Multiple Sclerosis and Related Disorders

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.

BackgroundPeople with multiple sclerosis (pwMS) often experience impaired quality of life (QoL) despite receiving standard care. Digital therapeutics (DTx) may offer support, but prior trials yielded mixed results, possibly due to active controls and high baseline QoL. We therefore evaluated a DTx (levidex) as an adjunct to treatment as usual (TAU) in pwMS with impaired QoL. MethodsIn this pragmatic, online randomised controlled trial (LAMONT; NCT06090305), n = 470 pwMS with a score [&ge;]2 on the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) were randomised to levidex + TAU or TAU alone. The primary endpoint was HAQUAMS total score at 6 months, analysed by intention-to-treat ANCOVA. ResultsCompared with TAU, levidex + TAU improved MS-specific QoL at 6 months (baseline-adjusted mean difference -0.10; 95% CI -0.18 to -0.03; p = 0.008; Cohens d = 0.26). Clinically relevant HAQUAMS improvement ([&ge;]0.22) occurred more often with levidex (39.5% vs 27.8%; number needed to treat = 9). Benefits also emerged for depressive symptoms and social/work functioning but not for anxiety. No serious adverse events occurred and user satisfaction was high. ConclusionsIn pwMS with impaired QoL, adding the scalable DTx levidex to TAU yields meaningful improvements in QoL and functioning.

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.

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

BackgroundMultiple sclerosis (MS) is a chronic neurodegenerative disease charac-terised by progressive neurological disability and heterogeneous symptom trajectories. Cur-rent clinical monitoring methods, including magnetic resonance imaging (MRI) and episodic neurological assessments, provide limited insight into subtle disease progression and real-world functional changes. Digital health technologies integrating multimodal biosignals and behavioural assessments may enable continuous monitoring and personalised rehabilitation for patients with MS. ObjectiveThis study aims to evaluate the clinical utility of the BodyMirror Clinical MS platform, a multimodal software-as-a-medical-device (SaMD) that combines wearable biosensors, neuroscience-based games, and machine learning algorithms to remotely monitor disease progression and deliver personalised neurorehabilitation for individuals with multiple sclerosis. MethodsThis study is a prospective, randomised, double-blind, controlled, multisite clinical trial enrolling 400 participants, including 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 a 24-month period 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 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. ConclusionsThis trial will provide the first large-scale clinical evaluation of a mul-timodal digital neurotechnology platform combining wearable biosensors and game-based neurorehabilitation for remote management of multiple sclerosis. If successful, BodyMirror Clinical MS may enable scalable remote monitoring, earlier detection of disease progres-sion, and personalised digital rehabilitation for individuals living with MS.

BackgroundMultiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that affects both the brain and spinal cord, although the brain has historically received greater attention. In the inducible, oligodendrocyte-specific knockout model of Myrf, which results in white matter damage to both the brain and spinal cord, our laboratory previously demonstrated that the brain undergoes partial remyelination following white matter damage, whereas the spinal cord fails to do so. We also observed that brain microglia display a much stronger activation than spinal cord microglia in this model. Microglia regulate remyelination by clearing myelin debris, processing resulting lipids, and modulating an inflammation response. ResultsHere, to test our hypothesis, we characterized microglial phenotypes during demyelination in both tissues. The brain exhibited greater early microglial recruitment and higher baseline expression of activation and phagocytic markers, suggesting a primed state for responding to damage. In contrast, spinal cord microglia showed delayed phagocytic marker expression, sustained inflammation, and a predominately amoeboid morphology during demyelination. ConclusionsTogether, these findings indicate that brain microglia mount a timely and coordinated response to demyelination that supports remyelination, whereas spinal cord microglia adopt a dysfunctional phenotype that may contribute to impaired myelin repair.

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.

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.

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.

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.

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.

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.

