Cognitive sequelae of cerebrovascular and gut dysfunction in post-acute COVID-19 syndrome.

急性后 COVID-19 综合征脑血管和肠道功能障碍的认知后遗症。

• 批准号: 10627220
• 负责人: Andrei A Vakhtin
• 金额: $ 73.73万
• 依托单位: LOVELACE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627220
• 关键词: 2019-nCoV; ACE2; Acute; Adult; Affect; Area; Attention; Autopsy; Binding; Biological Markers; Brain; Breath Tests; COVID-19; COVID-19 impact; COVID-19 mortality; COVID-19 pandemic effects; COVID-19 patient; Carbon Dioxide; Cerebrovascular system; Chronic; Clinical; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Color; Data; Disease; Encephalitis; Endothelium; Endotoxins; Etiology; Extramural Activities; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Gases; Gastroenterology; Glial Fibrillary Acidic Protein; Grant; Health; Impaired cognition; Impairment; Individual; Infection; Infiltration; Inflammatory; Internal Medicine; Intervention; Intestines; Lactulose; Left; Lipopolysaccharides; Long COVID; Measures; Modeling; Nature; Neurobehavioral Manifestations; Neuropsychology; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Peptidoglycan; Permeability; Phase; Physiological; Plasma; Proliferating; Recording of previous events; Recovery; Reporting; Research; Research Personnel; Respiration; Respiratory Signs and Symptoms; Role; SARS-CoV-2 infection; Short-Term Memory; Smooth Muscle Myocytes; Solid; Statistical Data Interpretation; Structure; Symptoms; System; Text; Time; Toxin; Vascular Diseases; Viral; Virus; Visit; Work; acronyms; brain fog; cerebrovascular; cerebrovascular imaging; cytokine; cytokine release syndrome; dysbiosis; executive function; experience; fatty acid-binding proteins; gastrointestinal system; gut dysbiosis; gut health; gut microbiota; gut-brain axis; innovation; inter-institutional; interest; intestinal barrier; intestinal epithelium; microbiota; multidisciplinary; multimodal neuroimaging; multimodality; neuroimaging; neuroinflammation; neuropathology; neurotoxic; neurovascular; neurovascular unit; novel; persistent symptom; precision medicine; processing speed; public health emergency; receptor; recruit; secondary analysis; zonulin

ABSTRACT: Approximately one third of non-hospitalized coronavirus disease of 2019 (COVID-19) patients report chronic symptoms after recovering from the acute stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some of the most persistent and common complaints of this post-acute COVID-19 syndrome (PACS) are cognitive in nature, described subjectively as “brain fog” and also objectively measured as deficits in executive function, working memory, attention, processing speed. The mechanisms of these chronic cognitive sequelae are currently not understood. Most studies to-date have focused on direct SARS-CoV-2 infection of the brain; however, while direct viral brain infection is plausible in acute cases of severe and fatal COVID-19, it is of interest to examine indirect mechanisms of chronic cognitive dysfunction that follow mild and asymptomatic disease cases. SARS-CoV-2 inflicts damage to cerebral blood vessels and the intestinal wall by binding to angiotensin-converting enzyme 2 (ACE2) receptors and also by producing high levels of systemic cytokines, compromising the brain’s neurovascular unit and degrading the intestinal barrier, potentially increasing the permeability of both to harmful substances. Such substances are hypothesized to be produced by pathogenic microbiota in the gut that, given the profound effects COVID-19 has on the gastrointestinal system, may flourish via intestinal dysbiosis. COVID-19 may therefore create a scenario in which neurotoxic and neuroinflammatory substances readily proliferate from the gut lumen and encounter a weakened neurovascular unit, gaining access to the brain and subsequently producing cognitive deficits. We intend to examine such effects of SARS-CoV-2 in PACS patients longitudinally over the course of 3 study visits (baseline, 4 months, and 8 months). The impairments of cerebrovascular function and intestinal barrier, as well as their effects on cognitive symptomology, will be examined in 80 former COVID-19 patients who recovered from non-hospitalized acute phases of COVID-19, yet report persistent cognitive symptoms (PACS+). These patients will be compared with 80 former similar COVID-19 patients without such symptoms (PACS-). Forty healthy control participants will also be recruited to establish general neurovascular, intestinal, and cognitive effects of COVID-19 history. Cerebrovascular function will be quantified via innovative functional magnetic resonance imaging of cerebrovascular reactivity (CVR) to respiration of CO2 gas, while the intestinal barrier will be assessed via concentrations of intestinal wall biomarkers in blood plasma such as fatty acid-binding protein 2 (FABP-2) and zonulin. Gut dysbiosis will be established via lactulose breath testing, and levels of subsequently produced and systemically released lipopolysaccharide (LPS), peptidoglycan (PGN) and pro-inflammatory cytokines will also be quantified. Impairments in the neurovascular unit and intestinal barrier in the context of gut dysbiosis are expected to be associated with greater cognitive deficits in PACS+ patients. This work may reveal immediate recourses for resolving PACS cognitive effects via existing treatments for vascular dysfunction and gut health.

摘要：2019年非住院性冠状病毒病的大约三分之一（COVID-19）患者 从严重急性呼吸综合征冠状病毒的急性阶段恢复后报告慢性症状 2（SARS-COV-2）感染。急性后共vid-19的一些最持久，最常见的抱怨 综合征（PACS）本质上是认知的，主观被描述为“脑雾”，也被客观地测量 如执行功能，工作记忆，注意力，处理速度所定义。这些慢性的机制 认知后遗症目前尚不清楚。大多数迄今为止的研究都集中在直接的SARS-COV-2上 大脑感染；但是，虽然在严重和致命的急性病例中，直接病毒脑感染是合理的 COVID-19，检查慢性认知功能障碍的间接机制遵循轻度和 无症状疾病病例。 SARS-COV-2通过 与血管紧张素转换酶2（ACE2）受体结合，也通过产生高水平的全身性 细胞因子，损害大脑的神经血管单元并降解肠屏障，可能会增加 两者对有害物质的渗透性。假设这种物质是通过致病性产生的 肠道中的微生物群，鉴于Covid-19对胃肠道系统产生深远影响，可能会氟 通过肠道营养不良。因此，COVID-19可能会产生一种神经毒性和神经炎症性的情况 物质很容易从肠道内腔增殖，并遇到弱化的神经血管单元，获得通道 到大脑，随后产生认知缺陷。我们打算检查SARS-COV-2的这种影响 在PACS患者中，在3次学习访问（基线，4个月和8个月）的过程中纵向。 脑血管功能和肠屏障的损害及其对认知的影响 症状学，将在80例前Covid-19患者中检查，这些患者从非住院急性中恢复过来 Covid-19的阶段，但报告了持续的认知症状（PACS+）。这些患者将与 80前类似的Covid-19患者没有这种症状（PACS-）。 40位健康控制参与者也将 被招募以建立Covid-19历史的一般神经血管，肠道和认知作用。 脑血管功能将通过创新的功能磁共振成像来量化 脑血管反应性（CVR）对CO2气体的呼吸，而肠壁将通过 血浆中肠壁生物标志物的浓度，例如脂肪酸结合蛋白2（FABP-2）和 Zonulin。将通过乳糖呼吸测试以及随后产生的水平以及 系统释放的脂多糖（LPS），辣椒粉（PGN）和促炎性细胞因子也将 被量化。在肠道营养不良的背景下，神经血管单元和肠屏障的障碍是 预计在PACS+患者中定义了更大的认知能力。这项工作可能立即显示 通过现有的血管功能障碍和肠道健康解决PACS认知效应的回复。