Granulocyte Activation and Astrocyte Damage Markers in CSF Differentiate Acute NMOSD and MOGAD from MS
David Leppert1, Mitsuru Watanabe2, Sabine Schaedelin3, Fredrik Piehl4, Katharina Fink4, Roberto Furlan5, Matteo Gastaldi6, Pascal Benkert3, Aleksandra Maleska1, Eline Willemse1, Johanna Oechtering1, Annette Orleth1, Stephanie Meier1, Daniel Anthony7, Jens Kuhle1
1Department of Neurology, Department of Neurology, University Hospital and University of Basel, 2Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3Department of Clinical Research, University Hospital and University of Basel, 4Neuroimmunology Unit, Dept Clinical Neuroscience, Karolinska Institutet, 5Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Institute of Experimental Neurology, San Raffaele Scientific Institute, 6Neuroimmunology Research Unit, IRCCS Mondino Foundation, 7Department of Pharmacology, University of Oxford
Objective:
To evaluate the capacity of granulocyte activation (GAM: Elastase-2, MPO, MMP-8, NGAL, TIMP-1) and astrocyte damage (ADM: GFAP, S100B) markers to differentiate NMOSD (including anti-aquaporin-4-antibody-negative patients) and MOGAD vs MS, and NMOSD vs MOGAD, respectively.
Background:
Granulocyte invasion into brain tissue is a prominent neuropathological feature of NMOSD and MOGAD, but not of MS; GFAP and S100B are known to be quantitatively increased in NMOSD vs MS and MOGAD. However, these proteins have not been evaluated as diagnostic biomarkers.
Design/Methods:
CSF levels of GAM and ADM from patients with NMOSD (n=67), MOGAD (n=6) and RRMS (n=86) were quantitated by ELISA. The association between biomarkers and disease groups was assessed in linear models. Receiver operating characteristic curves and area under the curve (AUC) were calculated to estimate the potential to differentiate NMOSD/MOGAD from RRMS. The association of biomarkers with EDSS in NMOSD and RRMS was assessed by Spearman correlation.
Results:
In acute (≤21 days post exacerbation) stages, GAM levels of NMOSD (including anti-aquaporin-4-antibody negative cases) vs RRMS (pall<0.003), and of MOGAD (3-44 days post exacerbation) vs RRMS (pall≤0.008, for MPO only numerically) were increased, while they were not different between NMOSD and MOGAD.
AUC values of Elastase-2, MMP-8, and TIMP-1 to differentiate NMOSD and MOGAD from RRMS were ≥0.81 and ≥0.82, respectively. The composite of S100B+GFAP>1000pg/ml levels provided an AUC value of 0.91 to differentiate NMOSD from MOGAD. GAM levels correlated with disability scores in NMOSD (pall≤0.002), but not in RRMS.
Conclusions:
GAM represent novel, readily applicable CSF biomarkers to differentiate MOGAD or NMOSD, independent of anti-aquaporin-4-antibody serostatus, from RRMS in periods after acute disease exacerbations. ADM can support the differential diagnosis of acute NMOSD vs MOGAD. The association of GAM with the degree of concurrent neurological impairment in RRMS provides evidence for their pathogenic role.