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.
Abstract
Background: Diagnostic evaluation of suspected neuromyelitis optica spectrum disorder (NMOSD) integrates AQP4-IgG testing, clinical assessment, neuroimaging, and exclusion of alternative inflammatory demyelinating disorders; nevertheless, some patients remain diagnostically unresolved or may be misclassified as multiple sclerosis (MS) or other disorders. Methods: This single-center retrospective exploratory study analyzed quantitative serum proteomics from 20 patients with MS and 20 with NMOSD. Proteins meeting nominal p < 0.05 together with prespecified fold-change criteria were considered exploratory candidates. VWF, PPBP, and SERPINA3 were subsequently assessed by ELISA in a separate, non-overlapping cohort from the same center, together with routine hematological variables. Results: Among 261 protein entries, 34 met the exploratory nominal threshold and fold-change criteria, but none remained significant after Benjamini–Hochberg correction (lowest q = 0.0734). VWF and PPBP showed no significant differences across the four validation groups. SERPINA3 differed across groups (Kruskal–Wallis H = 44.982, p = 9.34 × 10−10) and was higher in NMOSD than in MS, TBI, and HCs after Holm adjustment (adjusted p = 0.036, 1.49 × 10−9, and 1.13 × 10−5, respectively). In the full ELISA cohort, the AUC was 0.928 for NMOSD versus HC and 0.800 for NMOSD versus MS. In a post hoc sensitivity analysis excluding participants with preceding infection, the NMOSD–MS separation was attenuated. In smaller complete-case analyses, adding an additional laboratory variable to SERPINA3 did not significantly improve apparent discrimination. Conclusions: 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.
BACKGROUND
Neuromyelitis optica spectrum disorder (NMOSD) often coexists with systemic autoimmune disease, but the clinical meaning of this overlap remains incompletely defined, particularly in Latin American populations.
OBJECTIVE
To describe the prevalence, autoimmune spectrum, and clinical and serological features of systemic autoimmune overlap in a Mexican cohort of aquaporin 4 immunoglobulin G (AQP4-IgG)-positive NMOSD.
METHODS
We conducted a retrospective single center cohort study of patients who fulfilled the 2015 international diagnostic criteria for NMOSD and were followed between 2002 and 2023. The analytic cohort was restricted to AQP4-IgG-positive patients. Demographic, clinical, treatment, and systemic autoantibody data were collected from medical records. Analyses were primarily descriptive and comparative. Time to second relapse was assessed as an exploratory secondary outcome.
RESULTS
Among 86 AQP4-IgG-positive patients, 16 (18.6%) had a coexisting systemic autoimmune disease. Sjögren syndrome (37.5%) and systemic lupus erythematosus (12.5%) were the most frequent diagnoses. Patients with autoimmune overlap showed a broader burden of systemic autoantibody positivity, with antinuclear antibodies, anti-SSA, anti-SSB, and anti-dsDNA being the most commonly detected markers. Optic neuritis was the most common presenting event in the overlap group (68.8%), though disability measures at baseline and follow-up were otherwise similar between groups. Treatment regimens did not differ significantly between patients with and without systemic autoimmune disease. In exploratory analysis, an association between anti-SSB positivity and a shorter time to second relapse was observed (hazard ratio 2.30, 95% CI 1.05-5.10 in univariable analysis; hazard ratio 2.34, 95% CI 1.05-5.21 in multivariable analysis). However, this hypothesis-generating finding was based on a limited number of events and wide confidence intervals and should be interpreted with caution.
CONCLUSION
In this Mexican cohort of AQP4-IgG-positive NMOSD, systemic autoimmune overlap was present in approximately one in five patients. The overlap group showed more frequent systemic autoantibody positivity and a predominance of optic neuritis at onset, but disability measures, treatment patterns, and most clinical outcomes were similar between groups. The relapse-related findings, including the observed association with anti-SSB positivity, should be considered exploratory and interpreted strictly as hypothesis-generating. Confirmation in larger prospective multicenter studies with standardized antibody testing is required before any prognostic implications can be inferred.
Yazmin Martinez-Lopez, Alexis García-Sarreón, E. Tetlalmatzi-Azuara et al.· Multiple Sclerosis and Relat...· 0 citations
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.
