{
  "abstract": "Background and objectives Biologically informative markers like glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) may help predict confirmed disability worsening (CDW) in multiple sclerosis (MS). However, data on the prognostic value of their blood concentrations in progressive MS (PMS) are limited, and there are substantial discrepancies in the published literature. This international collaboration uses individual participant data to define the prognostic value of serum GFAP and NfL in people with PMS (pwPMS).Methods Data were collected from BioMS-eu network centres and collaborating cohorts. pwPMS with primary progressive MS (PPMS) or secondary progressive MS (SPMS) with at least one GFAP value and at least three follow-up expanded disability status scale (EDSS) scores were included. The prognostic value of serum GFAP and NfL age- and sex-adjusted Z-scores for future CDW was evaluated using Cox regression models, accounting for sex, age, baseline disease duration and EDSS, and dominant treatment during follow-up.Results 1058 participants and 7530 encounters were included (median age 53 years (IQR: 44 to 59), 57% female, follow-up 4.6 years (2.9 to 8.4)) with median baseline GFAP of 0.74 (−0.10 to 1.55) and NfL of 0.64 (−0.36 to 1.51). 723 CDW events were recorded. Each GFAP Z-score increase was associated with ~10% higher CDW risk (adjusted HR (aHR) 1.107 (1.001 to 1.225), p=0.049). Results were mainly driven by SPMS participants (n=613, aHR 1.242 (1.073 to 1.438), p=0.004). Higher NfL Z-scores predicted CDW only in PPMS participants (1.236 (1.092 to 1.399), p=0.001).Conclusions GFAP was a prognostic indicator for future CDW in pwPMS, especially in pwSPMS. On the other hand, NfL was predictive of CDW only in pwPPMS.",
  "authors": [
    {
      "affiliations": [
        "Department of Neurology, University of California San Francisco (UCSF), San Francisco, California, USA"
      ],
      "name": "Ahmed Abdelhak"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Ulm, Ulm, Germany"
      ],
      "name": "Franziska Bachhuber"
    },
    {
      "affiliations": [
        "Department of Neurology, University of California San Francisco (UCSF), San Francisco, California, USA"
      ],
      "name": "Kiarra Ning"
    },
    {
      "affiliations": [
        "Department of Clinical Research, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Pascal Benkert"
    },
    {
      "affiliations": [
        "Departments of Medicine and Epidemiology & Biostatistics, University of California at San Francisco (UCSF), San Francisco, California, USA"
      ],
      "name": "W John Boscardin"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital Basel, Basel, BS, Switzerland",
        "Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital Basel, Basel, BS, Switzerland"
      ],
      "name": "Aleksandra Maleska Maceski"
    },
    {
      "affiliations": [
        "Department of Clinical Research, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Sabine Schaedelin"
    },
    {
      "affiliations": [
        "Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland"
      ],
      "name": "Lutz Achtnichts"
    },
    {
      "affiliations": [
        "Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland"
      ],
      "name": "Sebastian Finkener"
    },
    {
      "affiliations": [
        "Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, Geneva, Switzerland"
      ],
      "name": "Patrice H Lalive"
    },
    {
      "affiliations": [
        "Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, Geneva, Switzerland"
      ],
      "name": "Marjolaine Uginet"
    },
    {
      "affiliations": [
        "Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland"
      ],
      "name": "Caroline Pot"
    },
    {
      "affiliations": [
        "Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland"
      ],
      "name": "Renaud Du Pasquier"
    },
    {
      "affiliations": [
        "Department of Neurology, Bern University Hospital and University of Bern, Bern, Switzerland"
      ],
      "name": "Robert Hoepner"
    },
    {
      "affiliations": [
        "Department of Neurology, Bern University Hospital and University of Bern, Bern, Switzerland"
      ],
      "name": "Andrew Chan"
    },
    {
      "affiliations": [
        "Neurology Clinic Lugano, Neurocenter of Southern Switzerland, Lugano, Switzerland"
      ],
      "name": "Claudio Gobbi"
    },
    {
      "affiliations": [
        "Neurology Clinic Lugano, Neurocenter of Southern Switzerland, Lugano, Switzerland",
        "Faculty of Biomedical Sciences, Università Della Svizzera Italiana (USI), Lugano, Switzerland"
      ],
      "name": "Chiara Zecca"
    },
    {
      "affiliations": [
        "Department of Neurology, University teaching and research hospital St. Gallen, St. Gallen, Switzerland"
      ],
      "name": "Stefanie Müller"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland"
      ],
      "name": "Patrick Roth"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital Basel, Basel, BS, Switzerland",
        "Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital Basel, Basel, BS, Switzerland",
