62 Chapter 3 often not strictly enforced; thus, deviations in scanning intervals between static and longitudinal scans are common. These discrepancies will increase variability and uncertainty, which will increase required sample sizes for SUVr. Differing underlying tau load in the sample studied will only increase the bias in SUVr further. It is worth noting that, in the current study, SUVr was extracted from the dynamically acquired data. In addition, scanning interval was strictly enforced in the context of the 2 scanning sessions within the dynamic protocol. For both these reasons, SUVr in this study was not affected by deviations in scanning, and the results may therefore be too optimistic in this respect. The discrepancies between methods using simulations may have important implications for longitudinal 18F-flortaucipir studies and intervention studies. Our findings imply that SUVr is not the parameter of preference when large variations in blood flow are expected, although to what order of magnitude remains to be elucidated. A consideration to address when using repeated dynamic scans is potential selection bias, because severely affected patients might not be able to undergo such a demanding procedure. In patients with moderate to severe AD, this is indeed debatable. However, pharmacotherapeutic trials currently show a shift in target population, primarily including patients with mild, prodromal, or preclinical autosomal-dominant AD. Those patients can tolerate the longer dynamic scan procedures. 18F-flortaucipir is useful for investigating pathologic tau load differences between SCD subjects and AD patients. However, in an early-dementia cohort for which we do not expect specific binding in the neocortex, measurement of tau deposition shows large variability. Indeed, in such a sample, 64% of the cortical signal variability can be explained by off-target binding (40). Partial-volume correction does not completely explain the variability in the cortical signal. Therefore, the variability in the signal in cohorts with low tau deposition related to off-target binding should be considered when examining early tau deposition using 18F-flortaucipir. CONCLUSION Static scanning protocols provide accurate estimates of specific 18F-flortaucipir binding in observational studies. Dynamic scanning protocols and fully quantitative data analysis methods are preferred when large(r) flow changes in the brain are expected (such as in later disease stages or pharmacotherapeutic interventions). Use of semiquantitative methods in such conditions carries the inherent risk that potential effective therapeutic interventions are discarded, especially when expected effect sizes are small.
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