The study of grey matter (GM) perfusion abnormalities in multiple sclerosis (MS) is gaining increasing interest, thanks to the recent developments in MRI techniques such as arterial spin labelling (ASL). Previous studies in small mixed cohorts have demonstrated reduced perfusion in different GM regions in patients with MS compared with controls, especially in the frontal/parietal lobes and deep GM. In this multi-centre study, we aimed to investigate the relationship between ASL-perfusion patterns and GM atrophy in a large cohort of MS patients. We hypothesized that GM hypoperfusion is a phenomenon not wholly associated with the presence of structural atrophy. Therefore, we have evaluated whether GM perfusion changes are directly explained by underlying atrophy or occur in the absence of detectable GM tissue loss. Moreover, the relationship between clinical (physical and cognitive) measures and global GM perfusion level was assessed. Conventional structural and pseudo-continuous ASL data were acquired using 3T MRI scanners and a standardized protocol in four European MS centres. We included in the analysis 170 subjects [96 relapsing-remitting MS (RRMS), 41 primary-progressive MS (PPMS) and 33 healthy controls (HC)] that exhibited acceptable data quality and compatible acquisition schemes/ASL maps. Global and regional cerebral blood flow (CBF) patterns were explored to identify group differences, statistically controlling for 'morphometric covariates' (i.e. total brain volume, cortical thickness or subcortical volume) along with age, sex, disease duration and total T2-lesion load in the analysis of covariance ('basic covariates'). Similarly, partial correlation analyses were performed to assess the association of global CBF with physical (Expanded Disability Status Scale) and cognitive (Symbol Digit Modalities Test) scores. Global GM CBF values were lower in RRMS (64.1 ± 20.9 mL/100 g/min) and PPMS (52.9 ± 16.1 mL/100 g/min) compared with HC (78.5 ± 21.1 mL/100 g/min), with significant differences for both MS types compared with controls using both sets of covariates (pBonf≤0.05). Moreover, regional perfusion reduction encompassing several cortical and subcortical GM regions were found in patients versus controls, even after the inclusion of the morphometric covariates, while there were no differences in GM perfusion levels between MS phenotypes. In all patients considered together, no significant associations between global GM CBF and physical disability/cognitive tests scores were found when controlling for the confounding factors. These findings suggest that GM hypoperfusion is at least partially dissociated with atrophy. In this scenario, ASL-based perfusion may be a promising functional paraclinical tool to quantify GM neurovascular impairment in MS, aiding the understanding of the pathological mechanisms.

Congenital myasthenic syndromes (CMS) are a rare, heterogeneous group of disorders caused by pathogenic variants in genes encoding proteins essential for neuromuscular transmission. DOK7 variants are among the most common causes of CMS and one of the subtypes that may worsen with pyridostigmine. We report two patients who presented in adulthood with fatigable limb girdle weakness, initially diagnosed with seronegative myasthenia gravis, who slowly progressed over time despite escalating treatment and eventually needed intensive care admission. Revisiting the history led to the diagnosis of DOK7 CMS. Both patients improved after stopping immunosuppressants and pyridostigmine and starting salbutamol. These cases highlight the importance of considering CMS in patients with seronegative myasthenia gravis.

Ramdas et al. propose renaming ‘congenital myasthenic syndrome’ as ‘genetic myasthenic syndrome’. They argue that ‘congenital’ misleadingly implies neonatal onset, which may contribute to delayed diagnosis and management, and that revised nomenclature could improve patient outcomes.

