Imaging Advancements in Small Vessel and CSF Flow Pathophysiology of Pre-clinical Alzheimer's Disease

临床前阿尔茨海默氏病小血管和脑脊液流病理生理学的成像进展

• 批准号: 10343792
• 负责人: HOWARD J AIZENSTEIN
• 金额: $ 73.76万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343792
• 关键词: Abeta clearance; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Brain; Brain imaging; Carbon Dioxide; Cardiac; Cerebral small vessel disease; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrum; Clinical; Collaborations; Dementia; Detection; Development; Elderly; Engineering; FDA approved; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Government; Guidelines; Head; Heating; Human; Hypertension; Image; Impaired cognition; Individual; Inflammatory; Institutes; Lesion; Link; Magnetic Resonance Imaging; Measures; Methods; Microcirculation; Microvascular Dysfunction; Minnesota; Molecular; Morphology; Neck; Neurologic; Observational Study; Pathology; Pathway interactions; Patients; Physiologic pulse; Population Study; Positron-Emission Tomography; Prevention; Protocols documentation; Pulsatile Flow; Resolution; Risk; Risk Factors; Role; Scanning; Scientist; Senile Plaques; Signal Transduction; System; Technology; Time; Venous; White Matter Hyperintensity; Work; arterial spin labeling; arteriole; cerebral microvasculature; cerebrovascular; clinically relevant; cognitive load; design; fluid flow; follow-up; human imaging; imaging biomarker; imaging modality; imaging study; improved; in vivo; indexing; magnetic resonance imaging biomarker; multimodality; neuropathology; pre-clinical; predictive modeling; prospective; radio frequency; recruit; tau Proteins; temporal measurement

Project Summary/Abstract: There is a well-established association between small vessel disease (SVD, microangiopathy) and Alzheimer's disease (AD). The underlying mechanisms for associations between small vessels and the AD cascade remain unclear. Some of the association between SVD and AD is due to the cumulative cognitive burden from independent pathologies (AD and SVD) leading to early manifestation of the clinical syndrome of AD. It is becomingly recognized that another way in which SVD and AD are related is through bi-directional interaction at molecular and cellular levels: e.g., inflammatory factors associated with Aβ plaques contribute to SVD. Furthermore, an emerging hypothesis is that decreased pulsatility of small arterioles decreases cerebral spinal fluid (CSF) clearance of amyloid, putting someone at risk of AD. A better understanding of the underlying mechanisms relating SVD and AD is especially important as it can identify prevention and treatment targets. This proposed transdisciplinary (Multi-PI) proposal aims to develop advanced MRI methods (hardware, acquisition, and analysis) with 7T human imaging and study the pathways linking small vessel and CSF flow pathophysiology to AD. It will be achieved through a consortium consisting of expertise at 1) U. of Pittsburgh - MRI acquisition and analysis-, and AD; 2) FDA -RF-heating matters in relation guidelines-; 3) U. of Minnesota - MRI acquisition-; 4) Quality Electrodynamics Inc. (QED) -integration of patient friendly hardware-; and Montreal Neurological Institute -MRI analysis-. We will examine small vessel morphology, cerebrovascular reactivity (CVR), and CSF flow, all of which are inter-related components in AD pathophysiology. For instance, small vessel lesions (in part due to amyloid angiopathy) may disrupt CVR, and consequently interfere with Aβ clearance. The study is designed as a prospective observational study of older adults without dementia: 30 amyloid positive, and 30 amyloid negative (n = 60). We will leverage two ongoing studies (RF1AG025516 & R01AG052446) of AD pathology for recruitment, clinical characterization and PET imaging. Individuals are scanned at baseline (Aim 1) using current state of the art technology. Throughout we will work on MRI development (Aim 2). At 2-year follow up individuals will be scanned again with the same protocol as at baseline, and will also undergo scanning with the newly developed technology (Aim 3). In summary, this study develops, applies and validates advanced imaging of small vessel morphology, CVR, and CSF flow and other traditional MRI biomarkers to characterize pre-clinical AD, and potentially identify targets for prevention and/or treatment. The proposal takes advantage of recent and proposed advances in a timely and recently FDA-approved technology (7T human MRI) and collaborations between: a) scientists, engineers, and clinicians; b) leading 7T human MRI centers and a coil company; and c) a governmental regulatory agency.

项目摘要/摘要： 小血管疾病（SVD、微血管病）和阿尔茨海默病之间存在明确的关联 疾病（AD）。小血管与 AD 级联之间关联的基本机制 仍不清楚。 SVD 和 AD 之间的一些关联是由于累积的认知负担造成的 独立的病理学（AD 和 SVD）导致 AD 临床综合征的早期表现。这是 人们逐渐认识到 SVD 和 AD 相关的另一种方式是通过双向交互 在分子和细胞水平上：例如，与 Aβ 斑块相关的炎症因子会导致 SVD。 此外，一个新出现的假设是，小动脉搏动减少会降低脑脊髓 脑脊液（CSF）清除淀粉样蛋白，使人面临 AD 的风险。更好地理解底层 SVD和AD的相关机制尤其重要，因为它可以确定预防和治疗目标。 这项跨学科（Multi-PI）提案旨在开发先进的 MRI 方法（硬件、 采集和分析）与 7T 人体成像并研究连接小血管和脑脊液流的通路 AD 的病理生理学。这将通过一个由 1) 匹兹堡大学的专业知识组成的联盟来实现 - MRI 采集和分析，以及 AD； 2) FDA -射频加热事宜相关指南-； 3）明尼苏达大学 - MRI 采集-； 4) Quality Electrodynamics Inc. (QED) -患者友好型硬件的集成-；和蒙特利尔 神经病学研究所-MRI分析-。我们将检查小血管形态、脑血管反应性 (CVR) 和脑脊液流量，所有这些都是 AD 病理生理学中相互关联的组成部分。例如，小 血管病变（部分由于淀粉样血管病）可能会破坏 CVR，从而干扰 Aβ 清除。 该研究旨在对没有痴呆症的老年人进行前瞻性观察研究：30 淀粉样蛋白阳性，30 名淀粉样蛋白阴性 (n = 60)。我们将利用两项正在进行的研究（RF1AG025516 和 R01AG052446) AD 病理学，用于招募、临床表征和 PET 成像。个人是 使用当前最先进的技术进行基线扫描（目标 1）。在整个过程中我们将致力于 MRI 发展（目标 2）。在 2 年随访时，将使用与当时相同的方案再次对个体进行扫描 基线，还将使用新开发的技术进行扫描（目标 3）。 总之，这项研究开发、应用和验证了小血管形态的先进成像， CVR、脑脊液流和其他传统 MRI 生物标志物来表征临床前 AD，并可能 确定预防和/或治疗的目标。该提案利用了最近和拟议的 最近 FDA 批准的技术（7T 人体 MRI）的进展以及以下方面的合作：a) 科学家、工程师和临床医生； b) 领先的7T人体MRI中心和线圈公司；和 c) 政府监管机构。