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/

Budget End Date: 6/30/2019


Central Theme

The central theme of the NINDS Udall Center at the University of Michigan (U-M) is 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, PhD) 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 (Nicolaas Bohnen, MD, PhD) 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.

Project 3 (Roger Albin, MD and William Dauer, MD) Utilizing a “personalized medicine” approach assessing only hypocholinergic subjects identified in Project 2, this study is employing novel PET and gait assessment methods in pilot target engagement/pharmacodynamics studies assessing the therapeutic potential and mechanism of action of alpha4beta2 (α4β2) nicotinic acetylcholine receptor (nAChR) stimulation, including whether agonism of this target improves laboratory-based measures of gait.

These projects are supported by the several Cores, including: Administrative (Dr. Dauer), Clinical Resource (Dr. Bohnen), Biostatistics and Data Management (Catherine Spino, DSc, and Ivo Dinov, PhD) and Education and Outreach (Kelvin Chou, MD).

Ongoing research at the U-M Udall Center addresses several NINDS PD2014 research priorities, including:

  • Clinical Recommendation 2: Develop effective treatments and companion biomarkers for dopa-resistant features of PD. These features include both motor symptoms, particularly gait and balance problems such as freezing of gait, and non-motor symptoms, especially cognitive impairment, psychosis, and dysautonomia.
  • Clinical Recommendation 3: Characterize the long-term progression of PD and understand the mechanisms that underlie its heterogeneity in clinical presentation and rates of progression. Factors related to disease heterogeneity may include clusters of clinical features as well as biological factors such as genotype and biomarkers.
  • Translational Recommendation 1: Develop patient stratification tools that define disease signatures of more homogeneous cohorts with emphasis on slow vs. fast progressing PD, prodromal PD, and non-motor symptoms.
  • Translational Recommendation 6: Develop intermediate markers of drug efficacy in early PD translational studies to support more efficient proof-of-concept studies.
  • Basic Recommendation 11: Advance our understanding of neural circuits, circuit analysis techniques, PD animal models, and optogenetic and related imaging technologies to improve existing therapies and generate next-generation therapies for PD.

 

Publications from the University of Michigan Udall Center
 

Resources Available

  • Rodent model of PD gait dysfunction: All relevant details for generating the novel rodent model of PD gait dysfunction, including the Michigan Complex Motor Task (MCMCT), are available in Kucinski, A, et.al., (J Neurosci. 2013; 33(42):16522–16539). U-M researchers are available to help interested investigators set up this model system in their laboratories.
  • FEOBV: U-M investigators will assist interested investigators in the generation of FEOBV and its use and quantification, as well as the methods to assess ɑ4β2 nAChR occupancy with flubatine.
  • DNA samples: DNA from all patients recruited for this study are also being deposited with the NINDS BioSEND biorepository and will be freely available for use.


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.

For further information: Parkinson@umich.edu