234 Kinetic analysis of dynamic 11C-verapamil PET study: Compartmental v adaptive mixture models comparison

Abstract

Background: Temporal aspects of dynamic positron emission tomography (PET) generally rely on compartmental models (CM), with questionable assumptions to summarise functional kinetics of injected radio-tracers in living tissues. Material and Methods: The tracer signal time-course is a combination of vascular delivery and tissue retention effects which do not always satisfy the assumptions of tissue homogeneity and instant mixing within compartments required by the CM. This tissue activity time-course can typically be expressed as a convolution between the signal of the tracer in the arterial supply and the tissue residue function. The residue represents the amount of tracer remaining in the tissue and provides a description of the tracer kinetics measurable by the PET scan. Thus, in statistical terms, the residue can be thought of as a survival function for the residence of the tracer in the tissue which does not require the physiological constraints intrinsic in the exponential-like residue needed for CM. Accordingly more flexible novel approaches − nonparametric and later adaptive mixture models − to estimate the residue based on a piecewise linear form have been developed. The new approaches have been successfully probed on two of the most well-established PET radiotracers, O-H2O and F-fluorodeoxyglucose, used for perfusion and glucose metabolism respectively. This study shows the extension of the new approaches to the multiple-drug resistance transporter P-glycoprotein (P-gp) highly present at the blood–brain barrier (BBB) using C-Verapamil (Vp) in healthy humans before and after inhibition of the P-gp by Cyclosporine (CsA) infusion. Previous PET studies on measuring BBB activity by CsA infusion using Vp have revealed difficulties for the CM to recover metabolic information as they require a full understanding of the tracers metabolisation in the tissue, which is still not certain for Vp. This problem is especially latent when the inhibition of the P-gp allows the tracer through the BBB where it is retained once at the brain tissue level. Results: This work examines and evaluate adaptive mixture model as an alternative to conventional compartment techniques in recovering metabolic information from dynamic PET studies with less biological restrictions. Key bioparameters such as flux, flow, blood volume and volume of distribution from the two different approaches are compared. Cross-validation is used to make regional comparisons and evaluate the fit of the two different estimated residue functions to the tissue activity curves. Conclusions: The accuracy of the standard models for Vp PET studies can be questionable, likely because behaviour of Vp metabolites in tissue is still unclear. Significant statistical evidence in favour of the new adaptivemixture models has been found. Supported by Science Foundation Ireland under SFI-PI 11/27 and by the National Institute of Health (NCI) under PO1-CA-42045.