Spreading Tau Pathology in Non-Amnestic Alzheimer's Disease

在非遗忘性阿尔茨海默病中传播 Tau 病理学

• 批准号: 10662937
• 负责人: Jeffrey S Phillips
• 金额: $ 95.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662937
• 关键词: Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amnestic Disorder; Amyloid beta-Protein; Anatomy; Anisotropy; Antibodies; Area; Atrophic; Attention; Attenuated; Autopsy; Award; Axon; Axonal Transport; Biology; Brain; Cerebrovascular Disorders; Characteristics; Clinical; Cognition Disorders; Cognitive; Complex; Data; Data Set; Deposition; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Episodic memory; Exhibits; Fast Blue; Hemorrhage; Heterogeneity; Histopathology; Human; Image; Impaired cognition; Impairment; Individual; Influentials; Investigation; Language; Link; Liquid substance; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Memory; Methods; Microvascular Dysfunction; Modeling; Molecular; Molecular Conformation; Mus; Myelin; Neocortex; Nerve Degeneration; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neurons; Nodal; Pathologic; Pathologic Processes; Pathology; Patients; Pattern; Phenotype; Positron-Emission Tomography; Predisposition; Primary Progressive Aphasia; Radial; Recovery; Research; Resolution; Risk Factors; Source; Stress; Syndrome; Testing; Time; Tissue Sample; Validation; Variant; Vascular Diseases; Visuospatial; White Matter Hyperintensity; age related; biomarker identification; burden of illness; cerebral atrophy; clinical diagnosis; clinical heterogeneity; clinical phenotype; corticobasal syndrome; digital; disorder risk; follow-up; gray matter; image guided; imaging biomarker; improved; in vivo; longitudinal positron emission tomography; mild cognitive impairment; mouse model; multimodality; neocortical; predictive modeling; prognostic model; serial imaging; sex; support network; tau Proteins; tau aggregation; theories; white matter; white matter change

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).

项目摘要 神经原纤维tau一直与阿尔茨海默病患者的神经退行性变和认知能力下降有关 (Ad)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。一种陶氏级数模型 最近引起了人们的注意，涉及病理性tau沿着轴突白质的区域到区域的运输 (Wm)联系；然而，小鼠模型中轴突运输的证据可能不会转化为复合体 人类阿尔茨海默病的生物学。轴突运输假说的一个潜在检验是WM是否改变 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扩散的常见机制，它应该留下与患者一致的标志性WM变化 解剖和临床表型。然而，在非遗忘型轻度患者中，WM的变化被研究得很少 认知功能障碍(MCI)与阿尔茨海默病(AD)的关系，很少在tau纵向变化的背景下研究。此外， WM改变的影像标志物可反映AD的病理过程或共生的特征 脑血管疾病。我们建议进行多模式的临床、影像和病理研究，以测试 假设WM改变可独立于心血管疾病预测区域到区域的tau扩散。目标1将结合 3-特斯拉磁共振西医Tau进展的正电子发射断层扫描(PET)研究 使用弥散磁共振成像评估WM改变在特定综合征中介导tau扩散的证据 举止。轴突运输模型预测，弥散磁共振的纵向变化将调节区域到 症状性脑网络中的区域tau PET进展。AIM 2将使用高分辨率7-特斯拉MRI 脑血管疾病相关的脑改变，包括WM高信号和微出血，以量化血管疾病 遗忘性和非遗忘性AD的负担，并评估CVD的共同病理是否为潜在的混淆 可以解释AD中的WM变化。根据初步数据，我们假设AD的所有临床变种 将显示年龄相关的CVD，包括WM高信号和微出血，但不能完全解释与tau相关的 WM发生了变化。最后，AIM 3将提供影像发现的尸检验证，并推进数字化 遗忘性和非遗忘性AD中AD和CVD相关病理的病理学方法。在这个目标中， 轴突运输模型预测灰质tau的纵向变化将由tau介导。 在连接的WM束中沉积和变性，但不是由CVD的病理负担所致。通过比较 不同的表型和认知网络，我们试图证明WM介导的tau传播是一种 MCI/AD认知亚型疾病进展的概括性机制 心血管疾病相关改变。这项研究将有助于AD和相关痴呆(ADRD)的多个里程碑 通过调查tau、CVD和WM变化之间的关系(里程碑2.1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(里程碑9.R)。