Exploring the Behavioural and Brain Basis of the Link Between Traumatic Brain Injury and Parkinson’s disease

Abstract

Accurately identifying individuals at risk for Parkinson's disease (PD) is crucial for developing effective treatment strategies. The recognition of non-motor symptoms preceding classical motor PD symptoms highlights the existence of the prodromal stage—an early phase marked by symptoms and signs before an official PD diagnosis, and emphasises the need for research to unravel the risk factors predicting PD onset. While the etiology of PD remains largely unknown and likely multifaceted—encompassing aging, genetics, and environmental influences —this thesis aims to explore the mechanisms via which two of the most widely reported risk factors, traumatic brain injury (TBI) and pesticide exposure, as well as the synergistic combination of the two, may drive the progression of PD pathogenesis. The first part investigates the impact of different severities of traumatic brain injury (TBI) on long-term motor performance, alterations in catecholaminergic signalling and chronic neuroinflammation, as such underlying abnormalities may set the stage for the later emergence of PD. The results from this thesis revealed that TBI severity is associated with persistent motor deficits, presented in a dose-dependent pattern in balance, gait and speed over 10 years post-injury. The exploration of neuropathology aligns with this pattern, with moderate-severe TBI demonstrating the most notable alterations in neuroinflammation and noradrenaline signalling in the nigrostriatal pathway, accompanied by subtle deficits in cognitive flexibility at 12 months post-injury. A different effect was observed, with single mild TBI animals displaying altered dopamine signalling in the prefrontal cortex that was found to be associated with reduced anxiety. To explore further, the second part of the thesis aims to develop a novel animal model for studying the contribution of low-level exposure to the pesticide rotenone and moderatesevere diffuse TBI, alone and in combination, to PD pathogenesis by conducting a comprehensive behavioural assessment at 1-month following injury in this model. It reveals that dual environmental risk factors lead to more pronounced deficits in balance, motor coordination, and learning ability than individual risks alone. While other functional tests assessing motor, cognition, and prodromal symptoms are preserved (with the possible exception of constipation), this may hint at an increased risk for future PD development. Taken together, this thesis demonstrates a possible association between TBI and the risk of developing PD, with this risk heightened with more severe TBI and the addition of environmental risk factors. This thesis also provides preliminary insights into predicting PD after such exposures, underscoring the significance of future investigations into the complex interplay of multiple risk factors, which is critical for advancing our knowledge in PD progression and enhancing the accuracy of PD diagnosis.