Multiple Sclerosis Journal

Background and Objectives: Cognitive impairment is common in multiple sclerosis (MS), but whether brain age gap (BAG) has greater cognitive relevance in MS than in people without brain disease is not known. We tested whether BAG was more strongly associated with cognitive processing speed (CPS) in MS. Methods: We performed a cross-sectional analysis of MRI-derived BAG and CPS from a UK Biobank study consisting of 21,117 normative reference subjects with no recorded brain disease and 97 subjects with MS. BAG and CPS were standardized to the normative reference distribution, and an age- and sex-adjusted interaction tested whether the association differed between groups. Separately, a meta-analysis of the relationship of BAG and CPS was performed using published data from five independent MS cohorts (n=1,250 subjects in total). Correlation statistics were pooled to establish the effect size, 95% confidence intervals and p-values. Results: In UK Biobank, there was a moderate negative association between BAG and CPS in MS (r=-0.35, 95% CI -0.52 to -0.17; P<.001), whereas the association in the normative reference group was negligible (r=-0.05, 95% CI -0.07 to -0.04; P<.001). There was a BAG-by-MS interaction indicating an MS-specific correlation (beta =-0.19, 95% CI -0.29 to -0.09; P<.001). Across five independent clinical MS cohorts, the pooled BAG-CPS correlation was r=-0.25 (95% CI -0.33 to -0.18; P<.001). Overall, the magnitude of the association between BAG and CPS was at least five-fold greater in MS than in the normative population. Conclusion: BAG was substantially more strongly associated with CPS in MS than in the normative population. These cross-sectional findings support further evaluation of BAG as an adjunctive MRI marker. Further studies are required to establish mechanism, prognosis, or clinical decision utility.

BackgroundIn multiple sclerosis (MS), 7 Tesla (7T) MRI improves the visualization of cortical (CLs) and white matter (WM) lesions with a paramagnetic rim (PRLs), associated with smoldering inflammation. Spinal cord (SC) atrophy is a critical determinant of clinical disability in MS, but its importance relative to PRLs and CLs in predicting neurological disability remains unclear. PurposeTo identify the most relevant predictors for baseline neurological disability and 4-year disease progression independent of relapse activity (PIRA) in a heterogeneous MS cohort. Materials and MethodsOne-hundred-twelve MS patients (83 relapsing-remitting, 29 secondary progressive) were prospectively recruited between 2010 and 2024. 7T T2*-susceptibility-weighted imaging was acquired to segment CLs, PRLs, and non-rim WM lesions, and 3T T1-weighted brain MRI to estimate cortical thickness, brain WM volume, and the SC C2-C3 cross-sectional area (CSA) using FreeSurfer and Spinal Cord Toolbox. Expanded Disability Status Scale (EDSS) was assessed at baseline and longitudinally, in 97/112 MS patients, after a mean follow-up of 4.0 years. Associations between imaging metrics and clinical outcomes were evaluated using regression models. ResultsBaseline EDSS was associated with non-rim WM lesion volume (p=<0.001), CL volume (p=0.001), brain WM volume (p=0.017), and C2-C3 CSA (p=0.003). At follow-up, 23/97 patients showed PIRA. PIRA was associated with PRL volume (p=0.030), CL volume (p=0.011), and brain WM volume (p<0.001). A stepwise logistic regression identified CL volume as the strongest independent predictor of PIRA (Nagelkerke R2=0.200, OR=1.0006, p=0.005). Patients with a CL load > 403 mm3 progressed in half of cases (70% sensitivity, 50% specificity) within 4 years. ConclusionIn MS, different imaging biomarkers are associated with either the current disability or PIRA. Spinal cord atrophy mainly explains the current EDSS, while brain WM atrophy and PRLs provide additional insights into future disability trajectory. Among all markers, CLs emerged as the main driver for PIRA.

