{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T13:23:29Z","timestamp":1793712209749,"version":"4.6.1"},"reference-count":35,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:00:00Z","timestamp":1734566400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R01NS126260\u201002"],"award-info":[{"award-number":["5R01NS126260\u201002"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01 CA167552"],"award-info":[{"award-number":["U01 CA167552"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>We prospectively evaluated how well combinations of signs and symptoms can identify individuals in the prodromal phase of Parkinson's disease (PD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study comprised 6,108 men who underwent repeated assessments of key prodromal features and were prospectively followed for the development of PD. Two composite measures of prodromal PD were evaluated: (i) the co\u2010occurrence of constipation, probable rapid eye movement (REM) sleep behavior disorder (pRBD), and hyposmia, and (ii) the probability of prodromal PD based on the Movement Disorders Society (MDS) research criteria. We also examined the progression and heterogeneity of the prodromal PD phase.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>One hundred three individuals were newly diagnosed with PD over an average follow\u2010up of 3.4\u2009years. Men with constipation, pRBD, and hyposmia had a 23\u2010fold higher risk of receiving a PD diagnosis in the subsequent 3\u2009years, compared with men without these features (risk ratio [RR]\u2009=\u200923.35, 95% confidence interval [CI]\u2009=\u200910.62\u201351.33). The risk of PD was 21\u2010fold higher in men with a probability of prodromal PD \u2265\u20090.8 compared with those with a probability &lt;\u20090.2 (RR\u2009=\u200921.96, 95% CI\u2009=\u200911.17\u201343.17). Both the co\u2010occurrence of the 3 non\u2010motor features and an MDS\u2010based probability \u2265\u20090.8 had comparable predictive values, and both were stronger predictors of PD than any of the features individually. We identified 2 prodromal PD subtypes where RBD and visual color impairment were key discriminators.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our study demonstrates that combinations of key signs and symptoms strongly predict future clinically manifest PD. These measures may be integrated into screening strategies to identify individuals who could be targeted for enrollment into PD prevention trials. 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Chan School of Public Health  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine C.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Optum Epidemiology  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3665-2006","authenticated-orcid":false,"given":"Marianna","family":"Cortese","sequence":"additional","affiliation":[{"name":"Department of Nutrition Harvard T.H. Chan School of Public Health  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert Y.","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Neurology Harvard Medical School  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C.","family":"Healy","sequence":"additional","affiliation":[{"name":"Department of Neurology Harvard Medical School  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Schwarzschild","sequence":"additional","affiliation":[{"name":"Department of Neurology Harvard Medical School  Boston MA"},{"name":"MassGeneral Institute for Neurodegenerative Disease, Department of Neurology Harvard Medical School, Massachusetts General Hospital  Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2892-6986","authenticated-orcid":false,"given":"Kjetil","family":"Bjornevik","sequence":"additional","affiliation":[{"name":"Department of Nutrition Harvard T.H. 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