Large Scale Biomarker Discovery and Validation for Parkinson's Disease (U01)

Diagnosis of Parkinson's disease (PD) is complicated by the overlap of its symptoms with those of other disorders, especially at early stages. Additionally, clinical management of PD is hampered by a lack of objective assessment of disease progression. These factors make discovery of objective biomarkers an urgent priority, but a number of challenges have impeded their development. Although CSF levels of some PD-related proteins are altered in PD patients, none discovered so far are specific enough to differentiate between parkinsonian disorders, diagnose PD at early stages, or trace its progression. Profiling experiments have identified large numbers of potential candidates, but the development of protein-specific assays, which often depend on high-quality, well-characterized antibody sets that may not be available, presents a significant bottleneck in carrying these candidates through further development. Therefore, in this study, we propose a multi-pronged effort including a variety of complementary strategies to optimize the possibility of identifying P biomarkers. First, we will further explore the maximal utility of proteins previously observed to change in CSF in PD, by determining whether these proteins, or with post-translationally modified forms of them, perform well in disease diagnosis or monitoring progression. Second, we will expand the search for CSF biomarkers by using a newly developed peptide-based platform, which will allow us to perform high-throughput targeted discovery, followed by mass spectrometry-based measurement of specific peptide biomarkers in samples from human patients. Additionally, we will develop several novel techniques for biomarker discovery, including profiling based on aptamers, or based on RNA screening/sequencing. Further, we will attempt to extend the biomarker discovery process to a more easily collected sample type, plasma, by examining the performance of our best-performing candidates in plasma samples from the same cohorts. Finally, we will test the best candidate biomarkers, whether in plasma or CSF, in a LRRK2 cohort, selected to include an enriched population of subjects at risk for PD, in order to identify biomarkers capable of diagnosing PD at its earliest stages, when treatment is likely most effective. Importantly, each step of this process provides a novel step forward in biomarker research, providing the opportunity to improve the PD diagnostic process facilitate the search for better treatments.

Goals of Project

• Discovery and Replication: Targeted biomarker discovery and replication in cerebrospinal fluid (CSF) by using protein- and peptide-based techniques to determine whether potential biomarkers identified in previous investigations can better distinguish between PD and control cases.
• Discovery and Replication: Targeted biomarker discovery and independent validation in peripheral plasma. Following identification and replication of CSF biomarkers, we will expand our study to test these markers in plasma, a sample type requiring less invasive collection.
• Discovery: Identification of early/premotor biomarkers. Identification of biomarkers for the earliest stages of PD is critical. Therefore, we will determine whether promising markers detect premotor/preclinical PD by applying all high-performing biomarkers replicated in CSF and plasma to a LRRK2 cohort.

Enrollment Goals

• 50 LRRK2 mutation carriers

Congratulations, to the University of Washington for enrolling 11 participants in their PD biomarkers program as of June 3, 2016 and completing, through the PDBP Data Management Resource, electronic documentation of 10 baseline visits!

Presentation from the NINDS PDBP Kick-off Meeting in November 2012: Zhang Project Kickoff Presentation (pdf)