BackgroundAccelerated long-term forgetting (ALF), defined as an increased rate of memory loss over extended intervals, has so far been detected in a pilot study of patients with mild multiple sclerosis (MS). This study aimed to (I) confirm the presence of ALF in a larger, heterogeneous MS sample, (II) explore associations with patient-reported outcomes, and (III) assess the diagnostic performance of ALF tests for subjective memory impairment. MethodsThis study compared 62 MS patients and 65 age-, sex-, and education-matched healthy controls using standardized memory tests (RAVLT, WMS-IV Logical Memory subtest). Recall was assessed immediately, after 30 minutes, and after 7 days. Seven-day/30-minute recall ratios (QRAVLT, QWMS) served as primary outcomes. Self-report measures included memory complaints, fatigue, depression, and sleep disturbances. Linear regression and Receiver operating characteristic (ROC) analyses assessed predictors and diagnostic accuracy. ResultsALF was observed in multiple sclerosis since QRAVLT was lower in patients than in controls (0.64 [95% CI 0.59-0.69] vs. 0.78 [0.73-0.82], p < 0.001), as was QWMS (0.79 [95% CI 0.74-0.84] vs. 0.95 [0.90-1.00], p < 0.001), despite comparable initial learning. Greater fatigue, higher memory complaints, longer disease duration, older age, and greater disability were associated with lower ALF scores. The combined ALF score moderately discriminated subjective memory impairment (AUC 0.74; sensitivity 0.73; specificity 0.73). ConclusionMS patients showed ALF despite normal initial learning, indicating a specific memory deficit undetected by standard tests. Long-delay recall using RAVLT and WMS-IV Logical Memory subtest may improve cognitive impairment detection in MS.

Background: Brain age is a biomarker of brain tissue integrity associated with disability in multiple sclerosis. While new lesion formation is central to MS diagnosis and treatment monitoring, its direct relationship to brain aging has not been established. Methods: We analyzed 163 people with MS with clinical and MRI assessments at baseline and years 3, 6, and 8. Brain age was estimated using BrainAgeNeXt. Annualized brain age acceleration was modeled as a function of radiological activity using generalized estimating equations, adjusting for age, sex, disease duration, baseline T2 lesion volume, normalized brain volume (NBV), brain age difference (BAD), and disease-modifying therapy. Secondary analyses examined dose-response effects, post-activity recovery, paramagnetic rim lesion (PRL) associations, and disability associations. Results: 105 participants had at least one new T2 lesion over 8 years. Radiologically active intervals (138 of 333) were associated with +0.19 yr/yr greater brain age acceleration than stable intervals (95% CI: 0.03-0.37; p=0.022), scaling with lesion count (beta=+0.18; p=0.001) and volume. Older age, greater baseline BAD, and NBV were independently associated with reduced brain age acceleration. Brain age acceleration in individuals with new lesions normalized during subsequent stable intervals (0.41 vs -0.06 yr/yr; p=0.001). Both PRLs and non-PRL lesions were associated with greater brain age acceleration than stable intervals. Baseline BAD, but not annualized acceleration, predicted Expanded Disability Status Scale (EDSS) and Nine-Hole Peg Test (9HPT) worsening. Conclusions: New focal lesion formation is associated with a quantifiable, dose-response acceleration of brain aging in MS that normalizes once lesion activity is suppressed.

Objective1) To assess fMRI-based functional connectivity (FC) anomalies in early multiple sclerosis (MS), 2) To determine the relation between FC changes and structural brain damage due to disease progression 3) To study the association between FC changes and cognitive and physical disability. MethodsStructural MRI and resting-state fMRI were acquired from 76 early relapsing-remitting MS patients at baseline (average disease duration 71.7 months {+/-} 63) and after five years. Ninety-four healthy controls (HCs) matched for age and sex were included at baseline. Independent component analysis (ICA) and network modelling were used to measure FC. FC variation was related to expanded disability status scale and neuropsychological outcomes. Brain and lesion volumes were quantified using standard methods. We used the 25 independent components obtained from ICA to estimate the longitudinal stability of the brain connectome as a proxy for functional reorganization over time. ResultsThe MS subjects were clinically and cognitively stable. Compared to HCs, FC abnormalities were detected within networks and in single connections in patients with early MS at baseline. Over time, FC was relatively invariable, but changes in FC were associated with progression of brain atrophy ({rho} = 0.39, p = .06). No significant relationship with clinical and cognitive measures or lesion load was detected. ConclusionPatients with MS showed evidence of altered FC in the early stages of the disease. Over time, changes in FC seem to be related to a progression of brain atrophy, which are known to precede changes in clinical and cognitive functioning.

