Multiple Sclerosis and Related Disorders

Background: Rituximab is used off-label for multiple sclerosis (MS), and biosimilar substitution raises a distinct extrapolation challenge, as MS is not an approved indication for the reference product. Real-world nonmedical switching data inform biosimilar appropriateness decisions by clinicians, societies, and payers. Objective: To report the effectiveness and tolerability of nonmedical switching from originator (MabThera) to biosimilar rituximab (Truxima) in people with MS (pwMS). Methods: A retrospective, single-center observational cohort study of 50 pwMS switched after at least two originator infusions, followed for two years. Results: Annualized relapse rate declined from 0.45 (95% CI 0.28 - 0.68) prerituximab to 0.02 (95% CI 0.00 - 0.13) on originator and 0.00 (95% CI 0.00 - 0.05) on biosimilar (p = 0.367 between products). In paired imaging analysis (n = 29), the proportion with active scans declined progressively (50.0%, 34.5%, 17.2%; Cochrans Q, p = 0.040), with no difference between the originator and biosimilar periods (McNemar, p = 0.227). B-cell depletion deepened progressively. All patients remained on biosimilar through the end of follow-up. Conclusion: Nonmedical switching from originator to biosimilar rituximab was associated with comparable clinical and radiological outcomes, supporting its use in pwMS without concern for inferior efficacy or diminished tolerability.

Treatment targeting progressive multiple sclerosis (MS) have limited efficacy, as central nervous system (CNS) resident B cells are resistant to peripheral B cell depletion by antiCD20 monoclonal antibodies. CD19 targeted chimeric antigen receptor (CAR)T cells offer the promise to deplete B cells more extensively in both the peripheral and CNS compartments. Two adult participants with treatment-refractory progressive MS were treated with 0.33e8 autologous anti CD19 CAR T cells (mivocabtagene autoleucel, miv-cel) intravenously after a preconditioning regimen. Participant 1 (50's year old female, EDSS 6) had no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Participant 2 (60's year old female, EDSS 4.5) had grade 1 CRS and no ICANS. Expansion of CAR T cells in the cerebrospinal fluid (CSF) at Day 14 was noted in both participants, remarkably with sustained disappearance of disease-associated oligoclonal band (OCB) or normalization of IgG index despite peripheral naive B cell reconstitution. MRI and clinical outcomes showed sustained stability at Week 48. Serologic studies showed a decline in anti-Epstein Barr Virus seropositivity. Single cell myeloid and proteomic signatures showed a decline in proinflammatory profiles. In the 2 subjects with progressive MS reported here, low dose anti CD19 CAR T cell therapy (miv-cel) was safe, penetrated the CSF effectively, reduced intrathecal humoral activity, modulated peripheral immune tone, and appeared to stabilize EDSS scores. Overall, these results support the continued investigation of CAR T cell therapy in MS.

Background: Pregnancy is a distinct neuroendocrine and immunological state in women with multiple sclerosis (MS). Relapse activity typically decreases during gestation and increases after delivery, but the relationship between peri-pregnancy brain volumetric measures and disability remains unclear. Methods: This retrospective longitudinal pilot study included 14 women with relapsing-remitting MS who underwent MRI examinations before pregnancy and after delivery. Thirty-eight MRI scans were analyzed, with a mean of 2.71 timepoints per patient (SD 0.99). Global and regional brain volumes were measured using the longitudinal FreeSurfer pipeline. Choroid plexus (CP) volume was evaluated as an exploratory neuroimmune imaging marker. Associations between volumetric measures and Expanded Disability Status Scale (EDSS) scores were assessed using linear mixed-effects modeling with forward stepwise selection. Results: The final EDSS model retained bilateral ventral diencephalon (ventral DC) volumes, left amygdala volume, right pallidum volume, left nucleus accumbens volume, and cerebral cortex volume. The most prominent association involved the left ventral DC, where lower volume was associated with higher EDSS scores (p = 0.0008). CP volume showed no significant longitudinal change across peri-pregnancy MRI timepoints (p = 0.21) and was not retained in the final EDSS model. Conclusion: Regional brain volumetric measures, particularly ventral DC volumes, were associated with disability across the peri-pregnancy period despite low EDSS levels. To our knowledge, this is the first longitudinal evaluation of CP volume across the peri-pregnancy period in women with MS; no significant change was observed over time. These exploratory findings require confirmation in larger prospective studies using standardized serial MRI protocols.

