Characterization of Parkinson's disease using blood-based biomarkers: A multicohort proteomic analysis.

Background Parkinson's disease (PD) is a progressive neurodegenerative disease affecting about 5 million people worldwide with no disease-modifying therapies. We sought blood-based biomarkers in order to provide molecular characterization of individuals with PD for diagnostic confirmation and prediction of progression. Methods and findings In 141 plasma samples (96 PD, 45 neurologically normal control [NC] individuals; 45.4% female, mean age 70.0 years) from a longitudinally followed Discovery Cohort based at the University of Pennsylvania (UPenn), we measured levels of 1,129 proteins using an aptamer-based platform. We modeled protein plasma concentration (log(10) of relative fluorescence units [RFUs]) as the effect of treatment group (PD versus NC), age at plasma collection, sex, and the levodopa equivalent daily dose (LEDD), deriving first-pass candidate protein biomarkers based on p-value for PD versus NC. These candidate proteins were then ranked by Stability Selection. We confirmed findings from our Discovery Cohort in a Replication Cohort of 317 individuals (215 PD, 102 NC; 47.9% female, mean age 66.7 years) from the multisite, longitudinally followed National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) Cohort. Analytical approach in the Replication Cohort mirrored the approach in the Discovery Cohort: each protein plasma concentration (log(10) of RFU) was modeled as the effect of group (PD versus NC), age at plasma collection, sex, clinical site, and batch. Of the top 10 proteins from the Discovery Cohort ranked by Stability Selection, four associations were replicated in the Replication Cohort. These blood-based biomarkers were bone sialoprotein (BSP, Discovery false discovery rate [FDR]-corrected p = 2.82 x 10(-2), Replication FDR-corrected p = 1.03 x 10(-4)), osteomodulin (OMD, Discovery FDR-corrected p = 2.14 x 10(-2), Replication FDR-corrected p = 9.14 x 10(-5)), aminoacylase-1 (ACY1, Discovery FDR-corrected p = 1.86 x 10(-3), Replication FDR-corrected p = 2.18 x 10(-2)), and growth hormone receptor (GHR, Discovery FDR-corrected p = 3.49 x 10(-4), Replication FDR-corrected p = 2.97 x 10(-3)). Measures of these proteins were not significantly affected by differences in sample handling, and they did not change comparing plasma samples from 10 PD participants sampled both on versus off dopaminergic medication. Plasma measures of OMD, ACY1, and GHR differed in PD versus NC but did not differ between individuals with amyotrophic lateral sclerosis (ALS, n = 59) versus NC. In the Discovery Cohort, individuals with baseline levels of GHR and ACY1 in the lowest tertile were more likely to progress to mild cognitive impairment (MCI) or dementia in Cox proportional hazards analyses adjusting for age, sex, and disease duration (hazard ratio [HR] 2.27 [95% CI 1.04-5.0, p = 0.04] for GHR, and HR 3.0 [95% CI 1.24-7.0, p = 0.014] for ACY1). GHR's association with cognitive decline was confirmed in the Replication Cohort (HR 3.6 [95% CI 1.20-11.1, p = 0.02]). The main limitations of this study were its reliance on the aptamer-based platform for protein measurement and limited follow-up time available for some cohorts. Conclusions In this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD. Author summaryWhy was this study done? No blood tests currently exist that distinguish people with Parkinson's disease (PD) from neurologically normal individuals or that predict the rate of disease progression in people who have already been diagnosed with PD. Blood tests that distinguish people with PD would be helpful for confirmation of diagnosis (diagnostic biomarkers), whereas blood tests that predict the rate of disease progression (prognostic biomarkers) would be helpful for clinical trials and clinical care. What did the researchers do and find? We screened more than 1,000 blood-based proteins from 527 people with PD, amyotrophic lateral sclerosis (ALS), or neither neurological disease in order to discover new diagnostic and prognostic biomarkers. We used one group of participants to identify potential biomarkers and then used a separate group of participants to confirm these biomarkers. We found that blood levels of four proteins-bone sialoprotein (BSP), osteomodulin (OMD), aminoacylase-1 (ACY1), and growth hormone receptor (GHR)-consistently differed in people with PD compared to people without PD. We found that lower GHR levels at baseline predicted a faster rate of cognitive decline in people with PD. What do these findings mean? Levels of some blood proteins consistently differ between people with versus without PD, and some of these proteins also predict which PD individuals may have faster progression of disease. It may be possible to develop blood-based tests to help confirm PD diagnosis and predict disease progression.