Gd-DTPA Concentration Research Articles

Inflow effect correction in fast gradient-echo perfusion imaging.

The purposes of this study were to assess the extent of the inflow effect on signal intensity (SI) for fast gradient-recalled-echo (GRE) sequences used to observe first-pass perfusion, and to develop and validate a correction method for this effect. A phantom experiment with a flow apparatus was performed to determine SI as a function of Gd-DTPA concentration for various velocities. Subsequently a flow-sensitive calibration method was developed, and validated on bolus injections into an open-circuit flow apparatus and in vivo. It is shown that calibration methods based on static phantoms are not appropriate for accurate signal-to-concentration conversion in images affected by high flow. The flow-corrected calibration method presented here can be used to improve the accuracy and robustness of the arterial input function (AIF) determination for tissue perfusion quantification using MRI and contrast media.

Measuring the arterial input function with gradient echo sequences.

The measurement of the arterial input function by use of gradient echo sequences was investigated by in vitro and in vivo experiments. First, calibration curves representing the influence of the concentration of Gd-DTPA on both the phase and the amplitude of the MR signal were measured in human blood by means of a slow-infusion experiment. The results showed a linear increase in the phase velocity and a quadratic increase in DeltaR(*) (2) as a function of the Gd-DTPA concentration. Next, the resultant calibration curves were incorporated in a partial volume correction algorithm for the arterial input function determination. The algorithm was tested in a phantom experiment and was found to substantially improve the accuracy of the concentration measurement. Finally, the reproducibility of the arterial input function measurement was estimated in 16 patients by considering the input function of the left and the right sides as replicate measurements. This in vivo study showed that the reproducibility of the arterial input function determination using gradient echo sequences is improved by employing a partial volume correction algorithm based on the calibration curve for the contrast agent used.

Investigating the BOLD effect during infusion of Gd-DTPA using rapid T2* mapping.

This work aimed to investigate the effects of administering Gd-DTPA on the BOLD effect, and to determine the feasibility of using this approach to measure fractional changes in blood volume and blood oxygenation on neuronal activation during a visual paradigm. A linear relationship between cortical R(2)(*) and the intravascular concentration of Gd-DTPA was demonstrated. The change in R(2)(*) in the visual cortex on activation at 3 T (in the absence of Gd-DTPA) was found to be 1.38 +/- 0.31 s(-1) (N = 4). The fractional change in total blood volume during visual activation was calculated to be 28% +/- 7% (N = 4). The absolute increase in venous blood oxygenation on activation (DeltaY) was estimated to be 21% +/- 4% (N = 4) (assuming HCT = 0.4, resting blood oxygenation = 60%, fraction of volume change that was venous = 36%, and the resting venous fraction of the blood volume = 70%). Simulations showed that the estimated change in venous blood oxygenation was sensitive to the assumed venous blood fraction, and that the estimated fractional change in blood oxygenation was insensitive to whether the change in blood volume occurred in the arterial or venous network.

Can MTR be used to assess cartilage in the presence of Gd-DTPA2-?

Magnetization transfer (MT) and T(1) and T(2) relaxation of normal, trypsinized, and interleukin-1beta (IL-1beta)-treated cartilage were measured in the absence and presence of Gd-DTPA(2-). Without the addition of Gd-DTPA(2-), neither T(1) nor T(2) showed any significant change with cartilage damage. However, with Gd-DTPA(2-), trypsinized cartilage exhibited substantially shorter T(1) than normal cartilage, as expected due to the glycosaminoglycan (GAG) loss in these samples, and associated increased Gd-DTPA(2-) concentration. The T(2) results were similar, but less dramatic. The MT pseudo first-order exchange rate, RM(0B), did not depend on the contrast agent concentration, as expected, and was significantly faster for trypsinized and slower for IL-1beta-treated cartilage. In both cases, the MT fraction of the macromolecular pool M(0B) decreased while only trypsinized cartilage showed an increase in MT exchange rate R. The MT ratio (MTR) decreased with increasing Gd-DTPA(2-) concentration. However, interpretation of the MTR results in the presence of Gd-DTPA(2-) was complicated due to competing effects of increased longitudinal relaxivity and MT exchange. Therefore, in a cartilage sample with an unknown degree of GAG depletion and some collagen damage, a full MT analysis might be used to probe the molecular state of cartilage, but it would not be possible to use a simple MTR measurement after the administration of Gd-DTPA(2-) to differentially determine the amount of cartilage degradation in the sample.

