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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017066-02
Application #
6509662
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Snyder, Stephen D
Project Start
2001-04-15
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
2
Fiscal Year
2002
Total Cost
$311,920
Indirect Cost
Name
University of California Irvine
Department
Miscellaneous
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Pop, Viorela; Head, Elizabeth; Berchtold, Nicole C et al. (2012) A? aggregation profiles and shifts in APP processing favor amyloidogenesis in canines. Neurobiol Aging 33:108-20
Pop, Viorela; Head, Elizabeth; Hill, Mary-Ann et al. (2010) Synergistic effects of long-term antioxidant diet and behavioral enrichment on beta-amyloid load and non-amyloidogenic processing in aged canines. J Neurosci 30:9831-9
Siwak-Tapp, Christina T; Head, Elizabeth; Muggenburg, Bruce A et al. (2008) Region specific neuron loss in the aged canine hippocampus is reduced by enrichment. Neurobiol Aging 29:39-50
Siwak-Tapp, Christina T; Head, Elizabeth; Muggenburg, Bruce A et al. (2007) Neurogenesis decreases with age in the canine hippocampus and correlates with cognitive function. Neurobiol Learn Mem 88:249-59
Wang, Huali; Golob, Edward J; Su, Min-Ying (2006) Vascular volume and blood-brain barrier permeability measured by dynamic contrast enhanced MRI in hippocampus and cerebellum of patients with MCI and normal controls. J Magn Reson Imaging 24:695-700
Tapp, P Dwight; Head, Kevin; Head, Elizabeth et al. (2006) Application of an automated voxel-based morphometry technique to assess regional gray and white matter brain atrophy in a canine model of aging. Neuroimage 29:234-44
Ray, Kimberly M; Wang, Huali; Chu, Yong et al. (2006) Mild cognitive impairment: apparent diffusion coefficient in regional gray matter and white matter structures. Radiology 241:197-205
Chen, Ya-Fang; Wang, Huali; Chu, Yong et al. (2006) Regional quantification of white matter hyperintensity in normal aging, mild cognitive impairment, and Alzheimer's disease. Dement Geriatr Cogn Disord 22:177-84
Su, Min-Ying; Tapp, P Dwight; Vu, Long et al. (2005) A longitudinal study of brain morphometrics using serial magnetic resonance imaging analysis in a canine model of aging. Prog Neuropsychopharmacol Biol Psychiatry 29:389-97
Tapp, P Dwight; Chu, Yong; Araujo, Joseph A et al. (2005) Effects of scopolamine challenge on regional cerebral blood volume. A pharmacological model to validate the use of contrast enhanced magnetic resonance imaging to assess cerebral blood volume in a canine model of aging. Prog Neuropsychopharmacol Biol Psychiatry 29:399-406

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