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Background: Spinal cord volume loss is associated with clinical disability in multiple sclerosis (MS). Aerobic capacity may mitigate the impact of central nervous system (CNS) damage accumulation, exerting beneficial effects on MS-related disability., Objectives: We investigated whether aerobic capacity could moderate the association between spinal cord atrophy and clinical disability in MS., Methods: In this cross-sectional analysis, expanded disability status scale (EDSS), peak of oxygen consumption (VO 2 peak), brain volumetric measures, and the normalized mean upper cervical cord area (nMUCCA) were collected from 51 MS patients and 33 healthy controls (HCs). Low aerobic capacity was defined as having a VO 2 peak z-score less than -1.64 standard deviations. In MS patients, we explored whether the association between nMUCCA and EDSS is moderated by the level of aerobic capacity., Results: The relationship between nMUCCA and EDSS was moderated by aerobic capacity, with a significant nMUCCA × aerobic capacity interaction (β = -0.099, 95% bootstrapped confidence interval [CI] = [-0.172; -0.014], p = 0.012). Lower nMUCCA was significantly associated with higher EDSS score in MS patients with low aerobic capacity (β = -0.073, p < 0.001), but not in those with high aerobic capacity (β = 0.026, p = 0.417)., Conclusions: In MS patients with mild disability, higher aerobic capacity can potentially mitigate the negative impact of spinal cord damage on clinical disability., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare that they have no competing interests in relation to this work.Potential conflicts of interest outside the submitted work are as follows:M. Albergoni, C. Dallari, A. Meani, and P. Valsasina have nothing to disclose. P. Preziosa received speaker honoraria from Roche, Biogen, Novartis, Merck, Bristol Myers Squibb, Genzyme, Horizon, and Sanofi. He has received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. M. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. M.A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders and Co-Associate Editor for Europe and Africa for Multiple Sclerosis Journal.

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: V.V.: nothing to disclose. C.Z. received compensation for speaking activities, and/or consulting services, from Alexion, AstraZeneca, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi. M.A.R. received consulting fees and speaker honoraria from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, AstraZeneca, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi, and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. M.F. is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services, direction of educational events, participation on Advisory Boards, and/or speaking activities from Alexion, Almiral, Bayer, Biogen, Bristol Myers Squibb, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda, and TEVA; he receives research support from Biogen Idec, Merck Serono, Novartis, Roche, the Italian Ministry of Health and Research, and Fondazione Italiana Sclerosi Multipla.

Background: The understanding of disease pathophysiology is pivotal for tailored treatments. The spatial distribution of brain damage relies on the regional antigen expression and the local balance of susceptibility and protective elements., Objective: As proof-of-concept, we investigated the spatial association between brain damage and gene expression in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD)., Methods: In this multicenter cross-sectional study, 90 AQP4 + NMOSD patients and 94 age-matched healthy controls underwent a brain magnetic resonance imaging (MRI). We used T2-hyperintense lesion probability maps and white/gray matter atrophy as proxies of inflammation and neurodegeneration. The association with the expression of 266 candidate genes was obtained with the Multimodal Environment for Neuroimaging and Genomic Analysis platform. A functional-enrichment analysis investigated overrepresented biological processes., Results: In AQP4 + NMOSD, T2-hyperintense lesions were mainly periventricular; atrophy mostly involved the visual pathway. The expression of AQP4 and complement (C4a and C5) was associated with both inflammation and neurodegeneration. Complement activation and regulation/uptake of the insulin-like growth factor were the most relevant enriched pathways. Nonspecific pathways related to DNA synthesis and repair were associated with brain atrophy., Conclusions: Quantitative MRI and gene expression atlas identified the key elements of AQP4 + NMOSD pathophysiology. This analysis could help in understanding the pathophysiology of antibody-mediated autoimmune disorders., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.C. received speaker and consultant honoraria from ACCMED, Roche, BMS Celgene, and Sanofi. L.S. received grants and contracts from FISM—Fondazione Italiana Sclerosi Multipla—within a fellowship program (cod. 2019/BR/009) and received speakers’ honoraria from Biogen. E.P. received speaker honoraria from Biogen Idec. P.P. received speaker honoraria from Roche, Biogen, Novartis, Merck Serono, Bristol-Myers Squibb, Genzyme, Horizon, and Sanofi; he received research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. S.M. has been an advisor or speaker for Medis, Merck, Teva, Hemofarm, and Roche. V.M. received honoraria for consulting services or speaking activity from Biogen, Merck, Novartis, TEVA, Almirall, and Sanofi. L.M. received compensation for speaking activities, and/or consulting services from Merck, Biogen, Novartis, Roche, Sanofi, and TEVA. M.R. reports no disclosures. J.I. reports no disclosures. O.T. has been a speaker for Medis, Merck, Teva, Hemofarm, Novartis, and Roche. J.D. has been an advisor or speaker for Bayer HealthCare, Sanofi-Genzyme, Medis, Merck, Teva, Novartis, Biogen, Hemofarm, and Roche. M.F. is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; he received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. M.A.R. received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, and Janssen, Roche; and speaker honoraria from AstraZeneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi, and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders.

