Sex Moderates the Association between Frailty and Mild Behavioral Impairment.

BACKGROUND: Frailty has been associated with cognitive markers of dementia but its relationship with behavioral markers of dementia are poorly understood. OBJECTIVES: To investigate the association between frailty and mild behavioral impairment (MBI), and whether this association is moderated by sex. DESIGN: Cross-sectional observational study. PARTICIPANTS/SETTING: 219 non-dementia participants (cognitively normal and mild cognitive impairment) from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. MEASUREMENTS: Frailty was measured using the frailty index (FI) with higher scores indicating more health deficits/greater frailty. MBI symptoms were derived from Neuropsychiatric Inventory Questionnaire scores using a published algorithm with a cut-off of >0 indicating MBI symptom presence and higher scores indicating greater severity. Multivariable logistic and linear regressions adjusted for age, sex, education, and cognitive diagnosis were used to test the association between FI and MBI symptom presence and severity, respectively, with MBI as the outcome variable. An FI-by-sex interaction term was included to test for sex-dependent effects. RESULTS: The FI mean and SD across the entire cohort was 0.14 ± 0.06 (median = 0.14, IQR = 0.09-0.17, range = 0.02-0.38). Higher FI scores were associated with the presence of MBI symptoms both globally and in the domains of decreased motivation, affective dysregulation, and psychosis. Higher FI scores were also associated with more severe MBI symptoms in a sex-dependent manner: both sexes reported similarly low MBI symptom severity at low (-1 SD) levels of FI but males reported 1.9x higher MBI symptom severity relative to females at high (+1 SD) levels of FI. CONCLUSIONS: The FI is associated with both the presence and severity of MBI, especially for males. This suggests that screening for early dementia risk should incorporate assessments of MBI for patients with frailty, and assessments of frailty for patients with MBI.

Moving Towards Common Data Elements and Core Outcome Measures in Frailty Research.

With aging populations around the world, frailty is becoming more prevalent increasing the need for health systems and social systems to deliver optimal evidence based care. However, in spite of the growing number of frailty publications, high-quality evidence for decision making is often lacking. Inadequate descriptions of the populations enrolled including frailty severity and frailty conceptualization, lack of use of validated frailty assessment tools, utilization of different frailty instruments between studies, and variation in reported outcomes impairs the ability to interpret, generalize and implement the research findings. The utilization of common data elements (CDEs) and core outcome measures (COMs) in clinical trials is increasingly being adopted to address such concerns. To catalyze the development and use of CDEs and COMs for future frailty studies, the Canadian Frailty Network (www.cfn-nce.ca; CFN), a not-for-profit pan-Canadian nationally-funded research network, convened an international group of experts to examine the issue and plan the path forward. The meeting was structured to allow for an examination of current frailty evidence, ability to learn from other COMs and CDEs initiatives, discussions about specific considerations for frailty COMs and CDEs and finally the identification of the necessary steps for a COMs and CDEs consensus initiative going forward. It was agreed at the onset of the meeting that a statement based on the meeting would be published and herein we report the statement.

An MDS-specific frailty index based on cumulative deficits adds independent prognostic information to clinical prognostic scoring.

The frailty index (FI) is based on the principle that the more deficits an individual has, the greater their risk of adverse outcomes. It is expressed as a ratio of the number of deficits present to the total number of deficits considered. We developed an MDS-specific FI using a prospective MDS registry and assessed its ability to add prognostic power to conventional prognostic scores in MDS. The 42 deficits included in this FI included measurements of physical performance, comorbidities, laboratory values, instrumental activities of daily living, quality of life and performance status. Of 644 patients, 440 were eligible for FI calculation. The median FI score was 0.25 (range 0.05-0.67), correlated with age and IPSS/IPSS-R risk scores and discriminated overall survival. With a follow-up of 20 months, survival was 27 months (95% CI 24-30.4). By multivariate analysis, age >70, FI, transfusion dependence, and IPSS were significant covariates associated with OS. The incremental discrimination improvement of the frailty index was 37%. We derived a prognostic score with five risk groups and distinct survivals ranging from 7.4 months to not yet reached. If externally validated, the MDS-FI could be used as a tool to refine the risk stratification of current clinical prognostication models.

