Humanized-Aquaporin-4-Expressing Rat Created by Gene-Editing Technology and Its Use to Clarify the Pathology of Neuromyelitis Optica Spectrum Disorder.

Conventional rodent neuromyelitis optica spectrum disorder (NMOSD) models using patient-derived immunoglobulin G (IgG) are potentially affected by the differences between the human and rodent aquaporin-4 (AQP4) extracellular domains (ECDs). We hypothesized that the humanization of AQP4 ECDs would make the rodent model lesions closer to human NMOSD pathology. Humanized-AQP4-expressing (hAQP4) rats were generated using genome-editing technology, and the human AQP4-specific monoclonal antibody (mAb) or six patient-derived IgGs were introduced intraperitoneally into hAQP4 rats and wild-type Lewis (WT) rats after immunization with myelin basic protein and complete Freund's adjuvant. Human AQP4-specific mAb induced astrocyte loss lesions specifically in hAQP4 rats. The patient-derived IgGs also induced NMOSD-like tissue-destructive lesions with AQP4 loss, demyelination, axonal swelling, complement deposition, and marked neutrophil and macrophage/microglia infiltration in hAQP4 rats; however, the difference in AQP4 loss lesion size and infiltrating cells was not significant between hAQP4 and WT rats. The patient-derived IgGs bound to both human and rat AQP4 M23, suggesting their binding to the shared region of human and rat AQP4 ECDs. Anti-AQP4 titers positively correlated with AQP4 loss lesion size and neutrophil and macrophage/microglia infiltration. Considering that patient-derived IgGs vary in binding sites and affinities and some of them may not bind to rodent AQP4, our hAQP4 rat is expected to reproduce NMOSD-like pathology more accurately than WT rats.

HLA-transgenic mouse models to study autoimmune central nervous system diseases.

It is known that certain human leukocyte antigen (HLA) genes are associated with autoimmune central nervous system (CNS) diseases, such as multiple sclerosis (MS), but their exact role in disease susceptibility and etiopathogenesis remains unclear. The best studied HLA-associated autoimmune CNS disease is MS, and thus will be the primary focus of this review. Other HLA-associated autoimmune CNS diseases, such as autoimmune encephalitis and neuromyelitis optica will be discussed. The lack of animal models to accurately capture the complex human autoimmune response remains a major challenge. HLA transgenic (tg) mice provide researchers with powerful tools to investigate the underlying mechanisms promoting susceptibility and progression of HLA-associated autoimmune CNS diseases, as well as for elucidating the myelin epitopes potentially targeted by T cells in autoimmune disease patients. We will discuss the potential role(s) of autoimmune disease-associated HLA alleles in autoimmune CNS diseases and highlight information provided by studies using HLA tg mice to investigate the underlying pathological mechanisms and opportunities to use these models for development of novel therapies.

The levels of circulating cytokines and risk of neuromyelitis optica spectrum disorder: a Mendelian randomization study.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease affecting the central nervous system (CNS). NMOSD pathogenesis involves systemic inflammation. However, a causal relationship between circulating cytokine levels and NMOSD remains unclear. Methods: Mendelian randomization (MR) approaches were used to investigate the potential association between genetically determined circulating 19 inflammatory cytokines and 12 chemokines levels and the risk of developing NMOSD. Results: After Bonferroni correction, the risk of aquaporin 4-antibody (AQP4-ab)-positive NMOSD was suggested to be causally associated with the circulating levels of three cytokines, including interleukin (IL)-4 [odds ratio (OR): 11.01, 95% confidence interval (CI): 1.16-104.56, P = 0.037], IL-24 (OR: 161.37; 95% CI: 2.46-10569.21, P = 0.017), and C-C motif chemokine 19 (CCL19) (OR: 6.87, 95% CI: 1.78-26.93, P = 0.006). Conclusion: These findings suggest that a genetic predisposition to higher levels of IL-4, IL-24, and CCL19 may exert a causal effect on the risk of AQP4-ab-positive NMOSD. Further studies are warranted to clarify how these cytokines affect the development of AQP4-ab-positive NMOSD.

A protective effect of lower MHC-II expression in MOGAD.

Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is a demyelinating central nervous system disorder. We aimed to uncover immune pathways altered in MOGAD to predict disease progression. Using nanostring nCounter technology, we analyzed immune gene expression in PBMCs from MOGAD patients and compare it with healthy controls (HCs). We found 35 genes that distinguished MOGAD patients and HCs. We then validated those results in a larger cohort including MS and NMOSD patients. Expressions of HLA-DRA was significantly lower in MOGAD patients. This reduction in HLA-DRA, correlated with a monophasic disease course and greater brain volume, enhancing our ability to predict MOGAD progression.

