Diffusion and Functional MRI Monitoring of Therapy Response in Alzheimer’s Disease Mouse Model

项目摘要 尽管广泛的研究，有效的治疗阿尔茨海默病（AD）仍然是不可用的。 其中一个重要因素是缺乏评估AD病理学的敏感工具 在干预措施最有可能成功的最早阶段就取得进展。两个正电子 发射断层扫描和解剖磁共振成像（MRI）已被应用于 这一目的在许多以前的AD研究，但他们提供的信息是有限的。特别是， 它们对脑组织的微观结构和功能连接不敏感， 被AD病理学改变。因此，具有灵敏度的替代成像方法， 微结构和功能可以帮助监测对潜在治疗药物的反应， 干预措施，以及支持研究的根本原因，AD，这仍然是不完全的 明白对于量化脑微结构，弥散MRI（dMRI）是最好的方法。 非侵入性成像模式，而对于脑功能连接，静息态功能MRI （rs-fMRI）是主要的方法。在我们的第一个融资期，我们已经证明，对于3xTG-AD， AD病理学的小鼠模型，即称为弥散峰度成像的特定dMRI方法 (DKI)能够在2个月大的时候就检测到大脑的微结构异常， 在淀粉样斑块和神经纤维缠结沉积之前， AD的标志物。此外，DKI指标对进一步的变化极为敏感 在AD病理学的整个进展过程中发生的微结构中，直到21个月大。 在本更新申请的目标1中，我们建议通过确定以下能力来扩展这项工作： DKI用于监测2至18个月龄的AD病理学对有希望的药物的反应 治疗称为神经营养因子肽模拟物（P021），已知其抑制 神经变性和防止淀粉样蛋白斑块和神经纤维缠结的沉积， 3xTg-AD小鼠。我们的目标是展示标准DKI和新扩展的实用性 被称为双脉冲DKI作为监测AD治疗反应的工具。由于DKI很容易 在临床MRI扫描仪上实现，转化为人类药物试验将是直截了当的。 在目标2中，我们将在相同的小鼠模型中获得rs-fMRI数据，以确定rs-fMRI的能力。 fMRI监测对P021治疗的反应。在目标3中，我们的DKI和rs-fMRI数据都将 与生物化学、形态学和行为学指标相关，以研究 观察到的成像变化的生物学意义。这个项目的顺利完成 将支持DKI和rs-fMRI作为有价值的成像工具的应用， AD药物治疗和提高我们对AD潜在机制的理解。

Project Summary Despite extensive research, effective therapies for Alzheimer's disease (AD) are still unavailable. One important contributing factor for this is a lack of sensitive tools for assessing AD pathology progression at its earliest stages when interventions are most likely to succeed. Both positron emission tomography and anatomical magnetic resonance imaging (MRI) have been applied for this purpose in many prior AD studies, but the information they provide is limited. In particular, they are insensitive to brain tissue microstructure and functional connectivity, which are known to be altered by AD pathology. Therefore, alternative imaging methods with sensitivity to microstructure and function could help in monitoring response to potential therapeutic interventions as well as support studies of the underlying causes of AD, which are still not fully understood. For quantifying brain microstructure, diffusion MRI (dMRI) is the pre-eminent noninvasive imaging modality, while for brain functional connectivity, resting-state functional MRI (rs-fMRI) is the leading approach. In our first funding period, we have shown, for the 3xTg-AD mouse model of the AD pathology, that a specific dMRI method called diffusional kurtosis imaging (DKI) is able to detect microstructural brain abnormalities as early as 2 months of age, which precedes the deposition of amyloid plaques and neurofibrillary tangles, the two classic histological markers of AD. In addition, DKI measures are found to be extremely sensitive to further changes in microstructure occurring throughout the progression of AD pathology up to 21 months of age. In Aim 1 of this renewal application, we propose to extend this work by determining the ability of DKI to monitor, from 2 to 18 months of age, the response of AD pathology to a promising drug treatment known as neurotrophic factor peptide mimetic (P021), which is known to inhibit neurodegeneration and prevent the deposition of amyloid plaques and neurofibrillary tangles in 3xTg-AD mice. The goal is to demonstrate the utility of both standard DKI and a novel extension known as double-pulsed DKI as tools for monitoring therapy response in AD. Since DKI is easily implemented on clinical MRI scanners, translation to human drug trials would be straightforward. In Aim 2, we will acquire rs-fMRI data in this same mouse model to determine the ability of rs- fMRI to monitor response to P021 treatment. In Aim 3, both our DKI and rs-fMRI data will be correlated with biochemical, morphological, and behavioral measures in order to investigate the biological significance of the observed imaging changes. The successful completion of this project will support the application of DKI and rs-fMRI as valuable imaging tools for the assessment of AD drug therapies and for improving our understanding of the mechanisms underlying AD.