In vivo distribution of alpha-synuclein in multiple tissues and biofluids in Parkinson disease

Abstract

Objective The Systemic Synuclein Sampling Study (S4) measured alpha-synuclein in multiple tissues and biofluids within the same patients with Parkinson disease (PD) vs healthy controls (HCs). Methods S4 was a 6-site cross-sectional observational study of participants with early, moderate, or advanced PD and HCs. Motor and nonmotor measures and dopamine transporter SPECT were obtained. Biopsies of skin, colon, submandibular gland (SMG), CSF, saliva, and blood were collected. Tissue biopsy sections were stained with 5C12 monoclonal antibody against pathologic alpha-synuclein; digital images were interpreted by neuropathologists blinded to diagnosis. Biofluid total alpha-synuclein was quantified using ELISA. Results The final cohort included 59 patients with PD and 21 HCs. CSF alpha-synuclein was lower in patients with PD vs HCs; sensitivity/specificity of CSF alpha-synuclein for PD diagnosis was 87.0%/63.2%, respectively. Sensitivity of alpha-synuclein immunoreactivity for PD diagnosis was 56.1% for SMG and 24.1% for skin; specificity was 92.9% and 100%, respectively. There were no significant relationships between different measures of alpha-synuclein within participants. Conclusions S4 confirms lower total alpha-synuclein levels in CSF in patients with PD compared to HCs, but specificity is low. In contrast, alpha-synuclein immunoreactivity in skin and SMG is specific for PD but sensitivity is low. Relationships within participants across different tissues and biofluids could not be demonstrated. Measures of pathologic forms of alpha-synuclein with higher accuracy are critically needed. Classification of evidence This study provides Class III evidence that total CSF alpha-synuclein does not accurately distinguish patients with PD from HCs, and that monoclonal antibody staining for SMG and skin total alpha-synuclein is specific but not sensitive for PD diagnosis.