Microstructural MRI Microscopy of Post-mortem Specimens to Identify and Improve Markers of Alzheimer's Disease Pathology

总结 显微结构MRI技术是神经影像学模式中的独特之处，因为它们探测组织 使用其他方法不可见的微米级特征。因此，这类MRI方法 有望解决阿尔茨海默病（AD）及相关疾病神经影像学的未满足需求 痴呆症：1.早期检测细微的细胞和蛋白质改变，以及2.共病描述 AD中的病理特别地，扩散MRI（dMRI）对细胞结构、细胞周期和细胞周期的改变敏感。 形态学和其他微结构变化以及弛豫MRI（rMRI）对 大分子含量这两种微结构MRI技术都与检测AD相关 病理学，即β-淀粉样蛋白（Ab）斑块和Tau缠结，以及共病病理学，如 路易体病（LBD）、海马硬化（HS）和TDP-43蛋白质病。在人类研究中， 已经开始使用其中的一些方法，有必要了解放射病理学 MRI变化与潜在组织病理学的对应关系，并且还确定 更先进的dMRI和rMRI方法最有希望转化为人类研究。为了 为了应对这些挑战，我们提出了一个“自下而上”的研究，使用MRI显微镜成像死后， 颞叶和脑干组织，来自在生活中有和没有临床诊断为AD的人。我们 第一个目标是识别AD病理学的dMRI和rMRI标记物，其中我们将优化和 对死后组织应用采集、处理和分析策略进行扩散张量MRI（DTI）， 平均表观传播子MRI（MAP-MRI），q空间轨迹成像（QTI），结合池分数（BPF） 和髓鞘水分数（MWF）作图。然后将组织针对磷酸化Tau（pTau）进行染色。 和Ab，并进行神经病理学检查和评分以及定量组织学检查。相关性 将在MRI指标和神经病理学结局之间进行统计，以确定放射学- 病理关系。在我们的第二个目标中，我们将通过额外的 a-突触核蛋白和TDP-43的染色和评分。类似的相关性分析将用于确定 与LBD和TDP-43蛋白质病相关的dMRI和rMRI度量特征。我们的最终目标是 比较不同颞叶结构（例如海马， 杏仁核、皮质和白色物质）和脑干区域（蓝斑、中缝背核和 白色物质束）。总的来说，我们的目标是建立关于最有前途的MRI的初步发现， 进一步开发和翻译用于AD研究和诊断的改进MRI标记物的方法。

Summary Microstructural MRI techniques are unique among neuroimaging modalities because they probe tissue features at the micron scale that are invisible using other methods. This class of MRI methods is therefore promising to address the unmet needs for neuroimaging in Alzheimer’s disease (AD) and related dementias: 1. early detection of subtle cellular and protein alterations and 2. delineation of comorbid pathologies in AD. In particular, diffusion MRI (dMRI) is sensitive to alterations in cellularity, cell morphology, and other microstructural changes and relaxometery MRI (rMRI) is sensitive to macromolecular content. Both of these microstructural MRI techniques are relevant for detecting AD pathology, namely beta-amyloid (Ab) plaques and Tau tangles, as well as comorbid pathologies such as Lewy body disease (LBD), hippocampal sclerosis (HS) and TDP-43 proteinopathy. While studies in humans have begun to use some of these approaches, there is a need to understand the radiologic-pathologic correspondence of MRI changes with the underlying tissue pathology and also to determine which of the more advanced dMRI and rMRI methods are the most promising for translation to human studies. In order to meet these challenges, we propose a “bottom-up” study using MRI microscopy to image post-mortem temporal lobe and brainstem tissue from humans with and without a clinical diagnosis of AD in life. Our first aim is the identification of dMRI and rMRI markers of AD pathology in which we will optimize and apply acquisition, processing and analysis strategies for post-mortem tissue for diffusion tensor MRI (DTI), mean apparent propagator MRI (MAP-MRI), q-space trajectory imaging (QTI), bound pool fraction (BPF) and myelin water fraction (MWF) mapping. Then the tissue will be stained for phosphorylated Tau (pTau) and Ab and undergo neuropathologic review and scoring as well as quantitative histology. Correlation statistics will be performed between MRI metrics and neuropathologic outcomes to identify radiologic- pathologic relationships. In our second aim, we will investigate comorbid pathologies by the additional staining and scoring of a-synuclein and TDP-43. Similar correlation analysis will be used to determine the dMRI and rMRI metric profiles associated with LBD and TDP-43 proteinopathy. Our final aim will then compare these radiologic-pathologic signatures in different temporal lobe structures (e.g. hippocampus, amygdala, cortex and white matter) and in brainstem regions (locus coeruleus, dorsal raphe nucleus and white matter tracts). Overall, our goal is to establish initial findings about the most promising MRI methods for further development and translation of improved MRI markers for AD research and diagnosis.