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.
Cholinergic Impairment and Fall Propensity
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 I (Dr. Sarter) »
Imaging of Cholinergic Systems
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 II (Dr. Bohnen) »
α4β2* nAChRs, gait, and balance
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.
Project III (Drs. Albin/Dauer) »
Clinical Assessment
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 I (Drs. Bohnen/Muller) »
Biostatistics and Data Management
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 II (Drs. Dinov/Spino) »
Education and Outreach
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.
Core III (Dr. Chou) »
Pilot Project
Positron emission tomography (PET) imaging allows quantification of the complex mechanisms
underlying Parkinson's diseases. Dr. Scott’s project uses PET imaging to
examine biomedically the progression of Parkinson’s disease.
Pilot Project (Dr. Scott) »
Pilot Project
Optogenetic interrogation of the role of dopamine in motor control. Dr. Leventhal’s project
aims to determine, at a behavioral level, how striatal dopamine influences
motor function. The expected outcome of this research is to clarify the specific roles of nigrostriatal
dopamine in fine motor control.
Pilot Project (Dr. Leventhal) »
