Multiple Sclerosis and Related Disorders

ImportanceIn multiple sclerosis (MS), high-efficacy disease-modifying therapies (HEDMTs) effectively control relapse-associated worsening (RAW), but progression independent of relapse activity (PIRA) remains inadequately addressed. As HEDMTs become the standard of care, developing new therapies that target this residual progression is a critical unmet need. ObjectiveThis study quantifies disability progression in MS patients treated with ocrelizumab to evaluate how confirmed EDSS disability progression (EDSS-CDP) would perform as an endpoint in future trials using HEDMT as comparators. DesignRetrospective longitudinal cohort study. SettingPooled dataset from four multicenter phase III and IV clinical trials. Participants1,859 people with (pw) relapsing MS (RMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS) who were treated with ocrelizumab within the OPERA I/II, ORATORIO, and CONSONANCE trials. InterventionOcrelizumab. Main Outcomes and MeasuresWe developed a hierarchical Bayesian model to analyze longitudinal EDSS trajectories using two components: an offset effect, used to capture changes occurring rapidly after treatment onset, followed by a steady, long term linear progression over time. We used this model to simulate future clinical trial scenarios, assuming different drug effects on the offset and the long term linear progression. ResultsOur model accurately describes longitudinal EDSS changes and the risk of EDSS-CDP in ocrelizumab-treated subjects. Disability improvement (offset effect) was most prominent in pwRMS, while pwPPMS exhibited the highest long-term progression rates. Baseline T1 gadolinium-enhancing lesions were associated with a greater initial benefit. Simulations of typical phase III trials suggest that the hazard ratio on the EDSS-CDP endpoint is mostly influenced by the magnitude of the offset effect rather than the impact on long-term linear progression. Conclusions and RelevanceWe attribute the disability improvement observed shortly after treatment onset to resolving focal inflammation, and the long-term steady progression rate to disease mechanisms not fully addressed by ocrelizumab. Our simulation results show that within the current trial paradigm, which uses EDSS-CDP as a measure of disability progression, the ability of a treatment to induce an initial improvement is the primary determinant of success. These results emphasize the urgent need for both innovative clinical trial designs and more sensitive endpoints to adequately assess the next generation of MS therapies targeting gradual disability progression. Key PointsO_ST_ABSQuestionC_ST_ABSWill the standard multiple sclerosis disability progression endpoint, confirmed EDSS disability progression (EDSS-CDP), prove to be an accurate measure of the efficacy of new therapies addressing long-term progression when compared against high-efficacy treatments (HET)? FindingsIn this modeling study of 10-year ocrelizumab data, observed changes in EDSS were characterized by an early improvement followed by a linear long-term worsening. EDSS-CDP was shown to be highly sensitive to initial improvement. Since this phenomenon strongly influences the overall treatment effect, trials that use ocrelizumab, or similar HET as a comparator may fail to identify novel treatments designed to further slow long-term progression. MeaningCurrent trial designs may be inadequate for evaluating next-generation MS therapies, necessitating the development of better metrics to capture treatment effects on gradual progression.

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.

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: Comorbidities are common in multiple sclerosis (MS) and may influence disability outcomes, but their dynamic impact on bidirectional disability transitions and long-term disability remains incompletely understood. Better understanding of this longitudinal relationship could inform personalized disability management strategies for people with MS. Methods: We leveraged two large electronic health record (EHR)-linked MS registries and applied multi-state Markov models (MSMs) to examine the extent to which individual comorbidities and overall comorbidity burden were associated with short-term disability transitions, long-term disability transition probabilities, and expected time spent in each disability state. We additionally compared MSM-based predictions of confirmed disability worsening (CDW) with Cox proportional hazards (CoxPH) model-based predictions using the integrated Brier score with bootstrap validation. Results: Among 3,723 patients with MS (74.6% female; 86.2% non-Hispanic White; mean age=41.9 years; mean disease duration=5.4 years) contributing 41,860 disability assessments over a mean follow-up of 7.3 years, higher cardiometabolic and psychiatric comorbidity burden was associated with increased transition intensity toward worse disability states and decreased transition intensity toward improvement, with a stepwise gradient across burden levels. Compared with patients without comorbidities, those with [&ge;]4 comorbidities had a 28% higher risk of worsening (HR=1.28 [1.06, 1.55]) and a 20% lower risk of improvement (HR=0.80 [0.67, 0.95]). Each individual comorbidity was significantly associated with worse disability transitions. Long-term estimates indicated a higher 5-year probability of severe disability and fewer years spent in the no-disability state among patients with greater comorbidity burden. CoxPH models showed directionally consistent associations but lower predictive accuracy for CDW compared with MSMs. Conclusion: Cardiometabolic and psychiatric comorbidities are associated with worse disability trajectories in MS, reducing improvement and accelerating progression. By providing a nuanced framework to quantify short-term disability transitions and long-term disability patterns, MSMs may have real-world clinical utility in disability prediction.

