Multi-scale and multi-modality imaging of neuropathology in VCID

项目摘要 MRI和组织病理学是所有与年龄相关的认知障碍和痴呆研究的两个关键方法，它们为疾病机制和治疗意义带来了关键见解。一个主要的挑战是表征这两种模式的综合特性，这两种模式在分辨率、覆盖范围和标记方面不同;此外，在体内，血管异常的性质很难在尸检中表征。死后核磁共振成像已经成为一种弥合差距的技术，但必要的技术仍然没有完全开发。在这项提案中，我们建议开发新的死后MR成像协议和计算工具，使多模式多尺度脑MR/组织病理学/蛋白质组学数据分析的收集，以促进我们对与血管对认知障碍和痴呆（VCID）的贡献相关的灰质和白色物质神经变性的理解。我们成立了一个跨学科的研究小组，成员包括拟议研究的几个关键方面的顶尖专家，以实现以下具体目标。目标1：为人脑尸检、固定和阻断/切片开发一个强大的、最先进的尸检管道，以满足AD/ADRD的MRI/组织病理学综合全面分析的需求。这些包括（a）死后间隔（PMI）和福尔马林固定（即，小时至数周），用于在空间和时间域中对这种效应进行建模;以及（B）建立标准化的离体MRI程序，该程序集中于简化固定和切片方案，以使成像和组织变形/降解最小化，使得能够在成像程序之间进行可靠的共配准，并确保与组织病理学和蛋白质组学分析的精确的自上而下的相关性。目标二：基于来自NYU Langone Health ADRC的充分表征队列的共同登记的多模态和多尺度MRI和神经病理学数据，开发人类内侧颞叶（MTL）和前额叶皮质（PFC）病理学的多模态图谱和数据库，包括AD、TBI相关和其他ADRD与对照受试者，重点关注Aβ、Tau、血管和微结构病理学。将重建多模态血管和显微结构图谱，并与血管病理学染色相结合。目标3：通过对死后MRI和组织病理学进行高保真度和多对比度体素标测，研究白色高信号（WMH），从而更好地了解小血管疾病（SVD）的体内和体外结果。这一目标解决了与VCID相关的SVD研究中的两个主要障碍：跨模态解释和WMH的异质性。目标4：开发成像和病理学协议，软件工具和大脑图谱的数字图书馆，以及相关的前和死后MRI和生物材料数据在研究界共享。总的来说，该项目将有助于开发标准化和可访问的MRI-组织学方案，新的尸检和配准工具，以及来自75个老年人大脑的所有成像和生物材料数据的资源，以推进AD/ADRD中VCID病理学的研究。

PROJECT SUMMARY MRI and histopathology are two key methods for all research into age-related cognitive impairment and dementia and they have brought key insights into disease mechanisms and therapeutic implications. A major challenge is to characterize the integrative properties of these two modalities, which differ in resolution, coverage, and markers; furthermore, in vivo, vascular abnormalities by nature are difficult to be characterized on post-mortem exams. Post-mortem MRI has emerged as a technique to bridge the gap but necessary techniques are still not fully developed. In this proposal, we propose to develop novel post-mortem MR imaging protocols and computational tools to enable the collection of multi-modal multi-scale brain MR/histopathology/ proteomics data analysis to advance our understanding of gray and white matter neurodegeneration associated with vascular contributions to cognitive impairment and dementia (VCID). We have assembled a multi-disciplinary research team with leading experts in several key aspects of the proposed study to achieve the following specific aims. Aim 1: Develop a robust, state-of-the-art post-mortem pipeline for human brain autopsy, fixation, and blocking/sectioning that meet the need for combined MRI/histopathology full-scale analysis of AD/ADRD. These include (a) characterization of the effects of post-mortem interval (PMI) and formalin fixation (i.e., hours to weeks) for modeling such effect in both spatial and temporal domains; and (b) establishing standardized ex vivo MRI procedures that focus on streamlining fixation and sectioning protocols to minimize imaging and tissue deformation/degradation, enabling dependable co-registration between imaging procedures and ensuring precise top-down correlation with histopathology and proteomic analysis. Aim 2: Develop a multi-modality atlas and database of the human medial temporal lobe (MTL) and prefrontal cortex (PFC) pathology based on co-registered multimodal and multiscale MRI and neuropathology data from a well-characterized cohort at NYU Langone Health ADRC that includes AD, TBI-related and other ADRD vs control subjects, focusing on Aβ, Tau, vascular, and microstructural pathology. The multi-modality vascular and microstructural atlases will be reconstructed and integrated with vascular pathology staining. Aim 3: Study white matter hyperintensities (WMHs) by performing high-fidelity and multi-contrast voxel-wise mapping of post-mortem MRI and histopathology that enable a better understanding of in vivo and ex vivo findings of small vessel disease (SVD). This aim tackles two major obstacles in the research of SVD associated with VCID: cross-modality interpretation and heterogeneity of WMHs. Aim 4: Develop digital libraries for imaging and pathology protocols, software tools, and brain atlases, as well as relevant pre- and post-mortem MRI and biomaterial data to be shared in the research community. Collectively, this project will make contributions to develop standardized and accessible MRI- histology protocols, novel post-mortem and co-registration tools, as well as resources of all imaging and biomaterial data from 75 elderly brains to advance the study of VCID pathology in AD/ADRD.