Can DCE-MRI Explain the Heterogeneity in Radiopeptide Uptake Imaged by SPECT in a Pancreatic Neuroendocrine Tumor Model?

Although efficient delivery and distribution of treatment agents over the whole tumor is essential for successful tumor treatment, the distribution of most of these agents cannot be visualized. However, with single-photon emission computed tomography (SPECT), both delivery and uptake of radiolabeled peptides can be visualized in a neuroendocrine tumor model overexpressing somatostatin receptors. A heterogeneous peptide uptake is often observed in these tumors. We hypothesized that peptide distribution in the tumor is spatially related to tumor perfusion, vessel density and permeability, as imaged and quantified by DCE-MRI in a neuroendocrine tumor model. Four subcutaneous CA20948 tumor-bearing Lewis rats were injected with the somatostatin-analog ¹¹¹In-DTPA-Octreotide (50 MBq). SPECT-CT and MRI scans were acquired and MRI was spatially registered to SPECT-CT. DCE-MRI was analyzed using semi-quantitative and quantitative methods. Correlation between SPECT and DCE-MRI was investigated with 1) Spearman’s rank correlation coefficient; 2) SPECT uptake values grouped into deciles with corresponding median DCE-MRI parametric values and vice versa; and 3) linear regression analysis for median parameter values in combined datasets. In all tumors, areas with low peptide uptake correlated with low perfusion/density/ /permeability for all DCE-MRI-derived parameters. Combining all datasets, highest linear regression was found between peptide uptake and semi-quantitative parameters (R²>0.7). The average correlation coefficient between SPECT and DCE-MRI-derived parameters ranged from 0.52-0.56 (p<0.05) for parameters primarily associated with exchange between blood and extracellular extravascular space. For these parameters a linear relation with peptide uptake was observed. In conclusion, the ‘exchange-related’ DCE-MRI-derived parameters seemed to predict peptide uptake better than the ‘contrast amount- related’ parameters. Consequently, fast and efficient diffusion through the vessel wall into tissue is an important factor for peptide delivery. DCE-MRI helps to elucidate the relation between vascular characteristics, peptide delivery and treatment efficacy, and may form a basis to predict targeting efficiency.     

Modeling the Effect of Intra-Voxel Diffusion of Contrast Agent on the Quantitative Analysis of Dynamic Contrast Enhanced Magnetic Resonance Imaging

Quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) provides estimates of physiologically relevant parameters related to tissue blood flow, vascular permeability, and tissue volume fractions which can then be used for prognostic and diagnostic reasons. However, standard techniques for DCE-MRI analysis ignore intra-voxel diffusion, which may play an important role in contrast agent distribution and voxel signal intensity and, thus, will affect quantification of the aforementioned parameters. To investigate the effect of intra-voxel diffusion on quantitative DCE-MRI, we developed a finite element model of contrast enhancement at the voxel level. For diffusion in the range of that expected for gadolinium chelates in tissue (i.e., 1×10⁻⁴ to 4×10⁻⁴ mm²/s), parameterization errors range from −58% to 12% for K^trans, −9% to 8% for v_e, and −60% to 213% for v_p over the range of K^trans, v_e, v_p, and temporal resolutions investigated. Thus the results show that diffusion has a significant effect on parameterization using standard techniques.     

Molecular magnetic resonance imaging with targeted contrast agents

Magnetic resonance imaging (MRI) produces high-resolution three-dimensional maps delineating morphological features of the specimen. Differential contrast in soft tissues depends on endogenous differences in water content, relaxation times, and/or diffusion characteristics of the tissue of interest. The specificity of MRI can be further increased by exogenous contrast agents (CA) such as gadolinium chelates, which have been successfully used for imaging of hemodynamic parameters including blood perfusion and vascular permeability. Development of targeted MR CA directed to specific molecular entities could dramatically expand the range of MR applications by combining the noninvasiveness and high spatial resolution of MRI with specific localization of molecular targets. However, due to the intrinsically low sensitivity of MRI (in comparison with nuclear imaging), high local concentrations of the CA at the target site are required to generate detectable MR contrast. To meet these requirements, the MR targeted CA should recognize targeted cells with high affinity and specificity. They should also be characterized by high relaxivity, which for a wide variety of CA depends on the number of contrast-generating groups per single molecule of the agent. We will review different designs and applications of targeted MR CA and will discuss feasibility of these approaches for in vivo MRI.     

