Friedrich M. Cavagna

Gadolinium chelates with weak binding to serum proteins. A new class of high-efficiency, general purpose contrast agents for magnetic resonance imaging.

RATIONALE AND OBJECTIVES The authors assess the effect of weak protein binding on the efficacy of gadolinium chelates as contrast agents for magnetic resonance imaging (MRI). METHODS Chelates with no (gadopentetate dimeglumine), weak (gadobenate dimeglumine), and strong (B-21326/7) protein binding were compared by in vitro MRI at 2T (spin echo [SE]: repetition time [TR]/echo time [TE] 350/8 mseconds) on solutions in 0.5 mM bovine serum albumin and in rat whole blood, and by in vivo MRI at 2T on rat models of brain tumors (SE TR/TE 350/10 mseconds) and of focal blood-brain barrier disruption (SE TR/TE 400/15 mseconds) after injection of MPP+. Relaxation rate enhancement in the blood of normal rabbits was measured in vivo after administration of contrast agents using IR-Snapshot FLASH. RESULTS Signal intensity enhancement measured in vitro for whole rat blood 0.1 mM in gadobenate was 142% relative to the same concentration of gadopentetate. Peak signal intensity enhancement in brain tumors was 87% +/- 8% and 64% +/- 5% after 0.1 mmol/kg intravenous administration of gadobenate and gadopentetate, respectively; in MPP+ lesions, the peak signal intensity enhancement was 22% +/- 9%, 32% +/- 7%, and 64% +/- 14% after 0.2 mmol/kg intravenous of gadopentetate, gadobenate, and B-21326/7, respectively. In rabbits, the relaxation enhancement of blood 5 minutes after B-21326/7 and gadobenate administration was 323% and 182%, respectively, relative to the same dose (0.1 mmol/kg intravenous) of gadopentetate. CONCLUSIONS Weak protein binding can substantially increase the efficacy of gadolinium chelates as general purpose contrast agents for MRI.

Detection of the effects of dopamine receptor supersensitivity using pharmacological MRI and correlations with PET

Receptor supersensitivity is an important concept for understanding neurotransmitter and receptor dynamics. Traditionally, detection of receptor supersensitivity has been performed using autoradiography or positron emission tomography (PET). We show that use of magnetic resonance imaging (MRI) not only enables one to detect dopaminergic supersensitivity, but that the hemodynamic time course reflective of this fact is different in different brain regions. In rats unilaterally lesioned with intranigral 6‐hydroxydopamine, apomorphine injections lead to a large increase in hemodynamic response (cerebral blood volume, CBV) in the striato‐thalamo‐cortico circuit on the lesioned side but had little effect on the intact side. Amphetamine injections lead to increases in hemodynamic responses on the intact side and little on the lesioned side in the same animals. The time course for the increase in CBV after either amphetamine or apomorphine administration was longer in striatum and thalamus than in frontal cortex. 11C‐PET studies of ligands which bind to the dopamine transporter (2‐β‐carbomethoxy‐3‐β‐(4‐fluorophenyl)tropane 1,5‐naphthalnendisulfonate, WIN 35, 428 or CFT) and D2 receptors (raclopride) confirm that there is a loss of presynaptic dopamine terminals as well as upregulation of D2 receptors in striatum in these same animals. Pharmacologic MRI should become a sensitive tool to measure functional supersensitivity in humans, providing a complementary picture to that generated using PET studies of direct receptor binding. Synapse 36:57–65, 2000.

