United Kingdom

Introduction: Lower-limb impairment is common after stroke, limiting independence of those affected. Early, accurate prediction of recovery could enable individualised rehabilitation and optimise outcomes. Previous evidence supports an effect of stroke-related damage to corticospinal tracts (CST) on functional recovery. However, effects of post-stroke sarcopenia, resultant muscle fiber-type shift and inflammation are unknown. An algorithm accounting for these changes, based on combined MRI imaging of the source-organ (brain) and end-organ (lower-limb skeletal muscle), may have superior accuracy compared with clinical assessments or isolated MRI biomarkers. We aim to assess the feasibility and utility of MRI biomarkers for predicting lower-limb recovery following stroke. Methods: 30 patients will be recruited from two North-East England NHS trusts within four weeks of their first-ever ischaemic stroke causing unilateral lower-limb weakness. Patients undergo brain and thigh muscle MRI, including volumetric sequences, lipid and oedema-based muscle imaging and diffusion tensor imaging of the CST. This is followed by baseline and 3-month clinical assessments of: lower-limb impairment (Fugl-Meyer; Motor NIHSS) strength (handheld-dynamometry) and function (Functional Ambulatory Category). Results: 10/30 participants have been recruited since 2019 and the study will close in 2021. Correlations between MRI, clinical and 3-month follow-up outcome data will assess relationships between biomarkers and outcomes to inform a predictive model incorporating baseline clinical and MRI data. Conclusion: This project will provide novel data on sarcopenia-based measures in stroke recovery. If our model has predictive value, a sample size estimate will be calculated to inform future multicentre studies with the aim of developing a robust predictive algorithm.

ISTRC 2021 - International Sarcopenia Translational Research Conference

Study in Novel Neuro-muscular Imaging Biomarkers for Motor Outcome in Stroke

neuromuscular

stroke

Welcome to the inaugural International Sarcopenia Translational Research Conference.  “Where Worlds Meet” – the event brings together a broad range of researchers and practitioners in a truly interdisciplinary forum, covering discovery science through to clinical practice.

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Access to this event requires a registration. Please email Eleanor Lockhart at sarcconf@ncl.ac.uk if you have any questions regarding your registration. 

poster

Background: Undertaking clinical trials for sarcopenia presents multiple challenges. The diagnosis is not commonly made in clinical practice in part due to the need to measure muscle mass and muscle strength. Finding participants with sarcopenia for clinical trials is therefore challenging and often requires screening large numbers of potential participants in order to identify those with sarcopenia. Sarcopenia registries are a potential method to improve recruitment to sarcopenia trials, which has proved challenging to date. We aimed to test the feasibility of setting up a UK sarcopenia registry, the feasibility of recruitment methods and to characterise the pilot registry population. Methods: Six diverse UK sites took part, selected to give a range of large and small cities, different geographies and different proportion of ethnic minority prevalence in the local population. Potential participants aged 65 and over were approached via mailshots from local primary care (GP) practices. Telephone pre-screening using the SARC-F score was followed by inperson screening and baseline visit. Comorbidities, medications, grip strength, Short Physical Performance Battery, bioimpedance analysis (Akern 101 system), Geriatric Depression Score, Montreal Cognitive Assessment and SarQoL score were performed. Permission was sought for future re-contact. We conducted an embedded randomised controlled trial of a simple intervention which aimed to boost mailshot response rates. Mailshot batches were randomised to the presence or absence of a Newcastle University logo on the mailshot envelope; we hypothesised that mailshots with the logo would be more likely to be opened and thus responded to, rather than treated as junk mail. Recruitment rates and baseline measures were analysed using descriptive statistics. For the embedded randomised trial, the primary outcome (the proportion of letters generating a positive reply (mail slip or telephone contact) was compared using Pearson's chi-squared test with 95% confidence intervals. Results: Sixteen GP practices contributed a total of 3508 letters. Details of response rates and progression through screening and recruitment for each site are given in Table 1. 150 participants were recruited (40% of those pre-screened) with 147 contributing baseline data. Conclusion: Recruitment to a multi-site UK sarcopenia registry is feasible, with high levels of consent for recontact. Different populations may require different contact approaches to maximise participation.

