This proposal is focused on three important public health problems: brain injury associated with cardiac surgery; leukoaraiosis (LA), a neurodegenerative disease of the white matter; and Alzheimer's disease (AD). Brain microemboli resulting from cardiac surgery occur by the millions, and cause focal ischemia that may contribute to the brain dysfunction seen in about 1/3 of these patients. We will determine whether the microemboli can be reduced by washout with increased cerebral blood flow. We will count the microemboli in the brains of dogs that have had different rates of cerebral blood flow after surgery. There will be several variables affecting blood flow in the series of dog experiments. We will also determine whether the severity of the brain injury correlates with the numbers of microemboli, by studying markers of brain injury in tissue sections: microglial activation; leukocytes; stress protein; and blood brain barrier leakage. In the CSF,we will quantitate leukocytes and the soluble brain injury markers, neuron-specific enolase and S100beta protein. LA is thought to be caused by chronic ischemia resulting from vascular pathology. In autopsy material of LA subjects (diagnosed by MRI), we will quantify the vascular density in LA lesions, normal appearing white matter, and cortex. Similar studies will be done in age-matched controls. We will also quantify the number of string vessels in those three areas. String vessels are very thin (1 micron) collagenous cords, presumably vessel remnants, with no lumen or endothelial cells. We will also quantify the number and type of cells undergoing apoptosis in the three areas. We believe that vascular pathology, with resultant ischemia, is a contributor to brain degeneration in a subset of AD patients. In the brains of AD subjects, we will quantify the vascular density in areas affected by plaques and tangles, other areas of cortex, and white matter. Similar studies will be done in controls. We will also quantify the number of string vessels in those areas. In AD subjects, we will investigate the occurrence of LA lesions (by MRI) and study two vascular pathologies: venous stenosis and occlusion caused by redundant layers of mural collagen and tortuous vessels that cause small brain cavities. Clinical impact: we expect the dog surgery experiments will lead to safer cardiac surgery, and the studies of cerebrovascular pathology in human brains from LA and AD subjects will promote a better understanding of the pathophysiolooy of these diseases and how to treat or prevent them.
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