Iotrol, iodixanol, and 2-deoxy-D-glucose effects on neural tissue CO2 production

In vivo and in vitro experiments have demonstrated that the myelographic agent metrizamide decreases neural tissue glucose metabolism whereas iohexol and iopamidol do not. This study compares the changes in slices of rat hippocampus CO2 production caused by the nonionic dimers iotrol and iodixanol with the effects of metrizamide and 2-deoxy-D-glucose. After 6-hr incubations, 70-mmol/l concentrations of iotrol and iodixanol increased CO2 production by 11 +/- 20% and 31 +/- 35%, respectively, as compared with the artificial CSF control medium. Metrizamide at 70 mmol/l and 2-deoxy-D-glucose at 35 mmol/l decreased CO2 production by 32 +/- 13% and 96 +/- 1%, respectively. The increases in CO2 production with iotrol and iodixanol appear to indicate that these molecules have some effect on cell metabolism. The mechanism for the increase in CO2 production could involve an effect on the glucose metabolic pathway or could be indirect via a mechanism that increases cell energy utilization. These in vitro effects have not been verified with in vivo experiments.     

Effect of field strength on gadolinium enhancement in MR imaging

This studv was designed to evaluate the influence of magnetic field strength on the relative enhancement effect (RE) of gadolinium (Gd)-chelates. Dilution series of two paramagnetic contrast agents (Gd-DTPA and Gd-DOTA) were examined in three commercially available MR systems. operating at different field strengths (02 T, 1. T, and 1.5 T). The RE was plotted against Gd concentration. The highest increases in signal intensity occurred with Gd concentrations of approximately L.0 mmol/L. No significant difference in RE was observed between MR systems ranging in field strength from 0.? T to 1.5 T. The RE of Gd-DTPA and Gd-DOTA was found to he equivalent.     

Gd-DOTA. Pharmacokinetics and tolerability after intravenous injection into healthy volunteers

The pharmacokinetics of Gd-DOTA meglumine in humans were evaluated in six healthy male volunteers. The agent was injected intravenously at 0.1 mmol/kg over approximately 2 minutes. Its behavior was found to be similar to that of urographic and angiographic iodinated contrast media with a plasma elimination half-life of 91 +/- 14 minutes (mean +/- standard deviation [SD]), a small distribution volume of 171.0 +/- 19.7 mL/kg and rapid urinary excretion. The results suggest rapid passive extravascular diffusion of gadolinium (Gd)-DOTA in the interstitial space without intracellular penetration, followed by a rapid urinary excretion via glomerular filtration. Furthermore, the results are consistent with animal data that showed that the compound does not cross the normal blood brain barrier. Its plasma pharmacokinetics appeared to be similar to those reported for Gd-DTPA. No relevant biological effects were seen with Gd-DOTA, especially in regard to serum iron and bilirubin levels.     

Dynamic studies of gadolinium uptake in brain tumors using inversion-recovery echo-planar imaging.

Echo-planar imaging has been used to observe the dynamics of Gd-DTPA uptake in brain tumors. It has been possible to examine both vascular uptake and diffusion across the blood-brain barrier in a single experiment, by using the IR-MBEST echo-planar sequence which combines a high temporal resolution (approximately 3 s) with strong T1 weighting. To model the uptake it is necessary to know the arterial concentration of Gd-DTPA; in this study the signal in the sagittal sinus was measured to avoid the need to take repeated blood samples. The time constant for transfer across the blood-brain barrier was measured to be between 20 and 1050 s for different tumors. The results of the modeling correlated with the results of other assessments of tumor vascularity.     

