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Blood GFAP as an emerging biomarker in brain and spinal cord disorders

Nature Reviews Neurology volume 18, pages 158–172 (2022)Cite this article

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Abstract

Blood-derived biomarkers for brain and spinal cord diseases are urgently needed. The introduction of highly sensitive immunoassays led to a rapid increase in the number of potential blood-derived biomarkers for diagnosis and monitoring of neurological disorders. In 2018, the FDA authorized a blood test for clinical use in the evaluation of mild traumatic brain injury (TBI). The test measures levels of the astrocytic intermediate filament glial fibrillary acidic protein (GFAP) and neuroaxonal marker ubiquitin carboxy-terminal hydrolase L1. In TBI, blood GFAP levels are correlated with clinical severity and extent of intracranial pathology. Evidence also indicates that blood GFAP levels hold the potential to reflect, and might enable prediction of, worsening of disability in individuals with progressive multiple sclerosis. A growing body of evidence suggests that blood GFAP levels can be used to detect even subtle injury to the CNS. Most importantly, the successful completion of the ongoing validation of point-of-care platforms for blood GFAP might ameliorate the decision algorithms for acute neurological diseases, such as TBI and stroke, with important economic implications. In this Review, we provide a systematic overview of the evidence regarding the utility of blood GFAP as a biomarker in neurological diseases. We propose a model for GFAP concentration dynamics in different conditions and discuss the limitations that hamper the widespread use of GFAP in the clinical setting. In our opinion, the clinical use of blood GFAP measurements has the potential to contribute to accelerated diagnosis and improved prognostication, and represents an important step forward in the era of precision medicine.

Key points

  • Glial fibrillary acidic protein (GFAP) levels reflect the clinical severity and extent of intracranial pathology after traumatic brain injury (TBI).

  • In 2018, the FDA authorized the marketing of a blood test for GFAP and ubiquitin carboxy-terminal hydrolase L1 for clinical use in mild TBI.

  • Growing evidence supports the potential clinical use of blood GFAP levels in numerous neuroinflammatory and neurodegenerative diseases, and in the context of CNS involvement in systemic diseases.

  • Successful validation of the GFAP point-of-care analysis platform might ameliorate the decision algorithms for acute neurological diseases with important economic implications.

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Fig. 1: Astrocytes have multiple physiological roles in the CNS.

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Authors and Affiliations

  1. Department of Neurology, University of California San Francisco (UCSF), San Francisco, CA, USA

    Ahmed Abdelhak & Ari J. Green

  2. Department of Neurology, University Hospital of Ulm, Ulm, Germany

    Ahmed Abdelhak, Samir Abu-Rumeileh, Andre Huss, Patrick Oeckl, Albert C. Ludolph, Markus Otto & Hayrettin Tumani

  3. Department of Neuroscience, Neurology Unit, S. Maria delle Croci Hospital – AUSL Romagna, ambito di Ravenna, Ravenna, Italy

    Matteo Foschi

  4. Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy

    Matteo Foschi

  5. Department of Neurology, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany

    Samir Abu-Rumeileh & Markus Otto

  6. Department of Neurosurgery, University of California San Francisco (UCSF), San Francisco, CA, USA

    John K. Yue & Geoffrey T. Manley

  7. Department of Stroke and Neuroscience, Charing Cross Hospital, Imperial College London NHS Healthcare Trust, London, UK

    Lucio D’Anna

  8. Department of Brain Sciences, Imperial College London, London, UK

    Lucio D’Anna

  9. German Center for Neurodegenerative Diseases (DZNE e.V.), Ulm, Germany

    Patrick Oeckl & Albert C. Ludolph

  10. Multiple Sclerosis Centre, Neurologic Clinic and Policlinic, Department of Head, Spine and Neuromedicine, University Hospital of Basel, Basel, Switzerland

    Jens Kuhle

  11. Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital of Basel, Basel, Switzerland

    Jens Kuhle

  12. Department of Biomedicine and Clinical Research, University Hospital of Basel, Basel, Switzerland

    Jens Kuhle

  13. Department of Clinical Research, University Hospital of Basel, Basel, Switzerland

    Jens Kuhle

  14. The National Hospital for Neurology and Neurosurgery, Queen Square, UCL Institute of Neurology, Moorfields Eye Hospital, London, UK

    Axel Petzold

  15. Neuro-ophthalmology Expert Center, Amsterdam UMC, Amsterdam, The Netherlands

    Axel Petzold

  16. Fachklinik für Neurologie Dietenbronn, Schwendi, Germany

    Hayrettin Tumani

Authors
  1. Ahmed Abdelhak
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  2. Matteo Foschi
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  3. Samir Abu-Rumeileh
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  6. Andre Huss
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  8. Albert C. Ludolph
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  9. Jens Kuhle
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Contributions

A.A., M.F., S.A.-R., J.K.Y., L.D’A., A.H. and P.O. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission. H.T., A.C.L., A.P., J.K., G.T.M, A.J.G., and M.O. made a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Hayrettin Tumani.

