Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury
Neil Graham, Karl Zimmerman, Federico Moro, Amanda Heslegrave, Samia Abed Maillard, Adriano Bernini, John‐Paul Miroz, Cornelius K. Donat, Maria Yanez Lopez, Niall Bourke, Amy Jolly, Emma‐Jane Mallas, Eyal Soreq, Mark H. Wilson, Gavin Fatania, Dylan Roi, Maneesh C. Patel, Elena Garbero, Giovanni Nattino, Camelia Baciu, Enrico Fainardi, Arturo Chieregato, Primož Gradišek, Sandra Magnoni, Mauro Oddo, Henrik Zetterberg, Guido Bertolini, David Sharp
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.