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Serum Biomarker Profiles Discriminate AQP4 Seropositive and Double Seronegative Neuromyelitis Optica Spectrum
Sara Carta1, Alessandro Dinoto1, Marco Capobianco1
1From the Department of Neuroscience, Biomedicine, and Movement Science (S.C., A.D., V.C., S.M., S.F.), University of Verona; S. Croce e Carle Hospital (M.C.), Cuneo; CRESM Biobank (M.C.), Orbassano; Neuroscience Institute Cavalieri Ottolenghi (NICO) (P.V., M.L.R.); CRESM Biobank (P.V., M.L.R.), University Hospital San Luigi, Orbassano; Neurobiology Laboratory, Department of Neurology (A.S.), University Hospital San Luigi, Orbassano; Neuroscience Institute Cavalieri Ottolenghi (NICO) (F.M.), University of Turin, Italy; Clinical Department of Neurology (M.R., K.S.), Innsbruck Medical University, Austria; Department of Neurology (P.B.), CHU de Caen Normandie; Department of Neurology (B.A.), Pôle de Neurosciences Cliniques, APHM, Hôpital de la Timone, Aix Marseille University; Department of Internal Medecine (J.A.), Centre Hospitalier National des Quinze-Vingts, Paris Cedex; Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (C.P.), Institut du Cerveau, CIC Neuroscience, ICM, Hôpital de la Pitié Salpêtrière, Sorbonne Université, Paris; Service de Neurologie and CIC INSERM 1434 (N.C.), CHU de Strasbourg, France; Centre Hospitalier de Luxembourg (P.K.), Luxembourg City, Luxemburg; Department of Neurology (H.Z.), U 1172, CRC-SEP, University Hospital of Lille, France; Service de Neurologie (A.C.), Centre de Ressources et de Compétences-Sclérose en Plaques, Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Université Paris-Est Créteil, Créteil; Department of Neurology (B.B.), Rouen University Hospital, France; Mayo Clinic College of Medicine and Science (E.P.F., V.R.), Department of Neurology, Department of Laboratory Medicine and Pathology, Rochester; Centre d'Esclerosi Múltiple de Catalunya (J.V.-Á., G.A., A.C.-C.), (CEMCAT), Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Servei de Neurologia-Neuroimmunologia, Barcelona; and Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (R.M.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, France.
Background And Objectives:
Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) serum levels are useful to define disease activity in different neurologic conditions. These biomarkers are increased in patients with aquaporin-4 antibody-positive NMOSD (AQP4+NMOSD) during clinical attacks suggesting a concomitant axonal and glial damage. However, there are contradictory results in double seronegative NMOSD (DS-NMOSD). The aim of this study was to characterize the neuronal, axonal, and glial damage of DS-NMOSD in comparison with AQP4+NMOSD.
Methods:
Patients with DS-NMOSD (i.e., for AQP4 and myelin oligodendrocyte glycoprotein antibodies-MOG-Abs) and age-matched AQP4+NMOSD diagnosed according to the latest diagnostic criteria and with available serum samples obtained within 3 months from onset/relapse were retrospectively enrolled from 14 international centers. Clinical and radiologic data were collected. Serum NfL, GFAP, tau, and UCH-L1 levels were determined using an ultrasensitive paramagnetic bead-based ELISA (SIMOA). Statistical analysis was performed using nonparametric tests and receiver-operating characteristic (ROC) curve analysis.
Results:
We included 25 patients with AQP4+NMOSD and 26 with DS-NMOSD. The median age at disease onset (p = 0.611) and female sex predominance (p = 0.072) were similar in the 2 groups. The most common syndromes at sampling in both AQP4+NMOSD and DS-NMOSD were myelitis (56% vs 38.5%) and optic neuritis (34.6% vs 32%), with no statistical differences (p = 0.716). Median EDSS at sampling was 3.2 (interquartile range [IQR] 2-7.7) in the AQP4+NMOSD group and 4 (IQR [3-6]) in the DS-NMOSD group (p = 0.974). Serum GFAP, tau, and UCH-L1 levels were higher in patients with AQP4+NMOSD compared with those with DS-NMOSD (median 308.3 vs 103.4 pg/mL p = 0.001; median 1.2 vs 0.5 pg/mL, p = 0.001; and median 61.4 vs 35 pg/mL, p = 0.006, respectively). The ROC curve analysis showed that GFAP, tau, and UCH-L1, but not NfL, values were able to discriminate between AQP4+ and DS-NMOSD (area under the curve (AUC) tau: 0.782, p = 0.001, AUC GFAP: 0.762, p = 0.001, AUC UCH-L1: 0.723, p = 0.006). NfL levels were associated with EDSS at nadir only in patients with AQP4+NMOSD.
Discussion:
Serum GFAP, tau, and UCH-L1 levels discriminate between AQP4+NMOSD and DS-NMOSD. The different biomarker profile of AQP4+NMOSD vs DS-NMOSD suggests heterogeneity of diseases within the latter category and provides useful data to improve our understanding of this disease.