A review of technical aspects of T1-weighted dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in human brain tumors

In the last few years, several imaging methods, such as magnetic resonance imaging (MRI) and computed tomography, have been used to investigate the degree of blood–brain barrier (BBB) permeability in patients with neurological diseases including multiple sclerosis, ischemic stroke, and brain tumors. One promising MRI method for assessing the BBB permeability of patients with neurological diseases in vivo is T₁-weighted dynamic contrast-enhanced (DCE)-MRI. Here we review the technical issues involved in DCE-MRI in the study of human brain tumors. In the first part of this paper, theoretical models for the DCE-MRI analysis will be described, including the Toft–Kety models, the adiabatic approximation to the tissue homogeneity model and the two-compartment exchange model. These models can be used to estimate important kinetic parameters related to BBB permeability. In the second part of this paper, details of the data acquisition, issues related to the arterial input function, and procedures for DCE-MRI image analysis are illustrated.     

Parametric Representation of Multiple White Matter Fascicles from Cube and Sphere Diffusion MRI

The characterization of the complex diffusion signal arising from the brain remains an open problem. Many representations focus on characterizing the global shape of the diffusion profile at each voxel and are limited to the assessment of connectivity. In contrast, Multiple Fascicle Models (MFM) seek to represent the contribution from each white matter fascicle and may be useful in the investigation of both white matter connectivity and diffusion properties of each individual fascicle. However, the most appropriate representation of multiple fascicles remains unclear. In particular, a multiple tensor representation of multiple fascicles has frequently been reported to be numerically challenging and unstable. We provide here the first analytical demonstration that when using a diffusion MRI acquisition with only one non-zero b-value, such as in conventional single-shell HARDI acquisition, a co-linearity in model parameters makes the precise model estimation impossible. Motivated by this theoretical result, we propose the novel CUSP (CUbe and SPhere) optimal acquisition scheme to achieve multiple non-zero b-values. It combines the gradients of a single-shell HARDI with gradients in its enclosing cube, in which varying b-values can be acquired by modulation of the gradient strength, without modifying the minimum echo time. Compared to a multi-shell HARDI acquisition, our scheme has significantly increased signal-to-noise ratio. We propose a novel estimation algorithm that enables efficient, robust and accurate estimation of the parameters of a multi-tensor model. In conjunction with a CUSP acquisition, it enables full estimation of the multi-tensor model. We present an evaluation of CUSP-MFM on both synthetic phantoms and invivo data. We report qualitative and quantitative experimental evaluations which demonstrate the ability of CUSP-MFM to characterize multiple fascicles from short duration acquisitions. CUSP-MFM enables rapid and effective investigation of multiple white matter fascicles, in both normal development and in disease and injury, in research and clinical practice.     

Dynamic Contrast-Enhanced and Diffusion-Weighted Magnetic Resonance Imaging Noninvasive Evaluation of Vascular Disrupting Treatment on Rabbit Liver Tumors

Evaluation of vascular disrupting treatment (VDT) is generally based on tumor size and enhancement on conventional magnetic resonance imaging (MRI) which, unfortunately, may be limited in providing satisfactory information. The purpose of the study is to evaluate consecutive changes of 20 rabbit VX2 liver tumors after VDT by dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI) at a 3.0 T MR unit. Twenty four hours after intravenous injection of Combretastatin A-4-phosphate (CA4P) at 20 mg/kg, DCE-MRI derived Maximum Slope of Increase (MSI) and Positive Enhancement Integral (PEI) decreased sharply due to sudden shutting down of tumor feeding vessels. DWI derived Apparent Diffusion Coefficient (ADC) in tumor periphery decreased because of ischemic cell edema. On day 4, an increase of MSI was probably caused by the recovery of blood supply. A remarkable increase of ADC represented a large scale of necrosis among tumors. On day 8, the blood perfusion further decreased and the extent of necrosis further increased, reflected by lower MSI and PEI values and higher ADC value. On day 12, a second decrease of ADC was noticed because the re-growth of periphery tumor. The experimental data indicate that the therapeutic effects of VDT may be noninvasively monitored with DCE-MRI (reflecting tumor blood perfusion) and DWI (reflecting the changes of histology), which provide powerful measures for assessment of anticancer treatments.     

