Plasma brain-derived neurotrophic factor (BDNF) and sphingosine-1-phosphat (S1P) are NOT the main mediators of neuroprotection induced by resistance training in persons with multiple sclerosis—A randomized controlled trial

Resistance training (RT) has been shown to elicit neuroprotective effects in persons with multiple sclerosis (pwMS). Brain-derived neurotrophic factor (BDNF) and Sphingosine-1-phosphat (S1P) have been put forward as potent mediators of the neuroprotective effects induced by RT. However, while increases have been shown in acute and chronic circulating BDNF levels in pwMS following aerobic exercise alone or in combination with other exercise regimes, no studies have examined this in response to RT. As a novel ‘proof-of-concept’ approach, we therefore examined the effects of 24 weeks of RT on acute and chronic circulating BDNF and S1P levels in the same pwMS whom our group had previously observed RT-induced neuroprotective effects in (i.e. increased cortical thickness and preservation of whole brain volume). A total of n = 30 relapsing-remitting pwMS were randomized into a training group (TG: 24 weeks of progressive high intensity resistance training, 2 sessions per week; n = 16, age 44[40:51] years, EDSS score 3.0[2.0:3.5] (median[IQR]) or a control group (CG: 24 weeks of habitual lifestyle; n = 14, age 45[37:47] years, EDSS score 3.0[2.5:3.5]). Plasma levels of BDNF and S1P were assessed by ELISA kits before and after the 24-week intervention period. No within- or between group changes were observed in acute or chronic circulating levels of BDNF. A substantial proportion of the participants had S1P levels below the detection limit, yet no within- or between changes were observed in chronic S1P plasma levels in the remaining samples. Thus, the present findings do not support that circulating plasma BDNF or S1P levels are the main mediators of the neuroprotective effects previously reported in the same group of pwMS.</p

Predictive Factors for Improvements in Pain and Physical Function After Progressive Resistance Training or Neuromuscular Exercise in Hip Osteoarthritis. An Exploratory Analysis From the Hip Booster Trial

OBJECTIVE: To investigate associations between baseline characteristics and changes in hip pain and physical function after exercise therapy in patients with hip osteoarthritis (OA). DESIGN: Prospective cohort study. METHOD: Exploratory analyses were conducted to assess the relationship between baseline characteristics and changes in pain and activities of daily life subscales from the Hip disability and Osteoarthritis Outcomes Score questionnaire (HOOS). Data were obtained from a randomized controlled trial that compared 12 weeks of progressive resistance training to neuromuscular exercise. Predictive factors assessed were baseline levels of dependent variables, prior exercise, use of analgesics, baseline muscle power, baseline 30-second chair stand test, sex, age, and BMI. Multivariate linear and binary regression models were conducted to estimate the adjusted regression coefficients. RESULTS: Among 150 participants, changes in HOOS pain and HOOS ADL function (0-100 points, higher is better) were positively associated with female sex (? [95% CI]: 4.43 [-1.84; 10.70] and 4.70 [-1.50; 10.90]) and negatively associated with baseline levels of the dependent variable (? [95% CI]: -.45 [-.61; -.29] and -.44 [-.58; -.30]), prior exercise therapy (? [95% CI]: -7.27 [-13.48; -1.06] and -5.46 [-11.66; .74]), use of analgesics (? [95% CI]: -5.67 [-10.39; -.95] and -7.24 [-11.72; -2.76]), and BMI (? [95% CI]: -.59 [-1.07; -.11] and -.55 [-1.03; -.08]). CONCLUSIONS: Female sex, no prior exercise therapy, no use of analgesics, lower BMI, and worse pain and physical function were associated with greater effects of exercise on pain and physical function in hip OA. These findings should be interpreted with caution due to study limitations.OBJECTIVE: To investigate associations between baseline characteristics and changes in hip pain and physical function after exercise therapy in patients with hip osteoarthritis (OA).DESIGN: Prospective cohort study.METHOD: Exploratory analyses were conducted to assess the relationship between baseline characteristics and changes in pain and activities of daily life subscales from the Hip disability and Osteoarthritis Outcomes Score questionnaire (HOOS). Data were obtained from a randomized controlled trial that compared 12 weeks of progressive resistance training to neuromuscular exercise. Predictive factors assessed were baseline levels of dependent variables, prior exercise, use of analgesics, baseline muscle power, baseline 30-second chair stand test, sex, age, and BMI. Multivariate linear and binary regression models were conducted to estimate the adjusted regression coefficients.RESULTS: Among 150 participants, changes in HOOS pain and HOOS ADL function (0-100 points, higher is better) were positively associated with female sex (β [95% CI]: 4.43 [-1.84; 10.70] and 4.70 [-1.50; 10.90]) and negatively associated with baseline levels of the dependent variable (β [95% CI]: -.45 [-.61; -.29] and -.44 [-.58; -.30]), prior exercise therapy (β [95% CI]: -7.27 [-13.48; -1.06] and -5.46 [-11.66; .74]), use of analgesics (β [95% CI]: -5.67 [-10.39; -.95] and -7.24 [-11.72; -2.76]), and BMI (β [95% CI]: -.59 [-1.07; -.11] and -.55 [-1.03; -.08]).CONCLUSIONS: Female sex, no prior exercise therapy, no use of analgesics, lower BMI, and worse pain and physical function were associated with greater effects of exercise on pain and physical function in hip OA. These findings should be interpreted with caution due to study limitations

