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Public Health Statement: Up to 70% of patients with Parkinson disease (PD) fall each year, quadrupling the rate of hip fractures, leading to extended hospitalizations, increased use of skilled nursing facilities and eventual nursing home placement, and increasing the risk of death. University of Michigan scientists developed evidence that falls and related gait problems, resistant to currently available treatments, arise from degeneration of brain cells that use the neurochemical messenger acetylcholine. Brain acetylcholine deficits likely contribute to cognitive deficits in PD and impair the integration of cognitive functions with motor performance. In studies in Parkinson’s disease participants and in animal models, we are working to further dissect the relationship between falls, other gait problems, impairments in cognition, and deficits of different populations of brain acetylcholine cells. Using new visualization methods, our team finds that abnormalities of nerve cells that use acetylcholine occur early in the disease process, and that changes in distinct groups of these nerve cells occur in patients with specific problems with gait and falls. These deficits may identify a subgroup of PD patients with a more aggressive clinical course. Complementary findings in animal models of PD are providing a detailed understanding of how these changes cause “freezing” of gait and falls, and deficits in spatial navigation. Together with other studies, this work is the precursor to investigating new treatments for PD.
Overview
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.
The University of Michigan Udall Center research team is a highly interactive and productive group of investigators from different disciplines. Members of the Udall team include investigators from the Departments of Neurology, Radiology, Psychology, and Biostatistics. Our group publishes extensively in several areas of PD research, including clinical characterization and molecular imaging of acetylcholine cells and related systems in PD participants and parallel experiments in rodent models of PD and related movement disorders.
Pioneering work in PD participants led by University of Michigan Udall Center investigator Dr. Nico Bohnen uses novel brain imaging methods to show that loss of acetylcholine brain cells is strongly associated with falls, other gait problems, and cognitive deficits. In particular, loss of specific groups of cholinergic cells robs patients of the ability to pay close attention to their movements and environment, reducing movement safety, particularly in complex environments. Loss of other types of cholinergic cells likely impairs perception of other forms of information important for movement. In closely related animal model work, the specific circuits underlying these problems are being investigated by Udall investigator Dr. Martin Sarter, casting light on how attentional information is integrated with movement mechanisms to produce gait coordination. In closely related work, Udall investigator Dr. Roger Albin is using brain imaging methods to probe how loss of acetylcholine cells causes cognitive deficits, and may identify a group of PD subjects at risk for faster progression. In parallel work, Udall investigator Dr. Omar Ahmed is studying the cellular mechanisms acetylcholine signaling in an important cognitive function, spatial navigation. A team of biostatisticians and data analysts led by Dr. F. DuBois Bowman 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. Drs. Prabesh Kanel and Robert Koeppe perform and analyze all PET and magnetic resonance imaging in the new Neuroimaging Resource Core. Parkinson’s disease outreach efforts are led by Dr. Kelvin Chou.
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Roger Albin, MD
Director, U-M Udall Center
Udall Project III Lead
Anne B. Young Collegiate Professor of Neurology
Co-director, Movement Disorders Division, Department of Neurology
Associate director of research, VAAAHS Geriatric Research, Education and Clinical Center–
Nicolaas Bohnen MD, PhD
Associate Director, U-M Udall Center
Udall Clinical Resource Core Co-Lead
Udall Project I Lead
Professor, Departments of Radiology and Neurology
Director, U-M Functional Neuroimaging, Cognitive and Mobility Laboratory -
Core A: Administrative Core
Core Lead: Roger Albin, MDThe 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.
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Core B: Clinical Resource Core
Core Co-Lead: Nicolaas Bohnen, MD, PhD
Core Co-Lead: Kirk Frey, MD, PhDThe Clinical Resource Core performs comprehensive assessments of all subjects (PD and control) enrolled for Projects I and III. All subjects are evaluated with established clinical, motor, and neuropsychological instruments. The Clinical Resource Core utilizes many of the Parkinson disease Common Data Elements (CDEs) for evaluations. The Clinical Resource Core collaborates with the Neuroimaging Resource Core for imaging assessments, with the Biostatistics and Data Management Core for data storage and analysis, and oversees transfer of data from collaborators in the University of Groningen DUPARC study.
