A Study of Diffusion Tensor Imaging as a Potential Surrogate Marker for the Management of Acute Ischemic Cerebral Stroke: a Clinical and Animal Model at 7t

Background The current imaging guidelines for thrombolytic treatment of acute ischemic stroke (AIS) within the first 3 hours of onset are based on CT findings with which patients show less than one-third infarct of the middle cerebral artery (MCA) territory and no acute hemorrhage are eligible. Recently, several multi-centric trials such as DIAS and DEFUSE began to move from CT to magnetic resonance imaging (MRI) in an attempt to find other indicators, which can be utilized to tailor for the individual patient’s need. For example, the MR-defined ischemic penumbras by lesion volume difference between perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) may potentially help to extend therapeutic time window more than 3 hours. However, the computations of MR-based ischemic penumbra are time-consuming which might not be appropriate for the acute setting. Therefore, a single and more straightforward MRI indicator is desirable for the same purpose. Diffusion tensor imaging (DTI) has shown capable of delineating the micro-structural changes of brain due to ischemic injury. In early cerebral ischemia, DTI parameters such as fractional anisotropy (FA) can be higher in infarcted region than that of contralateral normal brain, and then declines rapidly over the ensuing time course, suggesting irreversible structural damage. It is not known exactly, however, if the conversion of FA can be used as the indicator for therapeutic time window. In this study, we aim to study DTI parameters by animal and human models to see if FA could be used as a surrogate marker in the decision making of acute ischemic stroke therapy. In the first year study granted by NSC, our initial permanent MCA occlusion model in rat at 7T MRI experiment has shown a striking difference in time course of FA changes between core and penumbra regions. The FA changes inside in the infarct core had 30% higher in value than the contralateral normal brain within 6 hours of occlusion. The FA values decline to 10% higher than normal at 6-hour follow-up. On the contrary, the FA of ischemic penumbra was about 10% higher than that of corresponding normal brain in the beginning and remained 10% higher than normal with time. It is possible that the constant 10% increase in FA in penumbral region can be a marker for therapy if the volume of the penumbra remains 20% of the ischemic volume. We now apply for the 2nd and third year grant to continue our work as follows. Materials and Methods In the next two years period, we will enroll 30 AIS patients and 30 transient MCA occluded (MCAo) rats for imaging study. Animal model will be conducted on a 7 Tesla scanner and human on 1.5 Tesla. We will establish transient MCAo animal models (thread occlusion method) first at 7T MRI environment. Scanning parameters will be optimized for the different MR sequences at 7T and 1.5T, respectively. Post-processing methods will incorporate analyses of diffusion tensor, apparent diffusion coefficient maps, relative cerebral blood flow (rCBF) maps and susceptibility-weighted imaging (SWI). The difference of FA between infarct core and ischemic penumbra in transient model study will be determined and analyzed. Project Aims 1. To evaluate the time course of FA changes in acute MCA ischemic stroke and to compare these changes with the parallel DWI, PWI, as well as the volume evolution of ischemic penumbra. 2. To establish transient and permanent ischemic stroke models in animal at 7T so that the role of FA in AIS as a surrogate marker for thrombolytic therapy can be assessed. 3. To study the possible mechanism of reperfusion hemorrhage by SWI and its correlate with other diffusion and perfusion as well as metabolic parameters.