The Conceptual Definition of Sarcopenia: Delphi Consensus from the Global Leadership Initiative in Sarcopenia (GLIS).

IMPORTANCE: Sarcopenia, the age-related loss of muscle mass and strength/function, is an important clinical condition. However, no international consensus on the definition exists. OBJECTIVE: The Global Leadership Initiative in Sarcopenia (GLIS) aimed to address this by establishing the global conceptual definition of sarcopenia. DESIGN: The GLIS steering committee was formed in 2019-21 with representatives from all relevant scientific societies worldwide. During this time, the steering committee developed a set of statements on the topic and invited members from these societies to participate in a two-phase International Delphi Study. Between 2022 and 2023, participants ranked their agreement with a set of statements using an online survey tool (SurveyMonkey). Statements were categorised based on predefined thresholds: strong agreement (>80%), moderate agreement (70-80%) and low agreement (<70%). Statements with strong agreement were accepted, statements with low agreement were rejected and those with moderate agreement were reintroduced until consensus was reached. RESULTS: 107 participants (mean age: 54 ± 12 years [1 missing age], 64% men) from 29 countries across 7 continents/regions completed the Delphi survey. Twenty statements were found to have a strong agreement. These included; 6 statements on 'general aspects of sarcopenia' (strongest agreement: the prevalence of sarcopenia increases with age (98.3%)), 3 statements on 'components of sarcopenia' (muscle mass (89.4%), muscle strength (93.1%) and muscle-specific strength (80.8%) should all be a part of the conceptual definition of sarcopenia)) and 11 statements on 'outcomes of sarcopenia' (strongest agreement: sarcopenia increases the risk of impaired physical performance (97.9%)). A key finding of the Delphi survey was that muscle mass, muscle strength and muscle-specific strength were all accepted as 'components of sarcopenia', whereas impaired physical performance was accepted as an 'outcome' rather than a 'component' of sarcopenia. CONCLUSION AND RELEVANCE: The GLIS has created the first global conceptual definition of sarcopenia, which will now serve to develop an operational definition for clinical and research settings.

Recruitment methods and yield rates for a multisite clinical trial exploring risk reduction for Alzheimer's disease (rrAD).

INTRODUCTION: The risk reduction for Alzheimer's disease (rrAD) trial was a multisite clinical trial to assess exercise and intensive vascular pharmacological treatment on cognitive function in community-dwelling older adults at increased risk for Alzheimer's disease. METHODS: Eligibility, consent, and randomization rates across different referral sources were compared. Informal interviews conducted with each site's project team were conducted upon study completion. RESULTS: Initially, 3290 individuals were screened, of whom 28% were eligible to consent, 805 consented to participate (87.2% of those eligible), and 513 (36.3% of those consented) were randomized. Emails sent from study site listservs/databases yielded the highest amount (20.9%) of screened individuals. Professional referrals from physicians yielded the greatest percentage of consented individuals (57.1%). Referrals from non-professional contacts (ie, friends, family; 75%) and mail/phone contact from a site (73.8%) had the highest yield of randomization. DISCUSSION: Professional referrals or email from listservs/registries were most effective for enrolling participants. The greatest yield of eligible/randomized participants came from non-professional and mail/phone contacts. Future trials should consider special efforts targeting these recruitment approaches. Highlights: Clinical trial recruitment is commonly cited as a significant barrier to advancing our understanding of cognitive health interventions.The most cited referral source was email, followed by interviews/editorials on the radio, television, local newspapers, newsletters, or magazine articles.The referral method that brought in the largest number of contacts was email but did not result in the greatest yield of consents or eligible participants.The sources that yielded the greatest likelihood of consent were professional referrals (ie, physician), social media, and mail/phone contact from study site.The greatest yield of eligible/randomized participants came from non-professional contacts and mail/phone contact from a site.Findings suggest that sites may need to focus on more selective referral sources, such as using contact mailing and phone lists, rather than more widely viewed recruitment sources, such as social media or TV/radio advertisements.

