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

项目摘要/摘要 该项目的主要假设是外周免疫失调，独立于中枢 神经系统(CNS)免疫失调，是认知功能下降的关键驱动因素，这种关系是 更严重的阿尔茨海默病(AD)相关病理和最近的免疫健康事件加剧了这种情况。 流行病学研究表明，外周免疫标志物水平的升高明显早于 阿尔茨海默病的临床表现。尽管外周免疫功能障碍是一种危险因素 认知功能下降，许多关键没有回答如何有效地测量外围设备 2)如何理清外周免疫和中枢免疫的机制作用 对衰老结局的失调，以及3)如何评估免疫相关健康事件对 认知能力下降。为了解决实地工作中的差距，我们建议使用纵向、多模式测量 外周和中枢神经系统免疫标记物。除了检测循环血液中的免疫标志物和 我们将使用一种尖端的方法来分析外周和中枢神经系统携带的免疫标志物。 衍生的细胞外小泡(EVS)。电动汽车在细胞间通信和电动汽车方法学中发挥着关键作用 还允许指定始发信元。我们这项研究的主要目的是：确定如何 外周免疫标记物随着时间的推移与中枢神经系统免疫标记物相关(目标1)；以确定外周免疫标记物是否 中枢神经系统免疫标记物与认知结果显示出独立的关联，并描绘了AD- 相关的病理学影响这些联系(目标2)；并评估免疫健康史在 外周和中枢神经系统免疫标记物与认知功能下降的关系(目标3)。测试我们的 假设，我们将前瞻性地评估180例临床前AD患者的AoA(即AoA阳性 淀粉样蛋白PET脑扫描)与外周免疫标志物的基线和24个月随访测量 (即，在循环血液和外周来源的血液EV中)和中枢神经系统免疫标记物(即，在脑脊液和脑脊液中 中枢神经系统衍生的血液EV)，并将这些标志物与AD的认知指标和生物标志物(即， 淀粉样蛋白和p-tau)。我们将采用定向和探索性免疫标记物小组，并将记录 近期免疫健康事件确定其对免疫之间关系的潜在影响 调节失调和认知功能衰退。重要的是，这项研究将建立最全面的 免疫表型衰老队列到目前为止，将使我们能够解决关键问题有关的作用 典型和病理性衰老的外周免疫系统。通过确定外围设备的贡献(S)- 相对于中枢神经系统衍生的免疫信号到认知老化的轨迹，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)