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

摘要 显微结构核磁共振技术在神经成像技术中是独一无二的，因为它们探测组织 使用其他方法看不见的微米级特征。因此，这类MRI方法是 承诺解决阿尔茨海默病(AD)和相关疾病中未得到满足的神经成像需求 痴呆症：1.早期发现细胞和蛋白质的细微变化；2.共病的描述 阿尔茨海默病的病理学。尤其是弥散磁共振成像(Dmri)对细胞性、细胞 形态等微结构改变和松弛磁共振成像(RMRI)对 大分子含量。这两种显微结构MRI技术都与检测AD有关 病理，即β-淀粉样斑块和Tau缠结，以及共病病理，如 路易体病(LBD)、海马硬化(HS)和TDP-43蛋白病。虽然在人类身上进行的研究 已经开始使用其中的一些方法，有必要了解放射病理学 MRI的变化与潜在的组织病理学的对应关系也是为了确定 更先进的dMRI和RMRI方法是最有希望转换为人体研究的方法。按顺序 为了应对这些挑战，我们提出了一项“自下而上”的研究，使用mri显微镜对身体进行成像。 来自临床诊断为阿尔茨海默病和非阿尔茨海默病的人的颞叶和脑干组织。我们的 第一个目标是确定AD病理的dMRI和RMRI标记物，在其中我们将优化和 将身体组织的采集、处理和分析策略应用于扩散张量磁共振成像(DTI)， 平均表观传播因子磁共振成像(MAP-MRI)、Q空间轨迹成像(QTI)、结合池分数(BPF) 髓鞘水分数(MWF)标测。然后对组织进行磷酸化Tau(Ptau)染色。 并进行神经病理复查、评分和定量组织学检查。相关性 将在MRI指标和神经病理结果之间进行统计，以确定放射学- 病态关系。在我们的第二个目标中，我们将通过额外的 α-突触核蛋白和TDP-43的染色和评分。将使用类似的相关分析来确定 DMRI和RMRI指标与LBD和TDP-43蛋白病相关。我们的最终目标将是 比较不同颞叶结构(例如，海马体， 杏仁核、皮质和白质)和脑干区(蓝斑、中缝背核和中缝背核)。 白质束)。总体而言，我们的目标是建立关于最有希望的核磁共振成像的初步发现 进一步开发和翻译用于AD研究和诊断的改进的MRI标志物的方法。

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.