Aug 2026· Medicine· Vol 105· 0 citations· 45 references
Medicine
TL;DR
The roles of several CSF metabolites in NMOSD are elucidated, with specific glycerophosphocholine species showing risk associations in AQP4-IgG positive and AQP4-IgG negative subtypes, while ascorbate and N-acetylhexosamines demonstrate protective effects across both subtypes, thereby providing valuable insights.
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is a rare multifocal inflammatory disease that primarily affects the optic nerve and spinal cord, leading to visual loss and paralysis. Although current research has identified numerous biomarker changes in the cerebrospinal fluid (CSF), the causal relationships between these changes and NMOSD are not yet fully understood, and they are susceptible to confounding factors. In this study, Mendelian randomization (MR) analyses were conducted to estimate the role of CSF metabolites in aquaporin-4 (AQP4)-IgG positive and AQP4-IgG negative NMOSD. We strictly adhered to the 3 principles of MR when selecting instrumental variables, effectively reducing the impact of confounding variables. Additionally, we conducted a comprehensive and meticulous sensitivity analysis to ensure the robustness of positive outcomes. We have elucidated the roles of several CSF metabolites in NMOSD, with specific glycerophosphocholine species showing risk associations in AQP4-IgG positive and AQP4-IgG negative subtypes, while ascorbate and N-acetylhexosamines demonstrate protective effects across both subtypes, thereby providing valuable insights. No evidence of heterogeneity or horizontal pleiotropy was observed in MR analyses. These metabolites hold the potential to inform pathogenesis and guide the development of therapeutic strategies for these conditions.
DN-NMOSD is a heterogenous, severe and highly relapsing disease, where attacks lead to irreversible dysfunction, and the administration of maintenance immunotherapy reduces the relapse risk and should be considered early to prevent further disability.
A. Malvaso, F. Bovis, Giacomo Greco et al.· Neurology(R) neuroimmunology...· 0 citations
SERPINA3 is therefore an exploratory adjunctive serum biomarker candidate rather than a stand-alone diagnostic test; prospective external validation in clinically representative cohorts is required.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating condition of the central nervous system that chiefly affects the optic nerves and spinal cord. Optical coherence tomography angiography (OCTA), a non-invasive imaging method for viewing the retinal microvasculature, offers potential biomarkers for early detection, monitoring disease activity, and distinguishing NMOSD from multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).
To determine the potential of OCTA-derived retinal biomarkers in NMOSD and determine their clinical impact in diagnosis, disease monitoring, and therapeutic assessment.
A narrative review of PubMed-indexed studies was conducted, including NMOSD patient’s diagnosed according to the 2015 international consensus criteria. Κey OCTA parameters—radial peripapillary capillary density, macular vessel density, perfusion density, and foveal avascular zone (FAΖ)—were analyzed across NMOSD subgroups with and without optic neuritis and compared to healthy controls.
NMOSD patients were found to have reduced vessel density in the superficial macular and radial peripapillary capillary plexuses regardless of their history of optic neuritis. These findings suggest possible subclinical retinal involvement. FAZ findings were inconsistent across studies, with reports of enlargement, reduction, or no significant difference. Reduced vessel density was also demonstrated to be correlated with poorer visual acuity, higher expanded disability status scale (EDSS) scores, and altered visual cortex connectivity.
OCTA provides complementary information on retinal microvascular integrity in NMOSD and may help identify subclinical retinal involvement, particularly in the eyes without previous optic neuritis. Vessel density parameters, especially in the superficial macular and radial peripapillary capillary networks, appear more consistent than FAZ measurements, which remain heterogeneous and exploratory. OCTA may also contribute to multimodal differentiation among NMOSD, MS, and MOGAD, but it should not be considered a stand-alone diagnostic or monitoring tool. Standardized longitudinal studies with antibody stratification and rigorous confounder control are needed before OCTA-derived biomarkers can be incorporated into routine NMOSD decision-making.
Efstratia Amaxilati, C. Bakirtzis, Angeliki Fountouki et al.· Frontiers in Medicine· 0 citations
Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease of the central nervous system (CNS), characterized by an autoantibody response against the water channel aquaporin-4 (AQP4) on astrocyte endfeet. The disease primarily affects the spinal cord and optic nerves, leading to paralysis and loss of sight. Onset is associated with a breakdown of immune tolerance to AQP4 and the appearance of anti-AQP4 IgG in serum. These antibodies, along with complement deposition, are consistently found in CNS lesions and contribute to astrocyte damage, demyelination, and neurological deficits. The clinical efficacy of plasma exchange and anti-C5 therapies supports the pathogenic role of antibodies and complement in NMOSD.
We examined the contribution of anti-AQP4 antibodies and complement in a robust AQP4201-220-induced animal model. Wild-type (WT) and secretory immunoglobulin-deficient (AID⁻/⁻μS⁻/⁻) mice were immunized with AQP4201-220 and treated with pertussis toxin on days −2 and 0. Suboptimal anti-IFN-γ was used to enhance disease; IFN-γ receptor knockout (IFNGRKO) mice were similarly immunized. On day 21, spinal cord and optic nerve were collected for histology, while flow cytometry and transcriptomics assessed immune activation.
WT + anti-IFN-γ mice showed robust IgG and C5/C5b-9 deposition with CNS upregulation of complement genes (contrasting downregulation in spleen). AID⁻/⁻μS⁻/⁻ mice failed to develop disease, confirming antibody dependence. C3⁻/⁻ mice showed reduced incidence, milder clinical scores, and decreased C5/C5b-9, indicating C3 is required for C5 activation. Anti-C5 treatment delayed onset, reduced severity, and modulated immune responses similarly to genetic C3 loss.
Our data establish anti-AQP4 antibodies and the C3-C5 (MAC) complement axis as central drivers of NMOSD pathology, reinforcing their value as biomarkers and therapeutic targets.
R01 AI155678
Neuroimmunology (NEUR)
G. Arellano, Mac Zelazny, J. Podojil et al.· Journal of Immunology· 0 citations
A review of current evidence on established and emerging fluid biomarkers in NMOSD and MOGAD, with emphasis on analytical performance, biological relevance, and clinical utility, and outlines priorities for future research.
S. Mariotto, Á. Cobo-Calvo, Michael Khalil et al.· Neurology(R) neuroimmunology...· 0 citations
The findings confirm the significant role of polymorphisms in the IL6, SIRT1 and MMP9 genes as potential genetic markers of an increased risk of developing MS and NMOSD in the studied population.
D. Kasatkin, A. Menshikh, O. D. Samoilova et al.· Neurology, neuropsychiatry,...· 0 citations