Improved mapping of pharmacologically induced neuronal activation using the IRON technique with superparamagnetic blood pool agents

The use of functional magnetic resonance imaging (fMRI) techniques for evaluation of pharmacologic stimuli has great potential for understanding neurotransmitter dynamics for a number of brain disorders, such as drug abuse, schizophrenia, epilepsy, or neurodegeneration. Unfortunately, blood oxygenation level‐dependent (BOLD) imaging at common fields strengths, such as 1.5 or 3 T, has very low sensitivity and contrast‐to‐noise ratios (CNRs). We demonstrate here the utility of using an intravascular superparamagnetic iron oxide contrast agent with a long plasma half‐life for evaluation of hemodynamic changes related to dopaminergic stimuli using amphetamine or the cocaine analog 2β‐carbomethoxy‐3β‐(4‐fluorophenyl)tropane (CFT). We refer to this technique as increased relaxation with iron oxide nanoparticles (IRON). Results obtained here show that even at field strengths as high as 4.7 T, one can obtain increases in CNR by factors of 2–3 over BOLD imaging that lead to greater than an order of magnitude increase in statistical power with greatly increased sensitivity to hemodynamic changes in brain regions difficult to observe using BOLD imaging. Furthermore, use of the intravascular contrast agent allows for a meaningful physiologic parameter to be measured (relative cerebral blood volume (rCBV)), compared to conventional BOLD imaging. J. Magn. Reson. Imaging 2001;14:517–524.

Identification of myocardial reperfusion with echo planar magnetic resonance imaging. Discrimination between occlusive and reperfused infarctions.

BackgroundThe current treatment of many cases of acute myocardial infarction involves the use of thrombolytic agents. Evaluation of this therapy requires determination of the success of reperfusion and assessment of the presence and extent of infarction in the reperfused territory. The present study was designed to simulate in rat models several possible outcomes of reperfusion therapy: (1) successful reperfusion and absence of myocardial infarction, (2) successful reperfu-sion and presence of myocardial infarction, and (3) unsuccess-ful reperfusion. The usefulness of contrast-enhanced fast magnetic resonance (MR) imaging in defining the success of reperfusion was investigated. The dynamic effects were examined of low and high doses of gadolinium-BOPTA/dimeglu-mine (Gd-BOPTA/dimeg) on myocardial signal using MR inversion recovery echo planar imaging (IR-EPI) and gradient recalled echo planar imaging (GR-EPI), respectively. Methods and ResultsRats were subjected to one of the following regimens: reperfused reversible myocardial injury (n=9), reperfused irreversible myocardial injury (n=9), and occlusive infarction (n=9). MR echo planar images were acquired every 1 or 2 seconds before, during, and after administration of Gd-BOPTA/dimeg. In all groups, normal myocardial signal was sharply increased on IR-EPI and decreased on GR-EPI at the peak of the bolus, followed by a gradual decline to baseline. In animals subjected to reperfused reversible myocardial injury, normal and previously ischemic regions were indistinguishable during and after the passage of Gd-BOPTA/dimeg. On the other hand, enhancement of reperfused irreversibly injured myocardium was delayed but increased steadily to a higher level than normal myocardium on IR-EPI. The reperfused irreversibly injured myocardium was identified on IR-EPI as a zone of high signal (hot spot). On GR-EPI, signal loss in reperfused irreversibly injured myocardium was significantly less compared with normally perfused myocardium. In animals with occlusive infarctions, there was no change in signal intensity over the ischemic region on either IR-EPI or GR-EPI. Occlusive infarction was identified as zones of either low (cold spot) or high (hot spot) signal compared with normal myocardium, depending on MR pulse sequence and dose of the contrast medium. ConclusionsThe transit of Gd-BOPTA/dimeg monitored by fast MR imaging techniques can be used to distinguish between reperfused reversibly and reperfused irreversibly injured myocardium and between occlusive and reperfused infarctions.

