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

阿尔茨海默病模型脑微血管变化的超分辨率成像

• 批准号: 10430929
• 负责人: DANIEL A LLANO
• 金额: $ 42.15万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430929
• 关键词: Aerobic Exercise; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Anatomy; Animal Disease Models; Animals; Area; Automobile Driving; Autopsy; Behavior; Biological; Blood; Blood Vessels; Blood Volume; Blood capillaries; Blood flow; Brain; Brain Diseases; Brain imaging; Brain region; Cerebrovascular Circulation; Cerebrovascular system; Chronic; Cognition; Cognitive; Communities; Coupled; Data; Development; Diabetes Mellitus; Disease; Exercise; Functional Imaging; Goals; Hippocampus (Brain); Human; Hypertension; Illness impact; Image; Imaging Device; Imaging Techniques; Impaired cognition; Individual; Intervention; Life; Longevity; Measures; Microscopy; Mus; Nerve Degeneration; Obesity; Pathogenesis; Penetration; Physical Exercise; Physiology; Population; Public Health; Research; Resolution; Rest; Risk Factors; Science; Societies; Speed; Structure; Techniques; Therapeutic Intervention; Time; Tissue imaging; Tissues; Work; abeta deposition; age group; age related; aging population; angiogenesis; base; cardiovascular risk factor; cerebral microvasculature; cognitive change; cognitive function; effective therapy; high risk; histological studies; imaging approach; imaging study; microvascular pathology; middle age; millimeter; mouse model; novel; novel imaging technique; preservation; ultrasound; vascular risk factor

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.

项目概要 尽管生物医学在延长人类寿命方面取得了显着进展， 寿命的延长并不一定与认知能力的延长相匹配。年长的 个体患阿尔茨海默病（AD）的风险明显更高。因此，不断上升的 老年人数量以及与衰老相关的 AD 风险正迅速成为公众关注的焦点 健康危机。因此，了解衰退背后的机制非常重要。 AD 中的认知功能。尽管 AD 认知能力下降的许多机制已被证实 提出，两个普遍的发现推动了当前的工作：1）血管危险因素是 AD 的有力预测因素，2) 组织病理学研究表明， AD 大脑的微血管。尽管这些研究指出血管损害是一种 AD 相关认知能力下降的潜在促成因素，目前尚无技术 可以对深部和脑部的脑微血管进行详细评估 活体动物的浅表血管。因此，无法追踪血管 随时间的变化或确定治疗干预措施对 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 (ULM)。 ULM 可以成像 微米大小的血管深入大脑数毫米，并且可以捕获 组织学研究无法获得血流（速度、流动均匀性和方向）。 在这里，我们建议使用 ULM 来研究 AD 相关的血流动力学变化，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，我们将 确定是否有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态。成功的 这项工作的完成不仅将揭示以前知之甚少的微血管变化 AD 的动态变化，但也将推进一种具有广泛潜力的新型成像技术 应用程序来了解许多其他大脑疾病。