Word-finding difficulty (tip-of-the-tongue phenomenon) is among the most prevalent changes reported by persons with multiple sclerosis (MS), but we lack validated performance metrics to assess this common symptom. Antonyms is a novel task evaluating retrieval of target phonological codes via a brief, clinically-feasible paradigm that controls for other cognitive processes. Test-retest reliability was good (0.85). Among 660 patients, Antonyms demonstrated better criterion validity than traditional language tasks (e.g., animal generation, Boston Naming Test). Demonstrating discriminate validity, Antonyms was specifically related to patient-reported difficulties with expressive language rather than working memory, executive/speed, or episodic memory. The Antonyms task is provided herein.

Background: Real-world evidence evaluating the long-term effectiveness and safety of dimethyl fumarate (DMF) in relapsing-remitting multiple sclerosis (RRMS) remains limited, particularly in Middle Eastern populations. Furthermore, whether previous exposure to disease-modifying therapies influences longitudinal treatment response has not been adequately characterized. We evaluated the real-world effectiveness, safety, and temporal treatment dynamics of DMF in RRMS and compared outcomes between treatment-naive and previously treated patients. Methods: This longitudinal observational cohort study enrolled 120 adults with RRMS initiating DMF (TECRA (R)) at two multiple sclerosis centers in Iran. Clinical outcomes, magnetic resonance imaging (MRI) activity, disability progression, and adverse events were assessed over 18 months at 6-month intervals. Repeated Expanded Disability Status Scale (EDSS) measurements were analyzed using linear mixed-effects models, while relapse counts and MRI lesion activity were evaluated using generalized estimating equations. Prespecified subgroup analyses examined differences according to prior treatment status. Results: Ninety-five patients completed the study. DMF produced a marked suppression of disease activity, reducing the annualized relapse rate by 95% (1.56 {+/-} 0.93 to 0.08 {+/-} 0.24; P < 0.001). EDSS improved during the first year and remained near baseline after 18 months despite a modest increase during the final follow-up interval. MRI inflammatory activity declined significantly throughout follow-up, although a mild increase in gadolinium-enhancing lesions after 12 months suggested possible attenuation of treatment effect over time. Overall, 88.4% of patients remained relapse-free, 70.5% demonstrated no MRI disease activity, and 64.2% achieved no evidence of disease activity (NEDA-3). While overall clinical outcomes were comparable between treatment-naive and previously treated patients, longitudinal analyses revealed distinct temporal patterns of MRI activity between groups. DMF was well tolerated, with predominantly mild cutaneous and gastrointestinal adverse events and infrequent treatment discontinuation. Conclusions: In conclusion, DMF was well tolerated and effective in reducing clinical and radiological disease activity. These findings support the long-term effectiveness of DMF in routine clinical practice while highlighting the importance of continued clinical and radiological monitoring to optimize individualized treatment strategies.

Background: Relapsing-remitting multiple sclerosis (RRMS) often progresses to secondary-progressive MS (SPMS), but diagnosis is typically retrospective, delaying potential interventions. Existing rule-based and machine learning approaches often lack prospective validation and provide no uncertainty estimates, limiting clinical adoption. Objective: To prospectively evaluate a conformal prediction (CP)-enabled random forest model for reproducing clinician-recorded disease course labels in the Swedish Multiple Sclerosis Registry (SMSReg) and compare its classifications with the Lorscheider criteria. Methods: The CP model was trained and calibrated on SMSReg-2022 (10,787 individuals, 85,461 hospital visits) and then validated on SMSReg-2025 (15,719 individuals, 45,077 hospital visits; not included in the SMSReg-2022 training/calibration/testing datasets). Performance was assessed at the hospital visit and individual levels and compared with the Lorscheider criteria. Results: The model maintained good calibration on the prospective dataset. At the per-hospital visit-level, the model accuracies were 92% (RRMS) and 95% (SPMS). At the individual level, sensitivity was 98%, specificity 89%, and F1-score 0.75. With clinician-recorded labels as reference, the model showed higher sensitivity than the Lorscheider criteria (98% vs. 71%), more transition assignments (90% vs. 57%), and higher F1-score (0.76 vs. 0.69). Conclusion: The CP-enabled model prospectively reproduced clinician-recorded disease course labels with calibrated uncertainty, supporting harmonization and decision support.

