Cholinergic mechanisms of attentional-motor integration and gait dysfunction in Parkinson Disease

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OVERALL COMPONENT: SUMMARY/ABSTRACT Progressive gait-balance difficulties, associated falls, and cognitive impairments are common and disabling dopamine replacement therapy (DRT)-resistant features of Parkinson disease (PD), affecting nearly all patients. In the prior cycle, U-M Udall Center research demonstrated prominent, multifaceted, and dynamic impacts of cholinergic systems degeneration in PD gait and cognitive abnormalities. These insights led us to a novel approach to PD pathophysiology; a systems neuroscience model of deficient integration of attentional and motor functions. This concept and our prior work position us to pursue integrated clinical and basic research testing hypotheses embodied in this model of Attentional-Motor Integration (AMI) network disruption. Our results suggest that patterns of disrupted cholinergic neurotransmission within multiple AMI nodes are responsible for characteristic PD gait and balance abnormalities, that striatal cholinergic interneurons are crucial integrators of attentional and motor information, and that cholinergic denervation of key cortical AMI nodes has global cognitive effects and predicts more rapid disease progression. Project I will employ the cholinergic PET ligand [18F]FEOBV in PD subjects to prospectively test the hypothesis that specific regional patterns of cholinergic terminal degeneration associate with specific PD gait-balance abnormalities. Project II will dissect, in a rodent model, the role of cholinergic neurotransmission in detecting, transferring, and integrating attentional information as it traverses cortical and striatal circuits. Opto- and chemo-genetic strategies will be used to test whether manipulating cortical or striatal cholinergic neurotransmission affects fall propensity in the “Dual Lesion” (DL) rodent model of PD falls. Project III will assess if early anterior cingulate and insular cholinergic denervation has global effects on cognition and is a predictor of more rapid cognitive decline. Projects I and III take advantage of unique prospectively followed PD subject cohorts. The Catalyst Research Project will study cellular mechanisms of cholinergic signaling and its role in visual attention in a key AMI node, the retrosplenial cortex. U-M Udall Center projects are supported by Administrative, Clinical Resource, Neuroimaging Resource and Biostatistics and Data Management Cores. We will collaborate with members of the Pacific and University of Rochester Udall Centers. The Administrative Core will oversee mentorship of early stage investigators, including a Udall Research Fellow and the Catalyst Research Project Lead. The Administrative Core will direct outreach to the PD community. Our innovative approaches will advance the goal of the NINDS Udall Centers of Excellence program to “define the causes of and discover improved treatments for PD.” No other Udall Center is focused on gait and postural abnormalities in PD, on integration of cognitive and motor functions, on cholinergic deficits, or on use of a pathological predictor to define PD subgroups. The proposed U-M Udall Center will continue to play a unique and important role within the Udall Centers program.