New Quantitative Neuroimaging Metrics of Structural and Functional Connectivity of the Locus Coeruleus as a Novel Biomarker of Alzheimer's Disease Pathogenesis and Progression

Braak和Braak（1991）提出的原始理论--神经系统缠结病理学进展沿着-- 定义好发部位开始于内侧颞叶皮质-已被同一作者修改， 表明病理过程反而开始于下脑干（Braak等人，2011）。第一 现在认为可见的病理变化发生在蓝斑（LC），然后通过其轴突扩散 transentorhinal/entorhinal cortex（TEC）。我们建议使用一种新的 计算形态学方法，结合测量白色物质微观结构的新方法 跟踪和功能连接到TEC。这些新方法旨在克服主要的 当前神经MRI分析方法的局限性限制了检测细微结构和功能的能力， 与早期AD相关的变化。这种变化跨越衰老-MCI-AD连续体，以及在那些 具有AD风险因素的认知正常个体（例如，CSF AD生物标志物;载脂蛋白E ε4携带者）， 将为我们理解AD的发病机制提供重要的进展， 点并且可能在该“静默”时段期间（即，在传统AD生物标志物发生之前 积极性）。使用我们新开发的诊断和MRI指标，我们建议量化LC的变化， 形态学及其对TEC的投影（称为LC-TEC系统）。 目标1.检查蓝斑形态、对比度和相关皮质厚度。在这份补充中， 我们建议用我们新开发的联合估计来增强结构形态估计 扩散（JEDI）方法（Frank等人，2020年），以提高对灰质评估的敏感性 (GM)组织特征我们推测，这种更高的敏感性将产生更大的区别，在LC 形态学、对比度和相关皮质厚度-特别是在脆弱的TEC和海马 区域-沿老化-MCI-AD连续体。目标2.检查LC-TEC系统的结构连接性。 在本增刊中，我们建议用我们新开发的JEDI方法来增强扩散分析， 提供了对亚体素（微观）扩散各向异性的敏感性，便于评估GM组织状态， 以及改善白色物质（WM）中的各向异性估计。我们假设，这种更高的敏感性将 从局部各向异性测量中得出更准确的结构连通性估计， LC-TEC系统目标3.检查LC-TEC系统的功能连接。在本补充中，我们 建议用功能纤维束成像补充功能模式和连通性估计 通过从我们的JEDI方法得到的平均结构GM/WM组织约束来增强，以提供 提高了对功能模式和连接性评估的敏感性。我们假设， 敏感性将产生异常功能模式的更好聚类和连接性的更大区别 老化-MCI-AD连续体的模式。

The original theory offered by Braak & Braak (1991)—that neurofibrillary tangle pathology proceeds along well- defined predilection sites beginning in the medial temporal cortex—has been modified by the same author to suggest that the pathologic process instead commences in the lower brainstem (Braak et al. 2011). The first visible pathologic changes are now thought to occur in the locus coeruleus (LC) and then spread via its axonal projections to transentorhinal/entorhinal cortex (TEC). We propose to study LC change using a novel computational morphology method, combined with novel methods of measuring white matter microstructural tractography and functional connectivity to TEC. These new methods are designed to overcome major limitations in current neuro-MRI analysis methods that limit the ability to detect subtle structural and functional changes associated with early AD. Such alterations across the aging-MCI-AD continuum, as well as in those cognitively normal individuals with risk factors for AD (e.g., CSF AD biomarkers; apolipoprotein E ε4 carriers), would provide significant advances in our understanding of the pathogenesis of AD across clinical transition points and perhaps during this `silent' period (i.e., prior to the occurrence of traditional AD biomarker positivities). Using our newly developed diagnostic and MRI metrics, we propose to quantify variations in LC morphology and its projections to TEC (termed the LC-TEC system). Aim 1. Examine locus coeruleus morphology, contrast, and associated cortical thickness. In this supplement, we propose to augment the structural morphology estimates with our newly developed Joint Estimation Diffusion (JEDI) method (Frank et al., 2020) to provide improved sensitivity to the assessment of gray matter (GM) tissue characteristics. We hypothesize that this greater sensitivity will produce greater distinctions in LC morphology, contrast and associated cortical thickness—particularly in vulnerable TEC and hippocampal regions—along the aging-MCI-AD continuum. Aim 2. Examine structural connectivity of the LC-TEC system. In this supplement, we propose to augment the diffusion analysis with our newly developed JEDI method that provides sensitivity to sub-voxel (microscopic) diffusion anisotropy, facilitating assessment of GM tissue status, and improving anisotropy estimates in white matter (WM). We hypothesize that this greater sensitivity will produce more accurate estimates of structural connectivity derived from the local anisotropy measures in the LC-TEC system. Aim 3. Examine functional connectivity of the LC-TEC system.In this supplement, we propose to supplement the functional modes and connectivity estimates with functional tractography augmented by averaged structural GM/WM tissue constraints derived from our JEDI method to provide improved sensitivity to the assessment of functional modes and connectivity. We hypothesize that this greater sensitivity will produce better clustering of abnormal functional modes and greater distinctions in connectivity patterns for the aging-MCI-AD continuum.