Evaluation of noise regression techniques in resting-state fMRI studies using data of 434 older adults.

Subject motion is a well-known confound in resting-state functional MRI (rs-fMRI) and the analysis of functional connectivity. Consequently, several clean-up strategies have been established to minimize the impact of subject motion. Physiological signals in response to cardiac activity and respiration are also known to alter the apparent rs-fMRI connectivity. Comprehensive comparisons of common noise regression techniques showed that the "Independent Component Analysis based strategy for Automatic Removal of Motion Artifacts" (ICA-AROMA) was a preferred pre-processing technique for teenagers and adults. However, motion and physiological noise characteristics may differ substantially for older adults. Here, we present a comprehensive comparison of noise-regression techniques for older adults from a large multi-site clinical trial of exercise and intensive pharmacological vascular risk factor reduction. The Risk Reduction for Alzheimer's Disease (rrAD) trial included hypertensive older adults (60-84 years old) at elevated risk of developing Alzheimer's Disease (AD). We compared the performance of censoring, censoring combined with global signal regression, non-aggressive and aggressive ICA-AROMA, as well as the Spatially Organized Component Klassifikator (SOCK) on the rs-fMRI baseline scans from 434 rrAD subjects. All techniques were rated based on network reproducibility, network identifiability, edge activity, spatial smoothness, and loss of temporal degrees of freedom (tDOF). We found that non-aggressive ICA-AROMA did not perform as well as the other four techniques, which performed table with marginal differences, demonstrating the validity of these techniques. Considering reproducibility as the most important factor for longitudinal studies, given low false-positive rates and a better preserved, more cohesive temporal structure, currently aggressive ICA-AROMA is likely the most suitable noise regression technique for rs-fMRI studies of older adults.

Impact of psychological resilience on walking capacity in older adults following hip fracture.

BACKGROUND: Community-dwelling older adults experiencing hip fracture often fail to achieve adequate walking capacity following surgery and rehabilitation. Effects of psychological factors on post-fracture walking capacity are poorly understood. Accordingly, this paper investigates effects of psychological resilience on observed walking capacity measures in older adults following hip fracture, controlling for important covariates. METHODS: Data were drawn from the Community Ambulation Project, a clinical trial of 210 community-dwelling adults aged ≥60 years who experienced a minimal trauma hip fracture and were randomized to one of two 16-week home-based physical therapist-guided interventions. Psychological resilience was measured at study baseline using the 6-item Brief Resilience Scale (BRS); scores were classified into groups in order to distinguish levels of self-reported resilience. Walking capacity was assessed at study baseline and 16 weeks later using 4-Meter Gait Speed (4MGS), 50-Foot Walk Test (50FWT), and 6-Minute Walk Distance (SMWD). In multivariate analyses of covariance in which 16-week follow-up values of each walking measure were outcomes, covariates included clinical trial arm, gender, age, and baseline values of: walking measure corresponding to the outcome; body mass index; depressive symptom severity; degree of psychological optimism; cognitive status; informal caregiver need; and days from hospital admission to randomization. RESULTS: Increases between baseline and 16 weeks later in mean gait speed in meters/sec (m/s) and walking distance in meters (m) in 4MGS, 50FWT and SMWD were 0.06 m/s (p = 0.061), 0.11 m/s (p < 0.01), and 25.5 m (p = 0.056) greater, respectively, in the most resilient BRS group compared to the least resilient BRS group. CONCLUSION: Higher levels of psychological resilience were associated with greater walking speed and distance. Psychological resilience represents a potentially clinically important pathway and intervention target, toward the goal of improving walking capacity among older adults known to have substantial residual disability following hip fracture.

Balancing vision with pragmatism: The geriatric emergency department guidelines-realistic expectations from emergency medicine and geriatric medicine.

