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Research ArticleClinical Investigation

Investigating Tau and Amyloid Tracer Skull Binding in Studies of Alzheimer Disease

Shaney Flores, Charles D. Chen, Yi Su, Aylin Dincer, Sarah J. Keefe, Nicole S. McKay, Angela M. Paulick, Gloria Guzman Perez-Carrillo, Liang Wang, Russ C. Hornbeck, Manu Goyal, Andrei Vlassenko, Sally Schwarz, Michael L. Nickels, Dean F. Wong, Zhude Tu, Jonathan E. McConathy, John C. Morris, Tammie L.S. Benzinger and Brian A. Gordon
Journal of Nuclear Medicine February 2023, 64 (2) 287-293; DOI: https://doi.org/10.2967/jnumed.122.263948
Shaney Flores
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Charles D. Chen
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Yi Su
2Banner Alzheimer’s Institute, Phoenix, Arizona;
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Aylin Dincer
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Sarah J. Keefe
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Nicole S. McKay
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Angela M. Paulick
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Gloria Guzman Perez-Carrillo
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Liang Wang
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Russ C. Hornbeck
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Manu Goyal
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
3Department of Neurology, Washington University School of Medicine, St. Louis, Missouri;
4Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; and
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Andrei Vlassenko
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
3Department of Neurology, Washington University School of Medicine, St. Louis, Missouri;
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Sally Schwarz
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Michael L. Nickels
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Dean F. Wong
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Zhude Tu
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
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Jonathan E. McConathy
5University of Alabama at Birmingham, Birmingham, Alabama
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John C. Morris
3Department of Neurology, Washington University School of Medicine, St. Louis, Missouri;
4Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; and
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Tammie L.S. Benzinger
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
4Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; and
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Brian A. Gordon
1Department of Radiology, Washington University School of Medicine, St. Louis, Missouri;
4Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; and
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Abstract

Off-target binding of [18F]flortaucipir (FTP) can complicate quantitative PET analyses. An underdiscussed off-target region is the skull. Here, we characterize how often FTP skull binding occurs, its influence on estimates of Alzheimer disease pathology, its potential drivers, and whether skull uptake is a stable feature across time and tracers. Methods: In 313 cognitively normal and mildly impaired participants, CT scans were used to define a skull mask. This mask was used to quantify FTP skull uptake. Skull uptake of the amyloid-β PET tracers [18F]florbetapir and [11C]Pittsburgh compound B (n = 152) was also assessed. Gaussian mixture modeling defined abnormal levels of skull binding for each tracer. We examined the relationship of continuous bone uptake to known off-target binding in the basal ganglia and choroid plexus as well as skull density measured from the CT. Finally, we examined the confounding effect of skull binding on pathologic quantification. Results: We found that 50 of 313 (∼16%) FTP scans had high levels of skull signal. Most were female (n = 41, 82%), and in women, lower skull density was related to higher FTP skull signal. Visual reads by a neuroradiologist revealed a significant relationship with hyperostosis; however, only 21% of women with high skull binding were diagnosed with hyperostosis. FTP skull signal did not substantially correlate with other known off-target regions. Skull uptake was consistent over longitudinal FTP scans and across tracers. In amyloid-β–negative, but not –positive, individuals, FTP skull binding impacted quantitative estimates in temporal regions. Conclusion: FTP skull binding is a stable, participant-specific phenomenon and is unrelated to known off-target regions. Effects were found primarily in women and were partially related to lower bone density. The presence of [11C]Pittsburgh compound B skull binding suggests that defluorination does not fully explain FTP skull signal. As signal in skull bone can impact quantitative analyses and differs across sex, it should be explicitly addressed in studies of aging and Alzheimer disease.

  • off-target binding
  • human
  • tau PET
  • amyloid PET

Footnotes

  • Published online Aug. 11, 2022.

  • © 2023 by the Society of Nuclear Medicine and Molecular Imaging.
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Journal of Nuclear Medicine: 64 (2)
Journal of Nuclear Medicine
Vol. 64, Issue 2
February 1, 2023
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Investigating Tau and Amyloid Tracer Skull Binding in Studies of Alzheimer Disease
Shaney Flores, Charles D. Chen, Yi Su, Aylin Dincer, Sarah J. Keefe, Nicole S. McKay, Angela M. Paulick, Gloria Guzman Perez-Carrillo, Liang Wang, Russ C. Hornbeck, Manu Goyal, Andrei Vlassenko, Sally Schwarz, Michael L. Nickels, Dean F. Wong, Zhude Tu, Jonathan E. McConathy, John C. Morris, Tammie L.S. Benzinger, Brian A. Gordon
Journal of Nuclear Medicine Feb 2023, 64 (2) 287-293; DOI: 10.2967/jnumed.122.263948

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Investigating Tau and Amyloid Tracer Skull Binding in Studies of Alzheimer Disease
Shaney Flores, Charles D. Chen, Yi Su, Aylin Dincer, Sarah J. Keefe, Nicole S. McKay, Angela M. Paulick, Gloria Guzman Perez-Carrillo, Liang Wang, Russ C. Hornbeck, Manu Goyal, Andrei Vlassenko, Sally Schwarz, Michael L. Nickels, Dean F. Wong, Zhude Tu, Jonathan E. McConathy, John C. Morris, Tammie L.S. Benzinger, Brian A. Gordon
Journal of Nuclear Medicine Feb 2023, 64 (2) 287-293; DOI: 10.2967/jnumed.122.263948
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Keywords

  • off-target binding
  • human
  • tau PET
  • amyloid PET
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