The purpose of this award will be for the investigator to train in the experimental methodology of stroke in the laboratory and begin to apply this knowledge to human cerebrovascular disease using unique forms of magnetic resonance imaging (MRI). The investigator has been working on developing new methodologies to identify areas of early cerebral infarction. One such methodology -- diffusion weighted imaging (DWI) -- is capable of identifying areas of ischemic injury as early as 105 minutes in stroke patients, times when conventional T2-weighted MRI (T2WI) cannot. With another novel method, dynamic blood volume imaging by a susceptibility-weighted pulse sequence, the investigator demonstrated areas of poor tissue perfusion in acute stroke that match the areas of abnormality on DWI. DWI has enormous potential as an aid to the early quantitative assessment of brain injury in stroke, and therefore as an important tool in the testing of early therapeutic interventions. One of the major limitations in the study of stroke patients is the variability in the clinical course and the difficulty in determining the size and severity of ischemic injury based solely on the clinical examination. More rapid advances could be made if one could establish the anatomical diagnosis sooner and in a quantifiable manner. Recent progress indicates that drugs that block N-methyl-D-aspartate (NMDA) receptor mediated neurotoxicity can decrease the area of infarction after cerebral ischemia. One such drug, memantine, was effective in doses known to be clinically safe. The investigator proposes to apply the new methodology of DWI to experimental models to determine whether it will prove useful as an endpoint in assessing the effectiveness of such therapeutic interventions. To accomplish this goal the investigator will perform the following studies: 1. Using diffusion weighted imaging (DWI), the region of decreased diffusion at multiple time points from 0-48 hours will be compared to brain perfusion using dynamic blood volume imaging and to final infarct size by T2WI and histopathology at one week in a rat model of thromboembolic disease using the rose bengal photocoagulation method. 2. To extend these findings to humans, DWI will be used to study cerebral infarction in humans at similar time points and compared to tissue perfusion (by dynamic blood volume imaging) and infarct size (by T2WI) and clinical outcome (by the NIH stroke scale) at 7 days and 3 months. 3. The clinically safe NMDA antagonist memantine will be tested as a therapy to limit ischemic infarct size at similar time periods in the rat model using DWI, T2WI, and histopathology. 4. Memantine will be evaluated by DWI, T2WI and clinical outcome in patients who have occlusive cerebrovascular disease. It is expected that DWI will prove more sensitive than T2WI in detecting early ischemic lesions and will be a marker of potentially reversible ischemic injury. This reversibility will depend on four factors: time from ischemic onset, presence of tissue perfusion, magnitude of diffusion decrease, and treatment with memantine. In sum, the investigator seeks training to evaluate his new method of DWI as a tool to test promising new therapies to reduce the morbidity and mortality of cerebrovascular disease.
