{ "abstract": "Background-synuclein (Lewy body-type) co-pathology has been identified at autopsy in a subset of patients with amyotrophic lateral sclerosis (ALS). However, its prevalence and prognostic relevance in vivo remain poorly characterized.\n\nMethodsWe analyzed baseline cerebrospinal fluid (CSF) -synuclein seed amplification assay (Syn SAA) status in 443 patients with ALS from two cohorts (Nagoya, Japan, n = 248; Bologna, Italy, n = 195). Samples were classified as strong-positive, weak-positive, or negative based on RT-QuIC reactivity across replicate wells, using the assays established a priori criteria at initial and repeat testing; classifications were corroborated by quantitative kinetic parameters. We compared age- and sex-adjusted odds of positivity in ALS with those in cognitively unimpaired (CU; n = 999; stratified by amyloid-{beta} [A{beta}] status), A{beta}-positive mild cognitive impairment (n = 224), and Alzheimers disease dementia (n = 319) groups from the Swedish BioFINDER cohort. In ALS, we examined tracheostomy-free survival and longitudinal functional decline using cohort-stratified Cox and linear mixed-effects models, respectively. We also assessed interactions between Syn SAA status and baseline CSF neurofilament light chain (NfL). Prognostic analyses were performed in sporadic ALS and repeated after including familial or genetic cases.\n\nResultsStrong Syn SAA positivity was detected in 24/443 patients with ALS (5.4%); overall positivity, including weak-positive samples, was 37/443 (8.4%). Patients with ALS did not have significantly higher odds of SAA positivity than A{beta}-negative CU participants (age- and sex-adjusted odds ratio [OR] 1.33, 95% CI [0.82, 2.14]) and had significantly lower odds than patients with Alzheimers disease dementia (OR 0.44, [0.27, 0.70]). Among patients with sporadic ALS, strong Syn SAA positivity was associated with shorter tracheostomy-free survival after adjustment for established predictors including NfL (adjusted HR 2.08 [1.25, 3.45]), whereas weak positivity showed no clear survival association. In linear mixed-effects models, strong Syn SAA positivity modified the association between NfL and ALSFRS-R decline (NfL x Syn SAA x time interaction {beta}-0.70 points/month [-1.26, -0.14] per SD NfL). These findings persisted in analyses including familial or genetic ALS cases and in those restricted to A{beta}-negative patients. Neuropathological findings (n = 5) were concordant with the CSF Syn SAA classification.\n\nConclusionsA strong -synuclein seeding profile was uncommon in ALS but identified a subgroup with shorter survival and a stronger association between NfL and functional decline. These findings provide ante-mortem evidence that -synuclein co-pathology may contribute to prognostic heterogeneity in ALS.", "abstract_shown": true, "affiliations": [], "article_type": "PUBLISHAHEADOFPRINT", "arxiv": null, "author_total": 28, "authors": [ { "name": "Kazuki Obara", "orcid": "0009-0006-5170-9169" }, { "name": "Andrea Mastrangelo", "orcid": "0000-0003-1578-8112" }, { "name": "Agustina Ranieri", "orcid": "0009-0004-2967-6685" }, { "name": "Shorena Janelidze", "orcid": "0000-0003-2869-8378" }, { "name": "Daisuke Ito", "orcid": "0000-0002-5037-2289" }, { "name": "Munetaka Yamamoto", "orcid": "0009-0003-5627-2128" }, { "name": "Veria Vacchiano", "orcid": "0000-0002-3607-2394" }, { "name": "Rocco Liguori", "orcid": "0000-0002-1815-1013" }, { "name": "Serena Caldera", "orcid": "0009-0007-4975-7708" }, { "name": "Yuichi Riku", "orcid": "0000-0002-6493-8976" }, { "name": "Yasushi Iwasaki", "orcid": "0000-0002-0059-3104" }, { "name": "Sinh Tran", "orcid": "0000-0002-1259-0672" }, { "name": "Takahiro Kawase", "orcid": "0009-0006-8257-4906" }, { "name": "Yu Mori", "orcid": "0000-0001-5725-1925" }, { "name": "Keita Hiraga", "orcid": "0000-0002-0134-2956" }, { "name": "Shinichiro Yamada", "orcid": "0000-0002-6523-9288" }, { "name": "Koyo Tsujikawa", "orcid": "0000-0002-9316-2476" }, { "name": "Yosuke Nishio", "orcid": "0000-0003-3543-7491" }, { "name": "Tomoo Ogi", "orcid": "0000-0002-5492-9072" }, { "name": "Ryoichi Nakamura", "orcid": "0000-0002-4854-3579" }, { "name": "Naoki Atsuta", "orcid": "0000-0002-4911-2690" }, { "name": "Gen Sobue", "orcid": "0000-0003-4769-5922" }, { "name": "Erik Stomrud", "orcid": "0000-0002-0841-5580" }, { "name": "Sebastian Palmqvist", "orcid": "0000-0002-9267-1930" }, { "name": "Oskar Hansson", "orcid": "0000-0001-8467-7286" }, { "name": "Piero Parchi", "orcid": "0000-0002-9444-9524" }, { "name": "Masahisa Katsuno", "orcid": "0000-0001-9453-9311" }, { "name": "Niklas Mattsson-Carlgren", "orcid": "0000-0002-8885-7724" } ], "bibtex": "https://research.draconitic.com/paper/115zr4j9rkdrq.bib", "cited_by": 0, "doi": "10.64898/2026.10.23.26366349", "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.23.26366349v1.full", "id": "115zr4j9rkdrq", "issns": [], "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.23.26366349v1", "language": "en", "licence": "CC-BY-NC-ND", "licence_label": "CC BY-NC-ND", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Article" ], [ "medrxiv", "neurology" ], [ "openalex", "2728|Amyotrophic Lateral Sclerosis Research" ] ], "openalex": "W7223694924", "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.23.26366349v1.full.pdf", "pmcid": "PMC13734037", "pmid": "42990486", "published": "2026-10-23", "publisher": "Cold Spring Harbor Laboratory Preprints", "ris": "https://research.draconitic.com/paper/115zr4j9rkdrq.ris", "sources": [ { "first_seen": "2026-10-30T12:21:50Z", "native_id": "10.64898/2026.10.23.26366349", "source": "medrxiv", "url": "https://www.medrxiv.org/content/10.64898/2026.10.23.26366349v1" }, { "first_seen": "2026-11-08T12:23:41Z", "native_id": "PMC13734037", "source": "pmc", "url": "https://doi.org/10.64898/2026.10.23.26366349" } ], "subjects": [ { "field": "medicine", "origin": "medrxiv:neurology", "subfield": "neurology" } ], "title": "Cerebrospinal fluid alpha-synuclein seed amplification assay positivity identifies a prognostically distinct subgroup in amyotrophic lateral sclerosis", "title_text": "Cerebrospinal fluid alpha-synuclein seed amplification assay positivity identifies a prognostically distinct subgroup in amyotrophic lateral sclerosis", "type": "preprint", "updated_at": "2026-11-08T12:23:41Z", "url": "https://research.draconitic.com/paper/115zr4j9rkdrq", "venue": "medRxiv", "versions": [] }