Cerebrospinal Fluid in PASC: A Window into the COVID Mind

摘要 尽管严重急性呼吸综合征冠状病毒2(SARS-COV-2)被认为是一种呼吸道 病原体，无数的神经并发症，包括精神错乱，中风和神经肌肉疾病 在急性新冠肺炎期间。此外，注意力不集中、头痛、感觉不良等疾病 在感染后，精神障碍、抑郁甚至精神错乱可能会持续几个月，作为 一系列症状现在称为新冠肺炎急性后遗症(PASC)。病理生理学 神经系统PASC(NS-PASC)的机制尚不清楚，尽管迄今有证据表明 涉及免疫功能障碍，包括非特异性神经炎和抗神经自身免疫 失调症1.由于数百万人受到影响，神经系统并发症构成公共健康 康复和恢复方面的挑战以及劳动力的重大中断。有迫切的需要 了解这些疾病的病理生理学，并开发疾病修正疗法。通过 在耶鲁大学，我们已经开始了一项纵向研究，以探索致病机制 通过脑脊液(CSF)、血液和磁共振成像(MRI)检查NS-PASC， 以及患有NS-PASC患者的详细临床数据。在目标1中，我们将定义临床和 通过对脑脊液和血液进行深度免疫表型鉴定的免疫学特征，包括评估 大脑自身免疫和T细胞功能改变。在目标2中，我们将评估SARS-CoV-2在 脑脊液和血液通过单拷贝聚合酶链式反应和高灵敏的病毒抗原检测。在《目标3》中，我们将 通过脑MRI、神经认知测试和脑脊液测量神经系统功能障碍的客观标记物 和神经损伤的血液标记物，并将进行多因素分析来评估两者之间的关系 免疫紊乱、病毒持久性和神经损伤的客观测量之间的关系。

Abstract Although severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is considered a respiratory pathogen, myriad neurologic complications including confusion, stroke, and neuromuscular disorders manifest during acute COVID-19. Furthermore, maladies such as impaired concentration, headache, sensory disturbances, depression, and even psychosis may persist for months following infection, as part of a constellation of symptoms now called Post Acute Sequelae of COVID-19 (PASC). The pathophysiological mechanisms of nervous system PASC (NS-PASC) are not well understood, although evidence to date implicates immune dysfunction, including non-specific neuroinflammation and anti-neural autoimmune dysregulation1. With millions of individuals affected, nervous system complications pose public health challenges for rehabilitation and recovery and major disruptions in the workforce. There is an urgent need to understand the pathophysiology of these disorders and develop disease modifying therapies. Through the COVID Mind Study at Yale, we have initiated a longitudinal study to investigate the pathogenic mechanisms of NS-PASC through examination of cerebrospinal fluid (CSF), blood, and magnetic resonance imaging (MRI), alongside detailed clinical data in individuals with NS-PASC. In Aim 1, we will define the clinical and immunological features through deep immunophenotyping of the CSF and blood, including assessment of brain autoimmunity and altered T cell function. In Aim 2, we will assess for SARS-CoV-2 persistence in the CSF and blood through single copy PCR and highly sensitive viral antigen detection assays. In Aim 3, we will measure objective markers of nervous system dysfunction through brain MRI, neurocognitive testing, and CSF and blood markers of neuronal injury, and will perform multivariate analysis to assess for the relationship between immune perturbations, viral persistence, and objective measures of neurologic injury.