Cholinergic Mechanisms of Gait Dysfunction in Parkinson’s Disease

Title: Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease

PI Name: William T Dauer

URL: https://pdbp.ninds.nih.gov/study_profile/228

Repository: Parkinson's Disease Biomarker Program

Status: Controlled Access

Funding Source: NIH-NINDS

Abstract: Multiple neurochemical systems degenerate in PD, and several common and profoundly disabling symptoms are largely levodopa resistant. Progressive gait and balance difficulties, and associated falls, are among the most common levodopa resistant symptoms, eventually occurring in nearly all patients. The gravity of this problem is underscored by a lack of any effective therapy, leading the authors of the NINDS PD 2014 Research Report to list as ?highest priority recommendations? studies aimed at understanding the neural circuit mechanisms of gait and balance disorders in PD, and developing effective treatments for these dopa-resistant symptoms (Clinical recommendations 2, 3 & 4; Translational recommendation 1 & 6; Basic recommendation 3). Our team has made a series of discoveries in human subjects with PD and in a novel PD animal model that strongly implicate degeneration of cholinergic projections in the pathogenesis of gait dysfunction in PD. 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. We have assembled such a team, making our proposed work ideally suited for support under the P50 Udall Center mechanism. 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* nAChR stimulation. This innovative approach is critical for a highly heterogenous disease like PD.

Study ID: PDBP-STUDY0000228

Repository URL: https://pdbp.ninds.nih.gov/

Data Type: Clinical Assessment

Study Type: Natural History

Grant ID: P50 NS091856

Study Started On: 2014-09-30

Study Completed On: 2019-06-30

Estimated number of Subjects: 95