Bed rest and accelerated aging in relation to the musculoskeletal and cardiovascular systems and frailty biomarkers: A review.

Prolonged bed rest and lifelong physical inactivity cause deleterious effects to multiple physiological systems that appear to hasten aging processes. Many such changes are similar to those seen with microgravity in space, but at a much faster rate. Head down tilt bed rest models are used to study whole-body changes that occur with spaceflight. We propose that bed rest can be used to quantify accelerated human aging in relation to frailty. In particular, frailty as a measure of the accumulation of deficits estimates the variability in aging across systems, and moves away from the traditional single-system approach. Here, we provide an overview of the impact of bed rest on the musculoskeletal and cardiovascular systems as well as frailty-related biological markers and inflammatory cytokines. We also propose future inquiries to study the accumulation of deficits with head down bed rest and bed rest in the clinical setting, specifically to understand how unrepaired and unremoved subclinical and subcellular damage give rise to clinically observable health problems.

Proceedings of the Canadian Frailty Network Workshop: Identifying Biomarkers of Frailty to Support Frailty Risk Assessment, Diagnosis and Prognosis. Toronto, January 15, 2018.

The Canadian Frailty Network (CFN), a pan-Canadian not-for-profit organization funded by the Government of Canada through the Networks of Centres of Excellence Program, is dedicated to improving the care of older Canadians living with frailty. The CFN has partnered with the Canadian Longitudinal Study on Aging (CLSA) to measure potential frailty biomarkers in biological samples (whole blood, plasma, urine) collected in over 30,000 CLSA participants. CFN hosted a workshop in Toronto on January 15 2018, bringing together experts in the field of biomarkers, aging and frailty. The overall objectives of the workshop were to start building a consensus on potential frailty biomarker domains and identify specific frailty biomarkers to be measured in the CLSA biological samples. The workshop was structured with presentations in the morning to frame the discussions for the afternoon session, which was organized as a free-flowing discussion to benefit from the expertise of the participants. Participants and speakers were from Canada, Italy, Spain, United Kingdom and the United States. Herein we provide pertinent background information, a summary of all the presentations with key figures and tables, and the distillation of the discussions. In addition, moving forward, the principles CFN will use to approach frailty biomarker research and development are outlined. Findings from the workshop are helping CFN and CLSA plan and conduct the analysis of biomarkers in the CLSA samples and which will inform a follow-up data access competition.

Can a Prebiotic Formulation Reduce Frailty Levels in Older People?

OBJECTIVE: The purpose of this study was to examine whether a prebiotic formulation reduces frailty index (FI) levels in older people. DESIGN: We conducted secondary analysis of a placebo-controlled, randomized, double-blind design study. SETTING/PARTICIPANTS: The study included non-demented people over the age of 65 who were living in nursing homes and were able to walk. Fifty participants completed the study (75.3±7.3 years, 70% females). INTERVENTION: Participants were randomly assigned to either a group who received daily Darmocare Pre® (inulin and fructooligosaccharides) for 13 weeks or a placebo group (maltodextrin). MEASUREMENT: The primary outcome in this secondary analysis was change in level of a 62-item FI compared to baseline. RESULTS: At the 13-week follow-up, the placebo group had higher FI levels (preFI 0.23±0.11, postFI 0.24±0.12, p=0.012) and the intervention group had lower FI levels (preFI 0.22±0.09, postFI 0.20±0.08, p<0.001). There was an average increase of 0.01±0.01 in the FI score in the placebo group (0.4 deficits; Cohen's d 0.61; standardized response mean 0.59) and an average reduction of 0.02±0.02 in the intervention group (1.1 deficits; Cohen's d -1.35; standardized response mean -1.16). Among the 28 participants in the intervention group, FI levels were reduced for 25 people; five of them had an FI reduction greater than 0.03. The moderately/severely frail participants (FI >0.3, N=5) had the greatest reduction in their FI (0.04±0.01). CONCLUSION: A prebiotic intervention can reduce frailty levels in nursing home residents especially in those with higher levels of frailty.