Spatial assessment of articular cartilage proteoglycans with Gd-DTPA-enhanced T1 imaging.

In Gd-DTPA-enhanced T(1) imaging of articular cartilage, the MRI contrast agent with two negative charges is understood to accumulate in tissue inversely to the negative charge of cartilage glycosaminoglycans (GAGs) of proteoglycans (PGs), and this leads to a decrease in the T(1) relaxation time of tissue relative to the charge in tissue. By assuming a constant relaxivity for Gd-DTPA in cartilage, it has further been hypothesized that the contrast agent concentration in tissue could be estimated from consecutive T(1) measurements in the absence or presence of the contrast agent. The spatial sensitivity of the technique was examined at 9.4 T in normal and PG-depleted bovine patellar cartilage samples. As a reference, spatial PG concentration was assessed with digital densitometry from safranin O-stained cartilage sections. An excellent linear correlation between spatial optical density (OD) of stained GAGs and T(1) with Gd-DTPA was observed in the control and chondroitinase ABC-treated cartilage specimens, and the MR parameter accounted for approximately 80% of the variations in GAG concentration within samples. Further, the MR-resolved Gd-DTPA concentration proved to be an even better estimate for PGs, with an improved correlation. However, the linear relation between MR parameters and PG concentration did not apply in the deep tissue, where MR measurements overestimated the PG content. While the absolute [Gd-DTPA] determination may be prone to error due to uncertainty of relaxivity in cartilage, or to other contributing factors such as variations in tissue permeability, the experimental evidence highlights the sensitivity of this technique to reflect spatial changes in cartilage PG concentration in normal and degenerated tissue.

Does the application of gadolinium-DTPA have an impact on magnetic resonance phase contrast velocity measurements? Results from an in vitro study

Introduction/objective: To evaluate the potential influence of various concentrations of gadolinium (Gd)-DTPA on magnetic resonance phase contrast (MR PC) velocimetry. Material and methods: Imaging was done with a 1.0 T scanner using a standard Flash 2D sequence and a circular polarized extremity coil. In a validated flow phantom with a defined 75% area stenosis different concentrations of Gd-DTPA, diluted in a 10:1 water–yogurt mixture, MR PC measurements were correlated with a Doppler guide wire as gold standard. Results: MR PC measurements correlated well with the Doppler derived data ( r=0.99; P<0.01; maximum pre-stenotic velocity: 21.6±0.5 cm/s; maximum intra-stenotic velocity: 81.7±0.6 cm/s). Following Gd-DTPA administration no significant ( P>0.05; Student's t-test) flow measurement changes were noted (maximum pre-stenotic velocity: 21.3±1.3 cm/s; maximum intra-stenotic velocity: 84.0±3.6 cm/s). However, delineation of the perfused lumen was enhanced after the application of Gd-DTPA. Discussions and conclusion: The application of Gd-DTPA does not affect MR PC velocimetry. However, the application of contrast media allowed a more accurate vessel segmentation. MR PC measurements can be reliably carried out after application of Gd-DTPA.

T1 measurements in cell cultures: a new tool for characterizing contrast agents at 1.5T.

The objective of this work was to assess the feasibility and accuracy of T1 and relaxivity measurements in cell cultures using 1.5T magnetic resonance imaging (MRI) with the long-term goal to develop a tool for evaluation of novel paramagnetic agents in a realistic macromolecular environment. This initial study was carried out using MCF-7 cells treated with independently determined concentrations of Gd-DTPA. Two cell culture systems were evaluated: cell pellets and single layers of cells grown on microporous inserts. High-resolution T1 measurements of cell cultures were acquired with two dimensional Inversion Recovery Fast Spin Echo (2D-IR-FSE), three dimensional Inversion Recovery Fast Spin Echo (3D-IR-FSE), and 3D-SPGR sequences. The T1 and relaxivity accuracy of these sequences was confirmed with aqueous Gd-DTPA samples of known concentration. Relaxivities of 1.71 +/- 0.15 [mM(-1)second(-1)] and 1.55 +/- 0.50 [mM(-1)second(-1)] were measured in the cell pellets and cell monolayers, respectively, and were different from the value of 4.3 [mM(-1)second(-1)] for Gd-DTPA in water. Both cell pellets and monolayers are suitable for initial assessment of novel MR contrast agents.