In vitro study of relationship between signal intensity and gadolinium-DTPA concentration at high magnetic field strength

Although gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) has been used as a contrast material in MRI, it is known that the contrast enhancement effect is not uniform for high concentrations of Gd-DTPA. In order to evaluate the proper pulse sequences for dynamic MRI in aqueous solutions of Gd-DTPA, blood samples and melanoma cells, the signal intensity for several concentrations of Gd-DTPA were measured under inversion recovery (T1-weighted) at high magnetic field strength (7.0 Tesla). For aqueous solutions of Gd-DTPA, signal intensity correlated linearly with the concentration of Gd-DTPA between 0 mmol/L and 4 mmol/L. Using blood and melanoma cells, signal intensity correlated non-linearly with the concentration of Gd-DTPA between 0 mmol/L and 1.5 mmol/L. For concentrations of more than 4 mmol/L in aqueous solutions of Gd-DTPA, 1 mmol/L in blood and 1.5 mmol/L in melanoma, signal intensity decreased with increased Gd-DTPA concentration.     

A new gadolinium-based contrast agent for magnetic resonance imaging of brain tumors: kinetic study on a C6 rat glioma model

T1-weighted magnetic resonance imaging (MRI) was used to evaluate the potential interest of a new Gd-based contrast agent, termed P760, to characterize brain tumor heterogeneity and vascularization and to delineate regions containing permeable vessels. The C6 rat glioma model was used as a model of high-grade glioblastoma. The signal enhancement was measured as a function of time in the vascular compartment and in different regions of interest (ROIs) within the tumor after the injection of 0.02 mmol x kg(-1) of P760. The results were compared to those obtained after the injection of 0.1 mmol x kg(-1) of Gd-DOTA. We showed that P760, in spite of a Gd concentration five times smaller, produces an enhancement in the blood pool similar to that produced by Gd-DOTA. It was shown that P760 makes possible an excellent delineation of regions containing vessels with a damaged blood-brain barrier (BBB). Images acquired 5-10 minutes after P760 injection showed the location of permeable vessels more accurately than Gd-DOTA-enhanced images. The enhancement produced in the tumor by P760 was, however, less than that produced by Gd-DOTA. The extravasation and/or diffusion rate of P760 in the interstitial medium were found to be strongly reduced, compared to those found with Gd-DOTA. This study suggests that the new contrast agent has promising capabilities in clinical imaging of brain tumors.     

Gadolinium-DOTA enhanced MR imaging of intracranial lesions

Gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (Gd-DOTA) is the first of a new class of macrocyclic paramagnetic magnetic resonance (MR) contrast agents (gadolinium cryptelates) to be used in clinical practice. Gadolinium-DOTA possesses relaxation properties similar to those of gadolinium diethylene triamine pentaacetic acid (Gd-DTPA). We report our initial clinical experience in 38 patients with intracranial lesions studied with MR before and after injection of Gd-DOTA. Diseases included primary and metastatic brain tumor, cerebral infarct, vascular malformation, meningioma, hemangiopericytoma, schwannoma, and pituitary macroadenoma. Gadolinium-DOTA was administered intravenously in a dosage of 0.1 mmol/kg body weight. All studies were performed on a superconductive 0.5 T system. As compared to noncontrast T1- and T2-weighted images (WI), Gd-DOTA enhanced T1 WI were useful in defining the anatomy of malignant intraaxial tumors (high-grade glioma, metastasis) and in tumor versus edema differentiation. Low-grade gliomas did not enhance; in these cases the precontrast T2-weighted sequence was found to be more informative. In post-operative patients, Gd-DOTA allowed us to demonstrate residual tumor or tumor recurrence. Extraaxial tumors (meningioma, hemangiopericytoma, neuroma) enhanced markedly, presumably reflecting tumor vascularity. In our experience, the use of Gd-DOTA improves the anatomic definition of cerebral lesions and in some cases increases both MR sensitivity and specificity. We found Gd-DOTA to be a well tolerated and effective paramagnetic contrast agent. Gadolinium-DOTA can be considered as an alternative water-soluble MR contrast agent to Gd-DTPA.     

