Cerebrospinal fluid metabolomics signatures in paediatric MOGAD and POMS

Piera De Gaspari^1,2*Stefano Sartori^1,3Margherita Nosadini^1,3Anna Sartori⁴Sara Mariotto⁵Roberto Assandri⁶Chiara Trabatti⁷Paola Cogo^8,9Manuela Simonato^10,11*

• ¹Neuroimmunology group, Instituto di Ricerca Pediatrica Citta della Speranza, Padua, Italy
• ²Italian Euroimmun Laboratory, Padova, Italy
• ³Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, Universita degli Studi di Padova, Padua, Italy
• ⁴Department of Women's and Children's Health, Universita degli Studi di Padova, Padua, Italy
• ⁵Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, Universita degli Studi di Verona, Verona, Italy
• ⁶Clinical Investigation Laboratory, Ospedale Maggiore di Crema, Crema, Italy
• ⁷Pediatric and Neonatology Unit, Ospedale Maggiore di Crema, Crema, Italy
• ⁸PCare laboratory, Instituto di Ricerca Pediatrica Citta della Speranza, Padua, Italy
• ⁹Department of Medicine, Division of Pediatrics, Universita degli Studi di Udine, Udine, Italy
• ¹⁰Department of medicine-DIMED, Universita degli Studi di Padova, Padua, Italy
• ¹¹PCare laborotory, Instituto di Ricerca Pediatrica Citta della Speranza, Padua, Italy

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), and pediatric-onset multiple sclerosis (POMS) are, are acquired demyelinating disorders (ADS) that are increasingly recognized in paediatric care. They share clinical and magnetic resonance imaging (MRI) features, but they differ in prognosis and management, since POMS is a chronic inflammatory neurodegenerative disorder, whereas MOGAD is not. Early POMS diagnosis is essential to limit disability accumulation. Thus, early identification of these syndromes is key to for their adequate management, family counseling, and to improve the outcome. Cerebrospinal fluid (CSF) biochemistry and cell count, oligoclonal band, IgG index, and serum MOG antibodies, together with brain and spine MRI, are the most valuable diagnostic biomarkers to make the differential diagnosis. However, it is not always possible to rely on these specific biomarkers to correctly identify these syndromes, especially at disease onset. In this perspective, the metabolomic and lipidomic analysis has recently gained ground as a novel diagnostic approach. In the present study, high- sensitivity shotgun mass spectrometry was used to characterize the CSF metabolome and lipidome of children with MOGAD and POMS disorders compared with the CSF of children with non-demyelinating diseases, used as controls. The identification of 128 CSF hydrophilic metabolites and 210 lipidlipidss species revealed characteristic changes in the relative metabolic concentrations in MOGAD compared with POMS, mainly related to the energy metabolism pathways impairment. The lipidomic profiles revealed the accumulation of the plasmalogens PE and cholesterol-esters as specific features of the lipid metabolic derangement. For the POMS group, the elevation of very long PE and triglyceride content was a discriminatory and a newly identified feature of demyelination in children. In this exploratory cohort, POMS showed higher very long-chain PE and TAG signal intensities; after FDR correction and effect-size evaluation, these trends require confirmation in larger, independent cohorts. By exploring the CSF metabolomic and lipidomic profile, we demonstrate the usefulness of broad broad-range omics analysis as a fast and reliable method of biomarker discovery in children with demyelinating neurological disorders at the onset of the disease, which might be a valuable diagnostic complement to the existing biomarkers.