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Abstract

Purpose: Over two thirds of human ischemic stroke is caused by occlusion of the middle cerebral artery and its branches. The success of recovery from ischemic injury is heavily dependent on its timely detection. To this end, the ability to promptlymonitor cerebral ischemia is of crucial importance, since the extent of caused brain injury depends primarily on the ischemia duration. For instance, the extracellular Ca2+ decreases dramatically during ischemia. Therefore, an imaging method that tracks in vivo variations of [Ca2+]e, thus enabling monitoring of the intensity and duration of cerebral ischemia, would be of paramount importance. Here we report development of an fMRI method to monitor the progress of ischemia by means of Ca-responsive MRI probe.
Methods and Materials: Two probes, responsive Gd2L1 or nonresponsiveGd2L2, as a control were prepared and compared in vitro. Subsequently, they were intracranially infused in Wistar rats using osmotic pumps. Cerebral ischemia was caused using remote transient middle cerebral artery occlusion (tMCAo). fMRI consisted of a series of T1-weighted MRI acquisitions during the preischemia, ischemia, and postischemia periods, whereas controls included infusion of probes, without tMCAo. Data analysis was based on K-means clustering and the signal detrending.
Results: The relaxometric titrations and MRI experiments on tube phantoms showed suitability of Gd2L1 to report on changes in [Ca2+], whereas Gd2L2 remained Ca-insensitive. When both probes were administered in vivo and MRI experiments were performed, clustering of the obtained T1-weighted MRI signals displayed the co-centric pattern. Detrended clustered signals showed up to 5% signal change for tMCAo experiments with Gd2L1, whereas those with Gd2L2 and control experiments showed no signal alterations. The MRI signal changes completely followed the temporal pattern of tMCAo induction and the tissue reperfusion after the occluder retraction.
Conclusions: We developed an fMRI approach for monitoring of the cerebral ischemia using bioresponsive MRI probe. This method is successfully reporting on the physiological changes of tissue affected with ischemia; moreover, it detects the ischemic onset promptly, aswell as changes during reperfusion, the feature that is crucial for the choice of therapy and subsequent recovery. This molecular fMRI technique could become important tool to study the extent of brain injury caused by the cerebral ischemia. In addition, it could allow the visualization and mapping of neural signaling directly by sensing its direct indicator-calcium, thus supplementing the use of conventional fMRI based on BOLD signal.