Widening the spectrum of autoimmune astrocytopathies: a role for CSF glutamine synthetase and glial fibrillary acidic protein?
ECTRIMS Online Library. Kleerekooper I. 09/13/19; 279585; 340
Iris Kleerekooper
Iris Kleerekooper
Contributions
Abstract

Abstract: 340

Type: Scientific Session

Abstract Category: Scientific Session 17: Late Breaking News

I. Kleerekooper1,2, M.K. Herbert3,4, B.H. Kuiperij3, D.K. Sato5,6,7, K. Fujihara5, D. Callegaro7, R. Marignier8, A. Saiz9, M. Senel10, H. Tumani10, B.A. De Jong11, S.A. Trip1, I. Nakashima5, M.M. Verbeek12, A. Petzold2,13,14

1Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, 2Neuro-Ophthalmology, Moorfields Eye Hospital and UCL Institute of Neurology, London, United Kingdom, 3Laboratory Medicine, Radboud University, Nijmegen, The Netherlands, 4Medicine and Cancer, Harvard Medical School, Boston, MA, United States, 5Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan, 6Brain Institute, Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, 7Neurology, Hospital das Clínicas, Ribeirão Preto Medical School, University of de São Paulo, Sao Paolo, Brazil, 8Service de Neurologie et Sclérose en Plaques, Fondation EDMUS pour la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Lyon, France, 9Neurology, Hospital Clinic Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS) and Universitat de Barcelona, Barcelona, Spain, 10Neurology, University of Ulm, Ulm, Germany, 11Neurology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC - location VUmc, Amsterdam, 12Neurology, Radboud University, Nijmegen, The Netherlands, 13Neurology, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom, 14Neuro-Ophthalmology, VU Medical Centre Amsterdam / MS Centre Amsterdam, Amsterdam, The Netherlands

Objective: Pathogenesis of neuromyelitis optica spectrum disease (NMOSD) is better understood since the identification of pathogenic aquaporin-4 (AQP4) and myelin oligodendrocyte globulin (MOG) antibodies (Ab). However, despite a compatible clinical phenotype some patients remain seronegative. Here, we investigated astrocytopathy across NMOSD using two astrocytic biomarkers.
Methods: This international multi-centre study measured cerebrospinal fluid (CSF) concentrations of an astrocytic enzyme, glutamine synthetase (GS), and a structural astrocytic protein, glial fibrillary acidic protein (GFAP) by ELISA in patients with NMOSD (n=43, 28 AQP4-Ab-seropositive, 1 MOG-Ab-seropositive, 6 double-Ab-seronegative and 8 with unknown MOG-Ab-serostatus), multiple sclerosis (MS, n=69), optic neuritis (n=5) and non-neurological control subjects (n=37).
Results: In patients with NMOSD, both median GFAP (1.23 ng/mL) and GS (452.0 µg/L) levels were elevated compared with controls (0.50 ng/mL, p=0.021; 235.4 µg/L, p< 0.001). Only GFAP distinguished NMOSD from MS (0.60 ng/mL, p=0.037) and only GS distinguished controls from MS (329.4 µg/L; p=0.001). GFAP and GS levels correlated significantly (p< 0.001) and did not differ significantly between AQP4-Ab-seropositive and -seronegative NMOSD. Interestingly, GFAP levels of AQP4-Ab-seronegative NMOSD patients were markedly increased.
Conclusions: This study confirms that GFAP concentrations are elevated in NMOSD and adds a novel astrocytic biomarker, GS, to the laboratory test panel. Furthermore, the increased GFAP levels in seronegative NMOSD patients suggest that the spectrum of autoimmune astrocytopathies may be wider than only AQP4-Ab-seropositive cases, and there could be merit in hunting for novel autoimmune targets in these patients.
Disclosure: IK: received postdoctoral research exchange fellowship from ECTRIMS.
MH: no disclosures.
BK: no disclosures.
DS: has received a scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; a Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI 15K19472); research support from CNPq/Brasil (grant 425331/2016-4), FAPERGS/Ministry of Health/CNPq/SESRS (grant 17/2551-0001391-3) PPSUS/Brazil, TEVA (research grant for EMOCEMP Investigator Initiated Study), and Euroimmun AG (Neuroimmunological Complications associated with Arboviruses); and speaker honoraria from Biogen, Novartis, Genzyme, TEVA, Merck-Serono, Roche, Bayer and has participated in advisory boards from Shire, Roche, TEVA, Merck-Serono and Quest/Athena Diagnostics. AS has received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd, Novartis and Roche.
KF: serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serve as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and an advisory board member of Sri Lanka journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded as the secondary investigator (#22229008, 2010-2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present).
DC: no disclosures.
RM: no disclosures.
AS: has received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd, Novartis and Roche.
MK: no disclosures.
HT: received funding for research projects, lectures and travel from Bayer, Biogen, Genzyme, Fresenius, Merck, Mylan, Novartis, Roche, Siemens Health Diagnostics, Teva, and received research support from Hertie-Stiftung, BMBF, University of Ulm and Landesstiftung BW.
BJ: received speaker and consulting fees from Merck-Serono, Biogen, TEVA, Genzyme, Novartis.
SAT: receives support from the University College London Hospitals Biomedical Research Centre.
IN: Dr. Nakashima reports personal fees from Mitsubishi Tanabe Pharma, personal fees from Biogen Japan, personal fees from Takeda Pharmaceuticals, personal fees from Novartis Pharmaceuticals, grants from LSI Medience, grants from Ministry of Education, Science and Technology of Japan, and the Ministry of Health, Welfare and Labor of Japan
MV: received subsidies from ZonMw, Alzheimer Nederland, Weston Brain Institute, NIH
AP: member of the steering committee for the OCTiMS study (Novartis), no consulting fees. Performs OCT QC for the Passos study (Novartis), received consulting fees. Received speaker fees from Heidelberg Engineering.

