{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:06:34Z","timestamp":1788941194513,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019889","name":"Weston Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019889","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To provide a comprehensive description of disease progression in synuclein seeding assay (SAA) positive sporadic Parkinson Disease participants, using Neuronal Synuclein Disease integrated biological and functional impairment staging framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed 5\u2010year longitudinal data from 345 participants recruited in the Parkinson's Progression Markers Initiative with the diagnosis of early (less than 2\u2009years of clinical diagnosis at baseline and untreated) sporadic Parkinson's Disease, who were synuclein seeding assay positive. We assessed 5\u2010year progression in a spectrum of clinical and biomarker measures. We used Cox proportional hazards models to assess the association between baseline stage and time to survival, postural instability, cognitive impairment, and other meaningful milestones. Biomarker analysis included dopamine transporter binding measures, CSF\u2010SAA, amyloid\u2010beta, phosphorylated tau and total tau, as well as serum urate, and neurofilament light chain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At baseline there was clear separation of participants by Neuronal Synuclein Disease Stages (23% Stage 2b, 67% Stage 3, 10% Stage 4). Participants in stage 4 at baseline had a significantly higher rate of reaching disability, postural instability, cognitive decline, and the autonomic dysfunction milestones. There was a stage\u2010dependent increase in dopamine deficit at baseline. There was no difference in fluid biomarkers between the stages at baseline and longitudinally.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>This study highlights the heterogeneity in the early Parkinson's Disease population defined by clinical diagnostic criteria and underscores the importance of shifting from clinical to biologically and functional impairment defined inclusion criteria for clinical trials. Biological drivers of stage heterogeneity must be further explored.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70323","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T04:43:16Z","timestamp":1773204196000},"page":"1791-1806","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Five\u2010Year Disease Progression in Synuclein Seeding Positive Sporadic Parkinson's Disease"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6415-8286","authenticated-orcid":false,"given":"Paulina","family":"Gonzalez\u2010Latapi","sequence":"first","affiliation":[{"name":"The Ken and Ruth Davee Department of Neurology  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Gochanour","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5257-5741","authenticated-orcid":false,"given":"Seung Ho","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunkeun","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of Biostatistics University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea","family":"Caspell\u2010Garcia","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Coffey","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Brumm","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David\u2010Erick","family":"Lafontant","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuge","family":"Xiao","sequence":"additional","affiliation":[{"name":"The Michael J. Fox Foundation for Parkinson's Research  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Tropea","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Disorders  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Seibyl","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Disorders  New Haven Connecticut USA"},{"name":"Department of Neurology Yale University  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Tanner","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2394-9513","authenticated-orcid":false,"given":"Charles S.","family":"Venuto","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Rochester  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Kieburtz","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Rochester  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lana M.","family":"Chahine","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3424-7143","authenticated-orcid":false,"given":"Kathleen L.","family":"Poston","sequence":"additional","affiliation":[{"name":"Department of Neurology Stanford University  Palo Alto California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Siderowf","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Marek","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Disorders  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Simuni","sequence":"additional","affiliation":[{"name":"The Ken and Ruth Davee Department of Neurology  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The Parkinson's Progression Markers Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-021-00203-9"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002461"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26424"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05672-9"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61393-3"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00109-6"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200878"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-021-01276-6"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/mdc3.13710"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02160-8"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-021-01175-w"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.0792"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00404-0"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00405-2"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-024-00942-2"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(22)00120-X"},{"key":"e_1_2_11_18_1","unstructured":"J. F.Siegel \u201c(FDA Letter of Support for Alpha\u2010Synuclein Seed Amplification Assay \u201d(2024)."},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02886-y"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2011.09.005"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.317"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.644"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.22340"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.17.5.427"},{"key":"e_1_2_11_25_1","volume-title":"Projection Technique for Evaluating Surgery in Parkinson's Disease Third Symposium on Parkinson's Disease","author":"Schwab R. S. E. A.","year":"1969"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1006\/neur.1995.0011"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.20153"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3956(82)90033-4"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21740"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29410"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2005.53221.x"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51022"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.30111"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28715"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000208033"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-223433"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-020-00894-7"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2016.196"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27989"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28206"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25383"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.51.6.745"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx118"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27177"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2018-318337"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-022-00439-z"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-023-00581-2"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-202472"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.765765"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2202867"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.30191"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70323","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.70323","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70323","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T07:22:58Z","timestamp":1788938578000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.70323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,10]]},"references-count":50,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/acn3.70323"],"URL":"https:\/\/doi.org\/10.1002\/acn3.70323","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,10]]},"assertion":[{"value":"2025-09-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}