Magnetic resonance imaging in the diagnosis of the cranio-cervical manifestations of the mucopolysaccharidoses

Sixteen magnetic resonance (MR) studies were performed in eight patients with mucopolysaccharidosis (MPS). In patients with Hunter, Hurler, and Scheie syndromes, multiple areas of increased signal intensity were noted in the periventricular white matter. Computerized tomography (CT) frequently failed to demonstrate these white matter lesions. Other findings included spinal cord compression, hydrocephalus and airway obstruction due to soft tissue thickening around pharynx. In patients with Morquio syndrome, cervical spine dislocation, spinal cord compression and hydrocephalus were diagnosed by MR. MR was superior compared to CT, plain films and plain tomography, as the narrowing caused by bone and soft tissue changes were better seen with MR. Our experience suggests that MR should be the primary imaging modality for the detection of cranial abnormalities in patients with MPS. High resolution surface coil imaging may be preferable to invasive procedures such as myelography and CT with intrathecal contrast agents for the evaluation of cervical spine disease.     

Diffuse T1 reduction in gray matter of sickle cell disease patients: evidence of selective vulnerability to damage?

The objective of our study was to test the hypothesis that subtle brain abnormality can be present in pediatric sickle cell disease (SCD) patients normal by conventional MR imaging (cMRI). We examined 50 SCD patients to identify those patients who were normal by cMRI. Quantitative MR imaging (qMRI) was then used to map spin-lattice relaxation time (T1) in a single slice in brain tissue of all 50 patients and in 52 healthy age-similar controls. We also used a radiofrequency (RF) pulse to saturate blood spins flowing into the T1 map slice, to characterize the effect of blood flow on brain T1. Abnormalities were noted by cMRI in 42% (21/50) of patients, with lacunae in 32%, and encephalo malacia in 20%. Brain T1 in patients normal by cMRI was significantly lower than controls, in caudate, thalamus, and cortex (p < or =0.007), and regression showed that gray matter T1 abnormality was present in caudate and cortex by age 4 (p < or =0.002). In patients abnormal by cMRI, T1 reductions in gray matter were larger and more significant. White matter T1 was not significantly increased except in patients abnormal by cMRI. RF saturation in a slab below the T1 map produced no significant change in T1, compared to RF saturation in a slab above the T1 map, suggesting that inflow of untipped spins in blood does not cause an artifactual shortening of T1. Gray matter T1 abnormality was present in patients normal by cMRI, while white matter T1 abnormality was present only in patients also abnormal by cMRI. These findings suggest that gray matter is selectively vulnerable to damage in pediatric SCD patients and that white matter damage occurs later in the disease process. Our inability to find an effect from saturation of inflowing blood implies that rapid perfusion cannot account for T1 reduction in gray matter.     

AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging

Dynamic contrast-enhanced MRI (DCE-MRI) was used to noninvasively evaluate the effects of AG-03736, a novel inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, on tumor microvasculature in a breast cancer model. First, a dose response study was undertaken to determine the responsiveness of the BT474 human breast cancer xenograft to AG-013736. Then, DCE-MRI was used to study the effects of a 7-day treatment regimen on tumor growth and microvasculature. Two DCE-MRI protocols were evaluated: (1) a high molecular weight (MW) contrast agent (albumin-(GdDTPA)(30)) with pharmacokinetic analysis of the contrast uptake curve and (2) a low MW contrast agent (GdDTPA) with a clinically utilized empirical parametric analysis of the contrast uptake curve, the signal enhancement ratio (SER). AG-013736 significantly inhibited growth of breast tumors in vivo at all doses studied (10-100 mg/kg) and disrupted tumor microvasculature as assessed by DCE-MRI. Tumor endothelial transfer constant (K(ps)) measured with albumin-(GdDTPA)(30) decreased from 0.034+/-0.005 to 0.003+/-0.001 ml min(-1) 100 ml(-1) tissue (P<.0022) posttreatment. No treatment-related change in tumor fractional plasma volume (fPV) was detected. Similarly, in the group of mice studied with GdDTPA DCE-MRI, AG-013736-induced decreases in tumor SER measures were observed. Additionally, our data suggest that 3D MRI-based volume measurements are more sensitive than caliper measurements for detecting small changes in tumor volume. Histological staining revealed decreases in tumor cellularity and microvessel density with treatment. These data demonstrate that both high and low MW DCE-MRI protocols can detect AG-013736-induced changes in tumor microvasculature. Furthermore, the correlative relationship between microvasculature changes and tumor growth inhibition supports DCE-MRI methods as a biomarker of VEGF receptor target inhibition with potential clinical utility.     

