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: 10672353
• 负责人: CHRISTOPHER DIRK KEENE
• 金额: $ 99.02万
• 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/10672353
• 关键词: 3-Dimensional; Acceleration; Adult; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Autopsy; Biochemical; Biological; Biological Assay; Biological Markers; Blood Glucose; Body Fluids; Brain; Brain region; Cell Line; Cells; Clinical; Cognitive; Collaborations; Communities; Consensus; Data; 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; Investments; Knowledge; Leptomeninges; 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 Research; 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; tissue fixing; 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）一直是有价值的，并且经常 利用该行为队列的资源，并支持ACT存储库，那里是最慷慨的科学礼物 - 一个人的大脑 - 用于最大化对阿尔茨海默氏病的地方和国家科学的影响 相关痴呆症（ADRD）。 NP核心已经建立了用于尖端分子细胞的快速方案 分析并明显扩展了采样策略，以更好地捕捉区域​​变化，这是 阿尔茨海默氏病和相关痴呆症的异质性。 NP核心促进了 创新的，高度定量的方法来评估ADRD的神经病理学，以此为基础 传统通过整合成像技术和分析方法来靶向和量化总和 微观病理学。我们在每个大脑上执行验尸后MRI，生成3D虚拟脑重建 利用NP核心中的独特的大脑切片技术，《预期和档案法》的扫描幻灯片 传统定量图像分析的样本，并补充了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路复用溶液相测定到 比较ADRD中的细胞结构和生化病理学变化。所有这些创新都是设计的 为了使我们能够深刻地表征ADRD异质性的结构基板 和抗性，以及认知亚型的生物学基础以及大脑衰老和功能变化 痴呆支持每个法案核心。我们将这种对人类大脑的全面分析与 用于AD的机械探索的瘦脑细胞资源和神经病理学表征 病理生理学（项目3），并促进专注于细胞类型的现有合作 广告的各个阶段的脆弱性，以告知机理，诊断和治疗性研究。 NP核心 通过最先进 诊断并扩大了专门针对支持项目2的专门量身定制的解剖和评估方案。 这，我们的目标反映了我们致力于整合传统诊断卓越和广泛的组织和 数据共享具有射线照相知情的广泛抽样和高度定量的电池 特定的组织和用于精确测量ADRD神经病理学的硅方法。我们的具体目的是 （1）建立一个高度可访问的脑组织和流体的存储库，（2）根据 最新指南（3）开发创新的方法，以及（4）通过 支持ACT核心和项目。我们所有的研究活动都集中在增强研究价值上 来自认知健康的ACT参与者以及沿ADRD的组织和体液捐赠的组织和体液捐赠 频谱同时确保适当的保障措施。