Cerebrospinal 14-3-3 Protein Levels as a Neuroaxonal Biomarker in Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder

Abstract

Background and objectives: To investigate whether CSF 14-3-3 protein levels discriminate aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and multiple sclerosis (MS) and the association of CSF 14-3-3 protein levels with clinical features in patients with AQP4-NMOSD.

Methods: This was a multicentric retrospective cohort study of patients with AQP4-NMOSD, MOGAD, and MS, with available CSF samples. 14-3-3 protein levels were quantified using ELISA and compared between the 3 conditions. In patients with AQP4-NMOSD, the association between CSF 14-3-3 protein levels and disability outcomes was explored.

Results: A total of 134 patients were included (AQP4-NMOSD, n = 29; MOGAD, n = 43; MS, n = 62). Patients with AQP4-NMOSD had higher 14-3-3 protein levels (median [interquartile range] 4,441.37 [3,240.05-11526.41] arbitrary units (AU)/mL) compared with those with MS (3,169.86 [2,522.65-3,748.57], p = 0.001) and MOGAD (3,112.95 [2,367.37-3,889.43], p = 0.004). Patients with AQP4-NMOSD presenting with optic neuritis had lower 14-3-3 levels compared with those with other phenotypes (p < 0.001). In AQP4-NMOSD, 14-3-3 levels associated with Expanded Disability Status Scale (EDSS) at attack (β [95%CI] 0.33 [0.15-0.52], p = 0.003) and predicted final EDSS ≥ 6.0 (odds ratio 9.48 [1.69; 194.34]; p = 0.041) in patients with myelitis.

Discussion: The study suggests a potential role of CSF 14-3-3 protein levels as a biomarker of neuroaxonal damage in AQP4-NMOSD, because of its ability to correlate with disease severity and predict poor clinical recovery.

Classification of evidence: This study provides Class IV evidence that in individuals presenting with acute myelitis, CSF 14-3-3 differentiates AQP4-NMOSD from MS or MOGAD with a sensitivity of 0.60 (0.30-0.80) and specificity of 0.95 (0.84-1.00).

Figure 1. Potential of CSF 14-3-3 Levels for Discriminating Between Patients With AQP4-NMOSD, MOGAD, and MS

Boxplots depict the distribution of CSF levels of 14-3-3 protein between patients with AQP4-NMOSD, MOGAD and MS (A), between phenotypes within each disease and across diseases groups (B), and between acute and remission phases (C). Median values are represented by the horizontal bar, IQR by hinges, 1.5 × IQR by whiskers, and individual values by dots. p values are adjusted for age, EDSS, and topography at sampling, and represented by asterisks as follows: **<0.01, ***<0.001. Panel D depicts receiver operating characteristic curves of 14-3-3 protein for the discrimination between patients with AQP4-NMOSD and MS and MOGAD myelitis. Red dot indicates the best cutoff value of 14-3-3 protein. AQP4-NMOSD = aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder; AUC = area under the curve; MOGAD = myelin oligodendrocyte glycoprotein antibody–associated disease; MS = multiple sclerosis; SE = sensitivity; SP = specificity.

Figure 2. Association of 14-3-3 CSF Levels With Disability at Attack and at Last Follow-Up in Patients With AQP4-NMOSD

Panel A represents the association between CSF 14-3-3 protein log-transformed values and EDSS at attack in those patients with samples collected at the acute phase. Boxplots (B) depict the distribution of the 14-3-3 protein log-transformed values between patients with final EDSS ≥ 6.0 and those with final EDSS < 6.0. p Values are adjusted for age, EDSS, and phenotype at sampling and represented by asterisks as follows: **<0.01. EDSS = Expanded Disability Status Scale; AQP4-NMOSD = aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder.