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

项目概要/摘要 相当大比例（>35%）的急性感染SARS-CoV-2的患者表现出神经系统疾病， 症状范围从严重头痛到脑病、中风、癫痫和急性神经病。 然而，一些患者在数周至数月内出现挥之不去的或紧急的神经精神症状 急性感染后。COVID长途运输者的神经精神负担是一个主要问题;然而， 这些病症的潜在病理生理学仍然难以捉摸。SARS-Cov-2感染导致 循环促炎细胞因子/趋化因子水平和中间单核细胞升高 (CD14+ CD 16+）亚群。这些促炎性单核细胞被运输到患有糖尿病的个体的大脑中， 其他慢性病毒感染（例如，HIV）已经成为神经炎症、血脑 血脑屏障（BBB）破坏，并可能解释COVID长途运输者持续的神经后遗症。我们提出 为了验证我们的假设，即COVID长途运输者将具有与靶向相关的BBB破坏机制， 循环促炎性细胞因子/趋化因子和运输至 个脑袋响应于感染的单核细胞浸润是CNS炎症的标志，并且在CNS炎症中持续发生。 慢性病因此，我们进一步假设中间单核细胞对血脑屏障完整性的破坏， 激活和渗出促进持续的神经炎症和改变的神经元活动，有助于 神经精神后遗症COVID-19长途运输者。为此，我们提出了横断面成像，以评估 BBB完整性，神经精神评估，以及100名COVID长途运输者和100名 从急性COVID中康复的个体（对照组）。首先，我们的目标是评估BBB的完整性， COVID长途运输者（与对照组相比）及其对神经精神疾病的影响。我们将评估BBB的完整性 使用一种新的非对比磁共振成像技术， 对比动脉自旋标记（WEPCAST），以确定BBB对小分子的渗透性。我们已经表明 这对轻度认知障碍（阿尔茨海默病的前兆）的BBB变化敏感， 目前这种技术正在用于其他神经感染性疾病。其次，我们的目标是评估 循环可溶性标志物、PBMC相关标志物和BBB对小分子的通透性， 共同促进向脑内渗出。我们的目标是与活化的 PBMC穿过BBB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 新型冠状病毒长途运输车。经过3年的资助，R 01将促进我们对BBB完整性的理解， 相关的PBMC迁移到COVID长途运输者的大脑中，这可能有助于神经炎症， 相关的神经精神负担。研究结果将为治疗方法的下一步发展提供信息 以最大限度地减少PBMC对COVID长途运输者神经炎症的贡献。

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.