Multiple Sclerosis and Related Disorders

ObjectiveTo replicate and extend recent findings suggesting that higher serum alpha-linolenic acid (ALA) levels are associated with reduced disease activity and progression in multiple sclerosis (MS). MethodsWe reanalysed clinical trial data from 85 people with MS, who had serum ALA, magnetic resonance imaging (MRI), and clinical (EDSS, PASAT) assessments collected for two years, with additional follow-up at 12-years. Linear and mixed models were used to assess the relationship between ALA and clinical and MRI outcomes. Mediation analyses tested whether ALA mediated associations between brain volume or T2 lesion load, and disability. ResultsALA measures were consistent over time ({kappa}= 0.83). Higher ALA predicted lower EDSS ({beta} = -0.41, 95% CI [-0.73, -0.08]) and larger brain volume ({beta} = 0.22, 95% CI [0.09, 0.36]). ALA was a non-significant mediator of brain volume or lesion effects on EDSS and did not predict long-term clinical or cognitive change. DiscussionWe replicate prior associations between higher serum-ALA levels and reduced disability in MS and extend these by showing a beneficial association of serum-ALA with brain volume. However, ALA did not predict long-term progression, limiting its prognostic value.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterised by progressive neurological disability and heterogeneous symptom trajectories. Current clinical monitoring methods, including magnetic resonance imaging (MRI) and episodic neurological assessments, provide limited insight into subtle disease progression and functional changes. Digital health technologies integrating multimodal biosignals and behavioural assessments may enable continuous monitoring and personalised rehabilitation in patients with MS. This study aims to evaluate the clinical utility of the BodyMirror Clinical MS platform, a multimodal SaMD that combines wearable biosensors, neuroscience-based games, and machine learning to remotely monitor disease progression and deliver personalised neurorehabilitation for individuals with multiple sclerosis. This study is a prospective, randomised, double-blind, controlled, multisite clinical trial enrolling 400 participants (300 individuals with multiple sclerosis and 100 healthy controls). MS participants will be randomly assigned (1:1) to either an adaptive neurorehabilitation intervention group or a control group receiving non therapeutic digital activities matched for engagement and exposure. Participants will perform three 30-minute sessions per week over 24 months using the BodyMirror platform. The system integrates multiple biosignals, including electroencephalography (EEG), electromyography (EMG), inertial measurement unit (IMU) motion data, speech analysis, and behavioural performance metrics to generate digital biomarkers of neurological function. The primary endpoint is a change in Expanded Disability Status Scale (EDSS) score from baseline to 24 months. Secondary outcomes include changes in Multiple Sclerosis Functional Composite (MSFC), MRI brain volume, cognitive performance, patient-reported outcomes, adherence to digital rehabilitation, and health economic outcomes.

BackgroundChronic autoimmune diseases such as Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Multifocal Motor Neuropathy (MMN), and Thyroid Eye Disease (TED) impose a considerable burden on affected individuals. Patient-reported outcome measures (PROMs)--both disease-specific and generic--are widely used to assess functioning, quality of life, and treatment effects in these populations. However, most PROMs currently lack reference values derived from the general population, limiting the interpretability of patient scores. ObjectiveThe GENESIS (GENEral population normS--An International Survey) study aims to establish general population norms for a range of PROMs used in CIDP, MMN, and TED across six countries: Germany, Italy, Japan, Spain, the United Kingdom, and the United States. These norms will improve patient score interpretation and help quantify unmet needs in patients with these rare autoimmune diseases. MethodsGENESIS is an observational, cross-sectional, online survey of the adult general population (N=21,000). Participants will be recruited to be representative by age, gender, region, and education. The survey includes validated instruments such as the EQ-5D-5L, I-RODS, MMN-RODS, CAP-PRI, GO-QoL, BPI-SF, RT-FSS, FACIT-Fatigue, HADS, and WPAI, along with items on demographics, caregiver need, and healthcare utilization. To reduce respondent burden, participants will be randomized into two groups, each completing a subset of the full questionnaire. A subset of respondents (n=2,333) will be re-surveyed after two months to support psychometric validation. Data will be analyzed descriptively to generate normative values for each PROM by country and in aggregate. Results and DisseminationData collection is scheduled to begin in August 2025, with results expected by Q4 2025. Findings will be disseminated via peer-reviewed publications and conference presentations. ConclusionGENESIS will provide foundational normative data across six countries for PROMs commonly used in rare autoimmune diseases. These data will support more meaningful interpretation of PROM scores in both clinical practice and research settings.

