The Syn-Q study: detection of cutaneous phosphorylated alpha-synuclein in Parkinson’s disease progression: a trial protocol

Background: Parkinson's disease (PD) is a neurodegenerative condition with progressive phosphorylated alpha-synuclein (P-SYN) deposition. Skin biopsies are a sensitive and specific source of tissue to detect intra-axonal P-SYN in patients with PD. Further, isolated REM sleep behavior disorder (iRBD) is a prodromal condition with a high risk of phenoconversion to PD. The objective of the Synuclein-Quantification (Syn-Q) study is to quantify cutaneous P-SYN across a range of PD severity and in iRBD and measure changes in P-SYN over time. Methods: After consent, participants with iRBD and PD across Hoehn and Yahr stages 1, 2, 3 will complete neurological and cognitive evaluation, motor and olfactory assessments, orthostatic vitals, and questionnaires. Skin biopsies (3 mm diameter and 3-4 mm depth) will be taken from distal leg 10 cm above the lateral malleolus, distal thigh 10 cm above the lateral knee, and posterior cervical region 3 cm lateral to the C-7 spinous process with quantitation of cutaneous intra-axonal P-SYN. Participants will return for follow-up visits to repeat study procedures at 6, 12, and 18 months following the baseline visit. This study is funded by the Michael J. Fox Foundation and is registered on Clinicaltrial.org (NCT06621602). Expected results: We anticipate that patients with more severe stages of PD will have higher levels of quantitative P-SYN. We also predict that increases in P-SYN over time will be associated with worsening disease severity. Discussion: In patients with PD, the detection and quantification of P-SYN is a critical step to supporting clinical trials that seek to alter the natural history of disease. Skin biopsies offer a more accessible, repeatable and quantifiable approach to monitoring phosphorylated alpha-synuclein compared to cerebrospinal fluid. This study will define the longitudinal rates of P-SYN change in patients with PD from prodromal to advanced disease. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT06621602.