MRI estimation of gadolinium and albumin effects on water proton.

The longitudinal relaxivity on the protons of water of a Gd-chelate-albumin compound was measured at 7 T as a function of the macromolecular content of a cross-linked matrix. In agreement with previous works, the results demonstrate that the effect of gadolinium on water proton relaxivity is not constant, rising moderately with increase in the concentration of bovine serum albumin (BSA). About 35% variation in relaxivity was observed over a 0%-25% range of BSA concentrations (ℜ = 3.893 + 0.0502 × BSA [%], SE = 0.0119 and 0.1740, t = 4.215 and 22.383, p < 0.014 and 0.001).

Identification of variations in blood-brain barrier opening after cerebral ischemia by dual contrast-enhanced magnetic resonance imaging and T 1sat measurements.

BACKGROUND AND PURPOSE: Variations in blood-brain barrier (BBB) opening after ischemia have been suggested by some tracer and magnetization transfer studies, although direct in vivo proof is still lacking. Contrast-enhanced magnetic resonance imaging (MRI) is also often used to visualize BBB damage in stroke. We hypothesized that MR contrast agents of different sizes enhance differently when BBB openings vary in size and that magnetization transfer alterations, measured by T(1) in the presence of off-resonance radiofrequency saturation (T(1sat)), in these regions reflect such differences. METHODS: Male Wistar rats ( approximately 300 g, n=7) were subjected to 3 hours of suture occlusion of the middle cerebral artery followed by reperfusion. Status of the BBB at 24 hours after the ictus was assessed first by Gd-DTPA (554 Da) MRI and then by Gd-bovine serum albumin linked to Evans blue (Gd-BSA-EB; approximately 68 kDa) MRI for contrast enhancement; T(1sat) changes, cerebral blood flow, and blood-to-brain transfer constants (K(i)s) for the 2 contrast agents were measured. After MRI, rats were injected with fluorescent dextran and brains were studied by fluorescence microscopy. RESULTS: The Gd-BSA-EB-enhancing areas were always smaller (147+/-80 pixels) than those for Gd-DTPA (308+/-204 pixels) and were contained within the latter. The difference between the 2 areas was significant (P=0.024). Changes in T(1sat) were larger in Gd-BSA-EB-enhancing areas (ipsilateral to contralateral [I/C]=1.53+/-0.20) than in Gd-DTPA-enhancing areas (I/C=1.40+/-0.24, P=0.005). The differences in cerebral blood flow values between the 2 regions were not significant (P=0.62), but those for the K(i) values of the 2 tracers were different (P=0.01 to 0.02). Excellent agreement between regions of Gd-BSA-EB enhancement and EB fluorescence was also observed. CONCLUSIONS: These results substantiate earlier reports of regional differences in BBB opening after stroke and provide the first in vivo evidence for this phenomenon. They also support the possible use of T(1sat) in quantifying stroke-induced graded BBB damage in the absence of contrast-enhanced MRI.

Application of arsenazo III in the preparation and characterization of an albumin-linked, gadolinium-based macromolecular magnetic resonance contrast agent.

A macromolecular magnetic resonance contrast agent (MMCA) was prepared by linking bovine serum albumin (BSA) to gadolinium (Gd) via a chelating agent, diethylenetriaminepentaacetic acid (DTPA). Colorimetric testing with 2,7-bis(o-arsenophenylazo)-1,8-dihydroxynaphthalene-3,6-disulfonic acid (arsenazo III) was performed to check for the appearance of free gadolinium during preparation and to quantify the Gd content in the final product. The complex was purified by dialysis, concentrated by lyophilyzation and characterized by magnetic resonance (MR) proton relaxation times. The resultant product had a molecular weight of about 90 kDa, Gd:BSA ratio of 14:1, and T1 and T2 relaxation times of 128.3 and 48.9 ms, respectively, at a field strength of 7Tesla (T) and at 20% concentration. Contrast enhancement of Gadomer-17 (a dendritic MMCA) and Gd-linked to BSA (Gd-BSA) was sequentially evaluated in a rat brain gliosarcoma model (n = 5) by MR imaging (MRI). Following intravenous injection, the blood concentration of Gadomer-17 fell rapidly, whereas that of Gd-BSA was almost constant for the duration of imaging. The areas of enhancement of both MMCAs were comparable. The spatial distribution of Gd-BSA showed good agreement with Evans blue-tagged albumin. Treatment with dexamethasone decreased Gd-BSA enhancement in the tumor. These results suggest that the arsenazo III method is applicable in preparing Gd-BSA to image brain tumors and their response to treatment. This simple method may also be useful for preparing other gadolinium-linked MMCAs.

Acute neurovascular unit protection by simvastatin in transient cerebral ischemia.

Acute vascular- and neuroprotective effects of simvastatin were evaluated in a rat model of transient, focal cerebral ischemia. Male, Wistar rats (n=12) underwent transient middle cerebral artery (MCA) occlusion for 3 hours followed by 3 hours of reperfusion. After 30 minutes of MCA occlusion, four rats each were subcutaneously injected with either 20 or 40 mg/kg of simvastatin. At the end of 3 hours of reperfusion, tissue injury and blood-brain barrier (BBB) opening were quantified by histology and [(14)C]-alpha-aminoisobutyric acid (AIB)-based quantitative autoradiography (QAR), respectively. Compared with untreated rats, those treated with simvastatin (20 mg/kg) had reduced volumes of AIB leakage, tissue pallor and distribution space for AIB (p<0.05). No additional effects were seen with the higher drug dose (40 mg/kg). These data suggest that the acute neuroprotective effects of statins are in part owing to attenuation of stroke-induced changes in BBB permeability.