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

Title: Pacific Udall Center at Stanford University

Website: udallcenter.stanford.edu/

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. We strive to understand the basis of this prevalent unmet medical need and—through both clinical and basic research—to discover improved diagnostics and new therapeutic targets. Our Center brings together a multidisciplinary group of investigators focused on improving our understanding of cognitive impairment in Parkinson’s disease. Projects within and linked to the Center are designed to provide important insights into the pathophysiology of cognitive impairment in Parkinson’s disease. Equally important, the Pacific Udall 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.
 

Center Structure

The Pacific Udall Center includes four Research Projects and three Cores. Project 1: Genetic risk for PD-related cognitive impairment and its disease mechanisms (Dr. Thomas Montine): This research project leverages a productive team effort among Drs. Edwards, Mata, and Montine, and a national consortium of brain autopsies for PD, PD with dementia (PDD), and Dementia with Lewy bodies (DLB).  Project 2: MR-based systems imaging of PD-related cognitive impairment and inherited variants in APOE or GBA (Dr. Thomas Grabowski): 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. Project 3: Balance and gait disorders associated with genetic inheritance in PD (Dr. Fay Horak): 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 is characterized using novel, inertial-sensors worn on the feet, belt, and wrist with or without simultaneous tasks to determine the effects of divided attention. 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 the many regional and national groups that support and advocate for individuals with Parkinson’s disease. Training and community engagement continue to be high priorities. Clinical Core (Dr. Joseph Quinn): This Core focuses on generating a unique resource for translational and clinical research in Parkinson’s disease. Clinical Core subjects are followed at all three sites: in Portland directed by Dr. Quinn, in Seattle directed by Dr. Cyrus Zabetian, and in the San Francisco Bay Area directed by Dr. Kathleen Poston. The Clinical Core cohort is a large sample designed to allow investigation of genetic factors for cognitive impairment in Parkinson’s disease. Analytical Core (Dr. Cyrus Zabetian): This Core is the repository for collected blood, CSF, and autopsy material. It performs a standardized set of evaluations for genetic markers, plasma/serum and CSF biomarkers, and neuropathologic characterization of brain autopsy material.
 

Recent Advances

Major scientific advances for the Pacific Udall Center in the last year are

• Project 1: We continued to expand our knowledge of genetic risk for cognitive impairment in PD by completing the first cross-sectional genomic screen of dementia in PD and published our first work on genetic risk of PD progression.
   
• Project 2: We have found that BOLD variability, a simple measure of intrinsic activity, increases with PD duration in the posterior cingulate and superior frontal cortex, changes that are independent of those related to cerebrospinal levels of alpha-synuclein. We have observed that although there is no difference between PD OFF and controls on the AX Continuous performance task OFF levodopa, levodopa decreases PD performance to below that of controls. However, this decrease in performance masks heterogeneity in how levodopa affects the decision making process among subgroups of subjects who respond to levodopa with different speed/accuracy tradeoffs.Finally, we have identified significant structural correlates of lower cholinergic tone that include lower gray matter density in the cholinergic nuclei of the basal forebrain.
   
• Project 3: We are seeing subtle differences in gait between carriers and non-carriers of APOE4 in people with PD. Preliminary analysis indicates APOE4 carriers (n = 8) have increased cadence under dual-task conditions compared to none-APOE4 carriers (n = 20) when ‘off’ medication (p= 0.013). Under the same dual-task conditions, APOE4 carriers also demonstrate a reduced toe off angle (p = 0.002) and foot strike angle variability (p = 0.010) compared to non-carriers. This indicates a faster, shuffling gait in carriers when they are distracted, which may lead to increased falls risk.
   

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.