        "Department of Medicine and Biomedical Engineering, Translational Imaging in Neurology Basel, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Cristina Granziera"
    },
    {
      "affiliations": [
        "Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA",
        "Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Tanuja Chitnis"
    },
    {
      "affiliations": [
        "Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Evan Madill"
    },
    {
      "affiliations": [
        "Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Howard L Weiner"
    },
    {
      "affiliations": [
        "Department of Neurology, University of California San Francisco (UCSF), San Francisco, California, USA"
      ],
      "name": "Ari J Green"
    },
    {
      "affiliations": [
        "Department of Neurology, University of California San Francisco (UCSF), San Francisco, California, USA"
      ],
      "name": "Stephen L Hauser"
    },
    {
      "affiliations": [
        "Department of Neurology, University of California San Francisco (UCSF), San Francisco, California, USA"
      ],
      "name": "Bruce AC Cree"
    },
    {
      "affiliations": [
        "Institute of Clinical Neuroimmunology, University Hospital Munich, Ludwig Maximilian University Munich, Munich, Germany"
      ],
      "name": "Tania Kümpfel"
    },
    {
      "affiliations": [
        "Institute of Clinical Neuroimmunology, University Hospital Munich, Ludwig Maximilian University Munich, Munich, Germany"
      ],
      "name": "Joachim Havla"
    },
    {
      "affiliations": [
        "Department of Neurology, Hannover Medical School, Hannover, Germany"
      ],
      "name": "Thomas Skripuletz"
    },
    {
      "affiliations": [
        "Department of Neurology, Hannover Medical School, Hannover, Germany"
      ],
      "name": "Stefan Gingele"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Ulm, Ulm, Germany"
      ],
      "name": "Makbule Senel"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Ulm, Ulm, Germany"
      ],
      "name": "Ioannis Vardakas"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Ulm, Ulm, Germany"
      ],
      "name": "Daniela Taranu"
    },
    {
      "affiliations": [
        "Department of Neurology & Stroke, Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen, Tübingen, Germany"
      ],
      "name": "Ulf Ziemann"
    },
    {
      "affiliations": [
        "Department of Neurology & Stroke, Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen, Tübingen, Germany"
      ],
      "name": "Markus C Kowarik"
    },
    {
      "affiliations": [
        "Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany",
        "Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke, Berg, Germany"
      ],
      "name": "Ingo Kleiter"
    },
    {
      "affiliations": [
        "Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke, Berg, Germany"
      ],
      "name": "Muna-Miriam Hoshi"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Rostock, Rostock, Germany"
      ],
      "name": "Uwe K Zettl"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital of Würzburg, Würzburg, Germany"
      ],
      "name": "Axel Haarmann"
    },
    {
      "affiliations": [
        "The Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University and McGill University Health Centre (MUHC), Montreal, Quebec, Canada"
      ],
      "name": "Simon Thebault"
    },
    {
      "affiliations": [
        "Department of Medicine, The Ottawa Hospital & The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada"
      ],
      "name": "Mark S Freedman"
    },
    {
      "affiliations": [
        "Department of Medicine, The Ottawa Hospital & The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada"
      ],
      "name": "Hailey P Bergman"
    },
    {
      "affiliations": [
        "Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden",
        "Department of Neurology, Karolinska University Hospital, Stockholm, Sweden"
      ],
      "name": "Ellen Iacobaeus"
    },
    {
      "affiliations": [
        "Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden"
      ],
      "name": "Mohsen Khademi"
    },
    {
      "affiliations": [
        "Neurology Unit, Department of Neurosciences, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy"
      ],
      "name": "Diana Ferraro"
    },
    {
      "affiliations": [
        "Department of Biomedical, Metabolic and Neurosciences, University of Modena and Reggio Emilia, Faculty of Medicine and Surgery, Modena, Emilia-Romagna, Italy"
      ],
      "name": "Martina Cardi"
    },
    {
      "affiliations": [
        "Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy"
      ],
      "name": "Sara Mariotto"
    },
    {
      "affiliations": [
        "Servei de Neurologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain",
        "Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED) - ISCIII, Madrid, Spain"
      ],
      "name": "Manuel Comabella"
    },
    {
      "affiliations": [
        "Servei de Neurologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain",
        "Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED) - ISCIII, Madrid, Spain"
      ],
      "name": "Xavier Montalban"
    },
    {