Core C: Neuroimaging Resource Core
Core Co-Lead: Prabesh Kanel, PhD
Core Co-Lead: Robert Koeppe, PhDThe Neuroimaging Resource Core oversees acquisition and analysis of all imaging data for Projects I and III. The Neuroimaging Resource Core oversees performance and analysis of MRI studies, and [11C]DTBZ and [18]FEOBV PET studies. The Neuroimaging Resource Core has standard analysis pipelines for these studies and collaborates with Project I and III investigators-personnel on analysis of imaging data. The Neuroimaging Resource Core collaborates with the Biostatistics and Data Management Core on multimodal analysis of imaging datasets. The Neuroimaging Resource Core is responsible for the transfer and analysis of imaging data from our University of Groningen DUPARC study.
Core D: Biostatistics and Data Management Core
Core Co-Lead: Cathie Spino, Sc.D.
Core Co-Lead: F. DuBois Bowman, PhDThe Biostatistics and Data Management Core leads the Center efforts on design and analysis of all experiments conducted in the translational Projects. Core 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. It is also instrumental in training students and fellows to develop skills and expertise in analysis of imaging datasets, database management, and trial-type activities.
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Project I: Evolution of cholinergic deficits within multisensory, cognitive, and motor integration brain regions and development of PIGD features in people with Parkinson’s disease
Project Lead: Nicolaas Bohnen, MD, PhD[18F]FEOBV PET delineates specific cortical regions and deep brain structures, including striatum and thalamic subnuclei. PD subjects with falls vs those with falls and gait freezing exhibit distinct abnormal patterns, highlighted by reduced striatal [18F]FEOBV as a shared dysfunctional node. Dr. Bohnen and his team will prospectively test the hypothesis that the cholinergic AMI network dysfunctions they describe are core features of PD gait and balance dysfunction, and that distinct patterns of cholinergic pathology predict specific features of PD gait dysfunction. The serial assessments proposed will allow unique within-subject analysis for the temporal dissection of distinct and converging elements of mobility control deficits of gait-balance motor features in PD. Unlike the prior grant cycle where longitudinal assessment was limited, esp. for PwP converting from non-fallers/freezers to fallers/freezers, the current cycle will allow clinically meaningful follow-up assessments of up to 5-6 years of PwP who completed baseline [18F]FEOBV PET. Hypotheses to test: 1) whether incident fallers exhibit [18F]FEOBV defects in the caudate, visual thalamus, and prefrontal cortex (compared to non-converters), and 2) whether the subsequent emergence of gait freezing involves additional and more widespread cholinergic vulnerability of the striatum, limbic archicortex, including the cingulo-opercular and insular cortices. The existence of the unique PD subject cohort developed in the currently funded cycle, together with newly recruited subjects, will allow study of an enriched sample of those converting to falls and/or to gait freezing. The focus on visual thalamus, based on the repeated association of falls with cholinergic dysfunction (found with both [11C]PMP and [18F]FEOBV), is another important and novel element. Many thalamic nuclei are primarily interconnected with association cortices with these thalamic nuclei are increasingly viewed as partners and/or modulators of cortical functions. Emerging evidence supports critical roles of visual thalamus in mediating visual attention. LGN function is modulated by attention, indicating a key role for this relay structure in bottom-up attention. Dr. Bohnen has new data implicating cholinergic denervation of additional regions driving non-episodic PIGD deficits preceding falls and FoG. This data indicates that cholinergic deficits within the MGN and entorhinal cortex (EC) are robustly associated with non-episodic PIGD, independent of nigrostriatal dopaminergic deficits. MGN is involved in processing multi-sensory (auditory, vestibular and proprioceptive) inputs, implying a significant role of impaired sensorimotor integration underlying early PIGD features in PwP. EC is associated with visuospatial maps, suggesting deficient attention-visuomotor integration. Complementary work will be performed in the Catalyst Research Project. The analysis of cholinergic system changes of the evolution of balance and gait disturbances will be complemented by exploratory mechanistic multisensory and attentional-motor integration studies. These studies will identify the key patterns of cholinergic systems dysfunction underlying treatment-refractory gait and balance disorders in PwP.
