Smouldering‐Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions

Annals of Neurology, Journal Year: 2024, Volume and Issue: 96(5), P. 826 - 845

Published: July 25, 2024

Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition "progression independent relapsing activity." We propose concept smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, remain unmet targets. provide a consensus-based framework possible substrates manifestations MS, we discuss clinical, radiological, serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, share considerations optimizing disease surveillance implications clinical trials to promote integration MS into routine practice future research efforts. ANN NEUROL 2024;96:826-845.

Language: Английский

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No evidence for association between rs10191329 severity locus and longitudinal disease severity in 1813 relapse-onset multiple sclerosis patients from the MSBase registry

Multiple Sclerosis Journal, Journal Year: 2024, Volume and Issue: 30(9), P. 1216 - 1220

Published: March 21, 2024

Background: The International Multiple Sclerosis Genetics Consortium and MultipleMS recently reported a genetic variant associated with multiple sclerosis (MS) severity. However, it remains unclear if these variants remain more robust, longitudinal measures of disease Methods: We examined the top variant, rs10191329, from Harroud et al.’s study in 1813 relapse-onset MS patients MSBase Registry to assess association Results: Our analysis revealed no significant between rs10191329 genotype binary severity ( p > 0.05). Conclusion: These findings highlight complexity factors mediating long-term outcomes need for further research.

Language: Английский

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Choroid Plexus Volume Change—A Candidate for a New Radiological Marker of MS Progression

Diagnostics, Journal Year: 2023, Volume and Issue: 13(16), P. 2668 - 2668

Published: Aug. 14, 2023

(1) Background: Multiple sclerosis (MS) is an auto-immune, chronic, neuroinflammatory, demyelinating disease that affects mainly young patients. This progressive inflammatory process causes the chronic loss of brain tissue and results in a deterioration quality life. To monitor neuroinflammatory activity predict further development disease, it necessary to find suitable biomarker could easily be used. In this research, we verify usability choroid plexus (CP) volume, new MS biomarker, monitoring progression multiple disease. (2) Methods: A single-center, prospective study with three groups patients was conducted based on following groups: who received experimental cellular therapy (Treg), treatment-naïve healthy controls. (3) Results: concludes there correlation between CPV/TIV (choroid plexus/total intracranial volume) ratio progress disease-patients (MS + Treg) had larger volumes plexuses. ratios were constantly significantly growing. Treg group, relapses plexuses comparison group no MS. similar observed for GD+ (patients postcontrast enhancing plaques) compared against non-GD without plaques). (4) Conclusion: Choroid due its immunological function, correlates central nervous system. We consider become valuable radiological activity.

Language: Английский

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Whole-blood methylation signatures are associated with and accurately classify multiple sclerosis disease severity

Clinical Epigenetics, Journal Year: 2022, Volume and Issue: 14(1)

Published: Dec. 1, 2022

Abstract Background The variation in multiple sclerosis (MS) disease severity is incompletely explained by genetics, suggesting genetic and environmental interactions are involved. Moreover, the lack of prognostic biomarkers makes it difficult for clinicians to optimise care. DNA methylation one epigenetic mechanism which gene–environment can be assessed. Here, we aimed identify patterns associated with mild severe relapse-onset MS (RMS) test utility as a predictive biomarker. Methods We conducted an epigenome-wide association study between 235 females ( n = 119) or 116) RMS. Methylation was measured Illumina methylationEPIC array analysed using logistic regression. To generate hypotheses about functional consequence differential methylation, gene set enrichment analysis ToppGene . compared accuracy three machine learning models classifying severity: (1) clinical data available at baseline (age onset first symptoms) built elastic net (EN) regression, (2) EN regression (3) weighted risk score differentially methylated positions (DMPs) from main used conservative 70:30 test:train split classification modelling. A false discovery rate threshold 0.05 assess statistical significance. Results Females RMS had 1472 DMPs whole blood (839 hypermethylated, 633 hypomethylated group). Differential enriched genes related neuronal cellular compartments processes, B-cell receptor signalling. Whole-blood levels 1708 correlated CpG sites classified more accurately (machine model 2, AUC 0.91) than (model 1, 0.74) wMRS 3, 0.77). Of selected CpGs, 100 overlapped level. These overlapping were neuron projection dendrite extension, lending support our finding that rather immune implicated severity. Conclusion whole-blood structure function. assign diagnosis.

Language: Английский

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SOX10-Mediated Regulation of Enteric Glial Phenotype in vitro and its Relevance for Neuroinflammatory Disorders

Journal of Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 75(1)

Published: Feb. 21, 2025

Abstract The transcription factor SOX10 is a key regulator of myelinated glial cell phenotype and function, with known role in multiple sclerosis (MS). also expressed enteric cells (EGC) within the gut, yet its regulatory functions EGC remain poorly understood. This study aimed to identify target genes that influence may have implications for MS. An line was established doxycycline-inducible overexpression. Impact overexpression on assessed by genome-wide expression analysis results were validated via RT-qPCR western blot. Data compared ChIP-seq transcriptomic datasets from MS patients pan-glial potentially linked neuroinflammatory disorders. associated ectopic upregulation related myelin regulation differentiation, as evidenced increased PLP1 at mRNA protein levels. Comparison highlight genes, including , RNF130 NES APOD involved central peripheral manifestations pathology. Our findings support cell-specific through level SOX10-regulated relevant function. research advances understanding diversity provide information about targeting

