Acute blood-brain barrier opening in experimentally induced focal cerebral ischemia is preferentially identified by quantitative magnetization transfer imaging.

Pathologic changes in brain tissue during and after stroke may lead to injury of the blood-brain barrier (BBB) and subsequent hemorrhagic transformation (HT). In a rat model of HT, the apparent diffusion coefficient of water, cerebral blood flow, relaxation times, T(1) and T(2), and magnetization transfer (MT) related parameters (T(1sat), K(for) and the MT ratio) were repetitively measured during 3 h of focal ischemia and 2 h of reperfusion (n = 8). Areas of BBB opening were identified by sequential assay of the transcapillary influx of Gd-diethylenetriaminepentaacetic acid (Gd-DTPA) by MRI and (14)C-alpha-aminoisobutyric acid (AIB) by quantitative autoradiography. Ischemia-injured regions of interest were identified from the MRI data and divided into those with and without BBB opening. Of the several MRI parameters measured, the T(1sat) in the caudate-putamen and preoptic area during ischemia and the first 2 h of reperfusion correlated best with the regional pattern of BBB opening observed thereafter. These data suggest that an ipsilateral/contralateral T(1sat) ratio > 1.6 demarcates leakage of small molecules such as Gd-DTPA and AIB across the BBB. As to clinical relevance, the quantitation of MT parameters in acute stroke may enable the early detection of areas of BBB opening and potential HT.     

Quantitation and localization of blood-to-brain influx by magnetic resonance imaging and quantitative autoradiography in a model of transient focal ischemia.

The ability of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) enhanced MRI to localize and quantitate blood-brain barrier (BBB) opening was evaluated against quantitative autoradiographic (QAR) imaging of (14)C-alpha-aminoisobutyric acid (AIB) distribution. The blood-to-brain transfer constant (K(i)) for Gd-DTPA was determined by MRI in rats after 3 h of focal cerebral ischemia plus 2.5 h of reperfusion (n = 9), and that of AIB was determined by QAR shortly thereafter. Tissue regions of interest (ROIs) for Gd-DTPA leakage were identified by ISODATA segmentation of pre- and post-Gd-DTPA Look-Locker (L-L) T(1) maps. Patlak plots were constructed using time course of blood and tissue T(1) changes induced by Gd for estimating K(i). Among the nine rats, 14 sizable regions of AIB uptake were found; 13 were also identified by ISODATA segmentation. Although the 13 MRI-ROIs spatially approximated those of AIB uptake, the segmentation sometimes missed small areas of lesser AIB uptake that did not extend through more than 60% of the 2.0-mm-thick slice. Mean K(i)'s of AIB were highly correlated with those of Gd-DTPA across the 13 regions; the group means (+/-SD) were similar for the two tracers (7.1 +/- 3.3 x 10(-3) and 6.8 +/- 3.5 x 10(-3) ml.g(-1) . min(-1), respectively). In most instances, Gd-DTPA MRI accurately localized areas of BBB opening.     

Gadolinium DTPA in magnetic resonance. Clinical experience in intracranial pathology

Sixty-seven patients with various intracranial pathologies were studied using Gd-DTPA as a contrast medium applied to MRI. This paramagnetic substance was well tolerated by all patients, and proved particularly useful in improving the diagnosis of extra-axial tumors, in which a rich enhancement was always present. Gd-DTPA allowed a better definition of the tumor outlines, as well as its differentiation from edema, and the demonstration of its relationship to brain parenchyma and cerebral vessels. This was particularly true for meningiomas, which often display poor contrast enhancement at MRI. Even though acoustic neuromas had, as a rule, high signal intensity, Gd-DTPA was useful to precisely recognize the intracanalar part of the tumor. The value of Gd-DTPA was less evident in intra-axial lesions. It proved nonetheless useful in demonstrating the portions of the tumor where, due to alterations in BBB, enhancement was present. This allowed both to characterize the lesion and to perform accurate biopsies.     

Patlak plots of Gd-DTPA MRI data yield blood-brain transfer constants concordant with those of 14C-sucrose in areas of blood-brain opening.