In 2014 the Geriatric Emergency Department (GED) Guidelines were published and endorsed by four major medical organizations. The multidisciplinary GED Guidelines characterize the complex needs of the older emergency department (ED) patient and current best practices with the goal of promoting more cost-effective and patient-centered care. The recommendations are extensive and the vast majority of EDs then and now do not have either the resources nor hospital administrative support to provide this additional service. At the 2021 American Academy of Emergency Medicine's Scientific Assembly, a panel of emergency medicine physicians and geriatricians discussed the GED Guidelines and the current realities of EDs' capacity to provide best practice and guideline recommended care of GED patients. This article is a synthesis of the panel's presentation and discussion. With the substantial challenges in providing guideline recommended care in EDs, this article will explore three high impact GED clinical conditions to highlight guideline recommendations, challenges and opportunities, and discuss realistically achievable expectations for non-Geriatric ED accredited institutions. In 2014 the Geriatric Emergency Department Guidelines were published describing the current best practices for geriatric ED patients. Unfortunately, the vast majority of EDs worldwide do not provide the level of service recommended by the GED guidelines. The GED Guidelines can best be termed aspirational for U.S. EDs at the present time.

Balancing Vision With Pragmatism: The Geriatric Emergency Department Guidelines-Realistic Expectations From Emergency Medicine and Geriatric Medicine.

BACKGROUND: In 2014, the Geriatric Emergency Department (GED) Guidelines were published and endorsed by four major medical organizations. The multidisciplinary GED Guidelines characterized the complex needs of the older emergency department (ED) patient and current best practices, with the goal of promoting more cost-effective and patient-centered care. The recommendations are extensive and most EDs then and now have neither the resources nor the hospital administrative support to provide this additional service. DISCUSSION: At the 2021 American Academy of Emergency Medicine's Scientific Assembly, a panel of emergency physicians and geriatricians discussed the GED Guidelines and the current realities of EDs' capacity to provide best practice and guideline-recommended care of GED patients. This article is a synthesis of the panel's presentation and discussion. With the substantial challenges in providing guideline-recommended care in EDs, this article will explore three high-impact GED clinical conditions to highlight guideline recommendations, challenges, and opportunities, and discuss realistically achievable expectations for non-GED-accredited institutions. CONCLUSIONS: In 2014, the GED Guidelines were published, describing the current best practices for GED patients. Unfortunately, most of the EDs worldwide do not provide the level of service recommended by the GED Guidelines. The GED Guidelines can best be termed aspirational for U.S. EDs at the present time.

Using Treatment Fidelity Measures to Understand Walking Recovery: A Secondary Analysis From the Community Ambulation Project.

OBJECTIVES: Physical therapist intervention studies can be deemed ineffective when, in fact, they may not have been delivered as intended. Measurement of treatment fidelity (TF) can address this issue. The purpose of this study was to describe TF of a home-based intervention, identify factors associated with TF, and examine whether components of TF were associated with the outcome of change in 6-minute walk distance (∆6MWD). METHODS: This is a secondary analysis of community-dwelling hip fracture participants who completed standard therapy and were randomly assigned to the active intervention (Push). Push was 16 weeks of lower extremity strengthening, function, and endurance training. TF was defined as delivery (attendance rate, exercise duration) and receipt (progression in training load, heart rate reserve [HRR] during endurance training, and exercise position [exercise on floor]). The outcome was ∆6MWD. Independent variables included baseline (demographic and clinical) measures. Descriptive statistics were calculated; linear and logistic regressions were performed. RESULTS: Eighty-nine participants were included in this analysis; 59 (66%) had attendance of 75% or greater. Participants walked for 20 minutes or more for 78% of sessions. The average training load increased by 22%; the mean HRR was 35%; and 61 (69%) participants exercised on the floor for at least 75% of sessions. Regression analyses showed that a higher body mass index and greater baseline 6MWD were related to components of TF; 4 out of 5 components of TF were significantly related to ∆6MWD. The strongest TF relationship showed that those who exercised on the floor improved by 62 m (95% CI = 31-93 m) more than those who did not get on the floor. CONCLUSIONS: Measures of TF should extend beyond attendance rate. This analysis demonstrates how measures of TF, including program attendance, progression in training load, endurance duration, and exercising on the floor were significantly related to improvement in 6MWD in participants post hip fracture. IMPACT: This careful analysis of treatment fidelity assured that the intervention was delivered and received as intended. Analysis of data from a large trial with participants after hip fracture showed that regular attendance, frequent endurance training for 20 minutes, increases in lower extremity training loads, and exercising on the floor were associated with improvements in the outcome of 6-minute-walk distance. The strongest association with improvement was exercising on the floor.

