Ergys Subashi

Lung perfusion imaging in small animals using 4D micro-CT at heartbeat temporal resolution

PURPOSE Quantitative in vivo imaging of lung perfusion in rodents can provide critical information for preclinical studies. However, the combined challenges of high temporal and spatial resolution have made routine quantitative perfusion imaging difficult in small animals. The purpose of this work is to demonstrate 4D micro-CT for perfusion imaging in rodents at heartbeat temporal resolution and isotropic spatial resolution. METHODS We have recently developed a dual tube/detector micro-CT scanner that is well suited to capture first pass kinetics of a bolus of contrast agent used to compute perfusion information. Our approach is based on the paradigm that similar time density curves can be reproduced in a number of consecutive, small volume injections of iodinated contrast agent at a series of different angles. This reproducibility is ensured by the high-level integration of the imaging components of our system with a microinjector, a mechanical ventilator, and monitoring applications. Sampling is controlled through a biological pulse sequence implemented in LABVIEW. Image reconstruction is based on a simultaneous algebraic reconstruction technique implemented on a graphic processor unit. The capabilities of 4D micro-CT imaging are demonstrated in studies on lung perfusion in rats. RESULTS We report 4D micro-CT imaging in the rat lung with a heartbeat temporal resolution (approximately 150 ms) and isotropic 3D reconstruction with a voxel size of 88 microm based on sampling using 16 injections of 50 microL each. The total volume of contrast agent injected during the experiments (0.8 mL) was less than 10% of the total blood volume in a rat. This volume was not injected in a single bolus, but in multiple injections separated by at least 2 min interval to allow for clearance and adaptation. We assessed the reproducibility of the time density curves with multiple injections and found that these are very similar. The average time density curves for the first eight and last eight injections are slightly different, i.e., for the last eight injections, both the maximum of the average time density curves and its area under the curve are decreased by 3.8% and 7.2%, respectively, relative to the average time density curves based on the first eight injections. The radiation dose associated with our 4D micro-CT imaging is 0.16 Gy and is therefore in the range of a typical micro-CT dose. CONCLUSIONS 4D micro-CT-based perfusion imaging demonstrated here has immediate application in a wide range of preclinical studies such as tumor perfusion, angiogenesis, and renal function. Although our imaging system is in many ways unique, we believe that our approach based on the multiple injection paradigm can be used with the newly developed flat-panel slip-ring-based micro-CT to increase their temporal resolution in dynamic perfusion studies.

A comparison of radial keyhole strategies for high spatial and temporal resolution 4D contrast-enhanced MRI in small animal tumor models.

PURPOSE Dynamic contrast-enhanced (DCE) MRI has been widely used as a quantitative imaging method for monitoring tumor response to therapy. The simultaneous challenges of increasing temporal and spatial resolution in a setting where the signal from the much smaller voxel is weaker have made this MR technique difficult to implement in small-animal imaging. Existing protocols employed in preclinical DCE-MRI acquire a limited number of slices resulting in potentially lost information in the third dimension. This study describes and compares a family of four-dimensional (3D spatial + time), projection acquisition, radial keyhole-sampling strategies that support high spatial and temporal resolution. METHODS The 4D method is based on a RF-spoiled, steady-state, gradient-recalled sequence with minimal echo time. An interleaved 3D radial trajectory with a quasi-uniform distribution of points in k-space was used for sampling temporally resolved datasets. These volumes were reconstructed with three different k-space filters encompassing a range of possible radial keyhole strategies. The effect of k-space filtering on spatial and temporal resolution was studied in a 5 mM CuSO(4) phantom consisting of a meshgrid with 350-μm spacing and in 12 tumors from three cell lines (HT-29, LoVo, MX-1) and a primary mouse sarcoma model (three tumors∕group). The time-to-peak signal intensity was used to assess the effect of the reconstruction filters on temporal resolution. As a measure of heterogeneity in the third dimension, the authors analyzed the spatial distribution of the rate of transport (K(trans)) of the contrast agent across the endothelium barrier for several different types of tumors. RESULTS Four-dimensional radial keyhole imaging does not degrade the system spatial resolution. Phantom studies indicate there is a maximum 40% decrease in signal-to-noise ratio as compared to a fully sampled dataset. T1 measurements obtained with the interleaved radial technique do not differ significantly from those made with a conventional Cartesian spin-echo sequence. A bin-by-bin comparison of the distribution of the time-to-peak parameter shows that 4D radial keyhole reconstruction does not cause significant temporal blurring when a temporal resolution of 9.9 s is used for the subsamples of the keyhole data. In vivo studies reveal substantial tumor heterogeneity in the third spatial dimension that may be missed with lower resolution imaging protocols. CONCLUSIONS Volumetric keyhole imaging with projection acquisition provides a means to increase spatiotemporal resolution and coverage over that provided by existing 2D Cartesian protocols. Furthermore, there is no difference in temporal resolution between the higher spatial resolution keyhole reconstruction and the undersampled projection data. The technique allows one to measure complex heterogeneity of kinetic parameters with isotropic, microscopic spatial resolution.

