Validation of Noninvasive Tracer Kinetic Analysis of ¹⁸F-Florbetaben PET Using a Dual–Time-Window Acquisition Protocol

Abstract

Accurate amyloid PET quantification is necessary for monitoring amyloid-β accumulation and response to therapy. Currently, most of the studies are analyzed using the static SUV ratio (SUVR) approach because of its simplicity. However, this approach may be influenced by changes in cerebral blood flow (CBF) or radiotracer clearance. Full tracer kinetic models require arterial blood sampling and dynamic image acquisition. The objectives of this work were, first, to validate a noninvasive kinetic modeling approach for F-florbetaben PET using an acquisition protocol with the best compromise between quantification accuracy and simplicity and, second, to assess the impact of CBF changes and radiotracer clearance on SUVRs and noninvasive kinetic modeling data inF-florbetaben PET. Using data from 20 subjects (10 patients with probable Alzheimer dementia and 10 healthy volunteers), the nondisplaceable binding potential (BP) obtained from the full kinetic analysis was compared with the SUVR and with noninvasive tracer kinetic methods (simplified reference tissue model and multilinear reference tissue model 2). Various approaches using shortened or interrupted acquisitions were compared with the results of the full acquisition (0-140 min). Simulations were performed to assess the effect of CBF and radiotracer clearance changes on SUVRs and noninvasive kinetic modeling outputs. An acquisition protocol using time windows of 0-30 and 120-140 min with appropriate interpolation of the missing time points provided the best compromise between patient comfort and quantification accuracy. Excellent agreement was found between BP obtained using the full protocol and BP obtained using the dual-window protocol (for multilinear reference tissue model 2, BP [dual-window] = 0.01 + 1.00·BP [full], = 0.97; for simplified reference tissue model, BP [dual-window] = 0.05 + 0.92·BP [full], = 0.93). Simulations showed a limited impact of CBF and radiotracer clearance changes on multilinear reference tissue model parameters and SUVR. This study demonstrated accurate noninvasive kinetic modeling of F-florbetaben PET data using a dual-window acquisition, thus providing a good compromise between quantification accuracy, scan duration, and patient burden. The influence of CBF and radiotracer clearance changes on amyloid-β load estimates was small. For most clinical research applications, the SUVR approach is appropriate. However, for longitudinal studies in which maximum quantification accuracy is desired, this noninvasive dual-window acquisition with kinetic analysis is recommended.

Simulating the effect of cerebral blood flow changes on regional quantification of [18F]flutemetamol and [18F]florbetaben studies

“…The finding that DVR FLOW RLOGAN was robust against changes in CBF is in line with a previous study that found the same result for [ 11 C]PiB 5 and this robustness may be due to the linearity of the model. 24 In contrast, SRTM was found to be somewhat more sensitive to changes in CBF for both tracers, which is in agreement with work of Bullich et al 7 Their findings differ from the results reported here, in that they reported a slightly higher sensitivity of SRTM to cortical and a lower sensitivity to global CBF changes. This discrepancy may be attributed to differences in simulation design, the different cortical composite region and differences in fitter settings (such as parameter boundary values) between the studies.…”

“…This discrepancy may be attributed to differences in simulation design, the different cortical composite region and differences in fitter settings (such as parameter boundary values) between the studies. 7,22 In the present study, parameter boundary values were optimised to prevent fit parameters from becoming undetermined (i.e. k 2 and BP ND ), in particular for lower levels of amyloid.…”

“…3 The effect of CBF changes on amyloid load quantification has been assessed previously for [ 11 C]PiB, [ 18 F] florbetaben and semi-quantitative measures of [ 18 F] florbetapir. 5,7,18 These studies showed that large cortical CBF reductions resulted in a maximum change of AE10% in SUVr. For large global CBF reductions, a larger bias was observed for [ 11 C]PIB as compared with [ 18 F]florbetaben and [ 18 F]florbetapir.…”

“…As a compromise between the protocols mentioned above, dynamic data acquisitions from a dual-time-window protocol have gained attention, in which data are acquired separately for early and late phases of tracer uptake to reduce overall scanning time, maintain high quantitative accuracy and provide tracer delivery information. 7,8 Cerebral blood flow declines with age and differs per brain region. 9 Compared with young adults (25 years), elderly (late 70s) can present with up to 25% CBF reductions, with an average annual CBF decline in grey matter of approximately 0.5%.…”

“…For large global CBF reductions, a larger bias was observed for [ 11 C]PIB as compared with [ 18 F]florbetaben and [ 18 F]florbetapir. 5,7,18 These between tracer differences are to be expected due to differences in tracer kinetics and corresponding equilibrium times. However, the effect of CBF changes on quantification of [ 18 F]flutemetamol scans remains unknown, just as the potential effects of such changes on novel dual-time-window protocols.…”