Background: Paramagnetic rim lesions (PRL) are valuable for diagnosing and prognosing multiple sclerosis (MS) and detectable at 7T and 3T MRI. For translation into clinical practice, it is essential assessing their visibility on 1.5T clinical scanners., Objective: To evaluate the reliability of detecting PRL using commercially available susceptibility-weighted imaging (SWI) at 1.5 versus 3T MRI., Methods: SWI images were obtained in 20 people with MS at 1.5T and 3T MRI, with an average scan interval of 1.1 years. Only stable, non-enhancing lesions visible on both scans were analyzed. PRL at 3T were identified by two expert raters using NAIMS PRL criteria and used as a reference. Four raters, blinded to 3T results, assessed PRL at 1.5T. Discrepancies were resolved by consensus., Results: PRL were identified in 16 of 20 patients. At 3T, 95 PRL were identified by consensus (mean 5 PRL per patient, range 0-30). Blinded to 3T scans, 82% of PRL were visible at 1.5T (78 of 95 PRL). Interrater reliability was "almost perfect" for both 1.5 and 3T scans. Raters accurately classified all patients as having ⩾1PRL or not at 1.5T., Conclusion: The majority of PRL are detectable at 1.5T without significantly reducing the specificity of PRL identification or increasing the detection of pseudo-PRL. This may facilitate their clinical use in MS diagnosis and prognosis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.M. received compensations for speaking activities and/or for participating to advisory board from Merck, Celgene, Biogen, Sanofi, Novartis, Roche, Alexion, and Amgen. P.M. received consulting honoraria from Sanofi, Biogen, and Merck. S.B. received speaker/consulting honoraria from Sanofi, Roche, Janssen, Merck, and Novartis, and research grants from Roche and Sanofi. V.M. received honoraria for speaking and/or for consultancy and support for travel expenses and participation in congresses from Biogen, Roche, Merck, Novartis, Genzyme. M.A.R. received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. M.F. is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. M.A. received speaker and/or consulting honoraria from Biogen, Sanofi, Abata Therapeutics, GSK and Immunic Therapeutics. The other authors have no disclosures.

