Project 4: Integrative analysis of spatial molecular features and clinico-pathological characteristics

项目4：空间分子特征与临床病理特征的综合分析

• 批准号: 10555900
• 负责人: PHILIP L DE JAGER
• 金额: $ 160.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555900
• 关键词: 3-Dimensional; Affect; African American; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; American; Amyloid; Brain; Categories; Cell Nucleus; Cells; Cerebral Amyloid Angiopathy; Characteristics; Clinical; Cognitive; Complement; Data; Data Analyses; Data Set; Dedications; Dimensions; Elderly; Ensure; Evaluation; Genes; Genetic Variation; Goals; Heterogeneity; Impaired cognition; Impairment; Individual; Investigation; Knowledge Portal; Lewy Bodies; Link; Microglia; Molecular; Neocortex; Neurodegenerative Disorders; Neuropsychology; Not Hispanic or Latino; Older Population; Outcome; Participant; Pathologic; Pathology; Planet Mars; Population; Prefrontal Cortex; Proteins; Proteomics; Research Personnel; Resources; Risk Factors; Role; Sample Size; Sampling; Sister; Source; Stains; Superior temporal gyrus; Testing; Tissue Sample; Tissues; Variant; aging brain; brain tissue; cognitive performance; cohort; data framework; demented; design; distributed data; drug development; epigenomics; insight; multiple omics; neocortical; neuropathology; next generation; novel; programs; protein TDP-43; spatial integration; tau Proteins; trait; transcriptome sequencing; transcriptomics; whole genome

PROJECT 4: PROJECT SUMMARY/ABSTRACT Over the past two decades, we have come to appreciate that the aging brain harbors a multiplicity of neuropathologies and that AD proteinopathy often coexists with other pathologic features such as Lewy Bodies and TDP43 proteinopathy. However, the impact of co-occurrence remains poorly understood. Co-occurrence also increases with advancing age, highlighting that age is a critical risk factor for all of the neuropathologies that we examine in our 3D Aging & Alzheimer Brain Program. This project aims to profile brain tissue from a large (n=300) set of diverse individuals to create a complementary resource to those produced in Projects 1-3. Here, we profile a random sample of participants in the RUSH cohorts to capture the heterogeneity seen in the older population. In addition, we leverage their detailed ante-mortem characterization of neuropsychologic function to relate molecular data and the cellular attributes identified in Projects 1-3 to cognitive decline, the ultimate, clinically meaningful outcome in AD. Amyloid, tau and CAA all influence cognitive performance in the ROSMAP cohorts. In particular, preliminary results from single nucleus RNAseq data suggest a critical role for a new microglial subtype, Microglia 13 (Mi13), in AD and CAA. Thus, the new 3D dataset that we propose to generate and distribute as part of this Project will enable us to test a specific hypothesis that we have today and to uncover new insights from unbiased analyses. Our samples also include 100 African-American (AA) participants from the ROSMAP and MARS cohorts that have the same clinicopathologic traits and multiomic brain data as the 200 non-hispanic white (NHW) participants. Here, we therefore explicitly complement the other Projects, which focus on Non-Hispanic White participants, by sampling a large number of AA subjects so that we can assess the generalizability of our findings to a broader population. The integrated analysis of the data in this project with the attributes identified in the other three projects will lead to a new set of candidate proteins involved in cognitive decline, which will be used to profile a replication cohort of an independent set of participants. Thus, the key goals for us are (1) the creation of an easily repurposable, high-impact dataset, (2) the testing of a current hypothesis and (3) assembly of an important set of new insights into AD and CAA that can be used to seed further investigation, including some dedicated to AA. Overall, this Project creates a unique reference data set that can be repurposed for a multitude of uses and leveraged to design a next generation of spatial transcriptomic (ST) studies for other neurodegenerative diseases.

项目4：项目摘要/摘要 在过去的二十年里，我们逐渐认识到，老化的大脑中蕴藏着多种 神经病理和AD蛋白病通常与其他病理特征并存，如路易小体 TDP43蛋白病。然而，同时发生的影响仍然知之甚少。同现 也随着年龄的增长而增加，强调年龄是所有神经病理的关键风险因素 我们在我们的3D衰老和阿尔茨海默病大脑计划中进行了检查。这个项目的目的是从一个大型的 (n=300)一组不同的个人，以创造与项目1-3中产生的资源互补的资源。这里, 我们对匆忙队列中的参与者进行了随机抽样，以捕捉在老年人中看到的异质性 人口。此外，我们利用他们对神经心理功能的详细的死前描述来 将分子数据和项目1-3中确定的细胞属性与认知能力下降联系起来，最终， 阿尔茨海默病的临床意义转归。淀粉样蛋白、tau和CAA都影响ROSMAP的认知操作 一群人。特别是，来自单核RNAseq数据的初步结果表明，新的 AD和CAA的小胶质细胞亚型，小胶质细胞13(MI13)。因此，我们建议生成的新3D数据集 作为此项目的一部分进行分发，将使我们能够测试我们今天拥有的特定假设，并揭示 来自不偏不倚分析的新见解。我们的样本还包括100名非裔美国人(AA)参与者 ROSMAP和MARS队列具有与200名患者相同的临床病理特征和多组脑数据 非西班牙裔白人(Nhw)参与者。因此，在这里，我们明确补充了其他项目，这些项目的重点是 关于非西班牙裔白人参与者，通过对大量的再生障碍性贫血受试者进行抽样，以便我们可以评估 将我们的发现推广到更广泛的人群中。本项目中数据的综合分析与 在其他三个项目中确定的属性将导致一组新的候选蛋白质参与认知 拒绝，这将被用来描述一组独立参与者的复制队列。因此，关键是 我们的目标是(1)创建易于重复使用的、高影响的数据集，(2)测试当前 假说和(3)对AD和CAA的一组重要的新见解的集合，可用于种子 进一步的调查，包括一些专门针对AA的调查。总体而言，该项目创建了一个独特的参考数据集 可以被重新用于多种用途，并被用来设计下一代空间转录 (ST)其他神经退行性疾病的研究。