Multiple neurochemical systems degenerate in Parkinson's Disease (PD). Common and profoundly disabling PD symptoms remain 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 consequences of these levodopa resistant symptoms are devastating, and include bone fractures, hospitalizations, self-imposed isolation because of fear of falling, wheelchair confinement, and eventual nursing home placement.
The University of Michigan Udall Center of Excellence for Parkinson’s Disease Research conducts experimental, computational and human research to investigate the cause of cholinergic projections degeneration in the pathogenesis of gait dysfunction in PD. The central themes of the Udall Center are the role of cholinergic lesions in gait and balance abnormalities in PD and the development of novel treatment strategies targeted at cholinergic neurotransmission.
Data collected by Center investigators 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. The research team at the Center has developed preliminary data that lead to the development of 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.