinical heterogeneity of epilepsy, there is a critical need for novel metrics aimed at capturing its biological and phenotypic complexity. Frailty is increasingly recognized in various medical disciplines as a useful construct to understand differences in susceptibility to adverse outcomes. Here, we develop a frailty index (FI) for patients with epilepsy (PwE) and explore its association with demographic and clinical features., Methods: In this cross-sectional study, we consecutively enrolled 153 PwE from an outpatient epilepsy clinic. Participants were assessed for various health deficits to calculate the FI. Associations between FI and demographic/clinical features, antiseizure medications (ASMs), and patient-reported outcomes were analyzed using general linear models and Spearman correlation., Results: The median age at the time of study visit was 47 years (interquartile range = 33-60), and 89 (58.2%) patients were females. Multiple linear regression revealed that the developed 33-item FI showed an independent association with age, female sex, higher body mass index, family history of epilepsy, intellectual disability, and the number of ASMs used. A robust analysis of covariance showed higher FI levels in patients using cytochrome P450 3A4-inducer ASMs. We found a moderate positive correlation between FI and psychological distress, lower quality of life, and physical frailty, measured by the Hospital Anxiety and Depression Scale, Quality of Life in Epilepsy Inventory-10, and handgrip strength, respectively. Finally, a weak association was observed between higher FI scores and an increased number of epileptic falls., Significance: This study highlights the significance of frailty as a comprehensive health measure in epilepsy. It suggests that frailty in this specific population is not only a manifestation of aging but is inherently linked to epilepsy and treatment-related factors. Future research is warranted to validate and refine the FI in diverse epilepsy populations and investigate its impact on specific adverse outcomes in longitudinal studies., (© 2024 International League Against Epilepsy.)

Background and Purpose: The aim was to determine whether frailty is associated with the relationship between neuropsychological markers and global cognition in older adults., Methods: Cross-sectional analyzes were conducted of baseline data from three large cohort studies: National Alzheimer's Coordinating Center (NACC), Rush Memory and Aging Project (MAP) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Studies recruited North American participants along the spectrum of cognitive functioning (44% no cognitive impairment at baseline). A frailty index was computed in each dataset. Frailty indices, neuropsychological tests (including measures of processing speed, episodic, semantic and working memory) and Mini-Mental State Examination (MMSE) scores were the variables of interest, with age, sex, education and apolipoprotein E ε4 evaluated as confounders., Results: Across all studies, 23,819 participants aged 55-104 (57% female) were included in analyzes. Frailty index scores were significantly and inversely associated with MMSE scores and significantly moderated relationships between neuropsychological test scores and MMSE scores. In participants with higher frailty index scores, lower neuropsychological test scores were more strongly associated with lower MMSE scores (standardized interaction coefficients ranged from -0.19 to -1.17 in NACC, -0.03 to -2.27 in MAP and -0.04 to -0.38 in ADNI, depending on the neuropsychological test). These associations were consistent across the different databases and were mostly independent of the composition of frailty indices (i.e., after excluding possible symptoms of dementia)., Conclusions: Amongst older Americans, frailty is associated with the cognitive expression of neuropsychological deficits. Implementation of frailty assessment in routine neurological and neuropsychological practice should be considered to optimize care outcomes for older adults., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: Reciprocal connections exist between mental health and physical health, and conditions of cellular senescence/advanced biological age have been observed in association with certain psychiatric diseases. However, the construct of frailty has only preliminarily been explored in young adults and in relation to psychopathology so far. In the present study we aimed at further elucidating the relationships linking psychopathological phenomena with physical diseases in a sample of young adults., Methods: The sample was made of 527 Italian young adults (age range: 18-34). Participants were assessed on clinical/socio-demographic information as well as on the following measures: an ad hoc designed Frailty Index (FI), the Brief Symptroms Inventory (BSI), the Relationship Questionnaire (RQ), and the Childhood Trauma Questionnaire (CTQ)., Results: Individuals with clinically-relevant psychopathological symptoms (based on established BSI cut-off scores) showed significantly higher FI values than individuals without clinically-relevant psychopathological symptoms (p<0.001). Higher levels of childhood traumatic experiences and higher levels of insecure forms of attachment were significantly associated with higher FI scores. The severity of preoccupied attachment style was significantly independently associated with higher FI scores also when multiple confounding variables were controlled for., Discussion: Our findings provide novel pieces of insight on the complex relationship of frailty, conceptualized as a measure of deficit accumulation and an indicator of functional status and biological age, with psychopathology, childhood traumas and insecure attachment, with potential implications for the clinical management of young individuals., Competing Interests: All authors declare non conflicts of interest in relation to this manuscript.