Language: Английский

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Association of Functional Gene Variants in DYSF–ZNF638, MTSS1 and Ferroptosis-Related Genes with Multiple Sclerosis Severity and Target Gene Expression

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(11), P. 4986 - 4986

Published: May 22, 2025

Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative disease with yet-unresolved mechanisms of progression. To address MS severity and neurological deficits, we analyzed seven potentially functional genetic variants their haplotypes in 845 patients. Based on our previous results targeted RNAseq ferroptosis-related genes distinctive phenotypes, selected putative regulatory the top three DEGs (CDKN1A, MAP1B EGLN2) investigated association gene expression, plasma/serum parameters (EDSS, MSSS, gARMSS). The study included 604 patients relapsing–remitting (RR) 241 progressive (P) MS. CDKN1A rs3176326 rs3176336, EGLN2 rs111833532, rs62363242 rs1217817 previously reported DYSF-ZNF638 locus rs10191329, MTSS1 rs9643199 were genotyped using TaqMan®, HLA-DRB1*15:01 status was also determined. Significant rare allele PMS females, independent HLA-DRB1*1501, found. A allele-containing genotypes associated molecular components iron metabolism. significantly mRNA levels RRMS SPMS RAB4B-EGLN2 rs111833532 rs10191329 showed significant associations EDSS, MSSS gARMSS. We detected expression CDKN1A, part p53-p21 axis known to affect T cell activation/proliferation. RAB4B-EGLN2, an oxygen sensor critical regulator response hypoxia, variant along clinical severity. indicated, novel, sex-specific course remains be validated larger studies.

Language: Английский

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Relevance of Multiple Sclerosis Severity Genotype in Predicting Disease Course: A Real‐World Cohort

Annals of Neurology, Journal Year: 2023, Volume and Issue: 95(3), P. 459 - 470

Published: Nov. 17, 2023

Objective Currently, 233 genetic loci are known to be associated with susceptibility multiple sclerosis (MS). Two independent pivotal severity genome‐wide association studies recently found the first significant single‐nucleotide variant (SNV; rs10191329 A ) and several other suggestive overall disability outcomes. It is now important understand if these findings can influence individual patient management. Methods We assessed whether progression SNVs detailed clinical phenotypes in a well‐characterized prospective cohort of 1,455 MS patients. used logistic regression, survival analysis, propensity score matching predict relevant long‐term Results were unable detect any between range clinically outcomes (eg, time Expanded Disability Status Scale milestones, age‐related score, anatomical localization at onset or during subsequent relapses, annualized relapse rate). In addition, an extremes outcome case–control analysis using for genotype detected no disease . However, we able replicate two (rs7289446 G rs868824 C development fixed disability, albeit modest effect sizes, HLA‐DRB1*1501 age onset. Interpretation Identification considerable importance understanding pathophysiological processes severity. it unlikely that genotyping currently setting guide This study shows replication neurodegenerative disorders. ANN NEUROL 2024;95:459–470

Language: Английский

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Integrative single-cell analysis of neural stem/progenitor cells reveals epigenetically dysregulated interferon response in progressive multiple sclerosis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 9, 2024

SUMMARY Progressive multiple sclerosis (PMS) is characterized by a primary smouldering pathological disease process associated with superimposed inflammatory activity. Cellular and molecular processes sustaining the pathobiology of PMS remain to be identified. We previously discovered senescence signatures in neural stem/progenitor cells (NSCs) from people PMS. Applying direct reprogramming generate directly induced NSCs (iNSCs) somatic fibroblasts, we retain epigenetic information observe hypomethylation genes lipid metabolic IFN signalling only lines. Single-cell/nucleus transcriptomic profiling reveal an inflammatory, senescent-like, IFN-responsive radial glia (RG)-like cell subcluster mainly iNSCs that driven IFN-associated transcription factors. Lastly, identify population senescent, IFN-responsive, disease-associated RG-like (DARGs) brain share pseudotime trajectories vitro . describe existence non-neurogenic, dysfunctional DARG has potential fuel inflammation

Language: Английский

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Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(11), P. 1574 - 1590.e11

Published: Oct. 21, 2024

Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied senescent phenotype vitro. Senescence was strongly associated inflammatory signaling, hypermetabolism, senescence-associated secretory (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid cholesterol synthesis, which resulted accumulation lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme (CoA) reductase (HMGCR)-mediated lipogenic state found induce a SASP via cholesterol-dependent transcription factors. iNSC neurotoxicity mature neurons, treatment HMGCR inhibitor simvastatin altered SASP, promoting cytoprotective qualities reducing neurotoxicity. Our findings suggest disease-associated, cholesterol-related, hypermetabolic that leads neurotoxic signaling is rescuable pharmacologically.

Language: Английский

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Contribution of genomic variation to the severity of multiple sclerosis

Neurology neuropsychiatry Psychosomatics, Journal Year: 2025, Volume and Issue: 17(1), P. 78 - 84

Published: Feb. 17, 2025

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system polygenic nature, characterized by focal inflammation, demyelination and neurodegeneration. The clinical course MS great heterogeneity. consistency forms in families indicates involvement genomic variation development phenotype. Identifying genetic basis progression may not only explain nature observed heterogeneity but also contribute to new tools for appropriate prognosis personalized treatment disease. To describe MS, severity scores are used; they characterize degree (speed) progression. most important methods assessing based on Sclerosis Severity Score (MSSS) Age-Related (ARMSS) scales. This review summarizes data contribution polymorphic variants as assessed MSSS ARMSS These were obtained using "candidate gene" method genome-wide association studies.

Language: Английский

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