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.

摘要 尽管大脑缺乏传统的淋巴系统来清除废物， 大脑具有替代性通路，如胶质淋巴系统和壁内动脉周围 排水.阿尔茨海默病（AD）模型的最新实验证据表明淀粉样蛋白被清除 大脑中的β信号沿着这些通路产生。这些通路由心脏搏动驱动， 血管运动，其诱导脑脊液（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痴呆都有很强的联系， CVD调节废物清除。然而，血液流动和脑脊液流动动力学之间的相互作用， 对人类的研究不足，其与AD潜在病理生理学的关系最近才开始 得到关注。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风险富集人群的纵向研究。常用的MRI方法 如今，例如液体衰减（例如，白色物质高强度）和磁敏感性成像（例如， 微血管造影术）只能间接评估CVD，不能提供动态血管运动信息， 在动物模型中已经表明血液动力学现象影响AD病理学。本研究 将先前开发的MRI技术应用于对血液和CSF流动动力学敏感的AD。最近， 我们已经成功地使用非侵入性4D-Flow MRI来表征脑血管健康， AD.使用4D-Flow MRI，在临床诊断的AD受试者中发现了显著的脑血管变化 与认知正常的人相比这些变化包括颅内血管僵硬度增加， 血管舒缩减少;然而，这些研究中CVD-AD相互作用的假设检验受到以下因素的限制： 缺乏CSF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 血液和CSF流动动力学以及AD生物标志物数据的整合。血管生物标志物将 在临床前和受损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）相关 测定和PET）测量。这些数据将推动对血管改变的修正作用的假设检验 对认知障碍的症状表达、AD生物标志物积累和脑健康的影响。参与者 本研究的目标人群具有广泛的现有AD生物标志物数据，并正在进行纵向随访， 威斯康星州阿尔茨海默病研究中心的研究。在完成这项研究后，我们将 更好地了解颅内血管硬度和CSF脉动性对Aβ42/ Aβ40比值的影响（以及 淀粉样蛋白脑清除率的指标）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，我们还将收集初步数据， 提交更大的校外申请（例如NIA/NIH R 01）以支持重点研究的理由 了解脑血管健康在AD病理和AD相关痴呆中的作用。