A multi-center trial of exercise and testosterone therapy in women after hip fracture: Design, methods and impact of the COVID-19 pandemic.

BACKGROUND: Up to 75% of hip fracture patients never recover to their pre-fracture functional status. Supervised exercise that includes strength training can improve functional recovery after hip fracture. The role of testosterone replacement for augmenting the effects of exercise in older women after hip fracture is unknown. METHODS: The Starting Testosterone and Exercise after Hip Injury (STEP-HI) Study is a 6-month Phase 3 multicenter randomized placebo-controlled trial designed to compare supervised exercise (EX) plus 1% testosterone topical gel, with EX plus placebo gel, and with enhanced usual care (EUC). Female hip fracture patients age ≥ 65 years are being recruited from clinical centers across the United States. Participants are community dwelling and enrolled within 24 weeks after surgical repair of the fracture. The EX intervention is a center-based program of progressive resistance training. The EUC group receives a home exercise program and health education. Participants receive dietary counseling, calcium and vitamin D. The primary outcome is the Six Minute Walk Distance. Secondary outcomes include physical performance measures, self-reported function and quality of life, and dual energy x-ray absorptiometry measures of body composition and bone mineral density. RESULTS: Enrollment, interventions, and follow-up are ongoing. We describe the impact of the coronavirus disease 2019 pandemic on the trial, including modifications made to allow continuation of the interventions and outcome data collection using remote video and audio technology. CONCLUSIONS: Results from the STEP-HI study are expected to have important clinical and public health implications for management of the growing population of hip fracture patients.

Application of Cut-Points for Low Muscle Strength and Lean Mass in Mobility-Limited Older Adults.

BACKGROUND: The Sarcopenia Definitions and Outcomes Consortium (SDOC) is a collaborative initiative seeking to develop and evaluate cut-points for low muscle strength and lean mass that predict an increased risk for slowness (usual walking speed <.8 m/s) among older adults. OBJECTIVES: The goal of the present study was to provide clinicians and researchers with an understanding of the diagnostic implications of using SDOC variables and cut-points in mobility-limited older adults. Using data from older individuals with specific conditions that render them at increased risk for mobility limitation, we evaluated the performance characteristics (ie, sensitivity and specificity) of five putative sarcopenia parameters and then compared these values with previously recommended diagnostic criteria for sarcopenia. DESIGN: Retrospective analysis of six randomized controlled trials enriched in persons at risk for mobility limitation. SETTING: National and international geriatric clinical research centers. PARTICIPANTS: A total of 925 mobility-limited older adults (≥55 years of age; 58% women) were included in the analysis. MEASUREMENTS: The prevalence of low muscle strength and lean mass were assessed using five candidate metrics discriminative of slowness. Analyses of sensitivity and specificity were used to compare muscle weakness criteria with published diagnostics for sarcopenia. RESULTS: Odds ratios (ORs) supported maximal grip strength (Grip max <35.5 and 20.0 in men and women, respectively) as the most discriminative of slowness in both men and women (OR = 3.66 and 3.53, respectively). More men (58%) than women (30%) fell below sex-specific maximal grip cut-points. When applying previously recommended sarcopenia component definitions in our population, we found that fewer individuals met those criteria (range = 6%-32%). CONCLUSION: A greater number of individuals fall below SDOC Grip max cut-points compared with previous recommendations. Clinicians and researchers working with older adults may consider these thresholds as an inclusive means to identify candidates for low-risk lifestyle promyogenic and function-promoting therapies. J Am Geriatr Soc 68:1445-1453, 2020.

