多発性硬化症／視神経脊髄炎

BACKGROUND AND OBJECTIVES: Gray matter (GM) damage is a key determinant of clinical disability in multiple sclerosis (MS), but its relevance to very long-term outcomes remains insufficiently characterized. We assessed associations between baseline and 12-month MRI measures of GM and white matter (WM) damage and long-term outcomes in relapse-onset MS. METHODS: We conducted a prospective longitudinal single-center cohort study of relapse-onset MS patients enrolled between 1993 and 1998. Participants underwent clinical and 1.5T brain MRI assessments at baseline and after 12 months. MRI measures included T2-lesion and T1-lesion volumes, GM, WM, and thalamic volume fractions, magnetization transfer ratio (MTR) of GM, thalamus, normal-appearing WM, and WM lesions. Escalation to high-efficacy disease-modifying therapies (HE-DMTs) was recorded. Outcomes included Expanded Disability Status Scale (EDSS) worsening, evolution to a more severe disease stage, MS-related death, and cognitive deterioration. Associations were evaluated using LASSO-regularized logistic regression with internal bootstrap validation. RESULTS: Seventy-three relapse-onset MS patients (mean age = 33.0 years; female = 69.9%) were followed for a median of 25.9 years (interquartile range = 18.1-27.1; patients lost during follow-up = 11). EDSS worsening occurred in 79.5% of patients, 72.6% evolved to a more severe disease stage, 24.7% died from MS-related causes, and 39.5% of patients with cognitive data (17/43) experienced cognitive deterioration. EDSS worsening was associated with lower baseline GM fraction (GMF) (standardized-β = -0.561), escalation to HE-DMTs (standardized-β = 0.059), lower baseline thalamic fraction (standardized-β = -0.115), lower baseline normal-appearing WM MTR histogram peak height (standardized-β = -0.010), and greater 12-month decline in GM MTR histogram peak height (standardized-β = -0.115) (area under the curve [AUC] = 0.843, 95% CI 0.744-0.941). Evolution to a more severe disease stage was associated with higher 12-month EDSS score change (standardized-β = 0.167) and lower baseline GMF (standardized-β = -0.151) (AUC = 0.793, 95% CI 0.670-0.916). MS-related death was associated with male sex (standardized-β = 0.063), higher baseline EDSS score (standardized-β = 0.182), lower baseline GMF (standardized-β = -0.304), lower baseline GM MTR histogram peak height (standardized-β = -0.050), and greater 12-month decline in mean thalamic MTR (standardized-β = -0.370) (AUC = 0.887, 95% CI 0.813-0.961). Cognitive deterioration was associated with older baseline age (standardized-β = 0.197), lower baseline brain parenchymal fraction (standardized-β = -0.039), and lower baseline mean GM MTR (standardized-β = -0.376) (AUC = 0.891, 95% CI 0.788-0.994). DISCUSSION: Brain GM damage showed consistent associations with disability worsening and evolution, mortality, and cognitive deterioration over 26 years in relapse-onset MS, supporting the long-term clinical relevance of GM-focused MRI markers.

BACKGROUND: Left-truncation is an unrecorded interval between multiple sclerosis (MS) onset and initial data in observational studies. This delay may bias estimates of disease-modifying therapy (DMT) effectiveness, especially when determined by patient or disease characteristics. OBJECTIVES: To examine whether causal effect estimates of DMTs over the full disease course can be reliably derived from left-truncated registry data. METHODS: We analysed data from MSBase (144 centres, 41 countries) to assess the impact of left-truncation on causal treatment effect estimates. Cox marginal structural models (MSMs) estimated hazard ratios (HRs) for relapses, disability worsening and improvement, considering left-truncation at random and not-at-random. Fixed-time truncation and multivariable adjustment were applied to remediate bias. RESULTS: The study included 5588 patients tracked from true MS onset. The null model, without left-truncation, estimated the DMT effect on relapse risk (HR = 0.64; 95% confidence interval (CI) = 0.54-0.77). Left-truncation inflated this estimate. Shorter random truncation (1 year) produced greater bias (HR = 0.34), decreasing with longer durations (3-year HR = 0.48). Truncation not-at-random biased relapse estimates (HR = 0.37). Disability outcomes were less sensitive. CONCLUSION: MSMs can reliably estimate DMT effectiveness in left-truncated MS registry data, although accuracy depends on truncation mechanism and duration. Both random and not-at-random truncation impact relapse estimates. Disability outcomes appear less sensitive. Fixed-time truncation and covariate adjustment mitigated bias.

