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Misfolded alpha-synuclein (\u03b1-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded \u03b1-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in\u00a0<jats:italic>GBA<\/jats:italic>,\u00a0<jats:italic>parkin<\/jats:italic>,\u00a0<jats:italic>PINK1<\/jats:italic>,\u00a0<jats:italic>DJ1,<\/jats:italic> and\u00a0<jats:italic>LRRK2<\/jats:italic>. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to \u03b1-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC \u03b1-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive \u03b1-Syn seeding in 93% of patients carrying severe\u00a0<jats:italic>GBA<\/jats:italic>\u00a0mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe\u00a0<jats:italic>GBA<\/jats:italic>\u00a0mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with\u00a0<jats:italic>GBA<\/jats:italic>\u00a0mutations showed positive \u03b1-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between \u03b1-Syn seeding activity and reduced CSF levels of proteins linked to \u03b1-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF.<\/jats:p><jats:p>These findings highlight the value of \u03b1-Syn seeding activity as an\u00a0<jats:italic>in-vivo<\/jats:italic>\u00a0marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting \u03b1-Syn.<\/jats:p>","DOI":"10.1186\/s40478-021-01276-6","type":"journal-article","created":{"date-parts":[[2021,10,30]],"date-time":"2021-10-30T11:02:43Z","timestamp":1635591763000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":132,"title":["Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson\u2019s disease and dementia with Lewy bodies"],"prefix":"10.1186","volume":"9","author":[{"given":"Kathrin","family":"Brockmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Quadalti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Lerche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Wurster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Baiardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Roeben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Mammana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan","family":"Zimmermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Kathrin","family":"Hauser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Deuschle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Schulte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Waniek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingolf","family":"Lachmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Sj\u00f6din","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Brinkmalm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Gasser","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":[[2021,10,30]]},"reference":[{"key":"1276_CR1","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1016\/S1474-4422(09)70238-8","volume":"8","author":"DW Dickson","year":"2009","unstructured":"Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM et al (2009) Neuropathological assessment of Parkinson\u2019s disease: refining the diagnostic criteria. 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All participants gave written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"KW is employed by Roboscreen GmbH and receive income from that Company, which manufactures the ELISA kit for measurements of total human \u03b1-Syn used in the present study. IL is employed by Roboscreen GmbH and receive income from that Company, which manufactures the ELISA kit for measurements of total human \u03b1-Syn used in the present study. KB is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), of which biomarkers were measured for the present study. HZ is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), of which biomarkers were measured for the present study. KB, CQ, SL, MR, IW, SB, BR, MZ, AM, AKH, CD, CS, AB, and SS, TG, and PP have nothing to report.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"175"}}