Multiple sclerosis (MS) therapies primarily rely on lymphocyte depletion or trafficking blockade, carrying risks of systemic immunosuppression; however, such treatments have limited efficacy in secondary progressive multiple sclerosis (SPMS). Thus, drugs that target stage-specific inflammation without broad immunosuppression are an unmet clinical need. In this double-blind, placebo-controlled phase II trial, 30 patients with relapsing MS received weekly oral OCH or placebo for 24 weeks. In the pre-specified SPMS subgroup (n=12), OCH achieved complete relapse prevention (p=0.0003), prolonged relapse-free survival (p=0.0079), no new lesions (0/6), with no evidence of disease activity (NEDA-3) in 5/6 patients. In comparison, for the placebo-treated group, 5/6 patients suffered relapses, 2/6 patients developed new lesions, and no placebo-treated SPMS achieved NEDA-3. Invariant natural killer T (iNKT) cells, a regulatory lymphocyte population that is numerically and functionally impaired in MS, are a potential target for MS therapy. Glycolipid OCH is a selective iNKT cell stimulator, skewing the cytokine environment towards Th2. OCH treatment resulted in increased IL-4-producing Th cells in patient peripheral blood while decreasing pathogenic GM-CSF-producing Th cells. Parallel studies in mouse models of MS (EAE) corroborated this mechanism and further revealed that OCH activated gut iNKT cells. Disease amelioration by OCH depended on IL-4 and its efficacy was further enhanced by depletion of B cells. These data revealed the gut-brain axis mediation of progressive-stage pathology distinct from relapsing-remitting MS. Findings from this bidirectional translational study uncover mechanistic differences between SPMS and other types of MS and highlight divergent roles for B cells and Th cells. Furthermore, OCH exerts its therapeutic benefit via targeting mechanisms that are distinct from currently available drugs; exploiting iNKT cell regulatory potential to reprogram pathogenic T helper responses without lymphocyte depletion. The unique yet effective nature of OCH treatment positions it as an attractive future oral therapy for SPMS. One Sentence SummaryThe iNKT cell activating ligand OCH suppresses disease activity selectively in secondary progressive MS in a phase II clinical trial, revealing stage-specific IL-4-mediated immune cell interactions in MS pathology.

BackgroundThe prodromal phase of multiple sclerosis (MS) is increasingly recognized, but most studies have focused on isolated symptoms or static comorbidity counts, leaving the evolving structure of pre-onset disease burden underexplored. ObjectiveTo characterize dynamic disease trajectories preceding MS onset through longitudinal network modeling. MethodsHealth data from 10,273 MS patients and 47,167 matched controls in Sweden were analyzed. Disease co-occurrence networks were constructed for three pre-onset windows (0-5, 5-10, 10-15 years), with comparisons of centrality, clustering, and path length. Rewiring scores captured structural shifts, while Markov clustering and trajectory mapping identified comorbidity communities. ResultsMS networks were denser, more clustered, and showed shorter path lengths than controls, reflecting higher systemic interconnectivity. Psychiatric and metabolic diagnoses, especially depression, anxiety, diabetes, and abdominal pain, were hubs that gained prominence over time. Distinct clusters, including neuropsychiatric-toxicological and immune-endocrine constellations, were observed only in MS. Rewiring analysis revealed significant topological shifts in key diagnoses, such as inflammatory CNS disorders and substance use, as onset approached. ConclusionsMS is preceded by dynamic reorganization of the comorbidity landscape, marked by increasing connectivity and rewired hubs. This framework highlights systemic disruption before diagnosis and provides a novel, network-based tool for studying prodromes in complex disorders.