BackgroundMultiple sclerosis (MS) is characterized by focal white matter (WM) lesions, but subtle damage also occurs in normal-appearing white matter (NAWM). We developed a method to generate quantitative T1 maps from MPRAGE (Magnetization Prepared Rapid Gradient Echo) images and evaluated its ability to detect NAWM abnormalities across different MS phenotypes. MethodsT1 maps were derived from MPRAGE using a theoretical signal model and compared with MP2RAGE (Magnetization Prepared 2 Rapid Gradient Echoes) T1 values in four healthy volunteers. The method was then applied to 87 MS patients, divided into clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and primary progressive MS (PPMS), with age- and sex-matched healthy controls. T1 was measured in NAWM and lesions. Histogram analysis provided mean T1, full width at half maximum (FWHM), and skewness. ResultsIn healthy volunteers, T1 values matched MP2RAGE. In controls matched to the MS cohort, T1 increased with age (r = 0.35, p < 0.05). CIS patients showed no significant differences in any metric. RRMS and PPMS patients showed unchanged mean NAWM T1 but significantly different distributions, with higher FWHM (p<0.05) and skewness (p<0.001). An increase in T1 values was observed in MS lesions compared to NAWM in all groups. ConclusionThis study confirms the feasibility of deriving quantitative T1 maps from standard MPRAGE, offering reliable information to facilitate MS monitoring without additional acquisitions.

Introduction: Incomplete recovery from relapses contributes to long-term disability accumulation in relapsing remitting multiple sclerosis (RRMS), yet the relationship between immune regulation and relapse recovery remains poorly defined. Objective: To longitudinally characterize regulatory/effector immune cell dynamics in untreated RRMS patients and assess their association with immune balance and relapse recovery. Methods: Monocytic myeloid-derived suppressor cells (M MDSCs), regulatory T cells (Treg), and effector CD4 T cell subsets were measured in blood from 69 untreated RRMS patients sampled during relapse or remission and reevaluated after 12 months. Associations with clinical recovery after relapse were examined. Results: During relapse, patients exhibited higher M MDSC and Treg frequencies than in remission, while effector T cell subsets remained unchanged. Over one year, M-MDSCs increased consistently regardless of baseline clinical status, whereas Treg frequencies remained stable. Effector to M MDSC ratios were markedly elevated during relapse and declined over time, while effector-to-Treg ratios showed minimal variation. M MDSC levels during relapse were associated with sustained regulatory features at 12 month follow up. Importantly, higher baseline M MDSC levels, but not Treg frequencies, were associated with complete relapse recovery at one year. Conclusion: These findings suggest that circulating M-MDSCs, but not Treg, reflect interindividual differences in immune regulation and clinical recovery after relapse in early RRMS.

