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: 10549382
• 负责人: HOWARD J AIZENSTEIN
• 金额: $ 75.04万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549382
• 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; Disease; Elderly; Engineering; FDA approved; Friends; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Guidelines; Head; Heating; Human; Hypertension; Image; Impaired cognition; Individual; Inflammatory; 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; Venous; Visualization; White Matter Hyperintensity; Work; arterial spin labeling; arteriole; cerebral microvasculature; cerebrovascular; clinically relevant; cognitive load; design; fluid flow; follow-up; human imaging; human study; imaging biomarker; imaging modality; improved; in vivo; indexing; magnetic resonance imaging biomarker; multimodality; neuropathology; pre-clinical; predictive modeling; prospective; radio frequency; recruit; tau Proteins; temporal measurement; ultra high resolution

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.

项目概要/摘要： 在小血管疾病（SVD，微血管病）和阿尔茨海默病之间有一个很好的联系 疾病（AD）。小血管与AD级联反应之间相关性的潜在机制 仍然不清楚。SVD和AD之间的一些关联是由于来自AD的累积认知负担。 独立的病理学（AD和SVD）导致AD临床综合征的早期表现。是 同时认识到SVD和AD相关的另一种方式是通过双向相互作用 在分子和细胞水平：例如，与Aβ斑块相关的炎性因子促成SVD。 此外，一个新兴的假设是，小动脉的脉动性降低降低了脑脊髓损伤。 液体（CSF）清除淀粉样蛋白，使人处于AD的风险中。更好地了解潜在的 与SVD和AD相关的机制尤其重要，因为它可以确定预防和治疗目标。 这项拟议的跨学科（多PI）提案旨在开发先进的MRI方法（硬件， 采集和分析），并研究连接小血管和CSF流动的途径 AD的病理生理这项工作将通过一个由美国大学的专家组成的联盟来实现。匹兹堡- MRI采集和分析-和AD; 2）FDA -射频加热相关指南-; 3）U。明尼苏达州- MRI采集-; 4）Quality Electrodynamics Inc. (QED)- 整合方便病人的硬件;以及蒙特利尔 神经研究所-核磁共振分析-。我们将检查小血管形态，脑血管反应性 (CVR)和CSF流量，所有这些都是AD病理生理学中相互相关的组分。例如，小 血管病变（部分由于淀粉样血管病）可能破坏CVR，从而干扰Aβ 间隙 这项研究是一项针对无痴呆症的老年人的前瞻性观察性研究：30 淀粉样蛋白阳性30例，淀粉样蛋白阴性30例。我们将利用两项正在进行的研究（RF 1AG 025516和 R 01 AG 052446）进行AD病理学检查，用于招募、临床表征和PET成像。个人 使用当前最先进的技术在基线（Aim 1）处扫描。我们会一直研究核磁共振成像 发展（目标2）。在2年随访时，将使用与 此外，还将使用新开发的技术进行扫描（目标3）。 总之，本研究开发、应用和验证了小血管形态学的先进成像， CVR、CSF流量和其他传统MRI生物标志物来表征临床前AD， 确定预防和/或治疗目标。该提案利用了最近提出的 及时和最近FDA批准的技术（7 T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7 T人体MRI中心和线圈公司;以及c）a 政府监管机构。