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.

总结 成人思维变化（ACT）神经病理学（NP）核心（核心D）一直是一个有价值的，经常 利用ACT队列的资源，并支持ACT库，其中对科学最慷慨的礼物 - 一个人的大脑-是用来最大限度地影响当地和国家的科学阿尔茨海默病， 相关性痴呆（ADRD）NP核心已经制定了为尖端分子细胞设计的快速协议， 分析，并显着扩大了抽样战略，以更好地捕捉区域变化的基础， 阿尔茨海默病和相关痴呆的异质性。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，建立在这一重要的 传统的成像技术和分析方法相结合的目标和量化的总， 显微病理学我们对每个人的大脑进行死后核磁共振成像， 利用NP Core中独特的大脑切片技术，扫描前瞻性和存档ACT的幻灯片 用于传统定量图像分析的样本，辅以深度学习方法， 信息产量，并利用来自固定组织蛋白质提取物的多重液相测定， 比较ADRD的细胞结构和生化病理改变。所有这些创新都是为了 使我们能够深入描述ADRD异质性的结构基础， 和抵抗力，以及认知亚型的生物学基础和脑老化中的功能变化， 痴呆症，以支持每一个ACT核心。我们将联合收割机对人脑的全面分析与 软脑膜细胞资源和神经病理学特征用于AD的机制探索 病理生理学（项目3），并促进现有的合作，重点是表征细胞类型 在AD的所有阶段的脆弱性，为机械，诊断和治疗研究提供信息。NP核心 通过最先进的技术与其他ACT U19研究计划核心和项目互动并提供支持 诊断，并已扩大解剖和评估协议，专门为支持项目2。 因此，我们的目标反映了我们的承诺，将传统的诊断卓越和广泛的组织， 通过放射学信息的广泛采样和一组高度定量的、分子水平的 特定组织和计算机模拟方法来精确测量ADRD神经病理学。我们的具体目标是 (1)建立一个高度可访问的脑组织和液体库，（2）根据 最新指南，（3）开发创新方法，（4）通过以下方式促进持久的ADRD研究 支持ACT核心和项目。我们所有的研究活动都专注于提高研究价值 从认知健康的ACT参与者和那些沿着ADRD的人捐赠的组织和体液 频谱，同时确保适当的保障措施。