Blood brain barrier integrity and immune dynamics contributing to neuropsychiatric sequela in COVID long-haulers

项目摘要/摘要 相当一部分(35%)急性感染SARS-CoV-2的患者表现为神经系统疾病 症状从严重的头痛到脑病、中风、癫痫和急性神经病。 然而，一些患者会在几周到几个月内出现挥之不去的或紧急的神经精神症状。 在急性感染之后。COVID长途运输者的神经精神负担是一个主要问题；然而 这些疾病的潜在病理生理学仍然难以捉摸。SARS-CoV-2感染导致死亡人数增加 循环促炎细胞因子/趋化因子水平与中间单核细胞的升高 血液中(CD14+CD16+)亚群。这些促炎性单核细胞进入脑内的情况 其他慢性病毒感染(如人类免疫缺陷病毒(HIV)已成为神经炎、血脑的推定因素 屏障(BBB)中断，并可能解释COVID长途运输者正在进行的神经后遗症。我们建议 为了验证我们的假设，即COVID长途运输者的血脑屏障中断将与目标相关， 循环中的促炎细胞因子/趋化因子和转运到血管内的中间单核细胞的升高 大脑。单核细胞对感染的反应是中枢神经系统炎症的一个标志，在 慢性疾病。因此，我们进一步假设中间单核细胞对血脑屏障完整性的破坏 激活和排尿促进持续性神经炎症和神经元活动改变，有助于 神经精神后遗症新冠肺炎长途运输者。为此，我们提出了横断面成像来评估 100名COVID长途运输者和100名COVID长途运输者的血脑屏障完整性、神经精神评估和免疫表型 急性COVID恢复者(对照组)。首先，我们的目标是评估BBB在 COVID长途运输者(与对照组)及其对神经精神疾病的贡献。我们将评估BBB的完整性 使用一种新的非对比度磁共振成像技术，这种技术使用水相萃取- 对比动脉自旋标记(WEPCAST)，以确定血脑屏障对小分子的通透性。我们已经展示了 这对轻度认知障碍的BBB变化很敏感，这是阿尔茨海默病的先兆，而且 目前在其他神经感染性疾病中使用这项技术。第二，我们的目标是评估 循环中的可溶性标志物、PBMC相关标志物和血脑屏障对小分子的通透性 总而言之，这可能会促进大脑的渗入。我们针对与激活的轮回有关的因素 外周血单核细胞穿过血脑屏障进入大脑，在那里它们可能导致神经元损伤和神经精神负担 在COVID的长途运输车上。经过3年的资助，这款R01将增进我们对BBB完整性和 相关的PBMC迁移到COVID长途运输者的大脑中，这可能导致神经炎症和 相关的神经精神负担。这些发现将为开发治疗方法的下一步提供信息 以最大限度地减少外周血单核细胞对COVID长途运输者神经炎症的影响。

PROJECT SUMMARY/ABSTRACT A substantial (>35%) proportion of patients acutely infected with SARS-CoV-2 demonstrate neurological symptoms ranging from serious headaches to encephalopathy, stroke, seizure, and acute neuropathies. However, some patients experience lingering or emergent neuropsychiatric symptoms within weeks to months following acute infection. The neuropsychiatric burden among COVID long-haulers is a major issue; and yet the underlying pathophysiology of these conditions remains elusive. SARS-Cov-2 infection results in increased levels of circulating proinflammatory cytokines/chemokines and elevation of intermediate monocyte (CD14+CD16+) subsets in blood. Trafficking of these proinflammatory monocytes into the brain of individuals with other chronic viral infections (eg. HIV) has emerged a putative contributor to neuroinflammation, blood brain barrier (BBB) disruption and may explain the ongoing neurological sequalae in COVID long-haulers. We propose to test our hypothesis that COVID long-haulers will have BBB disruption mechanistically linked to targeted, circulating proinflammatory cytokines/chemokines and elevation of intermediate monocytes that traffic to the brain. Monocyte infiltration in response to infection is a hallmark of CNS inflammation and occurs consistently in chronic conditions. Thus, we further hypothesize that disruption in BBB integrity by intermediate monocyte activation and diapedesis promotes persistent neuroinflammation and altered neuronal activity, contributing to neuropsychiatric sequela COVID-19 long-haulers. To this end, we propose cross-sectional imaging to assess BBB integrity, with neuropsychiatric assessments, and immunophenotyping in 100 COVID long-haulers and 100 individuals who have recovered from acute COVID (control group). First, we aim to assess BBB integrity in COVID long-haulers (vs. control) and its contribution to neuropsychiatric conditions. We will assess BBB integrity using a novel, non-contrast magnetic resonance imaging technique that uses water-extraction-with-phase- contrast-arterial-spin-tagging (WEPCAST), to determine BBB permeability to small molecules. We have shown this to be sensitive to BBB change in mild cognitive impairment, a precursor to Alzheimer’s disease, and are currently using this technique in other neuro-infectious diseases. Second, we aim to assess the link between circulating soluble markers, PBMC-associated markers, and BBB permeability to small molecules, which collectively may promote diapedesis into brain. We target factors implicated in transmigration of activated PBMCs across the BBB into brain, where they may contribute to neuronal damage and neuropsychiatric burden in COVID long-haulers. After 3 years of funding, this R01 will advance our understanding of BBB integrity and related PBMC migration into the brains of COVID long-haulers, which may contribute to neuroinflammation and related neuropsychiatric burden. Findings will inform next steps in the development of therapeutic approaches to minimize PBMC contribution to neuroinflammation in COVID long-haulers.