Blood biomarkers for predicting disability worsening in progressive multiple sclerosis: a multinational, individual participant-level analysis

Ahmed Abdelhak¹, Franziska Bachhuber², Kiarra Ning³, Pascal Benkert⁴, W John Boscardin⁵, Aleksandra Maleska Maceski^{6

7}, Sabine Schaedelin⁴, Lutz Achtnichts⁸, Sebastian Finkener⁸, Patrice H Lalive⁹, Marjolaine Uginet⁹, Caroline Pot¹⁰, Renaud Du Pasquier¹⁰, Robert Hoepner¹¹, Andrew Chan¹¹, Claudio Gobbi¹², Chiara Zecca^{12

13}, Stefanie Müller¹⁴, Patrick Roth¹⁵, Cristina Granziera^{6

7

16}, Tanuja Chitnis^{17

18}, Evan Madill¹⁸, Howard L Weiner¹⁸, Ari J Green³, Stephen L Hauser³, Bruce Ac Cree³, Tania Kümpfel¹⁹, Joachim Havla¹⁹, Thomas Skripuletz²⁰, Stefan Gingele²⁰, Makbule Senel², Ioannis Vardakas², Daniela Taranu², Ulf Ziemann²¹, Markus C Kowarik²¹, Ingo Kleiter^{22

23}, Muna-Miriam Hoshi²³, Uwe K Zettl²⁴, Axel Haarmann²⁵, Simon Thebault²⁶, Mark S Freedman²⁷, Hailey P Bergman²⁷, Ellen Iacobaeus^{28

29}, Mohsen Khademi²⁸, Diana Ferraro³⁰, Martina Cardi³¹, Sara Mariotto³², Manuel Comabella^{33

34}, Xavier Montalban^{33

34}, Andreu Vilaseca-Jolonch³³, Eva M Strijbis^{35

36}, Mark Hj Wessels^{35

37}, Joep Killestein^{35

36}, Bernhard Hemmer^{38

39}, Friederike Held³⁸, Finn Sellebjerg⁴⁰, Helene Højsgaard Chow⁴⁰, Roberto Alvarez-Lafuente⁴¹, Maria Inmaculada Domínguez-Mozo⁴¹, Harald Hegen⁴², Klaus Berek⁴², Florian Deisenhammer⁴², Eric Thouvenot⁴³, Hanane Agherbi⁴³, Konrad Rejdak⁴⁴, Magda Gąsior⁴⁴, Dimitrios Tzanetakos⁴⁵, John S Tzartos^{45

46}, Maria Pia Sormani⁴⁷, Irena Dujmovic Basuroski⁴⁸, Georgina Arrambide³³, Michael Khalil^{49

50}, Fredrik Piehl^{28

29}, Charlotte E Teunissen^{36

37}, Jens Kuhle^{6

7

51}, Hayrettin Tumani²

Affiliations

¹ Department of Neurology, University of California San Francisco (UCSF), San Francisco, California, USA Ahmed.Abdelhak@ucsf.edu.
² Department of Neurology, University of Ulm, Ulm, Germany.
³ Department of Neurology, University of California San Francisco (UCSF), San Francisco, California, USA.
⁴ Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
⁵ Departments of Medicine and Epidemiology & Biostatistics, University of California at San Francisco (UCSF), San Francisco, California, USA.
⁶ Department of Neurology, University Hospital Basel, Basel, BS, Switzerland.
⁷ Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital Basel, Basel, BS, Switzerland.
⁸ Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
⁹ Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, Geneva, Switzerland.
¹⁰ Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.
¹¹ Department of Neurology, Bern University Hospital and University of Bern, Bern, Switzerland.
¹² Neurology Clinic Lugano, Neurocenter of Southern Switzerland, Lugano, Switzerland.
¹³ Faculty of Biomedical Sciences, Università Della Svizzera Italiana (USI), Lugano, Switzerland.
¹⁴ Department of Neurology, University teaching and research hospital St. Gallen, St. Gallen, Switzerland.
¹⁵ Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
¹⁶ Department of Medicine and Biomedical Engineering, Translational Imaging in Neurology Basel, University Hospital Basel, Basel, Switzerland.
¹⁷ Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁸ Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁹ Institute of Clinical Neuroimmunology, University Hospital Munich, Ludwig Maximilian University Munich, Munich, Germany.
²⁰ Department of Neurology, Hannover Medical School, Hannover, Germany.
²¹ Department of Neurology & Stroke, Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen, Tübingen, Germany.
²² Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.
²³ Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke, Berg, Germany.
²⁴ Department of Neurology, University of Rostock, Rostock, Germany.
²⁵ Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.
²⁶ The Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University and McGill University Health Centre (MUHC), Montreal, Quebec, Canada.
²⁷ Department of Medicine, The Ottawa Hospital & The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
²⁸ Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
²⁹ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
³⁰ Neurology Unit, Department of Neurosciences, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy.
³¹ Department of Biomedical, Metabolic and Neurosciences, University of Modena and Reggio Emilia, Faculty of Medicine and Surgery, Modena, Emilia-Romagna, Italy.
³² Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
³³ 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.
³⁴ Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED) - ISCIII, Madrid, Spain.
³⁵ Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands.
³⁶ Department of Neurodegeneration, Amsterdam Neurosciences, Amsterdam, The Netherlands.
³⁷ Department of Clinical Chemistry, MS Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands.
³⁸ Department of Neurology, TUM University Hospital, Technical University of Munich, Munich, Germany.
³⁹ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁰ Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
⁴¹ Grupo de Investigación de Esclerosis Múltiple, Instituto de Investigación Sanitaria San Carlos (IdISSC)/Hospital Clínico San Carlos, Madrid, Spain.
⁴² Department of Neurology, Innbruck Medical University, Innsbruck, Austria.
⁴³ Department of Neurology, University Hospital of Nîmes, Nîmes, France.
⁴⁴ Department of Neurology, Medical University of Lublin, Lublin, Poland.
⁴⁵ Second Department of Neurology, National & Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece.
⁴⁶ Tzartos NeuroDiagnostics, Athens, Greece.
⁴⁷ Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
⁴⁸ Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
⁴⁹ Department of Neurology, Medical University of Graz, Graz, Austria.
⁵⁰ Neurology Biomarker Research Unit, Medical University of Graz, Graz, Austria.
⁵¹ Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