FCGR3A-V158F gene polymorphism: A potential predictor for rituximab dosing optimization in Chinese patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown promise in managing neuromyelitis optica spectrum disorders (NMOSD) by depleting B cells and reducing relapses. However, there is no consensus on the optimal RTX dosing regimen, and genetic factors, such as FCGR3A-V158F polymorphism, may influence treatment outcomes. This study investigates how FCGR3A-V158F genotypes influence RTX efficacy in Chinese NMOSD patients under varying dosing regimens and aims to optimize treatment protocols. METHODS: We conducted a retrospective analysis of 25 Chinese NMOSD patients treated with RTX, grouped into standardized and low-dosage regimens. FCGR3A-V158F genotypes were determined, and treatment responses were evaluated, including relapse rates, time to first relapse (TFR), B-cell depletion, dose adjustments, and treatment retention. RESULTS: Among all patients, 15 received standardized dosages, while 10 received varied induction doses (500 mg to 1200 mg) in low-dose regimens. For FCGR3A-V158F genotypes, 15 had the FF genotype, and 10 were V carriers (3 VV genotype, 7 VF genotype). Regardless of dosing, FF genotype patients had a higher relapse rate post-RTX treatment compared to V carriers (P < 0.05). None of the 3 VV genotype patients in either dose group experienced relapses post-RTX. In both dose groups, FF genotype patients had significantly shorter TFR and required more RTX dose adjustments post-RTX treatment compared to V carriers in the standardized dosage group (P < 0.05). FF genotype patients in the low dosage group were more likely to experience insufficient B-cell depletion, had lower treatment retention rates, and more discontinuations than V carriers in the standardized dosage group (P < 0.05). Insufficient B-cell depletion significantly predicted clinical relapses after RTX treatment (P < 0.05). In survival analysis, FF genotype patients, regardless of dosing, experienced earlier relapses post-RTX treatment (P < 0.05). CONCLUSIONS: This study highlights the importance of RTX dosage selection in NMOSD treatment, particularly for FCGR3A-FF genotype patients. Standard-dose RTX therapy with vigilant monitoring of peripheral blood B-cell levels is recommended for these individuals to optimize treatment efficacy.

Sex hormones and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study.

BACKGROUND: Females are considered to have an increased susceptibility to neuromyelitis optica spectrum disorder (NMOSD) than males, especially aquaporin-4 (AQP4) antibody positive NMOSD, indicating that sex hormones may be involved in the NMOSD pathogenesis. However, the causality between sex hormones and NMOSD still remains unclear. METHODS: Based on the genome-wide association study (GWAS) data of three sex hormones (estradiol (E2), progesterone (PROG) and bioavailable testosterone (BAT)), sex hormone-binding globulin (SHBG), age of menarche, age of menopause, and NMOSD (total, AQP4 + and AQP4 -), we performed a two-sample bidirectional Mendelian randomization (MR) study. Sex-stratified GWAS data of E2, PROG, BAT, and SHBG was obtained for gender-specific MR analysis. Causal inferences were based on the inverse variance weighted method, MR-Egger regression, and weighted median method. The reverse MR analysis was also performed to assess the impact of NMOSD on hormone levels. RESULTS: PROG in females had aggravative effects on NMOSD (P < 0.001), especially AQP4 - NMOSD (P < 0.001). In the reverse MR analysis, total NMOSD was found to decrease the level of BAT (P < 0.001) and increase the level of SHBG (P = 0.001) in females. CONCLUSION: Findings of this MR analysis revealed mutual causal associations between sex hormones and NMOSD, which provided novel perspectives about the gender-related pathogenesis of NMOSD.

Machine Learning Analysis Using RNA Sequencing to Distinguish Neuromyelitis Optica from Multiple Sclerosis and Identify Therapeutic Candidates.

