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However, \u03b1Syn SAA diagnostic performance in early pathological stages or low Lewy body (LB) pathology\u00a0load has only been assessed in small cohorts. Moreover, the relationship between SAA kinetic parameters, the number of \u03b1Syn brain seeds and the LB\u00a0pathology burden assessed by immunohistochemistry has never been systematically investigated. We tested 269 antemortem CSF samples and 138 serially diluted brain homogenates from patients with and without neuropathological evidence of LBD in different stages by the \u03b1Syn Real-Time Quaking-Induced Conversion (RT-QuIC) SAA. Moreover, we looked for LB pathology by \u03b1Syn immunohistochemistry in a consecutive series of 604 Creutzfeldt\u2013Jakob disease (CJD)-affected brains. \u03b1Syn CSF RT-QuIC showed 100% sensitivity in detecting LBD in limbic and neocortical stages. The assay sensitivity was significantly lower in patients in early stages (37.5% in Braak 1 and 2, 73.3% in Braak 3) or with focal pathology (50% in amygdala-predominant). The average\u00a0number of CSF RT-QuIC positive replicates significantly correlated with LBD stage. Brain\u00a0homogenate RT-QuIC showed higher sensitivity than immunohistochemistry for the detection of misfolded \u03b1Syn. In the latter, the kinetic parameter lag phase (time to\u00a0reach\u00a0the positive threshold) strongly correlated with the \u03b1Syn seed concentration\u00a0in serial dilution experiments. Finally, incidental LBD prevalence was 8% in the CJD cohort. The present results indicate that (a) CSF RT-QuIC has high specificity and sufficient sensitivity to detect all patients with LB pathology at Braak stages\u2009&gt;\u20093 and most of those at stage 3; (b) brain deposition of misfolded \u03b1Syn precedes the formation of LB and Lewy neurites; (c) \u03b1Syn SAA provides \u201cquantitative\u201d information regarding the LB pathology burden, with the lag phase and the number of positive replicates being the most promising variables to be used in the clinical setting.<\/jats:p>","DOI":"10.1007\/s00401-023-02663-0","type":"journal-article","created":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T13:02:19Z","timestamp":1705669339000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":98,"title":["Performance of a seed amplification assay for misfolded alpha-synuclein in cerebrospinal fluid and brain tissue in relation to Lewy body disease stage and pathology burden"],"prefix":"10.1007","volume":"147","author":[{"given":"Giuseppe Mario","family":"Bentivenga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Mammana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Baiardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Ticca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Magliocchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Mastrangelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Poleggi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ladogana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Capellari","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":[[2024,1,19]]},"reference":[{"issue":"4","key":"2663_CR1","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1111\/j.1750-3639.2008.00147.x","volume":"18","author":"I Alafuzoff","year":"2008","unstructured":"Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H et al (2008) Staging of neurofibrillary pathology in Alzheimer\u2019s disease: a study of the BrainNet Europe consortium. 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