Cholinergic Mechanisms of Gait Dysfunction in Parkinson’s Disease
Up to 70% of patients with Parkinson's disease fall each year, quadrupling the rate of hip fractures, leading to extended hospitalizations, increased use of skilled nursing facilities and eventual nursing home placement. University of Michigan scientists have developed breakthrough evidence that these falls, which are resistant to currently available treatments, arise from the degeneration of brain cells that use the neurochemical acetylcholine. By integrating neuroimaging, behavioral and pharmacological studies in patients with Parkinson's disease and in animal models, we aim to further dissect the relationship between falls and abnormalities in these brain cells, and to develop the data necessary to launch a clinical trial of a novel treatment for these debilitating symptoms of Parkinson's disease.
The central themes of the proposed University of Michigan (U-M) Udall Center research program are the role of cholinergic lesions in gait and balance abnormalities in PD and the development of novel treatment strategies targeted at cholinergic neurotransmission. Considerable recent data indicates that gait and postural control are not purely motor functions but require complex integration of motor, sensory, and cognitive functions. Defining the relationship between cholinergic dysfunction and gait abnormalities requires a multidisciplinary approach in which investigators view the relationship between cholinergic function, gait, and cognition through different lenses, share insights and challenge each other in ways that yield progress far beyond that achievable were each project pursued separately. Our team has developed preliminary data that lead us to propose a 3-Hit model of gait dysfunction in PD which posits that the typical clinical progression of gait and postural abnormalities in PD is caused by the interaction of striatal dopamine loss with degeneration of cholinergic neurons in the basal forebrain (BF) and pedunculopontine (PPN) nucleus. The proposed research program will test the 3-Hit hypothesis and seek to develop proof-of-principle evidence for a novel cholinergic-based therapy for falls in PD. Project I will further develop and mechanistically dissect a recently published unique rodent model of PD gait abnormalities mimicking the combined cholinergic and dopaminergic lesions that occur in PD. These studies will define the cognitive-motoric impact of loss of PPN cholinergic neurons, alone and in combination with BF cholinergic and striatal dopaminergic loss and, in connection with Project III, examine the therapeutic benefit and circuit mechanism of action of stimulation of a defined molecular target (α4β2* nicotinic receptors). Project II will employ a novel PET ligand in PD patients that provides previously unattainable resolution of cholinergic nerve terminals; this ligand will enable, for the first time, delineation of PPN cholinergic projections that have been implicated in gait abnormalities in PD. Our preliminary data demonstrate that PD patients exhibit considerable heterogeneity of cholinergic degeneration, suggesting the presence of subgroups that may exhibit unique responses to pharmacological interventions. Utilizing a personalized medicine approach assessing only hypocholinergic subjects identified in Project II, Project III will employ novel PET and gait assessment methods in pilot target engagement/pharmacodynamic studies assessing the therapeutic potential and mechanism of action α4β2* nicotinic receptors nAChR stimulation. This innovative approach is critical for a highly heterogenous disease like PD.