The blood-to-brain transfer rate constant (K(i)) of Gd-DTPA was determined in MRI studies of a rat model of transient cerebral ischemia. The longitudinal relaxation rate, R(1), was estimated using repeated Look-Locker measurements. A model-independent analysis of deltaR(1), the Patlak plot, produced maps of K(i) for Gd-DTPA and the distribution volume of the mobile protons (V(p)) with intravascular-Gd changed R(1)'s. The K(i)'s of Gd-DTPA were estimated in regions of interest with blood-brain barrier (BBB) opening (regions of interest, ROIs) and compared to those of (14)C-sucrose determined shortly thereafter by quantitative autoradiography. The K(i)'s for both Gd-DTPA and sucrose were much higher than normal within the ROIs (n = 7); linear regression of K(i) for Gd-DTPA vs. K(i) for sucrose yielded a slope of 0.43 +/- 0.11 and r(2) = 0.72 (P = 0.01). Thus, K(i) for Gd-DTPA varied in parallel with, but was less than, K(i) for sucrose. In the ROIs, mean V(p) was 0.071 ml g(-1) and much higher than mean vascular volume estimated by dynamic-contrast-enhancement (0.013 ml g(-1)) or mean V(p) in contralateral brain (0.015 ml g(-1)). This elevated V(p) may reflect increased capillary permeability to water. In conclusion, K(i) can be reliably calculated from Gd-DTPA-MRI data by Patlak plots.     

Blood-brain barrier injury following intracarotid injection of radiographic contrast media. In vivo quantification using magnetic resonance imaging and Gd-DTPA

Changes in signal intensity of the brain at magnetic resonance (MR) imaging before and after Gd-DTPA were used for in vivo quantification of injury to the blood-brain barrier (BBB). Immediately following intracarotid injection of 2 ml/kg of radiographic contrast medium (CM) 0.4 mmol/kg of Gd-DTPA was injected intravenously. MR imaging was performed with a 400/25 partial saturation pulse sequence. The maximum percentage changes (mean +/- SD) in signal intensity of the brain after CM and Gd-DTPA were 1.6 +/- 1.6% with saline, 3.2 +/- 2.0% with iotrolan, 4.3 +/- 1.7% with iohexol, 6.6 +/- 3.6% with ioxaglate and 8.2 +/- 3.6% with diatrizoate. Not only the osmolality but also the ionicity and chemotoxicity seemed to influence Gd-DTPA leakage. A subtle BBB injury had a stronger tendency to occur in the basal ganglia than in the cerebral cortex. MR enhancement is proposed as a sensitive method for in vivo quantification of the BBB injury caused by intracarotid CM injection.     

Imaging of gliomas with Cis-4-[18F]fluoro-L-proline

Tumor imaging with cis-4-[18F]fluoro-L-proline (cis-FPro) was compared to that of L-[3H]proline and L-[3H]methionine in F98 rat gliomas by dual-tracer autoradiography. All tracers exhibited high accumulation in the tumors but in the normal brain significant uptake was observed for L-[3H]methionine only. Tumor extent on autoradiograms with L-[3H]proline and L-[3H]methionine was identical to that of histological staining while autoradiograms of cis-FPro showed diffuse uptake in the penumbra of some tumors. First PET studies in 7 patients with cerebral gliomas demonstrated accumulation of cis-FPro in tumor areas with enhancement of Gd-DTPA on MR scans. Uptake of cis-FPro in normal brain tissue was negligible. In one patient with a glioblastoma accumulation of cis-FPro was also found in two brain areas without enhancement of Gd-DTPA on MR scans. Control of MRI suggested tumor growth in these areas at further follow up. Our results indicate that in most gliomas increased cis-FPro uptake is restricted to areas with disruption of the BBB which limits its clinical utility.     

Quantification of myocardial blood flow and extracellular volumes using a bolus injection of Gd-DTPA: kinetic modeling in canine ischemic disease.

In order to clarify the relationship between coronary artery disease (including myocardial infarction) and image contrast in gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced MRI it was decided to model the myocardial tissue distribution and clearance of Gd-DTPA using the modified Kety equation. Using a canine model, myocardial tissue Gd-DTPA concentrations ([Gd-DTPA]m) were measured 1 or 5 min after a bolus injection of Gd-DTPA or immediately after the end of a constant infusion of Gd-DTPA in a total of 35 dogs. It was found that within 5 min of a bolus injection [Gd-DTPA]m is determined primarily by myocardial blood flow (MBF) and after about 10 min primarily by myocardial extracellular volumes (MECV). This study suggests that repeat, rapid (every 2-4 s) measurements of myocardial T1 relaxation rates following the bolus injection of Gd-DTPA are required to calculate MBF (i.e., myocardial tissue perfusion) and MECV.     

