Comprehensive Metabolic Fingerprints Characterize Neuromyelitis Optica Spectrum Disorder by Nanoparticle-Enhanced Laser Desorption/Ionization Mass Spectrometry.

Timely screening of neuromyelitis optica spectrum disorder (NMOSD) and differential diagnosis from myelin oligodendrocyte glycoprotein associated disorder (MOGAD) are the keys to improving the quality of life of patients. Metabolic disturbance occurs with the development of NMOSD. Still, advanced tools are required to probe the metabolic phenotype of NMOSD. Here, we developed a fast nanoparticle-enhanced laser desorption/ionization mass spectrometry assay for multiplexing metabolic fingerprints (MFs) from trace plasma and cerebrospinal fluid (CSF) samples in 30 s. Machine learning of the plasma MFs achieved the timely screening of NMOSD from healthy donors with an area under receiver operator characteristic curve (AUROC) of 0.998, and it comprehensively revealed the dysregulated neurotransmitter and energy metabolisms. Combining comprehensive MFs from both plasma and CSF, we constructed an integrated panel for differential diagnosis of NMOSD versus MOGAD with an AUROC of 0.923. This approach demonstrated performance superior to that of human experts in classifying two diseases, especially in antibody assay-limited regions. Together, this approach provides an advanced nanomaterial-based tool for identifying vulnerable populations below the antibody threshold of aquaporin-4 positivity.