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: 10612886
• 负责人: CHRISTOPHER DIRK KEENE
• 金额: $ 125.43万
• 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/10612886
• 关键词: Abbreviations; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; 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; Genes; Gliosis; Goals; Guidelines; Histologic; Human; Image Analysis; Immunoassay; Individual; Inflammation; Knowledge; Light; Maps; Measures; Methodology; Methods; Microglia; Microscopic; Modernization; Molecular; Molecular Analysis; Molecular Profiling; Molecular Target; Nerve Degeneration; Nervous System Trauma; Neurons; Oxidative Stress; Paraffin Embedding; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pattern; Peptides; Phase; Phenotype; Prevalence; Proteins; 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; 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; repository; research study; resilience; risk variant; spelling; 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的神经病理学方法 具有细胞类型和分子分析的传统和定量病理技术，以发展独特 促进下一代广告研究的资源。它利用了现有的合作关系 UW神经病理学以及UW ADRC和Kaiser成人在研究尸检的思想研究中的变化。 项目1将实施新开发的协议，以现代化的尸检抽样和保存大脑 适合最先进的细胞类型和分子分析技术的组织（AIM 1），如计划 项目2和3。两项研究的已故受试者，验尸级间隔很短，将进入项目1 组织管道，以确保合适的组织项目的高质量组织保存和可用性 质量控制措施在每个步骤中进行。每种ACT和ADRC尸检包括定性神经病理学 用广泛的采样和一系列特定于病理肽的免疫抑制剂检查 根据最新准则。每种情况的神经病理学数据将在定期会议上与 项目1调查人员；沿着AD病理的范围，但缺乏合并神经病理学， 将晋升为列入AIM 2和项目2和3管道的资格。 AIM 2扩展分析 选定的案件，包括项目2和3的所有感兴趣区域，但也包括与当前相关的区域 AD认知亚型和生物标志物研究，具有一系列免疫组织化学染色，图像分析， 和定量测定以表征神经变性（病理肽），神经毒性（神经元，，， 突触标记，白质和氧化应激的污渍）和反应性（星形胶质细胞，小胶质细胞， 炎）。在AIM 3中，项目2和3中的细胞类型和分子分析研究的结果将是 优先考虑早期AD发病机理中确定的靶标，验证并扩展到更广泛的尸检 队列确定相关性。这些分析的定量措施可能包括基于Luminex的 免疫测定和其他技术的蛋白质和神经变性，神经毒性和的代谢产物 感兴趣的区域和受试者的神经炎症/神经病。我们预测，根据最近五年 每年约有30例有资格纳入AIM 2和项目2和3管道的案例。每个 通过项目1管道进行的大脑，即使未选择包含在 - 组成分中的大脑 中心将根据这些新颖的协议保存，并深入特征，以供未来的AD研究 亚型，风险变体，相关疾病和暴露概况。