Investigating neurodegeneration after traumatic brain injury: a longitudinal study of axonal injury

Abstract

Traumatic brain injury (TBI) is associated with neurodegeneration and dementia, with Alzheimer’s disease (AD) reported to be more prevalent post-injury. Traumatic axonal injury (TAI) is suspected to trigger progressive neurodegeneration, with axonal damage leading to proteinopathies of tau and amyloid, also features of AD. However, while axonal injury has been difficult to assess clinically, advances in biomarkers now make this more amenable to quantification. This thesis uses advanced fluid and imaging biomarkers to investigate TAI longitudinally and assess how this relates to neurodegeneration post-TBI. I assess biomarkers in plasma and cerebral microdialysate after acute moderate-severe injuries, relating changes to diffusion tensor imaging (DTI) MRI measures of TAI, brain volumetric change and clinical outcomes. In a separate cohort in the chronic phase I assess how DTI measures predict neurodegeneration in comparison with other possible predictors, and characterise the neurodegenerative consequences of injury in comparison with AD and atrophy in healthy ageing. I found that axonal markers neurofilament light (NfL) and tau were markedly increased in concentration within brain extracellular fluid early post-TBI, correlating closely with plasma levels. Subacute plasma NfL related to DTI measures of TAI, predicted clinical outcomes and white matter neurodegeneration, with peak tau predicting grey matter atrophy. In the chronic phase, I found that DTI predicts the extent and pattern of brain atrophy and explains substantially more variance than clinical severity measures. Comparing post-traumatic atrophy with AD and ageing, I show that post-traumatic atrophy patterns are distinctive and reminiscent of axonal injury spatially. These findings provide evidence of axonal injury as a trigger of progressive neurodegeneration and show this can be sensitively measured with fluid and neuroimaging tools both early and late after single moderate-severe injury. These approaches have the potential to improve clinical diagnosis of TAI and its sequelae, prognostication, and facilitate trials of anti-neurodegeneration treatments.