Abstract
Skin α-synuclein deposition is considered a potential biomarker for Parkinson’s disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of α-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of α-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The α-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9% and showed a high degree of inter-rater agreement between the two laboratories (92.2%). Higher α-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The α-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson’s disease. Moreover, α-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.
Highlights
Clinical diagnosis of idiopathic Parkinson’s disease (PD) is primarily based on the presence of a parkinsonian syndrome along with supportive signs and absence of red flags suggestive of an alternate diagnosis[1]
Α-Syn seeding activity detected by Real-time quaking-induced conversion (RT-QuIC) is increased in skin biopsies from PD patients We performed RT-QuIC assay of multiple skin biopsies per subject, from subjects with PD and controls, in a blinded prospective
RT-QuIC results correlated with progression markers and NMSs of PD, suggesting that RT-QuIC has potential value as a biomarker in PD
Summary
Clinical diagnosis of idiopathic Parkinson’s disease (PD) is primarily based on the presence of a parkinsonian syndrome along with supportive signs and absence of red flags suggestive of an alternate diagnosis[1]. In spite of numerous follow-up studies that included different protocols for detection of α-syn aggregates and oligomers by IHC and proximity ligation assay, the method has not entered clinical practice[7,8,9,10,11,12,13]. Immunohistochemical detection of dermal α-syn is time-consuming, quantification is difficult, and the extent of deposits does not correlate with disease progression[5,6]. A more practical and validated method that allows for rapid analysis of a large number of samples is needed. Quantification of this biomarker should correlate with disease progression
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