Background: Frailty is an age-related state of increased risk for health-related adverse outcomes that reflects multisystem physiological changes and likely influences the clinical expression and disease progression of neurodegenerative disorders. The aim of the present study was to assess the potential relationship between frailty, as assessed by a frailty index (FI), and motor symptom severity, motor subtypes, and non-motor domains in Parkinson's disease (PD)., Methods: We consecutively enrolled 150 PD patients. We administered an FI specifically designed for PD that included 50 age-related multidimensional biological deficits. Patients underwent a clinical assessment that evaluated motor and non-motor manifestations of PD. Using the FI score, we classified PD patients as relatively fit (FI ≤ 0.10), less fit (0.10 < FI ≤ 0.21), or frail (FI > 0.21). A linear regression model was designed to explore possible associations between frailty level and PD motor and non-motor manifestations., Results: Frail patients showed greater motor symptom severity and motor complications than fitter patients. A trend towards a higher prevalence of the postural instability/gait disorder subtype was also observed in frail versus relatively fit and less fit patients. The global burden of non-motor symptoms was higher in frail patients. Increased frailty was associated with more severe motor and non-motor symptoms, as well as with more pronounced cognitive deficits. These associations remained significant even when "traditional" predictors of PD severity (age, disease duration, and levodopa equivalent daily dose) were considered., Conclusions: The present findings indicate that the FI is associated with both motor and non-motor features of PD., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Studies increasingly suggest that chronic exposure to psychological stress can lead to health deterioration and accelerated ageing, thus possibly contributing to the development of frailty. Recent approaches based on the deficit accumulation model measure frailty on a continuous grading through the "Frailty Index" (FI), i.e. a macroscopic indicator of biological senescence and functional status., Objectives: The study aimed at testing the relationship of FI with caregiving, psychological stress, and psychological resilience., Design: Cross-sectional study, with case-control and correlational analyses., Participants: Caregivers of patients with dementia (n=64), i.e. individuals a priori considered to be exposed to prolonged psychosocial stressors, and matched controls (n=64) were enrolled., Measurements: The two groups were compared using a 38-item FI condensing biological, clinical, and functional assessments. Within caregivers, the association of FI with Perceived Stress Scale (PSS) and Brief Resilience Scale (BRS) was tested., Results: Caregivers had higher FI than controls (F=8.308, p=0.005). FI was associated directly with PSS (r=0.660, p<0.001) and inversely with BRS (r=-0.637, p<0.001). Findings remained significant after adjusting for certain confounding variables, after excluding from the FI the conditions directly related to psychological stress, and when the analyses were performed separately among participants older and younger than 65 years., Conclusions: The results provide insight on the relationship of frailty with caregiving, psychological stress, and resilience, with potential implications for the clinical management of individuals exposed to chronic emotional strain., Competing Interests: The authors do not have conflicts of interest to declare.

Background: Frailty is an age-related status of increased vulnerability to stressors caused by the accumulation of multiple health deficits. This construct may allow to capture the clinical complexity of patients with multiple sclerosis (MS)., Objective: To investigate the relationship between frailty and the clinical manifestations of MS., Methods: Patients with MS were consecutively enrolled at five tertiary dedicated services. Disability and fatigue were assessed. The phenotypes of MS were also identified. Frailty was measured using a frailty index (FI), computed by cumulatively considering 42 age-related multidimensional health deficits., Results: Overall, 745 MS patients (mean age = 48.2 years, standard deviation = 11.7 years; women 68%) were considered. The median FI value was 0.12 (interquartile range = 0.05-0.19) and the 99th percentile was 0.40. FI scores were associated with MS disease duration, disability, fatigue, as well as with the number of previous disease-modifying treatments and current symptomatic therapies. A logistic regression analysis model showed that FI score was independently associated with the secondary progressive phenotype., Conclusion: Frailty is significantly associated with major characteristics of MS. The findings of the present cross-sectional investigation should be explored in future longitudinal studies.