Subjective memory complaints and incident dementia in a high risk older adult hypertensive population.

BACKGROUND: there is a growing body of evidence demonstrating an association between subjective memory complaints (SMC) and an increased risk of incident cognitive decline or dementia. To date this has not been examined in hypertensive older adults, a prevalent and growing population group at high risk of cognitive decline. METHODS: using data from participants in the Hypertension in the Very Elderly Trial cohort the association between baseline SMC and incident cognitive decline and dementia was examined using Cox proportional hazard regression. Cognitive function was assessed using the Mini-Mental State Exam and diagnoses of dementia were made using standard diagnostic criteria. SMC was assessed by the question 'do you feel that you have more problems with memory than most?' Analyses were rerun to examine the associations by level of baseline cognitive function, to evaluate the role of SMC by dementia type and by sex. RESULTS: baseline SMC were associated with an increased risk of developing any dementia (hazard ratio (HR)1.63 (95% confidence intervals (CI): 1.18:2.25)), Alzheimer's disease (HR1.59 (95% CI: 1.08:2.34)) and vascular dementia (HR2.05 (95% CI: 1.19:3.54)). Similar patterns were seen across all levels of baseline MMSE but were strongest in those with scores of 25-27. There were no clear differences by sex. DISCUSSION: a positive report of SMC assessed by a single question in an older adult with hypertension raises the possibility of increased risk of incident dementia. As such its use may be a useful addition to the repertoire of the general practitioner and geriatrician when assessing older adults.

Social and societal implications of frailty, including impact on Canadian healthcare systems.

Frailty has many social and societal implications. Social circumstances are key both as contributors to frail older adults' health outcomes and as practical facilitators or barriers to intervention and supports. Frailty also has important societal implications for health systems and social care policy. In this discussion paper, we use a social ecology framework to consider the social and societal implications and impact of frailty at each level, from the individual, through relationships with family and friend caregivers, institutions, health systems, neighborhoods and communities, to society at large. We conclude by arguing that attention to these issues at a policy level is critical. We identify three target actions: 1) Social dimensions of frailty should be systematically considered when frailty is assessed. 2) Action is needed at the level of policies and programs to improve support for caregivers. 3) Policy review across all portfolios will benefit from a social frailty lens.

Goal Attainment Scaling for haemophilia (GAS-Hem): testing the feasibility of a new patient-centric outcome measure in people with haemophilia.

INTRODUCTION: To address the need for a patient-reported outcome that can measure clinically and personally meaningful change in people with haemophilia (PwH) on prophylaxis, an approach based on Goal Attainment Scaling (GAS) was developed: the GAS-Hem. AIM: To establish real-world feasibility of GAS-Hem in PwH. METHODS: Patients aged 5-65 years were enroled from four North American centres for a 12-week study. The primary outcome was the proportion of participants who completed GAS-Hem interviews at baseline, 6 and 12 weeks. GAS-Hem scores were obtained by subject- and clinician-rated goal attainment at Weeks 6 and 12, and compared with quality of life (QoL) measures and annualized bleed rate (ABR) for construct validity. Goals were evaluated qualitatively for content validity. Responsiveness was calculated using standardized response means (SRM). RESULTS: Forty-two participants set 63 goals. Participants preferred to define (37/63) their own goals or further individualize (23/63) from the GAS-Hem menu. Thirty of the 37 self-defined goals were matched to goals on the GAS-Hem menu. The most common goal areas were: weight, exercise and nutrition (n = 17); leisure activities (n = 8); and joint problems (n = 7). Both participant- and clinician-rated GAS-Hem scores at 6 weeks (n = 40) and 12 weeks (n = 41) demonstrated satisfactory goal attainment (SRM [subject-rated] at 12 weeks for adult and paediatric groups was 1.25 and 1.16, respectively). Correlations of GAS-Hem scores with QoL measures and ABR were uniformly small. CONCLUSION: GAS-Hem was feasible and tapped constructs not captured by ABR or QoL measures.

Correlates of frailty phenotype and frailty index and their associations with clinical outcomes.

