Water exchange and inflow affect the accuracy of T1-GRE blood volume measurements: implications for the evaluation of tumor angiogenesis.

The goal of this study was to determine the degree to which vascular water exchange and blood flowing into an imaging slice affect the accuracy of blood volume measurements of brain and tumor tissue when using intravascular T(1) contrast agents. The study was performed using 2D and 3D gradient-echo imaging sequences, since these are two of the most commonly used MRI methods used to evaluate tissue blood volume fraction. Computer simulations were performed and measurements made in a rat 9L gliosarcoma brain tumor model. The computer simulations demonstrate that, with either water exchange or inflow effects alone, the dependence on the physiologic and imaging parameters can be well characterized and therefore potentially offset. In the exchange only case, the parametric dependence of 3D simulations suggest that the best accuracy is achieved with high flip angles, short TR, and low blood contrast agent concentrations. However, for a 2D GRE sequence which is influenced by both water exchange and inflow, the simulations predict that the error trend as a function of the imaging and physiologic parameters is unpredictable and therefore difficult to compensate. With both 2D and 3D GRE the measured blood volume data in rat brain and tumor tissue demonstrate tissue-specific trends, which reflect differences in the considered physiologic parameters. The experimental data strongly support the computer simulations and also indicate that minimization of the physiological effects by proper selection of imaging parameters, contrast concentration, and volume calculation methods is crucial for accurate assessment of absolute blood volume fraction.

MR-derived cerebral blood volume maps: issues regarding histological validation and assessment of tumor angiogenesis.

In an effort to develop MRI methods for the evaluation of tumor angiogenesis (new blood vessel formation), MRI-derived cerebral blood volume (CBV) information has been compared to histologic measures of microvessel density (MVD). Although MVD is a standard marker of angiogenesis, it is not a direct correlate of the volume measurements made with MRI, and therefore inappropriate for the development and validation of the MR techniques. Therefore, the goal of this study was to develop an approach by which MR measurements of CBV can be directly correlated. To this end, dynamic susceptibility contrast (DSC) MRI experiments were performed in six Fisher rats implanted with 9L gliosarcoma brain tumors. Subsequently, the circulation was perfused with a latex compound (Microfil), after which 50-microm tissue sections were analyzed for vessel count, diameter, and the fraction of area comprised of vessels. The results demonstrate that while fractional area (FA) does not provide a good measure of CBV, FA corrected for section thickness effects does. Whereas the FA in normal brain was found to be 13.03 +/- 1.83% the corrected FA, or fractional volume (FV), was 1.89 +/- 0.39%, a value in agreement with those reported in the literature for normal brain. Furthermore, while no significant difference was found between normal brain and tumor FA (P = 0.55), the difference was significant for FV (P = 0.036), as would be expected. And only with FV does a correlation with the MRI-derived CBV become apparent (r(S) = 0.74). There was strong correlation (r(s) = 0.886) between the tumor / normal blood volume ratios as estimated by each technique, although the MR-ratio (1.56 +/- 0.29) underestimated the histologic-ratio (2.35 +/- 0.75). Thus, the correlation of MRI CBV methods requires a measurement of fractional vessel area and correction of this area for section thickness effects. This new independent correlative measure should enable efficient and accurate progress in the development of MRI methods to evaluate tumor angiogenesis.