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are inflammatory disorders of the CNS with distinct immunopathologic mechanisms and treatment responses and partially overlapping clinical phenotypes. The identification of aquaporin-4 (AQP4)-IgG and MOG-IgG has transformed disease classification and diagnosis, enabled a classification of antibody-defined subgroups, and facilitated the development of targeted therapies. However, optimal use of these biomarkers in clinical practice requires careful interpretation within the appropriate clinical and radiologic context. This review synthesizes current evidence on established and emerging fluid biomarkers in NMOSD and MOGAD, with emphasis on analytical performance, biological relevance, and clinical utility. We review antibody detection using cell-based assays, highlighting differences between live and fixed platforms and the impact of antigen conformation on sensitivity and specificity, particularly for MOG-IgG. Common causes of false-positive and false-negative results are discussed, including low-titer reactivity, testing in low pretest probability populations, treatment-related antibody titer reduction, and assay-specific limitations. The diagnostic challenges posed by indiscriminate testing in adult cohorts with multiple sclerosis, in whom disease prevalence markedly exceeds that of MOGAD, are emphasized. We also discuss the role of repeat testing during acute attacks and paired serum-CSF analysis in improving diagnostic confidence when results are equivocal or discordant. Beyond disease-defining antibodies, we examine biomarkers of tissue injury and immune activation. Serum and CSF neurofilament light chain and glial fibrillary acidic protein provide complementary measures of neuroaxonal and astrocytic damage and show associations with attack severity, disease activity, relapse risk, and long-term disability. Cytokines, chemokines, and complement components reflect inflammatory pathways, including IL-6-driven immune activation in NMOSD and MOGAD and complement-mediated astrocytopathy in NMOSD, and may support mechanistic stratification and treatment monitoring in both conditions. We further review the contribution of CSF analysis, neuropathology, genetics, and antigen discovery platforms to refine disease classification, particularly in seronegative or atypical presentations. Finally, we outline priorities for future research, including assay harmonization, standardized sampling protocols, longitudinal biomarker profiling, and integrative multiomic approaches. Collectively, advances in biomarker science have the potential to improve diagnostic precision, guide individualized therapeutic strategies, and support de-escalation decisions in NMOSD and MOGAD.

Predicting relapses in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) when disability is relapse-dependent is crucial to guide treatment decisions including whether to treat from onset. MOG-AR, a relapse risk score, was recently developed in a Chinese cohort from disease onset. This study aimed to externally validate the MOG-AR score. MOGAD patients seen through the Oxford National NMO Service with ≥ 1-year disease duration and available data for MOG-AR score calculation (variables of age, sex, onset attack phenotype, treatment) were included. MOG-AR score and grade were calculated. Relapse occurrence at 3 years from onset was used as the primary outcome. MOG-AR performance was assessed by measures of discrimination and calibration. We included 284 MOGAD patients with a 4.7-year median disease duration. Relapse occurred in 38

BACKGROUND:Reliable biomarkers for predicting disease progression in multiple sclerosis (MS) are crucial for advancing precision medicine and optimising treatment strategies. This study evaluates the predictive potential of serum nuclear magnetic resonance (NMR)-based metabolomics, individually and in combination with well-established biomarkers of neuroinflammation (serum glial fibrillary acidic protein, sGFAP) and axonal damage (neurofilament light chain, sNfL), in an extreme-phenotype subset of the Swiss Multiple Sclerosis Cohort (SMSC). METHODS:Serum samples were analysed using NMR-based metabolomics, along with quantification of sNfL and sGFAP. Supervised multivariate analysis was performed to differentiate MS phenotypes and identify future progressors. Multivariable receiver operating characteristic (ROC) analysis evaluated predictive performance, with key metabolite findings validated in an independent Oxford MS cohort. RESULTS:NMR-based metabolomics reliably distinguishes relapsing-remitting MS (RRMS) from secondary-progressive MS (SPMS) and predicts individual transitions. The identified predictive metabolites (lipoproteins, glutamine, alanine, valine, glucose) are also associated with progression independent of relapse activity (PIRA), a clinically relevant marker of sustained disability worsening. This demonstrates that the approach can both stage disease and forecast progression irrespective of stage. ROC analysis shows strong predictive performance (AUC = 0.81, p = 0.001), with external validation confirming robustness. Integration of NMR-metabolomics with sGFAP and sNfL further improves accuracy, yielding AUCs of 0.91 (p < 0.0001) and 0.87 (p = 0.0002), respectively, supported by independent validation. CONCLUSIONS:The integration of metabolic and protein biomarkers enables both accurate staging of RRMS versus SPMS and, critically, early prediction of progression irrespective of stage. This dual capability provides a clinically actionable, serum-based tool that can refine monitoring, improve therapeutic decision-making, and support a shift towards stage-agnostic, progression-focused care in MS.

