The NIH National Institute of Neurological Disorders and Stroke (NINDS) Parkinson’s Disease Research Centers of Excellence program was developed in honor of former Congressman Morris K. Udall of Arizona. Mr. Udall was elected to the U.S. House of Representatives in 1961 in a special election to replace his brother Stewart, who left the position to become President John F. Kennedy’s Secretary of Interior. Representative Udall was diagnosed with Parkinson’s disease (PD) in 1979; however, he remained active in Congress until his retirement in May 1991. He died in 1998 after a long battle with the disease. On November 13, 1997, the President of the United States signed the Morris K. Udall Parkinson’s Disease Research Act of 1997 into law (P.L. 105-78). Nine Udall Centers across the country carry out important research on PD, including the identification and characterization of candidate and disease-associated genes, examination of neurobiological mechanisms, establishment of improved PD models, development and testing of potential therapeutics, and novel avenues of clinical research..
Up to 70% of patients with Parkinson’s disease fall each year, quadrupling the rate of hip fractures, leading to extended hospitalizations, increased use of skilled nursing facilities and eventual nursing home placement. The central theme of the University of Michigan Udall Center is the role of cholinergic lesions in gait and balance abnormalities in PD. University of Michigan scientists have developed evidence that these falls, which are resistant to currently available treatments, arise from the degeneration of brain cells that use the neurochemical acetylcholine. By integrating neuroimaging, behavioral and pharmacological studies in patients with Parkinson’s disease and in animal models, we are working to further dissect the relationship between falls and abnormalities in these brain cells, and to develop the data necessary to launch a clinical trial of novel treatments for these debilitating symptoms of Parkinson’s disease.
The University of Michigan Udall Center research team is a highly interactive and productive group of investigators. Our group has published extensively in all areas of research, including the clinical characterization and PET imaging of cholinergic and related neurochemical systems in patients with PD and assessments of motor and cognitive function in rodent models of PD and related movement disorders.
The pioneering work on patients with Parkinson’s disease by University of Michigan brain imaging (Dr. Nico Bohnen) suggests that the spread of cell loss to the cholinergic system creates a previously unrecognized effect. That is, loss of cholinergic cells robs patients of the ability to pay close attention to their movements, even as they’re already having trouble walking safely. The involvement of the cholinergic system likely explains why current treatments – focused on dopamine replacement – are ineffective. The Center conducts research to determine if it may be possible to increase cholinergic traffic in the brains of patients using an already-approved drug that targets acetylcholine receptors on the surface of brain cells. That drug, varenicline or Chantix, is already available by prescription to help people stop smoking. Dr. William Dauer and Dr. Roger Albin serve as the Center’s Director and Associate Director, respectively, and co-lead a project to develop “personalized medicine” approaches to Parkinson’s disease using specialized brain scanning and varenicline. Dr. Martin Sarter studies the cholinergic system and its role in controlling attention. In his work, he has shown in rats that the cholinergic system plays a key role in balance and walking, and that reduced cholinergic activity is associated with worse balance and more falls. A team of biostatisticians and data analysts led by Dr. Ivo Dinov and Dr. Cathie Spino enables the study design, high-throughput processing and data analytics using the multivariate data generated by the Center’s experiments and clinical studies. The Parkinson’s disease education and outreach efforts are led by Dr. Kelvin Chou.
William T. Dauer, MD
Director, University of Michigan Udall Center of Excellence for Parkinson’s Disease Research
Udall Project 3 Co-Lead
Elinor Levine Professor of Neurology
Director, U-M Movement Disorders Group
Associate Professor of Cell and Molecular Biology
Roger Albin, MD
Associate Director, University of Michigan Udall Center of Excellence for Parkinson’s Disease Research
Udall Project 3 Co-Lead
Anne B. Young Collegiate Professor
Vice Chair for Research, Department of Neurology
Chief of Neuroscience Research, VAAAHS Geriatric Research, Education and Clinical Center
Core A: Administrative Core
Core Lead: William Dauer, MD
The Administrative Core coordinates all scientific, administrative, and educational activities of the U-M Udall Center. The central objective is to facilitate the realization of the scientific and educational goals of the U-M Udall Center.
