Exploring the Relationship Between Tau Deposition and Neurovascular Health in Alzheimer's Disease

探索阿尔茨海默病中 Tau 沉积与神经血管健康之间的关系

• 批准号: 9975512
• 负责人: Susie Yi Huang
• 金额: $ 46.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975512
• 关键词: Adult; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Animal Disease Models; Animals; Area; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain region; Cerebrovascular Circulation; Clinical; Cognition Disorders; Cognitive; Complement; Data; Deposition; Development; Disease; Disease Marker; Elderly; Event; Functional disorder; Future; Goals; Grant; Health; Heterogeneity; Imaging Techniques; Immune; Impaired cognition; Impairment; Individual; Inflammation; Label; Lead; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Mediating; Morphology; Mus; Neurofibrillary Tangles; Noise; Pathologic; Patients; Perfusion; Perfusion Weighted MRI; Positron-Emission Tomography; Predisposition; Proteins; RNA; Research Design; Resolution; Risk; Secondary to; Senile Plaques; Severities; Severity of illness; Signal Transduction; Spin Labels; Symptoms; Time; Vascular Diseases; Work; abeta accumulation; angiogenesis; blood-brain barrier permeabilization; cell motility; cerebral atrophy; cerebrovascular; cerebrovascular imaging; contrast enhanced; gray matter; hemodynamics; imaging biomarker; imaging modality; imaging study; in vivo; microvascular pathology; neuron loss; neurovascular; non-invasive imaging; perfusion imaging; tau Proteins; two photon microscopy; vascular abnormality

Project Summary/Abstract There is a wealth of evidence indicating that vascular dysfunction is a prominent contributor to the development of Alzheimer's disease (AD). Pathological changes in vessel hemodynamics, angiogenesis, blood-brain barrier permeability and immune cell migration in AD have been attributed to the vasculotoxic effects of amyloid-β (Aβ) plaques, and more recently, tau, with animal studies suggesting that Aβ and tau lead to blood vessel abnormalities and blood-brain barrier breakdown. On the other hand, alterations in brain perfusion are known to be present long before the clinical symptoms of AD develop, perhaps even preceding amyloid-β (Aβ) plaque accumulation, tau deposition, and brain atrophy. It is critical to understand how vascular dysfunction develops early in AD and how it relates to the classical AD biomarkers of Aβ and tau in order to develop a reliable and accurate cerebrovascular biomarker of AD that can be used to identify AD in the early asymptomatic stages of disease. Imaging studies have shown that capillary dysfunction correlates to the severity of AD and cerebral blood flow (CBF) decreases in adults at risk for AD and in AD animal models. These findings support the importance of quantification of vascular changes as it may provide a more comprehensive and possibly more sensitive marker for detecting early AD changes. Recent studies in mice that develop either tangles or plaques uncovered surprising evidence of morphological and functional alterations in the capillaries. In vivo two-photon microscopy in these mice revealed tortuous capillaries with diminished blood flow, and the vessels showed specific RNA signatures of angiogenesis and inflammation. Additional studies within the last year have confirmed analogous microvascular and RNA changes in patients with AD, consistent with the hypothesis that microvascular pathology is critical in mediating the development of AD. Thus, although it is commonly assumed that reduced CBF is secondary to neuronal loss, we postulate that neuronal loss may be due to AD- induced vascular abnormalities. In this exploratory study, we propose to investigate imaging biomarkers for cerebrovascular alterations, by using cutting-edge perfusion magnetic resonance imaging (MRI) techniques, in individuals with known levels of Aβ and tau protein as quantified through PET. The study design will build on our preliminary work using advanced MRI techniques to probe cerebrovascular function together with high-sensitivity PET imaging markers of Aβ and tau in patients with AD and cognitively healthy older adults at risk for developing AD. We expect to identify the most promising cerebrovascular imaging biomarkers that are sensitive and specific to the cerebrovascular alterations that occur in AD in its early stages. Once identified, these imaging markers can be leveraged for defining the temporal sequence of events and relationships between abnormal protein deposition and cerebrovascular impairment in a large longitudinal study in the near future.

项目概要/摘要 大量证据表明，血管功能障碍是导致血管疾病的一个重要因素。 阿尔茨海默病（AD）的发展。血管血流动力学、血管生成的病理变化， AD 中的血脑屏障通透性和免疫细胞迁移归因于血管毒性 β 淀粉样蛋白 (Aβ) 斑块以及最近的 tau 蛋白的影响，动物研究表明 Aβ 和 tau 蛋白会导致 血管异常和血脑屏障破坏。另一方面，大脑的变化 众所周知，早在 AD 临床症状出现之前，甚至可能在 AD 出现之前，灌注就已经存在 β 淀粉样蛋白 (Aβ) 斑块积聚、tau 蛋白沉积和脑萎缩。了解血管如何运作至关重要 AD 早期出现的功能障碍及其与经典 AD 生物标志物 Aβ 和 tau 的关系如何 开发一种可靠、准确的 AD 脑血管生物标志物，可用于早期识别 AD 疾病的无症状阶段。 影像学研究表明，毛细血管功能障碍与 AD 的严重程度和脑血流量相关 在有 AD 风险的成年人和 AD 动物模型中，血流量 (CBF) 降低。这些发现支持了重要性 血管变化的量化，因为它可以提供更全面且可能更敏感的 用于检测早期 AD 变化的标记。最近对出现缠结或斑块的小鼠的研究 发现了毛细血管形态和功能改变的令人惊讶的证据。体内双光子 这些小鼠的显微镜检查显示，毛细血管弯曲，血流减少，并且血管显示 血管生成和炎症的特定 RNA 特征。去年的其他研究有 证实了 AD 患者中类似的微血管和 RNA 变化，与以下假设一致： 微血管病理学对于调节 AD 的发展至关重要。因此，尽管普遍 假设 CBF 减少是继发于神经元损失，我们假设神经元损失可能是由于 AD- 诱发血管异常。 在这项探索性研究中，我们建议通过以下方式研究脑血管改变的成像生物标志物： 使用尖端的灌注磁共振成像 (MRI) 技术，在已知水平的个体中进行 通过 PET 定量 Aβ 和 tau 蛋白。研究设计将建立在我们的初步工作的基础上，使用 先进的 MRI 技术与高灵敏度 PET 成像一起探测脑血管功能 AD 患者和有患 AD 风险的认知健康老年人的 Aβ 和 tau 标记物。我们 期望确定最有前途的脑血管成像生物标志物，这些生物标志物对以下疾病敏感且具有特异性 AD 早期发生的脑血管改变。一旦确定，这些成像标记就可以被 用于定义事件的时间顺序以及异常蛋白质沉积之间的关系 和脑血管损伤在不久的将来进行的一项大型纵向研究中。