Baseline Prevalence of Polypharmacy in Older Hypertensive Study Subjects with Elevated Dementia Risk: Findings from the Risk Reduction for Alzheimer's Disease Study (rrAD).

BACKGROUND: Little is known about the prevalence of polypharmacy, the taking of five or more medications a day, in older adults with specific dementia risk factors. OBJECTIVE: To examine the prevalence of polypharmacy in participants at baseline in a vascular risk reduction focused Alzheimer's disease (rrAD) trial targeting older patients with hypertension and elevated dementia risk. METHODS: We conducted a detailed review of medications in a cross-sectional study of community-dwelling older adults with hypertension and elevated dementia risk. Medications were identified in a structured interview process with an onsite pharmacist or qualified designee. Polypharmacy was defined as use of five or more medications on a regular basis. Descriptive analyses were conducted on the sample as well as direct comparisons of subgroups of individuals with hypertension, diabetes, and hyperlipidemia. RESULTS: The 514 rrAD participants, mean age 68.8 (standard deviation [sd] 6), reported taking different combinations of 472 unique medications at their baseline visit. The median number of medications taken by participants was eight [Range 0-21], with 79.2% exhibiting polypharmacy (n = 407). Sites differed in their prevalence of polypharmacy, χ2(3) = 56.0, p < 0.001. A nearly identical percentage of the 2,077 prescribed (51.8%) and over the counter (48.2%) medications were present in the overall medication profile. The presence of diabetes (87.5%), hyperlipidemia (88.2%), or both (97.7%) was associated with a higher prevalence of polypharmacy than participants who exhibited hypertension in the absence of either of these conditions (63.2%), χ2(3) = 35.8, p < 0.001. CONCLUSION: Participants in a dementia risk study had high levels of polypharmacy, with the co-existence of diabetes or hyperlipidemia associated with a greater prevalence of polypharmacy as compared to having hypertension alone.

Application of SDOC Cut Points for Low Muscle Strength for Recovery of Walking Speed After Hip Fracture.

BACKGROUND: Sarcopenia is often conceptualized as a precursor to loss of mobility, but its effect on recovery of mobility after a hip fracture is unknown. We determined the prevalence of low muscle strength (weakness) after hip fracture using putative sarcopenia metrics (absolute grip strength, and grip strength normalized to body mass index, total body fat, arm lean mass, and weight) identified by the Sarcopenia Definitions and Outcomes Consortium (SDOC). METHODS: We examined two well-characterized hip fracture cohorts of community-dwelling older adults from the Baltimore Hip Studies (BHS). The prevalence of muscle weakness was assessed using the SDOC cut points compared to published definitions at 2 and 6 months postfracture. We assessed associations of 2-month weakness with 6-month walking speed <0.6 m/s and calculated the sensitivity and specificity in predicting lack of meaningful change in walking speed (change < 0.1 m/s) at 6 months. RESULTS: Two hundred and forty-six participants (192 women; 54 men) were included; mean (SD) age of 81 (8) for women and 78 (7) for men. At 2 months, 91% women and 78% men exhibited slow walking speed (< 0.6 m/s). SDOC grip strength standardized by weight (<0.34 kg women, <0.45 kg men) was the most prevalent measure of weakness in men (74%) and women (79%) and provided high sensitivity in men (86%) and women (84%) predicting lack of meaningful change in walking speed at 6 months, although specificity was poor to moderate. CONCLUSIONS: SDOC cut points for grip strength standardized to weight provided consistent indication of poor walking speed performance post-hip fracture.

Effect of a Multicomponent Home-Based Physical Therapy Intervention on Ambulation After Hip Fracture in Older Adults: The CAP Randomized Clinical Trial.