Assessing Walking Ability in People with HTLV-1-Associated Myelopathy Using the 10 Meter Timed Walk and the 6 Minute Walk Test

Five to ten million persons, are infected by HTLV-1 of which 3% will develop HTLV-1-associated myelopathy (HAM) a chronic, disabling inflammation of the spinal cord. Walking, a fundamental, complex, multi-functional task is demanding of multiple body systems. Restricted walking ability compromises activity and participation levels in people with HAM (pwHAM). Therapy aims to improve mobility but validated measures are required to assess change.Prospective observational study.To explore walking capacity in pwHAM, walking endurance using the 6 minute walk (6MW), and gait speed, using the timed 10m walk (10mTW).Out-patient setting in an inner London Teaching hospital.Prospective documentation of 10mTW and 6MW distance; walking aid usage and pain scores measured twice, a median of 18 months apart.Data analysis was completed for twenty-six pwHAM, (8♂; 18♀; median age: 57.8 years; median disease duration: 8 years). Median time at baseline to: complete 10m was 17.5 seconds, versus 21.4 seconds at follow up; 23% completed the 6MW compared to 42% at follow up and a median distance of 55m was covered compared to 71m at follow up. Using the 10mTW velocity to predict the 6MW distance, overestimated the distance walked in 6 minutes (p<0.01). Functional decline over time was captured using the functional ambulation categories.The 10mTW velocity underestimated the degree of disability. Gait speed usefully predicts functional domains, shows direction of functional change and comparison with published healthy age matched controls show that these patients have significantly slower gait speeds. The measured differences over 18 months were sufficient to reliably detect change and therefore these assessments can be useful to detect improvement or deterioration within broader disability grades. Walking capacity in pwHAM should be measured using the 10mTW for gait speed and the 6MW for endurance

The benefits of exercise in patients with multiple sclerosis

Exercise can be a beneficial rehabilitation strategy for people with multiple sclerosis to manage symptoms, restore function, optimise quality of life, promote wellness, and boost participation in activities of daily living. However, this population typically engages in low levels of health-promoting physical activity compared with adults from the general population, a fact which has not changed in the past 25 years despite growing evidence of the benefits of exercise. To overcome this challenge, the main limitations to promoting exercise through the patient–clinician interaction must be addressed. These limitations are the inadequate quality and scope of existing evidence, incomplete understanding of the mechanisms underlying the beneficial effects of exercise in people with multiple sclerosis, and the absence of a conceptual framework and toolkit for translating the evidence into practice. Future research to address those limitations will be essential to inform decisions about the inclusion of exercise in the clinical care of people with multiple sclerosis

Study protocol: improving cognition in people with progressive multiple sclerosis: a multi-arm, randomized, blinded, sham-controlled trial of cognitive rehabilitation and aerobic exercise (COGEx)

