Quantification of regional blood volumes by rapid T1 mapping

A new method is presentd for the quantitative determination of regional blood volumes in vivo. It is based on rapid quantitative T₁ mapping by Snapshot FLASH MRI combined with the injection of an intravascular MR contrast agent. Regional blood volumes in four different tissues of the rat (skeletal muscle, heart, liver, kidney) were determined in an In vivo experiment.     

Comparison of albumin-(Gd-DTPA)30 and Gd-DTPA-24-cascade-polymer for measurements of normal and abnormal microvascular permeability

The purpose of this study was to compare a new MR macromolecular contrast medium (MMCM), gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-24-cascade-polymer, to a well-studied prototype MMCM, for the potential of distinguishing tissues of varying endothelial permeability. Three tissue models of varying capillary permeability were studied in a total of 46 rats: normal myocardium (normal capillaries), subcutaneously implanted adenocarcinoma (mild capillary leak), and reperfused infarcted myocardium (high capillary leak). T1-weighted MRI was performed before and dynamically after injection of either albumin-(Gd-DTPA)₃₀ or the cascade polymer (each .02 mmol gadolinium [Gd] per kg). Data analysis based on a two-compartment kinetic model yielded estimates of fractional blood volume (BV) (percentage) and fractional leak rate (FLR) (1 per hour). Permeability to the cascade polymer as reflected in FLR was considerable in normal myocardium (8.24 per hour), of similar value in tumors (8.55 per hour), but significantly greater in infarcted myocardium (39.17 per hour, P < .01) versus normal myocardium. The larger albumin-(Gd-DTPA)₃₀ demonstrated minimal extravasation in normal myocardium (FLR .33 per hour); FLR in tumors was 100% higher (.66 per hour, P < .002) and FLR in reperfused capillaries was significantly greater (7.94 per hour, P < .001). Based on capillary permeability measurements, the cascade polymer may have limited utility for detection of mildly increased microvascular permeabilities. For severe tissue injury, the cascade polymer can resolve abnormal microvascular integrity.     

Optimization of spoiled gradient-echo phase imaging for in vivo localization of a focused ultrasound beam

The parameters of a spoiled gradient-echo (SPGR) pulse sequence have been optimized for in vivo localization of a focused ultrasound beam. Temperature elevation was measured by using the proton resonance frequency shift technique, and the phase difference signal-to-noise ratio (SNR_{δ ϕ}) was estimated in skeletal muscle and kidney cortex in 10 rabbits. Optimized parameters included the echo time equivalent to T^*₂of the tissue, the longest repetition time possible with a 20-s sonication, and the flip angle equivalent to the Ernst angle. Optimal SPGR phase imaging can detect a sonication beam with a peak phase difference of 0.55 radian, which corresponds to a temperature elevation of 7.3°C. The sonication beam can be localized within one voxel (0.6 × 0.6 × 5 mm³) at power levels that are below the threshold for thermal damage of the tissue.     

Oxidation of acetate in rabbit skeletal muscle: Detection by 13C NMR spectroscopy in vivo

The results of a proton-decoupled and Overhauser-enhanced ¹³C NMR study of acetate metabolism in skeletal muscle are reported. [2-¹³C]Acetate was infused intravenously over 2 h into anesthetized rabbits, and skeletal muscle in the lateral thigh was monitored by ¹³C NMR spectroscopy at 4.7 T. Stable ¹³C enrichment in carbons 2, 3, and 4 of glutamate was observed at the end of the infusion, and the half-time for enrichment was 17 min for glutamate C4 and 50 min for glutamate C2 and C3. The contribution of exogenous acetate to acetyl-coenzyme A was nearly equal in skeletal muscle and heart in vivo (83–87%, measured in tissue extracts), comparable with earlier perfused heart studies in which acetate was the sole available substrate. Although relative flux through the combined anaplerotic pathways (relative to citric acid cycle flux) was higher in quiescent skeletal muscle (26%) compared with hearts (3%) from the same animals, actual anaplerotic flux was estimated to be substantially higher in heart than in skeletal muscle after correcting for differences in citric acid cycle flux in the two tissues.     