.Project II: Circuit Mechanisms of Attentional-Motor Interface Dysfunction in PD Falls
Project Lead: Martin Sarter, PhDThis project builds on Dr. Sarter’s published and preliminary work dissecting the mechanisms of the detection relevant cues, transfer of this information to striatum, and its integration with ongoing motor processing. Having established a role for BF cholinergic projections in the DL (dual lesion) rodent model of PD falling, he will use optogenetic techniques to test the hypothesis that the enhanced fall propensity caused by BF lesions is caused specifically by the loss of fast cholinergic signaling (i.e., “transients”) known to mediate attention. Additional experiments will define how BF-mediated cortical attentional information is integrated with motor selection processes. Frontostriatal circuitry (glutamatergic corticostriatal projections) is essential for action planning, particularly when habit-guided action is disrupted and task shifts are needed. Such adjustment depends critically on corticostriatal information transfer to guide adaptive movement selection and sequencing. Deficient cortical cholinergic activity impairs attentional shifts toward alternative actions, uncoupling striatal action selection from goals, causing ill-timed or absent responses. Guided by this framework, intrinsic to the AMI model, Dr. Sarter’s team acquired compelling preliminary data detecting the signals encoding attentional information transferred to the striatum (via corticostriatal terminals), where it is hypothesized to be integrated with vigor and kinematic signals supplied by nigrostriatal dopaminergic terminals. Utilizing a novel behavioral paradigm, they demonstrate that a cue instructing the animal to turn evokes a time-locked increase of striatal glutamate (that will be shown to originate from corticostriatal afferents), and a similarly timed burst of acetylcholine – hypothesized from ChIs. Dr. Sarter’s team will specifically test the hypothesis that this integrative function is essential for complex motor control, including PD gait dysfunction. Preliminary findings strongly support a role for ChIs in integrating the attentional and motor signals during gait; chemogenetic activation of these neurons reduces fall propensity in DL rats (often preceded by freezing-like motor behaviors in the animals), whereas their inhibition in intact animals mimics DL-type falls. These data support key aspects of the AMI model by implicating cholinergic neurotransmission at two successive nodes along the cortico-striatal pathway critical to support the attentional-motor interface – in cortex for signal detection, and in striatum for signal integration. These studies will identify key substrates of attentional-motor integration in the AMI.
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Project III: Cinculo-Opercular Task Control Network Cholinergic Dysfunction in PD
Project Lead: Roger Albin, MD
Our preliminary results indicate a global effect of key AMI node AC-I cholinergic denervation on cognitive functions. These cortical regions are key nodes of the COTC network and participate in higher level aspects of attentional function. We will confirm that AC-I denervation is associated with widespread cognitive deficits. Our established PD cohort, extensively characterized with dopaminergic and cholinergic PET, and with motor and cognitive assays, uniquely positions us to define the distinctive natural history of a PD subgroup based on a pathologic marker. Continued follow-up of this valuable cohort will assess if AC-I cholinergic denervation predicts significantly greater global cognitive decline. Quantification of cholinergic changes in the COTC subcortical and cortical (AC-I) network in this cohort will also allow the assessment that progressive cognitive changes coincide with more severe motor changes (aggressive or ‘malignant’ PD subtype). PET studies are costly and [18F]FEOBV is only operational in a handful of centers. A convenient, reliable predictor of AC-I cholinergic denervation is required to employ this phenotype as subgroup marker or stratifying method. We will capitalize on the thorough phenotyping of our cohort and apply more convenient MRI methods, complementing Project I analyses, to explore an accessible biomarker. Through collaboration with investigators at the University of Groningen (Netherlands), we have access to a similarly characterized and prospectively followed cohort of incident PD subjects who also undergo [18F]FEOBV PET. These subjects are part of the Dutch Parkinson and Cognition Study (DUPARC). This collaboration will enable us to rigorously test our hypotheses regarding the impacts and prognostic potential of AC-I cholinergic denervation and identification of a useful predictor in an independent replication cohort. Our Groningen colleagues agreed to share all phenotypic, MRI, and [18F]FEOBV imaging data to address, in parallel, the hypotheses driving Project III. These studies will identify a key substrate of cognitive impairments and predictor of more rapid cognitive decline in PwP.
