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

COVID-19相关的血脑屏障和脑微结构损伤；

• 批准号: 10584896
• 负责人: Emilie T. Reas
• 金额: $ 80.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584896
• 关键词: 2019-nCoV; ACE2; Acceleration; Acute; Adult; Age; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Anti-Inflammatory Agents; Attention; Binding; Blood; Blood - brain barrier anatomy; Blood brain barrier dysfunction; Brain; Brain Injuries; COVID-19; COVID-19 impact; COVID-19 mortality; COVID-19 pandemic; COVID-19 patient; COVID-19 risk; COVID-19 severity; COVID-19 survivors; Central Nervous System; Cerebrovascular Disorders; Cognitive; Cognitive deficits; Complex; Confusion; Dementia; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Drops; Elderly; Endothelial Cells; Estrogens; Exhibits; Extravasation; Genetic; Genetic Risk; Gonadal Steroid Hormones; Hippocampus; Hyperactivity; Immune; Immune response; Impaired cognition; Individual; Infection; Infiltration; Inflammation; Inflammatory; Injury; Investigation; Long COVID; Magnetic Resonance Imaging; Measures; Medial; Mediating; Memory; Menopause; Methods; Mission; Modification; Nerve Degeneration; Neurobehavioral Manifestations; Neurobiology; Neurologic; Neurologic Effect; Neurologic Symptoms; Neurological outcome; Neurons; Outcome; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Permeability; Plasma; Predisposition; Public Health; Reporting; Research; Restriction Spectrum Imaging; Risk; Risk Assessment; Risk Estimate; Risk Factors; Role; SARS-CoV-2 infection; Sex Differences; Structure; Symptoms; Techniques; Testing; Testosterone; Time; United States National Institutes of Health; Vascular Diseases; Viral; Woman; age related; aged; aging population; apolipoprotein E-4; biomarker identification; blood-brain barrier permeabilization; brain abnormalities; brain dysfunction; brain health; brain tissue; cerebrovascular; cognitive function; cognitive recovery; cognitive testing; comorbidity; contrast enhanced; executive function; genetic risk factor; hazard; high risk population; hormone regulation; human old age (65+); long term consequences of COVID-19; men; mental state; multimodal neuroimaging; nerve injury; neuroimaging; neuroinflammation; neurologic sequelae of COVID-19; neuropathology; neurovascular; outcome prediction; personalized approach; post SARS-CoV-2 infection; pre-clinical; preservation; respiratory virus; response; severe COVID-19; sex; synergism; tau-1; tool

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.

项目摘要 Covid-19与可能在感染后很长时间持续存在的认知障碍有关。 COVID-19风险 因素与阿尔茨海默氏病（AD）重叠的因素，包括年龄较大，APOE4等位基因和血管 功能障碍，表明一种条件的病理可能加剧另一种状况的发病机理。血- 脑屏障（BBB）功能障碍可能是一种常见的致病机制，因为BBB崩溃已经是 在有AD风险的个体中确定并可能通过结合SARS- COV-2至脑血管内皮细胞或通过病毒介导的神经炎症。性也是危险因素 对于这两种疾病，妇女的AD风险增加以及急性和慢性Covid-19的风险增加 症状可能是由SARS-COV-2结合，炎症的性恐怖调节部分介导的 免疫活性或BBB功能障碍。潜在AD神经病理学与神经炎症或 脑血管功能障碍是由COVID-19在老龄化人口中触发的 神经退行性变化。然而，目的地可能在预先融合19的大流行。 现有的痴呆症公共卫生危机，很少有研究专门了解机械 这些条件之间的重叠或其协同作用的潜在灾难性公共卫生后果。 拟议的研究将评估老年人Covid-19的神经生物学序列，以及 他们通过性别，AD病理和AD遗传风险进行修改。限制光谱成像以测量大脑 将对成人进行微结构和动态对比增强MRI估计BBB渗透率 年龄50岁以上，以前的Covid-19感染（CV）和与疾病相关的认知障碍，以及 关于未感染的健康对照。认知测试将在神经影像学时进行，每年进行 AD多基因危害评分（PHS），雌激素和睾丸激素水平以及血浆P- TAU181将针对所有参与者进行测量，并将为女性计算寿命暴露。 项目将检验CV暴露更大的BBB分解，微结构损害等的假设 严重的认知障碍和下降比对照组（AIM 1）。预计AD风险（AIM 2）和性别（AIM 3） 通过更严重的疾病相关的脑损伤来改变Covid-19对脑和认知措施的影响， pHS或异常P-TAU181以及女性的BBB渗透性和认知能力下降。在性爱中 - 分层分析，睾丸激素和雌激素有望与脑损伤，BBB分解和 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 为了澄清Covid-19对老年人的认知症状的难以捉摸的神经生物学作用 神经退行性变化的风险升高。它将提高我们对当前投机的理解 COVID-19与AD发病机理之间的协同作用以及性别和荷尔蒙调节的复杂作用 在19与19与19位相关的神经系统序列中。