Novel MRI Contrast Agent for Molecular Imaging of Fibrin

Molecular imaging of thrombus within fissures of vulnerable atherosclerotic plaques requires sensitive detection of a robust thrombus-specific contrast agent. In this study, we report the development and characterization of a novel ligand-targeted paramagnetic molecular imaging agent with high avidity for fibrin and the potential to sensitively detect active vulnerable plaques. The nanoparticles were formulated with 2.5 to 50 mol% Gd-DTPA-BOA, which corresponds to >50 000 Gd(3+) atoms/particle. Paramagnetic nanoparticles were characterized in vitro and evaluated in vivo. In contradistinction to traditional blood-pool agents, T1 relaxation rate as a function of paramagnetic nanoparticle number was increased monotonically with Gd-DTPA concentration from 0.18 mL. s(-1). pmol(-1) (10% Gd-DTPA nanoparticles) to 0.54 mL. s(-1). pmol(-1) for the 40 mol% Gd-DTPA formulations. Fibrin clots targeted in vitro with paramagnetic nanoparticles presented a highly detectable, homogeneous T1-weighted contrast enhancement that improved with increasing gadolinium level (0, 2.5, and 20 mol% Gd). Higher-resolution scans and scanning electron microscopy revealed that the nanoparticles were present as a thin layer over the clot surface. In vivo contrast enhancement under open-circulation conditions was assessed in dogs. The contrast-to-noise ratio between the targeted clot (20 mol% Gd-DTPA nanoparticles) and blood was approximately 118+/-21, and that between the targeted clot and the control clot was 131+/-37. These results suggest that molecular imaging of fibrin-targeted paramagnetic nanoparticles can provide sensitive detection and localization of fibrin and may allow early, direct identification of vulnerable plaques, leading to early therapeutic decisions.

Optimal dose of Gd-DTPA in dynamic MR studies.

The relationship between the administered dose d of Gd-DTPA and the accuracy of measurements of the glomerular filtration rate G and the cardiac output O was investigated. For a wide range of values the concentration of Gd-DTPA can be uniquely derived from MR signals and precontrast longitudinal relaxation time. Fixed and random errors in these measured variables were analyzed. Depending on noise level and the level of renal function, errors in G reach a minimum for d = 1.4-2.8 mmol. Random errors in G are relatively insensitive to d as long as d > 1.5 mmol. These results establish the feasibility of dynamic MR measurements using doses of Gd-DTPA that are several times lower than current standards.

The use of Gd-DTPA as a marker of myocardial viability in reperfused acute myocardial infarction.

At present, accurate assessment of the extent of myocardial viability after acute myocardial infarction is limited due to the spatial resolution of currently available imaging modalities. MR cardiac imaging, with its superior spatial resolution, would be used if viable and infarcted tissue could be separated based on signal intensity. In infarcted tissue, cell membrane breakdown allows the entry of the MR contrast agent Gd-DTPA which is normally extracellular. The increased space for Gd-DTPA distribution (partition coefficient, lambda) in this infarcted tissue results in increased Gd-DTPA concentration and hence increased signal intensity on T1-weighted MR images. In a canine model of ischemia/reperfusion injury, the partition coefficient in infarcted tissue increased as early as 1 min post reperfusion. lambda in infarcted tissue stayed increased over that in normal tissue for at least 8 weeks. The accuracy of contrast-enhanced MRI was confirmed by results of 201Tl SPECT and a cine MRI dobutamine wall motion study in a patient 1 week after an acute myocardial infarction. Thus, contrast-enhanced MRI shows great promise for the non-invasive determination of myocardial viability after acute myocardial infarction.