Artificial intelligence (AI) is increasingly being integrated into healthcare, particularly in data-intensive chronic diseases that rely on longitudinal monitoring and shared decision-making. Multiple sclerosis is a prototypical example of such care, but real-world benefit will depend on whether people accept AI support in different clinical roles. We conducted a cross-sectional, web-based survey among 241 people with MS (pwMS) to assess comfort with AI across eight clinical domains and to identify predictors of acceptance. We derived an artificial-intelligence attitudes composite with high internal consistency (Cronbach alpha = 0.90). Overall acceptance was moderate (mean 3.39 {+/-} 0.78). Acceptance differed across domains, demonstrating a responsibility gradient: comfort was highest for supportive applications such as chronic management (54.4%) and symptom screening (50.2%), but lower for treatment selection (38.6%) and diagnosis (35.3%; P < 0.001). In multivariable models, frequent general AI use (at least weekly; 30.7%) was the strongest independent predictor of acceptance (P < 0.001). Acceptance also differed by region (Eastern vs Western Germany, P = 0.025), whereas clinical disability was not significantly associated. Older age was associated with lower acceptance of AI-supported management. Most participants viewed AI as a logistical support tool but, assuming equal diagnostic accuracy, 78.8% preferred joint artificial-intelligence-clinician decision-making with clinician final responsibility. These findings indicate that acceptance is context-dependent and aligns more closely with prior familiarity than with disease severity. Implementation should move beyond technical validation to transparent, clinician-ledhuman-in-the-loop workflows with explicit accountability and staged adoption beginning with low-risk use cases. Author SummaryWe use artificial intelligence more and more in everyday life, and similar tools are now being introduced into medical care. For long-term conditions such as multiple sclerosis, digital systems could help manage large amounts of clinical information and support monitoring between visits. At the same time, these tools will only be useful if the people receiving care are willing to use them and understand what role they play. In this study, we asked 241 people living with multiple sclerosis in Germany how comfortable they would feel with artificial intelligence in different parts of care. We found that comfort depended strongly on the task. Participants were most open to artificial intelligence when it supported practical, lower-risk functions such as ongoing monitoring or symptom screening, and they were more cautious when it was described as influencing diagnosis or treatment choices. Most participants wanted clinicians to remain responsible for final decisions. Acceptance was higher among people who already used artificial intelligence frequently in everyday life, and it differed by age and by region. Our findings suggest that successful implementation will require more than technical performance: it should be introduced transparently, with clinician oversight, and in a stepwise way that builds familiarity without shifting responsibility away from the clinical team.

IntroductionThe 2024 McDonald criteria incorporate the central vein sign (CVS) and paramagnetic rim lesions (PRL) as supportive imaging biomarkers for MS diagnosis. While susceptibility-weighted-imaging (SWI) and T2*-weighted echo-planar-imaging (EPI) are generally used to assess CVS/PRL, their relative performance remains unclear. This study compared high-resolution isotropic-T2*-EPI with non-isotropic SWI for CVS/PRL detection. Materials and MethodsIn this multi-centre study, 21 patients with MS underwent harmonized 3T-MRI including EPI and SWI. CVS and PRL were evaluated according to NAIMS criteria. Whole-brain and controlled lesion analyses on 120 pre-selected lesions were performed independently for each contrast, with EPI serving as reference standard. ResultsIn whole-brain analyses, SWI showed good sensitivity for CVS eligibility and positivity (AC1=0.68-0.78) but significant directional disagreement with EPI (p<0.0001). Discrepancies were primarily attributed to limited lesion-parenchyma contrast and venous visibility on SWI, which improved using low-flip-angle SWI. Controlled lesion analyses supported these observations. For PRL, SWI demonstrated high sensitivity (88%) and precision (97%) compared to EPI, though systematic bias persisted (p<0.001). Controlled lesion analyses showed more balanced, albeit moderate performance. ConclusionSWI diverged systematically from EPI for CVS and PRL detection. When available, EPI should be preferred, while optimised low-flip-angle SWI may serve as an alternative to conventional SWI.

Background / ObjectivesWe investigated whether the interthalamic adhesion (IA), a midline structure connecting the thalami, is altered in MS and associated with thalamic damages and cognition. MethodsWe prospectively included 32 clinically isolated syndrome/early MS, 31 RRMS, 31 PPMS patients, and 103 matched controls. All underwent anatomical 3T MRI and completed a comprehensive cognitive battery. IA presence, subtype, and volume were assessed by two blinded readers. Thalamic nuclei and other brain structures were segmented automatically. We compared IA subtypes/volumes across groups, analyzed their predictors and explored cognitive associations with multivariate regressions. ResultsIA prevalence did not differ between MS and controls (81.9% vs 74.7%). MS patients showed a shift toward a short IA subtype and reduced IA volume (mean [SD], 146.8 [117.9] vs 230.2 [138.2] mm3; p<0.0001), worsening across phenotypes. Reduced IA volume was independently associated with medial and posterior thalamic nuclei volumes, but not with white matter lesion load or global atrophy. Among cognitive domains, smaller IA volume was independently associated only with executive dysfunction (OR = 0.89 [0.77-0.99], p = 0.021). ConclusionIA volume reduction in MS reflects vulnerability of adjacent thalamic nuclei and is associated with executive dysfunction, supporting IA as a marker of thalamic neurodegeneration. Trial RegistrationMICROSEP: NCT03692975; AUBACOG: NCT03768648; PROCOG: NCT03455582.

BackgroundDisorders affecting the spinal cord (myelopathies) can cause severe disability. Despite diagnostic advances, approximately 12-18% of myelopathy cases continue to elude an etiological diagnosis, hampering effective treatment. MethodsThis retrospective, multicenter, tertiary care cohort study conducted from 2014 to 2025 evaluated archived biofluids from patients with IM, known autoimmune myelitis, or other neurological diseases (ONDs). Proteome-wide phage display was used to discover novel autoantibodies. Targeted immunoassays were used to screen for a candidate autoantibody. Downstream metabolites were measured in the cerebrospinal fluid (CSF). ResultsAutoantibodies targeting the transcobalamin receptor (CD320) responsible for cellular transport of vitamin B12 were identified in 18 out of 32 IM patients (56%) in a discovery cohort. Bioactive B12 concentration was decreased in the CSF of anti-CD320 positive patients compared to OND controls (P = 0.0273), indicative of autoimmune B12 central deficiency (ABCD). Compared to anti-CD320 negative IM cases, anti-CD320 positive IM cases demonstrated a higher frequency of subacute time course (56% vs 7%, P = 0.008), normal CSF profile (83% vs 50%, P = 0.044), and dorsolateral spinal cord abnormalities on magnetic resonance imaging (MRI) (61% vs 7%, P = 0.003). In two independent validation cohorts comprising 94 and 25 patients with IM, anti-CD320 was detected in 43 (46%) and 12 (48%) patients, respectively. Comorbid anti-CD320 was detected in a smaller proportion of patients with other known autoimmune etiologies of myelopathy. Five anti-CD320 positive IM patients received B12 supplementation with or without concurrent immunosuppression, and four out of five clinically improved. ConclusionsABCD is associated with a substantial proportion of IM. Screening for anti-CD320 followed by metabolic confirmation of a CNS-restricted B12 deficiency may be considered in the diagnostic evaluation of myelopathy.

Clinical progression is strongly linked to grey matter atrophy in multiple sclerosis (MS), detectable early on MRI and progressing non-randomly across the brain. However, the mechanisms driving its spatio-temporal progression and individual variability remain unclear. Using MRIs from 2,187 participants, alongside normative data, we systematically investigated network-based mechanisms underlying MS-related atrophy. Regional atrophy colocalised with functional cortical hubs, supporting the nodal stress hypothesis, and propagated along anatomical and functional connections, consistent with transneuronal degeneration. Lesional disconnection and transcriptomic vulnerability played marginal roles. Patient- and subgroup-level analyses revealed that network-based mechanisms are specifically linked to MS-related neurodegeneration and may operate differently in distinct subtypes or disease phases. Atrophy patterns were anchored to the connectivity profiles of disease epicentres involving the visual, sensorimotor, and temporal cortices, and the hippocampi and thalami. Network-based measures enhanced the prediction of future atrophy progression in individual with MS, providing a mechanistic framework to understand neurodegeneration in MS.

