Large Scale Biomarker Discovery and Validation for Parkinson's Disease (U01)
Dr. Zhang and his team are experts in evaluating proteins which could be candidates for biomarkers (indicators of disease progression), in the cerebrospinal fluid (CSF) and blood collected from patients with Parkinson's disease and healthy control subjects. By applying cutting edge technology, this team has identified potential biomarker protein candidates, which differ between people with and without PD. To build additional evidence for these protein candidates as biomarkers for PD disease progression, they will measure these potential biomarkers, and variants of them, in CSF and blood samples collected through the Parkinson Associated Risk Study (PARS). PARS is led by a collaborative team of researchers from the Institute for Neurodegenerative Disorders and the Movement Disorders Center at the University of Pennsylvania, and is supported by a grant from the Neurotoxin Exposure Treatment Parkinson's Research (NETPR) program run by the Department of Defense. Since the approach used in these studies provides an unbiased survey of protein differences in CSF and plasma from people with and without PD, potential protein biomarker candidates identified will also be tested in biosamples from individuals at risk for PD, who carry mutations in the LRRK2 gene.
Dr. Zhang and his team will also develop alternative approaches for measuring these biomarker candidates, so that laboratories throughout the United States and internationally can reliably apply measurement of these proteins to their research. Because biomarkers for PD disease progression may be represented not only by differences in protein components of the CSF and blood, but also by changes in ribonucleic acid (RNA), Dr Zhang's team will work with the University of Miami, Morris K Udall Center of Excellence in Parkinson's disease to identify RNAs that differ between people with and without PD. Through the Parkinson's Disease Biomarkers Program (PDBP) Data Management Resource, Dr. Zhang's team will be able to share their results with other PDBP investigators looking for changes in RNA related to Parkinson's disease progression.
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.
- 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: