Revealing tissue microstructure in the brain gray matter in Alzheimer's disease using in vivo high-gradient diffusion MRI

使用体内高梯度扩散 MRI 揭示阿尔茨海默病大脑灰质的组织微观结构

• 批准号: 10254657
• 负责人: Hong Hsi Lee
• 金额: $ 42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10254657
• 关键词: 3-Dimensional; Address; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Applications Grants; Award; Axon; Biological Markers; Blood; Brain; Cell Size; Cells; Cerebrospinal Fluid Proteins; Clinic; Clinical; Computer software; Data; Dementia; Development; Diagnostic; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Doctor of Philosophy; Early Diagnosis; Early identification; Electron Microscopy; Ensure; Evaluation; Faculty; Family Caregiver; Future; General Hospitals; Geometry; Goals; High Performance Computing; Histologic; Histology; Histopathology; Human; Imaging Techniques; Impaired cognition; Interdisciplinary Study; Intervention; Joints; Knowledge; Laboratories; Leadership; Magnetic Resonance Imaging; Massachusetts; Measurement; Measures; Medicine; Mentorship; Microscopic; Microscopy; Monitor; Monte Carlo Method; Mus; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; Onset of illness; Paper; Pathologic; Patients; Peer Review; Physics; Positioning Attribute; Positron-Emission Tomography; Postdoctoral Fellow; Presenile Alzheimer Dementia; Radiology Specialty; Research; Resolution; Resource Sharing; Risk; Running; Scientist; Structure; Symptoms; System; Techniques; Technology; Testing; Three-dimensional analysis; Time; Tissues; Training; Translating; Treatment Efficacy; United States; Validation; Varicosity; Work; aging population; base; bioimaging; biophysical model; brain tissue; career; career development; clinical translation; cluster computing; connectome; density; experience; experimental study; graduate student; gray matter; high dimensionality; high risk; imaging biomarker; imaging facilities; in vivo; innovative technologies; instructor; light microscopy; magnetic resonance imaging biomarker; medical schools; meetings; microCT; mild cognitive impairment; neuronal cell body; next generation; non-invasive imaging; novel; novel therapeutics; prognostic; protein biomarkers; research study; senior faculty; simulation; skills; success; tau Proteins; tau-1; theories; tool; treatment response; white matter; white matter change

Project Summary/Abstract Alzheimer’s disease (AD) accounts for about 70% of dementia cases, and the number of AD patients continues to grow substantially due to the worldwide phenomenon of population aging, prompting the call for innovative technologies that will enable the early identification of patients at risk and monitoring of disease progression and therapeutic response. There is a known sequence of pathological alterations that develop in Alzheimer’s disease (AD) long before frank cognitive decline, offering potential targets for early detection of disease onset with subsequent interventions. While volumetric MRI changes are useful to assess the presence of neurodegeneration, regional cortical volume loss is a relatively late structural marker of neurodegeneration in AD. On the other hand, diffusion MRI (dMRI) is a non-invasive imaging technique sensitive to pathological changes on the cellular level, at least three orders of magnitude below the nominal spatial resolution of conventional MRI. So far, most AD studies using dMRI have largely focused on white matter changes. However, on histopathology, AD is primarily a cortical disease. The ability to probe early microstructural changes in GM in vivo would open the door to assessing disease onset and progression, facilitating the development of disease- modifying therapy. This project will bridge the gap in understanding changes in GM tissue microstructure in AD and mild cognitive impairment (MCI) using a combination of tools in multiple domains, such as biophysical modeling, ex vivo and in vivo dMRI, and histological validation. We will address this multi-faceted research challenge through the following aims: Aim 1: Establish time-dependent dMRI measurements to evaluate the density of axonal varicosities, size of cell body (soma), and soma/neurite density using a high-gradient MRI system. By leveraging the very strong diffusion gradients on the current and next-generation Connectome MRI scanner, we will develop a novel technique for evaluating the tissue microstructure in healthy subjects, AD and MCI patients. Aim 2: Validate in vivo and ex vivo dMRI measures of axonal and soma structure via Monte Carlo simulations of diffusion and histological analysis in three-dimensional realistic substrates based on light and electron microscopy, and micro-CT data. Aim 3: Assess the correlation of GM microstructural parameters with cognitive dysfunction, amyloid and tau PET scans, and blood and cerebrospinal fluid protein biomarkers, such as amyloid beta, total and phosphorylated tau (P-tau 181 and P-tau 217). In summary, building on our previous success in assessing white matter microstructure using dMRI, our study in GM promises to provide reliable noninvasive imaging markers of neurodegeneration, facilitating our understanding of the mechanisms underlying the progression of AD. Ultimately, the quantification of GM microstructure will offer prognostic and confirmatory biomarkers for neurodegenerative diseases, facilitating the assessment of treatment efficacy with the emergence of new therapies for AD and related dementias.

项目概要/摘要 阿尔茨海默病 (AD) 约占痴呆病例的 70%，且 AD 患者数量持续增加 由于世界范围内的人口老龄化现象，人口大幅增长，这促使人们呼唤创新 能够及早识别处于危险中的患者并监测疾病进展的技术 治疗反应。阿尔茨海默病中存在一系列已知的病理改变 （AD）早在明显的认知能力下降之前，就为早期发现疾病发作提供了潜在的目标 随后的干预。虽然体积 MRI 变化有助于评估是否存在 神经退行性变，区域皮质体积损失是神经退行性变的相对较晚的结构标志物 广告。另一方面，扩散磁共振成像（dMRI）是一种对病理学敏感的非侵入性成像技术。 细胞水平上的变化，至少比标称空间分辨率低三个数量级 常规 MRI。到目前为止，大多数使用 dMRI 的 AD 研究主要集中在白质变化上。然而， 在组织病理学上，AD主要是一种皮质疾病。能够探测 GM 的早期微观结构变化 vivo 将为评估疾病的发病和进展打开大门，促进疾病的发展- 修改治疗。该项目将弥合理解 AD 中 GM 组织微观结构变化的差距 和轻度认知障碍（MCI），使用多个领域的工具组合，例如生物物理 建模、离体和体内 dMRI 以及组织学验证。我们将进行多方面的研究 通过以下目标进行挑战： 目标 1：建立时间依赖性 dMRI 测量来评估 使用高梯度 MRI 测量轴突静脉曲张的密度、细胞体（胞体）的大小以及胞体/神经突密度 系统。通过利用当前和下一代连接体 MRI 上非常强的扩散梯度 扫描仪，我们将开发一种新技术来评估健康受试者、AD 和 MCI 患者。目标 2：通过蒙特卡罗验证轴突和体细胞结构的体内和离体 dMRI 测量 基于光和三维现实基质的扩散和组织学分析模拟 电子显微镜和显微 CT 数据。目标 3：评估 GM 微观结构参数与 认知功能障碍、淀粉样蛋白和 tau PET 扫描以及血液和脑脊液蛋白质生物标志物，例如 β 淀粉样蛋白、总 tau 蛋白和磷酸化 tau 蛋白（P-tau 181 和 P-tau 217）。 总之，基于我们之前使用 dMRI 评估白质微观结构的成功，我们 转基因研究有望提供可靠的神经退行性变无创成像标记物，促进我们的研究 了解 AD 进展的机制。最终，GM的量化 微观结构将为神经退行性疾病提供预后和确认性生物标志物，促进 随着 AD 和相关痴呆症新疗法的出现，评估治疗效果。