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

Abstract

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.

Figure 1

Examples of ¹⁴C-labeled sucrose plasma profiles after intravenous bolus injection (A) and step-down infusion (B). Notice the sharp rise and the steep fall in plasma levels in A and the sharp rise, but relatively constant plasma levels thereafter in B. Identical administration protocols were employed for MRCA injection in the present work.

Figure 2

Examples of changes in Gd-DTPA levels with time in the sagittal sinus shown by MR imaging for two inputs. The imaging duration is indicate on the abscissa, and the changes in Gd-DTPA relaxation rates, ΔR₁, at each time of measurement is plotted on the ordinate. The bolus input resulted in a quick rise in the blood levels that fell exponentially over the imaging period. The step-down infusion, however, resulted in an elevated blood level that remained more or less constant throughout the imaging interval. The similarity between the curves in Figure 1 from 3 min onward and those in Figure 2 is obvious. The Figure 1 curves from 0–180 min almost certainly indicate the data missing first 3 min of data in Figure 2. Values are mean ± SD of 7 experiments for each group.

Figure 3

Three examples of MR Look-Locker T₁ maps after Gd-DTPA enhancement observed after a typical bolus injection (left set of panels) and of the histologies obtained from within the MRI slices (right set of panels). The area of pallor is outlined in black on the histologies. The MR maps were generated by off-line analyses of the Look-Locker T₁ data. The subtraction maps for this group of bolus injection experiments are more highly pixilated than those from the step-down infusion (Fig. 4) and no leakage of Gd-DTPA was evident in example 4A, although an appreciable sized ischemic lesion was apparent on the accompanying histology (4B). In this example and the other two, the S/N ratio appeared to be fairly low, and the identification of the enhancing regions was, accordingly, more difficult. Despite sizable ischemic lesions in all seven rats, Gd-DTPA enhancement was either relatively modest (most cases) or none existent (one case) for the bolus injection experiments.

Figure 4

Three examples of MR images after Gd-DTPA enhancement observed after a typical step-down infusion (left set of panels) and of the histologies obtained from within the MRI slices (right set of panels). The pre-Gd-DTPA T₁WI images were subtracted from the post-Gd-DTPA T₁WI images to highlight the enhancing areas. The ischemic lesion seen on the Nissl stained sections from the respective experiments are outlined in black on the histological images on the right. It can be seen in the MR subtracted maps that the MR contrast images are relatively smooth. The S/N ratio appears to be quite high from the step-down infusion studies, and the identification of the enhancing regions is simple and straightforward from these images. Blood-brain barrier opening was, thus, readily detectable from the Gd-DTPA distribution data from the step-down infusion studies.

Figure 5

The distribution of ipsi- and contralateral pixel intensities are shown for the two modes of Gd-DTPA administration. In both groups, the range of pixel intensities on the contralateral side was lower than on the ipsilateral side. On both sides of the brain, the number of pixels on the higher end of the brightness scale was larger with the step-down infusion than with the bolus injection, and the range of brightness extended to higher values for the former than the latter. The data points are the mean ± SD (n=7 for both groups).