MR imaging of rat brain glioma: Gd-DTPA versus Gd-DOTA

The enhancement properties of gadolinium diethylenetriaminepentaacetic acid (DTPA) and gadolinium tetraazacyclododecanetetraacetic acid (DOTA) were compared using a rat glioma model. In vitro analysis included the calculation of T1 relaxivity and determination of characteristic curves. Enhancement of the intracerebral glioma was studied in 23 rats approximately 2 weeks after glioma implantation with Gd-DTPA in 12 rats and Gd-DOTA in 11 rats. Six rats were also studied 1 week after implantation. Gd-DTPA exhibited a slightly greater T1 relaxivity in vitro than Gd-DOTA. Enhancement of the glioma was also greater with Gd-DTPA than with Gd-DOTA (P less than .05).     

Improved contrast agent bolus tracking using T1 FARM.

Current MRI bolus tracking techniques, such as saturation recovery Turbo-FLASH (srTFL), suffer from signal saturation at high contrast concentrations. In this study T1 Fast Acquisition Relaxation Mapping (T1 FARM) was compared to srTFL. In phantoms, T1 FARM maps were linear with [Gd-DTPA] up to 7.0 mmol/L while srTFL images saturated above 2.0 mmol/L. In the canine left ventricle, blood concentration curves determined from T1 FARM saturated with bolus injections exceeding 0.075 mmol/kg, while srTFL curves saturated above 0.025 mmol/kg of Gd-DTPA. Also, T1 FARM improved contrast-to-noise ratio in tissue concentration curves since higher contrast concentrations could be measured without saturating.     

MR contrast enhancement of intracranial lesions with Gd-DTPA

Gd-DTPA is a paramagnetic contrast agent for MR that produces enhancement of lesions on T1-weighted images. Since it does not cross the intact blood-brain barrier (BBB), Gd-DTPA enhances only those pathologic processes that are associated with breakdown of the BBB and structures or lesions that are devoid of a BBB. Gd-DTPA improves conspicuity, helps characterize and delineate the extent of lesions, and increases the sensitivity for detection of cerebral abnormalities.     

MR imaging of acute cerebral infarction: experimental study with Gd-DTPA

To evaluate the sensitivity of MR imaging for acute cerebral infarction and the effectiveness of MR enhancement with Gd-DTPA, we created a canine model of cerebral infarction by transarterial embolization (TAE). The external and internal carotid arteries were embolized respectively through a transfemoral catheter. MR imaging was performed with the Yokogawa Medical System prototype superconducting MR machine "Resona" operating at 0.35 Tesla. MR enhancement was done with 0.4 mmol/kg of Gd-DTPA. Early detectability without Gd-DTPA was 60% (3/5) two hours after TAE and 67% (4/6) at three hours. MR imaging showed high-intensity lesions on the T2-weighted sequence (SE 2000/100). The T1-weighted sequence (SR 250-600/25-35) did not reveal any lesions four hours after TAE. Five animals which received Gd-DTPA showed abnormal enhancement in the brain parenchyma within 30 min after Gd injection on the T1 weighted sequence. Gd-DTPA enhancement not only improved early sensitivity for acute cerebral infarction when MR imaging without Gd-DTPA was negative, but also enhanced the size and number of lesions compared with SE 2000/100 images without enhancement. The breakdown of the blood-brain barrier was suggested to be an important factor in Gd-DTPA enhancement.     

Iopamidol and neural tissue metabolism. A comparative in vitro study

Metrizamide was the first water-soluble contrast medium with a neurotoxicity low enough to allow it to be used routinely in the entire subarachnoid space. However, neurologic complications are still observed in some patients following the use of metrizamide. The cause of this toxicity has not been established, but existing evidence suggests an interference with glucose metabolism. In previous studies, a depression in CO2 production in neural tissue slices was demonstrated when isotonic metrizamide was added but not isotonic iohexol. In addition to iohexol, there is another new, nonionic, monomeric, water-soluble CM, iopamidol, soon to be released for clinical use in the United States. Iopamidol, like iohexol, has shown fewer adverse reactions and seems to be safer for myelography than metrizamide. Direct comparative studies of iopamidol and iohexol are sparse and the cause of their toxicity is not yet understood. This study was performed to determine the effect of iopamidol on neural tissue glucose metabolism as compared with the effects of iohexol and metrizamide. Metrizamide decreased CO2 production in neural tissue slices by 23%. Iopamidol and iohexol did not produce significant depression. Moreover, this model could not demonstrate any significant difference between iopamidol and iohexol in direct comparisons. The new monomeric contrast media, iopamidol and iohexol, thus do not appear to interfere with glucose metabolism. Adverse reactions to these new media are most likely caused by other mechanisms.     

