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1.  A Self-Reported Screening Tool for Detecting Community-Dwelling Older Persons with Frailty Syndrome in the Absence of Mobility Disability: The FiND Questionnaire 
PLoS ONE  2014;9(7):e101745.
Background
The “frailty syndrome” (a geriatric multidimensional condition characterized by decreased reserve and diminished resistance to stressors) represents a promising target of preventive interventions against disability in elders. Available screening tools for the identification of frailty in the absence of disability present major limitations. In particular, they have to be administered by a trained assessor, require special equipment, and/or do not discriminate between frail and disabled individuals. Aim of this study is to verify the agreement of a novel self-reported questionnaire (the “Frail Non-Disabled” [FiND] instrument) designed for detecting non-mobility disabled frail older persons with results from reference tools.
Methodology/Principal Findings
Data are from 45 community-dwelling individuals aged ≥60 years. Participants were asked to complete the FiND questionnaire separately exploring the frailty and disability domains. Then, a blinded assessor objectively measured the frailty status (using the phenotype proposed by Fried and colleagues) and mobility disability (using the 400-meter walk test). Cohen's kappa coefficients were calculated to determine the agreement between the FiND questionnaire with the reference instruments. Mean age of participants (women 62.2%) was 72.5 (standard deviation 8.2) years. Seven (15.6%) participants presented mobility disability as being unable to complete the 400-meter walk test. According to the frailty phenotype criteria, 25 (55.6%) participants were pre-frail or frail, and 13 (28.9%) were robust. Overall, a substantial agreement of the instrument with the reference tools (kappa = 0.748, quadratic weighted kappa = 0.836, both p values<0.001) was reported with only 7 (15.6%) participants incorrectly categorized. The agreement between results of the FiND disability domain and the 400-meter walk test was excellent (kappa = 0.920, p<0.001).
Conclusions/Significance
The FiND questionnaire presents a very good capacity to correctly identify frail older persons without mobility disability living in the community. This screening tool may represent an opportunity for diffusing awareness about frailty and disability and supporting specific preventive campaigns.
doi:10.1371/journal.pone.0101745
PMCID: PMC4084999  PMID: 24999805
2.  Mobility Stress Test Approach to Predicting Frailty, Disability, and Mortality In High Functioning Older Adults 
Background
A major challenge to developing primary preventive interventions for frailty and disability in older adults is lack of validated simple clinical tools to identify high-risk individuals without overt signs of poor health.
Objectives
To examine the validity of the Walking While Talking test (WWT), a mobility stress test, to predict frailty, disability and death in high functioning older adults.
Design
prospective cohort study.
Setting
Community sample.
Participants
631 community-residing adults age 70 and older participating in the Einstein Aging Study (mean follow-up 32 months). High functioning status at baseline was defined as absence of disability, dementia, and normal walking speeds.
Main outcome measures
Hazard ratios for frailty, disability, and all-cause mortality. Frailty was defined as presence of three out of the following five attributes: weight loss, weakness, exhaustion, low physical activity and slow gait. We also compared predictive validity of WWT with Short Physical Performance Battery (SPPB) for study outcomes.
Results
218 subjects developed frailty, 88 disability, and 49 died. Each 10 cm/s decrease in WWT speed was associated with increased risk of frailty (Hazard ratio 1.12, 95% CI 1.06 to 1.18), disability (Hazard ratio 1.13, 95% CI 1.03 −1.23), and mortality (Hazard ratio 1.13, 95% CI 1.01 – 1.27). Most associations remained robust even after accounting for potential confounders and gait speed. Comparisons of HR and model fit suggest that WWT may better predict frailty whereas SPPB may better predict disability.
Conclusion
Mobility stress tests such as the WWT are robust predictors of risk of frailty, disability, and mortality in high functioning older adults.
doi:10.1111/j.1532-5415.2012.04145.x
PMCID: PMC3470773  PMID: 23002714
Mobility; Frailty; Disability; Mortality; Gait
3.  Frailty Intervention Trial (FIT) 
BMC Geriatrics  2008;8:27.
Background
Frailty is a term commonly used to describe the condition of an older person who has chronic health problems, has lost functional abilities and is likely to deteriorate further. However, despite its common use, only a small number of studies have attempted to define the syndrome of frailty and measure its prevalence. The criteria Fried and colleagues used to define the frailty syndrome will be used in this study (i.e. weight loss, fatigue, decreased grip strength, slow gait speed, and low physical activity). Previous studies have shown that clinical outcomes for frail older people can be improved using multi-factorial interventions such as comprehensive geriatric assessment, and single interventions such as exercise programs or nutritional supplementation, but no interventions have been developed to specifically reverse the syndrome of frailty.
We have developed a multidisciplinary intervention that specifically targets frailty as defined by Fried et al. We aim to establish the effects of this intervention on frailty, mobility, hospitalisation and institutionalisation in frail older people.
Methods and Design
A single centre randomised controlled trial comparing a multidisciplinary intervention with usual care. The intervention will target identified characteristics of frailty, functional limitations, nutritional status, falls risk, psychological issues and management of chronic health conditions. Two hundred and thirty people aged 70 and over who meet the Fried definition of frailty will be recruited from clients of the aged care service of a metropolitan hospital. Participants will be followed for a 12-month period.
Discussion
This research is an important step in the examination of specifically targeted frailty interventions. This project will assess whether an intervention specifically targeting frailty can be implemented, and whether it is effective when compared to usual care. If successful, the study will establish a new approach to the treatment of older people at risk of further functional decline and institutionalisation. The strategies to be examined are readily transferable to routine clinical practice and are applicable broadly in the setting of aged care health services.
Trial Registration
Australian New Zealand Clinical Trails Registry: ACTRN12608000250336.
doi:10.1186/1471-2318-8-27
PMCID: PMC2579913  PMID: 18851754
4.  Prevalence and Outcomes of Frailty in Korean Elderly Population: Comparisons of a Multidimensional Frailty Index with Two Phenotype Models 
PLoS ONE  2014;9(2):e87958.
Background
Frailty is related to adverse outcomes in the elderly. However, current status and clinical significance of frailty have not been evaluated for the Korean elderly population. We aimed to investigate the usefulness of established frailty criteria for community-dwelling Korean elderly. We also tried to develop and validate a new frailty index based on a multidimensional model.
Methods
We studied 693 participants of the Korean Longitudinal Study on Health and Aging (KLoSHA). We developed a new frailty index (KLoSHA Frailty Index, KFI) and compared predictability of it with the established frailty indexes from the Cardiovascular Health Study (CHS) and Study of Osteoporotic Fracture (SOF). Mortality, hospitalization, and functional decline were evaluated.
