Consideration of transmembrane water exchange in pharmacokinetic model significantly improves the accuracy of DCE-MRI in estimating cellular density: A pilot study in glioblastoma multiforme

Transmembrane water exchange (TWE) including transcytolemmal water exchange and transvascular water exchange is involved in many in vivo measurements and makes different contributions to the measuring results. In this study, we focus on the potential influence of TWE on the cell density parameter, intracellular water mole fraction pi, derived by dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) which has been reported as a technique to characterize perfusion and vascularization of tissues, but its accuracy in measuring cell density (or interstitial space) has been questioned. Sixteen patients with glioblastoma multiforme (GBM) were enrolled since GBM shows strong intratumor heterogeneity in both cell density and TWE. All the subjects were collected with DCE-MRI and apparent diffusion coefficient (ADC) map. The latter was considered as a valid surrogate of cell density. Extended Tofts (eTofts) model considering TWE as infinitely large variables and shutter-speed model (SSM) considering TWE as finite ones were used to fit DCE-MRI data. Monte Carlo (MC) and finite difference (FD) methods were used to simulate the influence of TWE on DCE-MRI-derived pi and ADC, respectively. The eTofts model shows a significant overestimation of pi in comparison with SSM in GBM (P < 0.001), which is in accordance with MC simulations, and this overestimation shows dependence on the intra-to-extracellular water exchange rate constant (kio). Significant negative correlations between ADC and SSM-derived pi were found in both voxel-wise analyses (t-test P < 0.001, average r = −0.74) and inter-subject comparisons (r = −0.63, P = 0.009). But no consistent voxel-wise correlations (P > 0.05) and a weaker inter-subject negative correlation (r = −0.56, P = 0.02) were found between ADC and eTofts-derived pi. Further experimental and FD results revealed that kio made a limited contribution to ADC values in the physiological kio range in GBM, supporting ADC as a valid biomarker of cell density. These results suggest that the DCE-MRI pharmacokinetic shutter-speed model could significantly improve its accuracy in cell density estimation because of the considering transmembrane water exchange.