Multiple Sclerosis and Related Disorders

BackgroundMultiple Sclerosis (MS) often results in gait impairment and disability. ObjectiveTo investigate differences in spatiotemporal gait characteristics of people with MS who have low versus high levels of disability. Between trial and inter-limb consistency and the association of gait variables with level of disability were also investigated. MethodsParticipants with MS who had either low-disability [n=7; 3 females; EDSS mean: 2.7{+/-}0.5, range 2.0-4.5; BMI=26.9{+/-}6.6] or high-disability [n=11; 6 females; EDSS mean: 2.7{+/-}0.5, range 6.0-6.5; BMI=27.8{+/-}1.5) performed 2 trials of self-selected walking on an instrumented walkway. Differences in group, limb, and group by limb interactions were assessed using analysis of variance, independent-measures t-tests, and Cohens d effect sizes (ES). Between-trial consistency of gait were assessed with intra-class correlation coefficients (2, k). ResultsParticipants in the high disability group had increased step time (ES=0.8), cycle time (ES=0.8), and ambulation time (ES=1.2) while taking shorter strides (ES=0.9) and more steps at a slower rate (ES=1.1). The high disability group demonstrated less between-trial consistency for 69% of gait variables when compared to the low disability group. ConclusionPeople with MS who have high levels of disability walk differently and with less consistency than those with lower levels of disability.

IntroductionPsychological distress is a major issue in multiple sclerosis (MS), having a significant impact on quality of life. Antidepressants are generally unhelpful for subsyndromal symptomatology, and psychological treatment approaches often not accessible or too cognitively demanding for some patients. There is an urgent need for low-cost interventions to improve wellbeing in MS. MethodsThis was a pilot randomised controlled trial (RCT) of Positive Mental Training (PosMT), a low intensity intervention providing training in positivity, optimism and resilience previously shown to improve anxious and depressive symptomotology. 28 patients with MS were randomised to the intervention and 30 to the control group. ResultsFollow-up data was obtained from 39 patents. The majority of participants receiving PosMT reported that they had used the intervention, with few reporting side effects. The intervention group reported a significant improvement in self-rated health as measured by the EuroQual visual analogue scale, F(4,34) = 3.204, p = 0.025, R2 = 0.274. DiscussionThis preliminary RCT found that PosMT in its current form could be used by patients with MS with little difficulty. Despite the small size of the study, allocation to the intervention was found to be associated with a significant improvement in self-rated health. Given the low cost of PosMT and its easy availability (it can simply be downloaded from a website), this pilot RCT suggests it could be a useful tool for MS patients. We believe this intervention warrants further study, ideally in a large multi-centre RCT.

IntroductionMultiple sclerosis (MS) is a chronic progressive neurological disease. There is ample evidence that exercise can be beneficial. The advancement of modern technology led to improvements in the way therapy can be offered and can make it more motivating, thereby increasing adherence. The primary objective of this two site single blinded randomized control trial (RCT) is to explore the feasibility of conducting a multicentre definite RCT trial with a neuroanimation intervention of high-dose practice in people with mild-to-moderate MS. The secondary objective is to collect data on the variability of outcome measures to inform sample size calculations for a RCT. The tertiary outcome is to assess if this intervention changes exercise behaviour. Methods and analysisThis study is in preparation for a future definitive randomised control trial (RCT) where the efficacy compared to a dose matched control therapy will be assessed. The setting for this study is a research laboratory at Edith Cowan University (ECU) and a neurological service provider, Multiple Sclerosis Society of Western Australia (MSWA). This feasibility study will recruit people with MS who have mild to moderate disability. Subjects will participate in 24 session, 2 times a week, of 60 minutes time-on-task intense arm training, using an exergaming system. Participants will undergo a follow up within 3 days and at 6 months after the final study visit. Ethics and disseminationThis study was approved by the local Ethics Committee of Edith Cowan University. Subjects will be included after signing informed consent. Study outcomes will be disseminated through presentations at scientific conferences and through peer-reviewed journals. Trial registrationACTRN12622000281796 Strengths and limitations of this studyO_LIThe study intervention is a newly developed exercise intervention protocol designed to be engaging and motivating C_LIO_LINext to investigating primary efficacy in order to determine sample size for a larger trial, the study also uses implementation science to assess future obstacles in a follow up randomized control trial C_LIO_LIThe feasibility of conducting a larger trial will be based on standardised criteria regarding process, resource, and management metrics C_LIO_LIThis study without a control group demonstrates feasibility rather than efficacy C_LI

