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While seed amplification assays (SAA) have demonstrated ultrasensitive detection of misfolded \u03b1Syn, they have been primarily used reliably to provide binary (positive\/negative) results for diagnostic purposes. We developed an SAA with enhanced specificity for Lewy-fold \u03b1-synucleinopathies and introduced a quantifiable measure correlating with clinical severity. Cerebrospinal fluid (CSF) of 170 patients with neurodegenerative diseases and controls was analyzed. Blinded measurements demonstrated 97.8% sensitivity and 100% specificity for Lewy-fold \u03b1-synucleinopathies, correctly identifying PD and DLB while excluding MSA. In addition, we validated the strain specificity of the assay by testing brain homogenates from 30 neuropathologically confirmed cases. A novel Lewy-fold pathology (LFP) score based on positive signals in a dilution series provided a quantitative measure of \u03b1Syn seeds. The LFP score significantly correlated with motor and cognitive impairment presented by Hoehn and Yahr stage, MDS-UPDRS III, and MoCA. Longitudinal tracking in seven PD cases showed progressive LFP score increases corresponding with clinical deterioration, highlighting the assay\u2019s potential for monitoring disease progression at an individual level. Our Lewy-fold-specific SAA enhances ante-mortem diagnosis and differentiates Lewy-fold \u03b1-synucleinopathies from MSA. Unlike previous assays, the LFP score offers a quantitative assessment, showing promise as a progression marker and pharmacodynamic biomarker for \u03b1Syn-targeting therapies. This represents an important step toward developing an \u03b1Syn SAA that could help to track disease progression quantitatively, with potential applications in both clinical diagnostics and therapeutic trials.<\/jats:p>","DOI":"10.1007\/s00401-025-02853-y","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T23:36:54Z","timestamp":1740008214000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["A quantitative Lewy-fold-specific alpha-synuclein seed amplification assay as a progression marker for Parkinson\u2019s disease"],"prefix":"10.1007","volume":"149","author":[{"given":"Alexander M.","family":"Bernhardt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Longen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja V.","family":"Trossbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Weckbecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"J\u00e4ck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Katzdobler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urban M.","family":"Fietzek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Endy","family":"Weidinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Palleis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoria","family":"Ruf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Baiardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Parchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter U.","family":"H\u00f6glinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Matthias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Levin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Giese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"2853_CR1","doi-asserted-by":"publisher","first-page":"1700","DOI":"10.1016\/j.bpj.2013.08.025","volume":"105","author":"M Algamal","year":"2013","unstructured":"Algamal M, Milojevic J, Jafari N, Zhang W, Melacini G (2013) Mapping the Interactions between the Alzheimer\u2019s A\u03b2-peptide and human serum albumin beyond domain resolution. 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Sebastian Longen reports full-time employment by AESKU.Diagnostics GmbH. In addition, he is inventor of a patent application related to this work.  Svenja V. Trossbach reports full-time employment by MODAG GmbH. In addition, she is inventor of a patent application related to this work.  Daniel Weckbecker reports full-time employment by MODAG GmbH, he is inventor of a patent application related to this work. He is beneficiary of the phantom share program of MODAG GmbH. Felix Schmidt reports full-time employment by MODAG GmbH. He is inventor of a patent application related to this work. He is beneficiary of the phantom share program of MODAG GmbH. G\u00fcnter H\u00f6glinger is inventor of patents related to the treatment of synucleinopathies (United States Patent No.: US 10,918,628 B2, European Patent Patent No.: EP 17 787 904.6\u20131109 \/ 3 525 788). Torsten Matthias is CEO and shareholder of MODAG GmbH and AESKU.Diagnostics GmbH. In addition, he is inventor of a patent application related to this work. Johannes Levin reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is beneficiary of the phantom share program of MODAG GmbH. He is inventor of a patent application related to this work.  Armin Giese reports employment by and being a shareholder of MODAG GmbH. He is inventor of a patent application related to this work.  All other authors have no other competing interests to report.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"20"}}