Project 1

项目1

• 批准号: 9120752
• 负责人: Todd E Golde
• 金额: $ 16.63万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9120752
• 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; potential biomarker; pre-clinical; preclinical study; prognostic; research study; tau Proteins; therapeutic development; tool; translational study

SUMMARY (Project I) Invariant pathological features of Alzheimer s 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） 阿尔茨海默氏病（AD）不变的病理特征是星形胶质细胞，小胶质细胞和先天性的变化 免疫信号传导因子共同表示大脑内的先天免疫激活状态。 尽管对针对创新和先天免疫的治疗策略一直存在兴趣 AD和轻度认知障碍（MCI），在该治疗领域的最近活动有限 即使针对先天免疫也可以提供治疗优势。两者的主要挑战 治疗性发育和致病理解是缺乏可轻松评估的轻松工具 具有不同程度的AD病理和认知和功能的人类中的先天免疫激活状态 障碍。最近开发了用于分析扩散磁共振成像（MRI）数据的算法 建议测定细胞外体积的自由水成像可以提供替代测量 整个人大脑的炎症。在这个项目中，我们将在对小鼠的并行研究中进行探索 模型和人类的假设是自由水成像1）是小鼠模型中炎症的标记， 2）将通过AD，晚期MCI，早期MCI和PER-MCI与健康对照区分开人类，3） 随着时间的推移，有价值的预后数据与天生有关 大脑中的免疫激活。提出了两个目标。目标1：使用慢性中枢神经系统的新型模型 神经炎症和小鼠模型，这些模型开发AD相关的病理（A和TAU），以提供 增强对基于MRI的自由水和检查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的水平。目的 2：检验以下假设：细胞外的自由水平从扩散MRI数据中得出 作为临床核心B评估AD，后期MCI，早期MCI和MCI的一部分，从 控件（CN）。这些翻译研究由初步数据良好支持，高度融合到 总体ADRC并利用PI和CO-IS在AD上的广泛经验和 神经炎性动物模型，小动物MR成像和人类主题MR成像。进一步 建立旨在跟踪创新并评估这些创新的基于MR的标记的病理基础 在大型临床队列中，这些研究将为这些方法作为生物标志物和潜力的实用性提供信息 AD的热标记。