T-cell activation may be contributing to severe psychiatric disorders. Soluble CD27 (sCD27) - a marker for T-cell activation and disease activity in several autoimmune diseases - was evaluated as a tool for distinguishing T-cell activity in selected patients with severe psychiatric disorders, multiple sclerosis (MS), and controls. We hypothesise that elevated sCD27 levels will be associated with comorbid autoimmune disease (AID). sCD27 was measured in cerebrospinal fluid (CSF) and blood from a population enriched for suspected immunological comorbidity: the Immunopsychiatry Cohort (IP; n=115) and patients with MS (n=37), where levels in both groups were higher when compared with age matched controls undergoing surgery (n=154). Positive sCD27 (sCD27+), was defined as values >97.5% of controls. In IP, 23% were CSF-sCD27+ and 15% blood-sCD27+, compared to patients with MS where 88% were CSF-sCD27+ and 22% were blood-sCD27+. CSF-sCD27+ was confirmed as a sensitive marker for MS. In IP, CSF-sCD27+ was associated with comorbid AID (X2=4.847, p =0.028;) and AID disease activity (OR=5.14, p=0.029). Associations with AID were stronger when CSF and/or blood sCD27+ were combined (X2=8.559, p=0.003). CSF-sCD27+ in IP was also associated with pleocytosis, CSF-Total-tau, and CSF-NfL. In patients with severe psychiatric disorders, the sCD27+ cases were more likely to have comorbid AID and established markers for neuroinflammation in CSF. Combining analyses of CSF and blood improved sensitivity and specificity for AID suggesting compartmentalized T-cell activation. Psychiatric symptoms may precede somatic symptoms - or be the prominent symptom - of AID and sCD27 is a candidate marker for identification of this subgroup.

BackgroundIn multiple sclerosis (MS), demyelination and degeneration of transcallosal pathways impair interhemispheric communication. While white matter damage is well documented, the impact of cortical lesions on transcallosal conduction remains unclear. ObjectiveTo determine whether cortical lesions in the sensorimotor hand area (SM1{square}HAND) contribute to impaired transcallosal motor interaction using ultra{square}high{square}field MRI and transcranial magnetic stimulation (TMS). MethodsTwenty healthy controls (HCs) and 38 MS patients underwent 7T structural and diffusion{square}weighted MRI. Structural scans were used to identify cortical lesions in SM1{square}HAND, while diffusion tensor imaging (DTI) quantified microstructural properties in the transcallosal tract connecting left and right SM1{square}HAND. Single{square}pulse TMS was delivered to each SM1{square}HAND during tonic first dorsal interosseous contraction to measure the ipsilateral silent period (iSP). Corticospinal conduction was measured with contralateral motor{square}evoked potentials (MEPs), while the iSP was used to compute transcallosal conduction time (TCT). ResultsAmong MS patients, 41 of 76 hemispheres contained an SM1{square}HAND lesion. TCT was significantly prolonged in MS relative to HCs (P<0.001). In patients, cortical lesions delayed transcallosal conduction from the non{square}lesion{square}bearing to the lesion{square}bearing hemisphere (P=0.026). This direction-specific delay was associated with an intracortical lesion type (P<0.001), but not with DTI{square}derived microstructural measures (P>0.05). ConclusionsThe presence of cortical lesions in the sensorimotor cortex affects transcallosal inhibition between homologous sensorimotor regions in MS, slowing the build-up of inhibitory influence on the corticospinal output in the lesioned cortex. This delayed inhibitory buildlup appears to be associated with an intracortical lesion type. HighlightsO_LIIpsilateral silent period reveals delayed transcallosal motor interaction in multiple sclerosis C_LIO_LICortical lesions in sensorimotor cortex delay the onset of transcallosal motor inhibition C_LIO_LIDelayed transcallosal inhibition is only present toward the lesioned cortex C_LIO_LIIntracortical lesions, not callosal microstructure, is linked to this directionlspecific delay C_LI

