Evaluation of pharmacokinetic models for perfusion imaging with dynamic contrast-enhanced magnetic resonance imaging in porcine skeletal muscle using low-molecular-weight contrast agents.

PURPOSE: Pharmacokinetic models for perfusion quantification with a low-molecular-weight contrast agent (LMCA) in skeletal muscle using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated. METHODS: Tissue perfusion was measured in seven regions of interest (ROIs) placed in the total hind leg supplied by the femoral artery in seven female pigs. DCE-MRI was performed using a 3D gradient echo sequence with k-space sharing. The sequence was acquired twice, first after LMCA and then after blood pool contrast agent injection. Blood flow was augmented by continuous infusion of the vasodilator adenosine into the femoral artery, resulting in up to four times increased blood flow. The results obtained with several LMCA models were compared with those of a two-compartment blood pool model (2CBPM) consisting of a capillary and an arteriolar compartment. Measurements performed with a Doppler flow probe placed at the femoral artery served as ground truth. RESULTS: The two-compartment exchange model extended by an arteriolar compartment (E2CXM) showed the highest fit quality of all LMCA models and the most significant correlation with the Doppler measurements, r = 0.78 (P < 0.001). The best correspondence between the capillary perfusion measurements of the LMCA models and those of the 2CBPM was found with the E2CXM (slope of the regression line equal to 1, r = 0.85, P < 0.001). The results for the clinical patient data corresponded very well with the results obtained in the animal experiments. CONCLUSIONS: Double-contrast agent DCE-MRI in combination with the E2CXM yields the most reliable results and can be used in clinical routine. Magn Reson Med 79:3154-3162, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Simultaneous multislice acquisition with multi-contrast segmented EPI for separation of signal contributions in dynamic contrast-enhanced imaging.

We present a method to efficiently separate signal in magnetic resonance imaging (MRI) into a base signal S0, representing the mainly T1-weighted component without T2*-relaxation, and its T2*-weighted counterpart by the rapid acquisition of multiple contrasts for advanced pharmacokinetic modelling. This is achieved by incorporating simultaneous multislice (SMS) imaging into a multi-contrast, segmented echo planar imaging (EPI) sequence to allow extended spatial coverage, which covers larger body regions without time penalty. Simultaneous acquisition of four slices was combined with segmented EPI for fast imaging with three gradient echo times in a preclinical perfusion study. Six female domestic pigs, German-landrace or hybrid-form, were scanned for 11 minutes respectively during administration of gadolinium-based contrast agent. Influences of reconstruction methods and training data were investigated. The separation into T1- and T2*-dependent signal contributions was achieved by fitting a standard analytical model to the acquired multi-echo data. The application of SMS yielded sufficient temporal resolution for the detection of the arterial input function in major vessels, while anatomical coverage allowed perfusion analysis of muscle tissue. The separation of the MR signal into T1- and T2*-dependent components allowed the correction of susceptibility related changes. We demonstrate a novel sequence for dynamic contrast-enhanced MRI that meets the requirements of temporal resolution (Δt < 1.5 s) and image quality. The incorporation of SMS into multi-contrast, segmented EPI can overcome existing limitations of dynamic contrast enhancement and dynamic susceptibility contrast methods, when applied separately. The new approach allows both techniques to be combined in a single acquisition with a large spatial coverage.

Validation of Blood Volume Fraction Quantification with 3D Gradient Echo Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Porcine Skeletal Muscle.

