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

项目总结 新冠肺炎与认知障碍有关，这种障碍可能会在感染后很长一段时间内持续存在。新冠肺炎风险 与阿尔茨海默病(AD)的因素有重叠，包括年龄较大、APOE4等位基因和血管 功能障碍，表明一种情况下的病理可能会加剧另一种情况的发病。血- 脑屏障(BBB)功能障碍可能是一种常见的致病机制，因为BBB的破坏 在AD的高危人群中被发现，并可能通过与SARS的结合而促进新冠肺炎相关的神经损伤 CoV-2对脑血管内皮细胞或通过病毒介导的神经炎症。性行为也是一个危险因素。 对于这两种疾病，女性患AD的风险增加，急性和慢性新冠肺炎的性别特定风险增加 症状，这可能部分由性激素调节SARS-CoV-2结合，炎症， 免疫活动，或BBB功能障碍。潜在阿尔茨海默病神经病理学与神经炎症或 新冠肺炎在老龄化人口中引发脑血管功能障碍或引发一场完美风暴 神经退行性改变。然而，尽管新冠肺炎大流行有可能在疫情前收敛 存在痴呆症的公共健康危机，很少有研究致力于了解其发病机制 这些情况之间的重叠或它们的协同作用可能造成灾难性的公共卫生后果。 拟议的调查将评估新冠肺炎对老年人的神经生物学后遗症，以及 它们因性别、AD病理和AD遗传风险而改变。限制谱成像用于脑测量 将在成人身上进行显微结构和动态增强MRI以评估血脑屏障通透性 50岁或以上，有新冠肺炎感染史和与疾病相关的认知障碍，以及 在未感染的健康对照上。认知测试将在神经成像时进行，UP每年进行一次 延长四年。AD多基因危险评分(PHS)、雌激素和睾酮水平以及血浆p- Tau181，将为所有参与者测量，并将计算女性的终生雌激素暴露。这 项目将测试假设，即CV表现出更大的BBB分解、微结构损伤等 比对照组(目标1)更严重的认知功能障碍和下降。预测了AD风险(目标2)和性行为(目标3) 为了修正新冠肺炎对大脑和认知措施的影响，使其具有更严重的疾病相关脑损伤， 血脑屏障通透性和认知功能下降，适用于高PHS或p-tau181异常的人群和女性。在性爱方面- 分层分析，睾丸激素和雌激素预计与脑损伤、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磁共振成像技术 为了阐明新冠肺炎对老年人认知症状的潜在神经生物学影响 神经退行性改变的风险增加。它将促进我们对当前投机的理解 新冠肺炎与AD发病机制的协同作用以及性别和激素调节的复杂作用 新冠肺炎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.