Alzheimer Biomarker Consortium - Down Syndrome (ABC-DS)

阿尔茨海默病生物标志物联盟 - 唐氏综合症 (ABC-DS)

• 批准号: 10530789
• 负责人: BENJAMIN L HANDEN
• 金额: $ 73.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530789
• 关键词: Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Autopsy; Biological Markers; Biology; Blood; Brain; Brain region; Cell Nucleus; Cerebrospinal Fluid; Clinical; Cognitive; DNA; Data Set; Dementia; Down Syndrome; Freezing; Funding; Gene Expression; General Population; Genomics; Goals; Health Promotion; Impaired cognition; Intervention; Lewy Bodies; Magnetic Resonance Imaging; Nerve Degeneration; Pathogenesis; Pathology; Persons; Positron-Emission Tomography; Proteins; Proteomics; Public Health; Research Personnel; Senile Plaques; Series; Testing; Tissue Banks; Tissues; United States National Institutes of Health; aging population; brain tissue; cerebrovascular pathology; cohort; data acquisition; digital pathology; high risk; individual variation; interest; metabolomics; mild cognitive impairment; neuroimaging; neuroinflammation; neuropathology; pre-clinical; predictive marker; prospective; protein TDP-43; tau Proteins; tau aggregation; transcriptome sequencing; transcriptomics

Abstract People with Down syndrome (DS) develop Alzheimer disease (AD) neuropathology, including Aβ plaques and tau neurofibrillary tangles by the age of 40 years. However, the age of onset of cognitive decline, mild cognitive impairment (MCI) and dementia can occur over 10 years later, with individual variability in the age of onset. The overarching goal of ABC-DS is to understand biomarkers that predict conversion from cognitively stable to MCI or dementia and potentially the age of onset. Biomarkers in ABC-DS includes neuroimaging (MRI and PET), proteomics, metabolomics and genomics (blood/cerebrospinal fluid/DNA). In this supplement to ABC-DS, we propose to leverage the neuropathology core's collection of tissue from brain donations prospectively as well as the legacy autopsy cohort (U01AG051412, R01HD064993) to accomplish 2 aims: (1) to create an amyloid/tau/neurodegeneration framework (AT(N)) for neuropathology in clinically characterized cases with age as the dependent variable and (2) to define DS-specific gene expression changes in a spatially resolved manner. Thus, we are requesting funds to allow us to examine the brains from 30 people with DS and make comparisons to 20 age matched neuropathology-free controls (from the NIH Neurobiobank) with tissue being at UCI. Studies for Aim 1 includes a series of immunohistochemical identification of proteins of interest involving Aβ, tau, neuroinflammation, cerebrovascular pathology as well as non-AD associated pathologies (e.g. Lewy bodies, TDP-43), in brain regions involved in AD pathogenesis, with digital pathology and quantification approaches. In parallel using frozen tissue from the same cases, we will use spatial transcriptomics and the 10X genomics Visium platform to conduct single nucleus RNA sequencing. The successful completion of these studies will provide a rich dataset that can be shared and made available to other researchers, permit the testing of hypotheses related to the Projects in U19AG068054, and set the stage for neuropathology data acquisition in prospective ABC-DS brain donations.

摘要 唐氏综合征(DS)患者会发展为阿尔茨海默病(AD)神经病理，包括Aβ斑块和 到40岁时，tau神经原纤维缠绕。但起病年龄认知功能下降，轻度 认知障碍(MCI)和痴呆症可在10年后发生，年龄在 开始了。ABC-DS的首要目标是了解从认知角度预测转化的生物标志物 对MCI或痴呆症和潜在的发病年龄都是稳定的。ABC-DS中的生物标志物包括神经成像(MRI 和PET)、蛋白质组学、代谢组学和基因组学(血液/脑脊液/DNA)。 在ABC-DS的这一补充中，我们建议利用神经病理学核心的组织收集来自 预期的脑捐赠以及遗留尸检队列(U01AG051412，R01HD064993) 实现两个目标：(1)建立淀粉样蛋白/tau/神经退行性变框架(AT(N))，用于神经病理学 以年龄为因变量的临床特征病例和(2)确定DS特异性基因 表情以空间分辨的方式变化。因此，我们正在申请资金，以便我们能够审查 来自30名DS患者的大脑，并与20名年龄匹配的无神经病理对照进行比较(来自 NIH神经生物库)，组织在UCI。AIM 1的研究包括一系列免疫组织化学 鉴定涉及Aβ、tau、神经炎症、脑血管病理以及 非阿尔茨海默病相关病理(例如，路易小体，TDP-43)，在参与AD发病的脑区， 数字病理学和量化方法。同时使用来自相同病例的冷冻组织，我们将 利用空间转录和10X基因组学维西姆平台进行单核RNA测序。 这些研究的成功完成将提供丰富的数据集，可供共享和使用 对于其他研究人员，允许测试与U19AG068054中的项目相关的假设，并设置 在预期的ABC-DS脑捐赠中获取神经病理学数据的阶段。