The aim of this proposal is to use MR imaging techniques to investigate the development of structural atrophy and vascular dysfunction and their relationship to pathology in a longitudinal study of canine brain aging. We currently have access to a colony of 48 beagle dogs that are subjects of a collaborative study between UCI, the University of Toronto and the Lovelace Respiratory Research Institute (LRRI) in Alburquerque, New Mexico, where the dogs are housed. Funding has been obtained for a study following the natural course of age dependent cognitive decline and the effects of three interventions in 9-10 year old dogs. These three interventions include (1) an antioxidant enriched diet; (2) environmental enrichment and additional problem solving experience and (3) a combination of the diet and experience. The potential for these interventions to slow age-dependent cognitive decline will be evaluated be comparing the rate of decline in treated dogs with nontreated dogs. The purpose of the current proposal is to take advantage of this ongoing experiment to obtain in vivo measures of brain function. The accumulation of brain amyloid (Abeta) in the walls of the cerebrovasculatureof aged canines can lead to vascular dysfunction via toxic effects on endothelial cells. One possible consequence of a loss of blood vessel integrity is damage to the blood-brain-barrier (BBB). Vascular dysfunction, such as BBB leakage and loss of vasoreactivity, may be early markers for the onset of pathological aging. MRI, with its excellent capability for providing structural details, can also be used to analyze vascular function. Regional vascular volume and BBB permeability can be measured with dynamic contrast enhanced MRI. The loss of vasoregulation resulting from smooth muscle damage and vascular Abeta angiopathy can be studied with the use of vascular challenges. During the study, serum levels of soluble Abeta will be monitored using sandwich ELISA procedures. At the conclusion of MRI studies, the brains of these dogs will be analyzed using quantitative anatomic techniques to obtain measures of the extent of Abeta deposition in the blood vessel walls and surrounding neuropil. The ability of MR measures obtained in vivo to predict brain pathology in the canine model provides insight into diagnostics that can be applied in the clinic. Noninvasive MR imaging techniques may offer a means of detecting early signs of pathological aging, allowing us the opportunity to initiate interventions to slow disease progression.
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