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Focusing on neural mechanisms of exercise training benefits in multiple sclerosis.
Sandroff, BM, Motl, RW, Salter, A
Multiple sclerosis and related disorders. 2024;:105633
Abstract
Exercise training (ET) should be a mainstay of comprehensive care in multiple sclerosis (MS), yet there is reluctance regarding its implementation among healthcare providers. This reluctance has its roots in the lack of evidence from randomized controlled trials (RCTs) that provide a neurobiological mechanism for beneficial outcomes. We argue that ET training is efficacious for improving mobility and cognitive dysfunction as hallmark consequences of MS, and propose an experimental medicine framework for guiding research focusing on CNS mechanisms-of-action for ET benefits. The framework establishes three hierarchical pathways as preconditions for applying a mediation framework in a fourth pathway for fully testing mechanistic research questions using a RCT. This paper describes the conceptual basis of the pathways, and then reviews the existing evidence within the pathways of the framework for ET effects on the CNS, mobility, and cognition in MS. Lastly, this paper discusses future directions and challenges for testing the pathways of the framework for advancing the evidence regarding CNS mechanisms of ET benefits in this population. Our objective is guiding the field toward evidence that facilitates the prescription and promotion of ET as a neurorestorative approach within MS clinical practice.
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Prevalence and Associated Clinical Characteristics of Walking-Related Motor, Cognitive, and Fatigability in Progressive Multiple Sclerosis: Baseline Results From the CogEx Study.
Ramari, C, D'hooge, M, Dalgas, U, Feinstein, A, Amato, MP, Brichetto, G, Chataway, J, Chiaravalloti, ND, Cutter, GR, DeLuca, J, et al
Neurorehabilitation and neural repair. 2024;:15459683241236161
Abstract
BACKGROUND People with progressive multiple sclerosis (PMS) present motor (eg, walking) and cognitive impairments, and report fatigue. Fatigue encompasses fatigability which is objectively measured by the capacity to sustain a motor or cognitive task. OBJECTIVE To investigate the prevalence of walking and cognitive fatigability (CF) and the associated clinical characteristics in a large sample of PMS patients. METHODS PMS patients (25-65 years old) were included from 11 sites (Europe and North America), having cognitive impairment (1.28 standard deviation below normative data for the symbol digit modality test [SDMT]). Walking fatigability (WF) was assessed using the distance walk index (DWI) and CF using the SDMT (scores from the last 30 seconds compared to the first 30 seconds). Additional measures were: cognitive assessment-Brief International Cognitive Assessment for multiple sclerosis (MS), cardiorespiratory fitness, 6-minute walk, physical activity, depressive symptoms, perceived fatigue-Modified Fatigue Impact Scale (MFIS), MS impact-MSIS-29, and walking ability. RESULTS Of 298 participants, 153 (51%) presented WF (DWI = -28.9 ± 22.1%) and 196 (66%) presented CF (-29.7 ± 15%). Clinical characteristics (EDSS, disease duration, and use of assistive device) were worse in patients with versus without WF. They also presented worse scores on MSIS-29 physical, MFIS total and physical and reduced physical capacity. CF patients scored better in the MSIS-29 physical and MFIS psychosocial, compared to non-CF group. Magnitude of CF and WF were not related. CONCLUSIONS Half of the cognitively-impaired PMS population presented WF which was associated with higher disability, physical functions, and fatigue. There was a high prevalence of CF but without strong associations with clinical, cognitive, and physical functions. TRIAL REGISTRATION NUMBER The "CogEx-study," www.clinicaltrial.gov identifier number: NCT03679468.
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Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis.
Vasileiou, ES, Hu, C, Bernstein, CN, Lublin, F, Wolinsky, JS, Cutter, GR, Sotirchos, ES, Kowalec, K, Salter, A, Saidha, S, et al
Neurology(R) neuroimmunology & neuroinflammation. 2023;(1)
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Abstract
BACKGROUND AND OBJECTIVES Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS. METHODS We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10-8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 × 10-5) and applying Mendelian randomization (MR) rather than using PGS. RESULTS Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR. DISCUSSION Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.
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Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis (CogEx): a randomised, blinded, sham-controlled trial.
