COVID-19-related blood-brain barrier and microstructural brain injury; Sex differences and synergy with Alzheimer's disease risk

项目摘要 COVID-19与感染后可能长期存在的认知障碍有关。COVID-19风险 与阿尔茨海默病（AD）的因素重叠，包括年龄较大，APOE 4等位基因和血管 功能障碍，表明一种疾病的病理可能会加剧另一种疾病的发病机制。血- 脑屏障（BBB）功能障碍可作为常见的致病机制，因为BBB破坏已被 在有AD风险的个体中发现，并可能通过结合SARS促进COVID-19相关的神经损伤- CoV-2通过病毒介导的神经炎症作用于脑血管内皮细胞。性也是一个危险因素 对于这两种疾病，女性AD风险增加，急性和慢性COVID-19的性别特异性风险增加 症状，这可能部分由SARS-CoV-2结合的性激素调节，炎症， 免疫活性或BBB功能障碍。潜伏性AD神经病理学与神经炎症或 在老龄化人口中，COVID-19引发的脑血管功能障碍可能会引发一场完美的风暴， 神经退行性改变然而，尽管2019冠状病毒病大流行有可能与前疫情趋同， 尽管存在痴呆症的公共卫生危机，但很少有研究致力于了解痴呆症的机制。 这些疾病之间的重叠或其协同作用可能造成灾难性的公共卫生后果。 拟议的研究将评估老年人沿着的COVID-19神经生物学后遗症， 它们通过性别、AD病理学和AD遗传风险进行修饰。限制光谱成像测量大脑 将对成人进行显微结构和动态对比增强MRI，以估计BBB渗透性 50岁或以上，既往有COVID-19感染（CV）和疾病相关认知障碍，以及 未受感染的健康对照组。认知测试将在神经成像时进行，每年进行一次， 延长四年AD多基因危害评分（PHS）、雌激素和睾酮水平以及血浆p- 将测量所有参与者的tau 181，并计算女性的终生雌激素暴露量。这 该项目将测试CV表现出更大的BBB击穿，微结构损伤等假设 严重的认知障碍和下降比对照组（目标1）。预测AD风险（目标2）和性别（目标3） 改变COVID-19对大脑和认知指标的影响，使疾病相关的脑损伤更严重， 对于PHS高或p-tau 181异常的人和女性来说，BBB渗透性和认知能力下降。在性方面- 分层分析显示，睾酮和雌激素与脑损伤、血脑屏障破坏和 认知缺陷（目标3）。这项研究将开创最先进的扩散和渗透性MRI技术 阐明COVID-19在老年人认知症状中的神经生物学效应， 神经退行性病变的风险增加它将促进我们对目前投机的理解 COVID-19和AD发病机制之间的协同作用以及性别和激素调节的复杂作用 与COVID-19相关的神经系统后遗症。

PROJECT SUMMARY COVID-19 is associated with cognitive impairment that may persist long after infection. COVID-19 risk factors overlap with those for Alzheimer’s disease (AD), including older age, the APOE4 allele, and vascular dysfunction, suggesting that pathology from one condition may exacerbate pathogenesis of the other. Blood- brain barrier (BBB) dysfunction may serve as a common pathogenic mechanism, as BBB breakdown has been identified in individuals at risk for AD and may facilitate COVID-19-related neural injury via binding of SARS- CoV-2 to cerebrovascular endothelial cells or via virally-mediated neuroinflammation. Sex is also a risk factor for both diseases, with increased AD risk for women and sex-specific risk for acute and chronic COVID-19 symptoms, which may be partially mediated by sex hormone regulation of SARS-CoV-2 binding, inflammation, immune activity, or BBB dysfunction. The intersection of latent AD neuropathology with neuroinflammation or cerebrovascular dysfunction triggered by COVID-19 among the aging population may ignite a perfect storm of neurodegenerative changes. Yet despite potential for convergence of the COVID-19 pandemic upon a pre- existing public health crisis of dementia, little research has been devoted to understanding the mechanistic overlap between these conditions or the potentially catastrophic public health consequences of their synergy. The proposed investigation will assess the neurobiological sequalae of COVID-19 in older adults along with their modification by sex, AD pathology, and AD genetic risk. Restriction spectrum imaging to measure brain microstructure and dynamic contrast-enhanced MRI to estimate BBB permeability will be conducted on adults aged 50 years or older with previous COVID-19 infection (CV) and disease-related cognitive impairment, and on uninfected healthy controls. Cognitive testing will be conducted at time of neuroimaging and annually for up to four additional years. AD polygenic hazard scores (PHS), estrogen and testosterone levels, and plasma p- tau181, will be measured for all participants, and lifetime estrogen exposure will be calculated for women. This project will test the hypotheses that CV exhibit greater BBB breakdown, microstructural damage, and more severe cognitive impairment and decline than controls (Aim 1). AD risk (Aim 2) and sex (Aim 3) are predicted to modify effects of COVID-19 on brain and cognitive measures, with more severe disease-related brain injury, BBB permeability, and cognitive decline for those with high PHS or abnormal p-tau181 and for women. In sex- stratified analyses, testosterone and estrogen are expected to correlate with brain injury, BBB breakdown, and cognitive deficits (Aim 3). This study will pioneer the most advanced diffusion and permeability MRI techniques to clarify the yet elusive neurobiological effects of COVID-19 underlying its cognitive symptoms in older adults at elevated risk for neurodegenerative changes. It will advance our understanding of the currently speculative synergy between COVID-19 and AD pathogenesis as well as the complex role of sex and hormonal regulation in COVID-19-related neurological sequalae.