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The objective was to develop a hypothesis-guided region\/tract of interest-based (ROI\/TOI) approach to use diffusion tensor imaging (DTI) targeted to analyze <jats:italic>in vivo<\/jats:italic> the regions that are prone to be involved at each neuropathological stage of PSP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two data cohorts were analyzed: cohort A of 78 PSP patients [55 Richardson\u2019s syndrome (PSP-RS) and 23 PSP with predominant parkinsonism (PSP-P)] and 63 controls, recorded at 3.0<jats:italic>T<\/jats:italic> at multiple sites, and a single-site cohort B constituted by 1.5<jats:italic>T<\/jats:italic> data of 66 PSP patients (46 PSP-RS and 20 PSP-P) and 44 controls. In cohort A, 21 PSP patients (13 PSP-RS and 8 PSP-P) and 17 controls obtained a follow-up scan after 17 months. Whole brain-based spatial statistics (WBSS) was used to identify the alterations in PSP patients vs. controls. The combined ROI- and TOI-based approach targeted structures that are prone to be involved during the course of PSP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>WBSS demonstrated alterations predominantly in brainstem\/midbrain, basal ganglia, and frontal lobe, more pronounced in the longitudinal data. Statistical analyses of the ROIs\/TOIs showed a sequential pattern of structures that were assigned to previously defined neuropathological steps.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The combined ROI- and TOI-based DTI approach was able to map the disease stages of PSP <jats:italic>in vivo<\/jats:italic> cross-sectionally and longitudinally, lending support to DTI as a technical marker for imaging disease progression according to PSP stages. This approach might be useful as a tool for stratification of PSP patients MRI with respect to its proposed neuropathological progression in future longitudinal and autopsy-controlled studies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2025.1569302","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T16:20:54Z","timestamp":1749226854000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Diffusion tensor imaging of sequential neuropathological patterns in progressive supranuclear palsy"],"prefix":"10.3389","volume":"17","author":[{"given":"Lavinia A.","family":"B\u00e2rlescu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter U.","family":"H\u00f6glinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"Volkmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert C.","family":"Ludolph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Del Tredici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"Braak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Peter","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Kassubek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the DESCRIBE-PSP Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1136\/jnnp-2017-317443","article-title":"Tracking brain damage in progressive supranuclear palsy: A longitudinal MRI study.","volume":"89","author":"Agosta","year":"2018","journal-title":"J. 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