A LONGITUDINAL STUDY IN THE CANINE MODEL OF HUMAN AGING

描述：（申请人摘要的逐字记录）：本提案的目的 是利用磁共振成像技术来研究结构性 萎缩和血管功能障碍及其与病理的关系 犬脑老化的纵向研究。我们现在可以进入一个殖民地 48只比格犬是UCI， 多伦多大学和Lovelace呼吸研究所（LRRI） 新墨西哥州的阿尔伯克基，狗被安置在那里。已获得资金 对于遵循年龄依赖性认知衰退的自然过程的研究， 三种干预措施对9-10岁犬的影响。这三 干预措施包括（1）富含抗氧化剂的饮食;（2）环境 丰富和额外的解决问题的经验和（3）结合 饮食和经验。这些干预措施减缓 年龄依赖性认知能力下降将通过比较 与未治疗犬相比，治疗犬下降。当前的目的 建议是利用这个正在进行的实验，以获得体内 大脑功能的测量。脑淀粉样蛋白（Abeta）的积累， 老年犬的血管壁会导致血管功能障碍 通过对内皮细胞的毒性作用。一个可能的后果是损失的 血管完整性是对血脑屏障（BBB）的损害。血管 功能障碍，如血脑屏障渗漏和血管反应性丧失， 病理性衰老开始的标志物。磁共振成像，以其出色的性能 提供结构细节，也可用于分析血管 功能局部血管体积和BBB渗透性可以用 动态增强MRI。血管调节的丧失导致平滑 肌肉损伤和血管性Abeta血管病可以使用 血管挑战在研究期间，将测定可溶性Abeta的血清水平。 使用夹心ELISA程序监测。在MRI研究结束时， 这些狗的大脑将用定量解剖学方法进行分析， 获得血液中Abeta沉积程度测量的技术 血管壁和周围神经鞘。获得的MR测量的能力， 在犬模型中预测脑病理学提供了对 可以应用于临床的诊断方法。非侵入性磁共振成像 这些技术可以提供一种检测病理性衰老的早期迹象的手段， 让我们有机会开始干预以减缓疾病 进展

DESCRIPTION: (Verbatim from the Applicant's Abstract): 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.