Noninvasive monitoring of therapy-induced microvascular changes in a pancreatic cancer model using dynamic contrast-enhanced magnetic resonance imaging with P846, a new low-diffusible gadolinium-based contrast agent

A predictive technique in the management of patients with cancer could improve the therapeutic index by allowing better individualization of treatment. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive technique that can provide anatomical and physiological information on the tumor and its microenvironment. We studied the effect of chemotherapy (gemcitabine), anti-angiogenesis therapy (sunitinib) and radiotherapy on the kinetics of DCE-MRI parameters in a preclinical model of pancreatic cancer using P846, a new low-diffusible contrast agent. Mice underwent DCE-MRI before treatment (MRI1), after 1 week of treatment (MRI2), and after 1 additional week (MRI3). Combined treatment with radiotherapy and sunitinib had a synergistic effect on tumor growth. In radiotherapy/sunitinib-treated mice, a decrease in K(trans) at MRI2 predicted its superior antivascular and antitumor effect at an early time. An increased K(trans) at MRI2, as seen in gemcitabine- and gemcitabine/sunitinib-treated mice, reflects increased permeability for P846 and might predict a smaller therapeutic effect at this early time. This study shows that the kinetics of DCE-MRI parameters depends on the contrast agent used. P846 appears to be a promising low-diffusible agent to monitor therapeutic effects in this preclinical cancer model, but further studies are needed to compare its behavior with Gd-DTPA and macromolecular-weight contrast agents. Sunitinib as a radiosensitizer is promising for future clinical trials in human pancreatic cancer.     

Modified test statistics by inter-voxel variance shrinkage with an application to f MRI

Functional magnetic resonance imaging (f MRI) is a noninvasive technique which is commonly used to quantify changes in blood oxygenation and flow coupled to neuronal activation. One of the primary goals of f MRI studies is to identify localized brain regions where neuronal activation levels vary between groups. Single voxel t-tests have been commonly used to determine whether activation related to the protocol differs across groups. Due to the generally limited number of subjects within each study, accurate estimation of variance at each voxel is difficult. Thus, combining information across voxels is desirable in order to improve efficiency. Here, we construct a hierarchical model and apply an empirical Bayesian framework for the analysis of group f MRI data, employing techniques used in high-throughput genomic studies. The key idea is to shrink residual variances by combining information across voxels and subsequently to construct an improved test statistic. This hierarchical model results in a shrinkage of voxel-wise residual sample variances toward a common value. The shrunken estimator for voxel-specific variance components on the group analyses outperforms the classical residual error estimator in terms of mean-squared error. Moreover, the shrunken test statistic decreases false-positive rates when testing differences in brain contrast maps across a wide range of simulation studies. This methodology was also applied to experimental data regarding a cognitive activation task.     

Functional and structural characteristics of tumor angiogenesis in lung cancers overexpressing different VEGF isoforms assessed by DCE- and SSCE-MRI

