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

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.

Grant Number: 5P50NS123067-05
NIH Institute/Center: NIH
Principal Investigator: Roger Albin