Project 1

摘要（项目一） Alzheimer病不变的病理特征阿尔茨海默病（AD）是星形胶质细胞、小胶质细胞和先天性 免疫信号传导因子共同表示脑内改变的先天免疫激活状态。 尽管过去对靶向炎症和先天免疫的治疗策略感兴趣， AD和轻度认知功能障碍（MCI），最近在这一治疗领域的活动较为有限 即使靶向先天免疫可以提供治疗优势。的一个重大挑战 治疗的发展和致病的理解是缺乏简便的工具， 具有不同程度AD病理学和认知和功能的人的先天免疫激活状态 损伤最近开发的用于分析扩散磁共振成像（MRI）数据的算法 表明测定细胞外容积的游离水成像可以提供 整个人类大脑的炎症。在这个项目中，我们将探讨在平行的研究小鼠 模型和人类的假设：自由水成像1）是小鼠模型中炎症的标志物， 2)将区分患有AD、晚期MCI、早期MCI和前MCI的人与健康对照，以及3）提供 关于随时间推移的认知变化的有价值的预后数据， 大脑中的免疫激活。提出了两个目标。目的1：使用新型慢性CNS模型 神经炎症和小鼠模型，发展AD相关病理（A和tau），以提供 增强了对基于MRI的自由水检测变化的生物学基础的理解， 这些模型中炎症反应和其他病理的调节如何改变自由水水平。目的 2：检验细胞外游离水水平来自扩散MRI数据的假设， 作为临床核心B评估的一部分，将AD、晚期MCI、早期MCI和前MCI与 对照组（CN）。这些转化研究得到了初步数据的充分支持，这些数据高度整合到 总体ADRC，并利用PI和Co-I在AD方面的广泛经验， 神经炎性动物模型、小动物MR成像和人类受试者MR成像。通过进一步 建立旨在追踪炎症的基于MR的标记物的病理学基础， 在一个大型的临床队列中，这些研究将告知这些方法作为生物标志物的效用和潜在的 AD的诊断标志物。

SUMMARY (Project I) Invariant pathological features of Alzheimers disease (AD) are changes in astrocytes, microglia and innate immune signaling factors that collectively denote altered innate immune activation states within the brain. Although there has been past interest in therapeutic strategies targeting inflammation and innate immunity in AD and mild cognitive impairment (MCI), there has been more limited recent activity in this therapeutic area even though targeting innate immunity may provide therapeutic advantages. A major challenge for both therapeutic development and pathogenic understanding is the lack of facile tools to non-invasively evaluate innate immune activation states in humans with varying degrees of AD pathology and cognitive and functional impairments. Recently developed algorithms for analyzing diffusion magnetic resonance imaging (MRI) data suggest that free-water imaging that assays extracellular volume can provide a surrogate measure of inflammation throughout the entire human brain. In this project we will explore in parallel studies of mouse models and humans the hypotheses that free-water imaging 1) is a marker of inflammation in mouse models, 2) will distinguish humans with AD, late-MCI, early-MCI, and pre-MCI from healthy controls, and 3) provides valuable prognostic data regarding cognitive changes over time that are specifically associated with innate immune activation in the brain. Two aims are proposed. Aim 1: Use novel models of chronic CNS neuroinflammation and mouse models that develop AD relevant pathologies (A¿ and tau) to provide an enhanced understanding of the biological basis for changes in MRI-based detection of free-water and examine how modulation of inflammatory responses and other pathologies in these models alters free-water levels. Aim 2: Test the hypothesis that extracellular free-water levels derived from the diffusion MRI data that will be acquired as part of the Clinical Core B assessments distinguishes AD, late-MCI, early-MCI, and pre-MCI, from controls (CN). These translational studies are well-supported by preliminary data, highly integrated into the overall ADRC and leverage the broad experience of the PI and Co-Is with respect to AD and neuroinflammatory animal models, small animal MR imaging, and human subject MR imaging. By further establishing the pathological basis of MR-based markers purported to track inflammation and evaluating these in a large clinical cohort these studies will inform on the utility of these methods as biomarkers and potential theragnostic markers for AD.