ObjectiveCardiopulmonary Exercise Testing (CPET) is challenging among persons with mobility disability. We sought the optimal adapted device to achieve a maximal CPET. DesignRandomized crossover trial, within-subjects, repeated measures design SettingPrimary Care and Referral Center ParticipantsClinic-referred persons with multiple sclerosis (PwMS) (n=10) with three-month stability, no exercise obstruction, MoCa>24, ability to walk with or without assistance, and sex- and age-matched ({+/-}3 years) Controls (n=7) recruited by convenience sampling InterventionsCPET on body weight-supported treadmill (BWST) and total body recumbent stepper (TBRS) Main Outcome MeasuresStandard aerobic metrics ([V]O2max, % normative values for [V]O2max [%[V]O2max], heart rate maximum [HRmax], age-predicted HRmax, and Respiratory Exchange Ratio) ResultsPwMS achieved similar [V]O2max (mL{middle dot}min-1{middle dot}kg-1) on the TBRS and BWST (26.53{+/-}8.7 vs. 24.24{+/-}7.8) while Controls obtained higher values on BWST than TBRS (40.27{+/-}7.6 vs. 34.32{+/-}7.1, p<0.001). PwMS more consistently achieved criteria for maximum CPET using TBRS. During the preliminary investigation of the MS subgroup with a higher mobility disability, CPET using BWST exaggerated already low CPET metrics. ConclusionsAlthough Controls achieved higher CPET values on BWST, [V]O2max between devices were similar among PwMS. Only when using BWST, PwMS [V]O2max and %[V]O2max were lower than Controls, likely because of leg fatigue and weakness. Using TBRS permits persons with mobility disability to achieve more criteria for a maximum CPET. Our results suggest that CPET using BWST, being reliant on the lower body, likely disadvantages PwMS, especially those with mobility disability.

Multiple sclerosis (MS) is an immune-mediated neurological disorder that affects one million people in the United States. Up to 50% of people with MS experience depression, yet the mechanisms of depression in MS remain under-investigated. Studies of medically healthy participants with depression have described associations between white matter variability and depressive symptoms, but frequently exclude participants with medical comorbidities and thus cannot be extrapolated to people with intracranial diseases. White matter lesions are a key pathologic feature of MS and could disrupt pathways involved in depression symptoms. The purpose of this study is to investigate the impact of brain network disruption on depression using MS as a model. We will obtain structured clinical and cognitive assessments from two hundred fifty participants with MS and prospectively evaluate white matter lesion burden as a predictor of depressive symptoms. Ethics approval was obtained from The University of Pennsylvania Institutional Review Board (Protocol #853883). The results of this study will be presented at scientific meetings and conferences and published in peer-reviewed journals. ARTICLE SUMMARYO_ST_ABSStrengths and Limitations of this StudyC_ST_ABSO_LIWe will use MS as a model to study how white matter disease contributes to both the pathophysiology of depression in MS and to general network mechanisms of depression. C_LIO_LIWe will leverage research-grade 3-tesla (3T) MRIs acquired as part of routine MS care and maximize scalability by using the Method for Inter-Modal Segmentation Analysis (MIMoSA) for automated white matter lesion segmentation. C_LIO_LIOur study will include participants with medical comorbidities, creating a more representative population and more broadly applicable results. C_LIO_LIWe will obtain detailed clinical and cognitive assessments from each participant to evaluate the inter-relationship of mood symptoms, anxiety symptoms, and cognitive deficits, and relate them to white matter disease. C_LIO_LIThis is a single-center study. C_LI

