Quantification of PET infusion studies without true equilibrium: A tissue clearance correction

Abstract

In some positron emission tomography (PET) studies, a reversibly binding radioligand is administered as a constant infusion to establish true equilibrium for quantification. This approach reduces scanning time and simplifies data analysis, but assumes similar behavior of the radioligand in plasma across the study population to establish true equilibrium in all subjects. Bias in outcome measurements can result if this assumption is not met. This work developed and validated a correction that reduces bias in total distribution volume ( VT) estimates when true equilibrium is not present. This correction, termed tissue clearance correction (TCC), took the form [Formula: see text], where β is the radioligand clearance rate in tissue, γ is a radiotracer-specific constant, and VT(A) is the apparent VT. Simulations characterized the robustness of TCC across imperfect values of γ and β and demonstrated reduction to false positive rates. This approach was validated with human infusion data for three radiotracers: [18F]FPEB, (−)-[18F]flubatine, and [11C]UCB-J. TCC reduced bias in VT estimates for all radiotracers and significantly reduced intersubject variance in VT for [18F]FPEB data in some brain regions. Thus, TCC improves quantification of data acquired from PET infusion studies.

Longitudinal imaging of metabotropic glutamate 5 receptors during early and extended alcohol abstinence

“…To correct for non-equilibrium conditions a tissue clearance correction was applied to all regional V T equilibrium estimates in all subjects using the [ 18 F]FPEB-specific value of γ = 4.3 min cm 3 / mL [41]. This correction significantly reduced variance in both study groups (Morgan-Pitman test), consistent with the initial validation results [41].…”

Longitudinal amyloid and tau PET imaging in Alzheimer's disease: A systematic review of methodologies and factors affecting quantification

“…Variability in cerebral blood flow (CBF) directly influences tracer delivery and clearance, 87,88 and can, therefore, add uncertainty, particularly to measures from static acquisitions where it is assumed a pseudo-equilibrium has been reached. [89][90][91] Longitudinal studies might be particularly impacted by the presence of CBF changes over time, 91 which may occur with increasing age, disease progression, and therapeutic interventions.…”

“…Variability in cerebral blood flow (CBF) directly influences tracer delivery and clearance, 87,88 and can, therefore, add uncertainty, particularly to measures from static acquisitions where it is assumed a pseudo‐equilibrium has been reached 89–91 …”

Improving SUVR quantification by correcting for radiotracer clearance in tissue

“…Previous work has developed a correction for this bias that is applicable if the conditions for transient equilibrium are met. 3,13 Transient equilibrium is established when the rate of clearance of the radiotracer in all tissues and plasma is not only small, but also identical ( β=βnormalT). While this paradigm is useful in the context of an imperfect tracer infusion, the conditions for transient equilibrium are largely unmet after most bolus injections.…”

“…This approach extends a correction developed for effects of non-equilibrium tracer clearance on late time tissue-to-plasma activity in bolus-infusion protocols. 13 The theory behind this correction was extended to adapt it for correcting SUVR after a bolus injection. Next, the SUVR correction was validated using simulations and human data for the PET radiotracers [ 11 C]LSN3172176, which has high affinity for the muscarinic (subtype M1) acetylcholine receptors, 14 and evaluation in human datasets with [ 18 F]FE-PE2I, which has high affinity for dopamine transporter (DAT).…”