An analysis of the uncertainty and bias in DCE-MRI measurements using the spoiled gradient-recalled echo pulse sequence

PURPOSE The pharmacokinetic parameters derived from dynamic contrast-enhanced (DCE) MRI have been used in more than 100 phase I trials and investigator led studies. A comparison of the absolute values of these quantities requires an estimation of their respective probability distribution function (PDF). The statistical variation of the DCE-MRI measurement is analyzed by considering the fundamental sources of error in the MR signal intensity acquired with the spoiled gradient-echo (SPGR) pulse sequence. METHODS The variance in the SPGR signal intensity arises from quadrature detection and excitation flip angle inconsistency. The noise power was measured in 11 phantoms of contrast agent concentration in the range [0-1] mM (in steps of 0.1 mM) and in onein vivo acquisition of a tumor-bearing mouse. The distribution of the flip angle was determined in a uniform 10 mM CuSO4 phantom using the spin echo double angle method. The PDF of a wide range of T1 values measured with the varying flip angle (VFA) technique was estimated through numerical simulations of the SPGR equation. The resultant uncertainty in contrast agent concentration was incorporated in the most common model of tracer exchange kinetics and the PDF of the derived pharmacokinetic parameters was studied numerically. RESULTS The VFA method is an unbiased technique for measuringT1 only in the absence of bias in excitation flip angle. The time-dependent concentration of the contrast agent measured in vivo is within the theoretically predicted uncertainty. The uncertainty in measuring K(trans) with SPGR pulse sequences is of the same order, but always higher than, the uncertainty in measuring the pre-injection longitudinal relaxation time (T10). The lowest achievable bias/uncertainty in estimating this parameter is approximately 20%-70% higher than the bias/uncertainty in the measurement of the pre-injection T1 map. The fractional volume parameters derived from the extended Tofts model were found to be extremely sensitive to the variance in signal intensity. The SNR of the pre-injection T1 map indicates the limiting precision with which K(trans) can be calculated. CONCLUSIONS Current small-animal imaging systems and pulse sequences robust to motion artifacts have the capacity for reproducible quantitative acquisitions with DCE-MRI. In these circumstances, it is feasible to achieve a level of precision limited only by physiologic variability.

Four‐dimensional MRI of renal function in the developing mouse

The major roles of filtration, metabolism and high blood flow make the kidney highly vulnerable to drug‐induced toxicity and other renal injuries. A method to follow kidney function is essential for the early screening of toxicity and malformations. In this study, we acquired high spatiotemporal resolution (four dimensional) datasets of normal mice to follow changes in kidney structure and function during development. The data were acquired with dynamic contrast‐enhanced MRI (via keyhole imaging) and a cryogenic surface coil, allowing us to obtain a full three‐dimensional image (isotropic resolution, 125 microns) every 7.7 s over a 50‐min scan. This time course permitted the demonstration of both contrast enhancement and clearance. Functional changes were measured over a 17‐week course (at 3, 5, 7, 9, 13 and 17 weeks). The time dimension of the MRI dataset was processed to produce unique image contrasts to segment the four regions of the kidney: cortex (CO), outer stripe (OS) of the outer medulla (OM), inner stripe (IS) of the OM and inner medulla (IM). Local volumes, time‐to‐peak (TTP) values and decay constants (DC) were measured in each renal region. These metrics increased significantly with age, with the exception of DC values in the IS and OS. These data will serve as a foundation for studies of normal renal physiology and future studies of renal diseases that require early detection and intervention. Copyright