Alterations in T1 of normal and reperfused infarcted myocardium after Gd‐BOPTA versus GD‐DTPA on inversion recovery EPI

This study tested whether Gd‐BOPTA/Dimeg or Gd‐DTPA exerts greater relaxation enhancement for blood and reperfused infarcted myocardium. Relaxivity of Gd‐BOPTA is increased by weak binding to serum albumin. Thirty‐six rats were subjected to reperfused infarction before contrast (doses = 0.05, 0.1, and 0.2 mmol/kg). ΔR1 was repeatedly measured over 30 min. Gd‐BOPTA caused greater ΔR1 for blood and myocardium than did Gd‐DTPA clearance of both agents from normal and infarcted myocardium was similar to blood clearance; plots of ΔR1myocardium/ΔR1blood showed equilibrium phase contrast distribution. Fractional contrast agent distribution volumes were approximately 0.24 for both agents in normal myocardium, 0.98 and 1.6 for Gd‐DTPA and Gd‐BOPTA, respectively, in reperfused infarction. The high value for Gd‐BOPTA was ascribed to greater relaxivity in infarction versus blood. It was concluded that Gd‐BOPTA/Dimeg causes a greater ΔR1 than Gd‐DTPA in regions which contain serum albumin.

Improved three-dimensional free-breathing coronary magnetic resonance angiography using gadocoletic acid (B-22956) for intravascular contrast enhancement

To evaluate gadocoletic acid (B‐22956), a gadolinium‐based paramagnetic blood pool agent, for contrast‐enhanced coronary magnetic resonance angiography (MRA) in a Phase I clinical trial, and to compare the findings with those obtained using a standard noncontrast T2 preparation sequence.

Detection of coronary stenoses with contrast enhanced, three-dimensional free breathing coronary MR angiography using the gadolinium-based intravascular contrast agent gadocoletic acid (B-22956)

PURPOSE To determine the diagnostic value of the intravascular contrast agent gadocoletic acid (B-22956) in three-dimensional, free breathing coronary magnetic resonance angiography (MRA) for stenosis detection in patients with suspected or known coronary artery disease. METHODS Eighteen patients underwent three-dimensional, free breathing coronary MRA of the left and right coronary system before and after intravenous application of a single dose of gadocoletic acid (B-22956) using three different dose regimens (group A 0.050 mmol/kg; group B 0.075 mmol/kg; group C 0.100 mmol/kg). Precontrast scanning followed a coronary MRA standard non-contrast T2 preparation/turbo-gradient echo sequence (T2Prep); for postcontrast scanning an inversion-recovery gradient echo sequence was used (real-time navigator correction for both scans). In pre- and postcontrast scans quantitative analysis of coronary MRA data was performed to determine the number of visible side branches, vessel length and vessel sharpness of each of the three coronary arteries (LAD, LCX, RCA). The number of assessable coronary artery segments was determined to calculate sensitivity and specificity for detection of stenosis > or = 50% on a segment-to-segment basis (16-segment-model) in pre- and postcontrast scans with x-ray coronary angiography as the standard of reference. RESULTS Dose group B (0.075 mmol/kg) was preferable with regard to improvement of MR angiographic parameters: in postcontrast scans all MR angiographic parameters increased significantly except for the number of visible side branches of the left circumflex artery. In addition, assessability of coronary artery segments significantly improved postcontrast in this dose group (67 versus 88%, p < 0.01). Diagnostic performance (sensitivity, specificity, accuracy) was 83, 77 and 78% for precontrast and 86, 95 and 94% for postcontrast scans. CONCLUSIONS The use of gadocoletic acid (B-22956) results in an improvement of MR angiographic parameters, asssessability of coronary segments and detection of coronary stenoses > or = 50%.

Whole-heart coronary vein imaging: a comparison between non-contrast-agent- and contrast-agent-enhanced visualization of the coronary venous system.

