The neurobiological basis of gait dysfunction in Parkinson’s disease: A cross-sectional and longitudinal approach

Abstract

Gait impairments are a cardinal feature of Parkinson’s disease (PD) and significantly affect the well-being of patients. However, current therapies are not effective at improving specific aspects of gait in PD nor preventing them from worsening over time. This is largely due to poor understanding of the mechanisms that the brain uses to control discrete gait characteristics in PD. The aim of this thesis was, therefore, to investigate associations between the brain and gait characteristics in PD, using both cross-sectional and longitudinal analytical approaches. Newly diagnosed PD participants (n=99) and age-matched controls (n=47) completed quantitative gait, structural magnetic resonance imaging and clinical assessments soon after diagnosis; additional gait assessments were completed every 18 months for up to six years. Partial correlations and linear regression analyses determined cross-sectional associations between regional brain volumes and gait. Linear mixed-effects models identified gait characteristics that changed over six years in PD, more so than in controls, and assessed the predictive nature of regional brain volumes on gait changes. Original contributions to knowledge were that regional brain volumes selectively associated with discrete gait characteristics in PD; many associations were unique to PD, even in early disease. Brain regions which primarily relate to both motor and non-motor functions correlated with PD gait impairment. Associations with non-motor structures might be attributable to contributions from the cortical cholinergic system, given its role in maintaining gait in PD. This thesis provides evidence for the reliance on alternative and compensatory neural mechanisms during PD gait. Additionally, this thesis demonstrates the first evidence for regional brain volumes predicting disease-specific changes in gait. This not only provides greater understanding of neural underpinnings of gait dysfunction in PD, but demonstrates the potential for regional brain volumes to be considered clinically as an indicator of those at greater risk of mobility loss and falls