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: 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 work on genetic risk of PD progression. Last year the team discovered two new genetic risk loci for cognitive impairment in PD and this year executed an independent validation study. Our molecular pathology work has focused on a novel quantitative technique that we call histelide. Our multivariate analysis of histelide assays on numerous brain regions from over 100 extensively clinically and genetically annotated cases is underway. As part of this work we have confirmed our discovery that APOE genotype is an independent risk factor for Lewy body disease. We have expanded our capacity to perform multiplex image analysis of human brain to 40 to 50 probes assayed simultaneously using a novel technique, invented by our collaborators at Stanford, called Multiplex Ion Beam Imaging (MIBI). We have completed the first application of MIBI to human brain and are now preparing to analyze samples from human neurodegenerative diseases.
• Project 2: Focus continued on understanding cognitive impairment in people with PD. Using MRI-based analysis, we analyzed APOE ε4-related differences in resting functional connectivity in participants with Parkinson’s disease and obtained evidence for an APOE ε4 allele effect on posterior default mode network connectivity in PD that is different from characteristic AD-related functional connectivity changes. To test hypotheses on the role of cholinergic signaling in cognitive impairement in PD, we have been collecting transcranial magnetic stimulation data and measuring short latency afferent inhibition (SAI) as an index of central cholinergic tone. Comparison of subjects with PD and age-matched control subjects provides evidence that SAI reflects effects of multiple neurotransmitter systems, including adaptive functioning of the cholinergic system in PD. We have also extensively studied the effect of dopaminergic medications on blood oxygenation level-dependent (BOLD) variability and functional connectivity of the anterior and posterior default mode network (DMN). Thus, dopaminergic medication status interacts with level of impairment to alter both BOLD variability and DMN functional connectivity in PD.
• Project 3:  Gait and balance impairments are cardinal features of Parkinson’s disease (PD) that require cognitive input. We developed models of gait and balance in a large PD cohort and determined which gait and balance characteristics best related to cognition. Gait domains of pace/turning and variability were strongly associated with attention and executive function. Sway area and jerkiness of balance associated with attention and visuospatial function.  Our next focus was on the influence of genotype on gait and balance in PD. Subjects with the GBA variants had more impaired gait (pace/turning and variability), balance (sway area and jerk) and cognition (executive function, attention and visuospatial ability). Structural equation models revealed poorer cognition mediated greater gait and balance impairments to a larger extent in those with the GBA variants compared to idiopathic PD. In addition to the GBA variants, we have also assessed differences in gait and balance performance in those with PD who are carriers and non-carriers of the APOE ε4 allele. When controlling for age, gender, testing site and disease duration there were no significant differences in any measures of gait or balance between carriers and non-carriers. This analysis suggests that in those with PD who carry the APOE ε4 allele, there is no impact on gait or balance.

Public Health Statement