Introduction: Neuroinflammation is a known pathophysiologic mechanism in multiple sclerosis and a proposed mechanism in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Positron Emission Tomography (PET) imaging of the translocator protein (TSPO) has been widely used to measure neuroinflammation, though second-generation ligands are highly sensitive to a single nucleotide polymorphism, rs6971, resulting in high, mixed, and low affinity binders. It is unknown whether this polymorphism is associated with neuroinflammatory disorders. Materials and Methods: Eighty-six total participant genotypes for TSPO binding affinity were identified through Sanger sequencing (30 fibromyalgia, 21 ME/CFS, 11 multiple sclerosis, and 24 healthy controls). Associations between patient group and genotype were assessed with Fishers Exact test. Associations between genotype and symptom severity from self-report questionnaires were assessed with Kruskal-Wallis tests. Results: In the present study individuals with fibromyalgia, (ME/CFS), or multiple sclerosis were more likely to have a mixed- or low-affinity genotypes compared to healthy controls. Presence of the low or mixed genotypes were also associated with greater self-reported fatigue severity and depressive symptoms. Discussion: These findings should be confirmed in larger samples but suggest functional consequences of rs6971 polymorphism that may be related to the pathophysiology of pain and fatigue illnesses.

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.

Background: Rituximab and ocrelizumab target the same CD20 receptor. Rituximab is off-patent and prescribed off-label; ocrelizumab is licensed and patent-protected. Whether the resulting differences in utilization and cost reflect clinical value or regulatory structure has not been examined. Objective: To determine whether utilization and cost of B-cell depleting therapy across six health systems track regulatory approval status more closely than comparative effectiveness. Methods: We examined rituximab and ocrelizumab utilization and cost in Sweden, France, Germany, the United Kingdom, Italy and the United States (2016-2024). Costs were drawn from published national sources on a consistent ex-factory basis. Utilization was registry-measured for Sweden, France and Germany, measured from national claims for the United States, and estimated from indirect data for the United Kingdom and Italy. Weighted annual costs per patient on B-cell depleting therapy were modeled by Monte Carlo simulation (10,000 iterations). Results: Rituximab constituted the near-totality of B-cell depleting therapy in Sweden but 2.3% to 18.7% of use in the other five systems. Mean annual cost per patient ranged from $3,014 (Sweden) to $52,506 (United States), a 17-fold difference, with the four other European systems between $18,140 and $26,262. Adopting Sweden's utilization pattern was associated with modeled five-year per-patient differences in drug acquisition cost of $76,000 to $248,000. Conclusion: Utilization and cost align more closely with regulatory approval status than with available effectiveness data. International reference pricing acts on the price of the licensed agent but leaves intact the regulatory asymmetry that determines which agent is prescribed.

OBJECTIVE: To prioritize novel measures of disease progression, we examined whether actigraphy-derived rest-activity rhythm (RAR) parameters relate to cognitive performance as well as disability in a multiple sclerosis (MS) cohort enrolled in a prospective brain donation program. METHODS: RAR parameters were assessed using a wrist actigraphy device (AX3 Axivity Actiwatch, Axivity Ltd.) over two weeks. The primary outcome measure was the Symbol Digit Modalities Test (SDMT, N=222). Secondary outcomes included Brixton Spatial Anticipation Test and self-reported disability. In 76 participants, volumetric measures were derived from repurposed clinical magnetic resonance imaging (MRI) data. We applied linear and logistic regression models, adjusting for age, sex, education, time since MS diagnosis, and body mass index. RESULTS: After correction for multiple comparisons, higher intradaily variability (IV) of RAR and lower relative amplitude were associated with worse SDMT performance; higher IV was also associated with greater odds of disability. A broader set of RAR parameters was associated with disability measure. No MRI parameters were related to RAR in the subset of individuals with available MRI data, although we note suggestive associations with hippocampal and choroid plexus volumes warranting further investigation. INTERPRETATION: More robust circadian rhythms were related to better cognition. These results highlight the utility of actigraphy and its more nuanced measures beyond the simple summaries of activity levels that quantitate the extent of motor disability. Selected RAR features may be an effective non-invasive approach to capture clinically relevant quantitative measures of brain function for persons with MS.