Objective Astrocyte activation is increasingly recognized as an important component of multiple sclerosis (MS) pathology. Natalizumab (NTZ), a highly effective therapy for relapsing-remitting MS (RRMS), primarily blocks leukocyte trafficking into the central nervous system. However, its effects on astrocytic metabolism remain unclear. We investigated astrocyte-associated metabolic changes after NTZ treatment using quantitative 1-11C-acetate positron emission tomography (PET). Methods Seven patients with RRMS underwent quantitative 1-11C-acetate PET before and after NTZ treatment. PET-derived k2, an index of oxidative acetate metabolism, was analyzed voxel-wise and within GM and white-matter volumes of interest. Clinical status and brain magnetic resonance imaging (MRI) findings were assessed, and cognitive performance was evaluated using Rao's Brief Repeatable Battery of Neuropsychological Tests. Results After NTZ treatment, k2 decreased in all patients compared with pretreatment levels. Both gray and white matter showed significant reductions, and voxel-based analysis demonstrated widespread decreases across cortical and subcortical regions of the cerebrum and cerebellum, with no regions showing significant posttreatment increases. MRI showed no worsening; Expanded Disability Status Scale scores were stable or improved, and cognitive performance was generally stable, with improvements in selected subtests. Interpretation Quantitative 1-11C-acetate PET demonstrated a whole-brain reduction in astrocyte-associated metabolism after NTZ treatment in RRMS, most prominently in gray matter. NTZ may modulate astrocyte activity, in addition to its established effects on peripheral immune cell trafficking.

BackgroundThe thalamus has emerged as a key region involved in cognitive dysfunction in multiple sclerosis (MS). While previous studies have identified associations between thalamic structural damage, altered functional connectivity, and cognitive performance, the specific contributions of individual thalamic nuclei and the added value of integrating structural and functional metrics remain poorly understood. MethodsT1-weighted MRI, diffusion MRI, resting-state fMRI, and neuropsychological data were collected from 102 individuals with MS and 27 healthy controls. Thalamic grey matter volume, white matter microstructural integrity, and functional controllability were calculated for each nucleus and compared between individuals with MS and healthy controls, as well as between MS cognitive subgroups. Partial Spearman correlations were used to examine the relationship between imaging metrics across the three modalities, and also between imaging metrics and cognitive performance in MS. Sparse canonical correlation analysis models were used to examine the covariance between thalamic imaging metrics and cognitive performance in MS. ResultsWidespread atrophy and microstructural damage were observed across all thalamic nuclei in individuals with MS, regardless of cognitive status. In contrast, alterations in functional controllability were more spatially specific, primarily affecting the medial dorsal anterior nuclei, and were most pronounced in cognitively impaired individuals. These functional controllability metrics were independent of grey matter volume, white matter integrity, and lesion load. Combining thalamic functional controllability with structural metrics yielded a stronger association with cognitive performance in MS than either modality alone. ConclusionThis study provides novel evidence that functional controllability in the thalamus, particularly within the medial dorsal anterior nuclei, plays a critical role in cognitive impairment in MS. By applying a network control framework, our findings offer a dynamic systems perspective that extends beyond traditional connectivity analyses, capturing the thalamuss role in supporting flexible cognitive transitions. The integration of structural and functional controllability metrics enhances the ability to characterise individual differences in cognitive performance and may inform future efforts to identify biomarkers of cognitive dysfunction in MS.

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 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.

Importance: As new treatments increase quality and length of life in people with multiple sclerosis (MS), effective prevention and management of common comorbidities, including Diabetes Mellitus (DM), is increasingly important. Objective: To compare incidence of DM and its associations with hospitalisation and mortality in adults with MS and matched controls. Design: Using English primary care data from the Clinical Practice Research Datalink (CPRD), linked to Hospital Episode Statistics and national mortality records, we matched adults with MS diagnosed between 2000 and 2023, with up to ten controls without MS by age, sex, and practice. We excluded individuals with preexisting DM, defined using diagnostic and management codes. Outcomes included all-cause hospitalisation (number and duration) and mortality. We used Poisson, negative binomial, linear, and Cox proportional hazards models, adjusting for demographic and socioeconomic factors, adding interaction terms to examine if ethnicity, deprivation, and urbanity were associated with outcomes. Results: We included 9,010 individuals with MS and 78,121 matched controls. Over a mean follow-up of 13.2 years, people with MS had over twice the incidence of DM compared with controls (adjusted incidence rate ratio [aIRR]=2.26, 95% CI: 1.96 to 2.61, p<0.001). Among people with MS, incident DM was associated with higher hospitalisation rates (aIRR=1.82, 95%CI: 1.47 to 2.28, p<0.001), longer hospitalisation duration (median 18 vs 4 days, adjusted beta;=0.53, 95%CI: 0.41 to 0.65, p<0.001), and increased all-cause mortality when incident DM was modelled as a time-varying exposure (adjusted hazard ratio=1.46, 95%CI: 1.17 to 1.82, p<0.001), compared to those who did not develop DM. Similar patterns were observed among controls (hospitalisation rates: aIRR = 2.96, 95% CI 2.63 to 3.23, p<0.001; hospitalisation duration: adjusted {beta} = 0.93, 95% CI: 0.86 to 0.99, p<0.001; mortality [time-varying]: HR = 1.50, 95% CI: 1.27 to 1.77, p<0.001). The relationship between DM and increased hospitalisation was stronger in rural areas among those with MS and stronger in White groups among controls. Conclusions: People with MS are more likely to be diagnosed with DM, resulting in greater all-cause hospitalisation and all-cause mortality. This highlights the importance of equitable screening, prevention, and management of DM in people living with MS, with particular attention to geographical health inequalities.

