Clinical features, biomechanics and advanced biomarkers across the spectrum of traumatic brain injury.

Abstract

Long-term outcomes after traumatic brain injury (TBI) are frequently poor, yet hard to predict. Acute clinical symptoms and conventional diagnostics currently used do not necessarily reflect underlying structural damage relevant to outcomes such as diffuse axonal injury (DAI) nor long-term risk of neuropathology. However, advanced fluid and imaging biomarkers, along with impact biomechanics may provide quantitative metrics better able to inform outcomes after a spectrum of TBI.

This thesis uses advanced neuroimaging and fluid biomarkers to assess the extent of DAI after TBI. I assess changes to diffusion tensor imaging (DTI) metrics of DAI and how they relate to fluid biomarkers and clinical outcomes after moderate-severe TBI. I further test whether these DTI measures, along serial structural MRI, also detect evidence of DAI and brain volumetric changes in athletes exposed to head impacts and mild TBIs (mTBI). In American footballers, I analyse impact biomechanics to explore the relationship of brain deformation metrics with acute clinical symptoms and long-term neuropathology.

I show imaging evidence of DAI after moderate-severe TBI, which correlate with neurofilament light concentrations and strongly predict functional outcomes at 12 months post injury. In professional rugby players, I find neuroimaging evidence of DAI irrespective of whether a player has suffered an mTBI recently. I also find abnormal trajectories of white matter volume change. In American footballers, I show that player position influences the magnitude of forces in the brain, and these appear relevant to both acute clinical symptoms and long term neuropathology.

My data highlights the utility of DTI and fluid biomarkers in detecting axonal injury across a spectrum of TBI severity. These approaches can improve current methods for diagnosing and classifying TBI patients. This is particularly relevant to mTBI and participation in contact sports, where risk of acute clinical symptoms doesn’t necessarily reflect risk of long term pathology.