Background. CNM-Au8, a catalytic nanocrystalline gold suspension, is proposed to support neuronal bioenergetics, but its effect on chronic lesion evolution in multiple sclerosis (MS) has not been reported. Objectives. To evaluate the effect of CNM-Au8 on chronic lesion tissue expansion (CLTE). Results. In this exploratory post hoc analysis of the VISIONARY randomised placebo-controlled trial, CLTE was quantified from serial FLAIR MRI. Fifty-five participants were included (CNM-Au8, n=40; placebo, n=15). Compared with placebo, CNM-Au8 was associated with lower lesion expansion rate (p=0.001; Cliffs =-0.58) and volume (p<0.001; Cliffs =-0.65). Conclusions. CNM-Au8 treatment was associated with substantially reduced chronic lesion tissue expansion.

INTRODUCTION Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune diseases of the neuromuscular junction resulting in fatigable muscle weakness. Rituximab (RTX) is used to treat patients refractory to standard immunosuppression, but evidence for its efficacy remains inconsistent. Here, we analyzed real-world data on the clinical course and side effects of RTX in MG and LEMS patients. METHODS This was a single-center study of all patients diagnosed with MG (n=64) or LEMS (n=5) treated with RTX from 2011 until 2021. Outcomes of RTX treatment were recorded retrospectively with Myasthenia Gravis Foundation of America Post-Intervention Status (MGFA-PIS), number of rescue therapies, myasthenic crises, and steroid dose at 1-year and 2-year follow-ups. RESULTS MGFA-PIS improved at both 1-year (y) and 2-y follow-up compared with baseline. Incidence rates of rescue therapies per 100 person-months (95% CI) decreased from 15.0 (11.8-18.8) at baseline to 7.5 (4.7-12.3) at 1-y and 4.3 (2.5-7.8) at 2y-follow-up. The number of patients without myasthenic crises within one year increased from baseline (49, 86.0%) to 1y-follow-up (55, 96.5%). Median (IQR) daily steroid dose decreased from 10 (5-22.5) mg/d at baseline to 4 (0-10) mg/d at 1y-follow-up, and to 2.5 (0-10) mg/d at 2y-follow-up. CONCLUSION This study indicates that RTX was associated with a stabilized clinical course and decreased steroid use in patients with autoimmune myasthenic syndromes, including those with thymoma-associated MG. Our data suggest that therapeutic benefit is apparent within the first year of treatment and is maintained through two years.

Background: Multiple sclerosis subpial cortical lesions are prevalent and associated with disability but difficult to detect on MRI. Inversion recovery susceptibility weighted imaging with enhanced T2 weighting (IR-SWIET) and T1/T2 ratio imaging have been proposed for cortical lesion detection on 3 tesla (T) MRI. Objectives: To assess cortical lesion detection using IR-SWIET and T1/T2 ratio imaging. Methods: Cortical lesions were identified in 20 persons with MS (pwMS) independently on six image sets: T1 weighted (w) magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) + T2w fluid attenuated inversion recovery (FLAIR) alone or with T1/T2, IR-SWIET single acquisition (x1), average of two (x2) or median of four (x4) acquisitions, or denoised single acquisition (IR-SWIETx1DN). In 10 additional pwMS with 7T-based cortical lesion segmentations, lesions were identified on MP2RAGE + FLAIR + IR-SWIETx1DN. Results: Median subpial lesions identified on MP2RAGE + FLAIR was 0 (interquartile range (IQR) 2) vs 0 with T1/T2 (IQR 1, p=0.07), 1 with IR-SWIETx1 (IQR 6, p=0.42), 5 with IR-SWIETx2 (IQR 5, p=0.008), 4 with IR-SWIETx4 (IQR 6, p=0.008), and 4 with IR-SWIETx1DN (IQR 6, p=0.008). Versus 7T, IR-SWIETx1DN detected subpial lesions with similar sensitivity to IR-SWIETx2. Conclusions: IR-SWIET, but not T1/T2, improves subpial cortical lesion detection. Denoising may be an efficient and sensitive alternative to multi-acquisition averaging.

