Combining skin and olfactory α-synuclein RT-QuIC - towards biomarker-driven phenotyping in synucleinopathies

Seeding assays, such as real-time quaking-induced conversion (RT-QuIC), are becoming commonly used in synucleinopathies to detect α-synuclein aggregates. Studies in Parkinson’s disease (PD) and isolated REM-sleep behavior disorder (iRBD) have shown a considerably lower sensitivity in the olfactory epithelium than in CSF or skin. To get an insight into α-synuclein (α-syn) distribution within the nervous system and reasons for low sensitivity, we compared RT-QuIC assessment of nasal brushings and skin biopsies in PD and iRBD patients and unaffected controls. We could show higher sensitivity of RT-QuIC in skin compared to nasal brushings and a higher deposition of misfolded α-synuclein across all sampled tissues in the iRBD cohort compared to PD, supporting the notion of RBD as a marker of a more malignant subtype of synucleinopathy. Interestingly, we identified a PD subgroup of patients with misfolded α-syn in the olfactory epithelium who did not show any dermal pathology, likely corresponding to the recently proposed brain-first subtype. Assaying α-syn of diverse origin (such as olfactory and peripheral nervous system) could allow better stratification of patients.