Automated tools quantifying multiple sclerosis (MS) imaging biomarkers often require non-routine MRI sequences and lack MS reference data. We developed an open-source quantitative report (QReport) that integrates validated 3D T2-FLAIR quantification methods with multi-centre MS and healthy reference models, and presents outputs in a structured graphical report to support contextualised interpretation of clinically relevant biomarkers. 2516 cross-sectional 3D T2-FLAIR scans from people with MS (pwMS) and healthy controls (HC) were retrospectively collected from 14 centres within Magnetic Resonance Imaging in MS (MAGNIMS) and affiliated sites, as well as open-source datasets. Validated T2-FLAIR-based algorithms quantified total and regional lesion count (LC), lesion volume (LV), brain volume (BV), and brain age gap estimation (BrainAGE). Distributions in pwMS and HC were estimated using quantile regression. A QReport was designed to present biomarkers and reference models in graphical formats. Four neuroradiologists assessed agreement between QReport outputs and their visual assessment, and evaluated its usefulness, in 22 cases. We analysed scans from 1723 HC (age, mean ± SD: 54.5 ± 16.0; range: 18–75; F/M: 949/774) and 793 pwMS (age, mean ± SD: 43.0 ± 11.1; range: 18–75; F/M: 538/255) across 14 centres. The QReport presents single-subject measures contextualised against the 95th, 50th, and 5th percentile distributions in pwMS and HC, and includes BrainAGE. In 94

BACKGROUND:Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare autoimmune disorders of the central nervous system whose diagnosis increasingly relies on highly sensitive antibody assays and timely access to targeted therapies. Despite major advances in the diagnosis and management of these disorders worldwide, substantial challenges continue to compromise patient care across Latin America (LATAM). METHODS:This consensus-informed regional perspective was developed as an initiative of the European Charcot Foundation (ECF) Young Investigators/Fellows, following discussions held during the "2025 Update on NMOSD & MOGAD" ECF Meeting in São Paulo/Brazil, and in collaboration with international and Latin American experts. This manuscript synthesizes current evidence on the epidemiology, clinical characteristics, diagnosis, treatment, and healthcare challenges of NMOSD and MOGAD in LATAM, together with a consensus-informed assessment of regional priorities and unmet needs. KEY FINDINGS:Recent epidemiological studies have improved understanding of the burden of NMOSD and MOGAD across LATAM. Nevertheless, delayed diagnosis, disease misclassification, unequal access to specialized neuroimmunology services, and considerable variability in antibody testing methodologies remain major barriers to optimal patient management. Although commercial fixed cell-based assays (fixed-CBAs) have become increasingly available throughout the region, access to gold-standard live cell-based assays (live-CBAs) remains restricted to a limited number of specialized centers, potentially compromising diagnostic accuracy in some settings. Likewise, despite growing evidence supporting early initiation of highly effective therapies, particularly for AQP4-IgG-positive NMOSD, access to these treatments is limited in many locations, resulting in continued reliance on conventional immunosuppressive agents. CONCLUSIONS:Based on the available evidence and expert consensus, this regional perspective identifies two strategic priorities for advancing the diagnosis and management of NMOSD and MOGAD in LATAM: (I) expanding access to locally performed live-CBA and (II) ensuring equitable access to highly effective emerging therapies. Together, these priorities have the potential to harmonize clinical practice and reduce healthcare disparities across countries. They may also foster regional neuroimmunology collaborations, facilitating the generation of reliable region-specific real-world evidence, ultimately benefiting patients with NMOSD and MOGAD throughout LATAM.