ImportanceElevated circulating low-density lipoprotein (LDL) cholesterol is associated with an increased risk of amyotrophic lateral sclerosis (ALS) onset. Previous studies have explored the relationship between statin use and ALS onset. However, findings have been inconsistent, potentially due to methodological limitations, such as confounding by indication, and failure to account for baseline differences in LDL cholesterol levels. ObjectiveTo compare the risk of ALS onset between new users of statins and ezetimibe among patients with hypercholesterolemia. DesignActive-comparator, new-user cohort study using inverse probability of treatment-weighted Cox proportional hazards models. The study period spanned April 2012 to February 2024. SettingTwo administrative claims databases in Japan. ParticipantsPatients with hypercholesterolemia who newly initiated statins or ezetimibe, and patients with dyslipidemia who newly initiated fibrates. All participants were required to have at least 365 days of baseline observation and no prior diagnosis of ALS. Exposure(s)Statin use compared with ezetimibe use. Fibrate use was assessed for benchmarking. Main Outcome(s) and Measure(s)The outcome was incident ALS, defined as a first definitive diagnosis of ALS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to compare ALS risk between statins and ezetimibe. ResultsThe study included 607,292 statin users (median [IQR] age, 61 [51-71] years; 51.4% male), 26,963 ezetimibe users (median [IQR] age, 59 [49-71] years; 50.1% male), and 114,871 fibrate users (median [IQR] age, 61 [51-71] years; 51.4% male). The incidence rate per 100,000 person-years of ALS was 6.8, 15.9, and 4.3, respectively. Statin use was associated with a lower hazard of ALS onset than ezetimibe use (adjusted HR [95% CI]: 0.42 [0.19-0.92]). The mean (SD) LDL cholesterol immediately prior to treatment initiation was 171.0 (28.6) mg/dL in the statin group and 162.8 (30.8) mg/dL in the ezetimibe group. After treatment, mean LDL cholesterol levels decreased to and stayed below 140 mg/dL in both groups. Conclusions and RelevanceThis study suggests that statins may lower the risk of ALS onset among patients with hypercholesterolemia. The mechanism underlying this association is not yet clear and may involve pathways beyond circulating LDL cholesterol reduction. Key pointsO_ST_ABSQuestionC_ST_ABSDoes statin use lower the risk of amyotrophic lateral sclerosis (ALS) onset among patients with hypercholesterolemia? FindingsIn this active-comparator, new-user cohort study of 607,292 statin users and 26,963 ezetimibe users with hypercholesterolemia, statin use was associated with a lower hazard of ALS onset compared with ezetimibe use. Prior to treatment initiation, mean LDL cholesterol levels were similar between statin and ezetimibe users. MeaningThese findings suggest that statins may lower the risk of ALS among patients with hypercholesterolemia.

PurposeThe purpose of this study was to analyze differences in physical therapy (PT) use among a nationally representative sample of adults with symptomatic arthritis according to the rurality of their residence. MethodsWe used data from the 2023 National Health Information Survey (adult sample) to identify individuals with symptomatic arthritis by using 2 survey items indicating whether a healthcare provider had diagnosed the participant with arthritis and whether the participant had experienced arthritis-related symptoms during the past 30 days. One survey item was used to identify whether the participant had participated in PT during the previous 12 months. Levels of rurality were defined, in ascending order, as "large central metropolitan," "large fringe metropolitan," "medium or small metropolitan," and "nonmetropolitan/rural," according to each participants county of residence. Univariate and multivariate statistics were used to determine the association of PT use with the level of rurality. National estimates were calculated using weighting variables. FindingsWe identified 5,749 adults (weighted = 40,358,683) meeting our definition of symptomatic arthritis. Compared to those living in large central metropolitan areas, participants living in medium or small metropolitan areas were 20% less likely to report PT use (weighted odds ratio: 0.80; 95% confidence interval: 0.66, 0.96) and those living in nonmetropolitan/rural areas were 30% less likely (weighted odds ratio: 0.70; 95% confidence interval: 0.56, 0.88). ConclusionsAmong adults with symptomatic arthritis, those living in more rural areas had lower odds of PT use than those living in less rural (more urban) areas.

