A model-constrained Monte Carlo method for blind arterial input function estimation in dynamic contrast-enhanced MRI:...

Accurate quantification of pharmacokinetic model parameters in tracer kinetic imaging experiments requires correspondingly accurate determination of the arterial input function (AIF). Despite significant effort expended on methods of directly measuring patient-specific AIFs in modalities as diverse as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), dynamic positron emission tomography (PET), and perfusion computed tomography (CT), fundamental and technical difficulties have made consistent and reliable achievement of that goal elusive. Here, we validate a new algorithm for AIF determination, the Monte Carlo blind estimation (MCBE) method (which is described in detail and characterized by extensive simulations in a companion paper), by comparing AIFs measured in DCE-MRI studies of eight brain tumor patients with results of blind estimation. Blind AIFs calculated with the MCBE method using a pool of concentration-time curves from a region of normal brain tissue were found to be quite similar to the measured AIFs, with statistically significant decreases in fit residuals observed in six of eight patients. Biases between the blind and measured pharmacokinetic parameters were the dominant source of error. Averaged over all eight patients, the mean biases were +7% in K(trans), 0% in k(ep), -11% in v(p) and +10% in v(e). Corresponding uncertainties (median absolute deviation from the best fit line) were 0.0043 min(-1) in K(trans), 0.0491 min(-1) in k(ep), 0.29% in v(p) and 0.45% in v(e). The use of a published population-averaged AIF resulted in larger mean biases in three of the four parameters (-23% in K(trans), -22% in k(ep), -63% in v(p)), with the bias in v(e) unchanged, and led to larger uncertainties in all four parameters (0.0083 min(-1) in K(trans), 0.1038 min(-1) in k(ep), 0.31% in v(p) and 0.95% in v(e)). When blind AIFs were calculated from a region of tumor tissue, statistically significant decreases in fit residuals were observed in all eight patients despite larger deviations of these blind AIFs from the measured AIFs. The observed decrease in root-mean-square fit residuals between the normal brain and tumor tissue blind AIFs suggests that the local blood supply in tumors is measurably different from that in normal brain tissue and that the proposed method is able to discriminate between the two. We have shown the feasibility of applying the MCBE algorithm to DCE-MRI data acquired in brain, finding generally good agreement with measured AIFs and decreased biases and uncertainties relative to the use of a population-averaged AIF. These results demonstrate that the MCBE algorithm is a useful alternative to direct AIF measurement in cases where acquisition of high-quality arterial input function data is difficult or impossible.