VASCULAR DYSFUNCTION IN AGED CANINE BRAIN

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The aim of this proposal is to develop reliable MRI techniques to measure the structure and vascular function of aged canine brain. Studies will be performed in a beagle colony provided by the Inhalation Toxicology Research Institute (ITRI) in New Mexico. The beagles are currently being cognitively assessed; neuropathology will be studied later. Imaging of this unique canine model will be used as a tool to bridge information regarding behavioral performance and neuropathology in a manner not possible in other models. The long term objective of this study, but beyond the scope of this current project, is the application of information gained from the canine model to studies of human aging. MRI provides detailed structural and vascular functional information on age or dementia related changes in the brain. Recently evidence suggests that accumulation of beta-amyloid in the brain of aged or demented canines can cause vascular pathology. Abeta can damage the integrity of the vessel wall causing blood-brain-barrier leakage. Additionally, the damaged smooth muscle cells of the cerebral vessels can initiate a cascade of events resulting in more Abeta and pathology. Therefore, vascular dysfunction, such as BBB leakage and loss of vasoreactivity due to damaged smooth muscle, may be early markers for the onset of pathological aging. To test this hypothesis, we will investigate the relationships between vascular dysfunction and the development of cortical atrophy. MRI, with its excellent capability for providing structural details, can also be used to analyze vascular function. Regional vascular volume and permeability can be measured by using a technique referred to as "dynamic contrast enhanced MRI" in conjunction with appropriate pharmacokinetic analysis. The loss of vasoregulation resulting from smooth muscle damage and vascular angiopathy will be studied by applying vascular challenges. Imaging techniques will be developed and tested for reliability, then applied to a study a group of dogs which are currently being tested at ITRI. Dogs that show early signs of aging will be followed to monitor the progression of vascular deficiency and cortical atrophy. The imaging results will be correlated with pathology data to determine the significance of beta-amyloid and other variables in vascular function. This data also will be correlated to the results of behavioral performance data to determine if any of the structural or functional parameters are predictive for a specific type of task. Ultimately, imaging may provide specific information to help link the nature of pathology to behavior and may provide non-invasive diagnostic means to detect early signs of pathological aging.