Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms^1,2,3. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease^4,5,6. Synaptic signalling of upper-layer excitatory neurons—which are evolutionarily expanded in humans⁷ and linked to cognitive function⁸—is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.

尽管 SARS-CoV-2 主要针对呼吸系统，但 COVID-19 患者和幸存者可能会出现神经系统症状^1,2,3 。然而，人们对 COVID-19 患者大脑中受影响的细胞和分子过程缺乏公正的了解。在这里，我们分析了 14 名对照个体（包括 1 名晚期流感患者）和 8 名 COVID-19 患者的 30 个额叶皮层和脉络丛样本的 65,309 个单核转录组。尽管我们的系统分析没有在大脑中发现 SARS-CoV-2 的分子痕迹，但我们观察到广泛的细胞扰动，表明脉络丛的屏障细胞感知周围炎症并将其传递到大脑中，并显示外周 T 细胞浸润实质。我们发现与 COVID-19 相关的小胶质细胞和星形胶质细胞亚群与先前在人类神经退行性疾病中报道的病理细胞状态具有相同的特征^4,5,6 。上层兴奋性神经元的突触信号——在人类中进化扩展⁷并与认知功能⁸相关——在 COVID-19 中优先受到影响。在不同的细胞类型中，与 COVID-19 相关的扰动与慢性脑部疾病中发现的扰动存在重叠，并且存在于与认知、精神分裂症和抑郁症相关的遗传变异中。我们的研究结果和公共数据集提供了一个分子框架，以了解当前对 COVID-19 相关神经系统疾病以及以后可能出现的任何此类疾病的观察结果。