Phosphorylated Alpha-Synuclein in Red Blood Cells as a Potential Diagnostic Biomarker for Multiple System Atrophy: A Pilot Study

Diagnosis of multiple system atrophy (MSA) remains a challenge, due to the complexity and overlapping of its symptoms with other Parkinsonian disorders. The critical role of alpha-synuclein (alpha-syn) in the pathogenesis of MSA makes it an ideal biomarker for the diagnosis of MSA. Although alpha-syn alterations in cerebrospinal fluid (CSF) and blood plasma have been extensively assessed for the utility in diagnosing MSA, inconsistent results have been obtained, presumably due to the contamination by hemolysis and other confounding factors. In this study, levels of serine 129-phosphorylated alpha-syn (pS-alpha-syn), a major pathologic form of alpha-syn, in red blood cells (RBCs), were measured using ELISA in a Chinese cohort consisting of 107 MSA patients and 220 healthy controls. A significant increase in the levels of pS-alpha-syn in RBCs (pS-alpha-syn-RBC) was observed in MSA patients than in healthy controls (14.02 +/- 4.02 ng/mg versus 11.89 +/- 3.57 ng/mg; p<0.0001). Receiver operating characteristic curve (ROC) indicated that pS-alpha-syn-RBC discriminated the patients well from the controls with a sensitivity of 80.37% (95% confidence interval (CI): 71.58%-87.42%), a specificity of 88.64% (95% CI: 83.68%-92.51%), and an area under the curve (AUC) of 0.91 (95% CI: 0.87-0.94). The levels of pS-alpha-syn-RBC were negatively correlated with RBD-HK scores and differed between MSA-P and MSA-C subtypes (13.27 +/- 1.91 versus 12.19 +/- 3.04; p=0.025). The difference between subtypes was seen at Hoehn and Yahr stages 3 and 4, and the age at onset (AAO) between 60 and 69 years (p=0.016). The results suggest that pS-alpha-syn-RBC is increased in MSA patients and can be used as a potential diagnostic biomarker for MSA.