Abstract
Finding robust biomarkers for Parkinson disease (PD) is currently hampered by inherent technical limitations associated with imaging or antibody-based protein assays. To circumvent the challenges, we adapted a staged pipeline, starting from our previous proteomic profiling followed by high-throughput targeted mass spectrometry (MS), to identify peptides in human cerebrospinal fluid (CSF) for PD diagnosis and disease severity correlation. In this multicenter study consisting of training and validation sets, a total of 178 subjects were randomly selected from a retrospective cohort, matching age and sex between PD patients, healthy controls, and neurological controls with Alzheimer disease (AD). From ∼14,000 unique peptides displaying differences between PD and healthy control in proteomic investigations, 126 peptides were selected based on relevance and observability in CSF using bioinformatic analysis and MS screening, and then quantified by highly accurate and sensitive selected reaction monitoring (SRM) in the CSF of 30 PD patients versus 30 healthy controls (training set), followed by diagnostic (receiver operating characteristics) and disease severity correlation analyses. The most promising candidates were further tested in an independent cohort of 40 PD patients, 38 AD patients, and 40 healthy controls (validation set). A panel of five peptides (derived from SPP1, LRP1, CSF1R, EPHA4, and TIMP1) was identified to provide an area under curve (AUC) of 0.873 (sensitivity = 76.7%, specificity = 80.0%) for PD versus healthy controls in the training set. The performance was essentially confirmed in the validation set (AUC = 0.853, sensitivity = 82.5%, specificity = 82.5%). Additionally, this panel could also differentiate the PD and AD groups (AUC = 0.990, sensitivity = 95.0%, specificity = 97.4%). Furthermore, a combination of two peptides belonging to proteins TIMP1 and APLP1 significantly correlated with disease severity as determined by the Unified Parkinson's Disease Rating Scale motor scores in both the training (r = 0.381, p = 0.038)j and the validation (r = 0.339, p = 0.032) sets. The novel panel of CSF peptides, if validated in independent cohorts, could be used to assist in clinical diagnosis of PD and has the potential to help monitoring or predicting disease progression.
Highlights
From the ‡Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98104; §School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China; ¶Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195; ʈGeriatric and Parkinson’s Disease Research, Education, and Clinical Centers, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108; **Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195; ‡‡Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington 98195; §§Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108; ¶¶Department of Neurology, Oregon Health and Science University, Portland, Oregon 97239; ʈ ʈDepartment of Neurosciences, University of California at San Diego, La Jolla, California 92093
Identification of cerebrospinal fluid (CSF) Peptide Biomarker Candidates—For biomarker candidate selection, we first integrated an extensive compilation of 15 Parkinson disease (PD)-related quantitative proteomic data sets generated from our previous studies (references (19 –25) and unpublished data)
We report a panel consisting of five peptides/proteins (SPP1, lipoprotein receptor-related protein 1 (LRP1), CSF1R, Ephrin type-A receptor 4 (EPHA4), and Tissue inhibitor of metalloproteinases-1 (TIMP1)) with fair robustness in regard to specificity and sensitivity in differentiating PD from healthy and diseased (AD) controls
Summary
From the ‡Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98104; §School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China; ¶Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195; ʈGeriatric and Parkinson’s Disease Research, Education, and Clinical Centers, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108; **Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195; ‡‡Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington 98195; §§Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108; ¶¶Department of Neurology, Oregon Health and Science University, Portland, Oregon 97239; ʈ ʈDepartment of Neurosciences, University of California at San Diego, La Jolla, California 92093. The current consensus is that CSF ␣-synuclein concentrations are generally lower in patients with PD compared with controls (5, 8 –10); the sensitivity and specificity, appear to be only moderate, and no correlation with PD severity or progression has been observed [8, 9] All these CSF protein markers are measured using antibody-based assays, which are often associated with relatively high variability, when different detection techniques (different antibodies, sample preparation, calibrators, etc.) are used, leading to discrepant results across laboratories [5]. Using brain tissue or CSF, these unbiased proteomic profiling studies have revealed disease-related alterations in hundreds of peptides fluid; CSF1R, Macrophage colony-stimulating factor 1 receptor; Con, healthy control; CP, ceruloplasmin; EPHA4, ephrin type-A receptor 4; LRP1, prolow-density lipoprotein receptor-related protein 1; MMSE, Mini Mental State Examination; MS, mass spectrometry; ROC, receiver operating characteristic; SCX, strong cation-exchange; SPP1, osteopontin; SRM, selected reaction monitoring; TIMP1, metalloproteinase inhibitor 1; UPDRS, Unified Parkinson’s Disease Rating Scale
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