Li Deng, Shiguang Ling, Linze Li et al.· Medicine· 0 citations
Background and Objectives CSF proteomics has emerged as a valuable strategy for identifying diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis (ALS). However, the limited availability and volumes of CSF samples restrict the broader clinical application of CSF-based biomarker panels. To address this challenge, we investigated whether the novel nucleic acid-linked immuno-sandwich assay (NULISA) multiplex platform—capable of quantifying multiple neural, glial, and inflammatory markers from minimal biofluid volumes—could validate previously proposed biomarkers and identify additional candidates relevant to ALS. Methods Using this platform, we measured a targeted panel of 131 biomarkers in cohorts of patients with C9orf72-associated ALS, sporadic ALS (sALS), and matched healthy controls. Results The 6 markers neurofilament heavy chain (NEFH) and neurofilament light chain (NEFL), chitinases—particularly chitotriosidase-1 (CHIT1) and chitinase-3-like protein-1 (CHI3L1), and chemokines CCL2 and CCL3 were significantly elevated in both ALS groups compared with controls. These biomarkers correlated with disease progression and demonstrated strong diagnostic performance when combined into aggregate scores, as reflected by a high area under the receiver operating characteristic curve for ALS. Notably, C9orf72-ALS patients exhibited higher levels of the oxidative stress-related markers PRDX6 and ENO2, compared with sALS patients, suggesting a genotype-specific molecular signature. Discussion Overall, our findings support the use of a multiplexed panel of diverse, inflammatory, glial, and neurodegeneration-associated biomarkers as a complementary diagnostic and prognostic tool alongside established measurements of neurofilaments. This approach may enhance biomarker robustness while minimizing CSF volume requirements, thereby improving clinical feasibility in ALS research and care.
Karthik Baskar, Christina Steffke, S. Bernsen et al.· Neurology(R) neuroimmunology...· 0 citations
Objective The study aimed to investigate risk factors for disease severity in acute aquaporin-4 (AQP4) -IgG-seropositive neuromyelitis optica spectrum disorders (NMOSD) patients. Methods This prospective cohort study enrolled 103 serum Aquaporin-4 Immunoglobulin G (AQP4-IgG)-positive NMOSD patients from the Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, between April 2022 and June 2025. Among them, 60 cases were in the acute phase and 43 in the remission phase. Additionally, 25 age-and sex-matched healthy controls (HCs) were included. Clinical characteristics of all participants were evaluated, and blood samples were collected for laboratory testing. The Expanded Disability Status Scale (EDSS) score was used to assess the severity of the disease. Receiver operating characteristic (ROC) curve analysis was performed using EDSS ≥ 4 as the definition of severe disability. Results Our cohort study revealed significant differences (P < 0.05) in white blood cell (WBC) count, neutrophil (NEUT) count, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), systemic immune inflammation index (SII), systemic inflammation response index (SIRI), and serum complement levels among patients in the acute phase, those in the remission phase, and HCs. Multivariate regression analysis demonstrated that age (p = 0.01; OR = 0.06; 95% CI = 0.02–0.11), NLR (p = 0.018; OR = 0.24; 95% CI = 0.05–0.44), and complement 3 (C3) (p < 0.001; OR = 7.24; 95% CI = 3.77–10.72) were independent and significant risk factors for predicting the severity of disability (as assessed by the EDSS score) during the acute phase. Further ROC curve analysis demonstrated that C3 had strong predictive performance (AUC = 0.84), with high sensitivity and specificity at the optimal cut-off value. NLR showed limited overall discrimination (AUC = 0.62) but high specificity, suggesting a potential role as a rule-in marker. Age exhibited modest predictive value (AUC = 0.64), with an optimal cut-off of 45.5 years. Conclusion Older age at onset, a higher NLR, and elevated serum C3 levels may predict greater disability in AQP4-IgG-positive NMOSD patients during the acute phase. Early identification of these predictive indicators could help guide initial treatment decisions.
