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

项目摘要 尽管进行了广泛的研究，但治疗阿尔茨海默病(AD)的有效方法仍然不可用。 造成这一现象的一个重要因素是缺乏评估AD病理的敏感工具 在干预措施最有可能取得成功的最早阶段取得进展。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 在以前的许多AD研究中都有这种目的，但他们提供的信息有限。特别是， 它们对脑组织的微结构和功能连通性不敏感，这是已知的 被AD病理改变。因此，具有敏感性的替代成像方法 微结构和功能有助于监测对潜在治疗的反应 干预措施以及支持对阿尔茨海默病根本原因的研究，这些研究仍然不完全 明白了。在定量脑微结构方面，弥散磁共振成像(Dmri)是最好的。 无创成像方式，而对于脑功能连接，静息状态功能MRI (RS-fMRI)是主要的检查方法。在我们的第一个资助期，我们已经展示了3xTg-AD 小鼠AD模型的病理，即一种特殊的dMRI方法，称为弥散峰度成像 (DKI)最早能够在2个月龄时检测到大脑微结构异常，这 在淀粉样斑块和神经原纤维缠结沉积之前，这两种经典的组织学 AD的标志物。此外，DKI措施被发现对进一步的变化极其敏感 在直至21个月龄的整个AD病理过程中都有微结构的改变。 在此续订申请的目标1中，我们建议通过确定以下能力来扩展这项工作 DKI将监测2至18个月大的AD病理对一种有前途的药物的反应 治疗称为神经营养因子多肽模拟物(P021)，它已知抑制 神经退行性变和防止淀粉样斑块和神经原纤维缠结的沉积 3xTg-AD小鼠。我们的目标是演示标准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。因为DKI很容易 在临床核磁共振扫描仪上实施，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取rS-fMRI数据以确定rS-fMRI的能力。 功能磁共振成像监测对P021治疗的反应。在目标3中，我们的dki和rs-fmri数据都将是 与生化、形态和行为测量相关联，以调查 观察到的影像变化的生物学意义。这项工程的圆满完成 将支持应用DKI和RS-fMRI作为有价值的成像工具来评估 AD药物治疗和提高我们对AD发病机制的理解。

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.