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<p>Flortaucipir PET imaging has significantly advanced our ability to visualize tau pathology in vivo. However, off-target Flortaucipir signal remains a considerable challenge for interpreting of imaging results, particularly in non-Alzheimer's tauopathies and non-tau pathologies. To better understand this off-target signal, we used an innovative voxel-to-voxel correlation approach, analyzing thousands of histology-Flortaucipir pairs from individual cases. This allowed us to quantitatively assess the relationship between Flortaucipir PET signal and three key biological factors: histological tau burden (CP-13 phospho-tau), ferric iron (Perls’ Prussian blue), and monoamine oxidase B (MAO-B). Our study included individuals with Alzheimer's disease (AD), various non-AD tauopathies, and a case of FTLD-TDP-43 type A. In AD, Flortaucipir signal showed a significant but moderate correlation with histological tau pathology, suggesting that while tau is a major contributor, other biological factors also influence Flortaucipir binding in AD. Conversely, in non-AD tauopathies and FTLD-TDP-43, correlations between Flortaucipir signal and tau pathology were weak or negligible. Instead, Flortaucipir signal correlated more strongly with ferric iron and MAO-B. However, these factors did not fully explain all the off-target signals, implying other unknown contributors are likely involved. These findings underscore the complexity of interpreting Flortaucipir PET scans. A thorough understanding of off-target binding mechanisms is crucial for improving the diagnostic accuracy of Flortaucipir PET and its specificity.</p>

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Disentangling on and off-target binding in flortaucipir PET: a voxel-to-voxel P-tau, ferric iron, and MAO-B histology-to-flortaucipir PET comparison

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月25日

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  • Yuheng Chen,
  • Renaud La Joie,
  • Felipe L. Pereira,
  • Ganna Blazhenets,
  • Lucile Zhu,
  • Salvatore Spina,
  • William W. Seeley,
  • Helmut Heinsen,
  • Daniela Ushizima,
  • Duygu Tosun,
  • Gil D. Rabinovici,
  • Lea T. Grinberg

摘要

Flortaucipir PET imaging has significantly advanced our ability to visualize tau pathology in vivo. However, off-target Flortaucipir signal remains a considerable challenge for interpreting of imaging results, particularly in non-Alzheimer's tauopathies and non-tau pathologies. To better understand this off-target signal, we used an innovative voxel-to-voxel correlation approach, analyzing thousands of histology-Flortaucipir pairs from individual cases. This allowed us to quantitatively assess the relationship between Flortaucipir PET signal and three key biological factors: histological tau burden (CP-13 phospho-tau), ferric iron (Perls’ Prussian blue), and monoamine oxidase B (MAO-B). Our study included individuals with Alzheimer's disease (AD), various non-AD tauopathies, and a case of FTLD-TDP-43 type A. In AD, Flortaucipir signal showed a significant but moderate correlation with histological tau pathology, suggesting that while tau is a major contributor, other biological factors also influence Flortaucipir binding in AD. Conversely, in non-AD tauopathies and FTLD-TDP-43, correlations between Flortaucipir signal and tau pathology were weak or negligible. Instead, Flortaucipir signal correlated more strongly with ferric iron and MAO-B. However, these factors did not fully explain all the off-target signals, implying other unknown contributors are likely involved. These findings underscore the complexity of interpreting Flortaucipir PET scans. A thorough understanding of off-target binding mechanisms is crucial for improving the diagnostic accuracy of Flortaucipir PET and its specificity.