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 (Martin Sarter) 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 (Nico 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 (Roger Albin) 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 four Cores, including:  Administrative (Dr. Dauer), Clinical Resource (Dr. Bohnen), Biostatistics and Data Management (Ivo Dinov) and Education and Outreach (Kelvin Chou).

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): To mechanistically dissect PD-related gait abnormalities, Dr. Sarter’s recent research has been developing a systems neuroscience approach to identify the cortico-striatal circuitry which, if disrupted, mediates an elevated propensity for falls. Dr. Sarter’s original work indicated that combined cortical cholinergic and striatal dopaminergic deafferentation increases the propensity for falls by impairing the attentional supervision of complex movements. New and exciting data indicate that disrupted cue processing in the cholinergically-deafferented cortex and impaired movement vigor and motor sequencing in the dopaminergically-deafferented striatum are integrated at the level of striatal cholinergic interneurons. Results obtained during the past year show that chemogenetically inhibiting these interneurons phenocopies key features of the falls seen following combined cholinergic-dopaminergic lesions. These findings provide a powerful platform from which to further dissect the neuronal circuitry critical for integrating cognitive-motor function in relation to PD falls. Current work is focused on exploring whether there is regional specificity to the effects of cholinergic interneuron inhibition that would advance understanding of a discrete circuit related to fall vulnerability.

In the past year, Dr. Sarter’s group has also developed a novel treadmill-based behavioral task focused on isolating the circuitry responsible for detecting cues signaling a change of motor program. This task allows assessment the presumed neurochemical substrate of the cue, cortico-striatal glutamatergic signaling. This work demonstrates that rats prone to fall in the complex (beam walking-based) “MCMCT” task are impaired in utilizing the motor cue in the treadmill task, and that cholinergic interneurons silencing reproduces this defect. Current studies are focused on real-time amperometric recordings of glutamate signaling in response to turn and stop-and-go cues on the treadmill. Such glutamatergic signals, if present, are expected to be attenuated in rats with cholinergic losses and they may be utilized to assess, at the circuitry level, potential treatments thought to improve the cortico-striatal transfer of movement-relevant extero- and interoceptive cues.

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). Outstanding progress continues to be made in recruiting subjects first-ever longitudinal assessment of cholinergic circuitry in PD subject. 102 subjects have been recruited and 11 have already returned for 2-year follow-up.

Preliminary findings from this unique cohort indicate and unanticipated and clinically important heterogeneity in cholinergic circuit change. Striatal, thalamic and anterior cortical (esp. frontal) regions exhibit upregulation of cholinergic activity, perhaps reflecting a compensatory response, whereas there is pronounced decrease in cholinergic activity in posterior (parieto-occipital) cortices. Clinical correlation of these findings indicates a striking relationship gait difficulties. Subjects with prominent hypocholinergic activity in anterior regions appear more likely to exhibit “PIGD” (postural instability gait disorder) features while hypercholinergic activity in anterior cortical regions is correlated with tremor-predominant symptoms.  Additional analyses linked hypocholinergic activity in posterior cortices with slower gait speed, reduced stride length and poorer measures on the Mini-BESTest Balance Evaluation. Further, there were associations decreased cholinergic activity in brainstem and cerebellar regions with deficits in anticipatory and reactive postural control and sensory orientation. Considered together, these findings suggest strongly that loss of cholinergic neurotransmission is heterogenous in PD, and that the clinical consequence depends upon the region impacted.

Project 3: α4β2* nAChRs, gait, and balance in Parkinson’s disease (Dr. Albin): 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, we completed the initial, dose-finding, experiment using [18F] flubatine PET imaging to determine the lowest oral dose of varenicline producing high α4β2* nAChR occupancy. We found high receptor occupancy (>70%) at 0.25 mg po bid with no subsequent increases at 0.5 mg po bid and 1 mg po bid.  Varenicline was well tolerated, including at 1 mg po bid.  We chose a dose of 0.5 mg po bid for subsequent studies. We initiated the planned double-blind cross-over intervention study using gait and balance measures as outcomes.  We have studied 6 subjects to date (out of a projected total of 36) in this experiment without any tolerability issues and high-quality data. Recruitment is going well for this study and we anticipate this experiment will be completed by the end of this year. 

Public Health Statement

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 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 brain imaging, behavioral and pharmacological studies in patients with Parkinson’s disease and in animal models, we are working 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 novel treatments for these debilitating symptoms of Parkinson’s disease.

Budget End Date: 2019/06/30

NIH Grant Number: P50 NS091856