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Here we established an ultra-sensitive single-molecule pull-down immunoassay combined with direct stochastic optical reconstruction microscopy (\n                    <jats:italic>d<\/jats:italic>\n                    STORM) to measure the number, size and shape of individual extracellular inflammasome ASC specks. We assayed human post-mortem brain, serum and cerebrospinal fluid of patients with Parkinson\u2019s and Alzheimer\u2019s as well as healthy elderly. The number of ASC specks increased and showed altered morphology in the blood of early-stage Parkinson\u2019s and Alzheimer\u2019s patients compared to controls, mimicking those found in the brain and cerebrospinal fluid. In serum samples we also measured the number of A\u03b2, p-tau and \u03b1-syn aggregates and formed a composite biomarker of (ASC\u2009+\u2009p-tau)\/A\u03b2 and (ASC\u2009+\u2009\u03b1-syn)\/A\u03b2 ratios that distinguished age-matched healthy controls from patients with early-stage Alzheimer\u2019s with AUC of 92% and early-stage Parkinson\u2019s with AUC of 97%. Our findings confirm ASC specks as a fluid candidate biomarker of inflammation for neurodegenerative diseases with blood being the main focus for further development as convenient sample for diagnostics and clinical trials.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-53547-0","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T05:02:54Z","timestamp":1731301374000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["ASC specks as a single-molecule fluid biomarker of inflammation in neurodegenerative diseases"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7605-5820","authenticated-orcid":false,"given":"Evgeniia","family":"Lobanova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu P.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derya","family":"Emin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Brelstaff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakmini","family":"Kahanawita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8923-9656","authenticated-orcid":false,"given":"Maura","family":"Malpetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"Quaegebeur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7473-6278","authenticated-orcid":false,"given":"Kathy","family":"Triantafilou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8489-2602","authenticated-orcid":false,"given":"Martha","family":"Triantafilou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7216-8679","authenticated-orcid":false,"given":"James B.","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2648-9743","authenticated-orcid":false,"given":"Caroline H.","family":"Williams-Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2924-0038","authenticated-orcid":false,"given":"Clare Elizabeth","family":"Bryant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7116-6954","authenticated-orcid":false,"given":"David","family":"Klenerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,11]]},"reference":[{"key":"53547_CR1","doi-asserted-by":"publisher","first-page":"5481","DOI":"10.1038\/s41380-021-01249-0","volume":"26","author":"H Hampel","year":"2021","unstructured":"Hampel, H. et al. 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The patent application has been filed on the methods of protein aggregate detection for diagnosis of neurodegenerative diseases including a method for detecting ASC specks in human biofluids, which is described in this manuscript. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9690"}}