Prevalence of alpha-synuclein seeding activity in the Olfactory Mucosa following SARS-CoV-2 infection: results from a pilot study

Olfactory dysfunction (OD) is a hallmark of SARS-CoV-2-infection where it is believed to result from neuroinflammation induced by viral invasion via the olfactory mucosa (OM). Hyposmia also affects the majority of patients with Parkinson's disease (PD) where it is caused by α-synuclein (aSyn) pathology in the olfactory system, and aSyn-seeding-activity can be detected in the OM using aSyn-seeding-amplification-assays (aSyn-SAA). The present pilot study aimed to investigate whether SARS-CoV-2-infection induces local aSyn-misfolding and -aggregation in OM samples using aSyn-SAA. We conducted an observational study including PD patients (n = 51), individuals with a history of documented symptomatic SARS-CoV-2-infection (post-COVID; n = 95), and healthy controls (HC; n = 42). Post-COVID-participants were stratified based on persistent OD (COVID+OD; n = 42) or normal olfaction (COVID-OD; n = 53) using Sniffin'-Sticks-Identification (SSI) and -Discrimination (SSD) tests. OM samples were obtained by ENT specialists and analyzed by aSyn-SAA at the University of Verona. Clinical phenotyping included MDS-UPDRS, MoCA, and the Innsbruck-RBD-Inventory. OM-SAA positivity rates were significantly different between PD and both post-COVID-participants and HCs (80.4% vs 24.2% vs 11.9%; p < 0.001). Within the post-COVID-group, positivity rates were higher in COVID+OD vs COVID-OD (35.7% vs 15.1%; p = 0.030), and COVID+OD differed from HC (p = 0.030), while COVID-OD did not (p = 0.65). Among post-COVID-participants, aSyn-SAA positivity was associated with lower SSI (p = 0.007) and SSD (p < 0.001) scores, but not with MDS-UPDRS, MoCA, or RBD measures. OM-SAA-positivity was enriched among individuals with persistent post-COVID-OD and correlated with olfactory impairment. These findings support the hypothesis that neuroinflammation following SARS-COV-2-infection might promote local aSyn-aggregation. The biological and prognostic relevance of OM-SAA positivity is unknown and needs further prospective investigation.