Dynamic gadolinium uptake in thermally treated canine brain tissue and experimental cerebral tumors

RATIONALE AND OBJECTIVES: Thermal coagulation of cerebral tumors induces reactive changes within adjacent brain tissue, which appear as Gd-DTPA enhancement in MR images. This makes assessment of therapeutic success difficult to establish radiographically because the reactive changes can mimic residual tumor. Dynamic Gd-DTPA uptake curves in reactive tissue and tumor were investigated to assess the utility of contrast enhanced (CE)-dynamic MRI to distinguish reactive changes from residual tumor in a canine model. MATERIALS AND METHODS: Cerebral thermal necrosis was induced using a 980 nm laser in 11 dogs with intracerebral transmissible venereal tumors (TVTs). A fast spin-echo T1-weighted imaging sequence was used for CE-dynamic MRI. Gd-DTPA uptake data were acquired with 10-second temporal resolution and for untreated TVTs for reactive tissue using a sigmoidal-exponential model. RESULTS: Characteristic gadolinium uptake curves were measured and characterized for reactive brain tissue, and untreated and treated TVTs. Both early and delayed dynamic responses were significantly different in reactive brain tissue compared with TVT. CONCLUSION: Reactive thermal changes in otherwise normal brain tissue can be distinguished from residual tumor after cerebral thermal therapy using CE-dynamic MRI.     

Quantification of the effect of water exchange in dynamic contrast MRI perfusion measurements in the brain and heart.

Measurement of myocardial and brain perfusion when using exogenous contrast agents (CAs) such as gadolinium-DTPA (Gd-DTPA) and MRI is affected by the diffusion of water between compartments. This water exchange may have an impact on signal enhancement, or, equivalently, on the longitudinal relaxation rate, and could therefore cause a systematic error in the calculation of perfusion (F) or the perfusion-related parameter, the unidirectional influx constant over the capillary membranes (K(i)). The aim of this study was to quantify the effect of water exchange on estimated perfusion (F or K(i)) by using a realistic simulation. These results were verified by in vivo studies of the heart and brain in humans. The conclusion is that water exchange between the vascular and extravascular extracellular space has no effect on K(i) estimation in the myocardium when a normal dose of Gd-DTPA is used. Water exchange can have a significant effect on perfusion estimation (F) in the brain when using Gd-DTPA, where it acts as an intravascular contrast agent.     

Gd-BOPTA增强MRI对小肝癌的诊断价值

目的　比较Gd BOPTA增强MRI与MRI平扫、Gd DTPA动态增强MRI在诊断小肝癌 (SHCC)方面的差异 ,进一步提高小肝癌检出率和诊断准确性并观察其不良反应。资料与方法　手术或穿刺病理证实为SHCC患者 2 5例。采用GESigna 1.5T磁共振扫描仪。行SE序列T1WI、FSE序列T2 WI及Gd DTPA快速动态增强多期扫描。Gd BOPTA增强扫描亦采用静脉团注快速动态增强扫描 (同Gd DTPA) ,并在团注后 15min、6 0min行SE序列T1WI和FMPSPGR序列T1WI扫描各 1次。观察MRI平扫、Gd DTPA快速动态增强和Gd BOPTA增强扫描及延迟扫描对病灶的检出率、包膜显示情况以及病灶的强化特征并行统计学分析。观察其不良反应。结果　 2 5例患者共发现病灶4 2个。对SHCC病灶的检出率 ,MRI平扫为 6 9.0 5 % ,Gd DTPA增强为 85 .71% ,Gd BOPTA增强 (动态 延迟 )为95 .2 4 % ,和Gd DTPA增强之间无统计学差异 ,和MRI平扫有统计学意义。病理检查发现 30个病灶有包膜。Gd BOPTA增强对SHCC包膜的显示 ...     

Assessment of myocardial viability using MRI during a constant infusion of Gd-DTPA: further studies at early and late periods of reperfusion.