The expressions of different vascular endothelial growth factor (VEGF) isoforms are associated with the degree of tumor invasiveness and the patient's prognosis in human cancers. We hypothesized that different VEGF isoforms can exert different effects on the functional and structural characteristics of tumor angiogenesis. We used dynamic contrast-enhanced MRI (DCE-MRI) and steady-state contrast-enhanced MRI (SSCE-MRI) to evaluate in vivo vascular functions (e.g., perfusion and permeability) and structural characteristics (e.g., vascular size and vessel density) of the tumor angiogenesis induced by different VEGF isoforms (VEGF121, VEGF165, and VEGF189) in a murine xenograft model of human lung cancer. Tumors overexpressing VEGF189 were larger than those overexpressing the other two VEGF isoforms. The K(trans) map obtained from DCE-MRI revealed that the perfusion and permeability functions of tumor microvessels was highest in both the rim and core regions of VEGF189-overexpressing tumors (p<0.001 for both tumor rim and core). The relative vessel density and relative vessel size indexes derived from SSCE-MRI revealed that VEGF189-overexpressing tumors had the smallest (p<0.05) and the most-dense (p<0.01) microvessels, which penetrated deeply from the tumor rim into the core, followed by the VEGF165-overepxressing tumor, whose microvessels were located mainly in the tumor rim. The lowest-density microvessels were found in the VEGF121-overexpressing tumor; these microvessels had a relatively large lumen and were found mainly in the tumor rim. We conclude that among the three VEGF isoforms evaluated, VEGF189 induces the most densely sprouting and smallest tumor microvessels with the highest in vivo perfusion and permeability functions. These characteristics of tumor microvessels may contribute to the reported adverse effects of VEGF189 overexpression on tumor progression, metastasis, and patient survival in several human cancers, including non-small cell lung cancer, and suggest that applying aggressive therapy may be necessary in human cancers in which VEGF189 is overexpressed.     

Simultaneous Measurement of Kidney Function by Dynamic Contrast Enhanced MRI and FITC-Sinistrin Clearance in Rats at 3 Tesla: Initial Results

Glomerular filtration rate (GFR) is an essential parameter of kidney function which can be measured by dynamic contrast enhanced magnetic resonance imaging (MRI-GFR) and transcutaneous approaches based on fluorescent tracer molecules (optical-GFR). In an initial study comparing both techniques in separate measurements on the same animal, the correlation of the obtained GFR was poor. The goal of this study was to investigate if a simultaneous measurement was feasible and if thereby, the discrepancies in MRI-GFR and optical-GFR could be reduced. For the experiments healthy and unilateral nephrectomised (UNX) Sprague Dawley (SD) rats were used. The miniaturized fluorescent sensor was fixed on the depilated back of an anesthetized rat. A bolus of 5 mg/100 g b.w. of FITC-sinistrin was intravenously injected. For dynamic contrast enhanced perfusion imaging (DCE-MRI) a 3D time-resolved angiography with stochastic trajectories (TWIST) sequence was used. By means of a one compartment model the excretion half-life (t1/2) of FITC-sinistrin was calculated and converted into GFR. GFR from DCE-MRI was calculated by fitting pixel-wise a two compartment renal filtration model. Mean cortical GFR and GFR by FITC-sinistrin were compared by Bland-Altman plots and pair-wise t-test. Results show that a simultaneous GFR measurement using both techniques is feasible. Mean optical-GFR was 4.34±2.22 ml/min (healthy SD rats) and 2.34±0.90 ml/min (UNX rats) whereas MRI-GFR was 2.10±0.64 ml/min (SD rats) and 1.17±0.38 ml/min (UNX rats). Differences between healthy and UNX rats were significant (p<0.05) and almost equal percentage difference (46.1% and 44.3%) in mean GFR were assessed with both techniques. Overall mean optical-GFR values were approximately twice as high compared to MRI-GFR values. However, compared to a previous study, our results showed a higher agreement. In conclusion, the possibility to use the transcutaneous method in MRI may have a huge impact in improving and validating MRI methods for GFR assessment in animal models.     

Dynamic contrast-enhanced magnetic resonance imaging of sunitinib-induced vascular changes to schedule chemotherapy in renal cell carcinoma xenograft tumors

