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.

与年龄相关的神经变性的重要资源用于动物研究 假设结果将帮助我们理解人类的并行过程，但目前还没有可靠的方法。 由于缺乏严格的研究，存在能够准确地将动物的脑血流或代谢数据转化为人类的数据。 物种间脑代谢参数的数学方法，有价值的研究数据的翻译 从老鼠到人类仍然是猜测，需要一个预测计算框架。 量化正常和患病人类大脑状态下的脑血流量和新陈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，以便了解它们的影响 可以减慢甚至部分逆转，目的是通过放大 MRI 分析的效用。 利用机械数学框架可检测人类与年龄相关的微循环变化。 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变化 先进 MRI 可检测到的血流动力学和/或氧灌注状态的扰动 在所有相关长度尺度上进行严格的大脑模拟指导时，技术的基本原理是至关重要的。 衰老大脑功能障碍的生理指标（=衰老生物标志物）将通过系统性暴露 基本的血液动力学和代谢过程的探索和模拟。 通过追求三个具体目标来进行测试： 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， 血管示踪剂转运特性和组织氧输送，并使用先进的方法验证预测 我们通过小鼠显微成像确定衰老和 AD 对老年啮齿类动物大脑的影响。 目标 2) 开发机械多尺度模型来预测脑灌注对氧的影响 正常和病理条件下人体皮质的新陈代谢。 人类脑循环模型将预测 AD 结构和功能变化对 通过 MRI 检测人脑中的氧气提取情况。 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 使用先进的 MRI 跨越人类大脑皮层的健康和疾病来验证机械翻译。 从小鼠到人类，我们将测量老年人和阿尔茨海默病队列中与年龄相关的代谢功能 我们确定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）。 这一贡献意义重大，因为它将预测血管形态测量和新陈代谢的变化 它将识别人类无创诊断成像中可见的生物标志物，从而导致神经功能衰退。 在症状出现之前发出与年龄相关的恶化信号 与获得的数据相关的机制框架。 小鼠对人类的研究将极大地提高动物数据与人类医学的相关性。