Skin as a promising biomatrix for the early detection of misfolded proteins by RT-QuIC in neurodegenerative diseases

Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive assay capable of detecting pathological aggregates of misfolded proteins in biospecimens. In recent years, efforts have been made to find a more feasible and convenient biomatrix as an alternative to CSF, and skin biopsy may be a suitable candidate. This project aimed to evaluate the diagnostic performance of skin RT-QuIC in 3 different cohorts of patients: 1. Creutzfeldt-Jakob disease (CJD), 2. Lewy body disease (LBD), and 3. Isolated REM sleep behavior disorder (iRBD). We studied 71 punch skin samples of 35 patients with CJD, including five assessed in vitam, using 2 two different substrates: Bank vole 23-230 (Bv23-230) and Syrian hamster 23-231 (Ha23-231) recombinant prion protein. Skin prion RT-QuIC showed a 100% specificity with both substrates and a higher sensitivity with the Bv23-230 than Ha23-231 (87.5% vs. 65.6%, respectively). Forty-one patients underwent both lumbar puncture (LB) and skin biopsy; CSF and skin RT-QuIC showed a high level of concordance (38/41, 92.7%). Then, we analyzed samples taken in vitam (n=69) or postmortem (n=49) from patients with Parkinson’s disease (PD), dementia with Lewy bodies (DLB), incidental Lewy body pathology, and neurological controls. Skin α-syn RT-QuIC distinguished LBD patients with an overall accuracy of 94.1% in the two cohorts (sensitivity, 89.2%; specificity, 96.3%). Seventy-nine patients underwent both CSF and skin α-syn RT-QuIC, and the two assays yielded similar diagnostic accuracy (skin, 97.5%; CSF, 98.7%). Finally, we studied 91 iRBD patients and 41 control. In the skin, RT-QuIC showed a sensitivity of 76.9%, specificity of 97.6%, and 82.0% accuracy. 128 participants (88 patients plus 40 controls) underwent both CSF and skin RT-QuIC. The two protocols showed 99.2% of concordance. These works confirmed that skin punch biopsies might represent a valid and convenient alternative to CSF analysis for an early diagnosis of prion diseases and LB-related pathologies.