BACKGROUND: Induced pluripotent stem cells (iPSCs) offer a novel approach to target microglia, key drivers of multiple sclerosis (MS) pathology. A promising therapeutic strategy involves depleting resident microglia using colony-stimulating factor 1 receptor (CSF-1R) inhibitors, followed by differentiating iPSCs into microglia in vitro and transplanting them into the central nervous system (CNS). However, no studies have yet specifically examined iPSC-derived microglial replacement in MS. OBJECTIVES: This review evaluates the feasibility of replacing pathogenic microglia in MS with iPSC-derived microglia. METHODS: A systematic literature search identified studies on microglial depletion, iPSC differentiation into microglia, and transplantation, as well as reports involving other MS-relevant neural cell types. RESULTS: Direct studies on iPSC-derived microglia transplantation in MS are currently lacking; however, several preclinical investigations using iPSC-derived neural stem cells and oligodendrocyte precursor cells in animal models demonstrate robust engraftment, targeted migration to demyelinated lesions, reduced inflammation, enhanced remyelination, and significant functional recovery in vivo. These findings, besides microglia-specific transplantation, depletion, and repopulation studies in other disease contexts, support the biological plausibility of iPSC-based CNS cell replacement and inform future microglial transplantation research. CONCLUSION: Replacing pathogenic microglia with iPSC-derived counterparts represents an emerging therapeutic avenue for progressive MS. Rigorous preclinical studies are needed to confirm safety, optimize transplantation, and evaluate long-term efficacy.

Multiple sclerosis (MS), an immune-mediated inflammatory demyelinating disorder of the central nervous system (CNS), is driven by microglia as key orchestrators of neuroinflammation. This study assessed the preventive potential of temporin-GHaR6R (GHaR6R), an antimicrobial peptide derived from Hylarana guentheri skin, using the experimental autoimmune encephalomyelitis (EAE) murine model of MS. Preventive administration of GHaR6R significantly reduced EAE incidence and alleviated clinical severity, while histopathological analyses (HE and LFB staining) revealed attenuated inflammatory cell infiltration and demyelination in the spinal cord. Mechanistically, GHaR6R suppressed M1 microglial polarization, thereby limiting excessive neuroinflammatory activation. In vitro, GHaR6R inhibited TNF-α and IL-6 secretion, reduced mitochondrial ROS production, preserved mitochondrial membrane potential in LPS-activated BV2 microglia, and promoted the shift from M1 to M2 microglial polarization. Consistent with these findings, GHaR6R downregulated mitochondrial fission protein Drp-1 while upregulating the fusion mediators MFN1 and MFN2 in both EAE-affected spinal cords and LPS-stimulated BV2 cells. Immunofluorescence analysis showed increased colocalization of Iba-1 with MFN1/2, indicating enhanced mitochondrial fusion in microglia. Taken together, these results demonstrate that GHaR6R ameliorates EAE progression by modulating microglial mitochondrial dynamics, mitigating neuroinflammation, and inhibiting M1 polarization, highlighting its potential as an early prophylactic intervention for MS.

BACKGROUND: Growing evidence supports choroid plexus (CP) involvement in MS pathophysiology, but phase-specific associations according to recent inflammatory activity and longitudinal dynamics remain unclear. OBJECTIVE: To characterize CP alterations in MS using volumetric and quantitative magnetic resonance imaging (MRI) and explore associations with neuroinflammation and neurodegeneration. METHODS: We analyzed cross-sectional and 2-year longitudinal data from 101 patients with active relapsing MS (RMS), 83 with inactive progressive MS (PMS), and 100 controls, with MS groups stratified by inflammatory activity within the prior year. CP volume, quantitative T1, and magnetization transfer saturation (MTsat) were assessed alongside imaging, serum, and clinical measures, with validation in a second cohort (62 active/357 inactive MS). RESULTS: CP volume was increased in both active RMS and inactive PMS and was associated with lower total and cortical brain volumes. Associations with brain microstructural damage were more pronounced in periventricular regions, compatible with a surface-in pattern. Similar associations were observed in controls, suggesting CP volume may reflect processes beyond MS-specific pathology, including physiological factors. Longitudinally, CP volume increased exclusively in active RMS, with faster expansion associated with thalamic atrophy. CP MTsat was associated with cortical and paramagnetic rim lesions in inactive PMS. CONCLUSION: CP enlargement is consistent across MS phases. Longitudinal expansion occurs in active inflammatory disease and is associated with neurodegenerative changes.