Quantification of liver blood volume: comparison of ultra short ti inversion recovery echo planar imaging (ulstir-epi), with dynamic 3d-gradient recalled echo imaging

An ultra-short TI inversion recovery echo-planar imaging (ULSTIR-EPI) sequence was designed to reduce the influence of water exchange on fractional tissue blood volume (BV) estimation by measurement of T₁-changes induced by a gadolinium-based macromolecular contrast medium (MMCM). Fractional liver BV in rats, estimated by ULSTIR-EPI was compared for accuracy to a fast T₁-weighted three-dimensional gradient-echo (3D-SPGR, 3D-spoiled gradient recalled acquisition in a steady state) sequence using an in vitro inductively coupled plasma atomic emission spectroscopy (ICP-AES) assay for BV as a standard. Liver images for fractional BV estimation were acquired in eight rats using both ULSTIR-EPI and 3D-SPGR before and after (within 3 to 12 min) intravenous bolus administration of albumin-Gd-DTPA₃₀ (0.05 mmol Gd/kg). Whereas both MR techniques may be useful for fractional tissue BV estimation, ULSTIR-EPI offers certain advantages including greater accuracy, direct T₁ maps, and minimization of transendothelial proton exchange effects. 3D-SPGR imaging offers better spatial resolution, current availability on standard clinical MR systems, and acceptable accuracy.     

Effect of oxygen inhalation on relaxation times in various tissues

The effect of the oxygen inhalation on relaxation times was evaluated in various tissues, including the myocardium, liver, spleen, skeletal muscle, subcutaneous fat, bone marrow, and arterial blood, with a [¹H]MR system. Statistically significant decrease of T1 relaxation times was observed in the myocardium, spleen, and arterial blood after inhalation of 100% oxygen, whereas no significant change was observed in liver, skeletal muscle, subcutaneous fat, or bone marrow. The T2 relaxation time of these tissues did not differ significantly between before and after inhalation of the oxygen. These results indicate that [¹H]MRI can be used to evaluate changes with oxygen inhalation and that the effect of the oxygen inhalation on T1 relaxation time is different among various tissues.     

Correlative dynamic contrast MRI and microscopic assessments of tumor vascularity in RIP‐tag2 transgenic mice

The purpose of this study was to define the feasibility of dynamic contrast‐enhanced magnetic resonance imaging (MRI) to estimate the vascular density and leakiness of spontaneous islet cell tumors in RIP‐Tag2 transgenic mice. Dynamic T₁‐weighted spoiled gradient echo (SPGR) imaging at 2.0 T was performed in 17 RIP‐Tag2 mice using a prototype blood pool macromolecular contrast medium (MMCM), albumin‐(Gd‐DTPA)₃₅. Kinetic analysis of the dynamic enhancement responses based on a two‐compartment model was used to estimate fractional plasma volume (fPV) and the coefficient of endothelial permeability (K^PS) for each tumor. The MRI estimate of fPV was correlated on a tumor‐by‐tumor basis with corresponding microscopic measurements of vascular density. The fPV assays by MMCM‐enhanced imaging ranged from 2.4%–14.1% of tissue volume. Individual tumor fPV values correlated significantly (r = 0.79, P < 0.001) with the corresponding microscopic estimates of vascularity consisting of the combined area densities of lectin‐perfused microvessels plus erythrocyte‐stained blood lakes. A biotinylated derivative of the albumin‐based MMCM confirmed extravasation of the contrast agent from some tumor blood vessels and accumulation in 25% of blood lakes. The K^PS values ranged from 0 (no detectable leak) to 0.356 mL/min/100 cm³. Dynamic MMCM‐enhanced MRI is feasible in RIP‐Tag2 pancreatic tumors, yielding estimates of vascular permeability and microscopically validated measurements of vascular richness. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Dipolar resonance frequency shifts in 1H MR spectra of skeletal muscle: Confirmation in rats at 4.7 T in Vivo and observation of changes postmortem

