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

摘要：2019年约三分之一的非住院冠状病毒病（COVID-19）患者 呈报严重急性呼吸系统综合症冠状病毒急性期康复后出现的慢性症状 2（SARS-CoV-2）感染。这种急性后COVID-19的一些最持久和最常见的投诉 综合征（PACS）本质上是认知性的，主观上被描述为“脑雾”， 执行功能、工作记忆、注意力和处理速度的缺陷。这些慢性疾病的机制 认知后遗症目前尚不清楚。迄今为止，大多数研究都集中在直接SARS-CoV-2上， 然而，虽然直接的病毒性脑感染在严重和致命的急性病例中是合理的， COVID-19，研究慢性认知功能障碍的间接机制是有意义的， 无症状的疾病病例。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（ACE 2）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和降解肠屏障，可能增加 两者对有害物质的渗透性。这些物质被假设是由致病性 考虑到COVID-19对胃肠道系统的深远影响，肠道中的微生物群可能会蓬勃发展 通过肠道生态失调因此，COVID-19可能会造成神经毒性和神经炎症 物质很容易从肠腔增殖，并遇到一个削弱的神经血管单位， 并随后产生认知缺陷我们打算研究SARS-CoV-2的这种影响， PACS患者在3次研究访视（基线、4个月和8个月）过程中的纵向数据。的 脑血管功能和肠屏障损害及其对认知功能的影响 将对80名从非住院急性 2019冠状病毒病阶段，但报告持续性认知症状（PACS+）。这些患者将与 80名既往无此类症状的类似COVID-19患者（PACS-）。40名健康对照参与者也将 招募来确定COVID-19病史对一般神经血管、肠道和认知的影响。 脑血管功能将通过创新的功能磁共振成像进行量化， 脑血管对CO2气体呼吸的反应性（CVR），而肠屏障将通过 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 小带蛋白肠道生态失调将通过乳果糖呼吸测试建立，随后产生的和 全身释放的脂多糖（LPS）、肽聚糖（PGN）和促炎细胞因子也将 要量化。在肠道生态失调的情况下，神经血管单位和肠屏障的损伤是 预期与PACS+患者的更大认知缺陷相关。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解决PACS认知效应的资源。

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.