多発性硬化症／視神経脊髄炎

OBJECTIVE: Studies have not shown an association between multiple sclerosis (MS) disease duration and depression among people with MS. However, whether antidepressant use influences this possible relationship remains unknown. The authors evaluated whether antidepressant use moderates the association between disease duration and clinically significant depressive symptoms among individuals with MS. METHODS: A consecutive sample of 1,076 adults with MS received psychometric testing during clinical care at a tertiary neuropsychiatry clinic in Toronto from 2020 to 2025. Demographic and disease-related data were gathered via retrospective chart review. A logistic regression analysis adjusted for age, sex, education, Expanded Disability Status Scale (EDSS) scores, and Symbol Digit Modalities Test scores was undertaken to evaluate whether the interaction between antidepressant use and disease duration predicted clinically significant depression (Hospital Anxiety and Depression Scale depression subscale score ≥8). Stratified by antidepressant use, secondary regression analyses controlling for the same covariates were used to evaluate whether disease duration was independently associated with depression. Statistical significance was set at p<0.05. RESULTS: Mean participant age was 43.9±11.5 years, 76% were women, the mean length of education was 16.0±3.1 years, and the median EDSS score was 2.0 (interquartile range 1.5-3.5). Antidepressant use significantly moderated the relationship between disease duration and clinically significant depressive symptoms (p=0.017). In the absence of antidepressants, increased disease duration predicted elevated odds of depression (OR=1.02, p=0.038) but not in the presence of antidepressants (OR=0.98). CONCLUSIONS: Antidepressant use is associated with a lessened influence of prolonged disease duration on an increased odds of clinically significant depression among people with MS.

BACKGROUND: Organizing pneumonia (OP) is a rare interstitial lung disease that may occur secondary to drug exposure. Although OP has been described during rituximab treatment, the association with ocrelizumab remains elusive, with evidence limited to a few recent cases. We aimed to characterize ocrelizumab-related OP in the context of the existing literature. METHODS: Clinical, radiological, laboratory, therapeutic, and outcome data were retrospectively collected from multiple sclerosis (MS) patients with ocrelizumab-associated OP at our center and descriptively compared with 17 cases identified through a literature review. RESULTS: Among 626 ocrelizumab-treated MS patients, five cases of OP were observed (0.8%) (3 females, median age=54 years, range=27-64). OP developed after a mean treatment exposure of 5.1 years (standard deviation (SD=2.9) and a mean interval of 10.8 weeks (SD=10.4) following the last infusion. Clinical presentation was characterized by persistent antibiotic-refractory fever, sometimes accompanied by nonproductive cough. Chest CT consistently showed patchy ground-glass opacities and consolidations. All patients received prednisone 0.5-1 mg/kg/day for a median duration of 30 days (range=15-60), followed by gradual tapering. Despite initial clinical response, respiratory relapses and residual radiological lung abnormalities were observed in four patients during a median follow-up of 29 months (range=4-47). Ocrelizumab was discontinued in all patients. Only one patient initiated ozanimod two years after OP onset. DISCUSSION: Our findings support the emerging evidence of ocrelizumab-related OP and show substantial consistency with previously reported cases. Further studies are needed to clarify the potential role of CD20+ lymphocyte depletion in OP pathogenesis.

Despite decades of research, the cellular and molecular events preceding multiple sclerosis (MS) relapse remain incompletely understood. Here, in this observational study of longitudinal blood samples from patients with relapsing-remitting MS, we used single-cell RNA sequencing, bulk transcriptomics, multiparameter flow cytometry and targeted viral reverse transcription quantitative polymerase chain reaction (RT-qPCR) to construct a time-resolved atlas of immune perturbations surrounding relapse. A reproducible pre-relapse signature in monocytes and B cells, emerging up to 3 months before clinical onset, was enriched for host genes responsive to Epstein-Barr virus (EBV) lytic reactivation factors. RT-qPCR confirmed elevated EBV LMP-1 transcripts in pre-relapse B cells, and flow cytometry demonstrated expansion of CD11c+ atypical B cell populations displaying EBV surface protein gp350. Pre-relapse transcriptional modules overlapped with MS genome-wide association study (GWAS) risk loci and EBNA-2-bound enhancers, suggesting that inherited MS susceptibility and EBV-responsive programs operate through shared regulatory elements. How this peripheral activation relates to central nervous system lesion formation remains to be established. These findings nonetheless suggest that EBV reactivation, when occurring within a genetically predisposed peripheral immune environment, is a proximal precursor of MS relapse.

