This project focuses on three important brain diseases in which microvascular alterations contribute materially to the process. We propose (1) to determine the etiology and significance of the ubiquitous exogenous intravascular material (called SCADs) in brains examined after cardiopulmonary bypass (CPB), (2) to establish the relation of vascular disease to leukoaraisosis in the deep white matter of elderly humans and to correlate leukoaraiosis with apoptosis, and (3) to quantify the morphologic and functional alterations found in arterioles and capillaries of Alzheimer's disease (AD) patients. First problem: Permanent mild-to severe intellectual dysfunction is observed in 6-34% of patients after surgery assisted by CPB. Recently, the alkaline phosphatase (AP) method of vascular staining has shown millions of SCADs in brains autopsied shortly after CPB. The outcome of CPB-assisted surgery may be improved if SCADs can be reduced and if we can elucidate the molecular pathways by which brain cells die (apoptosis). Second problem : We hypothesize that certain abnormal magnetic resonance (MR) imaging signals in the white matter are associated with intraparenchymal vascular diseases whose ultimate effect is chronic ischemia, and that the pathway by which the white matter degenerates is apoptosis (which can be arrested by certain drugs). Third problem: The contribution of vascular disease to the overall process of AD is an area of increasing interest. In addition to amyloid deposition in the wall of arterioles, extreme morphologic alteration has recently been observed in the capillaries of AD brains. These findings must be extended and correlated by other methods specifically designed to visualize microvascular pathology and neuronal loss. Cohorts to be studied are: (1) dogs that have undergone experiments, CPB, (2) hyperintensives and elderly normotensives, and (3) patients with AD. First project: CPB experiments on dogs are designed to determine the source of SCADs and to determine the biological consequences of these lipid microemboli. Second project: MR imaging of autopsy brain slices will identify areas with leukoaraiosis. Protocol areas will be histochemically stained with the AP technique to facilitate examination of the entire length of the afferent vasculature from the brain surface to, as well as the veins from, the lesion to be investigated. The proposed study will add significant predictive information concerning this common MR imaging abnormality. The degrees to which apoptosis contributes to this degenerative brain disease will be quantified. Third project: In autopsy material from patients with AD the extent of morphologic alteration of the brain microvessels will be qualified. The extent to which ischemia is associated with vascular alterations, and the extent to which vascular basement membrane constituents are incorporated into AD plaques, will be qualified.
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