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

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 75th 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.

Longitudinal follow-up of serum biomarkers in patients with neuromyelitis optica spectrum disorder

“…Based on this reliability and the largest area under the ROC curve to differentiate attacks from remissions, serum GFAP might be a more appropriate biomarker to monitor disease activity than serum NfL, in line with the recent studies. 8,9…”

“…This ongoing subclinical increase in serum biomarkers, especially in GFAP levels, in NMOSD has also been documented in the very recent studies. 9,10 Although MS manifests as subclinical disease progression, 26,27 this may be uncommon in NMOSD where disability is related to attacks. 28,29 Age-related changes and subclinical neurodegeneration may explain the substantial increase in the serum levels of NfL and GFAP over time in NMOSD.…”

“…Based on this reliability and the largest area under the ROC curve to differentiate attacks from remissions, serum GFAP might be a more appropriate biomarker to monitor disease activity than serum NfL, in line with the recent studies. 8,9 The serum levels of NfL and GFAP increased by approximately 20% during the main period in patients with no-baseline attack. This ongoing subclinical increase in serum biomarkers, especially in GFAP levels, in NMOSD has also been documented in the very recent studies.…”

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With the development of the ultrasensitive singlemolecule array (Simoa) assay, serum levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), which are neuronal and astrocytic cytoskeletal proteins, respectively, have been shown to be useful biomarkers for disease activity and disability in NMOSD. [6][7][8][9][10] The serum level of the GFAP/NfL quotient was also suggested to be a reliable biomarker that distinguished NMOSD from MS, especially when an attack occurs. 7 In this study, we aimed to investigate and compare the clinical value of these serum biomarkers (NfL, GFAP, and GFAP/NfL quotient) with baseline and follow-up serum samples in a longitudinal NMOSD cohort.

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Serum neurofilament light chain in adult and pediatric patients with myelin oligodendrocyte glycoprotein antibody‐associated disease: Correlation with relapses and seizures

“…In the last few years, several biomarkers for MOGAD, such as neurofilament light (NfL), have been investigated (Chang et al, 2021;Kim et al, 2020;Mariotto et al, 2017Mariotto et al, , 2019Mariotto et al, , 2021Schindler et al, 2021). NfL is a scaffolding protein of the neural cytoskeleton and is released into the cerebrospinal fluid (CSF) and blood following CNS axonal damage (Bacioglu et al, 2016;Khalil et al, 2018).…”