The relationship between serum astroglial and neuronal markers and AQP4 and MOG autoantibodies

Abstract

Background: Certain demyelinating disorders, such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) exhibit serum autoantibodies against aquaporin-4 (αAQP4) and myelin oligodendrocyte glycoprotein (αMOG). The variability of the autoantibody presentation warrants further research into subtyping each case.

Methods: To elucidate the relationship between astroglial and neuronal protein concentrations in the peripheral circulation with occurrence of these autoantibodies, 86 serum samples were analyzed using immunoassays. The protein concentration of glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL) and tau protein was measured in 3 groups of subcategories of suspected NMOSD: αAQP4 positive (n = 20), αMOG positive (n = 32) and αMOG/αAQP4 seronegative (n = 34). Kruskal-Wallis analysis, univariate predictor analysis, and multivariate logistic regression with ROC curves were performed.

Results: GFAP and NFL concentrations were significantly elevated in the αAQP4 positive group (p = 0.003; p = 0.042, respectively), and tau was elevated in the αMOG/αAQP4 seronegative group (p < 0.001). A logistic regression model to classify serostatus was able to separate αAQP4 seropositivity using GFAP + tau, and αMOG seropositivity using tau. The areas under the ROC curves (AUCs) were 0.77 and 0.72, respectively. Finally, a combined seropositivity versus negative status logistic regression model was generated, with AUC = 0.80.

Conclusion: The 3 markers can univariately and multivariately classify with moderate accuracy the samples with seropositivity and seronegativity for αAQP4 and αMOG.

Keywords: Aquaporin 4; Myelin oligodendrocyte glycoprotein; autoantibody; autoimmunity; glial fibrillary acidic protein; neurofilament-light; tau.

Figure 1:

Scatterplots of raw values of the 3 biomarkers analyzed in the αAQP4+, αMOG+ and αMOG-/αAQP4-groups. The horizontal lines represent the median of each group, and each dot represents the value of the marker in an individual sample. For numerical values and P-values, see Table 1.

Figure 2:

Pairwise plots of the 3 markers: GFAP, NFL and tau. The x and y axes represent the logarithmic protein serum values. (A) αMOG status, (B) αAQP4 status.

Figure 3:

(A) ROC curve for predicting αMOG+ from tau values. The bootstrapped optimism-adjusted AUC is 0.72 (unadjusted value =0.73). The AUC values from combining NFL+tau or GFAP+tau were lower than for tau alone (data not shown). (B) ROC curves for predicting αAQP4+ status using GFAP (red) and GFAP+tau (blue). The non-adjusted and bootstrapped AUC values of GFAP alone are 0.75 (adjusted) and 0.75 (non-adjusted) and for GFAP+tau are 0.78 and 0.77, respectively.

Figure 4:

Multivariable logistic regression was used to separate the cases with αAQP4+ or αMOG+ from the cases with a double negative status. (A)The scatterplot of the log-transformed GFAP vs tau. The dashed line indicates the prediction of αAQP4+ or αMOG+ versus αMOG−/ αAQP4−. (B) The ROC curve has an unadjusted AUC of 0.81 (0.80 after optimism-adjustment).