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.

Background: Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system marked by demyelination and neurodegeneration. Beyond physical symptoms, MS is often linked to clinically relevant sleep disturbances. The variability and unpredictability of symptoms and disease progression can also fuel fear of relapse (FoR), undermining well-being and potentially increasing morbidity through inflammatory processes. Understanding biopsychosocial risk factors, including childhood maltreatment (CM) and sleep, in relation to FoR remains an important gap in MS management and research. Methods: Data from N = 48 participants were collected via an online survey. We used the Pittsburgh Sleep Quality Index (PSQI), the Fear-of-Relapse Scale (FoR), and the Childhood Trauma Questionnaire (CTQ) to assess the variables of interest. In addition, time points of exposure to different CM subtypes were assessed. Linear regression analyses were conducted to examine associations within the proposed negative triad. Results: A significant negative association between overall sleep quality and FoR was observed. In the total cohort, the interaction between CM and sleep was not a significant predictor of FoR. However, exploratory analysis revealed a significant interaction between CM and sleep among male participants, whereas the same interaction was not significant among female participants. Conclusion: A history of CM and impaired sleep quality introduce new stressors in managing one's own illness that have received little attention to date. However, the present study found that these factors were at least partly influential on the FoR. The results underscore the translational need for additional support services to enhance prevention and personalized care.

Background: Detecting higher order relationships in datasets of complex traits, such as multiple sclerosis (MS), has been challenging. Conventional statistics largely rely on comparing averages across groups and thereby discard important information on the underlying distribution of datapoints. The Genomic Information Field Theory (GIFT) overcomes this limitation by ranking individuals based on linear measures, for example immunoglobulin titres. The exact role of humoral immune responses against several human herpes viruses in a sex-dependent manner in MS is currently unknown. Materials and methods: We compared the performance of GIFT with conventional statistical frameworks to detect differences in the humoral immune response against 4 highly prevalent herpes viruses linked to an individuals susceptibility to develop MS in 200 MS patients and 137 healthy controls. Results: GIFT validated the well-known association that the Epstein Barr Virus (EBV) protein EBNA1 is strongly linked to MS susceptibility in both sexes. In contrast to conventional statistics, GIFT also identified association between herpes simplex virus, varicella zoster virus and the EBV VCA protein and female susceptibility to develop MS, whereas male MS susceptibility was only linked to CMV immunoglobulin levels. None of these associations was observed using conventional statistical tools. Conclusion and discussion: We here show for the first time that GIFT is able to detect novel associations in human immunoglobulin data linked to MS susceptibility, which remained undetected by conventional statistical frameworks. This shows the power of GIFT to detect complex phenotype-trait associations and underlying subgroups within populations.

Objective To examine whether prospectively recorded maternal BMI in early pregnancy is associated with offspring multiple sclerosis (MS) risk, including childhood-onset and adult-onset MS. Design Nationwide population-based cohort study. Setting Swedish national health and demographic registers. Participants 1,524,863 singleton children born in Sweden from 1992 to 2007 and followed through 2025. Exposures Maternal BMI recorded at the first antenatal visit, categorised as underweight (<18.5), normal weight (18.5-24.9), overweight (25.0-29.9), and obesity ([&ge;]30.0), and also modelled continuously. Main outcome measures MS in offspring, identified as at least three ICD-10 G35 codes recorded on separate dates. Cox models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) adjusting for confounders. Results During follow-up, 1539 offspring (0.1%) were diagnosed with MS at a median age of 24 years (interquartile range, 20-27 years). MS incidence rates by maternal BMI category were 0.37 per 10,000 person-years for both underweight, and normal weight, 0.42 for overweight, and 0.45 for obesity. Compared with normal weight women, maternal overweight and obesity were associated with higher hazards of offspring MS, with adjusted HRs of 1.20 (95% CI, 1.05 to 1.37) and 1.35 (95% CI, 1.11 to 1.64), respectively. Onset-specific analyses showed similar findings for adult-onset MS and less precise but directionally consistent estimates for paediatric-onset MS. Each 1-unit increase in maternal BMI was associated with a 3%, 4%, and 3% higher hazard of overall, paediatric-onset, and adult-onset offspring MS, respectively. Conclusions In this population-based cohort study, higher maternal BMI were associated with an increased rate of MS in offspring. The findings provide large-scale prospective evidence that maternal adiposity may be related to offspring MS risk and support further investigation of the prenatal metabolic environment in the early-life origins of 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.

Patient registries play a key role in research on chronic conditions like multiple sclerosis (MS), but their success typically depends on patients' willingness to share data. Information provided about ethically relevant registry practices may strongly influence their willingness. This study explores what information about ethics practices people with MS consider important when deciding whether to contribute data to a patient registry, and how they prefer this information to be communicated. We conducted semi-structured online interviews with 21 people with MS and patient representatives from nine European countries. The interview guide first addressed general information needs and then seven predefined ethically relevant topics. The topics registry governance, registry funding, data handling, and use-and-access procedures were adapted from the literature, while communication, access, and rewards for contributing data provided contextual and practical insight. They also served as the initial coding categories for directed qualitative content analysis, after which categories were refined and reorganized during analysis, and subcategories were inductively developed. We found that trust emerged as a cross-cutting factor. Participants required less information about registry practices when they trusted the registry or associated parties and preferred registry communication through trusted intermediaries. When deciding whether to contribute data to a patient registry, participants emphasized the importance of clarity about how the data will be used, who would have access to it, and what privacy protections are in place, while information preferences for technical details regarding data use and access varied widely. Feedback on personal or aggregate results was highly valued and seen as types of personal and communal benefits for participating. In conclusion, patient registries should adopt flexible communication strategies that balance transparency and accessibility. Building and maintaining trust, potentially through trusted affiliates like universities or patient organizations, appears central to properly inform (potential) registry participants about ethically relevant registry practices.

Background: Identifying and longitudinally measuring cognitive decline remains challenging because traditional assessments rely largely on episodic, in-person administration of analog scales by trained examiners. Smartphone technology provides a scalable alternative capable of extracting distinct digital biomarkers from continuous sensor and event streams. Following the integration of several cognitive modules into the self-administered Neurological Functions Test Suite (NeuFun-TS), this study evaluates the clinical utility and incremental validity of a final candidate module: an equiprobable (50/50) continuous vigilance Go/No-Go paradigm. Methods: We analyzed 3,270 quality-controlled trials from 303 participants, focusing primary analyses on 488 first-trial observations across 34 healthy donors (HD) and 213 multiple sclerosis (MS) participants. From the raw event stream, we screened 16 candidate metrics and retained 10 based on their intrinsic psychometric properties. Using these 10 metrics, we evaluated diagnostic group separation, test-retest reliability, correlations with clinical and magnetic resonance imaging (MRI) benchmarks, and incremental validity over existing digital modules: the randomized Symbol Digit Modalities Test (rSDMT) and the Motor Sequencing Test (MST), using paired observations. Results: Although nine of the 10 outcomes significantly separated HD from MS and seven separated relapsing-remitting from progressive MS subtypes (all adjusted p < 0.05), discriminative power was driven almost entirely by response latency rather than commission errors or inhibitory metrics. Multi-predictor composite scores offered no diagnostic advantage over reaction time alone. Furthermore, the Go/No-Go task demonstrated poor-to-moderate longitudinal test-retest reliability and failed to provide incremental clinical value over existing modules. Conclusion: Although the smartphone-based Go/No-Go task reflects processing speed impairment in MS, its discriminative capability is redundant with simpler reaction time metrics already implemented in the platform. Consequently, the Go/No-Go module was excluded from NeuFun-TS to minimize patient testing burden without compromising diagnostic sensitivity.