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 national consortium of brain autopsies for PD, PD with dementia (PDD), and Dementia with Lewy bodies (DLB) to examine the molecular pathology of PDD with different genetic risk as well as the genetic risk of cognitive impairment and dementia in PD. 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 PD. Clinical Core (Dr. Joseph F. Quinn): This Core focuses on generating a unique resource for translational and clinical research in PD. Clinical Core subjects are followed at all three sites: in Portland directed by Clinical Core Leader, Dr. Quinn, in Seattle directed by Dr. Cyrus Zabetian, and in the San Francisco 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 biospecimens. It performs a standardized set of evaluations for genetic markers, plasma/serum and CSF biomarkers, and neuropathologic characterization of brain autopsy material. 

Recent Advances

• Project 1: Two new genetic risk loci for cogntiive impairment in PD were identified: investigators are confirming these findings in a validation cohort.  Molecular pathology work has focused on a novel quantitative technique, histelide, which has been used to assay numerous brain regions from over 100 extensively clinically and genetically annoted cases.  Analyses of these unique data are underway.
   
• Project 2: Prior studies demonstrated that BOLD variability, a simple measure of intrinsic activity, increases with disease duration; investigators subsequently conducted joint analyses of BOLD variability and functional connectivity. In the OFF state, a decrease in BOLD variability in the occipital cortex is related to an increase in connectivity within the default mode network, a finding that is reversed by levodopa, and is specifically related to disease duration. This pattern is interpreted as being related to observations of lower parietal-occipital metabolism, potentially caused by cholinergic denervation, resulting in decreasing ability to direct spatial attention in PD. Project investigators are examining functional correlates of short latency afferent inhibition (SAI) data, a marker of cholinergic activity, observing that lower functional connectivity from cholinergic nuclei is related to higher (better) inhibition. However, in PD, increases to functional connectivity ON vs OFF levodopa that are related to SAI indicate that not only does SAI in PD reflect an interaction between dopaminergic and cholinergic systems, but that this interaction has a resting state correlate.
   
• Project 3:  Recent data shows significant gait, balance, and attention differences between the genetic subgroups of people with PD. Gait and balance has been assessed in APOE4 carriers, GBA carriers and non-carriers with idiopathic Parkinson’s disease. Those with the GBA mutation had significantly worse stride time variability compared to non-carriers and APOE4 carriers; GBA mutations were also associated with slower turns. Assessment of cholinergic activity (TMS SAI), and attention data from PD non-carriers, PD E4 carriers, PD GBA, control non-carriers, and control E4 carriers.  The APOE4 carriers had significantly worse cholinergic activity (SAI), slower turns and slower complex reaction times than the control groups, suggesting that loss of cholinergic activity related to APOE4 may be related to poorer mobility and cognitive function in PD.

Public Health Statement