Feinstein, A, Amato, MP, Brichetto, G, Chataway, J, Chiaravalloti, ND, Cutter, G, Dalgas, U, DeLuca, J, Farrell, R, Feys, P, et al
The Lancet. Neurology. 2023;(10):912-924
Abstract
BACKGROUND Cognitive dysfunction in people with relapsing-remitting multiple sclerosis can improve with cognitive rehabilitation or exercise. Similar effects have not been clearly shown in people with progressive multiple sclerosis. We aimed to investigate the individual and synergistic effects of cognitive rehabilitation and exercise in patients with progressive multiple sclerosis. METHODS CogEx was a randomised, sham-controlled trial completed in 11 hospital clinics, universities, and rehabilitation centres in Belgium, Canada, Denmark, Italy, UK, and USA. Patients with progressive multiple sclerosis were eligible for inclusion if they were aged 25-65 years and had an Expanded Disability Status Scale (EDSS) score of less than 7. All had impaired processing speed defined as a performance of 1·282 SD or greater below normative data on the Symbol Digit modalities Tests (SDMT). Participants were randomly assigned (1:1:1:1), using an interactive web-response system accessed online from each centre, to cognitive rehabilitation plus exercise, cognitive rehabilitation plus sham exercise, exercise plus sham cognitive rehabilitation, or sham exercise plus sham cognitive rehabilitation. The study statistician created the randomisation sequence that was stratified by centre. Participants, outcome assessors, and investigators were blinded to group allocation. The study statistician was masked to treatment during analysis only. Interventions were conducted two times per week for 12 weeks: cognitive rehabilitation used an individualised, computer-based, incremental approach to improve processing speed; sham cognitive rehabilitation consisted of internet training provided individually; the exercise intervention involved individualised aerobic training using a recumbent arm-leg stepper; and the sham exercise involved stretching and balance tasks without inducing cardiovascular strain. The primary outcome measure was processing speed measured by SDMT at 12 weeks; least squares mean differences were compared between groups using linear mixed model in all participants who had a 12-week assessment. The trial is registered with ClinicalTrials.gov, NCT03679468, and is completed. FINDINGS Between Dec 14, 2018, and April 2, 2022, 311 people with progressive multiple sclerosis were enrolled and 284 (91%) completed the 12-week assessment (117/311 [38%] male and 194/311 [62%] female). The least squares mean group differences in SDMT at 12 weeks did not differ between groups (p=0·85). Compared with the sham cognitive rehabilitation and sham exercise group (n=67), differences were -1·30 (95% CI -3·75 to 1·16) for the cognitive rehabilitation plus exercise group (n=70); -2·78 (-5·23 to -0·33) for the sham cognitive rehabilitation plus exercise group (n=71); and -0·71 (-3·11 to 1·70) for the cognitive rehabilitation plus sham exercise group (n=76). 11 adverse events possibly related to the interventions occurred, six in the exercise plus sham cognitive rehabilitation group (pain, dizziness, and falls), two in the cognitive rehabilitation plus sham exercise group (headache and pain), two in the cognitive rehabilitation and exercise group (increased fatigue and pain), and one in the dual sham group (fall). INTERPRETATION Combined cognitive rehabilitation plus exercise does not seem to improve processing speed in people with progressive multiple sclerosis. However, our sham interventions were not inactive. Studies comparing interventions with a non-intervention group are needed to investigate whether clinically meaningful improvements in processing speed might be attainable in people with progressive multiple sclerosis. FUNDING MS Canada.
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Cardiovascular disease, associated risk factors, and risk of dementia: An umbrella review of meta-analyses.
Brain, J, Greene, L, Tang, EYH, Louise, J, Salter, A, Beach, S, Turnbull, D, Siervo, M, Stephan, BCM, Tully, PJ
Frontiers in epidemiology. 2023;:1095236
Abstract
INTRODUCTION Cardiovascular diseases (CVDs) have been associated with an increased risk of dementia; yet the evidence is mixed. This review critically appraises and synthesises current evidence exploring associations between dementia risk and CVD and their risk factors, including coronary heart disease, heart failure, atrial fibrillation, hypertension, hyperlipidaemia, and arterial stiffness. METHODS MEDLINE, Embase, PsycINFO, and the Cochrane Database of Systematic Reviews were searched to identify systematic reviews with meta-analyses investigating the association between at least one of the CVDs of interest and dementia risk. The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Systematic Reviews was used to assess methodological quality. RESULTS Twenty-five meta-analyses published between 2007 and 2021 were included. Studies largely consisted of cohorts from North America and Europe. Findings were variable, with coronary heart disease, heart failure, and atrial fibrillation consistently associated with increased risk for all-cause dementia, but results were inconsistent for Alzheimer's disease. Hypertension was more frequently associated with dementia during mid-life compared to late life. Findings concerning cholesterol were complex, and while results were inconsistent for low-density lipoprotein cholesterol and total cholesterol, there appeared to be no associations between triglycerides and high-density lipoprotein cholesterol. All meta-analyses investigating hypercholesterolaemia showed significant increases in dementia risk. There was a paucity of research on the association between arterial stiffness and dementia risk. CONCLUSION Targeted CVD dementia prevention strategies could reduce dementia prevalence. Future research should determine the underpinning mechanisms linking heart and brain health to determine the most effective strategies for dementia risk reduction in CVD populations.