Background. Poor sleep quality is common in people with multiple sclerosis (pwMS) and reduces quality of life. Objectives. To examine associations between modifiable factors and sleep quality in pwMS. Methods. In a prospective clinic cohort (2017-2023), we evaluated whether baseline measures of disability, depression, fatigue, and pain were associated with poor sleep quality (Pittsburgh Sleep Quality Index, PSQI) cross-sectionally using covariate-adjusted linear regression, structural equation modeling (SEM), and LASSO logistic regression, and longitudinally using mixed-effects models. Results. In this cohort (n=750; mean age 48.9 years; 80.3% women, 88.7% relapsing type), higher body mass index ({beta} [95% CI]: 0.06 [0.01, 0.12], p=.001) and area deprivation index (6.78 [2.17, 11.39], p<.001) were associated with worse baseline PSQI scores. In adjusted analyses (n=730), disability, depression, fatigue, and pain were each associated with worse sleep. In SEM, pain had a moderate direct effect on sleep ({beta} [95% CI]: 0.56 [0.48, 0.64], p<.001). LASSO models that included pain outperformed the benchmark (AUROC 0.741 vs 0.517). Longitudinally (n=382), time and higher baseline pain predicted worse sleep ({beta} [95% CI]: time in months 0.04 [0.02, 0.06], p<.001; pain 0.36 [0.31, 0.41], p<.001). Conclusion. Pain is a key, potentially modifiable driver of poor sleep quality in pwMS.

Objective: To systematically evaluate the efficacy and safety of Deep Brain Stimulation (DBS) for the management of disabling tremor in patients with Multiple Sclerosis (MS) by synthesizing data from available clinical studies. Methods: This systematic review and meta analysis followed PRISMA 2020 guidelines and was registered with PROSPERO (CRD420261347426). A comprehensive search of PubMed, Scopus, Web of Science, and Embase was performed from database inception until December 2025 with no time or language limitation. A pre-post meta analysis design was used to estimate the pooled effect size using the Standardized Mean Change (SMC) between baseline and follow up tremor severity. Because most included studies were single arm cohorts and clinical heterogeneity was anticipated, a random effects model using the Restricted Maximum Likelihood (REML) estimator with the Hartung-Knapp adjustment was applied. Safety outcomes including hardware complications and postoperative infections were pooled using random effects meta analysis of proportions. Results: Thirteen studies including 131 patients met the eligibility criteria. Eight studies with adequate outcome data were included in the pooled efficacy analysis. DBS was associated with a significant reduction in tremor severity with an overall pooled SMC of 1.42 (95% CI 1.07 to 1.77). Statistical heterogeneity was minimal (I2 = 0.0%, p = 0.6300), although this finding should be interpreted cautiously given the limited number of studies and clinical variability in surgical targets, most commonly the ventral intermediate nucleus (VIM), and follow up duration ranging from months to more than 20 years. The pooled incidence of postoperative infection was approximately 7% with substantial heterogeneity across studies (I2 = 74.1%). The most frequently reported adverse events were stimulation related effects such as dysarthria and disequilibrium, which were generally reversible after adjustment of stimulation parameters. Overall methodological quality of included studies was predominantly moderate. Conclusion: Deep brain stimulation may provide meaningful tremor reduction in selected patients with disabling and medication refractory MS tremor, with a large pooled treatment effect (SMC = 1.42). Although complications such as postoperative infection (approximately 7%) and transient stimulation related adverse effects can occur, these events appear manageable in most cases. However, the current evidence base remains limited by small sample sizes, heterogeneous study designs, and variability in surgical targets and outcome reporting. Larger prospective studies with standardized tremor outcome measures and consistent reporting of safety outcomes are needed to better define the long term efficacy and optimal clinical role of DBS in patients with MS related tremor.

