Projects & Cores

Project 1: Functional and anatomical analysis of dopaminergic projections that mediate cognition.  PI: Richard D. Palmiter, Ph.D.

This Project uses a combination of genetically engineered mice and virus-mediated gene transfer in conjunction with mouse behavioral tests of learning and memory to identify the neural circuits that may underlie the cognitive decline in patients with Parkinson’s disease. We are developing two novel transgenic mouse lines that will allow us either to block genetically the production of dopamine in discrete dopaminergic projection regions by viral-mediated recombination of the tyrosine hydroxylase gene or to ablate completely dopamine neurons. We will determine whether loss of dopamine signaling (by inactivation of tyrosine hydroxylase) or dopamine neuron death (by action of diphtheria toxin) leads to cognitive impairment and morphological changes within the striatum and/or prefrontal cortex (in conjunction with Project 2).

Project 2: Selective and restricted denervation in Parkinson's disease with cognitive impairment.  PI: Thomas J. Montine, M.D., Ph.D.

Age-related cognitive decline (ARCD) is a complex convergent phenotype that prominently involves impaired executive function (EF) likely through disruption of the dorsolateral prefrontal cortex (PFC) circuit; despite much speculation, the cellular and molecular mechanisms that underlie this presumed disruption have not been demonstrated in humans. Cognitive impairment (CI) or dementia (D) is highly prevalent among patients with Parkinson’s disease (PD) but remains an incompletely understood non-motor complication of this devastating illness. Indeed, many patients with PD have neuropsychologically determined “CI, no dementia” (PD-CIND) at the time of initial diagnosis. Like ARCD, patients with PD-CIND or PD-D prominently display EF impairment; however, also like ARCD, the cellular and molecular bases are not clear. We hypothesize that selective region- and neurotransmitter-specific degeneration in PFC or anterior neostriatum significantly contributes to impaired EF in ARCD, PD-CI, and PD-D. In this Project, we are testing our hypothesis through the following Specific Aims. (1) Determine the magnitude and regional distribution of dopamine (DA), norepinephrine, and serotonin degeneration in neocortex and neostriatum, and their associations with cognitive function test results, from aged individuals without PD or dementia but varying levels of ARCD, aged individuals with pathologic changes of PD but not a clinical diagnosis of PD and varying levels of CI, and patients with closely related neurodegenerative diseases. (2) Determine the magnitude, regional distribution, and associations with cognitive test results of neostriatal medium spiny neuron spinodendritic degeneration in the same people whose tissue was investigated in Aim 1. (3) Determine if selective loss of DA neurotransmission without neurodegeneration leads to regionally restricted spinodendritic degeneration in mice from Project 1. Completion of these Specific Aims will provide the first integrated clinical, behavioral, morphometric, and neurochemical analysis of PFC and neostriatum in ARCD and in PD with and without CI, as well as in novel transgenic mice.

Project 3: Genetic risk factors for cognitive impairment in Parkinson's disease. PI: Cyrus P. Zabetian, M.D., M.S.