Abstract: 340

Type: Scientific Session

Abstract Category: Scientific Session 17: Late Breaking News

I. Kleerekooper1,2, M.K. Herbert3,4, B.H. Kuiperij3, D.K. Sato5,6,7, K. Fujihara5, D. Callegaro7, R. Marignier8, A. Saiz9, M. Senel10, H. Tumani10, B.A. De Jong11, S.A. Trip1, I. Nakashima5, M.M. Verbeek12, A. Petzold2,13,14

1Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, 2Neuro-Ophthalmology, Moorfields Eye Hospital and UCL Institute of Neurology, London, United Kingdom, 3Laboratory Medicine, Radboud University, Nijmegen, The Netherlands, 4Medicine and Cancer, Harvard Medical School, Boston, MA, United States, 5Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan, 6Brain Institute, Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, 7Neurology, Hospital das Clínicas, Ribeirão Preto Medical School, University of de São Paulo, Sao Paolo, Brazil, 8Service de Neurologie et Sclérose en Plaques, Fondation EDMUS pour la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Lyon, France, 9Neurology, Hospital Clinic Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS) and Universitat de Barcelona, Barcelona, Spain, 10Neurology, University of Ulm, Ulm, Germany, 11Neurology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC - location VUmc, Amsterdam, 12Neurology, Radboud University, Nijmegen, The Netherlands, 13Neurology, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom, 14Neuro-Ophthalmology, VU Medical Centre Amsterdam / MS Centre Amsterdam, Amsterdam, The Netherlands

Objective: Pathogenesis of neuromyelitis optica spectrum disease (NMOSD) is better understood since the identification of pathogenic aquaporin-4 (AQP4) and myelin oligodendrocyte globulin (MOG) antibodies (Ab). However, despite a compatible clinical phenotype some patients remain seronegative. Here, we investigated astrocytopathy across NMOSD using two astrocytic biomarkers.
Methods: This international multi-centre study measured cerebrospinal fluid (CSF) concentrations of an astrocytic enzyme, glutamine synthetase (GS), and a structural astrocytic protein, glial fibrillary acidic protein (GFAP) by ELISA in patients with NMOSD (n=43, 28 AQP4-Ab-seropositive, 1 MOG-Ab-seropositive, 6 double-Ab-seronegative and 8 with unknown MOG-Ab-serostatus), multiple sclerosis (MS, n=69), optic neuritis (n=5) and non-neurological control subjects (n=37).
Results: In patients with NMOSD, both median GFAP (1.23 ng/mL) and GS (452.0 µg/L) levels were elevated compared with controls (0.50 ng/mL, p=0.021; 235.4 µg/L, p< 0.001). Only GFAP distinguished NMOSD from MS (0.60 ng/mL, p=0.037) and only GS distinguished controls from MS (329.4 µg/L; p=0.001). GFAP and GS levels correlated significantly (p< 0.001) and did not differ significantly between AQP4-Ab-seropositive and -seronegative NMOSD. Interestingly, GFAP levels of AQP4-Ab-seronegative NMOSD patients were markedly increased.
Conclusions: This study confirms that GFAP concentrations are elevated in NMOSD and adds a novel astrocytic biomarker, GS, to the laboratory test panel. Furthermore, the increased GFAP levels in seronegative NMOSD patients suggest that the spectrum of autoimmune astrocytopathies may be wider than only AQP4-Ab-seropositive cases, and there could be merit in hunting for novel autoimmune targets in these patients.
Disclosure: IK: received postdoctoral research exchange fellowship from ECTRIMS.
MH: no disclosures.
BK: no disclosures.
DS: has received a scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; a Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI 15K19472); research support from CNPq/Brasil (grant 425331/2016-4), FAPERGS/Ministry of Health/CNPq/SESRS (grant 17/2551-0001391-3) PPSUS/Brazil, TEVA (research grant for EMOCEMP Investigator Initiated Study), and Euroimmun AG (Neuroimmunological Complications associated with Arboviruses); and speaker honoraria from Biogen, Novartis, Genzyme, TEVA, Merck-Serono, Roche, Bayer and has participated in advisory boards from Shire, Roche, TEVA, Merck-Serono and Quest/Athena Diagnostics. AS has received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd, Novartis and Roche.
KF: serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; serve as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and an advisory board member of Sri Lanka journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; is funded as the secondary investigator (#22229008, 2010-2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present).
DC: no disclosures.
RM: no disclosures.
AS: has received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd, Novartis and Roche.
MK: no disclosures.
HT: received funding for research projects, lectures and travel from Bayer, Biogen, Genzyme, Fresenius, Merck, Mylan, Novartis, Roche, Siemens Health Diagnostics, Teva, and received research support from Hertie-Stiftung, BMBF, University of Ulm and Landesstiftung BW.
BJ: received speaker and consulting fees from Merck-Serono, Biogen, TEVA, Genzyme, Novartis.
SAT: receives support from the University College London Hospitals Biomedical Research Centre.
IN: Dr. Nakashima reports personal fees from Mitsubishi Tanabe Pharma, personal fees from Biogen Japan, personal fees from Takeda Pharmaceuticals, personal fees from Novartis Pharmaceuticals, grants from LSI Medience, grants from Ministry of Education, Science and Technology of Japan, and the Ministry of Health, Welfare and Labor of Japan
MV: received subsidies from ZonMw, Alzheimer Nederland, Weston Brain Institute, NIH
AP: member of the steering committee for the OCTiMS study (Novartis), no consulting fees. Performs OCT QC for the Passos study (Novartis), received consulting fees. Received speaker fees from Heidelberg Engineering.

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