Multi-Ethnic Study of Atherosclerosis- Cellular Exosomes in Neurodegeneration and Dementia (MESA-CEND)

项目摘要/摘要 在血液循环中发现的脑源性外切体导致了对其潜在作用的研究。 阿尔茨海默病和相关痴呆症的中介人和“液体活检”(ADRD)。迄今为止的研究 看起来很有希望，但有几个主要限制：在有限数量的存档样本中一次执行 单一时间点；忽略ADRD中的种族/民族、性别和遗传差异；缺乏同时评估 已建立的血管和AD相关神经成像生物标记物与认知判断配对；最后， 这些研究主要集中在神经元来源的外切体，而不包括其他细胞成分。 神经血管单位(NVU)。此外，最近的研究表明，血管紊乱与 与多种痴呆症相关的病理；然而，还没有研究能够系统地表征 NVU血浆外切体作为ADRD和缺氧生物标志物的研究我们已经开发了新的工具来分离和 描述来源于大脑NVU所有关键细胞类型的外切体[神经元源性外切体(NDE)， 星形胶质细胞来源的外切体(ADE)、内皮细胞来源的外切体(EDE)、周细胞来源的外切体(PDE) 和支持细胞小胶质细胞来源的外切体(MDE)和少突胶质细胞来源的外切体(ODE)]。我们 检测和量化NVU中装载的ADRD生物标记物(例如，Aβ1-40、Aβ1-42和神经细丝光) 维克森林AD研究中心受试者外显体水平与ADRD神经成像的关系 和生物流体生物标记物。接下来，我们试图将这一方法扩展到理解外体异质性。 不同的年龄、性别和种族/民族群体。为此，我们将利用多种族研究 阿尔茨海默病动脉粥样硬化多点研究(Mesa-Mind；R01AG058969，PI：Hughes) 不同的老年人队列。MESA-Mind旨在阐明亚临床血管疾病的作用 与ADRD的种族差异有关。我们将从代表这三个人的1000名参与者那里获取血液样本 美国最常见的种族/民族(白人：30%，非裔美国人：40%，西班牙裔：30%) 招募参加三个地点的正电子发射计算机断层扫描和核磁共振检查。Mesa-Mind的资源提供了一个独特的 增进我们对NVU衍生的血管和血管外体生物标记物的了解的机会 AD对痴呆症的特殊贡献。具体目标是：I.量化和关联ADRD生物标记物水平 NVU外显体与ADRD的认知和神经影像生物标志物。二、NVU的缺氧征象 带有ADRD生物流体和神经影像生物标记物的外体。在这两个目标中，我们都将研究 ADRD中重要亚组间NVU外体数量和含量的异质性(认知状态， 种族/民族、年龄、性别和载脂蛋白-ε4)，我们希望通过神经成像改变这些关系 ADR的生物标志物(β-PET和核磁共振)和认知功能下降。总体而言，本研究将导致 低氧和AD病理的新型血基外体生物标记物的开发。NVU 外体生物标记物还将提供对ADRD血管贡献中的分子联系的洞察。

Project Summary/Abstract The discovery of brain-derived exosomes in the circulation has led to studies examining their role as potential mediators as well as `liquid biopsies' for Alzheimer's disease and related dementias (ADRD). Studies to date appear promising but have several major limitations: performed in a limited number of archived samples at a single time-point; ignore racial/ethnic, gender, and genetic disparities in ADRD; lack concurrent assessment of established vascular and AD-related neuroimaging biomarkers paired with cognitive adjudication; and lastly, these studies are mainly focused on neuron-derived exosomes to the exclusion of other cellular constituents of the neurovascular unit (NVU). Further, recent studies have suggested that vascular disorders are associated with multiple dementia-related pathologies; however, no study has been able to systematically characterize plasma exosomes of NVU for biomarkers of ADRD and hypoxia. We have developed novel tools to isolate and characterize exosomes derived from all key cell types of the brain NVU [neuron-derived exosomes (NDE), astrocyte-derived exosomes (ADE), endothelial-derived exosomes (EDE), pericyte-derived exosomes (PDE) and supporting cells microglial-derived exosomes (MDE) and oligodendrocyte-derived exosomes (ODE)]. We detected and quantified ADRD biomarkers (e.g., Aβ1-40, Aβ1-42, and neurofilament light (NfL)) loaded in NVU exosomes from Wake Forest AD Research Center participants and related their levels to ADRD neuroimaging and biofluid biomarkers. Next, we seek to extend this approach to understand exosomal heterogeneity across various ages, gender, and races/ethnic groups in ADRD. To this end, we will leverage the Multi-Ethnic Study of Atherosclerosis Multisite Study of AD (MESA-MIND; R01AG058969, PI: Hughes) with a longitudinal diverse cohort of older adults. MESA-MIND aims to elucidate the contribution of subclinical vascular disorders to the ethnic disparities in ADRD. We will obtain blood samples from 1,000 participants representing the three most common racial/ethnic groups in the US (White: 30%, African American: 40%; and Hispanics: 30%) recruited to participate in both PET and MRI at three sites. The resources of MESA-MIND provide a unique opportunity to advance our understanding of NVU derived exosomal biomarkers of the vascular and AD specific contributions to dementia. Specific aims are: I. Quantify and relate ADRD biomarker levels in NVU exosomes with cognition and neuroimaging biomarkers of ADRD. II. Relate hypoxia signature in NVU exosomes with biofluid and neuroimaging biomarkers of ADRD. In both the aims, we will examine the heterogeneity of NVU exosomal number and content across important subgroups in ADRD (cognitive status, race/ethnicity, age, gender, and APOE-ε4), which we expect to modify the relationships with neuroimaging biomarkers of ADRD (Aβ-PET and MRI) and cognitive decline. Overall, the present study would lead to the development of novel blood-based exosomal biomarker development for both hypoxia and AD pathology. NVU exosomal biomarkers will also provide insight into the molecular links in the vascular contributions to ADRD.