Direct 4D parametric imaging for linearized models of reversibly binding PET tracers using generalized AB-EM reconstruction

Due to high noise levels in the voxel kinetics, development of reliable parametric imaging algorithms remains one of most active areas in dynamic brain PET imaging, which in the vast majority of cases involves receptor/transporter studies with reversibly binding tracers. As such, the focus of this work has been to develop a novel direct 4D parametric image reconstruction scheme for such tracers. Based on a relative equilibrium (RE) graphical analysis formulation (Zhou et al 2009b Neuroimage 44 661-70), we developed a closed-form 4D EM algorithm to directly reconstruct distribution volume (DV) parametric images within a plasma input model, as well as DV ratio (DVR) images within a reference tissue model scheme (wherein an initial reconstruction was used to estimate the reference tissue time-activity curves). A particular challenge with the direct 4D EM formulation is that the intercept parameters in graphical (linearized) analysis of reversible tracers (e.g. Logan or RE analysis) are commonly negative (unlike for irreversible tracers, e.g. using Patlak analysis). Subsequently, we focused our attention on the AB-EM algorithm, derived by Byrne (1998, Inverse Problems 14 1455-67) to allow inclusion of prior information about the lower (A) and upper (B) bounds for image values. We then generalized this algorithm to the 4D EM framework, thus allowing negative intercept parameters. Furthermore, our 4D AB-EM algorithm incorporated and emphasized the use of spatially varying lower bounds to achieve enhanced performance. As validation, the means of parameters estimated from 55 human (11)C-raclopride dynamic PET studies were used for extensive simulations using a mathematical brain phantom. Images were reconstructed using conventional indirect as well as proposed direct parametric imaging methods. Noise versus bias quantitative measurements were performed in various regions of the brain. Direct 4D EM reconstruction resulted in notable qualitative and quantitative accuracy improvements (over 35% noise reduction, with matched bias, in both plasma and reference-tissue input models). Similar improvements were also observed in the coefficient of variation of the estimated DV and DVR values even for relatively low uptake cortical regions, suggesting the enhanced ability for robust parameter estimation. The method was also tested on a 90 min (11)C-raclopride patient study performed on the high-resolution research tomograph wherein the proposed method was shown across a variety of regions to outperform the conventional method in the sense that for a given DVR value, improved noise levels were observed.