PurposeMyasthenia gravis (MG) is a rare neuromuscular disease. In-person appointments in specialized centers are not readily available, especially on short notice. The purpose of this study was to analyze patient-specialist communication through a telemedical platform. MethodsIn a randomized controlled study 45 MG patients were observed over three months. The intervention group (N=30) was monitored via a mobile application ( app) that enabled chat function and assessed MG-specific outcome measures and data from external devices. We quantitatively evaluated communication patterns for patients and specialists from the chat. Controls (N=15) received standard of care. Perceived MG specialist accessibility and contact with physicians outside the study team regarding MG-related issues was assessed in both groups. FindingsIn total, MG specialists were contacted a median of six times per patient via the chat concerning medical (54.5%), technical (25.3%), organizational (19.1%), and other (1.1%) topics. Specialists initiated contact a median of eight times per patient, most frequently addressing medical concerns (49.4%), 38.4% of which were recommendations for medication changes. Specialists also addressed technical (40.0%), organizational (9.4%) and other (1.3%) issues. Contacts with physicians outside the study team did not differ significantly between groups. Perceived specialist accessibility was rated significantly higher with telemedical support by the intervention group. ConclusionsMG patients have a significant demand for timely advice especially concerning treatment recommendations. Future studies should evaluate the potential of telemedical solutions to prevent worsening of symptoms. Trial registrationThe study was registered under DRKS00029907 on August 19, 2022.

An overlap syndrome of myositis and/or myocarditis associated with myasthenia gravis (MG) has emerged as a life-threatening immune-related adverse event (irAE) in cancer patients treated with immune checkpoint inhibitors (ICIs). This syndrome closely resembles a rare form of idiopathic inflammatory myopathy (IIM) seen in a subset of MG patients. In this systematic review, we searched PubMed for reports of concurrent MG and IIM as well as ICI-related overlap syndromes. By integrating clinical, serological, and pathological observations, we delineated a previously unrecognized clinicopathological subtype of myositis that overlaps with MG. This entity is defined by a strong association with striational antibodies (StrAbs) and frequent co- occurrence with thymoma as a paraneoplastic process, and we classify it as StrAb-associated myositis. The idiopathic and ICI-induced forms share similar, though not identical, clinical, serological, and histopathological characteristics. We found that AChR antibody positivity, independent of established clinical risk factors such as respiratory or cardiac involvement, predicted more severe ICI-myotoxicity. Together with supporting evidence, our findings suggest a pathogenic model in which thymoma-driven cytotoxic T-cell responses trigger secondary AChR autoimmunity. These results highlight the potential utility of StrAbs and anti-AChR antibodies as practical biomarkers for diagnosis, risk stratification, and early intervention in patients at risk for severe neuromuscular irAEs.

ObjectiveTo identify patient characteristics and medication factors associated with perceived comfort with migraine treatments and control of migraine symptoms. BackgroundPatient perceptions of migraine treatment influence adherence and outcomes, yet little is known about their underlying drivers. Our study objective was to identify clinical features of migraine associated with comfort and perceived control of symptoms, and medication classes associated with higher patient comfort and efficacy. MethodsParticipants in the Headache Assessment via Digital Platform in United States (HeAD-US) study completed a cross-sectional survey on demographics, migraine burden, mood, disability, and medication use. Comfort and control were defined using corresponding items from the Migraine Treatment Optimization Questionnaire (mTOQ-6) and categorized as "high" or "low". We compared patient characteristics, clinical features, and medication classes by reported comfort and control. ResultsAmong 5717 participants (mean age 41.5 {+/-} 13.1 years, 91.2% female), 58.5% reported high comfort with migraine treatments, while only 27.5% reported high control of migraine symptoms. High comfort was associated with fewer monthly headache days (mean 9.9 vs. 14.2, p<0.001), lower migraine symptom severity (median MSSS 18 vs. 19, p<0.001), and lower disability (MIDAS severe: 72.7% vs 91.2%, p<0.001) and mood symptom scores (PHQ-4 severe: 9.5% vs. 21.0%, p<0.001). High perceived control showed similar associations with employment (OR=1.25, CI 1.15-1.48, p = 0.013), monthly headache days (mean 9.0 vs 12.7,p<0.001), migraine severity (median MSSS 18 vs 19, p<0.0001), disability (severe: 66.0 vs 85.8, p<0.001), and mood symptoms (severe: 7.6 vs 16.9, p<0.001) but was not associated with income or education. Among those on monotherapy, gepants and triptans were associated with higher comfort and efficacy than OTC medications or opioids/barbiturates. For preventive therapy, beta blockers and botulinum toxin were associated with the lowest perceived comfort and efficacy. ConclusionPerceived comfort and control were linked to headache frequency, severity and disability and mood symptoms. Medication class use influenced perceptions, with gepants and triptans rated most favorably. These findings underscore the importance of incorporating patient perspectives into treatment planning, with particular attention to mood, disability, and choice of medication.