It was previously shown in a canine model of ischemia/reperfusion injury that the partition coefficient of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) (lambda) increases in infarcted tissue. That previous study used a non-magnetic resonance imaging (MRI) method to measure lambda and only investigated reperfusion times from 2 hr to 3 weeks. This study presents evidence suggesting that lambda starts to increase as early as 1 min after reperfusion of a 2 hr occlusion and continues to rise for up to 2 hr or more; lambda stays increased as late as 8 weeks, reaching peak values at 1-11 days and subsequently decreasing. It was also demonstrated that lambda can be accurately measured in vivo using a saturation recovery turbo fast low-angle shot (FLASH) sequence. The results of this study show that MRI during a constant infusion of Gd-DTPA has great potential for the non-invasive determination of myocardial viability as early as 1 min to as late as 8 weeks following reperfusion of acute myocardial infarction.     

血源性脑及脑膜转移瘤动物模型的建立及其MRI研究

目的 介绍建立血源性脑及脑膜转移瘤动物模型的方法,成瘤率的影响因素,讨论对脑膜及脑内转移瘤的检出效果及其表现基础。方法 ３８只新西兰大白兔随机分为３组,分别从颈总动脉行血脑屏障开放接种ＶＸ２癌细胞,单纯接种ＶＸ２癌细胞及单纯注射生理盐水。术后１周开始在不同时间行ＭＲＩ检查。病理取材ＨＥ及免疫组织化学染色光镜下观察。     

Evaluation of tumor angiogenesis using dynamic enhanced magnetic resonance imaging: comparison of plasma vascular endothelial growth factor, hemodynamic, and pharmacokinetic parameters

PURPOSE: To assess whether tumor angiogenesis of breast cancers can be predicted on the basis of dynamic magnetic resonance imaging (MRI). MATERIAL AND METHODS: Seventy-one patients with 71 breast cancers underwent Gd-DTPA enhanced dynamic MRI. Two regions of interest measurements were obtained in the periphery and in the center of the breast cancers. Hemodynamic parameters obtained by dynamic MRI included peak time, contrast enhancement ratio (CE ratio), and washout ratio. The triexponential concentration curve of Gd-DTPA was fitted to a theoretical model based on compartmental analysis. The transfer constant (or permeability surface product per unit volume of compartment "k") was obtained using this method. Tumor angiogenesis was assessed by plasma vascular endothelial growth factor (P-VEGF). RESULTS: The P-VEGF was positive in 28 of 71 tumors (39%). The CE ratio, washout ratio, and k in the periphery in P-VEGF positive breast cancers (mean 178%, 18%, and 1.5 x 10(-2) (s(-1)) were significantly greater (P<0.01, P<0.05, and P<0.03)) than those for P-VEGF negative breast cancers (mean: 151%, 14%, and 1.1 x 10(-2) (s(-1)). The peak time in the periphery in P-VEGF positive breast cancers was more marked than for P-VEGF negative breast cancers, but this difference was not significant. CONCLUSION: The hemodynamic and pharmacokinetic analysis of MRI provides valuable information about angiogenesis of breast cancers.     

Glomerular filtration rate measured using the Patlak plot technique and contrast-enhanced dynamic MRI with different amounts of gadolinium-DTPA

We determined the optimum gadolinium (Gd)-DTPA dose and time window for calculating the glomerular filtration rate (GFR) using contrast-enhanced (CE) dynamic MRI and the Patlak plot technique. Twelve adult volunteers with healthy kidneys were included in the study. As a reference method the GFR was measured by iopromide plasma clearance. A three-dimensional gradient-echo (GRE) sequence with a flip angle of 50 degrees was used for MRI. Signal was measured using a body surface coil with four elements. Each volunteer was examined on four days using 2 mL, 4 mL, 8 mL, or 16 mL of Gd-DTPA 0.5 mmol/mL dissolved with sodium chloride (NaCl) 0.9% to a total of 60 mL. The injection rate was 1 mL/second. A Patlak plot was calculated from the kidney and aorta signals. The mean reference GFR was 133 mL/min (min-max, 116-153 mL/min). The best correlation of GFR calculated from MRI data compared to the reference method was found in a time window 30-90 seconds after aortic signal rise using 16 mL Gd-DTPA. Pearson's correlation coefficient was r = 0.83, and the standard deviation (SD) from the line of regression was 10.5 mL/minute. We found a significantly lower average GFR(MR) using 16 mL Gd-DTPA compared to 4 mL and 2 mL in the late time window 60-120 seconds post aortic rise. A dose of 16 mL Gd-DTPA was optimal for measuring GFR using dynamic MRI and the Patlak plot technique. The slope should be measured in a time window of 30-90 seconds post aortic rise.     