OBJECTIVES: Frailty is a predictor of adverse health outcomes and can be measured across the life course, including among people living with HIV. The purpose of this study was to examine two commonly used measures of frailty - the frailty index (FI) and frailty phenotype - to assess common characteristics and to describe associations with multimorbidity, falls, and disability in people aging with HIV. METHODS: This was a cross-sectional observational study including 482 consecutive HIV-infected patients (mean age 53.9 ± SD 6.9 years; 75% male) attending the multidisciplinary metabolic clinic at the University of Modena, Italy. Frailty was measured with the frailty phenotype and a 37-item FI. RESULTS: The mean FI score was 0.28±0.1 and frailty phenotype categories were: 3.1% frail, 51.9% pre-frail, and 45% robust. The duration of antiretroviral therapy was significantly different across levels of frailty as measured by both frailty tools (P < 0.01), but the nadir CD4 count was only significant for the FI (P = 0.01); current CD4 count was not significantly different across frailty levels using either tool. Both frailty measures were associated with multimorbidity; the FI was associated with Instrumental Activities of Daily Living impairment and falls history, whereas the frailty phenotype was not. CONCLUSIONS: The frailty phenotype and the FI demonstrated similar characteristics in patients at a tertiary-level HIV clinic. The FI had a stronger association with age, nadir CD4 count, comorbidities, falls, and disability. Integrating frailty assessments in clinical practice will be crucial for the development of interventions in age-related conditions, including disability and falls, in older persons living with HIV.

Aging, frailty and complex networks.

When people age their mortality rate increases exponentially, following Gompertz's law. Even so, individuals do not die from old age. Instead, they accumulate age-related illnesses and conditions and so become increasingly vulnerable to death from various external and internal stressors. As a measure of such vulnerability, frailty can be quantified using the frailty index (FI). Larger values of the FI are strongly associated with mortality and other adverse health outcomes. This association, and the insensitivity of the FI to the particular health variables that are included in its construction, makes it a powerful, convenient, and increasingly popular integrative health measure. Still, little is known about why the FI works so well. Our group has recently developed a theoretical network model of health deficits to better understand how changes in health are captured by the FI. In our model, health-related variables are represented by the nodes of a complex network. The network has a scale-free shape or "topology": a few nodes have many connections with other nodes, whereas most nodes have few connections. These nodes can be in two states, either damaged or undamaged. Transitions between damaged and non-damaged states are governed by the stochastic environment of individual nodes. Changes in the degree of damage of connected nodes change the local environment and make further damage more likely. Our model shows how age-dependent acceleration of the FI and of mortality emerges, even without specifying an age-damage relationship or any other time-dependent parameter. We have also used our model to assess how informative individual deficits are with respect to mortality. We find that the information is larger for nodes that are well connected than for nodes that are not. The model supports the idea that aging occurs as an emergent phenomenon, and not as a result of age-specific programming. Instead, aging reflects how damage propagates through a complex network of interconnected elements.

A Frailty Index Based On Deficit Accumulation Quantifies Mortality Risk in Humans and in Mice.

Although many common diseases occur mostly in old age, the impact of ageing itself on disease risk and expression often goes unevaluated. To consider the impact of ageing requires some useful means of measuring variability in health in animals of the same age. In humans, this variability has been quantified by counting age-related health deficits in a frailty index. Here we show the results of extending that approach to mice. Across the life course, many important features of deficit accumulation are present in both species. These include gradual rates of deficit accumulation (slope = 0.029 in humans; 0.036 in mice), a submaximal limit (0.54 in humans; 0.44 in mice), and a strong relationship to mortality (1.05 [1.04-1.05] in humans; 1.15 [1.12-1.18] in mice). Quantifying deficit accumulation in individual mice provides a powerful new tool that can facilitate translation of research on ageing, including in relation to disease.

Is it better to be happy or not depressed? Depression mediates the effect of psychological well-being on adverse health outcomes in older adults.

