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Interventional studies for validation of non-invasive dual-tracer PET
T60
Poster Presentations / NeuroImage 31 (2006) T44 – T186
Poster Presentation No.: 017
Interventional studies for validation of non-invasive dual-tracer PET Robert A. Koeppe, A. Joshi J. Fessler University of Michigan, Ann Arbor, MI, USA
Introduction: We have previously reported PET studies demonstrating the feasibility of administering two different [11C]radiolabeled tracers in a single PET acquisition, using either arterial blood samples (Koppe et al., 2001) or a non-invasive reference-region-based protocol not requiring arterial sampling [2]. The reference-region approach simplifies the procedure for both volunteer and investigator, making dualtracer PET more practical for routine application. The present study reports non-invasive dual-tracer PET studies that validate the approach for detecting and quantifying pharmacologically induced changes in radioligand binding. We examine sensitivity and specificity of model parameters changes following a partial blocking dose of cold ligand. Theory: The key assumption required for non-invasive dual-tracer PET is that the first radiotracer must equilibrate rapidly such that its reference-region reaches steady-state prior to injection of the 2nd radiotracer. Assuming steady-state in the reference-region at all times postinjection of the 2nd tracer, model equations predict the radioactivity concentration for the first tracer throughout the remainder of the dualtracer study. This concentration time course is subtracted voxel-wise from the dual-tracer data, leaving dynamic images of the second radiotracer alone, which are then analyzed by a standard reference-region approach. Methods: PET studies were performed on 20 normal volunteers using one of two radiotracers pairs: [11C]flumazenil, FMZ plus [11C]dihydrotetrabenazine, DTBZ (n = 12), or [11C]FMZ plus [11C]N-methylpiperidinyl propionate, PMP (n = 8). Both injection orders were tested for FMZ + DTBZ (FMZ first, n = 8; DTBZ first, n = 4), while FMZ was always injected first for FMZ + PMP since PMP is trapped irreversibly. Dynamic scans were acquired for 80 min; half the subjects with 20 min offsets between injections, half with 30 min offsets. Each subject received 2 dual-tracer studies separated by 1 – 10 days: ‘‘baseline’’ and ‘‘intervention’’. The order of studies was counter-balanced, with half of each group receiving the ‘‘baseline’’ study first, half receiving ‘‘intervention’’ first. The intervention was a bolus + continuous infusion of non-radioactive flumazenil (0.005 mg/kg body weight followed by 0.0001 mg/kg/min). The bolus was given just prior to administration of the first radiotracer, with infusion continuing throughout the 80 min study. Kinetic analyses were performed as described previously (Koeppe et al., 2004), yielding parameter estimates for both ‘‘baseline’’ and ‘‘intervention’’ studies of K1R and BP for FMZ and DTBZ, and K1R, k2, and k3 for PMP. Results: For FMZ:DTBZ studies (n = 8), the ratios of ‘‘intervention’’/‘‘baseline’’ parameter estimates were: FMZ, BP = 0.62 T 0.10, K1R = 1.13 T 0.09; DTBZ, BP = 1.04 T 0.06, K1R = 1.01 T 0.09. For DTBZ:FMZ studies (n = 4), the ratios of parameter estimates were: DTBZ, BP = 1.05 T 0.11, K1R = 0.96 T 0.06; FMZ BP = 0.61 T 0.06, K1R = 1.08 T 0.09. For FMZ:PMP (n = 8) studies, the ratios of parameter estimates were: FMZ, BP = 0.63 T 0.08, K1R = 1.15 T 0.08; PMP, k3 = 0.95 T 0.07, K1R = 1.03 T 0.10, k2 = 1.00 T 0.06. In each group, there was a large (expected) and consistent decrease in FMZ binding during the ‘‘intervention’’ study (¨40%), a small unexpected increase in FMZ K1R, and minimal change in DTBZ or PMP parameters. Conclusions: Dual-tracer PET studies performed with a non-invasive protocol can, following pharmacological intervention, detect changes in model parameters with both adequate sensitivity and specificity. References: Koeppe et al., 2001. J. Cereb Blood Flow Metab 21, 1480 – 1492. Koeppe et al., 2004. Dual-tracer PET studies without arterial sampling. NeuroImage 22 (Suppl 2), T115. doi:10.1016/j.neuroimage.2006.04.051