Quantitative evaluation of the effect of propylene glycol on BBB permeability

PURPOSE: To establish the blood-brain barrier (BBB) blocking property of propylene glycol (PG) using the (14)C sucrose technique, quantitatively evaluate the effect of PG on BBB permeability using an MRI technique based on graphical analysis, and demonstrate the sensitivity of MRI for testing newer investigational drugs. MATERIALS AND METHODS: Brain uptake of sucrose was measured in treated (PG+) and untreated (PG-) rats using a (14)C sucrose technique in rat brains (N = 10) that had undergone two hours of middle cerebral artery occlusion (MCAO) and three hours of reperfusion. Another group of PG+ and PG- rats (N = 8) underwent MRI. T2-weighted (T2W) and diffusion-weighted (DW) images were acquired on a 4.7T MR system. A rapid T1 mapping protocol was implemented to acquire a baseline data set followed by postinjection data sets at regular intervals. The data were postprocessed pixelwise to generate permeability coefficient color maps. RESULTS: A significant (P < 0.05) reduction in (14)C sucrose space was observed on the ischemic side of PG+ rats only. Permeability coefficient estimates obtained by MRI from the ipsilateral hemisphere in PG+ rats were significantly lower than those in PG- rats (P < 0.05). There was no significant change on the contralateral side in PG+ rats. The results show that PG protects the BBB in ischemic stroke, and MRI measurements are sufficiently sensitive to noninvasively detect small drug effects. CONCLUSION: MRI is useful for evaluating the BBB blocking effect of PG in an ischemic stroke model of rat brain. The results from the MR experiment agree well with findings from the (14)C sucrose technique.     

Evaluation of acute renal failure with magnetic resonance imaging using gradient-echo and Gd-DTPA

Detection of acute renal failure (ARF) using fast-scan magnetic resonance imaging (MRI) with Gd-DTPA was studied in a dog model. ARF was produced in five dogs by infusion of norepinephrine (0.75 micrograms/kg/min) into the renal arteries for 40 minutes. MRI was performed 1 hour later and compared with baseline (pre-ARF) MRI. There was no significant difference in the ratios of signal intensity-vs.-time curves from 0 to 35 seconds after injection of Gd-DTPA. However, a difference between the outer and inner medulla was significant in the time period of 5 to 20 minutes after Gd-DTPA injection. These later signal intensity differences by fast-scan (gradient-echo) technique may be useful in the evaluation of ARF.     

Vascular volume and blood-brain barrier permeability measured by dynamic contrast enhanced MRI in hippocampus and cerebellum of patients with MCI and normal controls

PURPOSE: To measure the cerebrovascular volume and blood-brain barrier (BBB) permeability indices in hippocampus and cerebellum of patients with mild cognitive impairment (MCI) using dynamic contrast-enhanced MRI (DCE-MRI), and compare to that of normal controls. MATERIALS AND METHODS: A total of 11 MCI subjects and 11 healthy elderly controls participated in this prospective study. DCE-MRI was performed to measure the contrast enhancement kinetics. The early enhancement percentage (at 50 seconds after injection) was defined as the vascular volume index, and the ratio between the four to five-minute enhancement relative to the 50-second enhancement was defined as the BBB permeability index. RESULTS: The enhancement kinetics measured from hippocampus of MCI individuals demonstrated a lower magnitude and slower decay than healthy controls, suggesting that they had a smaller vascular volume (significant in the right side; P <0.001) and a higher BBB permeability (not reaching significance level). The vascular volume index was significantly correlated with naming ability (P 0.05). CONCLUSION: These results suggest that changes in cerebrovasculature may occur in hippocampus of MCI. DCE-MRI may provide a noninvasive means to measure the subtle BBB leakage associated with the cerebrovascular pathology commonly found in Alzheimer's disease.     

