Research Group Biomarkers for Infectious Diseases, TWINCORE Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625, Hannover, Germany.
Study Programme Medicine, Riga Stradins University, Riga, Latvia.
J Transl Med. 2024 Jul 3;22(1):620. doi: 10.1186/s12967-024-05422-1.
COVID-19 is primarily considered a respiratory tract infection, but it can also affect the central nervous system (CNS), which can result in long-term sequelae. In contrast to CNS infections by classic neurotropic viruses, SARS-CoV-2 is usually not detected in cerebrospinal fluid (CSF) from patients with COVID-19 with neurological involvement (neuro-COVID), suggesting fundamental differences in pathogenesis.
To assess differences in CNS metabolism in neuro-COVID compared to CNS infections with classic neurotropic viruses, we applied a targeted metabolomic analysis of 630 metabolites to CSF from patients with (i) COVID-19 with neurological involvement [n = 16, comprising acute (n = 13) and post-COVID-19 (n = 3)], (ii) viral meningitis, encephalitis, or myelitis (n = 10) due to herpes simplex virus (n = 2), varicella zoster virus (n = 6), enterovirus (n = 1) and tick-borne encephalitis virus (n = 1), and (iii) aseptic neuroinflammation (meningitis, encephalitis, or myelitis) of unknown etiology (n = 21) as additional disease controls.
Standard CSF parameters indicated absent or low neuroinflammation in neuro-COVID. Indeed, CSF cell count was low in neuro-COVID (median 1 cell/µL, range 0-12) and discriminated it accurately from viral CNS infections (AUC = 0.99) and aseptic neuroinflammation (AUC = 0.98). 32 CSF metabolites passed quality assessment and were included in the analysis. Concentrations of differentially abundant (fold change ≥|1.5|, FDR ≤ 0.05) metabolites were both higher (9 and 5 metabolites) and lower (2 metabolites) in neuro-COVID than in the other two groups. Concentrations of citrulline, ceramide (d18:1/18:0), and methionine were most significantly elevated in neuro-COVID. Remarkably, triglyceride TG(20:1_32:3) was much lower (mean fold change = 0.09 and 0.11) in neuro-COVID than in all viral CNS infections and most aseptic neuroinflammation samples, identifying it as highly accurate biomarker with AUC = 1 and 0.93, respectively. Across all samples, TG(20:1_32:3) concentration correlated only moderately with CSF cell count (ρ = 0.65), protein concentration (ρ = 0.64), and Q-albumin (ρ = 0.48), suggesting that its low levels in neuro-COVID CSF are only partially explained by less pronounced neuroinflammation.
The results suggest that CNS metabolite responses in neuro-COVID differ fundamentally from viral CNS infections and aseptic neuroinflammation and may be used to discover accurate diagnostic biomarkers in CSF and to gain insights into differences in pathophysiology between neuro-COVID, viral CNS infections and aseptic neuroinflammation.
COVID-19 主要被认为是一种呼吸道感染，但它也会影响中枢神经系统（CNS），从而导致长期后遗症。与经典神经嗜性病毒引起的中枢神经系统感染不同，SARS-CoV-2 通常不在 COVID-19 伴有神经受累的患者的脑脊液（CSF）中检测到，这表明发病机制存在根本差异。
为了评估神经 COVID 与经典神经嗜性病毒引起的中枢神经系统感染之间 CNS 代谢的差异，我们应用靶向代谢组学分析了 630 种代谢物，以评估 COVID-19 伴有神经受累的患者（i）急性 COVID-19 （n=13）和 COVID-19 后（n=3），（ii）单纯疱疹病毒（n=2）、水痘带状疱疹病毒（n=6）、肠道病毒（n=1）和蜱传脑炎病毒（n=1）引起的病毒性脑膜炎、脑炎或脊髓炎（n=10），和（iii）未知病因的无菌性神经炎症（脑膜炎、脑炎或脊髓炎）（n=21）的 CSF。
标准 CSF 参数表明神经 COVID 中不存在或低度神经炎症。事实上，神经 COVID 的 CSF 细胞计数较低（中位数为 1 个细胞/µL，范围 0-12），可准确区分病毒中枢神经系统感染（AUC=0.99）和无菌性神经炎症（AUC=0.98）。32 种 CSF 代谢物通过质量评估并纳入分析。与其他两组相比，神经 COVID 中差异丰度（fold change≥|1.5|，FDR≤0.05）的代谢物的浓度更高（9 种和 5 种代谢物）和更低（2 种代谢物）。瓜氨酸、神经酰胺（d18:1/18:0）和蛋氨酸的浓度在神经 COVID 中显著升高。值得注意的是，神经 COVID 中的甘油三酯 TG（20:1_32:3）浓度明显低于所有病毒性中枢神经系统感染和大多数无菌性神经炎症样本（平均 fold change=0.09 和 0.11），将其作为具有 AUC=1 和 0.93 的高度准确的生物标志物进行识别。在所有样本中，TG（20:1_32:3）浓度仅与 CSF 细胞计数（ρ=0.65）、蛋白浓度（ρ=0.64）和 Q-白蛋白（ρ=0.48）中度相关，表明其在神经 COVID CSF 中的低水平仅部分解释了神经炎症不明显。
结果表明，神经 COVID 中 CNS 代谢物的反应与病毒中枢神经系统感染和无菌性神经炎症有根本的不同，可用于发现 CSF 中的准确诊断生物标志物，并深入了解神经 COVID、病毒中枢神经系统感染和无菌性神经炎症之间的病理生理学差异。
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