A metabolomics view into perturbations of the plasma lipidome following traumatic brain injury

Traumatic Brain Injury (TBI) is a neurological disorder caused when a sudden external force is applied to the head, resulting in various pathophysiological changes dependent on the amount of force applied. There is an emerging interest in altering TBI diagnosis from a subjective to an objective measure. Multiple studies have demonstrated that various lipid classes and species show abnormal concentration levels from hours to months post-TBI, that can be used to differentiate between repetitive, mild, moderate, and severe TBI. The purpose of this thesis was to explore varying TBI injuries using liquid chromatography mass spectrometry to further elucidate lipidomic perturbations following a singular and repeated TBI in vivo, and further provide a comprehensive lipidomic signature of clinical mild traumatic brain injury (mTBI) at ≤48 hours and 28 days post injury. Study one utilised a rodent model to examine lipidomic changes associated in a singular mild traumatic brain injury (1x mTBI) and two consecutive mild traumatic brain injuries (2x mTBI) (sham control group n = 6, 1x mTBI n = 7, 2x mTBI n = 7). Lipidomic profiles indicated significant separation between the three study groups (i.e., sham control, 1x mTBI, and 2x mTBI). From multivariate analysis, a predictive model was constructed using the sham control and 2x mTBI groups that projected the metabolic position of 1x mTBI centrally in the model, indicating a progression of biomarker severity as the TBI intervention occurrence increases. Compared to sham controls, 1x and 2x mTBI rats both showed decreased levels of PS 14:0/18:2 and HCER d18:0/26:0 and PI 20:0/18:2 and increases in FFA 18:3. However, when comparing sham to 2x mTBI, decreases in concentrations of LPE 20:1, LPE 22:6, LPE 22:5, PI 16:0/18:2 and PI 16:0/18:3 were observed. Collectively these findings indicate that mTBI induces unique changes to lipid species in an injury dose-specific pattern. Study two (Chapter 4) we aimed to provide a comprehensive lipidomic signature of clinical mTBI patients at injury inception (i.e., time of diagnosis ≤48 hours) and follow-up (i.e., 35 days post mTBI injury) in 30 patients. Using liquid chromatography mass spectrometry 225 lipid species were deemed significantly different between the control and mTBI patients at the inception and follow-up timepoints. Multivariate analysis of this cohort displayed minimal variation between age and sex balanced controls and mTBI patients at inception. However, mTBI patients had a consistent metabolic shift from patient inception to follow-up, demonstrating perturbed plasma lipidome. Perturbation could be classified in patients regardless of the mTBI causing injury (i.e., fall, assault, or motor vehicle accident). Data from these studies will inform the design of future investigations of lipid metabolism and mechanisms following mTBI and repeat mTBI (rmTBI), allowing identification of novel biomarkers and the optimum ‘window of opportunity’ for therapeutic intervention in mTBI