Plasma acetylated α-synuclein as a novel quantitative biomarker for Parkinson's disease

BackgroundAggregation of -synuclein is a central pathological feature of Parkinsons disease (PD), yet reliable and broadly applicable fluid biomarkers reflecting disease-relevant -synuclein biology remain limited. We aimed to establish acetylated -synuclein (Ac-Syn), the predominant proteoform in vivo, as a novel biomarker for PD and to evaluate its diagnostic utility based on a sensitive immunoassay. MethodsUsing a single molecule array technique capable of quantitatively detecting N-terminally acetylated -synuclein, plasma Ac-Syn levels were measured in 110 samples obtained from 52 patients with PD, 24 patients with multiple system atrophy (MSA), and 34 healthy controls (HCs). In a subset of PD patients, plasma Ac-Syn measurements and 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy were performed in the same individuals, enabling direct comparison between these two testing modalities. Ac-Syn levels were also quantified in 91 cerebrospinal fluid (CSF) samples obtained from 51 patients with PD, 25 patients with MSA, and 15 non-parkinsonian disease controls (DCs). ResultsPlasma Ac-Syn levels robustly differentiated PD from both MSA and HCs (p < 0.0001). Receiver operating characteristic analysis demonstrated high diagnostic performance (area under the curve [AUC] = 0.89 for PD vs MSA; AUC = 0.94 for PD vs HCs), comparable to established imaging biomarkers. In the same individuals, plasma Ac-Syn levels correlated with the heart-to-mediastinum ratio derived from MIBG cardiac scintigraphy. CSF Ac-Syn levels also clearly differentiated PD from both MSA and DCs (p < 0.0001), with high diagnostic performance (AUC = 0.85 for PD vs MSA; AUC = 0.93 for PD vs DCs), supporting the biological relevance of plasma Ac-Syn as a biomarker. ConclusionThis study identifies Ac-Syn in plasma as a novel biomarker for PD, enabled by quantitative immunoassay-based detection. Plasma Ac-Syn represents a practical and minimally invasive biomarker that supports biology-based diagnosis of PD and discrimination from MSA.