| dc.description.abstract | Traumatic brain injury (TBI) is one of the largest causes of mortality and disability globally. The severity of TBI is clinically categorised into mild, moderate and severe injuries. Moderate and severe TBI often present with clear diagnostic criteria, such as loss of consciousness, skull fractures and/ or structural damage to the brain detectable by neuroimaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI) scans. However, mild TBI (mTBI), which is thought to represent almost 70% of TBI cases, is often difficult to recognise. In contrast to moderate and severe TBI, mTBI is incurred by a non-penetrating blow to the head, which may or may not result in loss of consciousness, and by most definitions, does not display abnormal neuroimaging findings. The spontaneous resolution of symptoms has also led to the perception that mTBI is a benign condition with no lasting consequences. However, in recent years, several reports have detailed a dementia-like condition in athletes and military veterans exposed to repetitive mTBI during the course of their careers. The condition is currently called chronic traumatic encephalopathy (CTE) and bears a close resemblance to a dementia condition described in the 1930s found to be prevalent in boxers, termed 'dementia pugilistica' or 'Punch Drunk Syndrome'. While moderate and severe TBI is known as one of the largest environmental risk factors in developing dementia, the link between mTBI and development of dementia-like conditions remains to be fully characterised. Accumulating evidence suggests that changes to the neurovasculature and the integrity of the blood-brain barrier (BBB) are early events in the development of several neurodegenerative conditions. The BBB is a highly specialised structure that maintains homeostasis of the central nervous system by limiting the passage of blood-based agents in to and from the neural space. As BBB dysfunction (BBBD) is a known consequence of TBI at all severities, changes to BBB integrity may result from repetitive mTBI and represent an underlying risk in dementia development. However, the magnitude and significance of changes in BBB integrity over time due to mTBI have yet to be fully explored. In this study, changes in BBB integrity as a result of participation in contact sports was investigated. To that end, two of amateur rugby union teams were recruited to undergo an extensive baseline assessment prior to the start of the competitive season, as well as after the season's competition. A sub-group of individuals underwent assessment shortly after completion of a competitive rugby match, to investigate acute changes in the BBB v following exposure to mTBI. The assessment consisted of MRI screening for changes in BBB integrity via novel dynamic contrast-enhanced MRI (DCE-MRI) analysis techniques and changes in neuroanatomical structure via diffusion tensor imaging (DTI). Blood samples were also collected at the time of MRI scanning, allowing for matched screening of potential blood-based biomarkers of TBI, as well the collection of peripheral blood mononuclear cells (PBMCs) to gauge potential adaptive changes in immune response to neural antigens. Together, this assessment represented a holistic approach to mTBI research. A total of 18 players were retained throughout the study period, completing the entire rugby season without a reported mTBI. However, even in the absence of a diagnosed mTBI, significant changes in the BBB integrity were detected in our cohort after a season of rugby, with a sub-group of individuals showing significant increases in BBB permeability compared to baseline. Increases in fractional anisotropy (FA) of axonal fibre tracks within the body of the corpus callosum were also observed after a season of rugby. The serological screening of potential mTBI markers: S100β brain-derived neurotrophic factor (BDNF) and monocyte chemoattractant protein 1 (MCP-1)/ chemokine (C-C motif) ligand 2 (CCL2), found a significant increase in BDNF after a season of rugby, accompanied by a significant decrease in S100β. However, post-match screening of plasma identified an increase in S100β even in the absence of injury. PBMC immune response, as measured by interleukin-1β (IL-1β) production, was found to be elevated in cells collected after a season of rugby compared to baseline cells when exposed to necrotic brain tissue. In addition to the clinical aspect of this study, presented here are 3 case studies are of dementia patients, whose history of TBI was thought to play a role in the development of their conditions. Characterisation of tight junction (TJ) components and BBB integrity displayed loss of the TJ protein, claudin-5, within regions of dense phospho-tau (p-tau) deposits in all three cases. Accompanying the loss of claudin-5 and overlapping with p-tau deposition was extensive extravasation of blood-based components IgG and fibrinogen, suggesting BBBD within these regions. The results obtained from in life assessment of the BBB suggest that the forces associated with contact sports, such as rugby, are sufficient to induced long term changes in BBB integrity. Serological results highlight the need for continued development of blood-based biomarkers for mTBI, particularly if they are to be used in the context of sport-related mTBI. Immune response also offers a possible avenue of future research to how vi changes in PBMCs may feed into long-term sequelae of repetitive TBI. The accompanying findings of BBBD in individuals with a history mTBI also suggest that mTBI may pose some degree of risk to long term neural health. | en |