Variation within the microtubule-associated protein tau (MAPT) and alpha-synuclein (SNCA) genes is associated with a wide range of neurodegenerative disorders. Point mutations in MAPT result in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and triplications of SNCA cause hereditary early-onset parkinsonism with dementia. These rare variants have well-studied and relatively large effects on gene function that include altering splice isoform ratios (tau) and increasing expression of wild-type protein (SNCA). Common haplotypes across MAPT are associated with susceptibility for Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Parkinson's disease (PD). The identity of the functional MAPT risk variants in these disorders has yet to be determined, but appears to be distinct between the tauopathies (AD, PSP, and CBD) and PD. Similarly, common haplotypes and a dinucleotide repeat polymorphism (REP1) in SNCA confer risk for PD through mechanisms that are not clearly understood. Finally, the APOE*4 allele is a well-established susceptibility factor for AD, and there is some evidence that it might increase risk for dementia in PD. Therefore, given that MAPT, SNCA, and APOE play a role in multiple disease traits characterized by parkinsonism and/or dementia, these three genes might well influence the occurrence of cognitive impairment (CI) and the rate of progression of CI in PD. We further hypothesize that genetic variation within MAPT and SNCA mediates the development of CI and rate of cognitive decline in PD by altering expression or splicing isoform ratios of tau and SNCA. Project 3 is testing these hypotheses through the following specific aims: (1) Determine whether MAPT, SNCA, and APOE genotypes or haplotypes are associated with cognitive function in a cross sectional analysis of 600 patients with PD; (2) Determine whether MAPT, SNCA, and APOE genotypes or haplotypes are associated with rate of cognitive decline in a longitudinal analysis of the same cohort of patients with PD; (3) Examine the association of MAPT and SNCA genotypes or haplotypes with tau and SNCA (total levels, phosphorylated species, isoform ratios) in CSF from 100 cognitively intact controls. The recent discovery of genetic risk factors for PD has uncovered a wealth of information that has opened exciting new avenues of research. Similar work to discover genetic risk factors for CI in PD is equally promising but has lagged behind, largely due to limited access to cognitively well-characterized patient populations. Successful completion of our Aims will address this issue, and the knowledge gained has the potential to generate novel experimental models, discover promising targets for therapeutic intervention, and identify subgroups of patients and at-risk subjects appropriate for specific clinical trials.

Linked R01: Post-translational modifications of proteins in Parkinson’s disease. PI: Jing Zhang, M.D., Ph.D.

It has become increasingly clear that Parkinson's disease (PD) is often associated with cognitive impairment. Pathological evaluations have repeatedly demonstrated that dementia in patients with PD (PD-D) is associated with either formation of Lewy bodies (LBs) or Alzheimer's changes such as the presence of neurofibrillary tangles (NFTs) and senile plaques (SPs) in the cortex. It is well known that formation of LBs, NFTs, and SPs are related to deposition of alpha-synuclein (SNCA), tau, and amyloid beta (Ab), respectively. However, the changes in these key proteins are not known in relationship to the development of PD-D. We hypothesize that development of cognitive impairment in PD is associated with unique post-translational modifications (PTMs) of SNCA, tau and Ab and that these PTMs are isoform/species-specific, as well as disease stage-specific. One of the major goals of this Project is characterizing the PTMs of various isoforms/species of SNCA, tau and Ab as a function of PD-D development using various state-of-the-art proteomic techniques. Additionally, since development of PD-D likely involves cellular processes beyond just SNCA, tau and Ab, for the purpose of discovering biomarkers that are clinically accessible, we will use a high-throughput proteomic technique to characterize one sub-proteome with a unique PTM (glycosylation) that is highly enriched in body fluids; such proteins carry great biomarker potential for PD-D. Both analyses (targeted and unbiased profiling) will initially be applied to pathologically confirmed brain tissue, followed by confirmation and validation in cerebrospinal fluid (CSF) and plasma. Confirmed and validated markers, whether in CSF or plasma, can then serve as the basis of highly sensitive and specific multiplex immunoassays (xMAP) to identify PD patients at risk for developing cognitive deficits.

Core A: Administrative and Outreach Core. PI: Thomas J. Montine, M.D., Ph.D.

This Core has overall responsibility for the goal of producing an integrated and collaborative multidisciplinary Udall Center that promotes cutting-edge research advances in PD and integrates effectively with local support and advocacy groups. The Director (PI) and Administrator, in full collaboration with the Executive Committee, will coordinate and integrate PANUC components, activities, and resources; solicit and review pilot project applications; foster productive interactions with other scientists and communities in the Pacific Northwest to assure progress in scientific and educational initiatives; ensure compliance with human subjects, animal welfare, scientific integrity, and financial policy requirements of the NIH, UW and OHSU; provide timely transmission of appropriate datasets to the PD Data Organizing Center (PD-DOC); collaborate fully with the Coriell Institute for submission to the NINDS Human Genetics Repository; and help train the next generation of researchers focused on PD.