Results
The prevalence of frailty was 9.2% (SOF index), 13.2% (CHS index), and 15.6% (KFI). The criteria from CHS and KFI correlated with each other, but SOF did not correlate with KFI. During the follow-up period (5.6±0.9 years), 97 participants (14.0%) died. Frailty defined by KFI predicted mortality better than CHS index (c-index: 0.713 and 0.596, respectively; p<0.001, better for KFI). In contrast, frailty by SOF index was not related to mortality. The KFI showed better predictability for following functional decline than CHS index (area under the receiver-operating characteristic curve was 0.937 for KFI and 0.704 for CHS index, p = 0.001). However, the SOF index could not predict subsequent functional decline. Frailty by the KFI (OR = 2.13, 95% CI 1.04–4.35) and CHS index (OR = 2.24, 95% CI 1.05–4.76) were associated with hospitalization. In contrast, frailty by the SOF index was not correlated with hospitalization (OR = 1.43, 95% CI 0.68–3.01).
Conclusion
Prevalence of frailty was higher in Korea compared to previous studies in other countries. A novel frailty index (KFI), which includes domains of comprehensive geriatric assessment, is a valid criterion for the evaluation and prediction of frailty in the Korean elderly population.
doi:10.1371/journal.pone.0087958
PMCID: PMC3913700  PMID: 24505338
5.  Preliminary Evidence for Subdimensions of Geriatric Frailty: The MacArthur Study of Successful Aging 
OBJECTIVES
To identify frailty subdimensions.
DESIGN
Longitudinal cohort (MacArthur Study).
SETTING
Three U.S. urban centers.
PARTICIPANTS
One thousand one hundred eighteen high-functioning subjects aged 70 to 79 in 1988.
MEASUREMENTS
Participants with three or more of five Cardiovascular Health Study (CHS) frailty criteria (weight loss, weak grip, exhaustion, slow gait, and low physical activity) in 1991 were classified as having the CHS frailty phenotype. To identify frailty subdimensions, factor analysis was conducted using the CHS variables and an expanded set including the CHS variables, cognitive impairment, interleukin-6 (IL-6), C-reactive protein (CRP), subjective weakness, and anorexia. Participants with four or more of 10 criteria were classified as having an expanded frailty phenotype. Predictive validity of each identified frailty subdimension was assessed using regression models for 4-year disability and 9-year mortality.
RESULTS
Two subdimensions of the CHS phenotype and four subdimensions of the expanded frailty phenotype were identified. Cognitive function was consistently part of a subdimension including slower gait, weaker grip, and lower physical activity. The CHS subdimension of slower gait, weaker grip, and lower physical activity predicted disability (adjusted odds ratio (AOR) =1.7, 95% confidence interval (CI) =1.3–2.2) and mortality (AOR =1.5, 95% CI =1.3–1.8). Subdimensions of the expanded model with predictive validity were higher IL-6 and CRP (AOR =1.2 for mortality); slower gait, weaker grip, lower physical activity, and lower cognitive function (AOR =1.8 for disability; AOR =1.5 for mortality), and anorexia and weight loss (AOR =1.2 for disability).
CONCLUSION
This study provides preliminary empirical support for subdimensions of geriatric frailty, suggesting that pathways to frailty differ and that subdimension-adapted care might enhance care of frail seniors.
doi:10.1111/j.1532-5415.2008.02041.x
PMCID: PMC2754409  PMID: 19016933
frailty; disability; aged; comorbidity
6.  The Lausanne cohort Lc65+: a population-based prospective study of the manifestations, determinants and outcomes of frailty 
BMC Geriatrics  2008;8:20.
Background
Frailty is a relatively new geriatric concept referring to an increased vulnerability to stressors. Various definitions have been proposed, as well as a range of multidimensional instruments for its measurement. More recently, a frailty phenotype that predicts a range of adverse outcomes has been described. Understanding frailty is a particular challenge both from a clinical and a public health perspective because it may be a reversible precursor of functional dependence. The Lausanne cohort Lc65+ is a longitudinal study specifically designed to investigate the manifestations of frailty from its first signs in the youngest old, identify medical and psychosocial determinants, and describe its evolution and related outcomes.
Methods/Design
The Lc65+ cohort was launched in 2004 with the random selection of 3054 eligible individuals aged 65 to 70 (birth year 1934–1938) in the non-institutionalized population of Lausanne (Switzerland). The baseline data collection was completed among 1422 participants in 2004–2005 through questionnaires, examination and performance tests. It comprised a wide range of medical and psychosocial dimensions, including a life course history of adverse events. Outcomes measures comprise subjective health, limitations in activities of daily living, mobility impairments, development of medical conditions or chronic health problems, falls, institutionalization, health services utilization, and death. Two additional random samples of 65–70 years old subjects will be surveyed in 2009 (birth year 1939–1943) and in 2014 (birth year 1944–1948).
Discussion
The Lc65+ study focuses on the sequence "Determinants → Components → Consequences" of frailty. It currently provides information on health in the youngest old and will allow comparisons to be made between the profiles of aging individuals born before, during and at the end of the Second World War.
doi:10.1186/1471-2318-8-20
PMCID: PMC2532683  PMID: 18706113
7.  Productive Activities and Development of Frailty in Older Adults 
Objective.
Our aim was to examine whether engagement in productive activities, including volunteering, paid work, and childcare, protects older adults against the development of geriatric frailty.
Methods.
Data from the first (1988) and second (1991) waves of the MacArthur Study of Successful Aging, a prospective cohort study of high-functioning older adults aged 70–79 years (n = 1,072), was used to examine the hypothesis that engagement in productive activities is associated with lower levels of frailty 3 years later.
Results.
Engagement in productive activities at baseline was associated with a lower cumulative odds of frailty 3 years later in unadjusted models (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.58–0.96) but not after adjusting for age, disability, and cognitive function (adjusted OR = 0.78, 95% CI = 0.60–1.01). Examination of productive activity domains showed that volunteering (but neither paid work nor childcare) was associated with a lower cumulative odds of frailty after adjusting for age, disability, and cognitive function. This relationship diminished and was no longer statistically significant after adjusting for personal mastery and religious service attendance.
Discussion.