Importance: Disability persists after hip fracture in older persons. Current rehabilitation may not be sufficient to restore ability to walk in the community. Objective: To compare a multicomponent home-based physical therapy intervention (training) with an active control on ability to walk in the community. Design, Setting, and Participants: Parallel, 2-group randomized clinical trial conducted at 3 US clinical centers (Arcadia University, University of Connecticut Health Center, and University of Maryland, Baltimore). Randomization began on September 16, 2013, and ended on June 20, 2017; follow-up ended on October 17, 2017. Patients aged 60 years and older were enrolled after nonpathologic, minimal trauma hip fracture, if they were living in the community and walking without human assistance before the fracture, were assessed within 26 weeks of hospitalization, and were not able to walk during daily activities at the time of enrollment. A total of 210 participants were randomized and reassessed 16 and 40 weeks later. Interventions: The training intervention (active treatment) (n = 105) included aerobic, strength, balance, and functional training. The active control group (n = 105) received transcutaneous electrical nerve stimulation and active range-of-motion exercises. Both groups received 2 to 3 home visits from a physical therapist weekly for 16 weeks; nutritional counseling; and daily vitamin D (2000 IU), calcium (600 mg), and multivitamins. Main Outcomes and Measures: The primary outcome (community ambulation) was defined as walking 300 m or more in 6 minutes at 16 weeks after randomization. The study was designed to test a 1-sided hypothesis of superiority of training compared with active control. Results: Among 210 randomized participants (mean age, 80.8 years; 161 women [76.7%]), 197 (93.8%) completed the trial (187 [89.0%] by completing the 6-minute walk test at 16 weeks and 10 [4.8%] by adjudication of the primary outcome). Among these, 22 of 96 training participants (22.9%) and 18 of 101 active control participants (17.8%) (difference, 5.1% [1-sided 97.5% CI, -∞ to 16.3%]; 1-sided P = .19) became community ambulators. Seventeen training participants (16.2%) and 15 control participants (14.3%) had 1 or more reportable adverse events during the intervention period. The most common reportable adverse events reported were falls (training: 6 [5.7%], control: 4 [3.8%]), femur/hip fracture (2 in each group), pneumonia (training: 2, control: 0), urinary tract infection (training: 2, control: 0), dehydration (training: 0, control: 2), and dyspnea (training: 0, control: 2). Conclusions and Relevance: Among older adults with a hip fracture, a multicomponent home-based physical therapy intervention compared with an active control that included transcutaneous electrical nerve stimulation and active range-of-motion exercises did not result in a statistically significant improvement in the ability to walk 300 m or more in 6 minutes after 16 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT01783704.

Effect of Enhanced Medical Rehabilitation on Functional Recovery in Older Adults Receiving Skilled Nursing Care After Acute Rehabilitation: A Randomized Clinical Trial.

Importance: Enhanced medical rehabilitation (EMR) is a systematic and standardized approach for physical and occupational therapists to engage patients. Higher patient engagement in therapy might lead to improved functional recovery in rehabilitation settings, such as skilled nursing facilities (SNFs). Objective: To determine whether EMR improves older adults' functional recovery. Design, Setting, and Participants: A double-blind, parallel-group, randomized clinical trial was conducted from July 29, 2014, to July 13, 2018, in 229 adults aged 65 years or older admitted to 2 US SNFs. Participants were randomized to receive EMR (n = 114) vs standard-of-care rehabilitation (n = 115). Intention-to-treat analysis was used. Interventions: The intervention group received their physical and occupational therapy from therapists trained in EMR. Based on models of motivation and behavior change, EMR is a toolkit of techniques to increase patient engagement and therapy intensity. The control group received standard-of-care rehabilitation from physical and occupational therapists not trained in EMR. Main Outcomes and Measures: The primary outcome was change in function in activities of daily living and mobility, as assessed with the Barthel Index, which measures 10 basic activities of daily living or mobility items (scale range, 0-100), from SNF admission to discharge; secondary outcomes were gait speed for 10 m, 6-minute walk test, discharge disposition, rehospitalizations, and self-reported functional status at days 30, 60, and 90. To examine the rehabilitation process, therapists' engagement with patients and patient active time during therapy were measured for a sample of the sessions. Results: Of the 229 participants, 149 (65.1%) were women; 177 (77.3%) were white, and 51 (22.3%) were black; mean (SD) age was 79.3 (8.0) years. Participants assigned to EMR showed greater recovery of function than those assigned to standard of care (mean increase in Barthel Index score, 35 points; 95% CI, 31.6-38.3 vs 28 points; 95% CI, 25.2-31.7 points; P = .007). There was no evidence of a difference in the length of stay (mean [SD], 23.5 [13.1] days). However, there were no group by time differences in secondary outcome measures, including self-reported function after SNF discharge out to 90 days as measured on the Barthel Index (mean [SE] score: EMR, 83.65 [2.20]; standard of care, 84.67 [2.16]; P = .96). The EMR therapists used a median (interquartile range) of 24.4 (21.0-37.3) motivational messages per therapy session vs 2.3 (1.1-2.9) for nontrained therapists (P < .001), and EMR patients were active during a mean (SD) of 52.5 (6.6%) of the therapy session time vs 41.2 (6.8%) for nontrained therapists (P = .001). Conclusions and Relevance: Enhanced medical rehabilitation modestly improved short-term functional recovery for selected older adults rehabilitating in SNFs. However, there was no evidence that the benefits persisted over the longer term. This study demonstrates the value of engaging and motivating older adults in rehabilitation therapy, but more work is needed to extend these benefits to longer-term outcomes after discharge home. Trial Registration: ClinicalTrials.gov identifier: NCT02114879.