Is [1-11C]putrescine useful as a brain tumor marker?

Our experience with 11C-putrescine underscores the difficulty of finding a selective brain tumor tracer, uniquely incorporated by neoplastic glia or metastatic cells within brain, but not by the proliferating, nontransformed cells which constitute a normal pathophysiological reaction to various disease processes. Thirty-three patients with 36 lesions were studied with 11C-putrescine to determine the specificity of labeled putrescine for tumor tissue. The uptake of 11C-putrescine was correlated with local cerebral glucose metabolic rate in various lesions, including different types of tumors, to assess the relationship between 11C-putrescine uptake and tumor biology. Carbon-11-putrescine uptake was similar in malignant tumor and benign, non-neoplastic lesions with blood-brain barrier breakdown, illustrating the lack of tumor specificity of this tracer. Carbon-11-putrescine was not well incorporated into poorly enhancing lesions, regardless of their pathology, emphasizing the requirement of a disrupted blood-brain barrier for 11C-putrescine uptake. The ratio of 11C concentration within lesions, compared to that in a region of interest in the contralateral brain, weakly correlated with an analogous ratio for local cerebral glucose metabolic rate in various lesions. Physiological processes not unique to tumors are associated with polyamine active transport and metabolism and contribute to the lack of tumor specificity of 11C-putrescine. Carbon-11-putrescine appear to have less diagnostic utility than 18FDG in brain tumors. The potential of 11C-putrescine for evaluating the effect of antineoplastic therapy and providing prognostic information on brain tumors remains to be investigated.     

Comparison of iron oxide particles (AMI 227) with a gadolinium complex (Gd-DOTA) in dynamic susceptibility contrast MR imagings (FLASH and EPI) for both phantom and rat brain at 1.5 Tesla

The goal of the study was to compare, in phantom and normally perfused rat brain tissue, a superparamagnetic iron oxide particle-based contrast agent (AMI 227) with a low-molecular-weight gadolinium chelate, gadolinium tetraazacyclododecanetetraacetic acid (Gd-DOTA), in two susceptibility contrast magnetic resonance imaging (MRI) modes [fast low-angle shot sequence (FLASH) and echoplanar imaging (EPI)]. A phantom consisting of dilution series of both contrast agents was manufactured. Dilutions were obtained with isotonic serum from the available agent solutions (0.5 mmol Gd/mL Gd-DOTA; 350 mumol Fe/mL AMI 227). Eighteen rats were studied. Contrast agent (0.1 mL) was bolus injected in each rat, and dynamic MRI was performed (first pass of the contrast agent) in rat brain. The doses of AMI 227 injected were extrapolated from the phantom experiment: 0.2 mmol/kg body weight of Gd-DOTA and 7, 14, and 28 mumol Fe/kg body weight of AMI 227 were injected. For both sequences, signal-to-noise ratios (S/N) were measured on each tube of the phantom and on rat brain from each image of the dynamic imaging. S/N was plotted versus contrast dilution (phantom) and versus time (rats). In the FLASH sequence, a well-shaped curve (S/N decrease, S/N peak decrease, S/N increase) of the first pass of the contrast agent was demonstrated for Gd-DOTA and for AMI 227 (7 mumol Fe/kg body weight). In the EPI sequence, a well-shaped curve was demonstrated for Gd-DOTA, and a plateau effect was noted for both concentrations of AMI 227. With the FLASH technique, dynamic susceptibility contrast imaging of rat brain can be performed with very low concentrations of AMI 227 compared with the Gd-DOTA concentration (0.2 mmol Gd/kg body weight) used in clinical practice. This could be of interest in perfusion imaging, because it may allow for first-pass susceptibility imaging after administration of a small volume in a narrow bolus.     

