Combining skin and olfactory α-synuclein seed amplification assays (SAA)-towards biomarker-driven phenotyping in synucleinopathies

Seed amplification assays (SAA) are becoming commonly used in synucleinopathies to detect alpha-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 alpha-synuclein (alpha-syn) distribution within the nervous system and reasons for low sensitivity, we compared SAA assessment of nasal brushings and skin biopsies in PD (n = 27) and iRBD patients (n = 18) and unaffected controls (n = 30). alpha-syn misfolding was overall found less commonly in the olfactory epithelium than in the skin, which could be partially explained by the nasal brushing matrix exerting an inhibitory effect on aggregation. Importantly, the alpha-syn distribution was not uniform: there was a higher deposition of misfolded alpha-syn 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) and in a subgroup of PD patients, misfolded alpha-syn was detectable only in the olfactory epithelium, suggestive of the recently proposed brain-first PD subtype. Assaying alpha-syn of diverse origins, such as olfactory (part of the central nervous system) and skin (peripheral nervous system), could increase diagnostic accuracy and allow better stratification of patients.

Automated summary

Seed amplification assays (SAA) are commonly used to detect alpha-synuclein aggregates in synucleinopathies. However, the sensitivity of SAA in the olfactory epithelium is lower compared to CSF or skin, which may be due to the inhibitory effect of the nasal brushing matrix. The distribution of misfolded alpha-synuclein is not uniform, with a higher deposition in iRBD patients and a subgroup of PD patients showing detection only in the olfactory epithelium.