Though high-functioning older adults who participate in productive activities are less likely to become frail, after adjusting for age, disability, and cognitive function, only volunteering is associated with a lower cumulative odds of frailty.
doi:10.1093/geronb/gbp105
PMCID: PMC2981447  PMID: 20018794
Productive activities; Volunteering; Frailty
8.  Prospective association of the SHARE-operationalized frailty phenotype with adverse health outcomes: evidence from 60+ community-dwelling Europeans living in 11 countries 
BMC Geriatrics  2013;13:3.
Background
Among the many definitions of frailty, the frailty phenotype defined by Fried et al. is one of few constructs that has been repeatedly validated: first in the Cardiovascular Health Study (CHS) and subsequently in other large cohorts in the North America. In Europe, the Survey of Health, Aging and Retirement in Europe (SHARE) is a gold mine of individual, economic and health information that can provide insight into better understanding of frailty across diverse population settings. A recent adaptation of the original five CHS-frailty criteria was proposed to make use of SHARE data and measure frailty in the European population. To test the validity of the SHARE operationalized frailty phenotype, this study aims to evaluate its prospective association with adverse health outcomes.
Methods
Data are from 11,015 community-dwelling men and women aged 60+ participating in wave 1 and 2 of the Survey of Health, Aging and Retirement in Europe, a population-based survey. Multivariate logistic regression analyses were used to assess the 2-year follow up effect of SHARE-operationalized frailty phenotype on the incidence of disability (disability-free at baseline) and on worsening disability and morbidity, adjusting for age, sex, income and baseline morbidity and disability.
Results
At 2-year follow up, frail individuals were at increased risk for: developing mobility (OR 3.07, 95% CI, 1.02-9.36), IADL (OR 5.52, 95% CI, 3.76-8.10) and BADL (OR 5.13, 95% CI, 3.53-7.44) disability; worsening mobility (OR 2.94, 95% CI, 2.19- 3.93) IADL (OR 4.43, 95% CI, 3.19-6.15) and BADL disability (OR 4.53, 95% CI, 3.14-6.54); and worsening morbidity (OR 1.77, 95% CI, 1.35-2.32). These associations were significant even among the prefrail, but with a lower magnitude of effect.
Conclusions
The SHARE-operationalized frailty phenotype is significantly associated with all tested health outcomes independent of baseline morbidity and disability in community-dwelling men and women aged 60 and older living in Europe. The robustness of results validate the use of this phenotype in the SHARE survey for future research on frailty in Europe.
doi:10.1186/1471-2318-13-3
PMCID: PMC3585820  PMID: 23286928
Frailty phenotype; Validation; Adverse outcomes; Population survey; SHARE; BADL disability; IADL disability; Morbidity
9.  Relationships of Cardiac, Pulmonary, and Muscle Reserves and Frailty to Exercise Capacity in Older Women 
Background
A decline in exercise capacity (EC) is a characteristic of frailty. We hypothesized that decline is the effect of decrements in several physiological systems. We assessed whether the relationship of three main physiological systems—cardiac, pulmonary, and musculoskeletal—to EC is independent or interactive and whether their effect on EC varies with respect to frailty status.
Methods
Observational study of 547 disabled women aged 65 years and older (Women’s Health and Aging Study I) including 131 frail who participated in a test of EC. EC (seated step test), cardiac function (chronotropic index), pulmonary function (forced vital capacity, FVC), musculoskeletal function (quadriceps strength, QS), and frailty status were measured and interactive effects were modeled using linear regression and differentiation.
Results
Each physiological system had a direct relationship with EC, which was lower in frail compared with nonfrail. The relationship between FVC and EC was positive and increased with increasing QS in nonfrail subjects. The effect of QS on EC was positive and increased with increasing FVC regardless of frailty. In subjects with low QS, frailty status was associated with lower EC and this effect became stronger with increasing FVC.
Discussion
Findings suggest but do not show that frailty status modifies the effects of physiological function in several systems on EC. Approaches to understanding emergent properties such as vulnerability to illness and death and clinical efforts to prevent and treat frailty should evaluate and possibly intervene on several physiological systems to be maximally effective.
doi:10.1093/gerona/glp147
PMCID: PMC2822279  PMID: 19822621
Frailty; Exercise capacity
10.  Effect of a multifactorial interdisciplinary intervention on mobility-related disability in frail older people: randomised controlled trial 
BMC Medicine  2012;10:120.
Background
Interventions that enhance mobility in frail older people are needed to maintain health and independence, yet definitive evidence of effective interventions is lacking. Our objective was to assess the impact of a multifactorial intervention on mobility-related disability in frail older people.
Methods
We conducted a randomised, controlled trial with 241 frail community-dwelling older people in Sydney, Australia. Participants were classified as frail using the Cardiovascular Health Study definition, did not have severe cognitive impairment and were recently discharged from an aged care and rehabilitation service. The experimental group received a 12 month multifactorial, interdisciplinary intervention targeting identified frailty components. Two physiotherapists delivered a home exercise program targeting mobility, and coordinated management of psychological and medical conditions with other health professionals. The control group received usual care. Disability in the mobility domain was measured at baseline and at 3 and 12 months using the International Classification of Functioning, Disability and Health framework. Participation (involvement in life situations) was assessed using the Life Space Assessment and the Goal Attainment Scale. Activity (execution of mobility tasks) was measured using the 4-metre walk and self-report measures.
Results
The mean age of participants was 83.3 years (SD: 5.9 years). Of the participants recruited, 216 (90%) were followed-up at 12 months. At this time point, the intervention group had significantly better scores than the control group on the Goal Attainment Scale (odds ratio 2.1; 95% confidence interval (CI) 1.3 to 3.3, P = 0.004) and Life Space Assessment (4.68 points, 95% CI 1.4 to 9.9, P = 0.005). There was no difference between groups on the global measure of participation or satisfaction with ability to get out of the house. At the activity level, the intervention group walked 0.05 m/s faster over 4 m (95% CI 0.0004 to 0.1, P = 0.048) than the control group, and scored higher on the Activity Measure for Post Acute Care (P < 0.001).
Conclusions
The intervention reduced mobility-related disability in frail older people. The benefit was evident at both the participation and activity levels of mobility-related disability.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ANZCTRN12608000507381.
doi:10.1186/1741-7015-10-120
PMCID: PMC3517433  PMID: 23067364
exercise; frail elderly; International Classification of Functioning, Disability and Health; RCT
11.  Frailty and falls among adult patients undergoing chronic hemodialysis: a prospective cohort study 
BMC Nephrology  2013;14:224.
