Quantitative Endogenous MRI Imaging of Neuroinflammation in AD

项目总结/摘要 神经炎症在阿尔茨海默病（AD）的发病机制中起着核心作用，并与阿尔茨海默病（AD）的发病机制密切相关。 AD的神经病理学特征，包括淀粉样斑块和神经纤维缠结。尽管已经 在过去的十年中，在开发新型脑脊液、基于血液的 尽管使用正电子发射断层扫描（PET）和磁共振成像（MRI）技术， 迫切需要一种临床成像模式，可以可靠地成像和量化神经炎症， 老化的大脑和促进识别的关键病理球员在不同阶段的AD。解决 这种未满足的需求和对FOA“PAR-21-038”的响应，我们提出了一个新的研究方向， 建立了一种全新的弥散磁共振成像（dMRI）技术-弥散字典成像（DDI）， 特异性内源性和经济的解决方案，用于AD的神经炎症成像。通过跟踪 使用FDA批准的扩散MRI序列和压缩传感的水分子随机游走 技术，DDI测量并专门提取与激活相关的微观结构变化 以及小胶质细胞和星形胶质细胞的浸润。此外，可以将先前收集的dMRI数据 回顾性分析了这项新技术。因此，我们处于一个独特的位置， 通过利用Knight阿尔茨海默病研究的纵向数据丰富的研究来开发DDI 中心（ADRC）在华盛顿大学（>800零星AD参与者）和多站点国际 显性遗传阿尔茨海默病网络（DIAN）观察性研究（>500例常染色体显性AD [ADAD]） 参与者）。在本计画中，我们将发展DDI技术并评估其成像能力 尸检AD脑中的神经炎症（目的1）。我们将研究DDI之间的关联 神经炎症指数和CSF和血浆炎症生物标志物（YKL-40、sTREM 2和GFAP）， Knight ADRC和DIAN队列（目标2）。我们还将横向和纵向量化 在Knight ADRC和DIAN队列中使用DDI检测神经炎症，并检查其与淀粉样蛋白的关系 通过PET示踪剂和临床结果（认知和进展）测量的tau蛋白沉积和tau蛋白病（目标3）。 神经炎症的定量内源性DDI成像生物标志物的成功开发将 代表了一个重要的技术飞跃。DDI神经炎症生物标志物整合到 DIAN和其他临床试验研究将提供临床可行的神经成像替代品， 提高我们对神经炎症在AD发病机制中的作用的理解。

PROJECT SUMMARY/ABSTRACT Neuroinflammation plays a central role in the pathogenesis of Alzheimer’s disease (AD) and links strongly with AD’s neuropathological hallmarks, including amyloid plaques and neurofibrillary tangles. While there have been tremendous strides over the last decade in the development of novel cerebrospinal fluid, blood-based assays, positron emission tomography (PET), and magnetic resonance imaging (MRI) techniques, there still is a desperate need for a clinical imaging modality that can reliably image and quantify neuroinflammation in the aging brain and facilitate the identification of the key pathological players in different stages of AD. To address this unmet need and response to FOA “PAR-21-038”, we propose a new research direction to develop and establish a brand-new diffusion MRI (dMRI) technique, Diffusion Dictionary Imaging (DDI), as a safe, specific endogenous, and economical solution for the neuroinflammation imaging in AD. By tracking the random walk of water molecules using FDA-approved diffusion MRI sequence and compressed sensing technique, DDI measures and specifically extracts the microstructural changes associated with the activation and infiltration of the microglia and astrocyte in AD. Moreover, the previously collected dMRI data can be retrospectively analyzed with this new technique. Therefore, we are in a unique position to cost-effectively develop DDI by leveraging the longitudinal data-rich studies from the Knight Alzheimer’s Disease Research Center (ADRC) at Washington University (>800 Sporadic AD participants) and the multi-site international Dominantly Inherited Alzheimer Network (DIAN) observational study (>500 autosomal-dominant AD [ADAD] participants). In this project, we will develop the DDI technique and evaluate its capability of imaging neuroinflammation in the postmortem AD brains (Aim 1). We will examine the associations between the DDI neuroinflammation index and CSF and plasma inflammation biomarkers (YKL-40, sTREM2, and GFAP) in the Knight ADRC and DIAN cohorts (Aim 2). We will also cross-sectionally and longitudinally quantify the neuroinflammation using DDI in the Knight ADRC and DIAN cohorts and examine its connections with amyloid deposition and tauopathy measured by PET tracers and clinical outcomes (cognitive and progression) (Aim 3). The successful development of a quantitative endogenous DDI imaging biomarker of neuroinflammation will represent an important technological leap forward. The integration of DDI neuroinflammation biomarker into the DIAN and other clinical trial studies will provide clinically feasible neuroimaging surrogates that can significantly improve our understanding of the role of neuroinflammation in AD pathogenesis.