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In-vivo 4R tau biomarkers are therefore crucial for PSP diagnosis, monitoring, and treatment evaluation. The tau-PET tracer [\n                      <jats:sup>18<\/jats:sup>\n                      F]PI-2620 binds to 4R tau and shows increased uptake in PSP-associated regions (e.g., globus pallidus), and is therefore a candidate 4R tau biomarker. However, commonly used cerebellar tau-PET reference regions show regional proximity to cerebellar 4R tau deposits in PSP, confounding semiquantitative [\n                      <jats:sup>18<\/jats:sup>\n                      F]PI-2620 assessments. Therefore, we employed bias-free image-derived input function (IDIF) PET quantification to identify an optimized data-driven reference region for assessing 4R tau in PSP.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Dynamic [\n                      <jats:sup>18<\/jats:sup>\n                      F]PI-2620 PET (60 min) was acquired in 58 PSP-Richardson Syndrome (PSP-RS) and 18 healthy controls (HC). IDIF-modelling with carotid timeseries derived total distribution volume (VT). Iteratively normalizing VT images to atlas-based white matter (WM), we identified reference candidates maximizing PSP-RS vs. HC pallidum differences. The best-performing WM references were combined to a temporo-orbital WM reference, validated in PSP-nonRS (\n                      <jats:italic>n<\/jats:italic>\n                      = 54), HC (\n                      <jats:italic>n<\/jats:italic>\n                      = 18), and disease controls (\u03b1-synucleinopathies,\n                      <jats:italic>n<\/jats:italic>\n                      = 21; Alzheimer\u2019s disease (AD,\n                      <jats:italic>n<\/jats:italic>\n                      = 22) using VT-ratios (VTr) and 20-40min static standardized uptake value ratios (SUVr).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Using the data-driven temporo-orbital WM reference, PSP patients showed significantly higher basal ganglia [\n                      <jats:sup>18<\/jats:sup>\n                      F]PI-2620 signal vs. HC compared to cerebellar normalization. Receiver operating curve (ROC) analysis confirmed higher diagnostic accuracy using the temporo-orbital WM reference. Pallidum [\n                      <jats:sup>18<\/jats:sup>\n                      F]PI-2620 showed significant associations with clinical disease severity exclusively when using the novel temporo-orbital WM reference.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      A data-driven temporo-orbital WM reference optimizes [\n                      <jats:sup>18<\/jats:sup>\n                      F]PI-2620 PET assessment for PSP diagnosis, outperforming conventional cerebellar references used in tau-PET imaging.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00259-025-07396-8","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T21:14:49Z","timestamp":1749503689000},"page":"5098-5112","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Developing a novel reference region for [18F]PI-2620-PET imaging to facilitate the assessment of 4-repeat tauopathies"],"prefix":"10.1007","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9321-956X","authenticated-orcid":false,"given":"Lukas","family":"Frontzkowski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Gn\u00f6rich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattes","family":"Gross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Dehsarvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian N.","family":"Roemer-Cassiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Palleis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Katzdobler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Dewenter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Steward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davina","family":"Biel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Hirsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Levin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew W.","family":"Stephens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman","family":"Koglin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e9rard N.","family":"Bischof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabor G.","family":"Kovacs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter U.","family":"H\u00f6glinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Brendel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolai","family":"Franzmeier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"issue":"11","key":"7396_CR1","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1093\/jnen\/61.11.935","volume":"61","author":"DW Dickson","year":"2002","unstructured":"Dickson DW, et al. 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A.W.S., A.M., N.K. and G.N.B. are employed by LMI. G.H. received research support from GE Healthcare and Neuropore; has ongoing research collaborations with Orion and Prothena; serves as a consultant for AbbVie, AlzProtect, Asceneuron, Biogen, Biohaven, Lundbeck, Novartis, Roche, Sanofi, UCB; received honoraria for scientific presentations from AbbVie, Biogen, Roche, Teva, UCB, and Zambon; and holds a patent on PERK Activation for the Treatment of Neurodegenerative Diseases (PCT\/EP2015\/068734). No other potential conflict of interest relevant to this article was reported.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee (LMU Munich\u2014application number 17\u2013569) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all patients. All patients provided informed written consent to PET imaging. The study was conducted in accordance with the principles of the Declaration of Helsinki, and approval for scientific data analysis was obtained from the local ethics committee (application number 17\u2013569).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}