This study aims to identify RNA biomarkers distinguishing neuromyelitis optica (NMO) from relapsing-remitting multiple sclerosis (RRMS) and explore potential therapeutic applications leveraging machine learning (ML). An ensemble approach was developed using differential gene expression analysis and competitive ML methods, interrogating total RNA-sequencing data sets from peripheral whole blood of treatment-naïve patients with RRMS and NMO and healthy individuals. Pathway analysis of candidate biomarkers informed the biological context of disease, transcription factor activity, and small-molecule therapeutic potential. ML models differentiated between patients with NMO and RRMS, with the performance of certain models exceeding 90% accuracy. RNA biomarkers driving model performance were associated with ribosomal dysfunction and viral infection. Regulatory networks of kinases and transcription factors identified biological associations and identified potential therapeutic targets. Small-molecule candidates capable of reversing perturbed gene expression were uncovered. Mitoxantrone and vorinostat-two identified small molecules with previously reported use in patients with NMO and experimental autoimmune encephalomyelitis-reinforced discovered expression signatures and highlighted the potential to identify new therapeutic candidates. Putative RNA biomarkers were identified that accurately distinguish NMO from RRMS and healthy individuals. The application of multivariate approaches in analysis of RNA-sequencing data further enhances the discovery of unique RNA biomarkers, accelerating the development of new methods for disease detection, monitoring, and therapeutics. Integrating biological understanding further enhances detection of disease-specific signatures and possible therapeutic targets.

Interferon Regulatory Factor 5 Gene Polymorphisms and mRNA Expression Levels Are Associated with Neuromyelitis Optica Spectrum Disorder.

Interferon regulatory factor 5 (IRF5) is a critical transcription factor in the toll-like receptor signaling pathway. It is associated with autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. However, the relationship between the functional single nucleotide polymorphisms (SNPs) of IRF5 and its mRNA expression level in patients with neuromyelitis optica spectrum disorder remains unclear. The present study aimed to investigate the relationship between polymorphisms and mRNA expression levels of the IRF5 gene with the incidence of neuromyelitis optica spectrum disorder (NMOSD) in northern Chinese Han people. Two loci of the IRF5 gene (rs2004640 and rs2280714) of 164 patients with NMOSD and 269 healthy subjects were genotyped using the multiple SNaPshot technique. The frequencies of alleles, genotypes, and haplotypes were compared. Stratified analysis was performed according to age, sex, AQP4 status, onset age, and Expanded Disability Status Scale (EDSS) score. The IRF5 mRNA levels in peripheral blood mononuclear cells (PBMCs) of 64 NMOSD patients (32 patients in the acute stage and 32 patients in the remission stage) and 35 healthy subjects were detected by real-time PCR. The association of SNP polymorphisms with the mRNA expression level was determined by nonparametric tests. Allele and genotype frequency distributions of rs2004640 showed significant differences between both groups. Compared to healthy controls, the frequency of rs2004640 T allele markedly increased in patients (OR = 1.51, 95% CI = 1.09-2.08, P = 0.005). Minor allele T and GT genotype of rs2004640 that significantly increases the risk of NMOSD were discovered using genetic inheritance models (codominant, dominant, and overdominant) and haplotype analyses. Subsequent haplotype analyses revealed that the major haplotype "T-A" containing the risk alleles (the SNP sequence of the alleles was rs2004640 and rs2280714) had adverse effects on NMOSD. Based on the stratification analysis according to the EDSS score, the GT genotype frequency in the EDSS ≥ 4 group (38.2%) was markedly lower than that in the EDSS < 4 group (61.8%) (OR = 0.32, 95% CI = 0.15-0.68, P = 0.0054), with a significant difference. The IRF5 mRNA expression level was increased in NMOSD patients compared to that in normal subjects. IRF5 gene polymorphisms may be tightly associated with the genesis and progression of NMOSD in northern Chinese Han people. IRF5 mRNA expression was increased in patients with NMOSD and significantly increased in patients with acute phase. Perhaps IRF5 expression levels can be used as a predictor of disease activity in the future.

Single-cell RNA sequencing reveals cell type-specific immune regulation associated with human neuromyelitis optica spectrum disorder.

Introduction: One rare type of autoimmune disease is called neuromyelitis optica spectrum disorder (NMOSD) and the peripheral immune characteristics of NMOSD remain unclear. Methods: Here, single-cell RNA sequencing (scRNA-seq) is used to characterize peripheral blood mononuclear cells from individuals with NMOSD. Results: The differentiation and activation of lymphocytes, expansion of myeloid cells, and an excessive inflammatory response in innate immunity are observed. Flow cytometry analyses confirm a significant increase in the percentage of plasma cells among B cells in NMOSD. NMOSD patients exhibit an elevated percentage of CD8+ T cells within the T cell population. Oligoclonal expansions of B cell receptors are observed after therapy. Additionally, individuals with NMOSD exhibit elevated expression of CXCL8, IL7, IL18, TNFSF13, IFNG, and NLRP3. Discussion: Peripheral immune response high-dimensional single-cell profiling identifies immune cell subsets specific to a certain disease and identifies possible new targets for NMOSD.

Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders.

Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.

Causal relationships between susceptibility and severity of COVID-19 and neuromyelitis optica spectrum disorder (NMOSD) in European population: a bidirectional Mendelian randomized study.

Background: Neurological disorders can be caused by viral infections. The association between viral infections and neuromyelitis optica spectrum disorder (NMOSD) has been well-documented for a long time, and this connection has recently come to attention with the occurrence of SARS-CoV-2 infection. However, the precise nature of the causal connection between NMOSD and COVID-19 infection remains uncertain. Methods: To investigate the causal relationship between COVID-19 and NMOSD, we utilized a two-sample Mendelian randomization (MR) approach. This analysis was based on the most extensive and recent genome-wide association study (GWAS) that included SARS-CoV-2 infection data (122616 cases and 2475240 controls), hospitalized COVID-19 data (32519 cases and 2062805 controls), and data on severe respiratory confirmed COVID-19 cases (13769 cases and 1072442 controls). Additionally, we incorporated a GWAS meta-analysis comprising 132 cases of AQP4-IgG-seropositive NMOSD (NMO-IgG+), 83 cases of AQP4-IgG-seronegative NMOSD (NMO-IgG-), and 1244 controls. Results: The findings of our study indicate that the risk of developing NMO-IgG+ is elevated when there is a genetic predisposition to SARS-CoV-2 infection (OR = 5.512, 95% CI = 1.403-21.657, P = 0.014). Furthermore, patients with genetically predicted NMOSD did not exhibit any heightened susceptibility to SARS-CoV2 infection, COVID-19 hospitalization, or severity. Conclusion: our study using Mendelian randomization (MR) revealed, for the first time, that the presence of genetically predicted SARS-CoV2 infection was identified as a contributing factor for NMO-IgG+ relapses.

Significant up-regulation of lncRNAs in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an immune-related demyelinating defect. Long non-coding RNAs (lncRNAs) might influence the pathobiology and progression of NMOSD. The current study assessed expression level of NEAT1, PANDAR, MEG3 and TUG1 lncRNAs in the peripheral blood of NMOSD patients compared with healthy individuals. All mentioned lncRNAs were shown to be over-expressed in total NMOSD cases, male NMOSD cases and female NMOSD cases compared with the matching control subgroups. MEG3 had the most robust over-expression in patients subgroups compared with normal subjects. There was no noteworthy difference in the expression of any of lncRNAs between female and male patients. MEG3 had an ideal performance in the differentiation of NMOSD cases from healthy persons (Sensitivity and specificity values = 100%). Other lncRNAs could also efficiently separate NMOSD cases from control subjects (AUC values = 0.97, 0.89 and 0.88 for PANDAR, NEAT1 and TUG1, respectively). Cumulatively, NEAT1, PANDAR, MEG3 and TUG1 lncRNAs can be considered as appropriate disease markers for NMOSD.

Methyl-CpG-Binding Protein 2 Emerges as a Central Player in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders.

MECP2 and its product methyl-CpG binding protein 2 (MeCP2) are associated with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), which are inflammatory, autoimmune, and demyelinating disorders of the central nervous system (CNS). However, the mechanisms and pathways regulated by MeCP2 in immune activation in favor of MS and NMOSD are not fully understood. We summarize findings that use the binding properties of MeCP2 to identify its targets, particularly the genes recognized by MeCP2 and associated with several neurological disorders. MeCP2 regulates gene expression in neurons, immune cells and during development by modulating various mechanisms and pathways. Dysregulation of the MeCP2 signaling pathway has been associated with several disorders, including neurological and autoimmune diseases. A thorough understanding of the molecular mechanisms underlying MeCP2 function can provide new therapeutic strategies for these conditions. The nervous system is the primary system affected in MeCP2-associated disorders, and other systems may also contribute to MeCP2 action through its target genes. MeCP2 signaling pathways provide promise as potential therapeutic targets in progressive MS and NMOSD. MeCP2 not only increases susceptibility and induces anti-inflammatory responses in immune sites but also leads to a chronic increase in pro-inflammatory cytokines gene expression (IFN-γ, TNF-α, and IL-1ß) and downregulates the genes involved in immune regulation (IL-10, FoxP3, and CX3CR1). MeCP2 may modulate similar mechanisms in different pathologies and suggest that treatments for MS and NMOSD disorders may be effective in treating related disorders. MeCP2 regulates gene expression in MS and NMOSD. However, dysregulation of the MeCP2 signaling pathway is implicated in these disorders. MeCP2 plays a role as a therapeutic target for MS and NMOSD and provides pathways and mechanisms that are modulated by MeCP2 in the regulation of gene expression.