Background and PurposeA pilot study to determine feasibility of detecting changes in structural connectivity (SC) and resting-state functional connectivity (RSFC) occur alongside motor improvements after participation in the Targeted Ballet Program (TBP) in adults with relapsing-remitting multiple sclerosis (RRMS). MethodsFive participants (four female) with RRMS between the ages of 38-64 with the following characteristics at baseline: Expanded Disability Status Scale 2.0-6.0, International Cooperative Ataxia Rating Scale (ICARS) > 7, Symbol-Digit Modality Test > 22, and no relapses or initiation of medications indicated to affect mobility within the past 30 days. Participants were asked to complete 12 weeks (one hour, twice per week) of the TBP. Magnetic resonance imaging data was collected pre- and post-intervention for SC and RSFC network analysis. ResultsIncreases in two RRMS-related graph theoretical measures (mean strength and mean clustering coefficient) for RSFC (p < 0.05) are detectable alongside significant reduction in ataxia (ICARS: p = 0.01012, Smoothness Index: p = 0.04995), and increase in balance (Mini-BESTest: p = 0.01474) following participation in the well-tolerated TBP. Discussion and ConclusionsSignificant increases in mean strength and mean clustering coefficient of RSFC suggest functional neurological improvements after participation in the TBP. The relationship between these network changes and clinical improvements in balance and amelioration of ataxia after participation in the TBP requires a larger randomized-controlled clinical trial of the TBP in persons with RRMS.

ImportanceMultiple sclerosis (MS) is an immune-mediated neurological disorder that affects 2.4 million people world-wide, and up to 60% experience anxiety. ObjectiveWe investigated how anxiety in MS is associated with white matter lesion burden in the uncinate fasciculus (UF). DesignRetrospective case-control study of participants who received research-quality 3-tesla (3T) neuroimaging as part of MS clinical care from 2010-2018. Analyses were performed from June 1st to September 30th, 2024. SettingSingle-center academic medical specialty MS clinic. ParticipantsParticipants were identified from the electronic medical record. All participants were diagnosed by an MS specialist and completed research-quality MRI at 3T. After excluding participants with poor image quality, 372 were stratified into three groups which were balanced for age and sex: 1) MS without anxiety (MS+noA, n=99); 2) MS with mild anxiety (MS+mildA, n=249); and 3) MS with severe anxiety (MS+severeA, n=24). ExposureAnxiety diagnosis and anxiolytic medication. Main Outcome and MeasureWe first evaluated whether MS+severeA patients had greater lesion burden in the UF than MS+noA. Next, we examined whether increasing anxiety severity was associated with greater UF lesion burden. Generalized additive models were employed, with the burden of lesions (e.g. proportion of fascicle impacted) within the UF as the outcome measure and sex and spline of age as covariates. ResultsUF burden was higher in MS+severeA as compared to MS+noA (T=2.02, P=0.045, Cohens f2=0.19). A dose-response effect was also found, where higher mean UF burden was associated with higher anxiety severity (T=2.08, P=0.038, Cohens f2=0.10). Conclusions and RelevanceWe demonstrate that overall lesion burden in UF was associated with the presence and severity of anxiety in patients with MS. Future studies linking white matter lesion burden in UF with treatment prognosis are warranted. KEY POINTSO_ST_ABSQuestionC_ST_ABSAre white matter lesions that impact the uncinate fasciculus (UF) associated with anxiety in patients with multiple sclerosis (MS)? FindingsThis retrospective, case-control study of 372 patients with MS included 3 anxiety severity groups: 1) MS without anxiety (MS+noA, n=99); 2) MS with mild anxiety (MS+mildA, n=249); and 3) MS with severe anxiety (MS+severeA, n=24). We identified associations between anxiety and UF lesion burden. Specifically, we showed that MS+severeA had higher UF lesion burden than MS+noA, and worsening anxiety severity increased with greater UF burden. MeaningLesion burden in the UF may contribute to anxiety comorbidity in MS.

In order to explore the effect of IFN{beta}-1b treatment on B cell phenotype and function in RRMS patients, blood was drawn from RRMS patients before treatment and again 2 and 6 months after every other day injections of IFN{beta}-1b. Cryopreserved peripheral blood mononuclear cells (PBMCs) were thawed and stained with panels of antibodies against B cell surface antigens and the intracellular cytokines, IL-10 and IL-6. At baseline, PBMCs from RRMS patients have increased frequencies of B1 cells and a decreased frequencies of memory B cells when compared with PBMCs from age- and gender-matched healthy controls. CpG-stimulated PBMCs from patients treated with IFN{beta}-1b show an increase in IL-10 production and a decrease in IL-6 production by naive, memory and B1 cells compared with healthy controls. In addition, this treatment alters the composition of circulating B cell subsets, leading to an increase after six months in circulating naive B cells and a decrease in both memory and B1 cells, both cell types of which are potentially pathogenic in RRMS. Patients were divided into two groups based on disease activity, no/low or moderate/high. A significantly higher frequency of B1 cells and higher expression of CD27 on these cells was seen at baseline in the moderate/high disease activity group to IFN{beta}-1b compared with patients in the no/low disease activity group. Although the number of subjects in this study was limited, these findings suggest that alterations in the B cell compartment may be a mechanism by which IFN{beta}-1b reduces disease activity.