Rationale and methods for a multicenter clinical trial assessing exercise and intensive vascular risk reduction in preventing dementia (rrAD Study).

Alzheimer's Disease (AD) is an age-related disease with modifiable risk factors such as hypertension, hypercholesterolemia, obesity, and physical inactivity influencing the onset and progression. There is however, no direct evidence that reducing these risk factors prevents or slows AD. The Risk Reduction for Alzheimer's Disease (rrAD) trial is designed to study the independent and combined effects of intensive pharmacological control of blood pressure and cholesterol and exercise training on neurocognitive function. Six hundred and forty cognitively normal older adults age 60 to 85 years with hypertension and increased risk for dementia will be enrolled. Participants are randomized into one of four intervention group for two years: usual care, Intensive Reduction of Vascular Risk factors (IRVR) with blood pressure and cholesterol reduction, exercise training (EX), and IRVR+EX. Neurocognitive function is measured at baseline, 6, 12, 18, and 24 months; brain MRIs are obtained at baseline and 24 months. We hypothesize that both IRVR and EX will improve global cognitive function, while IRVR+EX will provide a greater benefit than either IRVR or EX alone. We also hypothesize that IRVR and EX will slow brain atrophy, improve brain structural and functional connectivity, and improve brain perfusion. Finally, we will explore the mechanisms by which study interventions impact neurocognition and brain. If rrAD interventions are shown to be safe, practical, and successful, our study will have a significant impact on reducing the risks of AD in older adults. NCT Registration: NCT02913664.

AGS Report on Engagement Related to the NIH Inclusion Across the Lifespan Policy.

After passage of the 21st Century Cures Act, the National Institutes of Health held a workshop in 2017 to consider expanding its inclusion policy to encompass individuals of all ages. American Geriatrics Society (AGS) leaders and members participated in the workshop and formal feedback period. AGS advocacy clearly impacted the resulting workshop report and Inclusion Across the Lifespan policy that eliminates upper-age limits for research participation unless risk justified and changes the language used to describe older adults and other vulnerable groups. AGS recommendations that were not specifically stated in the updated policy were to encourage active recruitment of older adults, add standard measures of function and/or frailty, and change review criteria to ensure the health status of a study population mirrors typical clinical populations. The updated inclusion policy ultimately offers academic geriatrics programs the opportunities to expand knowledge about health in aging and to continue to provide leadership for research and advocacy efforts on behalf of older adults. J Am Geriatr Soc 67:211-217, 2019.

Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial.

