PD patients exhibit considerable heterogeneity of cholinergic degeneration, suggesting the presence of subgroups that may exhibit unique responses to pharmacological interventions. This first-ever target engagement assessment in hypocholinergic PD patients is therefore an example of “personalized medicine,” an innovative approach that is critical for a highly heterogenous disease like PD. Together, these innovative approaches will provide much needed insight into a devastating yet understudied symptom of PD and advance the goal of the NINDS Udall Centers of Excellence program “to define the causes of and discover improved treatments for PD.” No current Udall Center is focused on gait and postural abnormalities in PD, or on cholinergic deficits. The UMich Udall Center plays a unique and important role within the NINDS Udall Center National program.
Udall Center translational research projects are highly innovative.
Project I (Modeling and treating cholinergic impairment and fall propensity in PD) develops a unique rodent model of PD gait abnormalities, and includes studies of the motoric impact of loss of PPN cholinergic neurons alone and in combination with cortical cholinergic and striatal dopaminergic loss.
Project II (Imaging of cholinergic systems in Parkinson’s disease) will employ a novel PET ligand in PD patients that provides previously unattainable resolution of cholinergic nerve terminals; this will enable, for the first time, delineation of cholinergic pathways arising from the PPN that have been implicated in gait abnormalities in PD.
Project III (α4β2* nAChRs, gait, and balance in Parkinson’s disease) involves a clinical target engagement/pharmacodynamic study pursuing in vivo pharmacokinetic-pharmacodynamic studies to evaluate the engagement and function of a specific molecular target in the subgroup of PD patients with significant cholinergic degeneration–as determined by PET imaging in Project II.
Core I performs a comprehensive clinical assessment of all subjects (controls and PD patients) to be studied in Projects II and III. Subjects are comprehensively assessed with well-established clinical, motor, and neuropsychological instruments. We use the recently published consensus neuropsychological measures recently published by PANUC and the University of Pennsylvania Udall Center to facilitate our growing interactions with these Centers. This core also performs vesicular monoaminergic transporter type-2 (VMAT2) positron emission tomography (PET) using 11C-DTBZ brain and magnetic resonance (MR) imaging.
Core II leads the Center efforts on design and analysis of all experiments conducted in the translational Projects. Core II investigators also conduct statistical analyses using modern, state-of-the-art statistical models and methods. This core develops a HIPAA-compliant database all data from all three Projects. Core II is also instrumental in training students and fellows to develip skills and expertise in analysis of imaging datasets, database management, and trial-type activities.
Core III provides a comprehensive program to educate caregivers about the etiology, clinical features and state-of-the-art management of PD, including the clinical education of U-M Udall Center Fellows. This core will also direct an aggressive outreach program to inform and educate traditionally underserved communities about PD and related movement disorders. We aim to mitigate the significantly greater disability from which PD patients from underserved communities suffer.