The Clinical Resource Core 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.
The Biostatistics and Data Management Core 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 develop skills and expertise in analysis of imaging datasets, database management, and trial-type activities.
Core D: Education and Outreach Core
Core Lead: Kelvin Chou, MD
The Education and Outreach Core pursues a comprehensive program to educate caregivers about the etiology, clinical features and state-of-the-art management of Parkinson’s Disease (PD). This includes the clinical education of University of Michigan Udall Center Fellows. The core also directs an aggressive outreach program to inform and educate traditionally underserved communities about PD and related movement disorders. Core investigators mitigate the significantly greater disability from which PD patients from underserved communities suffer.
Project I: Modeling and treating cholinergic impairment and fall propensity in PD
Project Lead: Martin Sarter, PhD
Project I develops a novel rodent model of PD gait dysfunction demonstrating how attentional impairment, caused by partial BF cholinergic neuron loss, causes pronounced abnormalities of gait by “unmasking” striatal dysfunction caused by dorsal striatal dopaminergic denervation. These rodents exhibit a high propensity for falls in situations requiring attentional supervision of complex movements and freezing-type behavior when walking through model “doorways” that is strikingly reminiscent of PD symptomatology. Using these established methods and supported by extensive additional preliminary data, Project I defines the motoric impact of loss of PPN cholinergic neurons, alone and in combination with cortical cholinergic and striatal dopaminergic loss. Project investigators employ this model to explore mechanisms of cholinergic dysfunction directly relevant to therapeutic development. Using cutting-edge technology to record cholinergic neurotransmission at millisecond resolution in awake behaving rodents we investigate the circuit mechanisms that enable cholinergic neurons to compensate for striatal dysfunction prior to their degeneration; identification of these mechanisms is critical to develop novel therapeutic approaches to mimic these effects. Our preliminary data show that administering a combination of L-DOPA and the α4β2* nAChR agonist ABT-089 appears to reduce falls and freezing, supporting the value of this model for identifying the mechanisms underlying functional improvement. The α4β2* agonist varenicline (VCN) will also be tested, and comparisons with the effects VCN administration to PD patients will advance therapeutic validation of this model.
Project II: Imaging of cholinergic systems in Parkinson’s disease
Project Lead: Nicolaas Bohnen, MD, PhD
Project II images PD patients with varying degrees of gait and balance difficulty using a novel PET ligand ([18F]FEOBV) for the vesicular acetylcholine transporter (VAChT). This new ligand reveals selective visualization of presynaptic cholinergic terminals with previously unattainable resolution. The superior resolution enables investigators to delineate cholinergic pathways arising from the PPN that have been implicated in gait abnormalities in PD, including to the cerebellar vermis. The high resolution topology of cholinergic lesions identified in Project II enables prospectively evaluation and exploration of the unique roles of BF and PPN loss in PD-related gait abnormalities. The findings of Project II aid interpretation of the detailed analyses of gait and cognition that will be pursued in Project III and the Clinical Resource Core.
Our preliminary studies suggest that α4β2* nAChRs may be a viable molecular target on which to base a novel treatment strategy for gait abnormalities in PD. Two challenges to assessing α4β2* nAChRs as a therapeutic target are the heterogeneity of cholinergic degeneration in PD and the complexity of α4β2* function. Only the subgroup of hypocholinergic PD patients are expected to benefit from cholinomimetic strategies, an effect that may be obscured if tested in an unselected cohort of PD subjects. Moreover, nAChRs are highly regulated ligand-gated ion channels with complex responses to stimulation, raising the possibility that they may not function normally in the context of the hypocholinergic, degenerating PD brain.
Project III addresses clinical and experimental challenges by using novel methodology to test this important molecular target. In a “personalized medicine” approach, only PD subjects demonstrated to have significant cholinergic degeneration (in Project II) will be studied. Novel PET methods are used to examine therapeutically relevant pharmacological features of α4β2* nAChR in these hypocholinergic subjects. We test the hypothesis that agonism of the α4β2* nAChR in PD improves laboratory measures of gait, postural control and attentional function. Related information comes from the comparison of α4β2* nAChR agonism in patients and the rodent model developed in Project I.
