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; 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.

项目摘要/摘要 有大量证据表明血管功能障碍是造成的重要贡献者 阿尔茨海默氏病（AD）的发展。血管血流动力学的病理变化，血管生成， AD中的血脑屏障渗透性和免疫细胞迁移已归因于血管腔 淀粉样蛋白β（Aβ）斑块以及最近的动物研究的影响表明Aβ和Tau铅 血管异常和血脑屏障分解。另一方面，大脑的改变 已知灌注早在广告发育的临床症状之前就存在，甚至可能在 淀粉样蛋白β（Aβ）斑块积累，TAU沉积和脑萎缩。了解如何血管至关重要 功能障碍在AD早期发展及其与Aβ和TAU的经典AD生物标志物的关系 开发可靠，准确的脑血管生物标志物，可在早期识别AD 无症状的疾病阶段。 成像研究表明，毛细管功能障碍与AD和脑血的严重程度相关 在AD和AD动物模型中有风险的成年人的流量（CBF）降低。这些发现支持了重要性 数量的血管变化可能会提供更全面，更敏感的 用于检测早期广告变化的标记。在发展缠结或斑块的小鼠中的最新研究 发现了毛细血管中形态和功能改变的惊喜证据。体内两光子 这些小鼠的显微镜显示出血流减少的曲折毛细血管，并显示了血管 血管生成和炎症的特定RNA特征。去年的其他研究 确认AD患者的类似微血管和RNA变化与以下假设一致。 微血管病理学对于介导AD的发展至关重要。那，尽管通常是 假设CBF降低是继发神经元丧失的继发的，我们假设神经元丧失可能是由于AD- 诱导的血管异常。 在这项探索性研究中，我们建议通过通过 在具有已知水平的个体中，使用尖端的灌注磁共振成像（MRI）技术 通过PET量化的Aβ和Tau蛋白。研究设计将以我们的初步工作为基础 高级MRI技术探测脑血管功能以及高敏感性PET成像 Aβ和TAU的标记在AD和认知健康的老年人患者中有风险发展AD的患者。我们 期望识别最有前途的脑血管成像生物标志物，这些生物标志物敏感且特定于 脑血管变化在AD的早期阶段发生。一旦确定，这些成像标记可能是 利用用于定义事件的临时序列和异常蛋白沉积之间的关系 在不久的将来的一项大型纵向研究中，脑血管障碍。