BACKGROUND:Little is known about the causes of serum aquaporin 4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (AQP4-positive NMOSD) or how its pathophysiology differs from other demyelinating autoimmune diseases, which limits therapeutic and preventative opportunities despite available diagnostic biomarkers. By performing a pan-ancestry genome-wide association study (GWAS), we aimed to deepen our understanding of the genetic architecture of AQP4-positive NMOSD and to explore shared heritability with other autoimmune diseases. METHODS:We performed a pan-ancestry GWAS in 2833 individuals, including 1573 AQP4-positive NMOSD cases and 1260 controls (comprising non-affected relatives, healthy non-relatives, and those with other autoimmune diseases). Samples were collected from the International NMOSD Genetics Consortium, comprising 36 hospitals and research facilities across the world. All individuals with AQP4-positive NMOSD fulfilled the 2015 international consensus diagnostic criteria for NMOSD, including positive AQP4-IgG status. We also performed a second GWAS with only the 1857 samples of European ancestry (803 cases and 1054 controls). We then compared our GWAS findings to those from other autoimmune diseases. FINDINGS:We found three independent associations with AQP4-positive NMOSD that reached genome-wide significance: two within the MHC and a third within an intron of the STAT4 gene. In the pan-ancestry study, we identified a complement C4A-associatied variant, rs1150753 (chr6:32092090:A>G, p=1·61 × 10-29, odds ratio [OR] 2·95, 95% CI 2·44-3·56), rs607929 (chr6:32619221:C>G, p=2·87 × 10-24, OR 1·93, 95% CI 1·70-2·20), and a STAT4-associated variant, rs35593987 (chr2:191051800:AC>A, p=8·49 × 10-14, OR 1·75, 95% CI 1·51-2·03). In Europeans, we identified variants that were either in linkage disequilibrium with or the same as those from the pan-ancestry study: rs1270942 (chr6:31951083:A>G, p=2·52 × 10-28, OR 3·01, 95% CI 2·47-3·66), rs607929 (p=1·12 × 10-20, OR 1·99, 95% CI 1·72-2·30), and rs3821236 (chr2:191038032:G>A, p=1·20 × 10-10, OR 1·74, 95% CI 1·47-2·06). rs1270942 is in linkage disequilibrium with rs1150753 (r2=0·96) as well as two AQP4-positive NMOSD-associated HLA alleles, HLA-DRB1*03:01 (p=2·80 × 10-26, OR 2·79, 95% CI 2·30-3·37) and HLA-B*08:01 (p=1·02 × 10-24, OR 2·68, 95% CI 2·22-3·24). A priori testing of the P1104A variant (rs34536443, chr19:10352442:G>C) within the TYK2 gene, which acts upstream in the STAT4 pathway, found it to be protective (p=0·0008, OR 0·52, 95% CI 0·35-0·76 in the pan-ancestry study). Genetic sharing was observed with several comorbid autoimmune diseases for both the complement C4A-associated and STAT4-associated variants, including Sjögren's syndrome and systemic lupus erythematosus. INTERPRETATION:AQP4-positive NMOSD is more genetically similar to systemic autoimmune diseases than to multiple sclerosis, despite sharing overlapping clinical phenotypes. Specifically, a polymorphism associated with reduced complement C4 was identified as the biggest disease genetic risk factor, which has been shown to facilitate the development of autoantibody-producing B cells. Our findings also support a pathogenic role of HLA-restricted CD4+ T cells, owing to both a genome-wide significant association of HLA-DRB1*03:01 as well as heritable risk within the TYK2-STAT4 signalling pathway. Having already been shown to be a successful target for treating psoriatic arthritis and, potentially, systemic lupus erythematosus, we propose the TYK2-STAT4 pathway as a possible therapeutic target in AQP4-positive NMOSD. FUNDING:The OAK Foundation, The Guthy Jackson Charitable Trust Foundation, and the UK Medical Research Council.

The brain-predicted age difference (brain-PAD) is associated with measures of clinical interest in people with multiple sclerosis (pwMS). Most brain age models rely on 3D T1-weighted scans, which are not routinely acquired in MS clinical practice, limiting their potential for clinical translation. We aimed to develop a model predicting brain age using T2-FLAIR, the core sequence for MS diagnosis and monitoring, and validate the resulting brain-PAD values as a biomarker of MS severity and progression. We collected 3D T2-FLAIR and 3D T1-weighted brain MRI scans to compose (i) a multicentre cohort of healthy participants for brain age modeling, and (ii) a single-centre cohort of pwMS and healthy controls for external validation. We trained and evaluated 3D convolutional neural network models predicting brain age from T2-FLAIR or T1-weighted images. Models were compared using t-tests based on bootstrapped standard errors. Saliency maps were obtained with the SmoothGrad method to visualize regions that were most important for the predictions. Finally, using a linear model framework, we clinically validated the resulting brain-PAD metric by assessing its relationship with diagnosis (MS versus healthy controls), clinical phenotype, disease duration, and physical disability as measured with the Expanded Disability Status Scale (EDSS), adjusting for age and sex. The Inception-ResNet-V2 model based on T2-FLAIR scans yielded accurate brain age predictions (test set MAE = 3.31 years, R2 = 0.944, 5x ensemble MAE = 2.81, R2 = 0.955), which were comparable to those obtained with the T1w-based model (test set MAE = 3.34 years, R2 = 0.942, 5x ensemble MAE = 2.84, R2 = 0.955, p = 0.91). Brain age predictions were mostly driven by subcortical regions, particularly the thalamus. T2-FLAIR-based brain-PAD was higher in pwMS than healthy controls (7.07 vs -0.50 years, p < 0.0001). As with T1 brain-PAD, FLAIR brain-PAD correlated with MS disease duration (R = 0.24, p < 0.0001) and EDSS (R = 0.30, p < 0.0001). Brain age predictions relying on T2-FLAIR scans are as accurate as those derived from T1-weighted scans and could be used as an easily obtainable biomarker of MS severity and progression in clinical practice.