不同浓度钆喷替酸葡甲胺体外实验及MR直接法膝关节造影的临床研究

目的 探讨不同浓度钆喷替酸葡甲胺(Gd-DTPA)MRI体外信号的变化规律及MR直接法膝关节造影的最佳浓度。方法 配制不同浓度的Gd-DTPA溶液各50ml，采用1．5T MR设备SE序列扫描、观察、测量。然后，选择2mmol／L和100mmol/L浓度Gd-DTPA分别进行直接膝关节造影。结果 Gd-DTPA浓度为2mmol/L时，TlWI信号强度最高；浓度为1．5mmoL／L时，T1WI信号强度最高。T1、T2浓度与信号强度曲线呈“L形”曲线样变化。膝关节直接造影，100mmoL／L浓度Gd-DTPA呈低信号且关节软骨显示清晰，2mmoL／L浓度Gd-DTPA呈高信号且半月板显示清晰。结论 不同浓度Gd-DTPA MRI体外信号变化规律呈“L形”曲线，MR直接法关节造影时，应根据关节病变不同，选择不同浓度的Gd-DTPA。     

Measurement of blood-brain barrier permeability using dynamic Gd-DTPA scanning--a comparison of methods.

Two recently published methods of blood-brain barrier permeability measurement using Gd-DTPA scanning are compared by authors representing each group. The physiological models are reconciled. Results from both groups agree. These show that the transfer constant (the permeability surface area product per unit volume of tissue) of the defective blood-brain barrier in multiple sclerosis is in the range 1-12.10(-4) s-1.     

The effect of iohexol on glucose metabolism compared with metrizamide

In a previous in vitro study we demonstrated reduced CO2 production in rat hippocampal tissue when metrizamide was added. This metabolic depression is believed to be a result of the 2-deoxy-D-glucose (2-DG) portion of the metrizamide molecule since 2-DG is a known competitive inhibitor of glucose metabolism. This competitive inhibition probably occurs at the cell membrane since it has never been shown that metrizamide penetrates neural cells. Further the inhibition is most likely related to competition for the membrane glucose carrier. A new nonionic contrast medium, iohexol, does not contain a 2-DG component and if the hypothesis for the metabolic inhibition is valid we should not expect metabolic inhibition with iohexol. This hypothesis was tested using the rat hippocampus model previously used for metrizamide. We compared iohexol with metrizamide in isotonic concentrations and also examined the effect of hypertonicity. These experiments did not demonstrate inhibition of CO2 production with iohexol at near physiologic osmolalities, however, there was a marked depressive effect with increasing osmolality. This effect from hypertonicity is, however, probably of less importance in vivo where water will rapidly diffuse toward the hypertonic areas. The apparent lack of interference of the iohexol molecule on glucose metabolism should therefore make iohexol a more suitable contrast medium, for subarachnoid investigations than metrizamide.     

Improved evaluation of myocardial perfusion and viability with the magnetic resonance blood pool contrast agent p792 in a nonreperfused porcine infarction model

