Isolated REM sleep behaviour disorder (RBD) is an early-stage alpha-synucleinopathy in most, if not all, affected subjects. Detection of pathological alpha-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of alpha-synuclein seeding activity in CSF and olfactory mucosa of patients with alpha-synucleinopathies. The aim of this study was to explore RT-QuIC detection of alpha-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by alpha-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was alpha-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive alpha-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative alpha-synuclein RT-QuIC (P<0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P<0.001). We provide evidence that the alpha-synuclein RT-QuIC assay enables the molecular detection of neuronal alpha-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of alpha-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of alpha-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt alpha-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity.

Alpha-synuclein seeds in olfactory mucosa of patients with isolated REM sleep behaviour disorder

Perra, Daniela;Bongianni, Matilde;Sacchetto, Luca;Capaldi, Stefano;Cecchini, Maria Paola;Mariotto, Sara;Ferrari, Sergio;Fiorini, Michele;Brozzetti, Lorenzo;Monaco, Salvatore;Zanusso, Gianluigi
2021-01-01

Abstract

Isolated REM sleep behaviour disorder (RBD) is an early-stage alpha-synucleinopathy in most, if not all, affected subjects. Detection of pathological alpha-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of alpha-synuclein seeding activity in CSF and olfactory mucosa of patients with alpha-synucleinopathies. The aim of this study was to explore RT-QuIC detection of alpha-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson's disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson's disease patients and 59 matched control subjects were analysed by alpha-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was alpha-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson's disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson's disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive alpha-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative alpha-synuclein RT-QuIC (P<0.001). The extent of olfactory dysfunction was more severe in isolated RBD patients positive than negative for olfactory mucosa a-synuclein RT-QuIC (P<0.001). We provide evidence that the alpha-synuclein RT-QuIC assay enables the molecular detection of neuronal alpha-synuclein aggregates in olfactory mucosa of patients with isolated RBD and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as a simple, non-invasive test and might be useful as part of a screening battery to identify subjects in the prodromal stages of alpha-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of alpha-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated RBD to overt alpha-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity.
Parkinson’s disease
RBD
Real-Time Quaking-Induced Conversion
alpha-synucleinopathies
nasal swabbing
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/1042914
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