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

摘要：2019年非住院冠状病毒病(新冠肺炎)患者约占三分之一 报告严重急性呼吸综合征冠状病毒急性期康复后的慢性症状 SARS-CoV-2感染2例。后急性新冠肺炎的一些最持久和最常见的抱怨 综合征(PACS)本质上是认知的，主观上被描述为“脑雾”，客观上也被测量 如执行功能、工作记忆、注意力、处理速度等方面的缺陷。这些慢性疾病的发病机制 认知后遗症目前还不清楚。到目前为止，大多数研究都集中在直接的SARS-CoV-2上 脑部感染；然而，尽管在严重和致命的急性病例中，直接病毒性脑部感染是可信的 新冠肺炎，有兴趣研究轻度和慢性认知功能障碍的间接机制 无症状疾病病例。SARS-CoV-2通过以下途径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，也通过产生高水平的系统性 细胞因子，损害大脑的神经血管单位和降解肠道屏障，潜在地增加 两者对有害物质的渗透性。这种物质被认为是由致病原产生的 鉴于新冠肺炎对胃肠道系统的深刻影响，肠道中的微生物区系可能会蓬勃发展 通过肠道生物失调。因此，新冠肺炎可能会造成神经毒性和神经炎性 物质很容易从肠腔中扩散出来，与削弱的神经血管单位相遇，从而获得进入肠腔的途径。 对大脑造成损害，进而产生认知缺陷。我们打算研究SARS-CoV-2的这些影响 对PACS患者进行3次纵向研究访问(基线、4个月和8个月)。这个 脑血管功能和肠道屏障损害及其对认知功能的影响 症状学，将对80名从非住院急性呼吸综合征康复的前新冠肺炎患者进行检查 新冠肺炎的各个阶段，但报告持续性认知症状(PAC)。这些患者将与 80例既往无此类症状的新冠肺炎患者(Pacs-)。40名健康对照参与者也将 被招募来建立新冠肺炎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 血浆中肠壁生物标志物如脂肪酸结合蛋白2(FABP-2)和 佐灵灵。肠道生物失调将通过乳果糖呼气测试以及随后产生的和 系统释放的脂多糖(LPS)、肽聚糖(PGN)和促炎细胞因子也将 被量化。肠道生物失调背景下的神经血管单位和肠道屏障的损害是 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 通过血管功能障碍和肠道健康的现有治疗方法解决PACS认知影响的资源。

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.