Measurement of the extracellular volume of human melanoma xenografts by contrast enhanced magnetic resonance imaging

The magnitude of the extracellular volume fraction (ECV) of tumors is of importance for the transport of macromolecular therapeutic agents from the vessel wall to the tumor cells. The aim of this study was to develop a method for measurement of tumor ECV by contrast enhanced MRI. Tumors of two human amelanotic melanoma xenograft lines (A-07 and R-18) grown intradermally in Balb/c nu/nu mice were used as model system, and muscle tissue was used as control. The renal arteries of the mice were ligated prior to i.v. administration of Gd-DTPA, and an MRI protocol for calculating Gd-DTPA concentration in tissue was followed. ECV was calculated from the Gd-DTPA concentrations in the tissue and in a plasma sample. In muscle tissue, the concentration reached a constant level after 1 min and the ECV was calculated to be 0.12 (± 0.01), consistent with values reported in the literature. Individual tumors showed large differences in the uptake of Gd-DTPA. The Gd-DTPA concentration in the tissue at 40 min after the Gd-DTPA administration was used to calculate tumor ECV. The ECV was found to differ significantly among regions of individual tumors and among individual tumors. The ECV ranged from 0.075 to 0.33 for A-07 tumors and from 0.016 to 0.097 for R-18 tumors. The intra- and intertumor heterogeneity in ECV was confirmed by histologic findings, showing that contrast enhanced MRI is suitable for non-invasive studies of the ECV in experimental tumors without necrosis.

Gd-DTPA relaxivity depends on macromolecular content.

Gd-DTPA T(1) relaxivity of water protons was measured at 1.5 T and room temperature as a function of macromolecular content in model systems. Gd-DTPA relaxivity was found to increase with macromolecular concentration. The results of this study indicate that the Gd-DTPA relaxivity in tissue extracellular compartment could be as much as 30-70% higher than that of Gd-DTPA in saline. Quantitative MR analyses that use T(1) as an estimation of local Gd-DTPA concentration require a priori determination of the Gd relaxivity in tissue.

Phantom and in vivo study of the look–locher T 1 mapping method

This paper describes and tests the LL-EPI method for obtaining quantitative T 1 estimates in a few seconds thereby allowing dynamic T 1 studies. It is shown that the method works even when there is an inflow into the imaged volume, e.g., in a vessel. No calibration is needed. The method has been tested in a phantom study with several different scan parameter set-ups, with and without inflow. The method shows robustness and individual scan parameters and inflow rates do not influence the ability to calculate the Gd-DTPA concentration. Linearity prevail between the measured 1/T 1 and the Gd-DTPA concentration in the range 150 < T 1 < 2500 ms. In a dynamic Gd-DTPA phantom study, it was shown that the dynamic LL-EPI T 1 mapping technique was three times more sensitive than the signal from a T ∗ 2-weighted EPI sequence. In an in vivo study, dynamic T 1 mapping of the Gd-DTPA uptake in a meningioma was performed. Inspection of the uptake curves indicates that the method is feasible in clinical perfusion studies.

Determination of in vivo rat muscle Gd-DTPA relaxivity at 6.3 T.

For the in vivo relaxivity of Gd-DTPA at 6.3 T in rat muscle a value of 2.7+/-0.5 (mM s)(-1) was found, and for the in vitro value in water 3.00+/-0.56 (mM s)(-1) at 37 degrees C. The temperature dependence of the in vitro relaxivity was -0.087 (mM s degrees C)(-1). The relation between 1/T1 and the tissue Gd-DTPA concentration is linear for the normally used in vivo Gd-DTPA concentration range.

Equilibrium transcytolemmal water-exchange kinetics in skeletal muscle in vivo

It is commonly assumed that equilibrium transcytolemmal water exchange in tissue is sufficiently frequent as to be fast on any NMR time scale achievable with an extracellular contrast agent (CR) in vivo. A survey of literature values for cell membrane diffusional permeability coefficients (P) and cell sizes suggests that this should not really be so. To evaluate this issue experimentally, we used a programmed intravenous CR infusion protocol for the rat with several rate plateaus, each of which achieved an increased steady-state concentration of GdDTPA(2-) in the blood plasma. Interleaved rigorous measurements of (1)H(2)O inversion recoveries were made from arterial blood and from a region of homogeneous thigh muscle tissue throughout the CR infusion. We made careful relaxographic analyses for the blood and muscle (1)H(2)O longitudinal relaxation times. The combined data from several animals were evaluated with a two-site model for equilibrium transcytolemmal water exchange. An excellent fitting was achieved, with parameters that agreed very well with the relevant physiological properties available in the literature. The fraction of water in the extracellular space, 0.11, is quite consistent with published values, as well as with reported tissue CR concentrations when one accounts for the restriction of CR to this space. The derived average lifetime for a water molecule in the thigh muscle sarcoplasm, 1.1 +/- 0.4 sec, implies a sarcolemmal P of 13 x 10(-4) cm/sec, which is well within the range of literature values determined in vitro. Moreover, we find that because of the exchange, the (1)H(2)O longitudinal relaxation rate constant exhibits a decided nonlinear dependence on the tissue or thermodynamic (extracellular) concentration of GdDTPA(2-). The muscle system departs the fast-exchange limit at a [CR] value of <100 micromol/L. This has significant implications for the quantitative use of CRs as MRI tracers. Magn Reson Med 42:467-478, 1999. Published 1999 Wiley-Liss, Inc.

