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.

项目摘要/摘要 有大量证据表明，血管功能障碍是导致 阿尔茨海默病(AD)的发展。血管血流动力学、血管生成、 阿尔茨海默病的血脑屏障通透性和免疫细胞迁移被归因于血管毒性 淀粉样蛋白-β(Aβ)斑块的影响，以及最近的tau，动物研究表明Aβ和tau领先 血管异常和血脑屏障的破坏。另一方面，大脑的变化 众所周知，在AD的临床症状发展之前很久，甚至在此之前，血流灌注就已经存在。 淀粉样蛋白-β(A-β)斑块堆积、tau沉积和脑萎缩。了解血管是如何 功能障碍在AD的早期发展及其与经典AD生物标志物Aβ和tau的关系 建立可靠、准确的AD脑血管生物标志物，用于AD的早期识别 疾病的无症状阶段。 影像研究表明，毛细血管功能障碍与阿尔茨海默病的严重程度和脑血流有关 在AD高危成人和AD动物模型中，血流(CBF)减少。这些发现支持了 对血管变化的量化，因为它可以提供更全面和可能更敏感的 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 发现了令人惊讶的毛细血管形态和功能变化的证据。活体双光子 这些小鼠的显微镜下可见扭曲的毛细血管，血流量减少，血管显示 血管生成和炎症的特定RNA信号。在过去的一年中进行的其他研究 在AD患者中证实了类似的微血管和RNA变化，与以下假设一致 微血管病理在AD的发生发展过程中起着至关重要的作用。因此，尽管它通常是 假设CBF减少是继发于神经元丢失，我们假设神经元丢失可能是由于AD- 导致血管异常。 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记物 使用尖端的灌注磁共振成像(MRI)技术，在已知水平的 β和tau蛋白通过正电子发射计算机断层扫描进行定量。研究设计将建立在我们的前期工作的基础上 先进的磁共振成像技术结合高灵敏度的正电子发射计算机断层扫描探测脑血管功能 阿尔茨海默病患者和认知健康的老年人患阿尔茨海默病的A-β和tau标志物。我们 期望确定最有希望的脑血管成像生物标记物，这些标记物对脑血管成像具有敏感性和特异性 阿尔茨海默病早期发生的脑血管改变。一旦确定，这些成像标记就可以 用于定义事件的时间序列和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了一项大型纵向研究。