OBJECTIVES: To examine the relationship between psychological well-being and depression in older adults and the relative contribution these psychological factors have on risk of functional disability, frailty, and mortality. METHODS: This is a secondary analysis of 1668 community-dwelling older adults without dementia who participated in the second wave of the Canadian Study of Health and Aging. Baseline assessments of psychological well-being (Ryff scale) and depression (Geriatric Depression Scale; GDS) were collected. At 5-year follow-up, mortality data were collected; frailty and disability in activities of daily living were evaluated using the frailty index (FI) and the Lawton-Brody scale, respectively. RESULTS: Area under the receiver-operating characteristic curve indicated that GDS and Ryff scores were able to independently discriminate whether individuals were considered frail (C = 0.66; C = 0.59, respectively), had limitations in basic (C = 0.64; C = 0.57, respectively) or instrumental (C = 0.70; C = 0.57, respectively) activities of daily living, or had died (C = 0.63; C = 0.57) at follow-up (all P < 0.01). Regression models in which the Ryff and GDS were included in the same model demonstrated that the GDS significantly predicted frailty, disability, and mortality, whereas the Ryff effect was not significant. Mediation analysis determined that the effect of psychological well-being on adverse outcomes was fully mediated by depression. CONCLUSIONS: Our results suggest that although both depression and psychological well-being appear to modulate risk for adverse physical health outcomes, depression mediates this relationship. Detecting and treating depressive symptoms should be of high priority in older patients to mitigate risk of future physical health adversities including mortality. Copyright © 2016 John Wiley & Sons, Ltd.

Can an Intervention with Testosterone and Nutritional Supplement Improve the Frailty Level of Under-Nourished Older People?

OBJECTIVE: To examine whether a testosterone and a high calorie nutritional supplement intervention can reduce frailty scores in undernourished older people using multiple frailty tools. DESIGN: Randomized controlled trial. SETTING/PARTICIPANTS: 53 community-dwelling, undernourished men and women aged >65 years from South Australia, Victoria and New South Wales. INTERVENTION: Intervention group received oral testosterone undecanoate and a high calorie supplement (2108-2416 kJ/day) whereas the control group received placebo testosterone and low calorie supplement (142-191 kJ/day). MEASUREMENTS: Frailty was operationalized using three frailty indices (FI-lab, FI-self-report, FI-combined) and the frailty phenotype. RESULTS: There were no significant differences in changes in frailty scores at either 6 or 12 months follow up between the two treatment groups for all scales. Participants at the intervention group were 4.8 times more likely to improve their FI-combined score at both time points compared to the placebo group. CONCLUSION: A testosterone and a high calorie nutritional supplement intervention did not improve the frailty levels of under-nourished older people. Even so, when frailty was measured using a frailty index combining self-reported and lab data we found that participants who received the intervention were more likely to show persistent improvement in their frailty scores.

Recognizing the need for personalization of haemophilia patient-reported outcomes in the prophylaxis era.

The safety and efficacy of treatment options for patients with haemophilia have significantly improved over the last two decades, particularly with greater utilization of prophylactic approaches. Consequently, it is becoming increasingly difficult to differentiate the treatment benefits of available choices based on standard endpoints such as annualized bleeding rates and joint health scores. Patient-reported outcomes (PROs) have shown limited ability to discriminate between treatment outcomes, in part because of their comprehensive nature; i.e. differences in specific outcomes meaningful to individual patients are masked by a global scoring system based on a fixed set of items, many of which may be unimportant for any given patient. There is a clear need for new outcome measures. Initiatives to develop patient-centric outcomes that capture clinically meaningful change are ongoing. One such approach, goal attainment scaling (GAS), allows patients, in collaboration with a trained clinician, to select goals from a medical condition-specific menu of options and subsequently facilitates quantitative assessment of goal realization. Thus, it is fully personalized and sensitive to small, often idiosyncratic, treatment benefits, such as improvements in functional capacity. In this paper, we present the underlying rationale for GAS and one other novel approach to PRO personalization, and discuss their potential to augment current outcome measures by reliably detecting and quantifying treatment effects in individuals with haemophilia on prophylaxis.

Prevalence of and factors associated with frailty and disability in older adults from China, Ghana, India, Mexico, Russia and South Africa.

