Improved Assessment of Overall Health in Variably Aged Murine Models of Multiple Sclerosis With a Novel Frailty Index Tool.

The experimental autoimmune encephalomyelitis (EAE) model is the most commonly used animal model of multiple sclerosis (MS). However, phenotypic characterization of mice based on the traditional 5-point clinical paralysis scale does not fully capture disease progression. The frailty index (FI) conceptualizes frailty as the accumulation of health deficits and it is widely used to assess overall health in aging humans and preclinical models. Here, we adapted an established mouse FI tool for use in EAE mice and determined whether this could evaluate general signs of health in variably aged female EAE mice. The EAE-Clinical FI included 34 items related to clinical signs and deficits characteristic of aging and MS. This tool clearly showed more detailed EAE progression and severity at all ages, highlighting changes in systems other than motor paralysis measured with the traditional 5-point paralysis scale. When we induced disease at 3 and 6 months of age, mice showed typical EAE clinical manifestations with peak disease severity between 17 and 19 days post-induction and mean frailty scores of 0.36 ± 0.04 (3-month-old) and 0.43 ± 0.05 (6-month-old). By contrast, disease severity peaked after 14 days in 12-month-old mice. They showed atypical signs including wobbling, early belly drag, and splayed hindlegs that were better captured with the EAE-Clinical FI. Peak frailty scores also were higher than those of younger animals (0.54 ± 0.04). As MS most often develops in young to middle-aged people, this new tool may have significant value for use in EAE animal studies as a first step toward translation to people with MS.

Sex differences in frailty: Comparisons between humans and preclinical models.

Frailty can be viewed as a state of physiological decline that increases susceptibility to adverse health outcomes. This loss of physiological reserve means that even small stressors can lead to disability and death in frail individuals. Frailty can be measured with various clinical tools; the two most popular are the frailty index and the frailty phenotype. Clinical studies have used these tools to show that women are frailer than men even though they have longer lifespans. Still, factors responsible for this frailty-mortality paradox are not well understood. This review highlights evidence for male-female differences in frailty from both the clinical literature and in animal models of frailty. We review evidence for higher frailty levels in female animals as seen in many preclinical models. Mechanisms that may contribute to sex differences in frailty are highlighted. In addition, we review work that suggests frailty may play a role in susceptibility to chronic diseases of aging in a sex-specific fashion. Additional mechanistic studies in preclinical models are needed to understand factors involved in male-female differences in frailty in late life.

Frailty Assessment in Animal Models.

Although frailty has been extensively investigated for the last 2 decades, preclinical models of frailty have only been developed over the past decade. Frailty is a concept that helps to explain the difference between chronologic age and biologic age and to discuss health span along with lifespan. In general, a frail individual will be more susceptible to adverse health outcomes than a healthy, nonfrail individual of the same age. However, the biology and mechanisms of frailty are still unclear. The development of preclinical models of frailty and frailty assessment tools are invaluable to geriatric research. This review briefly describes the concept of frailty and discusses the newly developed animal models of frailty, specifically the frailty phenotype- and frailty index-based models. Mouse models are the most common models for preclinical frailty research, but rat and canine models for frailty assessment have also been developed. These models can facilitate the testing of frailty-specific treatments and help to investigate the effects of various interventions on frailty. Similarities and differences between human and animal models, including sex differences in frailty, are also discussed. The availability of animal models of frailty is a valuable and welcome addition to the study of frailty, aging, or the disorders of old age and will enable a better understanding of frailty mechanisms.

Differences in Cardiovascular Aging in Men and Women.

Cardiovascular diseases increase dramatically with age in both men and women. While it is clear that advanced age allows more time for individuals to be exposed to risk factors in general, there is strong evidence that age itself is a major independent risk factor for cardiovascular disease. Indeed, there are distinct age-dependent cellular, structural, and functional changes in both the heart and blood vessels, even in individuals with no clinical evidence of cardiovascular disease. Studies in older humans and in animal models of aging indicate that this age-related remodeling is maladaptive. An emerging view is that the heart and blood vessels accumulate cellular and subcellular deficits with age and these deficits increase susceptibility to disease in older individuals. Aspects of this age-dependent remodeling of the heart and blood vessels differ between the sexes. There is also new evidence that these maladaptive changes are more prominent in older animals and humans with a high degree of frailty. These observations may help explain why men and women are susceptible to different cardiovascular diseases as they age and why frail older adults are most often affected by these diseases.

A Comparison of Two Mouse Frailty Assessment Tools.

The mouse clinical frailty index and the mouse frailty phenotype assessment are two recently developed tools used to assess frailty in mice. The objectives of this study were to investigate whether the same mice are identified as frail with both tools and to examine the association of each of the assessment tools with age and frailty-related outcomes. Frailty was measured using both tools in old (~24 months; n = 36) C57BL/6 male mice. After 2 weeks, blood pressure and heart rate were measured and serum samples were collected for analysis of alanine aminotransferase, creatinine, and albumin levels. The mouse frailty phenotype assessment identified no mice as frail but modification of the assessment tool identified six mice as frail. The mouse clinical frailty index identified 16 mice as frail and the agreement between the two scales was 50.0%. Increasing clinical frailty index scores were correlated with low serum alanine aminotransferase, as well as decreased heart rate, and reduced heart rate variance. We conclude that, consistent with equivalent frailty assessment scales in humans, both tools have value but do not necessarily identify the same mice as frail.

Clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale change in relation to goal attainment in patients on cholinesterase inhibitors.

INTRODUCTION: The clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4-point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses. METHODS: This exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of ±3 points and/or functional improvement. RESULTS: Patients with ≥3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog "no change" (≤±3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5-19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14-0.64). DISCUSSION: ADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN26167328.

Heterogeneity of Human Aging and Its Assessment.

Understanding the heterogeneity in health of older adults is a compelling question in the biology of aging. We analyzed the performance of five measures of health heterogeneity, judging them by their ability to predict mortality. Using clinical and biomarker data on 1,013 participants of the Canadian Study of Health and Aging who were followed for up to 6 years, we calculated two indices of biological age using the Klemera and Doubal method, which controversially includes using chronological age as a "biomarker," and three frailty indices (FIs) that do not include chronological age: a standard clinical FI, an FI from standard laboratory blood tests and blood pressure, and their combination (FI-combined). Predictive validity was tested using Cox proportional hazards analysis and discriminative ability by the area under the receiver-operating characteristic curves. All five measures showed moderate performance that was improved by combining measures to evaluate larger numbers of items. The greatest addition in explanatory power came from the FI-combined that showed the best mortality prediction in an age-adjusted model. More extensive comparisons across different databases are required, but these results do not support including chronological age as a biomarker.

Assessment of Frailty in Animal Models.

Animal models have contributed greatly to our understanding of the biology of aging and have been used to test new potential interventions to enhance survival. However, whether these interventions can modify frailty in animals is not yet clear, in part because until recently, frailty had not been considered in animal studies of aging. This review is focused on investigations that have attempted to address the issue of frailty, or aspects of frailty, in animal models, including invertebrate and vertebrate models. Some studies have used skeletal muscle weakness or sarcopenia as a surrogate for frailty in aging animals. Others have used genetically altered mice, in which components of human frailty such as inflammation are enhanced. This review also explores a novel approach to quantify frailty with a 'frailty index' based on deficit accumulation in aging animals. The concept of the frailty index is well established in the clinical literature, but recent work suggests that this approach can also be used to measure frailty in aging animals. The ability to quantify frailty in animals is a major step forward in the effort to understand the biology of frailty and to develop new clinical interventions.

Reliability of a Frailty Index Based on the Clinical Assessment of Health Deficits in Male C57BL/6J Mice.

We investigated the reliability of a newly developed clinical frailty index (FI) that measures frailty based on deficit accumulation in aging mice. FI scores were measured by two different raters independently in a large cohort (n = 233) of 343-430 day-old male C57BL/6J mice. Inter-rater reliability was evaluated with correlation coefficients, the kappa statistic, and intra-class correlation coefficients (ICC) in three separate groups of mice (n = 45, 50, and 138 mice/group) sequentially over 3 months. After each group was evaluated, descriptions of techniques used to identify health deficits were amended. Mice had comparable overall FI scores regardless of rater (0.213±0.002 vs 0.212±0.002; p = .802), although discordant measures declined as techniques were refined. Correlation coefficients (r (2) values) between raters improved throughout the study and mean kappa values increased (mean ± SEM; 0.621±0.018, 0.764±0.017, and 0.836±0.009 for groups 1, 2, and 3; p < .05). Values for intra-class correlation coefficient also improved from .51 (95% confidence interval = 0.11-.73) to .74 (0.54-0.85) and .77 (0.67-.83). FI scores increased over 3 months (p < .05), but did not differ between raters. These results show a high overall inter-rater reliability when the clinical FI tool is used to assess frailty in a large cohort of mice.

New horizons in frailty: ageing and the deficit-scaling problem.

All the current frailty measures count deficits. They differ chiefly in which items, and how many, they consider. These differences are related: if a measure considers only a few items, to define broad risks those items need to integrate across several systems (e.g. mobility or function). If many items are included, the cumulative effect of small deficits can be considered. Even so, it is not clear just how small deficits can be. To better understand how the scale of deficit accumulation might impact frailty measurement, we consider how age-related, subcellular deficits might become macroscopically visible and so give rise to frailty. Cellular deficits occur when subcellular damage has neither been repaired nor cleared. With greater cellular deficit accumulation, detection becomes more likely. Deficit detection can be done by either subclinical (e.g. laboratory, imaging, electrodiagnostic) or clinical methods. Not all clinically evident deficits need cross a disease threshold. The extent to which cellular deficit accumulation compromises organ function can reflect not just what is happening in that organ system, but deficit accumulation in other organ systems too. In general, frailty arises in relation to the number of organ systems in which deficits accumulate. This understanding of how subcellular deficits might scale has implications for understanding frailty as a vulnerability state. Considering the cumulative effects of many small deficits appears to allow important aspects of the behaviour of systems close to failure to be observed. It also suggests the potential to detect frailty with less reliance on clinical observation than current methods employ.