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

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.

Keywords: amyloid PET; human; off-target binding; tau PET.

Graphical abstract

FIGURE 1.

MR, CT, and SUVr images from amyloid-negative participant with high skull binding in all 3 radiotracers. Images are in MNI-152 space. MPRAGE = magnetization-prepared rapid acquisition with gradient echo.

FIGURE 2.

Group average SUVr images for each tracer. Images are in MNI-152 space.

FIGURE 3.

(A and B) Partial correlations of FTP skull SUVr with FTP choroid plexus partial-volume–corrected (PVC) SUVr (A) and FTP basal ganglia PVC SUVr (B) for men and women. (C) Women with lower bone density displayed higher skull SUVrs, whereas men did not. Shaded regions are 95% CIs.

FIGURE 4.

Relationship between FTP skull SUVr and tauopathy summary measure without (A) and with (B) PVC. Shaded regions are 95% CIs.

FIGURE 5.

Cortical regions significantly associated (P < 0.05) with FTP skull partial-volume–corrected (PVC) SUVr and non-PVC SUVr for amyloid-negative and -positive individuals.

FIGURE 6.

(A and B) Multitracer comparisons between FTP skull SUVr and FBP (A) or PiB (B) skull SUVr. (C) Longitudinal relationship for skull uptake across FTP visits. Shaded regions are 95% CIs.