Unbiased Approaches to Novel Biomarker Discovery in Parkinson's Disease (U01)
Parkinson's disease (PD) can cause different types of symptoms in different people. For example, some people with PD have trouble with memory early on, while other individuals affected by PD may not have this problem, but face other symptoms associated with PD. In addition, for some people, PD may worsen more quickly than for other people. Dr. Chen-Plotkin and her team are working to identify risk factors for memory problems or different rates of worsening in Parkinson's disease, which could be important in preventative strategies for patients at risk for these problems. In order to not make assumptions about what kinds of proteins or biomarkers these might be, this team has used a non-biased approach, made possible through cutting edge technology, to identify potential biomarker candidates, and has successfully identified several potential candidates, which now need to be replicated in additional PD cases. To build the evidence for these promising biomarker candidates, in this study, they will further explore these potential risk factors to see if they can be replicated and subsequently moved forward for use as biomarkers. They will also continue their unbiased screen using cutting edge technologies, to search for additional factors which are markers of cognitive abnormalities or are biomarkers that can track different rates of progression in Parkinson's disease.
The need for well-validated, easily-accessible biomarkers for Parkinson's disease (PD) and endophenotypes within PD is great. Despite this need, candidate markers reported in the literature are few, and the most well-established biochemical biomarkers described to date in PD are cerebrospinal fluid (CSF) markers, creating a substantial barrier to widespread use. Until very recently, the search for biomarkers in PD and many other diseases was limited by the fact that a targeted approach was needed - that is, one could not find a biomarker unless there was a priori reason to believe that a particular gene/protein would be informative in the first place. In the past 10 years, however, technological advances have allowed the advent of large, unbiased screens of hundreds, if not thousands, of potential candidates, a radical change in approach pioneered in the world of genetics/genomics. We have previously used such an unbiased approach to discover, and subsequently replicate, a novel association between plasma levels of epidermal growth factor (EGF) and cognitive impairment in PD, demonstrating that low EGF levels may both correlate with and predate the onset of dementia in PD. In parallel, we have found that low plasma Apolipoprotein A1 (ApoA1) levels may indicate increased risk for loss of dopaminergic system integrity and uncovered five potential plasma-based biomarkers correlating with rate of decline in PD. Here, we propose to build on this hands-on experience to move our findings forward in a pipeline towards clinical translation while also conducting a de novo discovery screen of 450 plasma proteins for additional biomarkers for PD and endophenotypes within PD. Embedded in our approach is an understanding that unbiased biomarker discovery methods require replication in additional cohorts of subjects, followed by validation through across-site replication of findings and investigations into biological mechanisms. Thus, our aims are: 1) To validate two previously-replicated plasma-based biomarkers in PD -- determining whether plasma epidermal growth factor (EGF) levels are a biomarker for cognitive performance in PD, and whether plasma apolipoprotein A1 (ApoA1) levels are a biomarker for PD risk by evaluating their performance in additional cohorts of patients from independent clinical sites and exploring aspects of their biology and potential for clinical translation~ 2) To replicate five newly-discovered plasma-based biomarkers for rate of decline in PD -- determining whether levels of AXL receptor tyrosine kinase (AXL), matrix metalloproteinase-2 (MMP-2), interleukin-7 (IL-7), EGF, and C-reactive protein (CRP) correlate with rate of PD motor decline in additional cohorts of UPenn patients, using alternative platforms for measurement~ and 3) To perform an unbiased discovery screen for plasma-based biomarkers of motor and cognitive disease progression in PD using a novel, protein-DNA-aptamer-based technology for simultaneous measurement of 450 plasma proteins.
Goals of Project
- Validation: Validation of two previously replicated plasma based biomarkers for differential trajectories in PD progression determining whether plasma epidermal growth factor (EGF) level is a biomarker for cognitive performance in PD, and whether plasma apolipoprotein A1 (ApoA1) level is a biomarker for PD risk. Specifically, we will evaluate the performance of these two biomarkers in additional cohorts of patients from independent clinical sites and explore aspects of their biology and potential for clinical translation.
- Discovery and replication: To replicate five newly discovered plasma based biomarkers for rate of decline in PD determining whether levels of AXL receptor tyrosine kinase (AXL), matrix metalloproteinase2 (MMP2), interleukin7 (IL7), EGF, and C reactive protein (CRP) correlate with longitudinal rate of PD motor decline in additional cohorts of patients, using alternative platforms for measurement.
- Discovery: To perform an unbiased discovery screen for plasma based biomarkers of motor and cognitive disease progression in PD using a novel, protein DNA aptamer based technology for simultaneous measurement of 450 plasma proteins.