Initial clinical evaluation of gadolinium DTPA for contrast-enhanced magnetic resonance imaging

Gadolinium DTPA was evaluated as an intravenous contrast agent for magnetic resonance imaging in 15 patients with primary or secondary intracranial neoplastic disease. T1 and T2 weighted images were obtained prior to contrast administration. T1 weighted spin echo 35/800 (TE/TR) images were utilized to detect enhancement. The increase in signal intensity observed, identifying areas of breakdown of the blood-brain barrier (BBB), was similar in magnitude to the contrast enhancement observed on CT. This permitted differentiation of neoplastic tissue from surrounding cerebral edema on MRI. Direct visualization of otherwise "isomagnetic" lesions was also demonstrated. The use of intravenous contrast media should significantly extend the diagnostic potential and specificity of magnetic resonance imaging.     

Pharmacokinetic analysis and drug delivery efficiency of the focused ultrasound-induced blood-brain barrier opening in non-human primates

PurposeFocused Ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to open the Blood-Brain Barrier (BBB) locally, non-invasively and reversibly in rodents and non-human primates (NHP), suggesting the immense potential of this technique. The objective of this study entailed the investigation of the physiologic changes in the brain following the FUS-induced BBB opening and their relationship with the underlying anatomy.Materials and methodsPharmacokinetic analysis was implemented in NHP's that received FUS at various acoustic pressures. Relaxivity mapping enabled the robust quantitative detection of the BBB opening as well as grey and white matter segmentation. Drug delivery efficiency was measured for pre-clinical validation of the technique.ResultsBased on our results, the opening volume and the amount of the gadolinium delivered were found mostly contained in the grey matter, while FUS-induced permeability and drug concentration varied depending upon the underlying brain inhomogeneity, and increased with the acoustic pressure.ConclusionsOverall, apart from the in vivo protocols for BBB analysis developed here, this study also suggests the important role that FUS can have in efficient drug delivery via localized and transient BBB opening.     

Assessment of peripheral tissue perfusion disorder in streptozotocin-induced diabetic rats using dynamic contrast-enhanced MRI

Purpose

To assess peripheral tissue perfusion disorder in streptozotocin (STZ)-induced diabetic rats by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Materials and Methods

A rat diabetes model was produced by intravenous injection of STZ. Diabetic rats were sustainably treated with either saline or insulin using an Alzet osmotic pump. Hind paw tissue perfusion was measured by signal intensity (SI) enhancement after gadolinium diethylenetriaminepentaacetic acid injection in DCE-MRI study and quantified using the initial area under the SI-time curve (IAUC). Peripheral tissue uptake of [¹⁴C]iodoantipyrine (IAP) was also determined as a marker of tissue blood flow for comparison with the IAUC value indicating tissue perfusion.

Results

STZ caused hyperglycemia at 1 and 2 weeks after injection. Treatment with insulin significantly alleviated hyperglycemia. At 2 weeks after STZ injection, peripheral tissue perfusion was clearly reduced in the diabetic rats and its reduction was significantly improved in the insulin-treated diabetic rats. Tissue perfusion evaluated by DCE-MRI was similar to the tissue blood flow measured by [¹⁴C]IAP uptake.

Conclusion

Our findings demonstrated that DCE-MRI can assess peripheral tissue perfusion disorder in diabetes. DCE-MRI could be suitable for noninvasive evaluation of peripheral tissue perfusion in both preclinical and clinical studies. It may also be useful for developing novel drugs to protect against diabetic vascular complications.     

Reproducibility of the gadolinium concentration measurements and of the fitting parameters of the vascular input function in the superior sagittal sinus in a patient population

It is widely recognised that the measurement of the arterial input function (AIF) is a key issue and a major source of errors in the pharmacokinetic modelling of dynamic, contrast-enhanced magnetic resonance imaging (DCE-MRI) data, and the modality of the AIF determination is still a matter of debate. In this study we addressed the problem of the intrinsic variability of the AIF within the imaged volume of a DCE-MRI scan by systematically investigating the change in the concentration of contrast agent over time and the fit parameters of the derived vascular input function (VIF) obtained from the superior sagittal sinus (SSS) of a patient population that was scanned longitudinally during treatment for high grade glioma. From a total of 82 scanning sessions, we compared the results obtained with three different DCE-MRI protocols and between two different fitting functions. We applied a correction algorithm to the measured concentration-time curves to minimize the effect of the low temporal resolution on the VIF, and investigated the effect of this algorithm on the reproducibility. Finally, where possible, we compared the signal obtained in the SSS to the signal obtained in the middle cerebral artery. We found a good intrapatient reproducibility of both the measured gadolinium concentrations and VIF parameters, and that the variation of the parameters due to slice location within a patient was significantly lower than the intra patient variation. Intrapatient, interscan differences were significantly less marked than inter-patient differences showing a good intraclass correlation coefficient. We did encounter a MRI protocol dependence of the VIF fitting parameters. The correction algorithm significantly improved the reproducibility of the fitting parameters. These results support the idea that the use of a patient specific measured AIF, not necessarily averaged over a large volume, offers a significant benefit with respect to an external AIF or a measured cohort average AIF.     

Magnetization transfer of water T(2) relaxation components in human brain: implications for T(2)-based segmentation of spectroscopic volumes

Biexponential T(2) relaxation of the localized water signal can be used for segmentation of spectroscopic volumes. To assess the specificity of the components an iterative relaxation measurement of the localized water signal (STEAM, 12 echo times, geometric spacing from 30 ms to 2000 ms) was combined with magnetization transfer (MT) saturation (40 single lobe pulses, 12 ms duration, 1440 degrees nominal flip angle, 1 kHz offset, repeated every 30 ms). Voxels including CSF were examined in parietal cortex and periventricular parietal white matter (10 each), as well as 13 voxels in central white matter and 16 T(1)-hypointense non-enhancing multiple sclerosis lesions without CSF inclusion. Biexponential models (excluding myelin water) were fitted to the relaxation data. In periventricular VOIs the component of long T(2) (1736 +/- 168 ms) that is attributed to CSF was not affected by MT. In cortical VOIs this component had markedly shorter T(2)'s (961 +/- 239 ms) and showed both attenuation and prolongation with MT, indicating contributions from tissue. MS lesions and central WM showed a second tissue component of intermediate T(2) (160-410 ms). In white matter similar MT attenuation indicated strong exchange between the two tissue components, prohibiting segmentation. In MS lesions, however, markedly less MT of the intermediate component was found, which is consistent with decreased cellularity and exchange in a region that is large compared to diffusion motion.     

Magnetic resonance imaging contrast-enhanced relaxometry of breast tumors: an MRI multicenter investigation concerning 100 patients

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using extracellular contrast agents has proved to be useful for the characterization of breast tumors. DCE-MRI has demonstrated a high sensitivity (around 95%) but a rather poor and controversial specificity, varying, according to the different studies, from 45% to 90%. In order to increase (a) the specificity and (b) the robustness of this quantitative approach in multicenter evaluation (five MRI units), a quantitative approach called dynamic relaxometry has been developed. According to the proposed method, the time-dependent longitudinal relaxation rate measured on region of interest of the lesion was calculated during the contrast uptake, after intravenous bolus injection of contrast agent. A specifically developed method was used for fast R(1) measurements. Relaxometry time curves are fitted to the Tofts model allowing the measurement of the parameters describing the enhancement curve (maximum relation rate enhancement, initial, 30-s and 60-s slopes) and the tissue parameters [transfer constant (K(trans) min(-1)) and extracellular extravascular space fraction (v(e))]. Correspondence factorial analysis followed by hierarchical ascendant classification are then performed on the different parameters. Higher K(trans) values were observed in infiltrative ductal carcinomas than in infiltrative lobular carcinomas, in agreement with data published by other groups. Specificity of DCE-MRI has been increased up to 85%, with a sensitivity of 95% with K(trans)/v(e) and enhancement index I (ratio of initial slope by maximum relaxation rate enhancement). A multiparametric data analysis of the calculated parameters opens the way to include quantitative image-based information in new nosologic approaches to breast tumors.     

