Characterizing the Effect of Altered CSF and Blood Flow Dynamics on Alzheimer’s Disease Proteinopathy, Brain Health, and Cognition

表征脑脊液和血流动力学改变对阿尔茨海默病蛋白病、大脑健康和认知的影响

• 批准号: 10433391
• 负责人: Leonardo A Rivera Rivera
• 金额: $ 42.76万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433391
• 关键词: 4D MRI; Abeta clearance; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloidosis; Animal Model; Animals; Arteries; Attention; Biological Assay; Biological Markers; Blood; Blood Vessels; Blood flow; Brain; Cardiac; Cerebrospinal Fluid; Cerebrovascular Disorders; Cerebrovascular system; Clinical; Clinical Research; Cognition; Cognitive; Data; Dementia; Disease; Drainage procedure; Evaluation; Excision; Extramural Activities; Frequencies; Functional disorder; Genetic Risk; Goals; Health; Hemodynamic Phenomena; Human; Hypertension; Image; Image Analysis; Imaging Techniques; Immunoassay; Impaired cognition; Impairment; Intracranial Pressure; Link; Liquid substance; Longitudinal Studies; Lymphatic System; Magnetic Resonance Imaging; Measurement; Measures; Methods; Modeling; Motion; Nature; Neurofibrillary Tangles; Participant; Pathway interactions; Perfusion; Physiologic pulse; Physiological; Play; Population; Population Study; Positron-Emission Tomography; Predisposition; Production; Protocols documentation; Research; Risk; Role; Spinal Cord; Spinal Puncture; Structure; Symptoms; System; Techniques; Testing; Time; Tissues; United States National Institutes of Health; Vascular Diseases; Veins; Velocimetries; Venous; Waste Products; White Matter Hyperintensity; Wisconsin; Work; attenuation; blood-brain barrier permeabilization; brain health; brain tissue; cerebrospinal fluid flow; cerebrovascular; cerebrovascular amyloid; cerebrovascular health; clinical diagnosis; cohort; diagnostic value; endothelial dysfunction; glymphatic system; imaging modality; insight; mechanical force; mild cognitive impairment; nervous system disorder; pre-clinical; progression marker; recruit; repository; tau Proteins; theories; vasomotion; wasting; white matter damage

ABSTRACT Although the brain lacks a traditional lymphatic system for clearing waste products, it has been hypothesized that the brain possesses alternative pathways such as the glymphatic system and intramural periarterial drainage. Recent experimental evidence in Alzheimer's disease (AD) models suggests clearance of amyloid beta from the brain occurs along these pathways. These pathways are driven by cardiac pulsations and vasomotion which induce cerebrospinal fluid (CSF) flow dynamics and brain tissue motion. Cerebrovascular disease (CVD), has a strong link with both mild cognitive impairment and AD dementia, and there is potential that CVD modulates waste clearance. However, the interactions between blood flow and CSF flow dynamics in humans are understudied and their relationship to underlying pathophysiology of AD has only recently begun receiving attention. To provide insights into CVD-AD relationships, non-invasive Magnetic Resonance Imaging (MRI) is being utilized in longitudinal studies of AD risk-enriched populations. MRI methods commonly employed today such as fluid attenuation (e.g. white matter hyperintensities) and susceptibility imaging (e.g. microhemorrhages) only indirectly evaluate CVD and cannot inform on the dynamic vascular motion and hemodynamic phenomena that have been indicated in animal models to affect AD pathology. The present study applies previously develop MRI techniques to AD that are sensitive to blood and CSF flow dynamics. Recently, we have successfully use non-invasive 4D-Flow MRI to characterize cerebrovascular health in the context of AD. Using 4D-Flow MRI significant cerebrovascular changes were found in clinically diagnosed AD subjects when compared to cognitively normal. These changes included increased intracranial vessel stiffness and reduced vasomotion; however, hypothesis testing of CVD-AD interactions from these studies was limited by the lack of CSF flow and AD biomarker data. In this project, we propose using 4D-Flow MRI for the quantification of blood and CSF flow dynamics in addition to the integration of AD biomarker data. The vascular biomarkers will be studied in preclinical and impaired AD subjects and correlated with longitudinal amyloid and tau (from CSF assays and PET) measures. Such data will drive hypothesis testing on the modifying effect of vascular alterations on the symptom expression of cognitive impairment, AD biomarker accumulation, and brain health. Participants targeted for this study have extensive existing AD biomarker data and are being followed longitudinally through studies within the Wisconsin Alzheimer's Disease Research Center. Upon completion of this study, we will have a better understanding of the impact of intracranial vessel stiffness and CSF pulsatility on Aβ42/ Aβ40 ratios (an indicator of amyloid brain clearance) and the interacting effect of intracranial vessel stiffness and amyloid on AD pathology accumulation, brain health and cognition. Additionally, we would have collected preliminary data and rationale to submit a larger extramural application (e.g. NIA/NIH R01) to support studies focused on understanding the role of cerebrovascular health on AD pathology and AD related dementia.