Data on the post-diagnosis experience of individuals with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and their caregivers are limited. We explored post-diagnosis treatment experience and satisfaction with care in individuals with MOGAD and associated caregiver burden. An online 57-question survey was distributed internationally to adults (aged ≥ 16 years) or caregivers assisting an adult or answering on behalf of a child (aged < 16 years) from October to December 2024. Overall, 261 responses were collected (adults, 219; children, 42) across 27 countries. Of those prescribed a preventative treatment, 43

BACKGROUND:Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD) requires lifelong immunosuppression to prevent relapses and disability. However, long-term treatment can increase the risk of severe and opportunistic infections, which can lead to hospitalisation and death. OBJECTIVES:To describe severe infections in AQP4-IgG NMOSD, their outcomes and risk factors, to inform safer long-term management. METHODS:We retrospectively analysed prospectively collected data from 209 patients with AQP4-IgG NMOSD treated with immunosuppressive therapies and followed ⩾1 year at a UK national specialist service. Severe infections were defined as requiring intravenous therapy or hospitalisation. Predictors were identified using multivariate regression. RESULTS:Forty-nine severe/opportunistic infections occurred in 37 patients (18%), accounting for one-third of deaths (10/30). Independent predictors were longer disease duration (OR 1.10, 95% CI 1.01-1.21), older age at onset (OR 1.04, 95% CI 1.00-1.08), comorbid autoimmune disease (OR 3.91, 95% CI 1.95-7.84) and diabetes mellitus (OR 7.48, 95% CI 2.24-24.98). Four patients died after their first infection. Among survivors, nine developed recurrent infections, six of whom died. CONCLUSIONS:Severe infections can be a complication of immunosuppression in NMOSD, especially in older patients and those with comorbidities. Risk stratification, comorbidity management and infection prevention should guide therapy to balance safety and relapse control.

The 2024 revisions to the McDonald criteria mark a major shift in the diagnosis of multiple sclerosis (MS), reflecting advances in imaging and biomarker science. The updated framework adopts a more biologically anchored approach, integrating radiological and cerebrospinal fluid evidence to enable earlier and more accurate diagnosis. Key changes include recognition of the optic nerve as a fifth anatomical site for dissemination in space, incorporation of advanced MR imaging markers such as the central vein sign and paramagnetic rim lesions to improve specificity, and acceptance of the kappa free light chain index as a quantitative alternative to oligoclonal bands. In selected patients with highly characteristic clinical and imaging features, MS may now be diagnosed without demonstration of dissemination in time, reducing diagnostic delay. A unified pathway across relapsing and progressive phenotypes, including children, promotes consistency, while defined pathways also allow diagnosis in certain asymptomatic individuals, including those with radiologically isolated syndrome, when supported by biomarkers. Implementation will require access to advanced imaging, standardised laboratory testing, multidisciplinary expertise and careful clinical judgement to minimise misdiagnosis and ensure equitable access.

Objective To determine whether myelin-sensitive quantitative MRI reveals microstructural abnormalities in normal-appearing cortex (NACtx) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), indicating that conventional MRI underestimates remission residual cortical injury.Methods Forty-two patients with MOGAD in remission and 42 age- and sex-matched healthy controls (HCs) underwent cognitive testing (Rao Brief Repeatable Battery), disability rating (Expanded Disability Status Scale) and 3-T MRI, including three-dimensional T1-weighted, T2-weighted and double-inversion-recovery sequences to identify cortical lesions and delineate NACtx. T1- to T2-weighted ratio z-scores (T1/T2r), magnetisation transfer ratio (MTR) and magnetisation transfer saturation (MTsat) were derived in global and lobar NACtx; MT imaging was available in 22 patients and 24 controls. Linear mixed-effects models compared MOGAD with HCs and cortical (history of at least one acute cortical attack) with non-cortical phenotypes, adjusting for age, sex, site and cortical thickness with false-discovery-rate correction.Results Sixteen of 42 MOGAD patients had a cortical phenotype; cortical lesions at remission were present in 4 of 42 (9.5%), all with a cortical phenotype. MTsat metric, but not T1/T2r or MTR, detected NACtx alterations in the MOGAD cohort compared with HCs. Cortical MOGAD phenotype showed reduced MTsat in global, frontal, temporal, limbic, hippocampal and insular NACtx regions vs. HCs, whereas non-cortical MOGAD was similar to HCs. Exploratory analyses suggested lower MTsat in temporal, limbic, hippocampal and insular NACtx regions in cortical MOGAD with cognitive impairment than in cognitively preserved MOGAD.Interpretation Myelin-sensitive MTsat reveals persistent, regionally specific abnormalities in normal-appearing cortex in cortical MOGAD and is a promising marker of residual cortical damage linked to cognitive dysfunction.