Dynamic fractal signature dissimilarity analysis for therapeutic response assessment using dynamic contrast-enhanced MRI

PURPOSE To develop a dynamic fractal signature dissimilarity (FSD) method as a novel image texture analysis technique for the quantification of tumor heterogeneity information for better therapeutic response assessment with dynamic contrast-enhanced (DCE)-MRI. METHODS A small animal antiangiogenesis drug treatment experiment was used to demonstrate the proposed method. Sixteen LS-174T implanted mice were randomly assigned into treatment and control groups (n = 8/group). All mice received bevacizumab (treatment) or saline (control) three times in two weeks, and one pretreatment and two post-treatment DCE-MRI scans were performed. In the proposed dynamic FSD method, a dynamic FSD curve was generated to characterize the heterogeneity evolution during the contrast agent uptake, and the area under FSD curve (AUCFSD) and the maximum enhancement (MEFSD) were selected as representative parameters. As for comparison, the pharmacokinetic parameter K(trans) map and area under MR intensity enhancement curve AUCMR map were calculated. Besides the tumors mean value and coefficient of variation, the kurtosis, skewness, and classic Rényi dimensions d1 and d2 of K(trans) and AUCMR maps were evaluated for heterogeneity assessment for comparison. For post-treatment scans, the Mann-Whitney U-test was used to assess the differences of the investigated parameters between treatment/control groups. The support vector machine (SVM) was applied to classify treatment/control groups using the investigated parameters at each post-treatment scan day. RESULTS The tumor mean K(trans) and its heterogeneity measurements d1 and d2 values showed significant differences between treatment/control groups in the second post-treatment scan. In contrast, the relative values (in reference to the pretreatment value) of AUCFSD and MEFSD in both post-treatment scans showed significant differences between treatment/control groups. When using AUCFSD and MEFSD as SVM input for treatment/control classification, the achieved accuracies were 93.8% and 93.8% at first and second post-treatment scan days, respectively. In comparison, the classification accuracies using d1 and d2 of K(trans) map were 87.5% and 100% at first and second post-treatment scan days, respectively. CONCLUSIONS As quantitative metrics of tumor contrast agent uptake heterogeneity, the selected parameters from the dynamic FSD method accurately captured the therapeutic response in the experiment. The potential application of the proposed method is promising, and its addition to the existing DCE-MRI techniques could improve DCE-MRI performance in early assessment of treatment response.

4D MRI of polycystic kidneys from rapamycin‐treated Glis3‐deficient mice

Polycystic kidney disease (PKD) is a life‐threatening disease that leads to a grotesque enlargement of the kidney and significant loss of function. Several imaging studies with MRI have demonstrated that cyst size in polycystic kidneys can determine disease severity and progression. In the present study, we found that, although kidney volume and cyst volume decreased with drug treatment, renal function did not improve with treatment. Here, we applied dynamic contrast‐enhanced MRI to study PKD in a Glis3 (GLI‐similar 3)‐deficient mouse model. Cysts from this model have a wide range of sizes and develop at an early age. To capture this crucial stage and assess cysts in detail, we imaged during early development (3–17 weeks) and applied high spatiotemporal resolution MRI (125 × 125 × 125 cubic microns every 7.7 s). A drug treatment with rapamycin (also known as sirolimus) was applied to determine whether disease progression could be halted. The effect and synergy (interaction) of aging and treatment were evaluated using an analysis of variance (ANOVA). Structural measurements, including kidney volume, cyst volume and cyst‐to‐kidney volume ratio, changed significantly with age. Drug treatment significantly decreased these metrics. Functional measurements of time‐to‐peak (TTP) mean and TTP variance were determined. TTP mean did not change with age, whereas TTP variance increased with age. Treatment with rapamycin generally did not affect these functional metrics. Synergistic effects of treatment and age were not found for any measurements. Together, the size and volume ratio of cysts decreased with drug treatment, whereas renal function remained the same. The quantification of renal structure and function with MRI can comprehensively assess the pathophysiology of PKD and response to treatment. Copyright