Improved T(1)-weighted dynamic contrast-enhanced MRI to probe microvascularity and heterogeneity of human glioma

Dynamic contrast-enhanced (DCE) T(1)-weighted magnetic resonance imaging (MRI) is a powerful tool capable of providing quantitative assessment of contrast uptake and characterization of microvascular structure in human gliomas. The kinetics of the bolus injection doped with increasing concentrations of gadopentate dimeglumine (Gd-DTPA) depends on tissue as well as pulse sequence parameters. A simple method is described that overcomes the limitation of relative signal increase measurement and may lead to improved accuracy in quantification of perfusion indices of glioma. Based on an analysis of the contrast behavior of spoiled gradient-recalled echo sequence; a parameter K with arbitrary unit 5.0 is introduced, which provides a better approximation to the differential T(1) relaxation rate. DCE-MRI measurements of relative cerebral blood volume (rCBV) and cerebral blood flow (rCBF) were calculated in 25 patients with brain tumors (15=high-grade glioma, 10=low-grade glioma). The mean rCBV was 6.46 +/- 2.45 in high-grade glioma and 2.89 +/- 1.47 in the low-grade glioma. The rCBF was 3.94 +/- 1.47 in high-grade glioma while 2.25 +/- 0.87 in low-grade glioma. A significant difference in rCBF and rCBV was found between high- and low-grade gliomas. This simple and robust technique reveals the complexity of tumor vasculature and heterogeneity that may aid in therapeutic management especially in nonenhancing high-grade gliomas. We conclude that the precontrast medium steady-state residue parameter K may be useful in improved quantification of perfusion indices in human glioma using T(1)-weighted DCE-MRI.     

Curvilinear reconstruction of 3D magnetic resonance imaging in patients with partial epilepsy: A pilot study

In an attempt to better delineate the abnormalities associated with focal cortical dysgenesis, we performed curvilinear reformatting of the cortex from 3D magnetic resonance (MR) images. Illustrative patients with partial seizures and conventional orthogonal MRI evaluation show that small regions of cortical thickening suggestive of focal dysplastic lesions may not be recognized. In three such patients the curvilinear reformatting demonstrated two additional focal abnormalities of the cortical gyri and better defined the two focal lesions found on conventional orthogonal MR images. This method promises to a be useful tool in the evaluation of epileptic patients with proven or suspected subtle structural cortical abnormalities, particularly focal neuronal migration disorders where cortical thickening, abnormal gyral pattern, and poor delineation of the gray-white matter transition are the main findings.     

Prominent signal intensity of T1/T2 prolongation in subcortical white matter of the anterior temporal region on conventional screening MRI of late preterm infants with normal development

Purpose

This study discusses prominent signal intensity of T₁/T₂ prolongation of subcortical white matter within the anterior temporal region in premature infant brains that radiologists may encounter when interpreting conventional screening MRIs.

Materials and Methods

T₁- and T₂-weighted images of 69 preterm and term infants with no neurological abnormalities or developmental delays were evaluated retrospectively for areas of prominent signal intensity of T₁/T₂ prolongation in white matter. We measured signal intensities of anterior temporal white matter, deep temporal white matter, frontopolar white matter and subcortical white matter of the precentral gyrus. We accessed chronological changes in signal intensity in the anterior and deep temporal white matter. We also analyzed variance tests among the signal intensity ratios to the ipsilateral thalamus of white matter areas by gestational age.

Results

There was high frequency of prominent signal intensity of T₁/T₂ prolongation in the temporal tip, particularly at a gestational age of 36–38 weeks. Signal intensity ratio of the anterior temporal white matter was lower on T₁-weighted images and higher on T₂-weighted images, and the finding became less prominent with increasing gestational age. The signal intensity ratios of anterior temporal white matter at a gestational age of 36–37 weeks and 38–39 weeks were significantly different from other regions.

Conclusion

Prominent signal intensity of T₁/T₂ prolongation of subcortical white matter of the anterior temporal region is seen in normal premature infants, especially those at 36–39 gestational weeks. Although it is a prominent finding, radiologists should understand that these findings do not represent a pathological condition.     

The use of Gd DTPA as a perfusion agent and marker of blood-brain barrier disruption

To provide contrast enhancement in magnetic resonance imaging, a new class of compounds has been developed, the paramagnetic metal ion chelates. Gadolinium (Gd) DTPA, a prototype of this class, shows a sufficiently high in vivo stability and low toxicity for use in initial clinical trials. This type of agent, designed for rapid clearance by glomerular filtration, allows the assessment on MRI of renal function, alterations in tissue perfusion, myocardial ischemia, and perhaps most significantly disruption of the blood-brain barrier (BBB). Research at Vanderbilt has demonstrated these applications, with particular emphasis in three areas. Tissue perfusion changes, such as those produced by ligation of the arterial blood supply to portions of the spleen and kidney, cannot easily be detected on unenhanced MRI. These acute tissue infarcts can be readily identified following the administration of Gd DTPA. The question of field strength dependence of Gd DTPA has been addressed by experimentation at 0.15, 0.5, and 1.5 tesla. Furthermore, the ability to detect an alteration of the BBB, when present without associated edema, has been demonstrated with the application of control enhancement. The use of contrast agents in MRI will enhance both the sensitivity and specificity of magnetic resonance imaging.     

A variational approach to image registration in dynamic contrast-enhanced MRI of the human kidney

Kidney function can be accessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements which yield spatially resolved maps of physiological parameters like perfusion or filtration. The motion of the kidneys during the scan is a dominant limitation of the measurement quality, and image registration is necessary for accurate quantification. We analyzed the feasibility of applying an algorithm, originally developed for multimodal registration, to kidney perfusion time series. The algorithm uses a variational calculation scheme to align the images. In four out of five data sets, kidney motion could be reduced to below the spatial resolution of the images of 1.6 mm while preserving the enhancement pattern of kidney perfusion. Fitting a pharmacokinetic model to the data showed an average reduction of the Akaike fit error of 10% for the registered data, suggesting more stable parameters. We conclude that this image registration algorithm is feasible for correcting kidney motion in renal DCE-MRI.     

An MRI perfusion model incorporating nonequilibrium exchange between vascular and extravascular compartments

A model of MRI signal intensity which is a function of perfusion is developed based upon the assumption that biological tissue can be represented by a blood and tissue compartment. The longitudinal magnetization is derived from the Bloch equations which are modified to model the magnetization in both the blood and tissue as a function of the following physiological parameters: blood flow velocity; perfusion fraction, which in the model is parameterized in terms of the ratio of the cross-sectional areas of the tissue and blood compartments; diffusion; rate of exchange between the blood and extravascular tissue compartments. Simulations of slice profiles excited by a repetitive sequence of 90 degrees slice-selective pulses show that the signal intensity in the blood and tissue compartments are modulated by the physiological parameters. A key factor in the modulation of the MRI signal is a time-of-flight effect whereby unexcited spins perfuse the excited region and exchange with blood and tissue compartments, thus immediately increasing the slice signal intensity but also delaying the spin exits from the slice, thereby decreasing their contribution to slice signal intensity in future repetitive pulse measurements.     

Magnetization transfer and T2 quantitation in normal appearing cortical gray matter and white matter adjacent to focal abnormality in patients with traumatic brain injury

Traumatic brain injury (TBI) is one of the commonest causes of morbidity and mortality in the developed countries with posttraumatic epilepsy and functional disability being its major sequelae. The purpose of this study was to test the hypothesis whether the normal appearing adjacent gray and white matter regions on T2 and T1 weighted magnetization transfer (MT) weighted images show any abnormality on quantitative imaging in patients with TBI. A total of 51 patients with TBI and 10 normal subjects were included in this study. There were significant differences in T2 and MT ratio values of T2 weighted and T1 weighted MT normal appearing gray matter regions adjacent to focal image abnormality compared to normal gray matter regions in the normal individuals as corresponding contralateral regions of the TBI patient's group (p < 0.05). However the adjoining normal appearing white matter quantitative values did not show any significant change compared to the corresponding contralateral normal white matter values. We conclude that quantitative T2 and MT ratio values provide additional abnormality in patients with TBI that is not discernable on conventional T2 weighted and T1 weighted MT imaging especially in gray matter. This additional information may be of value in overall management of these patients with TBI.     