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Competing interests

A.A. received research grants from the German Multiple Sclerosis Society (DMSG). P.O. received research support from the Michael J. Fox Foundation for Parkinson´s Research (grant ID MJFF-010349) and Alzheimer Forschung Initiative e.V. (20059CB). J.K. received speaker fees, research support, travel support and/or served on advisory boards of the Swiss MS Society, Swiss National Research Foundation (320030_189140/1), University of Basel, Progressive MS Alliance, Bayer, Biogen, Celgene, Merck, Novartis, Roche and Sanofi. G.T.M. reports funding from the US Department of Defense – TBI Endpoints Development Initiative (grant #W81XWH-14-2-0176), TRACK-TBI Precision Medicine (grant #W81XWH-18-2-0042), TRACK-TBI NETWORK (grant #W81XWH-15-9-0001), NIH-NINDS – TRACK-TBI (grant #U01NS086090), National Football League (NFL) Scientific Advisory Board, with support from the NFL for the research efforts of TRACK-TBI NETWORK. In addition, the US Department of Energy supports G.T.M. for a precision medicine collaboration, Abbott Laboratories has provided funding for TRACK-TBI clinical studies, NeuroTrauma Sciences LLC has provided funding to support TRACK-TBI data curation efforts, One Mind has provided funding for TRACK-TBI patients stipends and support to clinical sites. J.K.Y. received funding from NIH-NINDS – TRACK-TBI (grant #U01NS086090). A.J.G. reports personal fees from Bionure, Mylan, Neurona and Viela Bio; other support from Pipeline Therapeutics; and grants and other support from Inception Sciences outside the submitted work. M.O. gave scientific advice to Axon, Biogen Idec, Fujirebio and Roche. H.T. reports funding for research projects, lectures and travel from Bayer, Biogen, Genzyme, Merck Serono, Novartis, Roche and Teva, and received research support from DMSG and the German Ministry for Education and Research (BMBF). No other disclosures are reported.

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Peer review information

Nature Reviews Neurology thanks C.A. Gonçalves, C. Foerch, S. Mondello, K. Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Review criteria

For this Review, we screened the published literature in PubMed using the following terms in the title or abstract: ‘GFAP’ OR ‘glial fibrillary acidic protein’, ‘blood’ OR ‘plasma’ OR ‘serum’, and the disease of interest. Hence, we added the following terms: ‘multiple sclerosis’, ‘MS’, ‘neuromyelitis optica’, ‘NMO’, ‘MOG antibody disease’, ‘MOG associated disease’, ‘traumatic brain injury’, ‘TBI’, ‘spinal trauma’, ‘spinal injury’, ‘stroke’, ‘cerebral ischemia’, ‘cerebral ischaemia’, ‘intracranial haemorrhage’, ‘intracranial hemorrhage, ‘subarachnoid haemorrhage’, ‘subarachnoid hemorrhage’, ‘Alzheimer’s’, ‘Parkinson’, ‘dementia’, ‘Creutzfeldt-Jakob disease’, ‘vascular cognitive impairment’, ‘vascular dementia’, ‘amyotrophic lateral sclerosis’, ‘motor neuron disease’, ‘ALS’, ‘MND’, ‘frontotemporal’, ‘prion’, ‘epilepsy’, ‘seizures’, ‘convulsions’, ‘encephalitis’, ‘encephalopathy’, ‘tumours’, ‘tumors’, ‘glioma’, ‘glioblastoma’, ‘COVID-19’, ‘SARS-CoV-2’, ‘cardiac arrest’, ‘hypoxic’ and ‘meningitis’. Animal studies, previous reviews, and studies reporting only GFAP values in CSF were considered beyond the scope of this article.

Glossary

Hook effect

An excess of the analyte of interest overwhelms the capture antibodies in immunoassays, resulting in a falsely low reading.

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Abdelhak, A., Foschi, M., Abu-Rumeileh, S. et al. Blood GFAP as an emerging biomarker in brain and spinal cord disorders. Nat Rev Neurol 18, 158–172 (2022). https://doi.org/10.1038/s41582-021-00616-3

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