TH-EF-BRA-10: High Spatiotemporal Resolution Self-Sorted 4D MRI

PURPOSE To describe a novel method for self-sorted 4D-MRI and to characterize the output image quality as measured by signal-to-noise ratio (SNR), spatiotemporal resolution, and level of artifact. METHODS A three-dimensional radial sampling function with a quasi-random distribution of polar/azimuthal k-space angles was implemented in a standard pulse sequence. Acquisition time was approximately 2 minutes. The DC component of the k-space signal was used to estimate and sort the breathing cycle into ten respiratory phases. For a given respiratory phase, the k-space data were combined with the periphery of the k-space data from all phases and reconstructed with the re-gridding algorithm onto a 1283 matrix. The extent of data sharing was controlled by the average breathing curve. The sampling and reconstruction technique were tested and validated in simulation, dynamic phantom, animal, and human studies with varying breathing periods/amplitudes. RESULTS The signal at the k-space center accurately measures respiratory motion over a large range of breathing periods (0.5-7.0 seconds) and amplitudes (5-30% of FOV). Sharing of high frequency k-space data driven by the average breathing curve improves spatial resolution and artifact level at a cost of an increase in noise floor. Although equal sharing of k-space data improves resolution and SNR, phases with large temporal changes accumulate considerable distortion artifacts. In the absence of view-sharing, no distortion artifacts are observed while spatial resolution is degraded. CONCLUSION The use of a quasi-random sampling function and view-sharing driven by the average breathing curve provide a feasible method for self-sorted 4D MRI at reduced acquisition times. This approach allows for the extent of data sharing to be inversely-proportional to the average breathing motion hence improving resolution and decreasing artifact levels. NIH-1R21CA165384.

A Spatiotemporal-Constrained Sorting Method for Motion-robust 4D-MRI: A Feasibility Study

PURPOSE To develop a spatiotemporal-constrained sorting technique for motion-robust 4 dimensional-magnetic resonance imaging. METHODS AND MATERIALS This sorting method implemented 2 new approaches for 4-dimensional imaging: (1) an optimized sparse k-space acquisition trajectory with self-gating signal derivation, and (2) a retrospective k-space sorting for reconstruction using a novel spatiotemporal-constrained strategy to minimize breathing variation-induced motion artifacts. Such sorting was regularized by a spatiotemporal index. Volumetric reconstruction was implemented iteratively with a secnd-order total generalized variation penalty. The proposed method was evaluated and compared with the conventional phase-sorting and amplitude-sorting methods in 2 studies. In a computer simulation study, 6 abdominal motion scenarios, including 2 cosine and 4 patient breathing motion patterns, were studied. Reconstruction accuracy was evaluated quantitatively in reference to the ground truth by average image relative error (IRE) in 10 phases and target Dice similarity coefficients (DSCs) in end-of-exhalation/inhalation phases. In addition, the proposed method was evaluated using a custom-made motion phantom. Reconstruction accuracy was evaluated by motion range measurement and image quality comparison in both fast and slow breathing motions. RESULTS In the simulation study, stitching motion artifacts in restricted images were lessened using the proposed method compared with those using the conventional methods. The average IRE and target DSC (end-of-exhalation/inhalation) were 0.031 and 0.95/0.94, respectively, suggesting better motion reconstruction accuracy than the phase-sorted method (IRE, 0.057; DSC, 0.89/0.89) and the amplitude-sorted method (IRE, 0.048; DSC, 0.91/0.88). In the phantom study, the moving target reconstructed by the proposed method demonstrated better rendering with less edge blurring. With fast breathing motion, the range measured using the proposed method was more accurate than that of the phase-sorted method and was comparable to the result of amplitude-sorted method and ground truths. CONCLUSIONS Preliminary results suggested that the proposed sorting technique could reconstruct high-quality images and accurate motion estimation with reduced artifacts in 4 dimensional-magnetic resonance imaging.

Evaluation of the effect of transcytolemmal water exchange analysis for therapeutic response assessment using DCE-MRI: a comparison study.

