Image-based cerebrovascular network snythesis(iCNS) to model Alzheimer's Disease

关于年龄相关性神经变性的重要资源是针对动物研究的， 假设结果将告知我们对人类平行过程的理解。然而，没有可靠的方法 存在将脑血流或代谢数据从动物准确地转换到人类。由于缺乏严格的 种属间脑代谢参数的数学方法，有价值的研究数据的翻译 从老鼠到人类遗骸的猜测需要一种预测计算框架， 量化正常和患病人脑状态下的脑血流量和代谢。我们的长期目标 是量化衰老和阿尔茨海默病（AD）的基本生理过程， 可以被减缓甚至部分逆转。其目的是通过放大MRI分析的 用一个机械的数学框架来检测人类与年龄相关的微循环变化。它 我们的假设是，年龄和AD相关的微循环变化也会产生宏观的 血流动力学和/或氧灌注状态的扰动，可通过高级MRI检测到 技术，当严格的大脑模拟在所有相关的长度尺度的指导下。理由是， 老年脑功能障碍的生理指标（=老化生物标志物）将通过系统的 探索和模拟基本的血液动力学和代谢过程。核心假设将 通过追求三个具体目标进行测试： 目的1）通过模拟毛细血管停滞， 血管示踪剂传输特性和组织氧输送，并使用先进的 小鼠的显微成像我们确定了老化和AD在老年啮齿动物大脑中的影响。 目的2）建立脑灌注对氧代谢影响的多尺度机制模型 在正常和病理条件下的人类皮质代谢。详细的解剖学机制 人的脑循环模型将预测AD的结构和功能变化对 用核磁共振成像来观察人脑的氧摄取。 目的3）评估机械多尺度建模对量化微血管特性的预测价值 在健康和疾病的人类大脑皮层中使用先进的MRI。为了验证机械翻译 从小鼠到人类，我们将测量老年人和阿尔茨海默病患者队列中与年龄相关的代谢功能。 患者我们确定了与认知能力下降相关的血流动力学和代谢指标（=生物标志物） 这一贡献是重要的，因为它将预测血管形态和代谢的变化 导致神经功能衰退。它将确定在人类非侵入性诊断成像中可见的生物标志物， 在症状出现之前就表明与年龄相关的恶化。与数据相关的机械框架， 小鼠到人类的实验将极大地提高动物数据对人类医学的相关性。

Significant resources on age-related neurodegeneration are directed toward animal research in the assumption that results will inform our understanding of parallel processes in human. Yet, no reliable method exists to accurately translate cerebral blood flow or metabolic data from animal to human. For lack of rigorous mathematical methods for cerebral metabolic parameters between species, translation of valuable research data from mouse to human remains guesswork. There is a need for a predictive computational framework that quantifies cerebral blood flow and metabolism in normal and diseased human brain states. Our long term goal is to quantify fundamental physiological processes of aging and Alzheimer’s disease (AD), so that their effects can be slowed or even partially reversed. The objective is to expand the utility of MRI analysis by magnifying the detectability of age-related microcirculatory changes in humans with a mechanistic mathematical framework. It is our hypothesis that age and AD related changes in the microcirculation also generate macroscopic perturbations of hemodynamic and/or oxygen perfusion states that will be detectable with advanced MRI techniques, when guided by rigorous brain simulations over all relevant length scales. The rationale is that critical physiological metrics for dysfunction in aged brains (=aging biomarkers) will be exposed by systematic exploration and simulation of fundamental hemodynamic and metabolic processes. The central hypothesis will be tested by pursuing three specific aims: Aim 1) Assess the predictive value of mechanistic modeling by simulating the link between capillary stalling, vascular tracer transit properties, and tissue oxygen delivery, and validate predictions using advanced microscopic imaging in mouse. We determine the effects of aging and AD in aged rodent brains. Aim 2) Develop mechanistic multiscale model for predicting the impact of cerebral perfusion on oxygen metabolism in the human cortex under normal and pathological conditions. Anatomically detailed mechanistic models of cerebral circulation in human will predict the effect of structural and functional changes in AD on oxygen extraction in the human brain with MRI. Aim 3) Assess the predictive value of mechanistic multiscale modeling to quantify microvascular properties across the human brain cortex in health and disease using advanced MRI. To validate the mechanistic translation from mouse to human, we will measure age-related metabolic functions in cohorts of aged and Alzheimer patients. We identify hemodynamic and metabolic metrics (=biomarkers) that correlate with cognitive decline This contribution is significant because it will predict how changes in vascular morphometry and metabolism lead to neurological decline. It will identify biomarkers visible in noninvasive diagnostic imaging in humans that signal age-related deterioration before symptoms develop. The mechanistic framework relating data acquired in mouse to human will dramatically boost the relevance of animal data for human medicine.