Non-isotropic contributions to ¹H MR spectra from human skeletal muscle in vivo have recently been observed in the 0-to 5-ppm region. One pair of peaks has been identified to be subject to dipolar couplings. The corresponding changes in resonance frequency are related to the orientation of muscle fibers with respect to the external magnetic field and are analogous to the behavior of small molecules dissolved in liquid crystals. Image-guided localized spectroscopy based on the STEAM method has been applied to verify these phenomena in rat skeletal muscle in vivo and to investigate the effect postmortem. Residual dipolar couplings and anisotropic contributions to ¹H MR spectra of skeletal muscle have been confirmed in animals and at a higher field strength—albeit with a slightly different spectral pattern compared to the human study. The most prominent dipolar doublet due to creatine and/or phosphocreatine vanishes postmortem with a rate similar to the disappearance of phosphocreatine, and is no longer observable 2 h postmortem.     

Detection and quantification of protein-losing enteropathy with indium-111 transferrin

Localisation and quantification of protein loss in protein-losing enteropathy (PLE) is useful in the clinical managment of hypoalbuminaemia. Indium-111 transferrin offers the opportunity of combining localisation and quantification using a single agent. Twenty-five studies were performed in 23 patients with suspected PLE:¹¹¹In-transferrin was prepared by incubating autologous cell-free plasma with¹¹¹In chloride in vitro for 15 min. Protein loss was quantified by comparing whole-body counts recorded with an uncollimated gamma camera at 3 h and 5 or 6 days after injection of¹¹¹In-transferrin. Gamma camera imaging performed at 3 and 24 h after injection demonstrated a site of protein loss in 15 studies. Whole-body¹¹¹In excretion was abnormally elevated in 13 of these, ranging from 16% to 34% (normal <10%), was not assessed in one and was less than 10% in a patient with carcinoid syndrome. In the ten studies that were negative on imaging, whole-body¹¹¹In excretion was normal in nine and elevated at 22% in a further patient with carcinoid syndrome. Overall, the mean whole-body¹¹¹In excretion in studies with positive imaging was 21.4% (SD 6.1%) (n=14), significantly higher (P<0.01) than in studies with negative imaging, in which it was 7.5% (SD 6.7%) (n=10). This technique should be useful for the combined approach of localising and quantifying protein loss in PLE.     

Histologic confirmation of microvascular hyperpermeability to macromolecular MR contrast medium in reperfused myocardial infarction

A macromolecular MR contrast medium (MMCM) designed to permit histochemical staining and specific tissue localization, albumin-(biotin)10-(Gd-DTPA)25 (Bio-Alb-Gd), was used in a rat model of reperfused myocardial infarction to confirm the presence and distribution of microvascular hyperpermeability. T1-weighted spin-echo images were acquired before and after administration of Bio-Alb-Gd. An avidin-biotin-complex (ABC) stain, specific for the biotinylated MR contrast medium, was used to define the MMCM distribution and to detect any regional change in micro-vascular permeability related to infarction. Immediately after Bio-Alb-Gd administration, the infarcted region was enhanced, with greatest signal intensity noted at the rim and less at the center. There was a gradual increase in signal intensity of the initially hypointense central region. The steady increase in signal intensity of the central region suggested convection transport of MMCM through the interstitial space and its influx into cellular compartment after leakage from the vascular compartment. Histologic findings confirmed regional microvascular hyperpermeability corresponding to the site of infarction and a predominant rim distribution of the MMCM. Bio-Alb-Gd was identified at high microscopic power in the intravascular, interstitial, and intracellular spaces at the periphery of reperfused infarcted myocardium. Bio-Alb-Gd can be used as an MR contrast medium in reperfused infarcted myocardium to confirm the existence and to localize altered microvascular permeability to macromolecules. Bio-Alb-Gd contrast technique removes all the ambiguity between the distribution of the MR or other imaging contrast agent and the distribution of the substrate for histochemical staining.     