Introduction: Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a debilitating condition characterised by severe fatigue and post-exertional malaise (PEM). Reported neuropsychophysiological abnormalities suggest ME/CFS is multifactorial, but current knowledge remains fragmented. This study protocol outlines a multimodal investigation designed to (1) compare neuropsychophysiological mechanisms between ME/CFS patients and healthy participants, (2) test an integrative model of ME/CFS, (3) identify neuropsychophysiological subgroups within the patient population, and (4) identify predictors of symptom response during rehabilitation. Methods and analysis: This study will enroll 115 ME/CFS patients and 55 healthy participants. Groups will be comparable in age, sex, and education level, with a larger patient sample enabling subgroup and longitudinal analyses. A cross-sectional assessment at baseline will be carried out in both groups. Patients will then be evaluated longitudinally throughout a standardized cognitive-behavioral therapy rehabilitation program delivered as routine care. Baseline measures include systemic inflammation and general health biomarkers, measures of autonomic and central nervous system function, neuroinflammation (magnetic resonance spectroscopy, [18F]DPA714 PET in a subsample), serum short-chain fatty acid levels, gut microbiota composition and function, and neuroendocrine and self-reported responses to psychosocial stress. Fatigue severity (physical and cognitive) and PEM will be assessed through validated questionnaires, ecological momentary assessment, and laboratory tasks. These will be re-evaluated during therapy, and all non-neuroimaging measures will be repeated after the rehabilitation program. Statistical analyses will comprise multivariate analysis of variance, general linear models, classification algorithms, structural equation models, least absolute shrinkage selection operator principal component regression (LASSO-PCR), cluster analysis and latent class growth analysis (LCGA).

Circulating proteins have been widely investigated as potential biomarkers in multiple sclerosis (MS), yet findings across studies are often inconsistent, likely reflecting differences in disease stage, treatment exposure, and cohort composition. Studying individuals at elevated risk of MS prior to disease onset offers a unique opportunity to identify immune alterations that precede clinical disease while minimizing confounders. Here, we investigated whether alterations in six previously MS-associated biomarkers are detectable and associate to underlying genetic susceptibility in two independent sample collections comprising people with MS (pwMS), healthy controls, and asymptomatic first-degree relatives of pwMS from the Genes & Environment in MS (GEMS) study cohort. The panel, representing complementary axes of MS immunopathology, included granzyme A (GZMA), MER tyrosine kinase (MERTK), interleukin-2 receptor alpha (IL2RA), osteopontin (SPP1), CD30 (TNFRSF8), and chitinase-3-like protein 1 (CHI3L1). None of the proteins demonstrated associations with MS. A composite score constructed from externally derived effect estimates was not associated with MS status in either collection or in meta-analysis. Among asymptomatic first-degree relatives, the composite score was not significantly associated with group status. In contrast, an inverse correlation between SPP1 and the MS genetic risk score among GEMS participants was found ({beta} = -0.246, p = 0.001). Together, these findings suggest that several circulating proteins recently proposed as MS biomarkers are not robust tools to distinguish MS from healthy individuals. However, SPP1 levels are highlighted for further evaluation among at-risk individuals, and further work is needed to determine whether circulating immune signatures can capture the earliest stages of MS in at-risk individuals.