Poster Presentations / NeuroImage 31 (2006) T44 – T186
Poster Presentation No.: 017
Interventional studies for validation of non-invasive dual-tracer PET Robert A. Koeppe, A. Joshi J. Fessler University of Michigan, Ann Arbor, MI, USA
Introduction: We have previously reported PET studies demonstrating the feasibility of administering two different [11C]radiolabeled tracers in a single PET acquisition, using either arterial blood samples (Koppe et al., 2001) or a non-invasive reference-region-based protocol not requiring arterial sampling [2]. The reference-region approach simplifies the procedure for both volunteer and investigator, making dualtracer PET more practical for routine application. The present study reports non-invasive dual-tracer PET studies that validate the approach for detecting and quantifying pharmacologically induced changes in radioligand binding. We examine sensitivity and specificity of model parameters changes following a partial blocking dose of cold ligand. Theory: The key assumption required for non-invasive dual-tracer PET is that the first radiotracer must equilibrate rapidly such that its reference-region reaches steady-state prior to injection of the 2nd radiotracer. Assuming steady-state in the reference-region at all times postinjection of the 2nd tracer, model equations predict the radioactivity concentration for the first tracer throughout the remainder of the dualtracer study. This concentration time course is subtracted voxel-wise from the dual-tracer data, leaving dynamic images of the second radiotracer alone, which are then analyzed by a standard reference-region approach. Methods: PET studies were performed on 20 normal volunteers using one of two radiotracers pairs: [11C]flumazenil, FMZ plus [11C]dihydrotetrabenazine, DTBZ (n = 12), or [11C]FMZ plus [11C]N-methylpiperidinyl propionate, PMP (n = 8). Both injection orders were tested for FMZ + DTBZ (FMZ first, n = 8; DTBZ first, n = 4), while FMZ was always injected first for FMZ + PMP since PMP is trapped irreversibly. Dynamic scans were acquired for 80 min; half the subjects with 20 min offsets between injections, half with 30 min offsets. Each subject received 2 dual-tracer studies separated by 1 – 10 days: ‘‘baseline’’ and ‘‘intervention’’. The order of studies was counter-balanced, with half of each group receiving the ‘‘baseline’’ study first, half receiving ‘‘intervention’’ first. The intervention was a bolus + continuous infusion of non-radioactive flumazenil (0.005 mg/kg body weight followed by 0.0001 mg/kg/min). The bolus was given just prior to administration of the first radiotracer, with infusion continuing throughout the 80 min study. Kinetic analyses were performed as described previously (Koeppe et al., 2004), yielding parameter estimates for both ‘‘baseline’’ and ‘‘intervention’’ studies of K1R and BP for FMZ and DTBZ, and K1R, k2, and k3 for PMP. Results: For FMZ:DTBZ studies (n = 8), the ratios of ‘‘intervention’’/‘‘baseline’’ parameter estimates were: FMZ, BP = 0.62 T 0.10, K1R = 1.13 T 0.09; DTBZ, BP = 1.04 T 0.06, K1R = 1.01 T 0.09. For DTBZ:FMZ studies (n = 4), the ratios of parameter estimates were: DTBZ, BP = 1.05 T 0.11, K1R = 0.96 T 0.06; FMZ BP = 0.61 T 0.06, K1R = 1.08 T 0.09. For FMZ:PMP (n = 8) studies, the ratios of parameter estimates were: FMZ, BP = 0.63 T 0.08, K1R = 1.15 T 0.08; PMP, k3 = 0.95 T 0.07, K1R = 1.03 T 0.10, k2 = 1.00 T 0.06. In each group, there was a large (expected) and consistent decrease in FMZ binding during the ‘‘intervention’’ study (¨40%), a small unexpected increase in FMZ K1R, and minimal change in DTBZ or PMP parameters. Conclusions: Dual-tracer PET studies performed with a non-invasive protocol can, following pharmacological intervention, detect changes in model parameters with both adequate sensitivity and specificity. References: Koeppe et al., 2001. J. Cereb Blood Flow Metab 21, 1480 – 1492. Koeppe et al., 2004. Dual-tracer PET studies without arterial sampling. NeuroImage 22 (Suppl 2), T115. doi:10.1016/j.neuroimage.2006.04.051