Targeted discovery and validation of plasma biomarkers of Parkinson's disease.
Despite extensive research, an unmet need remains for protein biomarkers of Parkinson's 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 (∼300 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's 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.
Department of Pathology, University of Washington School of Medicine , 325 9th Avenue, HMC 359635, Seattle, Washington 98104, United States.
Catherine
C
Pan
Yong
Y
Zhou
Romel
R
Dator
Carmen
C
Ginghina
Yanchun
Y
Zhao
James
J
Movius
Elaine
E
Peskind
Cyrus P
CP
Zabetian
Joseph
J
Quinn
Douglas
D
Galasko
Tessandra
T
Stewart
Min
M
Shi
Jing
J
Zhang
D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood*; D015331:Cohort Studies; D018450:Disease Progression; D006020:Glycopeptides / Q000097:blood; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010300:Parkinson Disease / Q000097:blood* / Q000175:diagnosis* / Q000473:pathology; D012680:Sensitivity and Specificity
D015415:Biomarkers; D006020:Glycopeptides; D006023:Glycoproteins
Parkinson’s disease; peripheral biomarkers; selected reaction monitoring; targeted mass spectrometry