A field comparison of r1 and r2* relaxivities of Gd-DTPA in aqueous solution and whole blood: 3T versus 7T

INTRODUCTION: Gd-DTPA (MagnevistTM) is one of the most widely used MRI contrast agents (CAs) today. The relaxation enhancement of Gd-DTPA depends on its relaxivity which in turn depends on factors like magnetic field strength, macromolecular content, pH and temperature.[1, 2, 3, 4] Knowledge of relaxivity is essential in many MRI areas. The Gd-DTPA concentration ([Gd]) is calculated from signal enhancement in DCE-MRI studies using r1 relaxivity value assuming a linear relationship between [Gd] and longitudinal relaxation rate (R1). While r1 relaxivity has been shown to slightly decrease [1] with increasing field strength, r2* relaxivity increases and can dominate signal changes especially at higher CA concentrations. In addition, the strong effect of compartmentalization on T2* shortening can also change the shape of the contrast enhancement curve in tissue and thus the quantification of pharmacokinetic parameters in DCE MRI studies. [5] By knowing the r1 and r2* values and hence the calibration curve for blood and aqueous solution one can potentially determine [Gd] in vivo for human blood and extravascular extracellular space. The goal of this study was to measure r1 and r2* relaxivity of Gd-DTPA in bovine blood and aqueous solution at 3T and 7T. To our knowledge this is the first time that the r2* characteristic for blood has been measured at 7T. METHODS: Commercially available formulation of Gd-DTPA (Magnevist, Bayer Healthcare Pharmaceuticals Inc. Wayne, NJ) having a concentration of 0.5 M was mixed with bovine blood and aqueous solution (pH 7) in 50 ml centrifuge tubes to obtain final concentrations of 20, 10, 5, 2.5, 1.0, 0.5, 0.25, 0.12, 0.06, 0.03, 0.01 and 0.008 mM by serial dilution. Bovine Blood was obtained from a slaughterhouse (Dakota Premium Foods, St Paul, MN). Bovine erythrocytes have similar shape, size, and water permeability as human cells [6].The blood was treated with Heparin (Elkins-Sinn, Cherry Hill, NJ) and used within 2 days. Sodium Azide was added to the blood samples as a preservative. Aqueous solutions of pH 7 were made using 1 M HEPES buffer solution (Sigma Aldrich, Switzerland).Thirteen test tubes of Gd-DTPA solutions were placed inside a plastic container which in turn was put in a plastic trough. Both the container and the trough were filled with 0.45% saline solution. This was done to ensure field homogeneity over the phantom, for loading the transmit coil and for efficient heat transfer from the water bath hoses. All studies were performed at a constant temperature of 37±1°C maintained by surrounding the plastic container with hoses from a heated bath (Thermo Scientific Neslab RTE7 Digital One). The complete phantom setup is shown in figure 1. The temperature was monitored using a thermistor (YSI 400 series) and DigiSense (Cole-Parmer) Temperature Controller. All 3T measurements were performed on a Siemens Magnetom Trio scanner. Signal detection was achieved using a 12 channel head coil. RF transmission was performed using the scanner body coil. All 7T measurements were done on a Magnex 7T, 90 cm bore magnet with Siemens console and head gradients using a trasceive head coil. T1 Measurement: An IR-Turbo Flash (TFL) sequence with a slice selective π pulse was used. Other values included: TR, 10 s; TE, 1.26ms; Flip angle, 8°; Acquisition matrix, 1282; Field of view, 180mm(7T), 280mm(3T) ; Slice thickness, 3.5mm; Number of Averages, 2. The inversion time (TI) was varied from 23ms to 8850ms. Average MR signal intensities were obtained from selected ROIs in the TFL images. We assumed a negligible T2* effect across each ROI after localized B0 shimming was performed.. The T1 values were obtained by fitting the ROI signal intensities for different TI values. A linear relationship between R1 (R1= 1/T1) and [Gd] was assumed to calculate r1. T1 IR-TFL Measurement Validation: T1 measurement done using the IR-TFL method was validated by using the inversion recovery spin echo (IRSE; TR, 3s; TE, 11ms; Flip angle, 90°; Acquisition matrix, 2562; Field of view, 300mm; Slice thickness, 5mm; Number of Averages, 1; TI, 23ms) sequence for the same measurement at 3T.A mono-exponential, three parameter curve fit program written in IDL (ITT, Visual Information Solutions, Boulder, CO) and linear fitting routines in Origin (OriginLab Corp., Northampton, MA) were used to calculate the T1 and T2* values. r1 Measurement: T1 values for lower concentrations (05mM) were obtained by the IR-TFL method. The DESPOT method (3D Acquisition, TR, 14ms; TE, 10ms; Flip angles, 20° and 60°; Acquisition matrix, 1282; Field of view, 300mm; Slice thickness, 2mm; Number of Averages, 1) was used to obtain the T1 values for high concentrations (5-25mM). T2* Measurement: A multi-echo gradient echo sequence was used. Other values included: TR, 100ms; min TE, 1.84ms(7T), 1.67ms(3T); Flip angle, 10°; Field of view, 280mm; Slice thickness, 3mm; Number of Averages, 4.RESULTS: The r1 values reported in table 1 are obtained from the IR-TFL method. The TFL values differed by 3% to those obtained using the IRSE method.The errors take into consideration the error propagation from volumetric analysis, non linear fit (T1& T2* calculation) and linear fits (r1 & r2* calculation). The standard error in the fitting parameters is calculated from the square root of a main diagonal value of the variance-covariance matrix. Linear relationship between the [Gd] and R1 was observed only till 5 mM using the IR-TFL method. The difference between the r1 values calculated using the IR-TFL and DESPOT method was ~ 16%. As can be seen from table 1, the r1 values for aqueous solution and bovine blood decrease with increasing magnetic field strength as expected. Table 2 shows that there exists a linear relationship between R2* and [Gd] for aqueous solutions. A quadratic relationship between the ΔR2* signal and [Gd] in blood has been demonstrated by Osch et al. [7] as shown in (1) where c1, c2 are constants and Hct is the hematocrit level. Table 2 shows that R2* relaxation rate follows a quadratic relationship with [Gd] in the case of blood given by