To identify serum biomarkers predictive of neuromyelitis optica spectrum disorder (NMOSD).

NMOSD is a rare demyelinating, autoimmune disease. The autoimmune target is the astrocyte water channel aquaoporin-4, and its antibodies (APQ4-IgG) are highly specific for NMOSD, though 10-27% of affected persons will be APQ4-IgG negative. Thus, some affected persons may experience highly variable diagnostic delays, including misdiagnoses. There are opportunities to identify novel NMOSD-specific biomarkers by comparing metabolomic profiles in NMOSD to multiple sclerosis (MS) and unaffected controls. 

This study was based on serum samples available through the Accelerated Cure Project, from 24 NMOSD (50% APQ4-IgG positive), 70 relapsing remitting (RR) MS, and 83 unaffected controls (UC) who self-identified as non-Hispanic whites. All NMOSD+RRMS cases were immunomodulatory therapy naïve/free (>90 days), <5 years from first symptom, and <2 years from diagnosis. Untargeted metabolomic profiles were generated, and after quality control and normalized/standardization, there were 952 named biochemical traits for analysis. A supervised machine-learning algorithm, Random forests, identified biochemical traits informative for NMOSD in comparison to MS+UC. Multivariable regression analyses characterized associations adjusting for age, sex, smoking status, and body mass index. Receiver operator curves (ROC) evaluated the predictive capacity of top-ranking metabolites.

Random forests determined 4 metabolites as informative for NMOSD vs MS+UC. They included a ceramide and 3 monoacylglycerols. They did not differ between APQ4-IgG positive and negative samples (p>0.2) nor between MS and UC samples (p>0.25). The metabolites were >1 standard deviation higher in NMOSD compared to MS+UC even with adjustment for potential confounders (p: 1x10^-5 to 2x10^-10), and were highly predictive of NMOSD status (area under ROC >80%) in comparison to MS+UC and versus UC alone. The full parameterized multivariable model was highly predictive (area under ROC=91.5%).

We observed a serum biosignature highly predictive of NMOSD, implicating sphingomyelin and triglyceride metabolic processes.