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Flortaucipir F-18 PET scans accurately detect tau pathology in Alzheimer's disease but can be influenced by iron and MAOB in other tauopathies. Understanding these factors is crucial for accurate diagnosis of neurodegenerative disorders.

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Area of Science:

  • Neuroimaging
  • Neuropathology
  • Molecular Imaging

Background:

  • Flortaucipir F-18 (FTP-PET) is the first FDA-approved PET tracer for detecting tau pathology.
  • FTP-PET shows sensitivity to Alzheimer's disease (AD) tau but limited utility in four-repeat tauopathies.
  • The neurobiological basis for reduced FTP-PET signal in non-AD tauopathies, particularly in the basal ganglia, remains unclear.

Purpose of the Study:

  • To investigate the contributions of phosphorylated tau (p-tau), iron (Fe(III)), and monoamine oxidase B (MAOB) to the FTP-PET signal across different tauopathies.
  • To correlate voxel-wise histological findings with PET-CT imaging data.

Main Methods:

  • Developed a computational/histopathology pipeline for 3D reconstruction of histological maps from tauopathy cases (AD, PSP, CBD, FTLD-MAPT, FTLD-TDP).
  • Performed immunohistochemistry for p-tau (Ser 202, CP-13) and MAOB, alongside Perl's iron staining on histological slides.
  • Quantified pathological changes per voxel and performed voxel-to-voxel correlation analyses between FTP-PET signal and histological markers (CP13, iron, MAOB) in different brain regions.

Main Results:

  • In AD, CP-13 (p-tau) showed the strongest correlation with FTP-PET signal, followed by iron and MAOB.
  • In non-AD tauopathies, FTP-PET signal correlated better with iron (in PSP and FTLD-MAPT) and MAOB (in TDP-43 proteinopathies), especially within the putamen and globus pallidus.
  • High Dice scores (0.88–0.95 hemisphere, 0.76–0.90 basal ganglia) indicate good spatial overlap between PET signal and histological findings.

Conclusions:

  • FTP-PET signal robustly reflects p-tau in AD but its interpretation in non-AD tauopathies and TDP-43 proteinopathies is complex due to non-tau substrates.
  • Iron and MAOB are significant contributors to FTP-PET signal in non-AD tauopathies, where FTP has low affinity for the specific tau conformations.
  • Future research should focus on identifying off-target contributors, refining tracer specificity, and integrating complementary markers for improved diagnostic accuracy in diverse neurodegenerative disorders.