Background
Patients undergoing hemodialysis are at high risk of falls, with subsequent complications including fractures, loss of independence, hospitalization, and institutionalization. Factors associated with falls are poorly understood in this population. We hypothesized that insights derived from studies of the elderly might apply to adults of all ages undergoing hemodialysis; we focused on frailty, a phenotype of physiological decline strongly associated with falls in the elderly.
Methods
In this prospective, longitudinal study of 95 patients undergoing hemodialysis (1/2009-3/2010), the association of frailty with future falls was explored using adjusted Poisson regression. Frailty was classified using the criteria established by Fried et al., as a combination of five components: shrinking, weakness, exhaustion, low activity, and slowed walking speed.
Results
Over a median 6.7-month period of longitudinal follow-up, 28.3% of study participants (25.9% of those under 65, 29.3% of those 65 and older) experienced a fall. After adjusting for age, sex, race, comorbidity, disability, number of medications, marital status, and education, frailty independently predicted a 3.09-fold (95% CI: 1.38-6.90, P=0.006) higher number of falls. This relationship between frailty and falls did not differ for younger and older adults (P=0.57).
Conclusions
Frailty, a validated construct in the elderly, was a strong and independent predictor of falls in adults undergoing hemodialysis, regardless of age. Our results may aid in identifying frail hemodialysis patients who could be targeted for multidimensional fall prevention strategies.
doi:10.1186/1471-2369-14-224
PMCID: PMC3852906  PMID: 24131569
Hemodialysis; Falls; Frailty
12.  Frailty in Mexican American Older Adults 
Objective
Identify sociodemographic characteristics and health performance variables associated with frailty in Mexican American older adults.
Design
A prospective population-based survey.
Setting
Homes of older adults living in the Southwest.
Participants
621 non-institutionalized Mexican American men and women aged 70 and older included in the Hispanic Established Population Epidemiological Study of the Elderly (EPESE) participated in a home based interview.
Interventions
None
Measurements
Interviews included information on sociodemographics, self-reports of medical conditions (arthritis, diabetes, heart attack, hip fracture, cancer, and stroke) and functional status. Weight and measures of lower and upper extremity muscle strength were obtained along with information on activities of daily living and instrumental activities of daily living. A summary measure of frailty was created based on weight loss, exhaustion, grip strength and walking speed. Multivariable linear regression identified variables associated with frailty at baseline. Logistic regression examined variables predicting frailty at one year follow-up.
Results
Gender was associated with frailty at baseline (F = 4.28, p = .03). Predictors of frailty in men included upper extremity strength, disability (activities of daily living), comorbidites and mental status scores (Nagelkerke R2 = 0.37). Predictors for women included lower extremity strength, disability (activities of daily living) and body mass index (Nagelkerke R2 = 0.29). At one year follow-up 83% of males and 79% of females were correctly classified as frail.
Conclusion
Different variables were identified as statistically significant predictors of frailty in Mexican American men and women over 70 years of age. The prevention, development and treatment of frailty in Mexican American older adults may require consideration of the unique characteristics of this population.
doi:10.1111/j.1532-5415.2005.53511.x
PMCID: PMC1388072  PMID: 16137282
13.  Physical Frailty Is Associated with Incident Mild Cognitive Impairment In Community-Based Older Persons 
Objectives
The objective of this study was to test the hypothesis that physical frailty is associated with an increased risk of MCI.
Design
Prospective, observational cohort study.
Setting
Approximately 40 retirement communities across the Chicago metropolitan area.
Participants
More than 700 older persons without cognitive impairment at baseline.
Measures
Physical frailty, based on four components (i.e., grip strength, timed walk, body composition and fatigue), was assessed at baseline and cognitive function was assessed annually. Proportional hazards models adjusted for age, sex, and education were used to examine the association of physical frailty with the risk of incident MCI, and mixed effect models were used to examine the association of frailty with the rate of change in cognition.
Results
During up to 12 years of annual follow-up, 305 of 761 (40%) persons developed MCI. In a proportional hazards model adjusted for age, sex, and education, physical frailty was associated with a substantially increased risk of incident MCI, such that each one unit increase in physical frailty was associated with a 63% increase in the risk of MCI (hazard ratio: 1.63; 95% CI: 1.27, 2.08). This association persisted in analyses that required MCI to persist for at least one year and after controlling for depressive symptoms, disability, vascular risk factors, and vascular diseases. Further, a higher level of physical frailty was associated with an increased rate of decline in global cognition and 5 cognitive systems (i.e., episodic memory, semantic memory, working memory, perceptual speed, and visuospatial abilities).
Conclusion
Physical frailty is associated with an increased risk of MCI and a more rapid rate of cognitive decline in aging.
doi:10.1111/j.1532-5415.2009.02671.x
PMCID: PMC3150526  PMID: 20070417
frailty; mild cognitive impairment; cognitive decline
14.  A multifactorial interdisciplinary intervention reduces frailty in older people: randomized trial 
BMC Medicine  2013;11:65.
Background
Frailty is a well known and accepted term to clinicians working with older people. The study aim was to determine whether an intervention could reduce frailty and improve mobility.
Methods
We conducted a single center, randomized, controlled trial among older people who were frail in Sydney, Australia. One group received an intervention targeting the identified characteristics of frailty, whereas the comparison group received the usual health care and support services. Outcomes were assessed by raters masked to treatment allocation at 3 and 12 months after study entry. The primary outcomes were frailty as assessed by the Cardiovascular Health Study criteria, and mobility as assessed by the Short Physical Performance Battery. Secondary outcome measures included disability, depressive symptoms and health-related quality of life.
Results
A total of 216 participants (90%) completed the study. Overall, 68% of participants were women and the mean age was 83.3 years (standard deviation, 5.9). In the intention-to-treat analysis, the between-group difference in frailty was 14.7% at 12 months (95% confidence interval: 2.4%, 27.0%; P = 0.02). The score on the Short Physical Performance Battery, in which higher scores indicate better physical status, was stable in the intervention group and had declined in the control group; with the mean difference between groups being 1.44 (95% confidence interval, 0.80, 2.07; P <0.001) at 12 months. There were no major differences between the groups with respect to secondary outcomes. The few adverse events that occurred were exercise-associated musculoskeletal symptoms.
Conclusions
Frailty and mobility disability can be successfully treated using an interdisciplinary multifaceted treatment program.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12608000250336
doi:10.1186/1741-7015-11-65
PMCID: PMC3751685  PMID: 23497404
activities of daily living; frail elderly; randomized controlled trial; therapeutics; walking
15.  Measures of frailty in population-based studies: an overview 
BMC Geriatrics  2013;13:64.
