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

项目概要/摘要 阿尔茨海默病（AD）约占痴呆病例的70%，AD患者数量仍在持续 由于世界范围内的人口老龄化现象， 能够早期识别风险患者和监测疾病进展的技术， 治疗反应阿尔茨海默氏病的病理改变有一个已知的顺序 (AD)早在坦率的认知能力下降之前，这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 在神经变性中，区域皮质体积损失是神经变性的相对晚期的结构标志物， AD.另一方面，扩散MRI（dMRI）是一种对病理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研究主要集中在白色物质的变化上。然而，在这方面， 在组织病理学上，AD主要是一种皮质疾病。在转基因植物中探测早期微结构变化的能力， vivo将打开评估疾病发作和进展的大门，促进疾病的发展- 改良疗法这个项目将弥合差距在了解变化的GM组织微观结构在AD 和轻度认知障碍（MCI），使用多个领域的工具组合，如生物物理 建模、离体和体内dMRI以及组织学验证。我们将解决这个多方面的研究 目标1：建立时间依赖性dMRI测量，以评估 使用高梯度MRI的轴突静脉曲张密度、细胞体（索马）大小和索马/神经突密度 系统通过利用当前和下一代Connectome MRI上非常强的扩散梯度， 扫描仪，我们将开发一种新的技术，用于评估健康受试者，AD和 MCI患者目的2：通过Monte Carlo模拟轴突和索马结构的体内和体外dMRI测量 基于光的三维现实基质中的扩散和组织学分析的模拟， 电子显微镜和显微CT数据。目的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生物标志物，如 作为淀粉样蛋白β，总的和磷酸化的tau（P-tau 181和P-tau 217）。 总之，基于我们先前使用dMRI评估白色物质微结构的成功，我们 GM的研究有望提供可靠的非侵入性神经退行性变成像标记物， 了解AD进展的潜在机制。最终，GM的量化 微结构将为神经退行性疾病提供预后和确证性生物标志物， 随着AD和相关痴呆症新疗法的出现，评估治疗效果。

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.