Objective, reliable, and reproducible biomarkers are clearly needed to assist with accurate diagnosis of Parkinson disease (PD), especially at early stages, as well as for facilitating differential diagnosis and disease monitoring. The proposal is designed to meet several major challenges of current biomarker research, specifically: 1) significant variations associated with antibody-based protein assays, 2) low sensitivity and specificity of blood based markers, and 3) detection of PD at early stages. To address the problems of antibody-based assays, our strategy is development of targeted mass spectrometry-based techniques, such as selected reaction monitoring (SRM), to identify unique peptide markers derived from proteins either showing promise in previous proteomics profiling, or known to be critical to PD pathogenesis, e.g., ?-synuclein, parkin and LRRK2, in human cerebrospinal fluid (CSF). To facilitate discovery and validation of blood based biomarkers, a specific population of central nervous system derived plasma exosomes, the cargo-carrying microvesicles recognized recently to transport biomolecules among different cells or organ systems, will be isolated before SRM analysis. The unique peptide markers will be tested in several large, well-established cohorts, e.g., Udall Centers affiliated with the University of Washington and University of Pennsylvania, DATATOP (Deprenyl and tocopherol antioxidative therapy of parkinsonism) and PPMI (Parkinson Progression Marker Initiative), with cross-sectional and longitudinal samples collected, along with extensive clinical characterization. Finally, to improve early diagnosis, we will make use of two cohorts consisting of subjects at elevated risk for PD (i.e., asymptomatic subjects with LRRK2 mutations or anosmia/hyposmia), with the goal of discovering biomarkers capable of identifying subjects with early or premotor PD. The studies designed for this project, if successful, have the potential to result in a panel(s of biomarkers that are robust, with less variation than can currently be achieved, and in a body fluid that is readily accessible in a regular clinical setting. Markers for early diagnosis and progression of PD are critical in understanding how to arrest or slow PD progression.

Public Health Relevance

Parkinson disease (PD) affects over one million Americans and many more worldwide. The disease is also costly, with 25 billion dollars spent per year, not only to patients but also to our society. This study aims to examine key biomarkers related to PD pathogenesis in human cerebrospinal fluid (CSF) and blood, allowing for better understanding of PD diagnosis and progression as well as assessment of treatment effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS091272-01A1
Application #
9028098
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sutherland, Margaret L
Project Start
2016-01-01
Project End
2020-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$531,329
Indirect Cost
$187,427
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Shi, Min; Tang, Lu; Toledo, Jon B et al. (2018) Cerebrospinal fluid ?-synuclein contributes to the differential diagnosis of Alzheimer's disease. Alzheimers Dement 14:1052-1062
Wang, Hua; Atik, Anzari; Stewart, Tessandra et al. (2018) Plasma ?-synuclein and cognitive impairment in the Parkinson's Associated Risk Syndrome: A pilot study. Neurobiol Dis 116:53-59
Cilento, Eugene M; Jin, Lorrain; Stewart, Tessandra et al. (2018) Mass Spectrometry: A Platform for Biomarker Discovery and Validation for Alzheimer's and Parkinson's Diseases. J Neurochem :
Yu, Zhenwei; Stewart, Tessandra; Aasly, Jan et al. (2018) Combining clinical and biofluid markers for early Parkinson's disease detection. Ann Clin Transl Neurol 5:109-114
Matsumoto, Junichi; Stewart, Tessandra; Sheng, Lifu et al. (2017) Transmission of ?-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson's disease? Acta Neuropathol Commun 5:71
Yang, Li; Stewart, Tessandra; Shi, Min et al. (2017) An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression. Proteomics Clin Appl 11:
Pottiez, Gwënaël; Yang, Li; Stewart, Tessandra et al. (2017) Mass-Spectrometry-Based Method To Quantify in Parallel Tau and Amyloid ? 1-42 in CSF for the Diagnosis of Alzheimer's Disease. J Proteome Res 16:1228-1238