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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001634-05
Application #
2431064
Study Section
NST-2 Subcommittee (NST)
Program Officer
Jacobs, Tom P
Project Start
1993-06-01
Project End
1999-05-31
Budget Start
1997-06-01
Budget End
1999-05-31
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Siewert, B; Wielopolski, P A; Schlaug, G et al. (1997) STAR MR angiography for rapid detection of vascular abnormalities in patients with acute cerebrovascular disease. Stroke 28:1211-5
Siewert, B; Schlaug, G; Edelman, R R et al. (1997) Comparison of EPISTAR and T2*-weighted gadolinium-enhanced perfusion imaging in patients with acute cerebral ischemia. Neurology 48:673-9
Schlaug, G; Siewert, B; Benfield, A et al. (1997) Time course of the apparent diffusion coefficient (ADC) abnormality in human stroke. Neurology 49:113-9
Schlaug, G; Sanes, J N; Thangaraj, V et al. (1996) Cerebral activation covaries with movement rate. Neuroreport 7:879-83
Warach, S; Dashe, J F; Edelman, R R (1996) Clinical outcome in ischemic stroke predicted by early diffusion-weighted and perfusion magnetic resonance imaging: a preliminary analysis. J Cereb Blood Flow Metab 16:53-9
Sanes, J N; Donoghue, J P; Thangaraj, V et al. (1995) Shared neural substrates controlling hand movements in human motor cortex. Science 268:1775-7
Warach, S; Gaa, J; Siewert, B et al. (1995) Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol 37:231-41