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, Mata and Zabetian, and a national consortium of Parkinson’s disease cases with (PDD) or without (PD) dementia and Dementia with Lewy body disease (DLB). In our first aim, we are investigating 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 previous award cycle and augmented by new collaborators. The second aim of this proposed project investigates of the genetic risk of cognitive impairment and dementia in Parkinson’s disease from a candidate gene approach using genomic approaches with longitudinal diagnostic and neuropsychological data.

Project 2 – Magnetic resonance-based systems imaging of Parkinson’s disease-related cognitive impairment and inherited variants in APOE or GBA (PI: T. Grabowski)

This Project tests the hypothesis that cognitive impairment in Parkinson’s disease is accompanied by alterations of specific systems-level neurophysiologic relationships that vary with APOE ε4 or GBA variant carriers.  In our first aim, we 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 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. In Aim 3, we analyze how omnibus and regional measures of system disruption bridge the relationship between CSF biomarkers of cerebral pathology and cognition. We will expand this 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 Parkinson’s disease (PI: F. Horak)

Cognitive deficits and balance and gait (B&G) disorders are both progressive and heterogeneous among people with Parkinson’s disease and may be due, in part, to genetic factors. Project 3 tests the hypothesis that the pattern of B&G abnormalities, in part an expression of various types of cognitive impairment, differ in Parkinson’s disease 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 is 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, Aim 2 focuses on mechanism, by relating central cholinergic tone measured with SAI to impairments of B&G, and Aim 3 is a longitudinal investigation that will determine the decline in B&G, attention, and cholinergic tone. This work expands our knowledge of genetic risk for severity and decline in mobility as they relate to cognitive impairments in Parkinson’s disease, in order to lay the foundation for potential cholinergic mechanisms linking cognition with B&G dysfunction.

Core A: Administrative and Outreach Core (PI: T. Montine)

Cognitive deficits and balance and gait (B&G) disorders are both progressive and heterogeneous among people with Parkinson’s disease and may be due, in part, to genetic factors. Project 3 tests the hypothesis that the pattern of B&G abnormalities, in part an expression of various types of cognitive impairment, differ in Parkinson’s disease 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 is 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, Aim 2 focuses on mechanism, by relating central cholinergic tone measured with SAI to impairments of B&G, and Aim 3 is a longitudinal investigation that will determine the decline in B&G, attention, and cholinergic tone. This work expands our knowledge of genetic risk for severity and decline in mobility as they relate to cognitive impairments in Parkinson’s disease, in order to lay the foundation for potential cholinergic mechanisms linking cognition with B&G dysfunction.

Core B: Clinical Core (PI: J. Quinn)

The Pacific Udall Center Clinical Core has recruited and characterized a cohort of more than 600 individuals with Parkinson’s disease (Parkinson’s disease) during the inaugural award. Data from the 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 Parkinson’s disease. 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 provide well-characterized Parkinson’s disease and control subjects of appropriate genotypes for Projects 2 and 3, and it will provide longitudinal data for subjects in all 3 projects. 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 (Project 3). Clinical Core subjects are currently followed at our sites in Portland and Seattle, with enrollment in the Palo Alto area coming soon.

Core C: Analytical Core (PI: C. Zabetian)

Dr. Zhang’s linked Parkinson’s disease Biomarker Program. The Core’s has two main areas of support. The Laboratory side includes genetic analysis for all three projects and the Clinical Core, management of biofluids from the Clinical Core and analysis of well-established biomarkers for Parkinson’s disease and Alzheimer’s disease neuropathology analysis: The Data side provide expert data management and statistical support for the Clinical Core and all three Projects and affiliated efforts. Together, 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.