Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder

Patrick Schindler,Friedemann Paul,Judith Bellmann-Strobl,Hanna G Zimmermann,Frederike C Oertel,Markus Reindl,Susanna Asseyer,Nadja Siebert,Klemens Ruprecht,Jens Kuhle,Ankelien S Duchow,Joseph Kuchling,David Leppert,Johanna Oechtering,Sven Jarius,Alexander U Brandt,Pascal Benkert,Ulrike Grittner

doi:10.1186/s12974-021-02138-7

Abstract

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG+) NMOSD.MethodssGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG+ patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG+ patients over a median observation period of 4.25 years.ResultsIn patients with AQP4-IgG+ NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG+ patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG+, but not MOG-IgG+ patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = − 1.28, p = 0.01). While in AQP4-IgG+, but not MOG-IgG+ patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = − 1.75, p = 0.06) in patients with AQP4-IgG+ NMOSD. Patients with AQP4-IgG+ NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3–105.6], p = 0.03). In contrast, baseline sNfL levels above the 75th age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG+ NMOSD.ConclusionThese findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG+ NMOSD in phases of clinical remission.

Highlights

Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course
MOGIgG has been associated with inflammatory demyelination and defines a disease entity termed MOG antibody disease (MOGAD), whose clinical presentation partially overlaps with NMOSD as defined by the International Panel for NMO Diagnosis (IPND) criteria [6, 9,10,11]
The vast majority of AQP4-IgG+ and MOGIgG+ patients was in clinical remission at study inclusion with a median time since last attack of 26 (11–56) months in AQP4-IgG+ patients and Healthy Controls standardized mean difference values (SMD) for AQP4- SMD for IgG+ vs. MOG-IgG+ AQP4-IgG+ vs. healthy controls (HC)

Summary

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. We evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG+) NMOSD. Neuromyelitis optica spectrum disorder (NMOSD) is a severe neuroinflammatory syndrome primarily affecting the optic nerves, spinal cord, and brainstem, with a relapsing and frequently disabling course, that is difficult to predict at the individual level [1, 2]. MOGIgG has been associated with inflammatory demyelination and defines a disease entity termed MOG antibody disease (MOGAD), whose clinical presentation partially overlaps with NMOSD as defined by the IPND criteria [6, 9,10,11]. Whereas astrocytes are considered the primary autoantibody target in AQP4-IgG+ NMOSD, in MOGAD, oligodendrocytes are considered the primary autoantibody target, as MOG is expressed on oligodendrocytes [9, 11]

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Results

Conclusion