In an attempt to develop better therapeutic approaches for metastatic renal cell carcinoma (RCC), the combination of the antiangiogenic drug sunitinib with gemcitabine was studied. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), we have previously determined that a sunitinib dosage of 20 mg/kg per day increased kidney tumor perfusion and decreased vascular permeability in a preclinical murine RCC model. This sunitinib dosage causing regularization of tumor vessels was selected to improve delivery of gemcitabine to the tumor. DCE-MRI was used to monitor regularization of vasculature with sunitinib in kidney tumors to schedule gemcitabine. We established an effective and nontoxic schedule of sunitinib combined with gemcitabine consisting of pretreatment with sunitinib for 3 days followed by four treatments of gemcitabine at 20 mg/kg given 3 days apart while continuing daily sunitinib treatment. This treatment caused significant tumor growth inhibition resulting in small residual tumor nodules exhibiting giant tumor cells with degenerative changes, which were observed both in kidney tumors and in spontaneous lung metastases, suggesting a systemic antitumor response. The combined therapy caused a significant increase in mouse survival. DCE-MRI monitoring of vascular changes induced by sunitinib, gemcitabine, and both combined showed increased tumor perfusion and decreased vascular permeability in kidney tumors. These findings, confirmed histologically by thinning of tumor blood vessels, suggest that both sunitinib and gemcitabine exert antiangiogenic effects in addition to cytotoxic antitumor activity. These studies show that DCE-MRI can be used to select the dose and schedule of antiangiogenic drugs to schedule chemotherapy and improve its efficacy.     

Advances in magnetic resonance imaging of lung physiology.

This review presents an overview of some recent magnetic resonance imaging (MRI) techniques for measuring aspects of local physiology in the lung. MRI is noninvasive, relatively high resolution, and does not expose subjects to ionizing radiation. Conventional MRI of the lung suffers from low signal intensity caused by the low proton density and the large degree of microscopic field inhomogeneity that degrades the magnetic resonance signal and interferes with image acquisition. However, in recent years, there have been rapid advances in both hardware and software design, allowing these difficulties to be minimized. This review focuses on some newer techniques that measure regional perfusion, ventilation, gas diffusion, ventilation-to-perfusion ratio, partial pressure of oxygen, and lung water. These techniques include contrast-enhanced and arterial spin-labeling techniques for measuring perfusion, hyperpolarized gas techniques for measuring regional ventilation, and apparent diffusion coefficient and multiecho and gradient echo techniques for measuring proton density and lung water. Some of the major advantages and disadvantages of each technique are discussed. In addition, some of the physiological issues associated with making measurements are discussed, along with strategies for understanding large and complex data sets.     

Lung inflammation and vascular remodeling after repeated allergen challenge detected noninvasively by MRI

Magnetic resonance imaging (MRI) has been used previously to follow noninvasively inflammatory processes in rat acute models of lung inflammation. Here the technique was applied to a model involving repeated intratracheal administration of ovalbumin (OA). Anatomical MRI was performed at different time points with respect to a single or multiple OA challenges in Brown Norway rats actively sensitized to the allergen. Vascular permeability was assessed using dynamic contrast-enhanced MRI (DCE-MRI). Bronchoalveolar lavage (BAL) fluid analysis and histology were performed to validate the MRI data. The time course of MRI signals after a single OA challenge reached a maximum at 48 h and decreased significantly at 96 h. After the second and subsequent challenges, the maximum signal occurred at 6 h with a time-dependent decline over the remainder of the time course. A reduction of the inflammatory response following repeated administration of OA was also detected by BAL fluid analysis. The decrease in vascular permeability assessed by DCE-MRI in repeatedly OA-challenged rats was consistent with the thickening of the vascular wall for vessels of diameter up to 300 microm revealed by histology. Angiogenesis of vessels smaller than 30 microm was also detected histologically. These results suggest that MRI can be used to detect the inflammatory response and vascular remodeling associated with chronic airway inflammation in rat models involving repeated administration of allergen. As the contrast agent used in the DCE-MRI experiments is approved for clinical use, there is potential to translate the approach to patients.     

