Adult Changes in Thought (ACT) Research Program Core D: Neuropathology Core

摘要 成人思维改变(ACT)神经病理学(NP)核心(核心D)一直是一个有价值的和频繁的 为ACT队列利用资源，并支持ACT存储库，在那里，对科学最慷慨的捐赠 -一个人的大脑-被用来最大限度地影响阿尔茨海默氏病的地方和国家科学，并 相关痴呆(ADRD)。NP Core已经建立了为尖端分子细胞设计的快速协议 并显著扩展了抽样策略，以更好地捕获构成 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，建立在这一重要的 通过集成成像技术和分析方法来确定目标和量化总量和 显微病理学。我们对每个大脑进行尸检核磁共振，生成3D虚拟大脑重建 利用NP Core中独特的脑切片技术，扫描预期和归档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，以最大限度地提高 信息产量，并利用从固定组织蛋白质提取物到 比较ADRD的细胞构筑和生化病理改变。所有这些创新都是专门设计的 为了使我们能够深入地表征ADRD异质性的结构基础，弹性机制 和抵抗力，以及认知亚型和脑老化和功能变异的生物学基础 支持每个ACT核心的痴呆症。我们将这种对人脑的全面分析与 阿尔茨海默病机制探讨的软脑膜细胞来源和神经病理学特征 病理生理学(项目3)和促进现有的专注于细胞类型特征的合作 AD所有阶段的漏洞，为机制、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所有ACT U19研究计划核心和项目互动并提供支持 并扩展了专门为支持项目2量身定做的解剖和评估协议。 因此，我们的目标反映了我们致力于将传统诊断的卓越与广泛的组织和 通过放射学知情的广泛采样和高定量、分子电池的数据共享 在特定的组织和电子技术方法中，精确测量ADRD神经病理。我们的具体目标是 (1)建立一个高度可访问的脑组织和体液储存库；(2)根据 最新的指导方针，(3)开发创新方法，以及(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集中在提升研究价值上 来自认知健康的ACT参与者和ADRD沿线的组织和体液捐赠 频谱，同时确保适当的保障措施。

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.