The focus of this proposal is the application of advanced magnetic resonance imaging techniques, specifically diffusion and perfusion weighted MRI, to study the evolution of ischemic brain injury in a model of stroke in nonhuman primates (macaques). The use of diffusion and perfusion MRI for assessing stroke in animal models is well established and is becoming increasingly popular for diagnosing and monitoring acute stroke in human patients. Their clinical application remains somewhat controversial however, primarily because of an apparent lack of validation of the methodology in humans. This proposal will address this deficiency using clinically applicable MRI techniques in a macaque stroke model that closely resembles human stroke, but with the advantages of a controlled experimental setting and histologically defined endpoints. The overall objective of this proposal is to distinguish reversible from nonreversible brain damage in ischemic stroke using MRI. We will also show that MRI provides a """"""""surrogate endpoint"""""""" to supplement or replace neurological testing in the assessment of stroke outcome in humans. We will use an endovascular stroke model in macaques, recently developed at MGH. Under fluoroscopic guidance, animals will receive 10, 20, 40, 60, 120, or 240 minutes of middle cerebral artery occlusion, or permanent occlusion.
The specific aims are (1) to measure the natural evolution of the brain lesion using continuous T2-diffusion-and perfusion-weighted MRI during and up to 30 days after transient and permanent focal cerebral ischemia and (2) determine the combination of MRI derived parameters that can reliably predict reversible/nonreversible brain damage after transient ischemia using a statistical model that incorporates all the imaging findings. In addition to MRI, we will perform serial neurological testing and finally histological analysis of the brain slices. We hypothesize that (1) injury indicated by diffusion abnormality is reversible beyond a critical ischemia duration and that stroke evolution in macaques is closer to that in humans than rats, and (2) acute MRI scans can predict regional brain tissue status at the endpoint and that the statistical model can predict infarct location and neurological outcome from the chronic MRI data. A successful outcome from this study on nonhuman primates will generate data that will be directly relevant to the study and management of stroke in humans.
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