Andrew J. Ridder, MD
Department of Neurology
Dr. Ridder is the first Udall Center Fellow. He is also a Movement Disorders Fellow in the Department of Neurology. He is receiving advanced clinical training in all aspects of movement disorders, from Parkinson’s Disease and its non-motor manifestations to genetic causes of degenerative ataxias. He is involved in clinical research on the impact of Deep Brain Stimulation on impulse control in Parkinson’s Disease as well as whether cholinergic stimulation improves balance and gait in people with Parkinson’s Disease Dementia, Lewy Body Disease and Alzheimer’s. He also participates in several patient and practitioner educational outreach programs for the Udall Center.
Dr. Ridder completed his Neurology residency as chief resident at the University of Michigan in June 2016. He graduated from the Sanford School of Medicine of South Dakota in 2012.
Aaron Kucinski, PhD
Postdoctoral Research Fellow
Department of Psychology
Aaron Kucinski, PhD is a Postdoctoral Research Fellow in the Sarter Lab (Project 1: Modeling and Treating Cholinergic Impairment and Fall Propensity in PD). He received his PhD at the University of Buffalo in Pathology and Anatomical Sciences where he began studying cholinergic circuits and nicotinic therapies in mouse models of Parkinson’s Disease (PD) and schizophrenia. Currently in the Sarter lab his primary research goal is to understand the cortico-striatal circuitry that mediates cognitive control of movement. PD patients with losses of cortical acetylcholine as well as cognitive impairments, specifically attentional deficits, exhibit gait and postural deficits and have a high propensity for falls. To help better understand these L-DOPA unresponsive symptoms, the Sarter team has developed a behavioral test system to assess complex movement and fall propensity in rats, the Michigan Complex Motor Control Task (MCMCT). This apparatus requires rats to perform traversals of narrow beams under cognitively demanding conditions, including rotating surfaces and with presentations of distractors.
Mélanie L. Beaulieu, PhD
Postdoctoral Research Fellow
Department of Radiology
Mélanie L. Beaulieu, PhD, is a Postdoctoral Research Fellow in the Functional Neuroimaging, Cognitive and Mobility Laboratory (directed by Nicolaas I Bohnen, MD, PhD and co-directed by Martijn LTM Müller, PhD) (Project II: Imaging of Cholinergic Systems in Parkinson’s Disease) within the Department of Radiology of the University of Michigan Medical School. After completing her undergraduate and Master’s degrees in Human Kinetics at the University of Ottawa in Canada, Dr. Beaulieu earned her doctoral degree in Kinesiology (Biomechanics) from the University of Michigan in 2014. Her doctoral dissertation focused on contributing factors to noncontact anterior cruciate ligament injury, including limited hip internal rotation secondary to hip impingement, ligament fatigue, and ligament entheseal microscopic anatomy.
Dr. Beaulieu’s research interests lie in two main areas: (1) understanding the pathomechanics of musculoskeletal injuries and diseases, particularly at the knee joint; and (2) understanding the etiology of balance and gait difficulties in Parkinson’s disease, as well as developing methods to better monitor these motor symptoms. She is investigating various contributors to these balance and gait problems, including cholinergic system impairments and disease-independent factors. She is also developing better methods to predict and identify freezing of gait in individuals with Parkinson’s disease. Her long-term goal is to improve the quality of life of these individuals by reducing the severity of their mobility difficulties, and thus their risk of falling.
Kara J. Wyant, MD
Movement Disorders Fellow
Department of Radiology
Kara J. Wyant, MD, is a clinical lecturer and Movement Disorders Fellow in the Department of Neurology. She received her bachelor’s degrees in mathematics and music from Ohio Northern University, and medical degree from the University of Toledo College of Medicine. Dr. Wyant completed her neurology residency training at the University of Pittsburgh Medical Center, where she served as chief resident from 2015-2016. She is currently pursuing a fellowship in movement disorders at the University of Michigan focusing on the medical and surgical management of patients with Parkinson disease and parkinsonism. Dr. Wyant also serves on the neurohospitalist service at University Hospital, and participates in teleneurology consults for MidMichigan Health.