Background
Although research productivity in the field of frailty has risen exponentially in recent years, there remains a lack of consensus regarding the measurement of this syndrome. This overview offers three services: first, we provide a comprehensive catalogue of current frailty measures; second, we evaluate their reliability and validity; third, we report on their popularity of use.
Methods
In order to identify relevant publications, we searched MEDLINE (from its inception in 1948 to May 2011); scrutinized the reference sections of the retrieved articles; and consulted our own files. An indicator of the frequency of use of each frailty instrument was based on the number of times it had been utilized by investigators other than the originators.
Results
Of the initially retrieved 2,166 papers, 27 original articles described separate frailty scales. The number (range: 1 to 38) and type of items (range of domains: physical functioning, disability, disease, sensory impairment, cognition, nutrition, mood, and social support) included in the frailty instruments varied widely. Reliability and validity had been examined in only 26% (7/27) of the instruments. The predictive validity of these scales for mortality varied: for instance, hazard ratios/odds ratios (95% confidence interval) for mortality risk for frail relative to non-frail people ranged from 1.21 (0.78; 1.87) to 6.03 (3.00; 12.08) for the Phenotype of Frailty and 1.57 (1.41; 1.74) to 10.53 (7.06; 15.70) for the Frailty Index. Among the 150 papers which we found to have used at least one of the 27 frailty instruments, 69% (n = 104) reported on the Phenotype of Frailty, 12% (n = 18) on the Frailty Index, and 19% (n = 28) on one of the remaining 25 instruments.
Conclusions
Although there are numerous frailty scales currently in use, reliability and validity have rarely been examined. The most evaluated and frequently used measure is the Phenotype of Frailty.
doi:10.1186/1471-2318-13-64
PMCID: PMC3710231  PMID: 23786540
Frailty; Frail elderly; Measure; Overview; Reliability; Validity
16.  A Frailty Instrument for primary care for those aged 75 years or more: findings from the Survey of Health, Ageing and Retirement in Europe, a longitudinal population-based cohort study (SHARE-FI75+) 
BMJ Open  2014;4(12):e006645.
Objective
To create and validate a frailty assessment tool for community-dwelling adults aged ≥75 years.
Design
Longitudinal, population-based study.
Setting
The Survey of Health, Ageing and Retirement in Europe (SHARE).
Participants
4001 women and 3057 men aged ≥75 years from the second wave of SHARE. 3325 women and 2587 men had complete information for the frailty indicators: fatigue, low appetite, weakness, observed gait (walking without help, walking with help, chairbound/bedbound, unobserved) and low physical activity.
Main outcome measures
The internal validity of the frailty indicators was tested with latent class analysis, by modelling an underlying variable with three ordered categories. The predictive validity of the frailty classification was tested against 2-year mortality and 4-year disability. The mortality prediction of SHARE-FI75+ was compared with that of previously operationalised frailty scales in SHARE (SHARE-FI, 70-item index, phenotype, FRAIL).
Results
In both genders, all frailty indicators significantly aggregated into a three-category ordinal latent variable. After adjusting for baseline age, comorbidity and basic activities of daily living (BADL) disability, the frail had an OR for 2-year mortality of 2.2 (95% CI 1.2 to 3.8) in women and 4.2 (2.6 to 6.8) in men. The mortality prediction of SHARE-FI75+ was similar to that of the other SHARE frailty scales. By wave 4, 49% of frail women (78 of 159) had at least one more limitation with BADL (compared with 18% of non-frail, 125 of 684; p<0.001); in men, these proportions were 39% (26 of 66) and 18% (110 of 621), respectively (p<0.001). A calculator is supplied for point-of-care use, which automatically replicates the frailty classification for any given measurements.
Conclusions
SHARE-FI75+ could help frailty case finding in primary care and provide a focus for personalised community interventions. Further validation in trials and clinical programmes is needed.
doi:10.1136/bmjopen-2014-006645
PMCID: PMC4275665  PMID: 25537787
Frail Elderly; Screening; Geriatric Assessment; Primary Health Care; Validation Studies; Longitudinal Survey
17.  Hyperglycemia is Associated with the Incidence of Frailty and Lower Extremity Mobility Limitations in Older Women 
Objectives
To determine the degree to which hyperglycemia predicts the development of frailty and/or lower extremity mobility limitations.
Design
Secondary data analysis of longitudinal data collected in a prospective cohort study.
Setting
Baltimore, Maryland
Participants
We examined 329 women from the Women’s Health and Aging Studies II aged 70–79 years at baseline who had all variables needed for analysis.
Methods
Hemoglobin A1c [HbA1c] at baseline was the independent variable and categorized as: <5.5%, 5.5 to 5.9%, 6.0–6.4%, 6.5–7.9%, ≥8%. The incidence of frailty and lower extremity mobility limitations (based on self-reported walking difficulty, walking speed, and short performance physical battery [SPPB] score) was determined (follow-up≈9 years). Frailty was assessed using the Cardiovascular Health Study criteria. Covariates included demographics, body mass index, interleukin-6, and clinical history of comorbidities. Statistical analyses included Kaplan-Meier survival curves and Cox regression models adjusting for key covariates.
Results
In time-to-event analyses, HbA1c category was associated with incidence of walking difficulty (p=0.049) and low physical performance (p=0.001); association with incidence of frailty and low walking speed had a trend towards significance (both p=0.10). In demographics-adjusted regression models, HbA1c≥8% (versus<5.5%) was associated with an approximately three-times increased risk of incident frailty and three-to-five times increased risk of lower extremity mobility limitations (all p<0.05). In fully adjusted models, HbA1c≥8% (versus<5.5%) was associated with incident frailty (hazard ratio[HR]=3.33, 95% confidence interval=1.24–8.93), walking difficulty (HR=3.47,1.26–9.55), low walking speed (HR=2.82,1.19–6.71), and low physical performance (HR=3.60,1.52–8.53).
Conclusions
Hyperglycemia is associated with the development of frailty and lower extremity mobility limitations in older women; future studies should identify mediators of these relationships.
doi:10.1111/j.1532-5415.2012.04099.x
PMCID: PMC4144067  PMID: 22882211
Hyperglycemia; Elderly; Frailty; Mobility; Disability
18.  Frailty in the critically ill: a novel concept 
Critical Care  2011;15(1):301.
