Discrimination of MSA-P and MSA-C by RT-QuIC analysis of olfactory mucosa: the first assessment of assay reproducibility between two specialized laboratories

• Published in: Molecular neurodegeneration Vol. 16; no. 1; pp. 82 - 19
• Main Authors: Bargar, Connor, De Luca, Chiara Maria Giulia, Devigili, Grazia, Elia, Antonio Emanuele, Cilia, Roberto, Portaleone, Sara Maria, Wang, Wen, Tramacere, Irene, Bistaffa, Edoardo, Cazzaniga, Federico Angelo, Felisati, Giovanni, Legname, Giuseppe, Di Fonzo, Alessio, Xu, Rong, Gunzler, Steven Alexander, Giaccone, Giorgio, Eleopra, Roberto, Chen, Shu Guang, Moda, Fabio
• Format: Journal Article
• Language: English
• Published: London BioMed Central 11.12.2021; BioMed Central Ltd; BMC
• Subjects: Age; Alpha-synuclein; Alzheimer's disease; Antibodies; Atrophy; Basal ganglia; Biomarkers; Biomedical and Life Sciences; Biomedicine; Central nervous system diseases; Cerebellum; Clinical trials; COVID-19; Diagnosis; Drug therapy; Ethics; Humans; Laboratories; Magnetic resonance imaging; Misfolding; Molecular Medicine; Movement disorders; Mucosa; Multiple System Atrophy - pathology; Neurodegenerative diseases; Neurology; Neuromuscular diseases; Neurosciences; Olfactory discrimination; Olfactory discrimination learning; Olfactory epithelium; Olfactory mucosa; Olfactory Mucosa - chemistry; Olfactory Mucosa - pathology; Parkinson Disease - diagnosis; Parkinson Disease - pathology; Parkinson's disease; Patients; Phenotypes; Real-Time Quaking-Induced Conversion; Reproducibility; Reproducibility of Results; Research Article; Seeding; Synuclein; Tomography; United States > US; Italy; Real-Time Quaking-Induced Conversion; Biomarkers; Misfolding; Alpha-synuclein; Olfactory mucosa
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-021-00491-y

Background Detection of the pathological and disease-associated alpha-synuclein (αSyn D ) in the brain is required to formulate the definitive diagnosis of multiple system atrophy (MSA) and Parkinson’s disease (PD). We recently showed that αSyn D can be detected in the olfactory mucosa (OM) of MSA and PD patients. For this reason, we have performed the first interlaboratory study based on α-synuclein Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC) analysis of OM samples collected from PD and MSA patients with the parkinsonian (MSA-P) and cerebellar (MSA-C) phenotypes. Methods OM samples were prospectively collected from patients with a probable diagnosis of MSA-P ( n  = 20, mean disease duration 4.4 years), MSA-C ( n  = 10, mean disease duration 4 years), PD ( n  = 13, mean disease duration 8 years), and healthy control subjects (HS) ( n  = 11). Each sample was analyzed by αSyn_RT-QuIC in two independent specialized laboratories, one located in Italy (ITA-lab) and one located in the USA (USA-lab). Both laboratories have developed and used harmonized αSyn_RT-QuIC analytical procedures. Results were correlated with demographic and clinical data. Results The αSyn_RT-QuIC analysis reached a 96% interrater agreement of results (IAR) between laboratories (Kappa = 0.93, 95% CI 0.83–1.00). In particular, αSyn_RT-QuIC seeding activity was found in the OM of 9/13 patients with PD (sensitivity 69%, IAR 100%) and 18/20 patients with MSA-P (sensitivity 90%, IAR 100%). Interestingly, samples collected from patients with MSA-C did not induce αSyn_RT-QuIC seeding activity, except for one subject in USA-lab. Therefore, we found that MSA-P and MSA-C induced opposite effects. Regardless of disease diagnosis, the αSyn_RT-QuIC seeding activity correlated with some clinical parameters, including the rigidity and postural instability. Conclusions Our study provides evidence that OM-αSyn D may serve as a novel biomarker for accurate clinical diagnoses of PD, MSA-P, and MSA-C. Moreover, αSyn_RT-QuIC represents a reliable assay that can distinguish patients with MSA-P from those with MSA-C, and may lead to significant advancements in patients stratification and selection for emerging pharmacological treatments and clinical trials.