Developing a UK sarcopenia registry: recruitment and baseline characteristics of the SarcNet pilot

Background: Frailty in older adults is a growing challenge, further exacerbated by recent COVID-related reductions in activity. Thankfully, there is now an established evidence base for the benefit of exercise and protein supplementation in counteracting frailty. Unfortunately, this this has not yet been adequately translated into practice. The aim of this study, Diet & Exercise for FRAILty (DEFRAIL), was to develop an effective intervention suitable for widespread uptake. Our first objective was to design an intervention suitable for a wide spectrum of frailty in older adults and deliverable in a community setting. The second was to evaluate its effect on frailty and related measures. Methods: Intervention: A multi-component exercise program combined with nutritional supplementation was developed by a modified Delphi process (Figure 1). A brief pilot trial allowed participant feedback and further modifications. The final DEFRAIL program consisted of a 1-hour group class: -Warm-up x 5 mins -Stretch x 5 mins -Circuits x 15 mins each -Upper limb resistance -Lower limb resistance -Aerobic/Balance -Cool-down x 5 mins The nutritional intervention was protein-supplemented milk (250ml twice daily). Three-day food diaries were completed pre-and intraintervention to monitor the effect on micro- & macro-nutrient intake Classes were delivered by 2 instructors in group of 10-12 participants per class. Results: Participant characteristics: 28 participants (22 female, 6 male) commenced the program, of which 22 (16 female, 6 male) completed follow-up assessments. Mean age was 84.5 years, mean FFC 3.55 prior to the intervention). Statistical approach: Analysis was conducted using SPSS. The mean change in outcome measures over the control and intervention periods were compared using paired t-tests. Primary outcome measure: A statistically significant improvement in FFC of -2.05 was seen in the primary outcome measure during the intervention period, compared with the control period (mean change over control period +0.32, mean change over intervention period -1.73). The mean FFC moved from 3.23 (frail) at baseline to 3.55 (frail) after eight weeks of regular activity but fell to 1.82 (pre-frail) following completion of the intervention. Improvements were seen in the individual criteria of ”Exhaustion”, “Low activity and “Slow gait speed” but not “Weight loss” or “Low grip strength”. Secondary outcome measures: A statistically significant improvement was seen in the Timed Up & Go (TUG) test, with a mean difference of - 3.19 seconds between the change during the intervention over the control period. A significant improvement was also seen in the Geriatric Depression Scale, with a mean difference of -1.41. Based on pre- and intra-intervention three-day food diaries, a significant increase in protein intake (daily mean difference of +11.22g) was observed. No significant change was observed for measures of body mass composition, arterial stiffness, cognition, pain or quality-of-life. Conclusion: The DEFRAIL intervention is feasible for delivery without the direct input of health professionals and effective at reversing frailty in a group of community-dwelling frail older adults. We propose that it provides an effective community-based means of reversing frailty and its associated adverse outcomes. Given the growing prevalence of frailty, we feel there is an urgent need to incorporate an intervention such as this into public health policy. 

Diet and Exercise for FRAILty (DEFRAIL): The effect of a novel community-based exercise and nutritional intervention on frailty and related measures in
frail older adults

