TY - JOUR
T1 - Granulocyte activation markers in cerebrospinal fluid differentiate acute neuromyelitis spectrum disorder from multiple sclerosis
AU - Leppert, David
AU - Watanabe, Mitsuru
AU - Schaedelin, Sabine
AU - Piehl, Fredrik
AU - Furlan, Roberto
AU - Gastaldi, Matteo
AU - Lambert, Jeremy
AU - Evertsson, Björn
AU - Fink, Katharina
AU - Matsushita, Takuya
AU - Masaki, Katsuhisa
AU - Isobe, Noriko
AU - Kira, Jun-Ichi
AU - Benkert, Pascal
AU - MacEski, Aleksandra
AU - Willemse, Eline
AU - Oechtering, Johanna
AU - Orleth, Annette
AU - Meier, Stephanie
AU - Kuhle, Jens
N1 - Funding Information: This investigation was supported by Swiss National Science Foundation (grant 320030_189140/1), the Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan (20FC1030) and Swedish MRC grant no. 2020-02700, Hjärnfonden. Publisher Copyright: © 2023 BMJ Publishing Group. All rights reserved.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - Background: Granulocyte invasion into the brain is a pathoanatomical feature differentiating neuromyelitis optica spectrum disorder (NMOSD) from multiple sclerosis (MS). We aimed to determine whether granulocyte activation markers (GAM) in cerebrospinal fluid (CSF) can be used as a biomarker to distinguish NMOSD from MS, and whether levels associate with neurological impairment. Methods: We quantified CSF levels of five GAM (neutrophil elastase, myeloperoxidase, neutrophil gelatinase-associated lipocalin, matrixmetalloproteinase-8, tissue inhibitor of metalloproteinase-1), as well as a set of inflammatory and tissue-destruction markers, known to be upregulated in NMOSD and MS (neurofilament light chain, glial fibrillary acidic protein, S100B, matrix metalloproteinase-9, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1), in two cohorts of patients with mixed NMOSD and relapsing-remitting multiple sclerosis (RRMS). Results: In acute NMOSD, GAM and adhesion molecules, but not the other markers, were higher than in RRMS and correlated with actual clinical disability scores. Peak GAM levels occurred at the onset of NMOSD attacks, while they were stably low in MS, allowing to differentiate the two diseases for ≤21 days from onset of clinical exacerbation. Composites of GAM provided area under the curve values of 0.90-0.98 (specificity of 0.76-1.0, sensitivity of 0.87-1.0) to differentiate NMOSD from MS, including all anti-aquaporin-4 protein (aAQP4)-antibody-negative patients who were untreated. Conclusions: GAM composites represent a novel biomarker to reliably differentiate NMOSD from MS, including in aAQP4- NMOSD. The association of GAM with the degree of concurrent neurological impairment provides evidence for their pathogenic role, in turn suggesting them as potential drug targets in acute NMOSD.
AB - Background: Granulocyte invasion into the brain is a pathoanatomical feature differentiating neuromyelitis optica spectrum disorder (NMOSD) from multiple sclerosis (MS). We aimed to determine whether granulocyte activation markers (GAM) in cerebrospinal fluid (CSF) can be used as a biomarker to distinguish NMOSD from MS, and whether levels associate with neurological impairment. Methods: We quantified CSF levels of five GAM (neutrophil elastase, myeloperoxidase, neutrophil gelatinase-associated lipocalin, matrixmetalloproteinase-8, tissue inhibitor of metalloproteinase-1), as well as a set of inflammatory and tissue-destruction markers, known to be upregulated in NMOSD and MS (neurofilament light chain, glial fibrillary acidic protein, S100B, matrix metalloproteinase-9, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1), in two cohorts of patients with mixed NMOSD and relapsing-remitting multiple sclerosis (RRMS). Results: In acute NMOSD, GAM and adhesion molecules, but not the other markers, were higher than in RRMS and correlated with actual clinical disability scores. Peak GAM levels occurred at the onset of NMOSD attacks, while they were stably low in MS, allowing to differentiate the two diseases for ≤21 days from onset of clinical exacerbation. Composites of GAM provided area under the curve values of 0.90-0.98 (specificity of 0.76-1.0, sensitivity of 0.87-1.0) to differentiate NMOSD from MS, including all anti-aquaporin-4 protein (aAQP4)-antibody-negative patients who were untreated. Conclusions: GAM composites represent a novel biomarker to reliably differentiate NMOSD from MS, including in aAQP4- NMOSD. The association of GAM with the degree of concurrent neurological impairment provides evidence for their pathogenic role, in turn suggesting them as potential drug targets in acute NMOSD.
KW - CSF
KW - clinical neurology
KW - molecular biology
KW - multiple sclerosis
KW - neuroimmunology
UR - http://www.scopus.com/inward/record.url?scp=85160216767&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/jnnp-2022-330796
DO - https://doi.org/10.1136/jnnp-2022-330796
M3 - Article
C2 - 37076291
SN - 0022-3050
VL - 94
SP - 726
EP - 737
JO - Journal of Neurology, Neurosurgery and Psychiatry
JF - Journal of Neurology, Neurosurgery and Psychiatry
IS - 9
M1 - jnnp-2022-330796
ER -