抽象的 尽管大脑缺乏清除废物的传统淋巴系统，但有人假设 大脑拥有替代通路，例如类淋巴系统和壁内动脉周围 引流。阿尔茨海默病 (AD) 模型的最新实验证据表明淀粉样蛋白的清除 来自大脑的β沿着这些途径发生。这些途径是由心脏搏动驱动的 血管舒缩诱导脑脊液 (CSF) 流动动力学和脑组织运动。脑血管 疾病（CVD），与轻度认知障碍和 AD 痴呆有很强的联系，并且有可能 CVD 调节废物清除。然而，血流和脑脊液流动动力学之间的相互作用 人类尚未得到充分研究，其与 AD 潜在病理生理学的关系最近才开始 受到关注。为了深入了解 CVD-AD 关系，非侵入性磁共振成像 (MRI) 正在用于 AD 风险较高人群的纵向研究。常用的MRI方法 今天，例如液体衰减（例如白质高信号）和磁敏感成像（例如 微出血）只能间接评估 CVD，不能提供动态血管运动和 动物模型中已表明血流动力学现象会影响 AD 病理学。目前的研究 将先前开发的 MRI 技术应用于对血液和脑脊液流动动力学敏感的 AD。最近， 我们已成功使用非侵入性 4D-Flow MRI 来表征脑血管健康状况 广告。使用 4D-Flow MRI 在临床诊断的 AD 受试者中发现显着的脑血管变化 与认知正常相比。这些变化包括颅内血管硬度增加和 血管舒缩减少；然而，这些研究对 CVD-AD 相互作用的假设检验受到以下因素的限制： 缺乏脑脊液流量和 AD 生物标志物数据。在这个项目中，我们建议使用 4D-Flow MRI 来量化 除了 AD 生物标志物数据的整合之外，还包括血液和脑脊液流动动力学。血管生物标志物将 在临床前和受损的 AD 受试者中进行研究，并与纵向淀粉样蛋白和 tau 蛋白（来自 CSF 化验和 PET）测量。这些数据将推动对血管改变的改变效应的假设检验 认知障碍、AD 生物标志物积累和大脑健康的症状表达。参加者 这项研究的目标是拥有大量现有的 AD 生物标志物数据，并且正在纵向跟踪 威斯康星州阿尔茨海默病研究中心的研究。完成这项研究后，我们将获得 更好地了解颅内血管硬度和脑脊液搏动对 Aβ42/Aβ40 比率的影响（ 淀粉样蛋白脑清除率指标）以及颅内血管硬度和淀粉样蛋白对 AD 的相互作用 病理积累、大脑健康和认知。此外，我们会收集初步数据并 提交更大的校外申请（例如 NIA/NIH R01）以支持重点研究的理由 了解脑血管健康对 AD 病理学和 AD 相关痴呆的作用。