Clinically silent MRI lesions occur frequently in people with relapsing-remitting multiple sclerosis (RRMS) despite disease modifying therapy (DMT). Guidelines only recommend DMT escalation after multiple silent lesions, and adherence is variable. We explored outcomes and the effect of treatment escalation following single and multiple on-treatment silent lesions. This cohort study and emulated target trial used MSBase registry data from 99 clinics in 26 countries between 2007 and 2025. Clinically stable participants receiving any DMT for RRMS with silent lesions versus without silent lesions were compared. Among participants with silent lesions while taking platform or moderate-efficacy DMTs, outcomes following treatment escalation within 6 months versus no treatment escalation (unless a post-MRI clinical event occurred) were compared. The primary outcome was an MS relapse, and the secondary outcome was 6-month confirmed disability worsening. A total of 10,232 participants met inclusion criteria (71.7% female, mean age 41 [SD 11]). The 2-year cumulative incidence of relapse was 27.8% (95% CI 25.7%-29.9%) in participants with silent lesions versus 14.3% (95% CI 13.5%-15.2%) without (adjusted hazard ratio [aHR] 1.76 [95% CI 1.57-1.97]). The 2-year cumulative incidence of disability worsening was 13.8% (95% CI 12.2%-15.5%) in participants with silent lesions versus 11.4% (95% CI 10.7%-12.2%) without (aHR 1.38 [95% CI 1.18-1.62]). Rates of relapse and disability worsening were higher following single and multiple silent lesions versus no silent lesions. The emulated trial included 2,264 participants with [&ge;]1 silent lesion on platform or moderate efficacy DMTs, 286 of whom escalated DMT within 6 months following silent lesions. The 4-year cumulative incidence of relapse was lower following treatment escalation (16.8% [95% CI 12.4%-23.4%]) versus continuation (38.9% [95% CI 35.8%-42.1%]), aHR 0.34 (95% CI 0.23-0.47), with similar aHRs following single and multiple silent lesions. The 4-year cumulative incidence of disability worsening was similar following treatment escalation (16.0% [95% CI 10.8%-22.2%]) versus continuation (17.7% [95% CI 15.3%-20.1%]), aHR 0.89 (95% CI 0.56-1.33). People with RRMS with single or multiple on-treatment silent MRI lesions have higher subsequent risks of relapse and disability worsening than people without silent lesions. DMT escalation mitigates the relapse risk, though disability worsening continues at a similar rate over 4 years. Contrary to guidelines, DMT escalation should be considered after single or multiple silent lesions.

ObjectiveTo evaluate the criterion-related and discriminant validity, test-retest reliability and minimal detectable difference of The Index of ME Symptoms (TIMES) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) MethodsPeople with ME/CFS in the UK completed the TIMES online (n=1055). Rasch-transformed interval data and parametric statistics were used: Pearson correlations (with the ME severity scale); analysis of variance; intra-class correlations (ICC) and standard error of measurement of ICC measured criterion-related and discriminant validity, test-retest reliability and minimal detectable difference respectively. ResultsHighly significant (P<0.001) moderate (r=0.400-0.528) correlations were seen between the TIMES scales and severity of ME/CFS except the gastro-intestinal and immune systems scales (r= 0.315 and 0.302 P<0.001 respectively). Discriminant validity was demonstrated with significant differences in TIMES scores between all five levels of ME severity, except between levels 4 and 5 in some cases, which were underpowered due to the small group numbers. Test-retest reliability was excellent (ICC>0.7, p<0.001) except the cranial nerves and immune system scales which were good (ICC = 0.681 and 0.669, p<0.001) and minimal detectable difference was excellent (3.95-17.45%). ConclusionsThe Index of ME Symptoms (TIMES) scales are valid, reliable, sensitive assessments of symptoms in ME/CFS. They are freely available for use.

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.

