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: 10370542
• 负责人: Kevin Michael Johnson
• 金额: $ 60.82万
• 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/10370542
• 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; Amyloid beta-Protein; Animal Model; Animals; 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; FarGo; Foundations; Frequencies; Functional disorder; Generations; Goals; Health; Hemodynamic Phenomena; Heterogeneity; Homeostasis; Human; Image; Imaging Techniques; Imaging technology; 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; Time; Tissues; Translating; United States; Vascular Diseases; White Matter Hyperintensity; Wisconsin; Work; alternative treatment; arterial spin labeling; arterial stiffness; attenuation; base; 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; imaging modality; improved; individual patient; innovation; insight; mild cognitive impairment; nervous system disorder; neuroimaging; neuroinflammation; neurovascular; non-invasive imaging; novel; novel strategies; optical imaging; premature; progression marker; protective factors; recruit; 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.

抽象的 阿尔茨海默病 (AD) 是美国第六大死因，其患病率持续上升 上升。 AD 尚无临床可用的治疗方法，并且来自积极的临床试验测试新颖的结果 迄今为止，疾病缓解疗法令人失望。因此，越来越紧迫 确定 AD 的早期标志物、导致痴呆的致病因素以及替代治疗方法 制止这种令人衰弱的状况所造成的全球危机。不仅有心血管疾病，还有脑血管疾病 疾病 (CVD)，与轻度认知障碍和 AD 痴呆有密切联系；然而，问题 CVD 是否调节 AD 的潜在病理生理学直到最近才开始受到关注。到 为了深入了解 AD 关系，非侵入性磁共振成像 (MRI) 被用于 对 AD 风险较高人群的纵向研究。目前的项目远远超出了目前可用的 MRI 缺乏敏感性和特异性的技术来解决 AD 中的关键血管假说。磁共振成像方法 目前常用的方法，例如液体衰减和磁化率成像只能间接测量 CVD 和 无法了解动物中已显示的动态血管运动和血流动力学现象 影响 AD 病理学的模型。为了弥补这些差距，该项目的总体目标是使 通过开发和研究整合描述 AD 脑血管受累的特征 一系列新型非侵入性、基于 MRI 的脑血管健康测量方法。建立在 我们机构的基础研究，这项工作提出了创新的 MRI 技术来改善表征 AD 中 CVD 的影响，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 MRI 技术，可提供自动调节流程的详细描述 宏观和微观脉管系统的动力学和血管硬度。在这个项目中，新颖的方法将 利用从大量先前成像数据中进行的深度学习进行技术开发，并通过光学成像进行验证， 并在健康人类受试者中进行表征。然后我们将获得表征脑血管的关键数据 AD 生物标志物研究中的变化证实了受试者的总体目标是确定改变效果 血管疾病对认知障碍症状表达、AD 生物标志物积累的影响 神经变性。我们的试验数据表明，患有 AD 的受试者的动脉僵硬度过早增加，并且 脑血流量波动减少。完成后，本研究将深入了解哪些具体 CVD 的各个方面是调节 AD 相互作用的主要因素。本研究的目标参与者 现有广泛的 AD 生物标志物数据，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。这些方法将具有独特的定位，可以纳入大型研究中。 纵向队列研究调查 AD 机制并评估假定的风险和保护因素。