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@ARTICLE{Frontzkowski:282975,
      author       = {Frontzkowski, Lukas and Gnoerich, Johannes and Gross,
                      Mattes and Dehsarvi, Amir and Roemer-Cassiano, Sebastian N
                      and Palleis, Carla and Katzdobler, Sabrina and Dewenter,
                      Anna and Steward, Anna and Biel, Davina and Hirsch, Fabian
                      and Zhu, Zeyu and Levin, Johannes and Stephens, Andrew W and
                      Müller, Andre and Koglin, Norman and Bischof, Gérard N and
                      Kovacs, Gabor G and Höglinger, Günter U and Brendel,
                      Matthias and Franzmeier, Nicolai},
      title        = {{D}eveloping a novel reference region for
                      [18{F}]{PI}-2620-{PET} imaging to facilitate the assessment
                      of 4-repeat tauopathies.},
      journal      = {European journal of nuclear medicine and molecular imaging},
      volume       = {52},
      number       = {13},
      issn         = {1619-7070},
      address      = {Heidelberg [u.a.]},
      publisher    = {Springer-Verl.},
      reportid     = {DZNE-2025-01427},
      pages        = {5098 - 5112},
      year         = {2025},
      abstract     = {Progressive supranuclear palsy (PSP) is a fatal 4-repeat
                      (4R) tauopathy with progressive movement phenotypes. In-vivo
                      4R tau biomarkers are therefore crucial for PSP diagnosis,
                      monitoring, and treatment evaluation. The tau-PET tracer
                      [18F]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 [18F]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.Dynamic
                      [18F]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 =
                      54), HC (n = 18), and disease controls
                      (α-synucleinopathies, n = 21; Alzheimer’s disease (AD, n
                      = 22) using VT-ratios (VTr) and 20-40min static standardized
                      uptake value ratios (SUVr).Using the data-driven
                      temporo-orbital WM reference, PSP patients showed
                      significantly higher basal ganglia [18F]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
                      [18F]PI-2620 showed significant associations with clinical
                      disease severity exclusively when using the novel
                      temporo-orbital WM reference.A data-driven temporo-orbital
                      WM reference optimizes [18F]PI-2620 PET assessment for PSP
                      diagnosis, outperforming conventional cerebellar references
                      used in tau-PET imaging.The online version contains
                      supplementary material available at
                      10.1007/s00259-025-07396-8.},
      keywords     = {Four-repeat tauopathies (Other) / Progressive supranuclear
                      palsy (Other) / Reference region (Other) / Tau (Other) /
                      [18F]PI-2620 (Other)},
      cin          = {AG Haass / Clinical Research (Munich) / AG Levin},
      ddc          = {610},
      cid          = {I:(DE-2719)1110007 / I:(DE-2719)1111015 /
                      I:(DE-2719)1111016},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40490537},
      pmc          = {pmc:PMC12589379},
      doi          = {10.1007/s00259-025-07396-8},
      url          = {https://pub.dzne.de/record/282975},
}