This study compares the shutter-speed (SS) and the Tofts models as used in assessing therapeutic response in a longitudinal DCE-MRI experiment. Sixteen nu/nu mice with implanted colorectal adenocarcinoma cell line (LS-174T) were randomly assigned into treatment/control groups (n  =  8/group) and received bevacizumab/saline twice weekly (Day1/Day4/Day8). All mice were scanned at one pre- (Day0) and two post-treatment (Day2/Day9) time points using a high spatiotemporal resolution DCE-MRI pulse sequence. The CA extravasation rate constant [Formula: see text] from the Tofts/SS model and the mean intracellular water residence time [Formula: see text] from the SS model were analyzed. A biological subvolume (BV) within the tumor was identified based on the [Formula: see text] intensity distribution, and the SS model parameters within the BV ([Formula: see text] and [Formula: see text]) were analyzed. It is found that [Formula: see text] and [Formula: see text] have a similar spatial distribution in the tumor volume. The Bayesian information criterion results show that the SS model was a better fit for all scans. At Day9, the treatment group had significantly higher tumor mean [Formula: see text] (p  =  0.021), [Formula: see text] (p  =  0.021) and [Formula: see text] (p  = 0.045). When BV from transcytolemmal water exchange analysis was adopted, the treatment group had higher mean [Formula: see text] at both Day2 (p  =  0.038) and Day9 (p  =  0.007). Additionally, at Day9, the treatment group had higher mean [Formula: see text] (p  =  0.045) and higher [Formula: see text] spatial heterogeneity indices (Rényi dimensions) d 1 (p  = 0.010) and d 2 (p  = 0.021). When mean [Formula: see text] and its coefficient of variation (CV) were used to separate treatment/control group samples using supporting vector machine, the accuracy of treatment/control classification was 68.8% at Day2 and 87.5% at Day9; in contrast, the Day2/Day9 accuracy were 62.5%/87.5% using tumor mean [Formula: see text] and its CV and were 50.0%/87.5% using tumor mean [Formula: see text] and its CV, respectively. These results suggest that the SS model parameters outperformed the Tofts model parameters in terms of capturing bevacizumab therapeutic effect in this longitudinal experiment.

SU-F-J-155: Evaluation of Transcytolemmal Water Exchange Analysis For Therapeutic Response Assessment Using Dynamic Contrast-Enhanced MRI

PURPOSE To compare the performance of shutter-speed(SS) model with transcytolemmal water exchange analysis against the Tofts model in the study of the efficacy of an anti-angiogenesis drug METHODS: 16 mice with LS-174T implanted were randomly assigned into treatment/control groups (n=8/group) and received bevacizumab/saline three times (Day1/Day4/Day8). All mice received one pre- (Day0) and two post-treatment (Day2/Day9) DCE scans. For each scan, the CA extravasation rate constant KTtrans /KStrans from the Tofts/SS model were calculated. The intracellular water residence time τi which reflects limited transcytolemmal water exchange between cell and extravascular-extracellular-space were also analyzed using SS model. A biological subvolume(BV) within the tumor was automatically segmented based on the τi intensity distribution, and the SS model parameters within the BV (KS,BVtrans and τi, BV ) were analyzed. Rank-sum tests were conducted to assess the differences of each parameters statistics (mean value/coefficient-of-variation (CV) /kurtosis/skewness/heterogeneity indices d1 and d2 ) between treatment/control groups. Experiment using support vector machine in a leave-one-out approach were performed to validate the use of the analyzed biomarkers for treatment/control classification. RESULTS The SS model was a better fit for all scans in terms of Bayesian information criterion. At Day9, the treatment group had significantly higher mean KTtrans (p=0.021), KStrans (p=0.021) and τi (p=0.045). In the identified BV, the treatment group had significantly higher mean KS,BVtrans at both Day2(p=0.038) and Day9(p=0.007). Additionally, at Day9, the treatment group had significantly higher mean τi , BV (p=0.045) and higher KS,BVtrans heterogeneity indices d1 (p=0.010) and d2 (p=0.021) values. When using KS,BVtrans statistics for treatment/control group classification, the highest accuracy was 68.8%/87.5% at Day2/Day9; this result was better than the result of 62.5%/87.5% using KStrans statistics and 50.0%/87.5% using KTtrans statistics. CONCLUSION The SS model parameters may be more reliable than the Tofts model parameters for therapeutic assessment. The proposed biological subvolume in this work may be useful for early therapeutic effect monitoring.