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：约三分之一的 2019 年非住院冠状病毒病 (COVID-19) 患者 报告从严重急性呼吸综合征冠状病毒急性期恢复后出现慢性症状 2 (SARS-CoV-2) 感染的一些最持久和常见的症状。 综合症（PACS）本质上是认知性的，主观描述为“脑雾”，也可以客观测量 如执行功能、工作记忆、注意力、处理速度等这些慢性机制的缺陷。 迄今为止，大多数研究都集中于直接 SARS-CoV-2 的认知后遗症。 脑部感染；然而，在严重和致命的急性病例中，直接病毒性脑部感染是可能的。 COVID-19，检查轻度和慢性认知功能障碍后的慢性认知功能障碍的间接机制是很有意义的。 无症状病例 SARS-CoV-2 通过以下方式对脑血管和肠壁造成损害。 与血管紧张素转换酶 2 (ACE2) 受体结合，并产生高水平的全身性 细胞因子，损害大脑的神经血管单位并降解肠道屏障，可能会增加 两者对有害物质的渗透性，这些物质被捕获并由病原体产生。 鉴于 COVID-19 对胃肠系统的深远影响，肠道中的微生物群可能会蓬勃发展 因此，COVID-19 可能会通过肠道菌群失调造成神经毒性和神经炎症。 物质很容易从肠腔增殖并遇到削弱的神经血管单元，从而进入 我们打算研究 SARS-CoV-2 的这种影响。 在 3 次研究访视（基线、4 个月和 8 个月）期间对 PACS 患者进行纵向研究。 脑血管功能和肠道屏障的损害及其对认知的影响 将对 80 名从非住院急性发作中康复的前 COVID-19 患者进行症状学检查 这些患者将与处于 COVID-19 阶段但报告持续认知症状 (PACS+) 的患者进行比较。 80 名以前没有此类症状的类似 COVID-19 患者 (PACS-) 也将有 40 名健康对照参与者。 被招募来确定 COVID-19 病史的一般神经血管、肠道和认知影响。 脑血管功能将通过创新的功能性磁共振成像进行量化 脑血管对二氧化碳气体呼吸的反应性（CVR），而肠道屏障将通过以下方式评估 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 肠道菌群失调将通过乳果糖呼气测试以及随后产生和的水平来确定。 全身释放的脂多糖（LPS）、肽聚糖（PGN）和促炎细胞因子也会 肠道菌群失调情况下神经血管单位和肠道屏障的损伤被量化。 预计与 PACS+ 患者更大的认知缺陷有关，这项工作可能会立即揭示。 通过现有的血管功能障碍和肠道健康治疗方法来解决 PACS 认知影响的资源。