Cerebrovascular neuroimaging markers and abnormal brain aging

项目摘要 人们越来越认识到脑血管功能障碍在阿尔茨海默病中的重要作用 (AD)发病机制和认知能力下降，占所有痴呆症的70%。脑小血管病 (SVD)通常发生在阿尔茨海默病（AD）患者中（高达80%），但目前SVD风险的标志物 进展很差。脑血管反应性（CVR）是血管健康的神经影像学标志物， 指示脑血管响应神经元需求或血管活性刺激的能力，例如 吸入二氧化碳CVR有望作为SVD和认知障碍的标志物，但一些研究未能发现 CVR和异常脑老化标志物之间的关联。越来越多的证据表明， 脑血管对刺激做出最大反应所需的时间，或CVRDELAY，可能是一种更敏感的 脑血管健康优于CVR。此外，由于技术和生理因素，CVR通常仅 在灰质中定量，因此白色物质CVR和大脑健康之间的联系并不好 表征了与传统的CVR处理不同，传统的CVR处理假设对CO2的反应时间一致 整个脑实质，我们建议使用更新颖的时间延迟处理来量化CVR， 高碳酸血症常氧激发血氧水平依赖性功能磁共振成像 （BOLD-fMRI）数据。本提案的目的是更好地理解时延处理的CVR指标 与SVD病理学更快的纵向增加和更快的认知能力下降相关。特别是， 我们将评估（1）脑白色物质中CVR受损和CVRDELAY升高是否与更快的增加有关 在白色高信号（WMH）和扩大的血管周围空间（ePVS）负荷，和（2）如果受损 灰质脑叶感兴趣区域的CVR和CVRDELAY升高与更快的纵向认知相关。 特定认知领域的衰退。为了实现F31应用程序的研究目标，我们将利用 来自范德比尔特记忆与阿尔茨海默氏症中心、范德比尔特记忆与衰老项目、 范德比尔特大学成像科学研究所、范德比尔特高级计算研究中心和 教育和范德比尔特大脑研究所。候选人哈德逊罗布将执行提议的 在跨学科导师团队的支持下进行研究，包括神经生物学专家， 阿尔茨海默氏病和小血管疾病，老年神经心理学，神经科学和脑MRI。的 并行培训计划将为候选人提供必要的知识和技能，以完成 提出了研究目标，并发展成为一个成功的神经科学家在神经生物学工作， SVD、AD和认知障碍的交叉点。这项研究的结果将提供关键的洞察力， 血管功能的一种相对新颖的生物标志物与SVD和认知障碍之间的关联。

PROJECT SUMMARY It is increasingly recognized that cerebrovascular dysfunction plays an important role in Alzheimer’s disease (AD) pathogenesis and cognitive decline, contributing to 70% of all dementias. Cerebral small vessel disease (SVD) often occurs (up to 80%) in those with Alzheimer’s disease (AD), but the current markers of SVD risk and progression are poor. Cerebrovascular reactivity (CVR) is a neuroimaging marker of vascular health which indicates of the ability of the brain vessels to respond to neuronal demand or a vasoactive stimulus, such as inhaled CO2. CVR shows promise as a marker of SVD and cognitive impairment, but some studies fail to see an association between CVR and markers of abnormal brain aging. Increasing evidence suggests that the time it takes for brain vessels to maximally respond to a stimulus, or CVRDELAY, may be a more sensitive of cerebrovascular health than CVR. Further, due to technical and physiological factors, CVR is often only quantified in the grey matter, and thus associations between white matter CVR and brain health are not well characterized. Rather than traditional CVR processing which assumes uniformly timed reactivity to CO2 across the entire brain parenchyma, we propose to use more novel time-delay processing to quantify CVR from hypercapnic normoxic challenge blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI) data. The purpose of this proposal is to better understand if time-delay processed CVR metrics are associated with a faster longitudinal increase in SVD pathology and faster cognitive decline. In particular, we will assess (1) if impaired CVR and elevated CVRDELAY in the cerebral white matter relate a faster increase in white matter hyperintensities (WMHs) and enlarged perivascular spaces (ePVS) burden, and (2) if impaired CVR and elevated CVRDELAY in grey matter lobar regions of interest are related to faster longitudinal cognitive decline in specific cognitive domains. To fulfill the research aims of this F31 application, we will leverage exceptional resources from the Vanderbilt Memory & Alzheimer’s Center, Vanderbilt Memory & Aging Project, Vanderbilt University Institute of Imaging Science, Vanderbilt Advanced Computing Center for Research and Education, and the Vanderbilt Brain Institute. The candidate, Hudson Robb, will carry out the proposed research with the support of an interdisciplinary mentorship team, including experts in the neurobiology of Alzheimer’s disease and small vessel disease, geriatric neuropsychology, neuroscience, and brain MRI. The parallel training plan will provide the candidate with the necessary knowledge and skillset to complete the proposed research aims and develop into a successful neuroscientist working at the neurobiological intersection of SVD, AD, and cognitive impairment. Results from this research will offer crucial insight into associations between a relatively novel biomarker of vascular function and SVD and cognitive impairment.