IntroductionThe balance between excitatory and inhibitory (E/I) neural processes is a fundamental principle of brain function, and its disruption has been implicated in the pathophysiology of multiple sclerosis (MS). In vivo assessment of E/I balance has traditionally relied on electrophysiological measures, and despite the abundance of fMRI data on MS, no fMRI-based technique has so far been presented to measure E/I balance in MS. MethodsRecently, a novel MRI-based method has been introduced to estimate E/I balance by integrating functional MRI and diffusion weighted imaging data. We use this approach to study E/I balance in MS at a global (over the whole head) and at the local level of specific resting state networks affected by MS: the somatomotor and Default Mode network (DMN). Furthermore, we perform the analysis using three different atlases: the Schaefer atlas, which is functionally defined, and the Automatic Anatomical Labeling (AAL) and Desikan Killany (DK) atlas, which are defined based on structural features. ResultsOur findings reveal a significant alteration in E/I balance within the somatomotor and default mode networks when using the functionally defined Schaefer atlas, suggesting a network-specific dysfunction in MS. We also find that the E/I balance inferred within the somatomotor network correlates with motor fatigue. ConclusionsThis study demonstrates a promising framework for investigating E/I balance alterations in neurological disorders and paves the way for validation in larger cohorts.

BackgroundMRI plays an essential role in diagnosing and monitoring neurological diseases. Conventional protocols rely on multiple sequences to obtain complementary contrasts, increasing scan time, cost, and tolerability. Generating multiple contrasts from a single acquisition may streamline workflow while maintaining clinical utility. PurposeTrain attention-based convolutional neural networks (ACNNs) to generate clinical-quality FLAIR, MPRAGE, R2*, and derived contrasts from a single Gradient Echo Plural Contrast Imaging (GEPCI) acquisition, enabling multi-contrast imaging from one scan. Study TypeRetrospective. Population43 MRI scans from individuals with multiple sclerosis (25/18 F/M, 49{+/-}11 years old). Field Strength/Sequence3T MRI was used to obtain 3D GEPCI, MPRAGE, and FLAIR sequences. AssessmentTechnical quality of the AI-generated contrasts was evaluated against directly acquired MRI images using structural similarity index (SSIM). Quantitative accuracy for R2* maps was evaluated using normalized root-mean-square error (NRMSE). Clinical image quality was assessed by expert physicians. Lesion volumes and counts were obtained using automated segmentation. ResultsAI-generated FLAIR and MPRAGE images achieved mean SSIM values of 0.923{+/-}0.028 and 0.935{+/-}0.022, respectively. The generated R2* maps achieved a mean SSIM of 0.996{+/-}0.006, with quantitative accuracy reflected by an NRMSE of 0.031{+/-}0.020. Physicians rated GEPCI-FLAIR images at 4.2 and GEPCI-MPRAGE images at 4.5 (on a 1-to-5 scale), both exceeding the clinically routine standard of 4.0. Lesion volume and count comparisons from automated segmentation showed strong agreement between AI-generated and ground-truth measurements (R{superscript 2}=0.988 and R{superscript 2}=0.933, respectively). ConclusionAI-GEPCI generated multiple clinically relevant MRI contrasts from a single GEPCI acquisition with high similarity to corresponding acquired images. Radiological reviews and quantitative analyses supported the feasibility of producing high-quality, intrinsically co-registered multi-contrasts for comprehensive brain evaluation.