PMID: 40506119
DOI: 10.1136/jnnp-2025-335831

Blood biomarkers for predicting disability worsening in progressive multiple sclerosis: a multinational, individual participant-level analysis

Ahmed Abdelhak et al. J Neurol Neurosurg Psychiatry. 2025.

. 2025 Jun 12:jnnp-2025-335831.

doi: 10.1136/jnnp-2025-335831. Online ahead of print.

Authors

Affiliations

¹ Department of Neurology, University of California San Francisco (UCSF), San Francisco, California, USA Ahmed.Abdelhak@ucsf.edu.
² Department of Neurology, University of Ulm, Ulm, Germany.
³ Department of Neurology, University of California San Francisco (UCSF), San Francisco, California, USA.
⁴ Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
⁵ Departments of Medicine and Epidemiology & Biostatistics, University of California at San Francisco (UCSF), San Francisco, California, USA.
⁶ Department of Neurology, University Hospital Basel, Basel, BS, Switzerland.
⁷ Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital Basel, Basel, BS, Switzerland.
⁸ Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
⁹ Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, Geneva, Switzerland.
¹⁰ Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.
¹¹ Department of Neurology, Bern University Hospital and University of Bern, Bern, Switzerland.
¹² Neurology Clinic Lugano, Neurocenter of Southern Switzerland, Lugano, Switzerland.
¹³ Faculty of Biomedical Sciences, Università Della Svizzera Italiana (USI), Lugano, Switzerland.
¹⁴ Department of Neurology, University teaching and research hospital St. Gallen, St. Gallen, Switzerland.
¹⁵ Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
¹⁶ Department of Medicine and Biomedical Engineering, Translational Imaging in Neurology Basel, University Hospital Basel, Basel, Switzerland.
¹⁷ Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁸ Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁹ Institute of Clinical Neuroimmunology, University Hospital Munich, Ludwig Maximilian University Munich, Munich, Germany.
²⁰ Department of Neurology, Hannover Medical School, Hannover, Germany.
²¹ Department of Neurology & Stroke, Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen, Tübingen, Germany.
²² Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.
²³ Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke, Berg, Germany.
²⁴ Department of Neurology, University of Rostock, Rostock, Germany.
²⁵ Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.
²⁶ The Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University and McGill University Health Centre (MUHC), Montreal, Quebec, Canada.
²⁷ Department of Medicine, The Ottawa Hospital & The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
²⁸ Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
²⁹ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
³⁰ Neurology Unit, Department of Neurosciences, Azienda Ospedaliero-Universitaria of Modena, Modena, Italy.
³¹ Department of Biomedical, Metabolic and Neurosciences, University of Modena and Reggio Emilia, Faculty of Medicine and Surgery, Modena, Emilia-Romagna, Italy.
³² Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
³³ 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.
³⁴ Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED) - ISCIII, Madrid, Spain.
³⁵ Department of Neurology, MS Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands.
³⁶ Department of Neurodegeneration, Amsterdam Neurosciences, Amsterdam, The Netherlands.
³⁷ Department of Clinical Chemistry, MS Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands.
³⁸ Department of Neurology, TUM University Hospital, Technical University of Munich, Munich, Germany.
³⁹ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁰ Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
⁴¹ Grupo de Investigación de Esclerosis Múltiple, Instituto de Investigación Sanitaria San Carlos (IdISSC)/Hospital Clínico San Carlos, Madrid, Spain.
⁴² Department of Neurology, Innbruck Medical University, Innsbruck, Austria.
⁴³ Department of Neurology, University Hospital of Nîmes, Nîmes, France.
⁴⁴ Department of Neurology, Medical University of Lublin, Lublin, Poland.
⁴⁵ Second Department of Neurology, National & Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece.
⁴⁶ Tzartos NeuroDiagnostics, Athens, Greece.
⁴⁷ Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
⁴⁸ Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
⁴⁹ Department of Neurology, Medical University of Graz, Graz, Austria.
⁵⁰ Neurology Biomarker Research Unit, Medical University of Graz, Graz, Austria.
⁵¹ Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

PMID: 40506119
DOI: 10.1136/jnnp-2025-335831

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.

Keywords: MULTIPLE SCLEROSIS; Prognosis.

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Competing interests: None declared.

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Blood biomarkers for predicting disability worsening in progressive multiple sclerosis: a multinational, individual participant-level analysis

Affiliations

Blood biomarkers for predicting disability worsening in progressive multiple sclerosis: a multinational, individual participant-level analysis

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Miscellaneous