Abstract

Background: Gait impairment has a detrimental effect on the lives of individuals with Parkinson's disease (PD). Although PD is typically characterized as a dopaminergic-depletion disorder, accumulating evidence implicates cholinergic dysfunction as an additional contributor. Whereas the dopaminergic system has been widely connected to cardinal motor signs, the cortical cholinergic system plays a crucial role in top-down cognitive processes that may be related to higher-order aspects of gait. Objective: Investigate the relationship between higher-order gait control and the cortical cholinergic system separate from any disease-related dopaminergic deficits. Methods: Twenty-two individuals with PD underwent structural MRI scans to assess gray matter volume of the Nucleus Basalis of Meynert (NBM), the key node in the cortical cholinergic network. Additionally, individuals performed a validated stepping-in-place task to assess gait variability and clinical motor assessments under several conditions: off all therapy, ON subthalamic nucleus (STN) deep brain stimulation (DBS), and off all therapy after three years of continuous DBS. Results: Atrophy of the NBM was associated with greater (i.e., worse) gait variability off all therapy. STN DBS significantly improved cardinal motor signs but did not improve gait variability. Gait variability continued to decline over three years of continuous STN DBS, and NBM atrophy predicted the degree of decline. In contrast, three years of continuous STN DBS arrested progression of cardinal motor signs. Conclusions: These results support a framework in which higher-order aspects of gait control are reliant on the cortical cholinergic system, separate from disease-related dopaminergic deficits, and which are not addressed by STN DBS.