HighlightsMultiple sclerosis disease duration was not associated with gait speed Multivariate models with gait kinematics are associated with disease duration Disease duration is linked to step width variability and ankle pitch at toe-off Declines in walking function commonly occur in people with multiple sclerosis (MS). Walking is a continuous movement and a complex motor task that requires precise timing and scaling of activation across many muscles. The objectives of this study were to identify kinematic gait characteristics during a 2-minute walk test that are associated with disease duration in individuals with relapsing-remitting MS (n=45). Participants were instrumented with inertial measurement units from APDM (APDM Inc, Portland, OR, USA) and performed the 2-minute walk test twice: once at their self-selected speed and another at their fastest, safe speed. Gait speed was not associated with MS disease duration (Self-selected: p= 0.180; Fast: p=0.167). Canonical correlation analysis showed that disease progression was strongly associated with lateral step width variability and ankle pitch at toe-off, which was also reflected in the multiple linear regression models. Both self-selected and fast-speed kinematics were associated with disease duration (Self-selected: p=0.007; Fast: p=0.004). Thus, we identified a multivariate model that is associated with disease duration in highly ambulatory MS individuals. Our study highlights the importance of considering individual differences in specific gait kinematics (such as lateral step width variability and ankle pitch at toe-off) when assessing disease progression in MS. This approach may provide more personalized insights into the impact of MS on mobility and help tailor interventions to improve gait and overall function in affected individuals. Future research should continue exploring these kinematic parameters to better understand their role in MS progression and develop targeted therapeutic strategies.

BackgroundOur prior work demonstrated that estimated structural and functional connectomes (eSC and eFC) generated using multiple sclerosis (MS) lesion masks and artificial intelligence (AI) models can predict disability as effectively as SC and FC derived from diffusion and functional MRI in MS. The goal of this study was to assess the ability of eSC and eFC in predicting baseline and 4-year follow-up cognition in MS patients. MethodsOne hundred seventy-one MS patients (age: 42.67{+/-}10.41, 74% females) were included. The Symbol Digit Modalities Test (SDMT), California Verbal Learning Test (CVLT), and Brief Visuospatial Memory Test (BVMT) were used to assess cognition. The Network Modification tool was performed to estimate SC, which was then used as an input to Krakencoder, an encoder-decoder model, to estimate FC. Ridge regression was performed to predict cognition using regional eSC and eFC, along with demographics and clinical information as well as conventional MRI metrics. Baseline cognition was added to the models that were used to predict the follow-up cognition. Spearmans correlation (r) was used to assess the prediction accuracy. ResultsThe highest accuracy was obtained when predicting follow-up SDMT using regional eSC or eFC (median r=0.58 for eSC and r=0.56 for eFC). Decreased eSC and eFC in the cerebellum and increased eFC in the default mode network were associated with lower follow-up SDMT scores. Baseline SDMT, clinical subtype, and age were the most important non-connectome metrics in predicting follow-up SDMT. ConclusionsOur findings demonstrate that eSC and eFC derived from clinically acquired MRI and AI models can effectively predict cognition. The use of lesion-based estimates of connectome disruptions may potentially improve cognition-related individualized treatment planning.

BackgroundMS significantly impacts motor and cognitive function, yet therapies to effectively address these impairments remain limited. This study explores acute intermittent hypoxia (AIH) as a novel intervention for enhancing neuroplasticity and functional improvement in individuals with MS. ObjectiveTo examine the efficacy of a single AIH session in improving spinal motor output and cognitive performance in MS. MethodsA randomized, blinded, placebo-controlled and crossover study was done in 10 individuals with relapsing-remitting MS. Participants underwent both AIH and sham AIH on separate days. AIH consisted of 15 brief exposures of low oxygen (9% O2) alternating with normoxia (i.e., room air). Sham AIH comprised of normoxic episodes. Pre- and post-intervention evaluations included isometric ankle torque to assess motor strength and standardized tests to evaluate cognitive function. ResultsParticipants showed a significant increase in both plantarflexion and dorsiflexion ankle torque (p < .05), alongside significant enhancements in cognitive processing speeds as measured by the Symbol Digit Modalities Test (p < .01) after AIH. No changes were observed in auditory/verbal memory, and no adverse events were reported. ConclusionAIH presents a promising intervention for inducing neuroplasticity and improving rehabilitation outcomes in MS, suggesting the need for further exploration into its long-term impacts and mechanisms.

BackgroundCalorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) through reduction of inflammation. The aim of this trial was to study the effects of 12-week iCR on metabolic, immunological and clinical outcomes in people with MS (pwMS). MethodsParticipants with relapsing-remitting MS were randomly assigned to intermittent CR (iCR) or a control group for 12 weeks. Primary outcome was change in leptin levels; secondary outcomes included changes in anthropometric and body composition measures, peripheral blood metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate differences. ResultsForty-two pwMS were randomized, 34 completed the study (17 iCR and 17 control). Leptin levels decreased in the iCR group and were significantly lower in the iCR than the control group at 6 (mean difference 11.49 mg/dL, 95% CI 32.54, 9.54; P=0.01) and 12 weeks (6.97 mg/dL, 95% CI 28.02, 14.06; P=0.03). We observed a significant reduction of weight, body mass index and body adiposity measures over the 6 and 12-weeks in the iCR group. Immune profiling showed a significant increase in CD45RO+ regulatory T cell numbers after 6 weeks of iCR. Lysophosphatidylcholine, lysophophatidylethanolamine and phosphatidylinositol lipid species were significantly increased after 12 weeks in the iCR group compared to baseline, and all three were higher at 12 weeks compared to controls. Exploratory cognitive testing demonstrated improvement in the symbol digit modality test score in the iCR group. ConclusionsShort term iCR is safe, feasible and can benefit metabolic and immunologic profiles in pwMS. ClinicalTrial.gov number: NCT03539094 (first patient screened on 11/14/17; first patient recruited on 1/29/2018; last patient recruited on 11/24/2021).

BackgroundTelemedicine is feasible and well-accepted by people with multiple sclerosis (MS). ObjectiveThe aim of this study is to validate a smartphone-based cognitive screening battery, icognition, to faster signal cognitive deterioration. Methodsicognition consists of three tests (Symbol Test, Dot Test and visual Backwards Digit Span (vBDS)) that are equivalents of validated paper-pencil tests. These are the Symbol Digit Modalities Test (SDMT), the 10/36 Spatial Recall Test (SPART) and the auditory Backwards Digit Span (aBDS), respectively. To establish the validity of icognition, 101 people with MS and 82 healthy subjects completed all tests. 21 healthy subjects repeated testing 2 to 3 weeks later. ResultsAll tests in icognition correlate well with their paper-pencil equivalent (Symbol Test: r=.63, p<.001; Dot Test: r=.31, p=0.002; vBDS: r=.71, p<.001), negatively correlate with the Expanded Disability Status Scale (EDSS: Symbol Test: rho=-.27, p=.01; Dot Test: rho=-.29, p=.006; vBDS: rho=- .23, p=.027) and show high test-retest reliability (Symbol Test: r=.81, p<.001; Dot Test: r=.75, p<.001; vBDS: r=.84, p<.001). Test performance was not significantly different between people with MS and healthy subjects for all cognitive tests, both in icognition and their paper-pencil equivalents. Conclusionicognition is a valid and reliable tool to remotely screen for cognitive functioning in persons with MS.