Multiple sclerosis (MS) is an autoimmune and neurological disorder characterized by myelin disruption and neuronal degeneration. Currently approved therapies focus on symptom relief but do not promote central nervous system (CNS) repair. In contrast, astrocytes proliferate and repopulate MS-related lesions. Moreover, in active lesions, they hinder regenerative processes such as neural progenitor migration. Here, we propose astrocytes as a potential target for myelin repair in the human diseased brain. To achieve this aim, we investigated whether glial fibrillary acidic protein (GFAP)+ astrocytes can be transdifferentiated into oligodendrocyte lineage cells through forced overexpression of transcription factors both in vitro and ex vivo organotypic cultures of human adult cortex. Our results show that overexpression of OLIG2 and SOX10 in human induced pluripotent stem cell-derived astrocytes gives rise to oligodendrocyte progenitor cells 12 days post-induction, as shown by morphological changes and O4 marker expression. Importantly, transdifferentiation of GFAP-expressing endogenous astrocytes in human adult cortical tissue give rise to mature oligodendrocytes, as shown by expression of CC1, after only 12 days of overexpression of OLIG2 and SOX10. To our knowledge, this is the first study to assess direct astrocyte-to-oligodendrocyte reprogramming in a human platform preserving the native three-dimensional architecture of the brain. Further work will be required to determine whether the reprogrammed cells can myelinate axons and to evaluate the potential of this approach for structural and functional repair in the demyelinated human CNS.

BackgroundMicroglia have become a cell type of interest in the neurodegenerative field given both genetic and pathological evidence for their role in disease development and progression. There has been a rapid growth of studies using iPSC-derived microglial models to understand the molecular mechanisms driving these neurological diseases. However, it remains difficult to transduce myeloid cells effectively which is critical when aiming to study the role of disease associated genes and pathways. Current methods require exposure to multiple viruses which is not suitable for all experimental paradigms. We have therefore sought and characterised a high efficiency promoter and plasmid design to allow high transduction efficacy with a single lentivirus. ResultsUsing the spleen focus-forming virus (SFFV) promoter in combination with central polypurine tract (cPPT) and Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) plasmid elements gave significantly higher transduction efficiency and transgene expression than was achieved with commonly used promoters CMV and EF1. This could then be further improved if required to over 90% transduction efficiency with the removal of lentivirus restriction factor SAM and HD domain-containing protein 1 (SAMHD1) by adding VPX. ConclusionsOur findings allow for a simpler, more efficient and streamlined approach to transgene expression in iPSC-derived microglia and macrophages using only a single lentivirus. This minimises potential unintended side effects such as additional cellular activation and increased cell death.

BackgroundChronic relapsing inflammatory optic neuropathy (CRION) is a steroid-dependent form of optic neuritis with incompletely understood pathophysiology. The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in a substantial patient subset has challenged the diagnostic and therapeutic management. The aim of this study was to investigate clinical profiles and treatment outcomes of patients with CRION, comparing MOG-IgG-positive (MOG+) and seronegative (MOG-) subgroups. MethodsPatients from six European tertiary centers fulfilling diagnostic criteria for CRION were included. All underwent cell-based autoantibody testing. Clinical outcomes (visual acuity, annualized relapse rate), laboratory and imaging findings (MRI, OCT), and treatment responses were retrospectively analyzed. ResultsSixty patients were included (median age 33 years; 70% female); 27 (45%) were MOG+. MOG+ CRION was associated with later onset, higher ARR before treatment (median [IQR] 2 [1-3] vs. 1 [1-2], p = 0.023), and a trend toward shorter inter-relapse intervals. Additional distinguishing features included higher frequencies of antinuclear antibody positivity, elevated CSF interleukin-6, and extensive optic neuritis on MRI. Relapse burden correlated with visual acuity decline and retinal thinning. In MOG+ patients, monoclonal antibody therapy reduced the ARR (n = 21; 2 [1-3] vs. 0 [0-2], p = 0.024), primarily driven by tocilizumab (n = 11; 2 [1-3] vs. 0 [0-1], p = 0.023). In MOG-patients, rituximab and azathioprine showed a trend toward ARR reduction. ConclusionCRION represents a heterogeneous syndrome encompassing distinct subgroups. MOG+ patients demonstrate higher disease activity but respond favorably to tocilizumab. Serological testing is critical for treatment stratification and preventing relapses.