Projects and Cores
Project 1 – Genetic risk for Parkinson’s disease-related cognitive impairment and its disease mechanisms (PI: T. Montine)
This Project leverages the most successful parts of our inaugural award, the productive team effort among Drs. Edwards, Montine, and Zabetian, and a national consortium of Parkinson’s disease with (PDD) or without (PD) dementia and Dementia with Lewy body disease (DLB). In our first aim, we propose to determine the molecular pathology of PDD with different genetic risk by using a novel technology developed by the Montine Laboratory to obtain robustly quantitative data on the regional concentration of neurotoxic and synaptic proteins in human brain from a large cohort assembled during the current award and augmented by new collaborators. The second aim of this proposed project will expand our investigation of the genetic risk of cognitive impairment and dementia in PD from our current candidate gene approach with cross sectional diagnostic and neuropsychological data to genomic approaches with longitudinal diagnostic and neuropsychological data.
Project 2 – Magnetic resonance-based systems imaging of PD-related cognitive impairment and inherited variants in APOE or GBA (PI: T. 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. In our first aim, we will apply 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 will test 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. We will determine whether functional connectivity markers predicting cognitive diagnosis and/or progression are invariant to dopaminergic replacement status. In preliminary studies we established that a dynamic functional connectivity measure of system disruption increases in proportion to the reduction of α-synuclein or Aβ42 concentration in CSF, linking CSF biomarkers of disease to MRI measures of neural systems function. In Aim 3, we will replicate this important and novel finding and then analyze how omnibus and regional measures of system disruption bridge the relationship between CSF biomarkers of cerebral pathology and cognition. Finally we will expand this novel approach to make contact with measures of disease being investigated in Project 3 and in Project 1.
Project 3 – Balance and gait disorders associated with genetic inheritance in PD (PI: F. Horak)
Cognitive deficits and B&G disorders are both progressive but heterogeneous among people with PD, and may be due in part to genetic factors. Project 3 will test the hypothesis that the pattern of B&G abnormalities, in part an expression of various types of cognitive impairment, differ in PD subjects with APOE ε4, GBA variants, or neither. B&G will be characterized in all Clinical Core participants using novel, inertial-sensors worn on the feet, belt, and wrist. A quick Instrumented Stand and Walk protocol that involves standing quietly for 30 seconds, followed by step-initiation, a 2-minute walk, and several 180 degree turns quantifies various domains of mobility disability, such as postural sway area, gait pace, and gait rhythm. The B&G protocol will also be repeated during simultaneous performance of a quantitative cognitive task to determine the effects of divided attention on B&G. 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 in these genetically-defined subsets of PD. Aim 2 focuses on mechanism, and in close integration with Project 2, will relate central cholinergic tone measured with SAI 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 is a longitudinal investigation and will determine the decline in B&G, attention, and cholinergic tone in genetically defined subsets of PD participants. This work is significant because it will expand our knowledge of genetic risk for severity and decline in mobility as they relate to cognitive impairments in PD, and will lay the foundation for potential cholinergic mechanisms linking cognition with B&G dysfunction. Insights from this project, integrated within the PANUC via the Analytical Core, will provide new biomarkers for cognitive and mobility decline for better prognosis and interventions for patients with PD.
Core A: Administrative and Outreach Core (PI: T. Montine)
The PANUC Administrative and Outreach (Admin) Core has overall responsibility for scientific direction and leadership of our integrated and collaborative multi-site and multidisciplinary center of excellence for research and training. The Center Director and Administrator, in full collaboration with the Advisory Committees and Executive Committee, coordinate and integrate PANUC components, activities, and resources as we pursue NINDS research priorities set forth in Parkinson’s Disease 2014: Advancing Research, Improving Lives and Alzheimer’s Disease Related Dementia (2013), which included cognitive impairment and dementia in PD. The Admin Core works closely with all components (Clinical and Analytical Cores and Projects) of PANUC to identify trainees and junior faculty who we will advise on collaborations, encourage to apply to our Pilot Award program, direct to fellowship and training grant opportunities, and invite to the PANUC retreat as well as multiple other forums at our institutions, locally and nationally, to help advance their knowledge and skills and prepare them for careers as independent investigators focused on PD.
Core B: Clinical Core (PI: J. Quinn, Portland Site & SC. Hu, Seattle Site )
The Pacific Northwest Udall Center (PANUC) Clinical Core has recruited and characterized a cohort of more than 600 individuals with Parkinson’s disease (PD) during the inaugural award. Data from the PANUC Clinical Core, in collaboration with other Udall Centers and other academic medical centers, have helped confirm Apolipoprotein E (APOE) and glucocerebrosidase (GBA) as genes that are relevant to the pathogenesis of cognitive decline in PD. Understanding the mechanisms underlying these gene effects is the focus of this renewal application, utilizing brain autopsy and genomic approaches (Project 1), neuroimaging (Project 2), and quantitative balance and gait (B&G) measurements (Project 3). The Clinical Core will provide longitudinal data for subjects in all 3 projects, and will provide well-characterized PD and control subjects of appropriate genotypes for Projects 2 and 3. B&G testing has been added to the test battery as an innovation that is thought to reflect higher order CNS function closely related to cognition. This innovation leverages the expertise of Dr. Fay Horak, an investigator introduced to PANUC by way of PANUC pilot award funding. As in the first cycle, Clinical Core subjects will be followed at two sites: one in Portland directed by Clinical Core Leader Dr. Joseph Quinn, and the other in Seattle directed by Clinical Core Co-Leader Dr. Shu-Ching Hu.
Core C: Analytical Core (PI: C. Zabetian)
The goal of the Analytical Core is to support the efforts of PANUC to understand and treat cognitive impairment in Parkinson’s disease (PD). The Analytical Core will continue providing laboratory-based and data analyses in support of all three PANUC projects and the Clinical Core, as well as to linked PD Biomarker Program project (U01 NS082137, PI: Dr. Zhang, also Analytical Core Co-Investigator). We will accomplish our goal of providing both types of analytical support through the following Specific Aims: Specific Aim 1. LABORATORY: Genetic analysis for all three projects and the Clinical Core. CSF biomarkers analysis: Provide management of biofluids from the Clinical Core and analysis of well-established biomarkers for PD and Alzheimer’s disease for Clinical Core, Project 2 and the linked U01. Neuropathology analysis: Provide expert analysis of tissue samples from Clinical Core and Project 1. Specific Aim 2. DATA MANAGEMENT and STATISTICAL ANALYSIS: Provide expert data management and statistical support for the Clinical Core and all three Projects and affiliated efforts. This Core serves multiple research priorities set by the NINDS Parkinson’s Disease 2014: Advancing Research, Improving Lives.
Read about the work done by the Zabetian Lab in a recent article, The Power to be Precise.