Investigating the Contribution of Peripheral versus Central Nervous System Immune Dysfunction to Cognitive Aging

项目概要/摘要 该项目的首要假设是，外周免疫失调，独立于中枢免疫失调， 神经系统（CNS）免疫失调是认知能力下降的关键驱动因素，这种关系是 阿尔茨海默病（AD）相关的病理学和最近的免疫健康事件加剧了这种疾病。 流行病学研究表明，外周免疫标记物水平的升高在免疫前几年就很明显。 老年痴呆症的临床表现虽然外周免疫功能障碍是一个危险因素， 认知能力下降，许多关键未回答如何有效地衡量周边 2）如何理清外周和中枢免疫系统的作用机制， 调节失调对衰老结果的影响，以及3）如何评估免疫相关健康事件对 认知能力下降为了解决该领域的差距，我们建议使用纵向，多模态测量 外周和中枢神经系统免疫标志物的变化。除了检查循环血液中的免疫标记物， CSF，我们将采用尖端的方法来分析外周和CNS携带的免疫标志物， 衍生的细胞外囊泡（EV）。电动汽车在电池间通信和电动汽车方法中发挥着关键作用 还允许指定始发小区。我们这项研究的主要目的是： 外周免疫标志物与CNS免疫标志物随时间的变化相关（目的1）;确定外周免疫标志物是否与CNS免疫标志物相关（目的2）。 和中枢神经系统免疫标志物显示与认知结果的独立相关性，并描述AD如何影响认知结果。 相关的病理学影响这些关联（目的2）;并评估免疫健康史对 外周和CNS免疫标志物与认知能力下降之间的关系（目的3）。来测试我们 假设，我们将前瞻性地评估180种富集临床前AD的AOA（即，AOA阳性 淀粉样蛋白PET脑扫描），并进行外周免疫标记物的基线和24个月随访测量 (i.e.,在循环血液和外周来源的血液EV中）和CNS免疫标记物（即，在CSF和 CNS来源的血液EV），并将这些标志物与AD的认知和生物标志物的度量（即， 淀粉样蛋白和p-tau）。我们将采用靶向和探索性免疫标志物面板，并将记录 最近的免疫健康事件，以确定其对免疫之间的关系的潜在影响， 失调和认知能力下降。重要的是，这项研究将建立最全面的 免疫表型老化队列，并将使我们能够解决关键问题的作用， 典型和病理性衰老的外周免疫系统。通过确定外围的贡献- 与CNS衍生的免疫信号到认知老化轨迹的对比，我们将准备更好地理解， 预测并最终治疗可能导致AD发病的早期致病性免疫事件。 问题仍然存在，包括：（1）

Project Summary/Abstract The overarching hypothesis of this project is that peripheral immune dysregulation, independent of central nervous system (CNS) immune dysregulation, is a critical driver of cognitive decline, and this relationship is exacerbated by higher Alzheimer's Disease (AD)-related pathology and by recent immune health events. Epidemiological studies indicate that elevated levels of peripheral immune markers are evident years prior to clinical manifestation of Alzheimer's Disease. Although peripheral immune dysfunction is a risk factor for cognitive decline, many key unanswered how to effectively measure peripheral and CNS immune changes; 2) how to disentangle the mechanistic role of peripheral and CNS immune dysregulation on aging outcomes, and 3) how to evaluate the effect of immune-related health events on cognitive decline. To address gaps in the field, we propose to use longitudinal, multimodal measurements of peripheral and CNS immune markers. In addition to examining immune markers in circulating blood and CSF, we will employ a cutting-edge method to analyze immune markers carried by periphery- and CNS- derived extracellular vesicles (EVs). EVs play key roles in cell-to-cell communication and EV methodologies also allow for specification of the originating cells. Our primary aims for this study are: to determine how peripheral immune markers relate to CNS immune markers over time (Aim 1); to determine whether peripheral and CNS immune markers show independent associations with cognitive outcomes, and to delineate how AD- related pathology influences these associations (Aim 2); and to evaluate the role of immune health history on the relationship between peripheral and CNS immune markers and cognitive decline (Aim 3). To test our hypotheses, we will prospectively assess 180 AOAs enriched for preclinical AD (i.e., AOAs with positive amyloid PET brain scans) with baseline and 24-month follow-up measurements of peripheral immune markers (i.e., in circulating blood and in periphery-derived blood EVs) and of CNS immune markers (i.e., in CSF and in CNS-derived blood EVs), and correlate these markers with metrics of cognition and biomarkers of AD (i.e., amyloid and p-tau). We will employ both a targeted and an exploratory immune marker panel, and will record recent immune health events to determine their potential impact on the relationship between immune dysregulation and cognitive decline. Importantly, this study will establish the most comprehensively immunophenotyped aging cohort to date and will allow us to address critical questions regarding the role of the peripheral immune system in typical and pathological aging. By determining the contribution(s) of peripheral- versus CNS-derived immune signals to cognitive aging trajectories, we will be poised to better understand, predict, and ultimately treat early pathogenic immune events that may drive AD pathogenesis. questions remain, including: 1)