The feasibility of three‐dimensional (3D) whole‐heart imaging of the coronary venous (CV) system was investigated. The hypothesis that coronary magnetic resonance venography (CMRV) can be improved by using an intravascular contrast agent (CA) was tested. A simplified model of the contrast in T2‐prepared steady‐state free precession (SSFP) imaging was applied to calculate optimal T2‐preparation durations for the various deoxygenation levels expected in venous blood. Non‐contrast‐agent (nCA)‐ and CA‐enhanced images were compared for the delineation of the coronary sinus (CS) and its main tributaries. A quantitative analysis of the resulting contrast‐to‐noise ratio (CNR) and signal‐to‐noise ratio (SNR) in both approaches was performed. Precontrast visualization of the CV system was limited by the poor CNR between large portions of the venous blood and the surrounding tissue. Postcontrast, a significant increase in CNR between the venous blood and the myocardium (Myo) resulted in a clear delineation of the target vessels. The CNR improvement was 347% (P < 0.05) for the CS, 260% (P < 0.01) for the mid cardiac vein (MCV), and 430% (P < 0.05) for the great cardiac vein (GCV). The improvement in SNR was on average 155%, but was not statistically significant for the CS and the MCV. The signal of the Myo could be significantly reduced to about 25% (P < 0.001). Magn Reson Med 57:1019–1026, 2007.

Mismatch between cerebral blood volume and flow index during transient focal ischemia studied with MRI and GD-BOPTA.

We investigated the regional and temporal changes in cerebral blood volume (CBV), cerebral blood flow (CBF), and vascular transit time in seven mongrel cats during 30 min transient focal ischemia, caused by occlusion of the middle cerebral artery. Dynamic susceptibility contrast magnetic resonance imaging was done at 4.7 T, using fast gradient echo T2* weighted imaging and intravenous injection of gadolinium-BOPTA/Dimeglumine. During occlusion, the areas showing a blood volume change were predominantly within the middle cerebral artery territory and could be divided into areas showing either CBV increases or decreases. The area with decreased blood volume also had decreased blood flow as measured by our flow-based index (p < 0.05) and was located in the central territory of the middle cerebral artery. Peripheral to this region was an area showing increased blood volume but without significant CBF changes (p > 0.05). During reperfusion, the CBF increased in the entire zone showing changes in blood volume during occlusion, and remained significantly elevated until 45 min post-occlusion, while CBV remained elevated in the hyperemic rim for at least 2 h. The presence of a peri-ischemic zone showing flow/volume mismatch identified a region wherein baseline CBF is maintained by means of compensatory vasodilatation, but where the ratio of CBF to CBV is decreased. Dynamic susceptibility contrast magnetic resonance imaging with gadolinium-BOPTA/Dimeglumine may be a valuable technique for the investigation of regional and temporal perturbations of hemodynamics during ischemia and reperfusion.

Single-session magnetic resonance coronary angiography and myocardial perfusion imaging using the new blood pool compound B-22956 (gadocoletic acid): initial experience in a porcine model of coronary artery disease.

Objective:The objective of this study was to evaluate a new blood pool contrast agent, B-22956, for detecting myocardial perfusion abnormality and coronary artery stenosis by magnetic resonance imaging (MRI) in 1 setting. Materials and Methods:Coronary artery atherosclerotic stenoses were created in 6 miniswine. Myocardial first-pass perfusion imaging was performed with a bolus injection of 0.015 mmol/kg B-22956 during pharmacologic stress followed by postcontrast coronary artery imaging after another injection of B-22956/1. The total doses for the 6 pigs were 0.1 mmol/kg (n = 3) and 0.15 mmol/kg (n = 3). Perfusion upslope maps were analyzed and MR coronary artery images were reviewed by 2 readers. Results:For all 6 pigs, the normalized upslopes of the perfusion curves were 0.83 ± 0.12, 0.74 ± 0.15, and 0.52 ± 0.05 (P < 0.01 vs. normal) with normal or mild (<50% area stenosis), moderate (<50% and <75%), and severe stenosis (>75%), respectively. Mean signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in right coronary artery images improved 90% and 200%, respectively, with a total dose of 0.1 mmol/kg of B-22956. Excellent agreements (kappa = 0.82) were achieved for evaluating the grade of stenosis between MR postcontrast coronary artery images and histopathology by 2 reviewers. Conclusion:The MR blood pool contrast agent B-22956 demonstrated the ability for detecting myocardial perfusion abnormalities and coronary artery stenosis in 1 setting.