Tagging of the magnetization with the transition zones of 360 degrees rotations generated by a tandem of two adiabatic DANTE inversion sequences

A new technique is presented for generating myocardial tagging using the signal intensity minima of the transition zones between the bands of 0 degrees and 360 degrees rotations, induced by a tandem of two adiabatic delays alternating with nutations for tailored excitation (DANTE) inversion sequences. With this approach, the underlying matrix corresponds to magnetization that has experienced 0 degrees or 360 degrees rotations. The DANTE sequences were implemented from adiabatic parent pulses for insensitivity of the underlying matrix to B(1) inhomogeneity. The performance of the proposed tagging technique is demonstrated theoretically with computer simulations and experimentally on phantom and on the canine heart, using a surface coil for both RF transmission and signal reception. The simulations and the experimental data demonstrated uniform grid contrast and sharp tagging profiles over a twofold variation of the B(1) field magnitude.     

Quantification of dynamic contrast-enhanced MR imaging of the knee in children with juvenile rheumatoid arthritis based on pharmacokinetic modeling

Improved management of arthritis requires a reliable, quantifiable, noninvasive method to monitor the degree of inflammation and therapeutic response during the early phase of the disease. For this purpose, the uptake of Gd-DTPA in the distal femoral physis and synovium in children with juvenile rheumatoid arthritis (JRA) was evaluated with a two-compartment pharmacokinetic model and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Employing a two-compartment pharmacokinetic model, the theoretical signal enhancement from Gd-DTPA enhanced dynamic 3D gradient-recalled echo (GRE) images was shown to have a simple linear relationship with tissue concentration independent of flip angle. The signal-enhancement patterns for each individual knee were found to be characterized by three pharmacokinetic parameters: k(ep) (min(-1)), the rate constant; k(el) (min(-1)), the elimination rate constant; and E(R) (min(-1)), the initial enhancement rate, which is proportional to the transfer constant K(trans) (min(-1)). Characteristic patterns were observed in the image signal intensity-time course. The initial enhancement rate, E(R), in regions of interest (ROIs) was found to have a wide range of variation: 5 to 38 min(-1) over the distal femoral physis and 1 to 10 min(-1) in the synovium. The E(R) of the synovium was correlated with the E(R) of the distal femoral physis (P<.05). In addition, the E(R) of the synovium was correlated to the clinical outcome measures of knee swelling. Further investigation is needed to determine whether wide variations in the pharmacokinetic parameters reflect the degree of disease activity, and whether there are changes in response to therapy. This method can also be applied in adults with rheumatoid arthritis (RA) and other disorders where T(1)-weighted contrast is used (breast cancer, brain tumors).     

Step-down infusions of Gd-DTPA yield greater contrast-enhanced magnetic resonance images of BBB damage in acute stroke than bolus injections

A rat model of transient suture occlusion of one middle cerebral artery (MCA) was used to create a unilateral reperfused cerebral ischemic infarct with blood-brain barrier (BBB) opening. Opening of the BBB was visualized and quantitated by magnetic resonance (MR) contrast enhancement with a Look-Locker T(1)-weighted sequence either following an intravenous bolus injection (n=7) or during a step-down infusion (n=7) of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). Blood levels of Gd-DTPA after either input were monitored via changes in sagittal sinus relaxation rate. Blood-to-brain influx constants (K(i)) were calculated by Patlak plots. On the basis of the MRI parameters and lesion size, the ischemic injury was determined to be similar in the two groups. The bolus injection input produced a sharp rise in blood levels of Gd-DTPA that declined quickly, whereas the step-down infusion led to a sharp rise that was maintained relatively constant for the period of imaging. Visual contrast enhancement and signal-to-noise (S/N) ratios were better with the step-down method (S/N=1.8) than with bolus injection (S/N=1.3). The K(i) values were not significantly different between the two groups (P>.05) and were around 0.005 ml/(g min). The major reason for the better imaging of BBB opening by the step-down infusion was the higher amounts of Gd-DTPA in plasma and tissue during most of the experimental period. These results suggest that step-down MR contrast agent (MRCA) administration schedule may be more advantageous for detection and delineation of acute BBB injury than the usually used bolus injections.