Novel platform for research brain banking and characterization using integrated traditional and quantitative analyses to promote precision neuropathology of Alzheimer's disease

使用集成的传统和定量分析来研究脑库和表征的新平台，以促进阿尔茨海默病的精确神经病理学

• 批准号: 10112802
• 负责人: CHRISTOPHER DIRK KEENE
• 金额: $ 124.76万
• 依托单位: ALLEN INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112802
• 关键词: Abbreviations; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Astrocytes; Atlases; Autopsy; BRAIN initiative; Biological Assay; Biological Markers; Brain; Cell physiology; Cells; Chemicals; Classification Scheme; Cognitive; Data; Data Analyses; Dementia; Development; Diagnostic; Disease; Eligibility Determination; Ensure; Evaluation; Experimental Models; Formalin; Fostering; Foundations; Functional disorder; Future; Gene Proteins; Gliosis; Goals; Guidelines; Histologic; Human; Image Analysis; Immunoassay; Individual; Inflammation; Knowledge; Light; Measures; Methodology; Methods; Microglia; Microscopic; Modernization; Molecular; Molecular Analysis; Molecular Genetics; Molecular Profiling; Molecular Target; Nerve Degeneration; Nervous System Trauma; Neurons; Oxidative Stress; Paraffin Embedding; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pattern; Peptides; Phase; Phenotype; Prevalence; Protocols documentation; Quality Control; Research; Research Infrastructure; Research Personnel; Resistance; Resolution; Resources; Role; Sampling; Science; Stains; Stratification; Supporting Cell; Synapses; Techniques; Technology; Testing; Therapeutic; Tissue Banks; Tissue Preservation; Tissue Sample; Tissues; Universities; Washington; Work; aging brain; base; biomarker development; brain research; brain tissue; cell type; clinical phenotype; cohort; comorbidity; design; disorder subtype; epigenomics; genetic information; genetic risk factor; human tissue; interest; meetings; nervous system disorder; neuroinflammation; neuropathology; neurotoxicity; next generation; novel; phase 2 study; precision medicine; preservation; protein metabolite; repository; research study; resilience; risk variant; spelling; stress reactivity; tau Proteins; therapeutic evaluation; tissue resource; transcriptomics; white matter

ABSTRACT (PROJECT 1) The underlying goal of Project 1 is to facilitate an integrated neuropathological approach incorporating traditional and quantitative pathology techniques with cell-type and molecular profiling to develop a unique resource to promote next generation AD research. It leverages existing collaborative relationships between UW Neuropathology and the UW ADRC and Kaiser Adult Changes in Thought studies for research autopsies. Project 1 will implement newly developed protocols for modernized autopsy sampling and preservation of brain tissue that are amenable to state-of-the-art cell type and molecular profiling techniques (Aim 1), as planned in Projects 2 and 3. Deceased subjects from both studies with short post-mortem intervals will enter Project 1 tissue pipeline to ensure high quality tissue preservation and availability for -omics Projects, with appropriate quality control measures at each step. Each ACT and ADRC autopsy includes qualitative neuropathological examination with extensive sampling and a battery of immunostains specific to pathologic peptides according to the latest guidelines. Neuropathological data from each case will be reviewed at regular meetings with Project 1 investigators; cases along the spectrum of AD pathology, but lacking co-morbid neuropathologies, will be promoted to eligibility for inclusion in Aim 2 and the Projects 2 and 3 pipelines. Aim 2 expands analysis of selected cases to include all regions of interest for Projects 2 and 3, but also regions of relevance to current AD cognitive subtypes and biomarker studies with a battery of immunohistochemical stains, image analysis, and quantitative assays to characterize neurodegeneration (pathologic peptides), neurotoxicity (neurons, synaptic markers, stains for white matter and oxidative stress), and reactivity (astrocytes, microglia, inflammation). In Aim 3, results from cell-type and molecular profiling studies in Projects 2 and 3 will be prioritized for targets identified in early AD pathogenesis, validated, and extended to the broader autopsy cohort to determine relevance. Quantitative measures for these analyses may include Luminex-based immunoassays and other techniques proteins and metabolites of neurodegeneration, neurotoxicity, and neuroinflammation/gliosis in regions and subjects of interest. We predict, based on the last five years, approximately 30 cases per year that are eligible for inclusion in Aim 2 and Project 2 and 3 pipelines. Each brain that goes through Project 1 pipeline, even if not selected for inclusion in the -omics components of the Center, will be preserved according to these novel protocols and deeply characterized for future studies of AD subtypes, risk variants, related disorders, and exposure profiles.

摘要(项目1) 项目1的基本目标是促进综合神经病理学方法 传统和定量病理学技术与细胞类型和分子图谱相结合，开发出独特的 促进下一代AD研究的资源。它利用现有的协作关系 威斯康星大学神经病理学和威斯康星大学ADRC和Kaiser成人在研究尸检中的思维研究变化。 项目1将实施新开发的现代化尸检取样和脑保存方案 能够适应最先进的细胞类型和分子图谱技术的组织(目标1)，计划在 项目2和项目3.两项研究中死亡的受试者尸检间隔较短，将进入项目1 组织管道，以确保高质量的组织保存和组学项目的可用性，并具有适当的 每一步都有质量控制措施。每一次ACT和ADRC尸检都包括定性神经病理 广泛采样和一系列针对病理性多肽的免疫染色检查 遵守最新的指导方针。每个病例的神经病理数据将在定期会议上进行审查 项目1调查人员；AD病理谱系的病例，但缺乏共病神经病理， 将被提升为有资格列入目标2和项目2和3管道。目标2扩展分析 包括项目2和3的所有感兴趣的区域，但也包括与当前项目相关的区域 AD认知亚型和生物标记物的研究，包括免疫组织化学染色，图像分析， 以及定量分析，以表征神经变性(病理性多肽)、神经毒性(神经元、 突触标记、白质染色和氧化应激)和反应性(星形胶质细胞、小胶质细胞、 炎症)。在目标3中，项目2和3中的细胞类型和分子图谱研究的结果将是 优先处理早期AD发病机制中确定的靶点，进行验证，并扩展到更广泛的尸检 确定相关性的队列。这些分析的定量措施可能包括基于Luminex的 神经变性、神经毒性、蛋白质和代谢物的免疫分析和其他技术 感兴趣区域和受试者的神经炎症/神经胶质增生症。根据过去五年的数据，我们预测， 每年约有30个案例符合纳入AIM 2和项目2和3管道的条件。每个人 通过项目1管道的大脑，即使没有被选为包括在-组学组件中 中心，将根据这些新的协议保存下来，并为未来的AD研究而深入描述 亚型、风险变种、相关疾病和暴露情况。