Alpha-synuclein seeds in olfactory mucosa of patients with isolated rapid-eye-movement sleep behaviour disorder

ABSTRACT Isolated REM sleep behaviour disorder is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological alpha-synuclein in peripheral tissues of isolated REM sleep behaviour disorder patients may identify those progressing to Parkinson’s disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. R eal- T ime Qu aking- I nduced C onversion provided evidence of α-synuclein seeding activity in cerebrospinal fluid and olfactory mucosa of patients with α-synucleinopathies. Aim of this study was to explore R eal- T ime Qu aking- I nduced C onversion detection of α-synuclein aggregates in olfactory mucosa of large cohort of subjects with isolated REM sleep behavior disorder compared to Parkinson’s disease and controls. This prospective bicentric case-control study was performed between October 2017 and December 2018 at the Medical University of Innsbruck, Austria, and the Hospital Clinic de Barcelona, Spain. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated REM sleep behavior disorder, 31 matched Parkinson’s disease patients and 59 matched controls were analysed by α-synuclein R eal- T ime Qu aking- I nduced C onversion in a blinded fashion at the University of Verona, Italy. Median age of isolated REM sleep behavior disorder patients was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein R eal- T ime Qu aking- I nduced C onversion positive in 44.4% isolated REM sleep behavior disorder patients, 41.9% Parkinson’s disease and 10.2% controls. While the sensitivity for isolated REM sleep behavior disorder plus Parkinson’s disease versus controls was 40.9%, specificity was high (89.8%). Among isolated REM sleep behavior disorder patients with positive α-synuclein R eal- T ime Qu aking- I nduced C onversion, 78.6% had olfactory dysfunction as compared to 21.4% with negative α-synuclein R eal- T ime Qu aking- I nduced C onversion, p<0.001. The extent of olfactory dysfunction was more severe in positive than in negative α-synuclein R eal- T ime Qu aking- I nduced C onversion olfactory mucosa isolated REM sleep behavior disorder patients (p<0.001). We provide evidence that α-synuclein R eal- T ime Qu aking- I nduced C onversion assay enables the molecular detection of neuronal α-synuclein aggregates in olfactory mucosa of patients with isolated REM sleep behavior disorder and Parkinson’s disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as simple, non-invasive test, with a potential of use as screening test to identify subjects in the prodromal stages of α-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of α-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated REM sleep behavior disorder to overt α-synucleinopathy.