OBJECTIVES: To investigate whether a magnetic resonance (MR) blood pool contrast agent enables both evaluation of myocardial perfusion and viability in nonreperfused infarction in pigs. MATERIALS AND METHODS: An optimized MR protocol using the blood pool contrast agent P792 (0.026 mmol/kg, twice the clinical dose, Guerbet, France) was investigated to evaluate nonreperfused myocardial infarction in an animal model. P792 was compared with the extracellular contrast agent Gd-DOTA (0.1 mmol/kg). The MRI findings were compared with histomorphometry performed with microspheres to evaluate perfusion and triphenyltetrazolium chloride (TTC) to evaluate viability. Contrast-enhanced MR imaging of the heart was performed on a 1.5-Tesla scanner 2 days after instrumentation in 6 minipigs. A saturation recovery steady-state free precession sequence was used for perfusion imaging and an inversion recovery fast low-angle shot sequence for evaluation of myocardial viability. RESULTS: P792 tended to depict areas of reduced perfusion more accurately than Gd-DOTA (17.2% +/- 11.1% versus 13.7% +/- 8.0%) in comparison to the gold standard of histomorphometry with microspheres (18.2% +/- 9.8%). Moreover, P792, but not Gd-DOTA, depicted ischemic areas for 30 minutes after intravenous injection. The change in myocardial signal intensity during first pass was not significantly different after P792 compared with Gd-DOTA (140.3% +/- 64.4% versus 123.3% +/- 22.5%, P = 0.56). P792 was highly accurate in depicting infarcted areas (11.1% +/- 7.1%) compared with Gd-DOTA (12.1% +/- 8.2%, r = 0.98, P < 0.001) and histomorphometry with TTC (12.2% +/- 8.0%, r = 0.99, P < 0.001). CONCLUSIONS: Unlike Gd-DOTA, the blood pool contrast agent P792 allows evaluation of myocardial perfusion for a period of 30 minutes and shows good agreement with histomorphometry. P792 must be examined in further studies to evaluate its potential in evaluating early myocardial lesions and reperfusion. In addition, P792 also allows for evaluation of myocardial viability.     

Cystic lesions accompanying extra-axial tumours

We examined the mechanism of cyst formation in extra-axial tumours in the central nervous system (CNS). Cyst fluid, cerebrospinal fluid (CSF) and blood plasma were analysed in eight patients with nine peritumoral cysts: four with meningiomas, two with intracranial and two spinal intradural schwannomas. Measuring concentrations of various proteins [albumin, immunoglobulin G (IgG), IgA, α₂-macroglobulin and IgM] in cyst fluid, CSF and blood plasma provides insight into the state of the semipermeability of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier. Peritumoral cysts accompanying intra-axial brain tumours are the end result of disruption of the BBB and oedema formation. Unlike intra-axial tumours which lie embedded within nervous tissue, extra-axial tumours tend to be separated from nervous tissue by arachnoid and pia mater. High concentrations of proteins were measured in the cyst fluid, approaching blood plasma levels, suggesting a local barrier disruption, and passage across the arachnoid, pia mater and cortical/medullary layer into the CNS parenchyma, leaving the protein concentrations of CSF practically unchanged. We confirmed that very high concentrations of protein are to be found in tumour cysts, plasma proteins forming almost 90 % of the total protein in the cyst. We review current hypotheses on the pathogenesis of cysts accompanying neoplasms, particularly meningiomas and schwannomas, and conclude that the majority of proteins in cyst fluid in extra-axial, intradural meningiomas and schwannomas are plasma proteins. This provides a strong argument for pathogenesis of extra-axial intradural tumour cysts in favour of leakage of plasma proteins out of the tumour vessels into the nervous tissue. Received: 16 May 1998 Accepted: 6 February 1998     

Local glucose utilization changes caused by subarachnoid contrast media in the rabbit

The glucose metabolism effects of six hour exposures to subarachnoid injections of metrizamide, iohexol, iodixanol and control solutions were studied in vivo in 18 rabbits. The brain tissue uptake of intravenously injected 14C labelled deoxyglucose was measured using autoradiographic techniques. Metrizamide and iodixanol caused significant (p less than 0.05) decreases in deoxyglucose uptake in the outer cortical areas where the contrast medium concentrations were highest. Iohexol and the control CSF solution did not cause significant effects. The results appear to indicate that iohexol has less effect on brain tissue glucose metabolism than either metrizamide or the new non-ionic dimer iodixanol.