Adult Changes in Thought (ACT) Research Program Core D: Neuropathology Core

成人思想变化 (ACT) 研究计划核心 D：神经病理学核心

• 批准号: 10404974
• 负责人: CHRISTOPHER DIRK KEENE
• 金额: $ 98.66万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404974
• 关键词: 3-Dimensional; Adult; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Archives; Autopsy; Biochemical; Biological; Biological Assay; Biological Markers; Blood Glucose; Body Fluids; Brain; Brain region; Cell Line; Cells; Clinical; Cognitive; Collaborations; Communities; Consensus; Custom; Data; Data Analyses; Dementia; Development; Diagnostic; Diagnostics Research; Dissection; Ensure; Equipment and supply inventories; Fostering; Foundations; Functional disorder; Funding; Genetic; Gifts; Goals; Growth; Guidelines; Heterogeneity; Human; Image; Image Analysis; Imaging technology; Immunoassay; Individual; Institutes; Investments; Knowledge; Life Cycle Stages; Liquid substance; Magnetic Resonance Imaging; Measures; Methods; Microscopic; Molecular; Natural History; Nerve Degeneration; Nervous System Trauma; Neurosciences; Participant; Pathologic; Pathologic Processes; Pathology; Peptides; Persons; Pharmacotherapy; Phase; Process; Productivity; Proteins; Protocols documentation; Psychometrics; Publications; Recommendation; Recording of previous events; Reporting; Research; Research Activity; Research Personnel; Research Subjects; Research Support; Resistance; Resources; Sampling; Scanning; Science; Sectioning technique; Slide; Specimen; Therapeutic Human Experimentation; Time; Tissues; United States National Institutes of Health; Variant; aging brain; biobank; biomarker discovery; brain research; brain tissue; cell type; cohort; data quality; data sharing; deep learning; design; in silico; innovation; loved ones; neuroimaging; neuroinflammation; neuropathology; neurotoxicity; non-demented; novel; programs; prospective; quantitative imaging; radiological imaging; reconstruction; repository; resilience; virtual

SUMMARY The Adult Changes in Thought (ACT) Neuropathology (NP) Core (Core D) has been a valuable and frequently utilized resource for the ACT cohort and supports the ACT Repository where the most generous gift to science – a person’s brain – is used to maximize impact on local and national science of Alzheimer’s disease and related dementias (ADRD). The NP Core has instituted rapid protocols designed for cutting edge molecular cell profiling and has markedly extended sampling strategies to better capture regional changes that underlie the heterogeneity of Alzheimer’s disease and related dementias. The NP Core has fostered development of innovative, highly quantitative approaches to assess the neuropathology of ADRD, building on this important tradition by integrating imaging technologies and analytical approaches to target and quantify gross and microscopic pathology. We perform post-mortem MRI on every brain, generate 3D virtual brain reconstructions leveraging unique brain sectioning techniques in the NP Core, scan slides of prospective and archival ACT samples for traditional quantitative image analysis supplemented with deep learning approaches to maximize information yield, and leverage multiplexed solution-phase assays from fixed-tissue protein extracts to compare cytoarchitectural and biochemical pathologic changes in ADRD. All of these innovations are designed to enable us to deeply characterize the structural substrate for ADRD heterogeneity, mechanisms of resilience and resistance, and the biological basis of cognitive subtypes and functional variations in brain aging and dementia in support of each of the ACT Cores. We combine this comprehensive analysis of human brains with a leptomeningeal cell resource and neuropathological characterization for mechanistic explorations of AD pathophysiology (Project 3) and promote existing collaborations focused on characterizing cell type vulnerabilities in all stages of AD to inform mechanistic, diagnostic, and therapeutic research. The NP Core interacts with and supports every other ACT U19 Research Program Core and Project through state-of-the-art diagnostics and has expanded dissection and assessment protocols specifically tailored to support Project 2. Thus, our Aims reflect our commitment to integrate traditional diagnostic excellence and extensive tissue and data sharing with radiographically informed extensive sampling and a battery of highly quantitative, molecularly specific tissue and in silico approaches to precisely measure ADRD neuropathology. Our specific Aims are to (1) build a highly accessible repository of brain tissue and fluids, (2) provide diagnostic expertise according to the latest guidelines, (3) develop innovative approaches, and (4) promote durable ADRD research through support of ACT Cores and Projects. All of our research activities are focused on enhancing the research value of tissue and body fluid donations from cognitively healthy ACT participants and those along the ADRD spectrum while ensuring proper safeguards.

概括 成人思想变化 (ACT) 神经病理学 (NP) 核心（核心 D）一直是有价值且频繁出现的 利用 ACT 队列的资源并支持 ACT 存储库，这是对科学最慷慨的礼物 – 一个人的大脑 – 用于最大限度地影响当地和国家的阿尔茨海默病科学 相关痴呆症 (ADRD) NP 核心制定了专为尖端分子细胞设计的快速方案。 分析并显着扩展了抽样策略，以更好地捕捉潜在的区域变化 阿尔茨海默病和相关痴呆症的异质性促进了 NP 的发展。 在此重要基础上，采用创新、高度定量的方法来评估 ADRD 的神经病理学 通过整合成像技术和分析方法来确定和量化总和 我们对每个大脑进行尸检 MRI，生成 3D 虚拟大脑重建。 利用 NP Core 中独特的脑切片技术，扫描前瞻性和存档 ACT 的幻灯片 传统定量图像分析的样本辅以深度学习方法以最大化 信息产量，并利用固定组织蛋白提取物的多重溶液相测定 比较 ADRD 中的细胞结构和生化病理变化。所有这些创新都是经过设计的。 使我们能够深入描述 ADRD 异质性的结构基础、恢复机制 和抵抗力，以及认知亚型和大脑衰老和功能变化的生物学基础 我们将对人类大脑的全面分析与支持每个 ACT 核心的痴呆症相结合。 用于 AD 机制探索的软脑膜细胞资源和神经病理学表征 病理生理学（项目 3）并促进专注于表征细胞类型的现有合作 AD 各个阶段的脆弱性，为机制、诊断和治疗研究提供信息。 通过最先进的技术与其他所有 ACT U19 研究计划核心和项目进行互动并提供支持 诊断，并扩展了专为支持项目 2 定制的解剖和评估协议。 因此，我们的目标反映了我们致力于整合传统诊断卓越性和组织广泛和 通过放射学信息的广泛采样和一系列高度定量的分子学数据共享数据 我们的具体目标是通过特定组织和计算机方法精确测量 ADRD 神经病理学。 (1) 建立一个高度可访问的脑组织和液体储存库，(2) 根据 最新的指南，(3) 开发创新方法，(4) 通过以下方式促进持久的 ADRD 研究 ACT 核心和项目的支持 我们所有的研究活动都致力于提高研究价值。 来自认知健康的 ACT 参与者和 ADRD 参与者的组织和体液捐赠 频谱，同时确保适当的保障措施。