Chitosan-gadopentetic acid complex nanoparticles for gadolinium neutron-capture therapy of cancer: preparation by novel emulsion-droplet coalescence technique and characterization.

The gadopentetic acid (Gd-DTPA)-loaded chitosan nanoparticles (Gd-nanoCPs) were prepared for gadolinium neutron-capture therapy (Gd-NCT) and characterized and evaluated as a device for intratumoral (i.t.) injection. Gd-nanoCPs were prepared by a novel emulsion-droplet coalescence technique. The effects of the deacetylation degree of chitosan and Gd-DTPA concentration in chitosan medium on the particle size and the gadolinium content in Gd-nanoCPs were examined. In vitro Gd-DTPA release from Gd-nanoCPs was evaluated using an isotonic phosphate-buffered saline solution (PBS, pH 7.4) and human plasma. In vivo Gd-DTPA retention in the tumor after i.t. injection of Gd-nanoCPs was estimated on mice bearing s.c. B16F10 melanoma. Gd-nanoCPs with the highest Gd content, which were obtained using 100% deacetylated chitosan in 15% Gd-DTPA aqueous solution, were 452 nm in diameter and 45% in Gd-DTPA content. A lower deacetylation degree of chitosan led to an increase in particle size and a decrease in Gd-DTPA content in Gd-nanoCPs. As Gd-DTPA concentration in the chitosan solution increased, Gd-DTPA content in Gd-nanoCPs increased but the particle size did not vary. Gd-DTPA loaded to Gd-nanoCPs was hardly released over 7 days in PBS (1.8%) despite the high water solubility of Gd-DTPA. In contrast, 91% of Gd-DTPA was released in plasma over 24 hours. When Gd-nanoCPs were i.t. injected, 92% of Gd-DTPA injected effectually without outflow was held in the tumor tissue for 24 hours, which was different from the case of gadopentetate solution injection (only 1.2%). Gd-nanoCPs highly incorporating Gd-DTPA were successfully prepared by the emulsion-droplet coalescence technique. Their releasing properties and their ability for long-term retention of Gd-DTPA in the tumor indicated that Gd-nanoCPs might be useful as an i.t. injectable device for Gd-NCT.

Preparation of gadopentetic acid-loaded chitosan microparticles for gadolinium neutron-capture therapy of cancer by a novel emulsion-droplet coalescence technique.

Biodegradable gadopentetic acid (Gd-DTPA)-loaded chitosan microparticles (Gd-microCPs) were prepared as a device for gadolinium neutron-capture therapy (Gd-NCT) by a novel emulsion-droplet coalescence technique: a water-in-oil (w/o) emulsion A containing chitosan and Gd-DTPA in droplets and a w/o emulsion B containing NaOH in droplets were mixed and stirred to solidify chitosan as a result of collision and coalescence between droplets of each emulsion. Gd-microCPs prepared by using 100% deacetylated chitosan in 25% Gd-DTPA solution were 4.1 microns (non-lyophilized) and 3.3 microns (lyophilized) in mass median diameter, and were 3.4% in gadolinium content, corresponding to 11.7% as Gd-DTPA. The particle size and gadolinium content of Gd-microCPs were not affected by Gd-DTPA concentration in the chitosan medium. However, the deacetylation degree of chitosan influenced the particle size; as the deacetylation degree of chitosan decreased, the particle size increased. The incorporated Gd-DTPA was not released entirely from Gd-microCPs in an isotonic phosphate buffered saline solution despite the high water-solubility of Gd-DTPA (less than 0.8% with every type of Gd-microCPs). These results indicated that ion-complex formation might be contributable to incorporation of Gd-DTPA. As a preliminary study, it was confirmed that the loss of gamma-ray emission by gadolinium-loading in microparticle was negligible in the thermal neutron irradiation test in vitro. These results suggested that Gd-microCPs could be a useful device for intratumoral injection into solid tumor on Gd-NCT.