Inebilizumab reduces neuromyelitis optica spectrum disorder risk independent of FCGR3A polymorphism.

Inebilizumab, a humanized, glycoengineered, IgG1 monoclonal antibody that depletes CD19+ B-cells, is approved to treat aquaporin 4 (AQP4) IgG-seropositive neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab is afucosylated and engineered for enhanced affinity to Fc receptor III-A (FCGR3A) receptors on natural killer cells to maximize antibody-dependent cellular cytotoxicity. Previously, the F allele polymorphism at amino acid 158 of the FCGR3A gene (F158) was shown to decrease IgG-binding affinity and reduce rituximab (anti-CD20) efficacy for NMOSD attack prevention. In contrast, our current findings from inebilizumab-treated NMOSD patients indicate similar clinical outcomes between those with F158 and V158 allele genotypes.

Causal associations between prodromal infection and neuromyelitis optica spectrum disorder: A Mendelian randomization study.

BACKGROUND AND PURPOSE: Prodromal infections are associated with neuromyelitis optica spectrum disorder (NMOSD), but it remains unclear which type of infection has a causal association with NMOSD. We aimed to explore the causal associations between four herpesvirus infections (chickenpox, cold sores, mononucleosis and shingles) and NMOSD, as well as between other types of infections and NMOSD. METHODS: For data on infections, we used the genome-wide association study (GWAS) summary statistics from the 23andMe cohort. For outcomes, we used the GWAS data of participants of European ancestry, including 215 NMOSD patients (132 anti-aquaporin-4 antibody [AQP4-ab]-positive patients and 83 AQP4-ab-negative patients) and 1244 normal controls. Single-nucleotide polymorphism (SNP) identification and two-sample Mendelian randomization (MR) analyses were then performed. RESULTS: In the 23andMe cohort, we identified one SNP for chickenpox (rs9266089 in HLA-B gene), one SNP for cold scores (rs885950 in the POU5F1 gene), one SNP for mononucleosis (rs2596465 in the HCP5 gene), and three SNPs for shingles (rs2523591 in the HLA-B gene; rs7047299 in the IFNA21 gene; rs9260809 in the MICD gene). The association between cold sores and AQP4-ab-positive NMOSD reached statistical significance (odds ratio [OR] 745.318; 95% confidence interval [CI] 22.176, 25,049.53 [p < 0.001, Q < 0.001]). The association between shingles and AQP4-ab-positive NMOSD was also statistically significant (OR 21.073; 95% CI 4.271, 103.974 [p < 0.001, Q < 0.001]). No significant association was observed between other infections and AQP4-ab-positive or AQP4-ab-negative NMOSD. CONCLUSION: These findings suggest there are positive associations between cold sores and shingles and AQP4-ab-positive NMOSD, indicating there may be causal links between herpes simplex virus and varicella-zoster virus infection and AQP4-ab-positive NMOSD.

COVID-19 and the risk of neuromyelitis optica spectrum disorder: a Mendelian randomization study.

Background: An increasing number of studies have elucidated a close nexus between COVID-19 phenotypes and neuromyelitis optica spectrum disorder (NMOSD), yet the causality between them remains enigmatic. Methods: In this study, we conducted a Mendelian randomization (MR) analysis employing summary data sourced from genome-wide association studies (GWAS) pertaining to COVID-19 susceptibility, hospitalization, severity, and NMOSD. The primary MR analysis employed the Inverse variance weighted (IVW) approach, which was supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. We implemented various sensitivity analyses including Cochran's Q test, MR-PRESSO method, MR-Egger intercept, leave-one-out analysis, and funnel plot. Results: The MR results demonstrated a nominal association between COVID-19 susceptibility and the risk of AQP4+ NMOSD, as evidenced by the IVW method (OR = 4.958; 95% CI: 1.322-18.585; P = 0.018). Conversely, no causal association was observed between COVID-19 susceptibility, hospitalization, or severity and the increased risk of NMOSD, AQP4-NMOSD, or AQP4+ NMOSD. The comprehensive sensitivity analyses further bolstered the robustness and consistency of the MR estimates. Conclusion: Our findings provide compelling evidence for a causal effect of COVID-19 phenotype on AQP4+ NMOSD, shedding new light on the understanding of the comorbidity between COVID-19 and NMOSD.