The present study aimed at investigating if the main biomarkers of Alzheimer's disease (AD) neuropathology and their association with cognitive disturbances and dementia are modified by the individual's frailty status. We performed a cross-sectional analysis of data from participants with normal cognition, mild cognitive impairment (MCI), and AD dementia enrolled in the Alzheimer's Disease Neuroimaging Initiative 2 (ADNI2) study. Frailty was operationalized by computing a 40-item Frailty Index (FI). The following AD biomarkers were considered and analyzed according to the participants' frailty status: CSF Aβ 1-42 , 181 P-tau, and T-tau; MRI-based hippocampus volume; cortical glucose metabolism at the FDG PET imaging; amyloid deposition at the 18 F-AV-45 PET imaging. Logistic regression models, adjusted for age, sex, and education, were performed to explore the association of biomarkers with cognitive status at different FI levels. Subjects with higher FI scores had lower CSF levels of Aβ 1-42 , hippocampus volumes at the MRI, and glucose metabolism at the FDG PET imaging, and a higher amyloid deposition at the 18 F-AV-45 PET. No significant differences were observed among the two frailty groups concerning ApoE genotype, CSF T-tau, and P-tau. Increasing frailty levels were associated with a weakened relationship between dementia and 18 F-AV-45 uptake and hippocampus volume and with a stronger relationship of dementia with FDG PET. Frailty contributes to the discrepancies between AD pathology and clinical manifestations and influences the association of AD pathological modifications with cognitive changes. AD and dementia should increasingly be conceived as "complex diseases of aging," determined by multiple, simultaneous, and interacting pathophysiological processes.

Background: Serious mental illnesses may be characterized by accelerated biological aging, and over the last years the research on the topic has been stimulated by studies exploring the molecular underpinnings of senescence., Methods: In the present manuscript we propose that measuring frailty, a general product of organismal ageing, through the "Frailty Index" (FI), a recently-emerged macroscopic indicator of functional status and biological age, adds an important marker to the measurements currently implemented in the study of accelerated biological age in psychiatric illnesses., Results: The FI quantifies functional negative health attributes and measures their cumulative effect, thus providing a useful estimate of the individual's biological age and risk profile. Recent studies in older adults have observed significant associations between FI and molecular measures of aging., Limitations: High FI values can be driven by causes different from aging per se, so FI may be a sensitive but not specific measure of biological aging., Conclusions: FI, which is extensively used in geriatrics and gerontology but it has rarely been used in relation to mental health, may be of relevance in the evaluation of age-related phenomena associated with psychiatric diseases., Competing Interests: Declaration of Competing Interest All authors have no actual or past potential conflict of interest to disclose, including any financial, personal or other relationships with other people or organizations that could inappropriately have influenced the results presented in this paper., (Copyright © 2020. Published by Elsevier B.V.)

In the present study, we explored the relationship between multimorbidity and frailty in a population of older individuals with cognitive disturbances attending a memory clinic. All subjects consecutively attending the Memory Clinic of the Department of Human Neuroscience, "Sapienza" University of Rome, between January 2017 and April 2018 for a first neurological evaluation were considered for the present analysis. Multimorbidity was defined as the simultaneous presence of two or more diseases in the same individual. A Frailty Index was computed by considering 44 age-related, multidimensional health deficits. Overall, 185 subjects were recruited in the study. A condition of multimorbidity was detected in 87.6% of the sample, whereas only the 44.6% of the study population was considered as frail. A poor agreement was observed between multimorbidity and frailty. The present findings confirm that counting diseases or health deficits may provide discordant information concerning the risk profile of older subjects.

Frailty is defined as a decline in an organism's physiological reserves resulting in increased vulnerability to stressors. In humans, a single continuous variable, the so-called Frailty Index (FI), can be obtained by multidimensionally assessing the biological complexity of an ageing organism. Here, we evaluate this variability in dogs and compare it to the data available for humans. In dogs, there was a moderate correlation between age and the FI, and the distribution of the FI increased with age. Deficit accumulation was strongly related to mortality. The effect of age, when combined with the FI, was negligible. No sex-related differences were evident. The FI could be considered in epidemiological studies and/or experimental trials to account for the potential confounding effects of the health status of individual dogs. The age-related deficit accumulation reported in dogs is similar to that demonstrated in humans. Therefore, dogs might represent an excellent model for human aging studies.

Neuropsychological tests, besides reflecting the cognitive reserves and deficits of the tested individual, might also be differently affected by his/her underlying biological asset. In this context, the construct of frailty may offer an opportunity for better weighting the results of traditional tests. We evaluated the relationships between a set neuropsychological measures and a 35-item Frailty Index (FI). The role played by the FI in the relationship between neuropsychological tests and global cognition was also explored. Data from the first neurological and neuropsychological assessments of 79 subjects attending our university memory clinic because complaining cognitive disturbances were considered for the present analysis. A statistically significant correlation between FI and Trail Making Test-B was observed (Spearman's rho 0.33; p = 0.02). The relationship between the performance at the Rey Complex Figure and global cognition (as measured by the Mini Mental State Examination) was influenced by the FI. In fact, participants with higher FI levels had a weakened association linking constructional/visual memory abilities and general cognitive functioning. The interpretation of the neuropsychological assessment can be biased by the frailty status of the tested individual. It can be hypothesized the need of developing new models of correction, that may better reflect the person's biology and complexity., (Copyright © 2019 Elsevier B.V. All rights reserved.)