Imaging Age-Related Changes in A Canine Model of Aging

描述(由申请人提供)：建议补充资金的研究的目标有三个：(1)纳入一组一直在接受我们最初建议中描述的相同抗氧化剂强化饲料的年轻狗；(2)增加正在接受新开发的认知任务的老年动物的样本量，以测量空间和物体识别记忆；以及(3)开发和测试使用Abeta探针和PET扫描检测在老化的犬脑中自然发展的Abeta神经病理的可行性。我们目前资助的项目正在测试这样的假设，即通过富含抗氧化剂的饮食减少氧化损伤，和/或通过提供丰富的环境来促进神经元存活，将显著增强36只老龄狗的认知功能，而不是12只未经治疗的对照组。我们将每年进行一次核磁共振研究，以监测这些狗的脑萎缩和脑血管异常的发展情况，这既是年龄的函数，也是治疗的反应。16只幼犬目前正在多伦多大学使用平行研究设计进行研究，并得到另一项NIA R01拨款(AG12694“犬类作为人类衰老的动物模型”)的支持。我们寻求资金将这16只幼年动物纳入目前资助的MRI研究，这将为我们提供一个独特的机会，获得幼年动物的治疗和比较数据。多伦多大学这项研究的另一个目标是研究与年龄相关的记忆衰退，因此这项提议的第二个目标是获得活体MRI测量，可能支持空间记忆比物体识别记忆衰退更快的假设。在接下来的4年里，将对36只狗进行研究。这项提案的第三个目标是获得补充资金，以优化使用带有正电子发射断层扫描(PET)扫描的Abeta特异性探针([18F]FDDNP，由加州大学洛杉矶分校开发)检测犬脑中的β-淀粉样蛋白(Abeta)的方法。这一令人兴奋的新研究领域特别适合用于犬类模型，因为随着年龄的增长，狗会自然地在大脑中沉积人型Abeta。该探针在体外和体内与老年斑中的Abeta结合的特性已经被证明。建议进行一项试点研究，将包括10只动物(8名老年动物和2名年轻动物)通过PET检测Abeta，并将体内数据直接与使用已建立的免疫细胞化学和成像方案确定的死后Abeta负荷进行比较。非侵入性成像技术可能提供一种检测病理性衰老早期迹象的手段，并使我们有机会在体内监测治疗效果。

DESCRIPTION (provided by applicant): The goal of the studies proposed for supplemental funding is threefold: (1) to include a group of young dogs that have been receiving the same antioxidant enriched diet described in our original proposal; (2) to increase the sample size of old animals that are being assessed on newly developed cognitive tasks measuring spatial and object recognition memory and; (3) to develop and test the feasibility of detecting Abeta neuropathology that naturally develops in aging canine brain using an Abeta probe and PET scans. Our currently funded project is testing the hypotheses that reducing oxidative damage with a diet rich in antioxidants, and/or promoting neuron survival by providing an enriched environment will significantly enhance cognitive function in 36 aging dogs relative to 12 untreated controls. We will perform annual MRI studies to monitor the development of brain atrophy and cerebrovascular abnormalities in these dogs both as a function of age and in response to treatment. Sixteen young dogs are currently being studied at the University of Toronto using a parallel study design and is supported by another NIA R01 grant (AG12694 "The Canine as an Animal Model of Human Aging"). We seek funding to include these 16 young animals into the currently funded MRI study, which will provide us with a unique opportunity to obtain both treatment and comparison data in young animals. Another goal of the research at the University of Toronto is to study age-related memory decline and thus the second goal of this proposal is to obtain in vivo MRI measures that may provide support for the hypothesis that spatial memory declines more rapidly than object recognition memory. Thirty-six dogs will be studied during the next 4 years. A third goal of this proposal is to obtain supplemental funding to optimize methods to detect beta-amyloid (Abeta) in the canine brain using an Abeta-specific probe ([18F]FDDNP, developed by UCLA group) with PET (Positron Emission Tomography) scans. This exciting new area of research is particularly well suited for use in the canine model because dogs naturally deposit human-type Abeta in the brain with age. The in vitro and in vivo binding characteristics of this probe to Abeta within senile plaques have been demonstrated. A pilot study is proposed that will include 10 animals (8 aged and 2 young) to detect Abeta by PET and to compare in vivo data directly to post mortem Abeta loads determine using established immunocytochemistry and imaging protocols. Noninvasive imaging techniques may offer a means of detecting early signs of pathological aging and allows us the opportunity to monitor treatment efficacy in vivo.