BackgroundProper identification of disability accumulation in the routine clinical care of progressive multiple sclerosis (PMS) patients is usually a challenging task. Patient-reported outcome measurements (PROMs) can provide a practical, cost-efficient, and remotely accessible tool to assess disease progression. MethodsEmBioProMS is a prospective, multicentric cohort, conducted in 7 specialized MS centers in Germany. PROMs were evaluated at inclusion and compared between patients with retrospective evidence of disease progression in the last two years and those with stable disease. Patients with either primary or secondary progressive MS according to the McDonald criteria 2017 were included in the analysis, while patients with incomplete PROMs scores, MS relapses, other neurological or systemic inflammatory diseases were excluded. The disease progression was assessed using a combined outcome parameter, including EDSS score, timed 25-foot walk test, and nine-hole-peg test. Results185 patients were included in the final analysis (SPMS, n=77; PPMS, n=108). The median age and disease duration were 55 years and 13 years, respectively. Disease progression was diagnosed in 114 of 185 patients (61.6%). BDI-II, MSIS-29, and FSMC scores were worse in patients with evidence of disease progression in the last two years. Patients with any of the included PROMs above the 90th percentile had an odds ratio of 3.8 (95% confidence interval: 1.4-10.6, P=0.01) for having progression in the last two years in a binomial regression model adjusted for age, sex, disease duration, treatment status, center effect, and Expanded Disability Status Scale (EDSS). Similar results were observed in patients with PROM scores in the 80th and 70th percentile (OR: 2.9 and 3.7, P=0.015 and 0.003, respectively). ConclusionPROMs can be a simple and effective way to detect disability worsening in a chronic neurological disease like PMS and, therefore, substantially contribute to better classification and prognostication of the disease course through objective and structural patient-doctor communication. Trial RegistrationGerman Clinical Trials Register (Deutsches Register Klinischer Studien - DRKS), DRKS00020132

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.

Background Social and geographic barriers contribute to worse outcomes in patients with multiple sclerosis (MS) and related disorders, but these factors remain poorly characterized among Latino patients. We evaluated associations between distance to specialty care, neighborhood deprivation, insurance status, and clinical outcomes among Latinos with MS and related disorders. Methods We conducted a retrospective study of Latino adults with MS, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease. Demographic, clinical, and socioeconomic variables were abstracted from the medical record. Distance to care was defined as residence [&ge;]50 vs. <50 miles from clinic and neighborhood deprivation as Area Deprivation Index (ADI) state rank. We used unadjusted and multivariable regression to evaluate associations with Expanded Disability Status Scale (EDSS) score, annualized relapse rate (ARR), and disease-modifying therapy (DMT) non-adherence. Results Among 99 Latino patients, 84 had MS, 11 MOGAD, and 4 NMOSD; 46.5% lived [&ge;]50 miles from clinic. Living [&ge;]50 miles from clinic was associated with higher EDSS scores in unadjusted analyses, but not after covariate adjustment. In multivariable analyses, Medicaid insurance was associated with higher EDSS compared with commercial insurance ({beta}=1.071, p=0.031) and higher ARR ({beta}=0.230, p=0.022). Higher ADI showed a non-significant trend toward higher EDSS ({beta}=0.147 per 1-decile increase, p=0.068). DMT non-adherence was not significantly associated with covariates. Conclusions In this cohort of Latinos with CNS demyelinating diseases, Medicaid insurance was associated with greater disability level and higher relapse activity. These findings suggest that insurance status should be considered when designing strategies to improve access to neuroimmunology care.

BackgroundMultiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) share overlapping clinical and imaging features, complicating differential diagnosis. The choroid plexus is increasingly recognized as a regulator of neuroinflammation and may play a critical role in the pathogenesis and differentiation of these conditions. Choroid plexus cysts (CPCs) are difficult to detect with conventional MRI resolution and standard anatomical approaches. High-resolution 7T MRI enables their visualization as readily identifiable and quantifiable morphological changes, offering a new direction for choroid plexus research. ObjectiveTo characterize choroid plexus cysts (CPCs) in aquaporin-4 antibody-positive NMOSD and relapsing-remitting MS (RRMS) using ultra-high-field 7T MRI. MethodsFourteen patients aged 16-30 years were prospectively recruited, including seven NMOSD (mean age 22.9 years) and seven MS (mean age 22.1 years). CPCs were assessed on UHR-T2WI-TSE images for number, maximum/minimum diameter, and cross-sectional area. Conventional brain lesions were evaluated on T2-FLAIR. Independent readings by two radiologists were adjudicated by a senior neuroradiologist. ResultsCPCs were present in all NMOSD patients (7/7) but only 57% of MS patients (4/7). Compared with MS, NMOSD showed a higher CPC burden with greater counts (median 4 vs 1; p=0.037) and non-significant trends toward larger diameters and areas (maximum diameter 4.17 mm vs 2.27 mm; minimum diameter 3.58 mm vs 1.82 mm; cross-sectional area 4.41 mm2 vs 2.02 mm2; p=0.072-0.095). Both groups demonstrated right-sided predominance. In contrast, brain lesions were more prevalent in MS (7/7) than in NMOSD (3/7; p=0.015). Conclusions7T MRI reveals distinct CPCs characteristics in NMOSD and MS. Despite fewer brain lesions in NMOSD compared with MS, CPCs burden remained consistently higher. These findings suggest that CPCs may represent a more sensitive and quantifiable structural change, serving as a potential imaging-biomarker for distinguishing NMOSD from MS. Validation in larger cohorts is warranted to advance understanding of neuroimmunological diseases and to clarify the role of CPCs in neuroinflammation. Key pointO_LIIdentifying additional differences in brain injury between NMOSD and MS is crucial for diagnosis and therapy. C_LIO_LICPCs are more prevalent and distinct in NMOSD than in MS, unveiling an "iceberg" of structural pathology hidden at conventional imaging resolution. C_LIO_LICPCs are readily identifiable and quantifiable, indicating their potential as a novel imaging biomarker for differential diagnosis in clinical practice. C_LI