巨噬细胞活性MRI对多发性硬化大鼠模型中枢神经系统病灶诊断价值的初步研究

目的 探讨巨噬细胞活性成像(MAI)对多发性硬化(MS)模型大鼠脑和脊髓病灶的诊断价值.方法 20只正常Lewis大鼠用数字表法随机分成实验组15只,对照组5只.应用髓鞘少突胶质细胞糖蛋白多肽35-55(MOG35-55)致敏实验组大鼠制备MS动物模型实验性自身免疫性脑脊髓炎(EAE),大鼠首次急性发病后第3天行MR检查.分别对大鼠脑和脊髓行T2WI、T1WI和Gd-DTPA增强T1WI的三维容积扫描.经大鼠尾静脉注入超微超顺磁性氧化铁(USPIO)24 h后行USPIO增强T2WI(即MAI).利用工作站专业软件获得大鼠脑和脊髓冠状面、横断面和矢状面的重组图像,并与常规图像进行比较.结果 成功建立MOG35-55-EAE模型大鼠15只.MOG35-55-EAE大鼠急性发病期相关的中枢神经系统病灶多数分布在脑内(58/63),少数位于脊髓(5/63).常规MRI上病灶表现为T2WI高信号、T1WI低信号,部分出现Gd-DTPA强化.在MAI图像上病灶呈低信号,部分USPIO强化病灶在T2WI上呈等信号,病灶的USPIO强化与Gd-DTPA强化表现不完全一致.T2WI(14/15)和MAI(13/15)对MOG35-55-EAE大鼠急性期病灶的敏感度高,两者联合对病灶的检出率高达100%(15/15),增强T1WI的敏感度相对较低(7/15).对照组大鼠MAI未见异常.结论 MAI弥补传统MR检查技术的不足,能监测EAE的炎症反应,与常规T2WI联合能提高MOG35-55-EAE大鼠病灶的检出率;Gd-DTPA增强能显示EAE血脑屏障破坏的早期活动性病灶,MAI与之联合成像对EAE病灶的诊断和监测有互补作用.     

Effect of tamoxifen in an experimental model of breast tumor studied by dynamic contrast-enhanced magnetic resonance imaging and different contrast agents

OBJECTIVES: The aim of this study was to compare the efficacy of gadoteridol, B22956/1 (a new protein binding blood pool contrast agent), and (Gd-DTPA)37-albumin in detecting, by dynamic contrast-enhanced magnetic resonance imaging (MRI), the effect in vivo of tamoxifen in an experimental model of breast tumor implanted in rats. MATERIALS AND METHODS: Tumors were induced by subcutaneous injection of 10 mammary adenocarcinoma cells (13762 MAT B III). Treatment with tamoxifen (or vehicle) started on day 4 after implantation. On day 10 after implantation, animals were observed by MRI using B22956/1 (or gadoteridol) and, 24 hours later, using (Gd-DTPA)37-albumin. RESULTS: Dynamic contrast-enhanced magnetic resonance imaging data showed that tamoxifen treatment decreased vascular permeability to B22956/1, whereas no difference was detectable in permeability to gadoteridol or to (Gd-DTPA)37-albumin. No effect on fractional plasma volume was detected with either of contrast agents. CONCLUSIONS: B22956/1 is superior to both small Gd chelates and macromolecular contrast agents in the assessment of the effect of tamoxifen treatment on tumor vasculature.     

Neurotolerability of gadobenate dimeglumine in a rat model of focal brain ischemia: EEG evaluation

RATIONALE AND OBJECTIVES: The neurologic pathologies for which contrast-enhanced MRI is indicated are often accompanied by a disruption of the blood-brain barrier (BBB), which allows the contrast agent to come into contact with the nervous tissue. Thus, assessment of the neurologic safety for a new contrast agent is of crucial importance. The objective of this study was to assess the neurotolerability of the new MRI contrast agent gadobenate dimeglumine using EEG in the presence of focal lesions of the BBB. METHODS: Lesions of the BBB were obtained inducing a photochemical ischemia in rats. Gadobenate dimeglumine was intravenously administered at 4.0 mmol/kg. An EEG was recorded during sleep/awake behavior and was analyzed for pathologic tracing and for changes in spectral content in terms of total power and frequency index. The presence of the BBB lesions was verified using high-performance liquid chromatography measurement of the gadobenate ion content in the brain. RESULTS: Gadobenate dimeglumine did not have any epileptogenic effect in ischemic rats. However, it caused a transitory shift of the EEG power spectrum toward the 0.5 to 9 Hz frequency bands of the lesioned hemisphere during quiet wake. In the lesioned cortex, higher levels of gadobenate ion were found until 3 hours after administration. CONCLUSIONS: In experimental conditions of focal brain ischemia associated with BBB lesions, gadobenate dimeglumine was well tolerated up to doses even 10 times higher than the maximum clinical dose (0.3 mmol/kg) intended for brain imaging procedures.