      "affiliations": [
        "Servei de Neurologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain"
      ],
      "name": "Andreu Vilaseca-Jolonch"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands",
        "Department of Neurodegeneration, Amsterdam Neurosciences, Amsterdam, The Netherlands"
      ],
      "name": "Eva M Strijbis"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands",
        "Department of Clinical Chemistry, MS Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands"
      ],
      "name": "Mark HJ Wessels"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands",
        "Department of Neurodegeneration, Amsterdam Neurosciences, Amsterdam, The Netherlands"
      ],
      "name": "Joep Killestein"
    },
    {
      "affiliations": [
        "Department of Neurology, TUM University Hospital, Technical University of Munich, Munich, Germany",
        "Munich Cluster for Systems Neurology (SyNergy), Munich, Germany"
      ],
      "name": "Bernhard Hemmer"
    },
    {
      "affiliations": [
        "Department of Neurology, TUM University Hospital, Technical University of Munich, Munich, Germany"
      ],
      "name": "Friederike Held"
    },
    {
      "affiliations": [
        "Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark"
      ],
      "name": "Finn Sellebjerg"
    },
    {
      "affiliations": [
        "Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark"
      ],
      "name": "Helene Højsgaard Chow"
    },
    {
      "affiliations": [
        "Grupo de Investigación de Esclerosis Múltiple, Instituto de Investigación Sanitaria San Carlos (IdISSC)/Hospital Clínico San Carlos, Madrid, Spain"
      ],
      "name": "Roberto Alvarez-Lafuente"
    },
    {
      "affiliations": [
        "Grupo de Investigación de Esclerosis Múltiple, Instituto de Investigación Sanitaria San Carlos (IdISSC)/Hospital Clínico San Carlos, Madrid, Spain"
      ],
      "name": "Maria Inmaculada Domínguez-Mozo"
    },
    {
      "affiliations": [
        "Department of Neurology, Innbruck Medical University, Innsbruck, Austria"
      ],
      "name": "Harald Hegen"
    },
    {
      "affiliations": [
        "Department of Neurology, Innbruck Medical University, Innsbruck, Austria"
      ],
      "name": "Klaus Berek"
    },
    {
      "affiliations": [
        "Department of Neurology, Innbruck Medical University, Innsbruck, Austria"
      ],
      "name": "Florian Deisenhammer"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital of Nîmes, Nîmes, France"
      ],
      "name": "Eric Thouvenot"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital of Nîmes, Nîmes, France"
      ],
      "name": "Hanane Agherbi"
    },
    {
      "affiliations": [
        "Department of Neurology, Medical University of Lublin, Lublin, Poland"
      ],
      "name": "Konrad Rejdak"
    },
    {
      "affiliations": [
        "Department of Neurology, Medical University of Lublin, Lublin, Poland"
      ],
      "name": "Magda Gąsior"
    },
    {
      "affiliations": [
        "Second Department of Neurology, National & Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece"
      ],
      "name": "Dimitrios Tzanetakos"
    },
    {
      "affiliations": [
        "Second Department of Neurology, National & Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece",
        "Tzartos NeuroDiagnostics, Athens, Greece"
      ],
      "name": "John S Tzartos"
    },
    {
      "affiliations": [
        "Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy"
      ],
      "name": "Maria Pia Sormani"
    },
    {
      "affiliations": [
        "Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA"
      ],
      "name": "Irena Dujmovic Basuroski"
    },
    {
      "affiliations": [
        "Servei de Neurologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain"
      ],
      "name": "Georgina Arrambide"
    },
    {
      "affiliations": [
        "Department of Neurology, Medical University of Graz, Graz, Austria",
        "Neurology Biomarker Research Unit, Medical University of Graz, Graz, Austria"
      ],
      "name": "Michael Khalil"
    },
    {
      "affiliations": [
        "Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden",
        "Department of Neurology, Karolinska University Hospital, Stockholm, Sweden"
      ],
      "name": "Fredrik Piehl"
    },
    {
      "affiliations": [
        "Department of Neurodegeneration, Amsterdam Neurosciences, Amsterdam, The Netherlands",
        "Department of Clinical Chemistry, MS Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands"
      ],
      "name": "Charlotte E Teunissen"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital Basel, Basel, BS, Switzerland",
        "Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital Basel, Basel, BS, Switzerland",
        "Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Jens Kuhle"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Ulm, Ulm, Germany"
      ],
      "name": "Hayrettin Tumani"
    }
  ],
  "title": "Blood biomarkers for predicting disability worsening in progressive multiple sclerosis: a multinational, individual participant-level analysis",
  "uid": "29817db6-f48e-58f1-8969-0a5a2081f421"
}