BACKGROUND: The severe burden imposed by frailty and disability in old age is a major challenge for healthcare systems in low- and middle-income countries alike. The current study aimed to provide estimates of the prevalence of frailty and disability in older adult populations and to examine their relationship with socioeconomic factors in six countries. METHODS: Focusing on adults aged 50+ years, a frailty index was constructed as the proportion of deficits in 40 variables, and disability was assessed using the World Health Organization Disability Assessment Schedule (WHODAS 2.0), as part of the Study on global AGEing and adult health (SAGE) Wave 1 in China, Ghana, India, Mexico, Russia and South Africa. RESULTS: This study included a total of 34,123 respondents. China had the lowest percentages of older adults with frailty (13.1%) and with disability (69.6%), whereas India had the highest percentages (55.5% and 93.3%, respectively). Both frailty and disability increased with age for all countries, and were more frequent in women, although the sex gap varied across countries. Lower levels of both frailty and disability were observed at higher levels of education and wealth. Both education and income were protective factors for frailty and disability in China, India and Russia, whereas only income was protective in Mexico, and only education in South Africa. CONCLUSIONS: Age-related frailty and disability are increasing concerns for older adult populations in low- and middle-income countries. The results indicate that lower levels of frailty and disability can be achieved for older people, and the study highlights the need for targeted preventive approaches and support programs.

Understanding Risk in the Oldest Old: Frailty and the Metabolic Syndrome in a Chinese Community Sample Aged 90+ Years.

OBJECTIVES: To investigate the relationship between frailty and the metabolic syndrome and to evaluate how these contribute to mortality in very old people. DESIGN: Secondary analysis of data from the Project of Longevity and Aging in Dujiangyan. SETTING: Community sample from Sichuan Province, China. PARTICIPANTS: People aged 90+ years (n=767; baseline age=93.7±3.4 years; 68.0% women. MEASUREMENTS: After a baseline health assessment, participants were followed for four years (54.0% died). A frailty index (FI) was calculated as the sum of deficits present, divided by the 35 health-related deficits considered. Relationships between the FI and the metabolic syndrome were tested; their effect on death was examined. RESULTS: The mean FI was 0.26 ±0.11. Higher FI scores were associated with a greater risk of death, adjusted for age, sex, education, and metabolic syndrome items. The hazard ratio was 1.03 (95% confidence interval 1.02, 1.04) for each 1% percent increase of the FI. The mortality risk did not change with the metabolic syndrome (odds ratio=0.99; 0.71-1.36). CONCLUSIONS: In the oldest old, frailty was a significant risk for near-term death, regardless of the metabolic syndrome. Even using age-adjusted models, the epidemiology of late life illness may need to account for frailty routinely.

Measuring frailty using self-report and test-based health measures.

BACKGROUND: previously, frailty indices were constructed using mostly subjective health measures. The reporting error in this type of measure can have implications on the robustness of frailty findings. OBJECTIVE: to examine whether frailty assessment differs when we construct frailty indices using solely self-reported or test-based health measures. DESIGN: secondary analysis of data from The Irish LongituDinal study on Ageing (TILDA). SUBJECTS AND METHODS: 4,961 Irish residents (mean age: 61.9 ± 8.4; 54.2% women) over the age of 50 years who underwent a health assessment were included in this analysis. We constructed three frailty indices using 33 self-reported health measures (SRFI), 33 test-based health measures (TBFI) and all 66 measures combined (CFI). The 2-year follow-up outcomes examined were all-cause mortality, disability, hospitalisation and falls. RESULTS: all three indices had a right-skewed distribution, an upper limit to frailty, a non-linear increase with age, and had a dose-response relationship with adverse outcomes. Levels of frailty were lower when self-reported items were used (SRFI: 0.12 ± 0.09; TBFI: 0.17 ± 0.15; CFI: 0.14 ± 0.13). Men had slightly higher frailty index scores than women when test-based measures were used (men: 0.17 ± 0.09; women: 0.16 ± 0.10). CFI had the strongest prediction for risk of adverse outcomes (ROC: 0.64-0.81), and age was not a significant predictor when it was included in the regression model. CONCLUSIONS: except for sex differences, characteristics of frailty are similar regardless of whether self-reported or test-based measures are used exclusively to construct a frailty index. Where available, self-reported and test-based measures should be combined when trying to identify levels of frailty.