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

动脉粥样硬化-细胞外泌体在神经变性和痴呆症中的多种族研究 (MESA-CEND)

• 批准号: 10301683
• 负责人: Gagan Deep
• 金额: $ 229.56万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301683
• 关键词: African American; Age; Alzheimer disease prevention; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Astrocytes; Biological Markers; Blood; Blood Circulation; Blood Vessels; Blood specimen; Brain; Cells; Cerebrovascular Disorders; Cognition; Cognitive; Collection; Constitution; Data; Dementia; Development; Elderly; Endothelial Cells; Endothelium; Ethnic Origin; Ethnic group; Exclusion; Gender; Genetic; Heterogeneity; Hippocampus (Brain); Hispanics; Hypoxia; Immune; Impaired cognition; Injury; Lead; Light; Link; Lipid Binding; Magnetic Resonance Imaging; Mediator of activation protein; Methods; MicroRNAs; Microglia; Molecular; Multi-Ethnic Study of Atherosclerosis; Nerve Degeneration; Neurites; Neurons; Oligodendroglia; Participant; Pathogenesis; Pathology; Pathway interactions; Pericytes; Plasma; Positron-Emission Tomography; Proteins; Race; Research; Resources; Role; Site; Subgroup; Supporting Cell; Thick; Time; Vascular Dementia; Vascular Diseases; Visit; White Matter Hyperintensity; abeta deposition; adjudicate; adjudication; age related; apolipoprotein E-4; base; biomarker development; cell type; cerebrovascular; cognitive testing; cohort; density; ethnic disparity; exosome; forest; imaging biomarker; insight; liquid biopsy; magnetic beads; multimodality; nanovesicle; neurofilament; neuroimaging; neuroimaging marker; neurovascular; neurovascular unit; novel; racial and ethnic; racial and ethnic disparities; recruit; sample archive; tau-1; tool; vascular contributions; vascular factor; vascular risk factor

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.

项目摘要/摘要 在循环中发现脑衍生的外泌体的发现导致研究了研究其潜力的作用 阿尔茨海默氏病和相关痴呆症（ADRD）的介体以及“液体活检”。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执行 单个时间点；忽略ADRD中种族/种族，性别和遗传差异；缺乏同时评估 已建立的血管和广告相关的神经影像学与认知调整配对；最后， 这些研究主要集中于神经衍生的外泌体，排除其他细胞构成的其他细胞构成 神经血管单元（NVU）。此外，最近的研究表明血管疾病与 具有多种与痴呆相关的病理；但是，没有研究能够系统地表征 NVU的血浆外泌体用于ADRD和缺氧的生物标志物。我们已经开发了新颖的工具来隔离和 表征源自脑NVU的所有关键细胞类型的外泌体[神经元衍生的外泌体（NDE）， 星形胶质细胞衍生的外泌体（ADE），内皮衍生的外泌体（EDE），周细胞衍生的外泌体（PDE） 以及支持细胞小胶质细胞衍生的外泌体（MDE）和少突胶质细胞衍生的外泌体（ODE）]。我们 在NVU中被检测和量化的ADRD生物标志物（例如Aβ1-40，Aβ1-42和神经丝（NFL）） Wake Forest广告研究中心参与者的外泌体和ADRD神经影像 和生物流体生物标志物。接下来，我们寻求扩展这种方法以了解整个跨沉症异质性 在ADRD的各种年龄，性别和种族/种族群体。为此，我们将利用多民族研究 AD的动脉粥样硬化多站点研究（Mesa-Mind; R01AG058969，PI：Hughes）具有纵向 多样的老年人队列。 Mesa Mind旨在阐明亚临床血管疾病的贡献 在ADRD中的种族差异。我们将从1,000名参与者中获得血液样本代表三个 美国最常见的种族/族裔群体（白人：30％，非裔美国人：40％；西班牙裔：30％） 招募在三个地点参加PET和MRI。台面的资源提供了独特的 有机会促进我们对NVU衍生的血管外泌体生物标志物的理解 广告对痴呆症的特定贡献。具体目的是：I。量化并关联ADRD生物标志物水平 NVU外泌体具有ADRD的认知和神经成像生物标志物。 ii。与NVU中的缺氧签名有关 ADRD的生物流体和神经影像标志物的外泌体。在这两个目标中，我们都将研究 NVU外泌体数和内容的异质性跨ADRD（认知状态， 种族/民族，年龄，性别和Apoe-ε4），我们希望它与神经影像的关系进行修改 ADRD（Aβ-PET和MRI）的生物标志物以及认知能力下降。总体而言，本研究将导致 缺氧和AD病理学的新型血液外泌体生物标志物发育的发展。 NVU 外泌体生物标志物还将洞悉对ADRD的血管贡献中的分子联系。