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The Morris K. Udall Center of Excellence for Parkinson's Disease Research at Stanford University


 

Director: Thomas J. Montine, M.D., Ph.D.

Title: Pacific Northwest Udall Center (PANUC)

Website: www.panuc.org

Budget End Date: 7/31/2020

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 problem for patients 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

Project 1: Genetic risk for PD-related cognitive impairment and its disease mechanisms (Dr. Thomas Montine):

This research project leverages a productive team effort among Drs. Edwards, Mata, and Montine, and a national consortium of brain autopsies for PD, PD with dementia (PDD), and Dementia with Lewy bodies (DLB). In the first aim, we are pursuing the molecular pathology of PDD with different genetic risk. The second aim expands our investigation of the genetic risk of cognitive impairment and dementia in PD from a candidate gene approach to genomic approaches with longitudinal diagnostic and neuropsychological data drawn from our national consortium, the Parkinson’s Disease Cognitive Genetics Consortium (PDCGC), to permit robust testing of our hypothesis.

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. Aim 1 applies 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. Aim 3 analyzes how omnibus and regional measures of system disruption bridge the relationship between CSF biomarkers of cerebral pathology and cognition.

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. 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. Aim 2, in close integration with Project 2, relates central cholinergic tone measured 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 determines the decline in B&G, attention, and cholinergic tone in genetically-defined subsets of PD participants.

Core A: Administrative and Outreach Core
Thomas J. Montine, MD, PhD

This Core provides administrative oversight for the Pacific Udall Center at our all three institutions and facilitates interaction between our Center and the many regional and national groups that support and advocate for individuals with Parkinson’s disease. Training and community engagement continue to be high priorities. Over the last year, Pacific Udall Center investigators have led or contributed to dozens of training sessions, opportunities for multiple clinical or research fellows utilizing Center resources, and over 25 community events. 

Core B: Clinical Core
Joseph F. Quinn, MD

This Core focuses on generating a unique resource for translational and clinical research in Parkinson’s disease. Clinical Core subjects are followed at all three sites: in Portland directed by Dr. Quinn, in Seattle directed by Dr. Cyrus Zabetian, and in the San Francisco Bay Area 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. Participants undergo motor and cognitive evaluation and blood draw for DNA and biomarkers. In addition, participants may undergo lumbar puncture for cerebrospinal fluid (CSF) biomarker studies and are asked to participate in the autopsy protocol. This Core has expanded its impact by entering into close collaboration with most other Udall Centers and other groups focused on cognitive impairment in PD through the PDCGC. 

Core C: Analytical Core
Cyrus Zabetian

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. The Analytical Core is closely linked with the NINDS Parkinson’s disease Biomarker Program to which it supplies CSF for analysis and participant data. The Analytical Core also collaborates extensively on projects supported by the Michael J. Fox Foundation (MJFF), several other Udall Centers, and other qualified investigators focused on translational research in Parkinson’s disease. 

Significant Scientific Advances

Major scientific advances for the Pacific Udall Center in the last year are (i) expand our knowledge of genetic risk for cognitive impairment in PD and begin investigation of genetic risk for progression of cognitive decline in PD, (ii) further application of advanced MRI techniques to examine the (patho)physiology of the brain in PD participants with differing genetic risk, and integrate our novel imaging data with cutting-edge biochemical biomarkers, (iii) develop novel tools to probe the molecular bases of cognitive decline in PD, (iv) and apply innovative technology to decipher the extent to which cognitive impairment expresses as gait and balance impairments in PD.   

Relation to PD 2014 Recommendations



Alignment of Pacific Udall Center Components with NINDS Goals
  “Parkinson’s disease 2014: Advancing Research, Improving Lives” “Alzheimer’s Disease Related Dementias”
Pacific Udall Center Component Research Priority # Research Priority #
Basic Translation Clinical Parkinson’s disease with Dementia
Project 1 2, 7, & 8 1, 4 3 1 & 2
Project 2 9 & 11 1 & 6 1, 2, 3, & 4 3, 5, & 6
Project 3 9 1 1, 2, 3, 4, & 7 1 & 4
Clinical Core 7 1 & 4 1, 3, & 7 2
Analytical Core 7 1 & 4 1, 3, & 7 2 & 4
PDBP U01 5 1, 2, 4, & 7 1, 2, 3, 4, & 8 2 & 6

 

Resources Available 

The major research resources of our Center consist of the extensive systematic clinical information, diagnosis, and neuropsychometric data harmonized across multiple sites coupled with DNA, plasma/serum, cerebrospinal fluid, and autopsy tissue. We have achieved full target enrollment of our Clinical Core. In addition, we also have assembled the PDCGC, in which multiple sites from 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 Parkinson’s disease. We share these resources widely within the Udall Program and with others focused on developing solutions for cognitive impairment in Parkinson’s disease.

 

Plans for the Coming Year

Overall, our plans for the next year are to pursue our Projects and continue our Core functions that focus on outreach, education, patient recruitment, detailed psychometric testing, and development of biological and data resources.  In addition, we plan to grow the Clinical Core site at Stanford University and bring it to a size comparable to the other sites in the Pacific Udall Center.

 

Select Recent Publications

  1. Madhyastha TM, Askren MK, Boord P, Zhang J, Leverenz JB, Grabowski TJ. Cerebral perfusion and cortical thickness indicate cortical involvement in mild Parkinson's disease. Mov Disord. 2015 Dec;30(14):1893-900.
  2. Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, Van Deerlin VM, Ritz B, Rausch R, Factor SA, Wood-Siverio C, Quinn JF, Chung KA, Peterson-Hiller AL, Goldman JG, Stebbins GT, Bernard B, Espay AJ, Revilla FJ, Devoto J, Rosenthal LS, Dawson TM, Albert MS, Tsuang D, Huston H, Yearout D, Hu SC, Cholerton BA, Montine TJ, Edwards KL, Zabetian CP. GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord. 2016 Jan;31(1):95-102.
  3. Mata IF, Davis MY, Lopez AN, Dorschner MO, Martinez E, Yearout D, Cholerton BA, Hu SC, Edwards KL, Bird TD, Zabetian CP. The discovery of LRRK2 p.R1441S, a novel mutation for Parkinson's disease, adds to the complexity of a mutational hotspot. Am J Med Genet B Neuropsychiatr Genet. 2016 Oct;171(7):925-30. 
  4. Shi M, Kovac A, Korff A, Cook TJ, Ginghina C, Bullock KM, Yang L, Stewart T, Zheng D, Aro P, Atik A, Kerr KF, Zabetian CP, Peskind ER, Hu SC, Quinn JF, Galasko DR, Montine TJ, Banks WA, Zhang J. CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease. Alzheimers Dement. 2016 epub ahead of print.
  5. Smulders K, Dale ML, Carlson-Kuhta P, Nutt JG, Horak FB. Pharmacological treatment in Parkinson's disease: Effects on gait. Parkinsonism Relat Disord. 2016 [Epub ahead of print]

 

Public Health Statement

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, challenging to caregivers, and costly to health care systems. 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 Modified October 19, 2016