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

项目总结/摘要 循环中脑源性外泌体的发现导致了研究它们作为潜在的 介质以及“液体活组织检查”的阿尔茨海默病和相关痴呆症（ADRD）。迄今为止的研究 似乎有希望，但有几个主要的限制：在有限数量的存档样本中进行， 单一时间点;忽略ADRD中的种族/民族、性别和遗传差异;缺乏对 建立血管和AD相关神经影像学生物标志物与认知判定配对;最后， 这些研究主要集中在神经元来源的外泌体上，而排除了神经元的其他细胞成分。 神经血管单位（NVU）此外，最近的研究表明，血管疾病与 有多种痴呆相关的病理;然而，没有研究能够系统地描述 NVU的血浆外泌体用于ADRD和缺氧的生物标志物。我们开发了新的工具来分离和 表征来源于脑NVU的所有关键细胞类型的外来体[神经元来源的外来体（NDE）， 星形胶质细胞来源的外泌体（ADE）、内皮细胞来源的外泌体（EDE）、周细胞来源的外泌体（PDE） 和支持细胞小胶质细胞来源的外来体（MDE）和少突胶质细胞来源的外来体（ODE）]。我们 检测和定量的ADRD生物标志物（例如，NVU中加载的Aβ1-40、Aβ1-42和神经丝轻（NfL） 来自维克森林AD研究中心参与者的外泌体，并将其水平与ADRD神经成像相关 和生物流体生物标记物。接下来，我们试图扩展这种方法来理解外泌体的异质性， ADRD中的不同年龄、性别和种族/民族。为此，我们将利用多民族研究 AD的动脉粥样硬化多中心研究（MESA-MIND; R 01 AG 058969，PI：Hughes）， 不同的老年人群体。MESA-MIND旨在阐明亚临床血管疾病的作用 ADRD中的种族差异。我们将从1,000名参与者中采集血液样本， 美国最常见的种族/族裔群体（白色：30%，非洲裔美国人：40%;西班牙裔：30%） 在三个研究中心招募参与PET和MRI。MESA-MIND的资源提供了一个独特的 有机会促进我们对NVU衍生的血管和神经系统外泌体生物标志物的理解， AD对痴呆症的具体贡献。具体目标是：一。定量并关联ADRD生物标志物水平， 具有ADRD的认知和神经影像学生物标志物的NVU外泌体。二.与NVU中的缺氧特征相关 外泌体与ADRD的生物流体和神经成像生物标志物。在这两个目标中，我们将研究 ADRD中重要亚组之间NVU外泌体数量和含量的异质性（认知状态， 种族/民族，年龄，性别和APOE-ε4），我们希望改变与神经影像学的关系 ADRD的生物标志物（Aβ-PET和MRI）和认知能力下降。总的来说，本研究将导致 开发用于缺氧和AD病理学的新的基于血液的外泌体生物标志物。NVU 外泌体生物标志物也将提供对血管对ADRD贡献的分子联系的深入了解。

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.