The concept of frailty has been defined as a multidimensional syndrome characterized by the loss of physical and cognitive reserve that predisposes to the accumulation of deficits and increased vulnerability to adverse events. Frailty is strongly correlated with age, and overlaps with and extends aspects of a patient's disability status (that is, functional limitation) and/or burden of comorbid disease. The frail phenotype has more specifically been characterized by adverse changes to a patient's mobility, muscle mass, nutritional status, strength and endurance. We contend that, in selected circumstances, the critically ill patient may be analogous to the frail geriatric patient. The prevalence of frailty amongst critically ill patients is currently unknown; however, it is probably increasing, based on data showing that the utilization of intensive care unit (ICU) resources by older people is rising. Owing to the theoretical similarities in frailty between geriatric and critically ill patients, this concept may have clinical relevance and may be predictive of outcomes, along with showing important interaction with several factors including illness severity, comorbid disease, and the social and structural environment. We believe studies of frailty in critically ill patients are needed to evaluate how it correlates with outcomes such as survival and quality of life, and how it relates to resource utilization, such as length of mechanical ventilation, ICU stay and duration of hospitalization. We hypothesize that the objective measurement of frailty may provide additional support and reinforcement to clinicians confronted with end-of-life decisions on the appropriateness of ICU support and/or withholding of life-sustaining therapies.
doi:10.1186/cc9297
PMCID: PMC3222010  PMID: 21345259
19.  Comparing frailty measures in their ability to predict adverse outcome among older residents of assisted living 
BMC Geriatrics  2012;12:56.
Background
Few studies have directly compared the competing approaches to identifying frailty in more vulnerable older populations. We examined the ability of two versions of a frailty index (43 vs. 83 items), the Cardiovascular Health Study (CHS) frailty criteria, and the CHESS scale to accurately predict the occurrence of three outcomes among Assisted Living (AL) residents followed over one year.
Methods
The three frailty measures and the CHESS scale were derived from assessment items completed among 1,066 AL residents (aged 65+) participating in the Alberta Continuing Care Epidemiological Studies (ACCES). Adjusted risks of one-year mortality, hospitalization and long-term care placement were estimated for those categorized as frail or pre-frail compared with non-frail (or at high/intermediate vs. low risk on CHESS). The area under the ROC curve (AUC) was calculated for select models to assess the predictive accuracy of the different frailty measures and CHESS scale in relation to the three outcomes examined.
Results
Frail subjects defined by the three approaches and those at high risk for decline on CHESS showed a statistically significant increased risk for death and long-term care placement compared with those categorized as either not frail or at low risk for decline. The risk estimates for hospitalization associated with the frailty measures and CHESS were generally weaker with one of the frailty indices (43 items) showing no significant association. For death and long-term care placement, the addition of frailty (however derived) or CHESS significantly improved on the AUC obtained with a model including only age, sex and co-morbidity, though the magnitude of improvement was sometimes small. The different frailty/risk models did not differ significantly from each other in predicting mortality or hospitalization; however, one of the frailty indices (83 items) showed significantly better performance over the other measures in predicting long-term care placement.
Conclusions
Using different approaches, varying degrees of frailty were detected within the AL population. The various approaches to defining frailty were generally more similar than dissimilar with regard to predictive accuracy with some exceptions. The clinical implications and opportunities of detecting frailty in more vulnerable older adults require further investigation.
doi:10.1186/1471-2318-12-56
PMCID: PMC3573890  PMID: 22978265
Frailty; Predictive accuracy; Agreement; Assisted living
20.  Validation and Comparison of 2 Frailty Indexes: The MOBILIZE Boston Study 
Objectives
To validate two established frailty indexes and compare their ability to predict adverse outcomes in a diverse elderly community-dwelling sample of men and women.
Design
Prospective observational study.
Setting
A diverse defined geographic area of Boston.
Participants
765 community-dwelling participants in the MOBILIZE Boston Study.
Measurements
Two published frailty indexes, recurrent falls, disability, overnight hospitalization, emergency room visits, chronic medical conditions, self-reported health, physical function, cognitive ability (including executive function) and depression. One index was developed from the Study of Osteoporotic Fractures (SOF) and the other from the Cardiovascular Health Study (CHS).
Results
The SOF frailty index classified 77.1% as robust, 18.7% as pre-frail and 4.2% as frail. The CHS frailty index classified 51.2% as robust, 38.8% as pre-frail and 10.0% as frail. Both measures of frailty (SOF; CHS) were similar in their ability to predict key geriatric outcomes such as recurrent falls (HRfrail=2.2 [1.2-4.0]; HRfrail=1.9 [1.2-3.1]), overnight hospitalization (ORfrail=3.5 [1.5,8.0]); ORfrail=4.4 [2.4-8.2]), emergency room visits (ORfrail=3.5 [1.4,8.8]); ORfrail=3.1 [1.6-5.9]) and disability (ORfrail=5.4[2.3,12.3]); ORfrail=7.7 [4.0,14.7]), as well as chronic medical conditions, physical function, cognitive ability and depression.
Conclusion
We validated two established frailty indexes using an independent elderly sample of diverse men and women and showed that both indexes are good at distinguishing relevant geriatric conditions and predicting recurrent falls, overnight hospitalization and emergency room visits by level of frailty. Though both indexes are good measures of frailty, the simpler SOF index may prove easier and more practical in a clinical setting.
doi:10.1111/j.1532-5415.2009.02394.x
PMCID: PMC2792729  PMID: 19682112
Frailty; community-dwelling; MOBILIZE Boston Study; Study of Osteoporotic Fracture; Cardiovascular Health Study
21.  Purpose in Life is Associated with a Reduced Risk of Incident Disability Among Community-Dwelling Older Persons 
Background
Purpose in life is thought to be associated with positive health outcomes in old age, but its association with disability is unknown.
Objective
Test the hypothesis that greater purpose in life is associated with a reduced risk of incident disability, including impairment in basic and instrumental activities of daily living and mobility disability, among community-based older persons free of dementia.
Design
Participants were from the Rush Memory and Aging Project, a large longitudinal clinical-pathologic study of aging.
Setting
Retirement communities, senior housing facilities, and homes across the greater Chicago metropolitan area.
Measurements
All participants underwent baseline assessment of purpose in life and detailed annual clinical evaluations to document incident disability.
Results
The mean score on the purpose in life measure at baseline was 3.6 (SD=0.5, range: 2 to 5). In a series of proportional hazards models adjusted for age, sex, and education, greater purpose in life was associated with a reduced risk of disability in basic activities of daily living (HR=0.60, 95% CI 0.45, 0.81), instrumental activities of daily living (HR=0.56; 95% CI 0.40, 0.78), and mobility disability (HR=0.61, 95% CI 0.44, 0.84). These associations did not vary along demographic lines and persisted after the addition of terms to control for global cognition, depressive symptoms, social networks, neuroticism, income, physical frailty, vascular risk factors, and vascular diseases.
