Project II images PD patients with varying degrees of gait and balance difficulty using a novel PET ligand ([18F]FEOBV) for the vesicular acetylcholine transporter (VAChT). This new ligand reveals selective visualization of presynaptic cholinergic terminals with previously unattainable resolution. The superior resolution enables investigators to delineate cholinergic pathways arising from the PPN that have been implicated in gait abnormalities in PD, including to the cerebellar vermis. The high resolution topology of cholinergic lesions identified in Project II enables prospectively evaluation and exploration of the unique roles of BF and PPN loss in PD-related gait abnormalities. The findings of Project II aid interpretation of the detailed analyses of gait and cognition that will be pursued in Project III and the Clinical Resource Core.

Our preliminary studies suggest that α4β2* nAChRs may be a viable molecular target on which to base a novel treatment strategy for gait abnormalities in PD. Two challenges to assessing α4β2* nAChRs as a therapeutic target are the heterogeneity of cholinergic degeneration in PD and the complexity of α4β2* function. Only the subgroup of hypocholinergic PD patients are expected to benefit from cholinomimetic strategies, an effect that may be obscured if tested in an unselected cohort of PD subjects. Moreover, nAChRs are highly regulated ligand-gated ion channels with complex responses to stimulation, raising the possibility that they may not function normally in the context of the hypocholinergic, degenerating PD brain.