Core B: Clinical Core. PI: James B. Leverenz, M.D.  OHSU Site PI:  Joseph F. Quinn, M.D.

Parkinson’s disease (PD) is a complex disorder with motor, cognitive, and behavioral dysfunctions that change over time. The methods to study PD have also become more complex, including the study of biomarkers, genetics, and postmortem-dependent neurobiology. Thus, a successful Clinical Core must not only characterize motor, cognitive, and behavioral function in PD subjects over time, but also carefully collect biological fluids during that same timeframe and later obtain postmortem material from these well-characterized subjects. The primary goal of the Clinical Core is to support the PANUC Projects through longitudinal characterization of PD subjects and through generation of biologic samples from these subjects. To accomplish this goal two PD subject samples will be established. The “community” sample (CS) will be a larger sample evaluated by Clinical Core study personnel, either at local movement disorder clinics or at the subjects’ homes, twice during the five-year Center funding cycle. This sample will generate the large number of blood samples, with clinical characterization, needed for the biomarker and genetic projects. The CS will also be the source of subjects for the “annual” sample (AS). The AS will be a smaller subject sample selected for clinical characteristics on screening (e.g. cognitive subtypes such as cognitive impairment without dementia). AS subjects will be evaluated annually at the study site and will have more detailed clinical characterization. In addition, these subjects will be recruited for lumbar punctures to supply CSF for biomarker studies and for autopsy. The Clinical Core will, therefore, develop PD subject samples with detailed clinical characterization, and collect biological samples from the subjects, to support Projects 2 and 3 in PANUC as well as closely aligned studies. Clinical data, DNA, and biofluids from control individuals will be obtained through the same protocols at each sites’ respective NIH-funded Alzheimer’s Disease Center. These unique and integrated data and samples from longitudinally evaluated PD subjects will be an invaluable resource for future studies by PANUC investigators, as well as for other investigators within and outside of the participating institutions.

Core C: Genetics, Biomarkers, and Neurolopathology (GBN) Core. PI: Jing Zhang, M.D., Ph.D.

The overall goal of this Core is to provide resources and expertise to PANUC investigators and other collaborators. This Core will accomplish three goals. GENETICS: Provide expert preparation of plasma and DNA from Clinical Core participant blood samples. DNA will be stored and used for genetic analysis by Project 3. Blood samples will be appropriately deposited with the NINDS Human Genetics Repository at the Coriell Institute for distribution to other investigators while insuring proper safeguards. BIOMARKERS: Provide analysis of CSF using validated biomarkers, and provide a platform for rapid translation of potential new biomarkers for cognitive impairment in Parkinson’s disease discovered in Project 3 and in Dr. Zhang‘s linked R01. Plasma obtained from blood samples will also be stored as a resource for future biomarker studies. NEUROPATHOLOGY: Provide diagnostic expertise to the Clinical Core by providing family members of the deceased and physicians involved in their care with timely autopsy reports based on the most current standardized diagnostic criteria. Optimally prepare brain donations to advance research in Project 2 and Dr. Zhang's linked R01.

Core D: Data Management and Biostatistics Core.  PI: Karen L. Edwards, Ph.D.

The goal of this Core is to provide statistical and study design support to achieve the overall goal of PANUC: understanding basic mechanisms that underlie cognitive impairment in PD. To achieve this goal, the Data Management and Biostatistics Core has four specific aims. Aim 1: Enhance research productivity by serving a coordinating role for database development, data cleaning and data organization for individual projects. Aim 2: Facilitate PANUC projects by providing statistical and methodological support, data analysis, and interpretation of results. Aim 3: Foster collaborative research by facilitating data sharing across PANUC projects. Aim 4: Facilitate dissemination of study results through assistance in manuscript development and preparation and in organization and preparation of data for submission to national repositories and databases as required by NIH.