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Comparison of effect of CTG + STan with CTG alone on emergency Cesarean section rate: STan Australian Randomized controlled Trial (START).
Kuah, S, Simpson, B, Salter, A, Matthews, G, Louise, J, Bednarz, J, Chandraharan, E, Symonds, I, McPhee, A, Mol, BW, et al
Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2023;(4):462-470
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Abstract
OBJECTIVE To investigate whether use of ST analysis of the fetal electrocardiogram (STan) as an adjunct to continuous cardiotocography (CTG) reduces the rate of emergency Cesarean section (EmCS) compared with CTG alone. METHODS This was a randomized controlled trial of patients with a singleton fetus in cephalic presentation at ≥ 36 weeks' gestation, requiring continuous electronic fetal monitoring during labor at a tertiary maternity hospital in Adelaide, Australia, between January 2018 and July 2021. Participants were randomized to undergo CTG + STan or CTG alone. The calculated sample size was 1818 participants. The primary outcome was EmCS. Secondary outcomes included metabolic acidosis, a composite adverse perinatal outcome, and other maternal and neonatal morbidity and safety outcomes. RESULTS The present study enrolled 970 women, of whom 967 were included in the primary analysis. EmCS occurred in 107/482 (22.2%) deliveries in the CTG + STan arm and in 107/485 (22.1%) in the CTG arm (adjusted relative risk, 1.02 (95% CI, 0.81-1.27); P = 0.89). There was no difference in the rate of adverse maternal or neonatal outcomes between arms. CONCLUSIONS The addition of STan as an adjunct to continuous CTG did not reduce the EmCS rate. The smaller-than-anticipated sample size meant that this study was underpowered to detect absolute differences of ≤ 5% and, therefore, this negative finding could be due to a Type-2 error. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
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Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study.
Veldkamp, R, D'hooge, M, Sandroff, BM, DeLuca, J, Kos, D, Salter, A, Feinstein, A, Amato, MP, Brichetto, G, Chataway, J, et al
Journal of neurology. 2023;(6):3120-3128
Abstract
BACKGROUND Performing cognitive-motor dual tasks (DTs) may result in reduced walking speed and cognitive performance. The effect in persons with progressive multiple sclerosis (pwPMS) having cognitive dysfunction is unknown. OBJECTIVE To profile DT-performance during walking in cognitively impaired pwPMS and examine DT-performance by disability level. METHODS Secondary analyses were conducted on baseline data from the CogEx-study. Participants, enrolled with Symbol Digit Modalities Test 1.282 standard deviations below normative value, performed a cognitive single task ([ST], alternating alphabet), motor ST (walking) and DT (both). Outcomes were number of correct answers on the alternating alphabet task, walking speed, and DT-cost (DTC: decline in performance relative to the ST). Outcomes were compared between EDSS subgroups (≤ 4, 4.5-5.5, ≥ 6). Spearman correlations were conducted between the DTCmotor with clinical measures. Adjusted significance level was 0.01. RESULTS Overall, participants (n = 307) walked slower and had fewer correct answers on the DT versus ST (both p < 0.001), with a DTCmotor of 15.8% and DTCcognitive of 2.7%. All three subgroups walked slower during the DT versus ST, with DTCmotor different from zero (p's < 0.001). Only the EDSS ≥ 6 group had fewer correct answers on the DT versus ST (p < 0.001), but the DTCcognitive did not differ from zero for any of the groups (p ≥ 0.039). CONCLUSION Dual tasking substantially affects walking performance in cognitively impaired pwPMS, to a similar degree for EDSS subgroups.
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The relationship between processing speed and verbal and non-verbal new learning and memory in progressive multiple sclerosis.
Chiaravalloti, ND, DeLuca, J, Salter, A, Amato, MP, Brichetto, G, Chataway, J, Dalgas, U, Farrell, R, Feys, P, Filippi, M, et al
Multiple sclerosis (Houndmills, Basingstoke, England). 2022;(11):1783-1792
Abstract
OBJECTIVE Processing speed (PS) deficits are the most common cognitive deficits in multiple sclerosis (MS), followed by learning and memory deficits, and are often an early cognitive problem. It has been argued that impaired PS is a primary consequence of MS, which in turn decreases learning. The current analysis examined the association between PS and learning in a large cohort of individuals with progressive MS. METHODS Baseline data from a randomized clinical trial on rehabilitation taking place at 11 centers across North America and Europe were analyzed. Participants included 275 individuals with clinically definite progressive MS (primary, secondary) consented into the trial. RESULTS Symbol Digit Modalities Test (SDMT) significantly correlated with California Verbal Learning Test-II (CVLT-II) (r = 0.21, p = 0.0003) and Brief Visuospatial Memory Test-Revised (BVMT-R) (r = 0.516, p < 0.0001). Receiver operating characteristic (ROC) analysis of the SDMT z score to distinguish between impaired and non-impaired CVLT-II performance demonstrated an area under the curve (AUC) of 0.61 (95% confidence interval (CI): 0.55-0.68) and a threshold of -1.62. ROC analysis between SDMT and BVMT-R resulted in an AUC of 0.77 (95% CI: 0.71-0.83) and threshold of -1.75 for the SDMT z score to predict impaired BVMT-R. CONCLUSION Results indicate little ability beyond chance to predict CVLT-II from SDMT (61%), albeit statistically significant. In contrast, there was a 77% chance that the model could distinguish between impaired and non-impaired BVMT-R. Several potential explanations are discussed.