Background and ObjectivesTreatment initiation strategies for disease modifying therapy in multiple sclerosis (MS) are debated, with recent trends favoring induction over escalation approaches. Whether this impacts risk of progressive disease and long-term accumulation of disability is unclear. MethodsAn observational study of a real-world cohort of patients diagnosed with MS registered in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Womens Hospital study and the Massachusetts General Hospital Pediatric Multiple Sclerosis Database was performed. Patients 12-50 years old at diagnosis were grouped by treatment initiated within 6 months of diagnosis into low-efficacy early therapy (LEET) and high-efficacy early therapy (HEET) groups. Risks of progression independent of relapse activity (PIRA), relapse associated worsening (RAW), and sustaining an Expanded Disability Status Scale (EDSS) score [&ge;] 5.0 were calculated. Results750 patients were analyzed (n = 583 LEET, 112 HEET). HEET vs LEET groups had a similar risk of PIRA (adjusted hazard ratio = 0.99, P-adjusted = 0.95) but a significantly lower risk of RAW (adjusted hazard ratio = 0.48, P-adjusted = 0.015). Sub-stratification of the HEET group into high- and very high-efficacy early therapy groups (i.e. ocrelizumab, natalizumab) showed similar risk of PIRA. Cox proportional hazards analysis revealed older age at diagnosis as a significant contributor to risk of PIRA. Nonetheless young patients still had substantial risk of PIRA, which was similar regardless of treatment efficacy group. In a subset of patients with MRI data, lower brain parenchymal also significantly increased risk of PIRA. LEET, HEET, and VHEET groups also had a similar risk of sustaining an EDSS score [&ge;] 5.0. HEET and VHEET patients, however, had a slightly lower change in EDSS over time. DiscussionWhile HEET reduces risk of RAW, it does not significantly affect the risk of PIRA, even in patients diagnosed before age 30. It also does not significantly affect the risk of sustaining an EDSS score [&ge;] 5.0, though may minimally decrease change in EDSS/year. This suggests inductive versus escalation strategies primarily influence patient outcomes by decreasing RAW, and underscores the need for emerging therapeutics to target PIRA, which continues to cause significant disability in patients on treatment.

OBJECTIVESTo analyze the symptoms and severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (pwMS) on immunotherapy using data from the COVID-19 in multiple sclerosis (MS) Global Data Sharing Initiative dataset provided by PhysioNet. METHODSThe open-access COVID-19 in MS Global Data Sharing Initiative dataset was obtained through credentialed access using PhysioNet. The variables analyzed included body mass index (BMI), symptoms of COVID-19, age, current use of disease-modifying therapy (DMT), efficacy of DMT, comorbidities, hospitalization status, and type of MS. A linear regression analysis was completed. Data analysis and visualization were completed using STATA v1.5, R-Studio v1.1.447, Python v3.8, and its associated libraries, including NumPy, Pandas, and Matplotlib. RESULTSA total of 1141 participants were included in the analysis. 904 women and 237 men were diagnosed with MS. Among the pwMS included in the study; 208 (19.54%) had a suspected infection with COVID-19 and only 49 (5.25%) were confirmed. Any COVID-19 symptom was present in 360 individuals. The commonly reported DMT agents included dimethyl fumarate (12.71%) and fingolimod (10.17%). 101 in total (8.85%) reported not using any DMT. Factors associated with hospitalization and/or admission to the ICU included having any comorbidity (p = 0.01), neuromuscular disorder (p = 0.046), hypertension (p = 0.005), chronic kidney disease (p < 0.001), and immunodeficiency (p = 0.003). The type of MS, the duration of the disease, and high-efficacy DMT therapy did not have a statistically significant influence on hospitalization. CONCLUSIONThis study underscores the importance of comorbidities, especially neuromuscular disorders, hypertension, chronic kidney disease (CKD), and immunodeficiencies, as possible prognostic indicators for worse outcomes of COVID-19 in pwMS. On the contrary, the type of MS, the duration of the disease, and the efficacy of disease-modifying therapy did not significantly affect the severity of the symptoms of COVID-19 in this cohort.