The purpose of this study was to assess the accuracy of fractional blood volume (vb) estimates in low-perfused and low-vascularized tissue using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The results of different MRI methods were compared with histology to evaluate the accuracy of these methods under clinical conditions. vb was estimated by DCE-MRI using a 3D gradient echo sequence with k-space undersampling in five muscle groups in the hind leg of 9 female pigs. Two gadolinium-based contrast agents (CA) were used: a rapidly extravasating, extracellular, gadolinium-based, low-molecular-weight contrast agent (LMCA, gadoterate meglumine) and an extracellular, gadolinium-based, albumin-binding, slowly extravasating blood pool contrast agent (BPCA, gadofosveset trisodium). LMCA data were evaluated using the extended Tofts model (ETM) and the two-compartment exchange model (2CXM). The images acquired with administration of the BPCA were used to evaluate the accuracy of vb estimation with a bolus deconvolution technique (BD) and a method we call equilibrium MRI (EqMRI). The latter calculates the ratio of the magnitude of the relaxation rate change in the tissue curve at an approximate equilibrium state to the height of the same area of the arterial input function (AIF). Immunohistochemical staining with isolectin was used to label endothelium. A light microscope was used to estimate the fractional vascular area by relating the vascular region to the total tissue region (immunohistochemical vessel staining, IHVS). In addition, the percentage fraction of vascular volume was determined by multiplying the microvascular density (MVD) with the average estimated capillary lumen, [Formula: see text], where d = 8µm is the assumed capillary diameter (microvascular density estimation, MVDE). Except for ETM values, highly significant correlations were found between most of the MRI methods investigated. In the cranial thigh, for example, the vb medians (interquartile range, IQRs) of IHVS, MVDE, BD, EqMRI, 2CXM and ETM were vb = 0.7(0.3)%, 1.1(0.4)%, 1.1(0.4)%, 1.4(0.3)%, 1.2(1.8)% and 0.1(0.2)%, respectively. Variances, expressed by the difference between third and first quartiles (IQR) were highest for the 2CXM for all muscle groups. High correlations between the values in four muscle groups-medial, cranial, lateral thigh and lower leg - estimated with MRI and histology were found between BD and EqMRI, MVDE and 2CXM and IHVS and ETM. Except for the ETM, no significant differences between the vb medians of all MRI methods were revealed with the Wilcoxon rank sum test. The same holds for all muscle regions using the 2CXM and MVDE. Except for cranial thigh muscle, no significant difference was found between EqMRI and MVDE. And except for the cranial thigh and the lower leg muscle, there was also no significant difference between the vb medians of BD and MVDE. Overall, there was good vb agreement between histology and the BPCA MRI methods and the 2CXM LMCA approach with the exception of the ETM method. Although LMCA models have the advantage of providing excellent curve fits and can in principle determine more physiological parameters than BPCA methods, they yield more inaccurate results.

Validation of Interstitial Fractional Volume Quantification by Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Porcine Skeletal Muscles.

OBJECTIVES: The aim of our study was to assess the accuracy of fractional interstitial volume determination in low perfused and low vascularized tissue by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: The fractional interstitial volume (ve) was determined in the medial thigh muscle of 12 female pigs by using a 3-dimensional gradient echo sequence with k-space sharing and administering gadolinium-based contrast agent (gadoterate meglumine). Analysis was performed using 3 pharmacokinetic models: the simple Tofts model (TM), the extended TM (ETM), and the 2-compartment exchange model (2CXM). We investigated the effect of varying acquisition durations (ADs) on the model parameter estimates of the 3 models and compared the ve values with the results of histological examinations of muscle sections of the medial thigh muscle. RESULTS: Histological measurements yielded a median value (25%-75% quartile) of 4.8% (3.7%-6.2%) for ve. The interstitial fractional volume determined by DCE-MRI was comparable to the histological results but varied strongly with AD for the TM and ETM. For the TM and the ETM, the results were virtually the same. Choosing arterial hematocrit to Hcta = 0.4, the lowest median ve value determined by DCE-MRI was 5.2% (3.3%-6.1%) for the ETM at a 6-minute AD. The maximum ve value determined with the ETM at a 15-minute AD was 7.7% (4.5%-9.0%). The variation with AD of median ve values obtained with the 2CXM was much smaller: 6.2% (3.1%-9.2%) for the 6-minute AD and 6.3% (4.3%-9.8%) for the 15-minute AD. The best fit for the 2CXM was found at the 10-minute AD with ve values of 6.6% (3.7%-8.2%). No significant correlation between the histological and any DCE-MRI modeling results was found. Considering the expected accuracy of histological measurements, the medians of the MR modeling results were in good agreement with the histological prediction. A parameter determination uncertainty was identified with the use of the TMs. This is due to underfitting and has a major effect even on the analysis of tissues with low vascularization and low perfusion, where the estimated ve values depend on the AD. For the TM and ETM, the results best matched the histological measurements for an AD of 6 minutes. CONCLUSIONS: Owing to more fitting parameters, the 2CXM yielded better fits and the median interstitium-to-plasma rate constant kep was less depending on the AD; however, the uncertainty expressed by the 25% to 75% quartile range was found to be larger. An AD of 10 minutes was needed for the 2CXM to achieve accuracy comparable to those of the TMs with shorter ADs.