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

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-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 α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-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 α-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 α-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 α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-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 α-synuclein RT-QuIC assay enables the molecular detection of neuronal α-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 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 RBD to overt α-synucleinopathy, as well the impact of timing, disease subgroups and sampling technique on the overall sensitivity.

[Sporadic and familial Parkinson's disease: comparative study]. / Enfermedad de Parkinson esporádica y familiar: estudio comparativo.

BACKGROUND: Several studies have shown that 13 to 33% of patients with Parkinson's disease (PD) exhibit a positive familial history. The goals of this work were to identify patients with familial PD and to analyse whether there existed distinctive features between familial and sporadic cases. PATIENTS AND METHOD: 402 patients with PD from the Hospital Clínic i Universitari of Barcelona were evaluated prospectively. Clinical assessment was done using different scales in 169 patients. The disease was classified as tremorigenic, rigid or mixed according to the predominant symptoms. RESULTS: The frequency of familial PD was 13%. The age at onset was not different between familial and sporadic cases but it was significantly higher in females (57.4 [13] years) than in males (54.8 [11.4] years) (p < 0.05). The tremorigenic type of PD was more common in familial cases (35.5%) (p < 0.05). In familial PD cases, the age at onset was lower in descendents (53 [13] years) than in parents (68 [7.8] years) (p = 0.001). CONCLUSIONS: Genetic factors may play an important role in the development of PD and gender-associated factors may modulate the age at onset. Familial PD cases differ from sporadic cases in the higher frequency of predominantly tremorigenic forms. The lower age at onset in descendents than in parents suggests the existence of a genetic anticipation phenomenon in familial PD.