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Mapping brain activity of gut-brain signaling to appetite and satiety in healthy adults: A systematic review and functional neuroimaging meta-analysis.
Althubeati, S, Avery, A, Tench, CR, Lobo, DN, Salter, A, Eldeghaidy, S
Neuroscience and biobehavioral reviews. 2022;:104603
Abstract
Understanding how neurohormonal gut-brain signaling regulates appetite and satiety is vital for the development of therapies for obesity and altered eating behavior. However, reported brain areas associated with appetite or satiety regulators show inconsistency across functional neuroimaging studies. The aim of this study was to systematically assess the convergence of brain regions modulated by appetite and satiety regulators. Twenty-five studies were considered for qualitative synthesis, and 14 independent studies (20-experiments) found eligible for coordinate-based neuroimaging meta-analyses across 212 participants and 123 foci. We employed two different meta-analysis approaches. The results from the systematic review revealed the modulation of insula, amygdala, hippocampus, and orbitofrontal cortex (OFC) with appetite regulators, where satiety regulators were more associated with caudate nucleus, hypothalamus, thalamus, putamen, anterior cingulate cortex in addition to the insula and OFC. The two neuroimaging meta-analyses methods identified the caudate nucleus as a key area associated with satiety regulators. Our results provide quantitative brain activation maps of neurohormonal gut-brain signaling in heathy-weight adults that can be used to define alterations with eating behavior.
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The late onset of emotional distress in people with progressive multiple sclerosis during the Covid-19 pandemic: longitudinal findings from the CogEx study.
Feinstein, A, Amato, MP, Brichetto, G, Chataway, J, Chiaravalloti, ND, Cutter, G, Dalgas, U, DeLuca, J, Farrell, R, Feys, P, et al
Journal of neurology. 2022;(12):6202-6210
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OBJECTIVE An earlier follow-up study from the CogEx rehabilitation trial showed little change in symptoms of depression, anxiety and psychological distress during the first COVID-19 lockdown compared to pre-pandemic measurements. Here, we provide a second follow-up set of behavioral data on the CogEx sample. METHODS This was an ancillary, longitudinal follow-up study in CogEx, a randomized controlled trial of exercise and cognitive rehabilitation in people with progressive MS involving 11 centres in North America and Europe. Only individuals impaired on the Symbol Digit Modalities Test (SDMT) were included. Participants repeated the COVID Impact survey administered approximately a year later and completed self-report measures of depression, anxiety and MS symptoms that had been obtained at the trial baseline and during the first COVID Impact survey. Participants who completed the second COVID Impact follow-up were included. To identify predictors of the participants' ratings of their mental and physical well-being, step-wise linear regression was conducted. RESULTS Of the 131 participants who completed the first COVID impact survey, 74 participants completed the second follow-up survey (mean age 52 (SD = 6.4) years, 62.2% female, mean disease duration 16.4 (SD = 9.0) years, median EDSS 6.0). Pandemic restrictions prevented data collection from sites in Denmark and England (n = 57). The average time between measurements was 11.4 (SD = 5.56) months. There were no significant differences in age, sex, EDSS, disease course and duration between those who participated in the current follow-up study (n = 74) and the group that could not (n = 57). One participant had COVID in the time between assessments. Participants now took a more negative view of their mental/psychological well-being (p = 0.0001), physical well-being (p = 0.0009) and disease course (p = 0.005) compared to their last assessment. Depression scores increased on the HADS-depression scale (p = 0.01) and now exceeded the clinically significant threshold of ≥ 8.0 for the first time. Anxiety scores on the HADS remained unchanged. Poorer mental well-being was predicted by HADS depression scores (p = 0.012) and a secondary-progressive disease course (p = 0.0004). CONCLUSIONS A longer follow-up period revealed the later onset of clinically significant depressive symptoms on the HADS and a decline in self-perceptions of mental and physical well-being associated with the COVID-19 pandemic relative to the first follow-up data point. TRIAL REGISTRATION The trial was registered on September 20th 2018 at www. CLINICALTRIALS gov having identifier NCT03679468. Registration was performed before recruitment was initiated.