61 E ect of flow on longitudinal tau PET mate of change in specific binding in both patient groups. There are several possible reasons for the differences in findings between the 2 studies. First, an important factor contributing to our findings could be the relatively small or nonexistent R1 differences in this cohort. Previously, using 11C-PiB (6), we reported larger R 1 changes in AD patients, which induced a large difference between SUVr and BPND. This effect might perhaps indicate that 11C-PiB is more sensitive to changes in R 1 than is 18F-flortaucipir. However, flow sensitivity may also depend on the scanning interval relative to tracer kinetics, as was seen previously for 11C-PIB (6). Similarly, this is the scenario for 18F-flortaucipir, and we therefore cannot directly compare the 2 tracers in this respect. Second, it has been reported that accumulation of tau pathology is a slowly developing process, with annual percentage changes of about 0.5%–3% in Aβ-positive cognitively unimpaired subjects and up to 3%–10% in Aβ-positive cognitively impaired subjects (34–37). The annual percentages change in the present study was generally comparable in SCD subjects (on average, 1.08% SUVr and 1.28% DVR) and slightly lower in AD subjects (2.73% SUVr and 2.52% DVR). The test–retest repeatability of 18F-flortaucipir, as reported previously (38), lies at around 1.98% (0.78–3.58) for DVR and 3.05% (1.28–5.52) for SUVr at 80–100 min. Although the test–retest repeatability was significantly better for DVR (38), annual percentage changes as found in the present study still fall within 1 SD of the test–retest repeatability for both DVR and SUVr, suggesting that observed changes might be too small to detect differences between analytic methods. Finally, differences with respect to tracer target affinity, isotope (11C vs. 18F), and pharmacokinetic behavior might have introduced differences that caused the differences in results. Currently, the effects of pharmacotherapeutic interventions on cerebral blood flow are unclear. Therefore, we performed simulations to investigate the impact of large(r) changes in relative cerebral blood flow/R1 on the accuracy of SUVr and DVR. The bias with SUVr relative to DVR was different for each flow condition, and this bias was additionally influenced by the underlying tau load, with decreasing bias in cases of low tau load/binding or constant bias for high tau load/binding. Depending on the underlying tau load, regional changes in flow resulted in variable changes in SUVr, which was not the scenario with DVR. Similar findings were previously observed using 18F-cyclofoxy (39). On top of flow condition and the underlying tau load, the choice of SUVr time interval also effected the accuracy, which was again different for different binding conditions. A previous study found large positive biases for SUVr using different time intervals when compared with dynamic methods (8). Furthermore, Golla et al. (8) observed that the bias in SUVr for a specific scanning interval is not constant but is dependent on the underlying tau load and the choice of SUVr scanning interval. This has important implications, since scanning intervals for static protocols are 3
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