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CSF levels of glutamine synthetase and GFAP to explore astrocytic damage in seronegative NMOSD
  1. Iris Kleerekooper1,2,
  2. Megan K Herbert3,
  3. H Bea Kuiperij4,
  4. Douglas Kazutoshi Sato5,6,
  5. Kazuo Fujihara5,
  6. Dagoberto Callegaro7,
  7. Romain Marignier8,
  8. Albert Saiz9,
  9. Makbule Senel10,
  10. Hayrettin Tumani10,11,
  11. Brigit A De Jong12,
  12. S Anand Trip1,
  13. Ichiro Nakashima5,13,
  14. Marcel M Verbeek3,4,
  15. Axel Petzold14,15
  1. 1 Department of Neuroinflammation, University College London, London, UK
  2. 2 Department of Neuro-Ophthalmology, Moorfields Eye Hospital, London, UK
  3. 3 Department of Neurology and Department of Laboratory Medicine, Radboud University Nijmegen Faculty of Medical Sciences, Nijmegen, The Netherlands
  4. 4 Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands
  5. 5 Department of Neurology, Tohoku University School of Medicine, Sendai, The Japan
  6. 6 Brain Institute, Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil
  7. 7 Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
  8. 8 Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, Centre de Référence pour les maladies inflammatoires rares du cerveau et de la moelle (MIRCEM), Hopital Neurologique et Neurochirurgical Pierre Wertheimer, Lyon, France
  9. 9 Service of Neurology, Hospital Clinic and Inistitut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
  10. 10 Department of Neurology, University of Ulm, Ulm, Germany
  11. 11 Specialist Clinic of Neurology Dietenbronn, Dietenbronn, Germany
  12. 12 Department of Neurology, MS Center Amsterdam, Amsterdam UMC—Locatie VUMC, Amsterdam, The Netherlands
  13. 13 Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
  14. 14 Institute of Neurology, Neuroimmunology and CSF Laboratory, University College London, London, UK
  15. 15 Neurology & Ophthalmology, VU University Medical Centre, Amsterdam, The Netherlands
  1. Correspondence to Dr Iris Kleerekooper, Department of Neuroinflammation, University College London, London WC1E 6BT, UK; iris.kleerekooper.18{at}ucl.ac.uk

Abstract

Objective To explore levels of astrocytopathy in neuromyelitis optica spectrum disorder (NMOSD) by measuring levels of the astrocytic enzyme glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), an established astrocytic biomarker known to be associated with disease activity in multiple sclerosis.

Methods Cerebrospinal fluid concentrations of GS and GFAP were measured by ELISA in patients with NMOSD (n=39, 28 aquaporin-4 (AQP4)-Ab-seropositive, 3 double-Ab-seronegative, 4 myelin oligodendrocyte glycoprotein (MOG)-Ab-seropositive and 4 AQP4-Ab-seronegative with unknown MOG-Ab-serostatus), multiple sclerosis (MS) (n=69), optic neuritis (n=5) and non-neurological controls (n=37).

Results GFAP and GS concentrations differed significantly across groups (both p<0.001), showing a similar pattern of elevation in patients with AQP4-Ab-seropositive NMOSD. GS and GFAP were significantly correlated, particularly in patients with AQP4-Ab-seropositive NMOSD (rs=0.70, p<0.001). Interestingly, GFAP levels in some patients with double-Ab-seronegative NMOSD were markedly increased.

Conclusions Our data indicate astrocytic injury occurs in some patients with double-Ab-seronegative NMOSD, which hints at the possible existence of yet undiscovered astrocytic autoimmune targets. We hypothesise that elevated GS and GFAP levels could identify those double-Ab-seronegative patients suitable to undergo in-depth autoimmune screening for astrocytic antibodies.

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Footnotes

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  • MMV and AP contributed equally.

  • Contributors MKH, IK and AP were responsible for data collection and statistical analysis, interpretation of the data, the drafting and revision of the manuscript. HBK assisted with the revision of the manuscript and reading the manuscript for intellectual content. DKS, KF, DC, RM, AS, HT, BADJ, SAT and IN were responsible for data collection, assisting with interpretation of the data and reading the manuscript for intellectual content. MMV and AP were responsible for the design and conceptualisation of the study and reading the manuscript for intellectual content and revision of the manuscript. All authors commented on the final version of the manuscript.

  • Funding This study was supported in part by Marató de TV3 (20141830, AS).

  • Competing interests IK: received postdoctoral research exchange fellowship from ECTRIMS. DKS: 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, 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, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma, Takeda Pharmaceuticals, Asahi Kasei Medical, 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, Novartis and Roche. MS: has received consulting and speaker honoraria as well as travel reimbursements from Bayer, Biogen, Celgene, Roche, Sanofi Genzyme and Teva and research funding from the Hertha-Nathorff-Program and University of UlmHT: 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: has received speaker and consulting fees from Merck-Serono, Biogen, Teva, Genzyme and Novartis. SAT: non-financial support and/or personal fees from Biogen, Merck Serono, Novartis, Roche and Teva. Involved with clinical trials run by Biogen and Sanofi Genzyme. Supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. IN: 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 grants 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.

  • Patient consent for publication Not required.

  • Ethics approval The cerebrospinal fluid samples were collected according to standard protocols with local ethics approval

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Any additional data that may not be available directly in the article are available from the corresponding author on reasonable request.

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