BACKGROUND: Neurodegenerative diseases may continue to progress even when a pathogenic protein aggregate is reduced, suggesting that downstream inflammatory and genotoxic circuits can become partly autonomous. This narrative review examines cGAS-STING as a context-dependent regulator of DNA-stress responses in the ageing and proteinopathic brain. METHODS: PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar were searched for mechanistic, translational, and human-tissue studies of cGAS-STING, DNA damage, mitochondrial quality control, neuroinflammation, and major neurodegenerative diseases. Evidence was separated into biochemical or cellular, animal, and human observations, and contradictory findings were retained. RESULTS: Mitochondrial DNA leakage is a recurrent candidate trigger, while activity-induced nuclear DNA breaks, defective repair, retrotransposon-derived cDNA, and micronuclear rupture provide conditional inputs. Microglial evidence is currently more extensive and causally developed than neuron-specific evidence; neuronal STING is most firmly supported in selected contexts such as excitotoxic or ischemic stress. Across Alzheimer disease, Parkinson disease, ALS/FTD, multiple sclerosis, and Huntington disease, cGAS-STING-associated inflammation is plausible but not uniform, and human validation remains limited. Therapeutic strategies therefore require cell-, source-, and stage-aware modulation rather than indiscriminate pathway ablation. CONCLUSION: cGAS-STING is best regarded as a testable kinetic-bottleneck model, not a universal driver of neurodegeneration. Longitudinal human studies and cell-resolved biomarkers are needed to determine when recalibration can suppress pathological inflammation while preserving antiviral and homeostatic functions.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder involving multiple systems, with motor neuron degeneration as its primary feature. This disease can be classified into sporadic and familial types. Genes such as SOD1, C9orf72, FUS, and TDP-43 have been identified as the main causative genes for familial ALS. Multiple bioinformatics tools combined with an experimental verification strategy have helped in understanding the association of a selective autophagy pathway called aggrephagy with the disease. RESULTS: The transcriptome data of spinal cord tissue from SOD1-G93A mice was obtained from the Gene Expression Omnibus (GEO) database. Based on the GSE281064 dataset, we investigated aggrephagy-related transcriptional alterations in the SOD1-G93A mouse model of ALS. After comparison with the aggrephagy-related genes (AGGRGs) set included in the GeneCards database, 49 candidate genes closely related to the autophagy process were obtained. Functional enrichment analysis showed these genes participate in extracellular matrix remodeling, hyaluronic acid and glycosaminoglycan metabolism, tumor necrosis factor regulation, and lysosomal function, indicating central roles in inflammation, apoptosis, and metabolic disorders. Based on feature selection algorithms, this study employed machine learning methods such as random forest (RF), extreme gradient boosting (XGBoost), and Boruta to conduct multi-angle screening of candidate genes. The intersection of the results ultimately identified three key genes: Ctsb, Kif11, and S100a6. CONCLUSIONS: In both the training data and external validation data, Ctsb and S100a6 showed significant upregulation and demonstrated excellent discriminatory capabilities. The nomogram constructed based on Ctsb and S100a6 expression showed potential for distinguishing SOD1-G93A model samples from nontransgenic controls. The predicted probability demonstrated the potential of these two as candidate biomarkers. Meanwhile, further validation is needed in larger independent population cohorts in the future. The SOD1-G93A mouse model and SOD1-G93A-expressing NSC34 cell model showed expression patterns of Ctsb and S100a6 consistent with the bioinformatics findings. Through S100a6 overexpression and knockdown experiments in an NSC34 motor neuron-like ALS model, we found that S100a6 impaired autophagy and promoted SOD1 aggregation. These findings further validate its potential as a biomarker and provide new insights into the pathogenesis of ALS.