Catalyst Research Project: Retrosplenial Cholinergic and Attentional-Motor Integration Dysfunction
Project Lead: Omar Ahmed, PhDIn this Catalyst Research Project, Dr. Ahmed will evaluate the hypotheses that thalamic input mediated spatial information is modulated by BF cholinergic afferents and that cholinergic receptor mediated responses in RSC neurons are critical for maintaining attentive navigation. RSC inter-hemispheric communication is necessary to maintain attentive navigation. Dr. Ahmed specifically hypotheses that cholinergic signaling is necessary for normal inter-hemispheric RSC function. Dr. Ahmed will evaluate these hypotheses in both normal animals and in the dual lesion (DL) model of combined striatal dopaminergic denervation and cortical cholinergic denervation developed by Dr. Sarter. This study will identify mechanisms of information transfer within a key AMI node. These experiments provide a cellular level examination of cholinergic functions within an AMI node, complementing the systems and circuit level approaches of the other projects. The focus on attentive spatial navigation also complements Project I studies assessing the roles of deficient sensorimotor and visuomotor integration in PwP.
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Former Trainees
Kara J. Wyant, MD
Assistant Professor, Department of Neurology
Former Movement Disorders Fellow
Kara J. Wyant, MD, is an Assistant Professor and former 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.
Aaron Kucinski, PhD
Research Lab Specialist Senior
Former Udall Trainee Postdoctoral Research Fellow
Aaron Kucinski, PhD is a Research Lab Specialist Senior in the Sarter Lab (Project II: Circuit Mechanisms of Attentional-Motor Interface Dysfunction in PD Falls). 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.
Benjamin Stewart, MD
Former Udall Fellow and Clinical Instructor
Department of Neurology
Dr. Stewart was a Udall Center movement disorders fellow in the Department of Neurology 2018-2020. His interests included Parkinson disease, Huntington disease, and dystonia. He was also involved in patient and practitioner outreach programs through the Udall Center. Dr. Stewart graduated from neurology residency at the University of Michigan in 2018. He graduated from the Feinberg School of Medicine at Northwestern University in 2014. After completing his Udall movement disorders fellowship in 2020, Dr. Stewart moved on to practice in Boise, Idaho.
Andrew J. Ridder, MD
Former Udall Fellow and Clinical Instructor
Department of Neurology
Dr. Ridder was the first Udall Center Fellow. He was also a Movement Disorders Fellow in the Department of Neurology. He received 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 was involved in clinical research on the impact of Deep Brain Stimulation on impulse control in Parkinson’s Disease as well as whether cholinergic stimulation improved balance and gait in people with Parkinson’s Disease Dementia, Lewy Body Disease and Alzheimer’s. He also participated 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. In July, 2018 he returned to South Dakota where he is a neurologist at Avera McKennan Hospital.
Mélanie L. Beaulieu, PhD
Former Udall Trainee Postdoctoral Research Fellow
Department of Radiology
Mélanie L. Beaulieu, PhD, was 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 investigated various contributors to these balance and gait problems, including cholinergic system impairments and disease-independent factors. She also developed 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..