Conclusions
Among community-based older persons without dementia, greater purpose in life is associated with maintenance of functional status, including a reduced risk of developing impairment in basic and instrumental activities of daily living and mobility disability.
doi:10.1097/JGP.0b013e3181d6c259
PMCID: PMC2992099  PMID: 20808115
purpose in life; activities of daily living; disability; functional status
22.  What is the utility of preoperative frailty assessment for risk stratification in cardiac surgery? 
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether frailty scoring can be used either separately or combined with conventional risk scores to predict survival and complications. Five hundred and thirty-five papers were found using the reported search, of which nine cohort studies represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. There is a paucity of evidence, as advanced age is a criterion for exclusion in most randomized controlled trials. Conventional models of risk following cardiac surgery are not calibrated to accurately predict the outcomes in the elderly and do not currently include frailty parameters. There is no universally accepted definition for frailty, but it is described as a physiological decline in multiple organ systems, decreasing a patient's capacity to withstand the stresses of surgery and disease. Frailty is manifest clinically as deficits in functional capacity, such as slow ambulation and impairments in the activities of daily living (ADL). Analysis of predictive models using area under receiver operating curves (AUC) suggested only a modest benefit by adding gait speed to a Society of Thoracic Surgeons (STS score)-Predicted Risk of Mortality or Major Morbidity (PROM) risk score (AUC 0.04 mean difference). However, a specialist frailty assessment tool named FORECAST was found to be superior at predicting adverse outcomes at 1 year compared with either EuroSCORE or STS score (AUC 0.09 mean difference). However, risk models incorporating frailty parameters require further validation and have not been widely adopted. Routine collection of objective frailty measures such as 5-metre walk time and ADL assessment will help to provide data to develop new risk-assessment models to facilitate risk stratification and clinical decision-making in elderly patients. Based on the best evidence currently available, we conclude that frailty is an independent predictor of adverse outcome following cardiac surgery or transcatheter aortic valve implantation, increasing the risk of mortality 2- to 4-fold compared with non-frail patients.
doi:10.1093/icvts/ivt197
PMCID: PMC3715194  PMID: 23667068
Review; Elderly; Cardiac surgery; Frailty; Outcome
23.  Exploration of transitional life events in individuals with Friedreich ataxia: Implications for genetic counseling 
Abstract
Background
Human development is a process of change, adaptation and growth. Throughout this process, transitional events mark important points in time when one's life course is significantly altered. This study captures transitional life events brought about or altered by Friedreich ataxia, a progressive chronic illness leading to disability, and the impact of these events on an affected individual's life course.
Methods
Forty-two adults with Friedreich ataxia (18-65y) were interviewed regarding their perceptions of transitional life events. Data from the interviews were coded and analyzed thematically using an iterative process.
Results
Identified transitions were either a direct outcome of Friedreich ataxia, or a developmental event altered by having the condition. Specifically, an awareness of symptoms, fear of falling and changes in mobility status were the most salient themes from the experience of living with Friedreich ataxia. Developmental events primarily influenced by the condition were one's relationships and life's work.
Conclusions
Friedreich ataxia increased the complexity and magnitude of transitional events for study participants. Transitional events commonly represented significant loss and presented challenges to self-esteem and identity. Findings from this study help alert professionals of potentially challenging times in patients' lives, which are influenced by chronic illness or disability. Implications for developmental counseling approaches are suggested for genetic counseling.
Background
Human development can be described in terms of key transitional events, or significant times of change. Transitional events initiate shifts in the meaning or direction of life and require the individual to develop skills or utilize coping strategies to adapt to a novel situation [1,2]. A successful transition has been defined as the development of a sense of mastery over the changed event [3].
Transitions can be influenced by a variety of factors including one's stage of development, such as graduation from high school, historical events, including war, and idiosyncratic factors, such as health status [4,5]. Of particular interest in the present study are transitional life events, brought about or altered by progressive chronic illness and disability, and the impact of these events on the lives of affected individuals.
It has been recognized that the clinical characteristics of a chronic illness or disability may alter the course and timing of many developmentally-related transitional events [6]. For example, conditions associated with a shortened lifespan may cause an individual to pursue a career with a shorter course of training [6]. Specific medical manifestations may also promote a lifestyle incongruent with developmental needs [6,7]. For example, an adolescent with a disability may have difficulty achieving autonomy because of his/her physical dependence on others.
In addition to the aforementioned effects of chronic illness and disability on developmentally-related transitional events, a growing body of literature has described disease-related transitional events: those changes that are a direct result of chronic illness and disability. Diagnosis has received attention as being a key disease-related transitional event [8,9]. Studies have also noted other disease transitions related to illness trajectory [10], as the clinical features of the disease may require the individual to make specific adaptations. Disease-related events have also been described in terms of accompanying psychological processes, such as one's awareness of differences brought about by illness [11].
While disease-related events are seemingly significant, the patient's perception of the events is varied. Some events may be perceived as positive experiences for the individual. For example, a diagnosis may end years of uncertainty. Some individuals may perceive these transitional events as insignificant, as they have accommodated to the continual change brought about by a chronic disease [12,13].
The aforementioned impact of disability and chronic illness on transitional events may create psychological stress. Developed by Lazarus and Folkman, the Transitional Model of Stress and Coping describes the process of adaptation to a health condition [14]. This model purports that individuals first appraise a stressor and then utilize a variety of coping strategies in order to meet the stressor's demands [14]. Thus, in the context of chronic illness, the ability of the individual to cope successfully with the stress of a health threat contributes to the process of overall adaptation to the condition.
The process of adaptation can be more complex when the chronic illness or disability is progressive. Each transition brought about or altered by the disability may also represent additional loss, including the loss of future plans, freedom in social life and the ability to participate in hobbies [15]. These losses may be accompanied by grief, uncertainty, and a continual need for adaptation [16,17].
Friedreich ataxia (FRDA) is one example of a progressive disorder, leading to adolescent and adult onset disability. To better understand patients' perceptions of key transitional events and the factors perceived to facilitate progression through these events, individuals with FRDA were interviewed.
