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

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

doi:10.1186/s12974-021-02138-7

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

J Neuroinflammation. 2021 May 1;18(1):105. doi: 10.1186/s12974-021-02138-7.

Authors

Patrick Schindler¹, Ulrike Grittner^{2

3}, Johanna Oechtering⁴, David Leppert⁴, Nadja Siebert^{5

6}, Ankelien S Duchow^{5

6}, Frederike C Oertel^{5

6

7}, Susanna Asseyer^{5

6}, Joseph Kuchling^{5

6}, Hanna G Zimmermann^{5

6}, Alexander U Brandt^{5

6

8}, Pascal Benkert⁹, Markus Reindl¹⁰, Sven Jarius¹¹, Friedemann Paul^{1

5

6}, Judith Bellmann-Strobl^#^{5

6}, Jens Kuhle^#⁴, Klemens Ruprecht^#¹²

Affiliations

¹ Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
² Institute for Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
³ Berlin Institute of Health (BIH), Berlin, Germany.
⁴ Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
⁵ NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁶ Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁷ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Neurology, University of California, Irvine, CA, USA.
⁹ Clinical Trial Unit, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
¹⁰ Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
¹¹ Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany.
¹² Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. klemens.ruprecht@charite.de.

^# Contributed equally.

Abstract

Background: Neuromyelitis 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.

Methods: sGFAP 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.

Results: In 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 75^th age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG⁺ NMOSD.

Conclusion: These 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.

Keywords: Aquaporin-4 immunoglobulin G; Biomarker; Glial fibrillary acidic protein; Myelin oligodendrocyte glycoprotein immunoglobulin G; Neurofilament light chain protein; Neuromyelitis optica spectrum disorder; Serum.

MeSH terms

Adult
Aged
Autoantibodies
Biomarkers / blood*
Female
Glial Fibrillary Acidic Protein / blood*
Humans
Male
Middle Aged
Neurofilament Proteins / blood*
Neuromyelitis Optica / blood*
Prognosis
Severity of Illness Index

Substances

Autoantibodies
Biomarkers
GFAP protein, human
Glial Fibrillary Acidic Protein
Neurofilament Proteins
anti-aquaporin 4 autoantibody
neurofilament protein L

Grants and funding

DFG Exc 257/Deutsche Forschungsgemeinschaft