Background: Cognitive dysfunction affects up to 70% of people with progressive MS (PMS). It can exert a deleterious effect on activities of daily living, employment and relationships. Preliminary evidence suggests that performance can improve with cognitive rehabilitation (CR) and aerobic exercise (EX), but existing data are predominantly from people with relapsing-remitting MS without cognitive impairment. There is therefore a need to investigate whether this is also the case in people with progressive forms of the disease who have objectively identified cognitive impairment. It is hypothesized that CR and EX are effective treatments for people with PMS who have cognitive impairment, in particular processing speed (PS) deficits, and that a combination of these two treatments is more effective than each individual treatment given alone. We further hypothesize that improvements in PS will be associated with modifications of functional and/or structural plasticity within specific brain networks/regions involved in PS measured with advanced MRI techniques. Methods: This study is a multisite, randomized, double-blinded, sham controlled clinical trial of CR and aerobic exercise. Three hundred and sixty subjects from 11 sites will be randomly assigned into one of four groups: CR plus aerobic exercise; CR plus sham exercise; CR sham plus aerobic exercise and CR sham plus sham exercise. Subjects will participate in the assigned treatments for 12 weeks, twice a week. All subjects will have a cognitive and physical assessment at baseline, 12 weeks and 24 weeks. In an embedded sub-study, approximately 30% of subjects will undergo structural and functional MRI to investigate the neural mechanisms underlying the behavioral response. The primary outcome is the Symbol Digit Modalities Test (SDMT) measuring PS. Secondary outcome measures include: indices of verbal and non-verbal memory, depression, walking speed and a dual cognitive-motor task and MRI. Discussion: The study is being undertaken in 6 countries (11 centres) in multiple languages (English, Italian, Danish, Dutch); with testing material validated and standardized in these languages. The rationale for this approach is to obtain a robustly powered sample size and to demonstrate that these two interventions can be given effectively in multiple countries and in different languages. Trial registration: The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated

At home e-based physical exercise programs in patients with multiple sclerosis: a scoping review

INTRODUCTION: Physical exercise (PE) improves symptoms and quality of life in people with multiple sclerosis (pwMS). However, incorporating PE into daily lives of pwMS pose difficulties. As an alternative to in-person PE, e-based PE has been proposed because of its advantages in terms of accessibility and convenience. OBJECTIVE: To synthesize existing evidence on e-based PE at home in adults MS and discuss study designs, rehabilitation programs, intervention effects and possible knowledge gaps. METHODS: In this scoping review, a systematic search in electronic databases including Embase, Medline, CINAHL and Cochrane Library was conducted following the PRISMA guidelines. Peer-reviewed articles in English on e-based PE interventional studies at home involving adult pwMS, published from 2008 until April 2023, were identified and exported to Covidence. Data from the included studies were extracted and synthesized. This scoping review identified different types of e-based PE interventions used in pwMS across different study designs, but when evaluating intervention effects, this review focused solely on randomized controlled trials (RCTs). RESULTS A total of 3,006 studies were retrieved and 179 studies were screened in full text, resulting in the inclusion of 54 studies with a total of 2,359 pwMS. Of those, 33 were RCTs and three were qualitative studies. The studies reported on various e-based interventions including video-based programs, telerehabilitation, and web-based programs. The interventions evaluated muscle strength, cardiorespiratory fitness, walking speed, endurance, balance, and fatigue, as well as symptoms of depression and cognitive dysfunction. E-based PE interventions at home in RCTs demonstrated improvement of depressive symptoms and anxiety, while inconsistent results were reported for fatigue, walking speed and balance. No significant benefits were observed regarding dexterity. Results were generally heterogeneous and were limited by small sample sizes. Several limitations were identified, such as lack of physical activity assessment prior to the intervention and poor reporting of duration, intensity, frequency and adherence to e-based PE interventions. CONCLUSION: E-based PE interventions in pwMS may improve MS-related symptoms, but the study quality is generally low, and findings are often inconsistent. Several important limitations of the existing literature have been identified in the present review, which can guide future research

Associations between fatigue impact and physical and neurobehavioural factors: An exploration in people with progressive multiple sclerosis