FRDA is a rare, progressive, neurodegenerative disorder affecting approximately one in 30,000 people in the United States [18]. It equally affects both men and women. Individuals with FRDA experience progressive muscle weakness and loss of coordination in the arms and legs. For most patients, ataxia leads to motor incapacitation and full-time use of a wheelchair, commonly by the late teens or early twenties. Other complications such as vision and hearing impairment, dysarthria, scoliosis, diabetes mellitus and hypertrophic cardiomyopathy may occur [19,20]. Cardiomyopathy and respiratory difficulties often lead to premature death at an average age of 37 years [21]. Currently, there are no treatments or cures for FRDA. Little is known about the specific psychological or psychosocial effects of the condition.
FRDA is an autosomal recessive condition. The typical molecular basis of Friedreich ataxia is the expansion of a GAA trinucleotide repeat in both copies of the FXN gene [22]. Age of onset usually occurs in late childhood or early adolescence. However, the availability of genetic testing has identified affected individuals with an adult form of the condition. This late-onset form is thought to represent approximately 10-15% of the total FRDA population [23].
Health care providers of individuals with progressive, neurodegenerative disorders can help facilitate their patients' progression through transitional events. Data suggest that improvements should be made in the care of these individuals. Shaw et al. [24] found that individualized care that helps to prepare patients for transition is beneficial. Beisecker et al. [25] found that patients desire not only physical care from their providers, but also emotional and psychosocial support.
Genetic counselors have an important opportunity to help patients with neuromuscular disorders progress through transitional events, as several of these conditions have a genetic etiology. Genetic counselors in pediatric and adult settings often develop long-term relationships with patients, due to follow-up care. This extended relationship is becoming increasingly common as genetic counselors move into various medical sub-specialties, such as neurology, ophthalmology, oncology and cardiology.
The role of the genetic counselor in addressing the psychosocial needs of patients has been advocated, but rarely framed in the context of developmental events [26]. Data suggest that patients may not expect a genetic counselor to address psychosocial needs [27]. In a survey of genetic counseling patients, Wertz [28] found a majority of respondents understood genetic conditions to have a moderate to serious effect on family life and finances, while almost half perceived there to be an effect on the spouse, quality of life, and the relationship between home and work. However, these topics were reportedly not discussed within genetic counseling sessions [27,28]. Overall, there is limited information about the experiences of transitional life events in FRDA, as well as a lack of recommendations for genetic counselors and other health care providers to assist patients through these events.
Our study investigated perceptions of patients with Friedreich ataxia to 1) identify key transitional events and specific needs associated with events; 2) describe perception of factors to facilitate progression through the identified events; and 3) explore the actual or potential role of the health care provider in facilitating adaptation to the identified events. Data were used to make suggestions for developmental genetic counseling approaches in the context of ongoing care of clients with hereditary, progressive, neurodegenerative conditions.
doi:10.1186/1744-9081-6-65
PMCID: PMC2987979  PMID: 20979606
24.  Effectiveness of interdisciplinary primary care approach to reduce disability in community dwelling frail older people: cluster randomised controlled trial 
Objective To evaluate whether an interdisciplinary primary care approach for community dwelling frail older people is more effective than usual care in reducing disability and preventing (further) functional decline.
Design Cluster randomised controlled trial.
Setting 12 general practices in the south of the Netherlands
Participants 346 frail older people (score ≥5 on Groningen Frailty Indicator) were included; 270 (78%) completed the study.
Interventions General practices were randomised to the intervention or control group. Practices in the control group delivered care as usual. Practices in the intervention group implemented the “Prevention of Care” (PoC) approach, in which frail older people received a multidimensional assessment and interdisciplinary care based on a tailor made treatment plan and regular evaluation and follow-up.
Main outcome measures The primary outcome was disability, assessed at 24 months by means of the Groningen Activity Restriction Scale. Secondary outcomes were depressive symptomatology, social support interactions, fear of falling, and social participation. Outcomes were measured at baseline and at 6, 12, and 24 months’ follow-up.
Results 193 older people in the intervention group (six practices) received the PoC approach; 153 older people in the control group (six practices) received care as usual. Follow-up rates for patients were 91% (n=316) at six months, 86% (n=298) at 12 months, and 78% (n=270) at 24 months. Mixed model multilevel analyses showed no significant differences between the two groups with regard to disability (primary outcome) and secondary outcomes. Pre-planned subgroup analyses confirmed these results.
Conclusions This study found no evidence for the effectiveness of the PoC approach. The study contributes to the emerging body of evidence that community based care in frail older people is a challenging task. More research in this field is needed.
Trial registration Current Controlled Trials ISRCTN31954692.
doi:10.1136/bmj.f5264
PMCID: PMC3769159  PMID: 24022033
25.  Polymorphisms in the Mitochondrial DNA Control Region and Frailty in Older Adults 
PLoS ONE  2010;5(6):e11069.
Background
Mitochondria contribute to the dynamics of cellular metabolism, the production of reactive oxygen species, and apoptotic pathways. Consequently, mitochondrial function has been hypothesized to influence functional decline and vulnerability to disease in later life. Mitochondrial genetic variation may contribute to altered susceptibility to the frailty syndrome in older adults.
Methodology/Principal Findings
To assess potential mitochondrial genetic contributions to the likelihood of frailty, mitochondrial DNA (mtDNA) variation was compared in frail and non-frail older adults. Associations of selected SNPs with a muscle strength phenotype were also explored. Participants were selected from the Cardiovascular Health Study (CHS), a population-based observational study (1989–1990, 1992–1993). At baseline, frailty was identified as the presence of three or more of five indicators (weakness, slowness, shrinking, low physical activity, and exhaustion). mtDNA variation was assessed in a pilot study, including 315 individuals selected as extremes of the frailty phenotype, using an oligonucleotide sequencing microarray based on the Revised Cambridge Reference Sequence. Three mtDNA SNPs were statistically significantly associated with frailty across all pilot participants or in sex-stratified comparisons: mt146, mt204, and mt228. In addition to pilot participants, 4,459 additional men and women with frailty classifications, and an overlapping subset of 4,453 individuals with grip strength measurements, were included in the study population genotyped at mt204 and mt228. In the study population, the mt204 C allele was associated with greater likelihood of frailty (adjusted odds ratio = 2.04, 95% CI = 1.07–3.60, p = 0.020) and lower grip strength (adjusted coefficient = −2.04, 95% CI = −3.33– −0.74, p = 0.002).
Conclusions
This study supports a role for mitochondrial genetic variation in the frailty syndrome and later life muscle strength, demonstrating the importance of the mitochondrial genome in complex geriatric phenotypes.
doi:10.1371/journal.pone.0011069
PMCID: PMC2883558  PMID: 20548781

Results 1-25 (1198501)