Plasma α-synuclein and QSM-derived susceptibility in Parkinson's disease: associations with clinical features

The pathological interplay between α-synuclein aggregation and iron dysregulation is central to the neurodegenerative process in Parkinson's disease (PD). Quantitative susceptibility mapping (QSM) allows in vivo assessment of regional brain iron burden, and blood assays enable measurement of plasma α-synuclein; however, their clinical relevance and mutual relationship remain insufficiently defined.

To evaluate plasma α-synuclein as a diagnostic biomarker (against controls) and to explore whether regional brain iron deposition, measured by QSM, correlates with clinical features and plasma α-synuclein within the PD group.

Fifty-two PD patients and sixty-two age- and sex-matched healthy controls were enrolled. Plasma α-synuclein concentrations were quantified by ELISA. Magnetic susceptibility values of seven deep gray-matter nuclei were obtained using QSM reconstructed from a multi-echo gradient-echo sequence on a 3.0 T MRI scanner. Motor and non-motor symptoms were assessed using MDS-UPDRS-III, H-Y staging, MoCA, MMSE, HAMD, and HAMA scales.

Plasma α-synuclein levels were significantly higher in PD than controls [median 54.9 (46.9-60.6) vs. 28.7 (24.4-33.7) pg/μL, p < 0.001]. ROC analysis showed strong diagnostic accuracy (AUC = 0.976, sensitivity = 100%, specificity = 88.7%). Within PD, plasma α-synuclein correlated inversely with Age (r = -0.371, p = 0.007) but not with other clinical parameters. In unadjusted analyses, regional QSM values showed nominal associations with motor severity and cognitive performance; however, these associations did not remain significant after adjustment for age and multiple comparisons.

Elevated plasma α-synuclein provides a highly discriminative diagnostic biomarker for PD, while regional iron accumulation measured by QSM-derived magnetic susceptibility exhibited nominal associations with clinical and cognitive measures, although these relationships did not remain significant after age adjustment and correction for multiple comparisons. The absence of a direct association between peripheral α-synuclein levels and regional brain iron burden suggests that these biomarkers may reflect partially independent pathological processes in Parkinson's disease. Future longitudinal studies are warranted to clarify the temporal dynamics and potential complementary roles of these biomarkers in disease characterization.