Spreading Tau Pathology in Non-Amnestic Alzheimer's Disease

项目摘要 神经元tau蛋白始终与阿尔茨海默病的神经变性和认知下降有关 (AD)在一系列临床表现和解剖表型，包括原发性 记忆、视觉空间、语言和躯体运动领域的损害。一种tau蛋白进展的模型， 涉及病理性tau蛋白沿轴突白质的区域间转运 (WM)连接;然而，在小鼠模型中轴突运输的证据可能不会转化为复合物， 人类AD的生物学轴突运输假说的一个潜在检验是WM的变化是否 连接预测tau阳性和tau阴性区域之间的疾病进展。如果轴突运输是一种 tau扩散的共同机制，它应该留下与患者的特征一致的WM变化。 解剖学和临床表型。然而，在非遗忘性轻度脑梗死患者中， 认知障碍（MCI）和AD，很少在纵向tau变化的背景下进行研究。此外，委员会认为， WM改变的影像学标志物可能反映AD病理过程的特征或同时发生 脑血管疾病我们提出了一个多模式的临床，成像和病理调查，以测试 WM变化预测区域到区域tau扩散独立于CVD的假设。AIM 1将联合收割机 纵向正电子发射断层扫描（PET）成像的tau进展与3-T MR成像的WM 使用扩散MRI评估WM变化介导tau蛋白在综合征特异性 方式轴突运输模型预测，扩散MRI的纵向变化将介导区域到区域的变化。 综合征特异性脑网络中的tau区PET进展。Aim 2将使用高分辨率7特斯拉MRI， 心血管疾病相关的脑部变化，包括WM高信号和微出血，以量化血管疾病 遗忘型和非遗忘型AD的负担，并评估CVD合并病理学作为潜在混杂因素， 可以解释AD中WM的变化。基于初步数据，我们假设所有临床上的AD变异 将表现出与年龄相关的心血管疾病，包括WM高信号和微出血，但无法完全解释与tau相关的心血管疾病 WM改变。最后，Aim 3将提供成像结果的死后验证，并推进数字化 病理学方法来量化遗忘型和非遗忘型AD中的AD和CVD相关病理学。在这一目标下， 轴突运输模型预测灰质tau纵向变化将由tau介导 在连接WM束的沉积和变性，但不是由CVD病理负担。通过比较 异质性表型和认知网络，我们试图证明WM介导的tau蛋白扩散是一种 在MCI/AD的认知亚型中疾病进展的普遍机制，并且独立于 CVD相关变化。这项研究将有助于AD和相关痴呆（ADRD）的多个里程碑 通过研究tau，CVD和WM变化之间的关系（Milestone 2.L和2.S）;并开发 用于纵向跟踪CVD相关脑变化的非侵入性标记物（里程碑9.R）。

PROJECT ABSTRACT Neurofibrillary tau is consistently linked to neurodegeneration and cognitive decline in Alzheimer’s disease (AD) over a range of clinical presentations and anatomical phenotypes, including patients with primary impairment in memory, visuospatial, language, and somatomotor domains. One model of tau progression that has attracted recent attention involves region-to-region transport of pathologic tau along axonal white matter (WM) connections; however, evidence for axonal transport in murine models may not translate to the complex biology of AD in humans. One potential test of the axonal transport hypothesis is whether changes in WM connections predict disease progression between tau-positive and tau-negative regions. If axonal transport is a common mechanism of tau spread, it should leave signature WM changes consistent with a patient’s anatomical and clinical phenotype. However, WM changes are underinvestigated in non-amnestic mild cognitive impairment (MCI) and AD and rarely studied in the context of longitudinal tau changes. Moreover, imaging markers of WM change may reflect features of the AD pathologic process or co-occurring cerebrovascular disease. We propose a multimodal clinical, imaging, and pathologic investigation to test the hypothesis that WM changes predict region-to-region tau spread independent of CVD. Aim 1 will combine longitudinal positron emission tomography (PET) imaging of tau progression with 3-Tesla MR imaging of WM changes using diffusion MRI to assess evidence that WM changes mediate tau spread in a syndrome-specific manner. The axonal transport model predicts that longitudinal changes in diffusion MRI will mediate region-to- region tau PET progression in syndrome-specific brain networks. Aim 2 will use high-resolution 7-Tesla MRI of CVD-related brain changes, including WM hyperintensities and microbleeds, to quantify vascular disease burden across amnestic and non-amnestic AD and to assess CVD co-pathology as a potential confound that would explain WM changes in AD. Based on preliminary data, we hypothesize that all clinical variants of AD will exhibit age-related CVD including WM hyperintensities and microbleeds but will not fully explain tau-related WM changes. Finally, Aim 3 will provide postmortem validation of imaging findings and advance digital pathologic methods to quantify AD- and CVD-related pathology in amnestic and non-amnestic AD. In this aim, the axonal transport model predicts that longitudinal change in grey matter tau will be mediated by tau deposition and degeneration in connecting WM tracts, but not by CVD pathologic burden. By comparing heterogeneous phenotypes and cognitive networks, we seek to demonstrate that WM-mediated tau spread is a generalizable mechanism of disease progression across cognitive subtypes of MCI/AD and is independent of CVD-related changes. This research will contribute to multiple milestones in AD and related dementias (ADRD) by investigating relationships between tau, CVD, and WM change (Milestones 2.L and 2.S); and developing non-invasive markers for longitudinal tracking of CVD-related brain changes (Milestone 9.R).