Background and Objectives.Real-time quaking-induced conversion (RT-QuIC) assay detects misfolded α-synuclein in the skin and CSF of patients with the synucleinopathies Parkinson disease and dementia with Lewy bodies. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of these synucleinopathies. We aimed to compare the ability of RT-QuIC to identify misfolded α-synuclein in the skin and CSF of IRBD patients.Methods.Cross-sectional study where consecutive patients with polysomnographic-confirmed IRBD and age-matched controls without RBD underwent skin biopsy and lumbar puncture the same day. 3-mm skin punch biopsies were obtained bilaterally in cervical region from dorsal C7 and C8 dermatomes, and in distal legs. RT-QuIC assessed misfolded α-synuclein in these six skin sites and CSF.Results.We recruited 91 IRBD patients and 41 controls. In skin, sensitivity to detect misfolded α-synuclein was 76.9% (95%CI 66.9–85.1), specificity 97.6% (95%CI 87.1–99.9) positive predictive value 98.6% (95%CI 91.0-99.8), negative predictive value 65.6% (95%CI 56.6-73.6) and accuracy 83.3% (95%CI 75.9–89.3). In CSF, sensitivity was 75.0% (95% CI 64.6–83.6), specificity 97.5% (95%CI 86.8–99.9) positive predictive value 98.5% (95%CI 90.5-99.8), negative predictive value 63.9% (95%CI 55.2-71.9) and accuracy 82.0% (95%CI 74.3–88.3). Results in skin and CSF samples showed 99.2% agreement. Compared with negative patients, RT-QuIC α-synuclein positive patients had higher likelihood ratio of prodromal Parkinson disease (p<0.001) and showed more frequently hyposmia (p<0.001), DAT-SPECT deficit (p=0.002) and orthostatic hypotension (p=0.014). No severe or moderate adverse effects were reported. There was no difference between percentage of participants reporting mild adverse events secondary to skin biopsy or lumbar puncture (9.1% versus 17.2%; p=0.053).83% participants stated they would accept to undergo again skin biopsy and 80% lumbar puncture, for research purposes.Discussion.Our study in IRBD shows that 1) RT-QuIC detects misfolded α-synuclein in skin and CSF with similar high sensitivity, specificity, and agreement, 2) α-synuclein RT-QuIC positivity is associated with supportive features and biomarkers of synucleinopathy, and 3) skin punch biopsy and lumbar puncture have comparable mild adverse effects, tolerance, and acceptance. α-synuclein RT-QuIC in skin or CSF might represent a patient selection strategy for future neuroprotective trials targeting α-synuclein in IRBD.Classification of Evidence:This study provides Class III evidence that RT-QuIC detected misfolded α-synuclein in the skin and CSF distinguishes patients with IRBD from controls.

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