A LONGITUDINAL STUDY IN THE CANINE MODEL OF HUMAN AGING

描述：(逐字摘自申请者摘要)：本提案的目的 就是利用磁共振成像技术来研究结构的发展 血管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。我们目前有权进入一个殖民地 在48只比格犬中，UCI、 多伦多大学和洛夫莱斯呼吸研究所(LRRI) 新墨西哥州阿尔伯克基，狗的住所。已获得资金 一项跟踪年龄依赖性认知能力下降和 3种干预措施对9-10岁犬的影响。这三个人 干预措施包括(1)富含抗氧化剂的饮食；(2)环境 丰富和额外的问题解决经验和(3)结合 饮食和体验。这些干预措施放缓的可能性 将通过比较年龄相关性认知功能下降的比率来评估 接受治疗的狗与未治疗的狗的发病率下降。当前的目的是 建议利用这项正在进行的实验在体内获得 测量大脑功能。脑内淀粉样蛋白(Abeta)的积聚 老龄犬脑血管壁可导致血管功能障碍 通过对内皮细胞的毒性作用。一个可能的后果是损失 血管完整性是对血脑屏障(BBB)的破坏。血管 功能障碍，如血脑屏障渗漏和血管反应性丧失，可能是早期的 病理性衰老开始的标志物。核磁共振，凭借其卓越的能力 为了提供结构细节，还可以用来分析血管 功能。局部血管容量和血脑屏障通透性可用 动态增强MRI。平滑导致的血管调节功能的丧失 肌肉损伤和血管Aβ血管病变可以用来研究 血管挑战。在研究期间，血清中可溶性Abeta的水平将是 使用夹心ELISA法进行监测。在核磁共振研究结束时， 这些狗的大脑将使用定量解剖学进行分析 获得血液中Abeta沉积程度的测量的技术 血管壁和周围的神经纤维束。中获得的MR测量的能力 活体预测犬脑病理模型提供了洞察力 可以应用于临床的诊断学。无创磁共振成像 技术可以提供一种检测病理性衰老的早期迹象的方法， 使我们有机会启动干预措施来减缓疾病 进步。

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.