Evaluating the Accuracy of Diffusion MRI Models in White Matter

Models of diffusion MRI within a voxel are useful for making inferences about the properties of the tissue and inferring fiber orientation distribution used by tractography algorithms. A useful model must fit the data accurately. However, evaluations of model-accuracy of commonly used models have not been published before. Here, we evaluate model-accuracy of the two main classes of diffusion MRI models. The diffusion tensor model (DTM) summarizes diffusion as a 3-dimensional Gaussian distribution. Sparse fascicle models (SFM) summarize the signal as a sum of signals originating from a collection of fascicles oriented in different directions. We use cross-validation to assess model-accuracy at different gradient amplitudes (b-values) throughout the white matter. Specifically, we fit each model to all the white matter voxels in one data set and then use the model to predict a second, independent data set. This is the first evaluation of model-accuracy of these models. In most of the white matter the DTM predicts the data more accurately than test-retest reliability; SFM model-accuracy is higher than test-retest reliability and also higher than the DTM model-accuracy, particularly for measurements with (a) a b-value above 1000 in locations containing fiber crossings, and (b) in the regions of the brain surrounding the optic radiations. The SFM also has better parameter-validity: it more accurately estimates the fiber orientation distribution function (fODF) in each voxel, which is useful for fiber tracking.     

Intravoxel Incoherent Motion Diffusion Weighted MR Imaging for Monitoring the Instantly Therapeutic Efficacy of Radiofrequency Ablation in Rabbit VX2 Tumors without Evident Links between Conventional Perfusion Weighted Images

ObjectiveTo investigate the intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) as a potential valuable marker to monitor the therapy responses of VX2 to radiofrequency ablation (RF Ablation).MethodsThe institutional animal care and use committee approved this study. In 10 VX2 tumor–bearing rabbits, IVIM-DWI examinations were performed with a 3.0T imaging unit by using 16 b values from 0 to 800 sec/mm². The true diffusion coefficient (D), pseudodiffusion coefficient (D^*) and perfusion fraction (f) of tumors were compared between before and instantly after RF Ablation treatment. The differences of D, D^* and f and conventional perfusion parameters (from perfusion CT and dynamic enhanced magnetic resonance imaging, DCE-MRI) in the coagulation necrosis area, residual unablated area, untreated area, and normal control had been calculated by compared t- test. The correlation between f or D^* with perfusion weighted CT including blood flow, BF (milliliter per 100 mL/min), blood volume, BV (milliliter per 100 mL/min), and capillary permeability–surface area, PMB (as a fraction) or from DCE-MRI: transfer constant (K_trans), extra-vascular extra-cellular volume fraction (V_e) and reflux constant (K_ep) values had been analyzed by region-of-interest (ROI) methods to calculate Pearson’s correlation coefficients.ResultsIn the ablated necrosis areas, f and D^* significantly decreased and D significantly increased, compared with residual unblazed areas or untreated control groups and normal control groups (P < 0.001). The IVIM-DWI derived f parameters showed significant increases in the residual unablated tumor area. There was no significant correlations between f or D^* and conventional perfusion parameters.ConclusionsThe IVIM-DW derived f, D and D^* parameters have the potential to indicate therapy response immediately after RF Ablation treatment, while no significant correlations with classical tumor perfusion metrics were derived from DCE-MRI and perfusion-CT measurements.     

Towards endometriosis diagnosis by gadofosveset-trisodium enhanced magnetic resonance imaging

Endometriosis is defined as the presence of endometrial tissue outside the uterus. It affects 10-15% of women during reproductive age and has a big personal and social impact due to chronic pelvic pain, subfertility, loss of work-hours and medical costs. Such conditions are exacerbated by the fact that the correct diagnosis is made as late as 8-11 years after symptom presentation. This is due to the lack of a reliable non-invasive diagnostic test and the fact that the reference diagnostic standard is laparoscopy (invasive, expensive and not without risks). High-molecular weight gadofosveset-trisodium is used as contrast agent in Magnetic Resonance Imaging (MRI). Since it extravasates from hyperpermeable vessels more easily than from mature blood vessels, this contrast agent detects angiogenesis efficiently. Endometriosis has high angiogenic activity. Therefore, we have tested the possibility to detect endometriosis non-invasively using Dynamic Contrast-Enhanced MRI (DCE-MRI) and gadofosveset-trisodium as a contrast agent in a mouse model. Endometriotic lesions were surgically induced in nine mice by autologous transplantation. Three weeks after lesion induction, mice were scanned by DCE-MRI. Dynamic image analysis showed that the rates of uptake (inwash), persistence and outwash of the contrast agent were different between endometriosis and control tissues (large blood vessels and back muscle). Due to the extensive angiogenesis in induced lesions, the contrast agent persisted longer in endometriotic than control tissues, thus enhancing the MRI signal intensity. DCE-MRI was repeated five weeks after lesion induction, and contrast enhancement was similar to that observed three weeks after endometriosis induction. The endothelial-cell marker CD31 and the pericyte marker α-smooth-muscle-actin (mature vessels) were detected with immunohistochemistry and confirmed that endometriotic lesions had significantly higher prevalence of new vessels (CD31 only positive) than the uterus and control tissues. The diagnostic value of gadofosveset-trisodium to detect endometriosis should be tested in human settings.     

