Director: Thomas J. Montine, M.D., Ph.D.
Title: Pacific Northwest Udall Center (PANUC)
The focus of the Pacific Northwest Udall Center (PANUC) is cognitive impairment in Parkinson’s disease. We strive to understand the basis of this prevalent problem for patients and, through both clinical and basic research, to discover improved diagnostics and new therapeutic targets.
PANUC 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, PANUC 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.
Project 1: Functional and anatomical analysis of dopaminergic projections that mediate cognition
Richard D. Palmiter, PhD.
This project uses a combination of genetically engineered mice and virus-mediated gene transfer to examine neural circuits that may underlie cognitive impairment in Parkinson’s disease.
Project 2: Selective and restricted denervation in Parkinson's disease with cognitive impairment
Thomas J. Montine, MD, PhD
This project determines neurochemical and anatomic substrates of cognitive impairment in mice generated in Project 1 and assesses their validity in autopsy brains donated by individuals who died with Parkinson’s disease.
Project 3: Genetic risk factors for cognitive impairment in Parkinson's disease
Cyrus P. Zabetian, MD, MS
This project examines the association between gene variations linked to Parkinson’s disease and cognitive impairment, as well as the rate of decline of cognitive impairment in Parkinson’s disease.
Core A: Administrative and Outreach Core
Thomas J. Montine, MD, PhD
This Core provides administrative oversight for PANUC at our two institutions (see Core B) and facilitates interaction between PANUC and many local and national groups that support and advocate for individuals with Parkinson’s disease. Training and community engagement continue to be high priorities for PANUC. Over the last year, PANUC investigators have led or contributed to two dozen training sessions, seven clinical or research fellows utilizing PANUC resources, and 30 community events.
Core B: Clinical Core
James B. Leverenz, MD. Oregon Health & Science University (OHSU) Site PI: Joseph F. Quinn, MD
This Core focuses on generating a unique resource for translation and clinical research in Parkinson’s disease. The Clinical Sample (CS) is a large sample designed to allow investigation of genetic factors for cognitive impairment in Parkinson’s disease. CS participants undergo a limited motor and cognitive evaluation and blood draw for DNA and biomarkers twice during the initial five-year cycle of PANUC. The Annual Sample (AS) is a smaller sample of patients with Parkinson’s disease who undergo more detailed annual motor and cognitive evaluations. In addition to blood draw for DNA and biomarkers, AS participants undergo lumbar puncture for cerebrospinal fluid (CSF) biomarker studies and are asked to participate in the autopsy protocol. Approximately 1 in 5 Clinical Core participants enter through the OHSU site. Core B has expanded its impact by entering into close collaboration with Northwest Neurological in Spokane, the University of Cincinnati, and Emory University.
Core C: Genetics, Biomarkers, and Neuropathology (GBN)
Jing Zhang, MD, PhD
This Core is the repository for collected blood, CSF, and autopsy material. It performs a standardized set of evaluations for genetic markers, plasma/serum and CSF biomarkers, and neuropathologic characterization of brain autopsy material. A major achievement has been demonstrating that alpha-synuclein and DJ-1 concentrations are decreased in Parkinson’s disease (PD) CSF compared to controls, a result that has been replicated by multiple centers. Our work also highlights the critical importance of controlling for blood contamination when measuring alpha-synuclein levels in CSF, a protocol that has been adopted by the Michael J. Fox Foundation (MJFF). Finally, in collaboration with the Udall Center at the University of Pennsylvania, we have developed a novel assay to measure a phosphorylated form of alpha-synuclein (ps-129) in CSF, that when used in combination with total alpha-synuclein, appears to differentiate PD from atypical parkinsonism.
Core D: Data Management and Biostatistics Core
Karen L. Edwards, PhD
This Core maintains the database for PANUC and is also an important resource for study design and statistical analysis. Achievements this year include data reporting systems to facilitate QC checks of all data, expansion to include longitudinal data, and algorithms to calculate Z-scores and percentiles for core neuropsychological tests that are included in consensus reports and can be requested as part of any dataset for analyses. Core D responded to a total of 27 data requests in the past year and generated a primary manuscript that is in press.
Project 1 has established a direct link between regional loss of striatal dopamine and cognitive behaviors in mice that are also implicated in patients with Parkinson’s disease. Our more recent work has established quantitative relationships between dopamine levels in the different regions of the neostriatum and motor and cognitive behaviors in mice. These results demonstrate that striatal dopamine neurotransmission is essential for normal cognitive function in mice and that the regional loss of striatal dopamine likely contributes to the cognitive impairment prevalent among patients with Parkinson's disease. Currently, this project is pursuing the relative contribution of mere loss of dopamine vs. dopaminergic neuron degeneration in these motor and behavioral changes. The implications of these results for therapeutic strategies are clear.