Introduction: 1) Frailty is independently associated with poor clinical outcomes such as impaired quality of life, as well as increased emergency hospital admission2 , disability 3 and earlier death. 2) Currently very few treatments, such as resistance training and nutrition high in protein have shown to have positive effects on reducing levels of frailty. 3) Given positive results in mouse studies, NAD+ supplementation may have potential as an intervention to prevent or reverse elements of poor physical function and frailty in older humans. 4) We aimed to systematically assess all available randomised controlled trials investigating effects of NAD+ precursor drugs on outcomes relevant to physical function or frailty. Methods: Figure 1. PRISMA flow chart for papers found through systematic search. 5) The Fried frailty phenotype criteria were used as a framework to construct the study’s systematic search, based on the five Fried domains: - Gait speed - Muscle strength - Fatigue and exhaustion - Physical activity - Weight loss 6) A systematic search strategy was used on several databases: MEDLINE, EMBASE, CINAHL, CENTRAL, ISRCTN, clinicaltrials.gov, NHS e-Library and Google Scholar. No language restrictions were used. Mean cohort age had to be >18 years. 7) Risk of bias was assessed using the Cochrane Risk-of-Bias 2 tool. Results were grouped by phenotype domain and described through narrative synthesis. 8) All stages of the review were conducted independently by two separate authors. Results: 1) Twenty studies met the inclusion criteria; sample sizes ranged from 2 to 77 participants. • Most studies assessed only a limited number of frailty domains. Interventions were mostly short term, with 10 (50%) of studies having an intervention period of 1 week or less • Risk of bias analysis showed high risk of bias in 12/20 studies and unclear risk of bias in 7/20 studies. This was frequently due to the adverse effect of flushing which impaired masking. 2) Only 3 studies enrolled cohorts with a participant mean age >65 years. No studies assessed for intracellular NAD+ levels before or after supplementation. Conclusions: 1) The current evidence on NAD+ precursor supplementation is insufficient to ascertain effects on the frailty phenotype or physical performance. • High-quality studies are required to explore the effects of NAD+ precursor supplementation on frailty and physical function more closely. Measures of physical function and/or frailty should be primary outcomes of these studies. 2) Previous studies on NAD+ levels in humans show that older people are more likely to be deficient than younger people, and therefore may respond differently to its treatment. Future studies should consider older people as key participants of NAD+ supplementation research.

Effects of nicotinamide adenine dinucleotide precursors on physical function and frailty: a systematic review

Background and Aims: • NAFLD is the most common liver condition worldwide and is directly linked to chronic excess calorie consumption, lack of physical activity and overweight/obesity. • NAFLD can progress to non-alcoholic steatohepatitis (NASH). Incidence of NASHrelated end stage liver disease is increasing. • Concurrent with an increasing prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) and sarcopenic obesity are rising. • There is growing evidence of a causal link between sarcopenia and the development of NAFLD. • A very low calorie diet (VLCD) has been postulated as a possible solution for NAFLD, however, there are concerns that a VLCD may induce further reduction of skeletal muscle mass (SMM). Methods: • 30 patients with advanced NAFLD were recruited to an 8-12 week VLCD (~800 kcal/day) using meal replacement products (Optifast, Nestlè Health Science). • 11 patients opted to extend the VLCD intervention beyond 8 weeks up to 12. • Anthropometrics, body composition, blood tests (liver enzymes, lipid profile, glucose, HbA1c, insulin), liver stiffness, Quality of life, and cardiovascular disease risk were measured at baseline and after the VLCD intervention. • Bioelectrical impedance analysis was used to determine body composition; fat mass (FM), fat-free mass (FFM) and skeletal muscle mass (SMM). • Anthropometrics and blood tests were also measured at weeks 1, 3, 5, 7 (and at weeks 9 and 11). • Given the intense caloric restriction, patients were not encouraged to partake in heavy exercise during a VLCD. Results: • Of the 45 patients approached to take part in this study, 30 consented to enrol. This study was fully recruited at a single site within 6 months and 27/30 retained post VLCD. • 68% of patients reached the weight loss target of 10%; mean weight loss was 13kg (3-39), equivalent to 11% (3-26). • Weight loss through an 8-12 week VLCD significantly improved (Table 1); -BMI and body composition -liver health (liver enzymes and liver stiffness) -cardiometabolic disease risk (blood pressure and QRISK2) -There was a moderate positive correlation between weight loss and change in SMM (r=0.444, p=0.034). -QOL and weight related symptom measure (WRSM) significantly improved from 44±26 to 55±20 (p=0.001) and 43±30 to 31±23 (p=0.039), respectively. Conclusions • Despite previous concerns that a VLCD may exacerbate sarcopenic characteristics, the VLCD intervention did not significantly affect SMM, but induced efficient weight loss. • it may be beneficial to encourage continuation of daily physical activity during the VLCD and an increase in physical activity/exercise after completion of the VLCD, to maintain long-term weight-loss and FFM/SMM.