BackgroundThe individual disease evolution of multiple sclerosis (MS) is very different from one patient to another. Therefore, the prediction of long-term disability evolution is difficult based on only clinical information. Magnetic resonance imaging (MRI) provides a very efficient tool to distinguish between healthy and abnormal brain tissue, monitor disease evolution, and help decision-making for personalized treatment of MS patients.\n\nObjectiveWe aim to develop a patient-specific model to predict individual disease evolution in MS, using demographic, clinical, and imaging data that were collected at study onset.\n\nMethodsThe study included 75 patients tracked over 5 years. The latent class linear mixed model was used to consider individual and unobserved subgroup variability. First, the clinical model was established with demographic and clinical variables to predict clinical disease evolution. Second, the imaging model was built using the multimodal imaging variables. Third, the imaging variables were added one by one, two by two, and all three together to investigate their contribution to the clinical model. The clinical disability is measured with the Expanded Disability Status Scale (EDSS). The performances of the clinical, imaging, and the combined models were compared mainly using the Bayesian Information Criterion (BIC). The mean of the posterior probabilities was also given as the secondary performance evaluation criterion.\n\nResultsThe clinical model gave higher BIC value than imaging and any combined models. The means of the posterior probabilities given by the three models were over 0.94. The clinical model clustered the patients into two latent classes: stable evolution class (n=6, 88%) and severe evolution class (n=9, 12%).\n\nConclusionThe latent class linear mixed model may provide a well-fitted prediction for the disability evolution in MS patients, thus giving further information for personalized treatment decisions after thorough validation with a larger and independent dataset.

BackgroundPeople with multiple sclerosis (MS) undergo magnetic resonance imaging (MRI) to monitor disease activity and treatment response. Current scan frequency recommendations are non-individualized, potentially increasing unnecessary imaging and costs. Risk-based tools could enable more personalized surveillance strategies. ObjectiveTo develop an algorithm that predicts new lesions in subsequent brain MRI. MethodsUsing longitudinal data from adults with MS at the Johns Hopkins MS Center (2017-2025) with [&ge;]2 visits and [&ge;]1 MRI scan, a logistic regression model with 5-fold stratified cross-validation predicted new lesions, using a sensitivity-prioritized threshold. Features included disease activity history, therapy class, and patient-reported outcomes. ResultsAmong 1,131 participants (3:1 female-to-male; mean age 48, SD 12.3), 8.8% developed new MRI lesions. At a 0.08 threshold, sensitivity was 0.72 and specificity 0.75, with AUC 0.80. The model identified 72 patients with new lesions and 772 without (low risk). Prior MRI activity and recent relapse predicted new lesions, while older age and high-efficacy DMT use were associated with lower risk. ConclusionThe algorithm accurately stratified patients by risk of MRI lesion activity and identified who could undergo longer surveillance intervals with low risk of missed inflammation. With validation and integration, it may enable personalized monitoring in MS care.

BackgroundTreatment strategy for relapsing multiple sclerosis (RMS) is increasingly shifting towards first-line use of high-efficacy DMT (H-DMT). However, DMT efficacy declines with increasing age and the benefit of first line H-DMT at higher age remains unclear. Here, we aimed to investigate whether the superiority of H-DMT over moderate-efficacy DMT (M-DMT) depends on age. MethodsUsing the Austrian MS database, we included previously DMT-naive RMS patients aged [&ge;]18 years, who i) initiated a DMT continuing it for [&ge;]12 months, ii) had MRI at baseline, and iii) had clinical follow-up for [&ge;]24 months. Cox regression analyses including age and DMT strategy (H-DMT vs. M-DMT) plus an interaction effect were employed to predict time to relapse. ResultsA total of 215 RMS patients (median age of 41 years [25th-75th percentiles: 32-53], 66% females) were observed over a median of 42 (28-58) months. During this period, eighty-one (38%) patients had a relapse. While increasing age was associated with decreased risk of relapse (hazard ratio (HR) 0.95 per year, 95% confidence interval [CI]: 0.93-0.98, p<0.001), the use of H-DMT lowered the risk of relapse compared to M-DMT (HR 0.06, 95%-CI: 0.01-0.45, p=0.007). In patients with H-DMT, the benefit of treatment was reduced by increasing age (HR: 1.06, 95%-CI: 1.01-1.11, per year, p=0.031). Superiority of H-DMT over M-DMT was estimated to be lost at the age of approximately 50 years. ConclusionThe benefit of H-DMT over M-DMT as first-line treatment decreases with increasing age and seems to vanish in patients above approximately 50 years. What is already known on this topicHigh-efficacy disease-modifying treatments (H-DMTs) are increasingly used as first-line therapy in relapsing multiple sclerosis (RMS) due to their superior effectiveness in reducing inflammatory disease activity. However, both clinical and radiological disease activity naturally decline with age, and prior meta-analyses suggest that the relative benefit of H-DMT over moderate-efficacy DMTs (M-DMTs) diminishes in older patients. These findings have largely been derived from clinical trials with restricted age ranges and enriched disease activity, limiting their generalizability to real-world, treatment-naive populations across the full adult age spectrum. What this study addsIn a real-world, national cohort of DMT-naive RMS patients across a wide range of age, this study shows that while H-DMTs significantly reduce the risk of relapse compared to M-DMTs, their superiority is progressively attenuated with advancing age. Notably, the benefit of initiating H-DMTs as first-line therapy becomes statistically indistinguishable from M-DMTs around the age of 50 years. These findings were independent of baseline disease duration and other covariates, emphasizing age as a key modifier of treatment effect. How this study might affect research, practice or policyThese findings support the integration of age as a critical factor in guiding first-line DMT decisions for RMS. For patients over 50 years, M-DMTs may offer a more appropriate initial treatment option, minimizing exposure to the higher risk profiles of H-DMTs in the absence of clearly superior efficacy. This study underscores the importance of personalized treatment approaches and highlights the need for future clinical trials to include broader age ranges, facilitating evidence-based, age-adjusted treatment strategies in multiple sclerosis.

