Super-resolution imaging of brain microvascular changes in a model of Alzheimer Disease

项目摘要 尽管生物医学在延长人类寿命方面取得了显著进展， 寿命的延长并不一定与认知的长寿相匹配。老年 个体发展为阿尔茨海默病（AD）的风险显著更高。因此， 老年人的数量，加上与年龄相关的AD风险，正在迅速成为公众 健康危机。因此，重要的是，我们要了解下降的机制， AD的认知功能尽管AD认知功能下降的许多潜在机制 提出，两个普遍的发现激发了目前的工作：1）血管危险因素是一个 AD的强预测因子和2）组织病理学研究显示， AD脑的微血管。尽管这些研究指出血管损伤是 AD相关认知功能下降的潜在促成因素，目前还没有技术 可用于详细评估深部脑微血管系统， 活体动物的表面血管。因此，不可能跟踪血管 随着时间的推移而变化，或确定治疗干预对 脑微血管为此，我们的团队一直在开发一种新型的超级- 分辨率血管成像，称为超声定位显微镜（乌尔姆）。乌尔姆可以成像 微米大小的血管深入大脑许多毫米，可以捕捉动态的 血液流动（速度、流动均匀性和方向），这是使用组织学研究无法获得的。 在这里，我们建议使用乌尔姆来研究AD相关的血流动力学变化， 将它们与AD小鼠模型中AD相关的行为变化联系起来。此外，我们将 确定是否有一种已知的干预措施可以减轻AD相关的认知变化-有氧运动 - 恢复AD模型动物的局部脑微血管动力学。成功 这项工作的完成不仅将揭示以前知之甚少的微血管变化， 动力学，但也将推进一种具有广泛潜力的新型成像技术 应用于了解许多其他大脑疾病。

Project Summary Although biomedical science has made remarkable progress in extending the human lifespan, this lengthening of life has not necessarily been matched by longevity in cognition. Older individuals are at significantly higher risk for developing Alzheimer Disease (AD). Thus, the rising numbers of older individuals, coupled with aging-related risk for AD, is rapidly becoming a public health crisis. It is therefore important that we understand the mechanisms underlying declining cognitive function in AD. Although many mechanisms underlying cognitive decline in AD have been proposed, two universal findings motivate the current work: 1) vascular risk factors are a strong predictor of AD and 2) histopathological studies have shown profound alterations in the microvasculature of the AD brain. Although these studies point to vascular compromise as a potential contributory agent of AD-associated cognitive decline, there are currently no techniques available that permit a detailed assessment of the cerebral microvasculature of deep and superficial blood vessels in a living animal. Thus, it has not been possible to track vascular changes over time or to determine the impact of therapeutic interventions on the cerebral microvasculature. To this end, our team has been developing a novel form of super- resolution vascular imaging known as ultrasound localization microscopy (ULM). ULM can image micron-size blood vessels many millimeters deep into the brain, and can capture dynamics of blood flow (speed, flow uniformity and direction) which are not available using histological studies. Here, we propose to use ULM to investigate AD-related changes in blood flow dynamics and will relate them to AD-related changes in behavior in a mouse model of AD. In addition, we will determine if an intervention known to mitigate AD-related cognitive changes – aerobic exercise – restores regional cerebral microvasculature dynamics in AD model animals. Successful completion of this work will not only unveil previously poorly understood changes in microvascular dynamics with AD, but will also advance a novel imaging technique with broad potential applications to understand many other disorders of the brain.