DCE-MRI of the Liver: Reconstruction of the Arterial Input Function Using a Low Dose Pre-Bolus Contrast Injection

Purpose

To assess the quality of the arterial input function (AIF) reconstructed using a dedicated pre-bolus low-dose contrast material injection imaged with a high temporal resolution and the resulting estimated liver perfusion parameters.

Materials and Methods

In this IRB–approved prospective study, 24 DCE-MRI examinations were performed in 21 patients with liver disease (M/F 17/4, mean age 56 y). The examination consisted of 1.3 mL and 0.05 mmol/kg of gadobenate dimeglumine for pre-bolus and main bolus acquisitions, respectively. The concentration-curve of the abdominal aorta in the pre-bolus acquisition was used to reconstruct the AIF. AIF quality and shape parameters obtained with pre-bolus and main bolus acquisitions and the resulting estimated hepatic perfusion parameters obtained with a dual-input single compartment model were compared between the 2 methods. Test–retest reproducibility of perfusion parameters were assessed in three patients.

Results

The quality of the pre-bolus AIF curve was significantly better than that of main bolus AIF. Shape parameters peak concentration, area under the time activity curve of gadolinium contrast at 60 s and upslope of pre-bolus AIF were all significantly higher, while full width at half maximum was significantly lower than shape parameters of main bolus AIF. Improved liver perfusion parameter reproducibility was observed using pre-bolus acquisition [coefficient of variation (CV) of 4.2%–38.7% for pre-bolus vs. 12.1–71.4% for main bolus] with the exception of distribution volume (CV of 23.6% for pre-bolus vs. 15.8% for main bolus). The CVs between pre-bolus and main bolus for the perfusion parameters were lower than 14%.

Conclusion

The AIF reconstructed with pre-bolus low dose contrast injection displays better quality and shape parameters and enables improved liver perfusion parameter reproducibility, although the resulting liver perfusion parameters demonstrated no clinically significant differences between pre-bolus and main bolus acquisitions.     

Validation of Perfusion Quantification with 3D Gradient Echo Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using a Blood Pool Contrast Agent in Skeletal Swine Muscle

The purpose of our study was to validate perfusion quantification in a low-perfused tissue by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with shared k-space sampling using a blood pool contrast agent. Perfusion measurements were performed in a total of seven female pigs. An ultrasonic Doppler probe was attached to the right femoral artery to determine total flow in the hind leg musculature. The femoral artery was catheterized for continuous local administration of adenosine to increase blood flow up to four times the baseline level. Three different stable perfusion levels were induced. The MR protocol included a 3D gradient-echo sequence with a temporal resolution of approximately 1.5 seconds. Before each dynamic sequence, static MR images were acquired with flip angles of 5°, 10°, 20°, and 30°. Both static and dynamic images were used to generate relaxation rate and baseline magnetization maps with a flip angle method. 0.1 mL/kg body weight of blood pool contrast medium was injected via a central venous catheter at a flow rate of 5 mL/s. The right hind leg was segmented in 3D into medial, cranial, lateral, and pelvic thigh muscles, lower leg, bones, skin, and fat. The arterial input function (AIF) was measured in the aorta. Perfusion of the different anatomic regions was calculated using a one- and a two-compartment model with delay- and dispersion-corrected AIFs. The F-test for model comparison was used to decide whether to use the results of the one- or two-compartment model fit. Total flow was calculated by integrating volume-weighted perfusion values over the whole measured region. The resulting values of delay, dispersion, blood volume, mean transit time, and flow were all in physiologically and physically reasonable ranges. In 107 of 160 ROIs, the blood signal was separated, using a two-compartment model, into a capillary and an arteriolar signal contribution, decided by the F-test. Overall flow in hind leg muscles, as measured by the ultrasound probe, highly correlated with total flow determined by MRI, R = 0.89 and P = 10⁻⁷. Linear regression yielded a slope of 1.2 and a y-axis intercept of 259 mL/min. The mean total volume of the investigated muscle tissue corresponds to an offset perfusion of 4.7mL/(min ⋅ 100cm³). The DCE-MRI technique presented here uses a blood pool contrast medium in combination with a two-compartment tracer kinetic model and allows absolute quantification of low-perfused non-cerebral organs such as muscles.     