Background and objectivesCortical lesions (CL) are common in multiple sclerosis (MS) and associate with disability and progressive disease. We asked whether CL continue to form in people with stable white matter lesions (WML) and whether the association of CL with worsening disability relates to pre-existing or new CL. MethodsA cohort of adults with MS were evaluated annually with 7 tesla (T) brain magnetic resonance imaging (MRI) and 3T brain and spine MRI for 2 years, and clinical assessments for 3 years. CL were identified on 7T images at each timepoint. WML and brain tissue segmentation were performed using 3T images at baseline and year 2. Results59 adults with MS had [&ge;]1 7T follow-up visit (mean follow-up time 2{+/-}0.5 years). 9 had "active" relapsing-remitting MS (RRMS), defined as new WML in the year prior to enrollment. Of the remaining 50, 33 had "stable" RRMS, 14 secondary progressive MS (SPMS), and 3 primary progressive MS. 16 total new CL formed in the active RRMS group (median 1, range 0-10), 7 in the stable RRMS group (median 0, range 0-5), and 4 in the progressive MS group (median 0, range 0-1) (p=0.006, stable RR vs PMS p=0.88). New CL were not associated with greater change in any individual disability measure or in a composite measure of disability worsening (worsening Expanded Disability Status Scale or 9-hole peg test or 25-foot timed walk). Baseline CL volume was higher in people with worsening disability (median 1010l, range 13-9888 vs median 267l, range 0-3539, p=0.001, adjusted for age and sex) and in individuals with RRMS who subsequently transitioned to SPMS (median 2183l, range 270-9888 vs median 321l, range 0-6392 in those who remained RRMS, p=0.01, adjusted for age and sex). Baseline WML volume was not associated with worsening disability or transition from RRMS to SPMS. DiscussionCL formation is rare in people with stable WML, even in those with worsening disability. CL but not WML burden predicts future worsening of disability, suggesting that the relationship between CL and disability progression is related to long-term effects of lesions that form in the earlier stages of disease, rather than to ongoing lesion formation.

BackgroundThe COVID-19 pandemic has negatively impacted the social fabric of people with multiple sclerosis (pwMS). ObjectiveTo evaluate the associations between personal social network environment and neurological function in pwMS and controls during the COVID-19 pandemic and compare with the pre-pandemic baseline. MethodsWe first analyzed data collected from 8 cohorts of pwMS and control participants during the COVID-19 pandemic (March-December 2020). We then leveraged data collected between 2017-2019 in 3 of the 8 cohorts for longitudinal comparison. Participants completed a questionnaire that quantified the structure and composition of their personal social network, including the health behaviors of network members. We assessed neurological disability using three interrelated patient-reported outcomes: Patient Determined Disease Steps (PDDS), Multiple Sclerosis Rating Scale - Revised (MSRS-R), and Patient Reported Outcomes Measurement Information System (PROMIS)-Physical Function. We identified the network features associated with neurologic disability using paired t-tests and covariate-adjusted regressions. ResultsIn the cross-sectional analysis of the pandemic data from 1130 pwMS and 1250 control participants, higher percent of network members with a perceived negative health influence was associated with greater neurological symptom burden in pwMS (MSRS-R: Beta[95% CI]=2.181[1.082, 3.279], p<.001) and worse physical function in controls (PROMIS-Physical Function: Beta[95% CI]=-5.707[-7.405, -4.010], p<.001). In the longitudinal analysis of 230 pwMS and 136 control participants, the networks of both pwMS and controls experienced an increase in constraint (pwMS p=.006, control p=.001) as well as a decrease in network size (pwMS p=.003, control p<.001), effective size (pwMS p=.007, control p=.013), maximum degree (pwMS p=.01, control p<.001), and percent contacted weekly or less (pwMS p<.001, control p<.001), suggesting overall network contraction during the COVID-19 pandemic. There was also an increase in percentage of kin (p=.003) in the networks of pwMS but not controls during the COVID-19 pandemic when compared to the pre-pandemic baseline. These changes in personal social network due to the pandemic were not associated with worsening neurological disability during the pandemic. ConclusionsOur findings suggest that perceived negative health influences in personal social networks are associated with worse disability in all participants during the COVID-19 pandemic. Despite the perturbation in social environment and connections during the pandemic, the stability in neurological function among pwMS suggests potential resilience.

