Non-Invasive Imaging Markers to Elicit the Role of Vascular Involvement in Alzheimer’s Disease

非侵入性成像标记物可揭示血管受累在阿尔茨海默病中的作用

• 批准号: 10560465
• 负责人: Kevin Michael Johnson
• 金额: $ 69.06万
• 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: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560465
• 关键词: 4D MRI; Abeta clearance; Acceleration; Address; Adoption; Affect; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Animal Model; Attention; Biological Markers; Blood Vessels; Blood capillaries; Blood flow; Caliber; Cardiac; Cardiovascular Diseases; Cause of Death; Cephalic; Cerebrovascular Circulation; Cerebrovascular Disorders; Clinical; Clinical Trials; Cognition; Cohort Studies; Complex; Data; Dementia; Development; Disease; Disease Marker; Early identification; FarGo; Frequencies; Functional disorder; Generations; Goals; Health; Hemodynamic Phenomena; Heterogeneity; Homeostasis; Human; Image; Impaired cognition; Institution; Knowledge; Link; Liquid substance; Longitudinal Studies; Longitudinal cohort study; Magnetic Resonance Imaging; Measures; Mediating; Methodology; Methods; Modeling; Motion; National Institute of Neurological Disorders and Stroke; Nature; Nerve Degeneration; Noise; Participant; Pathology; Patients; Perfusion; Physiologic pulse; Population; Population Study; Positioning Attribute; Predisposition; Prevalence; Protocols documentation; Regulation; Research; Resolution; Rest; Risk; Risk Factors; Role; Sampling; Sensitivity and Specificity; Specificity; Symptoms; Techniques; Technology; Testing; Therapeutic; Tissues; Translating; United States; Vascular Diseases; White Matter Hyperintensity; Wisconsin; Work; alternative treatment; arterial spin labeling; arterial stiffness; attenuation; capillary bed; cerebrovascular; cerebrovascular health; clinical translation; cohort; curative treatments; deep learning; dementia risk; elastography; endothelial dysfunction; hemodynamics; high risk; human subject; hypoperfusion; imaging biomarker; improved; individual patient; innovation; insight; mild cognitive impairment; nervous system disorder; neuroimaging; neuroinflammation; neuropathology; neurovascular; non-invasive imaging; novel; novel strategies; optical imaging; premature; progression marker; protective factors; recruit; technology validation; tool; vascular risk factor

ABSTRACT Alzheimer's disease (AD) is the 6th leading cause of death in the United States and its prevalence continues to rise. AD has no clinically available curative treatments and findings from active clinical trials testing novel disease-modifying therapeutics have thus far been disappointing. There is, therefore, a growing urgency to identify early markers of AD, causative factors leading to dementia, and alternative treatment approaches for halting the global crisis posed by this debilitating condition. Cardiovascular disease, as well as cerebrovascular disease (CVD), has a strong link with both mild cognitive impairment and AD dementia; however, the question of whether CVD modulates underlying pathophysiology of AD has only recently begun receiving attention. To provide insights into AD relationships, non-invasive Magnetic Resonance Imaging (MRI) is being utilized in longitudinal studies of AD risk-enriched populations. The present project goes far beyond currently available MRI techniques which lack sensitivity and specificity to address key vascular hypotheses in AD. MRI methods commonly employed today such as fluid attenuation and susceptibility imaging only indirectly measure CVD and cannot inform on the dynamic vascular motion and hemodynamic phenomena that have been indicated in animal models to affect AD pathology. To address these gaps, the overarching objective of this project is to enable characterization of cerebrovascular involvement in AD through the development and study integration of a novel battery of non-invasive, MRI-based measures of cerebrovascular health. Building upon foundational studies at our institution, this work proposes innovative MRI technology to improve characterization of CVD in AD, specifically vascular stiffening and its relationship with cerebrovascular flow dynamics. We propose an ensemble of motion encoded MRI techniques which provide detailed depiction of autoregulatory flow dynamics and vascular stiffness in both the macro and micro vasculature. In this project, the novel methods will be technically developed harnessing deep learning from vast prior imaging data, validated with optical imaging, and characterized in healthy human subjects. We then will obtain key data characterizing cerebrovascular changes in a study of AD biomarker confirmed subjects with the overall goal of identifying the modifying effect of vascular disease on the symptom expression of cognitive impairment, AD biomarker accumulation, and neurodegeneration. Our pilot data suggest subjects with AD have a premature increase in arterial stiffness and decreased fluctuations in cerebral blood flow. Upon completion, this study will provide insights into which specific aspects of CVD are primary factors moderating AD interactions. 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. The methodologies will be uniquely positioned for incorporation into large longitudinal cohort studies investigating AD mechanisms and evaluating putative risk and protective factors.

摘要 阿尔茨海默病(AD)是美国第六大主要死亡原因，其患病率仍在继续 站起来。AD没有临床上可用的治疗方法和测试新药的积极临床试验的结果 到目前为止，疾病修正疗法一直令人失望。因此，越来越迫切地需要 确定阿尔茨海默病的早期标志物、导致痴呆的致病因素以及替代治疗方法 阻止这一令人衰弱的状况带来的全球危机。心血管疾病以及脑血管疾病 疾病(CVD)与轻度认知障碍和AD痴呆症都有很强的联系；然而，问题是 心血管疾病是否调节阿尔茨海默病的潜在病理生理学直到最近才开始受到关注。至 提供对AD关系的洞察，非侵入性磁共振成像(MRI)正在 对AD风险增加人群的纵向研究。目前的项目远远超出了目前可用的核磁共振成像 缺乏敏感性和特异性来解决AD的关键血管假说的技术。磁共振成像方法 目前常用的如液体衰减和磁化率成像只能间接测量CVD和 不能告知已经在动物身上显示的动态血管运动和血流动力学现象 影响AD病理的模型。为了解决这些差距，本项目的总体目标是使 发展与研究相结合对阿尔茨海默病脑血管受累特征的研究 一组新的非侵入性、基于核磁共振的脑血管健康测量方法。建立在 在我们机构的基础研究中，这项工作提出了创新的MRI技术来改善特征性 阿尔茨海默病患者脑血管病变，特别是血管硬化及其与脑血管血流动力学的关系。我们 提出了一套运动编码的磁共振成像技术，提供了自动调节流程的详细描述 宏观和微观血管系统中的动力学和血管硬度。在这个项目中，新的方法将 利用大量先前成像数据的深度学习进行技术开发，并通过光学成像进行验证， 并以健康的人类受试者为特征。然后我们将获得表征脑血管的关键数据 AD生物标记物研究的变化证实了受试者的总体目标是确定修饰效果 血管疾病对认知功能障碍的症状表达、AD生物标志物的积聚，以及 神经退行性变。我们的试验数据表明，AD患者的动脉僵硬过早增加， 减少脑血流的波动。完成后，这项研究将提供关于哪些具体的 心血管疾病的各个方面是调节AD相互作用的主要因素。这项研究的目标参与者有 广泛的现有AD生物标记物数据，并通过威斯康星州的研究进行纵向跟踪 阿尔茨海默病研究中心。这些方法论将被独特地定位为整合到大型 纵向队列研究调查AD的发病机制，评估可能的风险和保护因素。