Amyotrophic Lateral Sclerosis (Lou Gehrigs disease) is a progressive neurodegenerative disease affecting hundreds of thousands of people worldwide. It is characterized by the degeneration of the neurons in the brain and spinal cord of the patients, leading to a loss of control of muscles. Over time, without nerves to stimulate them muscles tend to atrophy. ALS may occur sporadically or run in families; many mutations have been identified for the latter. Treatment of ALS is mostly limited to three approved therapeutic agents: riluzole, edaravone, and tauroursidiol/ sodium phenylbutyrate. Among these, riluzole remains the most effective despite its early discovery. There are no conclusive meta-analysis comparing riluzole monotherapy to all possible co-therapies present. In this work we have attempted to address such a concern and observed that no adjunct therapy significantly improved the performance of riluzole. However, mitochondrial/ oxidative stress modulator and neuroimmune/ neuroexcitability modulator co-therapy exhibited positive trends. Surprisingly, trials were mainly confined to the USA and European countries, indicating unequal demographic representation in ASL research. We have concluded that large double blinded inter-continental RCTs to be carried out for better understanding of the scenario.

IntroductionStroke disproportionately affects minoritised ethnicities. While quantitative evidence has shown a difference in stroke risk and type of care received between UK ethnicity groups, qualitative data is sparse. We sought to explore experiences of in-hospital and community-based care from stroke survivors and caregivers from minoritised ethnicities.DD MethodsAudio recorded semi-structured interviews were conducted with stroke survivors and caregivers who self-identified as a minoritised ethnicity (e.g., Black, South Asian). Interviews covered experiences of incorporating cultural, religious, and/or dietary needs into stroke care, whether they perceived care was affected by ethnicity or cultural background, and ways to make care more culturally inclusive. Interviews were transcribed verbatim and analysed using reflexive thematic analysis. ResultsTwenty-four participants (n=16 stroke survivors, n=8 caregivers) took part. Themes included feeling different from a "typical" stroke survivor and affinity with British cultural norms ("I Feel Different in Stroke Care"); valuing culturally inclusive care but not always receiving it ("Culturally Inclusive Stroke Care is Important but Inconsistent"); individual perceptions of whether ethnicity affected care ("Personal Interpretations of the Role of Ethnicity in Stroke Care"); and tensions between caregivers advocating for cultural needs versus community perspectives of stroke ("Families Champion Stroke Survivors Cultural Needs, What about the Community?"). ConclusionsStroke survivors from UK minoritised ethnicity groups may feel "out of place" in care and may not receive sufficient cultural support. Individual interpretations of ethnicity, and affinity to British culture, affected perspectives on stroke care. Further efforts should be made to include culture and religion within person-centred stroke care.DD

Epstein-Barr virus (EBV) is strongly implicated as an essential environmental trigger of multiple sclerosis (MS), yet the host genetic mechanisms governing EBV activity and how infection triggers the disease are not known. We developed a pipeline to quantify EBV DNA from whole-genome sequencing data and applied it to population-scale cohorts. Using this pipeline, we performed a cross-ancestry genome-wide association study (GWAS) of EBV DNA positivity in 617,186 individuals and identified 39 independent susceptibility risk loci, with the strongest associations in the HLA region. We validated this finding in our independent cohort (N=94) and found that quantitative PCR (qPCR)-confirmed EBV DNA positive individuals were enriched in the top decile of EBV polygenic risk scores (PRS) containing newly discovered loci. A significant overlap with genetic variants associated with MS risk was observed. PRS and Mendelian randomization analyses further supported a causal role of EBV activity on MS risk, which was also seen in other autoimmune diseases. A meta-analysis of qPCR based case-control studies showed elevated EBV DNA positivity in MS. By establishing a single-cell RNA-seq method optimized for EBV detection, we identified EBV-infected B cells, primarily in memory B cells, atypical B cells and antibody-secreting cells from MS and healthy individuals. Notably, EBV-infected memory B cells and atypical B cells showed strong upregulation of cytokines and costimulatory signals that influence T cell activation, IFNg secreting Tregs, and regulators of B cell differentiation and survival. EBV-infected memory B cells also upregulated risk genes from both the EBV and MS GWAS, suggesting that EBV-infected B cells constitute a critical hub that modulates T cell responses while simultaneously activating MS susceptibility pathways within the B cell compartment. Together, these findings define a genetic and cellular framework linking EBV infection to the initiation of MS.