Magnetic resonance microimaging for noninvasive quantification of myocardial function and mass in the mouse

The purpose of this work was to develop high-resolution cardiac magnetic resonance imaging techniques for the in vivo mouse model for quantification of myocardial function and mass. Eight male mice were investigated on a 7-Tesla MRI scanner. High-quality images in multiple short axis slices (in-plane resolution 117 μm², slice thickness 1 mm) were acquired with an ECG-gated cine sequence. Left ventricular end-diastolic and end-systolic volumes and mass were calculated from segmented slice volumes. There was precise agreement of left ventricular mass determined ex vivo and by MRI. lntraobserver (5%) and interobserver (5%) variability of in vivo MR measurements were low.     

Magnetic resonance-guided thermal surgery

A demonstration of MR guided thermal surgery involved experiments with imaging of focused ultrasound in an MRI system, measurements of the thermal transients and a thermal analysis of the resulting images. Both the heat distribution and the creation of focused ultrasound lesions in gel phantoms, in vitro bovine muscle and in vivo rabbit muscle were monitored with magnetic resonance imaging. Thermal surgical procedures were modeled by an elongated gaussian heat source where heat flow is controlled by tissue thermal properties and tissue perfusion. Temperature profiles were measured with thermocouples or calculated from magnetic resonance imaging in agreement with the model. A 2-s T₁-weighted gradient-refocused acquisition provided thermal profiles needed to localize the heat distribution produced by a 4-s focused ultrasound pulse. Thermal analysis of the images give an effective thermal diffusion coefficient of 0.0015 cm²/s in (gel and 0.0033 cm²/s in muscle. The lesions were detected using a T₂-weighted spin-echo or fast spin-echo pulse sequence in agreement with muscle tissue sections. Potential thermal surgery applications are in the prostate, liver, kidney, bladder, breast, eye and brain.     

Quantitative magnetic resonance imaging of capillary water permeability and regional blood volume with an intravascular MR contrast agent

A novel method is presented to simultaneously measure the permeability surface area product of water (PS), also known as capillary diffusion capacity, and the regional blood volume (RBV). It is based on magnetic resonance imaging of the longitudinal relaxation times of tissue and blood at different concentrations of an intravascular MR contrast agent. PS and RBV were measured in vivo in different regions of the brain and the skeletal muscle of the rat. The average PS values (n = 5) obtained in cerebral cortex, corpus callosum, hippocampus, thalamus, jaw muscle, and tongue muscle were 3.31 ± 0.20, 1.81 ± 0.25, 3.37 ± 0.36, 3.68 ± 0.44, 10.6 ± 1.1, and 14.1 ± 2.51 ml ± min^?1 ± g^?1, respectively. The corresponding average RBV values were 1.63 ± 0.18,1.22 ± 0.25,3.30 ± 0.37, 3.03 ± 0.36, 1.66 ± 0.30, and 1.38 ± 0.33 ml ± 100g^?1. These results are in good agreement with previously reported literature values obtained by means of autoradiography.     

MR assessment of fetal lung development using lung volumes and signal intensities