Background: Fatigue is common in people with multiple sclerosis (MS). Understanding the relationship between fatigue, physical and neurobehavioural factors is important to inform future research and practice. Few studies explore this explicitly in people with progressive MS (pwPMS). // Objective: To explore relationships between self-reported fatigue, physical and neurobehavioural measures in a large, international progressive MS sample of cognitively impaired people recruited to the CogEx trial. // Methods: Baseline assessments of fatigue (Modified Fatigue Impact Scale; MFIS), aerobic capacity (VO2peak), time in moderate-vigorous physical activity (MVPA; accelerometery over seven-days), walking performance (6-minute walk test; 6MWT), self-reported walking difficulty (MS Walking Scale; MSWS-12), anxiety and depression (Hospital Anxiety and Depression Scale; HADS and Beck Depression Inventory-II; BDI-II), and disease impact (MS Impact Scale-29, MSIS-29) were assessed. Participants were categorised as fatigued (MFISTotal >=38) or non-fatigued (MFISTotal ≤38). // Statistical Analysis: Differences in individuals categorised as fatigued or non-fatigued were assessed (t-tests, chi square). Pearson's correlation and partial correlations (adjusted for EDSS score, country, sex, and depressive symptoms) determined associations with MFISTotal, MFISPhysical, MFISCognitive and MFISPsychosocial, and the other measures. Multivariable logistic regression evaluated the independent association of fatigue (categorised MFISTotal) with physical and neurobehavioural measures. // Results: The sample comprised 308 pwPMS (62 % female, 27 % primary progressive, 73 % secondary progressive), mean age 52.5 ± 7.2 yrs, median EDSS score 6.0 (4.5–6.5), mean MFISTotal 44.1 ± 17.1, with 67.2 % categorised as fatigued. Fatigued participants walked shorter distances (6MWT, p = 0.043), had worse MSWS-12 scores (p < 0.001), and lower average % in MVPA (p = 0.026). The magnitude of associations was mostly weak between MFISTotal and physical measures (r = 0.13 to 0.18), apart from the MSWS-12 where it was strong (r = 0.51). The magnitude of correlations were strong between the MFISTotal and neurobehavioural measures of anxiety (r = 0.56), depression (r = 0.59), and measures of disease impact (MSIS-physical r = 0.67; MSIS-mental r = 0.71). This pattern was broadly similar for the MSIF subscales. The multivariable model indicated a five-point increase in MSWS-12 was associated with a 14 % increase in the odds of being fatigued (OR [95 %CI]: 1.14 [1.07–1.22], p < 0.0001) // Conclusion: Management of fatigue should consider both physical and neurobehavioural factors, in cognitively impaired persons with progressive MS

Cardiorespiratory fitness and free-living physical activity are not associated with cognition in persons with progressive multiple sclerosis: Baseline analyses from the CogEx study

Background: Aerobic exercise training (physical activity for improving cardiorespiratory fitness) represents a promising approach for managing cognitive impairment in multiple sclerosis (MS). However, there is limited evidence that levels of physical activity and fitness are associated with cognition in progressive MS. Objective: We examined associations among cardiorespiratory fitness, moderate-to-vigorous physical activity (MVPA), and cognitive performance in a large, international progressive MS sample. Methods: Two hundred forty European and North American persons with progressive MS underwent cardiorespiratory fitness measurement on a recumbent stepper, wore an ActiGraph GT3X + accelerometer for 7 days for measuring MVPA, and underwent the Brief International Cognitive Assessment in MS. Results: Cardiorespiratory fitness was not significantly correlated with Symbol Digit Modalities Test (SDMT; r = −0.01; r = −0.04), California Verbal Learning Test-II (CVLT-II; r = 0.05; r = 0.05), or Brief Visuospatial Memory Test–Revised (BVMT-R; r = −0.14; r = −0.14) z-scores controlling for age, sex, and education. MVPA and SDMT ( r = 0.05), CVLT-II ( r = −0.07), and BVMT-R ( r = 0.01) z-scores were not significantly correlated. Conclusion: Cardiorespiratory fitness and MVPA were not associated with cognition in this large progressive MS sample, yet these outcomes represent critical manipulation checks for documenting the success of the CogEx trial. This highlights the importance of examining other exercise-related mechanisms-of-action for improving cognition in progressive MS. </jats:sec