Project 1

项目1

• 批准号: 8848986
• 负责人: Todd E Golde
• 金额: $ 17.38万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848986
• 关键词: Affect; Algorithms; Alzheimer' s Disease; Animal Model; Animals; Area; Astrocytes; Autopsy; Award; Biological; Biological Assay; Biological Markers; Brain; Cerebellum; Chronic; Clinical; Clinical Research; Code; Cognition; Cognitive; Cohort Studies; Conflict (Psychology); Data; Deltastab; Detection; Diffusion Magnetic Resonance Imaging; Epidemiologic Studies; Florida; Genes; Genetic; Grant; Hippocampus (Brain); Human; Image; Immune; Impaired cognition; Inflammation; Inflammatory Response; Investigation; Literature; Magnetic Resonance Imaging; Measures; Medical center; Methods; Microglia; Modeling; Natural Immunity; Nerve Degeneration; Participant; Pathology; Pathway interactions; Phagocytosis; Prefrontal Cortex; Research; Risk; Role; Signal Transduction; Testing; Therapeutic; Time; Universities; Variant; Visit; Water; amyloid structure; base; cognitive change; cohort; experience; extracellular; follow-up; functional disability; human subject; immune activation; in vivo imaging; inflammatory marker; interest; mild cognitive impairment; mouse model; neuroinflammation; novel; pre-clinical; preclinical study; prognostic; research study; tau Proteins; therapeutic development; tool; translational study

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.

摘要(项目I) 阿尔茨海默病(AD)的不变病理特征是星形胶质细胞、小胶质细胞和先天的改变 免疫信号因子，共同表示大脑内改变的先天免疫激活状态。 尽管过去人们对针对炎症和先天免疫的治疗策略感兴趣 AD和轻度认知障碍(MCI)，最近在这一治疗领域的活动较为有限 尽管以先天免疫为靶点可能会提供治疗优势。对两人来说都是一个重大挑战 治疗进展和对致病机理的了解缺乏方便的工具来进行非侵入性评估 不同程度AD病理、认知和功能障碍患者的先天免疫激活状态 减损。最近开发的用于分析扩散磁共振成像(MRI)数据的算法 提示测定细胞外体积的游离水成像可以提供一种替代测量 遍及整个人类大脑的炎症。在这个项目中，我们将在小鼠的平行研究中进行探索 模型和人类的假设，即游离水成像是小鼠模型中炎症的标志， 2)将阿尔茨海默病、晚期MCI、早期MCI和MCI前期患者与健康对照组区分开来，以及3)提供 关于认知随时间变化的有价值的预测数据，这些数据与先天的认知变化特别相关 大脑中的免疫激活。提出了两个目标。目标1：使用新的慢性中枢神经系统模型 神经炎症和发展AD相关病理(A和tau)的小鼠模型，以提供 提高了对基于MRI的游离水检测和检查变化的生物学基础的理解 在这些模型中，炎症反应和其他病理的调节如何改变自由水水平。目标 2：测试从扩散磁共振数据得出的细胞外自由水水平将是 作为临床核心B评估的一部分，获得者将AD、晚期MCI、早期MCI和MCI前期与 控制(CN)。这些翻译研究得到了初步数据的良好支持，高度整合到 总体ADRC并利用PI和CO-IS在AD和 神经炎性动物模型、小动物磁共振成像和人体受试者磁共振成像。通过进一步 建立以磁共振为基础的标记物追踪炎症的病理基础并对其进行评估 在一个大型临床队列中，这些研究将为这些方法作为生物标志物和潜在的用途提供信息。 AD的不可知性标记物。