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

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谱，以开发一个独特的 促进下一代AD研究的资源。它利用现有的合作关系， 华盛顿大学神经病理学和华盛顿大学ADRC和凯撒成人思想变化研究的研究尸检。 项目1将实施新制定的现代化尸检取样和保存大脑的协议 组织，适合最先进的细胞类型和分子分析技术（目标1），如计划在 项目2和3。两项研究中死亡且死后间隔较短的受试者将进入项目1 组织管道，以确保高质量的组织保存和可用性的组学项目，与适当的 每一步的质量控制。每个ACT和ADRC尸检包括定性神经病理学检查， 检查与广泛的采样和电池特异性的病理肽，根据 最新的指导方针。每个病例的神经病理学数据将在定期会议上进行审查， 项目1研究者;病例沿着AD病理学谱，但缺乏共病神经病理学， 将被提升到有资格列入目标2和项目2和3管道。Aim 2扩展分析 选定的案例，包括项目2和3的所有感兴趣的区域，但也包括与当前 AD认知亚型和生物标志物研究，采用免疫组化染色，图像分析， 和定量分析来表征神经变性（病理性肽），神经毒性（神经元， 突触标记，白色物质和氧化应激的染色），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和项目3的细胞类型和分子谱研究结果将 优先考虑在早期AD发病机制中确定的靶点，验证并扩展到更广泛的尸检 以确定相关性。这些分析的定量测量可以包括基于Luminex的 免疫测定和其他技术神经变性、神经毒性和神经毒性的蛋白质和代谢物， 神经炎症/神经胶质增生。我们预测，基于过去五年， 每年约有30个案例有资格列入目标2和项目2和项目3管道。每个 通过Project 1管道的大脑，即使没有被选中包含在-omics组件中 中心，将根据这些新的协议保存，并为AD的未来研究进行深入表征 亚型、风险变体、相关疾病和暴露特征。

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.