BACKGROUND: Myostatin inhibits skeletal muscle growth. The humanised monoclonal antibody LY2495655 (LY) binds and neutralises myostatin. We aimed to test whether LY increases appendicular lean body mass (aLBM) and improves physical performance in older individuals who have had recent falls and low muscle strength and power. METHODS: In this proof-of-concept, randomised, placebo-controlled, double-blind, parallel, multicentre, phase 2 study, we recruited patients aged 75 years or older who had fallen in the past year from 21 investigator sites across Argentina, Australia, France, Germany, Sweden, and the USA. Eligible patients had low performance on hand grip strength and chair rise tests, tested with the procedure described by Guralnik and colleagues. Participants were stratified by country, age, hand grip strength, and performance on the chair rise test, and were randomly assigned (1:1) by a computer-generated random sequence to receive subcutaneous injections of placebo or 315 mg LY at weeks 0 (randomisation visit), 4, 8, 12, 16, and 20, followed by 16 weeks observation. The primary outcome was change in aLBM from baseline to 24 weeks. We measured physical performance as secondary outcomes (four-step stair climbing time, usual gait speed, and time to rise five times from a chair without arms, or with arms for participants unable to do it without arms) and exploratory outcomes (12-step stair climbing test, 6-min walking distance, fast gait speed, hand grip strength, and isometric leg extension strength). Efficacy analyses included all randomly assigned patients who received at least one dose and had a baseline and at least one subsequent measure. The primary analysis and all other tests of treatment effect (except physical performance tests) were done at a two-sided alpha level of 0·05. Tests of treatment effect on physical performance tests were done at a pre-specified two-sided alpha level of 0·1. This trial is registered with ClinicalTrials.gov, number NCT01604408. FINDINGS: Between June 19, 2012, and Dec 12, 2013, we screened 365 patients. 99 were randomly assigned to receive placebo and 102 to receive LY. Treatment was completed in 85 (86%) of patients given placebo and in 82 (80%) given LY. At 24 weeks, the least-squares mean change in aLBM was -0·123 kg (95% CI -0·287 to 0·040) in the placebo group and 0·303 kg (0·135 to 0·470) in the LY group, a difference of 0·43 kg (95% CI 0·192 to 0·660; p<0·0001). Stair climbing time (four-step and 12-step tests), chair rise with arms, and fast gait speed improved significantly from baseline to week 24 with differences between LY and placebo of respectively -0·46 s (p=0·093), -1·28 s (p=0·011), -4·15 s (p=0·054), and 0·05 m/s (p=0·088). No effect was detected for other performance-based measures. Injection site reactions were recorded in nine (9%) patients given placebo and in 31 (30%) patients given LY (p<0·0001), and were generally mild, and led to treatment discontinuation in two patients given LY. INTERPRETATION: Our findings show LY treatment increases lean mass and might improve functional measures of muscle power. Although additional studies are needed to confirm these results, our data suggest LY should be tested for its potential ability to reduce the risk of falls or physical dependency in older weak fallers. FUNDING: Eli Lilly and Company.

Association of functional polymorphisms from brain-derived neurotrophic factor and serotonin-related genes with depressive symptoms after a medical stressor in older adults.

Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S' 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor.

Short-term affective recovery from hip fracture prospectively predicts depression and physical functioning.

OBJECTIVE: The goals of the current study were to determine the average affective experiences in the weeks and months after a hip fracture and assess how these experiences relate to physical and mental health functioning over time. METHOD: Positive and negative affect were assessed over time in a sample of older adults recruited after surgery for hip fracture (n = 500) and a comparison sample of older adults without hip fracture (n = 102) for 1 year longitudinally. RESULTS: For most of the individuals with a hip fracture, positive affect tended to increase over time and negative affect tended to decrease over time, suggesting that most people had at least some recovery of affect. In addition, individuals who showed a slower decrease in negative affect had higher levels of depression 1 year later, and individuals who showed a sharper increase in positive affect had superior physical function 1 year later. CONCLUSION: The current study provides evidence that both positive and negative affect in the first 12 weeks of recovery from hip fracture are potential targets for intervention to maximize psychological and physical recovery in the ensuing year.