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--神经原纤维缠绕病理进展顺利-- 定义的好发部位始于内侧颞叶皮质--已由同一作者修改为 建议病理过程开始于脑干下部(Braak等人)。2011年)。第一 可见的病理改变现在被认为发生在蓝斑(LC)，然后通过其轴突扩散 经鼻/内嗅皮质(TEC)的投射。我们建议使用一种新的方法来研究LC的变化 计算形态学方法与测量白质微观结构的新方法相结合 跟踪成像和与TEC的功能连接。这些新方法旨在克服主要的 当前神经核磁共振分析方法的局限性，限制了检测细微结构和功能的能力 与AD早期相关的变化。在整个衰老-MCI-AD连续体中，以及在 认知正常的有AD危险因素的人(例如，脑脊液AD生物标志物；载脂蛋白Eε4携带者)， 将为我们在临床过渡期间对AD发病机制的理解提供重大进展 并且可能在这段静默期间(即，在传统AD生物标志物出现之前 积极因素)。使用我们新开发的诊断和MRI指标，我们建议对LC的变异进行量化 形态及其向TEC的投射(称为LC-TEC系统)。 目的1.检查蓝斑的形态、对比度和相关皮质厚度。在本增刊中， 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(绝地)方法(Frank等人，2020)，以提高灰质评估的敏感性 (GM)组织特征。我们假设，这种更高的敏感性将在LC中产生更大的差别 形态、对比度和相关皮质厚度--特别是脆弱的TEC和海马区 沿着老龄化-MCI-AD连续体的区域。目的2.研究LC-TEC体系的结构连接性。 在这份补充材料中，我们建议使用我们新开发的绝地方法来增强扩散分析 提供对亚体素(微观)扩散各向异性的敏感性，便于评估GM组织状态， 以及改进白质(WM)的各向异性估计。我们假设，这种更高的敏感性将 中的局部各向异性度量对结构连通性进行更准确的估计 LC-TEC系统。目的3.检查LC-TEC系统的功能连通性。在本补充资料中，我们 建议用功能牵引图补充功能模式和连通性估计 由绝地方法得出的平均结构GM/WM组织约束来增强，以提供 提高了对功能模式和连通性评估的敏感性。我们假设这一点比 敏感度将产生异常功能模式的更好聚集性和更大的连通性差异 衰老-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.