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This study compared progression milestones across previously defined clinical (tremor-dominant [TD], postural instability\/gait difficulty [PIGD], indeterminate), pathological (brain-first, body-first), and data-driven (diffuse malignant [DM], intermediate [IM], mild motor-predominant [MMP]) PD subtypes. Using data from the Parkinson\u2019s Progression Markers Initiative (PPMI), we analyzed milestone attainment across six functional domains and performed Cox proportional hazards regression. Randomized controlled trial sample size simulations evaluated the impact of subtyping on trial efficiency. Data-driven subtypes exhibited the highest progression rates, with DM patients attaining 63.0% of milestones, surpassing PIGD (55.6%) and body-first (54.0%) subtypes. Cox proportional hazards regression confirmed that DM patients had the highest hazard of progression compared to MMP, after adjusting for age at enrollment. Trial power simulations demonstrated that enrolling DM patients could reduce sample size requirements by approximately 50% using standard trial durations compared to unstratified PD cohorts. This analysis showed that data-driven subtyping, particularly the identification of the DM subtype, offers a promising strategy to optimize disease-modification trials in PD by capturing patients who meet progression milestones earlier.<\/jats:p>","DOI":"10.1038\/s41531-026-01430-8","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T15:26:00Z","timestamp":1781277960000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comparative analysis of progression milestones across Parkinson\u2019s disease clinical, pathological, and data-driven subtypes: a 10-year follow-up"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5363-6369","authenticated-orcid":false,"given":"Ahmed","family":"Negida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitai","family":"Mukhopadhyay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Berman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"1430_CR1","doi-asserted-by":"publisher","first-page":"S30","DOI":"10.1016\/j.parkreldis.2017.07.033","volume":"46","author":"DW Dickson","year":"2018","unstructured":"Dickson, D. 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Brian D. Berman has received research grant support from the Dystonia Coalition (which receives the majority of its funding through NIH grant NS065701 from NCATS and NINDS), the Parkinson\u2019s Foundation, the VCU School of Medicine, the Administration for Community Living, and the Dystonia Medical Research Foundation. He has served as a consultant for the Dystonia Medical Research Foundation and has received honoraria from the International Parkinson and Movement Disorder Society. He serves on the Medical and Scientific Advisory Council of the Dystonia Medical Research Foundation, is Director of the Medical Advisory Board of the Benign Essential Blepharospasm Research Foundation, and is a member of the National Spasmodic Torticollis Association. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"239"}}