Central and peripheral alpha-synuclein in Parkinson disease detected by seed amplification assay

Objectives: Detection of a-synuclein aggregates by seed amplification is a promising Parkinson disease biomarker assay. Understanding intraindividual relationships of a-synuclein measures could inform optimal biomarker development. The objectives were to test accuracy of a-synuclein seed amplification assay in central (cerebrospinal fluid) and peripheral (submandibular gland) sources, compare to total a-synuclein measures, and investigate within-subject relationships.Methods: The Systemic Synuclein Sampling Study aimed to characterize a-synuclein in multiple tissues and biofluids within Parkinson disease subjects (n = 59) and compared to healthy controls (n = 21). Motor and non-motor measures and dopamine transporter scans were obtained. Four measures of a-synuclein were compared: seed amplification assay in cerebrospinal fluid and formalin-fixed paraffin-embedded submandibular gland, total a-synuclein quantified in biofluids using enzyme-linked immunoassay, and aggregated a-synuclein in submandibular gland detected by immunohistochemistry. Accuracy of seed amplification assay for Parkinson disease diagnosis was examined and within-subject a-synuclein measures were compared. Results: Sensitivity and specificity of a-synuclein seed amplification assay for Parkinson disease diagnosis was 92.6% and 90.5% in cerebrospinal fluid, and 73.2% and 78.6% in submandibular gland, respectively. 25/38 (65.8%) Parkinson disease participants were positive for both cerebrospinal fluid and submandibular gland seed amplification assay. Comparing accuracy for Parkinson disease diagnosis of different a-synuclein measures, cerebrospinal fluid seed amplification assay was the highest (Youden Index = 83.1%). 98.3% of all Parkinson disease cases had =1 measure of a-synuclein positive.Interpretation: a-synuclein seed amplification assay (cerebrospinal fluid>submandibular gland) had higher sensitivity and specificity compared to total a-synuclein measures, and within-subject relationships of central and peripheral a-synuclein measures emerged.