BackgroundConventional clinical assessments in multiple sclerosis (MS), such as the Expanded Disability Status Scale (EDSS), often miss subtle functional changes. While accelerometry provides an objective measure of real-world motor activity, most daily summaries focus on average values, neglecting both peak performance and its variability throughout the day. This diurnal peak performance variability may reflect a persons capacity to sustain high-effort activity despite fatigue, a phenomenon we term observable movement reserve. ObjectiveTo evaluate whether upper diurnal activity quantiles derived from accelerometry data quantify observable movement reserve, and to examine their association with EDSS-measured disability in MS. MethodsIn a cohort of 248 adults with MS (mean age 54.8 years, 71% female; EDSS range 0-6.5), continuous wrist accelerometry was collected over two weeks. We used novel scalar-on-function regression (SOFR) to compare several diurnal activity characteristics: mean, variability, and 50th-100th percentiles. SOFR models adjusted for age, sex, and BMI, and their cross-validated R2 were used to assess the strength of the association between EDSS and each diurnal activity curve. ResultsThe upper diurnal activity quantiles, particularly the 95th to 100th percentiles, demonstrated the strongest association with EDSS, outperforming both diurnal mean and variability-based diurnal activity curves (crossvalidated R2 increased from 0.12 for the diurnal mean to 0.22 for the diurnal 100th percentile). The largest contribution to predictive power came from the late afternoon and evening hours, highlighting the importance of time-of-day in assessing disability. ConclusionDiurnal peak activity provides a sensitive, time-of-day-specific measure of observable movement reserve that closely aligns with EDSS-measured disability. This reserve fluctuates across the day, likely reflecting circadian patterns of energy and fatigue. By capturing both the timing and intensity of peak activity, the proposed metrics offer a clinically meaningful tool for monitoring functional change over time and may enhance the ability to track disease progression in MS.

Relapsing-remitting multiple sclerosis is the most common type of multiple sclerosis characterized by periods of relapses and generating various motor symptoms. These symptoms are associated with the corticospinal tract integrity, which is quantified by means of corticospinal plasticity which can be probed via transcranial magnetic stimulation and assessed with motor threshold, motor evoked potential and central motor conduction time. Several factors, such as exercise and interlimb coordination, can influence corticospinal plasticity. Previous work in healthy and in stroke patients showed that the greatest improvement in corticospinal plasticity occurred during in-phase bilateral arm exercises. Altered corticospinal plasticity due to bilateral cortical lesions is common in multiple sclerosis, yet, the impact of these type of exercises in this cohort is unclear. The aim of this concurrent multiple baseline design study is to investigate the effects of in-phase bilateral exercises on corticospinal plasticity and on clinical measures using transcranial magnetic stimulation and standardized clinical assessment, in five people with relapsing-remitting multiple sclerosis. The intervention protocol will last for 12 consecutive weeks (30-60 minutes /session x 3 sessions/week) and include in-phase bilateral movements of the upper limbs, adapted to different sports activities and to functional training. To define functional relation between the intervention and the results on corticospinal plasticity (i.e., resting motor threshold, motor evoked potential amplitude, latency) and on clinical measures (i.e., balance, gait, bilateral hand dexterity and strength, cognitive function), we will perform a visual analysis followed by multilevel modelling and the single case educational design-specific mean difference in order to estimate the magnitude of the effect size across cases. We assume that possible effects from our study, will introduce a type of exercise that will be effective during the disease progression.