Muscle-type nicotinic acetylcholine receptor (AChR) is the key signaling molecule in neuromuscular junctions. Here, we present the structures of full-length human adult receptors in complex with Fab35 in α-bungarotoxin (αBuTx)-bound resting states and ACh-bound desensitized states. In addition to identifying the conformational changes during recovery from desensitization, we also used electrophysiology to probe the effects of eight previously unstudied AChR genetic variants found in patients with congenital myasthenic syndrome (CMS), revealing they cause either slow- or fast-channel CMS characterized by prolonged or abbreviated ion channel bursts. The combined kinetic and structural data offer a better understanding of both the AChR state transition and the pathogenic mechanisms of disease variants.

Unusual seizure phenotypes in myelin-oligodendrocyte-glycoprotein (MOG) seropositive patients have previously been reported, although so far, no cases of sleep-related hypermotor epilepsy (SHE). In our case, a patient with a diagnosis of MOG antibody-associated disease (MOGAD) began reporting unusual sleep disturbances; video-audio documentation was in keeping with the clinical diagnosis of SHE. MRI brain was normal at the time of the assessment for seizures. Symptoms responded to antiepileptic drugs (AEDs). These unusual seizure events were thought to be indicative of the underlying autoimmune condition, suggesting that the clinical spectrum of MOGAD is wider than previously thought.

Disruptions to brain networks, measured using structural (sMRI), diffusion (dMRI), or functional (fMRI) MRI, have been shown in people with multiple sclerosis (PwMS), highlighting the relevance of regions in the core of the connectome but yielding mixed results depending on the studied connectivity domain. Using a multilayer network approach, we integrated these three modalities to portray an enriched representation of the brain's core-periphery organization and explore its alterations in PwMS. In this retrospective cross-sectional study, we selected PwMS and healthy controls with complete multimodal brain MRI acquisitions from 13 European centers within the MAGNIMS network. Physical disability and cognition were assessed with the Expanded Disability Status Scale (EDSS) and the symbol digit modalities test (SDMT), respectively. SMRI, dMRI, and resting-state fMRI data were parcellated into 100 cortical and 14 subcortical regions to obtain networks of morphological covariance, structural connectivity, and functional connectivity. Connectivity matrices were merged in a multiplex, from which regional coreness-the probability of a node being part of the multiplex core-and coreness disruption index (κ)-the global weakening of the core-periphery structure-were computed. The associations of κ with disease status (PwMS vs. healthy controls), clinical phenotype, level of physical disability (EDSS ≥ 4 vs. EDSS < 4), and cognitive impairment (SDMT z-score < -1.5) were tested within a linear model framework. Using random forest permutation feature importance, we assessed the relative contribution of κ in the multiplex and single-layer domains, in addition to conventional MRI measures (brain and lesion volumes), in predicting disease status, physical disability, and cognitive impairment. We studied 1048 PwMS (695F, mean ± SD age: 43.3 ± 11.4 years) and 436 healthy controls (250F, mean ± SD age: 38.3 ± 11.8 years). PwMS showed significant disruption of the multiplex core-periphery organization (κ = -0.14, Hedges' g = 0.49, p < 0.001), correlating with clinical phenotype (F = 3.90, p = 0.009), EDSS (Hedges' g = 0.18, p = 0.01), and SDMT (Hedges' g = 0.30, p < 0.001). Multiplex κ was the only connectomic measure adding to conventional MRI in predicting disease status and cognitive impairment, while physical disability also depended on single-layer contributions. In conclusion, we show that multilayer networks represent a biologically and clinically meaningful framework to model multimodal MRI data, with disruption of the core-periphery structure emerging as a potential connectomic biomarker for disease severity and cognitive impairment in PwMS.