Multi-modal Imaging of Angiogenesis in a Nude Rat Model of Breast Cancer Bone Metastasis Using Magnetic Resonance Imaging,Volumetric Computed Tomography and Ultrasound

Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell proliferation in the bone marrow cavity as well as for interaction of tumor and bone cells resulting in local bone destruction. Our aim was to develop a model of experimental bone metastasis that allows in vivo assessment of angiogenesis in skeletal lesions using non-invasive imaging techniques.For this purpose, we injected 10⁵ MDA-MB-231 human breast cancer cells into the superficial epigastric artery, which precludes the growth of metastases in body areas other than the respective hind leg¹. Following 25-30 days after tumor cell inoculation, site-specific bone metastases develop, restricted to the distal femur, proximal tibia and proximal fibula¹. Morphological and functional aspects of angiogenesis can be investigated longitudinally in bone metastases using magnetic resonance imaging (MRI), volumetric computed tomography (VCT) and ultrasound (US).MRI displays morphologic information on the soft tissue part of bone metastases that is initially confined to the bone marrow cavity and subsequently exceeds cortical bone while progressing. Using dynamic contrast-enhanced MRI (DCE-MRI) functional data including regional blood volume, perfusion and vessel permeability can be obtained and quantified^2-4. Bone destruction is captured in high resolution using morphological VCT imaging. Complementary to MRI findings, osteolytic lesions can be located adjacent to sites of intramedullary tumor growth. After contrast agent application, VCT angiography reveals the macrovessel architecture in bone metastases in high resolution, and DCE-VCT enables insight in the microcirculation of these lesions^5,6. US is applicable to assess morphological and functional features from skeletal lesions due to local osteolysis of cortical bone. Using B-mode and Doppler techniques, structure and perfusion of the soft tissue metastases can be evaluated, respectively. DCE-US allows for real-time imaging of vascularization in bone metastases after injection of microbubbles⁷.In conclusion, in a model of site-specific breast cancer bone metastases multi-modal imaging techniques including MRI, VCT and US offer complementary information on morphology and functional parameters of angiogenesis in these skeletal lesions.     

In vivo (31)P-NMR diffusion spectroscopy of ATP and phosphocreatine in rat skeletal muscle

The aim of this study was to measure the diffusion of ATP and phosphocreatine (PCr) in intact rat skeletal muscle, using (31)P-NMR. The acquisition of the diffusion-sensitized spectra was optimized in terms of the signal-to-noise ratio for ATP by using a frequency-selective stimulated echo sequence in combination with adiabatic radio-frequency pulses and surface coil signal excitation and reception. Diffusion restriction was studied by measuring the apparent diffusion coefficients of ATP and PCr as a function of the diffusion time. Orientation effects were eliminated by determining the trace of the diffusion tensor. The data were fitted to a cylindrical restriction model to estimate the unbounded diffusion coefficient and the radial dimensions of the restricting compartment. The unbounded diffusion coefficients of ATP and PCr were approximately 90% of their in vitro values at 37 degrees C. The diameters of the cylindrical restriction compartment were approximately 16 and approximately 22 microm for ATP and PCr, respectively. The diameters of rat skeletal muscle fibers are known to range from 60 to 80 microm. The modelling therefore suggests that the in vivo restriction of ATP and PCr diffusion is not imposed by the sarcolemma but by other, intracellular structures with an overall cylindrical orientation.