Project 2 has previously observed that Lewy body disease was present in lower brainstem in approximately 15%, in substantia nigra in approximately 8%, and in neocortical regions in approximately 4% of cognitively normal older adults. Our more recent advances evaluated the functional significance of Lewy body disease among community-dwelling older adults. Visuospatial function was the only cognitive domain that was primarily associated with Lewy body disease in our community sample that contains extensive co-morbid AD and vascular brain injury (VBI). Visuospatial impairment is often one of the earliest cognitive symptoms in Parkinson’s disease and is a primary feature of Lewy body dementia. The basis of impaired visuospatial abilities in Lewy body–related conditions is not well understood, but may be related to damage to posterior cortical regions, asymmetric dopamine loss in the right basal ganglia, disruptions in the fronto-striatal loop, or impairments in the dorsolateral prefrontal pathways. In addition to Lewy body disease, cortical and subcortical VBI also were associated with construction ability, consistent with previous findings that VBI may lead to reduced visuospatial function.
Project 3 has identified that the APOE4 allele is associated with poorer performance across multiple cognitive domains including memory and executive function in 915 PD subjects from multiple Udall Centers. We further explored the role of APOE in PD-related dementia (PDD) in a large multicenter autopsy series (organized by Project 2), seeking to address the question of whether the ε4 allele conveys disease risk solely in the presence of significant AD neuropathologic changes (ADNC). We found that APOE4 was strongly associated with PDD even after subjects with substantial ADNC were excluded. The same was true for subjects with “pure” dementia with Lewy bodies who lacked substantial ADNC. These results raise the possibility that apoE isoforms might contribute to neurodegeneration through novel mechanisms.
The major research resource being built by PANUC consists of the extensive systematic clinical information, diagnosis, and neuropsychometric data harmonized across multiple sites coupled with DNA, plasma/serum, cerebrospinal fluid, and autopsy tissue. This year we achieved full target enrollment of our Annual Sample (n=145) and Clinical Sample (n=456). In addition, we also have assembled a PANUC consortium (Emory University, University of Cinncinati, and Univeristy of Pennsylvania) in which multiple sites around the US employ common protocols, diagnostic criteria, and test batteries to further amplify sample sizes of uniformly evaluated subjects with PD. This cooperation provides a powerful resource for clinical, psychological, genetic, and biomarker research focused on cognitive impairment in PD. In the last year, PANUC has shared resources with five other Udall Centers (Mayo Clinic, Johns Hopkins University, University of California at Los Angeles, University of Miami, University of Pennsylvania) and 12 other research groups in support of 14 NIH and foundation awards including the “Parkinson’s Progression Biomarker Initiative” (PPMI, Ken Marek PI, J Leverenz Site PI) and “Biomarkers for Preclinical Parkinson’s Disease” (J Zhang PI).
PANUC Data Management and Biostatistics Core (Core D) has constructed web-based clinical data entry and management across the five sites within the PANUC Consortium that not only will facilitate collaborative clinical research, but also may serve as an initial template for clinical data management among Udall Centers.
Overall, our plans for the next year are to continue to focus on cognitive impairment in patients with Parkinson’s disease and to expand further the network of collaborations that involve PANUC patients or utilize PANUC resources. Project 1 will conclude its experiments on the relative contributions of regional dopamine depletion vs. dopaminergic degeneration to motor and behavioral changes in mice. Project 2 will focus on the correlation between lesions in specific regions of brain in patients with Lewy Body disease and the cognitive changes in specific domains. Project 3 will amplify its cohort of patients with Parkinson’s disease who are being followed longitudinally with detailed psychometric testing to enhance the search for genetic risks for cognitive impairment. The Cores will continue to focus on patient recruitment, detailed psychometric testing, and development of biological and data resources.
The National Institutes of Health (NIH) estimates that over a half million people in the United States suffer from Parkinson’s disease, causing untold suffering to patients as well as their caregivers and other loved ones. The physical, emotional, and societal costs of Parkinson's disease will increase over the coming decades as more of us live longer; in fact, the number of patients with Parkinson’s disease is expected to double in the United States by the year 2030 unless we find safe and effective means to cure, delay onset, or slow progression of this disease. Cognitive impairment is a common feature of Parkinson’s disease that is disabling for patients and challenging to caregivers. Our center is focused on the clear imperative to find better tools for diagnosis and better ways to treat cognitive impairment in patients with Parkinson’s disease.
Last updated December 23, 2013