Objective: The aim of this study was to explore the microstructural dynamics of the subventricular zone (SVZ) with aging and their associations with clinical disability and brain structural damage in pediatric-onset multiple sclerosis (MS) patients., Methods: One-hundred and forty-one pediatric-onset MS patients (67 pediatric and 74 adults with pediatric-onset) and 233 healthy controls (HC) underwent neurological and 3.0 T MRI assessment. Fractional anisotropy (FA) and mean diffusivity (MD) were extracted from the SVZ and the thalamus (as control region)., Results: In HC, SVZ FA was higher until age 40 then declined, whereas MD was lower until age 35 before rising (false discovery rate p value [pFDR] ≤ 0.008). Thalamic FA was higher until age 30 and then declined, whereas MD was higher until age 50 (pFDR ≤ 0.007). Pediatric MS patients showed significantly higher SVZ FA than pediatric HC (pFDR < 0.001), while adult patients showed no differences compared to adult HC (pFDR ≤ 0.724). Adult patients had lower thalamic FA and higher MD (pFDR < 0.001). Adults had lower SVZ FA and MD, but higher thalamic MD compared to pediatric patients (pFDR < 0.001). In pediatric MS, higher SVZ FA and MD were associated with higher white matter (WM) lesion volume (LV) and choroid plexus volume and lower brain and thalamic volumes (pFDR ≤ 0.047). In adult patients, higher SVZ MD associated with higher WM LV, lower brain volumes, and lower z-SDMT (pFDR≤0.019). Thalamic microstructural abnormalities were associated with more severe disability and brain damage in both groups (pFDR ≤ 0.018)., Interpretation: Our findings suggest that microstructural changes in the SVZ occur early in pediatric MS and are associated with brain structural damage but not with clinical impairment. ANN NEUROL 2025., (© 2025 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Vitamin D (VitD) affects the risk of multiple sclerosis (MS), but the impact on disease activity is controversial. We assessed whether VitD is associated with the No-Evidence of Disease Activity-3 (NEDA-3) status at 2 years from disease-modifying treatment (DMT) start, and whether this association is causal or the result of confounding factors. Furthermore, we explored if a genetic predisposition to higher VitD levels affects the risk of disease activity., Methods: 230 untreated relapsing-remitting MS patients underwent serum 25-OH-vitamin-D measurement, and the association between seasonally adjusted VitD and disease activity was tested. Modelling a Polygenic Risk Score from a Genome-Wide Association Study on ~400 000 individuals, we studied the impact of genetic predisposition to higher VitD on the NEDA-3 status in 1408 independent MS patients. Two-sample Mendelian randomisation (MR) was used to assess causality., Results: Lower baseline VitD was associated with decreased probability of NEDA-3 at 2 years (p=0.019). Particularly, VitD levels <20 ng/mL conferred an over twofold risk of disease activity (OR 2.36, 95% CI 1.30 to 3.88, p=0.0037). Genetic predisposition to higher VitD levels was associated with delayed age at MS onset (p=0.018) and with a higher probability of NEDA-3 status (p=0.034). MR confirmed causality between VitD and the risk of disease activity (p=0.041)., Conclusions: VitD levels before DMT start affect the risk of disease activity in MS. Genetic predisposition to higher VitD levels confers a lower risk of disease activity and is associated with delayed MS onset. Our work prompts future prospective studies regarding VitD supplementation and lifestyle interventions to hamper disease activity in MS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: In multiple sclerosis (MS), susceptibility-weighted imaging (SWI) may reveal white matter lesions (WML) with a paramagnetic rim ("paramagnetic rim lesions" [PRLs]) or diffuse hypointensity ("core-sign lesions"), reflecting different stages of WML evolution., Objective: Using the soma and neurite density imaging (SANDI) model on diffusion-weighted magnetic resonance imaging (MRI), we characterized microstructural abnormalities of MS PRLs and core-sign lesions and their clinical relevance., Methods: Forty MS patients and 20 healthy controls (HC) underwent a 3 T brain MRI. Using SANDI, the fractions of neurite (f neurite ) and soma (f soma ) and size of soma (r soma ) were quantified in PRLs (including their core and rim separately), and core-sign lesions identified on SWI-phase., Results: Among 1811 WMLs, 122 (6.7%) core-sign lesions and 97 (5.4%) PRLs were identified. Compared to HC and MS normal-appearing white matter, all MS WML showed significantly lower f neurite and f soma and higher r soma (FDR-p < 0.001). Compared to SWI-isointense WML, core-sign lesions showed a significantly higher f neurite , and lower f soma and r soma (FDR-p ≤ 0.005). Compared to SWI-isointense WML and core-sign lesions, PRLs showed a significantly lower f neurite , higher f soma, and higher r soma (FDR-p ≤ 0.001). The PRL-core showed significantly lower f neurite , and higher r soma than PRL-rim (FDR-p < 0.001). Lower PRL f neurite (β ≤ -0.006, FDR-p ≤ 0.015) and higher r soma (β ≥ 0.032, FDR-p ≤ 0.024) were significantly associated with a longer disease duration and more severe disability., Conclusions: In PRLs, the significant and clinically relevant neurite loss and increased soma fraction and size possibly reflect increased astrogliosis and activated microglia. Core-sign lesions exhibit milder axonal loss, microglia density and astrogliosis, supporting their less destructive nature., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no competing interests in relation to this work. Potential conflicts of interest outside the submitted work are as follows: P. Preziosa received speaker honoraria from Roche, Biogen, Novartis, Merck, Bristol Myers Squibb, Genzyme, Horizon and Sanofi, he has received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla; E. Pagani has nothing to disclose; A. Meani has nothing to disclose; M. Margoni reports grants and personal fees from Sanofi Genzyme, Merck Serono, Novartis and Almiral; M. Rubin has nothing to disclose; F. Esposito has nothing to disclose; M. Palombo has nothing to disclose; M. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology, received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi, speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA, participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda, scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme, he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla; M.A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche, and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva, she receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla, she is Associate Editor for Multiple Sclerosis and Related Disorders. Ethical approval: Approval was received from the institutional ethical standards committee on human experimentation of IRCCS Ospedale San Raffaele for any experiments using human subjects (Protocol N° 2015–33). Written informed consent was obtained from all subjects prior to study participation according to the Declaration of Helsinki., (© 2025. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: In multiple sclerosis (MS), brain reserve serves as a protective factor against cognitive impairment. Previous research has suggested a structural counterpart in the spine-spinal cord reserve-seemed to be associated with physical disability. This study aimed to investigate the potential of the cervical canal area (CCaA) as a proxy for spinal cord reserve in a multicentric cohort of people with MS (PwMS)., Methods: This retrospective, multicentric, longitudinal study included PwMS and healthy controls (HCs) from 9 European MAGNIMS sites. Baseline cervical 3D T1-weighted images were acquired, excluding poor-quality images. CCaA was estimated independently at the C2/C3 and C3/C4 levels. The Expanded Disability Status Scale (EDSS) score was assessed at baseline and 5-year follow-up. We analyzed mean CCaA differences between groups and the association of CCaA with baseline EDSS scores and disability progression using multivariable regression models adjusted for age, sex, spinal cord parenchymal fraction, and cervical cord lesions., Results: After quality check, the cohort included 177 HCs (mean age 39.8 years, 57.6% women) and 428 PwMS (mean age 46.5 years, 60.8% women), comprising 289 people with relapsing MS (PwRMS) and 139 people with progressive MS (PwPMS). No significant differences in CCaA were found between HCs and PwRMS at C2/C3 or C3/C4 levels. Conversely, PwPMS showed a smaller CCaA at the C2/C3 level (210.51 mm 2 ) than HCs (214.62 mm 2 , estimated mean difference [EMD] -4.11, 95% CI -6.28 to -1.00, p = 0.007) and PwRMS (213.68 mm 2 , EMD -3.17, 95% CI -5.22 to -0.34, p = 0.026). PwPMS also had a smaller CCaA at C3/C4 (165.16 mm 2 ) than HCs (169.67 mm 2 , EMD -4.51, 95% CI -5.50 to -1.60, p < 0.001) and PwRMS (169.44 mm 2 , EMD -3.81, 95% CI -5.22 to -0.34, p < 0.001). At the C3/C4 level, CCaA and baseline EDSS scores were significantly associated (β = -0.13, p < 0.001); in addition, PwMS with clinical worsening at 5-year follow-up displayed a smaller baseline CCaA (worsened vs stable: 167.03 mm 2 vs 169.13 mm 2 , EMD -2.10, 95% CI -3.98 to -023, p = 0.028)., Discussion: CCaA was associated with baseline EDSS scores and clinical worsening in a multicentric MS cohort, suggesting the existence of spinal cord reserve. PwPMS had a smaller CCaA, indicating that reduced spinal cord reserve might be characteristic of progressive MS. Therefore, spinal cord reserve may represent a novel radiologic marker for better understanding physical disability in MS.

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., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)