BackgroundThere is increasing evidence that Epstein-Barr virus (EBV) plays a causal role in MS. No treatments have been shown to reduce EBV turnover. We studied the effect of famciclovir on salivary EBV shedding in people with MS (NCT05283551). MethodsPeople with MS receiving natalizumab provided weekly saliva samples for 12 weeks before starting Famciclovir 500mg bd. 12 saliva samples were provided on treatment and 12 following treatment. A real-time quantitative PCR Taqman assay targeted to a non-repeated sequence of the EBV polymerase gene was used to detect EBV DNA in saliva. The proportion of saliva samples containing EBV DNA was compared using the Friedman test. Results30 patients were recruited (19F; mean age 41 years; median EDSS 3.5). 29 patients received famciclovir, 24 completed the 12-week course. 21 participants provided at least one usable saliva sample in all 3 epochs. 10/21 participants had shedding in at least one sample pre-drug; 7/21 when taking famciclovir (not significant). No difference in EBV DNA copy number was seen. There were no drug-related serious adverse events. ConclusionsNo significant effect of famciclovir on EBV shedding was seen. Salivary EBV shedding in this natalizumab-treated cohort was lower than in previous studies; this requires replication.

BackgroundB-cell depletion (BCD) therapies (e.g., ocrelizumab, ofatumumab, rituximab) and natalizumab (NTZ) are highly effective disease-modifying therapies (DMTs) for multiple sclerosis (MS). However, no randomized clinical trial and only limited observational studies compared the two DMT classes. ObjectiveWe compared BCD and NTZ in managing MS patient-reported disability progression using registry-linked electronic healthcare record (EHR) data. MethodsThe study population of an EHR cohort of MS patients included a subset enrolled in a clinic-based MS registry that provided gold-standard outcome labels. To estimate average treatment effects, we applied a doubly-robust semi-supervised approach to analyze all (not only registry) patients and comprehensively adjusted for confounders that included not only a priori standard features but also knowledge graph-derived EHR features. While gold-standard disability outcomes were available in registry patients, we imputed the baseline pre-treatment and post-treatment disability status for non-registry patients. We categorized patient-reported disability progression status as "sustained worsening", "sustained improvement", or "no sustained change" based on 3 or more observations or imputations of Patient Determined Disease Steps (PDDS) scores within 3 years after target treatment initiation as the primary endpoint. ResultsIn this MS cohort (n=1,738, Age=46{+/-}13 years, Non-Hispanic White=86.71%), there was no significant difference between BCD (n=1,245, 71.63%) and NTZ (n=495, 28.37%) in mitigating sustained worsening (ATE=-0.020, 95% CI [-0.149, 0.076], p=.755) or promoting sustained improvement (ATE=-0.073, 95% CI [-0.187, 0.009], p=.114) of patient-reported disability. Sensitivity analyses using a 2-year window after treatment initiation confirmed no difference in sustained worsening (ATE=-0.013, 95% CI [-0.069, 0.074], p=.819) or sustained improvement (ATE=-0.187, 95% CI [-0.264, 0.008], p=.135) between BCD and NTZ. In power analysis, the semi-supervised approach increased statistical power compared to the standard approach of using gold-standard data alone. ConclusionThis real-world comparative effectiveness analysis based on a novel doubly-robust semi-supervised approach found no difference between BCD and NTZ in managing MS disability progression. Key Messages{blacksquare} Evaluation of sustained disability accumulation requires long-term follow-up beyond the typical clinical trials, while the scarcity of patient-reported and certainly rater-assessed disability outcomes in routine clinical care hinders analysis using real-world clinical data. {blacksquare}Using a large registry-linked electronic healthcare record cohort and a novel semi-supervised, doubly-robust method that incorporates knowledge graph-derived clinically relevant covariates from EHR, we conducted a causal inference study to compare sustained change in patient-reported disability in people with MS. {blacksquare}The semi-supervised approach effectively leverages additional data from patients without observed outcome information and increases the statistical power of the comparative effectiveness study while retaining robustness properties and achieving more consistent treatment effect estimation in the causal analysis. {blacksquare}There was no statistically significant difference between B-cell depletion therapy and natalizumab in sustained patient-reported disability outcomes up to 3-years after treatment initiation.