The purpose of this study was to evaluate the monitoring and diagnostic potential of MRI in fetal lung development and disease using lung volume and signal intensity changes through gestation. Thirty-five healthy fetuses (22–42 weeks) were examined on a 1.5- T MR system using sagittal T2w single-shot fast spin-echo imaging (TR indefinite, TE 90 ms, slice thickness/gap 3–5/0 mm, FOV 26–40 cm, NEX 0.5). Fetal body and lung were segmented manually and volumes calculated. Signal intensities (SI) of fetal lung and three reference values were measured on the section best displaying the lung. Regions of interests were defined by including the maximal organ area possible. The following SI ratios were generated: lung/liver, lung/amniotic fluid, lung/muscle, liver/fluid and liver/muscle. Volumes and ratios were correlated with gestational age. Data from seven fetuses with pulmonary pathology were compared with these normative values. Absolute lung volume varied from 12.3 to 143.5 cm³ in correlation with gestational age (P<0.001); lung volume relative to total body volume ranged from 1.6 to 5.0%, decreasing with gestational age (P=0.001). All SI ratios measured were unrelated to gestational age. Diagnoses in the seven abnormal fetuses were hydrothorax (n=2), congenital cystic adenomatoid malformation (n=2), diaphragmatic hernia (n=2) and pulmonary sequestration (n=1); their absolute and relative lung volumes were below normal (P<0.001). The SI ratios did not differ significantly from those in the normal population. Normative MR fetal lung volumes may have important clinical applications in confirming and quantifying intrauterine pulmonary hypoplasia and in complementing ultrasound in the planning of fetal and post-natal surgery. No clinical relevance was found for fetal lung SI values.     

1H MR Spectroscopy in Patients with Metastatic Brain Tumors: A Multicenter Study

In a cooperative study involving six clinical MR centers, localized ¹H MR spectroscopy was used to characterize untreated metastatic brain tumors (40 cases, 45 lesions). Cubic volumes (3.4 or 8 cm³) filled for more than 50% by metastatic brain tissue were examined by single-voxel double spin echo MRS, by using chemical shift selective imaging (CHESS) pulses for water suppression and TE = 135 ms. Choline (Cho), creatine (Cr) and N-acetyl aspartate (NAA) levels in brain metastases of mammary carcinoma (n = 13), lung cancer (n = 11) and melanoma (n = 10) were similar. Metastasis NAA/Cho signal intensity ratio varied between 0.00 and 1.17, compared with 2.68 ± 0.56 (SD) in lobus occipitalis and 1.94 ± 0.63 in corpus nuclei caudati region (P < 0.0001, both). ¹H MR spectroscopy, although not suited to recognize the primary tumor of metastases, could serve as a clinical test for excluding (metastatic) tumor as cause of solitary focal brain disorders that are hard to diagnose with current imaging methods.     

Studies on bromobenzene-induced hepatotoxicity using in vivo MR microscopy with surgically implanted RF coils

Using surgically implanted RF coils at 300 MHz, three-dimensional microscopic MR images of rat liver were obtained in vivo to follow the development of pathology induced by bromobenzene exposure. Formalin fixed specimens of liver from these animals were also imaged using in vitro MR microscopy, followed by conventional optical microscopy. All MR images were acquired using a spin-warp pulse sequence with TR = 950 ms and TE= 23 ms. The in vivo images were reconstructed as 256² × 32 arrays with a voxel size of (50 μm)² × 219 pm, while the in vitro images were reconstructed as 256² × 128 arrays, giving an isotropic resolution at (39 μm)². Based on results from six animals, we have found in all animals exposed to bromobenzene, image intensity decreased in specific hepatic tissue regions. These regions were well correlated to low signal intensity areas observed in in vitro MR images at higher resolution. Conventional optical microscopy indicated that the low signal intensity regions corresponded to areas of necrosis. The decrease in signal intensity is consistent with increased local diffusion coefficients as a result of necrosis. This study demonstrates that MR microscopy with implanted RF coils can be successfully used to follow tissue pathological changes in living tissues.     

Time and temperature dependence of MR parameters during thermal coagulation of ex vivo rabbit muscle

Detailed measurements of the T₁-weighted, T₂-weighted, and MT-weighted signal were performed for ex vivo muscle samples heated to various temperatures for different times. Consistent, monotonic increases in signal intensity were observed with progressive thermal coagulation, corresponding to an increase in T₂ relaxation time and an increase in MT-weighted signal for temperatures above 60°C. The relationship for T₁ relaxation was more complex, showing a decrease in T₁ relaxation from 40 to 60°C and an increase above 60°C. These techniques provide a more direct measure of tissue thermal coagulation than that provided by MR thermometry and suggest MR imaging strategies for the optimization and monitoring of thermal coagulation therapy protocols that create thermal damage in target tissues.     

