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

项目摘要/摘要 阿尔茨海默病(AD)约占痴呆病例的70%，而且AD患者的数量仍在继续 由于全球人口老龄化现象，经济大幅增长，促使创新的呼声 将能够及早识别有风险的患者并监测疾病进展和 治疗反应。在阿尔茨海默病中有一系列已知的病理改变 (AD)早在坦率的认知能力下降之前，就为早期发现疾病发病提供了潜在的靶点 随后的干预措施。虽然容积MRI改变有助于评估是否存在 神经变性，局部皮质体积丢失是神经变性的相对较晚的结构标志 广告。另一方面，扩散磁共振成像(Dmri)是一种对病理敏感的非侵入性成像技术。 细胞水平的变化，至少比标称空间分辨率低三个数量级 常规核磁共振检查。到目前为止，大多数使用dMRI的AD研究主要集中在脑白质的变化上。然而， 在组织病理学上，阿尔茨海默病主要是一种皮质疾病。检测GM早期微结构变化的能力 VIVO将为评估疾病的发生和发展打开大门，促进疾病的发展-- 修正疗法。该项目将弥合了解AD中GM组织微结构变化的差距 和轻度认知障碍(MCI)，使用多个领域的工具组合，如生物物理 建模、体外和体内核磁共振成像和组织学验证。我们将解决这一多方面的研究 挑战通过以下目标：目标1：建立依赖时间的dMRI测量，以评估 高梯度MRI显示轴索静脉曲张密度、胞体大小和胞体/轴突密度 系统。通过利用当前和下一代Connectome MRI上非常强大的扩散梯度 ，我们将开发一种新的技术来评估健康受试者的组织微结构，AD和 MCI患者。目的2：用蒙特卡罗方法验证轴突和胞体结构的体内外dMRI测量 基于光和光的三维逼真衬底中的扩散和组织分析的模拟 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记物，如 作为淀粉样β蛋白、总的和磷酸化的tau(P-tau 181和P-tau 217)。 总而言之，基于我们之前使用dMRI评估脑白质微结构的成功，我们的 对GM的研究承诺为神经退行性变提供可靠的非侵入性成像标记，促进我们的 了解阿尔茨海默病进展的潜在机制。归根结底，转基因的量化 显微结构将为神经退行性疾病提供预测和确证的生物标志物，促进 随着AD和相关痴呆新疗法的出现，对治疗效果的评估。

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.