Stroke is the third most common cause of death in the United States and the largest cause of permanent disability in the country. Most strokes are thromboembolic in origin, profoundly decreasing blood flow to a focal area of tissue. This sustained reduction in the cerebral blood flow is not sufficient to maintain cellular function and ultimately causes irreversible neuronal injury in an ischemic core of tissue. This is surrounded by a zone of marginally perfused tissue which has been called the ischemic penumbra. Energy depletion in this tissue and changes in neurotransmitter release appear to be a critical components in the cascade of events mediating neuronal death. Traditional biochemical techniques have been used to study the complex metabolic changes that occur during ischemia and to study the effects of any proposed therapy. These techniques, however do not allow rapid serial measurements during the acute phase after the onset of ischemia. Recent advances in magnetic resonance imaging and magnetic resonance spectroscopy allow for noninvasive, real time, sequential study of the metabolic changes produced by cerebral ischemia. 31P MRS can give an accurate account of the relative intracellular concentrations of high energy phosphate metabolites, and 1H MRS can calculate pH, lactate, and concentrations of neurotransmitters. We propose to study the effects of cerebral ischemia in a feline model of focal stroke using state-of-the-art MR technology. Using a unique 20 cm horizontal-bore 9.4 Tesla magnet and new techniques for spatial localization of spectra developed at the university of Minnesota, we will identify the metabolic changes occurring in the ischemic core and penumbra, as well as neurotransmitter and pH changes, and follow them sequentially in time. This is the first and currently the only 9.4 T magnet of its kind in operation world-wide. We will also use intracerebral microdialysis to study pH and neurotransmitter release. In the second part of the proposal after characterization of these changes, we will study isovolemic hemodilution, which experimental studies have shown to be of benefit when instituted early after the onset of ischemia. The next step will be to determine the optimal timing within which hemodilution must be instituted to be of benefit. As the window of opportunity during which therapy is likely to be of benefit is short, we will be able to comprehensively and noninvasively define the changes that occur within the core and surrounding tissue. It will also likely demonstrate a time beyond which therapeutic interventional will be unlikely to rescue damaged neurons. This can then be used in experiments testing other novel forms of neuroprotection during this period of time.