In vivo measurement of T 1 and T 2 relaxivity in the kidney cortex of the pig—based on a two-compartment steady-state model

A two-compartment system for approximating five successive steady-state levels of gadopentetate dimeglumine (Gd-DTPA) concentration in pigs was developed. The method of calculating Gd-DTPA concentration was based on a simultaneous reference determination of 99mTc-DTPA. Experimental and theoretical results showed a steady state after 25 min. The nuclear magnetic resonance (NMR) relaxivities of Gd-DTPA were determined in vivo in pig kidneys during steady-state levels. T 1 relaxivity (R 1) and T 2 relaxivity (R 2) in the kidney cortex were found to be 1.1 ± 0.03 and 2.0 ± 0.2 (s −1 m M −1), respectively. R 1 and R 2, in in vitro human plasma solutions at 25°C were 5.3 ± 0.02 and 5.8 ± 0.06 s −1 m M −1 and at 37°C 4.3 ± 0.04 and 4.9 ± 0.01 s −1 m M −1. Thus, the in vivo relaxivities were reduced 3.9 and 2.5 times for R 1 and R 2, respectively, compared to the in vitro relaxivities. This marked difference in relaxivities between tissue and plasma may be the result of the difference in steric relations. In plasma, the mobility and distribution of the Gd-DTPA complex are unrestricted, whereas they may be reduced in the tissues because of the close proximity to the cell wall, to the proteins and to other extracellular elements and compartments. Keywords: Gd-DTPA; 99mTc-DTPA; Relaxivity; Kidney.

Magnetic resonance imaging relaxation times and gadolinium-DTPA relaxivity values in human cerebrospinal fluid.

This study was conducted to prove the feasibility of using cerebrospinal fluid (CSF) T1 and T2 measurements to assess the blood-brain barrier integrity in disease states not noted for focal blood-brain barrier disruption, such as Alzheimer's disease. T1 and T2 of human CSF samples were measured with and without gadolinium Gd-DTPA over a concentration range of 1.98 x 10(-3) to 6.32 mM, in a GE 1.5-T Signa scanner. T1 and T2 of human CSF without Gd-DTPA were measured as 2.39 and 0.23 s. K1 and K2 were calculated as 6.25 and 6.74 mM(-1) s(-1). The lowest Gd-DTPA concentration with measurable T1 and T2 was 1.98 x 10(-3) mM. There is no statistically significant difference in T2 and K2 at different repetition times. This work demonstrates that a single measurement of relaxation times after contrast-enhanced magnetic resonance imaging could be used to determine the Gd-DTPA concentration in CSF. It may thus be feasible, using this technique, to measure intersubject and intraregional variability in the quantity of Gd-DTPA transferred across the blood-brain barrier after intravenous injection of contrast agent.

MRI quantitative myocardial perfusion with compartmental analysis: A rest and stress study

K1 (first-order transfer constant from arterial plasma to myocardium for Gd-DTPA) and Vd (distribution volume of Gd-DTPA in myocardium) were measured in vivo in a canine model (n = 5) using MRI-derived myocardial perfusion curves and a compartmental model. Perfusion curves were obtained after a bolus injection of Gd-DTPA (0.04 mM/kg) with an inversion-prepared fast gradient echo sequence. Myocardium and blood signal intensity were converted to a concentration of Gd-DTPA, according to a model appropriate for short (<1 s) interimage intervals characteristic of cardiac-triggered acquisitions. Before dipyridamole-induced stress, K1 and Vd, obtained from the fit of the MRI-derived perfusion curves, were 6.2 +/- 1.4 (mHz) and 17.5 +/- 4.2%, respectively. After dipyridamole infusion, a K1 increase of a factor of 2.82 +/- 0.72 was measured (P = 0.003). No change was observed in Vd (P = 0.98). These results suggest that the K1 increase after dipyridamole reflects a flow-related effect that can be useful to quantify the MRI-derived perfusion curves.