Background and ObjectivesCortical lesions are common in multiple sclerosis (MS) and associated with disability, but their characterization in early MS has been limited. Here, we aimed to characterize cortical lesions in newly diagnosed MS with 7 tesla (T) brain MRI. MethodsAdults within 14 months of relapsing-remitting MS diagnosis underwent 7T brain MRI and clinical evaluation at Mount Sinai. Cortical lesions were identified using T1-weighted (w) (median of three acquisitions) and T2*w images (both at 0.5mm3). Non-cortical brain lesions were segmented on 0.7mm3 T1w images. Lesion burden in newly diagnosed MS was compared with a previously analyzed NIH cohort with longer time since diagnosis, imaged using a similar protocol. Results61 individuals were included in the newly diagnosed MS cohort (mean age 34 {+/-} 4 years; 72% female; median time since diagnosis 5 months, interquartile range [IQR] 6). Cortical lesions were identified in 50/61 (81%) individuals, and subpial cortical lesions were identified in 46 (75%). Median cortical lesion number was 5 (IQR 11), median volume 319 l (IQR 1049). Cortical lesions constituted a median of 14% of total brain lesion volume (IQR 43%), and in 21% of individuals, cortical lesions constituted >50% of total brain lesion volume. Cortical lesion number was associated with worse 9-hole peg test ({rho}=0.33, p=0.008) and Symbol Digit Modalities Test performance ({rho}=-0.29, p=0.02). When pooled with the NIH cohort (n=60, median time since diagnosis 12 years, IQR 17), non-cortical lesion volume was [~]3.5 times higher in people with time since diagnosis >36 months (median 4.7 ml, IQR 8.7) vs [&le;]36 months (median 1.2 ml, IQR 2.4, p<0.001). In contrast, cortical lesion volume was only [~]1.3 times higher in people with time since diagnosis >36 months (median 416 l, IQR 1013) vs [&le;]36 months (median 318 l, IQR 925, p=0.04). Non-cortical lesion volume was moderately associated with time since diagnosis ({rho}=0.54, p<0.001) vs {rho}=0.27 (p<0.001) for cortical lesions. DiscussionCortical lesions are prevalent in newly diagnosed MS and constitute a substantial portion of total lesion burden. Cortical lesion volume is similar in early vs established MS, suggesting most cortical lesions form early in disease.

Interpreting brain structure at the individual level remains a major challenge in neuroimaging, as population variability across age and sex limits the clinical utility of group-level findings. Here, we develop large-scale normative models of regional cortical and subcortical brain volumes from more than 62,000 healthy individuals across the lifespan and apply them to multiple sclerosis (MS) to enable individualised, reference-based assessments of grey matter morphology. We identify a temporally stable yet heterogeneous morphometric phenotype of MS, expressed as concordant deviations from age- and sex-adjusted reference values. Individual deviation profiles are clinically informative: both the magnitude and cumulative burden of lower-than-reference volumes are associated with disability cross-sectionally and longitudinally. Moreover, the profiles can be translated into interpretable stratification rules linked to disability trajectories and relapse dynamics. This work reframes known structural abnormalities into stable, individual-level deviation profiles, demonstrating how normative modelling can move neuroimaging beyond group averages toward clinically interpretable inference. Together, these findings establish a generalisable framework for translating population-level neuroimaging data into individual-level phenotypes with potential beyond multiple sclerosis.