The effect of a very low calorie diet on body composition in patients with non-alcoholic fatty liver disease

Introduction: Disability leads to immobilisation associated with profound changes in body composition. The potential risks involved with these changes i.e. loss of lean tissue mass (LM) vs. gain in fat mass (FM) in body composition have implications for the health of the disabled individuals. The investigation of sarcopenic obesity is important in populations with disabilities as they lead to metabolic disorders and concomitant diseases that aggravate the neurological picture. Purpose: The primary outcomes of the study were to investigate indicators of sarcopenic obesity and correlations with obesity and body mass indices. Secondary outcomes were investigation of sarcopenia indices and the relationship with sarcopenic obesity in people with neurological disabilities (strokes, spinal cord injuries, traumatic brain injuries). Methods – Material: The study Sarcopenic Obesity in NeuroDisabled Subjects (Acronym: SarcObeNDS) is an observational study of hospitalized patients and controls (90 and 30 respectively), aged 60.00 ± 14.22, who were examined with full body absorption dual energy absorption measurements in body composition measurements. Sarcopenic obesity was assessed with the indicators: fat mass%, and fat mass index to height 2 (Kg / m2 ) and sarcopenia with skeletal muscle index (peripheral muscle mass to height 2 (Kg / m2 ) - SMI. The study is registered in the international database ClinicalTrials.gov with unique number: NCT03863379. Results: A statistically significant difference was found in body mass index (26.70 ± 4.54 vs. 24.27 ± 4.55, p = 0.012) and in BMD (7.18 ± 0.95 vs. 6.00 ± 1.13, p <0.001). No statistical significance was found in total fat (%) (p = 0.793) and fat mass index to height2 (p = 0.143). A strong positive statistically significant correlation was found between BMI and total fat index (%) and between BMI and total fat mass (r= 0.616 p <0.001 vs. r = 0.728 p <0.001 and r = 0.420 p <0.001 vs. r = 0.868 p <0.001, respectively) in controls and people with disabilities. Conclusion: At the clinical level, the recognition of these diseases will prevent metabolic disorders in these vulnerable populations.

Sarcopenic Obesity in Neurodisabilities: The SarcObeNDS study

Background: This study examined the impact of sarcopenia on clinical outcome in patients who underwent infrainguinal bypass surgery or major lower limb amputation (MLLA). Methods: Patients undergoing infra-inguinal bypass and MLLA in 2016-2018 were included in this retrospective analysis. Sarcopenia was identified by CT of muscle area at L3 vertebral. Primary outcome was overall survival, analysed using Cox regression. Secondary outcomes for bypass included ipsilateral MLLA, length of hospital stay, myocardial infarction and surgical-site infection. For the MLLA cohort we included stump infection and breakdown. These were analysed using Fisher’s test (categorical), Mann-Whitney U test (non-parametric) and t-test (parametric). Results: 216 patients (116 bypass, 100 MLLA) were included. 14/116 (12%) of bypass patients and 13/100 (13%) of MLLA patients were sarcopenic. Age, other co-morbidities, and laboratory tests were similar in those with and without sarcopenia. Overall survival was worse for sarcopenic patients (HR for death 5.8; 95%CI 1.8-19.1; p=0.001) in the bypass cohort, however, this was not observed in the MLLA cohort (HR 1.29; 95%CI 0.23-2.62; p=0.7). MLLA occurred more frequently in patients with sarcopenia (7/14 [50%] vs 23/102 [23%]; p=0.046). There was no difference in other secondary outcomes in either cohort. Conclusion: In the cohort of patients undergoing infrainguinal lower limb bypass, sarcopenia defined using L3 muscle area was significantly associated with overall mortality and MLLA, however sarcopenia was not associated with worse survival in the MLLA group. Sarcopenia and frailty may be a key factor in stratifying those who should undergo an amputation-first approach to CLTI.

