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Real-Time Quaking-Induced Conversion (RT-QuIC) is an <jats:italic>in vitro<\/jats:italic> assay that, for the first time, specifically discriminates patients with prion disease. Here, using cerebrospinal fluid (CSF) samples from 239 patients with definite or probable prion disease and 100 patients with a definite alternative diagnosis, we compared the performance of the first (PQ-CSF) and second generation (IQ-CSF) RT-QuIC assays, and investigated the diagnostic value of IQ-CSF across the broad spectrum of human prions. Our results confirm the high sensitivity of IQ-CSF for detecting human prions with a sub-optimal sensitivity for the sporadic CJD subtypes MM2C and MM2T, and a low sensitivity limited to variant CJD, Gerstmann-Str\u00e4ussler-Scheinker syndrome and fatal familial insomnia. While we found no difference in specificity between PQ-CSF and IQ-CSF, the latter showed a significant improvement in sensitivity, allowing prion detection in about 80% of PQ-CSF negative CJD samples. Our results strongly support the implementation of IQ-CSF in clinical practice. By rapidly confirming or excluding CJD with high accuracy the assay is expected to improve the outcome for patients and their enrollment in therapeutic trials.<\/jats:p>","DOI":"10.1038\/s41598-017-10922-w","type":"journal-article","created":{"date-parts":[[2017,8,31]],"date-time":"2017-08-31T10:51:18Z","timestamp":1504176678000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":181,"title":["High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions"],"prefix":"10.1038","volume":"7","author":[{"given":"Alessia","family":"Franceschini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Baiardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.","family":"Hughson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"McKenzie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Moda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Capellari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Giaccone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byron","family":"Caughey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-9524","authenticated-orcid":false,"given":"Piero","family":"Parchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,6]]},"reference":[{"key":"10922_CR1","doi-asserted-by":"publisher","first-page":"13363","DOI":"10.1073\/pnas.95.23.13363","volume":"95","author":"SBP Prusiner","year":"1998","unstructured":"Prusiner, S. 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Cerebrospinal fluid real\u2010time quaking\u2010induced conversion is a robust and reliable test for sporadic creutzfeldt\u2013jakob disease: An international study. Ann Neurol \n                           80, 160\u2013165 (2016).","journal-title":"Ann Neurol"},{"key":"10922_CR26","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1007\/s12035-014-8709-6","volume":"51","author":"M Cramm","year":"2015","unstructured":"Cramm, M. et al. Characteristic CSF Prion Seeding Efficiency in Humans with Prion Diseases. Mol Neurobiol \n                           51, 396\u2013405 (2015).","journal-title":"Mol Neurobiol"},{"key":"10922_CR27","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1007\/s00401-017-1683-0","volume":"133","author":"F Lattanzio","year":"2017","unstructured":"Lattanzio, F. et al. Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease: diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and A\u03b242 levels. Acta Neuropathol \n                           133, 559\u2013578 (2017).","journal-title":"Acta Neuropathol"},{"key":"10922_CR28","doi-asserted-by":"crossref","unstructured":"Orr\u00fa, C. D. et al. Rapid and Sensitive RT-QuIC Detection of Human Creutzfeldt-Jakob Disease Using Cerebrospinal Fluid. mBio \n                           6,\u00a0e02451-14 (2015).","DOI":"10.1128\/mBio.02451-14"},{"key":"10922_CR29","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1002\/ana.24833","volume":"81","author":"A Foutz","year":"2017","unstructured":"Foutz, A. et al. Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. 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Towards an early clinical diagnosis of sporadic CJD VV2 (ataxic type). J Neurol Neurosurg Psychiatr\u00a088, 764\u2013772\u00a0(2017).","DOI":"10.1136\/jnnp-2017-315942"},{"key":"10922_CR33","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1111\/bpa.12264","volume":"26","author":"A Kobayashi","year":"2016","unstructured":"Kobayashi, A. et al. Sporadic Creutzfeldt\u2013Jakob Disease MM1+2C and MM1 are Identical in Transmission Properties. Brain Pathology \n                           26, 95\u2013101 (2016).","journal-title":"Brain Pathology"},{"key":"10922_CR34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004983","volume":"11","author":"Orr\u00f9","year":"2015","unstructured":"Orr\u00f9 et al. Bank Vole Prion Protein As an Apparently Universal Substrate for RT-QuIC-Based Detection and Discrimination of Prion Strains. 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Lancet Neurol\u00a011, 618\u2013628 (2012).","journal-title":"Lancet Neurol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10922-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10922-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10922-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T10:23:52Z","timestamp":1671791032000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10922-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,6]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["10922"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-10922-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,6]]},"assertion":[{"value":"24 May 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 August 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 September 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"10655"}}