Director: Thomas J. Montine, M.D., Ph.D.

Title: Pacific Udall Center at Stanford University

Website: udallcenter.stanford.edu/

Budget End Date: 6/30/2020

Central Theme

The focus of the Pacific Udall Center is a combined effort of Stanford University, the University of Washington and Oregon Health & Sciences University to develop solutions for cognitive impairment in Parkinson’s disease (PD). We strive to understand the basis of this prevalent problem for patients and—through both clinical and basic research—to discover improved diagnostics and new therapeutic targets.

Center Structure

The Pacific Udall Center brings together a multidisciplinary group of investigators focused on improving our understanding of cognitive impairment in PD, with research projects designed to provide important insights into the pathophysiology of cognitive impairment in PD. Equally important, the Center serves as a unique resource for other investigators interested in translational and clinical investigations of cognitive impairment in Parkinson’s disease, including those at other Udall Centers.

The Pacific Udall Center consists of three research Projects and three Cores:

Project 1: Genetic risk for PD-related cognitive impairment and its disease mechanisms (Thomas Montine, MD, PhD). In the first aim, we are pursuing the molecular pathology of Parkinson’s Disease Dementia (PDD) with different genetic risk.  The second aim will expands our investigation of the genetic risk of cognitive impairment and dementia in PD from a candidate gene approach to genomic approaches with longitudinal diagnostic and neuropsychological data.

Project 2: MR-based systems imaging of PD-related cognitive impairment and inherited variants in APOE or GBA (Thomas Grabowski, MD). This research project tests the hypothesis that cognitive impairment in PD is accompanied by alterations of specific systems-level neurophysiologic relationships that vary with APOE ε4 or GBA variant carriers. Aim 1 applies established and novel structural and physiologic imaging techniques to evaluate whether APOE ε4 or GBA variant carriers have different profiles of cortical system involvement.  Aim 2 tests whether novel dynamic functional connectivity measures are more sensitive and informative than either existing imaging markers or stationary functional connectivity at predicting future cognitive decline in Clinical Core participants. Aim 3 analyzes how omnibus and regional measures of system disruption bridge the relationship between CSF biomarkers of cerebral pathology and cognition.

Project 3: Balance and gait disorders associated with genetic inheritance in PD (Fay Horak, PhD, PT). This research project tests the hypothesis that the pattern of balance and gait (B&G) abnormalities, in part an expression of various types of cognitive impairment, differ in PD patients with APOE ε4, GBA variants, or neither. B&G will be characterized using novel, inertial-sensors worn on the feet, belt, and wrist with or without simultaneous tasks to determine the effects of divided attention. Aim 1 is a cross-sectional investigation of all Clinical Core participants to determine patterns of B&G dysfunction in PD with APOE ε4, GBA variants, or neither, and to relate B&G to psychometric test scores. Aim 2, in close integration with Project 2, relates central cholinergic tone measured to impairments of B&G and attention in genetically-defined subsets of healthy controls and PD participants both on and off PD medications. Aim 3 determines the decline in B&G, attention, and cholinergic tone in genetically-defined subsets of PD participants.

Administrative and Outreach Core (Dr. Montine): This Core provides administrative oversight for the Pacific Udall Center at our three institutions and facilitates interaction between our Center and many regional and national groups that support and advocate for individuals with PD.  Training and community engagement are continuing high priorities for the Center and are organized through the Core.

Clinical Core (Joseph F. Quinn, MD): Clinical core subjects are followed at three Pacific Udall sites: in Portland, in Seattle, and in San Francisco.  The Clinical Core cohort is a large sample designed to allow investigation of genetic factors for cognitive impairment in PD.

Analytical Core (Cyrus Zabetian, MD): This Core performs a standardized set of evaluations for genetic markers, plasma/serum and CSF biomarkers, and neuropathologic characterization of brain autopsy material.

Research at the Pacific Udall Center addresses several NINDS PD2014 research priorities, including:

• Clinical Recommendation 2: Develop effective treatments and companion biomarkers for dopa-resistant features of PD. These features include both motor symptoms, particularly gait and balance problems such as freezing of gait, and non-motor symptoms, especially cognitive impairment, psychosis, and dysautonomia.
• Clinical Recommendation 3: Characterize the long-term progression of PD and understand the mechanisms that underlie its heterogeneity in clinical presentation and rates of progression. Factors related to disease heterogeneity may include clusters of clinical features as well as biological factors such as genotype and biomarkers.
• Translational Recommendation 1: Develop patient stratification tools that define disease signatures of more homogeneous cohorts with emphasis on slow vs. fast progressing PD, prodromal PD, and non-motor symptoms.

Publications from the Pacific Udall Center at Stanford University
 

Public Health Statement

The National Institutes of Health (NIH) estimates that over a half million people in the United States suffer from Parkinson’s disease, causing untold suffering to patients as well as their caregivers and other loved ones. The physical, emotional, and societal costs of Parkinson's disease will increase over the coming decades as more of us live longer; in fact, the number of patients with Parkinson’s disease is expected to double in the United States by the year 2030 unless we find safe and effective means to cure, delay onset, or slow progression of this disease. Cognitive impairment (changes in brain-based functions such as memory, attention, and reasoning) is a common feature of Parkinson’s disease that is disabling for patients, challenging to caregivers, and costly to health care systems. Our Center is focused on the clear imperative to find better tools for diagnosis and better ways to treat cognitive impairment in patients with Parkinson’s disease.