Disability worsening is the critical long-term outcome in multiple sclerosis, yet the Expanded Disability Status Scale incompletely captures neurological deterioration and has limited sensitivity in the short time windows of clinical trials. Composite endpoints incorporating functional measures have been proposed to address these limitations, but whether they reliably improve detection of treatment effects has not been established across trials. We conducted a post-hoc analysis of individual patient data from ten phase III randomised controlled trials (ASCEND, BRAVO, CONFIRM, DEFINE, EXPAND, INFORMS, OLYMPUS, OPERA I/II, and ORATORIO; n = 9,369), spanning relapsing-remitting and progressive multiple sclerosis. Confirmed disability worsening was defined using harmonised criteria with the msprog package and confirmed at 24 weeks. Treatment effects were estimated using Cox proportional hazards models and combined across trials in a one-stage individual patient data framework. Composite endpoints were constructed from the Expanded Disability Status Scale, the timed 25-foot walk test, and the nine-hole peg test using logical unions (OR-type), intersections (AND-type), and majority-vote structures. Sensitivity to treatment effect was quantified using Z-scores (the ratio of the pooled log-hazard ratio to its standard error) and compared to the Expanded Disability Status Scale reference using interaction tests. Event rates varied across components: the timed walk test generated the highest rates (up to 46.8%) while the nine-hole peg test generated the lowest (as low as 2.1%). OR-type composite endpoints showed weaker treatment effects than the Expanded Disability Status Scale alone, with the largest reductions in sensitivity observed for endpoints incorporating the timed walk test ({Delta}Z up to +2.26; interaction p = 0.004). These findings were confirmed across disease subtypes and were pronounced in relapsing-remitting trials, where no composite endpoint outperformed the Expanded Disability Status Scale. In progressive multiple sclerosis, the combination of the Expanded Disability Status Scale and the nine-hole peg test showed numerically stronger treatment effects ({Delta}Z = -1.65), though interaction tests did not reach statistical significance (p = 0.051). Composite endpoints do not systematically improve treatment effect detection in multiple sclerosis trials. Increased event capture driven by the timed walk test introduces noise that dilutes the treatment signal rather than amplifying it, highlighting that event rate and endpoint quality are not interchangeable. Upper limb function assessed by the nine-hole peg test provides complementary and specific information, particularly in progressive disease. The combination of global disability and upper limb measures represents a promising direction for future endpoint development in progressive multiple sclerosis trials, warranting validation.

Background: Optic nerve involvement is common in multiple sclerosis (MS) and is now recognized as a key site for dissemination in space under the most recent revision of McDonald's criteria. Reliable detection of optic nerve lesions is essential for diagnosis and monitoring, yet the optimal MRI sequence remains uncertain. Objective: To compare the diagnostic performance of three MRI sequences - short tau inversion recovery (STIR), fat-suppressed FLAIR (fs-FLAIR), and double inversion recovery (DIR)- in detecting optic nerve lesions in MS patients. Methods: Fifty-nine MS patients underwent MRI with STIR, fs-FLAIR, and DIR sequences and visual evoked potential (VEP) testing. Lesion detection was assessed independently for each sequence, and results were compared to structural and functional standards. Results: No significant differences were found in lesion detection across the three sequences. All sequences showed similar sensitivity to structural and functional changes. The incremental benefit of adding orbita specific sequence to a whole-brain sequence was limited in the follow-up of MS. Conclusion: In patients with established MS, whole-brain sequences (fs-FLAIR, DIR) perform comparably to dedicated orbital sequences (STIR) in detecting optic nerve lesions. This supports the feasibility of MRI protocols by omitting additional orbital sequences in routine follow-up, thereby reducing scan time and patient burden without compromising diagnostic sensitivity.