Genetic Basis of Inflammatory Demyelinating Diseases of the Central Nervous System: Multiple Sclerosis and Neuromyelitis Optica Spectrum.

Demyelinating diseases alter myelin or the coating surrounding most nerve fibers in the central and peripheral nervous systems. The grouping of human central nervous system demyelinating disorders today includes multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) as distinct disease categories. Each disease is caused by a complex combination of genetic and environmental variables, many involving an autoimmune response. Even though these conditions are fundamentally similar, research into genetic factors, their unique clinical manifestations, and lesion pathology has helped with differential diagnosis and disease pathogenesis knowledge. This review aims to synthesize the genetic approaches that explain the differential susceptibility between these diseases, explore the overlapping clinical features, and pathological findings, discuss existing and emerging hypotheses on the etiology of demyelination, and assess recent pathogenicity studies and their implications for human demyelination. This review presents critical information from previous studies on the disease, which asks several questions to understand the gaps in research in this field.

Oily fish and raw vegetable consumption can decrease the risk of AQP4-positive neuromyelitis optica spectrum disorders: a Mendelian-randomization study.

Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory disorders of the central nervous system targeting aquaporin-4 (AQP4). The risk factors for NMOSD remain to be determined, though they may be related to diet and nutrition. This study aimed to explore the possibility of a causal relationship between specific food intake and AQP4-positive NMOSD risk. The study followed a two-sample Mendelian randomization (MR) design. Genetic instruments and self-reported information on the intake of 29 types of food were obtained from a genome-wide association study (GWAS) on 445,779 UK Biobank participants. A total of 132 individuals with AQP4-positive NMOSD and 784 controls from this GWAS were included in our study. The associations were evaluated using inverse-variance-weighted meta-analysis, weighted-median analysis, and MR-Egger regression. A high consumption of oily fish and raw vegetables was associated with a decreased risk of AQP4-positive NMOSD (odds ratio [OR] = 1.78 × 10-16, 95% confidence interval [CI] = 2.60 × 10-25-1.22 × 10-7, p = 0.001; OR = 5.28 × 10-6, 95% CI = 4.67 × 10-11-0.598, p = 0.041, respectively). The results were consistent in the sensitivity analyses, and no evidence of directional pleiotropy was observed. Our study provides useful implications for the development of AQP4-positive NMOSD prevention strategies. Further research is needed to determine the exact causal relationship and mechanisms underlying the association between specific food intake and AQP4-positive NMOSD.

Cerebellar connectome alterations and associated genetic signatures in multiple sclerosis and neuromyelitis optica spectrum disorder.

BACKGROUND: The cerebellum plays key roles in the pathology of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), but the way in which these conditions affect how the cerebellum communicates with the rest of the brain (its connectome) and associated genetic correlates remains largely unknown. METHODS: Combining multimodal MRI data from 208 MS patients, 200 NMOSD patients and 228 healthy controls and brain-wide transcriptional data, this study characterized convergent and divergent alterations in within-cerebellar and cerebello-cerebral morphological and functional connectivity in MS and NMOSD, and further explored the association between the connectivity alterations and gene expression profiles. RESULTS: Despite numerous common alterations in the two conditions, diagnosis-specific increases in cerebellar morphological connectivity were found in MS within the cerebellar secondary motor module, and in NMOSD between cerebellar primary motor module and cerebral motor- and sensory-related areas. Both diseases also exhibited decreased functional connectivity between cerebellar motor modules and cerebral association cortices with MS-specific decreases within cerebellar secondary motor module and NMOSD-specific decreases between cerebellar motor modules and cerebral limbic and default-mode regions. Transcriptional data explained > 37.5% variance of the cerebellar functional alterations in MS with the most correlated genes enriched in signaling and ion transport-related processes and preferentially located in excitatory and inhibitory neurons. For NMOSD, similar results were found but with the most correlated genes also preferentially located in astrocytes and microglia. Finally, we showed that cerebellar connectivity can help distinguish the three groups from each other with morphological connectivity as predominant features for differentiating the patients from controls while functional connectivity for discriminating the two diseases. CONCLUSIONS: We demonstrate convergent and divergent cerebellar connectome alterations and associated transcriptomic signatures between MS and NMOSD, providing insight into shared and unique neurobiological mechanisms underlying these two diseases.