Director: William T. Dauer, M.D.
Title: Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease
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.
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:
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