The influence of sarcopenia on lower limb bypass & major lower limb amputation outcomes

Background: Mitochondrial dysfunction is a potential therapeutic target to improve skeletal muscle function, but the contribution of mitochondrial dysfunction to impaired skeletal muscle performance in older people remains unclear. The aim of this analysis was to test the association between measures of skeletal muscle mitochondrial function and physical performance in older people. Methods: We analysed data from the Allopurinol in Functional Impairment trial. Participants aged 65 and over, who were unable to walk 400 m in 6 min, underwent 31P magnetic resonance spectroscopy of the calf after exercise at baseline and at 20 weeks follow up. The phosphocreatine recovery half-life time (t1/2) was derived as a measure of mitochondrial function. Participants undertook the 6-min walk test and the Short Physical Performance Battery. Muscle mass measured using the Akern 101 bio-impedance analysis system. Bivariate correlations and multivariable regression analyses were conducted to determine associations between t1/2 and baseline factors. Results: One hundred and seventeen participants underwent baseline 31P magnetic resonance spectroscopy, mean age 80.4 years (SD 6.0); 56 (48%) were female. Mean 6-min walk was 291 m (SD 80), mean SPPB score was 8.4 (SD 1.9); t1/2 correlated significantly with Short Physical Performance Battery score (r = 0.22, P = 0.02) but not with 6-min walk distance (r = 0.10, P = 0.29). In multivariable linear regression, muscle mass and total body weight, but not t1/2, were independently associated with Short Physical Performance Battery score and with 6-min walk distance. Change in t1/2 was not significantly associated with change in Short Physical Performance Battery score (r = 0.03, P = 0.79) or with change in 6-min walk distance (r = −0.11, P = 0.28). Conclusions: Muscle mass, but not phosphocreatine recovery time, was consistently associated with Short Physical Performance Battery score and 6-min walk distance in older people with functional impairment.

Is Mitochondrial Function Measured by 31p Magnetic Resonance Spectroscopy Associated With Physical Performance in Older People With Functional Impairment?

Background: Sarcopenia, defined as the age-related loss of muscle mass and strength, is a major health problem. The condition is common, affecting between 5 and 10% of communitydwelling people aged over 65. It is a major cause of multiple adverse outcomes for older people including falls, fractures, hospital admission, prolonged length of stay, need for care and reduced survival. The objectives of the LACE trial were to determine the efficacy of leucine and perindopril in improving physical function, muscle mass and quality of life in older people diagnosed with sarcopenia. Methods: LACE was a placebo-controlled, parallel group, double-blind, randomised two-by-two factorial trial. Participants: Adults aged ≥70 years with low muscle strength and low muscle mass, without contraindications to ACE inhibitors and without known diagnosis-specific skeletal myopathy recruited from 14 UK centres. Interventions: Eligible participants were randomised 1:1 to 4mg oral perindopril or matching placebo, and separately randomised 1:1 to oral leucine powder 2.5g or matching placebo powder taken thrice daily with meals. Interventions were given for 12 months. Outcome measures: The primary outcome was the between-group difference in the Short Physical Performance Battery score (measured at baseline, 6 and 12 months). Secondary outcomes included grip strength, quadriceps strength, six-minute walk distance, appendicular muscle mass measured by dual x-ray absorptiometry and quality of life (EQ5D tool). All adverse events and falls were recorded. Outcomes were analysed using repeated measures mixed models, adjusted for baseline values, age, sex and minimisation variables. Prespecified subgroup analyses for the primary outcome were also conducted for age, sex and baseline protein intake. An initial test for treatment interaction showed no evidence of interaction and thus the perindopril vs placebo and leucine vs placebo comparisons were conducted separately. Recruitment: We screened 320 people and randomised 145 participants, mean age 79 (SD 6) years; 78 (54%) were women and the mean SPPB was 7.0 (SD 2.4). Figure 1 shows the CONSORT diagram for recruitment. Conclusion: Perindopril did not improve physical performance, muscle mass or quality of life in older people with sarcopenia in this trial.

