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Research ArticleClinical Investigation

A Visual Interpretation Algorithm for Assessing Brain Tauopathy with 18F-MK-6240 PET

John P. Seibyl, Jonathan M. DuBois, Annie Racine, Jessica Collins, Qi Guo, Dustin Wooten, Eddie Stage, David Cheng, Roger N. Gunn, Lilly Porat, Alex Whittington, Phillip H. Kuo, Masanori Ichise, Robert Comley, Laurent Martarello and Cristian Salinas
Journal of Nuclear Medicine March 2023, 64 (3) 444-451; DOI: https://doi.org/10.2967/jnumed.122.264371
John P. Seibyl
1Institute for Neurodegenerative Disorders, New Haven, Connecticut;
2Invicro, New Haven, Connecticut;
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Jonathan M. DuBois
3Biogen, Cambridge, Massachusetts;
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Annie Racine
3Biogen, Cambridge, Massachusetts;
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Jessica Collins
3Biogen, Cambridge, Massachusetts;
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Qi Guo
4AbbVie, North Chicago, Illinois;
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Dustin Wooten
3Biogen, Cambridge, Massachusetts;
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Eddie Stage
4AbbVie, North Chicago, Illinois;
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David Cheng
2Invicro, New Haven, Connecticut;
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Roger N. Gunn
2Invicro, New Haven, Connecticut;
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Lilly Porat
2Invicro, New Haven, Connecticut;
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Alex Whittington
2Invicro, New Haven, Connecticut;
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Phillip H. Kuo
5University of Arizona, Tucson, Arizona; and
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Masanori Ichise
6National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
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Robert Comley
4AbbVie, North Chicago, Illinois;
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Laurent Martarello
3Biogen, Cambridge, Massachusetts;
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Cristian Salinas
3Biogen, Cambridge, Massachusetts;
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Abstract

In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials of Alzheimer disease (AD). 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (18F-MK-6240) is a radiotracer with high selectivity and subnanomolar affinity for neurofibrillary tangles that shows favorable nonspecific brain penetration and excellent kinetic properties. The purpose of the present investigation was to develop a visual assessment method that provides both an overall assessment of brain tauopathy and regional characterization of abnormal tau deposition. Methods: 18F-MK-6240 scans from 102 participants (including cognitively normal volunteers and patients with AD or other neurodegenerative disorders) were reviewed by an expert nuclear medicine physician masked to each participant’s diagnosis to identify common patterns of brain uptake. This initial visual read method was field-tested in a separate, nonoverlapping cohort of 102 participants, with 2 additional naïve readers trained on the method. Visual read outcomes were compared with semiquantitative assessments using volume-of-interest SUV ratio. Results: For the visual read, the readers assessed 8 gray-matter regions per hemisphere as negative (no abnormal uptake) or positive (1%–25% of the region involved, 25%–75% involvement, or >75% involvement) and then characterized the tau binding pattern as positive or negative for evidence of tau and, if positive, whether brain uptake was in an AD pattern. The readers demonstrated agreement 94% of the time for overall positivity or negativity. Concordance on the determination of regional binary outcomes (negative or positive) showed agreement of 74.3% and a Fleiss κ of 0.912. Using clinical diagnosis as the ground truth, the readers demonstrated a sensitivity of 73%–79% and specificity of 91%–93%, with a combined reader-concordance sensitivity of 80% and specificity of 93%. The average SUV ratio in cortical regions showed a robust correlation with visually derived ratings of regional involvement (r = 0.73, P < 0.0001). Conclusion: We developed a visual read algorithm for 18F-MK-6240 PET offering determination of both scan positivity and the regional degree of cortical involvement. These cross-sectional results show strong interreader concordance on both binary and regional assessments of tau deposition, as well as good sensitivity and excellent specificity supporting use as a tool for clinical trials.

  • neurology
  • PET
  • Alzheimer disease
  • MK-6240
  • PET
  • tau proteinopathies

Footnotes

  • Published online Sep. 29, 2022.

  • © 2023 by the Society of Nuclear Medicine and Molecular Imaging.
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Journal of Nuclear Medicine: 64 (3)
Journal of Nuclear Medicine
Vol. 64, Issue 3
March 1, 2023
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A Visual Interpretation Algorithm for Assessing Brain Tauopathy with 18F-MK-6240 PET
John P. Seibyl, Jonathan M. DuBois, Annie Racine, Jessica Collins, Qi Guo, Dustin Wooten, Eddie Stage, David Cheng, Roger N. Gunn, Lilly Porat, Alex Whittington, Phillip H. Kuo, Masanori Ichise, Robert Comley, Laurent Martarello, Cristian Salinas
Journal of Nuclear Medicine Mar 2023, 64 (3) 444-451; DOI: 10.2967/jnumed.122.264371

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A Visual Interpretation Algorithm for Assessing Brain Tauopathy with 18F-MK-6240 PET
John P. Seibyl, Jonathan M. DuBois, Annie Racine, Jessica Collins, Qi Guo, Dustin Wooten, Eddie Stage, David Cheng, Roger N. Gunn, Lilly Porat, Alex Whittington, Phillip H. Kuo, Masanori Ichise, Robert Comley, Laurent Martarello, Cristian Salinas
Journal of Nuclear Medicine Mar 2023, 64 (3) 444-451; DOI: 10.2967/jnumed.122.264371
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Keywords

  • neurology
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