Cerebrospinal Fluid in PASC: A Window into the COVID Mind

摘要 虽然严重急性呼吸综合征冠状病毒2（SARS-COV-2）被认为是一种呼吸系统疾病， 病原体，无数的神经系统并发症，包括混乱，中风，和神经肌肉疾病的表现 在急性COVID-19期间。此外，诸如注意力不集中、头痛、感觉不适、 干扰，抑郁症，甚至精神病可能持续数月后感染，作为一个部分， 这些症状现在被称为COVID-19急性后遗症（PASC）。的病理生理 神经系统PASC（NS-PASC）的机制还不清楚，尽管迄今为止的证据表明， 涉及免疫功能障碍，包括非特异性神经炎症和抗神经自身免疫 失调1.随着数百万人受到影响，神经系统并发症构成公共卫生 重建和恢复方面的挑战以及劳动力的重大中断。迫切需要 了解这些疾病的病理生理学，并开发疾病改善疗法。通过 在耶鲁大学的COVID心灵研究中，我们已经启动了一项纵向研究，以调查致病机制 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CSF和血液进行深度免疫表型分析， 脑自身免疫和改变的T细胞功能。在目标2中，我们将评估SARS-CoV-2在 通过单拷贝PCR和高灵敏度病毒抗原检测试验检测CSF和血液。在目标3中，我们 通过脑MRI、神经认知测试和CSF测量神经系统功能障碍的客观标志物 和神经元损伤的血液标志物，并将进行多变量分析，以评估 免疫紊乱、病毒持续存在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.