Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury

Neil S N Graham^{1

2}, Karl A Zimmerman^{1

2}, Federico Moro^{3

4}, Amanda Heslegrave^{5

6}, Samia Abed Maillard⁷, Adriano Bernini⁷, John-Paul Miroz⁷, Cornelius K Donat¹, Maria Yanez Lopez⁸, Niall Bourke^{1

2}, Amy E Jolly^{1

2}, Emma-Jane Mallas^{1

2}, Eyal Soreq^{1

2}, Mark H Wilson^{9

10}, Gavin Fatania¹¹, Dylan Roi¹¹, Maneesh C Patel¹¹, Elena Garbero¹², Giovanni Nattino¹², Camelia Baciu¹³, Enrico Fainardi¹⁴, Arturo Chieregato¹³, Primoz Gradisek¹⁵, Sandra Magnoni¹⁶, Mauro Oddo^{7

17}, Henrik Zetterberg^{18

19}, Guido Bertolini¹², David J Sharp^{1

2

20}

Affiliations

¹ Department of Brain Sciences, Imperial College London, London W12 0NN, UK.
² UK DRI Centre for Care Research and Technology, Imperial College London, London W12 0BZ, UK.
³ Laboratory of Acute Brain Injury and Therapeutic Strategies, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo 24126, Italy.
⁴ Fondazione IRCCS, Ca' Granda Ospedale Maggiore Policlinico, Dipartimento di Anestesia e Rianimazione, 20122, Milan, Italy.
⁵ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
⁶ UK Dementia Research Institute at UCL, London WC1N 3BG, UK.
⁷ Neuroscience Critical Care Research Group, Department of Intensive Care Medicine, CHUV Lausanne University Hospital and University of Lausanne, Lausanne 1011, Switzerland.
⁸ Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King's College London, London SE1 7EH, UK.
⁹ Department of Neurosurgery, Imperial College Healthcare NHS Trust, London W6 8RF, UK.
¹⁰ Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
¹¹ Department of Imaging, Imperial College Healthcare NHS Trust, London W6 8RF, UK.
¹² Laboratory of Clinical Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo 24126, Italy.
¹³ Neurorianimazione, ASST Grande Ospedale Metropolitano Niguarda, Milano 20162, Italy.
¹⁴ Department of Experimental and Clinical Sciences, Careggi University Hospital, University of Firenze, Florence 50139, Italy.
¹⁵ Clinical Department of Anaesthesiology and Intensive Therapy, University Medical Center, Ljubljana 1000, Slovenia.
¹⁶ Department of Anesthesia and Intensive Care, Santa Chiara Hospital, Trento 38122, Italy.
¹⁷ Medical Direction, CHUV Lausanne University Hospital, Lausanne 1011, Switzerland.
¹⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal 431 41, Sweden.
¹⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 431 41, Sweden.
²⁰ Centre for Injury Studies, Imperial College London, London SW7 2AZ, UK.

PMID: 34586833
DOI: 10.1126/scitranslmed.abg9922

Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury

Neil S N Graham et al. Sci Transl Med. 2021.

. 2021 Sep 29;13(613):eabg9922.

doi: 10.1126/scitranslmed.abg9922. Epub 2021 Sep 29.

Authors

Affiliations

¹ Department of Brain Sciences, Imperial College London, London W12 0NN, UK.
² UK DRI Centre for Care Research and Technology, Imperial College London, London W12 0BZ, UK.
³ Laboratory of Acute Brain Injury and Therapeutic Strategies, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo 24126, Italy.
⁴ Fondazione IRCCS, Ca' Granda Ospedale Maggiore Policlinico, Dipartimento di Anestesia e Rianimazione, 20122, Milan, Italy.
⁵ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
⁶ UK Dementia Research Institute at UCL, London WC1N 3BG, UK.
⁷ Neuroscience Critical Care Research Group, Department of Intensive Care Medicine, CHUV Lausanne University Hospital and University of Lausanne, Lausanne 1011, Switzerland.
⁸ Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King's College London, London SE1 7EH, UK.
⁹ Department of Neurosurgery, Imperial College Healthcare NHS Trust, London W6 8RF, UK.
¹⁰ Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
¹¹ Department of Imaging, Imperial College Healthcare NHS Trust, London W6 8RF, UK.
¹² Laboratory of Clinical Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo 24126, Italy.
¹³ Neurorianimazione, ASST Grande Ospedale Metropolitano Niguarda, Milano 20162, Italy.
¹⁴ Department of Experimental and Clinical Sciences, Careggi University Hospital, University of Firenze, Florence 50139, Italy.
¹⁵ Clinical Department of Anaesthesiology and Intensive Therapy, University Medical Center, Ljubljana 1000, Slovenia.
¹⁶ Department of Anesthesia and Intensive Care, Santa Chiara Hospital, Trento 38122, Italy.
¹⁷ Medical Direction, CHUV Lausanne University Hospital, Lausanne 1011, Switzerland.
¹⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal 431 41, Sweden.
¹⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 431 41, Sweden.
²⁰ Centre for Injury Studies, Imperial College London, London SW7 2AZ, UK.

PMID: 34586833
DOI: 10.1126/scitranslmed.abg9922

Abstract

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.

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Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury

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Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury

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