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

基于图像的脑血管网络合成（iCNS）来模拟阿尔茨海默病

• 批准号: 10561232
• 负责人: ANDREAS A LINNINGER
• 金额: $ 75.13万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561232
• 关键词: Address; Affect; Age; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Anatomy; Animal Experimentation; Animal Model; Area; Biological; Biological Markers; Biophysics; Blood Vessels; Blood capillaries; Blood flow; Brain; Cellular Stress; Cerebrovascular Circulation; Cerebrum; Circulation; Clinical; Cognitive; Computer Simulation; Core-Binding Factor; Data; Deterioration; Diagnosis; Diagnostic Imaging; Disease; Disease Progression; Early Diagnosis; Endothelium; Event; Exhibits; Functional disorder; Future; Goals; Health; Hemodynamic Processes; Heterogeneity; Homeostasis; Human; Image; Immune; Impaired cognition; Individual; Infarction; Intervention; Kinetics; Lead; Length; Leukocytes; Link; Magnetic Resonance Imaging; Maps; Mathematics; Measures; Mediating; Medicine; Metabolic; Metabolic Diseases; Metabolism; Methods; Microcirculation; Microscopic; Microvascular Dysfunction; Modeling; Monitor; Mus; Nerve Degeneration; Neurologic; Outcome; Oxygen; Pathologic; Pattern; Perfusion; Physiological; Physiological Processes; Predictive Value; Predisposition; Process; Property; Protocols documentation; Research; Resources; Risk; Rodent; Signal Transduction; Specificity; Symptoms; Techniques; Testing; Time; Tissues; Tracer; Translating; Translations; Validation; Vascular blood supply; age effect; age related; age related neurodegeneration; aged; aging brain; animal data; biomarker identification; cerebral hemodynamics; cerebrovascular; cerebrovascular pathology; cohort; computational platform; computer framework; digital; early detection biomarkers; experimental study; hemodynamics; human data; human disease; imaging biomarker; improved; insight; mathematical methods; microscopic imaging; models and simulation; morphometry; multi-scale modeling; network models; neuroimaging; neuron loss; noninvasive diagnosis; novel; pharmacologic; predictive modeling; prodromal Alzheimer' s disease; simulation; solute; spatiotemporal; theories; tissue oxygenation

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.

与年龄有关的神经变性的大量资源针对动物研究 假设结果将为我们对人类平行过程的理解提供理解。但是，没有可靠的方法 存在以准确地将脑血流或代谢数据从动物转换为人类。因为缺乏严格 物种之间脑代谢参数的数学方法，价值研究数据的翻译 从鼠标到人类仍然是猜测。需要一个预测的计算框架 量化正常和解散的人脑状态下的脑血流和代谢。我们的长期目标 是量化衰老和阿尔茨海默氏病（AD）的基本生理过程，以便它们的影响 可以放慢甚至部分逆转。目的是通过放大MRI分析的实用性 具有机械数学框架的人类与年龄相关的微循环变化的可检测性。它 我们的假设是，微循环的年龄和AD相关的变化也会产生宏观循环 血液动力学和/或氧灌注状态的扰动，可通过晚期MRI检测到 在所有相关长度尺度上以严格的大脑模拟为指导时，技术。理由是至关重要 老年大脑功能障碍的物理指标（=老化生物标志物）将通过系统暴露 基本血流动力学和代谢过程的探索和模拟。中心假设将 通过追求三个具体目标来测试： 目标1）通过模拟毛细管失速之间的联系来评估机械建模的预测价值， 血管示踪剂过境特性和组织氧递送，并使用先进的预测来验证预测 小鼠中的微观成像。我们确定衰老和AD在老化的啮齿动物大脑中的影响。 目标2）开发机械多尺度模型，以预测脑灌注对氧气的影响 在正常和病理条件下人类皮质中的代谢。解剖学上详细的机理 人类脑循环模型将预测AD的结构和功能变化的影响 MRI中人脑中的氧气提取。 目标3）评估机械多尺度建模的预测价值以量化微血管特性 使用晚期MRI，整个人类脑皮质在健康和疾病中。验证机械翻译 从小鼠到人，我们将测量与老年人和老年痴呆症同龄人的年龄相关代谢功能 患者。我们确定与认知能力下降相关的血液动力学和代谢指标（=生物标志物） 这种贡献很重要，因为它将预测血管形态计量学和代谢的变化 导致神经系统下降。它将确定在人类的无创诊断成像中可见的生物标志物 症状发生之前，与信号年龄相关的定义。与获取的数据有关的机械框架 小鼠到人类将大大提高动物数据与人类医学的相关性。