Targeted Discovery and Validation of Plasma Biomarkers of Parkinson鈥檚 Disease

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• 作者：Catherine Pan ; Yong Zhou ; Romel Dator ; Carmen Ginghina ; Yanchun Zhao ; James Movius ; Elaine Peskind ; Cyrus P. Zabetian ; Joseph Quinn ; Douglas Galasko ; Tessandra Stewart ; Min Shi ; Jing Zhang
• 刊名：Journal of Proteome Research
• 出版年：2014
• 出版时间：November 7, 2014
• 年：2014
• 卷：13
• 期：11
• 页码：4535-4545
• 全文大小：370K
• ISSN：1535-3907

文摘

Despite extensive research, an unmet need remains for protein biomarkers of Parkinson鈥檚 disease (PD) in peripheral body fluids, especially blood, which is easily accessible clinically. The discovery of such biomarkers is challenging, however, due to the enormous complexity and huge dynamic range of human blood proteins, which are derived from nearly all organ systems, with those originating specifically from the central nervous system (CNS) being exceptionally low in abundance. In this investigation of a relatively large cohort (鈭?00 subjects), selected reaction monitoring (SRM) assays (a targeted approach) were used to probe plasma peptides derived from glycoproteins previously found to be altered in the CNS based on PD diagnosis or severity. Next, the detected peptides were interrogated for their diagnostic sensitivity and specificity as well as the correlation with PD severity, as determined by the Unified Parkinson鈥檚 Disease Rating Scale (UPDRS). The results revealed that 12 of the 50 candidate glycopeptides were reliably and consistently identified in plasma samples, with three of them displaying significant differences among diagnostic groups. A combination of four peptides (derived from PRNP, HSPG2, MEGF8, and NCAM1) provided an overall area under curve (AUC) of 0.753 (sensitivity: 90.4%; specificity: 50.0%). Additionally, combining two peptides (derived from MEGF8 and ICAM1) yielded significant correlation with PD severity, that is, UPDRS (r = 0.293, p = 0.004). The significance of these results is at least two-fold: (1) it is possible to use a targeted approach to identify otherwise very difficult to detect CNS related biomarkers in peripheral blood and (2) the novel biomarkers, if validated in independent cohorts, can be employed to assist with clinical diagnosis of PD as well as monitoring disease progression.

Keywords:

Parkinson鈥檚 disease; targeted mass spectrometry; peripheral biomarkers; selected reaction monitoring