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

Rationale: Off-target binding of [¹⁸F]flortaucipir (FTP) can complicate quantitative positron emission tomography (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 (AD) 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, computerized tomography (CT) scans were used to define a skull mask. This mask was used to quantify FTP skull uptake. Skull uptake of amyloid-beta PET tracers [¹⁸F]florbetapir and [¹¹C]Pittsburgh Compound B (PiB; n=152) were 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 pathological quantification. Results: We found 50/313 (~16%) FTP scans had high levels of skull signal. The majority 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-beta 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 primarily found in women, and partially related to lower bone density. Presence of PiB skull binding suggests 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 AD.