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

项目总结 MRI和组织病理学是所有年龄相关性认知障碍和痴呆研究的两种关键方法，它们为疾病机制和治疗意义带来了关键的见解。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、覆盖范围和标志物上都不同；此外，在活体内，血管异常本质上很难在尸检中表征。尸检MRI已成为弥补这一差距的一种技术，但必要的技术仍未完全开发出来。在这项建议中，我们建议开发新的死后磁共振成像方案和计算工具，以收集多模式、多尺度的脑MR/组织病理学/蛋白质组学数据分析，以促进我们对与认知障碍和痴呆(VCID)的血管贡献相关的灰质和白质神经变性的理解。我们组建了一个多学科研究小组，由拟议研究的几个关键方面的主要专家组成，以实现以下具体目标。目的1：开发一种强大的、先进的人脑解剖、固定和阻断/切片管道，以满足对AD/ADRD的MRI/组织病理学联合全面分析的需要。这些措施包括(A)表征死后间隔时间(PMI)和福尔马林固定(即数小时至数周)的影响，以在空间和时间域对这种影响进行建模；以及(B)建立标准化的体外MRI程序，侧重于简化固定和切片方案，以最大限度地减少成像和组织变形/退化，使成像程序之间能够可靠地共同配准，并确保与组织病理学和蛋白质组分析的准确自上而下的关联。目的：建立人类内侧颞叶和前额叶病理的多模式图谱和数据库，其基础是联合注册的多模式和多尺度磁共振成像和来自纽约大学朗格尼健康发展研究中心的神经病理学数据，该队列包括AD、脑外伤相关和其他ADRD与对照组，重点关注Aβ、Tau、血管和微结构病理学。多模式血管和显微结构图谱将被重建，并与血管病理染色相结合。目的：通过对死后MRI和组织病理学进行高保真和多对比度体素标测，研究白质高信号，以便更好地了解小血管疾病(SVD)的体内和体外表现。这一目标解决了与VCID相关的奇异值分解研究中的两个主要障碍：跨通道解释和WMH的异质性。目标4：为成像和病理方案、软件工具和脑图谱以及相关的死前和死后核磁共振数据和生物材料数据开发数字图书馆，以便在研究界共享。总体而言，该项目将为开发标准化和可访问的MRI组织学方案、新的尸检和联合注册工具以及来自75个老年人大脑的所有成像和生物材料数据资源做出贡献，以推进AD/ADRD中VCID病理的研究。

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.