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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 andMaterials: 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.
