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Serum glial fibrillary acidic protein correlates with retinal structural damage in aquaporin-4 antibody positive neuromyelitis optica spectrum disorder

  • Author Footnotes
    1 These authors contributed equally to this work.
    Ting-Yi Lin
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Patrick Schindler
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Department of Neurology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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  • Ulrike Grittner
    Affiliations
    Institute for Biometry and Clinical Epidemiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany

    Berlin Institute of Health, Berlin, Germany
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  • Frederike C. Oertel
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    Department of Neurology, University of California San Francisco, CA, USA
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  • Angelo Lu
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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  • Seyedamirhosein Motamedi
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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  • Sunil Kumar Yadav
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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  • Ankelien S. Duchow
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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  • Sven Jarius
    Affiliations
    Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany
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  • Jens Kuhle
    Affiliations
    Neurology Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, Switzerland
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  • Pascal Benkert
    Affiliations
    Clinical Trial Unit, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland
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  • Alexander U. Brandt
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    Department of Neurology, University of California Irvine, CA, USA
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  • Judith Bellmann-Strobl
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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  • Tanja Schmitz-Hübsch
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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  • Friedemann Paul
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Department of Neurology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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  • Author Footnotes
    2 These authors contributed equally to this work.
    Klemens Ruprecht
    Footnotes
    2 These authors contributed equally to this work.
    Affiliations
    Department of Neurology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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  • Author Footnotes
    2 These authors contributed equally to this work.
    Hanna G. Zimmermann
    Correspondence
    Corresponding author at: Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Lindenberger Weg 80, Berlin 13125, Germany.
    Footnotes
    2 These authors contributed equally to this work.
    Affiliations
    Experimental and Clinical Research Center, A Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité – Universitätsmedizin Berlin, Berlin, Germany

    Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany

    NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Einstein Center Digital Future, Berlin, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    2 These authors contributed equally to this work.
Published:August 09, 2022DOI:https://doi.org/10.1016/j.msard.2022.104100

      Highlights

      • Increased sGFAP levels are associated with neuro-axonal retinal layer thinning in clinically stable AQP4-IgG+ NMOSD patients.
      • More profound functional visual impairment can be found in AQP4-IgG+ NMOSD patients with higher sGFAP levels.
      • The absence of associations between sGFAP and retinal or functional visual alterations in MOGAD supports the specificity of sGFAP as a marker for subclinical chronic disease activity in AQP4-IgG+ NMOSD.

      Abstract

      Background

      Aquaporin-4 immunoglobulin-G positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy associated with optic neuritis (ON). Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an oligodendrocytopathy with a similar phenotype. Serum glial fibrillary acidic protein (sGFAP), an astrocyte-derived protein, is associated with disease severity in AQP4-IgG+ NMOSD. Serum neurofilament light (sNfL) indicates neuroaxonal damage. The objective was to investigate the association of sGFAP and sNfL with subclinical afferent visual system damage in clinically stable AQP4-IgG+ NMOSD and MOGAD patients.

      Methods

      In this cross-sectional study, clinically stable patients with AQP4-IgG+ NMOSD (N = 33) and MOGAD (N = 16), as diseased controls, underwent sGFAP and sNfL measurements by single molecule array, retinal optical coherence tomography and visually evoked potentials.

      Results

      Higher sGFAP concentrations were associated with thinner ganglion cell-inner plexiform layer (β (95% confidence interval (CI)) = −0.75 (−1.23 to −0.27), p = 0.007) and shallower fovea (average pit depth: β (95%CI) = −0.59 (−0.63 to −0.55), p = 0.020) in NMOSD non-ON eyes. Participants with pathological P100 latency had higher sGFAP (median [interquartile range]: 131.32 [81.10–179.34] vs. 89.50 [53.46–121.91] pg/ml, p = 0.024). In MOGAD, sGFAP was not associated with retinal structural or visual functional measures.

      Conclusions

      The association of sGFAP with structural and functional markers of afferent visual system damage in absence of ON suggests that sGFAP may be a sensitive biomarker for chronic disease severity in clinically stable AQP4-IgG+ NMOSD.

      Keywords

      Abbreviations:

      AQP4 (aquaporin-4), NMOSD (neuromyelitisoptica spectrum disorder), MOG (myelin oligodendrocyte glycoprotein), MOGAD (MOG antibody-associated disease), IgG (immunoglobulin G), CBA (cell-based assay), ON (optic neuritis), OCT (optical coherence tomography), pRNFL (peripapillary retinal nerve fiber layer), mRNFL (macular retinal nerve fiber layer), GCIPL (combined macular ganglion cell and inner plexiform layer), ART (automatic real time), VEP (visually evoked potential), HCVA (high-contrast visual acuity), LCVA (low-contrast visual acuity), sGFAP (serum glial fibrillary acidic protein), sNfL (serum neurofilament light chain), EDSS (Expanded Disability Status Scale), SMD (standardized mean difference), LMM (linear mixed-effect model), β (standardized regression coefficient), CI (confidence interval), ηρ2 (partial eta squared), IQR (interquartile range)
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