Effect of perindopril on physical performance, muscle mass and quality of life in older people with sarcopenia: Results from the LACE randomised controlled trial

Background: Sarcopenia, defined as the age-related loss of muscle mass and strength, is a major health problem. The condition is common, affecting between 5 and 10% of communitydwelling people aged over 65. It is a major cause of multiple adverse outcomes for older people including falls, fractures, hospital admission, prolonged length of stay, need for care and reduced survival. The objectives of the LACE trial were to determine the efficacy of leucine and perindopril in improving physical function, muscle mass and quality of life in older people diagnosed with sarcopenia. Methods: LACE was a placebo-controlled, parallel group, double-blind, randomised two-by-two factorial trial. Participants: Adults aged ≥70 years with low muscle strength and low muscle mass, without contraindications to ACE inhibitors and without known diagnosis-specific skeletal myopathy recruited from 14 UK centres. Interventions: Eligible participants were randomised 1:1 to 4mg oral perindopril or matching placebo, and separately randomised 1:1 to oral leucine powder 2.5g or matching placebo powder taken thrice daily with meals. Interventions were given for 12 months. Outcome measures: The primary outcome was the between-group difference in the Short Physical Performance Battery score (measured at baseline, 6 and 12 months). Secondary outcomes included grip strength, quadriceps strength, six-minute walk distance, appendicular muscle mass measured by dual x-ray absorptiometry and quality of life (EQ5D tool). All adverse events and falls were recorded. Outcomes were analysed using repeated measures mixed models, adjusted for baseline values, age, sex and minimisation variables. Prespecified subgroup analyses for the primary outcome were also conducted for age, sex and baseline protein intake. An initial test for treatment interaction showed no evidence of interaction and thus the perindopril vs placebo and leucine vs placebo comparisons were conducted separately. Recruitment: We screened 320 people and randomised 145 participants, mean age 79 (SD 6) years; 78 (54%) were women and the mean SPPB was 7.0 (SD 2.4). Figure 1 shows the CONSORT diagram for recruitment. Conclusion: Leucine did not improve physical performance, muscle mass or quality of life in older people with sarcopenia in this trial.

Effect of leucine supplementation on physical performance, muscle mass and quality of life in older people with sarcopenia: Results from the LACE randomised controlled trial

Background: Anorexia of ageing is common but often not assessed in clinical practice despite the availability of simple tools such as the four-item Simplified Nutritional Appetite Questionnaire (SNAQ)1. Anorexia of ageing is associated with altered dietary pattern, weight loss and malnutrition, potentially contributing to the development of sarcopenia through loss of muscle mass. However, the association between appetite and muscle strength is less clear. Methods: Cross sectional observational study of community dwelling adults aged over 60 years, attending outpatient appointments in one hospital. Appetite was assessed using SNAQ; muscle strength by handgrip strength with a Jamar dynamometer and standard protocol. The association between appetite (SNAQ score between 5 and 20) and grip strength was assessed in unadjusted and adjusted continuous analyses. Results: We observed an association between poorer appetite and lower muscle strength in community dwelling older adults, independent of sex. This association was not robust when accounting for effects of age and comorbidity. Poor appetite may be associated with low muscle strength prior to older age and comorbidities but further investigation is needed. Appetite is simple to assess in older people using SNAQ and may prove useful in earlier identification of individuals at risk of developing sarcopenia.

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Study in Novel Neuro-muscular Imaging Biomarkers for Motor Outcome in Stroke

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