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

摘要 阿尔茨海默病（AD）是美国第六大死亡原因，其患病率持续上升， 上升. AD没有临床可用的治愈性治疗，并且来自测试新型 迄今为止，改善疾病的治疗方法令人失望。因此，越来越迫切需要 确定AD的早期标志物、导致痴呆的致病因素以及 阻止这一令人衰弱的状况所造成的全球危机。心血管疾病，以及脑血管疾病 疾病（CVD），与轻度认知障碍和AD痴呆都有很强的联系;然而， CVD是否调节AD的潜在病理生理学只是最近才开始受到关注。到 提供对AD关系的见解，非侵入性磁共振成像（MRI）正在被用于 AD风险富集人群的纵向研究。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中的关键血管假设。MRI方法 目前通常采用的诸如流体衰减和磁化率成像仅间接测量CVD， 不能提供关于在动物中已经指示的动态血管运动和血液动力学现象的信息 影响AD病理学的模型。为了弥补这些差距，本项目的总体目标是 通过开发和研究整合表征AD脑血管受累 一组新的非侵入性的，基于MRI的脑血管健康措施。基础上 在我们机构的基础研究，这项工作提出了创新的MRI技术，以改善表征 AD中CVD的发生率，特别是血管硬化及其与脑血管血流动力学的关系。我们 提出了一个运动编码MRI技术的集合，该技术提供了自动调节流的详细描述 在宏观和微观脉管系统中的动力学和脉管刚度。在这个项目中，新的方法将 在技术上开发利用从大量先前成像数据中进行深度学习，通过光学成像进行验证， 并在健康人受试者中表征。然后，我们将获得表征脑血管的关键数据 一项AD生物标志物研究的变化证实了受试者的总体目标是确定改变效应 血管疾病对认知功能障碍的症状表达、AD生物标志物积累和 神经变性我们的初步数据表明，AD受试者的动脉僵硬度过早增加， 减少脑血流的波动。完成后，这项研究将提供深入了解哪些具体 心血管疾病方面是调节AD相互作用的主要因素。本研究的目标参与者有 广泛的现有AD生物标志物数据，并正在通过威斯康星州内的研究进行纵向随访 阿尔茨海默病研究中心。这些方法将具有独特的地位，可纳入大型 研究AD机制并评估假定风险和保护因素的纵向队列研究。

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.