Helium‐3 MR q‐space imaging with radial acquisition and iterative highly constrained back‐projection

An undersampled diffusion‐weighted stack‐of‐stars acquisition is combined with iterative highly constrained back‐projection to perform hyperpolarized helium‐3 MR q‐space imaging with combined regional correction of radiofrequency‐ and T₁‐related signal loss in a single breath‐held scan. The technique is tested in computer simulations and phantom experiments and demonstrated in a healthy human volunteer with whole‐lung coverage in a 13‐sec breath‐hold. Measures of lung microstructure at three different lung volumes are evaluated using inhaled gas volumes of 500 mL, 1000 mL, and 1500 mL to demonstrate feasibility. Phantom results demonstrate that the proposed technique is in agreement with theoretical values, as well as with a fully sampled two‐dimensional Cartesian acquisition. Results from the volunteer study demonstrate that the root mean squared diffusion distance increased significantly from the 500‐mL volume to the 1000‐mL volume. This technique represents the first demonstration of a spatially resolved hyperpolarized helium‐3 q‐space imaging technique and shows promise for microstructural evaluation of lung disease in three dimensions. Magn Reson Med, 2010. © 2009 Wiley‐Liss, Inc.     

Spin-lattice relaxation time measurement by means of a TurboFLASH technique

Rapid measurements of in vivo proton spin-lattice relaxation times (T₁) in human tissues were performed by magnetic resonance imaging in a 1.5 T whole-body super-conducting MR scanner. The measurements employ serial TurboFLASH imaging (Snapshot-FLASH) with scan times for a single experiment below 4 s. Using centric phase encoding order, an appropriate fitling of the T₁-parameter from images with minimum motion artifacts is possible. Comparative T₁-determination with a multipoint inversion recovery and spin-echo technique was performed on phantoms containing Gd-DTPA solutions with different T₁-values. We found a maximum deviation of 3.3% for T₁ < 1100 ms and of 12.1% for 1100 ms < T₁ < 1700 ms from the results obtained by the IR technique. In vivo measurements of T₁-relaxation times were performed in white and grey matter, cerebrospinal fluid, kidney, liver, spleen, muscle, and bone marrow, and yielded values that are in good agreement with reported data.     

Accumulation of immunoglobulin G at focal sites of inflammation

To evaluate the factors responsible for the accumulation indium-111 immunoglobulin Gr (¹¹¹InIgG) at sites of inflammation, sequential measurements of tissue blood volume, interstitial fluid volume and accumulation of radiolabelled albumin and IgG were made in rats following Escherichia coli infection in the thigh. Compared with normal thigh muscle, there was two-fold increase in interstitial fluid volume and 1.5-fold increase in plasma and red blood cell volumes in infected muscle. For both proteins, there was a fivefold increase in influx rate constant (kin) in infected muscle. In normal muscle, the interstitial fluid concentration of labelled human serum albumin (¹¹¹In-HSA) was significantly higher than that of ¹¹¹In-IgG (P<0.01). In contrast, the concentrations in infected muscle were nearly identical. The concentration ratios (infected to normal muscle) were 1.7:1 for HSA and 3:1 for IgG. These data suggest that the infection imaging properties of ¹¹¹In-IgG are related to expansion of the space available to macromolecules in infected tissue and increased transport into this space. At clinically important imaging times (24–48 h after injection), the higher target-to-background ratio of ¹¹¹In-IgG compared with ¹¹¹In-HSA is not due to the higher accumulation IgG in infected tissue but rather to the higher accumulation of HSA in normal tissue.Departments of Radiology and Medicine, Harvard Medical School, Boston, Mass., USA Offprint requests to: A.J. Fischman