Udall Center - University of Michigan

Udall Center - University of Michigan

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Director: William T. Dauer, M.D.

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

Website: http://www.udallpd.umich.edu/

Central Theme

The overarching goal of the University of Michigan (U-M) Udall Center research program is to define the role of cholinergic lesions in gait and balance abnormalities in Parkinson’s Disease (PD). The Center is testing a hypothesis 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 the degeneration of cholinergic neurons in the basal forebrain and pedunculopontine nucleus.

Center Structure

The U-M Udall Center consists of an integrated set of rodent and human studies to explore directly whether and how degraded cholinergic function disrupts gait and balance in the setting of striatal dopamine deficiency. Project 1 (Dr. MartinSarter) is further developing and mechanistically dissecting a unique rodent model of PD gait abnormalities mimicking the combined cholinergic and dopaminergic lesions that occur in PD. Project 2 (Dr. Nicolaas Bohnen) is a prospective clinical study testing the hypothesis that basal forebrain and pedunculopontine deficits contribute to dissociable and additive components of PD gait and postural dysfunction. This study is utilizing the novel PET ligand FEOBV that provides previously unattainable resolution of cholinergic nerve terminals. Utilizing a “personalized medicine” approach assessing only hypocholinergic subjects identified in Project 2, Project 3 (Drs Roger Albin and William Dauer) is employing novel PET and gait assessment methods in pilot target engagement/pharmacodynamic studies assessing the therapeutic potential and mechanism of action α4β2* nAChR stimulation. These studies are supported by the Administrative (PI: Dauer), Clinical Resource (Dr. Bohnen and Dr. Martijn Müller), Biostatistics and Data Management (Dr. Kathleen Spino and Dr. Ivo Dinov) and Education and Outreach (Dr. Kelvin Chou) Cores.

Recent Advances

Several recent advances made by Center investigators support a key role for cholinergic dysfunction in PD gait and balance abnormalities.

Project 1: Modeling and treating cholinergic impairment and fall propensity in PD (Dr. Sarter): An essential concept of U-M Udall Center studies of cholinergic function in PD in relation to gait/complex motor control is dissecting the extent to which cholinergic processing is functioning to change behavior in a “top-down” or “bottom-up” fashion. Using a systems neurobiology approach, the team discovered that attentional differences in two groups of genetically normal but behaviorally distinct rodents were paralleled by distinct profiles of basal forebrain cholinergic cortical terminals (Koshy et al., J Neurosci. 2017;37:2947–2959). These findings provide additional support for Center studies documenting the importance of top-down attentional defects in gait dysfunction in PD.

Project 2: Imaging of cholinergic systems in Parkinson’s disease (Dr. Bohnen): The goal of this project is to perform a prospective neuroimaging study to test the distinct contributions of cholinergic projection system degenerations (i.e., basal forebrain and pedunculopontine nucleus) to PD gait and postural dysfunction. Cholinergic projections are imaged using the novel vesicular acetylcholine transporter (VAChT) PET imaging using the novel ligand [18F]FEOBV (and subjects are also assessed with [11C]DTBZ PET and brain MRI).  Preliminary findings indicate unanticipated and clinically important heterogeneity in cholinergic circuit change. Studies with this novel marker of cholinergic neurotransmission independently support roles for both BF and PPN cholinergic projections in the pathophysiology of PD gait dysfunction. Additional analysis of subjects with tendency toward falls demonstrated significantly reduced striatal FEOBV binding in freezers vs non-freezers, with stepwise logistical regression analysis yielding reductions in caudate as the single most robust predictor of freezing of gait (FoG) status. Identification of striatal cholinergic dysfunction reflects a unique capability of FEOBV PET imaging and enabled us to identify a novel neural substrate contributing to gait freezing that parallels findings in our rodent studies.

Project 3: α4β2* nAChRs, gait, and balance in Parkinson’s disease (Drs. Albin and Dauer): This project is a target engagement investigation of the a4β2 nicotinic cholinergic receptor (nAChR) to determine whether agonism of this target improves laboratory-based measures of gait. During the past year, the initial, dose-finding, experiment using [18F] flubatine PET imaging to determine the lowest oral dose of varenicline producing high α4β2* nAChR occupancy was completed.  Varenicline was well tolerated in PD subjects at all doses examined.  Normal control subjects were studies in the same paradigm and established that varenicline occupancy of  α4β2* nAChR is similar in control and PD subjects. A study of the distribution of [18F]FEOBV binding in normal human brain revealed some unique features of the distribution of cholinergic terminals in human neocortext, thalamus, and cerebellum.  The team observed regionally specific aging-related changes which may contribute to cholinergic-mediated clinical phenomenon in PD subjects. 

Public Health Statement

Up to 70% of patients with Parkinson disease (PD) 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 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 PD and in animal models, we are working to further dissect the relationship between falls and abnormalities in these brain cells. Using new visualization methods, our team finds that abnormalities of nerve cells that use acetylcholine occur early in the disease process, and that changes in distinct groups of these nerve cells occur in patients with specific problems with gait and falls. Complementary findings in an animal model of PD are providing a detailed understanding of how these changes cause “freezing” of gait and falls. Together with other studies, this work is helping us to develop the understanding necessary to launch a clinical trial of novel treatments for these debilitating symptoms of PD.

Budget End Date: 2019/06/30

NIH Grant Number: P50 NS091856