Yibo Zhan, Min Zhao, Jiahui Zhang et al.· Frontiers in Immunology· 0 citations
Background and Objectives Neuromyelitis optica spectrum disorder (NMOSD) is a severe condition usually associated with aquaporin-4 (AQP4) antibodies. A clinical presentation suggestive of NMOSD can also be associated with myelin oligodendrocyte glycoprotein (MOG) antibodies (MOGAD). NMOSD can be diagnosed in the absence of autoantibodies (double-negative NMOSD [DN-NMOSD]), but this subgroup has been poorly investigated. We conducted a systematic review and meta-analysis to define the clinical spectrum, prognosis, and treatment response in DN-NMOSD vs AQP4-NMOSD/MOGAD. Methods We searched on PubMed, Scopus, Embase, Google Scholar, Cochrane Library, and ClinicalTrials.gov databases of studies on patients fulfilling inclusion criteria. Patient characteristics, outcome measures, and treatment regimens were extracted. Results We included 41 of 1,027 articles screened and analyzed 671 patients with DN-NMOSD (median age 38.6 years [range IQR: 32.5–42.85]; female-to-male ratio 1.5:1; median follow-up 44.4 months [range 1–600]), 73.6% of which relapsed. In the meta-analysis, mean annualized relapse rate (ARR) was higher, albeit not significantly, in DN-NMOSD (1.08; 95% CI 0.73–1.43) vs AQP4-NMOSD (0.84; 95% CI 0.45–1.23) and MOGAD (0.61; 95% CI 0.39–0.83, p = 0.08). Administration of maintenance immunosuppression in DN-NMOSD led to a significant ARR reduction (pooled rate ratio 0.19, 95% CI 0.07–0.49; p = 0.001), with high heterogeneity (I2 = 90%, p < 0.0001). In meta-regression, no covariates were associated with ARR reduction, including the administration of specific drugs (rituximab, p = 0.288; azathioprine, p = 0.291; mycophenolate, p = 0.918). The pooled mean difference in pre‑ and post‑maintenance treatment Expanded Disability Status Scale values indicated a significant change in disability in MOGAD (−0.93, 95% CI −1.67 to −0.19, p = 0.02) but not in AQP4-NMOSD (−0.62, 95% CI −1.85 to 0.61, p = 0.27) or DN-NMOSD (−0.52 (95% CI −1.30 to 0.25, p = 0.16). Discussion DN-NMOSD is a heterogenous, severe and highly relapsing disease, where attacks lead to irreversible dysfunction. 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
Abstract Objectives Serum neurofilament light chain (sNfL) reflects neuroaxonal injury in relapsing-remitting multiple sclerosis (RRMS), but its clinical utility is limited by high interindividual variability and confounders such as renal function. Population-based thresholds may therefore be suboptimal for longitudinal monitoring. The reference change value (RCV), an intraindividual approach based on biological variation, remains insufficiently validated in real-world settings. Methods In this retrospective cohort study, 967 sNfL determinations from 295 RRMS patients were analyzed (LUMIPULSE G600II). Measurements were matched to clinical relapse and MRI activity within ±90 days. Associations with log-sNfL were assessed using linear mixed-effects models. RCV and population-based threshold (PBT) were compared as factors associated with inflammatory activity using cluster-robust logistic regression and ROC analysis. Correlation with new MRI lesion count was also evaluated. Results The intraclass correlation coefficient was 0.536. RCV elevation showed a highly significant association with active MRI (OR 4.93, 95 % CI 2.49–9.77) and clinical relapse (OR 6.48, 95 % CI 2.75–15.25), whereas PBT elevation did not reach statistical significance for either outcome (active MRI: OR 1.52, p=0.290; clinical relapse: OR 2.38, p=0.073). Clinical relapse and MRI activity were independently associated with mean sNfL increases of +72.1 % (95 % CI +53.7 %, +92.7 %) and +24.5 % (95 % CI +13.7 %, +36.3 %), respectively. Renal impairment was a major confounder, with sNfL elevations of +16.0 % in eGFR G2 and +67.8 % in G3–G5. Negative predictive values exceeded 91 % across all markers and outcomes. sNfL correlated with new MRI lesion count (Spearman ρ=0.498, p<0.0001), with a Youden-optimal threshold of ≥4 lesions. Conclusions sNfL measured on the LUMIPULSE platform is a valid real-world biomarker of inflammatory activity in RRMS. Its high interindividual variability makes RCV-based intraindividual interpretation substantially more informative than population-based thresholding for longitudinal monitoring. The consistently high negative predictive value supports its use as a rule-out tool for active neuroinflammation and provides a rational basis for risk-adapted MRI surveillance in clinically stable patients.
Silvia de las Heras Flórez, Gema García de la Rosa, V. Martín García et al.· Clinical Chemistry and Labor...· 0 citations
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