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步， 这种寿命的延长并不一定与认知上的长寿相匹配。更老的 个人患阿尔茨海默病(AD)的风险要高得多。因此，正在崛起的 老年人的数量，加上与衰老相关的阿尔茨海默病风险，正在迅速成为公众 健康危机。因此，重要的是我们要了解衰退背后的机制 阿尔茨海默病的认知功能。尽管阿尔茨海默病认知能力下降的许多机制 两个普遍的发现激励了目前的工作：1)血管风险因素是一种 AD的强烈预测因素和组织病理学研究表明， 阿尔茨海默病大脑的微血管构筑。尽管这些研究指出血管妥协是一种 AD相关认知功能减退的潜在致病因素，目前尚无相关技术 可用于详细评估大脑深部和深部微血管 活体动物的浅表血管。因此，还不可能跟踪血管 随着时间的变化或确定治疗干预对 脑微血管系统。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(ULM)。乌尔姆罐头图像 微米大小的血管深入大脑许多毫米深，可以捕捉到 血流(速度、流动均匀度和方向)，这在组织学研究中是无法获得的。 在这里，我们建议使用ULM来研究AD相关血流动力学的变化，并将 将它们与AD小鼠模型中与AD相关的行为变化联系起来。此外，我们还将 确定一种已知的可缓解AD相关认知变化的干预措施--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开之前知之甚少的微血管变化的面纱 AD的动力学，但也将推动一种具有广泛潜力的新成像技术 应用程序来了解许多其他的大脑疾病。

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.