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

Description Axonal injury after TBI can be reliably quantified using plasma NfL, which predicts long-term functional outcomes and progressive neurodegeneration. Circulating predictor Precise diagnosis of traumatic brain injury (TBI) and prediction of long-term outcome will help the development of better treatments. Axonal damage, a predictor of clinical outcomes, has been difficult to measure in patients. Here, Graham et al. performed a multicenter study and showed that the plasma concentration of the neurofilament light (NfL) protein increased after TBI in patients and correlated with a magnetic resonance imaging–based index of axonal damage. Plasma NfL concentration predicted white matter damage and clinical outcome. They validated the results in a rodent model, showing a positive correlation between axonal damage and plasma NfL. The results indicate that measuring plasma NfL could improve diagnosis and prognosis after TBI. 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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