Fatigue is common and disabling in multiple sclerosis, yet its mechanisms are poorly understood. In particular, overlap in measures of fatigue and depression complicates interpretation. A clearer understanding of relationships between fatigue and key clinical, neuropsychiatric and imaging variables including depression could yield clinically relevant mechanistic insight. We applied a data-driven multivariate network approach to quantify relationships between fatigue and other variables in early multiple sclerosis. Data were collected from Scottish patients with newly diagnosed, immunotherapy-naive, relapsing-remitting multiple sclerosis at baseline and month 12 follow-up in FutureMS, a nationally representative multicentre cohort. Subjective fatigue was assessed using the validated Fatigue Severity Scale. Detailed phenotyping included measures assessing physical disability, affective disorders, objective cognitive performance, subjective sleep quality, and structural brain imaging. Bivariate correlations between fatigue and other variables were calculated. Network analysis was then conducted to estimate partial correlations between variables, after accounting for all other included variables. Secondary networks included individual depressive symptoms, to control for overlapping symptom items in measures of fatigue and depression. Data from 322 participants at baseline, and 323 at month 12, were included. At baseline, 49.5% of the cohort reported clinically significant fatigue. Bivariate correlations confirmed that fatigue severity was significantly correlated with all included measures of physical disability, affective disturbance (anxiety and depression), cognitive performance (processing speed and memory/attention), and sleep quality, but not with structural brain imaging variables including normalized lesion and grey matter volumes. In the network analysis, fatigue showed strong correlations with depression, followed by Expanded Disability Status Scale. Weak connections with walking speed, subjective sleep quality and anxiety were identified. After separately controlling for measurement of "tiredness" in our measure of depression, some key depressive symptoms (anhedonia, subjective concentration deficits, subjectively altered speed of movement, and appetite) remained linked to fatigue. Conversely, fatigue was not linked to objective cognitive performance, white matter lesion volume, or grey matter volumes (cortical, subcortical or thalamic). Results were consistent at baseline and month 12. Depression was identified as the most central variable in the networks. Correlation stability coefficients and bootstrapped confidence intervals of the edge weights supported stability of the estimated networks. Our findings support robust links between subjective fatigue and depression in early relapsing-remitting multiple sclerosis, despite absence of links between fatigue and either objective cognitive performance, or structural brain imaging variables. Depression, including specific depressive symptoms, could be a key target of treatment and research in multiple sclerosis-related fatigue.

BackgroundMultiple sclerosis (MS) is a chronic autoimmune disorder affecting the central nervous system (CNS). Reactivation of Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) is observed in MS. ObjectivesThis study investigates immunoglobulins (Ig)G, IgM, and IgA directed against EBV nuclear antigen EBNA-366-406, HHV-6 and EBV deoxyuridine-triphosphatase (dUTPase), and different immune profiles in 58 patients with relapsing remitting MS (RRMS) compared to 60 healthy controls. MethodsWe employed enzyme-linked immunosorbent assays (ELISA) to measure the immunoglobulins to viral antigens. Multiplex immunoassays were used to measure cytokines, chemokines and growth factor levels that were used to compute immune profiles, including M1 macrophage, T helper (Th)-1, Th-17, and overall immune activation. We assessed disabilities using the Expanded Disability Status Scale (EDSS) and disease progression using the Multiple Sclerosis Severity Score (MSSS). ResultsIgG/IgA/IgM directed to the three viral antigens were significantly higher in RRMS than in controls. RRMS was significantly discriminated from controls by using IgG and IgM against HHV-6 dUTPase, yielding an accuracy of 91.5% (sensitivity=87.3% and specificity=95.2%). Neural network analysis showed that using IgG to EBV-dUTPase, IgM to EBV-dUTPase, and immune profiles yielded an area under the ROC curve of 1 and a predictive accuracy of 97.1%. There were strong associations between IgG/IgM responses to HHV-6 and EBV-dUTPases and the EDSS/MSSS scores and aberrations in M1, Th-17, profiles, and overall immune activation. ConclusionsHHV-6 and EBV reactivation play a key role in RRMS and these effects are mediated by activation of cytokine profiles.

IntroductionOften, an isolated clinical event suggestive of CNS demyelination confers a risk of conversion to multiple sclerosis. In this study, we investigate lymphocyte profiles after a first clinical event suggestive of multiple sclerosis (MS), which could contribute to the current understanding of early inflammatory responses in this demyelinating disease. MethodsTwenty treatment-naive clinically isolated syndrome (CIS) patients and fifteen healthy participants were included in our assessment of lymphocyte profiles and B cell subsets using multicolour flow cytometry. Analysis was made at 3-6 months (Baseline), 12, and 24 months after a first clinical event. We also performed a sub-analysis of patients that received glatiramer acetate (GLAT) after their baseline visit up to 24 months after the first clinical event. ResultsOur analysis revealed monocyte and B cell differences between groups. Percentages of CD19+CD20+ B cells were lower in CIS patients compared to healthy individuals at baseline. Additionally, monocyte distribution among groups was different. A subgroup analysis of patients treated with GLAT (n= 10) showed an increased percentage of naive (p<0.05) and memory pre-switched (p<0.01) B cells up to 24 months after their baseline visit compared to the untreated group (n= 10). ConclusionOur results showed early monocyte and B cell subsets alterations in pwCIS. Moreover, GLAT-treated patients showed an increased percentage of naive and memory pre-switched B cells after 24 months of treatment. Further research is needed to elucidate the role of B cells and monocyte disturbances during inflammatory processes after a first clinically-MS suggestive event.