Managing chronic diseases with unpredictable care demand creates significant operational challenges for healthcare systems. Mapping long-term care trajectories is crucial for improving resource allocation, anticipating service needs, and designing efficient care pathways. We used a data-driven approach to map six-year care trajectories for 962 newly diagnosed multiple sclerosis patients, identify utilization clusters, and determine predictors of high utilization. We analyzed Event logs of remote, outpatient, emergency, and inpatient contacts from one year pre- to five years post-diagnosis using K-means clustering to identify utilization clusters, logistic regression to identify predictors of high utilization, and process mining to model variation between care trajectories. We identified two distinctive utilization clusters: a high-utilization cluster (14.1 % of patients) with persistently elevated annual encounter volumes across all care settings and low-utilization cluster (85.9 % of patients) with lower and declining use. Median service costs were {euro}18,736 vs. {euro}6,052 in high- and low-utilization clusters, respectively. Two or more early relapses were the strongest predictor of high utilization (OR = 6.33, 95 % CI 3.49-11.50, p < 0.001), with number of planned early remote and outpatient care contacts being also associated with future service utilization (OR = 1.07, 95 % CI 1.04-1.10, p < 0.001). High-utilization trajectories were approximately three times longer (82.4 vs 25.9 events) and more variable (3.1 vs 2.4 unique events per patient). These utilization clusters and their distinct trajectories provide a pragmatic segmentation of multiple sclerosis patients to support early identification of high-utilization subgroups and more robust capacity planning in specialist care. HighlightsO_LIWe tracked the care trajectories of 962 people with relapsing-remitting multiple sclerosis using a Finnish population-based specialist-care datalake covering both inpatient and outpatient neurology services. C_LIO_LIPatients fell into two distinct utilization clusters: a high-utilization cluster with frequent contacts across all care settings and a low-utilization cluster with lower and declining use. C_LIO_LITwo or more early relapses, and the number of early outpatient and remote contacts were strong predictors of a patients long-term affiliation in the high-utilization cluster. C_LIO_LISegmented care trajectories showed that high-utilization patients followed longer, more varied, and acute-oriented care patterns and had much higher service encounter costs. C_LIO_LIThese findings can help clinicians and managers identify potential high-utilization patients early, target resources more effectively, and plan for future healthcare demand. C_LI

ObjectiveTo develop and psychometrically evaluate an assessment of symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) MethodsAn initial symptom list was devised from the relevant literature with the patient and clinician advisory groups. An online survey with 85 symptom items in eight domains was completed by people with ME/CFS. Each item had two response structures (assessing symptom frequency and severity on five-point scales). Rasch analysis assessed each domain for unidimensionality, targeting, internal reliability, item fit and local dependency. ResultsSurvey data (n=721) indicated various item anomalies and inter-item dependencies, leading to item re-formatting or removal. The frequency and severity-based responses broadly replicated each other, and a four-point response format appeared more appropriate than a five-point response format. Following Rasch-based scale amendments, a revised version with a single four-point response format was re-administered to test the modifications. Validation data (n=354) showed the modified scale had an improved response structure and functionality across all domains, satisfying Rasch model assumptions. Additionally, domain-level super-items allowed for a summated total score along with sub-scales summarising neurological and autonomic symptoms, again satisfying Rasch model assumptions. ConclusionsThe Index of ME Symptoms (TIMES) and its associated sub-scales and domain scales are stable, valid assessments of symptoms in ME/CFS.

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.

IntroductionNeurocognitive impairment (NCI) remains common among people living with HIV (PWH), particularly in low- and middle-income countries where accurate diagnostic tools are limited. In Peru, the lack of locally validated neuropsychological (NP) normative data in Spanish poses a major barrier to diagnosing HIV-associated NCI, especially among PWH who develop NCI at younger ages. This study aimed to develop regression-based NP norms for young and middle-aged Spanish-speaking adults in Lima, Peru and validate the norms in demographically similar PWH to improve diagnostic precision of HIV-associated NCI. MethodsA total of 164 healthy adults without HIV from Lima completed a comprehensive NP battery assessing memory, attention, executive function, and language, which are commonly affected in HIV-associated NCI. Multiple regression models were used to consider the influence of age, years of education, and sex on raw scores, yielding standardized demographically-adjusted norms for the population. The resulting norms were then applied to 310 PWH from Lima and then compared with previously published norms for Spanish speaking adults to evaluate performance differences. ResultsAge and education were the strongest predictors of performance across tests, while sex had minimal influence. Compared to people without HIV, PWH had significantly lower educational attainment (mean 12.6 vs. 13.7 years) and exhibited significantly worse performance on normed scores of Benson Figure Copy, Benson Figure Delayed Recall, Color Trails 1 and 2, Hopkins Verbal Learning Test - Revised, and WAIS-III Digit Symbol Coding, Digit Span, and Symbol Search. There were statistically significant differences between T-scores on nearly all tests between our population-specific norms and previously published norms in both directions, indicating potential over- and under-detection errors when applying norms from non-local samples. DiscussionOur findings highlight the utility of locally derived norms in detecting subtle cognitive changes among young and middle-aged PWH compared with previously published norms for Spanish-speakers. Application of these norms reveals significant between-group differences that may go undetected using non-local normative data or raw scores. Future efforts should focus on rural norm development and inclusion of individuals with lower educational backgrounds in Peru and other Latin American countries.